Clinical, histological and receptor profiles of invasive breast cancer and ductal carcinoma in situ in females with germline pathogenic variants in PTEN and implications for germline testing

PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant hereditary cancer syndrome, caused mostly by germline pathogenic variants in PTEN. Female carriers have an up to 80% lifetime risk of breast cancer. Pathological features of breast cancer in PHTS have seldom been reported. In a collaboration between all histopathology laboratories in our state and our statewide familial cancer service, we tracked the breast biopsies of 12 females with known PTEN pathogenic or likely pathogenic (P/LP) variants (January 1990 to January 2018). Two further cases were added by a Victorian cancer genetics unit. Breast cancer, inclusive of invasive cancer or ductal carcinoma in situ (DCIS), was diagnosed in 12 of 14 cases (85.7%). One case had a family history of PHTS, and six had a family history of breast cancer. The mean age at first breast cancer diagnosis was 41.6 years (range 27–63). Six cases developed more than one breast cancer. Five (42%) developed contralateral breast cancer. Ten of the 12 invasive cancers were of no special type, and two were reported as lobular carcinomas. None were grade 1. When reported, all cancers were hormone-receptor positive and HER2 negative. All were associated with DCIS. The DCIS spanned all grades. The two cases without breast cancer still required surgery for exuberant benign changes, including papillomas, fibroadenomatoid change, florid ductal epithelial hyperplasia, adenosis ​and stromal fibrosis. We note that the morphology and receptor profiles of breast cancer in individuals with P/LP PTEN variants are not distinctive. Contrary to prevalent beliefs, these cancers do not conform to the contemporary definition of apocrine breast carcinoma. Greater familiarity of healthcare professionals with the overall clinical and pathological findings in PHTS and the validated Cleveland Clinic PTEN calculator (http://www.lerner.ccf.org/gmi/ccscore) would improve the recognition of female PHTS individuals with breast cancer. Earlier identification of their cancer predisposition syndrome would benefit these patients and their families who are at high risk of a range of cancers.