Yu Sanhong, Sholl Lynette M, Siegmund Stephanie, Ulbright Thomas M, Collins Katrina, Colecchia Maurizio, Del Pilar Gonzalez-Peramato Maria, Michalová Květoslava, Gordetsky Jennifer B, Cornejo Kristine M, Kao Chia-Sui, Wobker Sara E, Vargas Sara O, Maclean Fiona, Idrees Muhammad T, Anderson William J, Fletcher Christopher D M, Acosta Andres M
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
Histopathology. 2023 Jun;82(7):1079-1088. doi: 10.1111/his.14895. Epub 2023 Mar 16.
Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal 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. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours 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 PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.
大细胞钙化性支持细胞瘤（LCCSCT）是一种睾丸性索间质肿瘤，可散发性发生，也可在卡尼综合征及其他遗传综合征背景下出现。一部分病例具有临床恶性特征，但其导致这种侵袭性行为的分子机制尚不清楚。方法与结果：我们对20例LCCSCT患者（12例无转移和8例有转移）的21个样本进行了PRKAR1A免疫组化（IHC）和二代测序分析。除2例（病例17和20，均有转移）外，所有肿瘤均显示PRKAR1A表达缺失。在11例测序结果可解读的病例中，均存在PRKAR1A的致病性单核苷酸变异。在所有可解读杂合性数据的肿瘤中均存在PRKAR1A杂合性缺失（LOH）证据，但无转移和有转移肿瘤的LOH机制不同。无转移肿瘤仅表现为拷贝中性LOH，而有转移肿瘤表现出一系列LOH机制，包括拷贝丢失LOH、两个并发突变或拷贝中性LOH。无转移LCCSCT的相关分子发现仅限于PRKAR1A变异。相比之下，所有测序结果可解读的有转移LCCSCT均存在其他致病性变异，包括（但不限于）有LOH证据的BRCA2突变和双等位基因CDKN2A/B缺失。3例患者携带推断为种系起源的PRKAR1A变异，其中1例患有卡尼综合征，2例无已知综合征特征。结论：本研究进一步证实PRKAR1A IHC对无转移和有转移肿瘤均是一种有用的诊断工具，并表明分子分析有助于在特定患者中识别具有恶性潜能的无转移肿瘤。重要的是，这些结果强调种系评估对所有LCCSCT患者可能有益。
