Anal canal neoplasms in the modern era: integrating HPV biology, LAST terminology, and evolving molecular...

Anal canal neoplasia comprises a heterogeneous and evolving group of precursor lesions and invasive malignancies whose classification increasingly depends on integrating morphology, human papillomavirus association, immunophenotype, and molecular alterations. This review summarizes current concepts in the pathology of anal canal neoplasms, with emphasis on practical application of Lower Anogenital Squamous Terminology, distinction between low-grade and high-grade squamous intraepithelial lesions, and the role of ancillary testing in diagnostically challenging cases. We discuss the expanding spectrum of invasive neoplasms, including human papillomavirus-driven and human papillomavirus-independent squamous cell carcinoma, anorectal neuroendocrine carcinoma, and anal adenocarcinoma, highlighting recently described subtypes and their clinicopathologic significance. Attention is given to emerging molecular correlates, including alterations in TP53, CYLD, and other oncogenic pathways, which may refine classification and prognostic stratification. The review also addresses unresolved issues, including precursor lesions for human papillomavirus-independent disease, evolving terminology for glandular and mixed lesions, and controversy regarding staging of anal adenocarcinoma. By combining contemporary terminology with morphologic, immunohistochemical, and molecular findings, this review provides a practical framework for pathologists navigating an uncommon but increasingly complex diagnostic area.