Pancreatic ductal adenocarcinoma and its subtypes: clinical relevance of histopathology and molecular characterization, integrating the key updates of the 2026 WHO classification.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, due to its late clinical presentation, early vascular, perineural, nodal and distant dissemination, and profound resistance to systemic therapies. Histologically, conventional PDAC is characterized by infiltrative gland-forming, mucin-producing neoplastic epithelium embedded in a dense desmoplastic stroma. However, recent advances have highlighted substantial morphological, molecular, and microenvironmental heterogeneity. In this review, the clinicopathological and molecular features of conventional PDAC and its recognized histological subtypes have been summarized, integrating the major updates introduced in the latest edition of the World Health Organization Classification of Tumours. Particular emphasis is placed on diagnostic histopathological hallmarks, grading criteria, morphological patterns, and clinically relevant subtypes. They include adenosquamous, colloid, medullary, hepatoid, poorly cohesive/signet-ring cell, and undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells. The biological basis of PDAC aggressiveness, including vascular and perineural invasion, stromal remodeling, early metastatic spread, immunosuppressive microenvironment, and the central role of classic genetic drivers, namely KRAS, CDKN2A, TP53 and SMAD4, are presented and discussed. Emerging issues include the reclassification of micropapillary morphology, the expanding differential diagnosis of hepatoid differentiation, the recognition of distinctive precursor and invasive lesions, and the unresolved challenge of assessing treatment response after neoadjuvant therapy. Lastly, a discussion regarding the future perspectives for pancreatic pathology in the era of precision oncology is provided, highlighting the need for integrated histological, molecular, spatial, and immunological approaches to improve diagnostic reproducibility, biomarker discovery, therapeutic stratification and, ultimately, patient outcomes.