Modern Pathology最新文献

{"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}

{"title":"Wnt/β-Catenin–Activated Nonpilomatrical Carcinoma of the Skin: A Case Series","authors":"Thibault Kervarrec ,&nbsp;Kuan Cheok Lei ,&nbsp;Pierre Sohier ,&nbsp;Nicolas Macagno ,&nbsp;Marie-Laure Jullie ,&nbsp;Eric Frouin ,&nbsp;Keisuke Goto ,&nbsp;Kohei Taniguchi ,&nbsp;Aymeric Hamard ,&nbsp;Antoine Taillandier ,&nbsp;Anne Tallet ,&nbsp;Christine Bonenfant ,&nbsp;Yusuf Sahin ,&nbsp;Fatoumata Barry ,&nbsp;Saleem Taibjee ,&nbsp;Kristof Cokelaere ,&nbsp;Roland Houben ,&nbsp;David Schrama ,&nbsp;Charlee Nardin ,&nbsp;Francois Aubin ,&nbsp;Serge Guyétan","doi":"10.1016/j.modpat.2024.100586","DOIUrl":"10.1016/j.modpat.2024.100586","url":null,"abstract":"<div><p>Among skin epithelial tumors, recurrent mutations in the <em>APC/CTNNB1</em> genes resulting in activation of the Wnt/β-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/β-catenin pathway without evidence of matrical differentiation, as well as 4 combined tumors in which a similar Wnt/β-catenin–activated carcinoma component was associated with Merkel cell carcinoma (MCC) or pilomatrical carcinoma. Among the pure tumor cases, 6 of 16 patients were women with a median age of 80 years (range, 58-98 years). Tumors were located on the head and neck (n = 7, 44%), upper limb (n = 4, 25%), trunk (n = 3, 18%), and leg (n = 2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in 1 patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid “squamoid” areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%), and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but 1 case. Nuclear β-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in <em>APC</em> (60%), <em>CTNNB1</em> (40%), and <em>RB1</em> (n = 47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogeneous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, MCC, and squamous cell carcinoma), although the 3 other cases lacking such morphologic features did not. In addition, we identified 4 combined neoplasms in which there was a component showing a similar poorly differentiated rosette-forming carcinoma demonstrating Rb loss and β-catenin activation associated with either MCC (n = 3) or pilomatrical carcinoma (n = 1). In conclusion, we describe a distinctive neoplasm, for which we propose the term “Wnt/β-catenin–activated rosette-forming carcinoma,” morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in <em>CTNNB1/APC</em> genes.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100586"},"PeriodicalIF":7.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879141","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":"Clinical-Grade Validation of an Autofluorescence Virtual Staining System With Human Experts and a Deep Learning System for Prostate Cancer","authors":"Pok Fai Wong ,&nbsp;Carson McNeil ,&nbsp;Yang Wang ,&nbsp;Jack Paparian ,&nbsp;Charles Santori ,&nbsp;Michael Gutierrez ,&nbsp;Andrew Homyk ,&nbsp;Kunal Nagpal ,&nbsp;Tiam Jaroensri ,&nbsp;Ellery Wulczyn ,&nbsp;Tadayuki Yoshitake ,&nbsp;Julia Sigman ,&nbsp;David F. Steiner ,&nbsp;Sudha Rao ,&nbsp;Po-Hsuan Cameron Chen ,&nbsp;Luke Restorick ,&nbsp;Jonathan Roy ,&nbsp;Peter Cimermancic","doi":"10.1016/j.modpat.2024.100573","DOIUrl":"10.1016/j.modpat.2024.100573","url":null,"abstract":"<div><p>The tissue diagnosis of adenocarcinoma and intraductal carcinoma of the prostate includes Gleason grading of tumor morphology on the hematoxylin and eosin stain and immunohistochemistry markers on the prostatic intraepithelial neoplasia-4 stain (CK5/6, P63, and AMACR). In this work, we create an automated system for producing both virtual hematoxylin and eosin and prostatic intraepithelial neoplasia-4 immunohistochemistry stains from unstained prostate tissue using a high-throughput hyperspectral fluorescence microscope and artificial intelligence and machine learning. We demonstrate that the virtual stainer models can produce high-quality images suitable for diagnosis by genitourinary pathologists. Specifically, we validate our system through extensive human review and computational analysis, using a previously validated Gleason scoring model, and an expert panel, on a large data set of test slides. This study extends our previous work on virtual staining from autofluorescence, demonstrates the clinical utility of this technology for prostate cancer, and exemplifies a rigorous standard of qualitative and quantitative evaluation for digital pathology.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 11","pages":"Article 100573"},"PeriodicalIF":7.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788627","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":"The Clinicopathological and Molecular Characteristics of Endocervical Gastric-Type Adenocarcinoma and the Use of Claudin18.2 as a Potential Therapeutic Target","authors":"Jing Yang ,&nbsp;Yang Peng ,&nbsp;Yan Ding ,&nbsp;Yueping Liu ,&nbsp;Yuxiang Wang ,&nbsp;Yan Liu ,&nbsp;Congrong Liu","doi":"10.1016/j.modpat.2024.100569","DOIUrl":"10.1016/j.modpat.2024.100569","url":null,"abstract":"<div><p>Endocervical gastric-type adenocarcinoma (GAS) is an aggressive type of endocervical mucinous adenocarcinoma characterized as being unrelated to human papillomavirus (HPV) and resistant to chemo/radiotherapy. In this study, we investigated the histology, immunohistochemistry patterns, and molecular characteristics in a large cohort of GAS (n = 62). Histologically, the majority of GAS cases exhibited a distinct morphology resembling gastric glands, although 2 exceptional cases exhibited HPV-associated adenocarcinoma morphology while retaining the characteristic histology of GAS at the invasive front. By immunohistochemistry, Claudin18.2 emerged as a highly sensitive and specific marker for GAS. Additionally, the strong expression of Claudin18.2 in patients with GAS indicated the potential of anti-Claudin18.2 therapy in the treatment of GAS. Other immunohistochemistry markers, including Muc6, p16, p53, Pax8, ER, and PR, may provide additional diagnostic clues for GAS. Quantitative methylation analysis revealed that the overexpression of Claudin18.2 in GAS was governed by the hypomethylation of the <em>CLDN18.2</em> promoter CpG islands. To further elucidate the pathogenic mechanisms of GAS and its relationship with gastric adenocarcinoma, we performed whole exome sequencing on 11 GAS and 9 gastric adenocarcinomas. <em>TP53</em>, <em>CDKN2A</em>, <em>STK11</em>, and <em>TTN</em> emerged as the most frequently mutated genes in GAS. Mutations in these genes primarily affected cell growth, cell cycle regulation, senescence, and apoptosis. Intriguingly, these top mutated genes in GAS were also commonly mutated in gastric and pancreaticobiliary adenocarcinomas. Regarding germline variants, we identified a probably pathogenic variant in <em>SPINK1</em>, a gene linked to hereditary pancreatic cancer syndrome, in one GAS sample. This finding suggests a potential pathogenic link between pancreatic cancers and GAS. Overall, GAS exhibits molecular characteristics that resemble those observed in gastric and pancreaticobiliary adenocarcinomas, thereby lending support to the aggressive nature of GAS compared with HPV-associated adenocarcinoma.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 10","pages":"Article 100569"},"PeriodicalIF":7.1,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001492/pdfft?md5=c32dc633e84e48db3525863a0b99f52d&pid=1-s2.0-S0893395224001492-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723944","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":"Multicenter Study on Tumor Budding in Lung Squamous Cell Carcinoma: Comparison Between Biopsy and Resection With Interobserver Variability Assessment","authors":"Marie Maillard ,&nbsp;Christina Neppl ,&nbsp;Philipp Zens ,&nbsp;Julie Anex ,&nbsp;Solange Peters ,&nbsp;Thorsten Krueger ,&nbsp;Sabina Berezowska","doi":"10.1016/j.modpat.2024.100571","DOIUrl":"10.1016/j.modpat.2024.100571","url":null,"abstract":"<div><p>Grading lung squamous cell carcinoma (LUSC) is controversial and not universally accepted. The histomorphologic feature of tumor budding (TB) is an established independent prognostic factor in colorectal cancer, and its importance is growing in other solid cancers, making it a candidate for inclusion in tumor grading schemes. We aimed to compare TB between preoperative biopsies and resection specimens in pulmonary squamous cell carcinoma and assess interobserver variability. A retrospective cohort of 249 consecutive patients primarily resected with LUSC in Bern (2000-2013, n = 136) and Lausanne (2005-2020, n = 113) with available preoperative biopsies was analyzed for TB and additional histomorphologic parameters, such as spread through airspaces and desmoplasia, by 2 expert pathologists (M.M., C.N.). Results were correlated with clinicopathologic parameters and survival. In resection specimens, peritumoral budding (PTB) score was low (0-4 buds/0.785 mm²) in 47.6%, intermediate (5-9 buds/0.785 mm²) in 27.4%, and high (≥10 buds/0.785 mm²) in 25% of cases (median bud count, 5; IQR, 0-26). Both the absolute number of buds and TB score were similar when comparing tumor edge and intratumoral zone (<em>P</em> = .192) but significantly different from the score obtained in the biopsy (<em>P</em> &lt; .001). Interobserver variability was moderate, regardless of score location (Cohen kappa, 0.59). The discrepant cases were reassessed, and consensus was reached in all cases with identification of causes of discordance. TB score was significantly associated with stage (<em>P</em> = .002), presence of lymph node (<em>P</em> = .033), and distant metastases (<em>P</em> = .020), without significant correlation with overall survival, tumor size, or pleural invasion. Desmoplasia was significantly associated with higher PTB (<em>P</em> &lt; .001). Spread through airspaces was present in 34% and associated with lower PTB (<em>P</em> &lt; .001). To conclude, despite confirming TB as a reproducible factor in LUSC, we disclose areas of scoring ambiguity. Preoperative biopsy evaluation was insufficient in establishing the final TB score of the resected tumor.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 10","pages":"Article 100571"},"PeriodicalIF":7.1,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001510/pdfft?md5=436d2a133269a6ef5b07a831d4ca6b68&pid=1-s2.0-S0893395224001510-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748579","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}