Mesonephric-like adenocarcinomas (MLA) are rare neoplasms arising in the uterine corpus and ovary which have been added to the recent 2020 World Health Organization Classification of Female Genital Tumors. They have similar morphology and immunophenotype and exhibit molecular aberrations similar to cervical mesonephric adenocarcinomas. It is debated as to whether they are of mesonephric or Mullerian origin. We describe the clinical, pathologic, immunohistochemical, and molecular features of 5 cases of extrauterine mesonephric-like proliferations (4 ovary, 1 extraovarian), all with novel and hitherto unreported features. These include an origin of MLA in extraovarian endometriosis, an association of ovarian MLA with high-grade serous carcinoma, mixed germ cell tumor and mature teratoma, and a borderline ovarian endometrioid tumor exhibiting mesonephric differentiation. Four of the cases exhibited a KRAS variant and 3 also a PIK3CA variant. In reporting these cases, we expand on the published tumor types associated with MLA and report for the first time a borderline tumor exhibiting mesonephric differentiation. We show the value of molecular testing in helping to confirm a mesonephric-like lesion and in determining the relationship between the different neoplastic components. We provide further evidence for a Mullerian origin, rather than a true mesonephric origin, in some of these cases. We also speculate that in the 2 cases associated with germ cell neoplasms, the MLA arose out of the germ cell tumor.

Background: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2, and TP53 in sporadic ILC and LCIS diagnosed in women ages 60 years. Methods: Access Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2, and PALB2 using a custommade targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls. Results: Case-control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2, and CDH1 in women with ILC. CHEK2 was the only gene that showed an association with pure LCIS [

Introduction Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2 , BRCA1 , CHEK2 , PALB2 and TP53 in DCIS in women aged less than 50 years of age. Methods After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls. Results Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56–119.26, P = 2.0 × 10 −10 ) and CHEK2 (OR = 8.04, 95%CI 2.93–22.05, P = 9.0 × 10 −6 ), with weaker associations with PALB2 ( P = 0.003), BRCA1 ( P = 0.007) and TP53 ( P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively. Conclusions This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2 , CHEK2 , PALB2 , BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS. Electronic supplementary material The online version of this article (10.1186/s13058-019-1143-y) contains supplementary material, which is available to authorized users.