Pinto Andre, Singhi Aatur D, Voltaggio Lysandra, Salimian Kevan, Birkness-Gartman Jacqueline, Montgomery Elizabeth A
Department of Pathology and Laboratory Medicine, University of Miami, Miami, Florida.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Mod Pathol. 2025 May;38(5):100721. doi: 10.1016/j.modpat.2025.100721. Epub 2025 Jan 23.
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.
人乳头瘤病毒（HPV）是导致约90%的肛门和肛周区域鳞状细胞癌（SCC）的病因。这些肿瘤通常与前驱病变相关，如肛门上皮内瘤变/高级别鳞状上皮内病变，而一小部分HPV阴性癌症可能存在TP53基因突变。最近，一种称为分化型外生性外阴上皮内病变/伴分化改变的外阴棘皮症的外阴病变已被确认为外阴癌的HPV非依赖性、TP53野生型前驱病变；然而，类似的肛门病变尚未见报道。我们回顾性地确定了具有诊断挑战性的、TP53野生型、HPV阴性且具有包括棘皮症和/或疣状结构等不寻常组织学特征的肛门鳞状病变病例。排除具有挖空细胞改变、表面成熟度缺乏或显著细胞学异型性的病变。通过p16免疫组化和/或低危和高危毒株原位杂交确定HPV状态，而TP53状态则在部分病例中通过免疫组化和分子研究进行评估，其中3例进行了靶向分子测序。所有病变（5/5）均发生于男性，年龄在55至78岁之间（中位数：65岁）。5例中有2例可见疣状结构，5例中有2例以棘皮症为主，5例中有1例同时具有疣状和棘皮症生长。病变的特征为角化过度（5/5）、颗粒层增厚（5/5）以及上皮上层细胞质苍白（2/5）。所有病例HPV均为阴性且p53表达为野生型。3例有足够测序材料的病例在TP53的整个编码序列中均未发现改变。5例中有3例同时存在浸润性SCC。总之，肛门和肛周区域的疣状和棘皮症样HPV非依赖性、TP53野生型鳞状上皮增生，本文称为肛门生长/（上皮）内病变（ANGEL），是具有侵袭潜能的癌前病变，因为我们的大多数病例都显示出同步的SCC。
