TP53 Wild-type, HPV-independent Anal Growth/(intra)Epithelial Lesion (ANGEL): a Potential Precursor of Anal Squamous Cell Carcinoma.

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Human papillomavirus (HPV) underpins approximately 90% of squamous cell carcinomas (SCC) of the anus and perianal region. These tumors usually arise in association with precursor lesions such anal intraepithelial neoplasia/ high-grade squamous intraepithelial lesion (AIN 3/ HSIL), 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 (DEVIL/VAAD) 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, while TP53 status was assessed using immunohistochemistry and molecular studies in a subset of cases, with targeted molecular sequencing performed in three of these. All lesions (5/5) arose in men, ages ranging from 55 to 78 years (median: 65). Verrucous architecture was seen in 2/5 cases, 2/5 were predominantly acanthotic, and 1/5 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 wildtype p53 expression. Three cases with sufficient material for sequencing lacked alterations within the entire coding sequencing of TP53. Invasive SCC was concurrently present in 3/5 cases. In summary, verrucous and acanthotic HPV-independent TP53 wild-type squamous proliferations of the anal and perianal region, referred herein as ANGELs (anal growth/(intra)epithelial lesions), are pre-malignant lesions that have the potential to become invasive, as most of our cases demonstrated synchronous SCC.