Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

Abstract

Two independent pathways of vulvar carcinogenesis have currently been identified, one related to infection with mucosal human papillomaviruses (HPVs) and a second related to chronic inflammatory or autoimmune processes. The goal of the study was to examine a possible role of cutaneous HPVs from the beta genus in vulvar carcinogenesis and to evaluate the distribution of intratypic variants of HPV 16 in HPV 16-positive vulvar cancer. Consecutive cases of vulvar carcinoma were retrieved from the files and included the following histologic subtypes: keratinizing (n ¼ 21), basaloid (n ¼ 7), warty (n ¼ 1), mixed basaloid-warty (n ¼ 4), verrucous (n ¼ 4), keratoacanthoma (n ¼ 1), basal cell carcinoma (n ¼ 1). All tumors were microdissected and tested for 25 beta HPV types and 25 mucosal HPV types. Cases identified as positive for HPV 16 were further tested for intratypic variants. All cases were immunostained for p16 INK4a . Beta HPVs were not detected in any of the tumor cases. Mucosal HPVs were detected in all but one basaloid/warty carcinomas; of these, nine cases (82%) were positive for HPV 16, including five European subtypes, one African subtype, one North American subtype and two indeterminate subtypes. Two of four verrucous carcinomas were positive for HPV 6. Mucosal HPVs were not detected in keratinizing carcinomas, keratoacanthoma and basal cell carcinoma. All cases of basaloid/warty carcinomas, but none of the remaining tumors, overexpressed p16 The pathogenesis of vulvar carcinoma is not entirely understood. Results of epidemiologic, clinicopathologic and virologic studies are in support of two independent pathways of vulvar carcinogenesis, one related to infection with oncogenic mucosal human papillomaviruses (HPVs) and a second related to a chronic inflammatory and/or autoimmune process involving vulvar mucosa and skin. [1][2][3][4][5][6] Vulvar cancers associated with oncogenic mucosal HPVs tend to occur in young women with past history of genital warts, cervical dysplasia and/or immunosuppression. These carcinomas typically belong to basaloid or warty histologic subtypes and develop from a well-characterized in situ lesion, namely, classic vulvar intraepithelial neoplasia grade 3 (VIN3).7 Approximately 80-90% of HPVpositive vulvar cancers are associated with HPV16 and nearly all remaining tumors are positive for HPV18 and HPV33. [4][5][6][8][9][10][11][12][13] Vulvar carcinomas not associated with mucosal HPVs occur in older women. These well-differentiated keratinizing squamous cell carcinomas histologically resemble conventional squamous cell carcinomas occurring in non-genital skin. 4 However, unlike the usual squamous cell carcinomas, vulvar cancers are not arising in the setting of actinic keratosis. In the vulva, these tumors develop in a background of squamous cell hyperplasia, a chronic inflammatory condition, or long-lasting lichen sclerosus, a lesion with strong links to autoimmune diseases. Although patients with lichen sclerosus

Biological activity of probable/possible high‐risk human papillomavirus types in cervical cancer

“…31 Briefly, DNA was released from the sections by incubation in 150 ll proteinase K solution (1 mg/ml) for 16 hr at 56 C, followed by enzyme deactivation at 72 C for 10 min. Ten microliters of paraffinfree extracted DNA were used for PCR.…”

“…34,35 The multiplex type-specific E7 PCR utilizes HPV type-specific primers targeting the E7 region for the detection of 19 HR-/pHR (HPV16, 18,26,31,33,35,39,45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, 82) and 2 LRtypes (HPV6, 11), with detection limits ranging from 10 to 1,000 copies of the viral genome. 34 Two primers for the amplification of b-globin were also included to provide a positive control for the quality of the template DNA.…”

“…1,2 Epidemiological studies have demonstrated that 20 mucosal HPV types from five phylogenetically related species of the genus alpha (a5, a6, a7, a9 and a11-termed as ''high-risk clade'') are consistently found as single HPV infections in CxCa worldwide. [3][4][5][6] Based on their frequency in CxCa and available biological data, 12 of these types, i.e., types 16,18,31,33,35,39,45, 51, 52, 56, 58 and 59 have been defined as carcinogens (IARC Group 1A)-hereafter referred to as high-risk (HR)-HPV. For eight other types, in the high-risk clade, i.e., types 26, 53, 66, 67, 68, 70, 73 and 82, the combination of their low frequency, lack of data on their active transcription and their transforming potential in model systems, has led them to be classified as only probable/possible carcinogens (IARC Groups 2A and 2B)-hereafter referred to as possible highrisk (pHR)-HPV types.…”

Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma

“…[4][5][6] Oral verrucous carcinoma has been associated with the chronic use of tobacco or with the practice of chewing betel nuts, 7 ultraviolet radiation has been associated with verrucous carcinoma arising from the skin 8 and chronic lesions like squamous cell hyperplasia and lichen sclerosus have been related to vulvar verrucous carcinoma development. 9 More recent studies suggest a potential role for human papillomavirus (HPV) in the pathogenesis of verrucous carcinoma, although the literature data are controversial. 10,11 HPV are non-enveloped, double-stranded DNA viruses belonging to the family of Papillomaviridae.…”

“…In those cases, low-risk HPV types may initiate the growth process and the chronic epithelial irritation could subsequently contribute to the development of a malignant phenotype. 9 The aim of this study was to analyse comprehensively verrucous carcinoma from different origins, that is, head and neck region, the anogenital area and extragenital skin for the presence of HPV, including both mucosal and cutaneous types, and to carefully review the histopathological diagnosis. Cases testing positive for low-risk HPV were also examined for viral E6 mRNA expression and p16 INK4a staining to determine their potential contribution to tumour development.…”