TP53 Wild-Type, Human Papillomavirus-Independent Anal Growth/(Intra)Epithelial Lesion (ANGEL): A Potential Precursor of Anal Squamous Cell Carcinoma.

Human papillomavirus (HPV) underpins ∼90% of squamous cell carcinomas (SCCs) of the anus and perianal region. These tumors usually arise in association with precursor lesions such as anal intraepithelial neoplasia/high-grade squamous intraepithelial lesion, whereas a small subset of HPV-negative cancers may harbor mutations in TP53. Recently, vulvar lesions termed differentiated exophytic vulvar intraepithelial lesion/vulvar acanthosis with altered differentiated have been recognized as HPV-independent, TP53 wild-type precursors for vulvar carcinoma; however, analogous anal lesions have not been described. Cases of diagnostically challenging, TP53 wild-type HPV-negative anal squamous lesions with unusual histologic features including acanthosis and/or verrucous architecture were retrospectively identified. Lesions with koilocytic changes, lack of surface maturation, or significant cytologic atypia were excluded. HPV status was determined by immunohistochemistry for p16 and/or in situ hybridization for low- and high-risk strains, whereas TP53 status was assessed using immunohistochemistry and molecular studies in a subset of cases, with targeted molecular sequencing performed in 3 of these. All lesions (5/5) arose in men, ages ranging from 55 to 78 years (median: 65 years). Verrucous architecture was seen in 2 of 5 cases, 2 of 5 were predominantly acanthotic, and 1 of 5 had both verrucous and acanthotic growth. The lesions were characterized by hyperkeratosis (5/5), hypergranulosis (5/5), and cytoplasmic pallor of upper epithelial layers (2/5). All cases were negative for HPV and had wild-type p53 expression. Three cases with sufficient material for sequencing lacked alterations within the entire coding sequencing of TP53. Invasive SCC was concurrently present in 3 of 5 cases. In summary, verrucous and acanthotic HPV-independent TP53 wild-type squamous proliferation of the anal and perianal region, referred to herein as anal growth/(intra)epithelial lesion (ANGEL), are premalignant lesions that have the potential to become invasive, as most of our cases demonstrated synchronous SCC.