Modern Pathology最新文献

{"title":"Polychromatic Polarization Microscopy Differentiates Collagen Fiber Signatures in Benign Pancreatic Tissue and Pancreatic Ductal Adenocarcinoma","authors":"Mahsa Chitsaz ,&nbsp;Linlin Yang ,&nbsp;Rania Rayes-Danan ,&nbsp;Omid Savari ,&nbsp;Bin Li ,&nbsp;Michael Shribak ,&nbsp;Kevin Eliceiri ,&nbsp;Agnes Loeffler","doi":"10.1016/j.modpat.2025.100768","DOIUrl":"10.1016/j.modpat.2025.100768","url":null,"abstract":"<div><div>The orientation of collagen fibers in relation to malignant epithelium is known to carry prognostic information in a variety of tissues. The data are the strongest for breast and pancreatic ductal adenocarcinoma. However, information inherent in collagen fiber topology in malignant tissues remains untapped in daily surgical pathology practice, largely because collagen fibers within areas of desmoplasia cannot be resolved with standard diagnostic microscopy. The methodologies used to visualize collagen fiber orientation are either of insufficient resolution to consistently capture collagen fiber topology or require resources in time and money that do not fit into the daily surgical pathology workflow. Polychromatic polarization microscopy has the potential to bring collagen topology to the attention of pathologists during their routine work. It has been demonstrated to be equivalent to the gold standard methodology used to research collagen, second harmonic generation. We use polychromatic polarization microscopy to visualize and describe the differences in collagen topology in normal pancreas, chronic pancreatitis, and pancreatic ductal adenocarcinoma with a standard microscope, using hematoxylin and eosin-stained sections. In the process, we propose a lexicon with which to describe the morphologic characteristics of collagen in benign and malignant pancreatic tissues.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 8","pages":"Article 100768"},"PeriodicalIF":7.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917342","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":"Cytoplasmic p53 Immunostaining in Salivary Duct Carcinoma: A Poor Prognostic Factor Associated With Characteristic TP53 Variants","authors":"Yoshitaka Utsumi ,&nbsp;Masato Nakaguro ,&nbsp;Daisuke Kawakita ,&nbsp;Hideaki Hirai ,&nbsp;Aoi Sukeda ,&nbsp;Shinji Kohsaka ,&nbsp;Kiyoaki Tsukahara ,&nbsp;Toyoyuki Hanazawa ,&nbsp;Satoshi Kano ,&nbsp;Keisuke Yamazaki ,&nbsp;Yushi Ueki ,&nbsp;Kenji Okami ,&nbsp;Yuki Saito ,&nbsp;Hiroyuki Ozawa ,&nbsp;Yoshitaka Honma ,&nbsp;Akira Shimizu ,&nbsp;Kenji Hanyu ,&nbsp;Shota Fujii ,&nbsp;Tomoyuki Arai ,&nbsp;Sho Iwaki ,&nbsp;Toshitaka Nagao","doi":"10.1016/j.modpat.2025.100766","DOIUrl":"10.1016/j.modpat.2025.100766","url":null,"abstract":"<div><div>Salivary duct carcinoma (SDC) is an uncommon, high-grade malignancy. Identifying suitable prognostic factors is crucial for developing effective treatment strategies for SDC. p53 Immunohistochemistry (IHC) is a potential prognostic marker for SDC. Traditionally, only the nuclear expression has been considered when evaluating aberrant p53 IHC patterns. However, recent studies on other organ cancers have highlighted the significance of the cytoplasmic p53 expression. We aimed to investigate the prognostic implications of cytoplasmic p53 positivity and its association with <em>TP53</em> variants in a large cohort of patients with SDC. p53 IHC was performed in 327 patients with SDC who had undergone primary curative resection. Based on the immunostaining patterns, patients were classified into 4 groups: wild-type (WT), overexpression (OE), complete absence (CA), and cytoplasmic (CY). Additionally, the <em>TP53</em> gene status was analyzed in 239 cases by Sanger and/or next-generation sequencing. The p53 IHC patterns of 327 cases were as follows: WT (n = 125; 38.2%), OE (n = 100; 30.6%), CA (n = 75; 22.9%), and CY (n = 27; 8.3%). A <em>TP53</em> genetic analysis of 239 cases revealed the following: WT status (n = 80; 33.5%), missense/inframe variants (n = 86; 36.0%), and truncating variants (n = 73; 30.5%). Notably, 24 of the 25 CY cases (96%) harbored <em>TP53</em> variants, which were predominantly located in the domains responsible for nuclear translocation. Of these, 22 exhibited truncating variants. In a multivariate analysis, CY cases demonstrated significantly shorter disease-free survival (DFS) than WT cases (<em>P</em> = .01). Furthermore, patients with aberrant p53 expression patterns (OE+CA+CY) had significantly worse DFS and overall survival than those with WT (<em>P</em> = .003 and .002, respectively). The presence of <em>TP53</em> variants was also associated with poorer DFS and overall survival (<em>P</em> = .003 and .02, respectively). Our findings suggest that the cytoplasmic expression of p53 in SDC represents a distinct aberrant pattern underlying characteristic genetic abnormalities and has significant prognostic implications.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100766"},"PeriodicalIF":7.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882592","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":"Toward Optimizing the Impact of Digital Pathology and Augmented Intelligence on Issues of Diagnosis, Grading, Staging and Classification.","authors":"Lewis A Hassell, Marika L Forsythe, Ami Bhalodia, Thanh Lan, Tasnuva Rashid, Astin Powers, Marilyn M Bui, Arlen Brickman, Qiangqiang Gu, Andrey Bychkov, Ian Cree, Liron Pantanowitz","doi":"10.1016/j.modpat.2025.100765","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100765","url":null,"abstract":"<p><p>The introduction of new diagnostic information in pathology requires effective dissemination and adoption strategies. While traditional methods like journals, meetings, and atlases have been used, they pose challenges in accessibility, interactivity, and performance validation. Digital pathology (DP) and artificial or augmented intelligence (AI) offer promising solutions to address these limitations. This paper advocates the use of DP and AI tools to facilitate the introduction of new diagnostic information in pathology. It highlights the importance of standardized training and validation sets, digital slide libraries, and AI-enhanced diagnostic tools. While AI can improve efficiency and accuracy, it's crucial to address potential pitfalls such as over-reliance on AI, bias and the need for human oversight. By leveraging DP and AI, the efficiency and accuracy of diagnosis, grading, staging, and classification can be augmented, ultimately improving patient care.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100765"},"PeriodicalIF":7.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023790","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":"Labor-Efficient Pathological Auxiliary Diagnostic Model for Primary and Metastatic Tumor Tissue Detection in Pancreatic Ductal Adenocarcinoma","authors":"Xinyi Ke ,&nbsp;Moxuan Yang ,&nbsp;Jingci Chen ,&nbsp;Ruping Hong ,&nbsp;Zheng Wang ,&nbsp;Shuhao Wang ,&nbsp;Hui Zhang ,&nbsp;Junliang Lu ,&nbsp;Boju Pan ,&nbsp;Yike Gao ,&nbsp;Xiaoding Liu ,&nbsp;Xiaoyu Li ,&nbsp;Yang Zhang ,&nbsp;Si Su ,&nbsp;Huanwen Wu ,&nbsp;Zhiyong Liang","doi":"10.1016/j.modpat.2025.100764","DOIUrl":"10.1016/j.modpat.2025.100764","url":null,"abstract":"<div><div>Accurate histopathological evaluation of pancreatic ductal adenocarcinoma (PDAC), including primary tumor lesions and lymph node metastases, is critical for prognostic evaluation and personalized therapeutic strategies. Distinct from other solid tumors, PDAC presents unique diagnostic challenges owing to its extensive desmoplasia, unclear tumor boundary, and difficulty in differentiating from chronic pancreatitis. These characteristics not only complicate pathological diagnosis but also hinder the acquisition of pixel-level annotations required for training computational pathology models. In this study, we present PANseg, a multiscale weakly supervised deep learning framework for PDAC segmentation, trained and tested on 368 whole-slide images (WSIs) from 208 patients across 2 independent centers. Using only image-level labels (2048 × 2048 pixels), PANseg achieved comparable performance with fully supervised baseline (FSB) across the internal test set 1 (17 patients/58 WSIs; PANseg area under the receiver operating characteristic curve [AUROC]: 0.969 vs FSB AUROC: 0.968), internal test set 2 (40 patients/44 WSIs; PANseg AUROC: 0.991 vs FSB AUROC: 0.980), and external test set (20 patients/20 WSIs; PANseg AUROC: 0.950 vs FSB AUROC: 0.958). Moreover, the model demonstrated considerable generalizability with previously unseen sample types, attaining AUROCs of 0.878 on fresh-frozen specimens (20 patients/20 WSIs) and 0.821 on biopsy sections (20 patients/20 WSIs). In lymph node metastasis detection, PANseg augmented the diagnostic accuracy of 6 pathologists from 0.888 to 0.961, while reducing the average diagnostic time by 32.6% (72.0 vs 48.5 minutes). This study demonstrates that our weakly supervised model can achieve expert-level segmentation performance and substantially reduce annotation burden. The clinical implementation of PANseg holds great potential in enhancing diagnostic precision and workflow efficiency in the routine histopathological assessment of PDAC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100764"},"PeriodicalIF":7.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811767","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":"Cover","authors":"","doi":"10.1016/S0893-3952(25)00056-0","DOIUrl":"10.1016/S0893-3952(25)00056-0","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100760"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834470","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":"POU4F3 Expression Distinguishes Wnt/Beta-Catenin–Activated Nonpilomatrical Carcinoma From Merkel Cell Carcinoma","authors":"Thibault Kervarrec ,&nbsp;Serge Guyétant","doi":"10.1016/j.modpat.2025.100751","DOIUrl":"10.1016/j.modpat.2025.100751","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100751"},"PeriodicalIF":7.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724355","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":"Methylation Analysis Reveals Epigenetic Congruence Between Bone Sarcomas With H3-3A Mutations and Malignant Giant Cell Tumors of Bone","authors":"Carla Saoud ,&nbsp;Jamal Benhamida ,&nbsp;Laetitia Borsu ,&nbsp;Liliana Villafania ,&nbsp;Konstantinos Linos ,&nbsp;A. Rose Brannon ,&nbsp;Hwang Sinchun ,&nbsp;Carol Morris ,&nbsp;Max Vaynrub ,&nbsp;Meredith Bartelstein ,&nbsp;John Healey ,&nbsp;William Tap ,&nbsp;Tejus A. Bale ,&nbsp;Benjamin A. Nacev ,&nbsp;Marc Ladanyi ,&nbsp;Meera R. Hameed","doi":"10.1016/j.modpat.2025.100763","DOIUrl":"10.1016/j.modpat.2025.100763","url":null,"abstract":"<div><div>Hotspot mutations in <em>H3-3A</em> gene are key drivers in giant cell tumor of bone (GCTB). Rare primary bone sarcomas also harbor this mutation, but their clinicopathologic characteristics and molecular profiles, as well as their relationship to conventional and malignant GCTB (MGCTB) and high-grade conventional osteosarcoma (HGOS), are largely undefined. Herein, we present a series of 10 <em>H3-3A</em> mutated bone sarcomas (BSH3-3A) with a comparative clinicopathologic, mutational, and epigenetic analysis with conventional GCTB, MGCTB, and HGOS. BSH3-3A comprised of 6 high-grade osteosarcomas, 4 undifferentiated pleomorphic sarcoma of bone and occurred in 7 women and 3 men with a mean age of 46 years (28-74 years). The tumors involved femur (n = 4), talus (n = 2), spine (n = 2), pelvis (n = 1), and 1 unknown site. Epiphysis involvement was noted in 2 femoral tumors. In majority of the cases, BSH3-3A showed cellular proliferation of epithelioid and/or spindle cells, hyperchromatic nuclei, and conspicuous pleomorphism with or without osteoid production. One case exhibited both low- and high-grade osteosarcoma components. The mutational profile of BSH3-3A was different than that of conventional HGOS with significantly less frequent <em>TP53</em> mutations. The genomic index, which reflects the degree of genomic complexity, was also significantly lower in BSH3-3A compared with HGOS, yet higher than GCTB. DNA methylation analysis revealed that most BSH3-3A and MGCTB cases form a distinct cluster, positioned near but separate from GCTB, and clearly separated from HGOS. Differential methylation analysis revealed that BSH3-3A exhibited the highest degree of similarity to MGCTB in comparison to HGOS and GCTB. Survival analysis showed that outcomes for BSH3-3A do not differ significantly from those observed in HGOS or MGCTB. Finally, BSH3-3A tumors, although radiologically and histologically identical to high-grade bone sarcomas lacking <em>H3-3A</em> mutations, display epigenetic features similar to MGCTB and have a significantly less complex genomic profile than HGOS, despite comparable clinical outcomes.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100763"},"PeriodicalIF":7.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743180","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":"Nosologic Reappraisal of the Recently Proposed Calcified Chondroid Mesenchymal Neoplasm Concept in a Series of 20 Cases","authors":"Shogo Nishino ,&nbsp;Taisuke Mori ,&nbsp;Hajime Umezu ,&nbsp;Kohtaro Eguchi ,&nbsp;Toshihide Hirai ,&nbsp;Ryouji Yamada ,&nbsp;Shinsuke Ohshima ,&nbsp;Yasushi Yatabe ,&nbsp;Seiichi Yoshimoto ,&nbsp;Akira Kawai ,&nbsp;Toru Motoi ,&nbsp;Akihiko Yoshida","doi":"10.1016/j.modpat.2025.100762","DOIUrl":"10.1016/j.modpat.2025.100762","url":null,"abstract":"<div><div>“Calcified chondroid mesenchymal neoplasm (CCMN)” is a recently proposed term for tumors with hypercellular chondroid histology and fusion genes. However, its impact on the present classification framework has not been extensively investigated. In this study, we analyzed 20 tumors with histology that would fit with that reported as “CCMN.” With the combined use of RNA sequencing and fluorescence in situ hybridization, 15 tumors were found to have gene fusions, including <em>FN1::FGFR2</em> (n = 4), <em>FN1::TEK</em> (n = 1), <em>FN1::MERTK</em> (n = 1), <em>PDGFRA::USP8</em> (n = 2), <em>FN1</em> rearrangements with undetermined non-<em>FGFR2</em> partners (n = 4), and <em>PDGFRA</em> rearrangements with undetermined partners (n = 3). <em>FN1</em> or <em>PDGFRA</em> rearrangement signals were restricted to epithelioid/polygonal cells, indicating that these were neoplastic elements mixed with abundant reactive cells. The fusion-positive tumors were found in 7 men and 8 women aged 29 to 82 years (median, 57 years), and most involved the temporomandibular joints or digits. Tumors showed a chondroid matrix with grungy calcification and cellular components with epithelioid/polygonal cells and were divided into 2 groups the histology of which corresponded to chondroid tenosynovial giant cell tumor or soft-tissue chondroma. Three fusion-positive tumors harbored calcium pyrophosphate dihydrate crystals. Nuclear atypia was frequent. Gene fusions were not detected in the remaining 5 tumors with abundant crystal/calcium deposition, and some may represent reactive conditions. All 20 tumors followed an indolent clinical course, and 4 patients with temporomandibular joint tumors were successfully followed up without surgery for 9 to 60 months. Using “CCMN” as an entity would entail mixed repercussions in diagnostic practice, and how and whether it should be used in diagnosis requires deliberate discussion. The concept may bring some benefits, but it may arguably cause more confusion because it would substantially restructure the conventional framework by drawing a boundary within the chondroma and conflating the chondroma with chondroid tenosynovial giant cell tumor.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100762"},"PeriodicalIF":7.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730674","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":"Multiregion Genomic Analysis of Human Pancreatic Mucinous Cystic Neoplasms","authors":"Michael J. Pflüger ,&nbsp;Kohei Fujikura ,&nbsp;Alicia M. Braxton ,&nbsp;Jae W. Lee ,&nbsp;Doreen M. Zucha ,&nbsp;Brian A. Pedro ,&nbsp;Davina Goodman ,&nbsp;Jiayun Lu ,&nbsp;Liping Jiang ,&nbsp;Xiaobing Wang ,&nbsp;Jiarun Zhu ,&nbsp;Marco Dal Molin ,&nbsp;Hao Wang ,&nbsp;Lodewijk A.A. Brosens ,&nbsp;Jin He ,&nbsp;Satomi Kawamoto ,&nbsp;Yuchen Jiao ,&nbsp;Laura D. Wood","doi":"10.1016/j.modpat.2025.100759","DOIUrl":"10.1016/j.modpat.2025.100759","url":null,"abstract":"<div><div>Mucinous cystic neoplasms (MCNs) are precursors to invasive pancreatic cancer. Conflicting clinical management recommendations call for better molecular characterization to improve our understanding of their tumorigenesis and risk assessment. We sampled epithelial tissue from a total of 18 surgically resected MCNs and performed dedicated multiregion analysis of somatic genetic alterations by targeted next-generation sequencing of 25 driver genes. In addition, we performed whole-exome sequencing and immunohistochemistry on selected samples to supplement our analyses. In total, 128 samples of epithelial MCN tissue were sequenced and analyzed, including samples from 13 small MCNs with low-grade (LG) dysplasia, 1 small MCN with high-grade (HG) dysplasia (HGD), and 4 large MCNs with HGD. Eight of 13 (61.5%) comprehensively sampled small LG MCNs lacked somatic driver gene mutations in all tissue blocks. These MCNs were lined by predominantly flat epithelium. In contrast, the majority of MCNs with driver gene mutations were predominantly lined by mucin-rich epithelium. No heterogeneity in <em>KRAS</em> mutations was seen across the sampled regions. Multiregion genetic analysis of 4 large MCNs with HGD provide insights into neoplastic progression, with shared somatic alterations suggesting that HGD arises from LG mucin-rich epithelium. These findings were supported by complementary whole-exome sequencing studies in 26 MCN epithelium samples. The neoplastic epithelium in the majority of small MCNs does not harbor somatic mutations in pancreatic driver genes. The genetic findings from multiregion analysis on MCNs contrast previous investigations in other mucin-producing pancreatic cysts, indicating distinct mechanisms in early tumorigenesis. This calls for a more nuanced risk assessment in MCNs, requiring improved preoperative assessment tools.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100759"},"PeriodicalIF":7.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692884","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":"Lower Degree of Microsatellite Instability in Colorectal Carcinomas From MSH6-Associated Lynch Syndrome Patients","authors":"Noah C. Helderman ,&nbsp;Fabian Strobel ,&nbsp;Lena Bohaumilitzky ,&nbsp;Diantha Terlouw ,&nbsp;Anne-Sophie van der Werf - ’t Lam ,&nbsp;Tom van Wezel ,&nbsp;Hans Morreau ,&nbsp;Magnus von Knebel Doeberitz ,&nbsp;Maartje Nielsen ,&nbsp;Matthias Kloor ,&nbsp;Aysel Ahadova","doi":"10.1016/j.modpat.2025.100757","DOIUrl":"10.1016/j.modpat.2025.100757","url":null,"abstract":"<div><div>Numerous observational and molecular studies focusing on Lynch syndrome (LS) have revealed significant variation in the phenotype and molecular characteristics among carriers of pathogenic variants in mismatch repair genes (<em>path_MMR</em>). Recently, we demonstrated that colorectal carcinomas in <em>path_MSH6</em> carriers exhibit fewer insertion/deletion mutations compared with cumulative colorectal cancers (CRCs) from other MMR groups, raising the question of whether <em>MSH6</em>-mutated CRCs might display a relatively lower degree of microsatellite instability (MSI). Mutations at 20 coding microsatellites (cMS) were analyzed in 39 <em>MSH6</em>-, 18 <em>MLH1</em>-, 16 <em>MSH2</em>-, and 22 <em>PMS2</em>-mutated CRCs and 35 sporadic MSI CRCs, and mutation frequencies and mutant allele ratios were compared among the different MMR-deficient groups. Considering factors such as <em>HLA-A</em>∗02:01 type, <em>B2M</em> status, and the anticipated immunogenicity of frameshift peptides derived from cMS mutations, the identified cMS mutation profiles of <em>MSH6</em>-mutated CRCs were further investigated to assess their potential impact on immunotherapeutic strategies. <em>MSH6</em>-mutated CRCs exhibited lower mutation frequencies and mutant allele ratios across most cMS. Variation in cMS mutation patterns was observed both between different tumor regions and between tumor tissue and adjacent adenomatous tissue. The cMS mutations in <em>MSH6</em>-mutated CRCs demonstrated inverse correlations with the predicted immunogenicity of the resulting frameshift peptides, which may suggest a negative selection of cell clones bearing highly immunogenic frameshift peptides. Overall, <em>MSH6</em>-mutated CRCs display a relatively lower degree of MSI and represent a biologically distinct subgroup of LS-associated CRCs. This lower MSI level may implicate an altered immune response compared with other MSI CRCs, which could have theoretical implications for the success of immunotherapy in <em>MSH6</em>-mutated CRCs. Future studies should carefully evaluate this possibility. If confirmed, these results would reinforce the notion of classifying LS as distinct syndromes associated with specific MMR genes.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 7","pages":"Article 100757"},"PeriodicalIF":7.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674392","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}