Familial Adrenocortical Carcinoma in Association With Lynch Syndrome

Abstract

Context:Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation.Case:A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister.Conclusion:Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes.

Landscape of Microsatellite Instability Across 39 Cancer Types

“…Of particular interest, we identified MSI in 4 (4.4%) of 92ACCcases. Previous studies of MSI in ACC have implicated Lynch syndrome as a risk factor for familial ACC 80,81 ; however, to our knowledge, NGS-based MSI analysis has not yet been applied to ACC.…”

“…In addition, there have been anecdotal reports of ACC 80,81 as a potential extracolonic manifestation of Lynch syndrome. If future studies indicate that MSI in ACC, CESC, and/or MESO is indeed a result of MMR deficiency, the findings of this study may implicate previously unappreciated cancer types as being part of Lynch syndrome.…”

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

“…ACC was not represented in these initial studies, but is a recognized Lynch syndrome associated malignancy [1], [2]. Whether sporadic or associated with an inherited tumor syndrome, the standard treatment for patients with good performance status and unresectable or metastatic ACC is currently combination chemotherapy consisting of etoposide, doxorubicin, cisplatin, and mitotane.…”

“…Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with limited therapeutic options for patients with advanced disease. In adults, the majority of ACC are sporadic; however, it is recognized that a subset of ACC is associated with Lynch syndrome, an autosomal dominant tumor syndrome caused by pathogenic mutations of DNA mismatch repair (MMR) genes ( MSH2, MSH6, PMS2 , and MLH1 ) [1], [2]. MMR-deficient tumors possess a high somatic mutation burden and present a diverse repertoire of neoantigens which in turn enhances tumor immunogenicity and thus tumor-specific T cell responses.…”

Inherited Endocrine Neoplasia— A Comprehensive Review from Gland to Gene

“…ACC tumours demonstrate mismatch repair deficiency. If TP53 testing is negative in ACC, MMR testing could be utilised to screen cases for LS [80]. At present, surveillance of ACC in LS is not recommended.…”