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This review outlines key histopathological features and diagnostic strategies for ACC, offering a practical framework for evaluation and grading in daily practice. The updated WHO classification reaffirms the central role of histopathology, employing multiparametric scoring systems that assess invasion, architectural and cytological features, mitotic activity, and necrosis. However, these parameters often pose interpretive challenges, and no single algorithm ensures complete sensitivity, specificity, or reproducibility. Therefore, combining diagnostic approaches is advisable, particularly in morphologically ambiguous cases. For tumor grading, the WHO employs a two-tiered system based on a mitotic count cut of 20 per 10 mm\n                    <jats:sup>2<\/jats:sup>\n                    , aiming to improve interinstitutional consistency. Immunohistochemistry remains essential for diagnostic confirmation and prognostic evaluation. Among available markers, SF1 is the most specific for adrenocortical origin, while Ki-67, mismatch repair proteins, p53, and \u03b2-catenin are useful for predicting patient outcomes or screening for hereditary predisposition. In this complex diagnostic setting, artificial intelligence holds potential to support ACC diagnostics. However, its application is limited by the rarity of the disease, histological variability, and the scarcity of large, well-annotated datasets necessary for algorithm development.\n                  <\/jats:p>","DOI":"10.1007\/s00428-025-04278-0","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T01:51:15Z","timestamp":1759888275000},"page":"193-210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Diagnosis and grading of adrenal cortical carcinoma"],"prefix":"10.1007","volume":"488","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-6994","authenticated-orcid":false,"given":"Giulia","family":"Vocino Trucco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4018-3983","authenticated-orcid":false,"given":"Eleonora","family":"Duregon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2713-1700","authenticated-orcid":false,"given":"Mauro","family":"Papotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0719-105X","authenticated-orcid":false,"given":"Marco","family":"Volante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"4278_CR1","doi-asserted-by":"publisher","first-page":"636","DOI":"10.14740\/jocmr3503w","volume":"10","author":"E Sharma","year":"2018","unstructured":"Sharma E, Dahal S, Sharma P et al (2018) The characteristics and trends in adrenocortical carcinoma: a United States population based study. 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