Roger Warnke

All Publications

• Unicentric Castleman Disease: Updates and Novel Insights Into Spindle Cell Proliferations and Aggressive Forms of a Localized Disease. International journal of laboratory hematology Alnoor, F., Rangel, A., Luo, M., Silva, O., Chisholm, K. M., O'Malley, D., Warnke, R., Kumar, J., Ohgami, R. S. 2024

  Abstract

  Castleman Disease (CD) is a rare lymphoproliferative disorder that can be separated into two primary forms: Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is localized, while MCD is systemic. Though UCD generally has a favorable prognosis following surgical resection, more aggressive forms of this disease have been identified, including cases associated with dendritic and spindle cell proliferation. Genetic analysis has deepened our understanding of UCD. Despite advancements in better understanding the pathophysiology of UCD, challenges persist in the diagnosis, management, and treatment due to its rarity and heterogeneity. Here, we review current knowledge on UCD, highlighting the epidemiology, clinical presentation, diagnostic criteria, and treatment options while emphasizing the need for further research and innovation in therapeutic strategies.

  View details for DOI 10.1111/ijlh.14395

  View details for PubMedID 39501556

• Indolent T-lymphoblastic proliferation: A systematic review of the literature analyzing the epidemiologic, clinical, and pathologic features of 45 cases. International journal of laboratory hematology Saglam, A., Singh, K., Gollapudi, S., Kumar, J., Brar, N., Butzmann, A., Warnke, R., Ohgami, R. S. 2022

  Abstract

  An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic malignancy. Since the first case was described in 1999, dozens more have been reported in the literature. However, the epidemiologic, clinical, pathologic, and biologic features of this disease have not been well described. Here, we retrospectively reviewed all known cases reported in the literature to better understand this entity. A PubMed search up to January 2022 highlighted 25 papers describing cases/case series of iT-LBP, one of which was a case presentation in a slide workshop. Except for 9 of the cases in one of the papers, where it was evident that the number of CD3+/TdT+ cells were too few to conform with a diagnosis of iT-LBP, all papers and all the cases reported were included in the study amounting to a total of 45 cases. Clinicopathologic characteristics were analyzed using descriptive statistics and frequencies. Our analysis highlighted the previously known association with Castleman disease and Castleman-like features and underlined its association with dendritic cell proliferations in general, as well as uncovering high frequency of concurrence with hepatocellular carcinoma and autoimmune diseases, most notably myasthenia gravis, paraneoplastic pemphigus and paraneoplastic autoimmune multiorgan syndrome. Furthermore, the co-expression of CD4 and CD8 and high prevalence of extranodal disease and recurrences were other less well described features that were revealed.

  View details for DOI 10.1111/ijlh.13873

  View details for PubMedID 35577551

• Case Report: Castleman Disease With an Associated Stromal Spindle Cell Proliferation, PDGFRB Mutation and p53 Expression: Clonal Origins of a Rare Disease. Frontiers in oncology Singh, K. I., Gollapudi, S., Kumar, J., Butzmann, A., Small, C., Kreimer, S., Saglam, E. A., Warnke, R., Silva, O., Ohgami, R. S. 2022; 12: 857606

  Abstract

  Castleman disease (CD) is a rare lymphoproliferative disorder with distinct clinical subtypes. However, our understanding of the underlying pathogenesis of particular subtypes of CD remains unclear. While the characteristic morphologic changes within UCD, including occasional cases of overgrowth of spindled stromal and follicular dendritic cells have been described, the nature and origin of these spindle cells remain elusive. Few reports have suggested that underlying stromal cells in UCD are clonally neoplastic and may be of fibroblastic reticular cell (FRC) or follicular dendritic cell (FDC) origins given their close clonal relationship. Although certain histomorphologic features may aid diagnosis, there are no specific biomarkers that can differentiate a reactive process mimicking UCD from true UCD. Hence, we describe an index case with morphology consistent with the hyaline vascular subtype of UCD with concomitant atypical smooth muscle actin (SMA)-positive stromal spindle cell proliferation containing a recurrent PDGFRB N666S mutation and upregulation of p53 expression. Further analysis of 21 additional cases of UCD identified increased p53 expression by digital image analysis and SMA positive stromal cells predominantly within the paracortical and intrafollicular areas further strengthening the hypothesis of the stromal cellular derivation and origins of UCD.

  View details for DOI 10.3389/fonc.2022.857606

  View details for PubMedID 35494027

  View details for PubMedCentralID PMC9043324

• Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma. The American journal of surgical pathology Koo, M., Zhang, J., Tan, B., Kurzer, J., Gratzinger, D., Zhao, S., Suarez, C., Lossos, I. S., Warnke, R. A., Natkunam, Y. 2021

  Abstract

  The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center-associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H-scores. Using H-scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.

  View details for DOI 10.1097/PAS.0000000000001852

  View details for PubMedID 34907996

• A comprehensive analysis of RHOA mutation positive and negative angioimmunoblastic T-cell lymphomas by targeted deep sequencing, expression profiling and single cell digital image analysis. International journal of molecular medicine Butzmann, A. n., Sridhar, K. n., Jangam, D. n., Kumar, J. n., Sahoo, M. K., Shahmarvand, N. n., Warnke, R. n., Rangasamy, E. n., Pinsky, B. A., Ohgami, R. S. 2020

  Abstract

  Angioimmunoblastic T‑cell lymphoma (AITL) is a uniquely aggressive mature T‑cell neoplasm. In recent years, recurrent genetic mutations in ras homolog family member A (RHOA), tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3 alpha (DNMT3A) and isocitrate dehydrogenase [NADP(+)] 2 (IDH2) have been identified as associated with AITL. However, a deep molecular study assessing both DNA mutations and RNA expression profile combined with digital image analysis is lacking. The present study aimed to evaluate the significance of molecular and morphologic features by high resolution digital image analysis in several cases of AITL. To do so, a total of 18 separate tissues from 10 patients with AITL were collected and analyzed. The results identified recurrent mutations in RHOA, TET2, DNMT3A, and IDH2, and demonstrated increased DNA mutations in coding, promoter and CCCTC binding factor (CTCF) binding sites in RHOA mutated AITLs vs. RHOA non‑mutated cases, as well as increased overall survival in RHOA mutated patients. In addition, single cell computational digital image analysis morphologically characterized RHOA mutated AITL cells as distinct from cells from RHOA mutation negative patients. Computational analysis of single cell morphological parameters revealed that RHOA mutated cells have decreased eccentricity (more circular) compared with RHOA non‑mutated AITL cells. In conclusion, the results from the present study expand our understanding of AITL and demonstrate that there are specific cell biological and morphological manifestations of RHOA mutations in cases of AITL.

  View details for DOI 10.3892/ijmm.2020.4686

  View details for PubMedID 32945366

• LMO2 Expression Distinguishes T-Lymphoblastic Leukemia/Lymphoma from Indolent T-Lymphoblastic Proliferations. Histopathology Brar, N. n., Butzmann, A. n., Kumar, J. n., Peerani, R. n., Morgan, E. A., Grigoriadis, G. n., Kumar, B. n., Tatarczuch, R. M., Warnke, R. A., Ohgami, R. S. 2020

  Abstract

  An indolent T-lymphoblastic proliferation (iT-LBP) is a benign, reactive expansion of immature TdT+ T-cells found in extrathymic tissues. iT-LBP can be challenging to distinguish from malignant processes, specifically T-lymphoblastic lymphoma (T-LBL), given the overlapping clinical and histologic features. Recently, it has been shown that LIM domain only 2 (LMO2) is overexpressed in T-LBL but not in reactive immature TdT+ T-cells in the thymus. Based on these findings, we investigated the expression of LMO2 by immunohistochemistry and its role in differentiating iT-LBPs from T-LBLs.We retrospectively identified cases of iT-LBP and T-LBL from the pathology archives of four institutions. Seven cases of iT-LBP (including five new cases that have not been reported in the literature) and 13 cases of T-LBL were analyzed. Clinical, morphologic, immunophenotypic and molecular data were analyzed. Immunohistochemical staining with LMO2 was performed on all cases of iT-LBP and T-LBL.A review of five new cases of iT-LBP showed similar morphologic, immunophenotypic and molecular features to prior reported cases. All cases of iT-LBP were negative for LMO2 (0/7) while 92% of T-LBL cases (12/13) expressed LMO2; sensitivity 92% (confidence interval 64-100%) and specificity 100% (confidence interval 59-100%).We confirm prior published findings that cases of iT-LBPs demonstrate highly overlapping morphologic and immunophenotypic features when compared to T-LBL. Importantly, expression of LMO2 is a sensitive and specific marker to rule out iT-LBP.

  View details for DOI 10.1111/his.14176

  View details for PubMedID 32526041

• CD20-Negative Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A 20-Year Consecutive Case Series From a Tertiary Cancer Center. Archives of pathology & laboratory medicine Menke, J. R., Spinner, M. A., Natkunam, Y. n., Warnke, R. A., Advani, R. H., Gratzinger, D. A. 2020

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma.To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution.A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted.Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naïve, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease.NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

  View details for DOI 10.5858/arpa.2020-0135-OA

  View details for PubMedID 32991677

• Expansion of PD1-positive T Cells in Nodal Marginal Zone Lymphoma: A Potential Diagnostic Pitfall. The American journal of surgical pathology Egan, C., Laurent, C., Alejo, J. C., Pileri, S., Campo, E., Swerdlow, S. H., Piris, M., Chan, W. C., Warnke, R., Gascoyne, R. D., Xi, L., Raffeld, M., Pittaluga, S., Jaffe, E. S. 2019

  Abstract

  The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.

  View details for DOI 10.1097/PAS.0000000000001414

  View details for PubMedID 31764221

• Indolent In Situ B-Cell Neoplasms With MYC Rearrangements Show Somatic Mutations in MYC and TNFRSF14 by Next-generation Sequencing. The American journal of surgical pathology Kumar, J., Butzmann, A., Wu, S., Easly, S., Zehnder, J. L., Warnke, R. A., Bangs, C. D., Jangam, D., Cherry, A., Lau, J., Nybakken, G., Ohgami, R. S. 2019

  Abstract

  Systemic high-grade B-cell lymphomas (HGBCLs) with MYC gene rearrangements are clinically aggressive. In situ lesions with indolent behavior have not been described to date. We have identified 2 cases of in situ B-cell neoplasms with MYC rearrangements (IS-BCN, MYC) occurring, and focally confined to ≤4 lymphoid follicles in otherwise healthy individuals and without clinical progression despite minimal intervention (surgical only). Morphologically similar to systemic HGBCLs, the low power view of these lesions showed a starry sky pattern with numerous mitotic figures. High power imaging demonstrated these cells to be medium-large in size with irregular nuclear contours, immature chromatin, and prominent nucleoli. Immunophenotypically these cells were light chain restricted, positive for CD20, CD10, c-Myc, and dim or negative for BCL2 with a Ki67 proliferative index of >95%. By fluorescence in situ hybridization studies, we detected MYC translocations in these cells but no rearrangements in BCL2 or BCL6. Microdissection of neoplastic cells in these patients followed by targeted next-generation sequencing identified a mutation in MYC, D2N, and an indel in TNFRSF14. Mutations in ID3 or TCF3 were not identified. Although rare, these lesions should be separated from HGBCLs involving follicles but with systemic spread which has been previously described. Unlike systemic lymphomas with MYC gene rearrangements, these in situ B-cell neoplasms with MYC rearrangements did not require systemic therapy and no progression has been seen in either patient beyond 1 year (29 and 16mo). Our work offers pathologic and biologic insight into the early process of B-cell neoplasia.

  View details for DOI 10.1097/PAS.0000000000001338

  View details for PubMedID 31368914

• Intralymphatic Rosai-Dorfman Disease Associated With Vulvar Lymphedema: A Case Report of an Extremely Rare Phenomenon. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Saleem, A., Hoffmann, J., Warnke, R., Rieger, K. E., Longacre, T. 2019

  Abstract

  Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD), is a self-limited histiocytic disorder of unclear etiology which most commonly presents with cervical lymphadenopathy. Purely extranodal presentation of RDD is uncommon, and isolated intralymphatic/intravascular confinement of this entity has not previously been described. We report a 16-yr-old female who presented with vaginal swelling and mass-like enlargement of the right labia. The mass had been present for nearly a year without pain or tenderness. Clinically, the lesion was thought to be a Bartholin gland cyst. Following surgical resection, histologic examination demonstrated a hypocellular myxedematous stroma with a mixture of ectatic thin and thick-walled vessels within which there were numerous collections of histiocytes, lymphocytes, and plasma cells. The histopathologic differential diagnosis included localized vulvar lymphedema, a specialized genital tract neoplasm, and childhood asymmetric labium majus enlargement. The histiocytes showed occasional plasma cells and lymphocytes within their cytoplasm, consistent with emperipolesis. Immunohistochemical studies showed that the histiocytes expressed CD163 and S100, while ERG and D2-40 highlighted their intralymphatic confinement, ultimately leading to the diagnosis of intralymphatic RDD. Intralymphatic RDD may present as vulvar lymphedema and can potentially mimic other myxedematous neoplasms of the vulvovaginal region.

  View details for DOI 10.1097/PGP.0000000000000619

  View details for PubMedID 31274698

• Indolent in situ High-Grade B-cell lymphoma with a MYC Translocation and Mutations Identified by Next Generation Sequencing Kumar, J., Wu, S., Butzmann, A., Lau, J., Zehnder, J., Warnke, R., Nybakken, G., Van de Rijn, M., Ohgami, R. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102331

• Indolent in situ High-Grade B-cell lymphoma with a MYC Translocation and Mutations Identified by Next Generation Sequencing Kumar, J., Wu, S., Butzmann, A., Lau, J., Zehnder, J., Warnke, R., Nybakken, G., Van De Rijn, M., Ohgami, R. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915501090

• Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas BLOOD ADVANCES Nagy, A., Bhaduri, A., Shahmarvand, N., Shahryari, J., Zehnder, J. L., Warnke, R. A., Mughal, T., Ali, S., Ohgami, R. S. 2018; 2 (5): 481–91

  Abstract

  Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8-/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

  View details for PubMedID 29496669

• Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications PLOS ONE Nybakken, G. E., Bala, R., Gratzinger, D., Jones, C. D., Zehnder, J. L., Bangs, C. D., Cherry, A., Warnke, R. A., Natkunam, Y. 2016; 11 (3)

  Abstract

  We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.

  View details for DOI 10.1371/journal.pone.0151735

  View details for Web of Science ID 000372582800093

  View details for PubMedCentralID PMC4798531

• An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified HUMAN PATHOLOGY Hoffmann, J. C., Chisholm, K. M., Cherry, A., Chen, J., Arber, D. A., Natkunam, Y., Warnke, R. A., Ohgami, R. S. 2016; 48: 9-17

  Abstract

  Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.

  View details for DOI 10.1016/j.humpath.2015.09.033

  View details for Web of Science ID 000368319200002

• An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified. Human pathology Hoffmann, J. C., Chisholm, K. M., Cherry, A., Chen, J., Arber, D. A., Natkunam, Y., Warnke, R. A., Ohgami, R. S. 2016; 48: 9-17

  Abstract

  Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.

  View details for DOI 10.1016/j.humpath.2015.09.033

  View details for PubMedID 26772393

• Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications. PloS one Nybakken, G. E., Bala, R., Gratzinger, D., Jones, C. D., Zehnder, J. L., Bangs, C. D., Cherry, A., Warnke, R. A., Natkunam, Y. 2016; 11 (3)

  Abstract

  We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.

  View details for DOI 10.1371/journal.pone.0151735

  View details for PubMedID 26991267

  View details for PubMedCentralID PMC4798531

• Immunoarchitectural patterns of progressive transformation of germinal centers with and without nodular lymphocyte-predominant Hodgkin lymphoma HUMAN PATHOLOGY Hartmann, S., Winkelmann, R., Metcalf, R. A., Treetipsatit, J., Warnke, R. A., Natkunam, Y., Hansmann, M. 2015; 46 (11): 1655-1661

  Abstract

  Progressive transformation of germinal centers (PTGC) has been frequently described in association with Hodgkin lymphoma, particularly nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The aim of this study was to evaluate morphologic features of PTGC for better delineation of PTGC from early involvement by NLPHL. A total of 160 cases of PTGC were evaluated and included in the following 3 groups: 93 patients with PTGC who never developed a lymphoma, 23 patients with synchronous PTGC and NLPHL, and 44 patients with PTGC with antecedent or subsequent history of lymphoma. By histopathologic evaluation, 5 patterns of PTGC that reflected progressive dismantling of germinal centers were identified. There was no difference in the distribution of patterns 1 to 4 among the 3 groups of PTGC; however, in patients showing synchronous involvement of PTGC and NLPHL, pattern 5, which resembles a naïve B-cell follicle, was significantly more frequently observed (14/23) when compared with patients with PTGC who never developed a lymphoma (30/93; P = .0161). Furthermore, recognition of the spectrum of immunoarchitectural patterns of PTGC, including architectural and cytologic features, was helpful to better differentiate nodules involved by PTGC from NLPHL.

  View details for DOI 10.1016/j.humpath.2015.07.006

  View details for Web of Science ID 000364360600011

  View details for PubMedID 26410017

• Systemic panniculitis-like T-cell lymphoma with involvement of mesenteric fat and subcutis. Journal of cutaneous pathology Lester, L., Ewalt, M., Warnke, R., Kim, J. 2015; 42 (1): 46-49

  Abstract

  Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon non-Hodgkins primary cutaneous lymphoma that typically presents as subcutaneous nodules on the extremities or trunk. Here, we report an unusual case of systemic panniculitic T-cell lymphoma with predominantly mesenteric extra-cutaneous involvement and an aggressive clinical course with histopathologic and immunophenotypic features that mimic SPTCL. This case serves to expand the body of literature regarding systemic SPTCL-like disorders with prominent extra-cutaneous involvement.

  View details for DOI 10.1111/cup.12436

  View details for PubMedID 25384366

• Indolent T-lymphoblastic proliferation: a name with specific meaning. Human pathology Ohgami, R. S., Natkunam, Y. n., Warnke, R. A. 2015

  View details for PubMedID 26363525

• Large B-cell lymphoma with T-cell-rich background and nodules lacking follicular dendritic cell meshworks: description of an insufficiently recognized variant HUMAN PATHOLOGY Treetipsatit, J., Metcalf, R. A., Warnke, R. A., Natkunam, Y. 2015; 46 (1): 74-83

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is characterized by nodular or nodular and diffuse growth of scattered large neoplastic B cells associated with follicular dendritic cell (FDC) meshworks. Variant patterns, which at least focally show a T-cell-rich background, and rare cases lacking FDC meshworks that overlap with T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) are also recognized. We reviewed 195 cases spanning the diagnostic spectrum of NLPHL and THRLBCL and identified 5 cases with distinctive features that were difficult to classify according to the World Health Organization criteria or previously described variants. Clinically, they involved peripheral and central lymph node sites or the mediastinum, and the majority also had recurrent disease. Four cases showed large T-cell-rich nodules with fibrosis, and 1 showed diffuse THRLBCL-like pattern with a minor component of nodularity. All cases completely lacked FDC meshworks despite a prominent nodular growth pattern. Large atypical cells in all cases were CD20+ CD30- CD15- B cells, although a small subset (<10%) of CD30+ and CD15+ large cells were seen in 1 case. In 4 cases, the background mainly contained CD4+ PD-1+ or CD57+ T cells that ringed large atypical B cells. In 1 case, B-cell predominance and a ringing pattern of CD57+ T cells were noted in nodules, whereas they were lacking in the diffuse areas. Recognition of these variant cases expands the spectrum between NLPHL and THRLBCL and points to the need for further refinement of diagnostic criteria for appropriate classification and clinical management.

  View details for DOI 10.1016/j.humpath.2014.09.009

  View details for Web of Science ID 000346540100010

  View details for PubMedID 25456392

• Variable Expression of B-cell Transcription Factors in Reactive Immunoblastic Proliferations A Potential Mimic of Classical Hodgkin Lymphoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Treetipsatit, J., Rimzsa, L., Grogan, T., Warnke, R. A., Natkunam, Y. 2014; 38 (12): 1655-1663

  Abstract

  Reactive immunoblastic proliferations can histologically mimic classical Hodgkin lymphoma (CHL), and show diffuse CD30 expression in large cells. The lack of expression of CD15 in a subset of CHL further complicates their separation from immunoblastic proliferations. Loss of expression of B-cell transcription factors is frequently exploited in making a diagnosis of CHL; however, the staining patterns of B-cell transcription factors in immunoblastic proliferations have not been extensively studied. Thirty-three cases of reactive immunoblastic proliferations were evaluated using a panel of immunohistochemistry for CD30, CD15, CD20, CD3, κ, λ, CD45RB, MUM1, PAX5, OCT2, and BOB.1, as well as Epstein-Barr virus (EBV)/EBV-encoded ribonucleic acid in situ hybridization. A newly developed dual-color chromogenic in situ hybridization technology for detection of κ/λ mRNAs was also used. The majority of immunoblasts expressed CD30 in 14 of 33 (42%) cases; none expressed CD15. Loss or weak expression of at least 1 transcription factor in B immunoblasts, most commonly PAX5, was noted in 24 of 29 (83%) cases. A polytypic light chain expression pattern was detected by immunohistochemistry in 14 of 22 (63.6%) cases and by dual-color chromogenic in situ hybridization in 9 of 10 (90%) cases studied. EBV-encoded ribonucleic acid was detected in 8 of 33 (24.2%) cases, 5 of which were clinically unrelated to infectious mononucleosis. We conclude that B-cell transcription factors can show loss or weak expression in a significant proportion of reactive immunoblastic proliferations, and, therefore, staining for B-cell transcription factors together with CD30 should be interpreted with caution before a diagnosis of CHL is made.

  View details for Web of Science ID 000345131700010

  View details for PubMedID 24921642

• Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression. American journal of surgical pathology Ohgami, R. S., Sendamarai, A. K., Atwater, S. K., Liedtke, M., Fleming, M. D., Natkunam, Y., Warnke, R. A. 2014; 38 (9): 1298-1304

  Abstract

  Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with disseminated multinodal involvement in an otherwise healthy 49-year-old woman. Multiple lymph node biopsies were performed over the course of several months demonstrating persistent and anatomically diffuse involvement. Over 18 months, and without therapy, she has remained healthy, and her lymphadenopathy significantly improved. No bone marrow or peripheral blood involvement was ever identified. Atypical T cells showed an immunophenotypic spectrum of T-cell antigen expression with partial CD33 on a subset of T cells detected by both flow cytometry and immunohistochemistry. Both T-cell clonality and Human Androgen Receptor Assay (HUMARA) studies, performed on lymph node biopsy specimens, were negative. This case represents the first detailed clinical, morphologic, molecular, and immunophenotypic description of disseminated multinodal involvement by nonclonal iT-LBP with partial CD33 expression on T cells.

  View details for DOI 10.1097/PAS.0000000000000197

  View details for PubMedID 24618611

• Kappa and lambda light chain mRNA in situ hybridization compared to flow cytometry and immunohistochemistry in B cell lymphomas DIAGNOSTIC PATHOLOGY Rimsza, L. M., Day, W. A., McGinn, S., Pedata, A., Natkunam, Y., Warnke, R., Cook, J. R., Marafioti, T., Grogan, T. M. 2014; 9

  Abstract

  Detection of B cell clonality is useful for assisting in the diagnosis of B cell lymphomas. Clonality assessment can be accomplished through evaluation of KAPPA and LAMBDA light chain expression. Currently, only slide based methods are available for the majority of patient biopsies and do not detect light chain protein or mRNA in many B-cell lymphomas. Herein we evaluated a new method, known as colorimetric in situ hybridization (CISH), with improved sensitivity and multiplexing capacity, for its usefulness in clonality detection in mature B cell malignancies.The KAPPA and LAMBDA ISH was performed on a Ventana Benchmark XT utilizing two color chromogenetic detection. The probes comprised 2 haptenated riboprobes each approximately 500 base pairs long directed against the conserved regions of either KAPPA or LAMBDA mRNA. The dual colors consisted of silver deposition (black) for KAPPA light chain and a novel (pink) chromogen for LAMBDA light chain. Following optimization, CISH allowed visualization of mRNA in benign B cells in reactive tissues including germinal center, mantle zone, and post-germinal center cells. We then identified 79 cases of B cell lymphoma with formalin-fixed paraffin-embedded (FFPE) biopsies including: follicular (36 cases), mantle cell (6 cases), marginal zone (12 cases), lymphoplasmacytic (6 cases), small lymphocytic (4 cases), and diffuse large B cell (15 cases), which were selected on the basis of either prior flow cytometry or immunohistochemistry (IHC) results to serve as the predicate, "gold standard," comparator.39/79 (49.4%) cases were classified as KAPPA and 29/79 (36.7%) as LAMBDA light chain restricted; while 9/79 (11.3%) cases were classified as indeterminate. Of the 70 cases with KAPPA or LAMBDA light chain restricted CISH, 69/70 (98.6%) were concordant with the reference method, while 1/70 (1.4%) was discordant.Optimized CISH detected lower levels of mRNA than can be visualized with current slide based methods, making clonality assessment in FFPE biopsies possible for mature B cell neoplasms. In this preliminary study, CISH was highly accurate compared to flow cytometry or IHC. CISH offers the possibility of wider applicability of light chain ISH and is likely to become a useful diagnostic tool.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1430491067123856.

  View details for DOI 10.1186/1746-1596-9-144

  View details for Web of Science ID 000341387600001

  View details for PubMedID 25047073

  View details for PubMedCentralID PMC4223387

• Uterine Rosai-Dorfman Disease (Sinus Histiocytosis With Massive Lymphadenopathy) INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Pan, L. Y., Offman, S. L., Warnke, R. A., Longacre, T. A. 2014; 33 (4): 432-436

  Abstract

  We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases.

  View details for DOI 10.1097/PGP.0b013e3182a03d23

  View details for Web of Science ID 000337737900016

  View details for PubMedID 24901405

• Indolent T-cell lymphoproliferative disease of the gastrointestinal tract BLOOD Perry, A. M., Warnke, R. A., Hu, Q., Gaulard, P., Copie-Bergman, C., Alkan, S., Wang, H., Cheng, J. X., Bacon, C. M., Delabie, J., Ranheim, E., Kucuk, C., Hu, X., Weisenburger, D. D., Jaffe, E. S., Chan, W. C. 2013; 122 (22): 3599-3606

  Abstract

  Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.

  View details for DOI 10.1182/blood-2013-07-512830

  View details for Web of Science ID 000329726200015

  View details for PubMedID 24009234

  View details for PubMedCentralID PMC3837508

• Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood Tan, D., Horning, S. J., Hoppe, R. T., Levy, R., Rosenberg, S. A., Sigal, B. M., Warnke, R. A., Natkunam, Y., Han, S. S., Yuen, A., Plevritis, S. K., Advani, R. H. 2013; 122 (6): 981-987

  Abstract

  Recent studies report an improvement in overall survival (OS) of patients with follicular lymphoma (FL). Previously untreated patients with grade 1-2 FL referred from 1960-2003 and treated at Stanford were identified. Four eras were considered: era 1, pre-anthracycline (1960-1975, n=180); era 2, anthracycline (1976-1986, n=426), era 3, aggressive chemotherapy/purine analogs (1987-1996, n=471) and era 4, rituximab (1997-2003, n=257). Clinical characteristics, patterns of care and survival outcomes were assessed. Observed OS was compared with the expected OS calculated from Berkeley Mortality Database life tables derived from population matched by gender and age at time of diagnosis. The median OS was 13.6 years. Age, gender and stage did not differ across the eras. Although primary treatment varied, event free survival after the first treatment did not differ between eras (p=0.17). Median OS improved from approximately 11 years in eras 1 and 2 to 18.4 years in era 3 and has not yet been reached for era 4 (p<0.001) with no suggestion of a plateau in any era. These improvements in OS exceeded improvements in survival in the general population during the same time period. Several factors, including better supportive care and effective therapies for relapsed disease, are likely responsible for this improvement.

  View details for DOI 10.1182/blood-2013-03-491514

  View details for PubMedID 23777769

• Indolent T-Lymphoblastic Proliferation (iT-LBP): A Review of Clinical and Pathologic Features and Distinction from Malignant T-Lymphoblastic Lymphoma ADVANCES IN ANATOMIC PATHOLOGY Ohgami, R. S., Arber, D. A., Zehnder, J. L., Natkunam, Y., Warnke, R. A. 2013; 20 (3): 137-140

  Abstract

  In recent years, a new pathologic entity has emerged: indolent T-lymphoblastic proliferation (iT-LBP). iT-LBPs share immunophenotypic similarities with T-lymphoblastic lymphoma; however, T-lymphoblastic proliferations are clinically indolent, and unlike the malignant counterpart, these expansions of nonclonal terminal deoxynucleotidyl transferase (TdT)+ T cells do not require treatment. Here we review the clinical and pathologic features, which are required for an accurate diagnosis of an iT-LBP. We demonstrate specific criteria can be used to accurately diagnose iT-LBP, notably: (1) confluent groups of TdT+ T cells in a biopsy specimen, (2) relative preservation of surrounding normal lymphoid architecture, (3) TdT+ T cells without morphologic atypia, (4) absence of thymic epithelium, (5) nonclonal TdT+ T cells, (6) immunophenotype of developmentally normal immature thymic T cells, and (7) clinical evidence of indolence (follow-up >6 mo without progression).

  View details for DOI 10.1097/PAP.0b013e31828d17ec

  View details for Web of Science ID 000317588700001

  View details for PubMedID 23574769

• Primary Cutaneous Gamma Delta T-Cell Lymphoma With Brain Involvement and Hemophagocytic Syndrome AMERICAN JOURNAL OF DERMATOPATHOLOGY Chakrapani, A., Avery, A., Warnke, R. 2013; 35 (2): 270-272

  Abstract

  Primary cutaneous gamma delta T-cell lymphoma is a rare diagnosis with only 40 reported cases. We describe a case of cutaneous gamma delta T-cell lymphoma with hemophagocytic syndrome and brain involvement that was not apparent morphologically on skin biopsy and was diagnosed as perifolliculitis and lobular panniculitis. The biopsy was sent later for molecular studies to the University of Washington, which demonstrated a T-cell clone. This case demonstrates that a T-cell clone may be present in a skin biopsy without morphologic or immunophenotypic evidence of lymphoma.

  View details for DOI 10.1097/DAD.0b013e3182624e98

  View details for PubMedID 22863906

• Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial ANNALS OF ONCOLOGY Advani, R. H., Hoppe, R. T., Baer, D., Mason, J., Warnke, R., Allen, J., Daadi, S., Rosenberg, S. A., Horning, S. J. 2013; 24 (4): 1044-1048

  Abstract

  To assess the efficacy of an abbreviated Stanford V regimen in patients with early-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS PATIENTS: with untreated nonbulky stage I-IIA supradiaphragmatic HL were eligible for the G4 study. Stanford V chemotherapy was administered for 8 weeks followed by radiation therapy (RT) 30 Gy to involved fields (IF). Freedom from progression (FFP), disease-specific survival (DSS) and overall survival (OS) were estimated.All 87 enrolled patients completed the abbreviated regimen. At a median follow-up of 10 years, FFP, DSS and OS are 94%, 99% and 94%, respectively. Therapy was well tolerated with no treatment-related deaths.Mature results of the abbreviated Stanford V regimen in nonbulky early-stage HL are excellent and comparable to the results from other contemporary therapies.

  View details for DOI 10.1093/annonc/mds542

  View details for PubMedID 23136225

• Selective Immunophenotyping for Diagnosis of B-cell Neoplasms: Immunohistochemistry and Flow Cytometry Strategies and Results APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Boyd, S. D., Natkunam, Y., Allen, J. R., Warnke, R. A. 2013; 21 (2): 116-131

  Abstract

  Determining the immunophenotype of hematologic malignancies is now an indispensable part of diagnostic classification, and can help to guide therapy, or to predict clinical outcome. Diagnostic workup should be guided by morphologic findings and evaluate clinically important markers, but ideally should avoid the use of overly broad panels of immunostains that can reveal incidental findings of uncertain significance and give rise to increased costs. Here, we outline our approach to diagnosis of B-cell neoplasms, combining histologic and clinical data with tailored panels of immunophenotyping reagents, in the context of the 2008 World Health Organization classification. We present data from cases seen at our institution from 2004 through 2008 using this approach, to provide a practical reference for findings seen in daily diagnostic practice.

  View details for DOI 10.1097/PAI.0b013e31825d550a

  View details for Web of Science ID 000315464500004

  View details for PubMedID 22820658

• A Detailed Clinicopathologic Review of Castleman Disease Demonstrates That Atypical/Dysplastic Follicular Dendritic Cells Positive for SOX11, S-100, CXCL13, or D2-40 Are a Frequent Finding in Hyaline Vascular and Plasma Cell Variants 102nd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) Ohgami, R. S., Alcasid, M., Warnke, R. A., Arber, D. A. NATURE PUBLISHING GROUP. 2013: 353A–353A

  View details for Web of Science ID 000314444402105

• TdT(+) T-lymphoblastic Populations Are Increased in Castleman Disease, in Castleman Disease in Association With Follicular Dendritic Cell Tumors, and in Angioimmunoblastic T-cell Lymphoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ohgami, R. S., Zhao, S., Ohgami, J. K., Leavitt, M. O., Zehnder, J. L., West, R. B., Arber, D. A., Natkunam, Y., Warnke, R. A. 2012; 36 (11): 1619-1628

  Abstract

  T-lymphoblastic lymphoma is an aggressive neoplasm requiring prompt clinical treatment. Conversely, indolent T-lymphoblastic proliferation mimics T-lymphoblastic lymphoma but consists of a proliferation of non-neoplastic TdT+ T cells, requiring no treatment. Recently, we identified several cases of indolent T-lymphoblastic proliferations in extrathymic lymphoid tissues: 1 in a patient suffering from Castleman disease (CD) associated with a follicular dendritic cell sarcoma/tumor, 1 in a patient with a history of angioimmunoblastic T-cell lymphoma (AITL), and 1 in association with acinic cell carcinoma. Interestingly, in the case of the patient with a history of AITL, these TdT+ T cells were seen in multiple anatomic sites over the span of 5 years. Here we review these 3 cases and extend our findings by demonstrating that TdT+ T-lymphoblastic populations are increased in lymph nodes of patients with CD (P=0.011), CD in association with follicular dendritic cell tumors, and AITL (P<0.01) compared with other T-cell or B-cell lymphomas or reactive lymph nodes. Finally, analysis of 352 nonhematolymphoid tumors including carcinomas, melanomas, and sarcomas demonstrates that TdT+ T cells are not increased in these tumors. Our studies not only present several detailed cases of indolent T-lymphoblastic proliferations, but also correlate these populations with specific hematologic diseases.

  View details for DOI 10.1097/PAS.0b013e318264e223

  View details for Web of Science ID 000310059600004

  View details for PubMedID 23060347

• CD137 Is Expressed in Follicular Dendritic Cell Tumors and in Classical Hodgkin and T-Cell Lymphomas Diagnostic and Therapeutic Implications AMERICAN JOURNAL OF PATHOLOGY Anderson, M. W., Zhao, S., Freud, A. G., Czerwinski, D. K., Kohrt, H., Alizadeh, A. A., Houot, R., Azambuja, D., Biasoli, I., Morais, J. C., Spector, N., Molina-Kirsch, H. F., Warnke, R. A., Levy, R., Natkunam, Y. 2012; 181 (3): 795-803

  Abstract

  CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy.

  View details for DOI 10.1016/j.ajpath.2012.05.015

  View details for Web of Science ID 000309251100009

  View details for PubMedID 22901750

  View details for PubMedCentralID PMC3432425

• Aggressive EBV-associated Lymphoproliferative Disorder: A Prodrome to Diffuse Large B-cell Lymphoma? APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Batra, R., Medeiros, B. C., Zehnder, J. L., Warnke, R. A., Natkunam, Y. 2012; 20 (3): 325-330

  Abstract

  A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter.

  View details for Web of Science ID 000303140100012

  View details for PubMedID 22505014

• IgG4-Related Systemic Sclerosing Disease of the Ocular Adnexa A Potential Mimic of Ocular Lymphoma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Karamchandani, J. R., Younes, S. F., Warnke, R. A., Natkunam, Y. 2012; 137 (5): 699-711

  Abstract

  IgG4-related sclerosing disease has been described in the orbit and ocular adnexa. Of 164 biopsies of the ocular region for suspected lymphoma, we identified 6 cases of IgG4 disease, 4 of which were previously unrecognized. All 6 cases demonstrated increased plasma cells in a background of sclerosis and increased absolute numbers of IgG4-expressing cells. Our results confirm the difficulty in diagnosing IgG4-related sclerosing disease in the ocular region. Based on the findings, we suggest that specimens from biopsies of the eye and ocular adnexa for which a definitive diagnosis of lymphoma is not established undergo further workup for IgG and IgG4, particularly if increased plasma cells and sclerosis are present. When IgG4-expressing plasma cells account for greater than 50% of IgG-expressing plasma cells, a diagnosis of IgG4 disease should be considered. Timely recognition would benefit patients by allowing appropriate management with corticosteroid therapy and avoiding more aggressive or unnecessary therapeutic options.

  View details for DOI 10.1309/AJCPE1G8DRHXRPIH

  View details for Web of Science ID 000303141300002

  View details for PubMedID 22523207

• In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Carvajal-Cuenca, A., Sua, L. F., Silva, N. M., Pittaluga, S., Royo, C., Song, J. Y., Sargent, R. L., Espinet, B., Climent, F., Jacobs, S. A., Delabie, J., Naresh, K. N., Bagg, A., Brousset, P., Warnke, R. A., Serrano, S., Harris, N. L., Swerdlow, S. H., Jaffe, E. S., Campo, E. 2012; 97 (2): 270-278

  Abstract

  Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called "in situ mantle cell lymphoma". The clinical significance of this lesion remains uncertain.The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied.Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11;14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1-19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern.In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention.

  View details for DOI 10.3324/haematol.2011.052621

  View details for Web of Science ID 000300766300024

  View details for PubMedID 22058203

• Diffuse large B-cell lymphoma with aberrant expression of the T-cell antigens CD2 and CD7. Applied immunohistochemistry & molecular morphology Sangle, N. A., Agarwal, A. M., Smock, K. J., Leavitt, M. O., Warnke, R., Bahler, D., Perkins, S. L. 2011; 19 (6): 579-583

  Abstract

  Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Although, aberrant expression of a single T-cell-associated antigen (exclusive of CD5) on diffuse large B-cell lymphoma has occasionally been described in the literature, cases that show coexpression of ≥2 T-cell antigens on a well-documented case of diffuse large B-cell lymphoma are extremely rare. Here, we describe a well-characterized case of diffuse large B-cell lymphoma that showed aberrant coexpression of 2 T-cell-associated antigens, CD2 and CD7. Recognition of these types of cases is important to help ensure accurate diagnoses are made.

  View details for DOI 10.1097/PAI.0b013e318221c672

  View details for PubMedID 21836500

• Diffuse Large B-cell Lymphoma With Aberrant Expression of the T-cell Antigens CD2 and CD7 APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Sangle, N. A., Agarwal, A. M., Smock, K. J., Leavitt, M. O., Warnke, R., Bahler, D., Perkins, S. L. 2011; 19 (6): 1579-1583

  View details for DOI 10.1097/PAI.0b013e318221c672

  View details for Web of Science ID 000297250300018

• Clonally identical Hodgkin's disease develops after allogeneic hematopoietic cell transplant for CLL BONE MARROW TRANSPLANTATION Tseng, D., Jones, C. D., Anderson, M., Warnke, R., Zehnder, J. L., Miklos, D. B. 2011; 46 (12): 1576-1578

  View details for DOI 10.1038/bmt.2010.340

  View details for Web of Science ID 000298326500015

  View details for PubMedID 21258419

• Immature T-Cell Populations in Lymph Nodes of Castleman Disease and Angioimmunoblastic T-Cell Lymphoma Suggest Alternate Sites of T-Cell Development 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Ohgami, R. S., Chun, S., Ohgami, J., Zehnder, J. L., Van de Rijn, M., Arber, D. A., Natkunam, Y., Warnke, R. AMER SOC HEMATOLOGY. 2011: 1395–96

  View details for Web of Science ID 000299597104588

• The Efficacy of HGAL and LMO2 in the Separation of Lymphomas Derived From Small B Cells in Nodal and Extranodal Sites, Including the Bone Marrow AMERICAN JOURNAL OF CLINICAL PATHOLOGY Younes, S. F., Beck, A. H., Ohgami, R. S., Lossos, I. S., Levy, R., Warnke, R. A., Natkunam, Y. 2011; 135 (5): 697-708

  Abstract

  We studied the efficacy of 2 germinal center B-cell markers, HGAL and LMO2, in the separation of lymphomas derived from small B cells, particularly follicular lymphoma (FL) and marginal zone lymphoma occurring in nodal, extranodal, splenic, and bone marrow sites using immunohistochemical analysis for CD10, BCL6, BCL2, HGAL, and LMO2. Our results showed that HGAL and LMO2 are sensitive and specific markers for detecting FL in nodal and extranodal sites. In contrast, all markers were down-regulated in FL infiltrates in the bone marrow. CD10 and HGAL were expressed in a subset of FLs in the bone marrow and were highly correlated with each other and with CD21, a marker of follicular dendritic cells. We conclude that HGAL and LMO2 should be considered in immunohistochemical panels used for the routine workup of lymphomas derived from small B cells. In the bone marrow, staining for HGAL or CD10 can be helpful in making a diagnosis of FL, although they are absent in a subset of cases.

  View details for DOI 10.1309/AJCP7Z2BIBUNQPLZ

  View details for Web of Science ID 000289743400007

  View details for PubMedID 21502424

• ALK-negative systemic intravascular anaplastic large cell lymphoma presenting in the skin JOURNAL OF CUTANEOUS PATHOLOGY Rieger, K. E., POLIDORE, T., Warnke, R., Kim, J. 2011; 38 (2): 216-220

  Abstract

  Systemic cases of the CD30-positive T-cell neoplasm, anaplastic large cell lymphoma (ALCL), are typically anaplastic lymphoma kinase (ALK)-positive. The failure to express ALK protein has been shown to portend a worse prognosis. We describe a case of ALK-negative systemic ALCL that presented as a violaceous plaque on the scalp of a 79-year-old man. Interestingly, the neoplastic cells were confined largely within vascular spaces, a configuration that is exceedingly rare in the skin and is more typically seen with intravascular large B-cell lymphoma. In addition, bcl-2 immunohistochemical staining was strongly positive in this case, which may portend a more aggressive clinical course. To our knowledge, this report represents the first case of an ALK-negative ALCL to present intravascularly in the skin. Therefore, the recognition of systemic anaplastic T-cell lymphoma present within the intravascular spaces is important to avoid misdiagnosis.

  View details for DOI 10.1111/j.1600-0560.2010.01528.x

  View details for Web of Science ID 000285754200009

  View details for PubMedID 20236372

• Programmed death 1 expression in variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma: comparison with CD57 and lymphomas in the differential diagnosis HUMAN PATHOLOGY Churchill, H. R., Roncador, G., Warnke, R. A., Natkunam, Y. 2010; 41 (12): 1726-1734

  Abstract

  Recent studies have exploited an antibody directed against programmed death 1 expressed by follicular helper T-cells in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma. We had previously described clinically relevant, variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma and, in this study, sought to address the diagnostic utility of programmed death 1 in comparison with CD57 in variant nodular lymphocyte predominant Hodgkin lymphoma. Immunohistologic staining for programmed death 1 was carried out on biopsies of 67 patients with variant nodular lymphocyte predominant Hodgkin lymphoma. Thirty-four additional cases of nodular lymphocyte predominant Hodgkin lymphoma with associated diffuse areas, de novo T-cell and histiocyte-rich large B-cell lymphoma, and lymphocyte-rich classic Hodgkin lymphoma were also studied. Our results show that programmed death 1 positivity was found in the majority of nodular lymphocyte predominant Hodgkin lymphoma cases with a classic nodular architecture (87%) as compared with 50% for CD57 and was particularly helpful in identifying extranodular large atypical cells. Nodular lymphocyte predominant Hodgkin lymphoma with diffuse areas showed a gradual decrease in programmed death 1 reactivity from nodular to diffuse areas, although a significant proportion (40%-50%) of cases retained programmed death 1 positivity also in diffuse areas. In addition, T-cell and histiocyte-rich large B-cell lymphoma and lymphocyte-rich classic Hodgkin lymphoma displayed programmed death 1 positivity in a significant subset of cases (33%-40%). In conclusion, our study supports the utility of programmed death 1 in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and shows greater sensitivity of staining of programmed death 1 as compared with CD57 across all variants of nodular lymphocyte predominant Hodgkin lymphoma. Loss of programmed death 1 reactivity did not correlate with diffuse areas, progression, or the ability to differentiate nodular lymphocyte predominant Hodgkin lymphoma from T-cell and histiocyte-rich large B-cell lymphoma. These findings suggest the need for continued vigilance in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and its immunoarchitectural variants as well as related lymphomas in their differential diagnosis.

  View details for DOI 10.1016/j.humpath.2010.05.010

  View details for Web of Science ID 000284975800009

  View details for PubMedID 20825974

• Immunoarchitectural Patterns in Follicular Lymphoma: Efficacy of HGAL and LMO2 in the Detection of the Interfollicular and Diffuse Components AMERICAN JOURNAL OF SURGICAL PATHOLOGY Younes, S. F., Beck, A. H., Lossos, I. S., Levy, R., Warnke, R. A., Natkunam, Y. 2010; 34 (9): 1266-1276

  Abstract

  Follicular lymphoma (FL) can exhibit variant histologic patterns that can lead to confusion with other B-cell lymphomas and reactive conditions. Diagnostic markers such as CD10 and BCL2 may be difficult to interpret in variant FL patterns, and are often diminished or absent in the interfollicular and diffuse components. We evaluated 2 recently characterized germinal center B-cell markers, human germinal center associated lymphoma (HGAL), and LIM-only transcription factor 2 (LMO2), in 127 FL patient biopsies (94 nodal, 33 extranodal), and correlated the findings with histologic pattern, cellular composition, grade, and additional immunostains (CD20, CD3, CD21, CD10, BCL2, and BCL6). Architectural patterns included predominantly follicular (75%) and follicular and diffuse components (25%); 10 cases showed marginal zone differentiation and 3 were floral variants. Eighty-nine cases were low grade (38 grade 1; 51 grade 2) and 38 were grade 3 (29 grade 3A and 9 grade 3B). HGAL had the highest overall sensitivity of detecting FL and was superior in detecting the interfollicular and diffuse components compared with BCL2, LMO2, CD10, and BCL6. All 28 cases that lacked CD10, expressed HGAL, and the majority also expressed LMO2. Our results show that HGAL and LMO2 are sensitive markers for FL diagnosis. The addition of HGAL and LMO2 to the immunohistologic panel is beneficial in the work-up of nodal and extranodal B-cell lymphomas and the efficacy of HGAL in detecting the follicular, interfollicular and diffuse components of FL is of particular value in the setting of variant immunoarchitectural patterns.

  View details for DOI 10.1097/PAS.0b013e3181e9343d

  View details for Web of Science ID 000281579800005

  View details for PubMedID 20697248

  View details for PubMedCentralID PMC2929284

• Rare presentation of classical Hodgkin lymphoma with a clonal T-cell receptor gene rearrangement in the tissue LEUKEMIA & LYMPHOMA Nguyen, T. T., Warnke, R. A., Seo, K., Rosenberg, S. A., Arber, D. A. 2010; 51 (7): 1356-1359

  View details for DOI 10.3109/10428194.2010.486094

  View details for Web of Science ID 000279485700026

  View details for PubMedID 20496992

• PD-1 Expression in T-cell Lymphomas and Reactive Lymphoid Entities: Potential Overlap in Staining Patterns Between Lymphoma and Viral Lymphadenitis AMERICAN JOURNAL OF SURGICAL PATHOLOGY Krishnan, C., Warnke, R. A., Arber, D. A., Natkunam, Y. 2010; 34 (2): 178-189

  Abstract

  Peripheral T-cell lymphomas are a heterogeneous group that often requires the use of ancillary testing for accurate diagnosis. This is particularly applicable to the diagnosis of angiommunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unclassified (PTCLU), because of their histologic and immunophenotypic overlap with reactive lymphoid proliferations. Recently, immunohistochemistry for programmed death-1 (PD-1), a marker of follicular helper T cells, was shown to be sensitive in the detection of AITL and PTCLU. The sensitivity of this marker in reactive entities, however, has not been adequately evaluated. We confirm that PD-1 staining is a highly sensitive marker in the diagnosis of peripheral T-cell lymphomas: increased extrafollicular PD-1-positive cells were seen in 93% (76/82) of AITL, 62% (16/26) of PTCLU, and 11% (2/18) of anaplastic-lymphoma-kinase (ALK)-negative anaplastic large-cell lymphomas. The majority of reactive lymphadenopathies including Cat-scratch disease, Kikuchi lymphadenitis, Castleman disease, and reactive follicular hyperplasia showed no PD-1 staining outside follicles. Some reactive lymph nodes, showed increased extrafollicular PD-1-positive cells in a pattern similar to AITL and PTCLU, and include progressive transformation of germinal centers, viral lymphadenitis (Epstein-Barr virusand human immunodeficiency virus) and Rosai-Dorfman disease. This study shows that PD-1-positive cells may be increased in a number of settings other than T-cell lymphomas. We conclude that staining for PD-1 in reactive and atypical lymphadenopathies should be interpreted with caution and in the context of other ancillary immunophenotypic and molecular studies before a diagnosis of AITL or PTCLU is entertained.

  View details for Web of Science ID 000274219800005

  View details for PubMedID 20087161

• Immunoarchitectural Patterns in Follicular Lymphoma: Efficacy of HGAL and LMO2 in the Detection of the Interfollicular Component 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Younes, S. F., Beck, A., Warnke, R. A., Lossos, I. S., Levy, R., Natkunam, Y. NATURE PUBLISHING GROUP. 2010: 330A–330A

  View details for Web of Science ID 000274337301489

• Follicular lymphomas with plasmacytic differentiation include two subtypes MODERN PATHOLOGY Gradowski, J. F., Jaffe, E. S., Warnke, R. A., Pittaluga, S., Surti, U., Gole, L. A., Swerdlow, S. H. 2010; 23 (1): 71-79

  Abstract

  Follicular lymphomas with plasmacytic differentiation were described more than two decades ago. However, the possibility that some of these reported cases are marginal zone lymphomas or composite lymphomas must be considered. In addition, it is also uncertain whether follicular lymphomas with plasmacytic differentiation have any unique cytogenetic or other features. Therefore, fluorescence immunophenotypic and interphase cytogenetic analysis of 14 well-characterized follicular lymphomas with plasmacytic differentiation was performed using a CD138 antibody to identify the plasma cells and with BCL2, BCL6, IGH@ and MALT1 break-apart probes and a chromosome 12 centromeric probe. CD10 was expressed in 12/14 cases, BCL6 in 12/12 cases and BCL2 in 12/14 cases. At least one cytogenetic abnormality was identified in 12/14 cases. The same abnormality was present in both the plasmacytic (CD138+) and non-plasmacytic (CD138-) component in all 10 evaluable cases. BCL2 rearrangements were present in seven cases (5 IGH@ rearranged, 1 IGH@-not rearranged, 1 IGH@-not evaluable), BCL6 rearrangement in two (1 also with BCL2/IGH@ rearrangement), +12 in 1, +MALT1 without +18 in 1, IGH@ rearrangement without other abnormalities in 1 and IGH@ rearranged or partially deleted in 1 case. No cases showed +BCL6 (3q27) or a MALT1 rearrangement. All six cases with an isolated BCL2 rearrangement had predominantly interfollicular plasmacytic cells whereas, 6/7 cases without the translocation had concentrations of intrafollicular or perifollicular plasmacytic cells (P<0.005), as did the case with BCL2 and BCL6 translocations. These results support the existence of bona fide follicular lymphomas with plasmacytic differentiation and support the clonal relationship of the neoplastic lymphoid and plasma cells in at least most of these cases. The differential distribution of the plasma cells, specifically in relation to the presence or absence of an isolated BCL2 rearrangement suggests that the latter cases may be distinctive, sharing some features with marginal zone lymphomas.

  View details for DOI 10.1038/modpathol.2009.146

  View details for Web of Science ID 000273248500016

  View details for PubMedID 19838161

• Immunoarchitectural Patterns in Nodal Marginal Zone B-Cell Lymphoma A Study of 51 Cases AMERICAN JOURNAL OF CLINICAL PATHOLOGY Salama, M. E., Lossos, I. S., Warnke, R. A., Natkunam, Y. 2009; 132 (1): 39-49

  Abstract

  Nodal marginal zone lymphoma (NMZL) represents a rare and heterogeneous group that lacks markers specific for the diagnosis. We evaluated morphologic and immunoarchitectural features of 51 NMZLs, and the following immunostains were performed: CD20, CD21, CD23, CD5, CD3, CD43, CD10, Ki-67, BCL1, BCL2, BCL6, HGAL, and LMO2. Four immunoarchitectural patterns were evident: diffuse (38 [75%]), well-formed nodular/follicular (5 [10%]), interfollicular (7 [14%]), and perifollicular (1 [2%]). Additional features included a monocytoid component (36 [71%]), admixed large cells (20 [39%]), plasma cells (24 [47%]), compartmentalizing stromal sclerosis (13 [25%]), and prominent blood vessel sclerosis (10 [20%]). CD21 highlighted disrupted follicular dendritic cell meshwork in 35 (71%) of 49 cases, and CD43 coexpression was present in 10 (24%) of 42 cases. A panel of germinal center-associated markers was helpful in eliminating cases of diffuse follicle center lymphoma. Our results highlight the histologic and immunoarchitectural spectrum of NMZL and the usefulness of immunohistochemical analysis for CD43, CD23, CD21, BCL6, HGAL, and LMO2 in the diagnosis of NMZL.

  View details for DOI 10.1309/AJCPZQ1GXBBNG8OG

  View details for Web of Science ID 000267206400007

  View details for PubMedID 19864232

  View details for PubMedCentralID PMC2894708

• Castleman Disease An Update on Classification and the Spectrum of Associated Lesions ADVANCES IN ANATOMIC PATHOLOGY Cronin, D. M., Warnke, R. A. 2009; 16 (4): 236-246

  Abstract

  Since its initial description, researchers have expanded the spectrum of Castleman disease to include not only the classic and well-recognized hyaline-vascular type, but also the plasma cell type and multicentric types of broader histologic range, including human herpes virus-8-associated Castleman disease. These less common subtypes of Castleman disease are less familiar, and may be under-recognized. Also of practical importance, current authors are restructuring the classification of multicentric Castleman disease to accommodate the emerging pathogenic role of human herpes virus-8 and its association with the recently described plasmablastic variant. In addition to an increased risk of lymphoma, patients with Castleman disease also are at increased risk for other related neoplasms, including Kaposi sarcoma and follicular dendritic cell tumors, which are of prognostic and therapeutic relevance. This review focuses on the histologic diagnosis of Castleman disease, current and emerging concepts in its pathogenesis and classification, and associated histopathologic entities.

  View details for Web of Science ID 000267480300005

  View details for PubMedID 19546611

• Cutaneous Peripheral T-Cell Lymphoma Associated With a Proliferation of B Cells AMERICAN JOURNAL OF CLINICAL PATHOLOGY Mattoch, I. W., Fulton, R., Kim, Y., Hoppe, R., Warnke, R. A., Sundram, U. N. 2009; 131 (6): 810-819

  Abstract

  Although the new World Health Organization-European Organization for Research and Treatment of Cancer classification focuses on providing uniformity in the diagnosis of cutaneous lymphomas, cutaneous peripheral T-cell lymphoma (PTL) remains a poorly defined subgroup. As follow-up to a study of systemic PTL complicated by a proliferation of B cells, we studied 16 cases of cutaneous PTL that contained morphologically atypical T cells associated with a significant infiltrate of B cells (about 20%-50%). A clonal T-cell receptor gamma chain gene rearrangement was present in all cases. In contrast, a clonal immunoglobulin heavy chain gene rearrangement was present in only 1 case. Clinical staging in 14 cases identified systemic involvement in 2. At last follow-up, both patients with systemic involvement had died of disease, and the majority of patients with primary cutaneous disease were alive (11/12). The presence of numerous atypical B cells and T cells caused diagnostic confusion in these cases. Comprehensive pathologic studies, coupled with clinical staging, are necessary for the accurate diagnosis of this unusual manifestation of cutaneous PTL.

  View details for DOI 10.1309/AJCP5W0VOCSVOBRA

  View details for Web of Science ID 000266238600010

  View details for PubMedID 19461087

• Intravascular ALK-Positive Anaplastic Large-Cell Lymphoma Mimicking Inflammatory Breast Carcinoma JOURNAL OF CLINICAL ONCOLOGY Krishnan, C., Moline, S., Anders, K., Warnke, R. A. 2009; 27 (15): 2563-2565

  View details for DOI 10.1200/JCO.2008.20.3984

  View details for Web of Science ID 000266195400024

  View details for PubMedID 19364961

• Lack of Utility of CD20 Immunohistochemistry in Staging Bone Marrow Biopsies for Diffuse Large B-cell Lymphoma APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Baiyee, D., Warnke, R., Natkunam, Y. 2009; 17 (2): 93-95

  Abstract

  The utility of CD20 immunohistochemistry in the evaluation of staging bone marrow biopsies of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients has not been extensively studied. We used 113 routinely processed bone marrow biopsies to study the extent and pattern of involvement by lymphoma and CD20 staining. Twelve (10.6%) of 113 cases had involvement by morphology, and 5 (41.7%) of these showed histologic discordance between the primary site and the bone marrow. All cases with morphologic evidence of bone marrow involvement showed staining for CD20. Four (3.5%) of 113 cases had non-neoplastic aggregates that stained for CD20. One case (0.9%) showed a small benign lymphoid aggregate by immunohistochemistry that was not evident by morphology. Our results demonstrate that CD20 staining did not detect any examples of bone marrow involvement by DLBCL that were not evident by morphology. We conclude that immunohistochemistry for CD20 adds no increase in the sensitivity of detection of bone marrow infiltration by DLBCL.

  View details for Web of Science ID 000263734200001

  View details for PubMedID 19521275

• The Frequency of Immunoglobulin Heavy Chain Gene and T-Cell Receptor gamma-Chain Gene Rearrangements and Epstein-Barr Virus in ALK(+) and ALK(-) Anaplastic Large Cell Lymphoma and Other Peripheral T-Cell Lymphomas JOURNAL OF MOLECULAR DIAGNOSTICS Tan, B. T., Seo, K., Warnke, R. A., Arber, D. A. 2008; 10 (6): 502-512

  Abstract

  We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.

  View details for DOI 10.2353/jmoldx.2008.080054

  View details for Web of Science ID 000260533600007

  View details for PubMedID 18832464

  View details for PubMedCentralID PMC2570633

• Immunohistochemical characterization of nasal-type extranodal NK/T-Cell lymphoma using a tissue microarray AMERICAN JOURNAL OF CLINICAL PATHOLOGY Schwartz, E. J., Molina-Kirsch, H., Zhao, S., Marinelli, R. J., Warnke, R. A., Natkunam, Y. 2008; 130 (3): 343-351

  Abstract

  Nasal-type extranodal natural killer (NK)/T-cell lymphoma is an uncommon malignancy. By using a tissue microarray, we characterized 84 cases of extranodal NK/T-cell lymphoma with regard to expression of 18 immunohistochemical markers and the presence of Epstein-Barr virus (EBV) RNA. In our series, CD2 was positive in 69 (93%) of 74 cases, CD3 in 68 (84%) of 81, CD5 in 22 (27%) of 81, CD20 in 0 (0%) of 82, CD29 in 75 (91%) of 82, CD30 in 29 (35%) of 84, CD43 in 81 (96%) of 84, CD54 in 58 (72%) of 81, CD56 in 46 (58%) of 79, CD62L in 23 (28%) of 83, CD183 in 66 (80%) of 83, BCL2 in 33 (39%) of 84, cutaneous lymphocyte antigen in 21 (25%) of 84, granzyme B in 70 (83%) of 84, Ki-67 in 59 (71%) of 83, linker for activation of T cells in 60 (71%) of 84, perforin in 66 (86%) of 77, TIA1 in 76 (90%) of 84, and EBV in 73 (87%) of 84. Hierarchical cluster analysis separated primary cutaneous cases from cases manifesting in other sites based on lower expression of the cell adhesion molecule CD54.

  View details for DOI 10.1309/V561QTM6854W4WAV

  View details for Web of Science ID 000258538900003

  View details for PubMedID 18701406

• Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone BLOOD Feldman, A. L., Arber, D. A., Pittaluga, S., Martinez, A., Burke, J. S., Raffeld, M., Camos, M., Warnke, R., Jaffe, E. S. 2008; 111 (12): 5433-5439

  Abstract

  Rare cases of histiocytic and dendritic cell (H/DC) neoplasms have been reported in patients with follicular lymphoma (FL), but the biologic relationship between the 2 neoplasms is unknown. We studied 8 patients with both FL and H/DC neoplasms using immunohistochemistry, fluorescence in situ hybridization (FISH) for t(14;18), and polymerase chain reaction (PCR)/sequencing of BCL2 and IGH rearrangements. There were 5 men and 3 women (median age, 59 years). All cases of FL were positive for t(14;18). The H/DC tumors included 7 histiocytic sarcomas, 5 of which showed evidence of dendritic differentiation, and 1 interdigitating cell sarcoma. Five H/DC tumors were metachronous, following FL by 2 months to 12 years; tumors were synchronous in 3. All 8 H/DC tumors showed presence of the t(14;18) either by FISH, or in 2 cases by PCR with the major breakpoint region (MBR) probe. PCR and sequencing identified identical IGH gene rearrangements or BCL2 gene breakpoints in all patients tested. All H/DC tumors lacked PAX5, and up-regulation of CEBPbeta and PU.1 was seen in all cases tested. These results provide evidence for a common clonal origin of FL and H/DC neoplasms when occurring in the same patient, and suggest that lineage plasticity may occur in mature lymphoid neoplasms.

  View details for DOI 10.1182/blood-2007-11-124792

  View details for Web of Science ID 000256786500012

  View details for PubMedID 18272816

• Improved prognosis after histologic transformation (HT) of follicular lymphoma (FL): The Stanford experience 1960-2003 10th International Conference on Malignant Lymphoma Tan, D., Rosenberg, S. A., Lavori, P., Levy, R., Hoppe, R., Warnke, R., Advani, R., Natkuunam, Y., Yuen, A., Horning, S. J. OXFORD UNIV PRESS. 2008: 111–112

  View details for Web of Science ID 000256693500106

• Closing the gap: A comparison of observed versus expected survival in follicular lymphoma (FL) at Stanford University from 1960-2003 Tan, D., Rosenberg, S. A., Lavori, P., Sigal, B. M., Levy, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Plevritis, S. K., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457403064

• Hydroa-like lymphoma with CD56 expression JOURNAL OF CUTANEOUS PATHOLOGY Doeden, K., Molina-Kirsch, H., Perez, E., Warnke, R., Sundram, U. 2008; 35 (5): 488-494

  Abstract

  Hydroa-like lymphoma is an extremely rare and aggressive lymphoma described in children from Latin American countries (Mexico, Guatemala and Peru) and Asia (Japan, Korea and Taiwan). Clinically, patients present with vesicles, ulcers and scars occurring on both sun-exposed and non-sun-exposed areas. In contrast to classical hydroa vacciniforme, hydroa-like lymphoma is associated with systemic lymphoma of T-cell type that expresses either CD4 or CD8. We report the findings from two unusual cases of hydroa-like lymphoma that, unlike the cases described thus far in the literature, express CD56 and resemble natural killer cell lymphomas. Two 9-year-old boys presented with clinical histories of waxing and waning ulcerative blistering lesions since 3 years of age. Histological examination of skin biopsies from both cases showed periappendigeal infiltrates of atypical lymphocytes. Immunohistochemical studies showed that the cells were highlighted by markers for CD3, CD56 and CD30, but did not express CD4 and CD8. Both patients were alive with disease 1 year later. Hydroa-like lymphoma with natural killer-cell phenotype may have a similar outcome to T-cell derived hydroa-like lymphoma, but the prognosis appears to be better than classic NK lymphomas, which in general behave in an aggressive fashion.

  View details for DOI 10.1111/j.1600-0560.2007.00836.x

  View details for Web of Science ID 000254808200010

  View details for PubMedID 17976208

• Nodular lymphocyte-predominant Hodgkin lymphoma presenting as fulminant hepatic failure in a pediatric patient: A case report with pathologic, immunophenotypic, and molecular findings APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Woolf, K. M., Wei, M. C., Link, M. P., Arber, D. A., Warnke, R. A. 2008; 16 (2): 196-201

  Abstract

  A 7-year-old boy presented with fulminant hepatic failure requiring liver transplant. Serologic testing ruled out infectious and autoimmune causes. During transplant surgery he was found to have enlarged periportal lymph nodes that were biopsied. Nodular lymphocyte-predominant Hodgkin lymphoma was diagnosed based on histologic examination of the lymph node and liver. The L&H cells within the lymph node were positive for CD20 whereas those within the liver were not, although they were positive for other B-cell markers. After extensive work-up, the cause of liver failure could only be attributed to the involvement by lymphoma. In addition, B-cell clonality was established among the neoplastic cells with the same clone detected in all sampled tissues. Hodgkin lymphoma as a cause of hepatic failure is rare and has not been previously reported in a pediatric patient.

  View details for Web of Science ID 000253788700016

  View details for PubMedID 18227720

• Light-chain-restricted germinal centres in reactive lymphadenitis: report of eight cases HISTOPATHOLOGY Nam-Cha, S. H., San-Millan, B., Mollejo, M., Garcia-Cosio, M., Garijo, G., Gomez, M., Warnke, R. A., Jaffe, E. S., Piris, M. A. 2008; 52 (4): 436-444

  Abstract

  Light-chain-restricted germinal centres are generally associated with the existence of a neoplastic lymphoproliferative disorder. The aim was to present a series of cases with persistent lymph node enlargement that featured some germinal centres showing light chain immunoglobulin restriction.A series of six reactive lymphadenitis and two Castleman's disease cases was analysed by immunohistochemistry, IgH-polymerase chain reaction (PCR) and microdissected PCR. In all cases some germinal centres contained a population of plasma cells and plasmacytoid germinal centre cells showing light chain immunoglobulin restriction. In three cases the monotypic cells also showed distinct Bcl-2 expression. Two of the cases showed a predominant IgH rearrangement on a florid polyclonal background and one had an IgH monoclonal rearrangement, as revealed by PCR. Microdissected germinal centre PCR revealed a dominant repeated band in one of three cases and in another case a non-repeated clonal peak was observed. One of the patients developed a follicular lymphoma, which became evident from a subsequent biopsy.These findings may be a manifestation of an underlying disorder in the regulation of the immune response, or an exaggeration of the germinal centre oligoclonal nature. This should be taken into account in the differential diagnosis of follicular hyperplasia.

  View details for DOI 10.1111/j.1365-2559.2008.02965.x

  View details for Web of Science ID 000253626500003

  View details for PubMedID 18315596

• Survival in follicular lymphoma: The Stanford experience, 1960-2003. 49th Annual Meeting of the American-Society-of-Hematology Tan, D., Rosenberg, S. A., Levy, R., Lavori, P., Tibshirani, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Yuen, A., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 1005A–1005A

  View details for Web of Science ID 000251100804465

• Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: A phenomenon with distinctive clinicopathologic features AMERICAN JOURNAL OF SURGICAL PATHOLOGY Balague, O., Martinez, A., Colomo, L., Rosello, E., Garcia, A., Martinez-Bernal, M., Palacin, A., Fu, K., Weisenburger, D., Colomer, D., Burke, J. S., Warnke, R. A., Campo, E. 2007; 31 (9): 1310-1322

  Abstract

  Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.

  View details for Web of Science ID 000249170300002

  View details for PubMedID 17721185

• Morphologic and immunophenotypic variants of nodal T-cell lymphomas and T-cell lymphoma mimics Workshop of the Society-for-Hematopathology/European-Association-for-Haematopathology Warnke, R. A., Jones, D., Hsi, E. D. AMER SOC CLINICAL PATHOLOGY. 2007: 511–27

  Abstract

  Given their relative rarity, one of the primary diagnostic difficulties in nodal T-cell lymphomas is recognizing their range of histologic patterns. This is complicated by the fact that most mature T-cell lymphomas retain some functional characteristics of nonneoplastic T cells, ie, the capacity to secrete cytokines and costimulate immune cell growth, and, thus, are associated with obscuring nonneoplastic immune cells. Sessions 2 and 3 of the Society for Hematopathology/European Association for Haematopathology Workshop focused on these issues and conditions that may simulate T-cell lymphomas. We summarize salient features of presented cases, including the varied patterns seen in angioimmunoblastic T-cell lymphoma (AITL) and other more poorly characterized morphologic and functional nodal T-cell lymphoma subsets. Many cases illustrated the difficulties distinguishing AITL from peripheral T-cell lymphoma, unspecified, when the neoplasms manifest only some AITL features. The usefulness of separately classifying T-cell lymphomas that demonstrate follicular, perifollicular, or T-zone patterns of infiltration; significance of immunophenotypically distinct subsets that express cytotoxic markers or have features of central memory T cells; diagnostic difficulties posed by B-cell proliferations that accompany T-cell lymphomas; and T-cell lymphoma mimics related to genetic disorders, immune dysregulation, and drug reactions are also discussed.

  View details for DOI 10.1309/QBLAMA321K9AD2XK

  View details for Web of Science ID 000245248100004

  View details for PubMedID 17369127

• The frequency of B- and T-cell gene Rearrangements and Epstein-Barr virus in T-cell lymphomas - A comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations JOURNAL OF MOLECULAR DIAGNOSTICS Tan, B. T., Warnke, R. A., Arber, D. A. 2006; 8 (4): 466-475

  Abstract

  We report on a series of 58 cases of angioimmunoblastic T-cell lymphoma (AILT) and 59 cases of peripheral T-cell lymphoma, unspecified (PTCL-NOS). Subsets of cases from both diagnostic groups were complicated by associated B-cell proliferations, and we performed B- and T-cell clonality studies and in situ hybridization for Epstein-Barr virus (EBV) to investigate the relationship between B-cell proliferation, B-cell clonality, and EBV. Using multiplex polymerase chain reaction assays based on the BIOMED-2 collaborative study, we detected TCRgamma T-cell clones in 78 and 81% of AILT and PTCL-NOS cases, respectively, and IGH B-cell clones in 34 and 35% of AILT and PTCL-NOS cases, respectively. The majority of cases contained EBV-positive cells, including 50% of AILT and 57% of PTCL-NOS cases, and cases with B-cell proliferations were more often EBV-positive. Although a relatively high rate of B-cell clonality has been shown for AILT, our findings for PTCL-NOS differ from previous reports in that B-cell clonality was relatively frequent. Overall, a positive B-cell clone correlated, in part, with the presence of a B-cell proliferation but not with EBV. Our findings demonstrate that B-cell clonality is a common finding in AILT and PTCL-NOS, and its presence should not negate the diagnosis established by morphologic, immunophenotypic, and clinical findings.

  View details for DOI 10.2353/jmoldx.2006.060016

  View details for Web of Science ID 000240256600010

  View details for PubMedID 16931587

  View details for PubMedCentralID PMC1867616

• CD10 expression in peripheral T-cell lymphomas complicated by a proliferation of large B-cells MODERN PATHOLOGY Reichard, K. K., Schwartz, E. J., Higgins, J. P., Narasimhan, B., Warnke, R. A., Natkunam, Y. 2006; 19 (3): 337-343

  Abstract

  CD10 expression by the neoplastic T cells in angioimmunoblastic T-cell lymphoma was recently described. As cases of peripheral T-cell lymphoma, unspecified, fail to show similar CD10 expression, this feature helps discriminate between these two entities, particularly in cases exhibiting morphologic overlap. Given these findings, we studied CD10 expression in a subtype of peripheral T-cell lymphoma known as peripheral T-cell lymphoma complicated by a proliferation of large B cells and compared it with angioimmunoblastic T-cell lymphoma and angioimmunoblastic T-cell lymphoma with a large B-cell proliferation. A total of 33 cases were identified including peripheral T-cell lymphoma complicated by a proliferation of large B cells (10), angioimmunoblastic T-cell lymphoma (10) and angioimmunoblastic T-cell lymphoma with a large B-cell proliferation (13). Diagnoses were established by hematoxylin and eosin (H&E) stain, immunohistochemistry and/or molecular findings (polymerase chain reaction for T-cell receptor-gamma gene rearrangement). Two of 10 cases of peripheral T-cell lymphoma complicated by a proliferation of large B cells showed aberrant CD10 expression (20%) compared to 9/10 cases of angioimmunoblastic T-cell lymphoma (90%) and 8/13 of angioimmunoblastic T-cell lymphoma with a large B-cell proliferation (62%). One case each of angioimmunoblastic T-cell lymphoma and angioimmunoblastic T-cell lymphoma with a large B-cell proliferation showed a rare, but not unequivocal, CD10+ atypical cell. Four cases of angioimmunoblastic T-cell lymphoma with a large B-cell proliferation were CD10 negative. Of the 2 CD10+ peripheral T-cell lymphoma complicated by a proliferation of large B cells, one had no H&E or IHC features of angioimmunoblastic T-cell lymphoma and showed only a rare positive cell. The second case, a lung biopsy, exhibited diffuse CD10 tumor cell positivity. The predominant staining pattern in the CD10+ cases was characterized by scattered, mostly individual, morphologically neoplastic cells. A rare case showed clusters of positive cells. Our data indicate that only 20% of cases of peripheral T-cell lymphoma complicated by a proliferation of large B cells show CD10 expression by the neoplastic T cells in contrast to angioimmunoblastic T-cell lymphoma and angioimmunoblastic T-cell lymphoma with a large B-cell proliferation which exhibit CD10 staining in 90 and 62% of cases, respectively. This finding does not reach statistical significance with a P-value of 0.57 (Fisher's exact test). As these entities appear to be biologically distinct and may portend different overall survivals, CD10 expression may serve as an additional discriminating criterion.

  View details for DOI 10.1038/modpathol.3800536

  View details for Web of Science ID 000235592800001

  View details for PubMedID 16400325

• Follicular dendritic cell immunohistochemical markers in angioimmunoblastic T-cell lymphoma APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Troxell, M. L., Schwartz, E. J., van de Ruin, M., Ross, D. T., Warnke, R. A., Higgins, J. P., Natkunam, Y. 2005; 13 (4): 297-303

  Abstract

  Angioimmunoblastic T-cell lymphoma is characterized by a paracortical proliferation of medium to large neoplastic T cells, often with clear cytoplasm, in a background of arborizing high endothelial venules, many surrounded by follicular dendritic cells (FDCs). IHC staining may be applied to highlight these extrafollicular FDCs, traditionally using CD21, or CD23. Several alternative FDC markers have been described, including CNA.42, cystatin A/acid cysteine proteinase inhibitor (ACPI, involved in antigen presentation), and fascin (an actin binding protein). The authors stained a collection of 45 angioimmunoblastic T-cell lymphomas with CD21, CD23, CNA.42, cystatin A, and fascin for direct comparison of FDC staining characteristics in this setting. CD21 highlighted the expected dendritic network of cell processes, within residual follicles and outside of follicles, often adjacent to proliferating vessels. CD23 exhibited similar staining quality but was less sensitive than CD21. CNA.42 showed only diffuse weak labeling of FDCs. Cystatin A stained the cytoplasm of follicular dendritic cells within and outside of follicles; however, staining was often not sharply localized to dendritic cell processes, and scoring was further complicated by reactivity with other cell types in over half of the cases. Likewise, fascin stained a variety of cell types, including strong staining of interdigitating dendritic-like cells, moderate staining of endothelial cells, and only weak staining of follicular dendritic cells within and outside of follicles. Thus, CD21 remains the most reliable marker of follicular dendritic cells in angioimmunoblastic T-cell lymphoma.

  View details for PubMedID 16280657

• Low-grade B-cell lymphomas with plasmacytic differentiation lack PAX5 gene rearrangements JOURNAL OF MOLECULAR DIAGNOSTICS George, T. I., Wrede, J. E., Bangs, C. D., Cherry, A. M., Warnke, R. A., Arber, D. A. 2005; 7 (3): 346-351

  Abstract

  The chromosomal translocation t(9;14)(p13;q32) has been reported in association with lymphoplasmacytic lymphoma (LPL). Although this translocation involving the paired homeobox-5 (PAX5) gene at chromosome band 9p13 and the immunoglobulin heavy chain (IgH) gene at 14q32 has been described in approximately 50% of LPL cases, the actual number of cases studied is quite small. Many of the initial cases associated with t(9;14)(p13;q32) were actually low-grade B-cell lymphomas with plasmacytic differentiation other than LPL. Thus, we analyzed a series of low-grade B-cell lymphomas for PAX5 gene rearrangements. We searched records from the Department of Pathology, Stanford University Medical Center for low-grade B-cell lymphomas, with an emphasis on plasmacytic differentiation, that had available paraffin blocks or frozen tissue. We identified 37 cases, including 13 LPL, 18 marginal zone lymphomas (nodal, extranodal, splenic, and alpha-heavy chain disease), and 6 small lymphocytic lymphomas. A novel dual-color break-apart bacterial artificial chromosome probe was designed to flank the PAX5 gene, spanning previously described PAX5 breakpoints, and samples were analyzed by interphase fluorescence in situ hybridization. All cases failed to demonstrate a PAX5 translocation, indicating that t(9;14)(p13;q32) and other PAX5 translocations are uncommon events in low-grade B-cell lymphomas with plasmacytic differentiation. This study also confirms recent reports that found an absence of PAX5 rearrangements in LPL, suggesting the reassessment of PAX5 rearrangements in LPL.

  View details for PubMedID 16049306

• Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation BLOOD Natkunam, Y., Lossos, L. S., Taidi, B., Zhao, S. C., Lu, X. Q., Ding, F. Y., Hammer, A. S., Marafioti, T., Byrne, G. E., Levy, S., Warnke, R. A., Levy, R. 2005; 105 (10): 3979-3986

  Abstract

  We identified the human germinal center-associated lymphoma (HGAL) in gene-expression profiling studies of diffuse large B-cell lymphoma (DLBCL). The expression of HGAL correlated with survival in patients with DLBCL. The HGAL gene is the human homolog of M17, a mouse gene expressed specifically in normal germinal center (GC) B cells. We generated a monoclonal antibody against the HGAL protein and show that HGAL is expressed in the cytoplasm of GC lymphocytes and in lymphomas of GC derivation. Among 727 lymphomas tested by immunohistochemistry on tissue microarrays, HGAL staining was found in follicular lymphomas (103 of 107), Burkitt lymphomas (40 of 40), mediastinal large B lymphomas (7 of 8), and in DLBCLs (103 of 151). Most marginal zone lymphomas lacked HGAL staining. Lymphocyte-predominant Hodgkin lymphomas (12 of 17) and, surprisingly, classical Hodgkin lymphomas (78 of 107) were found to be positive. Hierarchical clustering of comparative immunohistologic results in DLBCLs demonstrates that the expression of HGAL is similar to 2 other GC-associated proteins, BCL6 and CD10, but different from 2 markers associated with a non-GC phenotype, MUM1/IRF4 and BCL2. The restricted expression and GC specificity of HGAL protein suggest that it may have an important role in the diagnosis of specific lymphomas, and, potentially in the identification of subtypes associated with different prognoses.

  View details for DOI 10.1182/blood-2004-08-3112

  View details for Web of Science ID 000229009000042

  View details for PubMedID 15677569

  View details for PubMedCentralID PMC1895083

• Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nguyen, T. D., Schwartz, E. J., West, R. B., Warnke, R. A., Arber, D. A., Natkunam, Y. 2005; 29 (5): 617-624

  Abstract

  CD163, a hemoglobin scavenger receptor, is expressed in monocytes and macrophages. We tested the expression of the CD163 protein in 1,105 human malignancies and normal tissues using tissue microarrays and conventional paraffin-embedded tissue sections. Besides staining nonneoplastic monocytes and histiocytes (tissue macrophages), membranous/cytoplasmic staining for CD163 was primarily limited to neoplasms with monocytic/histiocytic differentiation. CD163 reactivity was not observed in normal tissues, lymphomas, carcinomas, and in a majority of mesenchymal neoplasms, including follicular dendritic cell tumors (0 of 4), although it stained admixed histiocytes. Staining for CD163 was seen in Rosai-Dorfman disease (5 of 6), histiocytic sarcoma (3 of 4), littoral cell angioma (6 of 6), and Langerhans cell histiocytosis (3 of 5). A subset of atypical fibrous histiocytomas (9 of 16), benign fibrous histiocytomas (6 of 9), and atypical fibroxanthomas (1 of 3) also showed CD163 staining. Our studies also confirm earlier work showing that CD163 is expressed in acute myeloid leukemia with monocytic differentiation (AML, FAB subtype M5) (2 of 6), as well as a majority of giant cell tenosynovial tumors (7 of 8). Its limited range of expression and tissue specificity indicate that CD163 may have significant diagnostic utility in separating specific tumors with monocytic and histiocytic derivation from other entities in their differential diagnosis.

  View details for Web of Science ID 000228707200007

  View details for PubMedID 15832085

• Immune signatures in follicular lymphoma NEW ENGLAND JOURNAL OF MEDICINE Hong, W. J., Warnke, R., Chu, G. 2005; 352 (14): 1496-1496

  View details for Web of Science ID 000228145200031

  View details for PubMedID 15818776

• The number of tumor-infiltrating CD3+ and CD25+ cells positively correlates with clinical response to rituximab in follicular lymphoma patients 94th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Park, C. Y., Bohen, S. P., Levy, R., Warnke, R., Nathunam, Y. NATURE PUBLISHING GROUP. 2005: 245A–245A

  View details for Web of Science ID 000226238601308

• The number of CD25+tumor-infiltrating cells may predict clinical response to rituximab in follicular lymphoma patients. 46th Annual Meeting of the American-Society-of-Hematology Park, C. Y., Bohen, S. P., Levy, R., Warnke, R. A., Natkunam, Y. AMER SOC HEMATOLOGY. 2004: 214A–214A

  View details for Web of Science ID 000225127500750

• Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin's disease: Mature data in early and advanced stage patients. 46th Annual Meeting of the American-Society-of-Hematology Horning, S. J., Hoppe, R. T., Advani, R., Warnke, R., Baer, D., Mason, J., Rosenberg, S. A. AMER SOC HEMATOLOGY. 2004: 92A–92A

  View details for Web of Science ID 000225127500310

• Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B cell derivation. 46th Annual Meeting of the American-Society-of-Hematology Natkunam, Y., Lossos, I. S., Taidi, B., Zhao, S. C., Lu, X. Q., Ding, F. Y., Hammer, A. S., Marafioti, T., Byrne, G. E., Levy, S., Warnke, R. A., Levy, R. AMER SOC HEMATOLOGY. 2004: 624A–624A

  View details for Web of Science ID 000225127502266

• Mutational analysis of IgV(H) and BCL-6 genes suggests thymic B-cells origin of mediastinal (thymic) B-cell lymphoma LEUKEMIA & LYMPHOMA Csernus, B., Timar, B., Fulop, Z., Bognar, A., Szepesi, A., Laszlo, T., Jakso, P., Warnke, R., KOPPER, L., Matolcsy, A. 2004; 45 (10): 2105-2110

  Abstract

  Mediastinal (thymic) large B-cell lymphoma (MBL) has been defined as a subtype of diffuse large B-cell lymphoma (DLBL) arising in the mediastinum with characteristic clinicopathological features. It has been postulated that MBL arise from non-circulating thymic B-cells and represent a distinct lymphoma entity, however, the histogenesis of the disease is not yet fully understood. In order to clarify the histogenetic derivation of MBL and to determine the relationship of MBL to thymic B-cells we have analyzed the nucleic acid sequences of immunoglobulin (Ig) heavy chain variable region (VH) and 5' noncoding region of BCL-6 genes in normal thymic B-cells and six cases of MBL. Thymic B-cells and tumor cells of MBLs displayed hypermutated VH and/or BCL-6 genes but intraclonal divergence did not associate with these mutations. Since somatic mutations of the IgVH and BCL-6 genes are histogenetic markers of B-cell transit through the germinal centre (GC), these results suggest that both thymic B-cells and MBLs derived from GC or an equivalent environment where B-cells underwent somatic hypermutation. The similar pattern of mutations of IgVH and BCL-6 genes found in thymic B-cells and MBLs further supports the theory that MBLs originate from thymic B-cells.

  View details for DOI 10.1080/1042819042000219467

  View details for Web of Science ID 000223523600019

  View details for PubMedID 15370257

• Immunophenotypic and genotypic characterization of progression in follicular lymphomas APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Natkunam, Y., Soslow, R., Matolcsy, A. A., Dolezal, M., Bhargava, V., Knowles, D. M., Warnke, R. 2004; 12 (2): 97-104

  Abstract

  Progression of follicular lymphomas (FLs) is often accompanied by a spectrum of histologic changes and an aggressive clinical course. Although molecular alterations have been implicated in this event, the underlying factors are largely unknown. We studied the expression of selected tumor suppressor genes (P53 and retinoblastoma [RB]), oncogenes (MYC and BCL2), and a transferrin-receptor related protein (Trump) in sequential biopsies in 16 patients. Eleven patients progressed from grade I or II FL to aggressive B-cell lymphomas with diffuse morphology, whereas 5 patients presented with diffuse aggressive lymphomas and recurred with indolent lymphomas. Immunoreactivity for P53 correlated with higher histologic grade in lymphomas progressing from indolent to aggressive; however, only 1 patient who presented with aggressive lymphoma demonstrated a P53 gene mutation. Neither P53 immunoreactivity nor genotypic alterations correlated with presentation with an aggressive histology and relapse with FL. Growth fraction, as assessed by Ki-67 staining, and Trump expression correlated with histologic grade. Immunoreactivity for RB, BCL2, and MYC was seldom associated with progression. Eight of 9 cases tested exhibited identical immunoglobulin heavy and light chain rearrangements or identical BCL2 gene rearrangements in the sequential lymphomas. We conclude that P53 and Trump protein expression and proliferation activity correlate with histologic grade, but not with recurrence or progression of FL. Our results further indicate that progression of FL to diffuse aggressive lymphomas and presentation of an aggressive B-cell lymphoma followed by FL are clonally related.

  View details for Web of Science ID 000221718400001

  View details for PubMedID 15354733

• CyclinD1/CyclinD3 ratio by real-time PCR improves specificity for the diagnosis of mantle cell lymphoma JOURNAL OF MOLECULAR DIAGNOSTICS Jones, C. D., Darnell, K. H., Warnke, R. A., Zehnder, J. L. 2004; 6 (2): 84-89

  Abstract

  We developed a real-time, quantitative, reverse transcription PCR assay for cyclin D1 (CCND1) expression to aid in the diagnosis of mantle cell lymphoma (MCL). The diagnosis of MCL can be problematic, and existing CCND1 expression assays show a lack of specificity, with elevated expression also detected in other lymphoproliferative disorders. We postulated that evaluating CCND1 expression relative to CCND3 expression by quantitative PCR could offer an improved specificity over an evaluation of CCND1 alone. This method quantitates both CCND1 and CCND3, each normalized to a housekeeping gene (GADPH), using the 5'-exonuclease technique. We analyzed 107 clinical specimens: MCL (17), chronic lymphocytic leukemias (CLL) (10), other non-MCL hematolymphoid disorders (41), non-malignant tissues with an epithelial component (7) and other normal samples (32). This method correctly identified 16 of 17 MCLs, and there were no false positives among any of the other diagnostic groups tested including CLL. CLL presents the major diagnostic dilemma at this institution when diagnosing MCL. Sensitivity studies showed that this method could detect an elevated CCND1/CCND3 ratio when the tumor infiltrate is at least 10% of the cells. We compared the specificity of CCND1 expression alone against the CCND1/CCND3 ratio to demonstrate the increased specificity for the latter. We conclude that the CCND1/CCND3 ratio is a sensitive and specific test for the diagnosis of MCL.

  View details for Web of Science ID 000221002500002

  View details for PubMedID 15096562

• Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fan, Z., Natkunam, Y., Bair, E., Tibshirani, R., Warnke, R. A. 2003; 27 (10): 1346-1356

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has traditionally been recognized as having two morphologic patterns, nodular and diffuse, and the current WHO definition of NLPHL requires at least a partial nodular pattern. Variant patterns have not been well documented. We analyzed retrospectively the morphologic and immunophenotypic patterns of NLPHL from 118 patients (total of 137 biopsy samples). Histology plus antibodies directed against CD20, CD3, and CD21 were used to evaluate the immunoarchitecture. We identified six distinct immunoarchitectural patterns in our cases of NLPHL: "classic" (B-cell-rich) nodular, serpiginous/interconnected nodular, nodular with prominent extranodular L&H cells, T-cell-rich nodular, diffuse with a T-cell-rich background (T-cell-rich B-cell lymphoma [TCRBCL]-like), and a (diffuse) B-cell-rich pattern. Small germinal centers within neoplastic nodules were found in approximately 15% of cases, a finding not previously emphasized in NLPHL. Prominent sclerosis was identified in approximately 20% of cases and was frequently seen in recurrent disease. Clinical follow-up was obtained on 56 patients, including 26 patients who had not had recurrence of disease and 30 patients who had recurrence. The follow-up period was 5 months to 16 years (median 2.5 years). The presence of a diffuse (TCRBCL-like) pattern was significantly more common in patients with recurrent disease than those without recurrence. Furthermore, the presence of a diffuse pattern (TCRBCL-like) was shown to be an independent predictor of recurrent disease (P = 0.00324). In addition, there is a tendency for progression to an increasingly more diffuse pattern over time. Analysis of sequential biopsies from patients with recurrent disease suggests that the presence of prominent extranodular L&H cells might represent early evolution to a diffuse (TCRBCL-like) pattern. We also report three patients who presented initially with diffuse large B-cell lymphoma and later developed NLPHL.

  View details for Web of Science ID 000185584800007

  View details for PubMedID 14508396

• Variation in gene expression patterns in follicular lymphoma and the response to rituximab PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bohen, S. P., Troyanskaya, O. G., Alter, O., Warnke, R., Botstein, D., Brown, P. O., Levy, R. 2003; 100 (4): 1926-1930

  Abstract

  Analysis of the patterns of gene expression in follicular lymphomas from 24 patients suggested that two groups of tumors might be distinguished. All patients, whose biopsies were obtained before any treatment, were treated with rituximab, a monoclonal antibody directed against the B cell antigen, CD20. Gene expression patterns in the tumors that subsequently failed to respond to rituximab appeared more similar to those of normal lymphoid tissues than to gene expression patterns of tumors from rituximab responders. These findings suggest the possibility that the response of follicular lymphoma to rituximab treatment may be predicted from the gene expression pattern of tumors.

  View details for DOI 10.1073/pnas.0437875100

  View details for Web of Science ID 000181073000087

  View details for PubMedID 12571354

  View details for PubMedCentralID PMC149935

• Lack of human herpesvirus 8 and Epstein-Barr virus in Kikuchi's histiocytic necrotizing lymphadenitis HUMAN PATHOLOGY George, T. I., Jones, C. D., Zehnder, J. L., Warnke, R. A., Dorfman, R. F. 2003; 34 (2): 130-135

  Abstract

  Kikuchi's histiocytic necrotizing lymphadenitis is a self-limited disorder that typically involves the cervical lymph nodes of young women. Although a viral etiology has been postulated, a definitive viral agent has not been identified. Recent reports have suggested that human herpesvirus 8 (HHV 8) or Epstein-Barr virus (EBV) may play an etiologic role. We investigated the presence of HHV 8 and EBV in archival tissue from 34 cases of Kikuchi's histiocytic necrotizing lymphadenitis. We examined 29 cases for HHV 8 using a nested polymerase chain reaction (PCR) on paraffin-embedded or frozen tissue, and 24 cases for EBV RNA using in situ hybridization (ISH) for EBER1. Controls included reactive lymph nodes from 8 adult women presenting with cervical or axillary lymphadenopathy. The study patients included 7 men and 27 women with a mean age of 28 years. All patients were previously healthy without evidence of immunocompromise and presented with cervical, axillary, or inguinal lymphadenopathy. Two cases exhibited EBV RNA by ISH; this was confirmed by PCR for EBV DNA. HHV 8 DNA was not amplified by nested PCR in any of the cases of Kikuchi's histiocytic necrotizing lymphadenitis or reactive lymph nodes; control PCR demonstrated the presence of amplifiable DNA in all cases. These findings suggest that HHV 8 and EBV do not play causative roles in Kikuchi's histiocytic necrotizing lymphadenitis.

  View details for DOI 10.1053/hupa.2003.11

  View details for PubMedID 12612880

• BCL-6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5 ' regulatory region of the BCL-6 gene LEUKEMIA Lossos, I. S., Warnke, R., Levy, R. 2002; 16 (9): 1857-1862

  Abstract

  Follicle center lymphoma (FCL) is an indolent low-grade B cell non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive diffuse large B cell lymphoma (DLBCL). Histological transformation of FCL is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is commonly implicated in the pathogenesis of DLBCL and its expression may be altered by clonal rearrangements and somatic point mutations in its 5' non-translated regulatory region. Recently, somatic mutations of the BCL-6 gene were associated with the transformation process. Here, we examined BCL-6 mRNA expression and BCL-6 mutations in paired biopsies from the same patients obtained at the time of FCL diagnosis and after transformation. BCL-6 mRNA expression markedly increased upon transformation (1.9- to 4.8-fold) in three cases, remained unchanged in one case and decreased compared to the diagnosis FCL specimens in four cases. The three specimens that demonstrated an increase in the BCL-6 mRNA expression upon transformation harbored BCL-6 gene mutations in the 5' region of the first intron that overlapped with the previously reported negative regulatory region of the gene. Accumulation of new mutations in this region was not observed in DLBCL biopsies in which the BCL-6 mRNA expression did not increase. The present study demonstrates that although BCL-6 gene mutations do accumulate during the transformation process and, depending on their location within the first intron, may deregulate BCL-6 mRNA expression, increase in BCL-6 mRNA expression is not uniformly required for transformation from FCL to DLBCL.

  View details for DOI 10.1038/sj.leu.2402578

  View details for Web of Science ID 000178019200039

  View details for PubMedID 12200704

• Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases HISTOPATHOLOGY Pileri, S. A., Grogan, T. M., Harris, N. L., Banks, P., Campo, E., Chan, J. K., Favera, R. D., Delsol, G., De Wolf-Peeters, C., Falini, B., Gascoyne, R. D., Gaulard, P., Gatter, K. C., Isaacson, P. G., Jaffe, E. S., Kluin, P., Knowles, D. M., Mason, D. Y., Mori, S., Muller-Hermelink, H. K., Piris, M. A., Ralfkiaer, E., Stein, H., Su, I. J., Warnke, R. A., Weiss, L. M. 2002; 41 (1): 1-29

  Abstract

  Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

  View details for Web of Science ID 000176745300001

  View details for PubMedID 12121233

• Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lossos, I. S., Alizadeh, A. A., Diehn, M., Warnke, R., Thorstenson, Y., Oefner, P. J., Brown, P. O., Botstein, D., Levy, R. 2002; 99 (13): 8886-8891

  Abstract

  The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of the cases of histological transformation. However, two different gene-expression profiles associated with the transformation process were defined, one in which c-myc and genes regulated by c-myc showed increased expression and one in which these same genes showed decreased expression. Further, there was a striking difference in gene-expression profiles between transformed DLBCL and de novo DLBCL, because the gene-expression profile of transformed DLBCL was more similar to their antecedent FL than to de novo DLBCL. This study demonstrates that transformation from FL to DLBCL can occur by alternative pathways and that transformed DLBCL and de novo DLBCL have very different gene-expression profiles that may underlie the different clinical behaviors of these two types of morphologically similar lymphomas.

  View details for DOI 10.1073/pnas.132253599

  View details for Web of Science ID 000176478200075

  View details for PubMedID 12077300

  View details for PubMedCentralID PMC124393

• The usefulness of immunohistochemistry in the diagnosis of follicular lymphoma in bone marrow biopsy specimens AMERICAN JOURNAL OF CLINICAL PATHOLOGY West, R. B., Warnke, R. A., Natkunam, Y. 2002; 117 (4): 636-643

  Abstract

  We used a panel of paraffin antibodies to determine whether neoplastic and nonneoplastic lymphoid aggregates in the bone marrow can be distinguished reliably. Formalin-fixed, paraffin-embedded bone marrow core biopsy specimens with lymphoid aggregates were stained using primary antibodies directed against bcl-2, bcl-6, CD5, CD10, CD20, and CD23. We studied 61 cases (26 follicular lymphoma and 35 benign or atypical aggregates). We found that no single stain is sufficient for identification of neoplastic lymphoid aggregates. However, this distinction was made possible by using a panel of antibodies. Under the conditions we tested, the most useful antibodies were CD10, bcl-2, CD5, and CD20. Most benign or atypical aggregates do not express CD10 and CD23. In addition, nonneoplastic aggregates had a large population of T cells. bcl-2 was useful in an architectural context for distinguishing neoplastic aggregates. bcl-6 often was expressed in both neoplastic and nonneoplastic aggregates and, thus, poorly discriminated between these processes. We studied the expression of CD10 and bcl-6 in selected lymph nodes in some cases.

  View details for Web of Science ID 000174715000018

  View details for PubMedID 11939740

• Characterization of variant patterns of lymphocyte predominance Hodgkin's disease with immunohistochemical correlation Fan, Z., Natkunam, Y., Warnke, R. NATURE PUBLISHING GROUP. 2002: 240A–240A

  View details for Web of Science ID 000173388901026

• Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma BLOOD Lossos, I. S., Jones, C. D., Warnke, R., Natkunam, Y., Kaizer, H., Zehnder, J. L., Tibshirani, R., Levy, R. 2001; 98 (4): 945-951

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Establishment of parameters that can predict outcome could help to identify patients who may benefit from risk-adjusted therapies. BCL-6 is a proto-oncogene commonly implicated in DLBCL pathogenesis. A real-time reverse transcription-polymerase chain reaction assay was established for accurate and reproducible determination of BCL-6 mRNA expression. The method was applied to evaluate the prognostic significance of BCL-6 expression in DLBCL. BCL-6 mRNA expression was assessed in tumor specimens obtained at the time of diagnosis from 22 patients with primary DLBCL. All patients were subsequently treated with anthracycline-based chemotherapy regimens. These patients could be divided into 2 DLBCL subgroups, one with high BCL-6 gene expression whose median overall survival (OS) time was 171 months and the other with low BCL-6 gene expression whose median OS was 24 months (P =.007). BCL-6 gene expression also predicted OS in an independent validation set of 39 patients with primary DLBCL (P =.01). BCL-6 protein expression, assessed by immunohistochemistry, also predicted longer OS in patients with DLBCL. BCL-6 gene expression was an independent survival predicting factor in multivariate analysis together with the elements of the International Prognostic Index (IPI) (P =.038). By contrast, the aggregate IPI score did not add further prognostic information to the patients' stratification by BCL-6 gene expression. High BCL-6 mRNA expression should be considered a new favorable prognostic factor in DLBCL and should be used in the stratification and the design of risk-adjusted therapies for patients with DLBCL. (Blood. 2001;98:945-951)

  View details for Web of Science ID 000170364100008

  View details for PubMedID 11493437

• Analysis of MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry MODERN PATHOLOGY Natkunam, Y., Warnke, R. A., Montgomery, K., Falini, B., van de Rijn, M. 2001; 14 (7): 686-694

  Abstract

  The gene encoding MUM1 was characterized as a possible translocation partner in chromosomal abnormalities involving a significant number of multiple myelomas. The overexpression of the MUM1 protein as a result of translocation t(6;14) (p25;q32) identified MUM1 as a putative regulatory molecule involved in B-cell differentiation and tumorigenesis. The expression of MUM1 protein in multiple myelomas supports this hypothesis. In the current study, using tissue microarray technology, we have tested the expression of the MUM1 protein in 1335 human malignancies and normal tissues. Our data show that the MUM1 protein is expressed in a wide spectrum of hematolymphoid neoplasms and in malignant melanomas but is absent in other human tumors. In addition, in tissue microarrays as well as in conventional paraffin sections, MUM1 staining was found to lack specificity in detecting plasmacytic differentiation as compared with two markers, CD138/Syndecan and VS38, commonly used in paraffin immunohistochemistry for detection of plasma cells.

  View details for Web of Science ID 000169927200008

  View details for PubMedID 11455001

• Genetic instability is associated with histological transformation of follicle center lymphoma LEUKEMIA Nagy, M., Balazs, M., Adam, Z., Petko, Z., Timar, B., Szereday, Z., Laszlo, T., Warnke, R. A., Matolcsy, A. 2000; 14 (12): 2142-2148

  Abstract

  Follicle center lymphoma (FCL) is an indolent B cell non-Hodgkin's lymphoma (NHL) characterized genetically by the t(14;18) translocation. Histological transformation and clinical progression of FCLs are frequently associated with secondary genetic alterations at both nucleic acid and chromosomal levels. To determine the type and pattern of genomic instability occurring in histological transformation of FCLs and the role of DNA mismatch repair defects in this procedure, we have performed microsatellite analysis, comparative genomic hybridization (CGH) and mutational analysis of hMLH1 and hMSH2 genes on serial biopsy specimens from patients with FCL transformed to diffuse large cell lymphoma (DLCL). Paired biopsy samples of eight patients were analyzed for microsatellite instability and structural alterations for hMLH1 and hMSH2 genes, and tumor samples of five patients were subjected to CGH analysis. A high level of microsatellite instability was associated with histological transformation of two cases of FCL, but no mutations of the hMLH1 and hMSH2 genes were detected in any of the lymphoma samples. In the five cases subjected to CGH analysis, the histological transformation of FCLs was associated with genomic imbalances at 21 chromosomal regions. The genomic abnormalities found were rather heterogeneous and none of the genetic changes were overrepresented in the transformed DLCLs. These data suggest that histological transformation of FCLs to DLCL is frequently associated with genome wide instability at both nucleic acid and chromosomal levels, although mutations of the hMSH1 and hMLH2 genes are not involved in this process.

  View details for Web of Science ID 000166207000017

  View details for PubMedID 11187904

• Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases JOURNAL OF CUTANEOUS PATHOLOGY Natkunam, Y., Warnke, R. A., Haghighi, B., Su, L. D., Le Boit, P. E., Kim, Y. H., Kohler, S. 2000; 27 (8): 392-399

  Abstract

  Natural killer and natural killer-like T-cell lymphomas presenting in the skin usually demonstrate aggressive behavior, an angiocentric distribution and a characteristic immunophenotype. In contrast, primary cutaneous CD30+ lymphoproliferative disorders form a heterogeneous spectrum including anaplastic large cell lymphomas, the majority of which display a good prognosis. Lymphomas with co-expression of CD56 and CD30 are extremely rare and the significance of this co-expression is unknown.Seven retrospectively identified cases of lymphomas with co-expression of CD56 and CD30 presenting in the skin comprise this study. Immunohistochemistry, in situ hybridization for Epstein-Barr virus and T-cell receptor gene rearrangement studies were performed on paraffin sections.This subset of cutaneous lymphomas showed a variable clinical course that ranged from resolution without treatment, treatment-failure and recurrence, to death from disease. Histologic, immunophenotypic and molecular studies were of limited utility in predicting prognosis.Cutaneous lymphomas co-expressing CD56 and CD30 share many clinicopathologic features with natural killer and natural killer-like T-cell lymphomas or anaplastic large cell lymphomas, two entities with widely disparate clinical behavior. It is important to recognize that these lymphomas may behave more aggressively than primary cutaneous anaplastic large cell lymphomas do. Longer follow-up and further investigations on larger numbers of cases are necessary to fully characterize this rare subset of cutaneous lymphomas.

  View details for Web of Science ID 000088444100003

  View details for PubMedID 10955685

• Peripheral T-cell lymphoma complicated by a proliferation of large B cells 88th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Higgins, J. P., van de Rijn, M., Jones, C. D., Zehnder, J. L., Warnke, R. A. AMER SOC CLINICAL PATHOLOGY. 2000: 236–47

  Abstract

  We studied 14 cases that showed a morphologic appearance of peripheral T-cell lymphoma and contained substantial numbers of CD20+ large B cells. In all but 2 cases, the CD20+ large cells showed a mix of kappa and lambda light chain expression. Two cases showed a focal predominance of kappa expression. In situ hybridization using the EBER1 probe for detection of Epstein-Barr virus (EBV) RNA was performed on every case. EBV RNA was present in 10 cases. Of 8 cases with EBV RNA stained by immunohistochemistry for the latent membrane protein of EBV, 6 were positive. Double-labeling immunohistochemistry and in situ hybridization confirmed that EBV was present in the large B cells. Polymerase chain reaction (PCR) analysis showed a clonal rearrangement of the T-cell receptor (TCR)-gamma chain gene in 12 of 13 cases tested. One additional case showed a clonal rearrangement of the TCR-beta chain gene by Southern blot hybridization. PCR analysis showed a clonal immunoglobulin gene rearrangement in 5 cases, a suggestion of a clonal rearrangement in 1, an oligoclonal pattern in 4, and a polyclonal pattern in 4. The finding of large B and T cells may result in a misdiagnosis of a reactive process or of T-cell-rich B-cell lymphoma. The presence of EBV in some cases could cause further confusion with the reactive T- and B-immunoblastic proliferation of infectious mononucleosis.

  View details for Web of Science ID 000088460700010

  View details for PubMedID 10941339

• PCR-heteroduplex analysis of T-cell receptor gamma gene rearrangement in paraffin-embedded skin biopsies AMERICAN JOURNAL OF DERMATOPATHOLOGY Kohler, S., Jones, C. D., Warnke, R. A., Zehnder, J. L. 2000; 22 (4): 321-327

  Abstract

  We developed a rapid, simple, and sensitive method for the detection of T-cell receptor-gamma (TCRgamma) gene rearrangements in paraffin-embedded skin biopsies. Available techniques often require either fresh tissue, several primer pairs, nested amplifications, or specialized electrophoresis steps such as denaturing gradient gel electrophoresis. Our method is based on heteroduplex analysis of polymerase chain reaction (PCR) products of the TCRgamma in a nondenaturing modified polyacrylamide gel using a single pair of primers and is adapted for paraffin-embedded tissue. When tested against Southern blot analysis, the PCR results correlated in 8 of 9 cases. Six mature cutaneous B-cell lymphomas and 29 inflammatory skin disorders all resulted in a polyclonal amplification pattern. When analyzing 3-mm or 4-mm punch biopsies of 51 cases of cutaneous T-cell lymphoma, 37 (72.5%) showed a clonal rearrangement with this technique. For 7 cases of patch stage mycosis fungoides, frozen tissue and formalin-fixed and paraffin-embedded tissue was available, and in 5 of 7 cases (71%), the results in frozen and paraffin-embedded tissue were concordant. One case showed a clonal pattern in frozen tissue but not in paraffin-embedded tissue, and one case was polyclonal in frozen tissue but monoclonal in paraffin-embedded tissue. Using serial dilutions of DNA from a T-cell ALL in a polyclonal background (tonsil), we established a sensitivity of 0.5%. Heteroduplex PCR of the TCRgamma is a rapid, sensitive, and inexpensive screening procedure as well as a useful adjunct to histologic analysis and immunophenotyping of cutaneous T-cell proliferations.

  View details for Web of Science ID 000088565400005

  View details for PubMedID 10949457

• Large B-cell lymphoma of thyroid - Two cases with a marginal zone distribution of the neoplastic cells AMERICAN JOURNAL OF CLINICAL PATHOLOGY Higgins, J. P., Warnke, R. A. 2000; 114 (2): 264-270

  Abstract

  We report 2 cases of B-cell lymphoma of the thyroid in which although a marginal zone distribution of the neoplastic cells was present, the cytologic features of the cells indicated large cell lymphoma. One of the cases showed an accumulation of crystalline inclusions within the cytoplasm of the neoplastic cells. Many of these inclusion-bearing cells showed plasmacytoid features. By immunohistochemical studies performed on formalin-fixed paraffin-embedded tissue, both of the cases showed a B-cell phenotype as indicated by CD20 expression, and 1 showed kappa light chain restriction. In both cases, Ki-67 staining corroborated the impression of an aggressive neoplasm with staining of 50% and 90% of the tumor cells. Both patients received cyclophosphamide, doxorubicin, vincristine, and prednisone with radiation therapy, and both are without evidence of disease after 17 and 18 months of follow-up. It is important to recognize this pattern of large B-cell lymphoma of the thyroid gland. While the indolent course typical of most low-grade extranodal marginal zone lymphomas is not likely in these cases, the outcome may be favorable if patients are treated aggressively with therapy for large cell lymphoma.

  View details for Web of Science ID 000088460700013

  View details for PubMedID 10941342

• Blastic/blastoid transformation of follicular lymphoma - Immunohistologic and molecular analyses of five cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Natkunam, Y., Warnke, R. A., Zehnder, J. L., Jones, C. D., Milatovich-Cherry, A., Cornbleet, P. J. 2000; 24 (4): 525-534

  Abstract

  Progression of follicular lymphoma to a higher-grade malignancy frequently heralds a poor prognosis. Clinical transformation is variably accompanied by a spectrum of histologic changes characterized by alteration in growth and cytology. Although several cytogenetic events and potential oncogenes have been documented in this progression, the underlying molecular mechanisms are largely unknown. We present five patients with an unusual histologic transformation of follicular lymphoma manifested by blastic/blastoid morphology. This transformation is histologically distinct from other types of transformation of follicular lymphoma. All five cases exhibited the t(14;18) translocation and expressed the BCL-2 protein. In addition, two of the five patients showed increased levels of the p53 protein within neoplastic cells implicating a possible role for this oncogene in blastic/blastoid transformation. The lack of BCL-1 and myeloid antigens by immunohistochemistry and flow cytometry studies served to distinguish blastic/blastoid transformation of follicular lymphoma from its morphologic mimics. This distinction is clinically important because lymphoblastic and myeloid leukemias require significantly different therapeutic modalities and show better prognosis. Moreover, the lack of Epstein-Barr virus-specific mRNA suggests that this virus is unlikely to participate in blastic/blastoid transformation of follicular lymphoma.

  View details for Web of Science ID 000086211700006

  View details for PubMedID 10757399

• Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas BLOOD Lossos, I. S., Okada, C. Y., Tibshirani, R., Warnke, R., Vose, J. M., Greiner, T. C., Levy, R. 2000; 95 (5): 1797-1803

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is a common type of non-Hodgkin's lymphoma (NHL) that is highly heterogeneous from both clinical and histopathologic viewpoints. The immunoglobulin (Ig) heavy (H) chain variable region genes were examined in 71 patients with untreated primary DLBCL. Fifty-eight potentially functional V(H) genes were detected in 53 DLBCL cases; V(H) genes were nonfunctional in 9 cases and were not detected in an additional 9 cases. The use of V(H) gene families by DLBCL tumors was unbiased without overrepresentation of any particular V(H) gene or gene family. Analysis of Ig mutations in comparison to the most closely related germline gene disclosed mutated V(H) genes in all but 1 DLBCL case. More than 2% difference from the most similar germline sequence was detected in 52 potentially functional and the 8 nonfunctional V(H) gene sequences, whereas less than 2% difference from the germline sequence was observed in 3 V(H) gene isolates. Only 3 V(H) gene isolates were unmutated. No correlation was found between V(H) gene use, mutation level, and International Prognostic Index (IPI) or survival. Six of 8 tested tumors showed evidence of ongoing somatic mutations. Evidence for positive or negative antigen selection pressure was observed in 65% of mutated DLBCL cases. Our findings indicate that the etiology and the driving forces for clonal expansion are heterogeneous, which may explain the well-known clinical and pathologic heterogeneity of DLBCL. (Blood. 2000;95:1797-1803)

  View details for Web of Science ID 000085564700037

  View details for PubMedID 10688840

• Somatic mutation of the 5 ' noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma AMERICAN JOURNAL OF PATHOLOGY Szereday, Z., Csernus, B., Nagy, M., Laszlo, T., Warnke, R. A., Matolcsy, A. 2000; 156 (3): 1017-1024

  Abstract

  Follicular lymphoma (FL) is a B cell non-Hodgkin's lymphoma (NHL) that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5' noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of the BCL-6 gene alterations in the histological transformation and clonal progression of FL, we analyzed serial biopsy specimens from 12 patients with FL. Two cases of FL showed no histological alteration in the second biopsy, and 10 cases of FL showed morphological transformation to DLCL in the second biopsy. Southern blot analysis was used to detect rearrangement of the BCL-6 gene, polymerase chain reaction-single strand conformation polymorphism and sequence analysis were performed for identification of mutations in the 5' noncoding region of the BCL-6 gene, and immunohistochemical analysis was applied to reveal the BCL-6 protein expression. No BCL-6 gene rearrangement was detected in any of the samples, but a total of 58 mutations were found in the 5' noncoding region of the BCL-6 gene in seven cases. In five cases, both the FL and the clonally related FL or DLCL, and in two cases only the DLCL samples were mutated. The mutations were identical in multiple biopsy specimens of FL that did not show morphological transformation. In six patients where FL cells underwent morphological transformation, considerable intraclonal sequence heterogeneity was observed, indicating an ongoing type of somatic mutation. Based on the pattern of shared and nonshared mutations, the genealogical relationship of neoplastic clones could be established. In all of these cases, the histological transformation of FL was associated with the emergence of a subpopulation marked by new sites of mutations in the BCL-6 5' noncoding sequences. In three of these six cases, the histological transformation is also associated with the reduced expression of the BCL-6 protein. These findings demonstrate that mutation of the 5' noncoding region of the BCL-6 gene developed in the clonal evolution of FL, and at different time points in the lymphoma evolution different clonotypes dominate.

  View details for Web of Science ID 000085702600031

  View details for PubMedID 10702417

• Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling NATURE Alizadeh, A. A., Eisen, M. B., Davis, R. E., Ma, C., Lossos, I. S., Rosenwald, A., Boldrick, J. G., Sabet, H., Tran, T., Yu, X., Powell, J. I., Yang, L. M., Marti, G. E., Moore, T., Hudson, J., Lu, L. S., Lewis, D. B., Tibshirani, R., Sherlock, G., Chan, W. C., Greiner, T. C., Weisenburger, D. D., Armitage, J. O., Warnke, R., Levy, R., Wilson, W., Grever, M. R., Byrd, J. C., Botstein, D., Brown, P. O., Staudt, L. M. 2000; 403 (6769): 503-511

  Abstract

  Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.

  View details for Web of Science ID 000085227300039

  View details for PubMedID 10676951

• Spontaneously relapsing clonal, mucosal cytotoxic T-cell lymphoproliferative disorder - Case report and review of the literature AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ranheim, E. A., Jones, C., Zehnder, J. L., Warnke, R., Yuen, A. 2000; 24 (2): 296-301

  Abstract

  Primary T-cell lymphoma of the gastrointestinal tract is a rare and usually aggressive disorder that may be associated with celiac disease. The authors describe a unique case of a clonal proliferation of CD8+ T cells involving the oral mucosa, ileum, and colon of a 35-year-old man that has regressed spontaneously and recurred numerous times over a 9-year period without treatment. The patient's symptoms were limited to occasional rectal bleeding and recurring painful oral ulcers. Within the intestine, these collections of small T cells induced minimal architectural distortions and did not show extensive epitheliotrophism. Polymerase chain reaction and sequencing analyses revealed that the identical T-cell clone has been present for more than 9 years and in different mucosal locations in this patient. This may represent a unique T-cell lymphoproliferative process akin to a mucosal counterpart of lymphomatoid papulosis of the skin.

  View details for Web of Science ID 000085133700017

  View details for PubMedID 10680899

• Gene expression in large B-cell lymphoma using cDNA microarray technology. Chan, W. C., Alizadeh, A., Eisen, M., Davis, R. E., Ma, C., Sabet, H., Tran, T., Powell, J. I., Yang, L., Greiner, T. C., Weisenburger, D. D., Armitage, J. O., Marti, G. E., Moores, T., Hudson, J., Lossos, I., Warnke, R., Levy, R., Botstein, D., Brown, P. O., Staudt, L. M. AMER SOC HEMATOLOGY. 1999: 698A–698A

  View details for Web of Science ID 000083790303136

• Herpes lymphadenitis in association with chronic lymphocytic leukemia CANCER Higgins, J. P., Warnke, R. A. 1999; 86 (7): 1210-1215

  Abstract

  Herpes simplex virus (HSV) infections range in severity from common cutaneous outbreaks to life-threatening central nervous system and deep organ involvement. HSV lymphadenitis is extremely rare but occurs both as a component of widely disseminated disease and as a localized, mild illness.Five patients with chronic lymphocytic leukemia (CLL) underwent lymph node biopsy and were found to have histologic and immunophenotypic evidence of HSV infection in association with CLL.The patients were 3 males and 2 females ranging in age from 50 to 86 years. Only 1 patient had clinical evidence of cutaneous herpes at any time; in that patient, herpes lymphadenitis preceded the cutaneous herpes by 3 years. Four patients received no therapy for herpes at any time, whereas one was treated with intravenous and oral acyclovir. One patient died of CLL approximately 20 months after herpes lymphadenitis was diagnosed. The remaining four patients are alive with CLL. No patient had a fulminant clinical course related to HSV or developed disseminated infection.Herpes lymphadenitis may not have a fulminant course even in immunosuppressed CLL patients, even if they receive no antiviral therapy.

  View details for Web of Science ID 000082749200016

  View details for PubMedID 10506706

• The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells NATURE Campbell, J. J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D. P., Warnke, R., Ruffing, N., Kassam, N., Wu, L., BUTCHER, E. C. 1999; 400 (6746): 776-780

  Abstract

  Lymphocytes that are responsible for regional (tissue-specific) immunity home from the blood to the intestines, inflamed skin or other sites through a multistep process involving recognition of vascular endothelial cells and extravasation. Chemoattractant cytokine molecules known as chemokines regulate this lymphocyte traffic, in part by triggering arrest (stopping) of lymphocytes rolling on endothelium. Here we show that many systemic memory T cells in blood carry the chemokine receptor CCR4 and therefore respond to its ligands, the chemokines TARC and MDC. These cells include essentially all skin-homing cells expressing the cutaneous lymphocyte antigen and a subset of other systemic memory lymphocytes; however, intestinal (alpha4beta7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity of venules and infiltration of many CCR4+ lymphocytes in chronically inflamed skin, but not in the gastrointestinal lamina propria. Moreover, TARC induces integrin-dependent adhesion of skin (but not intestinal) memory T cells to the cell-adhesion molecule ICAM-1, and causes their rapid arrest under physiological flow. Our results suggest that CCR4 and TARC are important in the recognition of skin vasculature by circulating T cells and in directing lymphocytes that are involved in systemic as opposed to intestinal immunity to their target tissues.

  View details for PubMedID 10466728

• CD30 expression is common in mediastinal large B-cell lymphoma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Higgins, J. P., Warnke, R. A. 1999; 112 (2): 241-247

  Abstract

  Large B-cell lymphoma manifesting in the mediastinum shows distinctive clinical and immunophenotypic features and is recognized as a unique type of large B-cell lymphoma in the Revised European-American Lymphoma classification. Fifty-one cases of primary mediastinal large B-cell lymphoma were retrieved from the immunodiagnosis laboratory database files and were stained with anti-CD30 (Ber-H2). Of the 51 cases, 35 (69%) stained for CD30. This staining ranged from strong membrane staining of all or almost all of the neoplastic cells to positivity of rare individual cells. Eleven cases (22%) were negative; 4 (8%) were equivocal. Only 1 case was uninterpretable owing to B-5 fixation and lack of a positive internal control. Thus, the majority of mediastinal large B-cell lymphomas express the Hodgkin marker CD30. This finding may result in misdiagnosis of large cell lymphoma as Hodgkin disease.

  View details for Web of Science ID 000081664800012

  View details for PubMedID 10439805

• B-lineage lymphoblastic lymphoma is a clinicopathologic entity distinct from other histologically similar aggressive lymphomas with blastic morphology 85th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Soslow, R. A., Baergen, R. N., Warnke, R. A. JOHN WILEY & SONS INC. 1999: 2648–54

  Abstract

  The authors present clinical, histopathologic, and immunophenotypic data regarding B-lineage lymphoblastic lymphoma (B-LBL), a rare entity that has not been extensively studied. To emphasize some of its unique clinical characteristics, the authors compare B-LBL with a group of histologically similar, very aggressive lymphomas, T-lineage lymphoblastic lymphoma (T-LBL) and the blastoid variant of mantle cell lymphoma (BVMCL); all were evaluated concurrently.Clinical data were obtained on 29 patients with very aggressive lymphomas (12 B-LBLs, 10 T-LBLs, and 7 BVMCLs) from whom paraffin-embedded material was available. The diagnoses were confirmed on review of the hematoxylin and eosin-stained slides and the immunophenotype data.The mean age of patients with B-LBL was 39 years. Patients presented with both lymph node and extranodal disease, although involvement of the mediastinum and bone marrow was infrequent. Four were Stage I, 3 were Stage II, 2 were Stage III, and 3 were Stage IV. B-LBL patients were treated primarily with cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP), and one patient underwent allogeneic bone marrow transplantation. The mean follow-up time was 30 months. Seven of 11 had no evidence of disease at 48 months, whereas 4 patients were dead of disease at 5.6 months. The overall median survival was 24 months. The clinical characteristics of B-LBL patients differed significantly from those of T-LBL patients; there was more frequent bone marrow and mediastinal involvement in T-LBL cases (P = 0.03 and 0.04, respectively). T-LBL patients were also less likely to achieve a complete remission than B-LBL patients (P = 0.02). The mean age of BVMCL patients significantly exceeded that of B-LBL patients (P = 0.03).The authors believe that the distinction of B-LBL from its histologic mimics, T-LBL and BVMCL, has important clinical implications. Patients with B-LBL present differently from those with the other very aggressive lymphomas studied, and they achieve complete remissions more often than T-LBL patients.

  View details for Web of Science ID 000080777900022

  View details for PubMedID 10375114

• Aggressive natural killer-like T-cell malignancy with leukemic presentation following solid organ transplantation AMERICAN JOURNAL OF CLINICAL PATHOLOGY Natkunam, Y., Warnke, R. A., Zehnder, J. L., Cornbleet, P. J. 1999; 111 (5): 663-671

  Abstract

  NK-like T-cell malignancies are part of a spectrum of lymphoproliferative diseases that complicate immunosuppression associated with solid organ transplantation. We describe 2 patients with long-standing immunosuppression following solid organ transplantation. Both patients had systemic symptoms that included fever, myalgia, and weight loss. Organ involvement and lymphadenopathy were not initially observed. Unique to these 2 cases are the initial leukemic symptoms, which led to further characterization and identification of NK-like T-cell malignancies. Both patients exhibited an anomalous T/NK phenotype, CD56 positivity, and atypical blastic architecture of the large granular lymphocytes. Clonal rearrangement of T-cell receptor genes was detected in both patients. In 1 patient, a cytogenetic abnormality involving 8q24 was demonstrated. The disease course in both patients was aggressive, with involvement of multiple sites and rapid demise. This study emphasizes the importance of including NK-like T-cell malignancies in the differential diagnosis of lymphoproliferative disorders associated with immunosuppression and recognizing that an aggressive clinical course may follow leukemic presentation of disease.

  View details for Web of Science ID 000079920500011

  View details for PubMedID 10230357

• Aggressive cutaneous NK and NK-like T-cell lymphomas - Clinicopathologic, immunohistochemical, and molecular analyses of 12 cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Natkunam, Y., SMOLLER, B. R., Zehnder, J. L., Dorfman, R. F., Warnke, R. A. 1999; 23 (5): 571-581

  Abstract

  Natural killer (NK) and NK-like T-cell lymphomas are rare hematolymphoid malignancies that predominate in the upper aerodigestive system. They also involve other extranodal sites, including the skin. Primary cutaneous manifestations of NK and NK-like T-cell lymphomas are uncommon, and the clinicopathologic features are poorly understood. We have studied 12 patients of varied ethnic backgrounds with CD56-positive lymphomas in the skin. Six patients subsequently progressed to disseminated disease. These lymphomas showed the following immunophenotype: CD56+, CD43+, TCRb-, CD3-/+, CD20-, CD30-/+, CD4-, and CD8-. Two cases exhibited T-cell receptor gene rearrangements supporting a T-cell origin for these lymphomas, whereas the remaining 10 cases were likely derived from NK cells. Our results show inconsistent association of these lymphomas with Epstein-Barr virus (EBV), the multidrug resistance phenotype, and expression of P53. In addition, we found a previously unreported correlation between lymphomas harboring EBV mRNA and the expression of the multidrug resistance phenotype. These lymphomas were aggressive and were associated with rapid clinical progression, treatment failure, multiple relapses, and an average survival of 15 months from the time of diagnosis. Our results indicate the importance of recognizing this disease as a distinct subset of aggressive cutaneous lymphomas that may be diagnosed on the basis of morphology, immunophenotype, and gene rearrangement studies.

  View details for Web of Science ID 000080178200012

  View details for PubMedID 10328090

• Establishing a KSHV+ cell line (BCP-1) from peripheral blood and characterizing its growth in Nod/SCID mice BLOOD Boshoff, C., Gao, S. J., Healy, L. E., Matthews, S., Thomas, A. J., Coignet, L., Warnke, R. A., Strauchen, J. A., Matutes, E., Kamel, O. W., Moore, P. S., Weiss, R. A., Chang, Y. 1998; 91 (5): 1671-1679

  Abstract

  Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) sequences are present in primary effusion lymphomas (PEL). KSHV+ cell lines have been established from such lymphomas. Here we report the first description of the establishment of a KSHV+, EBV- cell line (BCP-1) from the peripheral blood of a patient with PEL. Using this cell line and a KSHV+, EBV+ PEL cell line (HBL-6) previously established from ascitic fluid, we investigated whether in nonobese diabetic/severe combined immunodeficiency disease (Nod/SCID) mice tumors representing PEL can be established. When injected intravenously (IV) into Nod/SCID mice, BCP-1 and HBL-6 infiltrated organs, with only occasional macroscopic tumor formation. Intraperitoneal injections (ip) led to the development of ascites and diffuse infiltration of organs, without obviously solid lymphoma formation, resembling the diffuse nature of human PEL. To investigate a possible mechanism for the peculiar phenotype of PEL, we examine the presence of adhesion molecules and homing markers on PEL cells before and after growing in mice. Both BCP-1 and HBL-6 cells lack expression of important cytoadhesion molecules including CD11a and CD18 (LFA1 alpha and beta chains), CD29, CD31, CD44, CD54 (ICAM-1), and CD62L and E (L and E selectins).

  View details for Web of Science ID 000072127000024

  View details for PubMedID 9473233

• A novel five-transmembrane hematopoietic stem cell antigen: Isolation, characterization, and molecular cloning BLOOD Miraglia, S., Godfrey, W., Yin, A. H., Atkins, K., Warnke, R., Holden, J. T., Bray, R. A., Waller, E. K., Buck, D. W. 1997; 90 (12): 5013-5021

  Abstract

  Phenotypic analysis of hematopoietic stem and progenitor cells (HSCs) has been an invaluable tool in defining the biology of stem cell populations. We have recently described the production of AC133, a monoclonal antibody (MoAb) that binds to a novel cell surface antigen present on a CD34(bright) subset of human HSCs. This antigen is a glycosylated protein with a molecular weight of 120 kD. Here, we report the molecular cloning of a cDNA encoding this antigen and show that it does not share homology with any previously described hematopoietic or other cell surface antigen(s). The AC133 polypeptide has a predicted size of 97 kD and contains five-transmembrane (5-TM) domains with an extracellular N-terminus and a cytoplasmic C-terminus. Whereas the expression of tetraspan (4-TM) and 7-TM molecules is well documented on mature and immature hematopoietic cells and leukocytes, this 5-TM type of structure containing two large (255-amino acid [aa] and 290-aa) extracellular loops is unique and does not share sequence homology with any known multi-TM family members. Expression of this protein appears limited to bone marrow in normal tissue by immunohistochemical staining; however, Northern analysis suggests that the mRNA transcript is present in a variety of tissues such as the kidney, pancreas, placenta, and fetal liver. The AC133 antigen is also expressed on subsets of CD34+ leukemias, suggesting that it may be an important early marker for HSCs, as well as the first described member of a new class of TM receptors.

  View details for Web of Science ID A1997YJ90800041

  View details for PubMedID 9389721

• Dendritic cell ontogeny: A human dendritic cell lineage of myeloid origin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Olweus, J., Bitmansour, A., Warnke, R., Thompson, P. A., Carballido, J., Picker, L. J., LUNDJOHANSEN, F. 1997; 94 (23): 12551-12556

  Abstract

  Dendritic cells (DC) have been thought to represent a family of closely related cells with similar functions and developmental pathways. The best-characterized precursors are the epidermal Langerhans cells, which migrate to lymphoid organs and become activated DC in response to inflammatory stimuli. Here, we demonstrate that a large subset of DC in the T cell-dependent areas of human lymphoid organs are nonactivated cells and belong to a separate lineage that can be identified by high levels of the interleukin 3 receptor alpha chain (IL-3Ralphahi). The CD34+IL-3Ralphahi DC progenitors are of myeloid origin and are distinct from those that give rise to Langerhans cells in vitro. The IL-3Ralphahi DC furthermore appear to migrate to lymphoid organs independently of inflammatory stimuli or foreign antigens. Thus, DC are heterogeneous with regard to function and ontogeny.

  View details for Web of Science ID A1997YF39300056

  View details for PubMedID 9356487

• MIC2, TdT, bcl-2, and CD34 expression in paraffin-embedded high-grade lymphoma acute lymphoblastic leukemia distinguishes between distinct clinicopathologic entities HUMAN PATHOLOGY Soslow, R. A., Bhargava, V., Warnke, R. A. 1997; 28 (10): 1158-1165

  Abstract

  We propose that 12E7 (CD99) expression, along with TdT, bcl-2, and CD34 reactivity in lymphoblastic lymphoma (LyL)/acute lymphoblastic leukemia (ALL), distinguishes this group of neoplasms from small noncleaved cell lymphomas (SNCLs) in both pediatric and adult patients, thereby narrowing the differential diagnosis of high-grade non-Hodgkin's lymphomas and acute lymphoblastic leukemias in paraffin sections. 12E7 (CD99) is one of a group of available antibodies that recognizes the product of the mic-2 gene, which was originally identified in ALL. Despite this, most clinicopathological research has focused on the reactivity of 12E7 in a subset of the small round cell tumors of childhood. Although TdT is widely used in the subtyping of blastic leukemias, its use in the distinction of high-grade lymphomas in paraffin sections has been limited. We collected 24 cases of LyL/ALL (13 B-cell and 11 T-cell) and 15 cases of SNCL from 1984 through 1993. We confirmed the diagnoses using morphology and analysis of immunologic data. We performed immunohistochemistry with the 12E7 antibody, TdT, bcl-2, and CD34 on formalin-fixed, paraffin-embedded material. The patients' ages ranged from 4 to 81 years; nine of the study patients were children. Sixteen of the 24 LyL/ALLs stained with 12E7. In contrast, none of the 15 cases of SNCL reacted with this antibody (chi-square P < .0001). A larger percentage of T-cell LyL/ALLs reacted with 12E7 than did B-cell LyL/ALLs (82% v 54%). Sixteen of 20 LyL/ALLs reacted with the anti-TdT antibody, as compared with none of 11 SNCLs (chi-square P < .0001). Six LyL/ALLs were CD34 positive (of 23), and none of the SNCLs were CD34 positive (0 of 12) (chi-square P = .0519). Bcl-2-positive cases were found among both LyL/ ALLs and SNCLs, although they were more prevalent among LyL/ ALLs (92% v 25%; chi-square P < .0001). When one considers the differential diagnosis of a high-grade lymphoma/acute lymphoblastic leukemia, positive reactions with 12E7, TdT, bcl-2, and CD34 support the diagnosis of LyL/ALL over SNCL. Moreover, we present data that suggests that evaluating for TdT in formalin-fixed paraffin-embedded tissue is a more sensitive test than using either 12E7, bcl-2 or CD34 alone.

  View details for Web of Science ID A1997YD80100008

  View details for PubMedID 9343323

• BCL-1 (PRAD-1 cyclin D-1) overexpression distinguishes the blastoid variant of mantle cell lymphoma from B-lineage lymphoblastic lymphoma MODERN PATHOLOGY Soslow, R. A., Zukerberg, L. R., Harris, N. L., Warnke, R. A. 1997; 10 (8): 810-817

  Abstract

  The blastoid variant of mantle cell lymphoma (MCL-BV) can occur de novo or can represent a morphologic transformation of MCL associated with aggressive clinical disease. Its cytologic appearance is very similar to that of lymphoblastic lymphoma (LBL) because of its characteristic nuclear features and high proliferative rate. To assess the usefulness of antibodies to cyclin D-1 (BCL-1/ PRAD-1), CD99 (12E7), CD34, and TdT in distinguishing between MCL-BV and LBL in formalin-fixed, paraffin-embedded tissue, we studied from the Stanford data base 10 cases originally diagnosed as B-lineage LBL, 5 MCL-BVs, 2 cases thought likely to represent MCL-BV, and 2 blastic lymphomas whose morphology and immunophenotype were indeterminate. Six (60%) of 10 LBLs stained with CD99, as opposed to none of 7 MCL-BVs. Four (40%) of 10 LBLs reacted with CD34, as compared with none of 7 MCL-BVs. Eight (89%) of nine LBLs were positive for TdT, but all of the four MCL-BVs tested were negative. In contrast, the anti-cyclin D-1 antibody stained the nuclei of all of the MCL-BVs and none of the LBLs tested. On the basis of our evaluation, the probable MCL-BV cases were considered to be definite MCL-BV. Of the indeterminate cases, one was considered to be LBL, whereas we felt that the other represented MCL-BV. We conclude that staining formalin-fixed, paraffin-embedded, high-grade lymphomas with anti-cyclin D-1 antibody is useful in confirming the diagnosis of MCL-BV, whereas positive reactions with CD99, CD34, and particularly TdT are more characteristic of LBL.

  View details for Web of Science ID A1997XR36400009

  View details for PubMedID 9267824

• Extranodal head and neck lymphomas in guatemala: High frequency of Epstein-Barr virus-associated sinonasal lymphomas Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology VANDERIJN, M., Bhargava, V., MolinaKirsch, H., CarlosBregni, R., Warnke, R. A., Cleary, M. L., Kamel, O. W. W B SAUNDERS CO-ELSEVIER INC. 1997: 834–39

  Abstract

  Sinonasal lymphomas of T cell or natural killer cell (T/NK cell) phenotype represent a subset of extranodal head and neck lymphomas. T/NK cell sinonasal lymphomas have been described in diverse geographic settings, including China, Japan, Peru, Northern Europe, and North America. The frequency of these lymphomas is highly dependent on the geographic location in which they occur, their incidence being low in Europe and North America and relatively high in Asian countries and in Peru. Regardless of their geographic location, they are typically associated with the Epstein-Barr virus (EBV). Few studies have addressed the relative frequency of sinonasal lymphoma within the group of extranodal head and neck lymphomas. We investigated the anatomic distribution, immunophenotypical profile, and EBV status of 33 cases of extranodal head and neck lymphoma from patients in Guatemala. The anatomic distribution of these lymphomas is similar to that seen in Asian countries: 17 (52%) in the sinonasal area, five (15%) in the palate, and 11 (33%) in other locations. Fifteen (88%) of the 17 sinonasal lymphomas showed a T or null cell phenotype with a strong association with EBV by in situ hybridization. Most Guatemalan patients with these lymphomas were of Mayan descent. In Guatemala, the relative frequency of sinonasal lymphomas within the group of head and neck lymphomas is significantly higher than that reported for Western countries. In addition, the relative frequency of T/NK versus B cell sinonasal lymphomas is higher than that described in North America and similar to that observed in Asian countries and Peru.

  View details for Web of Science ID A1997XL66100014

  View details for PubMedID 9224753

• Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine ANNALS OF ONCOLOGY Advani, R., Warnke, R., Sikic, B. I., Horning, S. 1997; 8 (6): 601-603

  View details for PubMedID 9261530

• The significance of light chain-restricted bone marrow plasma cells after peripheral blood stem cell transplantation for multiple myeloma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Maia, D. M., Kell, D. L., Goates, J. J., Warnke, R. A. 1997; 107 (6): 643-652

  Abstract

  While plasmacytosis is a common occurrence in early post-bone marrow transplantation biopsy specimens, the significance of plasma cells in such specimens from patients with multiple myeloma (MM) is unknown. We attempted to retrospectively determine, by morphologic assessment of plasma cell percentage, immunohistologic assessment of plasma cell light chain ratio (LCR), and correlation with clinical outcome, the prevalence and significance of plasmacytosis in the posttransplantation bone marrow biopsy specimens of 25 patients with MM who underwent autologous peripheral blood stem cell transplantation (PBSCT). No pre-PBSCT morphologic or immunologic characteristics were significantly associated with the post-PBSCT outcome in this group of patients. While 9% of all biopsy specimens and 25% of hypocellular biopsy specimens obtained during the first 60 days after the PBSCT contained more than 10% plasma cells, 34% of all biopsy specimens obtained during this period had elevated LCRs. The dominant light chain in all cases with high LCRs was the same as that of the original tumors, implying that these plasma cells represent a portion of the patients' original tumors. However, the presence of tumoral plasma cells during the early post-PBSCT period was not associated with outcome (P>.5 at 30 days and 60 days after transplantation). Histologic features of recurrent MM and elevated LCR occurring at day 90 or later are correlated with progression of disease (P=.02 and P=.0001, respectively). We conclude that the presence of tumoral plasma cells in the early post-PBSCT period likely represents residual tumor and should not be regarded as indicating imminent relapse, while the presence of tumor as assessed by histologic or immunohistochemical evaluation during the late post-PBSCT period should raise the concern of relapse and disease progression.

  View details for Web of Science ID A1997XA22800005

  View details for PubMedID 9169660

• Endogenous avidin-binding activity in paraffin-embedded tissue revealed after microwave treatment APPLIED IMMUNOHISTOCHEMISTRY RodriguezSoto, J., Warnke, R. A., Rouse, R. V. 1997; 5 (1): 59-62

  View details for Web of Science ID A1997WM32500009

• Primary low-grade endometrial B-cell lymphoma 85th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology VANDERIJN, M., Kamel, O. W., Chang, P. P., Lee, A., Warnke, R. A., Salhany, K. E. LIPPINCOTT WILLIAMS & WILKINS. 1997: 187–94

  Abstract

  We describe three cases of primary low-grade B-cell lymphoma of the endometrium and contrast the histological, immunohistochemical, and molecular features with two examples of benign endometrial lymphoid infiltrates. The first case was an incidental finding in a curettage specimen, confirmed on a subsequent hysterectomy. The other two cases of lymphoma were incidental findings on hysterectomy procedures performed for prolapse and cervical dysplasia, respectively. All three lymphomas occurred in patients in their sixties; none formed gross tumors. Histologic examination revealed lymphoid nodules adjacent to endometrial glands. The lymphoid cells showed mild nuclear enlargement and slight irregularities of the nuclear contour. None of the three patients had evidence of disease outside the endometrium by physical examination, bone marrow biopsy, or sampling of pelvic lymph nodes. Immunohistochemistry demonstrated a B-cell phenotype of the lymphoid cells (CD20 positive, CD79a positive) with aberrant coexpression of the T-cell-associated marker CD43. Polymerase chain reaction (PCR) amplification of the VDJ region of the immunoglobulin heavy-chain was performed on DNA isolated from paraffin sections. These studies demonstrated a clonal proliferation of B-lymphocytes in two cases. In the third case, a faint band was found superimposed on a background smear, suggesting the presence of a B-cell clone. In contrast, the two examples of histologically benign lymphoid aggregates of the endometrium consisted predominantly of T cells with rare B-lymphocytes; there was no evidence of coexpression of CD43 by B-cells. The PCR amplification from the benign lymphoid aggregates did not support a clonal process. Primary lymphoid neoplasms of the endometrium are rare, and all cases described so far have been high-stage, high-grade neoplasms. To our knowledge, this is the first report of primary low-grade B-cell lymphoma of the endometrium, presumably arising from endometrial lymphoid tissue.

  View details for Web of Science ID A1997WH87300008

  View details for PubMedID 9042285

• Somatic mutations of the translocated bcl-2 gene are associated with morphologic transformation of follicular lymphoma to diffuse large-cell lymphoma 6th International Conference on Malignant Lymphoma Matolcsy, A., Warnke, R. A., Knowles, D. M. OXFORD UNIV PRESS. 1997: 119–122

  Abstract

  Ninety percent of low-grade follicular lymphomas (FLs) carry the t(14;18) translocation. This event juxtaposes the bcl-2 oncogene to the immunoglobulin (Ig) heavy-chain gene and leads to bcl-2 gene overexpression. Morphologic transformation of FL to high-grade lymphoma is associated with multiple secondary chromosomal abnormalities of the neoplastic cells.To analyze whether additional structural alterations of the translocated bcl-2 gene are associated with morphologic transformation of FL, we PCR-amplified, cloned, and sequenced the major breakpoint region (MBR) and the open reading frames (ORF) of the translocated bcl-2 oncogene in six paired samples of FL and subsequent diffuse large-cell lymphoma (DLL).In five cases, FL and DLL cells were clonally related, as suggested by the identical MBR sequences, but in one case they were different. PCR single-strand conformation polymorphism (SSCP) and sequence analyses were performed for identification of structural alterations of the bcl-2 gene in the OFR region corresponding to the 239 amino acid p26-bcl-2a protein. In three of the six patients, a total of 11 point mutations of the ORF were detected in the DLL cells. Four of them, at positions 29, 46, 59, and 106, yielded amino acid replacements.These findings demonstrate that FL and DLL cells may be clonally related or unrelated. They also show that transformation of FL cells can be associated with somatic point mutations of the bcl-2 oncogene ORF sequence resulting in alteration of the p26-bcl-2a gene product.

  View details for Web of Science ID A1997XH39900024

  View details for PubMedID 9209654

• VH4.21 gene segment utilization in human lymphomas Funkhouser, W. K., Hsu, F., Levy, R., Warnke, R. A. NATURE PUBLISHING GROUP. 1997: 728–28

  View details for Web of Science ID A1997WD48600743

• Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated bcl-2 gene BLOOD Matolcsy, A., Casali, P., Warnke, R. A., Knowles, D. M. 1996; 88 (10): 3937-3944

  Abstract

  Follicular lymphoma (FL) is a low-grade B-cell non-Hodgkin's lymphoma (NHL) that frequently transforms into diffuse aggressive NHL. The majority of FLs display a t(14; 18) translocation that places the bcl-2 gene into juxtaposition with the lg heavy-chain (H) gene locus. Morphologically transformed malignant FL cells retain their t(14;18) translocation and may acquire additional genetic abnormalities. We analyzed serial biopsy specimens from eight patients with FL for secondary alterations of the rearranged bcl-2 gene in the breakpoint and open reading frame (ORF) regions. Two cases of FL showed no histologic alteration in the second biopsy, and six cases of FL showed morphologic transformation to diffuse large-cell lymphoma (DLL) in the second biopsy. Polymerase chain reaction (PCR) amplification, cloning, and sequencing of the junctional region of the hybrid bcl-2/IgH genes showed identical nucleotide sequences in multiple biopsy specimens of FL that did not show morphologic transformation. In patients in whom FL cells underwent morphologic transformation, FL and autologous DLL cells displayed identical bcl-2/IgH gene nucleotide sequences in five cases and different sequences in one case. In the case for which FL and DLL cells showed different bcl-2/IgH junctional sequences, DLL cells incorporated larger bcl-2 and Ig-joining (JH) gene fragments than the corresponding FL cells, suggesting that DLL clones developed by a distinct t(14; 18) translocation rather than by alteration of the hybrid bcl-2/IgH gene detected in the FL cells. In all eight cases, neither FL nor DLL cells showed alterations of bcl-2 gene sequences in the breakpoint region, suggesting high conservation of the bcl-2 gene during both t(14; 18) translocation and morphologic transformation of the FL cells. PCR single-strand conformation polymorphism (SSCP) and sequence analyses were performed for identification of structural alterations of the bcl-2 gene in the ORF region corresponding to the 239-amino acid p26-bcl-2 alpha protein. A total of 11 point mutations of the ORF were detected in DLL cells of three transformed NHLs, but no alteration of the ORF was detected in FL cells. Four of 11 mutations, at positions 29, 46, 59, and 106, yielded amino acid replacements. These findings demonstrate that FL and DLL cells may be clonally related or unrelated. They also show that transformation of FL cells may be associated with somatic point mutations of the bcl-2 proto-oncogene ORF sequence resulting in alteration of the p26-bcl-2 alpha gene product.

  View details for Web of Science ID A1996VU98400030

  View details for PubMedID 8916960

• Pregnancy-associated lymphomas - A clinicopathologic study CANCER Gelb, A. B., VANDERIJN, M., Warnke, R. A., Kamel, O. W. 1996; 78 (2): 304-310

  Abstract

  The natural histories of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) during pregnancy are not well understood.All cases of HD and NHL diagnosed during pregnancy at Stanford University Medical Center since 1987 were reviewed and clinical follow-up was obtained. Various immunohistochemical studies and in situ hybridization for Epstein-Barr virus (EBV) encoded RNA were performed in a subset of cases.Seventeen cases of HD and 12 cases of NHL were accessioned (median age; 27 yrs). The HD cases were classified as 13 nodular sclerosis type, 3 mixed cellularity type, and 1 unclassified. Clinical follow-up revealed most of the patients had Stage II to III disease and were diagnosed on average at 22 weeks gestation. Most of the patients deferred therapy until after delivery and had no evidence of disease at the last follow-up except for one death with disease but not from it. NHL were classified according to the working formulation as high or intermediate grade lymphomas of various types, including both nodal and extranodal sites. Clinical follow-up revealed most had Stage II to IV disease and were diagnosed on average at 23 weeks gestation. Patients with HD tended to survive longer than those with NHL (raw mortality, P = 0.04). In situ hybridization failed to provide support for the presence of EBV in a subset of patients with NHL.The clinical behavior of these neoplasms during pregnancy does not appear to be significantly different from that outside of the setting of pregnancy. Treatment of selected HD patients apparently may be safely deferred until after delivery. Patients with NHL present with higher stage disease and have a poorer prognosis than those with HD.

  View details for Web of Science ID A1996UV02200018

  View details for PubMedID 8674008

• Methods to detect P-glycoprotein-associated multidrug resistance in patients tumors: Consensus recommendations CANCER RESEARCH Beck, W. T., Grogan, T. M., Willman, C. L., CORDONCARDO, C., Parham, D. M., Kuttesch, J. F., Andreeff, M., Bates, S. E., Berard, C. W., Boyett, J. M., BROPHY, N. A., Broxterman, H. J., Chan, H. S., Dalton, W. S., Dietel, M., Fojo, A. T., Gascoyne, R. D., Head, D., Houghton, P. J., Srivastava, D. K., Lehnert, M., Leith, C. P., Paietta, E., Pavelic, Z. P., Rimsza, L., Roninson, I. B., Sikic, B. I., Twentyman, P. R., Warnke, R., Weinstein, R. 1996; 56 (13): 3010-3020

  Abstract

  Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins.

  View details for Web of Science ID A1996UT39800027

  View details for PubMedID 8674056

• True histiocytic lymphoma following therapy for lymphoblastic neoplasms BLOOD Soslow, R. A., Davis, R. E., Warnke, R. A., Cleary, M. L., Kamel, O. W. 1996; 87 (12): 5207-5212

  Abstract

  True histiocytic lymphomas (THLs) are rare tumors in which the malignant cells show morphologic and immunophenotypic evidence of histiocytic differentiation. We describe THLs that arose after therapy for one case of T-lineage lymphoblastic lymphoma (LyL) and two cases of acute lymphoblastic leukemia (ALL) (both CD10+, one pre-B phenotype). The lymphoblastic neoplasms were not unusual in any way, and responded well to standard therapy. The THLs arose 10 to 20 months after complete remission was achieved for the lymphoblastic neoplasms, at which time there was still no clinical or pathologic evidence of the lymphoblastic neoplasms. All three THLs exhibited clinical and morphologic features of malignancy. Neoplastic cells in the THLs had abundant eosinophilic vacuolated cytoplasm and pleomorphic nuclei, and expressed histiocytic antigens in the absence of lymphocyte-specific lineage markers. Because THLs are rare neoplasms, their occurrence after otherwise successful therapy for lymphoblastic neoplasms in these three cases may constitute a distinct clinicopathologic entity.

  View details for Web of Science ID A1996UQ70900031

  View details for PubMedID 8652834

• Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis ARTHRITIS AND RHEUMATISM VANDERIJN, M., Cleary, M. L., Variakojis, D., Warnke, R. A., Chang, P. P., Kamel, O. W. 1996; 39 (4): 638-642

  Abstract

  A causative role for Epstein-Barr virus (EBV) in the development of lymphoma in patients with rheumatoid arthritis (RA) has been proposed. We investigated the molecular features of EBV-positive diffuse large cell lymphomas in 2 patients with RA.Southern blot analysis for immunoglobulin gene rearrangements, terminal repeat analysis for clonality of the EBV genome, and double-labeling of the lymphoma cells by in situ hybridization and immunoperoxidase staining were performed.In both cases, double-labeling studies localized the EBV genome to the malignant B cells. Both neoplasms contained clonal immunoglobulin gene rearrangements and clonal EBV genomes.Our data indicate that EBV infection was an early step in the development of these neoplasms. The findings further extend knowledge on the similarity of this subset of lymphomas to posttransplantation lymphomas and emphasize the role of immunosuppression in their genesis.

  View details for Web of Science ID A1996UD63800014

  View details for PubMedID 8630114

• Mycosis fungoides and Hodgkin's disease: Clinicopathologic features and lack of evidence for ebv infection by in situ hybridization Rodriguez, J., Weiss, L., Warnke, R., Dorfman, R., Hoppe, R., Kamel, O. NATURE PUBLISHING GROUP. 1996: 705–

  View details for Web of Science ID A1996TT75700736

• Distribution and density of CD57-positive infiltrate distinguish between follicular hyperplasia (FH), progressive transformation of germinal centers (PTGC) and lymphocyte predominant Hodgkin's disease (LPHD) Soslow, R. A., Chung, M. H., Warnke, R. A., Dorfman, R. NATURE PUBLISHING GROUP. 1996: 716–16

  View details for Web of Science ID A1996TT75700747

• CLONAL VDJ RECOMBINATION OF THE IMMUNOGLOBULIN HEAVY-CHAIN GENE BY PCR IN CLASSICAL HODGKINS-DISEASE AMERICAN JOURNAL OF CLINICAL PATHOLOGY Kamel, O. W., Chang, P. P., Hsu, F. J., DOLEZAL, M. V., Warnke, R. A., VANDERIJN, M. 1995; 104 (4): 419-423

  Abstract

  Although Hodgkin's disease (HD) has been a subject of much investigation, fundamental questions remain unanswered regarding its lineage and clonality. The authors used a polymerase chain reaction (PCR) technique to investigate whether clonal Variable-Diversity-Joining recombination of the immunoglobulin heavy (IgH) chain gene, a phenomenon that characterizes clonal B-cell proliferations, exists in nodular sclerosing (NSHD) and mixed cellularity (MCHD) Hodgkin's disease (so-called "classical" Hodgkin's disease). The isolation of DNA from paraffin-embedded tissue sections allowed for direct correlation of PCR results with the cell populations that were analyzed. Thirty-two cases were studied. These included 12 cases in which the Reed-Sternberg (RS) cells expressed the B-cell antigen, CD20, and 10 cases that were classified as syncytial variant of NSHD (3 CD20+, 7 B-cell antigen negative). Overall, clonal patterns of VDJ PCR products were found in 14 of 32 (44%) cases. These clonal patterns were identified in 7 of 12 (58%) cases of CD20+ classical HD and in 7 of 20 (35%) cases of B-antigen-negative classical HD. Clonal patterns were found in 3 of 10 cases of syncytial variant of NSHD, including 2 of 3 (67%) CD20+ cases and 1 of 7 (14%) B-cell antigen-negative cases. The results of this study provide support that a subset of HD represents a clonal B-cell neoplasm, and indicate that clonal IgH VDJ sequences are more frequently found in CD20+ HD.

  View details for Web of Science ID A1995RZ47500011

  View details for PubMedID 7572792

• LYMPHOCYTE ANTIGEN ABNORMALITIES IN INFLAMMATORY DERMATOSES APPLIED IMMUNOHISTOCHEMISTRY SMOLLER, B. R., Bishop, K., Glusac, E. J., Bhargava, V., Kim, Y. H., Warnke, R. A. 1995; 3 (2): 127-131

  View details for Web of Science ID A1995RB47200009

• TRUE HISTIOCYTIC LYMPHOMA - A STUDY OF 12 CASES BASED ON CURRENT DEFINITION LEUKEMIA & LYMPHOMA Kamel, O. W., Gocke, C. D., Kell, D. L., Cleary, M. L., Warnke, R. A. 1995; 18 (1-2): 81-86

  Abstract

  True histiocytic lymphoma (THL), as it is currently defined, is a rare entity. We report 12 cases of THL seen at Stanford over the last ten years. By definition, the neoplastic cells in each case showed histological and immunological evidence of histiocytic differentiation. Seven females and five males ranged in age from 9 to 67 years. Sites of involvement included lymph node, soft tissue, bone, stomach, small intestine, mediastinum, kidney, breast and salivary gland. Lymph nodes showed diffuse architectural effacement and/or a paracortical pattern of involvement. The infiltrates involved other tissues in a diffuse pattern. Cytologically the cells were characterized by abundant eosinophilic cytoplasm and enlarged, indented eccentrically placed nuclei containing prominent nucleoli. In all cases the cytological features were sufficiently atypical to indicate a neoplastic infiltrate. Paraffin section immunophenotyping demonstrated reactivity of the atypical cells for CD15, 43, 45RO, 45RB, 68, lysozyme and/or S100. In frozen sections, the atypical cells demonstrated reactivity for CD4 (cytoplasmic), 11c, 14, 15, and/or 68. Genotypic studies were performed on 3 cases, one of which showed rearrangements of immunoglobulin heavy and light chain genes. Follow-up was available on eleven patients, six of whom died of disease 0.5 to 36 months following diagnosis.

  View details for Web of Science ID A1995RN15600010

  View details for PubMedID 8580833

• A REVISED EUROPEAN-AMERICAN CLASSIFICATION OF LYMPHOID NEOPLASMS PROPOSED BY THE INTERNATIONAL LYMPHOMA STUDY-GROUP - A SUMMARY VERSION AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chan, J. K., BANKS, P. M., Cleary, M. L., Delsol, G., DeWolfPeeters, C., Falini, B., Gatter, K. C., Grogan, T. M., Harris, N. L., Isaacson, P. G., Jaffe, E. S., Knowles, D. M., Mason, D. Y., MULLERHERMELINK, H. K., Pileri, S. A., Piris, M. A., Ralfkiaer, E., Stein, H., Warnke, R. A. 1995; 103 (5): 543-560

  View details for Web of Science ID A1995QX17100003

  View details for PubMedID 7741099

• REASSESSMENT OF LYMPHOCYTE IMMUNOPHENOTYPING IN THE DIAGNOSIS OF PATCH AND PLAQUE STAGE LESIONS OF MYCOSIS-FUNGOIDES APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY SMOLLER, B. R., Bishop, K., Glusac, E. J., Kim, Y. H., Bhargava, V., Warnke, R. A. 1995; 3 (1): 32-36

  View details for Web of Science ID A1995QH64600003

• SOMATIC MUTATIONS IN TRANSLOCATED BCL-2 GENE ASSOCIATED WITH HISTOLOGIC TRANSFORMATION OF FOLLICULAR LYMPHOMA Casali, P., Matolcsy, A., Warnke, R., Knowles, D. M. FEDERATION AMER SOC EXP BIOL. 1995: A123–A123

  View details for Web of Science ID A1995QL98700719

• CD8-POSITIVE TUMOR-INFILTRATING LYMPHOCYTES INFLUENCE THE LONG-TERM SURVIVAL OF PATIENTS WITH MYCOSIS-FUNGOIDES JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Hoppe, R. T., Medeiros, L. J., Warnke, R. A., Wood, G. S. 1995; 32 (3): 448-453

  Abstract

  Nonneoplastic mononuclear cells commonly infiltrate lesions of mycosis fungoides.We sought to determine the immunophenotypic characteristics of these cells and to determine whether the presence of CD8+ tumor-infiltrating lymphocytes has an impact on prognosis.Skin biopsy specimens from 78 patients were stained with immunopleroxidase techniques to determine their phenotypic characteristics. The proportion of CD8+ tumor-infiltrating lymphocytes was quantified and compared with stage of disease and survival rate.Patients with more limited T-stage disease tended to have a higher proportion of CD8+ cells in their skin biopsy specimens, compared with patients with more advanced T-stage disease. Within each T-stage patients with a larger proportion of CD8+ cells had a better survival rate than those with fewer CD8+ cells (p < 0.05 for T1 and T3). A multivariate analysis confirmed the importance of T stage (p = 0.0006), overall stage (p = 0.0112), and CD8 positivity (p = 0.0335) in this cohort of patients.CD8+ tumor-infiltrating lymphocytes in mycosis fungoides correlate with improved survival rate and may exert an antitumor effect rather than being mere bystander cells.

  View details for Web of Science ID A1995QJ45800006

  View details for PubMedID 7868714

• IMMUNOSUPPRESSION-ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS IN RHEUMATIC PATIENTS LEUKEMIA & LYMPHOMA Kamel, O. W., VANDERIJN, M., Hanasono, M. M., Warnke, R. A. 1995; 16 (5-6): 363-368

  Abstract

  The association between rheumatic disease and the occurrence of hematolymphoid neoplasms has been a subject of investigation for many years. Recently, we and others have reported the development in rheumatic patients of lymphoproliferative disorders that are similar to those occurring in patients with known immunocompromised states. The lymphoid neoplasms that develop in patients with immunosuppression are characterized by several features including the presence of EBV genome in the neoplastic cells. The fact that lymphomas with features of those occurring in immunosuppressed patients can occur in patients with rheumatic disease suggests that immune system impairment secondary to the rheumatic disease, the treatment given for the rheumatic disease, or to a combination of these factors, might play a role in the development of lymphoma in these patients. This review will first describe the characteristics of lymphoproliferative disorders that occur in patients with known immunocompromised states. It will then review general aspects of lymphomas in rheumatic patients with a focus on more recent reports that have described the development of immunosuppression-associated lymphoproliferative disorders in rheumatic patients. Studies that investigate the relative contribution of the rheumatic disease versus therapy for rheumatic disease in the development of lymphoma in this patient group are still needed.

  View details for Web of Science ID A1995QJ55000001

  View details for PubMedID 7787745

• LYMPHOMA CLASSIFICATION PROPOSAL - CLARIFICATION BLOOD Harris, N. L., Jaffe, E. S., Stein, H., BANKS, P. M., Chan, J. K., Cleary, M. L., Delsol, G., DeWolfPeeters, C., Falini, B., Gatter, K. C., Grogan, T. M., Isaacson, P. G., Knowles, D. M., Mason, D. Y., MULLERHERMELINK, H. K., Pileri, S. A., Piris, M. A., Ralfkiaer, E., Warnke, R. A. 1995; 85 (3): 857-860

  View details for Web of Science ID A1995QD92300040

  View details for PubMedID 7833492

• EXPRESSION OF BCL-2 PROTEIN AND KI-67 NUCLEAR PROLIFERATION ANTIGEN IN BENIGN AND MALIGNANT CUTANEOUS T-CELL INFILTRATES JOURNAL OF CUTANEOUS PATHOLOGY Dummer, R., Michie, S. A., Kell, D., Gould, J. W., Haeffner, A. C., SMOLLER, B. R., Warnke, R. A., Wood, G. S. 1995; 22 (1): 11-17

  Abstract

  The bcl-2 protein prolongs cell life by inhibiting apoptosis. Its expression has been studied in a variety of normal tissues and lymphomas but there is minimal information available concerning bcl-2 expression by benign and malignant cutaneous T-cells. Therefore, we investigated bcl-2 expression in a wide variety of cutaneous T-cell infiltrates using one- and two-color immunohistologic techniques. bcl-2 was expressed by the majority of lesional CD3+ T-cells in most cases. This included 22/26 cases of mycosis fungoides (MF), 3/3 cases of non-MF cutaneous T-cell lymphoma, 5/5 cases of lymphomatoid papulosis, 4/4 cases of T-cell rich cutaneous lymphoid hyperplasia, 2/3 cases of bullous pemphigoid, 2/2 cases of discoid lupus erythematosus and 1/1 case of lichen planus. Titration experiments and comparative studies of tonsil section positive controls revealed that, relative to mantle zone B-cells, there was over- expression of bcl-2 by a variable subset of T-cells in most cases. Assessment of multiple biopsies in a subset of MF cases showed stable expression of bcl-2 over intervals of up to two years. In contrast to the widespread expression of bcl-2 in both early and advanced MF skin lesions, abundant expression of the nuclear proliferation antigen, Ki-67, was skewed toward advanced MF skin lesions. Ten percent or more Ki-67+ cells were present in 5% of patients with patches/thin plaques, 38% with moderate plaques, 64% with thick plaques and 100% with tumor nodules.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QL26000003

  View details for PubMedID 7751472

• VIRUS-ASSOCIATED HEMOPHAGOCYTIC SYNDROME CHARACTERIZED BY CLONAL EPSTEIN-BARR-VIRUS GENOME AMERICAN JOURNAL OF CLINICAL PATHOLOGY DOLEZAL, M. V., Kamel, O. W., VANDERIJN, M., Cleary, M. L., Sibley, R. K., Warnke, R. A. 1995; 103 (2): 189-194

  Abstract

  Virus-associated hemophagocytic syndromes are a heterogeneous group of disorders in which viral infection is associated with a proliferation of hemophagocytic histiocytes throughout the reticuloendothelial system. The authors report the case of a 24-year-old Vietnamese male who developed a hemophagocytic syndrome associated with Epstein-Barr virus (EBV) and who died following a rapidly progressive course. A proliferation of reactive-appearing lymphoid cells was associated with an extensive proliferation of erythrophagocytic histiocytes. Immunophenotypically, the lymphoid infiltrate consisted of CD56+ natural killer cells, predominantly CD8+ T-cells and rare B-cells (CD20+). Double-label immunohistochemical studies showed CD3+ T-cells and CD56+ natural killer cells to be distinct cell populations. Combined immunohistochemical-in situ hybridization studies localized EBV to CD43+, CD3-, CD68-, lymphoid-appearing cells, indicating the presence of EBV within natural killer cells. Southern hybridization analysis of EBV genomic termini revealed clonal EBV genome. However, there was no detectable immunoglobulin or T-cell receptor gene rearrangements. The findings indicate that this case of hemophagocytic syndrome represents a clonal proliferation of natural killer cells containing EBV and highlights the importance of the analysis of EBV genomic termini for determination of clonality in EBV-associated proliferations. It is possible that other cases of fulminant EBV-associated hemophagocytic syndromes represent clonal natural killer cell proliferations.

  View details for Web of Science ID A1995QF55100015

  View details for PubMedID 7856561

• DETECTION OF IMMUNOPHENOTYPIC ABNORMALITIES IN PARAFFIN-EMBEDDED B-LINEAGE NON-HODGKINS-LYMPHOMAS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gelb, A. B., Rouse, R. V., Dorfman, R. F., Warnke, R. A. 1994; 102 (6): 825-834

  Abstract

  The authors analyzed the frequency of immunophenotypic abnormalities in 1,474 cases of routinely fixed, paraffin-embedded B-lineage non-Hodgkin's lymphomas. B-lineage was determined by immunoreactivity for CD20 (L26, 92%); CD45RA (4KB5, an additional 3%) or immunoglobulin (Ig) light chain restriction (remaining 5%). CD45RA was found to be especially helpful on Bouin's-fixed or decalcified tissue and Ig staining was most helpful in plasmacytoid lesions. Coexpression of the T-cell marker CD43 (Leu-22) was the most common immunophenotypic abnormality, seen in 60% of mantle cell lymphomas (MCL), 39% of CLL/small lymphocytic lymphomas, 16% of diffuse large cell lymphomas (DLCL), but only 5% of follicular lymphomas (FL). Antibodies to CD45RO (A6 and UCHL1) and CD3 (polyclonal) were useful in distinguishing infiltrating T cells from B cells coexpressing CD43. Ig light chain restriction was the next commonest immunophenotypic abnormality, which was identified in 67% of plasmacytoid diffuse small cell lymphomas, 43% of MCLs, 35% of monocytoid B-cell lymphomas and 28% of FLs. Overexpression of bcl-2 oncogenic protein was observed in 71% of FLs (n = 96), but not in a control group of reactive follicular hyperplasias (n = 34). Combining two criteria increased the sensitivity of immunodiagnosis in certain circumstances.

  View details for Web of Science ID A1994PX40700024

  View details for PubMedID 7801900

• A PROPOSAL FOR CLASSIFICATION OF LYMPHOID NEOPLASMS (BY THE INTERNATIONAL LYMPHOMA STUDY-GROUP) HISTOPATHOLOGY Chan, J. K., BANKS, P. M., Cleary, M. L., Delsol, G., DeWolfPeeters, C., Falini, B., Gatter, K. C., Grogan, T. M., Harris, N. L., Isaacson, P. G., JAFFE, B. S., Knowles, D. M., Mason, D. Y., MULLERHERMELINK, H. K., Pileri, S. A., Piris, M. A., Ralfkiaer, E., Stein, H., Warnke, R. A. 1994; 25 (6): 517-536

  Abstract

  A new classification of lymphoid neoplasms, mostly based on existing terminology, is proposed by the International Lymphoma Study Group. The proposed classification was reached through a consensus of the members, despite their diverse backgrounds, and consists of a listing of currently recognized clinicopathological entities. These tumours are divided into three major categories: B-cell neoplasms, T-cell and postulated natural killer cell neoplasms, and Hodgkin's disease. The characterization of each entity is based on a synthesis of all available information. This concept departs from a purely morphological approach to lymphoma classification, which is considered to be inadequate, because many biologically distinctive lymphoma types can exhibit a broad and overlapping morphological spectrum. Some entities are provisional, pending further data to confirm that their recognition is reproducible. The salient clinicopathological features of each entity are summarized in this review.

  View details for Web of Science ID A1994PY47600002

  View details for PubMedID 7698729

• EPSTEIN-BARR VIRUS-ASSOCIATED NATURAL-KILLER LARGE GRANULAR LYMPHOCYTE LEUKEMIA HUMAN PATHOLOGY Gelb, A. B., VANDERIJN, M., Regula, D. P., CORNBLEET, J. P., Kamel, O. W., Horoupian, D. S., Cleary, M. L., Warnke, R. A. 1994; 25 (9): 953-960

  Abstract

  We describe the first case of an Epstein-Barr virus (EBV)-associated natural killer-large granular lymphocyte (NK-LGL) leukemia in the United States to the best of our knowledge. A 29-year-old woman of Japanese descent developed EBV infection after a blood transfusion as indicated by a rise in serum antibody titers. Peripheral blood and bone marrow aspirate smears demonstrated increased LGLs. Flow cytometry showed that these cells expressed NK-associated surface antigens. Cytogenetic analysis of the bone marrow aspirate showed two distinct but related clones with multiple copies of a modified 7 marker chromosome. Death followed colonic perforation. Findings at necropsy included bone marrow lymphocytosis and erythrophagocytosis, a mononucleosis-like lymphadenitis, atypical hepatitis with a mixed, predominantly T-cell infiltrate, interstitial pneumonitis, and multiorgan system vasculitis with perforation of the transverse colon. Epstein-Barr virus transcripts were identified in lymphocytes infiltrating liver and peripheral nerve by in situ hybridization. In addition, Southern blot analyses showed monoclonal bands superimposed on oligoclonal ladders of EBV termini in liver and lymph node. The identical episomal form of EBV was found in the bone marrow, lymph node, and liver. No immunoglobulin (Ig), T-cell receptor beta, or T-cell receptor gamma chain gene rearrangements were identified. These studies support the hypothesis that the LGL population was a neoplastic EBV-related clonal proliferation of NK cells.

  View details for Web of Science ID A1994PG35800018

  View details for PubMedID 8088773

• A REVISED EUROPEAN-AMERICAN CLASSIFICATION OF LYMPHOID NEOPLASMS - A PROPOSAL FROM THE INTERNATIONAL LYMPHOMA STUDY-GROUP BLOOD Harris, N. L., Jaffe, E. S., Stein, H., BANKS, P. M., Chan, J. K., Cleary, M. L., Delsol, G., DeWolfPeeters, C., Falini, B., Gatter, K. C., Grogan, T. M., Isaacson, P. G., Knowles, D. M., Mason, D. Y., MULLERHERMELINK, H. K., Pileri, S. A., Piris, M. A., Ralfkiaer, E., Warnke, R. A. 1994; 84 (5): 1361-1392

  View details for Web of Science ID A1994PE38700002

  View details for PubMedID 8068936

• LYMPHOID NEOPLASMS IN PATIENTS WITH RHEUMATOID-ARTHRITIS AND DERMATOMYOSITIS - FREQUENCY OF EPSTEIN-BARR-VIRUS AND OTHER FEATURES ASSOCIATED WITH IMMUNOSUPPRESSION HUMAN PATHOLOGY Kamel, O. W., VANDERIJN, M., LeBrun, D. P., Weiss, L. M., Warnke, R. A., Dorfman, R. F. 1994; 25 (7): 638-643

  Abstract

  We recently reported two cases of reversible Epstein-Barr virus (EBV)-associated lymphomas in patients undergoing methotrexate therapy for rheumatic disease. The current study was undertaken to investigate how frequently lymphoid neoplasms in patients with rheumatic disease show features of lymphoproliferations occurring in immunocompromised patients. Eighteen patients (including the two previously reported patients) with rheumatoid arthritis or dermatomyositis who developed lymphoproliferative lesions and on whom detailed clinical information was available were studied. As a group these patients developed a spectrum of lymphoproliferative lesions; however, a subset of patients developed neoplasms with features associated with immunosuppression. The neoplasms occurred in extranodal sites in 10 (56%) patients, showed a diffuse large-cell histology in nine (50%) patients, and contained EBV (EBER1) transcripts and EBV latent membrane protein in six (33%) patients. In three (17%) patients the neoplasms showed the entire constellation of features typical of immunosuppression-associated lymphoproliferations, including extranodal location, large-cell or polymorphous histology, geographic areas of necrosis, and the presence of EBV. These three patients were receiving both steroids and methotrexate at the time they developed their neoplasms. The findings of this study support the hypothesis that a subset of lymphoid neoplasms in rheumatic patients occurs in an immunocompromised setting and suggest that therapeutic immunosuppression may contribute, at least in part, to the development of these lymphoid neoplasms.

  View details for Web of Science ID A1994NX22700003

  View details for PubMedID 8026822

• HELICOBACTER-PYLORI INFECTION AND GASTRIC LYMPHOMA NEW ENGLAND JOURNAL OF MEDICINE Parsonnet, J., Hansen, S., Rodriguez, L., Gelb, A. B., Warnke, R. A., Jellum, E., Orentreich, N., Vogelman, J. H., Friedman, G. D. 1994; 330 (18): 1267-1271

  Abstract

  Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. We examined whether this infection is also a risk factor for primary gastric non-Hodgkin's lymphoma.This nested case-control study involved two large cohorts (230,593 participants). Serum had been collected from cohort members and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkin's lymphoma were identified, and each was matched to four controls according to cohort, age, sex, and date of serum collection. For comparison, 31 patients with nongastric non-Hodgkin's lymphoma from one of the cohorts were evaluated, each of whom had been previously matched to 2 controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples from all subjects were tested for H. pylori IgG by an enzyme-linked immunosorbent assay.Thirty-three cases of gastric non-Hodgkin's lymphoma occurred a median of 14 years after serum collection. Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9). The results were similar in both cohorts. Among the 31 patients with nongastric lymphoma, a median of six years had elapsed between serum collection and the development of disease. No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95 percent confidence interval, 0.5 to 3.0).Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.

  View details for Web of Science ID A1994NJ51200003

  View details for PubMedID 8145781

• EXPRESSION OF CLASS-II MAJOR HISTOCOMPATIBILITY ANTIGENS BY KERATINOCYTES IN CUTANEOUS T-CELL LYMPHOMA INTERNATIONAL JOURNAL OF DERMATOLOGY Wood, G. S., Michie, S. A., Durden, F., Hoppe, R. T., Warnke, R. A. 1994; 33 (5): 346-350

  Abstract

  Expression of various class II MHC antigens by lesional keratinocytes may play an important role in the pathophysiology of a wide variety of human dermatoses including cutaneous T cell lymphoma (CTCL). Nevertheless, there is relatively little information available concerning the concurrent expression of HLA-DR, -DP, and -DQ class II MHC antigens in CTCL. Therefore, our aim in this study was to determine the prevalence, localization, extent, temporal sequence, and consistency of class II MHC antigen expression by lesional keratinocytes in CTCL.We used a semiquantitative immunohistologic analysis to analyze HLA-DR, -DP, and -DQ expression by lesional keratinocytes in 66 skin biopsies obtained from 39 patients with CTCL.Class II MHC antigen expression by keratinocytes was observed in 77% of cases. Expression was detected on the cytoplasmic membrane and within the cytoplasm. It varied among cases from focal to confluent. There was a hierarchy of antigen expression in terms of both extent and time course. HLA-DR was expressed first and most extensively, followed by HLA-DP and then HLA-DQ. Comparative studies of multiple serial or concurrent active lesions from 13 cases indicated that the overall pattern and extent of antigen expression was relatively constant within individual patients.There was no apparent correlation between class II MHC antigen expression and the clinical stage of disease, the type of CTCL skin lesion, or the overall density of the lesional T cell infiltrate. The hierarchy of keratinocyte class II MHC antigen expression observed in this study paralleled that noted in earlier studies of cultured keratinocytes exposed to recombinant interferon-gamma in vitro. This suggests that lesional cytokine levels may be the critical factor governing class II MHC antigen expression by lesional keratinocytes in CTCL.

  View details for Web of Science ID A1994NJ59200011

  View details for PubMedID 8039974

• MYCOSIS-FUNGOIDES SKIN-LESIONS CONTAIN CD8+ TUMOR-INFILTRATING LYMPHOCYTES EXPRESSING AN ACTIVATED, MHC-RESTRICTED CYTOTOXIC T-LYMPHOCYTE PHENOTYPE JOURNAL OF CUTANEOUS PATHOLOGY Wood, G. S., Edinger, A., Hoppe, R. T., Warnke, R. A. 1994; 21 (2): 151-156

  Abstract

  In prior studies, we showed that most CD8+ cells infiltrating skin lesions of CD3+CD4+ mycosis fungoides were CD3+ T-lineage tumor-infiltrating lymphocytes (TIL) whose overall phenotype was suggestive of MHC-restricted cytotoxic T lymphocytes (CTL). However, their lack of cytotoxic-associated granzyme A mRNA suggested that they might be unactivated CTL precursors. In this study, we used single- and double-label immunohistologic techniques to assess the expression of TIA-1-reactive protein and HLA-DR by these CD8+TIL. Monoclonal antibody TIA-1 recognizes a novel family of proteins expressed preferentially by cytotoxic cells, including some that lack granzyme A. HLA-DR is a marker of T-cell activation. Single-label studies of 32 cases showed that CD8+TIL and TIA-1+ cells constituted a variable minority of the total cellular infiltrate and had a similar distribution. Double-label studies of 14 cases showed that in most instances the aggregate phenotype of the majority of CD8+TIL was CD3+TIA-1+HLA-DR+CD56-CD57-. These findings suggest that many of the CD8+TIL within skin lesions of CD3+CD4+ mycosis fungoides are activated, MHC-restricted CTL.

  View details for Web of Science ID A1994NL96900008

  View details for PubMedID 8040463

• THE BCL-2 ONCOGENE IN HODGKINS-DISEASE ARISING IN THE SETTING OF FOLLICULAR NON-HODGKINS-LYMPHOMA BLOOD LeBrun, D. P., Ngan, B. Y., Weiss, L. M., Huie, P., Warnke, R. A., Cleary, M. L. 1994; 83 (1): 223-230

  Abstract

  Expression of the bcl-2 proto-oncogene on chromosome 18 is deregulated by the 14; 18 chromosomal translocation, an abnormality that is consistently associated with follicular non-Hodgkin's lymphomas (NHL). Because bcl-2 is believed to function by prolonging cell survival rather than by increasing proliferation, the presence of t(14; 18) in Hodgkin's disease (HD) would have profound implications for the pathogenesis of this neoplasm. We evaluated 32 cases of HD for t(14; 18) by polymerase chain reaction (PCR). These results were correlated with expression of bcl-2 oncogenic protein by Hodgkin cells and with the presence of Epstein-Barr virus (EBV), as determined by immunohistochemistry or in situ hybridization. PCR provided evidence of t(14; 18) in only 2 HD cases (6%), both of which were associated with a prior history of follicular lymphoma, and both of which were among the 7 cases (22%) with strong bcl-2 expression in Hodgkin cells. In at least 1 of the cases, the translocation involved identical chromosomal breakpoints in both types of lymphoma. Furthermore, 7 additional cases of combined follicular NHL and HD showed strong bcl-2 staining in Hodgkin cells. Although EBV was detected in 6 of 30 cases, it was not associated with t(14; 18) and usually not with strong bcl-2 expression. These results suggest that a small proportion of HD cases might evolve from follicular NHL, possibly through molecular events superimposed on the t(14; 18). High-level bcl-2 expression in Hodgkin cells is a potentially useful but not definitive marker for these cases.

  View details for Web of Science ID A1994MQ09800029

  View details for PubMedID 8274737

• MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I AND CLASS-II ANTIGEN EXPRESSION IN DIFFUSE LARGE-CELL AND LARGE-CELL IMMUNOBLASTIC LYMPHOMAS - ABSENCE OF A CORRELATION BETWEEN ANTIGEN EXPRESSION AND CLINICAL OUTCOME AMERICAN JOURNAL OF PATHOLOGY Medeiros, L. J., Gelb, A. B., Wolfson, K., DOGGETT, R., McGregor, B., Cox, R. S., Horning, S. J., Warnke, R. A. 1993; 143 (4): 1086-1097

  Abstract

  The major histocompatibility complex (MHC) class I (HLA-A, B, C) and class II (HLA-DR) antigens are involved in cell-to-cell recognition and in regulating the immune response. Others have shown previously that MHC class I and class II antigens may be absent in a subset of malignant lymphomas, prompting the hypothesis that the absence of MHC antigen expression may be one of the mechanisms involved in the growth and dissemination of malignant lymphomas (by allowing a neoplasm to escape immune surveillance). To address this hypothesis, we analyzed MHC class I and class II (HLA-DR) antigen expression by diffuse large cell and large cell immunoblastic lymphomas in 88 and 117 patients, respectively, using frozen sections and the monoclonal antibodies W6/32 (HLA-A, B, C), anti-beta 2-microglobulin, and L203 (HLA-DR). Although there were no statistically significant clinical differences by MHC class II antigen expression, a small group of patients with MHC class I antigen-negative lymphomas were significantly younger (P = 0.03), less often had small neoplasms (P = 0.03), and were treated with doxorubicin-based chemotherapy more frequently (P = 0.04) than those with antigen-positive lymphomas. However, neither MHC class I nor class II antigen expression by the lymphomas consistently correlated with patient survival or freedom from relapse. This lack of correlation was true for all patients assessed, as well as for the subsets of patients with B-cell lymphomas, T-cell neoplasms, or those treated with doxorubicin-based chemotherapy. In accordance with previously published studies, stage, presence of B symptoms, and treatment with doxorubicin-based chemotherapy were of prognostic importance in univariate or multivariate analyses for survival or freedom from relapse. The findings may be considered evidence against the hypothesis that the absence of MHC class I or II antigen expression by malignant lymphomas plays a role in their tumorigenicity. However, we cannot completely exclude the possibility that the therapies used for this group of patients may have obscured any effect that MHC antigen expression exerts on prognosis.

  View details for Web of Science ID A1993MA82900013

  View details for PubMedID 8214004

  View details for PubMedCentralID PMC1887051

• TRANSFORMATION OF MYCOSIS-FUNGOIDES - T-CELL RECEPTOR-BETA GENE ANALYSIS DEMONSTRATES A COMMON CLONAL ORIGIN FOR PLAQUE-TYPE MYCOSIS-FUNGOIDES AND CD30+ LARGE-CELL LYMPHOMA JOURNAL OF INVESTIGATIVE DERMATOLOGY Wood, G. S., Bahler, D. W., Hoppe, R. T., Warnke, R. A., Sklar, J. L., Levy, R. 1993; 101 (3): 296-300

  Abstract

  It is well recognized that patients with classical mycosis fungoides (MF) may develop a large-cell lymphoma (LCL), a phenomenon known as "transformation." An unresolved issue regarding the transformation of MF is whether MF and LCL represent two separate lymphomas or whether they are derived from the same T-cell clone. We report the clinicopathologic, immunophenotypic, and immunogenotypic analysis of MF and LCL in a white male. He developed a rash at age 51 that was diagnosed at age 56 as clinical stage IA patch/plaque MF. After topical nitrogen mustard and total skin electron beam therapy for progressive generalized CD3+CD4+ patch/plaque lesions, he developed nodules of Ki-1+ (CD30+) T-LCL at age 72. Southern blot analysis of DNA digested with Bg/II or BamHI and probed with a T-cell receptor (TCR)-beta gene J beta 1/J beta 2 probe showed a single, identical rearranged band in both the MF and LCL skin lesions that had been obtained 4 years apart. V beta gene family--specific gene amplification assays demonstrated dominant V beta 6 PCR products in both types of lesions. These PCR products and lesional cDNA exhibited a monoclonal pattern when amplified with consensus TCR-beta gene VDJ joint primers and electrophoresed under conditions that allowed the resolution of small differences in size. Furthermore, sequence analysis of the V beta 6 PCR products amplified from both the MF and LCL lesions showed an identical nucleotide sequence involving V beta 6.4, D beta 1.1, J beta 1.2, and C beta 1. These findings indicate that both the MF and the LCL in this patient arose from the same T-cell clone and that these diseases developed at a stage in the clone's differentiation subsequent to rearrangement of the TCR-beta gene.

  View details for Web of Science ID A1993LX78600011

  View details for PubMedID 8396607

• Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. New England journal of medicine Kamel, O. W., van de Rijn, M., Weiss, L. M., Del Zoppo, G. J., HENCH, P. K., Robbins, B. A., Montgomery, P. G., Warnke, R. A., Dorfman, R. F. 1993; 328 (18): 1317-1321

  View details for PubMedID 8385742

• COEXISTENCE OF NODULAR LYMPHOCYTE PREDOMINANCE HODGKINS-DISEASE AND HODGKINS-DISEASE OF THE USUAL TYPE AMERICAN JOURNAL OF SURGICAL PATHOLOGY Gelb, A. B., Dorfman, R. F., Warnke, R. A. 1993; 17 (4): 364-374

  Abstract

  Recent literature suggests that usual Hodgkin's disease (nodular sclerosing and mixed cellularity types or UHD) and nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct clinical and pathologic entities. Thus, coexistence of NLPHD and UHD in the same patient is expected to be rare. We undertook a review of cases accessioned as NLPHD and UHD in the Laboratory of Surgical Pathology at Stanford University Hospital between January 1980 and May 1992 and found five patients with UHD that predated, followed, or coexisted with lesions histologically typical of NLPHD. All of the patients were male with ages ranging from 10 to 30 years at presentation (median, 22 years; mean, 22.2 years). The sites initially involved by disease were primarily peripheral lymph nodes in the region of the head and neck: cervical (three), supraclavicular (one), submandibular (one). One patient presented with mixed-cellularity Hodgkin's disease (MCHD), two with nodular sclerosis Hodgkin's disease including the cellular phase, one with NLPHD, and the remaining patient presented with a composite malignancy comprising MCHD and NLPHD. Development of the second lymphoma was associated with a somewhat more variable distribution of nodal involvement. The morphologic features in each biopsy specimen resembled either typical NLPHD or UHD, except for one case in which cells with features of both Reed-Sternberg cells and lymphocytic and histiocytes cells were identified. However, the immunophenotypic profiles obtained with a panel of monoclonal antibodies remained distinct for all cases studied. None of the cases showed reactivity with antibodies against the Epstein-Barr-virus latent membrane protein. Thus, NLPHD and UHD maintain a distinct phenotype, even when occurring in the same patient. A second conclusion is that the utility of Leu-7 (CD57) reactivity in distinguishing NLPHD applies to problematic as well as classic cases. Finally, Epstein-Barr virus is not implicated in NLPHD cases associated with UHD.

  View details for Web of Science ID A1993KT99100007

  View details for PubMedID 8494105

• HETEROGENEITY OF CD3 ANTIGEN EXPRESSION IN T-CELL LYMPHOMA HISTOPATHOLOGY Wood, K. M., PALLESEN, G., Ralfkiaer, E., Warnke, R., Gatter, K. C., Mason, D. Y. 1993; 22 (4): 311-317

  Abstract

  CD3 antigen expression was studied in a series of 98 T-cell lymphomas, using polyclonal antibodies which recognize this molecule in routinely processed, paraffin-embedded, tissue. We identified 40 cases in which CD3 was present on only a proportion of the neoplastic cells. This phenomenon of heterogeneous CD3 expression was commonest in pleomorphic T-cell lymphomas (22/42 cases) and in CD30 (Ki-1)-positive lymphomas (5/11 cases), and was less frequently observed in mycosis fungoides (4/18 cases) and not seen in T-cell lymphoblastic lymphoma (0/9 cases). CD3 expression was often related to cell morphology, with CD3 antigen being present on the smaller neoplastic cells but absent from the larger ones. The diagnostic significance of these observations is that, on occasion, it may be possible to diagnose a lymphoma as being of T-cell origin in paraffin sections by demonstrating a minor subpopulation of CD3-positive neoplastic cells.

  View details for Web of Science ID A1993LC90000002

  View details for PubMedID 8514274

• LEU-7 (CD57) REACTIVITY DISTINGUISHES NODULAR LYMPHOCYTE PREDOMINANCE HODGKINS-DISEASE FROM NODULAR SCLEROSING HODGKINS-DISEASE, T-CELL-RICH B-CELL LYMPHOMA AND FOLLICULAR LYMPHOMA AMERICAN JOURNAL OF PATHOLOGY Kamel, O. W., Gelb, A. B., Shibuya, R. B., Warnke, R. A. 1993; 142 (2): 541-546

  Abstract

  Several recent reports have suggested that nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct from other forms of Hodgkin's disease and may be more closely related to B-cell non-Hodgkin's lymphoma. This is primarily based on immunophenotypic studies that have shown that the L & H cells in NLPHD demonstrate a B-cell phenotype. In 1989, Poppema reported that the T cells in NLPHD differ from T cells in other forms of Hodgkin's disease in that they demonstrate reactivity for Leu 7 (CD57). In this study we tested the hypothesis that Leu 7 (CD57) reactivity of small lymphocytes in NLPHD is an immunophenotypic feature that distinguishes NLPHD from nodular sclerosing Hodgkin's disease and from certain B-cell lymphomas that may histologically simulate NLPHD, namely T-cell-rich B-cell lymphoma and follicular lymphoma. Using an image analysis method, we found Leu 7 (CD57) reactivity in an average of 18.9% of the small lymphocytes in the nodules of NLPHD compared with 3.9% in nodular sclerosing Hodgkin's disease, 4.3% in T-cell-rich B-cell lymphoma, and 2.1% in follicular lymphoma. Moreover, Leu 7 (CD57)-reactive small lymphocytes often showed a distinctive pattern in NLPHD, forming a ring of cells around the large L & H cells. While scattered Leu 7 (CD57)-reactive lymphocytes were found in the other disorders, the percentage of reactive cells and the pattern of reactivity were significantly different in NLPHD. These results suggest that Leu 7 (CD57) reactivity may be used as an additional immunophenotypic criterion in distinguishing NLPHD from nodular sclerosing Hodgkin's disease, T-cell-rich B-cell lymphoma, and follicular lymphoma. The clinical and biological significance of Leu 7 (CD57) reactivity of small lymphocytes in NLPHD merits further investigation.

  View details for Web of Science ID A1993KL85800023

  View details for PubMedID 7679553

• EBV-ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS OCCURRING IN THE SETTING OF METHOTREXATE THERAPY FOR RHEUMATOID-ARTHRITIS AND DERMATOMYOSITIS Kamel, O., VANDERIJN, M., Weiss, L., Warnke, R., Dorfman, R. NATURE PUBLISHING GROUP. 1993: A93–A93

  View details for Web of Science ID A1993KJ10200547

• MANTLE CELL LYMPHOMA - A PROPOSAL FOR UNIFICATION OF MORPHOLOGICAL, IMMUNOLOGICAL, AND MOLECULAR-DATA AMERICAN JOURNAL OF SURGICAL PATHOLOGY BANKS, P. M., Chan, J., Cleary, M. L., Delsol, G., DeWolfPeeters, C., Gatter, K., Grogan, T. M., Harris, N. L., Isaacson, P. G., Jaffe, E. S., Mason, D., Pileri, S., Ralfkiaer, E., Stein, H., Warnke, R. A. 1992; 16 (7): 637-640

  View details for Web of Science ID A1992JA44500001

  View details for PubMedID 1530105

• FOLLICULAR LYMPHOMAS OF THE GASTROINTESTINAL-TRACT - PATHOLOGICAL FEATURES IN 31 CASES AND BCL-2 ONCOGENIC PROTEIN EXPRESSION AMERICAN JOURNAL OF PATHOLOGY LeBrun, D. P., Kamel, O. W., Cleary, M. L., Dorfman, R. F., Warnke, R. A. 1992; 140 (6): 1327-1335

  Abstract

  The gastrointestinal tract is the most common site for extranodal lymphomas, but follicular lymphomas involving the gut are rare. To study their pathologic features and bcl-2 expression, 31 follicular lymphomas of the GI tract were reviewed and unstained paraffin sections from 24 of the cases were immunohistochemically stained using a monoclonal antibody for the peptide product of the proto-oncogene bcl-2. The most common site of lymphoma involvement was the small intestine, especially the terminal ileum. Gastric lymphomas tended to present clinically with symptomatic ulcers and small intestinal lesions presented with obstruction. Five cases involving the terminal ileum or colon had a gross appearance of multitudinous mucosal polyps and were considered to represent examples of "multiple lymphomatous polyposis." Enhanced expression of the bcl-2 oncogenic protein was detectable in lymphoma cells in 75% of cases and at lower levels in normal lymphoid cells in most cases. Small cleaved or mixed cell lymphomas were more likely to show enhanced expression than were large cell cases. Reactive germinal centers showed no bcl-2 staining. It is concluded that follicular GI lymphomas are associated with distinctive pathological features. In their tendency to express bcl-2, these neoplasms resemble their lymph node-based counterparts. Immunohistochemical staining for enhanced bcl-2 expression is of potential diagnostic utility in distinguishing between follicular lymphoma and follicular lymphoid hyperplasia in the gastrointestinal tract. The relevance of the results to lymphoma of mucosa-associated lymphoid tissue (MALT) is discussed.

  View details for Web of Science ID A1992HY13500007

  View details for PubMedID 1376556

• INFREQUENT DETECTION OF TOXOPLASMA-GONDII GENOME IN TOXOPLASMIC LYMPHADENITIS - A POLYMERASE CHAIN-REACTION STUDY HUMAN PATHOLOGY Weiss, L. M., Chen, Y. Y., Berry, G. J., Strickler, J. G., Dorfman, R. F., Warnke, R. A. 1992; 23 (2): 154-158

  Abstract

  The diagnosis of toxoplasmic lymphadenitis is currently established by histologic evaluation with confirmation by serologic studies. We used a sensitive and specific polymerase chain reaction methodology for the identification of toxoplasmic genomes previously reported by others to investigate whether this technology could contribute to the diagnosis. We were able to reliably detect toxoplasmic genomes in paraffin-embedded tissues of toxoplasmic encephalitis and myocarditis, and serial dilution studies indicated a high degree of sensitivity. Nonetheless, we identified toxoplasmic genomes in frozen tissue from only one of nine cases of toxoplasmic lymphadenitis. In the one positive case, only one of three frozen samples from the lymph node biopsy was positive, indicating a focal infection within the lymph node. It is concluded that polymerase chain reaction studies, at their current level of sensitivity, are not of great use in contributing to the evaluation of cases of suspected toxoplasmic lymphadenitis, which continues to be best diagnosed by accurate histopathologic examination.

  View details for Web of Science ID A1992HG31600010

  View details for PubMedID 1740299

• DIVERSITY OF T-CELL ANTIGEN RECEPTOR VARIABLE GENES USED BY MYCOSIS-FUNGOIDES CELLS AMERICAN JOURNAL OF PATHOLOGY Bahler, D. W., Berry, G., Oksenberg, J., Warnke, R. A., Levy, R. 1992; 140 (1): 1-8

  Abstract

  The expression of T-cell antigen receptor beta-chain variable genes (V beta) was evaluated in 28 cases of mycosis fungoides. A novel polymerase chain reaction (PCR) technique was used to associate expression of particular V beta genes with monoclonal T-cell populations. In addition, the same biopsies used for PCR analysis were also examined for reactivity with a panel of seven monoclonal antibodies that specifically recognized V beta proteins from four different families. Only three cases clearly stained with the antibodies, a result consistent with a diverse set of V beta genes being used. This was confirmed by PCR analysis, which indicated that V beta genes from many different families were expressed by these tumors. Preferential use of the V beta 8 family, which had been previously use of the V beta 8 family, which had been previously reported for this disease, was not evident among the cases analyzed.

  View details for Web of Science ID A1992GZ63600002

  View details for PubMedID 1731519

• MALIGNANT HISTIOCYTIC NEOPLASMS OF THE SMALL-INTESTINE AMERICAN JOURNAL OF SURGICAL PATHOLOGY Milchgrub, S., Kamel, O. W., Wiley, E., Vuitch, F., Cleary, M. L., Warnke, R. A. 1992; 16 (1): 11-20

  Abstract

  Immunologic studies have demonstrated that the vast majority of hematolymphoid neoplasms previously designated as "histiocytic" are lymphoid in origin. Consequently, malignancies of macrophage lineage are considered rare by most authors; indeed, their existence is doubted by some. Herein we report two cases of malignant histiocytic neoplasms (malignancies of macrophage lineage) of the small intestine. Both patients presented in the 7th decade with symptoms related to an abdominal mass. The polypoid tumors protruded into the intestinal lumen, extended through the entire thickness of the bowel wall, and involved regional lymph nodes. Microscopically, sheets of large pleomorphic histiocytic cells infiltrated around crypts and were associated with an admixture of bizarre giant cells and inflammatory cells. Mitotic figures were easily found. Ultrastructurally, the cells lacked desmosomes and had indented or kidney-shaped nuclei and cytoplasm containing mostly lysosomes and dense lipid droplets. In both cases, paraffin section immunohistochemistry revealed reactivity of tumor cells for CD45RB (LCA), CD45RO (A6), CD68 (KP1), CD15 (LeuM1), and lysozyme. Frozen section immunohistochemistry performed in one case further supported the macrophage phenotype. Southern blot studies of this case did not reveal immunoglobulin or T-cell receptor beta chain gene rearrangements. One patient initially treated by surgery only died of disease 3 years after diagnosis. The second patient is alive and disease-free 2 years following postoperative combination chemotherapy. The diagnosis of malignant histiocytic neoplasms requires the use of a panel of immunohistochemical markers and may be supported by electron-microscopic studies.

  View details for Web of Science ID A1992HC70200002

  View details for PubMedID 1728194

• PROGNOSTIC-SIGNIFICANCE OF HOST HELPER T-CELLS AND PROLIFERATING CELLS IN DIFFUSE SMALL LYMPHOCYTIC LYMPHOMAS - RESULTS OF A TREE-STRUCTURED SURVIVAL ANALYSIS Gelb, A., Davis, R., Mo, S., Halpern, J., Olshen, R., Nelson, E., Horning, S., Warnke, R. NATURE PUBLISHING GROUP. 1992: A77–A77

  View details for Web of Science ID A1992HA27600467

• ENHANCED STAINING FOR LEU-M1 (CD15) IN HODGKINS-DISEASE USING A SECONDARY ANTIBODY SPECIFIC FOR IMMUNOGLOBULIN-M AMERICAN JOURNAL OF CLINICAL PATHOLOGY LeBrun, D. P., Kamel, O. W., Dorfman, R. F., Warnke, R. A. 1992; 97 (1): 135-138

  Abstract

  The utility of staining for Leu M1 (CD15) as a diagnostic aid in Hodgkin's disease has been questioned because of a relative lack of specificity and sensitivity. Furthermore, interpretation is often made difficult by staining that tends to be weak and focal. Because the murine monoclonal anti-Leu M1 antibody is of immunoglobulin M type, it is reasonable to wonder whether improved immunohistochemical staining might result from use of a secondary goat antibody specific for the mouse mu heavy chain instead of the traditional one against mouse immunoglobulin. The two methods were compared, using a biotin-avidin detection system, on paraffin sections from 15 cases of Hodgkin's disease: 9 nodular sclerosing, 1 mixed cellularity, and 5 of nodular lymphocytic and histiocytic (L&H) type. In the nodular sclerosing/mixed cellularity group, the mu-specific detection method resulted in a greater number of cases with reactive Hodgkin's cells (7 versus 5), stained an average of more than three times as many neoplastic cells in each case (49% versus 14%), and usually produced staining that was distinctly more intense, often in a membrane and paranuclear distribution characteristic of Leu M1 in Hodgkin's cells. In the noLeu M1 in Hodgkin's cells. In the nodular L&H group, 1 case showed weak, focal staining with the newer method. None of the L&H cases stained using the traditional technique. It is concluded that use of a second-stage antibody that is directed specifically against mu heavy chains results in an improvement in immunohistochemical staining for Leu M1 in paraffin sections, which is of practical significance.

  View details for Web of Science ID A1992GZ46300023

  View details for PubMedID 1345892

• CLINICAL-SIGNIFICANCE OF MORPHOLOGICAL SUBDIVISION IN DIFFUSE LARGE CELL LYMPHOMA CANCER Kwak, L. W., Wilson, M., Weiss, L. M., Horning, S. J., Warnke, R. A., Dorfman, R. F. 1991; 68 (9): 1988-1993

  Abstract

  Although diffuse large cell lymphomas can be morphologically divided into large cell (DLC) and immunoblastic (IBL) subtypes, the clinical significance of this subdivision remains controversial. The initial diagnostic materials from 85 patients with recorded diagnoses of diffuse large cell lymphoma who were treated at Stanford between 1975 and 1986 with cyclophosphamide, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP); methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD); or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were retrospectively reviewed by a panel of hematopathologists and classified according to morphologic criteria of the Working Formulation. Based on the criterion of agreement of two of three observers, 60 patients were classified as having DLC, 19 as having IBL, and the lymphomas in 6 patients could not be additionally classified. No significant differences in complete response (CR) rate, freedom from disease progression (FFP), or overall survival were found between the DLC and IBL groups. There was also no significant difference in prognosis between DLC cases additionally subclassified as large cleaved cell (16 patients) and those with large non-cleaved cell (36 patients). Although IBL is considered to be a high-grade lymphoma, the authors concluded that it does not differ significantly in prognosis from DLC lymphoma and, therefore, does not justify a modified treatment selection based on IBL morphologic type alone. Definitive evaluation of the prognostic significance of morphologic subdivision may require a larger cohort of uniformly treated patients.

  View details for Web of Science ID A1991GK16800022

  View details for PubMedID 1913547

• METASTATIC CARCINOMA IN LYMPH-NODES SIMULATING SYNCYTIAL VARIANT OF NODULAR SCLEROSING HODGKINS-DISEASE AMERICAN JOURNAL OF CLINICAL PATHOLOGY Bacchi, C. E., Dorfman, R. F., Hoppe, R. T., Chan, J. K., Warnke, R. A. 1991; 96 (5): 589-593

  Abstract

  The authors report the histories of two patients with undifferentiated carcinoma metastatic to lymph nodes simulating the "syncytial variant" of nodular sclerosing Hodgkin's disease. One of the patients initially was treated for Hodgkin's disease, but the clinical evolution was more typical of carcinoma. Both lesions were characterized histologically by noncohesive aggregates of large neoplastic cells with abundant eosinophilic cytoplasm and conspicuous nucleoli. Although cells compatible with diagnostic Reed-Sternberg cells were identified in an "appropriate" cellular background in both patients, the diagnosis of carcinoma was supported by intense cytokeratin immunoreactivity. Subtle histologic clues that should suggest the possibility of metastatic carcinoma in a patient whose morphologic data suggests the syncytial variant of nodular sclerosing Hodgkin's disease include sinus infiltration, phagocytosis of neutrophils by tumor cells, marked nuclear anaplasia, and the presence of spindle-shaped tumor cells.

  View details for Web of Science ID A1991GN54700007

  View details for PubMedID 1719796

• VASCULAR TRANSFORMATION OF SINUSES IN LYMPH-NODES - A STUDY OF ITS MORPHOLOGICAL SPECTRUM AND DISTINCTION FROM KAPOSIS-SARCOMA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Chan, J. K., Warnke, R. A., Dorfman, R. 1991; 15 (8): 732-743

  Abstract

  Vascular transformation of lymph node sinuses (VTS) is characterized by conversion of nodal sinuses into capillary-like channels, often accompanied by fibrosis. A detailed study of this entity, based on 76 cases, showed that the morphologic spectrum was much broader than that originally described. The vasoproliferative process caused variable expansion of the subcapsular, intermediate, and medullary sinuses of the lymph nodes and involved single or multiple lymph nodes in a diffuse or segmental fashion. The proliferated vessels formed anastomosing narrow clefts, rounded spaces of different sizes, plexiform channels, or solid spindled to plump cellular foci and often were associated with variable degrees of sclerosis. The vascular spaces were empty, filled with lymph-like fluid, congested with blood, or occasionally thrombosed; extravasation of red cells was common. Several patterns were commonly observed in an individual case. Less common features included perivascular fibrin deposition and the presence of eosinophilic globules. Vascular thrombosis was identified only rarely in extranodal vessels available for histologic assessment. The more cellular forms of this vascular transformation may be mistaken for Kaposi's sarcoma, but can be distinguished from it by the pure sinusoidal distribution, a lack of well-formed spindle cell fascicles, the associated fibrosis, the maturation of the spindle cells into well-formed vascular channels toward the capsular aspect, and the failure of this process to involve the capsule itself, which is frequently affected by Kaposi's sarcoma.

  View details for Web of Science ID A1991FY36600003

  View details for PubMedID 2069211

• SIMILAR OUTCOME OF TREATMENT OF B-CELL AND T-CELL DIFFUSE LARGE-CELL LYMPHOMAS - THE STANFORD EXPERIENCE JOURNAL OF CLINICAL ONCOLOGY Kwak, L. W., Wilson, M., Weiss, L. M., DOGGETT, R., Dorfman, R. F., Warnke, R. A., Horning, S. J. 1991; 9 (8): 1426-1431

  Abstract

  Although previous studies have suggested a relatively poor prognosis for some patients with peripheral T-cell lymphoma, the clinical significance of immunologic phenotype in diffuse large-cell lymphoma (DLCL) remains controversial. One hundred one patients with a uniform morphologic diagnosis of DLCL treated at Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were studied with regard to immunologic phenotype. Immunologic analysis, performed on frozen or paraffin-embedded tissue, identified 77 cases of B-cell origin, 21 cases of T-cell origin, and three cases that lacked B-cell or T-cell markers. Analysis of complete remission (CR) rates (84% v 95%), 5-year actuarial freedom from disease progression (38% v 53%), and 5-year actuarial overall survival (52% v 79%) showed no statistically significant differences in prognosis between B- and T-cell patients, respectively. The 5-year actuarial survival of patients with stage IV T-cell DLCL (56%) also did not differ in a statistically significant way from stage IV B-cell patients (36%). We conclude that treatment selection for DLCL should not be based on immunologic phenotype alone.

  View details for Web of Science ID A1991FY95900016

  View details for PubMedID 1712837

• INFLAMMATORY PSEUDOTUMOR OF LYMPH-NODES - ADDITIONAL OBSERVATIONS AND EVIDENCE FOR AN INFLAMMATORY ETIOLOGY AMERICAN JOURNAL OF SURGICAL PATHOLOGY Davis, R. E., Warnke, R. A., Dorfman, R. F. 1991; 15 (8): 744-756

  Abstract

  Inflammatory pseudotumor of lymph nodes (IPT), a recently described benign cause of lymphadenopathy, was studied in 14 patients using paraffin-section immunohistochemistry. All biopsies showed a proliferation of spindle cells (small blood vessels, histiocytes, and "activated" fibroblasts resembling myofibroblasts) containing a mixture of inflammatory cells without atypia and involving the connective tissue framework (hilum and sinuses) of the lymph node. Ten patients had additional histologic features of IPT originally described (extranodal extension, obliterative vasculitis, and endothelial infiltration), and nine of these had associated fever of unknown origin, which in some was relieved by biopsy alone. Additional features observed focally in some cases but not previously described included lymph node parenchymal infarction, fibrinoid vascular necrosis, karyorrhexis, and involvement of only part of the lymph node. Immunostaining showed the lymphoid infiltrate to be predominantly of T-lineage (except for plasma cells), only a minority of which marked as T-helper cells. Numerous mononuclear cells resembling histiocytes were identified, some of which had a spindled shape but reacted with an antibody (KP1) of myelomonocytic specificity. Large fibroblastic cells expressed alpha-muscle actin but not desmin, similar to myofibroblasts in granulation tissue. The morphologic and immunohistologic features were similar to those in inflammatory pseudotumors of spleens and livers also studied, but the lack of simultaneous lymph node involvement argued against a common etiology. The findings suggest that the mass lesion of IPT is produced in response to localized lymph node inflammation or injury and further exclude hematolymphoid or mesenchymal neoplasia as a cause.

  View details for Web of Science ID A1991FY36600004

  View details for PubMedID 2069212

• MOST CD8+ CELLS IN SKIN-LESIONS OF CD3+CD4+ MYCOSIS-FUNGOIDES ARE CD3+ T-CELLS THAT LACK CD11B, CD16, CD56, CD57, AND HUMAN HANUKAH FACTOR MESSENGER-RNA AMERICAN JOURNAL OF PATHOLOGY Wood, G. S., DUBIEL, C., Mueller, C., Abel, E. A., Hoppe, R. T., Edinger, A., Weissman, I., Warnke, R. A. 1991; 138 (6): 1545-1552

  Abstract

  To define further the characteristics of CD8+ cells in skin lesions of CD3+ CD4+ mycosis fungoides (MF), the authors used single- and double-label immunohistologic techniques and in situ hybridization to detect antigens and transcripts associated with certain types of cytotoxic or suppressor function. The cytotoxic markers included CD16, CD56, CD57, and an anti-sense probe for human Hanukah factor (HuHf) mRNA. Analysis of 23 cases demonstrated that lesional CD8+ cells were CD3+ T cells that generally lacked expression of any of the cytotoxic markers studied. Analysis of another 10 cases confirmed the CD3+ T-cell lineage of lesional CD8+ cells and demonstrated that these cells also lacked expression of the suppressor-associated marker, CD11b. In aggregate, these results indicate that most CD8+ cells in CD3+ CD4+ MF skin lesions are of T-cell rather than NK-cell differentiation. Their overall phenotype suggests that they may be major histocompatibility complex (MHC)-restricted cytotoxic T cells lacking appreciable levels of HuHF serine protease. Because the induction of CD8+ suppressor T cells is mediated by CD4+ T cells expressing the CD45RA+ RO- phenotype, CD45 epitope expression was studied in 15 MF cases. The vast majority (13/15) contained CD3+ CD4+ tumor cells that were CD45+ RA- RB+ RO+ 2B11+. This phenotype is consistent with memory T cells rather than suppressor-inducer T cells, and correlates with the paucity of phenotypically defined suppressor T cells in CD3+ CD4+ MF skin lesions.

  View details for Web of Science ID A1991FR74600026

  View details for PubMedID 1828937

• CD45 EPITOPE MAPPING OF HUMAN CD1A+ DENDRITIC CELLS AND PERIPHERAL-BLOOD DENDRITIC CELLS AMERICAN JOURNAL OF PATHOLOGY Wood, G. S., FREUDENTHAL, P. S., Edinger, A., Steinman, R. M., Warnke, R. A. 1991; 138 (6): 1451-1459

  Abstract

  The authors studied the pattern of leukocyte common antigen (CD45) epitope expression on dendritic cells in sections of human epidermis, tonsillar epithelium, dermatopathic lymph nodes, and in isolates from blood. The monoclonal antibodies (MAb) used were specific for all known CD45 epitopes, including the seven different CD45 common epitopes as well as the four known CD45R epitopes (two CD45RA, one CD45RB, and one CD45RO). Dendritic cells in all sites were uniformly reactive for the CD45 common epitopes tested except 2B11, which may recognize a CD45R rather than CD45 epitope. By single-label immunoperoxidase and double-label immunofluorescence epitope mapping of CD1a+ dendritic cells in tissue sections, it was generally difficult or impossible to detect expression of CD45RA, CD45RB, CD45RO, or 2B11. In blood dendritic cells, however, low levels of these CD45R epitopes were detected consistently using single-label immunoperoxidase staining of cytocentrifuge preparations. Monocytes were similar to blood dendritic cells except that the staining with MAb to CD45RO and 2B11 was slightly stronger. The authors conclude that dendritic cells differ from most subpopulations of lymphocytes in that CD45 common epitopes are readily detectable but the existing RA, RB, and RO epitopes are either undetectable or expressed at relatively low levels. These studies raise the possibility that CD1a+ dendritic cells may express a novel dominant CD45 isoform.

  View details for Web of Science ID A1991FR74600016

  View details for PubMedID 1711291

• MONOCYTOID B-CELL LYMPHOMA - A STUDY OF 36 CASES HUMAN PATHOLOGY Ngan, B. Y., Warnke, R. A., Wilson, M., Takagi, K., Cleary, M. L., Dorfman, R. F. 1991; 22 (5): 409-421

  Abstract

  We have studied 36 cases of monocytoid B-cell lymphoma (MBCL). We confirm the predilection for females (30 of 36; ratio, five women to one man). The median age was 65 years (range, 29 to 85 years). Monocytoid B-cell lymphoma characteristically involves peripheral lymph nodes (30 of 36) with a propensity for paraparotid or intraparotid nodes. Salivary glands were affected in five patients. Other extranodal sites of involvement included breast, thyroid, stomach, and soft tissue of chest wall. Eight patients manifested with Sjögren's syndrome, one had systemic lupus erythematosus, one presented initially with Raynaud's phenomenon, and two had a monoclonal gammopathy. "Composite lymphomas" were encountered in seven patients. In addition, association with or progression to a higher-grade lymphoma, ie, mixed small and large cell (one) and large cell (six), was observed in seven patients and was associated with a more aggressive behavior of the lymphoma. Immunohistochemical studies performed on biopsy sections from 20 patients confirmed the B-cell nature of MBCL. An average reactivity of less than 10% of the monocytoid B cells with the proliferation marker Ki-67 was demonstrated, in keeping with the indolent behavior of MBCL. Despite our observation of follicular lymphomas frequently accompanying MBCL, the t(14;18) chromosomal translocation does not appear to play a pathogenetic role for MBCL, as determined by molecular studies for the t(14;18) chromosomal translocation and immunologic studies for the BCL2 protein. Our observations also provide support for the proposal that there is an overlap between MBCL and "MALT lymphomas" (those arising from mucosa-associated lymphoid tissue).

  View details for Web of Science ID A1991GJ45100002

  View details for PubMedID 2032691

• PRIMARY LARGE-CELL LYMPHOMA OF THE THYMUS - A DIFFUSE B-CELL NEOPLASM PRESENTING AS PRIMARY MEDIASTINAL LYMPHOMA HUMAN PATHOLOGY Davis, R. E., Dorfman, R. F., Warnke, R. A. 1990; 21 (12): 1262-1268

  Abstract

  Primary mediastinal nonlymphoblastic non-Hodgkin's lymphoma (NLNHL) has distinct clinical, histologic (diffuse large-cell morphology, often with sclerosis and clear cytoplasm), and immunohistochemical features (predominantly B-cell lineage, usually immunoglobulin-negative), which suggest origin from a unique B-cell population. The thymus has a resident population of B cells with a unique immunophenotype, and can be involved by primary mediastinal NLNHL, in some cases selectively. Fifteen cases of NLNHL involving the thymus were studied by paraffin-section immunohistochemistry using antibodies to formalin-resistant epitopes of B cells (4KB5 [CD45RA] and L26 [CD20]) and T cells (L60 [CD43] and UCHL1 [CD45RO]). All were diffuse large-cell or immunoblastic lymphomas with sclerosis, and were also similar to primary mediastinal NLNHL in clinical features. Neoplastic cells stained with L26 in all but one case, which stained with 4KB5 and an antibody to a leukocyte-common antigen (PD7/26 [CD45RB]), and were uniformly nonreactive with L60 (with one exception) and UCHL1. Intermingled small lymphocytes were uniformly L26-negative and positive for T-cell markers, even in one case with atypia suggesting a lymphoma of mixed morphology. These findings demonstrate that primary thymic and primary mediastinal NLNHL are similar B-lineage neoplasms, and support previous suggestions that both may originate in thymic B cells.

  View details for Web of Science ID A1990EQ06200013

  View details for PubMedID 2249839

• DISCORDANT EXPRESSION OF ANTIGENS BETWEEN INTRAEPIDERMAL AND INTRADERMAL T-CELLS IN MYCOSIS-FUNGOIDES AMERICAN JOURNAL OF PATHOLOGY Michie, S. A., Abel, E. A., Hoppe, R. T., Warnke, R. A., Wood, G. S. 1990; 137 (6): 1447-1451

  Abstract

  Using immunohistochemical methods, the authors studied the expression of pan-T- and majority-T-cell antigens (CD5, CD2, CD3, TCR-beta, CD7) and T-cell subset antigens (CD4, CD8) in cutaneous T cells in mycosis fungoides (MF) (177 biopsies from 124 patients) and a variety of inflammatory lesions (45 biopsies from 45 patients). The authors detected the absence of pan-T- or majority-T-cell antigens, or of both T-cell subset antigens, from T cells in the epidermis but not the dermis in 15 MF biopsies (8%) from 11 MF patients (9%), but in none of the inflammatory skin lesions. The opposite picture, characterized by lack of antigen expression by the dermal T cells only, was not seen in any of the MF or inflammatory lesions. The absence of antigen expression by epidermal but not dermal T cells, which the authors have termed antigen discordance, was most prevalent for CD5, CD7, and TCR-beta, each being discordant in 6% to 7% of MF cases or patients tested. Among the MF biopsies showing antigen discordance, 14 of 15 biospies (93%) from 10 of 11 patients (91%) were discordant for two or more antigens. Antigen discordance was not an artifact of treatment, because none of the patients showing discordance was receiving treatment at the time of their initial discordant biopsy. The discordance was the only immunophenotypic abnormality detected in 8 of 15 (53%) of the discordant MF biopsies. Thus, this antigen discordance was an important diagnostic feature that allowed the immunophenotypic distinction of MF from a variety of inflammatory skin lesions.

  View details for Web of Science ID A1990EP24300020

  View details for PubMedID 2260631

• MALIGNANT HISTIOCYTOSIS - A REASSESSMENT OF CASES PREVIOUSLY REPORTED IN 1975 BASED ON PARAFFIN SECTION IMMUNOPHENOTYPING STUDIES CANCER Wilson, M. S., Weiss, L. M., Gatter, K. C., Mason, D. Y., Dorfman, R. F., Warnke, R. A. 1990; 66 (3): 530-536

  Abstract

  Malignant histiocytosis (MH) is a term that has been used to describe a syndrome in which there is a systemic proliferation of cells that have the cytologic appearance of atypical histiocytes. Biopsy materials from 15 patients with malignant lymphoma diagnosed as malignant histiocytosis in a previous study reported in 1975 were analyzed by a panel of antibodies and reclassified using current nosologic concepts of malignant lymphoma. The antibodies used comprised reagents detecting a formalin-resistant epitope on B-cells (L26), T-cells (anti-CD3, anti-leu 22 [CD43], and UCHL1 [CD45RO]), monocyte/macrophage-derived cells (KP1 [CD68]), as well as antibodies that detect leukocyte common antigen (PD7 [CD45RB]), and a formalin-resistant epitope of Ki-1 (Ber-H2 [CD30]). The authors found that nine lymphomas had a profile consistent with T-lineage, including six in which Ki-1 (CD30) was coexpressed, and two were B-lineage. Three lymphomas showed no specific lineage characteristics although two were Ki-1 (CD30) positive, and none had expression of KP1 (CD68). The 12 lymph node biopsy specimens showed a variety of patterns of involvement, including sinusoidal, paracortical, and diffuse; the spleens showed predominantly red pulp involvement. A 15th case was believed most consistent with a virus-associated hemophagocytic syndrome. These findings support previous suggestions that the majority of cases diagnosed as MH represent T-lineage-associated hematolymphoid neoplasms, and that only a rare case will be of monocyte/macrophage origin. It is suggested that the term MH be subsumed under the rubric of large cell lymphoma and unless there are compelling immunohistochemical data to support a histiocytic origin, that the term MH be abandoned in favor of a more accurate descriptive term, such as sinusoidal large cell lymphoma.

  View details for Web of Science ID A1990DP79500020

  View details for PubMedID 2194647

• SPINDLE CELL NEOPLASMS OF LYMPH-NODES OF PROBABLE RETICULUM-CELL LINEAGE - TRUE RETICULUM-CELL SARCOMA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Weiss, L. M., Berry, G. J., Dorfman, R. F., Banks, P., Kaiserling, E., CURTIS, J., Rosai, J., Warnke, R. A. 1990; 14 (5): 405-414

  Abstract

  Primary spindle cell neoplasms involving hematolymphoid organs are extremely rare. We present four cases of spindle cell neoplasms of unusual phenotype arising within lymph nodes. Two of the four cases showed morphologic and immunophenotypic features suggestive of interdigitating reticulum cell lineage; these cases expressed several macrophage antigens and S-100 protein but not CD1. The other two cases showed evidence suggestive of dendritic reticulum cell lineage. Both cases expressed HLA-DR, several macrophage antigens, complement receptors C3b and C3d; one case expressed R4/23; both showed the presence of desmosomes on ultrastructural examination. A germline configuration for the immunoglobulin heavy chain and beta-T--cell receptor genes was detected in all four cases. Of the two patients in the first group, one had local recurrence of tumor; the other died of widespread metastases. Of the two patients in the second group, both are alive and well at 12 and 27 months follow-up, respectively.

  View details for Web of Science ID A1990DA42600001

  View details for PubMedID 2158241

• CD30-POSITIVE LARGE CELL LYMPHOMAS (KI-1 LYMPHOMA) ARE ASSOCIATED WITH A CHROMOSOMAL TRANSLOCATION INVOLVING 5Q35 BRITISH JOURNAL OF HAEMATOLOGY Mason, D. Y., Bastard, C., Rimokh, R., Dastugue, N., Huret, J. L., Kristoffersson, U., Magaud, J. P., Nezelof, C., Tilly, H., Vannier, J. P., Hemet, J., Warnke, R. 1990; 74 (2): 161-168

  Abstract

  A chromosomal translocation involving a breakpoint on the long arm of chromosome 5 at position q35 has been reported previously in 17 cases of neoplasia. In 14 of these cases the translocation involves exchange of material between chromosome 2 p23 and chromosome 5. Most cases had been diagnosed histologically as malignant histiocytosis but it was suggested recently, following the study of three cases in one of the author's laboratories, that such tumours are in reality lymphoid tumours. In the present paper we report on 12 further neoplasms with a translocation involving the 5q35 breakpoint and show that all were large cell lymphomas expressing the CD30 (Ki-1) antigen, often classifiable histologically as 'Ki-1 lymphoma'. In five cases there was evidence, based on antigen expression and/or genotypic studies, that the neoplasm was of T lymphoid derivation. These findings provide further evidence that translocations involving 5q35 are associated not with histiocytic malignancy, but with large cell lymphoid neoplasms, including typical cases of 'Ki-1 lymphoma' or 'anaplastic large cell lymphoma'. Since cell lines have been established from five of these cases it may be possible in the future to clone the breakpoint on chromosome 5 and to investigate whether there is a gene in its vicinity with oncogenic potential.

  View details for Web of Science ID A1990CM23800007

  View details for PubMedID 2156548

• MALIGNANT HISTIOCYTOSIS - A REASSESSMENT OF CASES PREVIOUSLY REPORTED IN 1975 BASED UPON PARAFFIN SECTION IMMUNOPHENOTYPING STUDIES Davis, E., Wilson, M., Weiss, L., Gatter, K., Mason, D., Dorfman, R., Warnke, R. NATURE PUBLISHING GROUP. 1990: A24–A24

  View details for Web of Science ID A1990CL03300150

• IMMUNOCYTOCHEMICAL DETECTION OF HUMAN T-CELL AND B-CELL ANTIGENS METHODS IN ENZYMOLOGY Warnke, R. A., Weiss, L. M. 1990; 184: 363-370

  View details for Web of Science ID A1990MC41800041

  View details for PubMedID 2201879

• AN EPITOPE OF THE TRANSFERRIN RECEPTOR IS EXPOSED ON THE CELL-SURFACE OF HIGH-GRADE BUT NOT LOW-GRADE HUMAN LYMPHOMAS BLOOD Esserman, L., Takahashi, S., Rojas, V., Warnke, R., Levy, R. 1989; 74 (8): 2718-2729

  Abstract

  In attempting to identify antigens that are differentially expressed on tumor cells following transformation from follicular small cleaved cell lymphoma (FSC) to immunoblastic lymphoma (IL), we identified a unique epitope of the transferrin receptor (TfR). The epitope is available for binding in aggressive lymphomas but not in indolent lymphomas or normal cells. An immunoglobulin G2a (IgG2a) antibody that binds this epitope, Trump, was produced by screening on tumor cells from a patient who initially had a low-grade lymphoma which subsequently converted to a high-grade lymphoma. Immunoprecipitation and comodulation studies show that Trump binds to the TfR, but blocking studies and immunostaining reveal that the TfR epitope seen by Trump is distinct from the OKT9 and anti-TfR binding sites. The ability of Trump to discriminate a separate population of more highly malignant cells suggests that the expression of the Trump epitope is determined by the state of activation or degree of malignancy of the cell. In addition, it may be possible to use the Trump antibody diagnostically or therapeutically in the management of lymphomas.

  View details for Web of Science ID A1989CB88100017

  View details for PubMedID 2479430

• DIAGNOSIS OF MYELOMONOCYTIC AND MACROPHAGE NEOPLASMS IN ROUTINELY PROCESSED TISSUE BIOPSIES WITH MONOCLONAL-ANTIBODY KP1 AMERICAN JOURNAL OF PATHOLOGY Warnke, R. A., Pulford, K. A., PALLESEN, G., Ralfkiaer, E., Brown, D. C., Gatter, K. C., Mason, D. Y. 1989; 135 (6): 1089-1095

  Abstract

  A new monoclonal antibody, KP1, against the CD68 antigen, which labels macrophages and other members of the mononuclear phagocyte lineage in routinely processed tissue sections, has been used to stain a range of lymphoid, histiocytic, and myelomonocytic proliferations. All 20 neoplasms of myeloid, myelomonocytic, and presumed macrophage derivation reacted with antibody KP1. None of the 22 cases of T cell neoplasia had positive reactions. Although 14 of 41 B lineage lymphomas and leukaemias were stained by antibody KP1, staining was usually confined to small dots of reactivity, in contrast to the strong and extensive cytoplasmic staining seen in the neoplasms of myeloid and macrophage/monocyte origin. Furthermore, positive B cell neoplasms were almost all small cell proliferations, which are unlikely to be confused with myelomonocytic malignancies. It was concluded that antibody KP1 is a valuable addition to a panel of monoclonal antibodies for phenotyping lymphomas, particularly in routinely fixed tissues. It should assist the pathologist in the recognition of extramedullary presentation of leukaemia, aid in the diagnosis of suspected cases of true histiocytic neoplasia, and allow for quantitation of macrophages infiltrating lymphomas and other solid tumors.

  View details for Web of Science ID A1989CE32300013

  View details for PubMedID 2688430

• VARIABILITY OF IMMUNOGLOBULIN EXPRESSION IN FOLLICULAR LYMPHOMA - AN IMMUNOHISTOLOGIC AND MOLECULAR GENETIC-STUDY AMERICAN JOURNAL OF PATHOLOGY Ngan, B., Warnke, R. A., Cleary, M. L. 1989; 135 (6): 1139-1144

  Abstract

  Immunohistochemical and molecular genetic studies were performed on tissues involved by follicular lymphomas that at some point in their course showed a lack of detectable surface or cytoplasmic immunoglobulins (Ig). The variable nature of Ig expression in these lymphomas was evidenced by three tumors biopsied from two different sites that showed an Ig-negative phenotype in one biopsy versus an Ig-positive phenotype in the other. The B lineage derivation of Ig-negative follicular lymphomas was confirmed by the presence of Ig heavy and light chain gene rearrangements in eight of eight lymphomas tested. In a way similar to Ig-expressing follicular lymphomas, the Ig-negative tumors were characterized by bcl-2 gene rearrangements (seven of eight) and overexpression of the Bcl-2 protein (eight out of nine). In two of the three lymphomas with Ig-positive and Ig-negative tumor cell populations, the clonal relationship of the Ig-expressing and nonexpressing cells was established by demonstration of identical t(14; 18) DNA rearrangements. The findings demonstrated that the variability of Ig expression in follicular lymphomas reflects the phenotypic heterogeneity of these tumors and is not a manifestation of separate clonal origins.

  View details for Web of Science ID A1989CE32300018

  View details for PubMedID 2480713

• CUTANEOUS LYMPHOID HYPERPLASIA - IMMUNOLOGICAL CHARACTERISTICS AND ASSESSMENT OF CRITERIA RECENTLY PROPOSED AS DIAGNOSTIC OF MALIGNANT-LYMPHOMA JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Medeiros, L. J., Picker, L. J., Abel, E. A., Hu, C. H., Hoppe, R. T., Warnke, R. A., Wood, G. S. 1989; 21 (5): 929-942

  Abstract

  Fifteen cases of cutaneous lymphoid hyperplasia were studied immunohistologically with a large panel of monoclonal antibodies to determine their immunoarchitectural composition and to determine whether immunologic criteria recently proposed to identify lymphoma ever occur in benign skin lesions. All lesions were composed of T cells, polytypic B cells, macrophages, and Langerhans cells. Although only six cases containing lymphoid follicles were recognized in routinely stained sections, an additional five were identified in immunoperoxidase-stained sections. These follicles were of both the primary and secondary types and contained dendritic reticulum cell networks. The immunophenotypic features of these follicles were similar to those of reactive follicles in lymphoid organs and contrasted sharply with those reported previously for follicular lymphomas. Helper T cells were predominant in 11 cases. With regard to proposed criteria for T cell lymphoma, we did not detect loss of pan T cell antigens CD2, CD3, CD5, or BF-1, nor did we find populations of T cells with abnormal co-expression or loss of subset antigens such as CD4-8- or CD4+8+. Two cases in which relatively sparse infiltrates were present, however, were moderately CD7-deficient. This finding suggests that the CD7 criterion for cutaneous T cell neoplasia be modified in this situation. As observed previously, Leu-8 antigen deficiency was a common, nonspecific finding. With regard to proposed criteria for B cell lymphoma, we did not detect populations of B cells that were immunoglobulin-negative, nor did we observe preferential loss of one or more B-lineage antigens, histocompatibility complex-associated antigens, or lymphocyte function-associated antigens. We also did not identify any CD5+ B cells. On the basis of a comparison of our current data with prior studies of cutaneous lymphomas, we conclude that the immunologic findings recently proposed as general criteria for the differentiation of lymphoma from lymphoid hyperplasia are, in fact, applicable to cutaneous lymphoid lesions.

  View details for Web of Science ID A1989AX59500005

  View details for PubMedID 2808829

• LYMPHOMAS PRESENTING AS HISTOLOGICALLY UNCLASSIFIED NEOPLASMS - CHARACTERISTICS AND RESPONSE TO TREATMENT JOURNAL OF CLINICAL ONCOLOGY Horning, S. J., CARRIER, E. K., Rouse, R. V., Warnke, R. A., Michie, S. A. 1989; 7 (9): 1281-1287

  Abstract

  Malignant lymphoma is frequently diagnosed when immunohistochemical techniques are applied to otherwise unclassified neoplasms. In this analysis of 35 patients with a histologically unclassified neoplasm that expressed leukocyte-common antigen(s) (LCA), actuarial survival was 63%, and 45% of patients were free from disease progression at 30 months following treatment as for lymphoma. The clinical features at diagnosis and the results of combination chemotherapy were found to be similar to a group of patients with a diagnosis of diffuse large-cell lymphoma (DLCL) concurrently treated at this institution. This study further emphasizes the importance of improved diagnostic techniques in the management of histologically unclassified tumors.

  View details for Web of Science ID A1989AM61500015

  View details for PubMedID 2671285

• MOLECULE DETECTED IN FORMALIN FIXED TISSUE BY ANTIBODIES MT1, DF-T1, AND L60 (LEU-22) CORRESPONDS TO CD43 ANTIGEN JOURNAL OF CLINICAL PATHOLOGY STROSS, W. P., Warnke, R. A., Flavell, D. J., Flavell, S. U., Simmons, D., Gatter, K. C., Mason, D. Y. 1989; 42 (9): 953-961

  Abstract

  Three monoclonal antibodies MT1, L60 (Leu-22), and DF-T1, were reported independently as recognising human T cells in routinely processed, paraffin wax embedded tissue. The present study was performed to compare these three reagents in terms of their immunocytochemical reactions and target molecule(s). On Western blotting of white cell extracts the three antibodies reacted with antigens of the same molecular weight (range 110-160 kilodaltons). Furthermore, their immunocytochemical reactivity with normal human cells, as analysed by two-colour flow cytometry, was essentially identical (labelling of monocytes, most T lymphocytes, and weak reactions with some B cells), and the antibodies gave closely similar reactions on 54 white cell derived neoplasms. To identify the target antigen for these three reagents, antibodies from the Third International Workshop on Leucocyte Antigens were reviewed and it was shown that the Western blotting and immunocytochemical reactions of MT1, L60 (Leu-22), and DF-T1 were identical with those of the reagents which defined the CD43 antigen (also known as leucosialin or sialophorin). Furthermore, all these antibodies reacted with cells transfected with a cDNA clone encoding CD43. It is concluded that antibodies MT1, L60 (Leu-22), and DF-T1 all recognise the heavily glycosylated myeloid/lymphoid associated CD43 antigen.

  View details for Web of Science ID A1989AN39900013

  View details for PubMedID 2794085

• ORIGIN OF REED-STERNBERG CELLS IN HODGKINS-DISEASE - REPLY NEW ENGLAND JOURNAL OF MEDICINE Weiss, L. M., MOVAHED, L. A., Warnke, R. A., Sklar, J. 1989; 321 (8): 544-544

  View details for Web of Science ID A1989AL70300016

• NUMBERS OF HOST HELPER T-CELLS AND PROLIFERATING CELLS PREDICT SURVIVAL IN DIFFUSE SMALL-CELL LYMPHOMAS JOURNAL OF CLINICAL ONCOLOGY Medeiros, L. J., Picker, L. J., Gelb, A. B., Strickler, J. G., BRAIN, S. W., Weiss, L. M., Horning, S. J., Warnke, R. A. 1989; 7 (8): 1009-1017

  Abstract

  Diffuse small-cell lymphomas of B-lineage comprise a group of immunophenotypically related lymphoid malignancies that display variable clinical aggressiveness. We compared a variety of clinical, pathologic, and immunologic characteristics of 64 B-lineage diffuse small-cell lymphomas to patient survival in an effort to define prognostically relevant subtypes of these neoplasms. Neither clinical parameters nor histological subclassification correlated with patient outcome. In contrast, three immunologic features of these lymphomas showed a statistically significant relationship with actuarial survival. Neoplasms that manifested greater than or equal to 25% Ki-67+ cells (proliferation-associated antigen), less than 25% Leu 4+ cells (pan-T antigen), or less than 15% Leu 3+ cells (helper/inducer T-subset antigen) were associated with significantly decreased patient survival as compared to neoplasms with the reverse phenotype (P = .02, P = .003, P = .0005, respectively). Leu 3 findings were of particular importance in initial biopsies (P = .0007), while the Ki-67 findings were significant regardless of time of biopsy (P = .01 for biopsies at diagnosis and P = .004 for other biopsies). These data indicate that immunologic analysis can demonstrate subsets of diffuse small-cell lymphoma with different biologic potential, and suggest that such analysis be included in the routine work-up of patients with this type of neoplasm.

  View details for Web of Science ID A1989AG85900006

  View details for PubMedID 2526862

• EXPRESSION OF T-CELL RECEPTOR ANTIGENS IN MYCOSIS-FUNGOIDES AND INFLAMMATORY SKIN-LESIONS JOURNAL OF INVESTIGATIVE DERMATOLOGY Michie, S. A., Abel, E. A., Hoppe, R. T., Warnke, R. A., Wood, G. S. 1989; 93 (1): 116-120

  Abstract

  Using immunohistologic methods, we studied the expression of the T-cell receptor (TCR)-associated antigens CD3, TCR-beta, and TCR-delta by cutaneous T cells in mycosis fungoides (MF) (36 patients) and a variety of inflammatory diseases (16 patients). Most T cells in the inflammatory diseases and patch/plaque mycosis fungoides expressed the immunophenotype characteristic of the vast majority of mature peripheral T cells: CD3+ TCR-beta+ TCR-delta-. In contrast, abnormal CD3/TCR-beta antigen expression was seen in 3 of 6 cases (50%) of tumor stage mycosis fungoides. Furthermore, we were able to document its evolution from the normal pattern present in earlier patch/plaque lesions of the two cases in which serial biopsies were available for study. Divergence of epidermal versus dermal CD3/TCR-beta antigen expression was seen in 2 of 34 (6%) of biopsies of patch/plaque mycosis fungoides but not in inflammatory controls. The TCR-delta+ cells were generally rare regardless of diagnosis. We conclude that inflammatory skin diseases and most patch/plaque mycosis fungoides are typically composed of T lymphocytes that resemble mature peripheral T cells in regard to their expression of TCR-associated antigens. In contrast, aberrant patterns of TCR-associated antigen expression can be seen in tumor stage MF, and, more rarely in patch/plaque MF.

  View details for Web of Science ID A1989AG41600020

  View details for PubMedID 2473133

• CLONAL REARRANGEMENTS OF IMMUNOGLOBULIN GENES AND PROGRESSION TO B-CELL LYMPHOMA IN CUTANEOUS LYMPHOID HYPERPLASIA AMERICAN JOURNAL OF PATHOLOGY Wood, G. S., Ngan, B. Y., Tung, R., HOFFMAN, T. E., Abel, E. A., Hoppe, R. T., Warnke, R. A., Cleary, M. L., Sklar, J. 1989; 135 (1): 13-19

  Abstract

  Cutaneous lymphoid hyperplasia (CLH) is a disorder characterized by the development of one or more skin lesions containing dense lymphoid infiltrates that exhibit the histopathologic features of a benign, reactive process. Nevertheless, some cases have been associated with the subsequent development of clinically overt lymphomas. This suggests that monoclonal populations may exist in some cases of CLH and that these cases may represent a subset more likely to evolve into lymphoma. To determine if such a subset of CLH can be distinguished, Southern blot analysis of DNA was used to study the immunogenotypic features of lesions from 14 patients with clinical, histopathologic, and immunopathologic findings characteristic of CLH. Five cases exhibited detectable clonal rearrangements of immunoglobulin genes. Furthermore, one of these five cases evolved into overt diffuse large cell lymphoma of B cell lineage during a 2-year follow-up of recurrent disease at the original cutaneous site. The immunoglobulin gene rearrangements of this lymphoma were identical to those of the prior CLH lesion. There was no evidence of detectable t(14;18) chromosomal translocations or clonal rearrangements of the beta gene of the T cell receptor in any case. It was concluded that CLH can be divided into two subsets based on the presence or absence of a clonal B cell population, and that overt lymphoma can arise from the former subset and contain the same B cell clone identified in the pre-existent CLH lesion.

  View details for Web of Science ID A1989AP09500003

  View details for PubMedID 2774056

• TREATMENT OF B-CELL LYMPHOMA WITH ANTI-IDIOTYPE ANTIBODIES ALONE AND IN COMBINATION WITH ALPHA-INTERFERON Brown, S. L., MILLER, R. A., Horning, S. J., BASHAM, T., Warnke, R. A., Merigan, T. C., Levy, R. LIPPINCOTT-RAVEN PUBL. 1989: 325–26

  View details for Web of Science ID A1989U688800062

• LACK OF INVOLVEMENT OF THE C-FMS AND N-MYC GENES BY CHROMOSOMAL TRANSLOCATION T(2-5)(P23-Q35) COMMON TO MALIGNANCIES WITH FEATURES OF SO-CALLED MALIGNANT HISTIOCYTOSIS BLOOD Morgan, R., Smith, S. D., Hecht, B. K., CHRISTY, V., MELLENTIN, J. D., Warnke, R., Cleary, M. L. 1989; 73 (8): 2155-2164

  Abstract

  We report the molecular, cytogenetic, and immunologic characterization of three hematologic malignancies that contained characteristic t(2;5) chromosomal translocations. The clinicopathologic features in all three cases fit the disease spectrum of so-called malignant histiocytosis (MH). All cases expressed activation antigens including Ki-1 (CD 30), but no lineage-restricted pattern of cellular antigen expression was observed. Cell lines SUP-M2 and SU-DHL-1 established from two of the cases showed rearranged beta T-cell receptor (beta TCR) genes nonproductive of full-length beta TCR mRNA and therefore not helpful in unequivocal establishment of lineage derivation. The common cytogenetic feature was a reciprocal translocation between chromosomes 2 and 5, involving bands 2p23 and 5q35 near the reported chromosomal locations of the N-myc and c-fms genes, respectively. Normal-sized and truncated c-fms RNAs were observed in both cell lines, whereas no N-myc transcripts were detected. Sequence analysis of the truncated fms RNA showed that it consisted of the 3' half of the c-fms mRNA, but its derivation was not the result of a structural alteration of the c-fms gene. Our studies show that the t(2;5) does not involve the N-myc and c-fms protooncogenes and that this cytogenetic abnormality may be characteristic of a subset of primitive malignancies with an indeterminate lineage but with clinicopathologic features of so-called MH.

  View details for Web of Science ID A1989U940100017

  View details for PubMedID 2525056

• IMMUNOPHENOTYPIC DIAGNOSIS OF NON-HODGKINS LYMPHOMA IN PARAFFIN SECTIONS - CO-EXPRESSION OF L60 (LEU-22) AND L26 ANTIGENS CORRELATES WITH MALIGNANT HISTOLOGIC-FINDINGS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Ngan, B. Y., Picker, L. J., Medeiros, L. J., Warnke, R. A. 1989; 91 (5): 579-583

  Abstract

  The recent availability of monoclonal antibodies immunoreactive to T- or B-lineage antigens in formalin-fixed, paraffin-embedded tissue has permitted the adaptation of frozen-section immunodiagnostic criteria to paraffin-embedded tissue. Among a variety of reactive lymphoid processes, monoclonal antibody L26 showed a pattern of staining consistent with pan-B reactivity. Antibodies L60 (Leu-22) and UCHL-1 showed a pan-T and T-subset pattern of reactivity, respectively. In benign processes, L26 and L60 (or UCHL-1) were not coexpressed. In contrast, among 77 B-lineage non-Hodgkin's lymphomas, 42% showed aberrant co-expression of L26 and L60. The L26+/L60+ phenotype was most common in small lymphocytic lymphomas (80%) but was also noted in one third of diffuse large cell lymphomas. Expression of UCHL-1 was not identified in B-lineage neoplasms but was found, along with L60, on four of five T-lineage lymphomas studied as controls. The authors conclude that the anomalous coexpression of L60 and L26 antigens is a unique feature of B-lineage lymphomas and can be used for the immunodiagnosis of these malignancies in routinely processed tissue.

  View details for Web of Science ID A1989U441300012

  View details for PubMedID 2718958

• HUMAN-LYMPHOCYTES BEARING T-CELL RECEPTOR GAMMA-DELTA ARE PHENOTYPICALLY DIVERSE AND EVENLY DISTRIBUTED THROUGHOUT THE LYMPHOID SYSTEM JOURNAL OF EXPERIMENTAL MEDICINE Groh, V., Porcelli, S., Fabbi, M., Lanier, L. L., Picker, L. J., ANDERSON, T., Warnke, R. A., Bhan, A. K., STROMINGER, J. L., Brenner, M. B. 1989; 169 (4): 1277-1294

  Abstract

  A direct quantitative and phenotypic cytofluorographic analysis of TCR-gamma/delta+ lymphocytes as well as an immunohistologic study of their tissue distribution and microanatomy was made possible by the availability of two mAbs (anti-TCR-delta 1 and anti-C gamma M1) specific for framework determinants on human TCR gamma and delta chains, respectively. TCR-gamma/delta+ lymphocytes, ranging between greater than 0.5 and 16% of CD3+ cells, were found in fetal and postnatal thymus, fetal and adult peripheral lymphoid organs, and adult peripheral blood. While TCR-gamma/delta+ lymphocytes comprised a small subpopulation of T cells (mean, approximately 4%) occasionally greater than 10-16% of CD3+ cells expressed TCR-gamma/delta. Virtually all TCR-gamma/delta+ thymocytes/lymphocytes expressed CD7, CD2, and CD5 but were heterogeneous with respect to their expression of CD1, CD4, CD8, CD28, CD11b, CD16, and Leu-7. Human TCR-gamma/delta+ cells populate both organized lymphoid tissues (thymus, tonsil, lymphnode, and spleen) as well as the gut- and skin-associated lymphoid systems at similar frequencies without obvious tropism for epithelial microenvironments. TCR-gamma/delta+ lymphocytes tend to be located within a given organ wherever TCR-alpha/beta+ lymphocytes are found. This study shows that TCR-gamma/delta+ lymphocytes constitute a small but numerically important, phenotypically diverse T cell population distributed throughout the body. These results support the concept that TCR-gamma/delta+ cells comprise a distinct, functionally heterogeneous, mature T cell sublineage that may substantially broaden the T cell repertoire at all immunologically relevant sites.

  View details for Web of Science ID A1989T962500006

  View details for PubMedID 2564416

• DETECTION OF EPSTEIN-BARR VIRAL GENOMES IN REED-STERNBERG CELLS OF HODGKINS-DISEASE NEW ENGLAND JOURNAL OF MEDICINE Weiss, L. M., MOVAHED, L. A., Warnke, R. A., Sklar, J. 1989; 320 (8): 502-506

  Abstract

  We used slot blot hybridization, Southern blot hybridization, and in situ hybridization to investigate the presence of Epstein-Barr virus (EBV) genomes in biopsy tissues from patients with Hodgkin's disease. Slot blot hybridization performed on DNA of tissue specimens from 16 patients revealed that biopsy tissue from 3 (19 percent) contained EBV DNA. Southern blot hybridization with a DNA probe containing the 500-base-pair tandem repeated sequences located at the termini of the EBV genome confirmed the findings of the slot blot hybridization in the three positive tissue specimens and indicated the monoclonality of the EBV-infected cells in such tissues. In situ hybridization performed on the three positive specimens and on two from a previous study localized EBV nucleic acid to the Reed-Sternberg cells and variants in all specimens, with intense hybridization to Reed-Sternberg cells in two, less intense but consistent hybridization to Reed-Sternberg cells in two, and focal hybridization to Reed-Sternberg cells in one. We conclude that EBV genomes are present within Reed-Sternberg cells and variants in some patients with Hodgkin's disease and that the infected cells are monoclonal.

  View details for Web of Science ID A1989T334000006

  View details for PubMedID 2536894

• EXPRESSION OF LFA-1 IN NON-HODGKINS LYMPHOMA CANCER Medeiros, L. J., Weiss, L. M., Picker, L. J., CLAYBERGER, C., Horning, S. J., KRENSKY, A. M., Warnke, R. A. 1989; 63 (2): 255-259

  Abstract

  Lymphocyte function-associated antigen 1 (LFA-1) is a glycoprotein involved in virtually all aspects of the immune response requiring direct cell to cell contact. It has been suggested that lack of LFA-1 expression in lymphomas may represent a mechanism of escape from immunologic surveillance. We investigated the expression of LFA-1 in a series of more than 250 lymphoid neoplasms and reactive lymphoid proliferations using a frozen section immunoperoxidase technique. LFA-1 was expressed by all lymphoid populations in the reactive cases. In contrast, absence of LFA-1 alpha or beta chains was found in 44% of non-Hodgkin's lymphomas, including 50% of B-cell lymphomas. These findings suggest that loss of LFA-1 expression may be of great use in the differential diagnosis of benign versus malignant lymphoproliferations. Eighty percent of initial biopsy specimens of low-grade lymphoma exhibited LFA-1 expression, whereas only 8% of recurrent specimens retained expression of both LFA-1 subunits. However, we found no correlation between LFA-1 expression and clinical course in a series of 64 patients with diffuse large cell lymphomas.

  View details for Web of Science ID A1989R775500008

  View details for PubMedID 2642732

• COMPARISON OF HOST-CELL INFILTRATES IN PATIENTS WITH FOLLICULAR LYMPHOMA WITH AND WITHOUT SPONTANEOUS REGRESSION AMERICAN JOURNAL OF CLINICAL PATHOLOGY Strickler, J. G., COPENHAVER, C. M., ROJAS, V. A., Horning, S. J., Warnke, R. A. 1988; 90 (3): 257-261

  Abstract

  The "host cell infiltrates" in five patients with low-grade follicular lymphoma who had spontaneous regression without therapy were studied with the use of immunohistochemical methods applied to frozen sections. These infiltrates were compared with the "host cell infiltrates" in six patients with follicular lymphoma with progressive disease. The group with progressive disease was selected to be similar to the group with spontaneous regression in age, sex, histologic characteristics, and stage of disease. The patients with spontaneous regression had significantly more T-helper cells in the host cell infiltrate than the control patients. There were no statistically significant differences between the two groups in numbers of cytotoxic/suppressor T-cells, macrophages, Tac-positive cells, Leu-7-positive cells, or proliferating cells.

  View details for Web of Science ID A1988P904100005

  View details for PubMedID 2970792

• LEUKOCYTE COMMON ANTIGEN EXPRESSION IN LYMPHOMAS ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Weiss, L. M., Warnke, R. A. 1988; 112 (9): 867-867

  View details for Web of Science ID A1988P862100003

  View details for PubMedID 2970830

• EXPRESSION OF T-CELL RECEPTOR-DELTA CHAINS IN BENIGN AND MALIGNANT T-LINEAGE LYMPHOPROLIFERATIONS AMERICAN JOURNAL OF PATHOLOGY Picker, L. J., Brenner, M. B., Michie, S., Warnke, R. A. 1988; 132 (3): 401-405

  Abstract

  Recent studies in both human and murine systems have demonstrated the existence of a second CD3-associated T cell receptor (the gamma delta-TCR) distinct from the alpha beta heterodimer associated with antigen recognition by classical T cells. Using a monoclonal antibody specific for the delta component of the human gamma delta-TCR, the expression of this antigen in both benign, reactive lymphoid tissues and T lineage lymphomas was studied with immunohistologic techniques. In the normal thymus, TCR-delta+ cells constituted less than 5% of the CD3+ thymocytes and were located primarily in the medulla or juxtamedullary cortex. Within the T zones of 16 histologically varied reactive peripheral lymphoid tissues, including four patients with marked predominantly paracortical hyperplasia, the authors identified from less than 1% to a maximum of 5% TCR-delta+ cells. While these results are consistent with the hypothesis that TCR-gamma delta+ cells comprise a small distinct subpopulation of peripheral T cells in humans, selective localization or recruitment of these cells could not be demonstrated in any of a number of tissues or reactive situations. Among 62 T lineage lymphomas, including 14 CD3+/TCR-beta- cases, only two TCR-delta+ neoplasms were identified, both lymphoblastic lymphomas displaying the CD3+/CD4-/CD8- phenotype known to be associated with normal TCR-gamma delta+ T cells. Because the majority of CD3+/TCR-beta- lymphomas did not display TCR-delta, these results argue against the hypothesis that the high incidence of CD3/TCR-beta discordance noted in T lineage lymphomas represents preferential transformation of the TCR-delta-expressing subset.

  View details for Web of Science ID A1988Q131200001

  View details for PubMedID 3261945

• CLONAL ANTIGEN RECEPTOR GENE REARRANGEMENTS AND EPSTEIN-BARR VIRAL-DNA IN TISSUES OF HODGKINS-DISEASE HEMATOLOGICAL ONCOLOGY Weiss, L. M., Warnke, R. A., Sklar, J. 1988; 6 (3): 233-238

  Abstract

  In an initial survey of 16 cases of Hodgkin's disease, tissues from one case of nodular sclerosing Hodgkin's disease, a recurrence with numerous Reed-Sternberg cells, demonstrated faint heavy- and light-chain immunoglobulin gene rearrangements. Analysis of seven additional similar cases with extremely numerous Reed-Sternberg cells revealed that six of these seven cases contained clonally rearranged heavy- or light-chain genes. In addition, the original biopsy specimen from the index case (obtained two years prior to the recurrence) had the same pattern of rearrangements of the immunoglobulin genes. In contrast, a germline configuration was observed for the beta T cell receptor gene in all cases. These cases of Hodgkin's disease were also investigated for the presence of Epstein-Barr viral (EBV) genomes by Southern and slot-blot DNA hybridization analysis. Tissues from four of the 21 case studied showed evidence of EBV DNA sequences. Uninvolved lymphoid tissue from two of the positive cases failed to demonstrate viral DNA. To assess clonality of the cells containing the EBV genomes, the tissues positive for EBV DNA were also hybridized with a restriction fragment probe for the terminal sequences of the EBV genome. By this analysis three of the four cases demonstrated a clonal population of EBV-infected cells.

  View details for Web of Science ID A1988P552700005

  View details for PubMedID 2841218

• EXPRESSION OF LYMPHOCYTE HOMING RECEPTOR ANTIGEN IN NON-HODGKINS LYMPHOMA AMERICAN JOURNAL OF PATHOLOGY Picker, L. J., Medeiros, L. J., Weiss, L. M., Warnke, R. A., BUTCHER, E. C. 1988; 130 (3): 496-504

  Abstract

  In man, lymphocyte binding to high endothelial venules (HEVs) involves specific 85-95 kd cell surface glycoprotein(s) recognized by the monoclonal antibodies Hermes-1 and Hermes-3. These putative "homing receptor" molecule(s) are believed to play an important role in the normal regulation of lymphocyte circulation. To investigate the possibility that homing receptors also play a role in the biology of lymphoid malignancies, the authors studied over 300 cases of non-Hodgkin's lymphoma by immunohistologic staining with Hermes-1 and -3, antibodies that define two distinct epitopes on the gp 85-95 putative homing receptor molecules. Furthermore, they directly compared expression of the Hermes-3 antigen with clinical extent of disease in 57 patients with diffuse large cell lymphoma. They found that staining of the various subtypes of lymphoma was heterogeneous, and in general correlated with patterns of expression seen in benign lymphoid populations. Essentially all normal lymphoid populations examined, except germinal center B cells and most cortical thymocytes, bear a high level of homing receptor antigen. Similarly, nearly all peripheral T-cell lymphomas, diffuse small cell lymphomas of B lineage, and plasma cell tumors were positive for homing receptor antigen (95%, 97%, and 100%, respectively). Small noncleaved cell, follicular, and diffuse large cell lymphomas of B lineage, tumors having morphologic or immunologic features resembling germinal center cells, frequently failed to express Hermes-defined epitopes (81%, 41%, 25% Hermes-3-, respectively). Antigen expression in T-lymphoblastic lymphomas strongly correlated with immunophenotypic subtypes: only 8% of CD4+/CD8+ were Hermes-1+ versus 86% of CD4-/CD8- and 43% of CD4+/CD8-. Hermes-3 expression by cases of diffuse, large cell lymphoma which showed generalized lymph node involvement (a pattern strongly suggestive of HEV-mediated spread; 100% Hermes-3+, mean intensity 3.4) was higher than that of cases with localized or multifocal, contiguous involvement (consistent with lymphatic spread; 69% Hermes-3+, mean intensity 2.2), but these differences did not achieve statistical significance. The results indicate that homing receptor antigen expression, although perhaps necessary for wide-spread blood-borne lymphoma dissemination to lymphoid sites, is not in and of itself sufficient to predict such behavior in this subtype of lymphoid malignancy.

  View details for Web of Science ID A1988M609900010

  View details for PubMedID 2450463

• LARGE CELL HEMATOLYMPHOID NEOPLASMS OF UNCERTAIN LINEAGE Weiss, L. M., Picker, L. J., Warnke, R. A., Sklar, J. WILLIAMS & WILKINS. 1988: A101–A101

  View details for Web of Science ID A1988P728900612

• T-CELL ANTIGEN DEFICIENCIES AND CLONAL T-CELL RECEPTOR (TCR) GENE REARRANGEMENTS IN PAGETOID RETICULOSIS Hu, C. H., Weiss, L. M., Abel, E. A., Hoppe, R. T., Warnke, R. A., Sklar, J., Wood, G. S. SLACK INC. 1988: A250–A250

  View details for Web of Science ID A1988L516801459

• WELL-DIFFERENTIATED LYMPHOCYTIC NEOPLASMS - IMMUNOLOGICAL FINDINGS CORRELATED WITH CLINICAL PRESENTATION AND MORPHOLOGIC FEATURES AMERICAN JOURNAL OF PATHOLOGY Medeiros, L. J., Strickler, J. G., Picker, L. J., Gelb, A. B., Weiss, L. M., Warnke, R. A. 1987; 129 (3): 523-535

  Abstract

  The authors studied 48 cases of well-differentiated lymphocytic neoplasms using a panel of monoclonal antibodies applied to frozen sections. Forty-seven tumors expressed monotypic immunoglobulin, one or more B-lineage antigens, and Ia (HLA-DR) antigen. Proliferation centers expressed the T9 antigen and increased numbers of Ki-67-positive cells. One tumor was of T-cell origin, had a cytotoxic/suppressor cell phenotype, and showed anomalous loss of Leu-1 antigen. Immunophenotypic findings were correlated to the clinical presentation and morphologic features of each neoplasm. Sixteen tumors were associated with peripheral lymphocytosis (greater than 4000/cu mm), 13 biopsies were obtained from extranodal sites, 16 tumors had proliferation centers, and 11 neoplasms had plasmacytoid features. The authors found no absolute and few statistically significant immunologic differences between the B-cell tumors according to their clinical presentation or morphologic features. Tumors associated with peripheral lymphocytosis more commonly expressed the Leu-1 antigen (P less than 0.01) and IgD (P less than 0.01) and less frequently were stained by BA-2 (P less than 0.05) and OKT9 (P less than 0.05). Plasmacytoid neoplasms more frequently expressed the Tac (P less than 0.01) and T9 antigens (P less than 0.05), and all expressed kappa light chain (P less than 0.05). Extranodal neoplasms more commonly expressed IgM (P less than 0.01). In contrast to the markedly different clinical presentation and morphologic appearance these tumors may have, the immunologic data suggest that B-cell small lymphocytic neoplasms are relatively homogeneous. For an individual case, immunophenotype does not predict clinical presentation or morphologic features.

  View details for Web of Science ID A1987L369400015

  View details for PubMedID 3322023

• DISCORDANT EXPRESSION OF CD3 AND T-CELL RECEPTOR BETA-CHAIN ANTIGENS IN T-LINEAGE LYMPHOMAS AMERICAN JOURNAL OF PATHOLOGY Picker, L. J., Brenner, M. B., Weiss, L. M., Smith, S. D., Warnke, R. A. 1987; 129 (3): 434-440

  Abstract

  Using an immunoperoxidase technique that identifies both surface and cytoplasmic antigen expression, the authors examined 28 benign reactive lymphorproliferative lesions and 55 T-lineage lymphomas for reactivity with CD3 (Leu-4; T-cell receptor-associated antigen) and beta F1 antibodies, the latter recognizing nonpolymorphic determinants on T-cell receptor beta chains. Consistent with previous observations that these two antigens are co-expressed on the vast majority of thymocytes, peripheral blood T cells and tonsillar T cells, all 28 reactive lymphoproliferations showed essentially identical patterns of CD3 and beta F1 expression. In contrast, only 29 of 55 T-lineage lymphomas displayed coexpression of these antigens. Among 33 peripheral T-cell lymphomas, 11 cases showed CD3/beta F1 discordance (7 CD3+/beta F1-; 4 CD3-/beta F1+), and 5 showed absence of both these antigens. Nine of 22 T-lymphoblastic lymphomas showed CD3/beta F1 discordance (all CD3+/beta F1-), and 1 case was CD3-/beta F1-. These patterns of CD3/beta F1 expression, along with the patterns of CD2, CD4, CD5, CD7, and CD8 antigen expression in these neoplasms, indicate that T-cell lymphomas can manifest phenotypes not apparently reflective of normal T populations and suggest the presence of abnormal gene expression in these malignancies. The existence of aberrant phenotypes in T-cell neoplasia suggests caution in interpretation of investigations using T-lineage malignancies as models of normal T-cell biology. Finally, the identification of phenotypic abnormalities in T-lineage populations can be of great diagnostic usefulness in the delineation of benign versus malignant T-cell proliferations.

  View details for Web of Science ID A1987L369400006

  View details for PubMedID 3501243

• PROLIFERATIVE RATES OF NON-HODGKINS-LYMPHOMAS AS ASSESSED BY KI-67 ANTIBODY HUMAN PATHOLOGY Weiss, L. M., Strickler, J. G., Medeiros, L. J., Gerdes, J., Stein, H., Warnke, R. A. 1987; 18 (11): 1155-1159

  Abstract

  The Ki-67 antibody, a monoclonal antibody that reacts with nuclei in actively proliferating cells, was used in an immunohistochemical study to assess the growth fractions of non-Hodgkin's lymphomas and related disorders. The lowest proliferative indices were found in small lymphocytic lymphoma/chronic lymphocytic leukemia and intermediate lymphocytic/mantle zone lymphoma. An intermediate proliferative index was seen in the follicular lymphomas and diffuse small cleaved cell and diffuse mixed cell lymphomas. A high index was seen in the diffuse large cell lymphoma and lymphoblastic lymphoma. The highest and most consistent proliferative index was seen in small noncleaved cell lymphoma. Cases of reactive follicular hyperplasia had a significantly higher proliferative index than those of follicular lymphoma. We conclude that the Ki-67 antibody has great utility in providing an estimate of the proliferative rate of non-Hodgkin's lymphomas. Prospective studies may show this information to have prognostic value independent of histologic classification.

  View details for Web of Science ID A1987K774200013

  View details for PubMedID 3679189

• EPSTEIN-BARR VIRAL-DNA IN TISSUES OF HODGKINS-DISEASE AMERICAN JOURNAL OF PATHOLOGY Weiss, L. M., Strickler, J. G., Warnke, R. A., Purtilo, D. T., Sklar, J. 1987; 129 (1): 86-91

  Abstract

  Tissue specimens from 21 cases of Hodgkin's disease were examined for the presence of Epstein-Barr virus (EBV) and cytomegalovirus DNA by molecular hybridization techniques. EBV DNA was detected in 4 cases, including 2 of 8 cases which had been previously shown to contain clonal immunoglobulin gene rearrangements. Two of the cases containing EBV DNA were of the nodular sclerosing type and had received prior therapy; the other 2 were classified as mixed cellularity Hodgkin's disease and had not received therapy before the biopsy tissue was obtained. Analyses of the terminal portions of EBV genomes indicated a monoclonal or oligoclonal proliferation of EBV-infected cells in the tissues studied. In contrast, none of the 21 cases had detectable cytomegalovirus DNA sequences. The identification of EBV DNA may reflect the proliferation of lymphoblastoid cells due to the reduced immune competence frequently noted in Hodgkin's disease or may indicate the presence of EBV genomes within Reed-Sternberg cells.

  View details for Web of Science ID A1987K355500010

  View details for PubMedID 2821817

• EXPRESSION OF THE LEU-8 ANTIGEN BY B-CELL LYMPHOMAS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Michie, S. A., Garcia, C. F., Strickler, J. G., Dailey, M. O., Rouse, R. V., Warnke, R. A. 1987; 88 (4): 486-490

  Abstract

  The Leu-8 antigen is found on the surface of many hematologic cells, including many T- and B-lymphocytes. With the use of a frozen-section immunoperoxidase technic, 152 B-cell non-Hodgkin's lymphomas were examined for Leu-8 expression. Of these lymphomas, 53% expressed Leu-8. Subclassification of the lymphomas with the use of the International Working Formulation showed that most small lymphocytic, intermediate lymphocytic, and diffuse large cell lymphomas and about half of diffuse small cleaved, diffuse mixed, and follicular lymphomas expressed Leu-8. In contrast, all 17 cases of small noncleaved cell (Burkitt's) lymphoma and 9 of 10 cases of multiple myeloma/plasmacytoma were Leu-8 negative. These results indicate that Leu-8 is expressed on a wide variety of B-cell lymphomas and that differences in Leu-8 expression may be useful in the diagnostic separation of small lymphocytic lymphoma with plasmacytoid features from multiple myeloma/plasmacytoma, and diffuse large cell lymphoma from Burkitt's lymphoma.

  View details for Web of Science ID A1987K388100016

  View details for PubMedID 3310610

• ABSENCE OF CELL-SURFACE LFA-1 AS A MECHANISM OF ESCAPE FROM IMMUNOSURVEILLANCE LANCET CLAYBERGER, C., Medeiros, L. J., Link, M. P., Warnke, R. A., Wright, A., KOLLER, T. D., Smith, S. D., KRENSKY, A. M. 1987; 2 (8558): 533-536

  Abstract

  During studies of T-cell recognition of autologous tumour cells, a number of tumour cell lines derived from patients with lymphoma proved to be poor stimulators of both autologous and allogeneic T-cell responses. Analysis of the tumour cell surface molecules indicated that expression of the lymphocyte-function-associated antigen, LFA-1, was lacking, whereas normal leucocytes from these patients expressed normal levels of LFA-1. Examination of other lymphoid tumours revealed that most high grade lymphomas, but not most low or intermediate grade lymphomas, do not express the LFA-1 molecule. Furthermore, in an initial survey, the tumours from 5 of 7 patients with non-relapsing large cell lymphomas expressed LFA-1 whereas only 3 of 18 patients with relapsing lymphomas had tumours that did so. These findings suggest that tumour cells lacking surface LFA-1 cannot initiate an effective immune response in vivo. This lack of immunogenicity might contribute to escape from immunosurveillance.

  View details for Web of Science ID A1987J846800004

  View details for PubMedID 2887833

• JH REARRANGEMENTS IN HODGKINS-DISEASE - REPLY HUMAN PATHOLOGY Weiss, L. M., Warnke, R., Sklar, J. 1987; 18 (8): 871-871

  View details for Web of Science ID A1987J614500024

• MONOCLONAL-ANTIBODIES REACTIVE IN ROUTINELY PROCESSED TISSUE-SECTIONS OF MALIGNANT-LYMPHOMA, WITH EMPHASIS ON T-CELL LYMPHOMAS HUMAN PATHOLOGY Strickler, J. G., Weiss, L. M., COPENHAVER, C. M., Bindl, J., McDaid, R., Buck, D., Warnke, R. 1987; 18 (8): 808-814

  Abstract

  The immunoreactivity of eight monoclonal antibodies was evaluated on 45 routinely processed lymphomas (22 T-cell lymphomas, 11 B-cell lymphomas, and 12 cases of Hodgkin's disease). Two antibodies reactive with leukocyte common (T200) antigens (PD7/26 and 2B11) stained most of the B- and T-cell lymphomas but did not stain the Reed-Sternberg cells and variants in Hodgkin's disease. Two antibodies known to stain B cells (LN-1 and LN-2) reacted with some of the B-cell lymphomas, but LN-2 also reacted with the neoplastic cells in six of 22 T-cell lymphomas and with the Reed-Sternberg variants in eight of 12 cases of Hodgkin's disease. The granulocyte antibody anti-Leu M1 reacted with most cases of Hodgkin's disease but also reacted with two of 11 B-cell non-Hodgkin's lymphomas. An antibody to epithelial membrane antigen (anti-EMA) stained some cases of T-cell lymphoma, B-cell lymphoma, and Hodgkin's disease. Leu 7 was expressed in one T-cell lymphoma and in one case of Hodgkin's disease. A novel antibody reactive with T cells (L60) stained all cases of T-cell lymphoma but also stained some cases of B-cell lymphoma and one case of Hodgkin's disease. We conclude that none of these antibodies, when used alone on routinely fixed paraffin-embedded material, is completely sensitive and specific for T-cell lymphoma, B-cell lymphoma, or Hodgkin's disease. However, a panel of antibodies is useful in distinguishing Hodgkin's disease from non-Hodgkin's lymphoma and in suggesting the B- or T-cell phenotype of non-Hodgkin's lymphomas.

  View details for Web of Science ID A1987J614500009

  View details for PubMedID 3301626

• IMMUNOPHENOTYPIC CRITERIA FOR THE DIAGNOSIS OF NON-HODGKINS-LYMPHOMA AMERICAN JOURNAL OF PATHOLOGY Picker, L. J., Weiss, L. M., Medeiros, L. J., Wood, G. S., Warnke, R. A. 1987; 128 (1): 181-201

  Abstract

  This study examines the immunohistologic profiles of a large series of histologically proven benign and malignant lymphoproliferative processes in order to define immunophenotypic criteria useful in the diagnosis of non-Hodgkin's lymphoma. Using a method of analysis relying solely on immunoarchitectural features of a given case, the authors were able to define immunologic criteria capable of differentiating benign from malignant lymphoid processes independent from conventional morphologic analysis. In general, these criteria involved identification of abnormal expression or loss of antigens in B- and T-lineage populations. Among B-lineage populations the following features were associated with malignant histology: 1) light-chain-restricted B lineage, 2) light chain -B lineage, 3) Leu-1+ B lineage, 4) L60+ B lineage, 5) 41H+, Ki-67+ B lineage, 6) loss of pan-B antigens, and 7) LFA-1-B lineage. Among T-cell populations outside the thymus, phenotypes associated with malignancy included 1) loss of pan-T antigens (including loss of the beta chain of the T-cell antigen receptor), 2) coexpression or loss of T-subset antigens, 3) Leu-6+ T-lineage, and 4) MB-1+ T lineage. Application of these criteria to a series of nearly 500 cases of lymphoma indicated that over 90% of B-lineage and about 80% of T-lineage neoplasms manifested immunophenotypic abnormalities that could distinguish them from benign, reactive lymphoid processes. It is concluded that immunophenotypic analysis of lymphoproliferative lesions is sufficiently sensitive and specific to confirm the histologic diagnosis of lymphoma in the vast majority of cases seen in clinical practice. Furthermore, in difficult cases or those with limited material or poor histology, immunophenotypic analysis may be the only means of making a definitive diagnosis.

  View details for Web of Science ID A1987J061000019

  View details for PubMedID 3111266

• NON-HODGKINS-LYMPHOMA CONTAINING BOTH B-CELL AND T-CELL CLONES BLOOD Hu, E., Weiss, L. M., Warnke, R., Sklar, J. 1987; 70 (1): 287-292

  Abstract

  We describe a patient in whom two lymph node biopsies removed 18 months apart disclosed histologic and immunophenotypic evidence of a non-Hodgkin's lymphoma containing neoplastic lymphocytes of both B and T type. Analyses of immunoglobulin and T cell receptor genes confirmed the presence of separate B and T cell clones. In addition, immunogenotyping revealed the possibility of a second B cell clone within the patient's tumor. Development of a multiclonal lymphoma in this patient may relate to the carcinogenic effects of chemotherapy or to a predisposition for neoplastic transformation of lymphocytes due to a previously diagnosed autoimmune condition. Another possible explanation is that the lymphoma implies the existence in this patient of a transformed lymphocyte-committed stem cell that is capable of generating both B and T lineage clones.

  View details for Web of Science ID A1987J078000043

  View details for PubMedID 2885049

• ENDOTHELIAL-CELL PHENOTYPIC DIVERSITY - INSITU DEMONSTRATION OF IMMUNOLOGICAL AND ENZYMATIC HETEROGENEITY THAT CORRELATES WITH SPECIFIC MORPHOLOGICAL SUBTYPES AMERICAN JOURNAL OF CLINICAL PATHOLOGY Turner, R. R., Beckstead, J. H., Warnke, R. A., Wood, G. S. 1987; 87 (5): 569-575

  Abstract

  Some endothelial cells share functional and phenotypic properties with cells of monocyte/macrophage lineage. The authors have performed frozen-section immunologic stains and plastic section enzyme histochemical stains on various human tissues to examine endothelial cell phenotypic properties in situ. They found that endothelial cells express heterogeneous phenotypes that correlate with vessel type. Several endothelial cell subsets were identified. These included arterioles, capillaries, and venules (HLA-ABC+, HLA-DR+, Factor VIII RA+, monocyte-, alkaline phosphatase+, ATPase+); high endothelial venules of lymphoid tissues and hepatic sinusoidal lining cells (HLA-ABC+, HLA-DR+, Factor VIII RA+, monocyte+); lymphatics and glomerular capillaries (HLA-ABC+, HLA-DR+/-, Factor VIII RA-, monocyte-, 5'nucleotidase+); splenic sinusoidal lining cells (HLA-ABC+, Leu-2+, HLA-DR+, Factor VIII RAweak+, monocyte-, alpha naphthyl acetate esterase+); umbilical cord vessels (Factor VIII RA+, HLA-ABCweak+, HLA-DR-, monocyte-). The expression of monocyte-related antigens by some endothelial cells appears to be acquired in extranodal inflammatory infiltrates and is probably modulated by lymphokines.

  View details for Web of Science ID A1987H085800002

  View details for PubMedID 3554972

• CLINICAL AND PATHOLOGICAL FEATURES OF FOLLICULAR LARGE CELL (NODULAR HISTIOCYTIC) LYMPHOMA CANCER Horning, S. J., Weiss, L. M., NEVITT, J. B., Warnke, R. A. 1987; 59 (8): 1470-1474

  Abstract

  Clinicopathologic correlations were made in 50 patients with follicular large cell (FLC) lymphoma to better define the influence of a variety of clinical and pathologic features on survival and the potential for continuous freedom from disease. The 5- and 10-year actuarial survivals for the entire group of patients are 77% and 63%, respectively, but disease-free survival is only 46% at 5 years and 22% at 10 years. No significant survival differences were found with various treatment approaches, although a single relapse occurred after 3 years among patients treated with modern combination chemotherapy containing doxorubicin. Median survivals of approximately 10 years despite recurrent disease are characteristic of the majority of follicular lymphomas. Furthermore, the reproducibility of cytologic diagnosis among follicular lymphomas is known to be variable. At this time, it is unclear whether intensive chemotherapy will cure a significant number of FLC patients or novel approaches are necessary as for the other follicular lymphomas.

  View details for Web of Science ID A1987G643900012

  View details for PubMedID 3545440

• QUANTITATION AND ESTIMATION OF LYMPHOCYTE SUBSETS IN TISSUE-SECTIONS - COMPARISON WITH FLOW-CYTOMETRY AMERICAN JOURNAL OF CLINICAL PATHOLOGY Garcia, C. F., Weiss, L. M., Lowder, J., KOMOROSKE, C., Link, M. P., Levy, R., Warnke, R. A. 1987; 87 (4): 470-477

  Abstract

  A quantitation method for lymphocyte subsets in immunoperoxidase-stained frozen tissue sections was compared with flow cytometry in 23 cases of non-Hodgkin's lymphoma. Close correlations were obtained, demonstrating the accuracy of the technic. Weak intensity of fluorescence and fragility of the tumor cells during the fluorescence-activated cell sorter (FACS) analyses were the most likely explanations for a number of the discrepancies observed. The tissue quantitation method was precise, particularly at low values, where it was better than the FACS. A simpler and faster estimation method employing categories within 10 percentage units was also tested in this study; this method correlated as well with the FACS as the quantitation method and gave the best interobserver correlations.

  View details for Web of Science ID A1987G546900006

  View details for PubMedID 3103419

• IMMUNOHISTOLOGY OF PITYRIASIS LICHENOIDES AND VARIOLIFORMIS ACUTA AND PITYRIASIS LICHENOIDES CHRONICA - EVIDENCE FOR THEIR INTERRELATIONSHIP WITH LYMPHOMATOID PAPULOSIS JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Wood, G. S., Strickler, J. G., Abel, E. A., DENEAU, D. G., Warnke, R. A. 1987; 16 (3): 559-570

  Abstract

  Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica are idiopathic, papular eruptions that exhibit certain clinicopathologic similarities to each other and to lymphomatoid papulosis. In order to determine if these disorders are also similar immunologically, we studied the immunopathology of five biopsy specimens from three cases of pityriasis lichenoides et varioliformis acuta and three biopsy specimens from three cases of pityriasis lichenoides chronica. We then compared them to our prior immunohistologic study of nine cases of lymphomatoid papulosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica both exhibited a dermal and epidermal infiltrate of CD4+ and CD8+ T cells expressing activation antigens. These were admixed with numerous macrophages. The lesional epidermis was diffusely human lymphocyte antigen (HLA)-DR+ and contained decreased CD1+ dendritic cells. Endothelial cells were also HLA-DR+. Cells bearing the phenotypes of B cells, follicular dendritic cells, or natural killer/killer cells were essentially absent. Except for the lack of large atypical cells, the results resembled those described previously for lymphomatoid papulosis. These findings indicate that pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, and lymphomatoid papulosis share several immunohistologic features. Together with certain clinicopathologic similarities, they are consistent with the hypothesis that these three disorders are interrelated.

  View details for Web of Science ID A1987G268200009

  View details for PubMedID 2434538

• CHARACTERIZATION AND EXPRESSION OF THE HUMAN ALPHA-BETA-T-CELL RECEPTOR BY USING A FRAMEWORK MONOCLONAL-ANTIBODY JOURNAL OF IMMUNOLOGY Brenner, M. B., McLean, J., Scheft, H., Warnke, R. A., Jones, N., STROMINGER, J. L. 1987; 138 (5): 1502-1509

  Abstract

  A monoclonal antibody (mAb) with framework reactivity against the T cell receptor (TCR) alpha beta complex is characterized. The mAb, beta Framework 1 (beta F1) is capable of immunoprecipitating the TCR alpha beta complex from 125I-labeled human T cell tumors, immunocompetent T cell clones, and peripheral blood lymphocytes (PBL). beta F1 recognizes the separated TCR beta subunit in Western blotting. Because it does not bind to the surface of viable T cells but does react with the plasma membrane form of the TCR after treatment with membrane solubilizing agents, the beta F1 mAb reacts with a "hidden" determinant on the TCR beta subunit. After solubilization with 70% ethanol, the TCR alpha beta complex is shown to exist on greater than 92% of T3+ human PBL, whereas 2 to 8% of T3+ PBL do not react with the mAb. The beta F1 mAb demonstrates the existence of differently glycosylated surface 125I-labeled TCR alpha-chains (alpha, alpha', alpha") in association with a common TCR beta-chain on the HPB-MLT T cell leukemia. Reactivity of the beta F1 mAb on thymus tissue sections is similar to that of anti-Leu-4 (anti-T3). The beta F1 mAb should prove useful as a research tool for both the immunochemical characterization and isolation of virtually any alpha beta T cell receptor, whether from individual T cell clones or polyclonal populations of T lymphocytes. Recognition of T cell receptors in histologic tissue sections suggests that the beta F1 mAb may be useful in the clinical diagnosis of T cell lineage neoplasms. In failing to recognize all T3+ lymphocytes, it allows the identification of novel populations of T3+ lymphocytes that may express non-alpha, non-beta T cell receptors.

  View details for Web of Science ID A1987G268700030

  View details for PubMedID 3492555

• CLONAL ANALYSIS OF T-CELLS IN LYMPHOMATOID PAPULOSIS NEW ENGLAND JOURNAL OF MEDICINE Weiss, L. M., Wood, G. S., Warnke, R. A., Sklar, J. 1987; 316 (6): 348-348

  View details for Web of Science ID A1987F852100025

• NECROSIS IN LYMPH-NODES PATHOLOGY ANNUAL Strickler, J. G., Warnke, R. A., Weiss, L. M. 1987; 22: 253-282

  Abstract

  When necrosis is identified in a lymph node biopsy, various entities should be considered in the differential diagnosis. Neoplastic conditions, especially lymphoma and metastatic carcinoma, must first be excluded. Numerous benign conditions also cause necrosis in lymph nodes, and the presence or absence of granulomatous inflammation as well as other histologic features are useful in suggesting various possibilities. Clinical information is very important in the differential diagnosis, and lymph node culture or other tests are often required to determine a specific diagnosis.

  View details for Web of Science ID A1987U581400008

  View details for PubMedID 3317224

• STUDIES ON B-LYMPHOID TUMORS TREATED WITH MONOCLONAL ANTIIDIOTYPE ANTIBODIES - CORRELATION WITH CLINICAL-RESPONSES BLOOD Lowder, J. N., MEEKER, T. C., Campbell, M., Garcia, C. F., Gralow, J., MILLER, R. A., Warnke, R., Levy, R. 1987; 69 (1): 199-210

  Abstract

  Monoclonal anti-idiotype antibodies can be made which are exquisitely specific for B lymphocytic malignancies. We have conducted a clinical trial in which some patients' tumors regressed after infusion of such antibodies. Here, we evaluated characteristics of the antibodies, the tumors, and the patients to determine which features best correlated with the clinical response. Neither the isotype of the murine antibodies, nor their avidity were predictive of clinical outcome. The specific epitope to which the antibodies bound was characterized by immunochemical techniques. Reactivity with a heavy-light chain combinatorial determinant correlated somewhat with clinical effect. Variations in the characteristics of the individual tumors such as antigen sites per cell and ability to modulate the surface immunoglobulin were not predictive of response. In one patient with prolymphocytic leukemia the anti-idiotype antibody had a direct antiproliferative effect on tumor cells in vitro. This patient's tumor response was explainable by such a direct mechanism. In the other patients, who had lymphomas, therapeutic outcome correlated with the number of host nontumor cells infiltrating the tumor. The vast majority of these nontumor cells were mature T lymphocytes of the Leu 4, Leu 3 (T3, T4) phenotype. Thus, a preexistent host-tumor interaction seems to be important in the in vivo effect of anti-idiotype antibodies in B cell tumors.

  View details for Web of Science ID A1987F547000034

  View details for PubMedID 2431729

• IMMUNOPHENOTYPIC DIAGNOSIS OF LYMPHOID MALIGNANCY PICKER, L., Weiss, L., Warnke, R. WILLIAMS & WILKINS. 1987: A60–A60

  View details for Web of Science ID A1987F618700368

• THE IMMUNOPATHOLOGY OF CUTANEOUS LYMPHOMAS - IMMUNOPHENOTYPIC AND IMMUNOGENOTYPIC CHARACTERISTICS SEMINARS IN DERMATOLOGY Wood, G. S., Weiss, L. M., Warnke, R. A., Sklar, J. 1986; 5 (4): 334-345

  View details for Web of Science ID A1986G241800005

• THE IMMUNOHISTOLOGY OF THE PERSISTENT GENERALIZED LYMPHADENOPATHY SYNDROME (PGL) AMERICAN JOURNAL OF CLINICAL PATHOLOGY Garcia, C. F., Lifson, J. D., Engleman, E. G., Schmidt, D. M., Warnke, R. A., Wood, G. S. 1986; 86 (6): 706-715

  Abstract

  The authors employed a large panel of monoclonal antibodies to characterize and quantitate lymphoid subpopulations within the paracortex, mantle, and germinal centers of frozen sections of lymph nodes from 18 patients with the persistent generalized lymphadenopathy (PGL) syndrome and five heterosexual controls. The authors' data indicate that Leu-3+ phenotypic T-helper cells (TH) are reduced within all three compartments, while T-cytotoxic-suppressor cells (Tcs) are increased. Using the antibody 9.3, which allows dissection of the Leu-2+ Tcs subset into 9.3+ cytotoxic cells (Tc) and 9.3- suppressor cells (Ts), the authors found that the Ts subset is increased in the lymph nodes of these patients. In contrast to acquired immune deficiency syndrome (AIDS) patients, paracortical total T-cells and Leu-8+ cells appear to be preserved in patients with PGL. Study of TH and Tcs subpopulations in peripheral blood in 12 of these patients revealed inverted ratios (mean, 0.59), which did not correlate with those seen in the lymph nodes. Although the paracortical TH/Tcs ratios were significantly reduced (mean, 1.44) they were not inverted, in contrast to some other reported series. In aggregate, these data suggest that, relative to AIDS, there is preservation of the paracortical T-cell microenvironment in PGL. Clinically, this correlates with more intact cell-mediated immunity and the absence of opportunistic infections and Kaposi's sarcoma in this patient group. Follicle lysis was present in 11 patients. Increased HLA-DR+ paracortical cells, aggregates of Leu-6+ dendritic cells, decreased TAC+ cells, increased OKT-10+ plasma cells, and increased interstitial immunoglobulin were among the other features observed in these patients.

  View details for Web of Science ID A1986F110100002

  View details for PubMedID 3491535

• A UNIQUE ANTIGEN ON MATURE B-CELLS DEFINED BY A MONOCLONAL-ANTIBODY JOURNAL OF IMMUNOLOGY Link, M. P., Bindl, J., MEEKER, T. C., CARSWELL, C., DOSS, C. A., Warnke, R. A., Levy, R. 1986; 137 (9): 3013-3018

  Abstract

  A novel 42,000 dalton antigen (MB-1) expressed by mature human B cells in blood and tonsil was identified and characterized by utilizing a hybridoma monoclonal antibody. A comparison of MB-1 with other known B cell antigens suggests that the MB-1 antigen has not been previously identified. From one-and two-color immunofluorescence studies, it appears that the MB-1 antigen is found on all normal immunoglobulin (Ig)-expressing cells, but not on T cells, thymocytes, granulocytes, or platelets. Studies of malignant B cell tumors reveal that the antigen is expressed by virtually all Ig-expressing B cell tumors but only 10% of SIg- B-lineage leukemias. Data from these studies suggest that the MB-1 antigen is expressed late in B cell ontogeny before the expression of SIg.

  View details for Web of Science ID A1986E489100045

  View details for PubMedID 3489782

• IDIOTYPE VARIANT CELL-POPULATIONS IN PATIENTS WITH B-CELL LYMPHOMA JOURNAL OF EXPERIMENTAL MEDICINE Carroll, W. L., Lowder, J. N., STREIFER, R., Warnke, R., Levy, S., Levy, R. 1986; 164 (5): 1566-1580

  Abstract

  Using isolated idiotype (Id) protein we generated panels of antibodies in two patients with follicular lymphoma, one of whom had never received prior chemo-or radiotherapy. Flow cytometry and frozen section tissue staining of tumor with these monoclonal antibodies (mAb) revealed multiple subpopulations within each tumor. Individual mAb stained between 7% and 83% of surface Ig+ cells in the tumor samples. These subpopulations were overlapping and no single antibody recognized all the tumor cells. However, combinations of antibodies seemed to capture total tumor in both cases. In some instances, the percentage of tumor stained by a single mAb varied over time, and differed between lymph nodes sampled at the same time. Because a single species of Id protein was used to generate mAb in each case, it appears that the antibodies were directed against idiotopes variably shared by different populations within each tumor, and this was confirmed by crossblocking studies. Tumor cells from one patient were fused to a nonsecreting heteromyeloma line K6H6/B5, and most of the resulting hybrids secreted Id protein. Four mAb were used to screen the Id proteins secreted by these hybrids, and 11 different variants (16 maximal) were found. Southern blot analysis of rearranged Ig genes was done in two hybrids and biopsy material. Identically rearranged light-chain genes were seen but it appeared as though extensive somatic variation had occurred in heavy chain genes. These studies indicate that: striking Id variation can exist at diagnosis in untreated patients, the percentage of tumor represented by an individual variant may change with time and may differ between tumor sampled from different anatomical locations, and somatic variation appears to be responsible for the observed heterogeneity. Although this degree of variation makes anti-Id antibody therapy more difficult, appropriate combinations of mAb should be more efficacious than single antibodies in such cases.

  View details for Web of Science ID A1986E624500015

  View details for PubMedID 3490533

• SINUSOIDAL HEMATOLYMPHOID MALIGNANCY (MALIGNANT HISTIOCYTOSIS) PRESENTING AS ATYPICAL SINUSOIDAL PROLIFERATION - A STUDY OF 9 CASES CANCER Weiss, L. M., Azzi, R., Dorfman, R. F., Warnke, R. A. 1986; 58 (8): 1681-1688

  Abstract

  A number of cases of sinusoidal hematolymphoid malignancy ("malignant histiocytosis") in which early lymph node biopsies have not allowed clear separation from benign histiocytic disorders have been observed. Nine such cases in which only a follow-up lymph node biopsy documented their malignant nature are reported. Seven of the nine patients were under 21 years of age; there was an even sex distribution. All had localized or generalized lymphadenopathy and three had hepatosplenomegaly at initial presentation. Histologically, the initial lymph node biopsy specimens showed an atypical sinusoidal proliferation, often with hemophagocytosis, but without sufficient atypia to allow a diagnosis of malignancy. The analysis of the follow-up biopsies, performed from 6 weeks to 5 years after the initial biopsy, showed a progression in histology with an increase in atypia, a greater tendency to efface lymph node architecture, and a decrease in hemophagocytosis. All patients were treated with chemotherapy. Six patients ultimately died; at autopsy, these patients showed a pattern of organ involvement typical of what has been described for malignant histiocytosis.

  View details for Web of Science ID A1986E241100016

  View details for PubMedID 3756790

• IMMUNOGLOBULIN GENE REARRANGEMENTS IN HODGKINS-DISEASE HUMAN PATHOLOGY Weiss, L. M., Strickler, J. G., Hu, E., Warnke, R. A., Sklar, J. 1986; 17 (10): 1009-1014

  Abstract

  An initial survey of biopsy specimens from 16 cases of Hodgkin's disease revealed clonal immunoglobulin gene rearrangements in one specimen, which contained large numbers of Reed-Sternberg (R-S) cells. As a result of this finding, the configuration of immunoglobulin and T-cell receptor gene DNA was investigated in biopsy tissues from other cases that were histologically and immunophenotypically consistent with Hodgkin's disease and contained numerous R-S cells. In six of seven such specimens (all of the nodular sclerosing subtype), selected solely on the basis of high R-S cell content and sufficient frozen tissue for study, at least one immunoglobulin gene was found to be rearranged in a clonal manner. Additionally, tissue samples obtained at two different time points from the original patient who showed immunoglobulin gene rearrangements revealed identical patterns of rearrangement. In the majority of cases, only a single gene showed rearrangement, and the rearranged bands in Southern blot autoradiograms were usually considerably less intense than the germline bands. No rearrangements of T-cell receptor DNA were detected in any case with a probe for the beta T-cell receptor gene. The results suggest that clonal cell populations possessing uniform immunoglobulin gene rearrangements are present in tissue in some cases of Hodgkin's disease. It is not possible to determine which cells contain these rearranged genes, but the increased incidence of detectable rearrangements in cases with high numbers of R-S cell raises the possibility that immunoglobulin gene rearrangement occurs in these cells.

  View details for Web of Science ID A1986E333000006

  View details for PubMedID 3530971

• LYMPHOMATOID PAPULOSIS EXPRESSES IMMUNOPHENOTYPES ASSOCIATED WITH T-CELL LYMPHOMA BUT NOT INFLAMMATION JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Wood, G. S., Strickler, J. G., DENEAU, D. G., Egbert, B., Warnke, R. A. 1986; 15 (3): 444-458

  Abstract

  Twelve skin biopsy specimens of lymphomatoid papulosis from nine patients were studied immunohistologically. The large atypical cells morphologically resembled Reed-Sternberg cells in six cases and large cerebriform mononuclear cells in three cases. These cells expressed pan-T cell antigens (Leu-4 and/or Leu-5) and helper T cell antigen (Leu-3) in each case. They also expressed activation antigens: HLA (human lymphocyte antigen)-DR, HLA-DQ, Tac, and T9. Reactivity of many nuclei with Ki-67 indicated a high proliferative index. Phenotypic abnormality of the large atypical cells was evident by their deficiency of T cell antigens Leu-1 and/or Leu-9 in eight of nine cases. Neither Ki-1 nor Leu-M1 were reliable markers for lymphomatoid papulosis in this series, since large atypical cells were Ki-1-positive in only three of eight cases and were Leu-M1-negative in all eight cases tested. The remainder of the cutaneous infiltrate consisted of small T cells, macrophages, Langerhans cells, and granulocytes. The small T cells expressed a normal phenotype except in some cases associated with mycosis fungoides in which they were deficient in various T cell antigens. Comparison of concurrent lymphomatoid papulosis and mycosis fungoides skin biopsy specimens in two patients revealed that they were composed of phenotypically distinct T cell subpopulations. These results indicate that the large atypical cells of lymphomatoid papulosis are a proliferating population of activated helper T cells that are deficient in certain T cell antigens. Such abnormal T cell phenotypes are common in T cell lymphoma but are rarely, if ever, observed in cutaneous inflammation. In conjunction with the cytologic atypia, aneuploidy, and association with other lymphomas documented in this or previous reports, these data suggest that lymphomatoid papulosis represents a T cell lymphoproliferative disorder rather than an inflammatory disorder.

  View details for Web of Science ID A1986D769600003

  View details for PubMedID 3489740

• CLONAL T-CELL POPULATIONS IN LYMPHOMATOID PAPULOSIS - EVIDENCE OF A LYMPHOPROLIFERATIVE ORIGIN FOR A CLINICALLY BENIGN DISEASE NEW ENGLAND JOURNAL OF MEDICINE Weiss, L. M., Wood, G. S., Trela, M., Warnke, R. A., Sklar, J. 1986; 315 (8): 475-479

  Abstract

  Lymphomatoid papulosis is a chronic, clinically benign skin disorder that, when examined histologically, is seen to include numerous large, atypical lymphoid cells that display antigenic markers of T lymphocytes. To investigate the disparity between the clinical behavior of this disease and its malignant histologic appearance, we analyzed the DNA from skin lesions of six patients for rearrangements of beta and gamma T-cell receptor genes. Lesions from five of these patients showed between one and three clonal rearrangements for at least one T-cell receptor gene. Three separate biopsy specimens from a single patient showed different patterns of rearrangements for the beta gene in each specimen. Our results indicate that lymphomatoid papulosis is a clonal T-cell lymphoproliferative process that may possibly be multiclonal in origin. We conclude that this disease has both biologic and histologic features consistent with a malignant T-cell neoplasm despite its indolent course.

  View details for Web of Science ID A1986D663400002

  View details for PubMedID 3488502

• THE SYNCYTIAL VARIANT OF NODULAR SCLEROSING HODGKINS-DISEASE AMERICAN JOURNAL OF SURGICAL PATHOLOGY Strickler, J. G., Michie, S. A., Warnke, R. A., Dorfman, R. F. 1986; 10 (7): 470-477

  Abstract

  The histologic and immunologic features of an unusual morphologic expression of nodular sclerosing Hodgkin's disease, which ahs been termed the "syncytial variant," are described. In biopsy material from 18 cases, numerous Reed-Sternberg cell variants were observed in sheets and cohesive clusters, and at least focal evidence of nodular sclerosis was present in each case. The granulocyte antibody anti-Leu M1 reacted with antigenic determinants in Reed-Sternberg cells and atypical variants thereof in 13 of the 18 cases; the lack of staining with antibodies reactive with the leukocyte common (T200) antigen (PD7/26), keratin (AE1), and S100 protein (polyclonal anti-S100) was helpful in excluding non-Hodgkin's lymphoma, carcinoma, and melanoma, respectively. This unusual form of nodular sclerosing Hodgkin's disease is important to recognize, since it may simulate metastatic neoplasms, thymoma, and non-Hodgkin's lymphoma.

  View details for Web of Science ID A1986C932300004

  View details for PubMedID 2425645

• CUTANEOUS FOLLICULAR LYMPHOMA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Garcia, C. F., Weiss, L. M., Warnke, R. A., Wood, G. S. 1986; 10 (7): 454-463

  Abstract

  Fifteen cases of cutaneous follicular lymphoma were evaluated clinically, histologically, and immunologically. Nine of the patients presented with skin disease alone, which showed a predilection for the scalp and forehead. The six remaining cases had either concurrent or secondary cutaneous involvement. All of the cases had a nodular configuration which was evident histologically or immunologically. In many cases, the diagnostic microscopic fields were in the deep dermis or subcutis, with nonspecific inflammation in the superficial dermis. The cases consisted of five small cleaved, seven mixed, and three large cell follicular lymphomas. A senior dermatopathologist diagnosed four of the 15 cases as benign, indicating the difficulty of diagnosis by morphology alone when the biopsy is small or the inflammatory component is prominent. This underscores the importance of large, deep biopsies for accurate histologic diagnosis. Immunological studies confirmed the B cell lineage of these lesions. An unexpectedly high proportion of immunoglobulin-negative cases (eight cases) was found, especially among the primary cutaneous follicular lymphomas (six of nine cases). Immunoglobulin-expressing cases exhibited monotypic immunoglobulin light-chain staining of tumor cells. In all cases, the dendritic reticulum cell network within lymphoma follicles lacked the polytypic immunoglobulin complexes characteristic of reactive follicles. As described previously for follicular lymphomas in lymph nodes, many cases exhibited polytypic follicular mantle zones similar to reactive follicles. The low-grade nature of these lymphomas was supported by clinical follow-up. We conclude that given adequate sampling, cutaneous follicular lymphomas can usually be diagnosed by histologic criteria similar to those used for lymph nodes; however, immunohistologic studies are an important adjunct.

  View details for Web of Science ID A1986C932300002

  View details for PubMedID 3524282

• CLINICAL AND PHENOTYPIC DIVERSITY OF T-CELL LYMPHOMAS BLOOD Horning, S. J., Weiss, L. M., CRABTREE, G. S., Warnke, R. A. 1986; 67 (6): 1578-1582

  Abstract

  Forty-one cases of T cell lymphoma were identified on the basis of morphology and the expression of two or more T cell antigens with an absence of B cell markers. Mycosis fungoides and lymphoblastic lymphoma were excluded. Marked clinical, morphological, and immunologic diversity was observed. Cutaneous lymphoma was found in approximately 50% of the patient group, and 27% had a prior history of dermatologic or immunologic disease. No correlations among immunologic and morphologic phenotypes and clinical course were apparent. Survival data was comparable to that of a concurrent group of non-T cell lymphoma patients studied at this institution, suggesting that, contrary to previous reports, T cell lymphoma may not necessarily confer a more unfavorable prognosis. Prospective studies using uniform treatments are necessary to address the clinical significance of the T cell phenotype definitively, independent of established histologic and clinical features.

  View details for Web of Science ID A1986C606500007

  View details for PubMedID 3011148

• FOLLICULAR LARGE CELL LYMPHOMA - AN IMMUNOPHENOTYPE STUDY AMERICAN JOURNAL OF PATHOLOGY Garcia, C. F., Warnke, R. A., Weiss, L. M. 1986; 123 (3): 425-431

  Abstract

  The authors investigated 17 cases of follicular large cell lymphoma using monoclonal antibodies applied to frozen sections. The neoplastic cells in 11 cases (65%) showed evidence of immunoglobulin expression similar to the reported percentage of immunoglobulin expressing diffuse large cell lymphomas and lower than seen in low grade follicular lymphomas. All cases showed expression of the B lineage markers T015, B1, and 4G7, and HLA-DR. CALLA was present in all but 1 case, similar to that reported for follicular lymphomas, and much higher than reported for diffuse large cell lymphoma. Approximately one-half of the cases showed weak expression of Tac, 5 cases expressed B2 (C3d), and 3 cases expressed T05 (C3b). Variable expression was seen for the Ki-67 antigen. A CR4/23+, B2+, T05+ dendritic population was identified in all cases. An interfollicular host T-cell infiltrate was noted, mainly phenotypic helper cells. This study demonstrates that follicular large cell lymphoma has immunologic similarities to both diffuse large cell lymphoma and the low grade follicular lymphomas.

  View details for Web of Science ID A1986C756200004

  View details for PubMedID 3521302

• LEU-8 AND LEU-9 ANTIGEN PHENOTYPES - IMMUNOLOGICAL CRITERIA FOR THE DISTINCTION OF MYCOSIS-FUNGOIDES FROM CUTANEOUS INFLAMMATION JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Wood, G. S., Abel, E. A., Hoppe, R. T., Warnke, R. A. 1986; 14 (6): 1006-1013

  Abstract

  The distinction of mycosis fungoides from reactive cutaneous inflammation can be difficult. Unfortunately, since many reactive processes exhibit predominantly a mature helper T cell phenotype similar to that expressed by most cases of mycosis fungoides, standard immunologic marker studies have not been very helpful in differential diagnosis. To determine whether novel immunophenotypic criteria could be developed that correlate with the diagnosis of cutaneous involvement by mycosis fungoides, we studied the expression of Leu-8 and Leu-9 antigens by T cells in forty-one skin biopsy specimens from twenty-seven patients with mycosis fungoides and thirty-four skin biopsy specimens from thirty-three controls with a variety of benign cutaneous diseases. These antigens are expressed by the majority of normal T cells in the blood and lymphoid tissues but are often absent in T cell lymphomas or expressed by only a minority of tumor cells. Semiquantitative grading of the percentage of Leu-8+ and Leu-9+ T cells in our patients revealed that deficiency of these antigens (i.e., expression by less than or equal to 33% of T cells) was more prevalent among mycosis fungoides patients than among controls and became more specific for mycosis fungoides as the percentage of Leu-8+ and Leu-9+ T cells decreased. In initial biopsies, less than or equal to 33% of T cells were Leu-8+ in 82% of mycosis fungoides patients versus 15% of controls, while less than or equal to 10% of T cells were Leu-8+ in 52% of mycosis fungoides patients versus only 3% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1986C559600006

  View details for PubMedID 3088069

• MALIGNANT FIBROUS HISTIOCYTOMA TUMOR-CELLS RESEMBLE FIBROBLASTS AMERICAN JOURNAL OF SURGICAL PATHOLOGY Wood, G. S., Beckstead, J. H., Turner, R. R., Hendrickson, M. R., Kempson, R. L., Warnke, R. A. 1986; 10 (5): 323-335

  Abstract

  The malignant fibrous histiocytomas (MFHs) are a histologically heterogeneous group of sarcomas that have been postulated to be derived from, or have the capacity to differentiate into, histiocytes. To determine whether MFH tumor cells actually express the features of histiocytes, i.e., bone marrow-derived cells of monocyte-macrophage lineage, we studied the antigenic and enzymatic phenotype of 13 MFHs in situ using frozen and plastic sections, respectively. Five pleomorphic three fibrous, two myxoid, two giant cell, and one histiocytic MFH were studied. While tumor cells in 12 of 13 cases were positive for HLA-A,B,C, tumor cells in all cases failed to express antigens present on bone marrow-derived macrophages, i.e., leukocyte common antigen (L3B12), HLA-DR, Leu-M3, and Leu-3a. Interestingly 8 of 13 cases were positive for CALLA. Although nonspecific, this may prove useful in differential diagnosis. Enzyme histochemistry demonstrated that tumor cells in 9 of 13 cases were positive for membrane 5' nucleotidase (5'N+). Four of these were also alkaline phosphatase positive (ALKP+). All cases were either negative or weakly positive for acid phosphatase (ACIDP) and alpha-naphthyl acetate esterase (ANAE). Tumor cells were unreactive for alpha-naphthyl butyrate esterase (ANBE) and adenosine triphosphatase (ATP). These findings indicate that MFH tumor cells do not express the enzymatic profile of cells of monocyte/macrophage lineage which are membrane 5'N-/ALKP- and ACIDP+/ANAE+/ANBE+/ membrane ATP+. In fact, these data suggest a similarity to fibroblasts which are membrane 5'N+, variably ALKP+, weakly ACIDP+/ANAE+, and ANBE-/membrane ATP-. Osteoclast-like giant cells present in two cases did express a histiocytic phenotype, suggesting that they are reactive elements not derived from admixed tumor cells. These results suggest that MFHs are primitive mesenchymal neoplasms, most likely sarcomas composed of poorly differentiated fibroblasts, and are unrelated to true histiocytic neoplasms.

  View details for Web of Science ID A1986C250200004

  View details for PubMedID 3010748

• SMALL NONCLEAVED CELL LYMPHOMA - AN IMMUNOPHENOTYPIC STUDY OF 18 CASES AND COMPARISON WITH LARGE CELL LYMPHOMA HUMAN PATHOLOGY Garcia, C. F., Weiss, L. M., Warnke, R. A. 1986; 17 (5): 454-461

  Abstract

  Eighteen cases of small noncleaved cell lymphoma (SNCL) were studied with a large panel of monoclonal antibodies applied to tissue frozen sections and compared with 18 cases of immunoglobulin-expressing diffuse large cell lymphoma (DLCL). Immunoglobulin expression was seen in all cases of SNCL, with a predominance of cases showing lambda light chain restriction. Expression of mu and delta heavy chains was common, but gamma and alpha chain expression was uncommon. In the cases of SNCL T015, B1, B2, 41H, BA-1, BA-2, Ia, CALLA, and OKT10 were generally expressed, and a large percentage of cells expressed Ki-67. Only rare expression of T05, Leu-8, and Leu-9 was seen, and in no case was reactivity with anti-Tac antibodies observed. In contrast, the immunoglobulin-expressing DLCLs showed the typical predominance of cases of kappa light chain restriction, a lower proportion of cases with mu or delta expression, and a higher proportion of cases with gamma expression. A lower incidence of Leu-8, T05, and Tac expression and a higher incidence of BA-1, CALLA, Ki-67 and OKT10 were seen in the SNCLs as compared with the DLCLs. It is concluded that immunologic studies may be of considerable aid in the differential diagnosis of SNCL and DLCL.

  View details for Web of Science ID A1986C247600007

  View details for PubMedID 3699808

• A PRIMARY LYMPH-NODE MALIGNANCY WITH FEATURES SUGGESTIVE OF DENDRITIC RETICULUM-CELL DIFFERENTIATION - A REPORT OF 4 CASES AMERICAN JOURNAL OF PATHOLOGY MONDA, L., Warnke, R., Rosai, J. 1986; 122 (3): 562-572

  Abstract

  Four cases are described of a nonlymphomatous primary lymph node malignancy characterized by the proliferation of oval and spindle cells, occasionally multinucleated, and arranged in a nesting, swirling, and storiform pattern. The combination of light-microscopic, ultrastructural, and immunohistochemical features suggests that these tumors might be derived from dendritic reticulum cells.

  View details for Web of Science ID A1986A494500020

  View details for PubMedID 2420185

• DIAGNOSIS OF B-CELL LYMPHOMA BY ANALYSIS OF IMMUNOGLOBULIN GENE REARRANGEMENTS IN BIOPSY SPECIMENS OBTAINED BY FINE NEEDLE ASPIRATION JOURNAL OF CLINICAL ONCOLOGY Hu, E., Horning, S., Flynn, S., Brown, S., Warnke, R., Sklar, J. 1986; 4 (3): 278-283

  Abstract

  Histologic diagnosis of lymphoma is far more difficult in the disaggregated cells obtained by percutaneous aspiration of lymph nodes than in tissue sections prepared from excisional biopsy specimens. However, the simplicity, economy, and safety of aspiration biopsy makes this an attractive diagnostic option in certain situations. In the present study, we demonstrate that lymph node aspirates provide material that is both suitable and sufficient for accurately detecting clonal proliferations of B cells by analysis of immunoglobulin gene rearrangements. The rearrangements detected in aspirated tissue serve as clonal markers that can be directly compared with the rearrangements found in histologically confirmed lymphoma removed by open biopsy. The application of gene rearrangements to aspirated material therefore offers a useful method of diagnosing lymphoma, particularly for the purposes of more thorough staging at initial presentation or the evaluation of tissues for possible relapse.

  View details for Web of Science ID A1986A378100003

  View details for PubMedID 3081690

• INSITU QUANTITATION OF LYMPH-NODE HELPER, SUPPRESSOR, AND CYTOTOXIC T-CELL SUBSETS IN AIDS BLOOD Wood, G. S., Burns, B. F., Dorfman, R. F., Warnke, R. A. 1986; 67 (3): 596-603

  Abstract

  We have used the novel monoclonal antibodies 9.3 and anti-Leu-8 in conjunction with other T cell markers to quantify T cell subpopulations in the paracortex, mantle, and germinal center compartments of frozen sections of lymph nodes from seven homosexual men with acquired immunodeficiency syndrome (AIDS) and five heterosexual controls. Antibody 9.3 allows dissection of the Leu-2+ cytotoxic/suppressor subset (Tcs) into 9.3+ cytotoxic cells (Tc) and 9.3- suppressor cells (Ts). Anti-Leu-8 allows dissection of the Leu-3+ helper subset (TH) into functionally distinct subpopulations. The data indicate that the T cells in patients with AIDS exhibit normal antigen expression but altered subset ratios. In this series, the data suggested that the reversal of the paracortical TH-Tcs ratio was due to an increase in Ts with a concomitant decrease in TH and Tc. These changes were also reflected in a reversal of the normal paracortical Tc-Ts ratio (3.0) to less than 1.0. Furthermore, the data suggested a marked decrease in paracortical Leu-3+8+TH, which are known to have inducer function in cellular immune reactions and exert feedback inhibition of immunoglobulin production through a suppressor T cell intermediary. In contrast, there was preservation of the Leu-3+8-TH population within the germinal center. This T cell subset is known to help B cell differentiation. This microenvironmentally specific constellation of T cell subset alterations within lymph nodes may in part explain several of the immunologic findings associated with AIDS.

  View details for Web of Science ID A1986A373200007

  View details for PubMedID 2936405

• LYMPHOBLASTIC LYMPHOMA - AN IMMUNOPHENOTYPE STUDY OF 26 CASES WITH COMPARISON TO T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA BLOOD Weiss, L. M., BINDL, J. M., Picozzi, V. J., Link, M. P., Warnke, R. A. 1986; 67 (2): 474-478

  Abstract

  A series of 26 lymphoblastic lymphomas (LLs) and 13 T cell acute lymphoblastic leukemias (ALLs) were investigated using a battery of monoclonal antibodies applied to tissue frozen sections. Twenty-one of the LLs were of T lineage. All but one of the T cell LLs were of immature thymic phenotype, mostly corresponding to stage II cortical thymocyte development. The T cell LLs expressed Leu-1 in 100%, Leu-4 and Leu-9 in 95%, and Leu-5 in 85% of the cases. The high percentage of Leu-4 expression in this series is probably due to detection of cytoplasmic antigen with our methods. One LL was of pre-B or B cell and two cases were of common ALL phenotype. Two cases were of undefined phenotype, expressing markers of both B and T cell differentiation. Pediatric cases showed a greater tendency toward T cell phenotype than did adult cases. The cases of T cell ALL were immunophenotypically similar to the cases of T cell LL but showed a tendency toward a more immature phenotype.

  View details for Web of Science ID A1986AZK8500035

  View details for PubMedID 3080041

• LEU-6-EXPRESSING CELLS IN LYMPH-NODES - DENDRITIC CELLS PHENOTYPICALLY SIMILAR TO INTERDIGITATING CELLS HUMAN PATHOLOGY Weiss, L. M., Beckstead, J. H., Warnke, R. A., Wood, G. S. 1986; 17 (2): 179-184

  Abstract

  Leu-6 is an antigen expressed by immature T cells, Langerhans cells, and indeterminate cells, the latter two of which are dendritic cells found predominantly within the skin. In dermatopathic lymphadenopathy, the paracortex is expanded by T cells and dendritic cells, including Langerhans cells. While the paracortex also contains Leu-6+ cells, the nature of such cells in lymph nodes has been controversial. To determine the characteristics of Leu-6+ paracortical cells, their morphologic, antigenic, and enzymatic features were studied in lymph nodes showing dermatopathic lymphadenopathy or reactive follicular hyperplasia. Immunologic studies with plastic, frozen, and paraffin sections demonstrated a dendritic cell morphology, a dendritic cell lineage phenotype (L3B12+, HLA-A,B,C+, HLA-DR+, S-100+), and the absence of T-cell lineage phenotype. These findings were corroborated by the enzymatic phenotype of these cells observed in plastic sections (membrane ATPase+, weak paranuclear acid phosphatase+, weak paranuclear alpha-napthylacetate esterase+). Although all paracortical dendritic cells were otherwise identical, only a subset of these cells were Leu-6+. The close phenotypic similarity between these Leu-6+ and Leu-6- paracortical dendritic cell subsets suggests a close ontogenetic relation. Furthermore, the greater abundance of the Leu-6+ subset in dermatopathic lymph nodes than in nodes exhibiting only reactive follicular hyperplasia, in conjunction with the presence of Leu-6+ dendritic cells within the sinuses of dermatopathic lymph nodes, suggests that at least some of the paracortical Leu-6+ cells are Leu-6+ Langerhans cells or indeterminate cells derived from the skin via the afferent lymphatics.

  View details for Web of Science ID A1986A096400012

  View details for PubMedID 3081423

• MEDIASTINAL NONLYMPHOBLASTIC LYMPHOMAS IN CHILDREN - A CLINICOPATHOLOGICAL STUDY JOURNAL OF CLINICAL ONCOLOGY Bunin, N. J., Hvizdala, E., Link, M., Callihan, T. R., HUSTU, H. O., Wharam, M., Warnke, R. A., Berard, C. W., Murphy, S. B. 1986; 4 (2): 154-159

  Abstract

  The records of 25 pediatric patients with mediastinal nonlymphoblastic lymphoma (NLBL) were reviewed. These patients comprise approximately 5% of all patients with non-Hodgkin's lymphoma (NHL) in the pediatric age group. There were 15 females and ten males. The median age was 13.5 years (range, 2 to 19). Most patients presented with symptoms attributable to a large mediastinal mass, and superior vena cava syndrome was a common feature. Disease was localized to the supradiaphragmatic area in 17 patients (71%) at diagnosis. Pathologic review revealed 22 of these lymphomas to be diffuse histiocytic type in the Rappaport classification, and 20 were large-cell immunoblastic type in the Working Formulation. Treatment regimens were not uniform, but included multiagent chemotherapy in 23 patients and radiation to the mediastinum in 20 patients. Twenty-three patients (92%) attained a complete remission (CR). Of these, 17 (74%) remain disease-free 13 to 65 months from diagnosis (median, 43 months). No CNS relapses have been observed. Mediastinal NLBL in the pediatric age group has distinctive clinicopathologic features that warrant special consideration in the design of treatment protocols.

  View details for Web of Science ID A1986AZC1500006

  View details for PubMedID 3753718

• ANGIOIMMUNOBLASTIC LYMPHADENOPATHY AND ANGIOIMMUNOBLASTIC LYMPHADENOPATHY-LIKE LYMPHOMA - EVIDENCE FOR A FREQUENT CLONAL T-CELL PROLIFERATIVE ETIOLOGY Weiss, L. M., Strickler, J. G., Dorfman, R. F., Horning, S. J., Warnke, R. A., Sklar, J. WILLIAMS & WILKINS. 1986: A68–A68

  View details for Web of Science ID A1986AXX6300420

• MALIGNANT FIBROUS HISTIOCYTOMA TUMOR-CELLS DO NOT EXPRESS THE ANTIGENIC OR ENZYME HISTOCHEMICAL FEATURES OF CELLS OF MONOCYTE MACROPHAGE LINEAGE Wood, G. S., Beckstead, J. H., Turner, R. R., Hendrickson, M. R., Kempson, R. L., Warnke, R. A. NATURE PUBLISHING GROUP. 1985: A78–A78

  View details for Web of Science ID A1985TZ83200388

• PRACTICAL APPROACH TO THE IMMUNODIAGNOSIS OF LYMPHOMAS EMPHASIZING DIFFERENTIAL-DIAGNOSIS CANCER SURVEYS Warnke, R. A., Weiss, L. M. 1985; 4 (2): 349-358

  Abstract

  Immunological studies on tissue sections are often useful for supporting a diagnosis of lymphoma in cases with unusual histological or clinical findings and for identifying clinically important subgroups of lymphoma. Recent advances in both reagents and immunohistochemical methods allow the construction of monoclonal antibody panels for use both on routinely-fixed and processed tissues and on fresh frozen tissues. Commercially available monoclonal antibodies that are reactive with fixation-resistant antigenic determinants on lymphoid and related differentiation antigens often allow the distinction of lymphoma from non-lymphoid neoplasms. Better reagents and/or methods are needed for the identification of subset and lineage-specific markers on B cells and T cells and on the atypical cells of Hodgkin's disease. The use of fresh frozen tissue allows the application of a wide range of monoclonal antibodies to B-cell, T-cell and accessory cell differentiation antigens, many of which react only in fresh tissue. Appropriate monoclonal antibody panels distinguish B-cell lymphoma and Ig- B lineage lymphoma from hyperplasia. A broad panel of antibodies to T-cell differentiation antigens is needed to identify the abnormal T-cell phenotypes which are observed in T-cell lymphoma.

  View details for Web of Science ID A1985AXK0700004

  View details for PubMedID 3879857

• NON-HODGKINS LYMPHOMAS OF THE LUNG - A STUDY OF 19 CASES EMPHASIZING THE UTILITY OF FROZEN SECTION IMMUNOLOGICAL STUDIES IN DIFFERENTIAL-DIAGNOSIS AMERICAN JOURNAL OF SURGICAL PATHOLOGY Weiss, L. M., Yousem, S. A., Warnke, R. A. 1985; 9 (7): 480-490

  Abstract

  Nineteen cases of possible non-Hodgkin's lymphoma of the lung were studied by conventional morphologic methods and by immunohistochemical methods employing monoclonal antibodies applied to frozen tissue sections. In five of the 19 cases, the original histologic diagnoses were revised after review of the immunologic findings. Problem areas clarified by immunodiagnosis included the differential diagnoses of pseudolymphoma versus small lymphocytic lymphoma (two cases), Hodgkin's disease versus non-Hodgkin's lymphoma (two cases) and non-Hodgkin's lymphoma versus lymphomatoid granulomatosis (one case). Of the seven lymphomas presenting exclusively in the lung without a prior history of lymphoma, three were small lymphocytic, one was diffuse mixed small cleaved and large cell, and three were diffuse large-cell lymphomas. Four of these lymphomas typed as B-cell, two typed as T-cell, and one was of undefined phenotype.

  View details for Web of Science ID A1985ASJ2600003

  View details for PubMedID 3879107

• HUMAN DENDRITIC CELLS AND MACROPHAGES - INSITU IMMUNOPHENOTYPIC DEFINITION OF SUBSETS THAT EXHIBIT SPECIFIC MORPHOLOGIC AND MICROENVIRONMENTAL CHARACTERISTICS AMERICAN JOURNAL OF PATHOLOGY Wood, G. S., Turner, R. R., Shiurba, R. A., Eng, L., Warnke, R. A. 1985; 119 (1): 73-82

  Abstract

  Using a panel of monoclonal antibodies and antisera in situ, the authors have defined subsets of human dendritic cells and macrophages that exhibit specific morphologic and microenvironmental characteristics. All subsets contained cells that reacted with antibodies directed against HLA-A,B,C, HLA-Dr, leukocyte common, Leu-M3, and Leu-3(T4) antigens. R4/23 and anti-S100 defined three major subsets. R4/23+, S100- cells constituted the B-cell-related follicular dendritic cells, which were identified only within the germinal center/mantle microenvironment of lymphoid follicles. R4/23-, S100+ cells constituted the T-cell-related dendritic cell subset. Anti-Leu-6(T6) further subdivided this group into Leu-6(T6)- interdigitating cells within the T-cell microenvironments of lymphoid organs and Leu-6(T6)+ Langerhans cells found predominantly in epithelial microenvironments, especially the skin. R4/23-, S100- cells constituted the nondendritic tissue macrophage subset which was widely distributed, primarily outside of dendritic-cell microenvironments. These data indicate that although dendritic cells and macrophages share several common antigenic features, morphologically and microenvironmentally distinct subsets express distinct immunologic phenotypes. Such data may provide insight into the ontogeny and function of these subsets and constitute a basis for the comparison of normal dendritic cells and macrophages to various histiocytic proliferative disorders.

  View details for Web of Science ID A1985AFL2100009

  View details for PubMedID 3985124

• GASTROINTESTINAL LYMPHOMAS - IMMUNOHISTOCHEMICAL STUDIES ON THE CELL OF ORIGIN AMERICAN JOURNAL OF SURGICAL PATHOLOGY Grody, W. W., Weiss, L. M., Warnke, R. A., MAGIDSON, J. G., Hu, E., Lewin, K. J. 1985; 9 (5): 328-337

  Abstract

  The classification of primary malignant lymphomas of the gastrointestinal tract by their cell of origin has been a subject of great controversy in recent years, with the proportion of histologic subtypes varying substantially in different published series. Much of this controversy was initially due to the widely recognized inherent difficulty of classifying lymphomas based on routine histologic sections alone. However, the advent of immunohistochemical techniques has also yielded disparate results. Particularly contentious has been the notion of true histiocytic lymphomas, which some investigators have claimed to be relatively frequent in the gastrointestinal tract, whereas others doubt whether they exist at all. We present here a classification of 25 gastrointestinal lymphomas seen in the surgical pathology services of UCLA Hospital and Stanford University Medical Center. Unlike all previously reported series, we have utilized frozen tissue sections for the performance of immunohistochemical studies, which we and others have found to be far more reliable than the use of formalin-fixed, paraffin-embedded tissues, particularly in detecting monoclonal surface staining of immunoglobulin light- and heavy-chain markers. We find that this technique lessens the likelihood of overinterpreting the stains for histiocyte markers (alpha 1-antitrypsin and lysozyme), which are often difficult to read owing to strong positive staining of benign reactive histiocytes within the tumor. Utilizing these techniques, we have been able to classify definitely 21 of our 25 lymphomas (84%) as of B-cell origin, whereas none appeared to be histiocytic. We conclude that true histiocytic lymphomas of the gastrointestinal tract must be very rare, and we recommend the routine use of frozen tissue sections for more accurate classification of these interesting lesions.

  View details for Web of Science ID A1985AQW5100002

  View details for PubMedID 3911777

• DIFFUSE MALIGNANT-LYMPHOMA WITH CEREBRIFORM NUCLEI - A B-CELL LYMPHOMA STUDIED WITH MONOCLONAL-ANTIBODIES AMERICAN JOURNAL OF CLINICAL PATHOLOGY Burke, J. S., Warnke, R. A., Connors, J. M., Beckstead, J. H. 1985; 83 (6): 753-759

  Abstract

  A lymph node biopsy performed on a 55-year-old woman with asymptomatic generalized lymphadenopathy revealed a diffuse, malignant lymphoma composed of small to intermediate-sized lymphocytes with cerebriform-shaped nuclei; electron microscopy confirmed the nuclear complexity. The cerebriform nuclear configuration, coupled with an interfollicular pattern of nodal involvement with encroachment upon residual germinal centers, was presumptive of either mycosis fungoides or a peripheral T-cell lymphoma. Immunologic evaluation, however, indicated that the cerebriform lymphocytes represented a monoclonal B-cell population (IgM-IgD, lambda). Staining with monoclonal antibodies disclosed a phenotype of Ia+, B1+, BA-1+, BA-2+, Leu-1+; the neoplastic cells were unreactive with T-cell, lineage-specific antibodies (anti-Leu-2a, -3a, -4, -5) and with J5 (CALLA). In light of the immunophenotype and the distributional pattern, the cerebriform-shaped lymphocytes may represent an extreme morphologic variant of intermediate lymphocytic lymphoma.

  View details for Web of Science ID A1985AJC0200018

  View details for PubMedID 3923824

• IMMUNOPHENOTYPIC DIFFERENCES BETWEEN DERMATOPATHIC LYMPHADENOPATHY AND LYMPH-NODE INVOLVEMENT IN MYCOSIS-FUNGOIDES AMERICAN JOURNAL OF PATHOLOGY Weiss, L. M., Wood, G. S., Warnke, R. A. 1985; 120 (2): 179-185

  Abstract

  The authors applied a battery of monoclonal antibodies to T cells and other hematolymphoid cells on frozen tissue sections of lymph nodes with involvement by MF and DL, both with and without a history of MF. All 13 lymph nodes showing histologic involvement with MF showed immunophenotypic abnormalities. All of these cases showed significant loss of Leu-9 expression, and 10 cases showed significant loss of Leu-8 expression. In addition, occasional cases showed loss of the pan-T-cell markers Leu-1, 4, and 5. All cases of DL of histologic grade LN-0 or 1, with or without a history of MF, showed a predominance of T helper cells in paracortical regions without evidence of immunophenotypic abnormalities. Three of the 4 cases of DL of histologic grade LN-2 or 3 showed significant loss of Leu-8 and/or Leu-9 expression identified by a decrease in the ratio of paracortical Leu-8/Leu-4 or Leu-9/Leu-4-expressing cells, all cases with a history of possible or definite MF. These results raise the possibility that the immunologic methods employed may be able to identify cases of DL with early involvement by MF.

  View details for Web of Science ID A1985APF0400002

  View details for PubMedID 3161334

• PRIMARY MEDIASTINAL NON-HODGKINS LYMPHOMAS - A MORPHOLOGIC AND IMMUNOLOGICAL STUDY OF 19 CASES AMERICAN JOURNAL OF CLINICAL PATHOLOGY Yousem, S. A., Weiss, L. M., Warnke, R. A. 1985; 83 (6): 676-680

  Abstract

  Nineteen, primary, non-lymphoblastic, non-Hodgkin's lymphomas were investigated by conventional morphologic studies as well as immunologic studies using the application of a battery of monoclonal antibodies to frozen tissue sections. Seventeen of the lymphomas were diffuse large cell; one was large cell immunoblastic and one was a follicular and diffuse lymphoma of intermediate differentiation. Thirty-seven percent of the lymphomas showed prominent sclerosis, sometimes associated with the superior vena cava syndrome. Six of the cases showed evidence of immunoglobulin production with light chain restriction. Twelve additional cases were shown to be of B-cell lineage by B1/T015 expression but did not show evidence of immunoglobulin production. One case was a T-cell lymphoma of helper phenotype. Ia expression was found in 14 of 18 cases studied.

  View details for Web of Science ID A1985AJC0200003

  View details for PubMedID 3923821

• FOLLICULAR LYMPHOMA WITH BLASTIC CONVERSION - A REPORT OF 2 CASES WITH CONFIRMATION BY IMMUNOPEROXIDASE STUDIES ON BONE-MARROW SECTIONS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weiss, L. M., Warnke, R. A. 1985; 83 (6): 681-686

  Abstract

  Two cases of low-grade follicular lymphoma are presented in which evolution to a blastic phase with marrow and peripheral blood involvement occurred. One case was a follicular and diffuse mixed-cell lymphoma, while the second was a follicular and diffuse small cleaved-cell lymphoma. In both cases, at two and three years after initial presentation, a clinical picture resembling acute leukemia developed, with immature blastic-appearing infiltrates in the bone marrow and circulating blastic cells. Immunoperoxidase studies on fresh frozen sections of bone marrow in both cases confirmed the B-cell nature of the infiltrates and excluded the clinical impression of acute non-lymphocytic leukemia. The differential diagnosis of hematolymphoid infiltrates in the bone marrow in patients with follicular lymphoma is discussed.

  View details for Web of Science ID A1985AJC0200004

  View details for PubMedID 3890516

• DIFFERENCES IN HOST INFILTRATES AMONG LYMPHOMA PATIENTS TREATED WITH ANTI-IDIOTYPE ANTIBODIES - CORRELATION WITH TREATMENT RESPONSE JOURNAL OF IMMUNOLOGY Garcia, C. F., Lowder, J., MEEKER, T. C., Bindl, J., Levy, R., Warnke, R. A. 1985; 135 (6): 4252-4260

  Abstract

  To correlate treatment responses with numbers and types of "host cell infiltrates," lymphoid tissues from 10 patients with low-grade B cell malignancies were stained before, during, and after anti-idiotype therapy with a panel of monoclonal antibodies applied to frozen sections. Tissue penetration by the anti-idiotype antibodies was confirmed in five patients by these immunoperoxidase methods. Large numbers of phenotypic T helper cells were the main component of the "host infiltrate" in most patients. Two patients showed a complete and a near-complete clinical remission, four others had partial responses, and four did not respond to therapy. The two patients that developed clinical remission demonstrated the largest number of T cells, T helper cells, TAC+ cells, Leu-7+ cells, and in general the smallest number of proliferating cells as measured by the Ki-67 antibody. Other major differences in host cells were not evident among the patients. These preliminary data suggest that the type and amount of "host infiltrate" in low-grade B cell lymphomas may predict which patients will respond to anti-idiotype therapy.

  View details for Web of Science ID A1985AUL1400096

  View details for PubMedID 2933460

• EPSTEIN-BARR VIRUS ASSOCIATED B-CELL PROLIFERATIONS OF DIVERSE CLONAL ORIGINS AFTER BONE-MARROW TRANSPLANTATION IN A 12-YEAR-OLD PATIENT WITH SEVERE COMBINED IMMUNODEFICIENCY NEW ENGLAND JOURNAL OF MEDICINE Shearer, W. T., Ritz, J., Finegold, M. J., Guerra, I. C., Rosenblatt, H. M., LEWIS, D. E., Pollack, M. S., Taber, L. H., Sumaya, C. V., GRUMET, F. C., Cleary, M. L., Warnke, R., Sklar, J. 1985; 312 (18): 1151-1159

  Abstract

  A 12-year-old boy with severe combined immunodeficiency who had been kept in a gnotobiotic environment since birth received bone marrow from a histoincompatible sibling in an attempt to reconstitute immunologic function. To prevent graft versus host disease, the donor's marrow was treated in vitro with monoclonal antibody and complement to remove alloreactive T cells. Eighty days after transplantation, the patient had a systemic illness characterized by fever, thrombocytopenia, gastrointestinal pain, and bleeding; he died on the 124th post-transplantation day. Postmortem examination revealed multiple tumor-like B-cell proliferations, recipient in origin, in numerous organs. Epstein-Barr virus (EBV) was isolated from the patient's pharyngeal secretions; EBV nuclear antigen was found in spontaneously transformed peripheral-blood lymphocytes, inflammatory cells from peritoneal fluid, and bone marrow cells; and EBV genomes were discovered in all tumor tissues. The donor's serum showed evidence of past EBV infection. Analysis of cellular immunoglobulin and immunoglobulin gene DNA from the tumors indicated both monoclonal and oligoclonal B-cell proliferations. These findings provide evidence for the evolution of EBV-induced polyclonal activation of B cells to oligoclonal B-cell proliferation and finally to monoclonal B-cell lymphoma.

  View details for Web of Science ID A1985AGA9500004

  View details for PubMedID 2984567

• FREQUENT IMMUNOGLOBULIN AND T-CELL RECEPTOR GENE REARRANGEMENTS IN HISTIOCYTIC NEOPLASMS AMERICAN JOURNAL OF PATHOLOGY Weiss, L. M., TRELA, M. J., Cleary, M. L., Turner, R. R., Warnke, R. A., Sklar, J. 1985; 121 (3): 369-373

  Abstract

  The authors have analyzed the DNA of immunoglobulin and T-cell receptor genes in a series of 6 malignancies which were judged to be of histiocytic derivation on the basis of morphologic criteria. They found that 4 of these cases showed rearrangements of the beta T-cell receptor genes in spite of the lack of any specific immunohistochemical markers for B or T cells. One case showed rearrangements of both heavy and light chain immunoglobulin genes and probably represents either a sinusoidal large cell lymphoma or a B-cell lymphoma with activation of histiocytes simulating malignant histiocytosis. A single case lacked both immunoglobulin and T-cell receptor rearrangements consistent with immunologic analyses that suggested its origin from an interdigitating reticulum cell. The result of this study in conjunction with the authors' previous immunologic observations suggests that many presumed histiocytic malignancies actually represent T-cell lymphomas. Alternatively, beta T-cell receptor rearrangement may be a common feature of tumors that show monocyte/histiocytic differentiation.

  View details for Web of Science ID A1985AVY4000001

  View details for PubMedID 3907361

• A CLINICAL-TRIAL OF ANTI-IDIOTYPE THERAPY FOR B-CELL MALIGNANCY BLOOD MEEKER, T. C., Lowder, J., Maloney, D. G., MILLER, R. A., Thielemans, K., Warnke, R., Levy, R. 1985; 65 (6): 1349-1363

  Abstract

  Eleven patients with B lymphocytic malignancy were treated with mouse monoclonal anti-idiotype antibodies. All but one of the patients in this study had received extensive prior treatment with conventional lymphoma therapy. All antibodies were prepared against, and uniquely reactive with, the patient's own tumor. Ten patients were treated with a single antibody, but one patient received three antibodies concurrently. The treatment protocol initially used an escalating dose schedule that was intended to evaluate toxicity, pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last two patients received substantial initial doses. Tumor sampling was performed before and during therapy to evaluate tissue penetration by antibody. None of the patients had serum paraproteins by routine clinical testing, but six had idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/mL, two of which were greater than 200 micrograms/mL. Plasmapheresis was capable of reducing these levels temporarily. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig, which occurred in five of the 11 patients. Once an immune response had begun, further infusions of antibody were not capable of reaching the tumor or inducing tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 42 months after receiving antibody. Five of ten additional patients have had objective remissions that were also clinically significant. However, these remissions were not complete and were of relatively short duration. This therapy shows promise as an alternative modality for the treatment of B cell malignancy. Further study will be needed to determine the mechanisms of the antitumor effect and to improve the clinical results.

  View details for Web of Science ID A1985AJZ7200007

  View details for PubMedID 3888313

• DISCORDANCE BETWEEN SURFACE AND CYTOPLASMIC EXPRESSION OF THE LEU-4 (T3) ANTIGEN IN THYMOCYTES AND IN BLAST CELLS FROM CHILDHOOD T-LYMPHOBLASTIC MALIGNANCIES JOURNAL OF CLINICAL INVESTIGATION Link, M. P., Stewart, S. J., Warnke, R. A., Levy, R. 1985; 76 (1): 248-253

  Abstract

  We have examined the expression of the Leu-4 (T3) antigen on the cell surface and in the cytoplasm of blast cells from 23 patients with T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma. In the majority of cases (17), the Leu-4 antigen was absent from the cell surface; however, in 16 of these 17 cases, blast cells demonstrated cytoplasmic expression of Leu-4. This discordance between surface and cytoplasmic expression of Leu-4 was also found in thymocytes and appeared to be restricted to Leu-4, in that tests of other T cell antigens rarely revealed discordance between surface and cytoplasmic expression. To study further the cytoplasmic determinant identified by anti-Leu-4 in malignant T lymphoblasts, immunoprecipitation studies were performed that utilized biosynthetic labeling of established T cell lines derived from T lymphoblastic malignancies. By one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, identical Leu-4 polypeptide families were immunoprecipitated from surface Leu-4+ and surface Leu-4-/cytoplasmic Leu-4+ cell lines. Because T lymphoblastic malignancies represent proliferations of immature T cells, and because the cases studied demonstrated surface phenotypes corresponding to all of the proposed stages of T cell ontogeny, it appears that cytoplasmic expression of Leu-4 occurs early in T cell development. The reason for the failure of these immature T cells to transport the Leu-4 molecule to their surface remains to be elucidated.

  View details for Web of Science ID A1985AMF6100035

  View details for PubMedID 2410458

• FREQUENT BICLONALITY AND IG GENE ALTERATIONS AMONG B-CELL LYMPHOMAS THAT SHOW MULTIPLE HISTOLOGIC FORMS JOURNAL OF EXPERIMENTAL MEDICINE Siegelman, M. H., Cleary, M. L., Warnke, R., Sklar, J. 1985; 161 (4): 850-863

  Abstract

  Configurations of Ig gene DNA were examined in multiple biopsy specimens from seven cases of human B cell lymphoma that showed histologic differences among the specimens within each case. Analysis by Southern blot hybridizations with DNA probes for each of the three Ig loci revealed that the configurations of DNA within these loci were identical among the specimens in two of the cases. This result indicated the monoclonality of these lymphomas, despite differences in histology between biopsy specimens. In contrast, no common nongermline configurations of Ig gene DNA were detected among multiple biopsies in each of three other cases. Therefore, different histologies correlated with separate clones of proliferating B cells in these cases. In the last two cases, the configurations of light chain gene DNA were the same among biopsies in each case, consistent with a monoclonal origin in both lymphomas. However, differences were detected in the configuration of the heavy chain gene DNA. Analysis with a series of DNA probes of the mu heavy chain region indicated that the differences in the DNA configurations of the heavy chain genes from the biopsies probably arose from postrearrangement deletions of either the switch or constant regions of the mu gene. These studies indicate that, contrary to the conventional belief, individual tumors that contain different histologic types of lymphoma within the same patient frequently arise from separate clones of neoplastic cells. Furthermore, the heavy chain genes of monoclonal tumors may show postrearrangement deletions, often resulting from instability of DNA sequences within or around the mu switch region.

  View details for Web of Science ID A1985AFC1800015

  View details for PubMedID 2984307

• EXPRESSION OF LEU-8 ANTIGEN, A MAJORITY T-CELL MARKER, IS UNCOMMON IN MYCOSIS-FUNGOIDES JOURNAL OF INVESTIGATIVE DERMATOLOGY Abel, E. A., Wood, G. S., Hoppe, R. T., Warnke, R. A. 1985; 85 (3): 199-202

  Abstract

  Predominance of mature helper T cells with the Leu-1+, 2-, 3+, 4+, 5+ phenotype was confirmed in 22 biopsy specimens of mycosis fungoides from 15 patients. Dissection of the T helper/inducer cells into phenotypically distinct subsets was performed with the use of a new monoclonal antibody, anti-Leu-8. One might predict a predominance of Leu-8+ in mycosis fungoides, as the known ratio of Leu-8+/Leu-8- cells is approximately 70/30 in the peripheral blood. Unexpectedly, a deficiency of Leu-8 was demonstrated in 18 of the 22 specimens from 13 of 15 patients. This finding could not be attributed to an artifact of the staining method or to therapy, and was present in early- as well as late-stage disease. Whether neoplastic cells in mycosis fungoides derive from Leu-8-subset of T cells at risk for malignant transformation, or whether there is antigen loss with malignant transformation remains to be determined. Implications of our finding with regard to etiopathogenesis of mycosis fungoides are discussed.

  View details for Web of Science ID A1985AQB1500006

  View details for PubMedID 3161956

• MOST NULL LARGE CELL LYMPHOMAS ARE B-LINEAGE NEOPLASMS LABORATORY INVESTIGATION Cleary, M. L., TRELA, M. J., Weiss, L. M., Warnke, R., Sklar, J. 1985; 53 (5): 521-525

  Abstract

  DNA of immunoglobulin and the beta T cell receptor genes was analyzed for rearrangements in 34 diffuse large cell lymphomas that failed to express immunoglobulins or T cell antigens. Twenty-eight cases had both heavy and light chain immunoglobulin rearrangements, two cases had only heavy chain gene rearrangements, three cases had only light chain gene rearrangements, and one case failed to show rearrangements for any of the immunoglobulin genes. None of the cases showed rearrangements for the beta T cell receptor gene. These results indicate that the vast majority of diffuse large cell lymphomas that lack definitive B or T cell phenotypic markers are actually B cell in origin.

  View details for Web of Science ID A1985ATZ7000003

  View details for PubMedID 3932778

• MORPHOLOGIC AND IMMUNOLOGICAL CHARACTERIZATION OF 50 PERIPHERAL T-CELL LYMPHOMAS AMERICAN JOURNAL OF PATHOLOGY Weiss, L. M., CRABTREE, G. S., Rouse, R. V., Warnke, R. A. 1985; 118 (2): 316-324

  Abstract

  Fifty T-cell lymphomas, excluding mycosis fungoides and lymphoblastic lymphoma, were studied morphologically and immunohistochemically with a panel of monoclonal antibodies reactive with T-cell differentiation antigens in fresh frozen tissue. Histologically, 36% of the lymphomas were large-cell immunoblastic, 26% were diffuse large-cell, 22% were diffuse mixed small and large-cell, and 16% were monomorphic medium-sized-cell lymphomas. By immunologic studies, 64% of the lymphomas were of helper phenotype, 12% were of cytotoxic/suppressor phenotype, 8% expressed both helper and cytotoxic/suppressor suppressor antigenic markers, and 16% lacked detectable markers for either helper or cytotoxic/suppressor cells. There was no correlation between histologic category and immunophenotype. A common finding, and one which may prove to be helpful in the diagnosis of T-cell lymphomas, was the loss of one or more of the pan-T antigens Leu 1, 4, and 5 or the T-cell antigen Leu 9 in 32 cases. The expression of Leu 1 and Leu 9 was lost in 46% of cases, expression of Leu 4 was lost in 26%, and expression of Leu 5 was lost in 24%. About three-quarters of the lymphomas expressed Ia antigens.

  View details for Web of Science ID A1985ABR8300016

  View details for PubMedID 3155915

  View details for PubMedCentralID PMC1887884

• CLONAL REARRANGEMENTS OF T-CELL RECEPTOR GENES IN MYCOSIS-FUNGOIDES AND DERMATOPATHIC LYMPHADENOPATHY NEW ENGLAND JOURNAL OF MEDICINE Weiss, L. M., Hu, E., Wood, G. S., MOULDS, C., Cleary, M. L., Warnke, R., Sklar, J. 1985; 313 (9): 539-544

  Abstract

  Histologic diagnosis of mycosis fungoides may be difficult, especially in lymph nodes that show changes frequently associated with chronic skin disease. As an alternative approach to diagnosis, we have analyzed the configuration of DNA for the beta T-cell receptor genes in biopsy tissues from 14 patients with mycosis fungoides. Clonal rearrangements of these genes were found in each specimen tht contained histologically unambiguous mycosis fungoides. Clonal rearrangements were also found in seven of nine lymph nodes removed from patients with mycosis fungoides and considered histologically to contain only benign lymphadenopathy. Matching rearrangements of beta T-cell receptor genes were detected in benign lymph nodes and histologically involved tissues when paired specimens were available from the same cases. Our findings provide molecular evidence for the clonal T-cell origin of mycosis fungoides and indicate the high incidence of extracutaneous disease in patients with palpable lymphadenopathy. In addition, this study demonstrates that the detection of rearranged T-cell receptor genes can be a sensitive and practical method for the diagnosis and characterization of T-cell neoplasms.

  View details for Web of Science ID A1985APP1400003

  View details for PubMedID 4022090

• EMERGENCE OF IDIOTYPE VARIANTS DURING TREATMENT OF B-CELL LYMPHOMA WITH ANTI-IDIOTYPE ANTIBODIES NEW ENGLAND JOURNAL OF MEDICINE Meeker, T., Lowder, J., Cleary, M. L., Stewart, S., Warnke, R., Sklar, J., Levy, R. 1985; 312 (26): 1658-1665

  Abstract

  We studied two patients with malignant B-cell lymphoma that manifested resistance to the therapeutic effects of anti-idiotype antibody because of the emergence of subclones with changes in their immunoglobulin idiotypes. In both patients, tumor-cell populations arose that were unreactive with anti-idiotype antibody but that retained surface immunoglobulin. One of the patients had an additional subpopulation of tumor cells that had switched from mu to gamma heavy-chain expression. Study of the immunoglobulin genes in the tumors confirmed that the subpopulations were derived from the same original clone of neoplastic B cells in each patient. The available data suggest that the idiotypic variation observed was the result of somatic mutation in the variable region of the active immunoglobulin genes. The fact that such mutations became evident over a short time and in the context of a partial tumor response suggests that the antibody therapy exerted a strong selective force against tumor cells that expressed the idiotype determinant. Multiple anti-idiotype antibodies may therefore be needed to identify all cells of a malignant clone, and some patients may require treatment with more than one monoclonal antibody.

  View details for Web of Science ID A1985AKT8700002

  View details for PubMedID 3923352

• MONOCLONAL ANTI-KERATIN (AE1) REACTIVITY IN ROUTINELY PROCESSED TISSUE FROM 166 HUMAN NEOPLASMS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Spagnolo, D. V., Michie, S. A., CRABTREE, G. S., Warnke, R. A., Rouse, R. V. 1985; 84 (6): 697-704

  Abstract

  A large number of human neoplasms were tested for their keratin expression in routinely processed tissues by a simple, three-stage immunoperoxidase method using a broadly reactive monoclonal anti-keratin antibody AE1, which recognizes a number of keratin polypeptides distributed in a wide variety of epithelia. All carcinomas, with the exception of hepatocellular, adrenocortical, and basal cell carcinomas and occasional renal cell, pulmonary small-cell, and pulmonary large-cell anaplastic carcinomas, reacted with this antibody irrespective of differentiation, in most instances displaying staining of strong or moderate intensity in the majority of tumor cells. Equivocal results were obtained in some seminomas and dysgerminomas. Malignant melanoma, large-cell lymphoma, Hodgkin's disease, malignant histiocytosis, and stromal mesenchymal elements in all tumors did not show any reactivity with AE1. Even after routine processing, the determinant detected by AE1 is conserved and restricted to epithelial neoplasms. This suggests that AE1 would be valuable in the diagnostic distinction of anaplastic carcinoma from lymphoma and melanoma in routinely processed tissues.

  View details for Web of Science ID A1985AVP2300002

  View details for PubMedID 2416215

• THE IMMUNOHISTOLOGY OF NON-T-CELLS IN THE ACQUIRED IMMUNODEFICIENCY SYNDROME AMERICAN JOURNAL OF PATHOLOGY Wood, G. S., Burns, B. F., Dorfman, R. F., Warnke, R. A. 1985; 120 (3): 371-379

  Abstract

  The authors employed a panel of monoclonal antibodies to characterize B cells, histiocytes, and natural killer cells in lymph node biopsies obtained from 7 homosexual men with the acquired immune deficiency syndrome (AIDS) and 5 heterosexual controls. Six of the AIDS patients, each with cutaneous and/or nodal Kaposi's sarcoma, exhibited reactive follicular hyperplasia, as did the 5 controls. The seventh AIDS patient had opportunistic infections and exhibited a lymphocyte depletion pattern in lymph nodes. In AIDS patients, reactive B-cell follicles often exhibited attenuation of their mantle zones. Many were regressively transformed and composed predominantly of dendritic reticulum cells. Occasional germinal center dendritic reticulum cell networks exhibited fragmentation reminiscent of the "follicle lysis" described previously in the persistent generalized lymphadenopathy syndrome. In the 1 AIDS patient with the lymphocyte depletion pattern of lymph node histology, germinal center elements, including dendritic reticulum cells, were totally absent. In all cases, the mononuclear-cell subsets exhibited normal patterns of antigen expression. Quantitative studies, however, revealed a significant increase (P less than or equal to 0.01) in natural killer cells and histiocytes within the paracortical T-cell domain of lymph nodes obtained from patients with AIDS. There was no significant difference in the number of natural killer cells within the mantle or germinal center B-cell domains. While there was no significant difference in the absolute number of paracortical B cells, they were relatively increased due to an absolute decrease in T cells. It is concluded that quantitative alterations in mononuclear-cell subsets in patients with AIDS are not restricted to T cells and that these alterations are microenvironmentally specific.

  View details for Web of Science ID A1985AQT2900006

  View details for PubMedID 3898858

• THE IMMUNOHISTOLOGY OF FOLLICLE LYSIS IN LYMPH-NODE BIOPSIES FROM HOMOSEXUAL MEN BLOOD Wood, G. S., Garcia, C. F., Dorfman, R. F., Warnke, R. A. 1985; 66 (5): 1092-1097

  Abstract

  Follicle lysis is a characteristic alteration of B cell follicles described recently in lymph node biopsies from homosexual men. It consists of disruption of germinal centers by aggregates of small mature lymphocytes variably associated with erythrocyte extravasation. We studied the immunohistology of follicle lysis identified in lymph node biopsies from 11 homosexual men. The results indicate that follicle lysis has two principal immunohistologic features: (1) intrafollicular aggregates of small lymphocytes predominantly of polytypic mantle B cell phenotype (T015+/Leu-8+/mu+/delta+/k+ or lambda+), and (2) disruption of the normal, unified follicular meshwork of R4/23+ dendritic reticulum cells by these B cell aggregates. These structural alterations may affect the functional integrity of the germinal center as it pertains to the abnormal B cell effector function and the increased prevalence of B cell lymphoma recently documented in the acquired immunodeficiency syndrome and related disorders. Because dendritic reticulum cells weakly express the Leu-3 (T4) antigen, which is known to be an essential component of the receptor for human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) retrovirus infection, it is possible that retroviral infection of dendritic reticulum cells may play a role in the pathogenesis of follicle lysis.

  View details for Web of Science ID A1985AUP7600014

  View details for PubMedID 3876855

• LIMITATIONS ENCOUNTERED IN THE APPLICATION OF TISSUE SECTION IMMUNODIAGNOSIS TO THE STUDY OF LYMPHOMAS AND RELATED DISORDERS HUMAN PATHOLOGY Warnke, R. A., Rouse, R. V. 1985; 16 (4): 326-331

  View details for Web of Science ID A1985AFT5100002

  View details for PubMedID 2579887

• CLINICAL RELEVANCE OF IMMUNOLOGICAL PHENOTYPE IN DIFFUSE LARGE CELL LYMPHOMA BLOOD Horning, S. J., Doggett, R. S., Warnke, R. A., Dorfman, R. F., Cox, R. S., Levy, R. 1984; 63 (5): 1209-1215

  Abstract

  The immunologic phenotypes of 78 diffuse large cell lymphomas were determined by an immunoperoxidase technique using a panel of monoclonal antibodies. The phenotypes were correlated with clinical and morphological parameters by univariate and multivariate analysis. Forty-one lymphomas (53%) expressed immunoglobulin (Ig+). Of the 37 cases that did not express immunoglobulin (Ig-), 9 expressed T cell antigens. Although the T cell phenotypes were antigenically heterogeneous, all cases represented mature T cell phenotypes. The majority of the remaining 28 cases expressed the B cell-associated antigen, B1. At 5 yr, actuarial survival for the Ig- patients was 63%, compared with 15% for the Ig+ patients. A significantly greater proportion of patients with Ig+ lymphomas were over the age of 65 at diagnosis. All of the 9 patients with marrow involvement were Ig+. Multiple factors were analyzed by the Cox regression procedure for their impact on survival, including antigenic profile, histologic grade, morphological classification, and numerous clinical parameters previously recognized to be of prognostic significance. In this analysis, stage, age greater than 65 yr, systemic symptoms, and marrow involvement had the greatest influence on survival. The survival difference between Ig- and Ig+ patients is explained by a higher proportion of Ig+ patients with these unfavorable prognostic factors. With our current immunologic methods, retrospective cell phenotyping analysis has not provided independent prognostic significance in diffuse large cell lymphoma. A prospective evaluation of similarly treated patients is needed to characterize the influence of phenotype fully and to determine its potential usefulness for therapy.

  View details for Web of Science ID A1984SQ45700034

  View details for PubMedID 6370335

• PAN-LEUKOCYTE MONOCLONAL ANTIBODY-L3B12 - CHARACTERIZATION AND APPLICATION TO RESEARCH AND DIAGNOSTIC PROBLEMS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Wood, G. S., Link, M., Warnke, R. A., Dilley, J., Levy, R. 1984; 81 (2): 176-183

  Abstract

  In this report, the authors describe a murine anti-human monoclonal antibody, L3B12, which defines a pan-leukocyte cell surface antigen of approximately 180,000 m.w. Extensive screening against a variety of tissues indicates that L3B12 is sensitive and specific for leukocytes, related cells of bone marrow lineage, and their corresponding neoplasms. Unlike many lymphoid antigens that are not detectable following routine fixation and embedding, those recognized by L3B12 and related antibodies are variably preserved. L3B12 has proven useful in studying the antigen expression of normal leukocytic elements, lymphomas, and related disorders, and in enriching or depleting leukocytes from heterogeneous cell populations. From a diagnostic standpoint, L3B12 staining of tissue sections or cell suspensions is useful for distinguishing large cell lymphomas from undifferentiated carcinomas and in distinguishing lymphomas and leukemias from other small round cell tumors of childhood.

  View details for Web of Science ID A1984SD84900005

  View details for PubMedID 6364781

• HISTIOCYTIC MALIGNANCIES - MORPHOLOGIC, IMMUNOLOGICAL, AND ENZYMATIC HETEROGENEITY AMERICAN JOURNAL OF SURGICAL PATHOLOGY Turner, R. R., Wood, G. S., Beckstead, J. H., Colby, T. V., Horning, S. J., Warnke, R. A. 1984; 8 (7): 485-500

  Abstract

  We have studied 14 hematopoietic malignancies with histologic features of histiocytic differentiation, using frozen section immunologic stains, plastic section enzyme histochemistry, and paraffin section immunocytochemistry. There was morphologic, immunologic, and enzymatic heterogeneity, including findings in seven cases that suggested differentiation toward specialized subsets of histiocytes. Four cases expressed a mature monocyte/macrophage phenotype by frozen section monoclonal antibody staining and three of these had histologic patterns diagnostic of malignant histiocytosis; two other cases had ATPase and S100 protein reactivity and morphologic features consistent with interdigitating (reticulum) cell proliferations; and one case was alkaline phosphatase positive, suggestive of differentiation toward fibroblastic reticulum cells. Four cases had histologic findings consistent with malignant histiocytosis, but weak or unreactive staining patterns and were considered poorly differentiated histiocytic or primitive hematopoietic malignancies. Three other cases, also morphologically consistent with malignant histiocytosis, were identified as probably T-cell lymphomas. The morphologic and phenotypic characteristics of non-neoplastic histiocytes and dendritic cell types and their related neoplasms are discussed. Histiocytic malignancies comprise a diverse group that can be identified and subclassified by immunologic and enzymatic techniques.

  View details for Web of Science ID A1984TB65700001

  View details for PubMedID 6204546

• STRATEGIES FOR PRODUCTION OF MONOCLONAL ANTI-IDIOTYPE ANTIBODIES AGAINST HUMAN B-CELL LYMPHOMAS JOURNAL OF IMMUNOLOGY Thielemans, K., Maloney, D. G., Meeker, T., Fujimoto, J., Doss, C., Warnke, R. A., Bindl, J., Gralow, J., MILLER, R. A., Levy, R. 1984; 133 (1): 495-501

  Abstract

  Murine monoclonal antibodies (MAB) against the idiotype (Id) of B lymphocyte malignancies are powerful reagents for the study of these diseases, and are potentially useful for treatment. Different strategies for the production of these anti-Id MAB have been compared. Initially, the Id Ig from nonsecreting B cell tumors was "rescued" by human X mouse or human X human hybridization. These somatic cell hybridizations resulted in the secretion of human Ig in 10 and 100% of the fusions, respectively. In a second step, anti-Id MAB were produced by using the "rescued" Id Ig as immunogen. A more streamlined approach is based on a one-step procedure in which the tumor cell suspension is used as immunogen. This method of immunization, coupled with a four-layer ELISA, results in the detection of anti-Id MAB in a frequency of approximately 1% of the total hybrids. By using a pool of 10 different anti-Id MAB, each reactive with the tumor of one patient, we searched for idiotypic relatedness among a panel of 50 additional tumors. No cross-reactions were found, indicating that our current strategy results in the identification of unique idiotypic determinants among human B cell tumors. Idiotypic Ig can be found in the serum of patients with B cell tumors. Among groups of patients, there is a wide spectrum of serum Id levels, ranging from less than 0.01 microgram/ml to greater than 500 micrograms/ml.

  View details for Web of Science ID A1984SW96300082

  View details for PubMedID 6609992

• A UNIQUE HUMAN LYMPHOCYTE-B ANTIGEN DEFINED BY A MONOCLONAL-ANTIBODY HYBRIDOMA MEEKER, T. C., MILLER, R. A., Link, M. P., Bindl, J., Warnke, R., Levy, R. 1984; 3 (4): 305-320

  Abstract

  We produced a hybridoma designated 4G7 from a mouse immunized with chronic lymphocytic leukemia cells. The 4G7 hybridoma secretes an IgG1 antibody that is specific for normal and malignant B lymphocytes. Using dual color immunofluorescence staining, this antibody reacted with all immunoglobulin-positive cells but no T cells in normal peripheral blood. There was no detectable 4G7 antigen on monocytes, platelets, red cells, granulocytes, or phytohemagglutinin-activated T cells. When PBL were depleted of 4G7 positive cells and stimulated with pokeweed mitogen, secreted immunoglobulin levels fell to less than 10% of control values on Day 5 and less than 1% of control on Day 7. This antibody was reactive with 155 of 176 B lineage neoplasms on which it was screened. Thirty-five cases of myeloid or T-lymphoid malignancy were negative. Our studies show that the 4G7 antigen modulates in the presence of excess antibody. Free 4G7 antigen was not found circulating in human serum. The cell surface antigen identified by 4G7 was sensitive to pronase proteolysis but resistant to trypsin and chymotrypsin digestion. A comparison of 4G7 with other known B-cell antibodies indicates that the 4G7 antigen has not been previously identified. This antibody is of use for the identification of normal B lymphocytes, the study of B-cell differentiation, and the characterization of lymphoid malignancies.

  View details for Web of Science ID A1984AAF5100001

  View details for PubMedID 6441771

• MONOCLONAL-ANTIBODY AND ENZYMATIC PROFILES OF HUMAN-MALIGNANT LYMPHOID-T CELLS AND DERIVED CELL-LINES CANCER RESEARCH Smith, S. D., Shatsky, M., Cohen, P. S., Warnke, R., Link, M. P., Glader, B. E. 1984; 44 (12): 5657-5660

  Abstract

  Recently, four distinct cell lines were established from patients whose malignancies had been defined by immunological and biochemical markers. Each patient had a distinct subtype of a T-cell cancer, and each possessed elevated adenosine deaminase and reduced nucleoside phosphorylase activity. Cell lines cultured in vitro possessed the same basic immunophenotype and biochemical enzyme activity as the patients' original malignant cells. In a direct comparison of the immunophenotype of the cell lines and the patients' malignant cells, full concordance existed for 48 of 52 paired antibody tests performed. However, when compared to the corresponding patient's sample, each cell line showed some minor changes in antigen expression or enzyme level. Antigen loss, de novo antigen expression, or elevated adenosine deaminase levels occurred in the cell lines, and these changes were stable on repeated analysis. While there was good general concordance between the patient's cancer and the established cell line, minor biological differences in the cell lines may reflect cellular maturation or subpopulation selection in vitro.

  View details for Web of Science ID A1984TU47100032

  View details for PubMedID 6437672

• MONOCLONALITY OF LYMPHOPROLIFERATIVE LESIONS IN CARDIAC-TRANSPLANT RECIPIENTS - CLONAL ANALYSIS BASED ON IMMUNOGLOBULIN-GENE REARRANGEMENTS NEW ENGLAND JOURNAL OF MEDICINE Cleary, M. L., Warnke, R., Sklar, J. 1984; 310 (8): 477-482

  Abstract

  Whether lymphoproliferative disorders arising in immunosuppressed recipients of organ transplants are primarily neoplastic or hyperplastic in nature is a matter of controversy. Reports of polyclonal B-cell proliferations in these lesions suggest the presence of hyperplasia, but these disorders resemble lymphoma histologically and are clinically aggressive and often rapidly fatal, as expected of a malignant neoplastic disease. We examined tissue specimens from 10 cases of lymphoproliferative disease that occurred in immunosuppressed recipients of cardiac transplants. Specimens from nine of these patients lacked cellular immunoglobulin; however, analysis of DNA extracted from these tissues revealed that each lesion contained large numbers of cells possessing uniform, clonal rearrangements of immunoglobulin-gene DNA. Therefore, when first seen clinically these proliferations contained a notable monoclonal-cell population typical of conventional B-cell lymphomas that are not associated with immunosuppression. We therefore suggest that lymphoproliferative disorders in recipients of cardiac transplants are neoplastic at the earliest stages of detectable disease.

  View details for Web of Science ID A1984SD74900001

  View details for PubMedID 6363929

• IMMUNOGLOBULIN GENE REARRANGEMENT AS A DIAGNOSTIC CRITERION OF BETA-CELL LYMPHOMA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES Cleary, M. L., Chao, J., Warnke, R., Sklar, J. 1984; 81 (2): 593-597

  Abstract

  We describe the use of the Southern blot hybridization technique to diagnose B-cell lymphoma by detecting clonal immunoglobulin gene rearrangements in lymph node and other biopsy tissues. DNA was isolated from a wide variety of neoplastic and non-neoplastic specimens and analyzed for the presence of rearranged immunoglobulin genes using radiolabeled DNA probes specific for the heavy- and light-chain immunoglobulin constant region genes. Among the specimens examined, clonal immunoglobulin gene rearrangements were found only in biopsy samples of B-cell lymphoma and not in samples containing reactive lymphoid processes or non-B-cell cancers. In lymphomas, the presence of rearrangements for either the kappa or lambda light-chain gene correlated with expression of one or the other of these chains when cellular immunoglobulins could be detected by frozen-section immunophenotyping techniques. The analysis of immunoglobulin gene rearrangements offers several advantages over conventional diagnostic methods for lymphomas, including improved sensitivity in detecting minor populations of neoplastic lymphocytes composing as little as 1% of the total cell population. In addition, clonal immunoglobulin gene rearrangements are demonstrable in a subset of lymphomas that lack detectable surface or cytoplasmic immunoglobulin, thus offering positive evidence for both malignancy and the B-cell origin of these tumors. Our studies indicate that detection of immunoglobulin gene rearrangements is a valuable method for diagnosis and classification of various lymphoproliferative disorders that are difficult to evaluate histologically or that lack distinctive antigenic markers.

  View details for Web of Science ID A1984SC15300065

  View details for PubMedID 6607475

• IMMUNOGLOBULIN GENE REARRANGEMENTS IN HAIRY-CELL LEUKEMIA BLOOD Cleary, M. L., Wood, G. S., Warnke, R., Chao, J., Sklar, J. 1984; 64 (1): 99-104

  Abstract

  Studies of hairy cell leukemia have yielded conflicting data about the cell of origin in this disease. To investigate this issue, we have examined the state of immunoglobulin genes in the cells of 11 randomly selected spleens showing histologic involvement with hairy cell leukemia. DNA was extracted from splenic tissue samples and digested with restriction endonucleases. Following agarose gel electrophoresis and transfer to nitrocellulose filters or activated nylon membranes, splenic DNA was hybridized with radiolabeled DNA fragment probes specific for the constant regions of the immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiograms of the hybridized DNA in each case revealed rearrangements of a heavy chain gene and at least one light chain gene. In addition, immunophenotyping of cellular immunoglobulin polypeptides was carried out on frozen tissue sections from all but one case. In each case in which an immunoglobulin polypeptide could be detected, a rearrangement was present in the DNA of the corresponding immunoglobulin gene. These studies offer strong evidence for endogenous immunoglobulin synthesis in hairy cells and for the B lymphocytic character of this leukemia.

  View details for Web of Science ID A1984SY61300014

  View details for PubMedID 6329381

• BICLONAL B-CELL LYMPHOMA NEW ENGLAND JOURNAL OF MEDICINE Sklar, J., Cleary, M. L., Thielemans, K., Gralow, J., Warnke, R., Levy, R. 1984; 311 (1): 20-27

  Abstract

  The cells of most tumors are considered to be genetically homogeneous because they are assumed to represent a single clone descended from one abnormal cell. We have discovered three cases of B-cell lymphoma for which this generalization is not true. In each case, the tumor was composed of two subpopulations of cells, each expressing a different immunoglobulin molecule. Antibodies directed against these immunoglobulins were used to separate the two cell subpopulations of each tumor on a fluorescence-activated cell sorter. DNA extracted from the original tumor and the two fractionated subpopulations was analyzed to determine the configuration of immunoglobulin genes. Differences were found in the arrangement of DNA in at least one immunoglobulin gene for each of the two subpopulations. Thus, biclonality of these tumors was revealed by examination of both protein markers (cell-surface immunoglobulin) and DNA markers (immunoglobulin-gene rearrangements). Our results indicate that the incidence of biclonal B-cell lymphoma may be higher than previously recognized, possibly as high as 10 per cent of all B-cell lymphomas. Furthermore, our findings may have important implications for the diagnosis and therapy of lymphoid cancers.

  View details for Web of Science ID A1984SX98200004

  View details for PubMedID 6427612

• THE IMMUNOLOGICAL CHARACTERIZATION OF 95 NODAL AND EXTRANODAL DIFFUSE LARGE CELL LYMPHOMAS IN 89 PATIENTS AMERICAN JOURNAL OF PATHOLOGY Doggett, R. S., Wood, G. S., Horning, S., Levy, R., Dorfman, R. F., Bindl, J., Warnke, R. A. 1984; 115 (2): 245-252

  Abstract

  Ninety-five diffuse large cell lymphomas in 89 patients were stained in cryostat sections with a panel of monoclonal antibodies. Lymphoma cells from 47 patients (53%) expressed either kappa or lambda light chains, usually in combination with mu heavy chains. Fifteen samples from 12 patients (14%) expressed two or more T-cell antigens and commonly expressed Ia antigens. Lymphoma cells from 10 of these patients uniformly lacked one or more pan T-cell antigens; lymphoma cells from 4 of these patients also lacked both T-subset antigens--findings which should prove useful in diagnosis. Lymphomas from 28 patients (31%) did not express immunoglobulin or T-cell antigens but commonly expressed the B-lineage antigen B1; and the remaining 9 cases generally expressed Ia antigens, common ALL antigens, or both. Our findings confirm the marked immunologic heterogeneity of diffuse large cell lymphomas; the phenotypic heterogeneity observed in T-cell cases in many instances is difficult to reconcile with current models of T-cell differentiation.

  View details for Web of Science ID A1984SQ54100012

  View details for PubMedID 6232854

• LYMPHOCYTIC INFILTRATES OF THE CONJUNCTIVA AND ORBIT - IMMUNOHISTOCHEMICAL STAINING OF 16 CASES AMERICAN JOURNAL OF CLINICAL PATHOLOGY Turner, R. R., Egbert, P., Warnke, R. A. 1984; 81 (4): 447-452

  Abstract

  The authors have performed frozen section immunologic stains on 16 cases of ocular lymphocytic infiltrates and correlated the results with clinical and histologic findings. Their cases included inflammatory pseudotumor (3), reactive lymphoid hyperplasia (3), atypical lymphocytic infiltrate (9), and small cleaved cell lymphoma (1). Seven of the nine cases with an atypical lymphocytic infiltrate expressed one immunoglobulin light chain, while only one of six considered reactive on histologic evaluation had immunologic results suggestive of a neoplastic B cell proliferation. The case of follicular small cleaved cell lymphoma expressed B lineage antigens but did not express immunoglobulin; this patient died of disseminated lymphoma two years after conjunctival involvement. Percentages and subset ratios of T lymphocytes were quantitated and showed similar results in reactive and neoplastic lesions. There is no apparent difference in clinical presentation or follow-up information between patients with reactive lesions and those having an atypical lymphocytic infiltrate with monotypic immunoglobulin.

  View details for Web of Science ID A1984SL52500006

  View details for PubMedID 6608261

• EXPRESSION OF A T-CELL ANTIGEN (LEU-1) BY B-CELL LYMPHOMAS AMERICAN JOURNAL OF PATHOLOGY Burns, B. F., Warnke, R. A., Doggett, R. S., Rouse, R. V. 1983; 113 (2): 165-171

  Abstract

  The Leu-1 antigen has been defined by monoclonal antibodies (L17F12, T101, and OKT-1) as a pan-T-cell antigen present on all human peripheral blood T cells and thymocytes. Although originally thought to be confined to T-cell lineage, some cases of B-cell chronic lymphocytic leukemia have been found to react with these antibodies. Using a frozen section immunoperoxidase staining technique, 125 lymphomas with B-cell differentiation were examined for the presence of Leu-1 antigen. Leu-1 antigen was detected in 4 of 11 cases of diffuse small lymphocytic lymphoma (Rappaport's DWDL) and 3 of 4 cases of diffuse intermediate lymphocytic lymphoma. Follicular lymphomas less often expressed this antigen--2 of 29 cases of the small cleaved cell type (Rappaport's NPDL), none of 13 cases of mixed small cleaved and large cell type (Rappaport's NM), and 1 of 6 cases of large cell type (Rappaport's NH). Diffuse lymphomas of presumed follicular center cell origin expressed this antigen infrequently as well--1 of 3 cases of the small cleaved cell type (Rappaport's DPDL), neither of 2 cases of mixed small cleaved and large cell type (Rappaport's DM), and 3 of 43 of large cell type (cleaved/noncleaved) (Rappaport's DH). Diffuse large cell, immunoblastic lymphoma of B-cell type expressed Leu-1 in 1 of 6 cases. None of the 3 cases of Burkitt's lymphoma or of the three small noncleaved non-Burkitt's lymphoma (Rappaport's undifferentiated) expressed detectable Leu-1. B-lymphoblastic lymphoma (1 case) and B-cell unclassified lymphoma (1 case) both failed to express detectable Leu-1. It appears that this pan-T-cell antigen is mainly found on those B-cell lymphomas composed predominantly of small lymphocytes. This finding may be of use in distinguishing extranodal neoplastic collections of small lymphocytes from lymphocytic hyperplasias.

  View details for Web of Science ID A1983RQ20600005

  View details for PubMedID 6605688

  View details for PubMedCentralID PMC1916369

• METHODS FOR DECREASING INTERSTITIAL IMMUNOGLOBULIN IN TISSUE-SLICES AND CRYOSTAT SECTIONS HISTOCHEMICAL JOURNAL Warnke, R. A., Bindl, J., DOGGETT, R. 1983; 15 (7): 637-644

  Abstract

  To determine whether lymphoid antigens and cellular morphology can be preserved after long-distance transport in buffer or cell culture medium, we stained cryostat sections prepared from human tonsil samples that had been kept at 4 degrees C or 20 degrees C for 24, 48 or 72 h. B-Cell antigens, T-cell antigens, and Ia antigens were well preserved after storage up to 72 h in buffer or medium at 4 degrees C. Interstitial immunoglobulin (Ig) was decreased following all incubation procedures. We then investigated methods to diminish interstitial Ig in cryostat sections, since it would be inconvenient to keep 2-3 mm tissue slices in buffer or medium prior to freezing and subsequent Ig staining. Cryostat sections were air dried or briefly fixed in acetone prior to washing in buffer or medium at 4 degrees C, 20 degrees C or 37 degrees C for 1, 2 or 24 h. Then sections were air dried or washed prior to acetone fixation and immunostaining. A method for washing cryostat sections was developed which diminished interstitial Ig without compromising the quality of immunostaining or cellular detail. These methods are especially useful for studying samples of lymphoid tissue in which the presence of large quantities of interstitial Ig obscures the detection of monotypic Ig staining patterns.

  View details for Web of Science ID A1983QY93600004

  View details for PubMedID 6576991

• ANTI-LEU-3/T4 ANTIBODIES REACT WITH CELLS OF MONOCYTE-MACROPHAGE AND LANGERHANS LINEAGE JOURNAL OF IMMUNOLOGY Wood, G. S., Warner, N. L., Warnke, R. A. 1983; 131 (1): 212-216

  Abstract

  Anti-Leu-3a, anti-Leu-3b, OKT4, and anti-T4 murine monoclonal antibodies react with a membrane component expressed by mature peripheral blood helper T cells and certain thymocyte subsets. Using a variety of immunologic staining techniques, we have demonstrated the reactivity of these antibodies with other cell types. Normal and neoplastic cells of monocyte/macrophage lineage bear the Ia+/Leu-6-/Leu-3+ phenotype, whereas histiocytosis X cells bear the Ia+/Leu-6+/Leu-3+ phenotype. The Ia+/Leu-6- cells of malignant histiocytosis and the Ia+/Leu-6+ epidermal Langerhans cells were variably Leu-3+. Normal monocyte/macrophage reactivity with anti-Leu-3/T4 appears to be primarily intracytoplasmic, whereas on U937 monocyte tumor cells, marked membrane reactivity is also observed. These results strongly suggest that certain cells other than helper T cells and thymocytes can express and, at least in some cases, synthesize a component previously regarded as T-lineage specific.

  View details for Web of Science ID A1983QX45700039

  View details for PubMedID 6408171

• A SINGLE MONOCLONAL-ANTIBODY IDENTIFIES T-CELL LINEAGE OF CHILDHOOD LYMPHOID MALIGNANCIES BLOOD Link, M., Warnke, R., Finlay, J., Amylon, M., Miller, R., Dilley, J., Levy, R. 1983; 62 (4): 722-728

  Abstract

  Immunophenotyping studies with monoclonal antibodies have revealed the heterogeneity of childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The lymphoid malignancies of T-cell lineage are particularly heterogeneous and, until now, no single monoclonal antibody has been found to identify all cases of T-ALL and T-NHL. A monoclonal antibody, 4H9, recognizes an antigen of 40,000 molecular weight on normal and malignant T cells. Thirty-six cases of childhood T-ALL and T-NHL were tested, and in all cases, the malignant blast cells were reactive with 4H9, whereas malignant cells from 61 cases of non-T ALL and NHL were not reactive with 4H9. Monoclonal antibody 4H9 is a sensitive and specific reagent for the identification of childhood T-cell ALL and NHL and should be extremely useful in immunophenotyping studies of lymphoid malignancies.

  View details for Web of Science ID A1983RK80600002

  View details for PubMedID 6603882

• DIAGNOSIS OF HUMAN LYMPHOMA WITH MONOCLONAL ANTI-LEUKOCYTE ANTIBODIES NEW ENGLAND JOURNAL OF MEDICINE Warnke, R. A., Gatter, K. C., Falini, B., HILDRETH, P., WOOLSTON, R. E., Pulford, K., Cordell, J. L., Cohen, B., DeWolfPeeters, C., Mason, D. Y. 1983; 309 (21): 1275-1281

  Abstract

  Two monoclonal antibodies have been produced that react with antigens present on human white cells. These reagents differ from other monoclonal antibodies of similar specificity in that the antigens they recognize are resistant to conventional tissue-fixation and embedding procedures. These reagents can therefore be used in immunocytochemical staining of paraffin-embedded tissue sections. We assessed the practical usefulness of this technique in the histopathological diagnosis of human lymphoid neoplasms by staining a wide range of routine surgical biopsy specimens of normal and neoplastic tissue (gathered from five institutions), using an indirect immunoperoxidase technique. In all 40 cases of non-Hodgkin's lymphoma, positive labeling of neoplastic cells was obtained with one or both antibodies. In contrast, no staining of neoplastic cells was observed in 60 samples of nonlymphoid neoplasms. We conclude that many of the difficulties encountered by histopathologists in distinguishing between lymphoid and nonlymphoid neoplasms may be overcome by immunohistologic labeling with monoclonal antibodies such as the ones we have studied.

  View details for Web of Science ID A1983RR64500002

  View details for PubMedID 6355845

• THE IMMUNOLOGICAL AND CLINICOPATHOLOGIC HETEROGENEITY OF CUTANEOUS LYMPHOMAS OTHER THAN MYCOSIS-FUNGOIDES BLOOD Wood, G. S., Burke, J. S., Horning, S., Doggett, R. S., Levy, R., Warnke, R. A. 1983; 62 (2): 464-472

  Abstract

  Twenty-one cases of non-Hodgkin's lymphoma with cutaneous involvement, other than mycosis fungoides, were evaluated immunologically, histologically, and clinically. Ten patients presented with skin disease alone, seven with concurrent cutaneous and extracutaneous disease, and four with extracutaneous disease only. Twenty of the 21 cases were nonepidermotropic tumors and were equally likely to express B or T phenotypes. None of the cases expressed a true histiocytic phenotype. Almost all cases expressed la and class 1 HLA determinants. Immunophenotypes were stable regardless of time interval, therapy, or body site sampled in seven of eight patients studied serially. In contrast to mycosis fungoides, the T lymphomas exhibited noncerebriform cytology, tumor la expression, lack of mature helper T-cell phenotype, nonepidermotropic histology, a tendency for marrow involvement, and presented as nodules rather than patches or plaques. Since each T lymphoma expressed an abnormal but uniform T-cell phenotype other than mature cytotoxic/suppressor or helper, the neoplastic population could be distinguished from reactive T cells. Reactive elements averaged one-third of the cellular infiltrates and were mainly T cells and macrophages. Langerhans cells were generally normal in number and distribution. Several histopathologic subtypes were identified with diffuse large cell lymphomas, including immunoblastic lymphomas, comprising 71% of cases (15/21). Prediction of the immunophenotype based on cytologic criteria was correct in 67% of cases (14/21). All errors occurred among the 13 high-grade lymphomas. Survival data were consistent with those of prior studies that have indicated that clinical course is dependent on stage and histologic subtype. Non-Hodgkin's cutaneous lymphomas constitute an immunologically, histologically, and clinically heterogeneous group of neoplasms.

  View details for Web of Science ID A1983RC87400034

  View details for PubMedID 6603242

• IDENTIFICATION AND SIGNIFICANCE OF CELL MARKERS IN LEUKEMIA AND LYMPHOMA ANNUAL REVIEW OF MEDICINE Warnke, R. A., Link, M. P. 1983; 34: 117-131

  Abstract

  The identification of markers of human hematopoietic cell differentiation and function has revealed the nature of the proliferating cell in many lymphoid neoplasms and demonstrated marked phenotypic heterogeneity in traditional subgroups. Selected markers are described that define common subgroups of lymphoid leukemia and non-Hodgkin's lymphoma. The identification of cell markers has significant implications for accuracy of diagnosis, for predicting clinical characteristics, and for understanding the biology of these diseases.

  View details for Web of Science ID A1983QJ82600010

  View details for PubMedID 6407386

• MORPHOLOGIC TYPES OF DIFFUSE LARGE-CELL LYMPHOMA CANCER Warnke, R. A., Strauchen, J. A., Burke, J. S., Hoppe, R. T., Campbell, B. A., Dorfman, R. F. 1982; 50 (4): 690-695

  Abstract

  One hundred eighty-seven patients with confirmed diffuse non-Hodgkin's lymphoma were selected from a consecutive series of 391 patients who were evaluated and treated at Stanford University Medical Center. Lymphomas with any degree of nodularity and diffuse lymphomas of "well-differentiated" and "poorly differentiated" lymphocytic type were excluded from this study. Each of four observers identified cases of diffuse large-cell lymphoma from the 187 cases and further subdivided these cases into six morphologic types in accordance with criteria proposed by Strauchen et al. Initial intraobserver and interobserver agreement was relatively low but was greatly enhanced when the initial six morphologic types were grouped as either follicular center-cell or nonfollicular center-cell types. When individual observer results were pooled, statistically significant differences were seen between survival of patients in these two groups, with the patients in the nonfollicular differences were seen between survival of patients in these two groups, with the patients in the nonfollicular center-cell group having a worse prognosis (P = 0.04). This effect of morphologic type appeared to be independent of pathologic stage. Mitotic counts did not correlate with survival.

  View details for Web of Science ID A1982NZ72200011

  View details for PubMedID 7093905

• HISTOCHEMISTRY OF HODGKINS-DISEASE CANCER TREATMENT REPORTS Beckstead, J. H., Warnke, R., Bainton, D. F. 1982; 66 (4): 609-613

  Abstract

  The histochemistry of Hodgkin's cells is controversial. Limited numbers and the variety of techniques used make comparisons difficulty. Acid phosphatase and nonspecific esterase have been the two enzymes most frequently tested because the presence of these enzymes has been thought to be characteristic of histiocytes. Despite the controversial results, these studies have frequently figured prominently in arguments about the cell of origin in Hodgkin's disease. Authors identifying the presence of acid phosphatase and nonspecific esterase have generally favored a mononuclear phagocyte origin; those with negative results have favored a lymphoid origin. We have evaluated a series of 21 cases of Hodgkin's disease using tissues embedded in plastic and tested for acid phosphatase and nonspecific esterase. We found that Hodgkin's cells were frequently positive for acid phosphatase (20 to 21 cases) and/or nonspecific esterase (18 of 21). The reactions are weak and sensitive to inhibition by processing procedures. The reaction patterns are unusual for lymphoid cells and histiocytes. The finding is similar to that seen in interdigitating reticulum cells, a specialized cell found in the paracortex of human lymph nodes.

  View details for Web of Science ID A1982NQ55100002

  View details for PubMedID 7074633

• THE IMMUNOLOGICAL PHENOTYPING OF BONE-MARROW BIOPSIES AND ASPIRATES - FROZEN SECTION TECHNIQUES BLOOD Wood, G. S., Warnke, R. A. 1982; 59 (5): 913-922

  Abstract

  Techniques were developed for the preparation of frozen sections from undecalcified bone marrow biopsy cores and bone marrow aspirates. Selected indirect antibody and biotin-avidin detection systems, employing immunoperoxidase or immunofluorescent labels, were studied to determine which were best suited for bone marrow frozen section immunohistopathology. Methods employing murine hybridoma monoclonal antibodies illustrate the immunophenotyping of representative lymphoid neoplasms, involving bone marrow. The results of immunohistologic staining were comparable to those of fluorescence-activated cell sorter (FACS) analysis of cell suspensions. The advantages and limitations of immunohistologic techniques are discussed as they relate to immunophenotypic studies previously feasible only with bone marrow cell suspensions. Frozen section immunohistologic techniques serve as useful adjuncts to the conventional evaluation of bone marrow aspirates and biopsies.

  View details for Web of Science ID A1982NP41900008

  View details for PubMedID 7042005

• TREATMENT OF B-CELL LYMPHOMA WITH MONOCLONAL ANTI-IDIOTYPE ANTIBODY NEW ENGLAND JOURNAL OF MEDICINE MILLER, R. A., Maloney, D. G., Warnke, R., Levy, R. 1982; 306 (9): 517-522

  View details for Web of Science ID A1982ND27300006

  View details for PubMedID 6173751

• LYMPHOCYTE-T SUBSETS IN FOLLICULAR LYMPHOMAS COMPARED WITH THOSE IN NON-NEOPLASTIC LYMPH-NODES AND TONSILS HUMAN PATHOLOGY Dvoretsky, P., Wood, G. S., Levy, R., Warnke, R. A. 1982; 13 (7): 618-625

  Abstract

  Using monoclonal antibodies on frozen sections, the authors define the anatomic localization of T-lymphocyte subsets in follicular lymphomas as well as in nonneoplastic lymph nodes and tonsils. The percentage of Leu-1+ T cells in the follicles of follicular lymphomas (20 per cent) was virtually identical to that seen in the follicles of nonneoplastic lymph nodes or tonsils (22 per cent). There were 50 per cent T cells in the interfollicular regions of follicular lymphomas and 75 per cent in the paracortical regions of the nonneoplastic specimens. In neoplastic follicles the number of Leu-3a+ cells was 67 per cent of the number of Leu-1+ cells, whereas, virtually the entire T-cell population in the nonneoplastic follicles expressed the Leu-3a antigen. These T cells of helper phenotype may facilitate the neoplastic process or an immune response against it or may be bystanders to the B-cell proliferation. Hum Pathol 13:618-625, 1982

  View details for Web of Science ID A1982NX32700003

  View details for PubMedID 7044948

• HODGKINS-DISEASE - A CLINICOPATHOLOGIC STUDY OF 659 CASES CANCER Colby, T. V., Hoppe, R. T., Warnke, R. A. 1982; 49 (9): 1848-1858

  Abstract

  A large number of histologic and clinical parameters were assessed, tabulated and intercorrelated in 659 patients with Hodgkin's disease evaluated and treated at Stanford University Medical Center. Nodular sclerosis was the most common pattern (60%) and also had the best total survival, but lymphocyte predominance had the best relapse-free survival. While a number of histologic parameters showed a significant correlation with relapse-free survival, multivariate analysis showed that age, stage, and treatment were relatively more important. Of the histologic parameters, only the number of lymphocytes, fibroblasts, and amount of sclerosis remained significant after multivariate analysis. The positive correlation of sclerosis, negative correlation of the number of fibroblasts and lack of correlation of lacunar cells with relapse free survival in patients with nodular sclerosis suggested that the type of mesenchymal reaction was of prime importance in determining prognosis in that form of Hodgkin's disease. The number of lymphocytes did not independently affect prognosis in patients with nodular sclerosis but did so for the entire group. The cellular phase of nodular sclerosis was found to have an overall survival and some clinical features more akin to mixed cellularity Hodgkin's disease.

  View details for Web of Science ID A1982NL22000017

  View details for PubMedID 7074584

• EXPRESSION OF T-CELL ANTIGENS BY CELLS IN MOUSE AND HUMAN PRIMARY AND SECONDARY FOLLICLES ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Rouse, R. V., Weissman, I. L., LEDBETTER, J. A., Warnke, R. A. 1982; 149: 751-756

  View details for Web of Science ID A1982PL44700105

  View details for PubMedID 6128883

• SUBTYPES OF CUTANEOUS T-CELL LYMPHOMA DEFINED BY EXPRESSION OF LEU-1 AND IA BLOOD Wood, G. S., DENEAU, D. G., MILLER, R. A., Levy, R., Hoppe, R. T., Warnke, R. A. 1982; 59 (5): 876-882

  Abstract

  Monoclonal antibodies were used to characterize immunohistologically the expression of cellular antigens in 25 patients with cutaneous T-cell lymphoma (CTCL). Although all cases expressed the Leu-2a-/Leu-3a+ immunophenotype characteristic of helper T cells, four subtypes were defined based on variable expression of Leu-1 and Ia. In individual patients, the immunophenotype was constant irrespective of body compartment sampled or interim therapy. Ia+ non T-cells typically constituted one-third of the cellular infiltrate. Along with neoplastic cells, Ia+/T6+ dendritic cells were observed within Pautrier microabscesses, dermis, and individually throughout the epidermis. It will be important to determine if different CTCL immunophenotypes represent different biologic subsets of disease or have prognostic relevance. Prospective studies will be facilitated by single- and double-label immunohistologic techniques that allow the simultaneous evaluation of cellular antigen expression and architectural detail.

  View details for Web of Science ID A1982NP41900002

  View details for PubMedID 7042004

• A COMPARATIVE-STUDY OF BURKITTS AND NON-BURKITTS UNDIFFERENTIATED MALIGNANT-LYMPHOMA - IMMUNOLOGICAL, CYTOCHEMICAL, ULTRASTRUCTURAL, CYTOLOGIC, HISTOPATHOLOGIC, CLINICAL AND CELL-CULTURE FEATURES CANCER Grogan, T. M., Warnke, R. A., KAPLAN, H. S. 1982; 49 (9): 1817-1828

  Abstract

  Nine patients with "undifferentiated" lymphoma (DUL) of Burkitt's (AMB, four cases) and non-Burkitt's (NB, five cases) types were studied. All specimens stained for a single immunoglobulin light chain indicating a monoclonal B-cell lymphoid proliferation. Striking methyl green pyronine and punctate Oil-Red O staining were demonstrated in both groups. Histologic and cytologic examination demonstrated a lymphoid proliferation with a high mitotic count, a "starry-sky" pattern, prominent cytoplasmic basophilia and vacuolation in both subtypes. The AMB cases showed a predominance of regular nuclei with 3-5 basophilic nucleoli, while the NB cases showed slightly greater nuclear variability with a greater proportion of nuclei containing 1-2 eosinophilic nucleoli. The AMB patients were all children (median, 12 age years) and those with NB were adults (median, age 54 years). The site of presentation in both groups was predominantly extranodal and abdominal. This report emphasizes the considerable immunologic, morphologic, cytochemical and clinical overlap present among the subtypes of "undifferentiated" lymphoma.

  View details for Web of Science ID A1982NL22000013

  View details for PubMedID 6804087

• DIFFERENTIATION OF CHRONIC LYMPHOCYTIC-LEUKEMIA FROM HODGKINS-DISEASE USING IMMUNOLOGICAL MARKER STUDIES AMERICAN JOURNAL OF SURGICAL PATHOLOGY Colby, T. V., Warnke, R. A., Burke, J. S., Dorfman, R. F. 1981; 5 (7): 707-710

  Abstract

  Four consecutive lymph node biopsies from one patient showed features typical of lymphocyte-pre-dominant Hodgkin's disease. When the patient developed lymphocytosis of the peripheral blood and a staging bone marrow biopsy was found to have nodular lymphoid infiltrates atypical for Hodgkin's disease, the fourth node biopsy was performed in order to perform immunologic marker studies. A monoclonal cell population was identified and the lymph nodes were interpreted as chronic lymphocytic leukemia mimicking lymphocyte-predominant Hodgkin's disease. The diagnostic usefulness of immunologic marker studies stressed.

  View details for Web of Science ID A1981MT55300010

  View details for PubMedID 7039376

• SUPPRESSION OF ENDOGENOUS AVIDIN-BINDING ACTIVITY IN TISSUES AND ITS RELEVANCE TO BIOTIN-AVIDIN DETECTION SYSTEMS JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY Wood, G. S., Warnke, R. 1981; 29 (10): 1196-1204

  Abstract

  As biotin-avidin systems continue to be developed for applications involving single cells, cell suspensions, and especially tissue sections, the need arises for a method of blocking endogenous avidin-binding activity. One such method is described and its proposed mechanism is discussed. Utilizing this method, endogenous avidin-binding activity was detected and suppressed in selected human and murine tissues, thus facilitating the interpretation of specific immunohistochemical staining utilizing hybridoma monoclonal antibodies in a biotin-avidin-horseradish peroxidase detection system.

  View details for Web of Science ID A1981MG07500011

  View details for PubMedID 7028859

• STUDIES OF A HUMAN LYMPHOCYTE-T ANTIGEN RECOGNIZED BY A MONOCLONAL-ANTIBODY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES Engleman, E. G., Warnke, R., FOX, R. I., Dilley, J., Benike, C. J., Levy, R. 1981; 78 (3): 1791-1795

  Abstract

  A monoclonal antibody (designated L17F12) detects an antigen present on 95-100% of human peripheral T lymphocytes, the majority of thymocytes, and acute lymphocytic leukemia T cells but not B cells, B-cell lines, or monocytes. Examination of frozen tissue sections by the immunoperoxidase method revealed that the cells expressing this antigen were found predominantly in the medulla of thymus and in T-cell zones of lymph node and spleen. The antigen recognized by L17F12 was associated with a cell-surface glycoprotein of 67,000 daltons. L17F12 was used to isolate this molecule from human thymocytes, normal peripheral T cells, leukemic T cells, and T-cell lines. Expression of this antigen on normal T cells was not diminished by prolonged exposure in vitro to various T-cell stimuli. In the absence of complement, L17F12 bound to T cells without altering proliferative functions, thus enabling rapid purification of functionally intact T cells. In the presence of complement, L17F12 was cytolytic for T cells, providing the basis for depletion of T cells from heterogeneous populations. These data suggest that the monoclonal antibody L17F12 recognizes a specific T-cell differentiation protein. This antibody will be useful in studies of the human immune system.

  View details for Web of Science ID A1981LJ93300097

  View details for PubMedID 7015346

• HODGKINS-DISEASE AT AUTOPSY - 1972-1977 CANCER Colby, T. V., Hoppe, R. T., Warnke, R. A. 1981; 47 (7): 1852-1862

  Abstract

  The autopsies of 80 patients with Hodgkin's disease (HD) were reviewed. Nearly one-third of the patients died without evidence of HD at autopsy. Four patients died with clinically unsuspected HD. Infection was the most common cause of death but a significant number of patients died of complications of therapy, both benign and malignant, including five patients with hematologic or de novo lymphoid malignancies. There was wide histologic variation of HD at autopsy and many cases had a pleomorphic appearance with few of the typical features of Hodgkin's disease. Fibrous nodules interpreted as sites of eradicated HD were found in many organs, most commonly lymphoreticular. Nonfatal histopathologic effects of therapy were common and specifically assessed thyroid and gonads.

  View details for Web of Science ID A1981LJ46400022

  View details for PubMedID 7226080

• DETECTION OF T-CELL AND B-CELL ANTIGENS WITH HYBRIDOMA MONOCLONAL ANTIBODIES - A BIOTIN-AVIDIN-HORSERADISH PEROXIDASE METHOD JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY Warnke, R., Levy, R. 1980; 28 (8): 771-776

  Abstract

  Acetone-fixed frozen sections of reactive lymph node, spleen, three B cell lymphomas, and three T cell lymphomas were studied for the presence of Ia-like antigens and two T cell antigens. Detection of the binding of the hybridoma monoclonal antibodies to these antigens took advantage of the biotin-avidin interaction. The detection method employed a biotin conjugate of goat anti-mouse antibody and an avidin conjugate of horseradish peroxidase. B cell lymphoma cells stained for Ia. The cell lymphomas were shown to be heterogeneous for the expression of the two T cell antigens. these three antigens were generally not detectable after 10% formalin fixation of B-5 fixation. Detection of these antigens and the method employed should prove useful in the immunologic categorization of human lymphomas.

  View details for Web of Science ID A1980KV02100004

  View details for PubMedID 7003003

• HISTOLOGY OF THE INITIAL RELAPSE OF HODGKINS-DISEASE CANCER Colby, T. V., Warnke, R. A. 1980; 45 (2): 289-292

  Abstract

  The histology of relapsing Hodgkin's disease was compared with that of the original diagnostic biopsy in 56 patients. A criterion for inclusion in this study was relapse in an untreated site, thereby excluding all patients initially treated with chemotherapy. THose patients selected for study were initially treated with local radiotherapy, and relapsed outside the initial radiation fields. There was an impressive maintenance of the histologic appearance in the relapse biopsies: a change in histology was seen only in a small percentage of cases. The histologic relationship of so-called "cellular phase" of nodular sclerosing Hodgkin's disease to classical nodular sclerosing Hodgkin's disease was confirmed. Those patients with a relapse-free interval greater than one year more often had an epithelioid cell reaction (granulomatous reaction) in their biopsy material in contrast to those who relapsed in less than one year.

  View details for Web of Science ID A1980JC10100014

  View details for PubMedID 7351011

• IMMUNOLOGICAL PHENOTYPE IN 30 PATIENTS WITH DIFFUSE LARGE-CELL LYMPHOMA NEW ENGLAND JOURNAL OF MEDICINE Warnke, R., Miller, R., Grogan, T., Pederson, M., Dilley, J., Levy, R. 1980; 303 (6): 293-300

  Abstract

  Frozen sections of 30 diffuse large-cell ("histiocytic") lymphomas that had arisen in both nodal and extranodal sites were stained with immunoglobulin light-chain and heavy-chain reagents, with nonoclonal antibodies to THAT HAD ARISEN IN BOTH NODAL AND EXTRANODAL SITES WERE STAINED WITH IMMUNOGLOBULIN LIGHT-CHAIN AND HEAVY-CHAIN REAGENTS, WITH MONOCLONAL ANTIBODIES TO T and B-cell antigens, and with an esterase marker for macrophages. Fourteen lymphomas expressed immunoglobulin light chains and were shown to be monoclonal; F(ab')2 fragments were sometimes necessary to demonstrate their monoclonal nature. Mu (IgM) was the most frequently expressed heavy chain, but in many patients other heavy chains were found. None of the lymphomas stained with T-cell antibodies or the esterase; 15 did not stain for immunoglobulin, but 13 of these 15 did express Ia antigen. These immunologic markers identified eight different phenotypes. Retrospective clinical analysis of the patients suggested that those who were immunoglobulin-positive had more advanced disease and shorter survival, but confirmation of the clinical relevance of immunologic phenotype will require prospective studies.

  View details for Web of Science ID A1980KB76200001

  View details for PubMedID 6770268

• PATHOLOGY AND HOMING OF A TRANSPLANTABLE MURINE B CELL LEUKEMIA (BCL1) JOURNAL OF IMMUNOLOGY Warnke, R. A., Slavin, S., Coffman, R. L., BUTCHER, E. C., Knapp, M. R., Strober, S., Weissman, I. L. 1979; 123 (3): 1181-1188

  Abstract

  The pathology and homing characteristics of a murine B cell leukemia are described. Experiments utilizing autoradiography to determine the early homing pattern of the leukemic cells revealed a pronounced localization of the labeled cells to the spleen. The cells that were seen in the white pulp showed preferential localization to the follicles or B cell domains. Tissue section immunofluorescence with antibodies to kappa- and lambda-light chains was used to study the initial mouse with this disease as well as to study the mice that were injected with in vivo passaged cells. These mice also showed predominant involvement of the spleen. Although the initial mouse with this disease had 200,000 lambda-bearing B lymphocytes per mm3 in the peripheral blood and closely resembled a human chronic lymphocytic leukemia patient, the studies described suggest that this murine B cell neoplasm is a lymphoma with a striking predilection for splenic involvement. The other organs including the bone marrow as well as the peripheral blood appeared to be involved secondarily. This unusual spontaneously occurring murine B cell disease provides a useful model for the investigation of certain commonly occurring human lymphomas and leukemias.

  View details for Web of Science ID A1979HH67000037

  View details for PubMedID 381519

• IMMUNOBIOLOGY OF A SPONTANEOUS MURINE B-CELL LEUKEMIA (BCL1) IMMUNOLOGICAL REVIEWS Strober, S., GRONOWICZ, E. S., Knapp, M. R., Slavin, S., Vitetta, E. S., Warnke, R. A., Kotzin, B., Schroder, J. 1979; 48: 169-195

  View details for Web of Science ID A1979JB62400008

  View details for PubMedID 121100

• NON-HODGKINS LYMPHOMA - STUDY OF THE EVOLUTION OF THE DISEASE BASED UPON 92 AUTOPSIED CASES CANCER RISDALL, R., Hoppe, R. T., Warnke, R. 1979; 44 (2): 529-542

  Abstract

  The evolution of the disease process in 92 patients with non-Hodgkin's lymphoma has been analyzed by comparing the initial histopathologic material with that obtained at autopsy. The distribution of lymphoma did not differ substantially among the subtypes, but the gross appearance of the lesions was different among certain subtypes, particularly between the "small cell" and "large cell" types. The diffuse lymphomas showed a remarkable constancy of subtype in the same patient, whereas the nodular lymphomas showed a high frequency of change to a diffuse pattern and/or a larger cell type. Diffuse histiocytic lymphomas with plasmacytoid features showed a striking propensity for involvement of the gastrointestinal tract. The occurrence and significance of bizarre pleomorphic giant cells, epithelioid histiocytes, a "starry-sky" pattern, erythrophagocytosis, hemosiderosis and extramedullary hematopoiesis are reported. All patients received anti-lymphomatous chemotherapy and/or radiotherapy. A second malignancy was observed in 8 patients. Thirteen patients showed no residual lymphoma at autopsy. The cause of death was considered to be related to lymphoma in all 92 patients; 67 had infections identified.

  View details for Web of Science ID A1979HK47500021

  View details for PubMedID 383257

• HUMAN THYMUS-LEUKEMIA ANTIGEN DEFINED BY HYBRIDOMA MONOCLONAL-ANTIBODIES PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Levy, R., Dilley, J., FOX, R. I., Warnke, R. 1979; 76 (12): 6552-6556

  Abstract

  A series of mouse hybridomas producing monoclonal antibodies against human acute lymphocytic leukemia (ALL) cells was generated and screened for tumor specificity. Among 1200 primary cultures, 60 produced an antibody that could distinguish between the immunizing leukemia cells and an isologous B lymphoblastoid cell line. Of these, two produced an antibody that detects an antigen expressed preferentially on ALL cells and on a subpopulation of normal cells found in the cortex of the thymus. Other normal human lymphoid cells from lymph nodes, spleen, bone marrow, and peripheral blood express only low levels of this antigen. High levels of this "thymus-leukemia" antigen were found on T-ALL cells, T-ALL-derived cell lines, and some "null" ALL cells. By contrast, B-cell leukemias, B lymphoblastoid cell lines, and normal and malignant myeloid cells contain either low or undetectable amounts of this antigen. The thymus-leukemia antigen has been isolated from the membranes of leukemia cells by detergent solubilization and subsequent immunoprecipitation with the monoclonal antibody. Preliminary biochemical characterization shows the antigen to be associated with a polypeptide of Mr approximately 28,000.

  View details for Web of Science ID A1979JA38200114

  View details for PubMedID 316541

• MALIGNANT-LYMPHOMA WITH A HIGH CONTENT OF EPITHELIOID HISTIOCYTES - DISTINCT CLINICOPATHOLOGIC ENTITY AND A FORM OF SO-CALLED LENNERTS LYMPHOMA CANCER Kim, H., Jacobs, C., Warnke, R. A., Dorfman, R. F. 1978; 41 (2): 620-635

  View details for Web of Science ID A1978EQ15900028

  View details for PubMedID 630541

• NEPHROTIC SYNDROME IN MASSIVE OBESITY - STUDY BY LIGHT, IMMUNOFLUORESCENCE, AND ELECTRON-MICROSCOPY ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Warnke, R. A., Kempson, R. L. 1978; 102 (8): 431-438

  Abstract

  The morphologic features observed in the renal biopsy specimens from three patients with massive obesity complicated by the nephrotic syndrome are described. In the two patients with active disease, the majority of the glomeruli showed focal to extensive fibrin deposition both within and adjacent to capillary loops, associated with adhesions to Bowman's capsule, with a variable endocapillary proliferative response. In the patient with inactive disease, the majority of the glomeruli appeared normal. However, fibrin-like material, similar to that seen in the active phase, was infrequently found ultrastructurally in the subendothelial portion of the capillary loops. Subendothelial vacuolated material was also observed. Although intravascular coagulation was suggested in this disorder, only minor coagulation abnormalities were discovered. In two of the patients, the massive proteinuria has resolved with weight reduction.

  View details for Web of Science ID A1978FK66000012

  View details for PubMedID 580886

• LYMPHOID SYSTEM - ITS NORMAL ARCHITECTURE AND POTENTIAL FOR UNDERSTANDING SYSTEM THROUGH STUDY OF LYMPHOPROLIFERATIVE DISEASES HUMAN PATHOLOGY Weissman, I. L., Warnke, R., BUTCHER, E. C., Rouse, R., Levy, R. 1978; 9 (1): 25-45

  Abstract

  This article presents a view of lymphoid tissue architecture as defined by the traffic of defined lymphoid cell classes. The compartmentalization of lymphocytes is discussed in reference to specific cell-cell interactions that occur in antigen-driven immune responses. Finally, the distribution of normal and neoplastic lymphocytes in humans is defined and compared with animal model systems.

  View details for Web of Science ID A1978EK34700004

  View details for PubMedID 344190

• IMMUNOPATHOLOGY OF FOLLICULAR LYMPHOMAS - MODEL OF LYMPHOCYTE-B HOMING NEW ENGLAND JOURNAL OF MEDICINE Warnke, R., Levy, R. 1978; 298 (9): 481-485

  Abstract

  To investigate whether follicular lymphoma has a monoclonal origin, we stained frozen tissue sections from 22 afflicted patients for kappa and lambda light chains with an immunofluorescence technic. F(ab')2 antibody fragments were used to avoid binding by Fc receptors. In 20 cases the lymphoma nodules comprised a monoclonal population of immunoglobulin-producing cells. The nodules were usually surrounded by a normal, polyclonal population of B lymphocytes. Reactive lymphoid follicles were easily differentiated from lymphoma nodules on the basis of clonality. Eight cases contained multiple immunoglobulin heavy chains. All the lymphoma nodules in the same tissue or in multiple tissues in the same patient showed identical light-chain and heavy-chain staining even if different histologic subtypes were identified. Follicular lymphoma is the outgrowth of a single clone of immunoglobulin-bearing cells that retain the tissue-homing characteristics of B lymphocytes.

  View details for Web of Science ID A1978EM83500003

  View details for PubMedID 414136

• EXOGENOUS IMMUNOGLOBULIN AND MACROPHAGE ORIGIN OF REED-STERNBERG CELLS IN HODGKINS-DISEASE NEW ENGLAND JOURNAL OF MEDICINE Kadin, M. E., Stites, D. P., Levy, R., Warnke, R. 1978; 299 (22): 1208-1214

  Abstract

  We studied Reed-Sternberg cells from 14 patients with Hodgkin's disease to learn whether they had monoclonal immunoglobulin synthesized by the cell or polyclonal immunoglobulin of external origin. Double-label immunofluorescence with F(ab')2 anti-serums to human light chains showed that cytoplasmic immunoglobulin of individual Reed-Sternberg cells is always polyclonal and usually associated with membrane-bound immunoglobulin of the same type. The predominant immunoglobulin was IgG; in one case IgM was also present. In vitro studies confirmed the internalization of exogenous IgG and phagocytosis of immune complexes by viable Reed-Sternberg cells. Their exclusion of trypan blue dye and lack of albumin and fibrinogen suggests relatively specific uptake of immunoglobulin, mediated by the Fc receptor or antigen (or antigens) associated with Hodgkin's disease at the cell membrane. Our studies support other recent evidence that the Reed-Sternberg cell is derived from a macrophage.

  View details for Web of Science ID A1978FY28800003

  View details for PubMedID 101841

• STUDY OF LYMPHOPROLIFERATIVE DISEASES COMPARING IMMUNOFLUORESCENCE WITH IMMUNOHISTOCHEMISTRY AMERICAN JOURNAL OF CLINICAL PATHOLOGY Warnke, R., Pederson, M., Williams, C., Levy, R. 1978; 70 (6): 867-875

  View details for Web of Science ID A1978GC69100006

• CARCINOMA OF NASOPHARYNX - SIGNIFICANCE OF HISTOLOGY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hoppe, R. T., Williams, J., Warnke, R., Goffinet, D. R., Bagshaw, M. A. 1978; 4 (3-4): 199-205

  View details for Web of Science ID A1978FC06900002

  View details for PubMedID 640890

• MONOCLONALITY OF HUMAN B-CELL LYMPHOMAS JOURNAL OF EXPERIMENTAL MEDICINE Levy, R., Warnke, R., Dorfman, R. F., Haimovich, J. 1977; 145 (4): 1014-1028

  Abstract

  Human tissues involved with lymphoma have been examined in frozen sections for immunoglobulin-bearing cells by a technique involving double-label immunofluorescence with mixed anti-kappa and anti-lambda antibodies. F (ab')2 fragments of purified antibodies were employed to avoid any binding via Fc receptors. B cell lymphomas were shown to be composed of monoclonal populations of Ig bearing cells, whereas normal or reactive lymphoid follicles contained a mosaic of Ig-bearing cells derived from multiple clones. Nodules of lymphoma were often surrounded by normal polyclonal B cell populations. We anticipates that the approach described here will be useful in the diagnosis of lymphoma, differentiating it from reactive lymphoid hyperplasia by the demostration of monoclonality. In addition, it should provide a sensitive and reliable tool for investigating the immunobiology of human lymphoma.

  View details for Web of Science ID A1977DB75600017

  View details for PubMedID 404386

• CELLULAR INFILTRATE IN CARDIAC ALLOGRAFT-REJECTION IN MICE TRANSPLANTATION Billingham, M., Warnke, R., Weissman, I. L. 1977; 23 (2): 171-176

  View details for Web of Science ID A1977CW63800015

  View details for PubMedID 319582

• COEXISTENCE OF NODULAR AND DIFFUSE PATTERNS IN NODULAR NON-HODGKINS LYMPHOMAS - SIGNIFICANCE AND CLINICOPATHOLOGIC CORRELATION CANCER Warnke, R. A., Kim, H., Fuks, Z., Dorfman, R. F. 1977; 40 (3): 1229-1233

  Abstract

  One hundred and twenty-six cases of nodular lymphoma have been classified cytologically by the criteria of Rappaport, and have been divided into three architectural groups, based on the degree of nodularity. Eighty-five percent of the patients have been followed for at least 5 years after initial therapy. Analysis of actuarial survival curves reveals that patients in the poorly differentiated lymphocytic and mixed histiocytic-lymphocytic categories with the three architectural patterns ("nodular only," "nodular with focal diffuse," and "nodular with diffuse") have similar long-term and disease-free survivals. Nevertheless, any degree of nodularity imparts a more favorable prognosis than diffuse lymphoma of coreresponding cell type. In the small number of patients with a nodular lye than in the other two histiocytic type, associated with diffuse areas, the prognosis is less favorable than in the other two histologic groups. Thus, a nodular lymphoma of so-called histiocytic type with diffuse areas may behave more like a diffuse than nodular lymphoma, and warrants appropriate therapy.

  View details for Web of Science ID A1977DX06500035

  View details for PubMedID 332322

• CLINICAL AND SURGICAL (LAPAROTOMY) EVALUATION OF PATIENTS WITH NON-HODGKINS LYMPHOMAS CANCER TREATMENT REPORTS Goffinet, D. R., Warnke, R., Dunnick, N. R., Castellino, R., Glatstein, E., NELSEN, T. S., Dorfman, R. F., Rosenberg, S. A., KAPLAN, H. S. 1977; 61 (6): 981-992

  Abstract

  A consecutive unselected series of 423 patients with non-Hodgkin's lymphomas was staged prospectively at the Stanford Medical Center between June 1971 and June 1976. The histopathologic classification of Rappaport was used exclusively. Staging laparotomies were performed in 197 of the patients, but another 226 patients were excluded from the staging procedure for a variety of reasons, including stage IV involvement, poor surgical risk, and diagnostic celiotomy before referral to Stanford. Gastrointestinal, splenic, bone marrow, hepatic, and mesenteric lymph node involvement was very common in these patients, whereas systemic symptoms and mediastinal sites of disease were less frequently noted. After staging laparotomy, 15 patients (8%) were downstaged to a lesser extent of involvement while 62 (31%) were upstaged, primarily from clinical stage III to pathologic stage IV. Correlations were made between clinical and pathologic staging and the sites of involvement were compared between those with nodular and those with diffuse lymphomas. The accuracy of diagnostic radiologic procedures was also assessed. Although it is valuable in sequentially determining the extent of subdiaphragmatic involvement by lymphomas, we believe that staging laparotomy should still be regarded as a research procedure which will be undertaken only as indicated in centers of clinical research.

  View details for Web of Science ID A1977DX62400006

  View details for PubMedID 902261

• RADIOGRAPHIC MANIFESTATIONS OF MALIGNANT HISTIOCYTOSIS AMERICAN JOURNAL OF ROENTGENOLOGY Dunnick, N. R., Parker, B. R., Warnke, R. A., Castellino, R. A. 1976; 127 (4): 611-616

  Abstract

  Twenty-six cases of histologically proven malignant histiocytosis are presented. Patient ages ranged from 20 months to 82 years, and a 10:3 male preponderance was seen. Clinical presentation is similar to that of malignant lymphoma and leukemia; histologic differentiation is required. The frequency of intrathoracic involvement at the time of presentation is similar to that of non-Hodgkin's lymphoma. Retroperitoneal lymph node invasion was readily seen on five of the eight lymphograms performed. Hepatosplenomegaly was a common finding, and three of the patients had evidence of bone involvement during the course of their illness. While there are no radiographic findings specific to malignant histiocytosis, the presence of hepatomegaly should suggest this possibility. The establishment of the correct diagnosis is important to guide choices in chemotherapy.

  View details for Web of Science ID A1976CH11300013

  View details for PubMedID 970532

• MALIGNANT HISTIOCYTOSIS (HISTIOCYTIC MEDULLARY RETICULOSIS) .1. CLINICOPATHOLOGIC STUDY OF 29 CASES CANCER Warnke, R. A., Kim, H., Dorfman, R. F. 1975; 35 (1): 215-230

  Abstract

  The clinical records and histologic material from 29 cases of malignant histiocytosis (MH) have been reviewed, as well as autopsy findings in 14 cases. The mean age was 31 years, with a 2.2:1 male to female preponderance. Major physical findings included temperature elevation, lymphadenopathy, hepatomegaly, splenomegaly, and preterminal jaundice. Common laboratory findings were anemia, leukopenia, and thrombocytopenia. The median survival was 6 months, the mean 14 months, and the range from 1 month to 8 years. The histologic features observed in lymph nodes, liver, spleen, and bone marrow have been emphasized, as well as features useful in differential diagnosis. In contrast to our experience with the non-Hodgkin's lymphomas, bone marrow aspiration was superior to biopsy in assessing marrow involvement. Unusual manifestations included soft tissue infiltration in 5 cases; 2 of these patients presented with a soft tissue mass. The distinctive clinical as well as histologic findings warrant recognition and separation of MH from other hematopoietic disorders.

  View details for Web of Science ID A1975V410500025

  View details for PubMedID 1167345

• LYMPHADENOPATHY SIMULATING MALIGNANT LYMPHOMAS HUMAN PATHOLOGY Dorfman, R. F., Warnke, R. 1974; 5 (5): 519-550

  View details for Web of Science ID A1974T969800005

  View details for PubMedID 4137045