American Journal of Surgical Pathology最新文献

{"title":"Consensus in Oral Epithelial Dysplasia Classification: A Comparative Analysis of H&E-stained Sections With and Without p53/p16 Immunohistochemistry.","authors":"Ivan J Stojanov, Kelly Yi Ping Liu, Christina McCord, Julia Yu-Fong Chang, Yi-Ping Wang, Chia-Cheng Li, Lingxin Zhang, Victoria L Woo, Elizabeth M Philipone, Paras B Patel, Kelly R Magliocca, Iona Leong, Hemlata Shirsat, Vincent Cracolici, Christopher C Griffith, William H Westra, Emilija Todorovic, Elizabeth A Bilodeau, William C Faquin, Lynn N Hoang, Ilena S Yim, Natyra Haxhiavdija, Martial Guillaud, Brandon M Veremis, Yen Chen Kevin Ko","doi":"10.1097/PAS.0000000000002385","DOIUrl":"10.1097/PAS.0000000000002385","url":null,"abstract":"<p><p>Diagnosis and classification of oral epithelial dysplasia (OED) is critical to identifying and prognosticating patients at risk of squamous cell carcinoma (SCC). However, conventional 3-tiered and 2-tiered grading systems suffer from poor inter-pathologist agreement, and SCC may arise from all grades of OED. This study evaluated pathologist agreement in OED classification as p53 wildtype, p53 abnormal, and HPV-associated based on recent evidence demonstrating the utility of p53/p16 immunohistochemistry (IHC) in this setting and increased risk of p53 abnormal OED progression to SCC, regardless of histologic grade. Fifty digital biopsy specimens were evaluated for diagnosis by 18 subspecialty-trained pathologists, with OED graded utilizing 3-tiered, 2-tiered, and p53 wildtype/p53 abnormal/HPV-associated schemata. Cases were reviewed first without and subsequently with p53/p16 IHC. The cohort consisted of 8 cases of p53 wildtype, 24 cases of p53 abnormal, and 18 cases of HPV-associated OED. Inter-pathologist agreement in OED grading according to 3-tiered (κ=0.32) and 2-tiered (κ=0.39) systems by H&E was poor, but fair-to-good (κ=0.59) in classification as p53 wildtype/p53 abnormal/HPV-associated by H&E and IHC. Classification of OED as p53 wildtype, p53 abnormal, or HPV-associated using p53/p16 IHC outperformed conventional grading in this cohort enriched for p53 abnormal OED, which required correct interpretation of p53 IHC, historically deemed challenging. Routine use of IHC also identifies a wider histologic spectrum of HPV-associated OED than is currently appreciated. More work is needed to determine the efficacy of this classification system in predicting patient outcomes and in guiding management decisions in real-world cohorts.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"601-609"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810340","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":"Enterovirus Placentitis is an Underrecognized Cause of Placental Pathology.","authors":"Andrew P Norgan, Elizabeth Ann L Enninga, Bohdana Fedyshyn, Matthew Wolf, Jeffery A Goldstein, Elisheva D Shanes","doi":"10.1097/PAS.0000000000002378","DOIUrl":"10.1097/PAS.0000000000002378","url":null,"abstract":"<p><p>The placenta is susceptible to infection by a number of viral pathogens, including severe acute respiratory syndrome coronavirus 2, which is associated with poor fetal outcomes. The histologic pattern of injury, termed severe acute respiratory syndrome coronavirus 2 placentitis, is characterized by a triad of increased perivillous fibrin deposition, intervillous histiocytes, and trophoblast necrosis. While the etiology of massive perivillous fibrin deposition (MPVFD) is mostly unknown, previous case reports of MPVFD in association with maternal Enterovirus (ENT) suggest that a subset of these cases are a consequence of undiagnosed viral infection. We evaluated 46 placentas collected between 2011 and 2022 with a diagnosis of MPVFD (n = 41) or chronic histiocytic intervillositis (CHI; n = 4). Combining methods of pan-viral metagenomic sequencing and targeted viral PCR, we detected Enterovirus DNA in 8 of 45 (18%) MPVFD and/or CHI cases. Seven of these positive cases were from MPVFD, and 1 was associated with a CHI diagnosis. Enterovirus A species (n = 7) were commonly identified, whereas one case had Enterovirus B. Histologic evaluation of these cases, including immunohistochemical staining for CD68, demonstrated increased intervillous histiocytes in Enterovirus -positive MPVFD cases in comparison with Enterovirus- negative, as well as evidence of trophoblast necrosis. Thus, we favor the terminology Enterovirus placentitis to describe this pathology. Overall, these findings suggest that Enterovirus is an underrecognized etiology of histologic MPVFD and, possibly, CHI. Further study to evaluate the recurrence risk of Enterovirus placentitis in comparison to MPVFD may help inform future fertility planning in patients with these diagnoses.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"594-600"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646793","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":"Revisit of Histopathology in Rheumatoid Lung Nodules.","authors":"Wipawi Klaisuban, Chuying Su, Matthew Koslow, Jay H Ryu, Henry D Tazelaar, Sarah M Jenkins, Eunhee S Yi","doi":"10.1097/PAS.0000000000002374","DOIUrl":"10.1097/PAS.0000000000002374","url":null,"abstract":"<p><p>Diagnosing pulmonary rheumatoid nodules (RN) is challenging because they are rare and share clinical, radiologic, and histopathologic features with other necrotizing granulomatous diseases such as infectious granulomas (IG) and granulomatosis with polyangiitis (GPA). Herein, we revisit the histopathologic features of RN and the findings in the adjacent lung tissue, in comparison with IG and GPA, to identify distinguishing features. Twenty-eight cases with surgically resected RN evaluated at our institution (1991 to 2024), 33 IG (10 mycobacterial infection, 10 histoplasmosis, 13 coccidiomycosis), and 10 GPA cases were included in the study. All available slides with H&E and special stains were reviewed for various histologic parameters within the nodules and in surrounding lung tissue. Many histopathologic features of RN overlap with the necrotizing granulomas seen in infections and GPA. However, some findings in the adjacent lung tissue showed significant differences. The lack of airspace granulomas/non-necrotizing granuloma and the absence of necrotizing vasculitis in the setting of RN can help to differentiate between infection cases and GPA, respectively. Given their considerable overlap, correlation with clinical context, serologic and microbiologic studies, as well as careful evaluation of special stains is crucial in the diagnosis of RN.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"588-593"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673164","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 Dublin International Society of Urological Pathology (ISUP) Consensus Conference on Urachal Neoplasms and Urinary Bladder Glandular Lesions: It's About Time!","authors":"Gladell P Paner, Glen Kristiansen, Henning Reis","doi":"10.1097/PAS.0000000000002404","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002404","url":null,"abstract":"","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075475","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":"Prognostic and Predictive Value of SARIFA-status Within Molecular Subgroups of Colorectal Cancer: Insights From the Netherlands Cohort Study.","authors":"Nic G Reitsam, Kelly Offermans, Colinda C J M Simons, Bianca Grosser, Jessica Zimmermann, Heike I Grabsch, Bruno Märkl, Piet A van den Brandt","doi":"10.1097/PAS.0000000000002408","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002408","url":null,"abstract":"<p><p>We recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF, and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF, RAS, and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs (P<0.001). BRAF-mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HRrange: 1.47 to 1.78) and overall survival (HRrange: 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HRCRC-specific: 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF-mutant and BRAF-mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF, RAS, and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958969","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":"Uncloaking the Fimbria Ovarica: Histologic Recognition of an Elusive Anatomic Structure.","authors":"Jeffrey D Seidman, Rebecca Stone, Vasiliki A Moragianni, Jayashree Krishnan, Russell Vang","doi":"10.1097/PAS.0000000000002414","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002414","url":null,"abstract":"<p><p>A portion of the fimbriated end of the fallopian tube known as the fimbria ovarica extends along the lateral edge of the mesosalpinx to the ovary to which it is attached at its lateral pole. Seventy-four examples of fimbrial plicae that were attached to the ovary or broad ligament and lacked features of adhesions were studied. The fimbrio-ovarian attachments were characterized by one or more of the following: continuity between the tubal epithelium and either the ovarian surface epithelium, peritoneum, or both, in 51 cases; direct continuity of the ovarian stroma into the stroma of the fimbria ovarica in 42 cases; and direct insertion of plicae into the ovarian surface or ovarian stroma in 18 cases. In 21 cases, there was a direct attachment of plicae to the broad ligament close to the ovary. The mean size of the fimbria ovarica was 6.6 mm. The plicae were lined by normal tubal-type epithelium. The plical morphology was typically abnormal displaying one or more of the following features: short and blunted in 24 (32%), thickened in 18 (24%), elongated in 14 (19%), fusion in 13 (18%), edema in 13 (18%), and fibrosis in 11 (15%). Also noted were a mesothelial component in 69 cases (93%), the tubal-peritoneal junction in 53 cases (72%), transitional cell metaplasia/Walthard cell nests in 11 cases (15%), and foci resembling incipient fimbrial adenofibroma in 7 cases (9%). An understanding of the microanatomy and histology of the fimbria ovarica has important implications, particularly as: (a) portions may be left behind after prophylactic salpingectomy, providing a nidus for future development of high grade serous carcinoma (HGSC); (b) it constitutes an anatomic connection that may facilitate the spread of HGSC to the ovary, and (c) epithelial junctions are hotspots for carcinogenesis, and stem cells arising in such regions may be a source of HGSCs. In addition, understanding the fimbria ovarica has implications for the pathogenesis of ovarian surface epithelial inclusions, endosalpingiosis, and certain types of infertility. Its potential role as a site of origin of extrauterine HGSC, which typically arises in the fimbriae as serous tubal intraepithelial carcinoma, remains to be investigated.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956270","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":"Adult Granulosa Cell Tumors of the Ovary With Tubular Differentiation: A Report of 80 Examples of an Underemphasized Feature With Clinicopathologic and Genomic Differences From Other Sex Cord-Stromal Tumors.","authors":"Lauren J Ray, Robert H Young, Mark F Sabbagh, Adam S Fisch, Esther Oliva, Kyle M Devins","doi":"10.1097/PAS.0000000000002407","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002407","url":null,"abstract":"<p><p>Occasional ovarian sex cord-stromal tumors exhibit features suggestive of more than 1 subtype, including some with areas of both \"female\" (granulosa) and \"male\" (Sertoli and/or Leydig) cell types. These tumors, historically often referred to as \"gynandroblastomas,\" are frequently difficult to classify due to considerable clinical and morphologic heterogeneity. Herein, we describe a particular pattern of differentiation in which tubules occurred within tumors whose overall clinicopathologic features indicate that they are best characterized as adult granulosa cell tumors (AGCT). Eighty tumors were identified. Patient ages ranged from 15 to 87 (median: 52) years, and 28 had endocrine manifestations (25 estrogenic; 3 androgenic). Follow-up was available in 13 patients and ranged from 10 to 266 (median: 60) months, disclosing recurrence in 2. Microscopically, all tumors not only contained areas of typical granulosa cell morphology (diffuse, trabecular, corded, and others), which often dominated, but also contained variable amounts of hollow and/or solid tubules resembling those seen in Sertoli cell tumors. Next-generation sequencing was successful in 11 tumors. Two of these harbored FOXL2 p.C134W variants, and 2 others had FOXL2 copy number gains; none had DICER1 mutations. On the basis of the average age of the patients, frequency of estrogenic manifestations, abundance of standard AGCT morphology, and occasional late recurrences, we suggest that these tumors form a distinct group and propose the term \"AGCTs with tubular differentiation\" to denote them.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956563","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":"\"Early\" Clear Cell Proliferations (Clear Cell Carcinoma in Situ) in Ovarian Endometriotic Cysts: Report of a Case Series With Recommendations for Terminology.","authors":"Nesa S Karunadhas, Mark Catherwood, Helen Stringfellow, Rupali Arora, W Glenn McCluggage","doi":"10.1097/PAS.0000000000002415","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002415","url":null,"abstract":"<p><p>Clear cell carcinoma (CCC) is an uncommon malignancy accounting for ∼12% of ovarian carcinomas. Most cases arise from endometriosis, frequently an endometriotic cyst. We report a series of 6 cases where clear cell proliferations, morphologically, and immunophenotypically consistent with CCC, involve the epithelial lining of an endometriotic cyst without invasion into the surrounding stroma. The patients were aged 29 to 63 years (mean 45). In all cases, epithelial proliferations composed of cells with atypical nuclei, sometimes with a hobnail morphology, and clear or eosinophilic cytoplasm involved the epithelial lining of an ovarian endometriotic cyst. In areas, the proliferations comprised a monolayer, but in all cases, there was also significant epithelial stratification and multilayering, sometimes with a pseudopapillary architecture. There was no invasion of the atypical cells into the surrounding ovarian stroma. The proliferations were positive for Napsin A (6 of 6; 4 diffuse, 2 focal), racemase (5 of 5; 3 diffuse, 2 focal), hepatocyte nuclear factor 1-beta (5 of 5; all diffuse), oestrogen receptor (5 of 6; 2 diffuse, 3 focal), and PAX8 (3 of 3; all diffuse). p53 was wild-type in all 6 cases and WT1 and progesterone receptor were negative in the 4 and 6 cases tested, respectively. Mismatch repair immunohistochemistry was retained in the 3 cases tested. Next-generation sequencing was performed in 2 cases. In 1 case, a sole pathogenic MSH6 variant (p.Ser65fs) was identified. Follow-up (2 to 24 months) was available in 5 cases and there was no tumour recurrence. In reporting these \"early\" clear cell proliferations in endometriotic cysts, we provide recommendations for the reporting pathologist regarding the most appropriate terminology, which is important in patient management. We suggest that these proliferations be termed \"CCC in situ\" and that identification of such a lesion should prompt extensive sampling in order to exclude an invasive CCC component within the stroma outside the endometriotic cyst lining. We also stress the importance of close dialogue between the pathologist and the clinician and between the clinician and the patient in order to avoid overtreatment in such cases.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960281","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":"Confocal Laser Microscopy for Intraoperative Margin Assessment in Breast-Conserving Surgery: A New Procedure in the Pathology Laboratory Workflow.","authors":"Julien Colard-Thomas, Antonia Pialoux-Guibal, Pierre Gemival, Aurélie Maran-Gonzalez, Lakhdar Khellaf, Cristina Leaha, Evelyne Verdanet, Anne Mourregot, Marian Gutowski, Didier Pourquier","doi":"10.1097/PAS.0000000000002409","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002409","url":null,"abstract":"<p><p>One of the breast-conserving surgery goals is to achieve negative resection margins and avoid reoperation. Therefore, accurate intraoperative margin assessment is essential, but still challenging. Recently, confocal microscopy devices, such as Histolog Scanner (HS), have shown promise for intraoperative margin assessment. The aim of this study was to assess HS for the intraoperative examination of lumpectomy specimens by the pathologists of our institute. Intraoperative margin assessment was performed by macroscopic assessment and by HS imaging to provide information for re-excision decision-making. The specific contribution of HS was evaluated by comparing the HS-based findings with the final pathology reports based on formalin-fixed paraffin-embedded tissue analysis. The study population included 20 women with histologically confirmed invasive breast carcinoma who underwent breast-conserving surgery (mean age of 62.9 y; 41 to 88 y; 21 tumors in total). HS led to the same decision as macroscopic examination in 76.2% of cases and prompted additional re-excisions in 19% of cases. Compared with the pathology reports, the accuracy rates of the macroscopic and HS assessments were 81% (58.1 to 94.6) and 95.2% (76.2 to 99.9), respectively. Moreover, 5 cases are described to illustrate HS practical contribution and limitations. In conclusion, HS is user-friendly, generally reliable, and enhances the routine macroscopic examination by providing detailed imaging of lumpectomy specimens. In combination with macroscopic examination, HS is an effective tool for intraoperative margin assessment, assisting both pathologists and surgeons in making accurate intraoperative decisions regarding margin re-excision, thereby preventing the need for new surgical operations.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966107","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":"Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases: Morphologic and Molecular Overlap With TSC/MTOR-mutated Eosinophilic Renal Neoplasms and MiT Family Translocation Renal Cell Carcinoma.","authors":"Pedram Argani, Ezra Baraban, Oksana Yaskiv, Huili Li, Swati Bhardwaj, Katya Dombrowski, Tamara L Lotan, Ying S Zou, Sunil H Patel, Betina Katz, Qi Cai, Rohit Mehra, Norman Barker, Jonathan Dudley, Doreen N Palsgrove","doi":"10.1097/PAS.0000000000002413","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002413","url":null,"abstract":"<p><p>Germline mutations in the folliculin (FLCN) gene define Birt-Hogg-Dubé syndrome, which is associated with a variety of renal neoplasms; however, the role of FLCN mutations in sporadic renal neoplasms has not been well-defined. We identified 8 oncocytic/cystic renal neoplasms that presented as sporadic tumors and harbored FLCN mutations and no other genetic alterations characteristic of another established subtype. On further workup, 5 seem to harbor true somatic FLCN mutations, whereas the other 3 represent neoplasms associated with occult Birt-Hogg-Dubé syndrome. Patients were all females ranging in age from 25 to 77 years, and all neoplasms were confined to the kidney. The neoplasms overlapped morphologically with TSC/MTOR-mutated eosinophilic renal neoplasms and TFE3/TFEB-rearranged renal cell carcinoma. All neoplasms extensively expressed GPNMB, a downstream marker of TFE3/TFEB pathway activation, which is logical given the known molecular interplay of folliculin with TSC/MTOR/TFE3/TFEB. All 3 occult syndromic cases demonstrated multiple chromosome losses and gains not seen in the 5 sporadic neoplasms. In conclusion, diffuse GPNMB expression in the absence of TSC/MTOR/TFE3/TFEB alterations, particularly when the morphology suggests the presence of the latter, is a clue to FLCN-mutated renal epithelial neoplasms, which in a subset of cases may be a clue to occult Birt-Hogg-Dubé syndrome.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964173","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}