Contemporary diagnostic criteria for adrenocortical neoplasms: from morphology to molecular classification

The diagnosis of adrenocortical tumors has undergone substantial changes in recent years owing to the introduction of reproducible morphological scoring systems combined with validated immunohistochemical and molecular markers. Updates to the WHO Classification of Endocrine and Neuroendocrine Tumours (2025), ICCR datasets, and contemporary clinical guidelines have strengthened requirements for morphological diagnostic standards, immunohistochemical profiling, and interpretation of pathological findings.

Purpose of the study. To systematize contemporary morphological, immunohistochemical, and molecular criteria for adrenocortical tumors and to provide a practical algorithm for their stepwise application in pathological diagnosis.

Materials and methods. An analytical review of publications from 2021 to 2025 on the pathology and molecular oncoendocrinology of adrenocortical tumors was performed, including the WHO-2025 classification, ICCR datasets, updates to European clinical guidelines, and multicenter studies.

Results. Classical morphological criteria, including assessment of mitotic activity, capsular and vascular invasion, and cytological atypia, remain fundamental for the diagnosis of adrenocortical tumors. The review systematizes the principal morphological tools, including the Weiss criteria and their modifications, the Helsinki score, and the reticulin algorithm. Diagnostic features of oncocytic (Lin–Weiss–Bisceglia), myxoid, and pediatric variants of adrenocortical tumors are discussed. Current evidence regarding the role of SF-1 as a highly specific marker of adrenocortical origin is summarized, together with the significance of a high Ki-67 index as one of the most important diagnostic and prognostic indicators of malignancy, taking into account established threshold values and strict counting methodology. Increased IGF2 expression is also highlighted as an additional marker of malignancy. Furthermore, the review provides a comprehensive overview of major molecular drivers, including TP53, CTNNB1/β-catenin, ZNRF3, and TERT-promoter alterations, as well as DNA methylation signatures and microRNA profiles (miR-483). The contribution of single-cell and spatial transcriptomics and emerging noninvasive biomarkers, including steroid metabolomics and liquid biopsy, is also discussed.

Conclusion. The transition toward integrated morphomolecular stratification improves diagnostic and prognostic accuracy in adrenocortical tumors, enhances the comparability of pathology reports, and facilitates patient selection for surveillance and treatment.

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