Hereditary and Familial Tumor Syndromes: When to Think of Them? The Emerging Role of Pathologists as Sentinels of Genetic Cancer Predisposition

Germline predisposition contributes to at least 10% of human malignancies and is identified in ∼8.5% to 10% of pediatric cancers, with notably higher frequencies in specific tumor types, including over 60% in adrenocortical carcinoma and 17% to 20% in osteosarcoma. In certain tumors, hereditary predisposition is a defining or highly characteristic feature. Advances in next-generation sequencing have significantly reshaped our understanding of hereditary tumor biology, revealing molecularly distinct neoplasms linked by shared germline alterations and enabling the recognition of new cancer predisposition syndromes. This evolving knowledge is reflected in the WHO Classification of Tumors: Genetic Tumor Syndromes, which provides an integrated, cross-disciplinary diagnostic framework. Surgical pathologists play a central role in this landscape. Careful morphologic assessment, supported by targeted immunohistochemistry and clinical context, often allows the pathologist to identify features of germline predisposition-sometimes as the first or only clinician to do so, even in the absence of a relevant family history. This review highlights 13 practical morphologic and clinicopathological clues that should prompt consideration of a hereditary tumor syndrome, summarizes key immunohistochemical tools for syndromic triage, and presents an organ-based overview of major hereditary cancer syndromes. The goal is to provide a practical framework to support the pathologist's role in recognizing hereditary cancer.