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Adrenocortical carcinoma is generally considered a single entity by pathologists and clinicians. Nevertheless, the knowledge cumulated along the last decade on the pathological characterization, the clinical outcome and the molecular pathogenesis of adrenocortical carcinoma demonstrate that one of the most relevant emerging issues is related to its heterogeneity. Three major morphological variants have been described (oncocytic, myxoid and sarcomatoid) but are not included in the current WHO classification, yet. Moreover, even "conventional" adrenocortical carcinomas have a high degree of morphological heterogeneity as well as different mitotic/proliferative capacity, either among different cases or within individual lesions. Furthermore, immunohistochemical and molecular studies, based on a wide set of different methodologies, identified novel biomarkers in adrenocortical carcinoma of diagnostic and prognostic relevance, which claimed again the concept that this tumor type represents an heterogeneous group of neoplasms which cannot be considered a unique entity. The integration between morphology, immunophenotype and molecular data is expected in the next years to build a novel concept of adrenocortical carcinoma classification into specific subgroups, as it is currently approached for other types of neoplasms such as breast or lung cancer, which are not merely descriptive, but also characterized by a specific biological and clinical behavior.

Dissecting morphological and molecular heterogeneity in adrenocortical carcinoma