{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T22:04:25Z","timestamp":1789596265907,"version":"build-2803163510"},"reference-count":15,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Aims<\/jats:title><jats:sec><jats:label\/><jats:p>Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord\u2010stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We analysed 21 samples from 20 patients with LCCSCT (12 non\u2010metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next\u2010generation sequencing. All\u00a0tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of <jats:italic>PRKAR1A<\/jats:italic>. Evidence of loss of heterozygosity (LOH) of <jats:italic>PRKAR1A<\/jats:italic> was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non\u2010metastasising and metastasising tumours. Non\u2010metastasising tumours demonstrated only copy\u2010neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy\u2010loss LOH, two concurrent mutations or copy\u2010neutral LOH. Relevant molecular findings in non\u2010metastasising LCCSCT were limited to <jats:italic>PRKAR1A<\/jats:italic> variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) <jats:italic>BRCA2<\/jats:italic> mutations with evidence of LOH and bi\u2010allelic <jats:italic>CDKN2A\/B<\/jats:italic> deletions. Three patients harboured <jats:italic>PRKAR1A<\/jats:italic> variants of inferred germline origin, including one with Carney complex and two without known syndromic features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non\u2010metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non\u2010metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.14895","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:25:00Z","timestamp":1679012700000},"page":"1079-1088","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non\u2010metastasising and metastasising neoplasms"],"prefix":"10.1111","volume":"82","author":[{"given":"Sanhong","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-9735","authenticated-orcid":false,"given":"Lynette M","family":"Sholl","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Siegmund","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M","family":"Ulbright","sequence":"additional","affiliation":[{"name":"Department of Pathology Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9603-6731","authenticated-orcid":false,"given":"Katrina","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Pathology Indiana University School of Medicine  Indianapolis IN 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of Pathology, Microbiology and Immunology Vanderbilt University Medical Center  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine M","family":"Cornejo","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Sui","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University  Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E","family":"Wobker","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of North Carolina School of Medicine  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara O","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pathology Boston Children's Hospital and Harvard 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