Modern Pathology最新文献

{"title":"Malignant Sertoli-Leydig Cell Tumor With CTNNB1 Mutation Arising in a Cryptorchid Testis","authors":"Mariko Yasui , Yoshinao Kikuchi , Yoshiki Mikami , Takako Kiyokawa , Kosuke Miyai , Maiko Tsuchiya , Shiori Watabe , Tomoyuki Kaneko , Taketo Kawai , Tohru Nakagawa , Yuko Sasajima , Hiroshi Uozaki","doi":"10.1016/j.modpat.2024.100587","DOIUrl":"10.1016/j.modpat.2024.100587","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 10","pages":"Article 100587"},"PeriodicalIF":7.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036385","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: Interresponder Agreement and Comparison Between Pulmonary and General Pathologists","authors":"Michelle Garlin-Politis ,&nbsp;Anjali Saqi ,&nbsp;Mari Mino-Kenudson","doi":"10.1016/j.modpat.2024.100596","DOIUrl":"10.1016/j.modpat.2024.100596","url":null,"abstract":"<div><p>Spread through air spaces (STAS), an important prognostic indicator included in the 2015 World Health Organization classification, is defined as micropapillary, solid, and/or single tumor cell clusters beyond the edge of the main mass and distinct from processing artifacts. This study aimed to assess the interresponder agreement on current STAS criteria vs artifacts, identify discrepancies, and compare responses between pulmonary and general pathologists. A multiple-choice online questionnaire illustrating multiple criteria for STAS vs artifacts was available internationally for 6 days to Pulmonary Pathology Society members, thoracic pathology course attendees, and International Association for the Study of Lung Cancer pathology committee members. Additional 4 questions gathered demographic and practice setting information. One hundred thirty-six unique responses were analyzed. The majority were from North America and Europe (42.6% and 30.2%), practicing pulmonary pathology (70.6%) in academia (64.7%), and with &gt;20 years of experience (31.6%). Excluding trainees, the greatest overall agreement was in defining solid and micropapillary tumor clusters of STAS located ≥3 alveolar spaces from the main tumor edge (91.5%) and recognizing strips of ciliated cells as artifacts (97.7%). Lesser agreement on STAS was evident when tumor cell clusters were immediately adjacent to the tumor edge, a single tumor cell cluster was present at the tissue edge, tumor cell clusters were jagged edged, or tumor cell clusters were admixed with ciliated cell strips (artifacts). There was no significant difference in agreements on STAS for multiple criteria between pulmonary and general pathologists. Significant interresponder agreement on STAS vs artifacts was achieved only for a few criteria. To improve the reproducibility of STAS vs artifacts, areas of lesser agreement require further clarification.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100596"},"PeriodicalIF":7.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017989","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":"An Immunofluorescence-Guided Segmentation Model in Hematoxylin and Eosin Images Is Enabled by Tissue Artifact Correction Using a Cycle-Consistent Generative Adversarial Network","authors":"Marcel Wiedenmann ,&nbsp;Mariya Barch ,&nbsp;Patrick S. Chang ,&nbsp;Jennifer Giltnane ,&nbsp;Tyler Risom ,&nbsp;Andries Zijlstra","doi":"10.1016/j.modpat.2024.100591","DOIUrl":"10.1016/j.modpat.2024.100591","url":null,"abstract":"<div><p>Despite recent advances, the adoption of computer vision methods into clinical and commercial applications has been hampered by the limited availability of accurate ground truth tissue annotations required to train robust supervised models. Generating such ground truth can be accelerated by annotating tissue molecularly using immunofluorescence (IF) staining and mapping these annotations to a post-IF hematoxylin and eosin (H&amp;E) (terminal H&amp;E) stain. Mapping the annotations between IF and terminal H&amp;E increases both the scale and accuracy by which ground truth could be generated. However, discrepancies between terminal H&amp;E and conventional H&amp;E caused by IF tissue processing have limited this implementation. We sought to overcome this challenge and achieve compatibility between these parallel modalities using synthetic image generation, in which a cycle-consistent generative adversarial network was applied to transfer the appearance of conventional H&amp;E such that it emulates terminal H&amp;E. These synthetic emulations allowed us to train a deep learning model for the segmentation of epithelium in terminal H&amp;E that could be validated against the IF staining of epithelial-based cytokeratins. The combination of this segmentation model with the cycle-consistent generative adversarial network stain transfer model enabled performative epithelium segmentation in conventional H&amp;E images. The approach demonstrates that the training of accurate segmentation models for the breadth of conventional H&amp;E data can be executed free of human expert annotations by leveraging molecular annotation strategies such as IF, so long as the tissue impacts of the molecular annotation protocol are captured by generative models that can be deployed prior to the segmentation process.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100591"},"PeriodicalIF":7.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988339","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":"ARX, PDX1, ISL1, and CDX2 Expression Distinguishes 5 Subgroups of Pancreatic Neuroendocrine Tumors With Correlations to Histology, Hormone Expression, and Outcome","authors":"Elisa Moser ,&nbsp;Ayako Ura ,&nbsp;Loreen Vogel ,&nbsp;Katja Steiger ,&nbsp;Carolin Mogler ,&nbsp;Matthias Evert ,&nbsp;Bruno Märkl ,&nbsp;Klemens Scheidhauer ,&nbsp;Marc Martignoni ,&nbsp;Helmut Friess ,&nbsp;Alexander von Werder ,&nbsp;Ilaria Marinoni ,&nbsp;Aurel Perren ,&nbsp;Günter Klöppel ,&nbsp;Atsuko Kasajima","doi":"10.1016/j.modpat.2024.100595","DOIUrl":"10.1016/j.modpat.2024.100595","url":null,"abstract":"<div><p>Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and investigating their correlation with histologic, hormonal, molecular, and prognostic findings. One hundred eighty-five PanNETs (nonfunctioning 165 and functioning 20), resected between 1996 and 2023, were classified into 5 subgroups (A1, A2, B, C, and D) by cluster analysis based on ARX, PDX1, islet-1 (ISL1), and CDX2 expressions and correlated with trabecular vs solid histology, expression of insulin, glucagon, polypeptide (PP), somatostatin, serotonin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), DAXX/ATRX, MEN1, and alternative lengthening of telomerase status by fluorescence in situ hybridization, and disease-free survival. A1 (46%, ARX+/ISL1+/PDX1−/CDX2−) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2−) showed trabecular histology and glucagon/PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX−/CDX2−) showed solid histology, insulin, and somatostatin expression (<em>P</em> &lt; .001). It included all insulinomas and had the best outcome (<em>P</em> &lt; .01). C (15%, ARX−/PDX1−/ISL1−/CDX2−) showed solid histology and frequent expression of serotonin, calcitonin, and ACTH. D (5%, PDX1+/CDX2+/ISL1−/ARX−) showed solid histology, expressed ACTH/serotonin, and was an independent poor prognosticator (<em>P</em> &lt; .01). Differential expressions of ARX, PDX1, ISL1, and CDX2 stratified PanNETs into 5 subgroups with different histologies, hormone expressions, and outcomes. Subgroups A1 and A2 resembled the alpha-cell-like type, and subgroup B, the beta-cell-like type. Subgroup C with almost no transcription factor signature was unclear in cell lineage, whereas the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help establish the diagnosis, predict the outcome, and guide the treatment.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100595"},"PeriodicalIF":7.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001753/pdfft?md5=1dda03a0292647c37d53715d80f578a0&pid=1-s2.0-S0893395224001753-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988340","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":"Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of “Fusion-Positive” Cases","authors":"Josephine K. Dermawan ,&nbsp;Faizan Malik ,&nbsp;John M. Gross ,&nbsp;Ezra Baraban ,&nbsp;Christine Pratilas ,&nbsp;Wadad Mneimneh ,&nbsp;Matteo Trucco ,&nbsp;Wenyue Sun ,&nbsp;Frederic G. Barr ,&nbsp;Felipe D’Almeida Costa ,&nbsp;Karen J. Fritchie","doi":"10.1016/j.modpat.2024.100594","DOIUrl":"10.1016/j.modpat.2024.100594","url":null,"abstract":"<div><p>Alveolar rhabdomyosarcoma (ARMS) with <em>FOXO1</em> gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Here, we report 2 cases of ARMS with <em>PAX3::MAML3</em> fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children’s Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic <em>FOXO1</em> rearrangements and ARMS with variant <em>PAX3</em>::<em>NCOA1/INO80D</em> fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with <em>PAX3::MAML3/NCOA2/FOXO1/YAP1</em> fusions nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical responses, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic <em>FOXO1</em> rearrangement. We conclude that <em>PAX3::MAML3</em> is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar <em>PAX3</em> fusions. These findings highlight the utility of methylation profiling in classifying ARMS with noncanonical fusions.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100594"},"PeriodicalIF":7.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001741/pdfft?md5=7e63a37169059ebfebdd851f98d62c9b&pid=1-s2.0-S0893395224001741-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988341","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":"Prognostic Impact and Genomic Backgrounds of Renal Parenchymal Infiltration or Micronodular Spread in Nonmetastatic Clear Cell Renal Cell Carcinoma","authors":"Hajime Tanaka ,&nbsp;Yuki Fukawa ,&nbsp;Kouhei Yamamoto ,&nbsp;Kousuke Tanimoto ,&nbsp;Akira Takemoto ,&nbsp;Takayasu Mori ,&nbsp;Hisashi Hasumi ,&nbsp;Mayumi Kinoshita ,&nbsp;Takumi Kanazawa ,&nbsp;Asuka Furukawa ,&nbsp;Koichiro Kimura ,&nbsp;Hiroyuki Sato ,&nbsp;Akihiro Hirakawa ,&nbsp;Shohei Fukuda ,&nbsp;Yuma Waseda ,&nbsp;Soichiro Yoshida ,&nbsp;Steven C. Campbell ,&nbsp;Yasuhisa Fujii","doi":"10.1016/j.modpat.2024.100590","DOIUrl":"10.1016/j.modpat.2024.100590","url":null,"abstract":"<div><p>A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness is incomplete. Here, we show that the morphology of the tumor interface with normal renal parenchyma is robustly associated with cancer recurrence after surgery, even when compared with the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosin–stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups based on our classification algorithms for assessing the tumor interface with normal renal parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival, independently of existing pathological factors including the TNM staging system and WHO/ISUP nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4 (2.11) and ≥pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients without RPI/MNS. Results showed that alterations in <em>SETD2</em> and <em>TSC1</em> might be associated with RPI/MNS phenotypes, whereas alterations in <em>PBRM1</em> might be associated with non-RPI/MNS phenotypes. These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC, although more comprehensive analyses with a larger sample size are required. Future studies may further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of adjuvant treatment after nephrectomy.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100590"},"PeriodicalIF":7.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982761","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":"Claudin-18.2 Immunohistochemical Evaluation in Gastric and Gastroesophageal Junction Adenocarcinomas to Direct Targeted Therapy: A Practical Approach","authors":"Matteo Fassan ,&nbsp;Takeshi Kuwata ,&nbsp;Kristina A. Matkowskyj ,&nbsp;Christoph Röcken ,&nbsp;Josef Rüschoff","doi":"10.1016/j.modpat.2024.100589","DOIUrl":"10.1016/j.modpat.2024.100589","url":null,"abstract":"<div><p>Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several preanalytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation; thus, this article provides practical guidance on CLDN18.2 testing and scoring in gastric and gastroesophageal junction adenocarcinomas to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cutoff for clinical use of monoclonal antibody anti-CLDN18.2 (zolbetuximab).</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100589"},"PeriodicalIF":7.1,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001698/pdfft?md5=838824eb948dd42b0618ff343922c020&pid=1-s2.0-S0893395224001698-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889753","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":"Histopathologic, Molecular, and Clinical Profiling of Lymphoepithelioma-like Carcinoma of the Bladder","authors":"Florestan Johannes Koll ,&nbsp;Lillian Weers ,&nbsp;Andreas Weigert ,&nbsp;Severine Banek ,&nbsp;Jens Köllermann ,&nbsp;Luis Kluth ,&nbsp;Mike Wenzel ,&nbsp;Cristina Cano Garcia ,&nbsp;Tibor Szarvas ,&nbsp;Michael Wessolly ,&nbsp;Marc Ingenwerth ,&nbsp;Jan Jeroch ,&nbsp;Claudia Döring ,&nbsp;Felix K.-H. Chun ,&nbsp;Peter J. Wild ,&nbsp;Henning Reis","doi":"10.1016/j.modpat.2024.100588","DOIUrl":"10.1016/j.modpat.2024.100588","url":null,"abstract":"<div><p>Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell (IC) infiltrates. A better prognosis and favorable response rates to immune checkpoint inhibitors have been described. We aimed to characterize the molecular profiles and IC infiltration of LELC-B for a better understanding of its therapeutic implications. We identified 11 muscle-invasive bladder cancer cases with pure and mixed LELC-B. Programmed cell death ligand-1 (PD-L1) expression and mismatch repair proteins were evaluated using immunohistochemistry. We calculated the tumor mutational burden and characterized mutational profiles using whole-exome DNA sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 Panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, α-SMA, vimentin, CD45, and Ki67) and T cells (CD4, CD3, PD-1, CD163, CD8, and FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median tumor proportion score/tumor cell, 70%; range, 20%-100%; median combined positive score, 100; range, 50-100) and mismatch repair proficient and negative for Epstein-Barr virus infection. IC infiltrates were characterized by a high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in IC response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high tumor mutational burden with a median of 39 mutations/Mb (IQR, 29-66 mutations/Mb). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD-1/PD-L1 and making immune checkpoint inhibitors a promising treatment option.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100588"},"PeriodicalIF":7.1,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001686/pdfft?md5=672104b24931fcebd0cfce87595b7d0f&pid=1-s2.0-S0893395224001686-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889754","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":"Whole-Exome Sequencing of Vulvar Squamous Cell Carcinomas Reveals an Impaired Prognosis in Patients With TP53 Mutations and Concurrent CCND1 Gains","authors":"Oriol Ordi ,&nbsp;Adela Saco ,&nbsp;Núria Peñuelas ,&nbsp;Odei Blanco-Irazuegui ,&nbsp;Marta del Pino ,&nbsp;Núria Carreras-Dieguez ,&nbsp;Lorena Marimon ,&nbsp;Maria Teresa Rodrigo-Calvo ,&nbsp;Alba Morató ,&nbsp;Lia Sisuashvili ,&nbsp;Mariona Bustamante ,&nbsp;Adrià Cruells ,&nbsp;Katarzyna Darecka ,&nbsp;Naiara Vega ,&nbsp;Silvia Alós ,&nbsp;Isabel Trias ,&nbsp;Pere Fusté ,&nbsp;Genis Parra ,&nbsp;Marta Gut ,&nbsp;Meritxell Munmany ,&nbsp;Natalia Rakislova","doi":"10.1016/j.modpat.2024.100574","DOIUrl":"10.1016/j.modpat.2024.100574","url":null,"abstract":"<div><p>Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor (human papillomavirus [HPV]-associated [HPV-A], HPV-independent [HPV-I] with <em>TP53</em> mutation [HPV-I/<em>TP53</em>mut], and HPV-I with wild-type <em>TP53</em> [HPV-I/<em>TP53</em>wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities.Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/<em>TP53</em>mut, and 13 (21.6%) as HPV-I/<em>TP53</em>wt. <em>TP53</em> was the most frequently mutated gene (66.7%), followed by <em>FAT1</em> (28.3%), <em>CDKN2A</em> (25.0%), <em>RNF213</em> (23.3%), <em>NFE2L2</em> (20%) and <em>PIK3CA</em> (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed <em>CCND1</em> gain. Bivariate analysis, adjusted for International Federation of Gynecology and Obstetrics stage, revealed that <em>TP53</em> mutation, <em>CCND1</em> gain, and the combination of the 2 alterations were strongly associated with impaired recurrence-free survival (hazard ratio, 4.4; <em>P</em> &lt; .001) and disease-specific survival (hazard ratio, 6.1; <em>P</em> = .002). Similar results were obtained when p53 IHC status was used instead of <em>TP53</em> status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with <em>CCND1</em> gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with <em>CCND1</em> gain represent a prognostically adverse category among HPV-I/<em>TP53</em>mut tumors. All patients with VSCCs are potential candidates for targeted therapy.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 10","pages":"Article 100574"},"PeriodicalIF":7.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001546/pdfft?md5=44022f159fe23532416045717b46fb40&pid=1-s2.0-S0893395224001546-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875349","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":"SWI/SNF Complex-Deficient Undifferentiated Carcinoma of the Pancreas: Clinicopathologic and Genomic Analysis","authors":"Aslihan Yavas ,&nbsp;Kerem Ozcan ,&nbsp;N. Volkan Adsay ,&nbsp;Serdar Balci ,&nbsp;Zeynep C. Tarcan ,&nbsp;Jaclyn F. Hechtman ,&nbsp;Claudio Luchini ,&nbsp;Aldo Scarpa ,&nbsp;Rita T. Lawlor ,&nbsp;Andrea Mafficini ,&nbsp;Michelle D. Reid ,&nbsp;Yue Xue ,&nbsp;Zhaohai Yang ,&nbsp;Kester Haye ,&nbsp;Andrew M. Bellizzi ,&nbsp;Alessandro Vanoli ,&nbsp;Jamal Benhamida ,&nbsp;Vinod Balachandran ,&nbsp;William Jarnagin ,&nbsp;Wungki Park ,&nbsp;Olca Basturk","doi":"10.1016/j.modpat.2024.100585","DOIUrl":"10.1016/j.modpat.2024.100585","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Inactivating alterations in the SWItch/Sucrose NonFermentable (SWI/SNF) Chromatin Remodeling Complex subunits have been described in multiple tumor types. Recent studies focused on &lt;em&gt;SMARC&lt;/em&gt; subunits of this complex to understand their relationship with tumor characteristics and therapeutic opportunities. To date, pancreatic cancer with these alterations has not been well studied, although isolated cases of undifferentiated carcinomas have been reported. Herein, we screened 59 pancreatic undifferentiated carcinomas for alterations in SWI/SNF complex–related (&lt;em&gt;SMARCB1&lt;/em&gt; [BAF47/INI1], &lt;em&gt;SMARCA4&lt;/em&gt; [BRG1], &lt;em&gt;SMARCA2&lt;/em&gt; [BRM]) proteins and/or genes using immunohistochemistry and/or next-generation sequencing. Cases with alterations in SWI/SNF complex–related proteins/genes were compared with cases without alterations, as well as with 96 conventional pancreatic ductal adenocarcinomas (PDAC). In all tumor groups, mismatch repair and PD-L1 protein expression were also evaluated. Thirty of 59 (51%) undifferentiated carcinomas had a loss of SWI/SNF complex–related protein expression or gene alteration. Twenty-seven of 30 (90%) SWI-/SNF-deficient undifferentiated carcinomas had rhabdoid morphology (vs 9/29 [31%] SWI-/SNF-retained undifferentiated carcinomas; &lt;em&gt;P&lt;/em&gt; &lt; .001) and all expressed cytokeratin, at least focally. Immunohistochemically, &lt;em&gt;SMARCB1&lt;/em&gt; protein expression was absent in 16/30 (53%) cases, &lt;em&gt;SMARCA2&lt;/em&gt; in 4/30 (13%), and &lt;em&gt;SMARCA4&lt;/em&gt; in 4/30 (13%); both &lt;em&gt;SMARCB1&lt;/em&gt; and &lt;em&gt;SMARCA2&lt;/em&gt; protein expressions were absent in 1/30 (3%). Five of 8 (62.5%) SWI-/SNF-deficient undifferentiated carcinomas that displayed loss of &lt;em&gt;SMARCB1&lt;/em&gt; protein expression by immunohistochemistry were found to have corresponding &lt;em&gt;SMARCB1&lt;/em&gt; deletions by next-generation sequencing. Analysis of canonical driver mutations for PDAC in these cases showed &lt;em&gt;KRAS&lt;/em&gt; (2/5) and &lt;em&gt;TP53&lt;/em&gt; (2/5) abnormalities. Median combined positive score for PD-L1 (E1L3N) was significantly higher in the undifferentiated carcinomas with/without SWI/SNF deficiency compared with the conventional PDACs (&lt;em&gt;P&lt;/em&gt; &lt; .001). SWI-/SNF-deficient undifferentiated carcinomas were larger (&lt;em&gt;P&lt;/em&gt; &lt; .001) and occurred in younger patients (&lt;em&gt;P&lt;/em&gt; &lt; .001). Patients with SWI-/SNF-deficient undifferentiated carcinoma had worse overall survival compared with patients with SWI-/SNF-retained undifferentiated carcinoma (&lt;em&gt;P&lt;/em&gt; = .004) and PDAC (&lt;em&gt;P&lt;/em&gt; &lt; .001). Our findings demonstrate that SWI-/SNF-deficient pancreatic undifferentiated carcinomas are frequently characterized by rhabdoid morphology, exhibit highly aggressive behavior, and have a negative prognostic impact. The ones with &lt;em&gt;SMARCB1&lt;/em&gt; deletions appear to be frequently &lt;em&gt;KRAS&lt;/em&gt; wild type. Innovative developmental therapeutic strategies targeting this genomic basis of the SWI/SNF complex and the therapeutic implications of EZH2 inhibition (NCT","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100585"},"PeriodicalIF":7.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879140","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}