Human papillomavirus (HPV) is an oncogenic virus associated with the development of several human cancers. Primary vaginal, vulvar, and anal adenocarcinomas are rare and, to date, have rarely been shown to be associated with HPV infection. We report a series of nine HPV-related adenocarcinomas of the lower anogenital tract distal to the cervix. The tumors involved the vagina (4), anorectum (3), and vulva (2). Two of the three anorectal cases involved men. Patients presented with a vulvar or vaginal mass/nodule, painless rectal bleeding, or during screening colonoscopy. Lesions ranged in size from 3.2 to 8.4 cm. The most salient morphologic characteristic was the presence of papillary or villiform/villoglandular architecture in all cases. Tumors displayed features similar to those of usual type high-risk HPV-related endocervical adenocarcinoma, namely, mucinous or mucin-poor (pseudoendometrioid) features or a hybrid of these, with columnar cells with crowded, cigar-shaped to ovoid irregular nuclei. Mitoses (mostly apical) and apoptotic bodies were easily identified. Adenosis was present in two vaginal cases. One anal tumor featured abundant intracytoplasmic mucin that was multivacuolated in some areas imparting a “clear cell”-like appearance. All tumors were diffusely and strongly positive for p16. Seven of seven tested cases were positive for high-risk HPV by in situ hybridization or polymerase chain reaction. Follow-up information, available in five patients, revealed two local recurrences but no tumor related deaths or distant metastases. We report the first well-documented series of HPV-associated primary adenocarcinomas of the vagina, vulva, and anorectum and broaden the spectrum of HPV-related neoplasia involving the lower anogenital tract in both women and men.
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Centers for Disease Control and Prevention. Cancers associated with human papilloma virus, United States—2011–2015. USCS data brief, no. 4. Atlanta, GA: Centers for Disease Control and Prevention; 2018.
Ikenberg H, Runge M, Göppinger A, Pfleiderer A. Human papillomavirus DNA in invasive carcinoma of the vagina. Obstet Gynecol. 1990;76:432–8.
Waggoner SE, Anderson SM, Van Eyck S, Fuller J, Luce MC, Herbst AL. Human papillomavirus detection and p53 expression in clear-cell adenocarcinoma of the vagina and cervix. Obstet Gynecol. 1994;84:404–8.
Talia KL, Otton G, Garland S, Phillips S, Scurry J. Human papillomavirus-associated adenocarcinoma in-situ of the vestibule. J Low Genit Trac Dis. 2017;21:e45–7.
Paczos TA, Ackers S, Odunsi K, Lele S, Mhawech-Fauceglia P. Primary vaginal adenocarcinoma arising in vaginal adenosis after CO2 laser vaporization and 5-fluorouracil therapy. Int J Gynecol Pathol. 2010;29:193–6.
Koulos J, Symmans F, Chumas J, Nuovo G. Human papillomavirus detection in adenocarcinoma of the anus. Mod Pathol. 1991;4:58–61.
Herfs M, Roncarati P, Koopmansch B, Peulen O, Bruyere D, Lebeau A, et al. A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine. Br J Cancer. 2018;118:1302–12.
Shamir ER, Devine WP, Pekmezci M, Umetsu SE, Krings G, Federman S, et al. Identification of high-risk human papillomavirus and Rb/E2F pathway genomic alterations in mutually exclusive subsets of colorectal neuroendocrine carcinoma. Mod Pathol. 2019;32:290–305.
Staats PN, Clement PB, Young RH. Primary endometrioid adenocarcinoma of the vagina: a clinicopathologic study of 18 cases. Am J Surg Pathol. 2007;31:1490–501.
Staats PN, McCluggage WG, Clement PB, Young RH. Primary intestinal-type glandular lesions of the vagina: clinical, pathologic, and immunohistochemical features of 14 cases ranging from benign polyp to adenoma to adenocarcinoma. Am J Surg Pathol. 2014;38:593–603.
Carleton C, Hoang L, Sah S, Kiyokawa T, Karamurzin YS, Talia KL, et al. A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. Am J Surg Pathol. 2016;40:636–44.
Talia KL, Scurry J, Manolitsas T, McCluggage WG. Primary vaginal mucinous adenocarcinoma of gastric type arising in adenosis: a report of 2 cases, 1 associated with uterus didelphys. Int J Gynecol Pathol. 2012;31:184–91.
Wong RW, Moore M, Talia KL, Ganesan R, McCluggage WG. Primary vaginal gastric-type adenocarcinoma and vaginal adenosis exhibiting gastric differentiation: report of a series with detailed immunohistochemical analysis. Am J Surg Pathol. 2018;42:958–70.
Cormio G, Carriero C, Loizzi V, Gissi F, Leone L, Putignano G, et al. “Intestinal-type” mucinous adenocarcinoma of the vulva: a report of two cases. Eur J Gynaecol Oncol. 2012;33:433–5.
Kojima N, Yoshida H, Uehara T, Ushigusa T, Asami Y, Shiraishi KT, et al. Primary clear cell adenocarcinoma of the vulva: a case study with mutation analysis and literature review. Int J Surg Pathol. 2019;27:792–7. 1066896919848823.
Kurita T, Matuura Y, Hisaoka M, Hachisuga T. Adenocarcinoma of intestinal type of the vulva. Int Cancer Conf J. 2019;8:89–93.
Lisovsky M, Patel K, Cymes K, Chase D, Bhuiya T, Morgenstern N. Immunophenotypic characterization of anal gland carcinoma: loss of p63 and cytokeratin 5/6. Arch Pathol Lab Med. 2007;131:1304–11.
Meriden Z, Montgomery EA. Anal duct carcinoma: a report of 5 cases. Hum Pathol. 2012;43:216–20.
Kleter B, van Doorn LJ, ter Schegget J, Schrauwen L, van Krimpen K, Burger M, et al. Novel short-fragment PCR assay for highly sensitive broad-spectrum detection of anogenital human papillomaviruses. Am J Pathol. 1998;153:1731–9.
Kleter B, van Doorn LJ, Schrauwen L, Molijn A, Sastrowijoto S, ter Schegget J, et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol. 1999;37:2508–17.
Saitoh M, Hayasaka T, Ohmichi M, Kurachi H, Motoyama T. Primary mucinous adenocarcinoma of the vagina: possibility of differentiating from metastatic adenocarcinomas. Pathol Int. 2005;55:372–5.
McCluggage WG, Price JH, Dobbs SP. Primary adenocarcinoma of the vagina arising in endocervicosis. Int J Gynecol Pathol. 2001;20:399–402.
urman RJ, Carcangiu ML, Herrington CS, Young RH WHO classification of tumors of female reproductive organs. Lyon: IARC; 2014.
Kojima A, Mikami Y, Sudo T, Yamaguchi S, Kusanagi Y, Ito M, et al. Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol. 2007;31:664–72.
Kusanagi Y, Kojima A, Mikami Y, Kiyokawa T, Sudo T, Yamaguchi S, et al. Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. Am J Pathol. 2010;177:2169–75.
Wada T, Ohishi Y, Kaku T, Aman M, Imamura H, Yasutake N, et al. Endocervical adenocarcinoma with morphologic features of both usual and gastric types: clinicopathologic and immunohistochemical analyses and high-risk HPV detection by in-situ hybridization. Am J Surg Pathol. 2017;41:696–705.
Chiesa-Vottero AG, Malpica A, Deavers MT, Broaddus R, Nuovo GJ, Silva EG. Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma. Int J Gynecol Pathol. 2007;26:328–33.
Yemelyanova A, Ji H, Shih IeM, Wang TL, Wu LS, Ronnett BM. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33:1504–14.
Lam AK, Ong K, Giv MJ, Ho YH. p16 expression in colorectal adenocarcinoma: marker of aggressiveness and morphological types. Pathology. 2008;40:580–5.
Sui Y, Zou J, Batchu N, Lv S, Sun C, DU J, et al. Primary mucinous adenocarcinoma of the vulva: a case report and review of the literature. Mol Clin Oncol. 2016;4:545–8.
Tulek F, Kahraman A, Taskin S, Yuksel S, Sertcelik A, Ortac F. Primary mucinous carcinoma of the vulva with signet ring cells deriving from the cloaca. Eur J Gynaecol Oncol. 2016;37:554–7.
Kaltenecker B, Manos R, McCall M, Sparzak P. Intestinal-type adenocarcinoma of the vulva: a case study. Gynecol Oncol Rep. 2019;28:133–5.
Lee IH, Kim MK, Lee YK, Hong SR, Lee KH. Primary mucinous adenocarcinoma of the vulva, intestinal type. Obstet Gynecol Sci. 2017;60:369–73.
Matsuzaki A, Saio M, Kosuge N, Aoyama H, Tamaki T, Matsumoto H, et al. Primary villoglandular mucinous adenocarcinoma of the vulva. Case Rep Pathol. 2017;2017:1765460.
We are indebted to Ms Kara Lombardo and Mr Hiro Nonogaki for their assistance with methodology and to Norm Barker, MA, MS, RBP, FBCA, FRPS for his assistance with the photomicrographs.
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Voltaggio, L., McCluggage, W.G., Iding, J.S. et al. A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas. Mod Pathol 33, 944–952 (2020). https://doi.org/10.1038/s41379-019-0437-z
Pathology - Research and Practice (2020)