Expanding the Spectrum of High-Risk Human Papilloma Virus (HPV)-Associated Glandular Neoplasms of the Anorectum.

Human papilloma virus (HPV)-related glandular neoplasms were first described in the uterine cervix and later identified in the anorectum. Although anorectal tumors were initially described as indolent neoplasms, we have encountered several examples with aggressive features. In this study, we describe the findings in a larger series of cases to further characterize these tumors and expand upon understanding of the spectrum of their behavior. Materials from 10 patients with HPV-related anorectal glandular neoplasms were prospectively collected from 2020 to 2026 from 2 academic centers. Most (7/10) were consultation cases. Morphologic features, immunohistochemical stains, and in situ hybridization for high-risk HPV were assessed. Clinical and outcome data were obtained from electronic medical records. The neoplasms arose in 8 women and 2 men, ranging in age from 30 to 81 years (median, 66 years). All had areas of noninvasive lesions characterized by glandular or villoglandular architecture, apical mitoses, and conspicuous apoptotic bodies. In addition to an exophytic in situ lesion as initially described, 4 cases were associated with invasive carcinomas (1 high-grade carcinoma with heterogenous components, 1 moderately differentiated adenocarcinoma, and 1 small cell--type neuroendocrine carcinoma). Two patients had concurrent high-grade squamous dysplasia/intraepithelial lesions and 1 had a concurrent low-grade squamous dysplasia/intraepithelial lesion. High-risk HPV transcripts were demonstrated in all cases using in situ hybridization in both the in situ and any invasive component. Follow-up data were available for 8 patients; 2 experienced a recurrence, 1 had multiple recurrences, 1 had persistent disease, and the patient with small cell--type neuroendocrine carcinoma died in hospice. HPV-associated anorectal glandular lesions arise in older adults, usually women. They can mimic colorectal adenomas and adenocarcinomas, coexist with squamous intraepithelial lesions, and may be associated with high-grade carcinomas. We propose the term "high-risk HPV-associated adenoma" for noninvasive lesions instead of the previously introduced terminology ("high-risk HPV-related adenocarcinoma") to avoid confusion, reserving carcinoma terminology for invasive neoplasms.