We report the first case of familial adrenocortical carcinoma (ACC) in association with hereditary non-polyposis colorectal cancer (HNPCC) in a family with a MSH2 germline mutation.
HNPCC, an autosomal dominant disorder caused by mutations in one of the DNA mismatch repair (MMR) genes, is the commonest cause of hereditary colon carcinoma, and is associated with an increased risk of certain non-colonic cancers (e.g. endometrial, ovarian, urinary tract, biliary tract). Currently, ACC is not a recognised feature of the HNPCC syndrome, and there are only two previous reports of ACC arising in the context of HNPCC, both of which were non-familial tumours.
The Amsterdam II/Revised Bethesda criteria are used to select patients, based on family history of colorectal cancer or other HNPCC-associated tumours, for immunohistochemical (IHC) analysis to detect loss of MMR protein expression, or for microsatellite instability (MSI) in the tumour DNA. Those with loss of MMR expression or MSI are offered mutation analysis of the four MMR genes that are associated with HNPCC MLH1, MSH2, MSH6 and PMS2.
The proband presented aged 54 years with generalised abdominal pain. Her past medical history included ovarian cancer (age 44 years) and a malignant colonic polyp (age 47 years). Investigation showed an extensive right adrenal mass, which was surgically resected. Histology confirmed an ACC with capsular, vascular and lymphatic invasion. Review of the family history revealed several individuals with colorectal cancer and other HNPCC-associated tumours. In addition, her mother had died of metastatic ACC. IHC analysis demonstrated loss of MSH2 protein expression in both the ACC from the proband and her mother. Mutation analysis confirmed a germline MSH2 mutation (deletion of exons 13) in the proband and several other family members.
The familial occurrence of a rare tumour in this HNPCC family, strongly argues for a causal link with the underlying MMR defect.