Modern Pathology最新文献

{"title":"Extraaxial Poorly Differentiated Chordoma: Clinicopathologic and Molecular Genetic Characterization","authors":"William J. Sande ,&nbsp;Andrew L. Folpe ,&nbsp;Paige O’Connor ,&nbsp;Daniel Graham ,&nbsp;Jeremy F. Molligan ,&nbsp;Ying-Chun Lo ,&nbsp;Yvonne Y. Cheung ,&nbsp;Baptiste Ameline ,&nbsp;Daniel Baumhoer ,&nbsp;Dorothee Harder ,&nbsp;Kevin A. Raskin ,&nbsp;Christopher W. Mount ,&nbsp;Yin P. Hung ,&nbsp;Gunnlaugur Petur Nielsen ,&nbsp;Darcy A. Kerr ,&nbsp;Darya Buehler ,&nbsp;Doris E. Wenger ,&nbsp;Judith Jebastin Thangaiah","doi":"10.1016/j.modpat.2024.100664","DOIUrl":"10.1016/j.modpat.2024.100664","url":null,"abstract":"<div><div>Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only 5 cases of extraaxial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied 6 cases of EAPDC, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in 4 women and 2 men, ranging from 37 to 68 years of age (median, 57.5 years) and involved or originated in the left knee joint (3 cases), right knee joint (2 cases), and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial PDC, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1 deficient. Molecular genetic analysis identified <em>SMARCB1</em> loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of EAPDC showed clustering with axial PDC. Clinical follow-up (6 patients; median, 11.5 months; range, 1-26 months) showed 4 patients to have received transfemoral amputation and 1 extraarticular resection. None received neoadjuvant radiotherapy; 1 received neoadjuvant chemotherapy and 1 adjuvant chemotherapy/immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), 1 died of disease (20 months), and 3 were disease free (1-26 months). We conclude that EAPDC are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100664"},"PeriodicalIF":7.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spread Through Air Spaces: Comment","authors":"Hinpetch Daungsupawong ,&nbsp;Viroj Wiwanitkit","doi":"10.1016/j.modpat.2024.100634","DOIUrl":"10.1016/j.modpat.2024.100634","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100634"},"PeriodicalIF":7.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary Vulvar and Vaginal Adenocarcinomas of Intestinal Type Are Closer To Colorectal Adenocarcinomas Than To Carcinomas of Müllerian Origin","authors":"Alexis Trecourt ,&nbsp;Isabelle Treilleux ,&nbsp;Daniel Pissaloux ,&nbsp;Marie Donzel ,&nbsp;Brice Thamphya ,&nbsp;Franck Thirode ,&nbsp;Aurélie Houlier ,&nbsp;Sandrine Paindavoine ,&nbsp;Tatiana Franceschi ,&nbsp;Aline Baltrès ,&nbsp;Witold Gertych ,&nbsp;Pierre-Adrien Bolze ,&nbsp;Pierre Antoine Chaix ,&nbsp;Charlotte Roux-Terrier ,&nbsp;Françoise Descotes ,&nbsp;Isabelle Ray-Coquard ,&nbsp;Jonathan Lopez ,&nbsp;Mojgan Devouassoux-Shisheboran","doi":"10.1016/j.modpat.2024.100649","DOIUrl":"10.1016/j.modpat.2024.100649","url":null,"abstract":"<div><div>Primary vulvar and vaginal adenocarcinomas of intestinal type (VVAIts) are very rare tumors, displaying morphologic and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Here, we studied a series of 8 VVAIts (4 vulvar and 4 vaginal) using a large panel of immunohistochemistry and DNA and RNA sequencing with clustering analyses. All tumors shared a similar morphology with colorectal adenocarcinomas and diffuse CK20 and CDX2 expression. SATB2 diffuse positivity was observed in 62.5% of tumors and CK7 in 82.5%, whereas PAX8, SOX17, p16, and estrogen and progesterone receptors were always negative. A p53 mutated-type expression was observed in 75% of tumors. All tumors were mismatch repair proficient. Neither human papillomavirus DNA nor pathogenic transcript fusions were detected. The most frequent molecular alterations were <em>TP53</em> and <em>KRAS</em> variants in 71.4% and 42.9%, respectively. The transcriptomic analysis highlighted a robust VVAIts cluster distinct from endocervical, ovarian, lung, thyroid, salivary glands, breast, and renal carcinomas but failed to differentiate vulvar from vaginal intestinal-type tumors. On 2 different clustering analyses, VVAIts clustered altogether, very close to colorectal adenocarcinomas. Compared with endocervical adenocarcinomas of intestinal type, VVAIts had a significantly lower expression of <em>SOX17</em> and epithelial-mesenchymal transition genes and a higher mitogen-activated protein kinase pathway gene expression. These results suggest that Müllerian structures leading to cervical adenocarcinomas may undergo intestinal-type transdifferentiation via an epithelial-mesenchymal transition phenomenon. Conversely, mitogen-activated protein kinase pathway activation in VVAIts, which plays a major role in colorectal adenocarcinomas, may indicate a close relationship in the carcinogenesis of these tumors. Our results indicate that adenocarcinomas of intestinal type, in the distal vagina or vestibular vulva, might be a unique and single entity, probably originating from cloacogenic embryonic remnants and/or ectopic colorectal mucosae inclusions. An open question would be to explore the efficacy of systemic drugs prescribed in colorectal cancers, in VVAIts.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100649"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Weakly Supervised Classification of Mohs Surgical Sections Using Artificial Intelligence","authors":"Daan J. Geijs ,&nbsp;Lisa M. Hillen ,&nbsp;Stephan Dooper ,&nbsp;Veronique Winnepenninckx ,&nbsp;Vamsi Varra ,&nbsp;David R. Carr ,&nbsp;Kathryn T. Shahwan ,&nbsp;Geert Litjens ,&nbsp;Avital Amir","doi":"10.1016/j.modpat.2024.100653","DOIUrl":"10.1016/j.modpat.2024.100653","url":null,"abstract":"<div><div>Basal cell carcinoma (BCC) is the most frequently diagnosed form of skin cancer, and its incidence continues to rise, particularly among older individuals. This trend puts a significant strain on health care systems, especially in terms of histopathologic diagnostics required for Mohs micrographic surgery (MMS), which is used to treat BCC in sensitive locations to minimize tissue loss. This study aims to address the challenges in BCC detection within MMS whole-slide images by developing and evaluating a deep learning model that bridges weakly supervised learning with interpretable segmentation-based methods through attention maps. Utilizing data sets from 2 medical centers, the model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.958 on internal testing and an AUC of 0.934 on an independent third external data set despite no fine-tuning or preprocessing for the latter. Attention maps provided insights into the model’s decision making, highlighting critical regions for slide-level classification. The sensitivity of the attention maps in localizing tumor regions was 0.853 when no filtering was applied and gave 8 revision false positives per slide on average and was reduced to an average of 2 false positives per slide with a sensitivity of 0.873 when detections smaller than 200 μm were removed from the attention maps. These findings indicate that the deep learning model is highly effective in detecting BCC in MMS whole-slide images, with robust performance across different data sets and conditions. The use of attention maps enhances the model’s interpretability, making it a promising tool for aiding dermatopathologists and MMS surgeons.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100653"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Intratumoral Budding in Colorectal Cancer Using Computational Pathology: A Biopsy-Based Evaluation","authors":"Sonay Kuş Öztürk ,&nbsp;John-Melle Bokhorst ,&nbsp;Elias Baumann ,&nbsp;Kieran Sheahan ,&nbsp;Cornelis J.H. van de Velde ,&nbsp;Corrie A.M. Marijnen ,&nbsp;Geke A.P. Hospers ,&nbsp;Michail Doukas ,&nbsp;Michael Vieth ,&nbsp;Alessandro Lugli ,&nbsp;Iris D. Nagtegaal","doi":"10.1016/j.modpat.2024.100655","DOIUrl":"10.1016/j.modpat.2024.100655","url":null,"abstract":"<div><div>Owing to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared with peritumoral budding (PTB). The distribution of ITB in the uppermost 5 mm of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least 1 superficial ITB hotspot. ITB (hazard ratio, 3.5; 95% CI, 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio, 0.3; 95% CI, 0.1-0.7; <em>P</em> = .007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100655"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Alternative Lengthening of Telomeres via Chromogenic In Situ Hybridization for the Prognostication of PanNETs and Other Neoplasms","authors":"Christopher M. Heaphy ,&nbsp;Simmi Patel ,&nbsp;Katelyn Smith ,&nbsp;Anne R. Wondisford ,&nbsp;Michelle L. Lynskey ,&nbsp;Roderick J. O’Sullivan ,&nbsp;Kimberly Fuhrer ,&nbsp;Xiaoli Han ,&nbsp;Raja R. Seethala ,&nbsp;Ta-Chiang Liu ,&nbsp;Dengfeng Cao ,&nbsp;Onur Ertunc ,&nbsp;Qizhi Zheng ,&nbsp;Marija Stojanova ,&nbsp;Amer H. Zureikat ,&nbsp;Alessandro Paniccia ,&nbsp;Kenneth Lee ,&nbsp;Melanie C. Ongchin ,&nbsp;James F. Pingpank ,&nbsp;Herbert J. Zeh ,&nbsp;Aatur D. Singhi","doi":"10.1016/j.modpat.2024.100651","DOIUrl":"10.1016/j.modpat.2024.100651","url":null,"abstract":"<div><div>Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all <em>P</em> &lt; .004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100651"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Architecture of Single-Cell and Vasculature in Tumor Microenvironment Predicts Clinical Outcomes in Triple-Negative Breast Cancer","authors":"Haoyang Mi ,&nbsp;Ravi Varadhan ,&nbsp;Ashley M. Cimino-Mathews ,&nbsp;Leisha A. Emens ,&nbsp;Cesar A. Santa-Maria ,&nbsp;Aleksander S. Popel","doi":"10.1016/j.modpat.2024.100652","DOIUrl":"10.1016/j.modpat.2024.100652","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between antitumor immunity and clinical outcomes; however, such connections remain underexplored. Here, we employed a data set derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multiscale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified 10 recurrent cellular neighborhoods—a collection of local TME characteristics with unique cell components. The prevalence of cellular neighborhoods enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich long-term survivors. Furthermore, relative spatial colocalization of SMA^hi fibroblasts and tumor cells compared with B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean area under the receiver operating characteristic curve of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles and suggest novel imaging-based biomarkers for the treatment development in the context of TNBC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100652"},"PeriodicalIF":7.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Superficial Neurocristic FET::ETS Fusion Tumor: Expanding the Clinicopathological and Molecular Genetic Spectrum of a Recently Described Entity","authors":"Carina A. Dehner ,&nbsp;Laura M. Warmke ,&nbsp;Brandon Umphress ,&nbsp;Faizan Malik ,&nbsp;Jeffrey M. Cloutier ,&nbsp;Josephine K. Dermawan ,&nbsp;Mike Fritz ,&nbsp;Syril Keena T. Que ,&nbsp;Baptiste Ameline ,&nbsp;Karen J. Fritchie ,&nbsp;Darcy A. Kerr ,&nbsp;Konstantinos Linos ,&nbsp;Daniel Baumhoer ,&nbsp;Steven D. Billings ,&nbsp;Andrew L. Folpe","doi":"10.1016/j.modpat.2024.100656","DOIUrl":"10.1016/j.modpat.2024.100656","url":null,"abstract":"<div><div>Superficial neurocristic <em>EWSR1</em>::<em>FLI1</em> fusion tumor is a very recently described, clinically indolent tumor of the skin and superficial soft tissues, which differs in essentially all ways from Ewing sarcoma, despite harboring an identical fusion event. The <em>EWSR1</em> and <em>FLI1</em> genes are members of the FET and ETS gene family, respectively, and very rare examples of Ewing sarcoma harbor alternative FET::ETS fusion events, such as <em>EWSR1::ERG</em>, <em>FUS::FLI1</em>, <em>FUS::ERG</em>, <em>EWSR1::ETV4,</em> and others. We report 5 new cases of this very rare entity, harboring in 3 cases alternative FET::ETS fusion events. The tumors occurred in 2 males and 3 females (median age, 14 years, range, 8-69 years) and presented as solitary dermal/subcutaneous masses of the thigh, foot, shoulder, arm, and back (median size, 1.8 cm; range, 1-2 cm). All patients underwent wide excisions; one received adjuvant chemotherapy. Clinical follow-up on 3 patients (median, 24 months; range, 18-31 months) showed all to be without disease. Morphologically, all tumors displayed typical features of this entity as described, with nests of cytologically bland, diffusely S100 protein/SOX10-positive round cells without mitotic activity, surrounded by fibrous bands containing spindled cells with similar nuclear features. The tumors also showed membranous CD99 (4/5) and nuclear NKX2.2 (3/3) expression. RNA sequencing (5 cases) demonstrated <em>FUS::FLI1</em>, <em>FUS::ERG</em>, <em>EWSR1::FLI1</em>, <em>EWSR1::ERG</em>, and a novel <em>FUS::ETV5.</em> Methylation profiling (4 cases) showed all to cluster with previously reported superficial neurocristic <em>EWSR1</em>::<em>FLI1</em> fusion tumors and apart from conventional and “adamantinoma-like” Ewing sarcoma. Our findings confirm the distinctive clinicopathological features of this very rare, recently described entity and expand its molecular genetic spectrum. Reflecting on these findings, we propose modifying the name of this entity to “superficial neurocristic FET::ETS fusion tumor.”</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100656"},"PeriodicalIF":7.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximal and Classic Epithelioid Sarcomas are Distinct Molecular Entities Defined by MYC/GATA3 and SOX17/Endothelial Markers, Respectively","authors":"Luca Sigalotti ,&nbsp;Anna Maria Frezza ,&nbsp;Marta Sbaraglia ,&nbsp;Elisa Del Savio ,&nbsp;Davide Baldazzi ,&nbsp;Beatrice Valenti ,&nbsp;Elena Bellan ,&nbsp;Ilaria De Benedictis ,&nbsp;Michele Doni ,&nbsp;Marco Gambarotti ,&nbsp;Bruno Vincenzi ,&nbsp;Antonella Brunello ,&nbsp;Giacomo Giulio Baldi ,&nbsp;Emanuela Palmerini ,&nbsp;Sandro Pasquali ,&nbsp;Maria Elena Ciuffetti ,&nbsp;Veronica Varano ,&nbsp;Filippo Cappello ,&nbsp;Viviana Appolloni ,&nbsp;Chiara Pastrello ,&nbsp;Roberta Maestro","doi":"10.1016/j.modpat.2024.100647","DOIUrl":"10.1016/j.modpat.2024.100647","url":null,"abstract":"<div><div>Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory. To elucidate the molecular underpinnings of ES, and to identify diagnostic biomarkers and potential therapeutic vulnerabilities, we performed an integrated omics profiling (RNA sequencing and methylation array) of 24 primary, untreated ESs. Transcriptome and methylome analysis identified 2 distinct molecular clusters that essentially corresponded to the morphologic variants of ES, classic ES (C-ES) and the more aggressive proximal ES (P-ES). The P-ES group was characterized by hyperactivation of GATA3 and MYC pathways, with extensive epigenetic rewiring associated with <em>EZH2</em> overexpression. Both DNA methylation and gene expression analysis indicated a striking similarity with the “MYC subgroup” of atypical teratoid/rhabdoid tumor, another SMARCB1-deficient tumor, implying a shared molecular background and potential therapeutic vulnerabilities. Conversely, the C-ES group exhibited an endothelial-like molecular profile, with expression of vascular genes and elevated proangiogenic SOX17 signaling. Immunohistochemistry validated the overexpression of the chromatin regulators GATA3 (9/12 vs 0/16) and EZH2 (7/7 vs 2/6) in P-ESs, and of the vascular factors SOX17 (8/8 vs 1/10) and N-cadherin (5/9 vs 0/10) in C-ESs. Therefore, these molecules emerge as potential diagnostic tools to fill the gap represented by the lack of ES subtype-specific biomarkers. In summary, our study shows that P-ES and C-ES represent distinct molecular entities defined by MYC/GATA3 and SOX17/endothelial molecular traits, respectively. Besides providing insights into the biology of ES, our study pinpoints subtype-specific biomarkers and potential therapeutic vulnerabilities.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100647"},"PeriodicalIF":7.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach","authors":"Catalina Amador ,&nbsp;Dennis D. Weisenburger ,&nbsp;Ana Gomez ,&nbsp;Alyssa Bouska ,&nbsp;Ahmad Alshomrani ,&nbsp;Sunandini Sharma ,&nbsp;Ab Rauf Shah ,&nbsp;Timothy C. Greiner ,&nbsp;Francisco Vega ,&nbsp;Andreas Rosenwald ,&nbsp;German Ott ,&nbsp;Andrew L. Feldman ,&nbsp;Elaine S. Jaffe ,&nbsp;Neval Ozkaya ,&nbsp;Sarah L. Ondrejka ,&nbsp;James R. Cook ,&nbsp;Philipp W. Raess ,&nbsp;Kerry J. Savage ,&nbsp;Graham W. Slack ,&nbsp;Joo Y. Song ,&nbsp;Javeed Iqbal","doi":"10.1016/j.modpat.2024.100646","DOIUrl":"10.1016/j.modpat.2024.100646","url":null,"abstract":"<div><div>Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [T_FH] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n = 22; 34%) and PTCL-TBX21 (n = 41; 66%), and a significant association (<em>P</em> &lt; .02) with overall survival was reaffirmed. Histopathologic assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared with PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (<em>P</em> &lt; .05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4⁺CD8^- and associated with significantly higher LEF1, MYC, and CD30 expression (<em>P</em> &lt; .05). PTCL-TBX21 displayed a more diverse biomarker profile with the following 2 subgroups: one expressing cytotoxic antigens and enriched in CD8⁺CD4⁻ or CD8⁻CD4⁻ phenotype, and another lacking cytotoxic markers but showing a CD4⁺CD8⁻ phenotype with increased ICOS expression, but devoid of other T_FH markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma gene signature, had more Epstein-Barr encoding region-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of angioimmunoblastic T-cell lymphoma (<em>P</em> &lt; .01). This study highlights the unique morphologic and phenotypic variations within the newly identified PTCL subtypes and should enable a more precise diagnosis and tailored therapeutic strategies in the future.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100646"},"PeriodicalIF":7.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}