Mitochondrial complex II genetic characterization and enzymatic expression profile in tumours of the adrenal cortex and medulla

Abstract

Introduction: The adrenal gland is an endocrine organ comprised of two parts, the adrenal medulla and the adrenal cortex. The neoplasms of the adrenal medulla include pheochromocytoma and neoplasms of the adrenal cortex include adrenocortical adenomas and carcinomas. Mutations in genes encoding for succinate dehydrogenase subunits (SDHx) have been identified in familial and sporadic pheochromocytoma and recently in a small series of adrenocortical carcinomas. Aim: To describe our hospital series of adrenal cortex and medulla tumours and characterize SDHx involvement using immunohistochemistry, followed by mutational analysis. Methods: Retrospective review of the clinico-pathological records of 62 pheochromocytoma, 106 cortical adenoma and 17 cortical carcinoma patients diagnosed in Centro Hospitalar de S. João. SDHB immunohistochemistry was performed in all cases. SDHA immunohistochemistry and SDHB mutation analysis were performed in those with negative SDHB staining and in those with a positive staining with negative areas. Results: All tumours were more prevalent in the fifth decade and in women. Asymptomatic cases frequency was higher in adenomas. Carcinomas were always symptomatic, larger than adenomas, and displayed more frequently necrosis and haemorrhage. Pheochromocytomas presented the highest frequency of associated genetic susceptibility syndromes. SDHB immunohistochemistry was positive in all adenomas and carcinomas. Two pheochromocytomas (3.2%) were classified as negative. All the tumours selected for SDHA immunohistochemistry had a positive staining. SDHB mutations were detected in three pheochromocytomas (4.8%): two negative cases (c.487 T>C, p.S163P; c.136C>T, p.Arg46*) and one positive case with negative areas (c.418G>T, p.V140F). Discussion: This is the first work to study pheochromocytomas, adrenocortical adenomas and carcinomas as individual entities, describing its population and evaluating SDHx alterations. Our series was demographically similar to others recently described. Alterations in SDHB immunohistochemistry triggered the mutational analysis in pheochromocytomas: the mutation c.487T>C, p.S163P is considered a rare polymorphism, non-pathogenic; the mutations c.136C>T, p.Arg46* and c.418G>T, p.V140F are pathogenic. We did not find any SDHB immunohistochemistry alterations triggering the genetic analysis in cortex tumours.