Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

Abstract

Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n = 138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with nonclassic histology (P = 0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P = 0.007 and P = 0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P = 0.008 and P = 0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies. Extrauterine Müllerian carcinomas (ovarian, fallopian tube, and peritoneal) are the eighth most common malignancy in women and the fifth most common cause of death from cancer among women in the United States. 1 The 5-year survival for highgrade serous carcinoma, the most common and most lethal of all pelvic Müllerian carcinomas, is approximately 40%. 2 These tumors are difficult to detect in early stage and thus frequently present with metastatic disease. Although most high-grade serous carcinomas are associated with a poor prognosis, some patients with the disease have significantly better outcomes. [3][4][5] Germline mutations in BRCA1 and BRCA2 account for the majority of inherited cases of high-grade serous carcinomas, and the recognition of these germline mutations has led to the widespread use of prophylactic bilateral salpingo-oophorectomies to

Pathology of Hereditary Breast and Ovarian Cancer

“…Prior to the recognition of SET features in high-grade serous carcinoma, tumors exhibiting these morphological findings were often misdiagnosed as high-grade endometrioid, transitional cell, or undifferentiated carcinomas. In a more recent study, Ritterhouse et al confirmed that tumors with homologous recombination deficiency, including those diagnosed in BRCA1 and BRCA2 mutation carriers, are six times more likely to exhibit non-classical (SET or ambiguous) features of high-grade serous carcinoma (50). Although the aforementioned features are associated with BRCA-mutated tumors, the data to date have not been able to demonstrate differences to accurately distinguish tumors associated with germline mutations versus somatic mutations and BRCA promoter methylation based on morphology alone.…”

“…Prior to the recognition of SET features in high-grade serous carcinoma, tumors exhibiting these morphological findings were often misdiagnosed as high-grade endometrioid, transitional cell, or undifferentiated carcinomas. In a more recent study, Ritterhouse et al confirmed that tumors with homologous recombination deficiency, including those diagnosed in BRCA1 and BRCA2 mutation carriers, are six times more likely to exhibit non-classical (SET or ambiguous) features of high-grade serous carcinoma ( 50 ).…”

“…Importantly, the identification of an germline-associated BRCA1/2-mutated tumor indicates not only an underlying germline defect (in the patient and perhaps also in her family members), but also implies certain important prognostic and treatment connotations. For example, mutations involving genes whose protein products are involved in homologous recombination have been shown to be associated with chemotherapeutic platinum sensitivity and improved survival in both breast and tubo-ovarian cancer patients (46,50,83). Similarly, triple-negative breast cancer patients harboring defects in homologous recombination proteins have been shown to exhibit increased sensitivity to both platinum-based and standard chemotherapy regimens (84,85), although the effect on prognosis is more complex (86).…”

Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

“…Other features more frequently observed in BRCA1-associated HGSOC are necrosis, a higher mitotic index, and an increased number of tumor-infiltrating lymphocytes (TILs; refs. [18][19][20]. On a molecular level, gBRCA-associated breast cancers and OCs share similar somatic copy-number profiles [somatic copy-number alteration (SCNA)-high] and frequent TP53 mutations (16)(17)(18)(20)(21)(22).…”

Ovarian Cancer: A Heterogeneous Disease

“…HGSC show a relatively high number of somatic copy number variations and structural variations with >100 recurrent amplifications and deletions identified [13][14][15]. Distinct clinical features and several morphological patterns of HGSC have been described and linked to specific genomic mutations, such as BRCA1/ BRCA2, which confer a better prognosis, but this needs to be validated [16,17].…”