The American Journal of Surgical Pathology最新文献

{"title":"Clinicopathologic and Immunohistochemical Characterization of Sarcomatoid Chromophobe Renal Cell Carcinoma","authors":"R. Whaley, Liang Cheng","doi":"10.1097/PAS.0000000000001926","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001926","url":null,"abstract":"Sarcomatoid differentiation in chromophobe renal cell carcinoma (ChRCC) is a rare finding and a significant predictor of worse outcomes. When the sarcomatoid component overgrows the conventional component or is the only component on a biopsy, the differential diagnoses encompass a variety of entities. Therefore, we reviewed 22 sarcomatoid ChRCCs and characterized the immunophenotype. Given that renal carcinomas with sarcomatoid features may benefit from immune checkpoint inhibitor-based therapy we also assessed the programmed death-ligand 1 (PD-L1) (28-8) expression. DOG1, CD117, cytokeratin 7, and PAX8 were negative in 100%, 88%, 63%, and 44% of the sarcomatoid components, respectively. GATA3 was expressed in 31% of the conventional components and in 50% of the sarcomatoid components. One conventional and 3 sarcomatoid components expressed PD-L1. Sarcomatoid ChRCCs have a high propensity for metastases and cancer progression. Distant metastatic disease was seen in 73% of the cases and median survival in this cohort was <1 year. The sarcomatoid portion had increased expression of PD-L1 and frequent loss of expression of multiple immunohistochemical markers associated with ChRCC. Half of the sarcomatoid ChRCC exhibited GATA3 expression, 3 of which did not express PAX8.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"83 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133503084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Malignant Mesenchymoma” Revisited","authors":"Sanhong Yu, J. Hornick","doi":"10.1097/PAS.0000000000001928","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001928","url":null,"abstract":"Leiomyosarcoma (LMS) is the most common sarcoma in adults. Rarely, LMS dedifferentiates into an undifferentiated sarcoma. Very few cases of LMS with heterologous osteosarcomatous differentiation (OS) have been reported. The purpose of this study was to evaluate the clinicopathologic features of LMS with OS. Of 5570 LMS cases diagnosed from 2006 to 2022, 15 cases (0.2%) of LMS with OS were identified, affecting 13 females and 2 males; ages ranged from 32 to 66 years (median: 53 y). Ten tumors arose in the uterus, 2 in the retroperitoneum, and 1 each in the mesentery, mediastinum, and rectum. Primary tumors ranged from 7 to 20 cm (mean: 16 cm). The LMS components showed conventional spindle cell morphology in most cases; 3 cases showed marked pleomorphism; 3 cases contained an epithelioid component; and 1 case showed myxoid features. In 5 cases OS was identified in the primary tumor, whereas in 10 cases OS was first detected in metastases. One metastatic and 2 primary LMS showed both OS and chondrosarcomatous differentiation. Prominent osteoclastic giant cells were seen in the OS components in 11 cases. Mitotic activity ranged from 17 to 61/10 HPF with tumor necrosis in 10 cases. Twelve patients developed metastases; sites included lungs, diaphragm, kidney, adrenal glands, colon, small intestine, liver, bone, and pancreas. At last follow-up, 8 patients had died of disease, and 4 patients were alive with metastases. The interval between OS and death ranged from 3 weeks to 18 months (median: 6.5 mo). Development of OS in LMS is exceptionally rare. This form of heterologous differentiation may occur in both primary tumors and metastases. LMS with OS is highly aggressive with poor outcomes. Awareness of this phenomenon is important to avoid misdiagnosis as osteosarcoma.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125242676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemolysis in Early Infancy: Still a Cause of Cholestatic Neonatal Giant Cell Hepatitis.","authors":"Hao Wu,&nbsp;Oya Tugal,&nbsp;Antonio R Perez-Atayde","doi":"10.1097/PAS.0000000000001841","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001841","url":null,"abstract":"<p><p>Before the prophylactic use of anti-D antibodies in pregnancy, hemolytic anemia of the newborn was the most common cause of hyperbilirubinemia. Nowadays, given the rarity of hemolytic anemia of the newborn, hepatobiliary abnormalities, perinatal infections, and metabolic disorders have become the most common conditions in the differential diagnosis of neonatal cholestasis. Here, we report 3 instances of cholestatic giant cell hepatitis in 3 infants who had Coombs' positive hemolysis due to ABO incompatibility in 1, Rh incompatibility in another, and combined ABO and Rh incompatibility in the third. Although rare, cholestatic neonatal giant cell hepatitis associated with hemolysis still needs to be considered in patients with neonatal cholestasis. A marked elevation of aspartate aminotransferase over alanine aminotransferase can be a helpful clue to an early diagnosis.</p>","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"801-808"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39798565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UHRF1 Immunohistochemical Staining Separates Benign Reactive Spindle Cell Mesothelial Proliferations From Sarcomatoid Mesotheliomas.","authors":"Hang Yang,&nbsp;Simon Cheung,&nbsp;Andrew Churg","doi":"10.1097/PAS.0000000000001840","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001840","url":null,"abstract":"<p><p>The separation of benign from malignant mesothelial proliferations is often a difficult pathologic problem. UHRF1 (ubiquitin-like with plant homeodomain and ring finger domains-1) is a regulator of DNA methylation and an epigenetic driver of various human cancers. It has recently been reported that UHRF1 is overexpressed in mesotheliomas. We asked whether UHRF1 immunohistochemistry could be used to separate benign from malignant mesothelial proliferations. Initial studies showed that UHRF1 stained mesothelial cells but also endothelial and other non-neoplastic cells, so that accurate counting of positive mesothelial cells was difficult. Therefore, we ran dual UHRF1-AE1/AE3 stains on 2 tissue microarrays containing 40 reactive mesothelial proliferations and 61 mesotheliomas and only counted UHRF1 staining in keratin-positive cells. On average 10.3±8.6% (mean±SD; range: 0% to 36, median: 6.8%) of epithelioid mesothelioma cells stained compared with 5.3±4.8% (range: 0% to 15%, median: 4.1%) of reactive epithelial mesothelial cells. This difference was statistically significant but there was too much overlap to use diagnostically. In contrast, 37±26% (range: 2.5% to 95%, median: 31%) of cells in sarcomatoid mesotheliomas compared with 1.2±1.2% (range: 0% to 3.0%, median: 1.0%) of cells in reactive spindle cell mesothelial proliferations stained. To confirm this difference we stained whole sections of 21 sarcomatoid mesotheliomas and 19 cases of organizing pleuritis. Staining of mesothelial cells was seen in 2.1±2.4% (range: 0% to 6.8%, median: 1.0%) of organizing pleuritis cases and 44±22% (range: 14% to 90%, median: 41%) of sarcomatoid mesotheliomas. We conclude that dual UHRF1-AE1/AE3 immunohistochemistry is very useful for separating benign spindle cell mesothelial proliferations from sarcomatoid mesotheliomas.</p>","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"840-845"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39727654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Critical Assessment of Current Grading Schemes for Diffuse Pleural Mesothelioma With a Proposal for a Novel Mesothelioma Weighted Grading Scheme (MWGS).","authors":"Talia L Fuchs,&nbsp;Angela Chou,&nbsp;Yagiz Aksoy,&nbsp;Mahiar Mahjoub,&nbsp;Amy Sheen,&nbsp;Loretta Sioson,&nbsp;Mahsa Ahadi,&nbsp;Anthony J Gill","doi":"10.1097/PAS.0000000000001854","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001854","url":null,"abstract":"<p><p>Although there is early support for schemes based on nuclear grade, necrosis and mitotic rate, there is currently no widely implemented grading system for diffuse pleural mesothelioma (DPM). We investigated current systems and propose a novel Mesothelioma Weighted Grading Scheme (MWGS). The MWGS assigns weighted scores from 0 to 10 based on age (≤74, >74 yrs: 0,1); histologic type (epithelioid, biphasic, sarcomatoid: 0,1,2); necrosis (absent, present: 0,2); mitotic count per 2 mm2 (≤1, 2 to 4, ≥5: 0,1,2); nuclear atypia (mild, moderate, severe: 0,1,2); and BRCA1-associated protein 1 (BAP1) expression (lost, retained: 0,1). A score of 0 to 3 is low grade, 4 to 6 intermediate grade, and 7 to 10 high grade. In 369 consecutive DPMs, median survival was 17.1, 10.1, and 4.1 months for low, intermediate, and high grades (P<0.0001). A progressive increase in score correlated with worsening overall survival (P<0.0001). Interobserver concordance was substantial (κ=0.588), with assessment of nuclear grade being the most subjective parameter (κ=0.195). We compared the MWGS to the 2-tiered system discussed in the World Health Organization (WHO) fifth edition. The WHO system predicted median survival in epithelioid (median 18.0 vs. 11.3 mo, P=0.003) and biphasic (16.2 vs. 4.2 mo, P=0.002), but not sarcomatoid DPM (5.4 vs. 4.7 mo, P=0.407). Interestingly, the WHO grading system was prognostic in cases with BAP1 loss (median survival 18.7 vs. 10.4 mo, P<0.0001), but not retained BAP1 expression (8.9 vs. 6.2 mo, P=0.061). In conclusion, the WHO scheme has merit in epithelioid/biphasic and BAP1-deficient DPM, however, the MWGS can be used for risk stratification of all DPMs, regardless of histologic subtype and BAP1 status.</p>","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"774-785"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39726465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composite Classic Hodgkin Lymphoma and Follicular Lymphoma: A Clinicopathologic Study of 22 Cases With Review of 27 Additional Cases in the Literature.","authors":"Yuhua Huang,&nbsp;Shimin Hu,&nbsp;Daniel P Larson,&nbsp;Min Shi,&nbsp;Rong He,&nbsp;Bhavana J Dave,&nbsp;Timothy C Greiner,&nbsp;Kai Fu,&nbsp;Ellen D McPhail,&nbsp;Rhett P Ketterling,&nbsp;L Jeffrey Medeiros,&nbsp;Ji Yuan","doi":"10.1097/PAS.0000000000001828","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001828","url":null,"abstract":"Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"793-800"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39850871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation.","authors":"Camille Laurent,&nbsp;Charlotte Syrykh,&nbsp;Maxime Hamon,&nbsp;José Adélaïde,&nbsp;Arnaud Guille,&nbsp;Frederic Escudié,&nbsp;Gael Jalowicki,&nbsp;Frederic Fina,&nbsp;Alexandre Bardet,&nbsp;Lenaïg Mescam,&nbsp;Thierry J Molina,&nbsp;Peggy Dartigues,&nbsp;Marie Parrens,&nbsp;Pierre Sujobert,&nbsp;Caroline Besson,&nbsp;Daniel Birnbaum,&nbsp;Luc Xerri","doi":"10.1097/PAS.0000000000001834","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001834","url":null,"abstract":"<p><p>Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n=6), double-hit high-grade B-cell lymphoma (n=1), and Burkitt lymphoma (n=2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance.</p>","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"742-753"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39640525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinusoidal Growth Pattern of Hepatic Melanoma Metastasis: Implications for Histopathologic Diagnosis.","authors":"Julianne M Szczepanski,&nbsp;Mishal Mendiratta-Lala,&nbsp;Jiayun M Fang,&nbsp;Won-Tak Choi,&nbsp;Dipti M Karamchandani,&nbsp;Maria Westerhoff","doi":"10.1097/PAS.0000000000001835","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001835","url":null,"abstract":"<p><p>Metastatic tumors interface with liver in multiple patterns, of which, the rare \"sinusoidal\" growth pattern can be subtle and easily overlooked on biopsy. We sought to characterize the metastasis-to-liver interface patterns of melanoma compared with other tumor types and assess the incidence of metastatic melanoma in histologically normal-appearing targeted liver lesion biopsies. Liver lesion samples from 54 melanoma patients were assessed. Nearly normal-appearing cases, defined as no obvious malignancy on routine hematoxylin and eosin stain (n=24), were stained with SOX10 and confirmed with MelanA. Tumor-to-liver interface patterns were determined in biopsies overtly positive for metastatic melanoma (n=30) versus other hepatic metastases as controls (colon, n=28; breast, n=20; pancreaticobiliary, n=20; and neuroendocrine, n=28). Of the 24 nearly normal-appearing liver biopsies from melanoma patients, 3 had subtle melanoma cells detected in sinusoids, confirmed with immunohistochemistry. Of 30 livers overtly positive for melanoma, 8 showed the sinusoidal pattern, compared with none in other metastases. In total, 11/33 (33%) cases of metastatic melanoma liver biopsies demonstrated the sinusoidal pattern. We describe 11 metastatic melanoma cases in liver with the rare sinusoidal pattern, 3 of which were subtle and easy to miss on routine hematoxylin and eosin stain. Given that sinusoidal metastasis does not elicit a tissue reaction, it is prudent for the pathologists to be aware of this pattern of metastases and have a low threshold to order immunostains for accurate diagnosis and optimal patient care.</p>","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":" ","pages":"832-839"},"PeriodicalIF":5.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39640069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Combined Tumor Budding-Poorly Differentiated Clusters Grading System Predicts Recurrence and Survival in Stage I-III Colorectal Cancer","authors":"S. Shivji, D. Cyr, Cherry Pun, K. Duan, A. Sari, Rossi Tomin, D. Ng, A. Brar, S. Zerhouni, E. Kennedy, M. Brar, C. Swallow, J. Conner, R. Kirsch","doi":"10.1097/PAS.0000000000001920","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001920","url":null,"abstract":"Tumor budding (TB) and poorly differentiated clusters (PDCs) are powerful prognostic factors in colorectal cancer (CRC). Despite their morphologic and biological overlap, TB and PDC are assessed separately and are distinguished by an arbitrary cutoff for cell cluster size. This cutoff can be challenging to apply in practice and its biological significance remains unclear. We developed a novel scoring system that incorporates TB and PDC into a single parameter (“Combined Score”; CS), eliminating the need for such cutoffs and allowing the prognostic value of PDC to be captured alongside TB. In a cohort of 481 stage I-III CRC resections, CS was significantly associated with American Joint Committee on Cancer (AJCC) stage, T-stage, N-stage, histologic grade, tumor deposits, lymphovascular invasion, and perineural invasion (P<0.0001). In addition, CS was significantly associated with decreased 5-year recurrence-free survival, overall survival, and disease-specific survival (P<0.0001). TB and PDC showed similar associations with oncologic outcomes, with hazard ratios consistently lower than for CS. The association between CS and oncologic outcomes remained significant in subgroup analyses stratified by AJCC stage, anatomic location (rectum/colon) and neoadjuvant therapy status. On multivariable analysis, CS retained its significant association with oncologic outcomes (P=0.0002, 0.005, and 0.009) for recurrence-free survival, disease-specific survival, and overall survival, respectively. In conclusion, CS provides powerful risk stratification in CRC which is at least equivalent to that of TB and PDC assessed individually. If validated elsewhere, CS has practical advantages and a biological rationale that may make it an attractive alternative to assessing these features separately.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"213 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126099754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced PD-L1 Expression in LMP1-positive Cells of Epstein-Barr Virus–associated Malignant Lymphomas and Lymphoproliferative Disorders","authors":"A. Kume, A. Shinozaki-Ushiku, A. Kunita, A. Kondo, T. Ushiku","doi":"10.1097/PAS.0000000000001919","DOIUrl":"https://doi.org/10.1097/PAS.0000000000001919","url":null,"abstract":"Epstein-Barr virus (EBV) is associated with various types of human malignancies and with programmed death ligand (PD-L) 1 expression in neoplastic cells. However, in EBV-associated malignant lymphomas and lymphoproliferative disorders (LPDs), there is limited information regarding PD-L1 expression profiles among different histologic types and patterns of EBV latency. First, we investigated PD-L1 and EBV latent gene expression using conventional immunohistochemistry and in situ hybridization in 42 EBV-associated malignant lymphomas and LPDs. Classic Hodgkin lymphoma showed the highest PD-L1 expression with diffuse expression in all cases, followed by diffuse large B-cell lymphoma/Burkitt lymphoma, LPDs, and extranodal NK/T-cell lymphoma. EBV latency at the case level was not associated with PD-L1 expression. We further evaluated the expression of PD-L1 and EBV latent genes in tumor cells at single-cell resolution using multiplex fluorescence imaging. This analysis revealed that positivity rates of latent membrane protein (LMP) 1 in tumor cells were 1.0% to 89.5% (mean 35.4%) in latency type II/III cases, and LMP1+ cells showed more frequent PD-L1 expression than LMP1− cells (P<0.0001, paired t test). In contrast, no association was observed between EBV nuclear antigen 2 and PD-L1 expression. Notably, tumor cells exhibiting Hodgkin/Reed-Sternberg cell-like morphology co-expressed PD-L1 and LMP1 more often than those that do not. Our observations suggested that LMP1 upregulates PD-L1 expression and is a potential biomarker for predicting the efficacy of immune checkpoint inhibitors. In addition, the heterogeneous expression of PD-L1 and EBV latent genes may produce diverse tumor cells with different oncogenic and immune-evasive properties, leading to resistance to targeted therapies.","PeriodicalId":275221,"journal":{"name":"The American Journal of Surgical Pathology","volume":"31 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125752419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}