American Journal of Surgical Pathology最新文献

{"title":"Marginal Zone Lymphoma With T-Follicular Helper Hyperplasia: Paving the Way for New Concepts in Cellular Plasticity and Unveiling Histopathologic Pitfalls.","authors":"Marie Donzel, Alexis Trecourt, Juliette Fontaine, Edith Julia, Emmanuel Bachy, Hervé Ghesquières, Lucile Baseggio, Claire Mauduit, Alexandra Traverse-Glehen","doi":"10.1097/PAS.0000000000002567","DOIUrl":"10.1097/PAS.0000000000002567","url":null,"abstract":"<p><p>The expression of T-follicular helper (TFH) markers, initially described in nodal T-cell lymphomas arising from TFH-cells, has been reported in several non-TFH lymphomas, including B-cell lymphomas. It has also been observed in marginal zone lymphomas (MZL), whereas it is poorly characterized in nodal MZL (NMZL). The present study, therefore, aimed to characterize MZL with TFH cell expansions, by providing an extensive description of their histologic and molecular features. Thirty-two MZL with nodal involvement (25 primary nodal, 4 extranodal, and 3 primary splenic) showing TFH hyperplasia and 2 sequential cases [successive occurrences of angioimmunoblastic T-cell lymphoma (AITL) and MZL in the same patients] were retrospectively identified. Four histologic patterns were observed: AITL-like (44%), MZL-like (38%), biphasic (12%), and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)-like (6%). PD1 expression patterns differed significantly among subtypes ( P =0.037); found in the center of the B-cell nodules in MZL-like cases, expanded in interfollicular areas in AITL-like and biphasic cases, and displaying rosettes around B cells in THRLBCL-like cases. Targeted next-generation sequencing identified recurrent MZL-type associated variants ( KMT2D , KLF2 , and TNFAIP3 ) and the absence of TFH-lymphoma specific variants ( RHOA , IDH2 ). In 4 cases, clonal T-cell populations coexisted with B-cell populations, yet the integration of molecular and histologic data supported a MZL diagnosis. The present study highlights that TFH hyperplasia is challenging in the differential diagnosis of MZL and AITL, both morphologically and immunophenotypically. An integrated approach combining histology, immunohistochemistry, clonality studies, and molecular profiling is essential to establish the correct diagnosis, given that misinterpretation may lead to inappropriate treatment.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"986-997"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939578","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":"Endometrioid Intraepithelial Neoplasia in the Secretory Phase: Morphologic and Biomarker Diagnostic Features in a Common, Overlooked Setting.","authors":"Amanda M Means, Elena Lucas, Song Zhang, Glorimar Rivera-Colon, Shuang Niu, Ling Chen, Wenxin Zheng, Kelley S Carrick, Katja Gwin, Jessica Grubman, Hao Chen, Diego H Castrillon","doi":"10.1097/PAS.0000000000002548","DOIUrl":"10.1097/PAS.0000000000002548","url":null,"abstract":"<p><p>Endometrioid intraepithelial neoplasia (EIN) is a preinvasive precursor of endometrial carcinoma, yet its recognition in secretory-phase endometrium remains diagnostically challenging. Current criteria for EIN diagnosis do not account for female reproductive physiology, including the effects of endogenous progestins on the endometrium or EIN. Because women spend a substantial proportion of reproductive life in the secretory phase, failure to recognize EIN in this context represents an important gap in early detection. We systematically analyzed 40 cases of EIN arising in unequivocal physiological secretory endometrium, excluding patients with exogenous hormone exposure or other confounding factors. All cases exhibited architectural and cytologic distinctiveness relative to the background endometrium. Paradoxically, most lesions demonstrated diminished or absent secretory differentiation, challenging prevailing assumptions. Morules were identified in 38% of cases and represented a useful diagnostic clue. Additional features, including eosinophilic cytoplasm, epithelial stratification, mitotic activity, and apoptotic bodies, were variably present and functioned as supportive but nonessential findings. Immunohistochemistry demonstrated aberrancy for at least 1 of 3 established biomarkers (PAX2, PTEN, or β-catenin) in 95% of cases, underscoring the diagnostic value of this panel in the secretory phase, whereas Ki-67 proved unreliable. Collectively, these findings delineate morphologic and immunophenotypic features of EIN in secretory phase endometrium. Because most lesions have diminished secretory differentiation, the term \"secretory EIN\" is diagnostically problematic. We recommend adoption of the term \"EIN in the secretory phase\" and emphasize that improved recognition of this entity has direct implications for diagnostic accuracy and cancer prevention.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"834-848"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669816","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":"Expanding the Molecular Landscape of Deep Penetrating Nevus-like Melanomas Beyond CTNNB1 and APC Mutations : A Clinicopathologic and Molecular Study of 14 Cases.","authors":"Woo Cheal Cho, Priyadharsini Nagarajan, Jonathan L Curry, Phyu P Aung, Victor G Prieto, Carlos A Torres-Cabala","doi":"10.1097/PAS.0000000000002546","DOIUrl":"10.1097/PAS.0000000000002546","url":null,"abstract":"<p><p>Deep penetrating nevus (DPN)-like melanomas are believed to arise through sequential activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, followed by additional mutations. Due to their rarity and lack of standardized diagnostic criteria, their molecular landscape and clinical behavior remain still poorly understood. Here, we report the largest cohort to date of 14 DPN-like melanomas. These tumors predominantly affected middle-aged adults (median, 46 y), with the head and neck skin as the most common site. One rare case involved a mucosal site (epiglottis). DPN-like melanomas exhibited infiltrative growth, prominent vertical growth phase, severe nuclear atypia with occasional multinucleation, and increased mitotic activity (median, 3.5/mm 2 ). The median Breslow thickness was 3.3 mm (range: 1.2 to 9.2 mm), with all cases showing microscopic satellitosis, sentinel lymph node positivity, or synchronous metastasis. Most cases (93%) harbored MAPK pathway-activating mutations, predominantly in BRAF (77%), followed by NRAS and EGFR (an upstream regulator of the MAPK pathway). In addition, 79% of cases had mutations activating the canonical Wnt/β-catenin signaling pathway, mainly in CTNNB1 and APC . Two CTNNB1 / APC wild-type cases exhibited alternative mutations in genes indirectly modulating this pathway, such as ARID1A , EZH2 , FAT1 , and SETD2 , along with other mutations, including TERT promoter mutations (TPMs). TPMs were present in 56%, and the median tumor mutational burden was 30 mutations/Mb. After a median follow-up of 33.5 months, 36% of patients developed distant metastases, and 2 patients died of disease 8 and 32 months, respectively, after initial diagnosis. These findings expand the molecular diversity of DPN-like melanomas and provide valuable insights into their clinical outcomes.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"779-790"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607783","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":"Urinary Bladder Leiomyomas: A Clinicopathological Series With Hormone Receptor, HMGA2, 2SC, and Fumarate Hydratase Status Assessment.","authors":"Raul E Perret, Melissa Hruby, Carina A Dehner, Stephanie E Siegmund, Valérie Velasco, Mokrane Yacoub, Gregoire Robert, Jennifer B Gordetsky, Adeboye O Osunkoya, Muhammad T Idrees, Andres M Acosta","doi":"10.1097/PAS.0000000000002538","DOIUrl":"10.1097/PAS.0000000000002538","url":null,"abstract":"<p><p>Leiomyomas (LMs) represent the most frequent mesenchymal tumors of the urinary bladder. Despite their relative frequency, large clinicopathological studies are scarce, and their pathogenesis remains poorly understood. In this study, we performed a clinicopathological analysis of 35 bladder LMs and explored whether they share pathogenic mechanisms previously documented in uterine LMs. The tumors occurred in 18 women and 17 men, with a median age of 55 years (range: 20 to 78 y). Clinical data were available for 30 cases (85%). Most tumors were incidentally discovered (16/30, 53%), while the remaining patients presented predominantly with lower urinary tract symptoms. Ten patients had a prior history of cancer, and 3 women had a history of uterine LM. Tumor size, available in 12 cases, ranged from 6 to 66 mm (mean, 31 mm). Histologically, most tumors showed a uniform morphology, consisting of well-circumscribed nodules composed of bland smooth muscle cells without mitotic activity. Rare findings included extensive necrosis (3/35, 8%) and a pseudohyperplastic appearance (1/20, 5%). On immunohistochemistry, a subset of tumors, predominantly in females, expressed estrogen receptors (7/28, 25%), progesterone receptors (5/24, 21%), and androgen receptors (10/23, 43%). HMGA2 expression was observed in one case (1/27, 4%). Fumarate hydratase (FH) expression was retained in all tested tumors (n=31); 2SC expression was detected in 4 tumors (4/32; 12%), all with preserved FH and lacking distinctive histomorphological features of FH-deficient LMs. DNA sequencing of 2SC-positive tumors identified a pathogenic FH variant in one of the 4 analyzed cases at a low variant allele frequency. No other known pathogenic variants, including MED12 commonly seen in uterine LMs, were detected. Altogether, this study characterizes the clinicopathological features of large cohort of bladder LMs, highlighting unrecognized morphologic features, including cases with massive necrosis. Our findings suggest that bladder LMs differ pathogenetically from their uterine counterparts, with a more limited role for hormone receptor signaling and distinct genetic alterations.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"705-715"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430253","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":"Clear Cell Papillary Renal Cell Tumor Revisited: Comparison of Histologic and Immunohistochemical Profiles in Relation to VHL Allelic Status.","authors":"Kanako Sagan, Fumiyoshi Kojima, Ibu Matsuzaki, Keisuke Hanada, Fidele Y Musangile, Takahiro Nakamoto, Hiroyuki Hayashi, Chisato Ohe, Riuko Ohashi, Yoji Nagashima, Yasuo Kohjimoto, Shin-Ichi Murata","doi":"10.1097/PAS.0000000000002535","DOIUrl":"10.1097/PAS.0000000000002535","url":null,"abstract":"<p><p>Clear cell papillary renal cell tumor (CCPRCT), formerly known as clear cell papillary renal cell carcinoma, is a low-grade renal neoplasm characterized by cytokeratin 7 and cup-like carbonic anhydrase 9 immunopositivity and absence of von Hippel-Lindau ( VHL ) abnormalities. Given the prognostic differences, distinguishing CCPRCT from clear cell renal cell carcinoma (CCRCC) is clinically important. However, some tumors diagnosed morphologically and immunohistochemically as CCPRCT have been found to harbor VHL abnormalities, which complicates clinical management. This study aimed to clarify how clinical, histologic, and immunohistochemical characteristics varied based on VHL status. Among 17 CCPRCTs analyzed, VHL abnormalities were identified in 10 (58.8%) cases, including VHL mutations in 6 cases and 3p loss of heterozygosity in 7 cases. Tumors were stratified into 3 groups based on VHL allele status: 3 cases with biallelic VHL inactivation (CCPRCT-bi VHL ), 7 with monoallelic VHL inactivation (CCPRCT-mono VHL ), and 7 with wild-type VHL (CCPRCT-wt VHL ). We integrated the molecular with morphologic and immunohistochemical findings, and reclassified 17 cases into 5 CCRCCs mimicking CCPRCT, 5 CCPRCTs-mono VHL , and 7 CCPRCTs-wt VHL cases. All tumors exhibited favorable clinical courses, with no instances of metastasis or recurrence. No significant differences in clinical, pathologic, or immunohistochemical features were observed among the 3 groups or between CCRCCs mimicking CCPRCT and CCPRCTs. This study demonstrated that strict morphologic and immunohistochemical criteria can distinguish most CCRCCs mimicking CCPRCT from CCPRCT. The diagnosis of CCPRCT should be expanded to include tumors with monoallelic VHL alteration exhibiting typical morphologic and immunohistochemical features.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"758-769"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376031","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":"Histopathologic Features of Chimeric Antigen Receptor (CAR) T-cell Therapy-associated Gastrointestinal Mucosal Injury: A Case Series and Review of Literature.","authors":"Ihsan Baroudi, Ibrahim Abukhiran, Reetesh Pai, Akila Mansour","doi":"10.1097/PAS.0000000000002544","DOIUrl":"10.1097/PAS.0000000000002544","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment for refractory hematologic malignancies; however, gastrointestinal adverse events (GI-AEs) are increasingly recognized as its use expands. We identified 6 patients with GI-AEs following CAR-T therapy over a 5-year period at our institution and conducted a comprehensive PubMed literature review to characterize histopathologic patterns and highlight differential diagnostic considerations. In the institutional cohort, the colon was most frequently involved (83%), followed by the small bowel (67%) and stomach (33%). Most patients developed watery diarrhea (83%) with negative infectious studies. Symptom onset occurred at a median of 107 days after infusion (range, 19 to 236 d). Twenty-one gastrointestinal biopsies were evaluated; 15 (71%) showed histologic abnormalities. Four histologic patterns were identified: active inflammation (33%), chronic active inflammation (27%), apoptosis-predominant injury (27%), and chronic inflammation (13%). Crypt epithelial apoptosis or intraepithelial apoptotic bodies were present in 67% of biopsies. Site-specific patterns included active colitis in the colon, chronic or chronic active duodenitis in the duodenum, apoptosis-predominant ileal injury, and active gastritis in the stomach. The literature review identified 22 additional patients, with histopathologic data available in 21 cases. Findings overlapped substantially with the institutional cohort and most commonly involved the colon and small intestine, with heterogeneous clinical outcomes. Overall, CAR-T-associated GI-AEs demonstrate reproducible yet nonspecific clinicopathologic features that overlap with immune-mediated, drug-related, infectious, and inflammatory conditions, necessitating careful clinicopathologic correlation and exclusion of alternative etiologies.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"739-757"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669766","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":"FOS and FOSB Immunohistochemistry and Molecular Testing Reveal Novel Patterns in Proliferative Fasciitis and Myositis, FOSB Rearrangement in Proliferative Funiculitis, and FOSL1 :: RELA Fusion in Pediatric Proliferative Fasciitis.","authors":"Sanhong Yu, Fleur Cordier, Esther Baranov, Igor Odintsov, Linda Magnusson, Joni Van der Meulen, Siebe Loontiens, Liesbeth Ferdinande, Jo Van Dorpe, Felix Haglund de Flon, Fredrik Mertens, Christopher D M Fletcher, David Creytens, David J Papke","doi":"10.1097/PAS.0000000000002540","DOIUrl":"10.1097/PAS.0000000000002540","url":null,"abstract":"<p><p>Proliferative fasciitis (PFA) and proliferative myositis (PM) are related benign neoplasms that show large ganglion-like neoplastic cells and harbor recurrent FOS fusions. Proliferative funiculitis (PFU) is a benign mesenchymal lesion of the spermatic cord, with small ganglion-like cells and unknown etiology. Ischemic fasciitis (IFA) is a possibly reactive lesion that shows cytomorphologic overlap with PFA/PM. Here, we assessed FOS and FOSB immunohistochemistry (IHC) in PFA (adult and pediatric), PM, PFU, and IFA. Diffuse nuclear FOS expression was detected in adult PFA (15/26 cases; 58%) and PM (6/10; 60%), while FOSB was consistently negative (19 adult PFA, 5 PM). FOS FISH demonstrated rearrangement in only 4 of 12 tested adult PFA/PM, all of which were FOS-positive by IHC. A FOS fusion ( FOS::TSHZ2 ) was detected in only 1 of 9 adult PFA/PM (11%) tested by RNA sequencing (RNAseq); 5 tumors without detected FOS fusions by RNAseq were FOS-positive by IHC. The pediatric PFA lacked expression of FOS (all 9 tumors) and FOSB (4 tested tumors) by IHC. Compared with FOS-positive PFA/PM, pediatric PFA and adult FOS-negative PFA/PM were more frequently cellular, and pediatric tumors were less infiltrative. DNA sequencing demonstrated FOSL1 :: RELA fusions in 2 of 5 tested pediatric PFAs, both in infants. Six of 18 PFU (33%) expressed FOS and/or FOSB by IHC. FISH demonstrated FOSB rearrangement in 1 of 6 PFU, while all 6 tested PFU were negative for FOS rearrangement. Nine of 20 IFA (45%) expressed FOS and/or FOSB; 2 tested tumors were negative for FOS or FOSB fusions by RNAseq. We conclude that about 60% of adult PFA/PM strongly express FOS, and 5 of these tumors were proven to harbor FOS rearrangements, including a novel FOS :: TSHZ2 fusion. Some PFU and pediatric PFA harbored alterations in related genes FOSB and FOSL1 , respectively. RNAseq and FISH might have imperfect sensitivity for FOS alterations in PFA/PM, likely due to the low relative neoplastic cell content in these tumor types.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"726-738"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508801","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":"Whole-Exome Sequencing Identifies Frequent AHNAK2 Mutations With Prognostic Significance in Undifferentiated Primary Liver Carcinoma.","authors":"Ziqi Zhu, Qing Tao, Liangyin Chen, Hanwen Zhu, Nanjing Li, Zhenru Wu, Changli Lu, Yujun Shi","doi":"10.1097/PAS.0000000000002554","DOIUrl":"10.1097/PAS.0000000000002554","url":null,"abstract":"<p><p>Undifferentiated primary liver carcinoma (UPLC) is an exceedingly rare hepatic malignancy lacking hepatocytic or cholangiocytic differentiation, and its clinicopathologic and molecular characteristics remain poorly defined. We retrospectively analyzed 25 UPLC cases from a single Chinese institution over an 8-year period and performed whole-exome sequencing (WES) to delineate the genomic landscape, combined with multiplex immunofluorescence (mIF), routine histopathology, and immunohistochemistry (IHC) for phenotypic assessment. UPLC exhibits marked histologic and immunophenotypic heterogeneity, with all cases negative for classic hepatobiliary differentiation markers; albumin RNA in situ hybridization (Alb-ISH) demonstrates limited diagnostic utility due to low positivity. Compared with conventional hepatocellular carcinoma (HCC) from the Cancer Genome Atlas (TCGA), UPLC demonstrates a distinct mutational profile, with frequent alterations in 5 key oncogenic pathways (Hippo, NOTCH, WNT, RTK-RAS, and TP53) in 96.0% of cases and a higher mutation frequency of core pathway genes than HCC. TERT promoter hotspot mutations were identified in a subset but showed no association with clinicopathologic features or survival. AHNAK2 was the most frequently mutated gene (68.0%) and is rarely altered in HCC or intrahepatic cholangiocarcinoma (ICC). Patients with AHNAK2 -mutated UPLC had significantly shorter overall survival, elevated tumor mutational burden (TMB), and markedly reduced infiltration of CD4⁺, CD8⁺, CD20⁺, and CD68⁺ immune cells. These findings support the recognition of UPLC as a clinically aggressive and molecularly distinct entity and indicate that the AHNAK2 mutation may serve as a potential prognostic biomarker in this rare malignancy.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"849-863"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759925","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":"GLI1 -Rearranged Tumors of the Gynecologic Tract : A Detailed Clinicopathologic Study of 10 Cases.","authors":"Roman E Zyla, Brooke E Howitt, Tjalling Bosse, Freek E van Slooten, Amit Oza, Deqin Ma, David L Kolin, Sabrina Croce, Ludovic Merck, Holly Buist, Rupali Arora, Anthony Karnezis, Hala Alnuaim, Anjelica Hodgson, W Glenn McCluggage, Blaise A Clarke","doi":"10.1097/PAS.0000000000002545","DOIUrl":"10.1097/PAS.0000000000002545","url":null,"abstract":"<p><p>GLI1 -rearranged tumors of the gynaecologic tract are rare, but likely under-recognised, neoplasms, which have recently been reported in the ovary and uterus. It is important to identify these neoplasms due to their malignant potential and possible responsiveness to tyrosine kinase inhibition in the metastatic setting. We present the largest series to date of GLI1 -rearranged tumours of the gynaecologic tract with comprehensive clinicopathologic analysis. Ten cases (7 primary ovarian tumors and 3 primary uterine corpus tumours) with GLI1 rearrangements were identified in the case files of the contributing authors, and clinical findings, histomorphology, and immunophenotype were reviewed. Patients ranged in age from 26 to 60 years of age. Three of the 10 tumours in our series recurred, including one late recurrence 180 months postoperatively. The 10 cases, in keeping with previous reports in the literature, showed 2 main morphologic patterns: (i) variable admixture of trabecular, nested and tubular/microfollicular growth, akin to sex cord-stromal morphology; and (ii) cytologically bland, elongated spindle cells with abundant admixed blood vessels and variably myxoid matrix, morphologically suggestive of a low-grade mesenchymal neoplasm such as low-grade endometrial stromal sarcoma. In both scenarios, the immunophenotype was not supportive of the morphologic impression (with the sex cord-like tumours typically showing negative staining for calretinin, inhibin, and WT-1, whereas the tumours resembling low-grade endometrial stromal sarcomas were consistently hormone receptor-negative), and the diagnosis was ultimately made after next-generation sequencing. GLI1 fusion partners included PTCH1 (4 cases), ACTB (4 cases), CHD4 (1 case), and TXNIP (1 case). Morpho-molecular correlation suggested that tumours with PTCH1::GLI1 fusions were enriched in sex cord-like morphology, whereas tumours with ACTB::GLI1 fusions were enriched in low-grade endometrial stromal sarcoma-like morphology. Given that our cases were identified in a relatively short time period, it is likely that GLI1 -rearranged tumours are more common in the female genital tract than is realised and a high index of suspicion is required to initiate appropriate testing and establish the diagnosis. In the absence of readily available appropriate molecular testing, GLI1 immunohistochemistry can serve as an acceptably accurate surrogate biomarker for GLI1 rearrangement, since we found that GLI1 immunohistochemistry showed strong, diffuse nuclear staining in 6 GLI1 -rearranged gynaecologic tumours stained for this study, whereas this was consistently negative, or at most weak/focal, in an array of 135 morphologic mimics.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"804-813"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147607743","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":"MUC4-Positive Fibroblastoma: Clinicopathological and Molecular Analysis of 7 Cases.","authors":"Akihiko Yoshida, Naohiro Makise, Ken-Ichi Yoshida, Azusa Sakai, Fumihiko Nakatani, Hironari Tamiya, Tsukasa Yonemoto, Akira Kawai, Kaishi Satomi, Koichi Ichimura, Takashi Kubo, Hitoshi Ichikawa","doi":"10.1097/PAS.0000000000002549","DOIUrl":"10.1097/PAS.0000000000002549","url":null,"abstract":"<p><p>In soft tissue pathology, MUC4 is considered a sensitive and specific immunohistochemical marker for low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), which are characterized by FUS/EWSR1 :: CREB3L2/1 fusions. Recently, MUC4-positive fibroblastoma has been proposed as a novel entity, and we herein describe 7 cases that align with this disease concept. These tumors occurred in 7 female patients aged 14 to 60 years, and they were located in the neck (2 cases), temple, arm, chest wall, pharynx, and thigh, with 5 being deep-seated. All tumors were surgically removed. No patients experienced recurrence during follow-up periods of 2 to 113 months. The well-circumscribed tumors comprised hypocellular fibrous tissue, populated by nonatypical spindle cells. Myxoid stroma was absent. Common features included thin-walled patent vessels, extremely long vessels, and mast cells. In some cases, fat entrapment/overgrowth was conspicuous. All tumors tested positive for MUC4 and nuclear β-catenin expression. The tumors were molecularly investigated with fluorescence in situ hybridization, RNA sequencing, DNA panel sequencing, DNA methylation analysis, and/or nanopore sequencing. Genetic analysis showed the absence of FUS/EWSR1 fusions in all 7 cases. All 5 tested tumors harbored APC alterations, with 3 having inactivating mutations and 2 showing copy number loss. DNA methylation profiles of 2 tumors did not match those of any references, including LGFMS or SEF, as indicated by t-SNE. Overall, our study supports the recent proposal of MUC4-positive fibroblastoma as a distinct entity and further delineates its phenotypic and molecular characteristics. These tumors should be distinguished from LGFMS, SEF, desmoid fibromatosis, and other fibrous or fibroadipose tumors.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"825-833"},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939563","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}