Xiaoming Zhang

All Publications

• High-Grade Transformation of Ovarian Serous Borderline Tumors: A Series and Literature Review, Emphasizing Distinctive Morphology with Abundant Dense Eosinophilic Cytoplasm, Driver Mutations, and Extremely Dismal Prognosis Zhang, X., Devereaux, K., Ryan, E., Fei, F., Kunder, C., Longacre, T. ELSEVIER SCIENCE INC. 2023: S1008-S1010

  View details for Web of Science ID 000990969802145

• PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma is Associated with Poor Progression-Free Survival and is Mutually Exclusive with CCNE1 Amplification. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Zhang, X., Wang, A., Han, L., Liang, B., Allard, G., Diver, E., Howitt, B. E. 2023; 36 (5): 100106

  Abstract

  As a critical tumor suppressor, PTEN has gained much attention in cancer research. Emerging evidence suggests an association between PTEN status and clinical outcome in certain tumors, and may be predictive of response to several therapies. However, the significance of PTEN deficiency in tubo-ovarian high-grade serous carcinomas (HGSCs) is still poorly understood. We evaluated PTEN expression in HGSCs and determined its clinical relevance. A cohort of 76 HGSC specimens was profiled using tissue microarray. Immunohistochemistry (IHC) of PTEN, ER, PR, AR, CD8, FOXP3, and PD-L1 was performed. Targeted gene panel testing by massively parallel sequencing was performed in 51 cases. PTEN deficiency (complete or subclonal loss) detected by IHC was identified in 13 of the 62 HGSCs (21%) and was significantly correlated with reduced expression of ER and worse first progression-free survival (P < .05) but not with PD-L1 expression, the density of intratumoral T lymphocytes, or overall survival. In our cohort, tumor progression within 1 year of PARP inhibitor therapy was found more frequently in PTEN-deficient cases than in PTEN-intact cases (100% vs 52%). Molecular profiling showed that intragenic mutation or deletion was not the predominant mechanism for PTEN inactivation in HGSCs. In addition, CCNE1 amplification was found to be mutually exclusive with PTEN deficiency at both protein and DNA levels. An analysis of the genomic data from 1702 HGSC samples deposited with The Cancer Genome Atlas database obtained from cBioPortal confirmed the low rate of detection of PTEN gene alterations and the mutually exclusive nature of PTEN loss and CCNE1 amplification in HGSCs. These findings indicate that PTEN deficiency defines a distinct clinically significant subgroup of HGSCs with a tendency for ER negativity, wild-type CCNE1 status, inferior clinical outcomes, and potential drug resistance. These tumors may benefit from PI3K pathway inhibitors in combination with other ovarian cancer regimens, which deserves further investigation.

  View details for DOI 10.1016/j.modpat.2023.100106

  View details for PubMedID 36805789

• ASSESSING ROBUSTNESS OF AN ARTIFICIAL INTELLIGENCE DERIVED HISTOLOGICAL BIOMARKER ACROSS DIFFERENT SITES OF DISEASE AND IN SERIAL SECTIONS IN TUBOOVARIAN HIGH-GRADE SEROUS CARCINOMA Krishnan, R., Tiu, E., Krishna, V., Nimgaonkar, V., Bhambhvani, H., O'Donoghue, O., Vrabac, D., Joshi, A., Liang, B., Zhang, X., Han, L., Wang, A., Krishna, V., Howitt, B. BMJ PUBLISHING GROUP. 2022: A45-A46

  View details for DOI 10.1136/ijgc-2022-igcs.87

  View details for Web of Science ID 000899252300084

• PREDICTING RESPONSE TO PLATINUM-BASED CHEMOTHERAPY FOR TUBO-OVARIAN HIGHGRADE SEROUS CARCINOMA USING AN ARTIFICIAL INTELLIGENCE HISTOPATHOLOGY PLATFORM Tiu, E., Krishna, V., Nimgaonkar, V., Krishnan, R., Bhambhvani, H., O'Donoghue, O., Vrabac, D., Joshi, A., Liang, B., Zhang, X., Han, L., Wang, A., Krishna, V., Howitt, B. BMJ PUBLISHING GROUP. 2022: A46-A47

  View details for DOI 10.1136/ijgc-2022-igcs.88

  View details for Web of Science ID 000899252300085

• Hepatic Macrophage Types Cluster with Disease Etiology in Chronic Liver Disease and Differ Compared to Normal Liver: Implications for Their Biologic and Diagnostic Role INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Zhang, X., Thompkins-Johns, A., Ziober, A., Zhang, P. J., Furth, E. E. 2022: 10668969221099630

  Abstract

  Introduction. Macrophages are phenotypically heterogeneous cells that play a vital role in hepatic fibrogenesis. We aimed to compare the macrophage profiles between normal livers and those with various chronic liver diseases in the precirrhotic fibrosis stage. Methods. Immunohistochemistry was performed for three macrophage markers (CD163, CD68, and IBA1) on 48 liver biopsies. Digital image analysis and automated cell count were used to calculate the densities of immunostained cells in two selected regions of interest: the periportal region and the perivenous region. Results. The absolute and relative densities of the macrophage phenotypes in relationship with zones and etiologies showed four distinct patterns by hierarchical cluster analysis: (1) no significant increase in the macrophage densities in either periportal or perivenous regions - nonalcoholic steatohepatitis; (2) significant increase in the selected macrophage densities in both periportal and perivenous regions - Hepatitis C; (3) significant increase in the macrophage densities only in periportal region - alcoholic liver disease, primary sclerosing cholangitis, and primary biliary cholangitis; and (4) significant increase in the densities of all types of macrophages in both periportal and perivenous regions - autoimmune hepatitis. Conclusions. There are distinct macrophage phenotypic and zonal geographic signatures correlating to etiologies of chronic liver disease in the precirrhotic stage.

  View details for DOI 10.1177/10668969221099630

  View details for Web of Science ID 000796552800001

  View details for PubMedID 35521912

• PTEN Loss in High-Grade Serous Carcinomas is Associated with Reduced Expression of Hormonal Receptors and Poor Progression-Free Survival, and Mutually Exclusive with CCNE1 Amplification Zhang, X., Han, L., Liang, B., Wang, A., Howitt, B. SPRINGERNATURE. 2022: 856-858

  View details for Web of Science ID 000770360202137

• Keratin Granulomas in the Peritoneum on Frozen Section: A Case Report with Multiple Suspects and the Search for the Culprit. International journal of surgical pathology Katsakhyan, L., Zhang, X., Reyes, M. C., Schwartz, L. E., Haggerty, A. F., Cooper, K. 2022; 30 (1): 46-49

  Abstract

  Keratin granulomas in the peritoneum are a rare finding with multiple etiologies and can be especially challenging for both the pathologist and the surgeon when these lesions are grossly visible. We report a case of a unique frozen section diagnostic scenario of evaluation of keratin granulomas in the peritoneum of a 47-year-old woman in the setting of multiple potential culprits: endometrial endometrioid adenocarcinoma following fertility sparing treatment, and a concurrent dermoid cyst. We discuss the various etiologies of keratin granulomas in the peritoneum, mechanism of their formation, diagnostic significance, as well as implications of fertility sparing treatments. To the best of our knowledge, this is the only case of keratin granulomas in the peritoneum with multiple distinct potential pathologic culprits as well the only case following fertility sparing treatment.

  View details for DOI 10.1177/10668969211016045

  View details for PubMedID 33939556

• TP53 Mutation and Extraneural Metastasis of Glioblastoma: Insights From an Institutional Experience and Comprehensive Literature Review. The American journal of surgical pathology Zhang, X., Katsakhyan, L., LiVolsi, V. A., Roth, J. J., Rassekh, C. H., Bagley, S. J., Nasrallah, M. P. 2021; 45 (11): 1516-1526

  Abstract

  Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.

  View details for DOI 10.1097/PAS.0000000000001762

  View details for PubMedID 34366423

• Ionized Calcium Binding Adaptor Molecule 1 (IBA1). American journal of clinical pathology Zhang, X., Wang, L. P., Ziober, A., Zhang, P. J., Bagg, A. 2021; 156 (1): 86-99

  Abstract

  Ionized calcium binding adaptor molecule 1 (IBA1), a marker of microglia/macrophages, has not been investigated in human hematopathologic contexts. We evaluated its expression in mature and immature neoplasms of monocytic/histiocytic and dendritic cell (DC) origin.Immunohistochemistry for IBA1, CD14, CD68, and CD163 was performed on a total of 114 cases, including a spectrum of monocytic/histiocytic and DC neoplasms (20 tissue based and 59 bone marrow based) and several nonhistiocytic/monocytic/DC neoplasms as control groups (15 tissue based and 20 bone marrow based).IBA1 expression was observed in all types of mature tissue-based histiocytic/DC neoplasms (20/20) but not in the corresponding control group (0/15). In bone marrow-based cases, IBA1 was expressed in most acute myeloid leukemias (AMLs) with monocytic differentiation (48/53), both blastic plasmacytoid dendritic cell neoplasms (2/2), and all chronic myelomonocytic leukemias (4/4), while it was positive in only one nonmonocytic AML (1/15) and none of the acute lymphoblastic leukemias (0/5). Collectively, IBA1 showed much higher sensitivity and specificity (93.7%, 97.1%) compared with CD14 (65.4%, 88.2%), CD68 (74.4%, 74.2%), and CD163 (52.6%, 90.6%).IBA1 is a novel, highly sensitive, and specific marker for diagnosing neoplasms of monocytic/histiocytic and DC origin.

  View details for DOI 10.1093/ajcp/aqaa209

  View details for PubMedID 33582751

• Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary-Clinical significance of BRCA2 gene variants in genomically stable tumors. Gynecologic oncology Zhang, X., Devins, K., Ko, E. M., Reyes, M. C., Simpkins, F., Drapkin, R., Schwartz, L. E., Yoon, J. Y. 2021; 161 (3): 762-768

  Abstract

  The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced or recurrent LGSC/SBT patients who underwent molecular profiling.Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel sequencing. Microsatellite stability and tumor mutation burdens (TMBs) were determined based on panel sequencing data.The mean TMB was 5.2 mutations/megabase (range 3-10) in 14 cases. Twelve of twelve (12/12) cases were microsatellite stable. Clear driver mutations were identified in 11 cases, namely KRAS (5/17), BRAF (2/17), NRAS (2/17) and ERBB2 (2/17). Five cases harbored BRCA2 alterations (allele fractions: 44-51%), including two classified as likely benign/benign variants, and three classified as variants of uncertain significance (VUSs), with two variants being confirmed to be germline. The three BRCA2 VUSs were missense variants that were assessed to be of unlikely clinical significance, based on family cancer history and expected impact on protein function. Two patients received PARP inhibitors during their disease course, with neither of the patients demonstrating appreciable response.The mutational spectra in 17 clinically aggressive SBT/LGSC cases demonstrate genomically stable tumors, frequently driven by the RTK/RAS/MAPK pathway. While BRCA2 variants were identified, our data demonstrate BRCA2 gene variants are at most VUSs and of dubious clinical significance, in contrast to disease-associated BRCA1/2 variants that may be identified in high-grade serous carcinoma. Germline testing and PARP inhibitors are thus expected to provide limited benefit to patients with LGSC/SBTs.

  View details for DOI 10.1016/j.ygyno.2021.03.019

  View details for PubMedID 33773808

• Vasculitis Involving the Gastrointestinal System Is Often Incidental but Critically Important. American journal of clinical pathology Zhang, X., Furth, E. E., Tondon, R. 2020; 154 (4): 536-552

  Abstract

  This study was aimed to investigate the significance of unexpected vasculitis identified in gastrointestinal (GI) specimens by determining its prevalence and correlation with clinical outcomes.GI specimens with histologic evidence of vasculitis were identified in our pathology database over a 10-year period (January 2008 to August 2018). Clinical history, treatment, and follow-up were reviewed.Of the 131,367 GI pathology cases received over the 10-year study period, 29 (0.02%) cases showed histologic evidence of GI vasculitis. The majority (69%, 20/29) were not clinically suspected. Of these, 20% (4/20) of patients were subsequently diagnosed with systemic vasculitis. During the mean follow-up period of 34.0 months, 24% (4/17) of the patients with this unexpected diagnosis died as the result of direct complications of GI vasculitis. We also found that 95% of cases with unexpected vasculitis in their GI pathology specimens were communicated in a timely manner to the ordering physicians, which necessitated the immediate initiation of additional workups in 85% of these patients.The GI involvement of vasculitis is rarely encountered by pathologists, but its diagnosis carries tremendous clinical significance with a high mortality rate. Therefore, timely communication is highly recommended for the early diagnosis and treatment of this disease.

  View details for DOI 10.1093/ajcp/aqaa083

  View details for PubMedID 32789454

• The significance of mucinous metaplasia in Warthin tumor: a frequent occurrence and potential pitfall. Human pathology Zhang, X., Baloch, Z. W., Cooper, K., Zhang, P. J., Puthiyaveettil, R., LiVolsi, V. A. 2020; 99: 13-26

  Abstract

  Mucinous metaplasia in Warthin tumor (WT) is a recognized phenomenon. Nevertheless, its presence can create a diagnostic challenge in the distinction from the newly proposed variant of mucoepidermoid carcinoma (MEC), Warthin-like MEC. In this study, we evaluated the significance and diagnostic relevance of mucinous metaplasia in WTs. A total of 30 WTs diagnosed based on resection specimens formed the basis of this retrospective study. Mucicarmine staining was performed to identify mucinous metaplasia, and fluorescence in situ hybridization (FISH) analysis was used to detect MAML2 gene rearrangement. After review, one MAML2 rearranged case was reclassified as Warthin-like MEC as the classic bilayered epithelium in WT was not identified. The diagnosis of WT was confirmed in the remaining 29 cases. Mucinous metaplasia was encountered in 24 WTs (83%), with 14% (4/29) having an abundant amount. We found that mucinous metaplasia correlated with tumor size (p < 0.05). Age and sex distribution were similar in WT cases with or without mucinous metaplasia. In addition, neither the presence of squamous metaplasia nor the time interval between fine-needle aspiration and surgery was related to mucinous metaplasia (p > 0.05). The MAML2 FISH analyses performed in 18 WTs with variable amounts of mucinous metaplasia were negative for rearrangement. In conclusion, mucinous metaplasia is fairly common in WTs and shows a significant correlation with tumor size. Therefore, caution should be taken to avoid overinterpretation of WT with mucinous metaplasia as MEC in cases showing the classic bilayered oncocytic lining epithelium.

  View details for DOI 10.1016/j.humpath.2020.03.008

  View details for PubMedID 32223989

• Pancreatic schwannoma, an extremely rare and challenging entity: Report of two cases and review of literature. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] Zhang, X., Siegelman, E. S., Lee, M. K., Tondon, R. 2019; 19 (5): 729-737

  Abstract

  Pancreatic schwannoma is a rare benign tumor, for which the preoperative and intraoperative definitive diagnosis is quite challenging. We present the clinical, radiological and pathologic features of two primary pancreatic schwannomas identified in our pathology database over a period of 30 years at our tertiary care hospital. To better understand the clinico-pathological and radiological features of this entity, we provide a comprehensive review of 73 cases described in the English literature, along with our two cases. This review will especially focus on preoperative and intraoperative diagnosis to assess their accuracy for pancreatic schwannoma. The three most common preoperative diagnoses based on imaging for pancreatic schwannomas were cystic neoplasm (56%), pancreatic neuroendocrine tumor (29%) and mucinous cystic neoplasm (26%). Imaging could not definitely diagnose pancreatic schwannoma in any of the reported cases. To obtain a definite diagnosis before surgery, 25 cases underwent imaging-guided fine-needle aspiration (FNA)/biopsy, of which 60% were correctly reported as benign with definite diagnosis of pancreatic schwannoma in 48%. A higher diagnostic accuracy was observed in biopsies (71%) than FNA (37%). In addition, an intraoperative frozen section was carried out in 15 cases, and 47% were correctly diagnosed. Despite relatively low accuracy, preoperative histological assessment can be helpful in surgical managment. A core tissue specimen is recommended to improve the diagnostic accuracy in this setting.

  View details for DOI 10.1016/j.pan.2019.05.460

  View details for PubMedID 31153779

• Isolated Langerhans Cell Histiocytosis of the Lacrimal Gland in Conjunction With Mucosa-Associated Lymphoid Tissue Lymphoma and Elevated IgG4 Plasma Cells. Ophthalmic plastic and reconstructive surgery Peck, T., Bagg, A., Zhang, X., Armstrong, B., Eagle, R. C., Milman, T. 2019; 35 (4): e92-e94

  Abstract

  Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type cells. Orbital LCH is infrequent, typically manifesting as an isolated lytic bony lesion with an adjacent soft tissue mass in a child. Isolated lacrimal gland involvement by LCH is extremely rare, with only 2 previously reported cases. The authors describe a 37-year-old woman with a 6-month history of painless right upper eyelid swelling and diffuse right lacrimal gland enlargement without bony changes on computed tomography scan. Excisional biopsy of the lacrimal gland demonstrated concurrent LCH, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, and increased IgG4-expressing plasma cells. Work-up was negative for systemic hematolymphoid malignancy and IgG4-related disease. This case illustrates the association between LCH, mucosa-associated lymphoid tissue lymphoma, and elevated IgG4 plasma cells in the lacrimal gland, and we review the emerging theories proposed to explain this phenomenon.

  View details for DOI 10.1097/IOP.0000000000001399

  View details for PubMedID 31219941

• [MicroRNA expression signature profile and its clinical significance in endometrioid carcinoma]. Zhonghua bing li xue za zhi = Chinese journal of pathology Wang, Y., Adila, S., Zhang, X., Dong, Y., Li, W., Zhou, M., Li, T. 2014; 43 (2): 88-94

  Abstract

  OBJECTIVE: To determine the microRNA (miRNA) expression signature and its clinical significance in endometrioid carcinoma (EC).METHODS: The miRNA profiles were analyzed by miRNA microarray in 73 cases of EC. The expression level of the eight selected miRNAs were measured by real-time fluorescent quatitative PCR(qRT-PCR). Immunohistochemistry (IHC) was performed to assess the status of PTEN, a potential target of the selected miRNAs.RESULTS: (1) Using TaqMan low-density arrays, 47 miRNAs that differed between EC and normal controls were identified, including 26 down-regulated and 21 up-regulated miRNAs. (2) To confirm the miRNA expression pattern in typeIEC, the expression levels of the eight selected miRNAs were evaluated in a new set of 58 cases of typeIEC by individual miRNA qRT-PCR assays. Three miRNAs (miR-141, miR-200a, miR-205) were up-regulated and two miRNAs (miR-143, miR-145) were down-regulated. These were significantly differentially expressed in typeIEC and normal controls (P < 0.05), whereas such difference was not present in type II tumors compared to normal controls. (3) In typeIEC, loss of PTEN was more frequent in the miR-141 or miR-200a up-regulated subgroups, and the correlation between the PTEN and miR-200a status in typeItumors was statistically significant (P < 0.05).CONCLUSIONS: EC may have a unique miRNA expression profile. The expression levels of the five miRNAs (miR-141, miR-200a, miR-205, miR-143, miR-145) are significantly deregulated in typeIEC compared to normal control but not in typeIItumors. The findings suggest that the miRNAs related to type Iand typeIIEC might be different. PTEN might be a potential target of miR-141 and miR-200a in endometrial carcinogenesis.

  View details for PubMedID 24742567

• Down-regulation of miR-145 and miR-143 might be associated with DNA methyltransferase 3B overexpression and worse prognosis in endometrioid carcinomas. Human pathology Zhang, X., Dong, Y., Ti, H., Zhao, J., Wang, Y., Li, T., Zhang, B. 2013; 44 (11): 2571-80

  Abstract

  The aim of this study was to determine the clinicopathologic significance of miR-145 and miR-143 down-regulation in endometrial cancers. The microRNA profiles were analyzed by microRNA microarray. The expression levels of miR-145 and miR-143 in 73 endometrial cancers were further determined by quantitative real-time polymerase chain reaction. Potential targets of miR-145/143 were defined. The status of DNA methyltransferase 3B (DNMT3B), mutL homologs 1, and phosphatase and tensin homolog was assessed using immunohistochemistry. miR-145 and miR-143 frequently co-down-regulated in endometrial cancers, but the expression levels varied greatly between endometrioid carcinomas (ECs) and non-ECs (NECs); they were significantly lower in ECs than in NECs (P < .05). DNMT3B was defined as a potential target of miR-145/143 by Internet algorithms. In ECs, DNMT3B overexpression occurred more often in the miR-145 and miR-143 down-regulation subgroups, and the correlation between DNMT3B and miR-145 status reached statistical significance (P = .021), whereas such phenomena were not present in NECs (P > .05). In univariate analysis, the combination of DNMT3B overexpression and miR-145 or miR-143 down-regulation was more powerful in predicting shorter survival (P < .05) than use of the biomarkers individually (P > .05). In multivariate analysis, such combination was not an independent predictor of disease-free survival (P > .05). Our findings suggest that the target and function of miR-145 and miR-143 may differ in ECs versus NECs. DNMT3B might be a potential target of miR-145 and miR-143 in ECs. Furthermore, the combined miR-145 or miR-143 and DNMT3B status may have a prognostic impact on ECs.

  View details for DOI 10.1016/j.humpath.2013.07.002

  View details for PubMedID 24071015

• [Vulvar intraepithelial neoplasia]. Zhonghua bing li xue za zhi = Chinese journal of pathology Dong, Y., Zhang, X., Zhao, F., Wang, C., Bi, H., Li, T. 2013; 42 (8): 557-61

  View details for PubMedID 24246927

• [Endometrial metaplasia]. Zhonghua bing li xue za zhi = Chinese journal of pathology Zhang, X., Dong, Y., Li, T. 2013; 42 (8): 561-5

  View details for PubMedID 24246928

• Analysis of 142 Northern Chinese patients with peripheral T/NK-Cell lymphomas: subtype distribution, clinicopathologic features, and prognosis. American journal of clinical pathology Ren, Y. L., Nong, L., Zhang, S., Zhao, J., Zhang, X. M., Li, T. 2012; 138 (3): 435-47

  Abstract

  Peripheral T- and natural killer (NK)-cell lymphomas (PTNKLs) are a heterogeneous group of lymphoid malignancies. We reclassified 142 cases and investigated their clinicopathologic features and outcome. Results showed that the most prevalent subtypes were extranodal NK/T-cell lymphoma, nasal type (eNK/T) (38.0%); angioimmunoblastic T-cell lymphoma (16.9%); and peripheral T-cell lymphoma, not otherwise specified (16.2%). Follow-up was available in 124 patients whose overall survival ranged from 3 days to 134 months, with a median of 11 months. Multivariate analysis demonstrated that thrombocytopenia (P = .001), elevated lactate dehydrogenase (P = .007), high Ki-67 index (P = .002), and T-bet expression in more than 20% of cells (P = .036) were independent factors for all cases-among which only the factor of T-bet indicated good outcome-and that thrombocytopenia (P = .011) and radiotherapy (P = .026) were significant for the eNK/T group. Thus, eNK/T was the commonest subtype in this series. The significance of T-bet in predicting outcome should be further confirmed.

  View details for DOI 10.1309/AJCPWKJ3GPFRT7GA

  View details for PubMedID 22912362

• PIK3CA mutations in endometrial carcinomas in Chinese women: phosphatidylinositol 3'-kinase pathway alterations might be associated with favorable prognosis. Human pathology Dong, Y., Yang, X., Wong, O., Zhang, X., Liang, Y., Zhang, Y., Wong, W., Nong, L., Liao, Q., Li, T. 2012; 43 (8): 1197-205

  Abstract

  The aim of this study was to determine the clinicopathological impact of PIK3CA mutations and phosphatidylinositol 3'-kinase pathway alterations in endometrial cancers in Chinese women. The PIK3CA mutation status was analyzed by sequencing in 94 tumors. The status of phosphatase and tensin homolog, p-(Ser/Thr)AKT, human epidermal growth factor receptor 2, p53, and estrogen and progesterone receptor was assessed in 102 tumors using immunohistochemistry. Biomarker status was correlated with clinicopathologic variables and with patient survival. We found that 28 mutations occurred in the helical domain encoded by exon 9 of PIK3CA and 16 occurred in the kinase domain (exon 20). Mutations of both exons were more common in low-grade than in high-grade endometrioid carcinomas, and the correlation between exon 9 mutation and lower grade was statistically significant (P = .045). In univariate analysis, phosphatidylinositol 3'-kinase pathway activation (defined as PIK3CA mutation and/or phosphatase and tensin homolog loss) was associated with a favorable prognosis (P = .034) and showed an increased predictive power when combined with expression of p-AKT, the phosphatidylinositol 3'-kinase pathway downstream effector (P = .022). In multivariate analysis, phosphatidylinositol 3'-kinase pathway activation was not an independent predictor of disease-free survival (P = .091). Interestingly, in the estrogen receptor-negative subgroup, the phosphatidylinositol 3'-kinase pathway alteration was significantly related to prolonged patient survival (P = .048), whereas this association was not present in the estrogen receptor-positive subgroup (P > .05). Our findings suggest that phosphatidylinositol 3'-kinase pathway alteration might have a favorable prognostic impact on endometrial cancers in Chinese women. Furthermore, the function of the phosphatidylinositol 3'-kinase pathway might be affected by estrogen receptor status.

  View details for DOI 10.1016/j.humpath.2011.08.021

  View details for PubMedID 22209294

• [Correlations of p-AKT with PTEN, P53, HER-2 expressions in endometrial carcinoma and their relationship with patient survival]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences Zhang, X., Liang, Y., Dong, Y., Zhang, Y., Wang, Y., Meng, Y., Li, T. 2012; 44 (1): 135-41

  Abstract

  OBJECTIVE: To investigate the correlation of phosphorylated protein kinase B(p-AKT) with phosphatase and tensin homolog(PTEN), P53,human epidermal growth factor receptor 2(HER-2) expressions in endometrial carcinoma and their significance.METHODS: The expressions of p-AKT with PTEN, HER-2, P53 and Ki67 were assessed in 95 endometrial carcinomas using immunohistochemistry. The biomarker expressions correlated with clinicopathologic variables and with patient survival.RESULTS: (1) p-AKT was positive in 53.7% (51/95) of tumors and was found to express almost similarly in endometrioid adenocarcinoma(EC) and non-enometrioid adenocarcinoma (NEC). There was no significant difference of patient survival between p-AKT positive and negative subgroups (P=0.757). (2) PTEN loss was found in 56.8%(54/95) of tumors, and occurred more often in EC(60.7%, 51/84) than in NEC (27.3%, 3/11), which was of statistical significance (P=0.035). The patients with PTEN loss had a longer survival than those without (P=0.015). (3) Although there was no significant correlation between p-AKT and PTEN expression, the extended analysis showed that the predictive value of PTEN loss in p-AKT positive subgroup (P=0.148) was lower than that in p-AKT negative expression subgroup (P=0.055). Meanwhile p-AKT positive and PTEN loss might have synergic effect on tumor proliferation, Ki67 positive rate was highest in PTEN+/p-AKT+ subgroup (40.0%) and lowest in PTEN-/p-AKT- subgroup (8.7%), which was of significant difference (P=0.015). (4) No correlation was found between p-AKT expression and P53 or HER-2 status (P>0.05). On the other hand, HER-2 and P53 positive correlated significantly (r=0.209, P=0.041) and occurred more frequently in NEC (45.5%, 100.0%) than in EC(6.0%, 42.9%)(P <0.05), which were found to predict poor survival (P<0.05).CONCLUSION: p-AKT was activated equally in EC and NEC. p-AKT positive alone might have limited effect on patient survival, however, p-AKT expression might lower the predictive value of PTEN loss in endometrial carcinoma. Moreover, p-AKT positive and PTEN loss might have synergic effect on tumor proliferation. On the other hand, as p-AKT expression did not have any correlations with PTEN, P53 and HER-2 status in this cohort, there might be other important factors involved in p-AKT activation in endometrial carcinoma. In sum, further investigation should be conducted in the targeted therapy based on p-AKT and associated molecular mechanism in advanced endometrial carcinoma.

  View details for PubMedID 22353917

• [Significance of phosphoinositide 3 kinase/AKT pathway alterations in endometrial carcinoma]. Zhonghua bing li xue za zhi = Chinese journal of pathology Yang, X., Dong, Y., Zhang, X., Liang, Y., Zhang, Y., Meng, Y., Wang, Y., Wang, W., Nong, L., Li, T., Liao, Q. 2011; 40 (12): 799-804

  Abstract

  OBJECTIVE: To investigate the clinicopathologic and prognostic implications of phosphoinositide 3 kinase (PI3K)/AKT pathway alterations in endometrial cancers of Chinese women.METHODS: The expression of PTEN, p-AKT, and ER/PR was assessed in 71 cases of endometrial carcinoma by immunohistochemistry (EnVision method). The PIK3CA mutation at exon 9 and exon 20 was analyzed by PCR and direct sequencing in 34 tumors.RESULTS: (1) Of the 71 cases of endometrial carcinoma, 65 cases were endometrioid adenocarcinoma (EEC) and 6 cases were nonendometrioid adenocarcinoma (NEEC). PTEN loss of expression was found in 63.4% (45/71) of tumors, and more commonly occurred in EEC (66.2%, 43/65) than that in NEEC (2/6, P = 0.18). Patients with PTEN loss in their tumors (45 cases) had a better survival than those without (26 cases, P = 0.07). In ER negative subgroup, the patients with PTEN loss of expression (12 cases) had longer survival than those with normal PTEN expression (7 cases; P = 0.04). (2) The frequency of PIK3CA mutation was 41.2% (14/34) with a hot mutation spot at T544 in exon 9. PIK3CA mutations more commonly occurred in EEC (44.8%, 13/29) than in NEEC (1/5, P > 0.05). The mutations at exon 9 more commonly occurred in EEC, well- and moderately-differentiated EEC, and tumors at early stage (P > 0.05). On the contrary, in tumors at early stages, the frequency of mutations in exon 20 (14.3%, 4/28) was significantly lower than that at late stages (4/6, P = 0.01). (3) p-AKT was positive in 59.2% (42/71) of tumors that were more frequently found in EEC (60.0%, 39/65) than that in NEEC (3/6, P = 0.68). However, the significant difference of p-AKT expression was found between well- and moderately-differentiated EEC (75.0%, 21/28; 53.6%, 15/28) and poorly-differentiated EEC (3/9, P = 0.02). Moreover, p-AKT expression was significantly correlated with positive ER (r = 0.339, P = 0.00).CONCLUSIONS: Endometrial carcinoma patients with loss of PTEN and p-AKT positivity have a favorable prognosis. PIK3CA mutations at exon 9 or 20 may have different impact on the prognosis. The function of PTEN loss and p-AKT expression may vary according to different hormone status.

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