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.

Figure 1.

Pedigree of family with the germline MSH2 mutation. NM, carriers of the mutation; NN, wild-type individuals.

Figure 2.

A, a) High-magnification image of hematoxylin and eosin-stained photomicrograph demonstrating confluent tumor necrosis (arrowhead) in ACC from patient II:2. (A, b) Medium-magnification image demonstrating capsular invasion (arrowhead) in ACC from patient II:2. (A, c) Medium-magnification image of ACC from patient III:2 demonstrating atypical nuclei, mitotic activity, and areas of necrosis. (B) Immunohistochemical analyses of MLH1, PMS2, MSH2, and MSH6 protein expression in ACCs resected from patients II:2 (B, a–d) and III:2 (B, e–h), and endometrial tumor resected from patient III:1 (B, i–l) (×400). All analyzed tumors retained expression of MLH1 (B, a, e, i) and PMS2 (B, b, f, j) (short arrowhead), but expression of MSH2 (B, c, g, k) and MSH6 (B, d, h, l) was absent (solid arrow), with adjacent normal stromal cells exhibiting positive staining (dashed arrow).