The pathological diagnosis of adrenocortical carcinoma (ACC) which is based on gross and microscopic criteria, still causes controversies due to its subjectivity. None of such features is absolutely indicative of malignancy, although their combination in a scoring system may correctly identify ACCs. The Weiss system, nowadays the most popular, combines nine morphological parameters, including three structural (“dark” cytoplasm, diffuse architecture, necrosis), three cytological (atypia, mitotic count, atypical mitotic figures) and three related to invasion (of sinusoids, veins and tumour capsule). Although strictly defined criteria for each feature appeared in the original and subsequent publications, it has become apparent that some of them are straightforward and objective, while others are potentially more problematic (diffuse architecture, necrosis, sinusoidal, venous and capsular invasions). The classification of oncocytic and paediatric adrenocortical tumours is even more challenging, given that not all the above morphological parameters are predictors of malignancy in these tumour types. Alternative to the morphological approach, a wide array of chromosomal, genetic, molecular and immunohistochemical markers have been tested in ACC to identify reliable diagnostic and prognostic factors. Among them, genetic and epigenetic alterations of p53, IGF-2 and of molecules involved in cancer cell invasive properties seem the most promising. These molecular markers may not only play a role in the biology of these tumours and have prognostic implications, but also be used as potential targets for therapy. It should be noticed, however, that to date these markers have not proven to be sensitive and specific enough to replace conventional morphological criteria.
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