Adrenocortical carcinoma is a lynch syndrome-associated cancer

Abstract

Purpose: Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC.

Patients and methods: One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency.

Results: Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene-positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status.

Conclusion: The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.

Fig 1.

Immunohistochemistry stains of adrenocortical carcinoma (ACC) tumors. Patient 1 demonstrates absence of nuclear staining for MSH2 and MSH6 in the ACC tumor with positive nuclear staining in the adjacent normal adrenal tissue as shown in the inset photo. Retention of nuclear staining of MLH1 and PMS2 in the ACC tumor is shown. Patient 2 demonstrates absence of nuclear staining in the ACC tumor for MLH1 and PMS2 and positive nuclear staining in the adjacent normal adrenal tissue as shown in the inset photo. Retention of nuclear staining of MSH2 and MSH6 in the ACC tumor is shown. Patient 3 demonstrates retention of the nuclear staining in the ACC tumor tissue for all four proteins (MLH1, MSH2, MSH6, and PMS2). Patient 4 demonstrates absence of nuclear staining for MSH2 and MSH6 in the ACC tumor with positive nuclear staining in the adjacent normal adrenal tissue as shown in the inset photo. Retention of nuclear staining of MLH1 and PMS2 in the ACC tumor is shown.

Fig A1.

Microsatellite instability assay profiles of adrenocortical carcinomas of (A) Proband 1 and (B) Proband 2 demonstrating a microsatellite stable pattern in normal versus tumor.

Fig A2.

Microsatellite instability assay profiles of adrenocortical carcinomas of (A) Proband 4 and (B) Proband 3 demonstrating a microsatellite stable pattern in normal and tumor.