Clinicopathologic Features and Viral Status of Low-risk HPV6 and HPV11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva

Abstract

Despite being designated as "noncarcinogenic" human papillomavirus (HPV) types, mono-infection with HPV6 or HPV11 has been found in squamous cell carcinomas (SCCs) at specific sites, including the larynx, penis, anus, and rarely, the lower female genital tract. The association between clinicopathologic features, viral status, and the carcinogenic mechanisms related to these low-risk HPVs remains unclear. The current study characterizes a series of low-risk HPV6 and HPV11-associated SCCs of the uterine cervix (6 cases) and vulva (2 cases). The diagnosis of SCC was made through the identification of stromal invasion in 6 cases. In case 2, the diagnosis of cancer was made after metastases to the sigmoid colon and liver. The patient in case 6 was diagnosed with intramucosal papillary SCC given multiple recurrences. While all tumors displayed a similar verruco-papillary architecture, the cytologic features, and immunostaining patterns suggest 2 groups of lesions: one with high-grade cytology and a high Ki-67 proliferation index (>60% of lesional cells), and the other with low-grade cytology and a low Ki-67 (20% to 30% of lesional cells). The detection of HPV6 in 7 of 8 cases underscores its critical role in carcinogenesis at these anatomic sites. Case 8 represented the only patient who was infected with HPV11 and who had a well-controlled human immunodeficiency virus infection. Correlating with viral status, all cases, except case 7, demonstrated a negative or focal p16 staining pattern. In case 7, despite a block pattern of p16 staining often seen in predicting high-risk HPV, we employed several methods to confirm HPV6 as the sole HPV infection. Although this descriptive study does not establish an etiological mechanism for how HPV6/11 leads to malignant transformation, our results exclude the possibility of viral integration through a quantitative polymerase chain reaction-based analysis of the E2/E6 ratio. Our study highlights and expands upon the clinicopathologic features of a distinct group of low-risk HPV6/11-associated SCCs in the cervix and vulva. Although rare, recognizing this group of lesions is important for pathologists and oncologists, as it provides a basis for guiding appropriate prevention strategies and treatment modalities based on the viral type.

Keywords: HPV11; HPV6; cervix; squamous cell carcinoma; vulva.

FIGURE 1.

Representative histopathologic features of HPV6/11-associated SCC. The lesions are composed of an exuberant florid undulating verruco-papillary squamous proliferation with invaginated/endophytic (A, case 3) and exophytic (B, case 5; C, case 6) architecture. On high power, the vast majority of lesions show hypercellularity, immaturity, increased mitotic activity, and high-grade cytologic features (D, case 5; E, case 6). Superficial stromal invasion is seen (F, case 3).

FIGURE 2.

Representative histopathologic features of HPV6/11-associated SCC. In case 2, the exophytic component has features of a condyloma acuminatum (A). Contiguous with the exophytic component, there is extensive endocervical gland involvement with bland cytology, mimicking papillary immature metaplasia/immature condyloma (B). The base exhibits features concerning but not fully diagnostic for stromal invasion (C). In case 4, the lesion is composed of an exuberant squamous proliferation with verruciform and bulbous papillae arranged in an exophytic and endophytic pattern (D). The lesion exhibits focal koilocytosis and a superficial infiltrative growth (E and F).

FIGURE 3.

Case 7 shows a papillary lesion (A) with high-grade cytologic features (B) and evident stromal invasion (C). The lesional cells exhibit a “block” pattern p16 expression (D) and a significantly increased Ki-67 proliferation index (E). Extensive HPV6/11 signal is detected by RNA ISH (F), and the sequencing analysis only detects HPV6 (G).

FIGURE 4.

The hysterectomy specimen in case 8 demonstrates exuberant exophytic verruco-papillary squamous proliferation (A) with stromal invasion (B and C). The tumor is negative p16 (D), and shows a significantly increased Ki-67 proliferation index (E). RNA ISH detects HPV6/11 in the tumor cells (F) and the sequencing analysis confirms the presence of HPV11 (G).

FIGURE 5.

Quantitative PCR-based HPV integration analysis. E2/E6 ratios range from 0.699 to 1.278 in the HPV6-infected group. E2/E6 ratio is 0.759 in case 8 which contained HPV11. In contrast, an HPV16-related cervical SCC has an E2/E6 ratio of 0.458, indicating a mixed episomal and integrated state.