Dita Gratzinger

All Publications

• Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States Tajima, T., Bernstein, D., Boyd, S. D., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Twist, C. J., Weinberg, K., Robien, M. A., Brown, M., Armstrong, B., Desai, D., Mazariegos, G., Chin, C., Fishbein, T. M., Tekin, A., Venick, R. S., Martinez, O. M., Krams, S. M., Esquivel, C. O. WILEY. 2023

  View details for Web of Science ID 001002465500078

• Small volume biopsy diagnostic yield at initial diagnosis versus recurrence/transformation of follicular lymphoma: Aretrospective Cyto-Heme Interinstitutional Collaborative study. Cancer cytopathology Fitzpatrick, M. J., Sundaram, V., Ly, A., Abramson, J. S., Balassanian, R., Cheung, M. C., Cook, S. L., Falchi, L., Frank, A. K., Gupta, S., Hasserjian, R. P., Lin, O., Long, S. R., Menke, J. R., Mou, E., Reed, D. R., Ruiz-Cordero, R., Volaric, A. K., Wang, L., Wen, K. W., Xie, Y., Zadeh, S. L., Gratzinger, D. 2022

  Abstract

  BACKGROUND: Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL).METHODS: The authors performed a multi-institutional retrospective analysis of SVBs including fine-needle aspiration (FNA) and needle core biopsy (NCB) for initial FL diagnosis and suspected recurrence or transformation of FL. A total of 676 workups beginning with SVB were assessed for the mean number of biopsies per workup, the proportion of workups requiring multiple biopsies, and the proportion with a complete diagnosis including grade, on initial biopsy.RESULTS: Compared to workups performed for question transformation/recurrence, those done for initial FL diagnosis were significantly more likely to require multiple biopsies (p<.01), had a higher mean number of biopsies per workup (1.7 vs. 1.1, absolute standardized difference=1.1), and a lower complete diagnosis rate at initial biopsy (39% vs. 56%). At initial FL diagnosis, NCB +/- FNA was associated with fewer biopsies per workup compared to FNA +/- CB (1.2 vs. 1.9), fewer workups requiring multiple biopsies (23% vs. 83%), and a higher complete diagnosis rate (71% vs. 18%). In contrast, during assessment for transformation/recurrence, NCB and FNA showed a similar mean number of biopsies per workup (1.2 vs. 1.2) and few workups required multiple biopsies (6% vs. 19%).CONCLUSIONS: SVB at initial FL diagnosis often required additional biopsies to establish a complete diagnosis. In contrast, when assessing for transformed/recurrent FL, additional biopsies were generally not obtained regardless of SVB type, suggesting that in these clinical settings SVB may be sufficient for clinical decision-making.

  View details for DOI 10.1002/cncy.22676

  View details for PubMedID 36573933

• Diagnostic Discrepancies in Small-volume Biopsy for the Initial Diagnosis, Recurrence, and Transformation of Follicular Lymphoma: A Multi-Institutional Collaborative Study. The American journal of surgical pathology Volaric, A. K., Lin, O., Balassanian, R., Cook, S., Falchi, L., Fitzpatrick, M. J., Frank, A. K., Gupta, S., Hasserjian, R. P., Long, S., Ly, A., Menke, J. R., Mou, E., Natkunam, Y., Reed, D. R., Ruiz-Cordero, R., Wang, L., Wen, K. W., Xie, Y., Zadeh, S. L., Gratzinger, D. 2022

  Abstract

  Small-volume biopsies (SVBs) including fine-needle aspiration (FNA), cell block, and needle core biopsies (NCB) are increasingly utilized to diagnose and guide the clinical management of lymphoma. We established a multi-institutional interdisciplinary collaboration of cytopathologists, hematopathologists, and oncologists focused on the role of SVB in the management of patients with follicular lymphoma (FL). To assess the performance characteristics of SVB in this setting, we evaluated all consecutive SVBs performed for clinical indications of initial diagnosis, recurrence, or transformation of FL over a 5-year period and focused on the 182 that had at least one subsequent biopsy within 3 months as part of the same clinical work-up. The most common outcome of a subsequent biopsy as part of the same clinical work-up was a more specific diagnosis usually assigning the pathologic grade (111/182, 61%), followed by a complete agreement with the SVB (24/182, 13%), and change from nondiagnostic on initial biopsy to diagnostic on subsequent biopsy (21/182, 12%). A minority resulted in a diagnostic change from benign to lymphoma (17/182, 9%), a change in FL grade (5/182, 3%), or change in the lymphoma diagnostic category (4/182, 2%). There were no cases where an initial diagnosis of lymphoma was overturned. The distribution of discrepancies was similar across initial SVB types (FNA, FNA + cell block, NCB with or without FNA). Tissue limitations were noted in a minority of cases (53/182, 29%) and were enriched among initially nondiagnostic biopsies (16/21, 76%). Flow cytometry immunophenotyping was performed in the majority of cases both at the first and last biopsy (147/182, 81%). SVB can be a powerful method to detect FL in various clinical indications, with discrepant cases mostly resulting from a refinement in the initial diagnosis.

  View details for DOI 10.1097/PAS.0000000000001985

  View details for PubMedID 36537240

• Systemic Presentation of Somatic TET2 Mutated B-Cell Lymphoma in a Child With Kabuki Syndrome and a Germline KMT2D Variant. American journal of clinical pathology Kumar, J., Alspach, A. E., Zucker, J. P., Gratzinger, D. 2022

  Abstract

  OBJECTIVES: Kabuki syndrome (KS) is a rare congenital malformation syndrome associated with germline KMT2D mutations. Recurrent somatic mutations in KMT2D have frequently been observed in B-cell lymphoma, but limited studies are available that evaluate the genetic landscape of B-cell lymphomas in the setting of KS.METHODS: We describe a unique case of B-cell lymphoma that illustrates histologic features of pediatric-type follicular lymphoma (FL) in a young patient with KS and autoimmune disease who showed a systemic presentation of widespread lymphadenopathy and clonal lymphocytosis.RESULTS: We present the first reported case of a young patient with KS harboring a germline KMT2D variant and presenting with a systemic CD10-positive, BCL2-negative B-cell lymphoma of follicle center origin illustrating histologic features of pediatric-type FL. Targeted next-generation sequencing of the B-cell lymphoma showed somatic TET2 and subclonal CXCR4 variants. These findings suggest that abnormal epigenetic regulation caused by alterations in KMT2D and TET2 may have played critical roles in promoting lymphomagenesis in this patient.CONCLUSIONS: This unique case presentation highlights the importance of close clinical monitoring and the value of clinical context in the diagnosis of pediatric FL-like lesions in patients with KS.

  View details for DOI 10.1093/ajcp/aqac104

  View details for PubMedID 36048893

• The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia Alaggio, R., Amador, C., Anagnostopoulos, I., Attygalle, A. D., Araujo, I. B., Berti, E., Bhagat, G., Borges, A. M., Boyer, D., Calaminici, M., Chadburn, A., Chan, J. K., Cheuk, W., Chng, W., Choi, J. K., Chuang, S., Coupland, S. E., Czader, M., Dave, S. S., de Jong, D., Du, M., Elenitoba-Johnson, K. S., Ferry, J., Geyer, J., Gratzinger, D., Guitart, J., Gujral, S., Harris, M., Harrison, C. J., Hartmann, S., Hochhaus, A., Jansen, P. M., Karube, K., Kempf, W., Khoury, J., Kimura, H., Klapper, W., Kovach, A. E., Kumar, S., Lazar, A. J., Lazzi, S., Leoncini, L., Leung, N., Leventaki, V., Li, X., Lim, M. S., Liu, W., Louissaint, A. J., Marcogliese, A., Medeiros, L. J., Michal, M., Miranda, R. N., Mitteldorf, C., Montes-Moreno, S., Morice, W., Nardi, V., Naresh, K. N., Natkunam, Y., Ng, S., Oschlies, I., Ott, G., Parrens, M., Pulitzer, M., Rajkumar, S. V., Rawstron, A. C., Rech, K., Rosenwald, A., Said, J., Sarkozy, C., Sayed, S., Saygin, C., Schuh, A., Sewell, W., Siebert, R., Sohani, A. R., Tooze, R., Traverse-Glehen, A., Vega, F., Vergier, B., Wechalekar, A. D., Wood, B., Xerri, L., Xiao, W. 2022

  Abstract

  We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

  View details for DOI 10.1038/s41375-022-01620-2

  View details for PubMedID 35732829

• Diagnostic Impact of Next-Generation Sequencing Panels for Lymphoproliferative Neoplasms on Small-Volume Biopsies. American journal of clinical pathology Fei, F., Natkunam, Y., Zehnder, J. L., Stehr, H., Gratzinger, D. 2022

  Abstract

  We investigated the feasibility and utility of next-generation sequencing (NGS)-based targeted somatic mutation panels and IG/TR gene rearrangement assays in the diagnosis of lymphoproliferative disorders (LPDs) in small-volume biopsies.We performed a retrospective, single-institution review of all NGS assays requested over a 3-year period by hematopathologists for diagnostic purposes on small-volume biopsies.We identified 59 small-volume biopsies. The TR assay was most commonly requested (42 [71%]), followed by the somatic mutation panel (32 [54%]) and IG assay (26 [44%]). NGS studies were associated with a change in the diagnostic line in about half of cases (28 [47%]) and in a change in the likelihood of a diagnosis in a further 16 cases (27%); there was no diagnostic impact of NGS testing in 15 cases (25%).Implementation of NGS panel somatic mutation or IG/TR gene rearrangement assays on small-volume biopsies contributes to the diagnosis of LPDs in the majority of select cases for diagnostic purposes. The molecular diagnosis is considered in the context of the clinical, histologic, and immunophenotypic findings and does not by itself lead to a definitive diagnosis in small-volume biopsies.

  View details for DOI 10.1093/ajcp/aqac045

  View details for PubMedID 35552630

• Global Cytopathology-Hematopathology Practice Trends. American journal of clinical pathology Zadeh, S. L., Balassanian, R., Cheung, M. C., Falchi, L., Hasserjian, R., Lin, O., Long, S. R., Menke, J. R., Mou, E., Natkunam, Y., Ruiz-Cordero, R., Volaric, A. K., Wang, L., Wen, K. W., Gratzinger, D. 2021

  Abstract

  OBJECTIVES: Small-volume biopsy-fine-needle aspiration biopsy (FNAB) with or without core biopsy-is in increasing use in diagnosis and management of lymphoma patients. Our objective was to survey the current practice in small-volume biopsy diagnosis of lymphoma, focusing on the interaction among hematopathologists and cytopathologists and the integration of FNAB, core biopsy, and flow cytometry studies at sign-out.METHODS: This study used a cross-sectional survey design employing the RedCap database distributed via nine pathology professional society email listservs. The survey consisted of 25 multiple-choice questions and several free text fields. In total, 128 pathologists participated.RESULTS: Most respondents indicated that FNAB specimens in which lymphoma is a diagnostic consideration (FNAB-L) are seen daily or weekly (68/116; 58.6%). However, most institutions have separate hematopathology and cytopathology services (72/116; 62.1%) with inconsistent communication. When communication occurred, respondents were frequently inclined to reconsider their original diagnoses. Barriers identified included lack of communication, inadequate access to diagnostic studies, no formal subspecialty training, and various opinions regarding FNAB in diagnosing lymphoma.CONCLUSIONS: This survey showed that FNAB-L specimens are common, with a lack of uniformity in how complementary fine-needle aspiration and core biopsy specimens or flow immunophenotyping results are shared across hematopathology and cytopathology services.

  View details for DOI 10.1093/ajcp/aqab111

  View details for PubMedID 34508545

• Impact of initial biopsy type on the time to final diagnostic biopsy in patients with follicular lymphoma and suspected histologic transformation. Leukemia & lymphoma Mou, E., Falchi, L., Sundaram, V., Abramson, J. S., Balassanian, R., Beygi, S., Fitzpatrick, M. J., Frank, A. K., Gupta, S., Lin, O., Long, S. R., Menke, J. R., Reed, D. R., Ruiz-Cordero, R., Volaric, A. K., Xie, Y., Wang, L., Wen, K. W., Zadeh, S. L., Natkunam, Y., Cheung, M. C., Gratzinger, D., Cyto-Heme Institutional Collaborative (CHIC) consortium 2021: 1-9

  Abstract

  Diagnosis of histologic transformation (HT) of follicular lymphoma (FL) requires tissue biopsy. While surgical biopsy represents the gold standard, less invasive procedures such as fine-needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are frequently performed. In this retrospective multi-institutional study including 269 patients with FL and suspected HT, the median time from initial clinical suspicion to final diagnostic biopsy was similar whether the workup began with FNAB, CNB, or surgical biopsy (4, 9, and 6days, respectively; p=.27), despite more subsequent biopsies performed following initial FNAB. Periprocedural complications were uniformly minimal. Biopsy-proven HT was more common in the initial surgery group and in workups including positron emission tomography/computed tomography (PET/CT). Our findings, derived from US academic centers with specialized procedural and pathology expertise, suggest that FNAB, CNB, and surgical biopsy are all viable initial diagnostic procedures that can inform clinical decision-making in select FL patients with suspected HT.

  View details for DOI 10.1080/10428194.2021.1941936

  View details for PubMedID 34176413

• Entrustable Professional Activities in Hematopathology Pathology Fellowship Training: Consensus Design and Proposal. Academic pathology White, K., Qualtieri, J., Courville, E. L., Beck, R. C., Alobeid, B., Czuchlewski, D. R., Teruya-Feldstein, J., Soma, L. A., Prakash, S., Gratzinger, D. 2021; 8: 2374289521990823

  Abstract

  Hematopathology fellowship education has grown in complexity as patient-centered treatment plans have come to depend on integration of clinical, morphologic, immunophenotypic, molecular, and cytogenetic variables. This complexity is in competition with the need for timely hematopathology care with stewardship of patient, laboratory, and societal resources. Accreditation Council for Graduate Medical Education Milestones provide a guidance document for hematopathology training, but fellows and their educators are in need of a simple framework that allows assessment and feedback of growth toward independent hematopathology practice. Entrustable professional activities provide one such framework, and herein, we provide proposed Hematopathology Fellowship Entrustable Professional Activities based on review of pertinent guidelines and literature, with multiple rounds of expert and stakeholder input utilizing a modified mini-Delphi approach. Ten core entrustable professional activities deemed essential for graduating hematopathology fellows were developed together with skills and knowledge statements, example scenarios, and corresponding Accreditation Council for Graduate Medical Education Milestones. Application of these entrustable professional activities in program design, fellow evaluation, and decisions regarding level of supervision is discussed with consideration of benefits and barriers to implementation. These entrustable professional activities may be used by hematopathology fellowship directors and faculty to provide fellows with timely constructive feedback, determine entrustment decisions, provide the Clinical Competency Committee with granular data to support Milestone evaluations, and provide insight into areas of potential improvement in fellowship training. Fellows will benefit from a clear roadmap to independent hematopathology practice with concrete and timely feedback.

  View details for DOI 10.1177/2374289521990823

  View details for PubMedID 33644302

• Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Go, R. S., Jacobsen, E., Baiocchi, R., Buhtoiarov, I., Butler, E. B., Campbell, P. K., Coulter, D. W., Diamond, E., Flagg, A., Goodman, A. M., Goyal, G., Gratzinger, D., Hendrie, P. C., Higman, M., Hogarty, M. D., Janku, F., Karmali, R., Morgan, D., Raldow, A. C., Stefanovic, A., Tantravahi, S. K., Walkovich, K., Zhang, L., Bergman, M. A., Darlow, S. D. 2021; 19 (11): 1277-1303

  Abstract

  Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

  View details for DOI 10.6004/jnccn.2021.0053

  View details for PubMedID 34781268

• Laboratory Workup of Lymphoma in Adults. Archives of pathology & laboratory medicine Kroft, S. H., Sever, C. E., Bagg, A., Billman, B., Diefenbach, C., Dorfman, D. M., Finn, W. G., Gratzinger, D. A., Gregg, P. A., Leonard, J. P., Smith, S., Souter, L., Weiss, R. L., Ventura, C. B., Cheung, M. C. 2020

  Abstract

  CONTEXT.: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery led to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.OBJECTIVE.: To develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.DESIGN.: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were derived based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework.RESULTS.: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.CONCLUSIONS.: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions on specimen suitability, diagnostic capabilities, and correct use of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.

  View details for DOI 10.5858/arpa.2020-0261-SA

  View details for PubMedID 33175094

• Human Aging Alters the Spatial Organization between CD34+ Hematopoietic Cells and Adipocytes in Bone Marrow. Stem cell reports Aguilar-Navarro, A. G., Meza-León, B. n., Gratzinger, D. n., Juárez-Aguilar, F. G., Chang, Q. n., Ornatsky, O. n., Tsui, H. n., Esquivel-Gómez, R. n., Hernández-Ramírez, A. n., Xie, S. Z., Dick, J. E., Flores-Figueroa, E. n. 2020

  Abstract

  Age-related clonal hematopoiesis is a major risk factor for myeloid malignancy and myeloid skewing is a hallmark of aging. However, while it is known that non-cell-autonomous components of the microenvironment can also influence this risk, there have been few studies of how the spatial architecture of human bone marrow (BM) changes with aging. Here, we show that BM adiposity increases with age, which correlates with increased density of maturing myeloid cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) and an increased proportion of HSPCs adjacent to adipocytes. However, NGFR+ bone marrow stromal cell (NGFR+ BMSC) density and distance to HSPCs and vessels remained stable. Interestingly, we found that, upon aging, maturing myeloid cell density increases in hematopoietic areas surrounding adipocytes. We propose that increased adjacency to adipocytes in the BM microenvironment may influence myeloid skewing of aging HSPCs, contributing to age-related risk of myeloid malignancies.

  View details for DOI 10.1016/j.stemcr.2020.06.011

  View details for PubMedID 32649902

• Role of FNA with core biopsy or cell block in patients with nodular lymphocyte-predominant Hodgkin lymphoma. Cancer cytopathology Gupta, S. n., Long, S. R., Natkunam, Y. n., Kong, C. S., Gupta, N. K., Gratzinger, D. n. 2020

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) represents a diagnostic challenge on surgical excisional or incisional biopsy. Classification is further challenging on fine needle aspiration (FNA) material accompanied by needle core and/or cell block biopsy (FNA+core/CB).The authors studied all FNA+core/CB and surgical excisional or incisional biopsies to evaluate for lymphoma in patients who had a prior history of NLPHL or subsequent diagnosis of NLPHL over a 5-year period from 2012 through 2016.Patients who ultimately were diagnosed with NLPHL represented <0.5% of those who underwent FNA+core/CB for an initial suspicion of lymphoma. FNA+core/CB resulted in a definitive diagnosis in 7 of 13 cases, and surgical excisional or incisional biopsy specimens resulted in a definitive diagnosis in 13 of 13 cases (chi-square statistic, 9.6; P = .002). At initial diagnosis, FNA+core/CB was negative in 2 cases and atypical or suspicious in 3 cases; all 5 of those patients required surgical excisional or incisional biopsy for a definitive lymphoma diagnosis. By contrast, patients who underwent FNA+core/CB for recurrent lymphoma required surgical excisional or incisional biopsy in only 1 of 8 cases (chi-square statistic, 9.5; P = .002). Flow cytometry was positive for a light-chain-restricted B-cell population in only 1 of 11 biopsies that were involved by lymphoma.Surgical excisional or incisional biopsy remains the gold standard for NLPHL diagnosis and for distinguishing progression to a T-cell/histiocyte-rich large B-cell lymphoma pattern. At a tertiary cancer center with routine collaborative diagnosis of lymphoma on FNA+core/CB by cytopathologists and hematopathologists, FNA+core/CB performs well to assess for recurrent or transformed NLPHL, rarely requiring subsequent surgical excisional or incisional biopsy. FNA+core/CB has limited sensitivity in the initial diagnosis setting.

  View details for DOI 10.1002/cncy.22286

  View details for PubMedID 32343479

• Histology-Independent Signature Distinguishes Kikuchi-Fujimoto Disease/Systemic Lupus Erythematosus-Associated Lymphadenitis From Benign and Malignant Lymphadenopathies. American journal of clinical pathology Scott, G. D., Kumar, J. n., Oak, J. S., Boyd, S. D., Raess, P. W., Gratzinger, D. A. 2020

  Abstract

  Kikuchi-Fujimoto disease (KFD) and systemic lupus erythematosus (SLE) are benign entities with histologic features that raise concern about malignancy and infection. We searched for a histology-independent KFD/SLE signature relying on only immunophenotype and basic clinical characteristics.A histology-independent KFD/SLE signature was generated using 975 excised lymph nodes with flow immunophenotyping, including 16 cases of KFD/SLE. This signature was then evaluated in 1,198 fine-needle aspiration (FNA) specimens.The top flow cytometry discriminant for KFD/SLE was uniform CD38+ expression on CD19+ events. Immunohistochemistry demonstrated nodules of IgD+, IgM- B cells surrounding necrotizing and activated T-cell areas. A signature combining 6 flow cytometry criteria with age and sample site had a positive predictive value of 88% for KFD/SLE, which had a prevalence of 1.6%. All 4 signature-positive FNA cases with follow-up excision were KFD/SLE. At a second institution, 4 of 5 KFD/SLE cases passed the top discriminant.A flow cytometry signature combined with age and biopsy site identifies KFD/SLE independent of histology, suggesting a shared immune composition and independently confirming that KFD/SLE represents a distinct entity. Unexpectedly, an IgD+CD38+ small B-cell population is a distinctive feature of KFD/SLE, suggesting a possible pathologic role for anergic/autoreactive B cells.

  View details for DOI 10.1093/ajcp/aqaa036

  View details for PubMedID 32367142

• 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

• Flow Immunophenotyping of Benign Lymph Nodes Sampled by FNA: Representative With Diagnostic Pitfalls. Cancer cytopathology Scott, G. D., Lau, H. D., Kurzer, J. H., Kong, C. S., Gratzinger, D. A. 2018

  Abstract

  BACKGROUND: Fine-needle aspiration with flow cytometry (FNA-FC) is routinely used in the evaluation of lymph nodes suspicious for lymphoma, yet data comparing immunophenotype distributions and outliers in benign lymph nodes sampled by fine-needle aspiration (FNA) versus excision are lacking.METHODS: Flow cytometry data from 289 benign lymph node FNA cases were assessed for the overall antigen distribution, with a focus on outliers relevant to the diagnosis of lymphoma. Distributions and outlier proportions were compared with those of a separate cohort of 298 excisional biopsies.RESULTS: Compared with excisional biopsies, FNA specimens overrepresented CD3+ events (72% vs 63%), underrepresented CD19+ events (22% vs 29%), and had 25% fewer large cell-gated events. Normalized antigen distributions in FNA were equivalent to those in excisional biopsy. Twenty-three percent of FNA-FC cases exhibited an outlier, including a skewed kappa:lambda light-chain ratio, increased CD5+ or CD10+ B-cell events, a skewed CD4:CD8 ratio, and increased CD7 loss on T cells, with no significant differences in frequency or type in comparison with excisional specimens. Outliers for the light-chain ratio and T-cell antigens were enriched among older patients and included patients with a variety of autoimmune/rheumatologic conditions.CONCLUSIONS: Benign lymph node FNA yields flow immunophenotypes remarkably similar to those from excisional biopsies. Outlier flow immunophenotypes are identified in benign lymph nodes sampled by FNA at a frequency similar to that with excisional biopsies. Older patients, who have a higher baseline risk of lymphoma, are more likely to exhibit lymphoma-mimicking outliers such as a light-chain predominance on B cells and skewed CD4:CD8 ratios or increased CD7 loss on T cells, and they warrant additional diagnostic caution.

  View details for PubMedID 30194715

• Development of Professionalism in Graduate Medical Education: A Case-Based Educational Approach From the College of American Pathologists' Graduate Medical Education Committee ACADEMIC PATHOLOGY Conran, R. M., Powell, S., Domen, R. E., McCloskey, C. B., Brissette, M. D., Cohen, D. A., Dixon, L., George, M., Gratzinger, D. A., Post, M. D., Roberts, C. A., Rojiani, A. M., Timmons, C., Johnson, K., Hoffman, R. D. 2018; 5: 2374289518773493

  Abstract

  Professionalism and physician well-being are important topics in academic medicine. Lapses in professional judgment may lead to disciplinary action and put patient's health at risk. Within medical education, students and trainees are exposed to professionalism in the institution's formal curriculum and hidden curriculum. Development of professionalism starts early in medical school. Trainees entering graduate medical education already have developed professional behavior. As a learned behavior, development of professional behavior is modifiable. In addition to role modeling by faculty, other modalities are needed. Use of case vignettes based on real-life issues encountered in trainee and faculty behavior can serve as a basis for continued development of professionalism in trainees. Based on the experience of program directors and pathology educators, case vignettes were developed in the domains of service, research, and education and subdivided into the areas of duty, integrity, and respect. General and specific questions pertaining to each case were generated to reinforce model behavior and overcome professionalism issues encountered in the hidden curriculum. To address physician burnout, cases were generated to provide trainees with the skills to deal with burnout and promote well-being.

  View details for PubMedID 30014035

• Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal? Blood Natkunam, Y. n., Gratzinger, D. n., Chadburn, A. n., Goodlad, J. R., Chan, J. K., Said, J. n., Jaffe, E. S., de Jong, D. n. 2018

  Abstract

  Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. The World Health Organization (WHO), however, classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of post-transplant lymphoproliferative disorders (PTLD), but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a three-part unifying nomenclature that includes the name of the lesion, associated virus and the specific immunodeficiency setting for all IA-LPDs. B-cell LPDs are usually EBV-positive and show a spectrum of lesions including hyperplasias, polymorphic LPDs, aggressive lymphomas and, rarely, indolent lymphomas. HHV8-associated LPDs also include both polyclonal and monoclonal proliferations. EBV-negative B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important as it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.

  View details for PubMedID 30082493

• T- and NK-Cell Lymphomas and Systemic Lymphoproliferative Disorders and the Immunodeficiency Setting 2015 SH/EAHP Workshop Report-Part 4 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., De Jong, D., Jaffe, E. S., Chadburn, A., Chan, J. K., Goodlad, J. R., Said, J., Natkunam, Y. 2017; 147 (2): 188-203

  Abstract

  The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related T- and natural killer (NK)-cell lymphoproliferations.The Workshop Panel reviewed 88 T- or NK-cell lymphoproliferations and rendered consensus diagnoses.Hyperplasias of T-cell subsets may be clonal; retained architecture and the clinical setting support a benign diagnosis. Specific associations include hepatosplenic T-cell lymphoma with iatrogenic immunosuppression and breast implants with an indolent variant of anaplastic large cell lymphoma. Epstein-Barr virus (EBV)-positive T-cell lymphomas rarely occur in the acquired immunodeficiency setting. Systemic T- and NK-cell lymphoma of childhood overlaps with chronic active EBV and reversible hemophagocytic lymphohistiocytosis-related T-cell lymphoproliferations.Immunodeficiencies predispose to T-cell hyperplasias, which must not be overdiagnosed as lymphoma. Many T-cell lymphomas in the immunodeficiency setting are likely coincidental, with specific exceptions. Systemic T- or NK-cell lymphomas are part of a spectrum of EBV+ T or NK lymphoproliferations and can present in the acquired immunodeficiency setting.

  View details for DOI 10.1093/ajcp/aqw213

  View details for PubMedID 28395105

• Primary/Congenital Immunodeficiency 2015 SH/EAHP Workshop Report-Part 5 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., Jaffe, E. S., Chadburn, A., Chan, J. K., De Jong, D., Goodlad, J. R., Said, J., Natkunam, Y. 2017; 147 (2): 204-216

  Abstract

  The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review primary immunodeficiency and related lymphoproliferations.Primary immunodeficiencies were divided into immune dysregulation, DNA repair defects, low immunoglobulins, and combined immunodeficiencies.Autoimmune lymphoproliferative syndrome (ALPS) is a prototypical immune dysregulation-type immunodeficiency, with defects in T-cell signaling or apoptosis, expansion of T-cell subsets, and predisposition to hemophagocytic lymphohistiocytosis. DNA repair defects directly predispose to malignancy. Low immunoglobulin immunodeficiencies such as common variable immunodeficiency (CVID) have underlying T-cell repertoire abnormalities predisposing to autoimmunity and B-cell lymphoproliferations. The full spectrum of B-cell lymphoproliferative disorders occurs in primary immunodeficiency.Lymphoproliferations in primary immunodeficiency mirror those in other immunodeficiency settings, with monomorphic B- and sometimes T lymphoproliferative disorders enriched in DNA repair defects. Distinctive T-cell subset expansions in ALPS, CVID, and related entities can mimic lymphoma, and recognition of double-negative T-cell or cytotoxic T-cell expansions is key to avoid overdiagnosis.

  View details for DOI 10.1093/ajcp/aqw215

  View details for PubMedID 28395106

• Immunodeficiency and Dysregulation: Report of the 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology. American journal of clinical pathology Natkunam, Y. n., Gratzinger, D. n., de Jong, D. n., Chadburn, A. n., Goodlad, J. R., Chan, J. K., Said, J. n., Jaffe, E. S. 2017; 147 (2): 124–28

  View details for PubMedID 28395103

• Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy. Journal of clinical pathology Scott, G. D., Atwater, S. K., Gratzinger, D. A. 2017

  Abstract

  To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers.Clinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course.We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma.Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.

  View details for DOI 10.1136/jclinpath-2017-204687

  View details for PubMedID 28916595

• The Recent Pathology Residency Graduate Job Search Experience: A Synthesis of 5 Years of College of American Pathologists Job Market Surveys. Archives of pathology & laboratory medicine Gratzinger, D. n., Johnson, K. A., Brissette, M. D., Cohen, D. n., Rojiani, A. M., Conran, R. M., Hoffman, R. D., Post, M. D., McCloskey, C. B., Roberts, C. A., Domen, R. E., Talbert, M. L., Powell, S. Z. 2017

  Abstract

  - Pathology residents and fellows tailor their training and job search strategies to an actively evolving specialty in the setting of scientific and technical advances and simultaneous changes in health care economics.- To assess the experience and outcome of the job search process of pathologists searching for their first non-fellowship position.- The College of American Pathologists (CAP) Graduate Medical Education Committee has during the past 5 years sent an annual job search survey each June to CAP junior members and fellows in practice 3 years or less who have actively searched for a non-fellowship position.- Job market indicators including job interviews, job offers, positions accepted, and job satisfaction have remained stable during the 5 years of the survey. Most survey respondents who had applied for at least 1 position had accepted a position at the time of the survey, and most applicants who had accepted a position were satisfied or very satisfied. However, most attested that finding a non-fellowship position was difficult. Despite a perceived push toward subspecialization in surgical pathology, the reported number of fellowships completed was stable. Respondent demographics were not associated with job search success with 1 significant exception: international medical school graduate respondents reported greater perceived difficulty in finding a position, and indeed, fewer reported having accepted a position.- Pathology residents and fellows seeking their first position have faced a relatively stable job market during the last 5 years, with most accepting positions with which they were satisfied.

  View details for PubMedID 29210592

• A replicable CD271+ mesenchymal stromal cell density score: bringing the dysfunctional myelodysplastic syndrome niche to the diagnostic laboratory. Leukemia & lymphoma Gars, E., Yousry, S. M., Babu, D., Kurzer, J. H., George, T. I., Gratzinger, D. 2016: 1-3

  View details for PubMedID 27808583

• Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression. Leukemia & lymphoma Nybakken, G., Gratzinger, D. 2016; 57 (8): 1893-1902

  Abstract

  Iron overload and transfusion dependance portend poor risk in myelodysplastic syndromes (MDS); bone marrow macrophages store iron and limit oxidative damage through heme oxygenase-1 (HO1). We assessed iron stores and macrophage HO1 expression in MDS using image analysis of intact diagnostic bone marrow biopsies and qualitative scoring of marrow aspirate iron among 129 cytopenic patients, 67 with MDS and 62 similarly aged patients with benign cytopenias. Using double immunofluorescence and sequential iron and immunohistochemistry staining, we showed that marrow iron colocalizes with HO1 and H-ferritin to CD163 + macrophages. Marrow iron was elevated in MDS independent of transfusion status, a finding of potential utility in distinguishing benign cytopenia from MDS. Among MDS patients only, CD163 + macrophage density and HO1 and H-ferritin expression by CD163 + macrophages increased in tandem with marrow iron. High HO1 was significantly associated with shorter overall survival among MDS patients independent of IPSSR and history of transfusion.

  View details for DOI 10.3109/10428194.2015.1121259

  View details for PubMedID 26758041

• A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells NATURE MEDICINE Reinisch, A., Thomas, D., Corces, M. R., Zhang, X., Gratzinger, D., Hong, W., Schallmoser, K., Strunk, D., Majeti, R. 2016; 22 (7): 812-821

  Abstract

  Xenotransplantation models represent powerful tools for the investigation of healthy and malignant human hematopoiesis. However, current models do not fully mimic the components of the human bone marrow (BM) microenvironment, and they enable only limited engraftment of samples from some human malignancies. Here we show that a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment, formed by in situ differentiation of human BM-derived mesenchymal stromal cells, enables the robust engraftment of healthy human hematopoietic stem and progenitor cells, as well as primary acute myeloid leukemia (AML) samples, at levels much greater than those in unmanipulated mice. Direct intraossicle transplantation accelerated engraftment and resulted in the detection of substantially higher leukemia-initiating cell (LIC) frequencies. We also observed robust engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs in these malignancies. This humanized ossicle xenotransplantation approach provides a system for modeling a wide variety of human hematological diseases.

  View details for DOI 10.1038/nm.4103

  View details for PubMedID 27213817

• Beyond the Niche: Myelodysplastic Syndrome Topobiology in the Laboratory and in the Clinic INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Flores-Figueroa, E., Gratzinger, D. 2016; 17 (4)

  Abstract

  We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche can usefully be approached in the context of its topobiology, and we provide a model that incorporates in vitro and in vivo models as well as in situ findings from intact human marrow to explain the changes seen in myelodysplastic syndrome patients. We highlight the clinical application of the study of the bone marrow microenvironment and its topobiology in myelodysplastic syndromes.

  View details for DOI 10.3390/ijms17040553

  View details for Web of Science ID 000374585300132

  View details for PubMedID 27089321

• Alkylator-Induced and Patient-Derived Xenograft Mouse Models of Therapy-Related Myeloid Neoplasms Model Clinical Disease and Suggest the Presence of Multiple Cell Subpopulations with Leukemia Stem Cell Activity. PloS one Jonas, B. A., Johnson, C., Gratzinger, D., Majeti, R. 2016; 11 (7)

  Abstract

  Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS. First, we modeled alkylator-induced t-AML/MDS by exposing wild type adult mice to N-ethyl-N-nitrosurea (ENU), resulting in several models of AML and MDS that have clinical and pathologic characteristics consistent with human t-AML/MDS including cytopenia, myelodysplasia, and shortened overall survival. These models were limited by their inability to transplant clinically aggressive disease. Second, we established three patient-derived xenograft models of human t-AML. These models led to rapidly fatal disease in recipient immunodeficient xenografted mice. LSC activity was identified in multiple HSPC subpopulations suggesting there is no canonical LSC immunophenotype in human t-AML. Overall, we report several new t-AML/MDS mouse models that could potentially be used to further define disease pathogenesis and test novel therapeutics.

  View details for DOI 10.1371/journal.pone.0159189

  View details for PubMedID 27428079

  View details for PubMedCentralID PMC4948781

• Selective quantitation of microvessel density reveals sinusoidal expansion in myelodysplastic syndromes. Leukemia & lymphoma Ewalt, M. D., Gratzinger, D. n. 2016: 1–4

  View details for PubMedID 27104365

• Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow LABORATORY INVESTIGATION Flores-Figueroa, E., Varma, S., Montgomery, K., Greenberg, P. L., Gratzinger, D. 2012; 92 (9): 1330-1341

  Abstract

  Mesenchymal stromal cells (MSCs) support hematopoiesis and are cytogenetically and functionally abnormal in myelodysplastic syndrome (MDS), implying a possible pathophysiologic role in MDS and potential utility as a diagnostic or risk-stratifying tool. We have analyzed putative MSC markers and their relationship to CD34+ hematopoietic stem/progenitor cells (HSPCs) within intact human bone marrow in paraffin-embedded bone marrow core biopsies of benign, MDS and leukemic (AML) marrows using tissue microarrays to facilitate scanning, image analysis and quantitation. We found that CD271+, ALP+ MSCs formed an extensive branching perivascular, periosteal and parenchymal network. Nestin was brightly positive in capillary/arteriolar endothelium and occasional subendothelial cells, whereas CD146 was most brightly expressed in SMA+ vascular smooth muscle/pericytes. CD271+ MSCs were distinct by double immunofluorescence from CD163+ macrophages and were in close contact with but distinct from brightly nestin+ and from brightly CD146+ vascular elements. Double immunofluorescence revealed an intimate spatial relationship between CD34+ HSPCs and CD271+ MSCs; remarkably, 86% of CD34+ HSPCs were in direct contact with CD271+ MSCs across benign, MDS and AML marrows, predominantly in a perivascular distribution. Expression of the intercrine chemokine CXCL12 was strong in the vasculature in both benign and neoplastic marrow, but was also present in extravascular parenchymal cells, particularly in MDS specimens. We identified these parenchymal cells as MSCs by ALP/CXCL12 and CD271/CXCL12 double immunofluorescence. The area covered by CXCL12+ ALP+ MSCs was significantly greater in MDS compared with benign and AML marrow (P=0.021, Kruskal-Wallis test). The preservation of direct CD271+ MSC/CD34+ HSPC contact across benign and neoplastic marrow suggests a physiologically important role for the CD271+ MSC/CD34+ HSPC relationship and possible abnormal exposure of CD34+ HSPCs to increased MSC CXCL12 expression in MDS.

  View details for DOI 10.1038/labinvest.2012.93

  View details for Web of Science ID 000308274600008

  View details for PubMedID 22710983

• Entrustable Professional Activities for Pathology: Recommendations From the College of American Pathologists Graduate Medical Education Committee. Academic pathology McCloskey, C. B., Domen, R. E., Conran, R. M., Hoffman, R. D., Post, M. D., Brissette, M. D., Gratzinger, D. A., Raciti, P. M., Cohen, D. A., Roberts, C. A., Rojiani, A. M., Kong, C. S., Peterson, J. E., Johnson, K. n., Plath, S. n., Powell, S. Z. ; 4: 2374289517714283

  Abstract

  Competency-based medical education has evolved over the past decades to include the Accreditation Council for Graduate Medical Education Accreditation System of resident evaluation based on the Milestones project. Entrustable professional activities represent another means to determine learner proficiency and evaluate educational outcomes in the workplace and training environment. The objective of this project was to develop entrustable professional activities for pathology graduate medical education encompassing primary anatomic and clinical pathology residency training. The Graduate Medical Education Committee of the College of American Pathologists met over the course of 2 years to identify and define entrustable professional activities for pathology graduate medical education. Nineteen entrustable professional activities were developed, including 7 for anatomic pathology, 4 for clinical pathology, and 8 that apply to both disciplines with 5 of these concerning laboratory management. The content defined for each entrustable professional activity includes the entrustable professional activity title, a description of the knowledge and skills required for competent performance, mapping to relevant Accreditation Council for Graduate Medical Education Milestone subcompetencies, and general assessment methods. Many critical activities that define the practice of pathology fit well within the entrustable professional activity model. The entrustable professional activities outlined by the Graduate Medical Education Committee are meant to provide an initial framework for the development of entrustable professional activity-related assessment and curricular tools for pathology residency training.

  View details for PubMedID 28725792

• National pilot of entrustable professional activities in pathology residency training. Academic pathology Bryant, B. H., Anderson, S. R., Brissette, M., Childs, J. M., Gratzinger, D., Johnson, K., Powell, D. E., Zein-Eldin Powell, S., Timmons, C. F., Chute, D., Cummings, T. J., Furlong, M. A., Hébert, T. M., Reeves, H. M., Rush, D., Vitkovski, T., McCloskey, C. B. 2024; 11 (2): 100110

  Abstract

  Entrustable professional activities (EPAs) are observable clinical skills and/or procedures that have been introduced into medical education at the student and resident levels in most specialties to determine readiness to advance into residency or independent practice, respectively. This publication describes the process and outcomes of a pilot study looking at the feasibility of using two anatomic pathology and two clinical pathology EPAs in pathology residency in 6 pathology residency programs that volunteered for the study. Faculty development on EPAs and their assessment was provided to pilot program faculty, and EPA assessment tools were developed and used by the pilot programs. Pre- and post-study surveys were given to participating residents, faculty, and program directors to gauge baseline practices and to gather feedback on the EPA implementation experience. Results demonstrated overall good feasibility in implementing EPAs. Faculty acceptance of EPAs varied and was less than that of program directors. Residents reported a significant increase in the frequency with which faculty provided formative assessments that included specific examples of performance and specific ways to improve, as well as increased frequency with which faculty provided summative assessments that included specific ways to improve. EPAs offered the most benefit in setting clear expectations for performance of each task, for providing more specific feedback to residents, and in increasing Program director's understanding of resident strengths abilities and weaknesses.

  View details for DOI 10.1016/j.acpath.2024.100110

  View details for PubMedID 38560425

  View details for PubMedCentralID PMC10978478

• Leveraging faculty development to support validation of entrustable professional activities assessment tools in anatomic and clinical pathology training. Academic pathology Bryant, B. H., Anderson, S. R., Brissette, M., Childs, J. M., Gratzinger, D., Johnson, K., Powell, D. E., Zein-Eldin Powell, S., Timmons, C. F., McCloskey, C. B. 2024; 11 (2): 100111

  Abstract

  Entrustable professional activities (EPAs) are observable activities that define the practice of medicine and provide a framework of evaluation that has been incorporated into US medical school curricula in both undergraduate and graduate medical education. This manuscript describes the development of an entrustment scale and formative and summative evaluations for pathology EPAs, outlines a process for faculty development that was employed in a pilot study implementing two Anatomic Pathology and two Clinical Pathology EPAs in volunteer pathology residency programs, and provides initial validation data for the proposed pathology entrustment scales. Prior to implementation, faculty development was necessary to train faculty on the entrustment scale for each given activity. A "train the trainer" model used performance dimension training and frame of reference training to train key faculty at each institution. The session utilized vignettes to practice determination of entrustment ratings and development of feedback for trainees as to strengths and weaknesses in the performance of these activities. Validity of the entrustment scale is discussed using the Messick framework, based on concepts of content, response process, and internal structure. This model of entrustment scales, formative and summative assessments, and faculty development can be utilized for any pathology EPA and provides a roadmap for programs to design and implement EPA assessments into pathology residency training.

  View details for DOI 10.1016/j.acpath.2024.100111

  View details for PubMedID 38560424

  View details for PubMedCentralID PMC10978475

• An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome. Nature communications Liu, S., Ezran, C., Wang, M. F., Li, Z., Awayan, K., Long, J. Z., De Vlaminck, I., Wang, S., Epelbaum, J., Kuo, C. S., Terrien, J., Krasnow, M. A., Ferrell, J. E. 2024; 15 (1): 2188

  Abstract

  Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

  View details for DOI 10.1038/s41467-024-46070-9

  View details for PubMedID 38467625

  View details for PubMedCentralID 1540572

• The 5th edition of the World Health Organization Classification of mature lymphoid and stromal tumors - an overview and update. Leukemia & lymphoma Attygalle, A. D., Chan, J. K., Coupland, S. E., Du, M. Q., Ferry, J. A., Jong, D. d., Gratzinger, D., Lim, M. S., Naresh, K. N., Nicolae, A., Ott, G., Rosenwald, A., Schuh, A., Siebert, R. 2024: 1-17

  Abstract

  The purpose of this review is to give an overview on the conceptual framework and major developments of the upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid tumours (WHO-HAEM5) and to highlight the most significant changes made in WHO-HAEM5 compared with the revised 4th edition (WHO-HAEM4R) of lymphoid and stromal neoplasms. The changes from the revised 4th edition include the reorganization of entities by means of a hierarchical system that is realized throughout the 5th edition of the WHO classification of tumors of all organ systems, a modification of nomenclature for some entities, the refinement of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. For the first time, tumor-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms are included in the classification.

  View details for DOI 10.1080/10428194.2023.2297939

  View details for PubMedID 38189838

• 311.2: Risk factors for Epstein-Barr virus DNAemia in pediatric transplantation: A multicenter study in the United States. Transplantation Tajima, T., Bernstein, D., Boyd, S. D., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Weinberg, K., Armstrong, B., Brown, M., Chin, C., Desai, D., Fishbein, T. M., Mazariegos, G., Robien, M. A., Tekin, A., Twist, C. J., Venick, R. S., Krams, S. M., Martinez, O. M., Esquivel, C. O. 2023; 107 (10S1): 71-72

  View details for DOI 10.1097/01.tp.0000993400.94644.c0

  View details for PubMedID 37845955

• A personalized approach to lymphoproliferations in patients with inborn errors of immunity. Seminars in diagnostic pathology Naor, S., Adam, E., Schiby, G., Gratzinger, D. 2023

  Abstract

  Biopsies from patients with inborn error of immunity (IEI) may pose a diagnostic challenge due to the abnormal anatomy of their lymphoid organs and the tendency for the development of lymphoproliferations in various organs, some of which may lead to the wrong impression of malignant lymphoma which may prompt aggressive unnecessary treatment. In this article we will review typical histologic findings in various IEI's described in the literature and discuss the appropriate approach to the diagnosis of lymphoproliferations in these patients by presenting illustrative cases.

  View details for DOI 10.1053/j.semdp.2023.07.001

  View details for PubMedID 37479638

• Identification and confirmation via in situ hybridization of Merkel cell polyomavirus in rare cases of posttransplant cutaneous T-cell lymphoma. Journal of cutaneous pathology Lawrence, L., Wang, A., Charville, G., Liu, C. L., Garofalo, A., Alizadeh, A., Jangam, D., Pinsky, B. A., Sahoo, M., Gratzinger, D., Khodadoust, M., Kim, Y., Novoa, R., Stehr, H. 2023

  Abstract

  Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens.Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip.Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes.Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting.

  View details for DOI 10.1111/cup.14486

  View details for PubMedID 37394808

• Impact of Induction Therapy on Rejection in Pediatric Transplantation: A Multicenter Study in the United States Tajima, T., Gallo, A., Bernstein, D., Bonham, C., Boyd, S., Gratzinger, D., Krams, S. M., Lum, G., Sasaki, K., Tan, B., Weinberg, K., Armstrong, B., Brown, M., Chin, C., Desai, D., Fishbein, T., Mazariegos, G., Robien, M., Tekin, A., Twist, C., Venick, R., Martinez, O. M., Esquivel, C. O. ELSEVIER SCIENCE INC. 2023: S1015

  View details for Web of Science ID 001087126904251

• End of Treatment Positron Emission Tomography Response and Outcomes in Post-Transplant Lymphoproliferative Disorder (PTLD) Marks, L., Green, M., Gratzinger, D., Agarwal, M., Goss, C., Dharnidharka, V., PTLD-MSMS Grp ELSEVIER SCIENCE INC. 2023: S940

  View details for Web of Science ID 001087126904083

• Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders in Pediatric Transplantation: A Prospective Multicenter Study in the United States Tajima, T., Bernstein, D., Boyd, S., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Twist, C., Weinberg, K., Robien, M., Brown, M., Armstrong, B., Desai, D., Mazariegos, G., Chin, C., Fishbein, T., Tekin, A., Venick, R., Martinez, O. M., Krams, S. M., Esquivel, C. O. ELSEVIER SCIENCE INC. 2023: S590

  View details for Web of Science ID 001087126901240

• Comparison of two immunohistochemical staining protocols for ALK demonstrates non-inferiority of a 5A4 clone-based protocol versus an ALK01 clone-based protocol for the diagnosis of ALK + anaplastic large cell lymphoma. Journal of hematopathology Fernandez-Pol, S., Ferreira, C. R., Manohar, V., Sanches, J. A., Lage, L. A., Pereira, J., Zerbini, M. C., Gratzinger, D., Natkunam, Y. 2023; 16 (1): 1-5

  Abstract

  Detection of ALK rearrangement and/or expression of the ALK protein is an essential component in the evaluation of many neoplasms. Variability has been reported in the ability of different antibody clones to detect ALK expression. The ALK01 clone is commonly used to detect ALK expression in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). However, this clone has been shown to lack sensitivity when used for solid tumors. The aim of this study was to determine if our high-sensitivity 5A4-based immunohistochemistry protocol is non-inferior to our ALK01-based protocol for the detection of ALK expression in ALK + ALCL. To compare the two protocols, we stained tissue microarrays of 126 hematolymphoid neoplasms and an additional 21 primary cutaneous ALK-negative anaplastic large cell lymphomas with both protocols. All 28 ALK + ALCL samples that were positive for the ALK01 antibody were also positive for the 5A4 clone. Three cases on the tissue microarray that were negative with the ALK01 antibody were clearly positive with the 5A4 antibody. We subsequently stained whole tissue sections of these three cases with the ALK01 antibody and found that these three cases were indeed positive with the ALK01 protocol, suggesting that the absence of staining on the tissue microarray samples was due to a combination of sampling error as well as a dimmer signal with the ALK01 protocol. Our study demonstrates that our 5A4-based protocol is non-inferior to the ALK01 antibody for the diagnosis of ALK-positive anaplastic large cell lymphoma, thus allowing our laboratory to discontinue the use of the ALK01-based protocol.

  View details for DOI 10.1007/s12308-023-00531-0

  View details for PubMedID 38175372

• Mutations In Latent Membrane Protein 1 of Epstein-Barr Virus are Associated with Increased Risk for Post-Transplant Lymphoproliferative Disorder in Children. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Martinez, O. M., Krams, S. M., Robien, M. A., Lapasaran, M. G., Arvedson, M. P., Reitsma, A., Balachandran, Y., Harris-Arnold, A., Weinberg, K., Boyd, S. D., Armstrong, B., Trickey, A., Twist, C. J., Gratzinger, D., Tan, B., Brown, M., Chin, C., Desai, D. M., Fishbein, T. M., Mazariegos, G. V., Tekin, A., Venick, R. S., Bernstein, D., Esquivel, C. O. 2023

  Abstract

  Epstein-Barr virus (EBV)+ post-transplant lymphoproliferative disorder (PTLD) results in significant morbidity and mortality in pediatric transplant recipients. Identifying individuals at increased risk of EBV+ PTLD could influence clinical management of immunosuppression and other therapies, improving post-transplant outcomes. A seven-center prospective, observational clinical trial of 872 pediatric transplant recipients evaluated the presence of mutations at position 212 and 366 of EBV latent membrane protein 1 (LMP1) as an indicator of risk for EBV+ PTLD (Clinical Trials: NCT02182986). DNA was isolated from peripheral blood of EBV+ PTLD cases and matched controls (1:2 nested case-control), and the cytoplasmic tail of LMP1 sequenced. Thirty-four participants reached the primary endpoint of biopsy-proven EBV+ PTLD. DNA was sequenced from 32 PTLD cases and 62 matched controls. Both LMP1 mutations were present in 31/32 PTLD cases (96.9%) and in 45/62 matched controls (72.6%) (p=0.005, OR=11.7, 95% CI 1.5, 92.6). The presence of both G212S and S366T carries a nearly 12-fold increased risk for development of EBV+ PTLD. Conversely, transplant recipients without both LMP1 mutations carry a very low risk of PTLD. Analysis of mutations at positions 212 and 366 of LMP1 can be informative in stratifying patients for risk of EBV+ PTLD.

  View details for DOI 10.1016/j.ajt.2023.02.014

  View details for PubMedID 36796762

• Comparison of two immunohistochemical staining protocols for ALK demonstrates non-inferiority of a 5A4 clone-based protocol versus an ALK01 clone-based protocol for the diagnosis of ALK plus anaplastic large cell lymphoma JOURNAL OF HEMATOPATHOLOGY Fernandez-Pol, S., Ferreira, C. R., Manohar, V., Sanches, J., Lage, L. C., Pereira, J., Zerbini, M. N., Gratzinger, D., Natkunam, Y. 2023

  View details for DOI 10.1007/s12308-023-00531-0

  View details for Web of Science ID 000922500000001

• End of Treatment Positron Emission Tomography Response and Outcomes in Post-Transplant Lymphoproliferative Disorder Marks, L. J., Green, M., Agarwal, M., Goss, C., Storch, G., Gratzinger, D., Dharnidharka, V. AMER SOC HEMATOLOGY. 2022: 9559-9560

  View details for DOI 10.1182/blood-2022-165443

  View details for Web of Science ID 000893230302246

• TREATMENT OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD): A MULTI-CENTER PEDIATRIC SERIES Marks, L., Green, M., Storch, G., Gratzinger, D., Gu, H., Goss, C., Dharnidharka, V. WILEY. 2022

  View details for Web of Science ID 000859203900049

• Trichodysplasia Spinulosa Polyomavirus Endothelial Infection, California, USA. Emerging infectious diseases Lawrence, L., Wang, A., Charville, G., Toland, A., Pinsky, B., Natkunam, Y., Younes, S., Stehr, H., Gratzinger, D. 2022; 28 (9): 1935-1937

  Abstract

  We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.

  View details for DOI 10.3201/eid2809.220856

  View details for PubMedID 35997483

• Histiocytic Sarcoma With CCND1 Gene Rearrangement Clonally Related and Transdifferentiated From Mantle Cell Lymphoma. American journal of clinical pathology Kumar, J., Al-Kawaaz, M., Martin, B. A., Hegazi, M. M., Tan, B., Gratzinger, D. 2022

  Abstract

  OBJECTIVES: Histiocytic neoplasms demonstrate shared gene translocations and clonal immunoglobulin gene rearrangements in cases of associated B-cell lymphomas. However, the evolution of these related disease processes remains largely uncertain, especially in the setting of a prior mantle cell lymphoma.METHODS: We describe a unique case of a histiocytic sarcoma that transdifferentiated from blastoid mantle cell lymphoma after extensive therapy. Cytogenic and molecular studies were performed and provided evidence for clonal progression.RESULTS: We present the first reported case of a patient with blastoid mantle cell lymphoma harboring a CCND1 rearrangement that progressed despite multiple therapeutic regimens and ultimately transdifferentiated into histiocytic sarcoma. The histiocytic sarcoma demonstrated a CCND1 rearrangement and targeted next-generation sequencing showed a pathogenic variant in NRAS, a gene involved in the RAS/MAPK pathway, known to play a role in the pathogenesis of histiocytic sarcomas. TP53, NOTCH2, CREBBP, and NFKBIE variants were also identified, which are often seen in B-cell lymphomas, while rarely described in histiocytic sarcoma.CONCLUSIONS: To our knowledge, this is the first report to provide evidence for clonal evolution of histiocytic sarcoma from blastoid mantle cell lymphoma based on cytogenic and molecular findings. The patient's protracted therapeutic course may have acted as an evolutionary driver promoting this transdifferentiation process.

  View details for DOI 10.1093/ajcp/aqac087

  View details for PubMedID 35964234

• EBV plus PTLD Tumor MicroRNAs Detected in Circulating Extracellular Vesicles Are Decreased in Pediatric Transplant Recipients with EBV plus PTLD. Sen, A., Enriquez, J., Rao, M., Glass, M., Balachandran, Y., Syed, S., Twist, C., Weinberg, K., Boyd, S. D., Bernstein, D., Trickey, A., Gratzinger, D., Tan, B., Lapasaran, M. G., Robien, M. A., Brown, M., Armstrong, B., Sever, M., Desai, D., Mazariegos, G., Chin, C., Fishbein, T., Venick, R. S., Tekin, A., Zimmermann, H., Trappe, R. U., Esquivel, C. O., Martinez, O. M., Krams, S. M. WILEY. 2022: 360

  View details for Web of Science ID 000842606302062

• Primary central nervous system histiocytic sarcoma presenting as neuromyelitis optica Nirschl, J., Rogawski, D., McDonald, J., Nie, E., Schwartz, N., Scott, B., Gratzinger, D., Gold, C., Kipp, L., Vogel, H. OXFORD UNIV PRESS INC. 2022: 491

  View details for Web of Science ID 000798368400189

• Mutations in latent membrane protein 1 of Epstein Barr virus are associated with increased risk of post-transplant lymphoproliferative disorder Martinez, O. M., Krams, S. M., Robien, M., Lapasaran, M. M., Arvedson, M., Reitsma, A., Weinberg, K., Boyd, S., Armstrong, B., Twist, C., Gratzinger, D., Tan, B., Trickey, A., Sever, M., Brown, M., Bernstein, D., Esquivel, C., CTOC 06 Investigators WILEY. 2022

  View details for Web of Science ID 000783167500008

• Diagnostic Impact of Next Generation Sequencing Panels for Lymphoproliferative Neoplasms on Small Volume Biopsies Fei, F., Natkunam, Y., Zehnder, J., Gratzinger, D. SPRINGERNATURE. 2022: 948-949

  View details for Web of Science ID 000770360202222

• NGS Clonality Assessment Shows that Many Synchronous or Metachronous PTLD Lesions are Clonally Distinct if EBV-Positive but Often Clonally Related if EBV-Negative Moore, E., Parikh, B., Dharnidharka, V., Gratzinger, D., Swerdlow, S., Ruzinova, M. SPRINGERNATURE. 2022: 993-994

  View details for Web of Science ID 000770360202260

• Molecular Characterization of Chronic Lymphocytic Leukemia with Progression to Classic Hodgkin Lymphoma Tiu, G., Xu, G., Gratzinger, D., Fernandez-Pol, S. SPRINGERNATURE. 2022: 1029-1030

  View details for Web of Science ID 000770360202293

• Tissue Fragment Assessment in Small Volume Biopsies by Computer Vision Rojansky, R., Long, S., Gratzinger, D. SPRINGERNATURE. 2022: 295-296

  View details for Web of Science ID 000770360200273

• Diagnostic Impact of Next Generation Sequencing Panels for Lymphoproliferative Neoplasms on Small Volume Biopsies Fei, F., Natkunam, Y., Zehnder, J., Gratzinger, D. SPRINGERNATURE. 2022: 948-949

  View details for Web of Science ID 000770361802222

• Diagnostic Discrepancies in the Clinical Workup of Follicular Lymphoma Using Small Volume Biopsies: A Multi-Institutional Collaborative Study Volaric, A., Lin, O., Zadeh, S., Gupta, S., Reed, D., Fitzpatrick, M., Ly, A., Hasserjian, R., Balassanian, R., Frank, A., Long, S., Ruiz-Cordero, R., Wang, L., Wen, K., Xie, Y., Menke, J., Natkunam, Y., Gratzinger, D. SPRINGERNATURE. 2022: 308-309

  View details for Web of Science ID 000770360200284

• Flow Cytometry Forward Scatter as a Predictor of Large Cell Transformation in Follicular Lymphoma: A Retrospective Cyto-Heme Inter-Institutional Collaborative (CHIC) study Menke, J., Wang, L., Xie, Y., Yakubu, R., Balassanian, R., Frank, A., Gupta, S., Kurzer, J., Long, S., Natkunam, Y., Ruiz-Cordero, R., Wen, K., Gratzinger, D. SPRINGERNATURE. 2022: 989-990

  View details for Web of Science ID 000770360202256

• Small Volume Biopsy Diagnostic Yield at Initial versus Recurrence/Transformation of Follicular Lymphoma: A Retrospective Cyto-Heme Inter-Institutional Collaborative (CHIC) Study Fitzpatrick, M., Sundaram, V., Ly, A., Balassanian, R., Gupta, S., Hasserjian, R., Lin, O., Long, S., Menke, J., Natkunam, Y., Ruiz-Cordero, R., Volaric, A., Wang, L., Wen, K., Xie, Y., Zadeh, S., Gratzinger, D. SPRINGERNATURE. 2022: 949-951

  View details for Web of Science ID 000770360202223

• NGS Clonality Assessment Shows that Many Synchronous or Metachronous PTLD Lesions are Clonally Distinct if EBV-Positive but Often Clonally Related if EBV-Negative Moore, E., Parikh, B., Dharnidharka, V., Gratzinger, D., Swerdlow, S., Ruzinova, M. SPRINGERNATURE. 2022: 993-994

  View details for Web of Science ID 000770361802260

• Molecular Characterization of Chronic Lymphocytic Leukemia with Progression to Classic Hodgkin Lymphoma Tiu, G., Xu, G., Gratzinger, D., Fernandez-Pol, S. SPRINGERNATURE. 2022: 1029-1030

  View details for Web of Science ID 000770361802293

• Tissue Fragment Assessment in Small Volume Biopsies by Computer Vision Rojansky, R., Long, S., Gratzinger, D. SPRINGERNATURE. 2022: 295-296

  View details for Web of Science ID 000770361800274

• Small Volume Biopsy Diagnostic Yield at Initial versus Recurrence/Transformation of Follicular Lymphoma: A Retrospective Cyto-Heme Inter-Institutional Collaborative (CHIC) Study Fitzpatrick, M., Sundaram, V., Ly, A., Balassanian, R., Gupta, S., Hasserjian, R., Lin, O., Long, S., Menke, J., Natkunam, Y., Ruiz-Cordero, R., Volaric, A., Wang, L., Wen, K., Xie, Y., Zadeh, S., Gratzinger, D. SPRINGERNATURE. 2022: 949-951

  View details for Web of Science ID 000770361802223

• Diagnostic Discrepancies in the Clinical Workup of Follicular Lymphoma Using Small Volume Biopsies: A Multi-Institutional Collaborative Study Volaric, A., Lin, O., Zadeh, S., Gupta, S., Reed, D., Fitzpatrick, M., Ly, A., Hasserjian, R., Balassanian, R., Frank, A., Long, S., Ruiz-Cordero, R., Wang, L., Wen, K., Xie, Y., Menke, J., Natkunam, Y., Gratzinger, D. SPRINGERNATURE. 2022: 308-309

  View details for Web of Science ID 000770361800285

• Flow Cytometry Forward Scatter as a Predictor of Large Cell Transformation in Follicular Lymphoma: A Retrospective Cyto-Heme Inter-Institutional Collaborative (CHIC) study Menke, J., Wang, L., Xie, Y., Yakubu, R., Balassanian, R., Frank, A., Gupta, S., Kurzer, J., Long, S., Natkunam, Y., Ruiz-Cordero, R., Wen, K., Gratzinger, D. SPRINGERNATURE. 2022: 989-990

  View details for Web of Science ID 000770361802256

• Host microRNAs are decreased in pediatric solid-organ transplant recipients during EBV+ Post-transplant Lymphoproliferative Disorder. Frontiers in immunology Sen, A., Enriquez, J., Rao, M., Glass, M., Balachandran, Y., Syed, S., Twist, C. J., Weinberg, K., Boyd, S. D., Bernstein, D., Trickey, A. W., Gratzinger, D., Tan, B., Lapasaran, M. G., Robien, M. A., Brown, M., Armstrong, B., Desai, D., Mazariegos, G., Chin, C., Fishbein, T. M., Venick, R. S., Tekin, A., Zimmermann, H., Trappe, R. U., Anagnostopoulos, I., Esquivel, C. O., Martinez, O. M., Krams, S. M. 2022; 13: 994552

  Abstract

  Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3'untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.

  View details for DOI 10.3389/fimmu.2022.994552

  View details for PubMedID 36304469

• "Human, mouse and dog bone marrow show similar mesenchymal stromal cells within a distinctive microenvironment". Experimental hematology Meza-Leon, B., Gratzinger, D., Aguilar-Navarro, A. G., Juarez-Aguilar, F. G., Rebel, V. I., Torlakovic, E., Purton, L. E., Dorantes-Acosta, E. M., Escobar-Sanchez, A., Dick, J. E., Flores-Figueroa, E. 2021

  Abstract

  Bone marrow stromal cells (BMSCs) are a key part of the hematopoietic niche. Mouse and human BMSCs are recognized by different markers (LepR and NGFR/CD271, respectively). However, there has not been a detailed in situ comparison of both populations within the hematopoietic microenvironment. Moreover, dog BMSCs have not been characterized in situ by any of those makers. We conducted a systematic histopathological comparison of mouse, human and dog BMSCs within their bone marrow architecture and microenvironment. Human and dog CD271+ BMSCs showed similar morphology, frequency, and distribution within trabecular bone marrow to mouse LepR+ BMSCs. However, mouse bone marrow showed higher cellularity and megakaryocyte content. In conclusion, highly comparable bone marrow mesenchymal stromal cells distribution among the three species establishes the validity of using mouse and dog as a surrogate experimental model of hematopoietic stem cell (HSC):BMSCs interactions. However, the distinct differences in adipocyte and megakaryocyte microenvironment content of mouse bone marrow and how they might influence HSC interactions as compared to humans require further study.

  View details for DOI 10.1016/j.exphem.2021.06.006

  View details for PubMedID 34228982

• Pitfalls in the Diagnosis of Nodular Lymphocyte Predominant Hodgkin Lymphoma: Variant Patterns, Borderlines and Mimics CANCERS Younes, S., Rojansky, R. B., Menke, J. R., Gratzinger, D., Natkunam, Y. 2021; 13 (12)

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) represents approximately 5% of Hodgkin lymphoma and typically affects children and young adults. Although the overall prognosis is favorable, variant growth patterns in NLPHL correlate with disease recurrence and progression to T-cell/histiocyte-rich large B-cell lymphoma or frank diffuse large B-cell lymphoma (DLBCL). The diagnostic boundary between NLPHL and DLBCL can be difficult to discern, especially in the presence of variant histologies. Both diagnoses are established using morphology and immunophenotype and share similarities, including the infrequent large tumor B-cells and the lymphocyte and histiocyte-rich microenvironment. NLPHL also shows overlap with other lymphomas, particularly, classic Hodgkin lymphoma and T-cell lymphomas. Similarly, there is overlap with non-neoplastic conditions, such as the progressive transformation of germinal centers. Given the significant clinical differences among these entities, it is imperative that NLPHL and its variants are carefully separated from other lymphomas and their mimics. In this article, the characteristic features of NLPHL and its diagnostic boundaries and pitfalls are discussed. The current understanding of genetic features and immune microenvironment will be addressed, such that a framework to better understand biological behavior and customize patient care is provided.

  View details for DOI 10.3390/cancers13123021

  View details for Web of Science ID 000666631300001

  View details for PubMedID 34208705

• Gain of Function Mutations in Latent Membrane Protein 1 of Epstein Barr Virus are Associated with Increased Risk of Post-Transplant Lymphoproliferative Disorder Martinez, O. M., Krams, S. M., Robien, M., Lapasaran, M., Arvedson, M., Weinberg, K., Boyd, S., Armstrong, B., Twist, C., Gratzinger, D., Tan, B., Trickey, A., Sever, M., Brown, M., Bernstein, D., Esquivel, C. O. WILEY. 2021: 349-350

  View details for Web of Science ID 000705310101135

• Positive Job Search Experience for New Pathologists Seeking First Employment Between 2017-2019. Archives of pathology & laboratory medicine Shyu, I. n., Johnson, K. A., Gratzinger, D. n., Brissette, M. D., Childs, J. M., Dixon, L. R., George, M. R., McCloskey, C. B., Prieto, V. G., Rojiani, A. M., Timmons, C. F., Hoffman, R. D. 2021

  Abstract

  An aging population calls for an adequate response in the workforce of medical professionals. The field of pathology has seen a downward trend in numbers of graduating US allopathic medical students choosing the specialty. Concerns about the job market after residency and fellowship graduation may be a contributing factor.To provide an update on the trends emerging from a survey of pathology graduates' job search experience for their first nonfellowship position.Data from an annual job search survey sent by The College of American Pathologists Graduate Medical Education Committee between 2017 and 2019 to The College of American Pathologists junior members and fellows in practice 3 years or less, actively looking for a nonfellowship position, was analyzed. Various indicators of the job search experience were compared year to year and with the previously published 2012 to 2016 benchmark data.Analysis revealed positive trends between the 2017 to 2019 data and the 2012 to 2016 benchmark data, including participants' perceiving more ease in finding a position, improved availability of jobs in their subspecialty choice, and higher ratings of satisfaction with the position accepted, as well as a greater proportion of respondents finding a position within 6 months of initiating their job search.The job market for pathology residents and fellows looking for their first nonfellowship position has improved with respect to multiple indicators, such as ease of finding a position, length of job search, and satisfaction with the position accepted when comparing 2017 to 2019 data with the 2012 to 2016 benchmark data.

  View details for DOI 10.5858/arpa.2020-0455-CP

  View details for PubMedID 33417677

• Machine Learning Predictability of Clinical Next Generation Sequencing for Hematologic Malignancies to Guide High-Value Precision Medicine. AMIA ... Annual Symposium proceedings. AMIA Symposium Kim, G. Y., Noshad, M., Stehr, H., Rojansky, R., Gratzinger, D., Oak, J., Brar, R., Iberri, D., Kong, C., Zehnder, J., Chen, J. H. 2021; 2021: 641-650

  Abstract

  Advancing diagnostic testing capabilities such as clinical next generation sequencing methods offer the potential to diagnose, risk stratify, and guide specialized treatment, but must be balanced against the escalating costs of healthcare to identify patient cases most likely to benefit from them. Heme-STAMP (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) is one such next generation sequencing test. Our objective is to assess how well Heme-STAMP pathological variants can be predicted given electronic health records data available at the time of test ordering. The model demonstrated AUROC 0.74 (95% CI: [0.72, 0.76]) with 99% negative predictive value at 6% specificity. A benchmark for comparison is the prevalence of positive results in the dataset at 58.7%. Identifying patients with very low or very high predicted probabilities of finding actionable mutations (positive result) could guide more precise high-value selection of patient cases to test.

  View details for PubMedID 35308914

• 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

• The Impact of the COVID-19 Pandemic on the 2019-2020 Job Search for Newly Trained Pathologists. Archives of pathology & laboratory medicine George, M. R., Johnson, K. A., Childs, J. M., Dixon, L. R., Gratzinger, D. A., Hoffman, R. D., Holloman, A., Karp, J. K., Knollmann-Ritschel, B. E., Lofgreen, A., Prieto, V. G., Timmons, C. F., McCloskey, C. B. 2020

  View details for DOI 10.5858/arpa.2020-0688-LE

  View details for PubMedID 33179038

• Laboratory Workup of Lymphoma in Adults. American journal of clinical pathology Kroft, S. H., Sever, C. E., Bagg, A., Billman, B., Diefenbach, C., Dorfman, D. M., Finn, W. G., Gratzinger, D. A., Gregg, P. A., Leonard, J. P., Smith, S., Souter, L., Weiss, R. L., Ventura, C. B., Cheung, M. C. 2020

  Abstract

  OBJECTIVES: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.THE AIM OF THIS REVIEW IS TO: develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.METHODS: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework.RESULTS: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.CONCLUSIONS: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.

  View details for DOI 10.1093/ajcp/aqaa191

  View details for PubMedID 33219376

• Factors Influencing US Allopathic Medical Students to Choose Pathology as a Specialty. Academic pathology McCloskey, C. B., Johnson, K., Brissette, M., Conran, R., Childs, J., George, M., Gratzinger, D., Prieto, V. G., Rojiani, A. M., Shyu, I., Timmons, C., Hoffman, R. 2020; 7: 2374289520951924

  Abstract

  The SARS-CoV-2 pandemic has highlighted the crucial role of pathologists in the health care system at a time of significant decline in the number of US medical students matching to pathology residency positions. To understand this decline, a national survey of fourth-year US allopathic medical students was conducted to assess experiences, knowledge, and attitudes of pathology and factors that impact specialty choice. Participating in a separate pathology course did not increase the probability of choosing pathology. Experiences significantly associated with choosing pathology included clinical or research opportunities in pathology during the last 2 years of medical school, autopsy observation/participation, and participation in pathology interest groups. Many respondents felt they were not sufficiently exposed to pathology to consider it as a specialty. Those who considered pathology but did not choose it were less likely to report understanding the activities of pathologists and being recruited by pathology faculty and more likely to express a preference for more direct patient contact as compared to those entering pathology. In general, respondents agreed that pathology has a good work-life balance and a satisfying degree of intellectual challenge. On the other hand, respondents generally agreed that information on social media and perception of the pathology job market do not seem to be positive and few agreed that pathology is a highly regarded specialty. We identify steps to address these issues and increase the number of US medical students choosing pathology as a specialty crucial to the future of medicine and public health.

  View details for DOI 10.1177/2374289520951924

  View details for PubMedID 33110939

  View details for PubMedCentralID PMC7557358

• Factors Influencing US Allopathic Medical Students to Choose Pathology as a Specialty ACADEMIC PATHOLOGY McCloskey, C. B., Johnson, K., Brissette, M., Conran, R., Childs, J., George, M., Gratzinger, D., Prieto, V. G., Rojiani, A. M., Shyu, I., Timmons, C., Hoffman, R. 2020; 7

  View details for DOI 10.1177/2374289520951924

  View details for Web of Science ID 000573797300001

• Myeloid Cell Nuclear Differentiation Antigen (MNDA) Positivity in Primary Follicles: Potential Pitfall in the Differential Diagnosis With Marginal Zone Lymphoma APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Manohar, V., Peerani, R., Tan, B., Gratzinger, D., Natkunam, Y. 2020; 28 (5): 384–88

  View details for DOI 10.1097/PAI.0000000000000738

  View details for Web of Science ID 000533995200010

• Transplant Monitoring and PTLD Detection with B Cell Receptor Repertoire Analysis in a Large Prospective Pediatric Cohort Jackson, K., Martinez, O., Krams, S., Robien, M., Lapasaran, M., Armstrong, B., Twist, C., Weinberg, K., Gratzinger, D., Tam, B., Sever, M., Brown, M., Bernstein, D., Esquivel, C., Boyd, S. D. WILEY. 2020: 321

  View details for Web of Science ID 000546629501153

• Genetic Subtypes of Systemic Anaplastic Large Cell Lymphoma Show Distinct Differences in PD-L1 Expression and Regulatory and Cytotoxic T Cells in the Tumor Microenvironment. Applied immunohistochemistry & molecular morphology : AIMM Ferreira, C. R., Manohar, V. n., Zhao, S. n., Bangs, C. D., Cherry, A. n., Azevedo, R. S., Lage, L. A., Pereira, J. n., Zerbini, M. C., Gratzinger, D. n., Natkunam, Y. n. 2020; 28 (1): 10–16

  Abstract

  Anaplastic large cell lymphomas (ALCL) encompass several subgroups that differ in their clinical presentation, genetic features, and prognosis. We characterized the genetic subgroups of 74 patients with ALCL and correlated programmed death ligand 1 (PD-L1) protein expression and compared the densities and ratios of FOXP3+ T regulatory cells and CD8+ tumor-infiltrating lymphocytes (TILs) in tumor cells and the immune microenvironment. The subgroups included anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and ALK-negative (ALK-) ALCL and DUSP22-rearranged and nonrearranged ALK- ALCL. None of our cases represented the TP63-rearrangement ALK- ALCL subgroup. Our results showed that ALK+ ALCL had a higher expression of PD-L1 in the tumor cells, in contrast to ALK- ALCL, which expressed high PD-L1 in tumor-associated macrophages (TAMs). DUSP22-rearranged ALK- ALCL lacked PD-L1 expression in the tumor cells and instead expressed PD-L1 only in TAMs. There was a significant positive correlation of PD-L1 expression between tumor and TAMs in ALK+ ALCL with a negative correlation in ALK- ALCL. Systemic ALCL subgroups had similar densities of CD8+ tumor-infiltrating lymphocytes and FOXP3 T regulatory cells, but differences were observed in the ratio of CD8/FOXP3. Our results suggest that alterations in tumor microenvironment and immune responses exist among systemic ALCL subgroups and these features may account for different clinical behavior and prognosis.

  View details for DOI 10.1097/PAI.0000000000000798

  View details for PubMedID 31809310

• Entry of Graduates of US Pathology Residency Programs Into the Workforce: Cohort Data Between 2008 and 2016 Remain Positive and Stable. Academic pathology Timmons, C. F., Black-Schaffer, W. S., Naritoku, W. Y., Powell, S. Z., Johnson, K. A., Brissette, M. D., Childs, J. M., Conran, R. M., Dixon, L. R., George, M. R., Gratzinger, D. n., McCloskey, C. B., Prieto, V. G., Roberts, C. A., Rojiani, A. M., Shyu, I. n., Hoffman, R. D. 2020; 7: 2374289520901833

  Abstract

  The pathologist workforce in the United States is a topic of interest to the health-care community as a whole and to institutions responsible for the training of new pathologists in particular. Although a pathologist shortage has been projected, there has been a pervasive belief by medical students and their advisors that there are "no jobs in pathology." In 2013 and again in 2017, the Program Directors Section of the Association of Pathology Chairs conducted surveys asking pathology residency directors to report the employment status of each of their residents graduating in the previous 5 years. The 2013 Program Directors Section survey indicated that 92% of those graduating in 2010 had obtained employment within 3 years, and 94% of residents graduating in 2008 obtained employment within 5 years. The 2017 survey indicated that 96% of those graduating in 2014 had obtained employment in 3 years, and 97% of residents graduating in 2012 obtained positions within 5 years. These findings are consistent with residents doing 1 or 2 years of fellowship before obtaining employment. Stratification of the data by regions of the country or by the size of the residency programs does not show large differences. The data also indicate a high percentage of employment for graduates of pathology residency programs and a stable job market over the years covered by the surveys.

  View details for DOI 10.1177/2374289520901833

  View details for PubMedID 32083168

  View details for PubMedCentralID PMC7005983

• Gender Parity in Gainful Employment and Other Gender Trends in the Job Market for Recent Pathology Graduates. Archives of pathology & laboratory medicine Shyu, I., Johnson, K. A., George, M. R., Gratzinger, D., Brissette, M. D., Childs, J. M., Conran, R. M., Dixon, L. R., McCloskey, C. B., Prieto, V. G., Roberts, C. A., Rojiani, A. M., Timmons, C. F., Hoffman, R. D. 2019

  Abstract

  CONTEXT.: Gender-based barriers to equal salary, career advancement, and leadership still exist in medicine. Herein we provide the first report of data comparing the experiences of men and women seeking their first nonfellowship position in pathology.OBJECTIVE.: To identify gender trends regarding pathologists taking their first job after training and the relationship to various demographic factors, job search satisfaction, and outcome.DESIGN.: Aggregate data from the College of American Pathologists Graduate Medical Education Committee Job Market surveys (2015-2018) were analyzed across multiple domains including residency focus, number and subspecialty of fellowships completed, and extent to which expectations were met in regard to work duties, geographic preference, benefits, and salary. These data were examined in the context of assessing gender-based differences.RESULTS.: Comparable results were identified in all measured outcomes according to gender. There were no differences between gender and medical school type, relocation, residency training focus, number of fellowships completed, overall satisfaction with position accepted, salary, or extent to which the position met expectations. Similarly, there were also no discrepancies between gender and the geographic region in which positions were accepted, practice setting, practice subspecialty, partnership track, length of job search, or difficulty finding a position.CONCLUSIONS.: Analysis from 4 years of job market survey data shows equivalent results between men and women looking for their first nonfellowship position in pathology. There were no significant differences with regard to difficulty finding a position, overall satisfaction with the position accepted, salary, benefits, or access to partnership track.

  View details for DOI 10.5858/arpa.2019-0354-CP

  View details for PubMedID 31816267

• Clinicopathologic and microenvironmental analysis of primary cutaneous CD30-positive lymphoproliferative disorders: a 26year experience from an academic medical center in Brazil. Diagnostic pathology Ferreira, C. R., Zhao, S., Sanches, J. A., Miyashiro, D., Cury-Martins, J., Azevedo, R. S., Zerbini, M. C., Natkunam, Y., Gratzinger, D. 2019; 14 (1): 115

  Abstract

  BACKGROUND: Primary cutaneous CD30+ lymphoproliferative disorders (pc-CD30-LPD) are a group of clonal T cell lymphoproliferative disorders that despite very similar tumor histology follow different and characteristic clinical courses, suggesting a homeostatic role of the tumor microenvironment. Little is known about tumor microenvironment and there is almost no literature about PD-L1 expression in pc-CD30-LPD.METHODS: This retrospective study presents a fully clinicopathologically characterized series of pc-CD30-LPDs from an academic medical center in Brazil, including 8 lymphomatoid papulomatosis (LyP), 9 primary cutaneous anaplastic large cell lymphoma (pcALCL) and 4 borderline lesions. All the cases were scored for FOXP3+ regulatory T-cells (Treg) and CD8+ cytotoxic tumor infiltrating lymphocytes (TIL) densities, as well as PD-L1 expression in tumor cells and tissue associated macrophages. The CD8+/FOXP3+ ratio was also evaluated.RESULTS: Among the 21 cases of pc-CD30-LPD, PD-L1 expression is frequent in both tumor cells and tissue associated macrophages in pc-CD30-LPD across categories, suggesting that the PD-L1 axis may be a common feature of pc-CD30-LPDs. While reactive T cell infiltrates vary widely from case to case, a common feature across pc-CD30-LPDs is higher density of CD8 than FOXP3+T cells. The distribution of T cells within the lesions however differed between LyP and pcALCL: we found that LyP lesions tend to be permeated by CD8+ and FOXP3+ T cells, whereas pcALCL tend to be surrounded by a rim of CD8+ TIL and FOXP3+ Tregs with relatively lower density infiltrates in the center of the lesion.CONCLUSIONS: LyP has a trend to have denser immune cells throughout the lesion, with higher FOXP3+ Treg and CD8+ TIL in the center than the edge comparing with pcALCL. PD-L1+ is frequent in tumor cells and tissue associated macrophages in pc-CD30-LPD. The differential distribution of CD8+ and FOXP3+ TILs in LyP as compared to pcALCL could provide a clue to the relapsing/remitting course of LyP as compared to the less frequent spontaneous regression of pcALCL.

  View details for DOI 10.1186/s13000-019-0900-7

  View details for PubMedID 31640798

• Will I Need to Move to Get My First Job?: Geographic Relocation and Other Trends in the Pathology Job Market. Archives of pathology & laboratory medicine George, M. R., Johnson, K. A., Gratzinger, D. A., Brissette, M. D., McCloskey, C. B., Conran, R. M., Dixon, L. R., Roberts, C. A., Rojiani, A. M., Shyu, I., Timmons, C. F., Hoffman, R. D. 2019

  Abstract

  CONTEXT.: There is an ongoing perception that the pathology job market is poor, which may be discouraging medical students from pursuing the specialty. Academic pathologists believe that jobs are available but relocation may be necessary.OBJECTIVE.: To identify trends regarding the geographic relocation of pathologists taking their first job after training.DESIGN.: The College of American Pathologists (CAP) Graduate Medical Education Committee has sent an annual job search survey from 2012-2016 to CAP junior members and fellows in practice for 3 years or less and seeking their first job. Data were analyzed across demographics and geographic domains consisting of the following: stayed at same institution/city, relocated within the same region, or relocated to a different region. Standard statistical methods were used.RESULTS.: Of 501 respondents, 421 reported completing combined anatomic pathology (AP)/clinical pathology (CP) training, while 80 reported AP- or CP-only training. Of the 421 AP/CP respondents, 109 (26%) stayed at the same institution or city, while of the 80 AP- or CP-only respondents, 36 (45%) stayed at the same institution or city. One hundred ninety-nine respondents completed surgical pathology fellowships with 124 (62%) general/oncologic surgical pathology and 75 (38%) subspecialty surgical pathology trainees. Job seekers who completed general surgical pathology/surgical oncologic pathology fellowship accounted for 34 of 52 (65%) of those remaining at the same institution or city, while those with subspecialty training accounted for 40 of 77 (52%) of those relocating to a different region. Relocation did not demonstrate any significant trends in regard to other demographics studied.CONCLUSIONS.: The pathology job market appears stable with no precedent for geographic hardship.

  View details for DOI 10.5858/arpa.2019-0150-CP

  View details for PubMedID 31596620

• Flow Cytometry Signature for Kikuchi-Fujimoto/Lupus Lymphadenitis Derived From 975 Benign and Malignant Lymphadenopathies Kumar, J., Scott, G., Oak, J., Raess, P., Gratzinger, D. OXFORD UNIV PRESS INC. 2019: S105–S106

  View details for DOI 10.1093/ajcp/aqz121.004

  View details for Web of Science ID 000504321700231

• Treatment and outcomes in classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in children PEDIATRIC BLOOD & CANCER Twist, C. J., Hiniker, S. M., Gratzinger, D., Gutkin, P. M., Merriott, D. J., Iagaru, A., Link, M. P., Donaldson, S. S. 2019; 66 (8)

  View details for DOI 10.1002/pbc.27803

  View details for Web of Science ID 000472549200013

• Treatment and outcomes in classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in children. Pediatric blood & cancer Twist, C. J., Hiniker, S. M., Gratzinger, D., Gutkin, P. M., Merriott, D. J., Iagaru, A., Link, M. P., Donaldson, S. S. 2019: e27803

  Abstract

  Classic Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) has been rarely reported in children, with limited data available to guide treatment decisions. We report a retrospective review of five children diagnosed with classic HL-PTLD following solid organ transplant between 2007 and 2013 at Stanford University. Patients were treated with Stanford V chemotherapy and involved field radiation therapy. With a median follow-up of 7.2 years (range, 4.7-10.5 years) since diagnosis, all patients remain in remission from HL-PTLD and free from graft failure. In this series, combined modality therapy with risk-adapted chemotherapy and radiation therapy was a successful strategy for the treatment of classic HL-PTLD.

  View details for PubMedID 31062898

• CD20-negative nodular lymphocyte-predominant Hodgkin lymphoma is enriched for variant patterns and shows aggressive clinical features Menke, J., Spinner, M., Shrestha, B., Advani, R., Natkunam, Y., Gratzinger, D. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102345

• Autoimmune Lymphoproliferative Syndrome with Histopathologic Features of Castleman Disease Lo, R., Gratzinger, D., Keiser, E., Chang, K., Gernez-Goldhammer, Y. SPRINGER/PLENUM PUBLISHERS. 2019: S103–S104

  View details for Web of Science ID 000463709600168

• Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints MOLECULAR IMAGING AND BIOLOGY Chapelin, F., Khurana, A., Moneeb, M., Hazard, F., Chan, C., Nejadnik, H., Gratzinger, D., Messing, S., Erdmann, J., Gaur, A., Daldrup-Link, H. E. 2019; 21 (1): 95–104

  View details for DOI 10.1007/s11307-018-1218-7

  View details for Web of Science ID 000458989800011

• Myeloid Cell Nuclear Differentiation Antigen (MNDA) Positivity in Primary Follicles: Potential Pitfall in the Differential Diagnosis With Marginal Zone Lymphoma. Applied immunohistochemistry & molecular morphology : AIMM Manohar, V., Peerani, R., Tan, B., Gratzinger, D., Natkunam, Y. 2019

  Abstract

  Myeloid cell nuclear differentiation antigen (MNDA) is an immunohistochemical marker that is used to distinguish marginal zone lymphomas (MZLs) from other small B-cell lymphomas. An index case that showed MNDA staining in primary follicles prompted the current study to evaluate whether MNDA expression is widespread in primary follicles and to address whether it poses a potential diagnostic pitfall. Of the 15 cases with primary follicles identified by a search of the laboratory information system, 7 had positive MNDA staining. In all cases, there was weak nuclear staining similar to what is typical of MNDA staining in MZLs. All cases showed intense nuclear signal in myeloid lineage cells such as neutrophils, which served as positive internal controls. The histologic and cytologic features of primary follicles and MZLs showed overlapping features, particularly in small biopsies. Our results indicate that weak nuclear MNDA staining can act as a potential pitfall in the evaluation of small B-cell lymphomas. Correlation with other immunohistochemical markers that are useful in the workup of small B-cell lymphomas, as well as those that outline immunoarchitectural features of lymphoid follicles, is suggested when both entities are part of the differential diagnosis. Our results underscore the need for caution in the interpretation of weak nuclear MNDA staining in the evaluation of small B-cell lymphomas.

  View details for PubMedID 30640752

• Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal? BLOOD Natkunam, Y., Gratzinger, D., Chadburn, A., Goodlad, J. R., Chan, J. C., Said, J., Jaffe, E. S., de Jong, D. 2018; 132 (18): 1871–78

  View details for DOI 10.1182/blood-2018-04-842559

  View details for Web of Science ID 000448958500007

• Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis HAEMATOLOGICA Gars, E., Purington, N., Scott, G., Chisholm, K., Gratzinger, D., Martin, B. A., Ohgami, R. S. 2018; 103 (10): 1635–41

  View details for DOI 10.3324/haematol.2017.186627

  View details for Web of Science ID 000445883500026

• Understanding the tumor microenvironment in the primary cutaneous CD30-positive lymphoproliferative disorders Ferreira, C., Miyashiro, D., Sanches Junior, J., Zhao Shuchun, Zerbini, M., Azevedo, R., Natkunam, Y., Gratzinger, D. ELSEVIER SCI LTD. 2018: S1–S2

  View details for DOI 10.1016/j.ejca.2018.07.143

  View details for Web of Science ID 000443008600003

• Flow Immunophenotyping of Benign Lymph Nodes Sampled by FNA: Representative With Diagnostic Pitfalls CANCER CYTOPATHOLOGY Scott, G. D., Lau, H. D., Kurzer, J. H., Kong, C. S., Gratzinger, D. A. 2018; 126 (9): 797–808

  View details for DOI 10.1002/cncy.22038

  View details for Web of Science ID 000454533300007

• Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation CLINICAL CANCER RESEARCH Aghighi, M., Theruvath, A. J., Pareek, A., Pisani, L. L., Alford, R., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D., Luna-Fineman, S., Advani, R., Spunt, S. L., Daldrup-Link, H. E. 2018; 24 (17): 4110–18

  View details for DOI 10.1158/1078-0432.CCR-18-0673

  View details for Web of Science ID 000444040400008

• Orbital and chorioretinal manifestations of Erdheim-Chester disease treated with vemurafenib. American journal of ophthalmology case reports Huang, L. C., Topping, K. L., Gratzinger, D., Brown, R. A., Martin, B. A., Silva, R. A., Kossler, A. L. 2018; 11: 158–63

  Abstract

  Purpose: We report a patient with severe multi-organ dysfunction of unknown origin who presented with bilateral orbital and chorioretinal manifestations that led to the diagnosis of Erdheim-Chester Disease (ECD).Observations: ECD is a rare, histiocytic, proliferative disorder characterized by multi-systemic organ involvement that has historically lacked effective therapy. Our patient underwent genetic testing that was positive for the BRAF V600E mutation; therefore, the patient was treated with vemurafenib.Conclusions and importance: This case demonstrates the rare orbital and intraocular manifestations of ECD and the unfortunate impact of a delayed diagnosis, the importance of early gene therapy testing for management decisions, and the utilization of targeted directed therapy to improve visual outcomes and quality of life.

  View details for PubMedID 30094395

• Prospective Analysis of EBV plus PTLD in a Multi-Center Study of Pediatric Transplant Recipients Martinez, O. M., Krams, S. M., Lapasaran, M., Boyd, S. D., Bernstein, D., Twist, C., Weinberg, K., Gratzinger, D., Tan, B., Armstrong, B., Ikle, D., Brown, M., Robien, M., Esquivel, C. O. LIPPINCOTT WILLIAMS & WILKINS. 2018: S319

  View details for Web of Science ID 000444541200511

• Prospective Analysis of EBV plus PTLD Incidence in Pediatric Transplant Recipients in the Modern Era. Martinez, O., Krams, S., Lapasaran, M., Boyd, S., Bernstein, D., Twist, C., Weinberg, K., Gratzinger, D., Tan, B., Armstrong, B., Ikle, D., Brown, M., Robien, M., Esquivel, C., CTOTC-06 Investigators WILEY. 2018: 352–53

  View details for Web of Science ID 000431965401270

• Comparison of MYC Fluorescent In Situ Hybridization Testing of Diffuse Large B-cell Lymphomas in Fine Needle Aspiration and Surgical Specimens Menke, J., Gupta, S., Bangs, C. D., Kong, C., Natkunam, Y., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 162

  View details for Web of Science ID 000429308601095

• Nodular Lymphocyte Predominant Hodgkin Lymphoma: Cytopathologic and Immunophenotypic Correlation and Diagnostic Pitfalls Gupta, S., Natkunam, Y., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 146

  View details for Web of Science ID 000459341000400

• Comparison of MYC Fluorescent In Situ Hybridization Testing of Diffuse Large B-cell Lymphomas in Fine Needle Aspiration and Surgical Specimens Menke, J., Gupta, S., Bangs, C. D., Kong, C., Natkunam, Y., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 162

  View details for Web of Science ID 000459341000444

• Large-scale flow immunophenotyping of benign lymph nodes sampled by fine needle aspiration: representative specimens with diagnostic pitfalls Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 173

  View details for Web of Science ID 000459341000475

• Immunophenotype signatures for Kikuchi's Disease, Castleman's Disease, and Angiomyomatous Hamartoma: rare diseases drawn out of large-scale normative data using an informatics approach Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 550

  View details for Web of Science ID 000459341002414

• Large-scale flow immunophenotyping of benign lymph nodes sampled by fine needle aspiration: representative specimens with diagnostic pitfalls Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 173

  View details for Web of Science ID 000429308601126

• Immunophenotype signatures for Kikuchi's Disease, Castleman's Disease, and Angiomyomatous Hamartoma: rare diseases drawn out of large-scale normative data using an informatics approach Scott, G. D., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 550

  View details for Web of Science ID 000429308603414

• Nodular Lymphocyte Predominant Hodgkin Lymphoma: Cytopathologic and Immunophenotypic Correlation and Diagnostic Pitfalls Gupta, S., Natkunam, Y., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2018: 146

  View details for Web of Science ID 000429308601051

• Nodal Involvement by CD30+ Cutaneous Lymphoproliferative Disorders and Its Challenging Differentiation From Classical Hodgkin Lymphoma. Archives of pathology & laboratory medicine Lezama, L. S., Gratzinger, D. n. 2018; 142 (1): 139–42

  Abstract

  Primary cutaneous lymphomas are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. Mycosis fungoides is the most common type of primary cutaneous T-cell lymphoma, representing almost 50% of primary cutaneous T-cell lymphomas, and primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common group (30%). Transformed mycosis fungoides is usually CD30+ and can involve multiple nodal sites; other primary cutaneous CD30+ T-cell lymphoproliferative disorders can also involve draining regional nodes. Nodal involvement by CD30+ T-cell lymphoproliferative disorders can mimic classical Hodgkin lymphoma, which can aberrantly express T-cell antigens. The aim of this article is to briefly review salient clinical, histologic, immunophenotypic, and molecular features that can be used to distinguish lymph node involvement by CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders from classical Hodgkin lymphoma, a clinically important differential diagnosis that represents a challenging task for the pathologist.

  View details for PubMedID 29257929

• Defining Normal: Flow Cytometry Immunophenotyping of Benign Lymph Nodes Sampled by Fine Needle Aspiration or Surgical Biopsy Scott, G., Gratzinger, D. OXFORD UNIV PRESS INC. 2018: S85

  View details for Web of Science ID 000422938200201

• Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Chapelin, F. n., Khurana, A. n., Moneeb, M. n., Gray Hazard, F. K., Chan, C. F., Nejadnik, H. n., Gratzinger, D. n., Messing, S. n., Erdmann, J. n., Gaur, A. n., Daldrup-Link, H. E. 2018

  Abstract

  While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants.Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur in ten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6 weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants.Implants in group 1 showed a significantly increased two-dimensional area at week 2 (p = 0.0092), 4 (p = 0.003), and 6 (p = 0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1 were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance.ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.

  View details for PubMedID 29869062

• Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation. Clinical cancer research : an official journal of the American Association for Cancer Research Aghighi, M. n., Theruvath, A. J., Pareek, A. n., Pisani, L. n., Alford, R. n., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D. n., Luna-Fineman, S. n., Advani, R. H., Spunt, S. L., Daldrup-Link, H. E. 2018

  Abstract

  Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

  View details for PubMedID 29764855

• Bone marrow histomorphologic criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica Gars, E. n., Purington, N. n., Scott, G. n., Chisholm, K. n., Gratzinger, D. n., Martin, B. A., Ohgami, R. S. 2018

  Abstract

  Hemophagocytic lymphohistiocytosis is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH-2004 trial. Hemophagocytosis is the only histomorphologic criterion, but in isolation is neither specific nor sensitive for the diagnosis of hemophagocytic lymphohistiocytosis. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphologic evidence of hemophagocytosis in hemophagocytic lymphohistiocytosis have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphologic hemophagocytosis could be identified, and if such criteria would aid in the diagnosis of hemophagocytic lymphohistiocytosis. We analyzed the morphologic features of hemophagocytosis in 78 patients presenting with clinical features suspicious for hemophagocytic lymphohistiocytosis: 40 patients with hemophagocytic lymphohistiocytosis and 38 patients without hemophagocytic lymphohistiocytosis. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes (1 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.86, 0.99), nucleated erythrocytes (4 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (area under the curve: 0.91, 95% confidence interval: 0.85, 0.95) are strongly associated with hemophagocytic lymphohistiocytosis. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively distinguished between hemophagocytic lymphohistiocytosis and non-hemophagocytic lymphohistiocytosis (cross-validated area under curve: 0.90, 95% confidence interval: 0.83, 0.97).

  View details for PubMedID 29903767

• Clinical Impact of the 2016 Update to the WHO Lymphoma Classification (vol 18, 45, 2017) CURRENT TREATMENT OPTIONS IN ONCOLOGY Lynch, R. C., Gratzinger, D., Advani, R. H. 2017; 18 (10): 60

  View details for PubMedID 28861885

• KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study (vol 50, pg 123, 2016) LEUKEMIA RESEARCH Swords, R. T., Greenberg, P. L., Wei, A. H., Durrant, S., Advani, A. S., Hertzberg, M. S., Lewis, I. D., Rivera, G., Gratzinger, D., Fan, A. C., Felsher, D. W., Cortes, J. E., Watts, J. M., Yarranton, G. T., Walling, J. M., Lancet, J. E. 2017; 59: 65

  View details for PubMedID 28575698

• B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency 2015 SH/EAHP Workshop Report-Part 2 AMERICAN JOURNAL OF CLINICAL PATHOLOGY De Jong, D., Roemer, M. G., Chan, J. K., Goodlad, J., Gratzinger, D., Chadburn, A., Jaffe, E. S., Said, J., Natkunam, Y. 2017; 147 (2): 153-170

  Abstract

  The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency.Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings.Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings.Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.

  View details for DOI 10.1093/ajcp/aqw216

  View details for PubMedID 28395108

• EBV-Positive B-Cell Proliferations of Varied Malignant Potential 2015 SH/EAHP Workshop Report-Part 1 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Natkunam, Y., Goodlad, J. R., Chadburn, A., de Jong, D., Gratzinger, D., Chan, J. C., Said, J., Jaffe, E. S. 2017; 147 (2): 129–52

  View details for DOI 10.1093/ajcp/aqw214

  View details for Web of Science ID 000397228900001

• HHV8/KSHV-Positive Lymphoproliferative Disorders and the Spectrum of Plasmablastic and Plasma Cell Neoplasms 2015 SH/EAHP Workshop Report-Part 3 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chadburn, A., Said, J., Gratzinger, D., Chan, J. C., de Jong, D., Jaffe, E. S., Natkunam, Y., Goodlad, J. R. 2017; 147 (2): 171–87

  View details for DOI 10.1093/ajcp/aqw218

  View details for Web of Science ID 000397228900003

• B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency 2015 SH/EAHP Workshop Report-Part 2 AMERICAN JOURNAL OF CLINICAL PATHOLOGY de Jong, D., Roemer, M. M., Chan, J. C., Goodlad, J., Gratzinger, D., Chadburn, A., Jaffe, E. S., Said, J., Natkunam, Y. 2017; 147 (2): 153–70

  View details for DOI 10.1093/ajcp/aqw216

  View details for Web of Science ID 000397228900002

• Primary/Congenital Immunodeficiency 2015 SH/EAHP Workshop Report-Part 5 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., Jaffe, E. S., Chadburn, A., Chan, J. C., de Jong, D., Goodlad, J. R., Said, J., Natkunam, Y. 2017; 147 (2): 204–16

  View details for DOI 10.1093/ajcp/aqw215

  View details for Web of Science ID 000397108600006

• T- and NK-Cell Lymphomas and Systemic Lymphoproliferative Disorders and the Immunodeficiency Setting 2015 SH/EAHP Workshop Report-Part 4 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., de Jong, D., Jaffe, E. S., Chadburn, A., Chan, J. C., Goodlad, J. R., Said, J., Natkunam, Y. 2017; 147 (2): 188–203

  View details for DOI 10.1093/ajcp/aqw213

  View details for Web of Science ID 000397108600005

• Combined Fine Needle Aspiration Cytology and Flow Cytometric Immunophenotyping Is an Effective Method for Diagnosis of Hematolymphoid Disease Lau, H., Wu, S., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2017: 103A

  View details for Web of Science ID 000394467300396

• Combined Fine Needle Aspiration Cytology and Flow Cytometric Immunophenotyping Is an Effective Method for Diagnosis of Hematolymphoid Disease Lau, H., Wu, S., Long, S., Gratzinger, D. NATURE PUBLISHING GROUP. 2017: 103A

  View details for Web of Science ID 000393724400396

• EBV-Positive B-Cell Proliferations of Varied Malignant Potential 2015 SH/EAHP Workshop Report-Part 1 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Natkunam, Y., Goodlad, J. R., Chadburn, A., De Jong, D., Gratzinger, D., Chan, J. K., Said, J., Jaffe, E. S. 2017; 147 (2): 129-152

  Abstract

  The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review B-cell proliferations of varied malignant potential associated with immunodeficiency.The Workshop Panel reviewed all cases of B-cell hyperplasias, polymorphic B-lymphoproliferative disorders, Epstein-Barr virus (EBV)-positive mucocutaneous ulcer, and large B-cell proliferations associated with chronic inflammation and rendered consensus diagnoses. Disease definitions, boundaries with more aggressive B-cell proliferations, and association with EBV were explored.B-cell proliferations of varied malignant potential occurred in all immunodeficiency backgrounds. Presentation early in the course of immunodeficiency and in younger age groups and regression with reduction of immunosuppression were characteristic features. EBV positivity was essential for diagnosis in some hyperplasias where other specific defining features were absent.This spectrum of B-cell proliferations show similarities across immunodeficiency backgrounds. Localized forms of immunodeficiency disorders arise in immunocompetent patients most likely due to chronic immune stimulation and, despite aggressive histologic features, often show indolent clinical behavior.

  View details for DOI 10.1093/ajcp/aqw214

  View details for PubMedID 28395107

• HHV8/KSHV-Positive Lymphoproliferative Disorders and the Spectrum of Plasmablastic and Plasma Cell Neoplasms 2015 SH/EAHP Workshop Report-Part 3 AMERICAN JOURNAL OF CLINICAL PATHOLOGY Md, A. C., Said, J., Gratzinger, D., Chan, J. K., De Jong, D., Jaffe, E. S., Natkunam, Y., Goodlad, J. R. 2017; 147 (2): 171-187

  Abstract

  The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related lymphoproliferative disorders with plasmablastic and plasma cell differentiation.The workshop panel reviewed human herpes virus 8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV)-associated lesions and other lesions exhibiting plasma cell differentiation, including plasmablastic proliferations with features of myeloma/plasmacytoma, plasmablastic neoplasms presenting in extranodal sites and effusion-based lymphomas, and rendered a consensus diagnosis.The spectrum of HHV8/KSHV-associated proliferations ranged from multicentric Castleman disease (MCD) to MCD with plasmablastic aggregates to HHV8+ diffuse large B-cell lymphoma and germinotrophic lymphoproliferative disorder. Comparisons across effusion-based lymphomas with and without HHV8/KSHV and plasmablastic lymphomas in immunodeficient and immunocompetent patients were discussed.The presence or absence of HHV8/KSHV is a defining feature in disorders associated with Castleman disease, although their differential diagnosis and recognition of progression may be challenging. Plasmablastic proliferations overlap with myeloma/plasmacytoma as well as extranodal and effusion-based lymphomas. The involvement of Epstein-Barr virus is typically variable.

  View details for DOI 10.1093/ajcp/aqw218

  View details for PubMedID 28395104

• Perceptions of Unprofessional Attitudes and Behaviors: Implications for Faculty Role Modeling and Teaching Professionalism During Pathology Residency. Archives of pathology & laboratory medicine Brissette, M. D., Johnson, K. A., Raciti, P. M., McCloskey, C. B., Gratzinger, D. A., Conran, R. M., Domen, R. E., Hoffman, R. D., Post, M. D., Roberts, C. A., Rojiani, A. M., Powell, S. Z. 2017

  Abstract

  - Changes occurring in medicine have raised issues about medical professionalism. Professionalism is included in the Core Competencies and Milestones for all pathology residents. Previous studies have looked at resident professionalism attitudes and behaviors in primary care but none have looked specifically at pathology.- To examine behavior and attitudes toward professionalism within pathology and to determine how professionalism is taught in residency programs.- Surveys were sent to all College of American Pathologists junior members and all pathology residency program directors, and responses were compared.- Although no single behavior received the same professionalism rating among residents and program directors, both groups identified the same behaviors as being the most unprofessional: posting identifiable patient information or case images to social media, making a disparaging comment about a physician colleague or member of the support staff on social media or in a public space, and missing work without reporting the time off. Faculty were observed displaying most of these behaviors as often or more often than residents by both groups. The most common means to teach professionalism in pathology residencies is providing feedback as situations arise and teaching by example. Age differences were found within each group and between groups for observed behaviors and attitudes.- As teaching by example was identified as a common educational method, faculty must be aware of the role their behavior and attitudes have in shaping resident behavior and attitudes. These results suggest a need for additional resources to teach professionalism during pathology residency.

  View details for DOI 10.5858/arpa.2016-0477-CP

  View details for PubMedID 28686498

• Clinical Impact of the 2016 Update to the WHO Lymphoma Classification. Current treatment options in oncology Lynch, R. C., Gratzinger, D. n., Advani, R. H. 2017; 18 (7): 45

  Abstract

  The 2016 revision of the WHO classification of lymphoid neoplasms includes new entities along with a clearer definition of provisional and definitive subtypes based on better understanding of the molecular drivers of lymphomas. These changes impact current treatment paradigms and provide a framework for future clinical trials. Additionally, this update recognizes several premalignant or predominantly indolent entities and underscores the importance of avoiding unnecessarily aggressive treatment in the latter subsets.

  View details for PubMedID 28670664

• KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study. Leukemia research Swords, R. T., Greenberg, P. L., Wei, A. H., Durrant, S., Advani, A. S., Hertzberg, M. S., Lewis, I. D., Rivera, G., Gratzinger, D., Fan, A. C., Felsher, D. W., Cortes, J. E., Watts, J. M., Yarranton, G. T., Walling, J. M., Lancet, J. E. 2016; 50: 123-131

  Abstract

  EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

  View details for DOI 10.1016/j.leukres.2016.09.012

  View details for PubMedID 27736729

• Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma. Human pathology Fernandez-Pol, S., Bangs, C. D., Cherry, A., Arber, D. A., Gratzinger, D. 2016; 55: 39-43

  Abstract

  Histiocytic sarcoma is rare and difficult to distinguish from histologic mimics such as myeloid sarcoma due to its relatively nonspecific immunoprofile. A subset of histiocytic sarcomas are clonally related to synchronous or metachronous follicular lymphomas. Interestingly, the histiocytic tumor component has been shown to harbor BCL2 gene translocations that are identical to those found in the lymphoma. We present one case of histiocytic sarcoma and initially occult follicular lymphoma in which detection of a BCL2 gene translocation helped support the diagnosis. We also provide follow up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma. Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis. Testing for an IGH/BCL2 translocation should be considered in the diagnostic workup of difficult to characterize neoplasms with histiocytic/monocytic morphology and immunoprofile.

  View details for DOI 10.1016/j.humpath.2016.04.004

  View details for PubMedID 27134111

• A REPLICABLE CD271+MESENCHYMAL STROMAL CELL DENSITY SCORE: BRINGING THE DYSFUNCTIONAL MYELODYSPLASTIC SYNDROME NICHE TO THE DIAGNOSTIC LABORATORY Gars, E., Yousry, S., Babu, D., Kurzer, J., George, T., Gratzinger, D. ELSEVIER SCIENCE INC. 2016: S73

  View details for DOI 10.1016/j.exphem.2016.06.137

  View details for Web of Science ID 000382184600122

• Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood Louissaint, A., Schafernak, K. T., Geyer, J. T., Kovach, A. E., Ghandi, M., Gratzinger, D., Roth, C. G., Paxton, C. N., Kim, S., Namgyal, C., Morin, R., Morgan, E. A., Neuberg, D. S., South, S. T., Harris, M. H., Hasserjian, R. P., Hochberg, E. P., Garraway, L. A., Harris, N. L., Weinstock, D. M. 2016; 128 (8): 1093-1100

  Abstract

  Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy-number analysis, exome and/or targeted sequencing of 26 PTNFLs (16 pediatric, 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22), and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (p=0.35). PTNFL was otherwise genomically bland, and specifically lacked recurrent mutations in epigenetic modifiers (e.g. CREBBP, KMT2D). Copy number aberrations (CNAs) affected a mean of only 0.5% of PTNFL genomes, compared to 10% of limited-stage typical FL genomes (p<0.02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAP kinase pathway mutations and a near absence of mutations in epigenetic modifiers.

  View details for DOI 10.1182/blood-2015-12-682591

  View details for PubMedID 27325104

• Mucocutaneous ulcer: a mimic of EBV?+?diffuse large B cell lymphoma in the immunodeficiency setting. Leukemia & lymphoma Gratzinger, D., Jaffe, E. S. 2016; 57 (8): 1982-1983

  View details for DOI 10.3109/10428194.2016.1166492

  View details for PubMedID 27071493

• Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood Matthews, J. M., Bhatt, S., Patricelli, M. P., Nomanbhoy, T. K., Jiang, X., Natkunam, Y., Gentles, A. J., Martinez, E., Zhu, D., Chapman, J. R., Cortizas, E., Shyam, R., Chinichian, S., Advani, R., Tan, L., Zhang, J., Choi, H. G., Tibshirani, R., Buhrlage, S. J., Gratzinger, D., Verdun, R., Gray, N. S., Lossos, I. S. 2016; 128 (2): 239-248

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), yet 40-50% of patients will eventually succumb to their disease demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNA's that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that Germinal Center Kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Since the majority of DLBCL tumors (~80%) exhibit activation of GCK, this therapy may be applicable to most patients.

  View details for DOI 10.1182/blood-2016-02-696856

  View details for PubMedID 27151888

• Plasmacytic posttransplant lymphoproliferative disorder with hyperviscosity syndrome in a child after liver transplant. Hepatology Yang, C. H., Gombar, S., Twist, C. J., Gratzinger, D., Esquivel, C. O., Lau, A. H. 2016

  View details for DOI 10.1002/hep.28657

  View details for PubMedID 27227484

• Pure Erythroid Leukemia and Erythroblastic Sarcoma Evolving From Chronic Myeloid Neoplasms AMERICAN JOURNAL OF CLINICAL PATHOLOGY Li, H., Hasserjian, R. P., Kroft, S. H., Harrington, A. M., Wheaton, S. E., Pildain, A., Ewalt, M. D., Gratzinger, D., Hosking, P., Olteanu, H. 2016; 145 (4): 538-551

  Abstract

  Pure erythroid leukemia (PEL) is an extremely rare entity that may, even more rarely, evolve from a preexisting chronic myeloid neoplasm (CMN); there is minimal literature regarding this latter phenomenon.We describe 14 patients with PEL that represented progression from a preexisting myelodysplastic syndrome (MDS, n = 8) or myeloproliferative neoplasm (MPN, n = 6), three of which manifested as erythroblastic sarcoma (EBS), a rare entity. These patients had a highly complex karyotype with prominent clonal evolution and a very aggressive clinical course.Patients with PEL from MDS showed a more rapid progression time to PEL and had lower platelet counts compared with PEL from MPN. No other significant differences were found between the two groups.These data represent the largest cohort of patients with PEL and an antecedent CMN, as well as the largest series of EBS reported to date, and underscore the unique morphologic, cytogenetic, immunophenotypic, and clinical features of this uncommon entity.

  View details for DOI 10.1093/ajcp/aqw033

  View details for Web of Science ID 000376947200012

  View details for PubMedID 27124944

• 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

• Professionalism in Pathology: A Case-Based Approach as a Potential Educational Tool. Archives of pathology & laboratory medicine Domen, R. E., Johnson, K. n., Conran, R. M., Hoffman, R. D., Post, M. D., Steinberg, J. J., Brissette, M. D., Gratzinger, D. A., McCloskey, C. B., Raciti, P. M., Roberts, C. A., Rojiani, A. M., Powell, S. Z. 2016

  Abstract

  -Professionalism issues in residency training can be difficult to assess and manage. Generational or role-based differences may also exist between faculty and residents as to what constitutes unprofessional behavior and how to manage it.-To examine and compare how faculty and residents would approach the same 5 case scenarios detailing various aspects of unprofessional behavior.-Five case scenarios highlighting various unprofessional behaviors were presented in a workshop at an annual meeting of pathology department chairs, residency program directors, and undergraduate pathology medical educators (ie, pathologists involved in medical student pathology education). The same cases were presented to a cohort of pathology residents currently in training. A standard set of responses were offered to the participants, polling results were collected electronically, and results were compared.-Faculty and residents were fairly consistent within their respective groups. In a subset of cases, faculty were more likely to favor working with the individual in the scenario, whereas resident respondents were more likely to favor either no response or a severe response. Generational or role-based differences were also potentially evident.-Assessing expectations and differences around professionalism for both faculty and residents should be considered as part of any educational and management approach for professionalism. Although a level of generational differences appears to be evident in this study regarding the recognition and management of unprofessional behavior, there was also agreement in some cases. Further exploration into the discrepant responses between faculty and residents may prove useful in developing educational, assessment, and remediation resources.

  View details for DOI 10.5858/arpa.2016-0217-CP

  View details for PubMedID 27763788

• Dasatinib-related Follicular Hyperplasia: An Underrecognized Entity With Characteristic Morphology. American journal of surgical pathology Ozawa, M. G., Ewalt, M. D., Gratzinger, D. 2015; 39 (10): 1363-1369

  Abstract

  Dasatinib, a second-generation tyrosine kinase inhibitor with activity against BCR-ABL1 and other Src family tyrosine kinases, is approved as a first-line treatment option for Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. Recently, lymphadenopathy with morphologic features of reactive follicular hyperplasia was described in a cohort of patients with CML on long-term dasatinib therapy. However, the complete morphologic and immunophenotypic features of this previously underappreciated adverse effect have not been fully described. Herein, we report 3 cases of unexplained lymphadenopathy resulting in multiple diagnostic procedures in patients with CML and a history of long-term dasatinib therapy. Morphologic examination demonstrated preserved nodal architecture showing hybrid features of progressive transformation of germinal centers and Castleman-type changes in a background of florid follicular hyperplasia. Large germinal centers were disrupted by complex infolding of IgD mantle zones arranged as cuffs surrounding perforating capillaries. Other abnormalities variably present included decreased CD20 expression among polytypic B cells and increased Epstein-Barr virus reactivity in scattered paracortical cells and/or individual germinal centers. B-cell clonality studies showed no predominant clonal rearrangements. Consideration of dasatinib-related lymphadenopathy may pre-empt unnecessary repeat diagnostic procedures in patients with CML or other dasatinib-susceptible malignancies and persistent lymphadenopathy.

  View details for DOI 10.1097/PAS.0000000000000488

  View details for PubMedID 26360368

• Occult Dermal Lymphatic Involvement Is Frequent in Primary Cutaneous Anaplastic Large Cell Lymphoma. American Journal of dermatopathology Gratzinger, D., Million, L., Kim, Y. H. 2015; 37 (10): 767-770

  Abstract

  Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent T-cell lymphoproliferative disorder managed with low-dose radiation therapy, surgery, and/or mild chemotherapy; patients with extensive limb disease (ELD) have a more aggressive clinical course. We have previously demonstrated that histologically apparent vascular involvement in pcALCL is lymphatic. We hypothesized that histologically occult lymphatic involvement may be associated with particular patterns of disease spread that could involve lymphangitic spread including locoregional spread of disease in the form of ELD and extracutaneous spread of disease. We have therefore set out to quantitate the incidence of occult lymphovascular involvement in pcALCL and to assess for an association between lymphovascular involvement and these patterns of disease. We performed immunohistochemistry for the lymphovascular marker D2-40 on skin biopsies from 29 patients with pcALCL followed in the Stanford Cutaneous Lymphoma Clinic. Immunohistochemically evident dermal lymphovascular involvement was found in nearly half of cases examined (48%; 95% confidence interval, 29%-67%). There was a nonsignificant trend toward a higher prevalence of ELD among patients with pcALCL involving dermal lymphatics (7% vs. 29%; p = 0.12). In this small cohort, there was no indication of a significantly more aggressive disease course in patients with lymphatic involvement either in the form of disease-related mortality (one each in the lymphatic and nonlymphatic groups) or in time to extracutaneous involvement.

  View details for DOI 10.1097/DAD.0000000000000377

  View details for PubMedID 26381026

• Lymph node involvement by mycosis fungoides and Sezary syndrome mimicking angioimmunoblastic T-cell Lymphoma HUMAN PATHOLOGY LeBlanc, R. E., Lefterova, M. I., Suarez, C. J., Tavallaee, M., Kim, Y. H., Schrijver, I., Kim, J., Gratzinger, D. 2015; 46 (9): 1382-1389

  Abstract

  Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

  View details for DOI 10.1016/j.humpath.2015.05.024

  View details for Web of Science ID 000360779200017

• Lymph node involvement by mycosis fungoides and Sézary syndrome mimicking angioimmunoblastic T-cell lymphoma. Human pathology LeBlanc, R. E., Lefterova, M. I., Suarez, C. J., Tavallaee, M., Kim, Y. H., Schrijver, I., Kim, J., Gratzinger, D. 2015; 46 (9): 1382-9

  Abstract

  Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

  View details for DOI 10.1016/j.humpath.2015.05.024

  View details for PubMedID 26193796

• Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2 NATURE GENETICS Ungewickell, A., Bhaduri, A., Rios, E., Reuter, J., Lee, C. S., Mah, A., Zehnder, A., Ohgami, R., Kulkarni, S., Armstrong, R., Weng, W., Gratzinger, D., Tavallaee, M., Rook, A., Snyder, M., Kim, Y., Khavari, P. A. 2015; 47 (9): 1056-?

  Abstract

  Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

  View details for DOI 10.1038/ng.3370

  View details for Web of Science ID 000360394100016

• Bone Marrow Heme Oxygenase-1+Macrophages Are Aberrantly Increased in Transfused Patients With Myelodysplastic Syndromes and Portend Poor Outcome Gratzinger, D., Nybakken, G. NATURE PUBLISHING GROUP. 2015: 347A

  View details for Web of Science ID 000349502202098

• Bone Marrow Heme Oxygenase-1+Macrophages Are Aberrantly Increased in Transfused Patients With Myelodysplastic Syndromes and Portend Poor Outcome Gratzinger, D., Nybakken, G. NATURE PUBLISHING GROUP. 2015: 347A

  View details for Web of Science ID 000348948002407

• A Novel Humanized Bone Marrow Niche Xenotransplantation Model Allows Superior Engraftment of Human Normal and Malignant Hematopoietic Cells and Reveals Myelofibrosis-Initiating Cells in the HSC Compartment Reinisch, A., Gratzinger, D., Hong, W., Majeti, R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233806032

• Classical Endothelial Markers Fail to Highlight Bone Marrow Sinusoids in the Marrow of Healthy Patients and Patients with Myelodysplastic Syndromes Ewalt, M., Gratzinger, D. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233807161

• Mesenchymal Stromal Cell Density Is Increased in Higher Grade Myelodysplastic Syndromes and Independently Predicts Survival AMERICAN JOURNAL OF CLINICAL PATHOLOGY Johnson, R. C., Kurzer, J. H., Greenberg, P. L., Gratzinger, D. 2014; 142 (6): 795-802

  Abstract

  We retrospectively tested the prognostic and diagnostic significance of CD271+ mesenchymal stromal cell (MSC) density in cytopenic patients who underwent bone marrow biopsy to evaluate for myelodysplastic syndromes (MDS).CD271+ MSC density was quantitated by automated image analysis of tissue microarray cores in 125 cytopenic patients: 40 lower grade MDS (<5% marrow blasts), 24 higher grade MDS, and 61 benign.CD271+ MSC density was increased in higher grade MDS compared with benign (P = .006) and lower grade MDS (P = .02). CD271+ MSC density was predictive of survival among patients with MDS independent of Revised International Prognostic Scoring System (IPSS-R), history of transfusion, therapy-related MDS, and fibrosis (hazard ratio, 3.4; P < .001). Among low or intermediate IPSS-R patients, median survival was significantly shorter in the high CD271+ MSC density group (47 vs 18 months, P < .02).High CD271+ MSC density is characteristic of higher grade MDS and is associated with poor risk independent of known prognostic factors.

  View details for DOI 10.1309/AJCP71OPHKOTLSUG

  View details for Web of Science ID 000345053900011

• Intralymphatic Cutaneous Anaplastic Large Cell Lymphoma/Lymphomatoid Papulosis: Expanding the Spectrum of CD30-positive Lymphoproliferative Disorders. American journal of surgical pathology Samols, M. A., Su, A., Ra, S., Cappel, M. A., Louissant, A., Knudson, R. A., Ketterling, R. P., Said, J., Binder, S., Harris, N. L., Feldman, A. L., Kim, J., Kim, Y. H., Gratzinger, D. 2014; 38 (9): 1203-1211

  Abstract

  Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

  View details for DOI 10.1097/PAS.0000000000000217

  View details for PubMedID 24805854

• Vascular endothelial growth factor: the salt in the Hodgkin cytokine stew? Leukemia & lymphoma Gratzinger, D. 2014; 55 (3): 474-475

  View details for DOI 10.3109/10428194.2013.818144

  View details for PubMedID 23795806

• Intralymphatic Localization of Anaplastic Large Cell Lymphoma in Skin Biopsies May Represent Part of the Spectrum of Cutaneous Anaplastic Large Cell Lymphoma Samols, M. A., Kim, Y. H., Kim, J., Cappel, M. A., Louissaint, A., Knudson, R. A., Ketterling, R. P., Harris, N. L., Feldman, A. L., Gratzinger, D. NATURE PUBLISHING GROUP. 2014: 376A

  View details for Web of Science ID 000331502202098

• Intralymphatic Localization of Anaplastic Large Cell Lymphoma in Skin Biopsies May Represent Part of the Spectrum of Cutaneous Anaplastic Large Cell Lymphoma Samols, M. A., Kim, Y. H., Kim, J., Cappel, M. A., Louissaint, A., Knudson, R. A., Ketterling, R. P., Harris, N. L., Feldman, A. L., Gratzinger, D. NATURE PUBLISHING GROUP. 2014: 376A

  View details for Web of Science ID 000331155802098

• Update on Myelodysplastic Syndromes Classification and Prognosis. Surgical pathology clinics Gratzinger, D., Greenberg, P. L. 2013; 6 (4): 693-728

  Abstract

  Myelodysplastic syndromes (MDS) are a collection of cytogenetically heterogeneous clonal bone marrow (BM) failure disorders derived from aberrant hematopoietic stem cells in the setting of an aberrant hematopoietic stem cell niche. Patients suffer from variably progressive and symptomatic bone marrow failure with a risk of leukemic transformation. Diagnosis of MDS has long been based on morphologic assessment and blast percentage as in the original French-American-British classification. The recently developed Revised International Prognostic Scoring System provides improved prognostication using more refined cytogenetic, marrow blast, and cytopenia parameters. With the advent of deep sequencing technologies, dozens of molecular abnormalities have been identified in MDS.

  View details for DOI 10.1016/j.path.2013.08.005

  View details for PubMedID 26839194

• Intravascular ALK-negative Anaplastic Large Cell Lymphoma With Localized Cutaneous Involvement and an Indolent Clinical Course Toward Recognition of a Distinct Clinicopathologic Entity AMERICAN JOURNAL OF SURGICAL PATHOLOGY Metcalf, R. A., Bashey, S., Wysong, A., Kim, J., Kim, Y. H., Gratzinger, D. 2013; 37 (4): 617-623

  Abstract

  Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.

  View details for DOI 10.1097/PAS.0b013e318280aa9c

  View details for Web of Science ID 000316184000019

  View details for PubMedID 23480896

• IgG4-positive Sclerosing Orbital Inflammation Involving the Conjunctiva: A Case Report OCULAR IMMUNOLOGY AND INFLAMMATION Paulus, Y. M., Cockerham, K. P., Cockerham, G. C., Gratzinger, D. 2012; 20 (5): 375-377

  Abstract

  To describe IgG4-positive sclerosing orbital inflammation with prominent conjunctival and scleral involvement.Case report.Clinical, radiologic, and pathologic correlation.A 66-year-old man presented with right eye redness and irritation. Examination revealed unilateral scleritis and nongranulomatous anterior uveitis with elevated p-ANCA and CRP. Orbital CT scan showed inferotemporal scleral thickening. Biopsy revealed sclerosis and IgG4-positive plasma cells in the conjunctiva and inferior rectus.IgG4-mediated sclerosing inflammation is well-recognized in the orbit and adnexa, particularly the lacrimal gland. Scleritis with anterior uveitis should be recognized as a possible presentation for this entity, which has important systemic associations.

  View details for DOI 10.3109/09273948.2012.709574

  View details for Web of Science ID 000309471900011

  View details for PubMedID 23030356

• Histoplasmosis Presenting with Ulcers on the Soft Palate JOURNAL OF GENERAL INTERNAL MEDICINE Ozdalga, E., Gratzinger, D. 2012; 27 (9): 1219-1219

  View details for DOI 10.1007/s11606-012-2042-4

  View details for Web of Science ID 000307511300024

  View details for PubMedID 22539064

  View details for PubMedCentralID PMC3515000

• In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study BLOOD Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J. D., Czerwinski, D. K., Ai, W. Z., Morales, A., Abdulla, F., Xing, L., Navi, D., Tibshirani, R. J., Advani, R. H., Lingala, B., Shah, S., Hoppe, R. T., Levy, R. 2012; 119 (2): 355-363

  Abstract

  We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.

  View details for DOI 10.1182/blood-2011-05-355222

  View details for PubMedID 22045986

• Increased CD271+CXCL12 Chemokine Overproducing Mesenchymal Stromal Cells Maintain Distinctive Association with CD34+Hematopoietic Progenitor/Stem Cells in Myelodysplastic Syndrome 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Flores-Figueroa, E., Varma, S., Montgomery, K., Greenberg, P. L., Gratzinger, D. AMER SOC HEMATOLOGY. 2011: 1202–

  View details for Web of Science ID 000299597104140

• In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J., Czerwinski, D., Xing, L., Morales, A., Ai, W., Abdulla, F., Navi, D., Tibshirani, R. J., Advani, R., Natkunam, Y., Hoppe, R. T., Levy, R. AMER SOC HEMATOLOGY. 2010: 130–30

  View details for Web of Science ID 000289662200287

• In Situ Tissue Microarray Cell-Lineage Specific Analysis of Protein Expression In Intact Myelodysplastic Bone Marrow: Data on Putative Poor Prognosis Biomarkers 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Gratzinger, D., Odegaard, J. I., Marinelli, R. J., Sridhar, K. J., Greenberg, P. L. AMER SOC HEMATOLOGY. 2010: 787–87

  View details for Web of Science ID 000289662202111

• CD81 protein is expressed at high levels in normal germinal center B cells and in subtypes of human lymphomas HUMAN PATHOLOGY Luo, R. F., Zhao, S., Tibshirani, R., Myklebust, J. H., Sanyal, M., Fernandez, R., Gratzinger, D., Marinelli, R. J., Lu, Z. S., Wong, A., Levy, R., Levy, S., Natkunam, Y. 2010; 41 (2): 271-280

  Abstract

  CD81 is a tetraspanin cell surface protein that regulates CD19 expression in B lymphocytes and enables hepatitis C virus infection of human cells. Immunohistologic analysis in normal hematopoietic tissue showed strong staining for CD81 in normal germinal center B cells, a cell type in which its increased expression has not been previously recognized. High-dimensional flow cytometry analysis of normal hematopoietic tissue confirmed that among B- and T-cell subsets, germinal center B cells showed the highest level of CD81 expression. In more than 800 neoplastic tissue samples, its expression was also found in most non-Hodgkin lymphomas. Staining for CD81 was rarely seen in multiple myeloma, Hodgkin lymphoma, or myeloid leukemia. In hierarchical cluster analysis of diffuse large B-cell lymphoma, staining for CD81 was most similar to other germinal center B cell-associated markers, particularly LMO2. By flow cytometry, CD81 was expressed in diffuse large B-cell lymphoma cells independent of the presence or absence of CD10, another germinal center B-cell marker. The detection of CD81 in routine biopsy samples and its differential expression in lymphoma subtypes, particularly diffuse large B-cell lymphoma, warrant further study to assess CD81 expression and its role in the risk stratification of patients with diffuse large B-cell lymphoma.

  View details for DOI 10.1016/j.humpath.2009.07.022

  View details for Web of Science ID 000276493600015

  View details for PubMedID 20004001

  View details for PubMedCentralID PMC2813949

• Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP) BRITISH JOURNAL OF HAEMATOLOGY Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Shyam, R., Horning, S., Sehn, L. H., Farinha, P., Briones, J., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. 2010; 148 (2): 235-244

  Abstract

  Diffuse large B cell lymphoma (DLBCL) is clinically and biologically heterogeneous. In most cases of DLBCL, lymphoma cells co-express vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, suggesting autocrine in addition to angiogenic effects. We enumerated microvessel density and scored lymphoma cell expression of VEGF, VEGFR1, VEGFR2 and phosphorylated VEGFR2 in 162 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone)-like regimens. VEGFR2 expression correlated with shorter overall survival (OS) independent of International Prognostic Index (IPI) (P = 0.0028). Phosphorylated VEGFR2 (detected in 13% of cases) correlated with shorter progression-free survival (PFS, P = 0.044) and trended toward shorter OS on univariate analysis. VEGFR1 was not predictive of survival on univariate analysis, but it did correlate with better OS on multivariate analysis with VEGF, VEGFR2 and IPI (P = 0.036); in patients with weak VEGFR2, lack of VEGFR1 coexpression was significantly correlated with poor OS independent of IPI (P = 0.01). These results are concordant with our prior finding of an association of VEGFR1 with longer OS in DLBCL treated with chemotherapy alone. We postulate that VEGFR1 may oppose autocrine VEGFR2 signalling in DLBCL by competing for VEGF binding. In contrast to our prior results with chemotherapy alone, microvessel density was not prognostic of PFS or OS with R-CHOP-like therapy.

  View details for DOI 10.1111/j.1365-2141.2009.07942.x

  View details for PubMedID 19821819

• Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Horning, S. J., Levy, R., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605490

• The Transcription Factor LMO2 Is a Robust Marker of Vascular Endothelium and Vascular Neoplasms and Selected Other Entities AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., Zhao, S., West, R., Rouse, R. V., Vogel, H., Gil, E. C., Levy, R., Lossos, I. S., Natkunam, Y. 2009; 131 (2): 264-278

  Abstract

  The transcription factor LMO2 is involved in vascular and hematopoietic development and hematolymphoid neoplasia. We have demonstrated that LMO2 is expressed nearly ubiquitously in native and neoplastic vasculature, including lymphatics. LMO2 reactivity is otherwise virtually absent in nonhematolymphoid tissues except in breast myoepithelium, prostatic basal cells, and secretory phase endometrial glands. Vasculature is LMO2- in adult and fetal heart, brain of older adults, hepatic sinusoids, and hepatocellular carcinoma. LMO2 is uniformly expressed in benign vascular and lymphatic neoplasms and in most malignant vascular neoplasms with the exception of epithelioid vascular neoplasms of pleura and bone. Among nonvascular neoplasms, LMO2 reactivity is present in giant cell tumor of tendon sheath, juvenile xanthogranuloma, a subset of gastrointestinal stromal tumors, small round blue cell tumors, and myoepithelial-derived neoplasms. The restricted expression pattern, nuclear localization, and crisp staining of LMO2 in paraffin blocks make it an attractive candidate for the diagnostic immunohistochemistry laboratory.

  View details for DOI 10.1309/AJCP5FP3NAXAXRJE

  View details for PubMedID 19141387

• The Transcription Factor LMO2 Is a Robust Marker of Vascular Endothelium and Vascular Neoplasms and Selected Other Entities AMERICAN JOURNAL OF CLINICAL PATHOLOGY Gratzinger, D., Zhao, S., West, R., Rouse, R. V., Vogel, H., Gil, E., Levy, R., Lossos, I. S., Natkunam, Y. 2009; 131 (2): 264-278

  View details for DOI 10.1309/AJCP5FP3NAXAXRJE

  View details for Web of Science ID 000925581000013

• VEGF-C: putting the 'lymph' back in lymphoma? LEUKEMIA & LYMPHOMA Gratzinger, D. 2009; 50 (3): 311-312

  View details for DOI 10.1080/10428190902763525

  View details for Web of Science ID 000265361100002

  View details for PubMedID 19347719

• CD81 Protein Is Expressed in Normal Germinal Center B-Cells and in Subtypes of Human Non-Hodgkin Lymphomas Luo, R. F., Zhao, S., Tibshirani, R., Lossos, I. S., Advani, R., Gratzinger, D., Wong, A., Talrega, N., Levy, R., Levy, S., Natkunam, Y. NATURE PUBLISHING GROUP. 2009: 275A

  View details for Web of Science ID 000262486301249

• CD81 Protein Is Expressed in Normal Germinal Center B-Cells and in Subtypes of Human Non-Hodgkin Lymphomas 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Luo, R. F., Zhao, S., Tibshirani, R., Lossos, I. S., Advani, R., Gratzinger, D., Wong, A., Talrega, N., Levy, R., Levy, S., Natkunam, Y. NATURE PUBLISHING GROUP. 2009: 275A–275A

  View details for Web of Science ID 000262371501249

• Lymphoma-Expressed VEGF-a,VEGFR-1, VEGFR-2, and Microvessel Density Are Not Predictive of Overall Survival in Follicular Lymphoma. 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Gratzinger, D., Zhao, S., Ai, W., Tibshirani, R., Levy, R., Natkunam, Y. AMER SOC HEMATOLOGY. 2008: 1290–90

  View details for Web of Science ID 000262104704385

• Neither CD68+Nor CD163+Macrophages Are Associated with Decreased Survival in Follicular Lymphoma 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Gratzinger, D., Ai, W., Tibshirani, R., Levy, R., Natkunam, Y. AMER SOC HEMATOLOGY. 2008: 1284–84

  View details for Web of Science ID 000262104704365

• The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms with rare exceptions Gratzinger, D., Zhao, S., Vogel, H., Gil, E. C., Levy, R., Lossos, I., Natkunam, Y. FEDERATION AMER SOC EXP BIOL. 2008

  View details for Web of Science ID 000208467800092

• Ameloblastoma, calcifying epithelial odontogenic tumor, and glandular odontogenic cyst show a distinctive immunophenotype with some myoepithelial antigen expression JOURNAL OF ORAL PATHOLOGY & MEDICINE Gratzinger, D., Salama, M. E., Poh, C. F., Rouse, R. V. 2008; 37 (3): 177-184

  Abstract

  Odontogenic neoplasms have some morphologic overlap with salivary gland neoplasms, many of which show myoepithelial differentiation. In the 1980s, an ultrastructural study identified a population of myoepithelial-like cells in calcifying epithelial odontogenic tumor. Myoepithelial derived tumors have since been shown to have distinct immunohistochemical profiles.We examined a series of odontogenic neoplasms, including 11 ameloblastomas, four calcifying epithelial odontogenic tumors, five glandular odontogenic cysts (GOCs), and five keratocystic odontogenic tumors with a panel of myoepithelial-associated immunohistochemical stains. We also assessed representative control examples of oral mucosa, odontogenic rests, and dentigerous cysts.All of the neoplastic and non-neoplastic oral epithelium-derived entities share a p63-positive, high molecular weight cytokeratin (CK5/6)-positive immunophenotype. Calponin reactivity was at least focally present in two of four calcifying epithelial odontogenic tumors, three of five GOCs, and 10 of 11 ameloblastomas; the sole completely non-reactive ameloblastoma represents a lung metastasis. One case of calcifying epithelial odontogenic tumor was focally positive for glial fibrillary acidic protein. However, other more definitive markers of myoepithelial differentiation, including S-100 and smooth muscle actin, were negative. Two of three calcifying epithelial odontogenic tumors and five of five GOCs were also positive for a low molecular weight cytokeratin (CK7).Ameloblastomas, GOCs, and calcifying epithelial odontogenic tumors show a distinctive immunophenotype which overlaps with that of myoepithelial-derived salivary gland neoplasms but does not provide definitive support for myoepithelial differentiation.

  View details for DOI 10.1111/j.1600-0714.2007.00613.x

  View details for Web of Science ID 000252812000008

  View details for PubMedID 18251942

• LMO2 protein expression predicts survival in patients with diffuse large B-Cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab JOURNAL OF CLINICAL ONCOLOGY Natkunam, Y., Farinha, P., Hsi, E. D., Hans, C. P., Tibshirani, R., Sehn, L. H., Connors, J. M., Gratzinger, D., Rosado, M., Zhao, S., Pohlman, B., Wongchaowart, N., Bast, M., Avigdor, A., Schiby, G., Nagler, A., Byrne, G. E., Levy, R., Gascoyne, R. D., Lossos, I. S. 2008; 26 (3): 447-454

  Abstract

  The heterogeneity of diffuse large B-cell lymphoma (DLBCL) has prompted the search for new markers that can accurately separate prognostic risk groups. We previously showed in a multivariate model that LMO2 mRNA was a strong predictor of superior outcome in DLBCL patients. Here, we tested the prognostic impact of LMO2 protein expression in DLBCL patients treated with anthracycline-based chemotherapy with or without rituximab.DLBCL patients treated with anthracycline-based chemotherapy alone (263 patients) or with the addition of rituximab (80 patients) were studied using immunohistochemistry for LMO2 on tissue microarrays of original biopsies. Staining results were correlated with outcome.In anthracycline-treated patients, LMO2 protein expression was significantly correlated with improved overall survival (OS) and progression-free survival (PFS) in univariate analyses (OS, P = .018; PFS, P = .010) and was a significant predictor independent of the clinical International Prognostic Index (IPI) in multivariate analysis. Similarly, in patients treated with the combination of anthracycline-containing regimens and rituximab, LMO2 protein expression was also significantly correlated with improved OS and PFS (OS, P = .005; PFS, P = .009) and was a significant predictor independent of the IPI in multivariate analysis.We conclude that LMO2 protein expression is a prognostic marker in DLBCL patients treated with anthracycline-based regimens alone or in combination with rituximab. After further validation, immunohistologic analysis of LMO2 protein expression may become a practical assay for newly diagnosed DLBCL patients to optimize their clinical management.

  View details for DOI 10.1200/JCO.2007.13.0690

  View details for Web of Science ID 000254177200020

  View details for PubMedID 18086797

• Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy LABORATORY INVESTIGATION Gratzinger, D., Zhao, S., Tibshirani, R. J., Hsi, E. D., Hans, C. P., Pohlman, B., Bast, M., Avigdor, A., Schiby, G., Nagler, A., Byrne, G. E., Lossos, I. S., Natkunam, Y. 2008; 88 (1): 38-47

  Abstract

  Vascular endothelial growth factor-mediated signaling has at least two potential roles in diffuse large B cell lymphoma: potentiation of angiogenesis, and potentiation of lymphoma cell proliferation and/or survival induced by autocrine vascular endothelial growth factor receptor-mediated signaling. We have recently shown that diffuse large B cell lymphomas expressing high levels of vascular endothelial growth factor protein also express high levels of vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. We have now assessed a larger multi-institutional cohort of patients with de novo diffuse large B cell lymphoma treated with anthracycline-based therapy to address whether tumor vascularity, or expression of vascular endothelial growth factor protein and its receptors, contribute to patient outcomes. Our results show that increased tumor vascularity is associated with poor overall survival (P=0.047), and is independent of the international prognostic index. High expression of vascular endothelial growth factor receptor-1 by lymphoma cells by contrast is associated with improved overall survival (P=0.044). The combination of high vascular endothelial growth factor and vascular endothelial growth factor receptor-1 protein expression by lymphoma cells identifies a subgroup of patients with improved overall (P=0.003) and progression-free (P=0.026) survival; these findings are also independent of the international prognostic index. The prognostic significance of overexpression of this ligand-receptor pair suggests that autocrine signaling via vascular endothelial growth factor receptor-1 may represent a survival or proliferation pathway in diffuse large B cell lymphoma. Dependence on autocrine vascular endothelial growth factor receptor-1-mediated signaling may render a subset of diffuse large B-cell lymphomas susceptible to anthracycline-based therapy.

  View details for DOI 10.1038/labinvest.3700697

  View details for Web of Science ID 000251820600004

  View details for PubMedID 17998899

• Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy Gratzinger, D., Zhao, S., Tibshirani, R. J., Hsi, E. D., Hans, C. P., Pohlman, B., Bast, M., Avigdor, A., Schiby, G., Nagler, A., Byme, G. E., Lossos, L. S., Natkunam, Y. AMER SOC HEMATOLOGY. 2007: 24A–25A

  View details for Web of Science ID 000251100800054

• Microvessel density and expression of vascular endothelial growth factor and its receptors in diffuse large B-cell lymphoma subtypes AMERICAN JOURNAL OF PATHOLOGY Gratzinger, D., Zhao, S., Marinelli, R. J., Kapp, A. V., Tibshirani, R. J., Hammer, A. S., Hamilton-Dutoit, S., Natkunam, Y. 2007; 170 (4): 1362-1369

  Abstract

  Angiogenesis is known to play a major role in neoplasia, including hematolymphoid neoplasia. We assessed the relationships among angiogenesis and expression of vascular endothelial growth factor and its receptors in the context of clinically and biologically relevant subtypes of diffuse large B-cell lymphoma using immunohistochemical evaluation of tissue microarrays. We found that diffuse large B-cell lymphoma specimens showing higher local vascular endothelial growth factor expression showed correspondingly higher microvessel density, implying that lymphoma cells induce local tumor angiogenesis. In addition, local vascular endothelial growth factor expression was higher in those specimens showing higher expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. The germinal center-like and nongerminal center-like subtypes of diffuse large B-cell lymphoma were biologically and prognostically distinct. Interestingly, only in the more clinically aggressive nongerminal center-like subtype were microvessel densities significantly higher in specimens showing higher vascular endothelial growth factor expression; the same was true for the finding of higher vascular endothelial growth factor receptor-1 expression in conjunction with higher vascular endothelial growth factor expression. These differences may have important implications for the responsiveness of the two diffuse large B-cell lymphoma subtypes to anti-vascular endothelial growth factor and anti-angiogenic therapies.

  View details for DOI 10.2353/ajpath.2007.060901

  View details for Web of Science ID 000245233000022

  View details for PubMedID 17392174

  View details for PubMedCentralID PMC1829468

• Angiogenesis in immunophenotypic subtypes of diffuse large B cell lymphoma Gratzinger, D., Zhao, S., Marinelli, R. J., Natkunam, Y. FEDERATION AMER SOC EXP BIOL. 2006: A1324

  View details for Web of Science ID 000236326204316

• Immunohistochemical characterization of selected odontogenic tumors: A case for myoepithelial differentiation? Gratzinger, D., Poh, C. F., Salama, M. E. NATURE PUBLISHING GROUP. 2006: 207A–208A

  View details for Web of Science ID 000234207601398

• Immunohistochemical characterization of selected odontogenic tumors: A case for myoepithelial differentiation? Gratzinger, D., Poh, C. F., Salama, M. E. NATURE PUBLISHING GROUP. 2006: 207A–208A

  View details for Web of Science ID 000234094501403

• Identification of the regions of PECAM-1 involved in beta- and gamma-catenin associations BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Biswas, P., Zhang, J., Schoenfeld, J. D., Schoenfeld, D., Gratzinger, D., Canosa, S., Madri, J. A. 2005; 329 (4): 1225-1233

  Abstract

  Platelet endothelial cell adhesion molecule-1 (PECAM-1) binds tyrosine-phosphorylated beta-catenin and modulates beta-catenin localization and sequestration. The biological significance of this interaction, while still unclear, it has been postulated to be involved in modulating adherens junction dynamics in response to perturbants [J. Clin. Invest. 109 (2002) 383]. Here we demonstrate that tyrosine-phosphorylated beta-catenin, and to a lesser extent unphosphorylated beta-catenin, interact with a portion of the cytoplasmic domain of PECAM-1 encoded by exon 15. Using RT-PCR, we obtained products representing alternatively spliced PECAM-1 isoforms from mouse kidney total mRNA and generated PECAM-1-GST constructs expressing full length and naturally occurring alternatively spliced PECAM-1 variants. Co-precipitation assays revealed that the protein sequence encoded by exon 15 is necessary for beta-catenin binding. Transfections using deletion mutants confirmed the importance of the exon 15 sequence in this interaction. In contrast, gamma-catenin-PECAM-1 interactions are thought to be modulated by an as yet undefined PECAM-1 serine phosphorylation and appear to mediate dynamic PECAM-1 intermediate filament cytoskeletal interactions [J. Biol. Chem. 275 (2000) 21435]. Here we demonstrate that the PECAM-1-gamma-catenin interaction occurs via an exon 13-mediated process. GST-pull-down assays illustrated the importance of the exon 13 sequence in this interaction. Further, using site-directed mutagenesis of S(673) to C and D and S(669 and 670) to C, we confirmed the importance of S(673) and its phosphorylation state as a mediator of gamma-catenin-PECAM-1 binding. Our studies define the exons of the PECAM-1 cytoplasmic domain that is involved in mediating these PECAM-1-catenin family member interactions and will allow investigators to better define the biological functions resulting from these interactions.

  View details for DOI 10.1016/j.bbrc.2005.02.095

  View details for Web of Science ID 000227886300008

  View details for PubMedID 15766557

• Platelet endothelial cell adhesion molecule-1 modulates endothelial cell motility through the small G-protein Rho FASEB JOURNAL Gratzinger, D., Canosa, S., Engelhardt, B., Madri, J. A. 2003; 17 (11): 1458-1469

  Abstract

  Platelet endothelial cell adhesion molecule-1 (PECAM-1), an immunoglobulin family vascular adhesion molecule, is involved in endothelial cell migration and angiogenesis (1, 2). We found that endothelial cells lacking PECAM-1 exhibit increased single cell motility and extension formation but poor wound healing migration, reminiscent of cells in which Rho activity has been suppressed by overexpressing a GTPase-activating protein (3). The ability of PECAM-1 to restore wound healing migration to PECAM-1-deficient cells was independent of its extracellular domain or signaling via its immunoreceptor tyrosine-based inhibitory motif. PECAM-1-deficient endothelial cells had a selective defect in RhoGTP loading, and inhibition of Rho activity mimicked the PECAM-1-deficient phenotype of increased chemokinetic single cell motility at the expense of coordinated wound healing migration. The wound healing advantage of PECAM-1-positive endothelial cells was not only Rho mediated but pertussis toxin inhibitable, characteristic of migration mediated by heterotrimeric G-protein-linked seven-transmembrane receptor signaling such as signaling in response to the serum sphingolipid sphingosine-1-phosphate (S1P) (4, 5). Indeed, we found that the wound healing defect of PECAM-1 null endothelial cells is minimized in sphingolipid-depleted media; moreover, PECAM-1 null endothelial cells fail to increase their migration in response to S1P. We have also found that PECAM-1 localizes to rafts and that in its absence heterotrimeric G-protein components are differentially recruited to rafts, providing a potential mechanism for PECAM-1-mediated coordination of S1P signaling. PECAM-1 may thus support the effective S1P/RhoGTP signaling required for wound healing endothelial migration by allowing for the spatially directed, coordinated activation of Galpha signaling pathways.

  View details for DOI 10.1096/fj.02-1040com

  View details for Web of Science ID 000185345100039

  View details for PubMedID 12890700

• Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2 JOURNAL OF CELL BIOLOGY Enciso, J. M., Gratzinger, D., Camenisch, T. D., Canosa, S., Pinter, E., Madri, J. A. 2003; 160 (4): 605-615

  Abstract

  Atrioventricular (AV) septal defects resulting from aberrant endocardial cushion (EC) formation are observed at increased rates in infants of diabetic mothers. EC formation occurs via an epithelial-mesenchymal transformation (EMT), involving transformation of endocardial cells into mesenchymal cells, migration, and invasion into extracellular matrix. Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A). This effect is reversed with exogenous recombinant mouse VEGF-A165, whereas addition of soluble VEGF receptor-1 blocks EMT. We show that disruption of EMT is associated with persistence of platelet endothelial cell adhesion molecule-1 (PECAM-1) and decreased matrix metalloproteinase-2 (MMP-2) expression. These findings correlate with retention of a nontransformed endocardial sheet and lack of invasion. The MMP inhibitor GM6001 blocks invasion, whereas explants from PECAM-1 deficient mice exhibit MMP-2 induction and normal EMT in high glucose. PECAM-1-negative endothelial cells are highly motile and express more MMP-2 than do PECAM-1-positive endothelial cells. During EMT, loss of PECAM-1 similarly promotes single cell motility and MMP-2 expression. Our findings suggest that high glucose-induced inhibition of AV cushion morphogenesis results from decreased myocardial VEGF-A expression and is, in part, mediated by persistent endocardial cell PECAM-1 expression and failure to up-regulate MMP-2 expression.

  View details for DOI 10.1083/jcb.200209014

  View details for Web of Science ID 000181090200014

  View details for PubMedID 12591918

  View details for PubMedCentralID PMC2173755

• Platelet-endothelial cell adhesion molecule-1 modulates endothelial migration through its immunoreceptor tyrosine-based inhibitory motif BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Gratzinger, D., Barreuther, M., Madri, J. A. 2003; 301 (1): 243-249

  Abstract

  Coordinated migration of endothelial cells models the remodeling of existing endothelia as well as angiogenesis and vasculogenesis. Platelet-endothelial cell adhesion molecule-1, PECAM-1, a transmembrane endothelial adhesion protein, binds and activates the tyrosine phosphatase SHP-2 via phosphotyrosines 663 and 686. PECAM-1 phosphorylation and recruitment of SHP-2 are regulated by cell-cell and cell-substrate adhesion. We found that PECAM-1 is dephosphorylated on tyrosine 686 during endothelial migration, resulting in diffuse dispersal of PECAM-1 and SHP-2. Overexpression of native PECAM-1 slowed, and nonphosphorylatable PECAM-1 increased, endothelial migration, implying that the SHP-2-regulatory phosphotyrosines negatively regulate migration. Using differentially phosphorylated recombinant proteins we found that phosphotyrosine 686 preferentially mediates binding and 663 mediates activation of SHP-2 by PECAM-1. In PECAM-1-null endothelial cells, SHP-2 bound and dephosphorylated an alternative set of phosphoproteins and its distribution to the cytoskeletal fraction was significantly decreased. Tyrosine phosphorylation of beta-catenin and focal adhesion kinase was increased in endothelial cells overexpressing nonphosphorylatable PECAM-1. Thus homophilically engaged, tyrosine-phosphorylated PECAM-1 locally activates SHP-2 at cell-cell junctions; with disruption of the endothelial monolayer, selective dephosphorylation of PECAM-1 leads to redistribution of SHP-2 and pro-migratory changes in phosphorylation of cytoskeletal and focal contact components.

  View details for DOI 10.1016/S0006-291X(02)02982-0

  View details for Web of Science ID 000181052800040

  View details for PubMedID 12535670

• Interpreting a medium-resolution model of tubulin: Comparison of zinc-sheet and microtubule structure JOURNAL OF MOLECULAR BIOLOGY Wolf, S. G., Nogales, E., Kikkawa, M., Gratzinger, D., Hirokawa, N., Downing, K. H. 1996; 262 (4): 485-501

  Abstract

  We previously used electron crystallography of zinc-induced two-dimensional crystalline sheets of tubulin to construct a medium-resolution three dimensional (3-D) reconstruction (at 6.5 A) of this protein. Here we present an improved model, and extend the interpretation to correlate it to microtubule structure. Secondary sequence predictions and projection density maps of subtilisin-cleaved tubulin provide information on the location of the C-terminal portion, which has been suggested to be involved in the binding of microtubule-associated proteins. The zinc-sheet tubulin model is compared to microtubules in two ways; comparison of electron diffraction from the zinc-sheets to electron diffraction from microtubules, and by docking the zinc-sheet protofilament 3-D model into a helical reconstruction from ice-embedded microtubules. By correlating the zinc-sheet protofilament to a reconstruction of axonemal protofilaments, we assigned polarity to the protofilament in our model. The polarity assignment together with our model for dimer boundaries and the assignment of alpha- and beta-monomers in our reconstruction, provides a microtubule model where the alpha-monomer crowns the plus- (or fast-growing) end of the microtubule and contact is made in the centrosome with gamma-tubulin via the beta-monomer.

  View details for Web of Science ID A1996VK74900009

  View details for PubMedID 8893858