From Familial Clustering to a Dedicated Classification: The Historical Recognition of Hereditary Tumor Syndromes in the WHO Classification of Tumors

BACKGROUND: Familial cancer aggregation has been recognized for more than 150 years. For much of that period, hereditary tumor predisposition was incorporated into tumor classification in a fragmented, organ-specific manner. Across successive editions, the WHO classification of tumours moved from morphology-based histologic typing toward an integrated classification that includes molecular pathology, inherited predisposition and, in the fifth edition, a dedicated framework for genetic tumour syndromes. SCOPE: This review traces the historical development of genetic tumor syndrome recognition, from 19th-century familial cancer pedigrees and mid-20th-century clinical syndrome delineation to the molecular definition of classic predisposition syndromes. It also examines how these entities were gradually incorporated into the WHO Blue Book editions. Particular emphasis is placed on the transition from organ-based coverage to a pathway-based classification organized around major cellular mechanisms, molecular pathways, clinical syndromes, and affected genes or genomic loci. CONCLUSIONS: The dedicated WHO framework for genetic tumour syndromes represents an important classificatory shift. It recognizes that constitutional and mosaic cancer predisposition cannot be adequately represented by organ-specific tumor taxonomy alone. For pathologists, this framework reinforces the diagnostic importance of tumor morphology, immunohistochemistry, and molecular findings as sentinel indicators of possible genetic predisposition. It also provides a standardized structure for comparing established syndromes, incorporating emerging entities and supporting clinical genetics, surveillance, family counseling, and epidemiological ascertainment.