Vulvar and vaginal intraepithelial neoplasia in patients with HIV infection

INTRODUCTION — Patients with HIV infection are at an increased risk of vulvar and vaginal neoplasia [1-5]. As with cervical neoplasia, the incidence and severity of vulvar and vaginal premalignant and malignant disease appear to correlate with worsening immunosuppression [6-8]. Furthermore, despite standard therapy, patients with HIV with vulvar or vaginal neoplasia have higher rates of persistence and recurrence than the general population, again similar to cervical neoplasia [9,10].

Screening, diagnosis, and treatment for vulvar and vaginal intraepithelial neoplasia (VIN and VaIN) in patients with HIV infection will be reviewed here. Vulvar and vaginal neoplasia in the general population are discussed separately. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)" and "Vaginal intraepithelial neoplasia".)

TERMINOLOGY — The Vulvar Oncology Subcommittee of the International Society for the Study of Vulvar Disease (ISSVD) published a classification system for VIN in 2004 [11]. The term VIN was limited to histologically high-grade squamous lesions (formerly termed VIN 2 and VIN 3), for which treatment is indicated to prevent progression to cancer [11]. Lesions previously referred to as VIN 1 were no longer classified as VIN. This topic review will adhere to the 2004 ISSVD nomenclature except when data are reported from studies that used the previous classification. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Terminology and epidemiology'.)

INCIDENCE — VIN and VaIN are precursors to vulvar and vaginal cancer and are more common in patients infected with HIV [12-14]. In the general United States population, the estimated incidence of VIN and VaIN is 2.9 and 0.2 to 0.3 per 100,000 females, respectively. (See "Vaginal intraepithelial neoplasia", section on 'Epidemiology' and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Epidemiology'.)

The incidence of VIN and VaIN in patients with HIV infection has not been extensively studied, but the available data are consistent with increased risk:

●In a prospective study, 5 of 385 patients with HIV followed for a median of 3.2 years developed new high-grade vulvar/perianal intraepithelial neoplasia compared with 0 of 341 patients without HIV infection [12].

●In another prospective study, the incidence of VaIN at six-year follow-up was 3 of 192 patients with HIV compared with 0 of 88 patients without HIV infection [13].

●A prospective study (n = 410) of patients who had undergone hysterectomy found a statistically significantly increased rate of VaIN 2 or vaginal cancer in patients with compared to without HIV infection (0.2 versus 0.01 per 100 person-years) [15].

PATHOPHYSIOLOGY — Human papillomavirus (HPV) infection is the primary etiology of vulvar, vaginal, and cervical neoplasia [16]. HPV and HIV interact in several ways that are relevant to VIN and VaIN:

●HPV and HIV infection share a sexual route of transmission, and therefore, the vulnerable populations often coincide.

●HIV-mediated immunosuppression results in exacerbation of HPV infection, and an increased incidence and severity of high-grade vulvar and vaginal lesions [17,18].

●HIV infection appears to impair local mechanisms of lower genital tract immunity, as demonstrated by a decreased Langerhans cell density in vulvar tissue in patients with HIV infection [19].

PREVENTION — Human papillomavirus (HPV) vaccination decreases the incidence of vulvar and vaginal neoplasia. This was demonstrated in a randomized trial of 5455 healthy females ages 16 to 24 years with no history of genital warts or abnormal cervical cytology who were assigned to receive the quadrivalent HPV vaccine (HPV types 6, 11, 16, 18) or a placebo injection [20]. At an average of three-year follow-up, there were fewer cases of grade 2 or 3 VIN or VaIN in patients in the vaccine group than in the placebo group (0.1 versus 0.2 percent); however, the trial did not have sufficient statistical power to assess whether the difference was significant (efficacy 62 percent, 95% CI <0-89). At the start of the study, 13 to 14 percent of patients tested positive for infection with one or more of the HPV types included in the vaccine. Excluding these patients from the analysis did not alter the magnitude of the effect of vaccination; the rates of grade 2 or 3 VIN or VaIN for the vaccine and placebo groups were 0.04 versus 0.1 percent. Additional details of this trial are discussed separately. (See "Human papillomavirus vaccination", section on 'Efficacy'.)

The safety or efficacy of the available HPV types 16 and 18 vaccine in preventing vulvar or vaginal neoplasia in patients with HIV infection is unknown. It appears that it can be used in immunosuppressed patients, since it is not a live vaccine. (See "Human papillomavirus vaccination", section on 'Patients with HIV or immunocompromising conditions'.)

However, the vaccine may be less effective since the distribution of HPV subtypes in patients with HIV infection is typically different from that seen in HIV-negative patients. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection", section on 'Role of HPV vaccination' and "Human papillomavirus infections: Epidemiology and disease associations", section on 'Females'.)

Given that HPV vaccination may offer some benefit to patients with HIV infection and is not contraindicated in patients with immunosuppression, we suggest HPV vaccination in patients with HIV. Either the quadrivalent (HPV types 6, 11, 16, 18) or bivalent (HPV types 16 and 18) formulation can be used, but the quadrivalent vaccine offers the additional potential benefit of prevention of anogenital warts associated with HPV types 6 and 11, which can be extensive in immunosuppressed patients. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)

Preexisting lower genital neoplasia is not a contraindication to HPV vaccination, since an individual may be infected with one but not all of the HPV subtypes included in the vaccine. Current HPV vaccines are for subtypes 16 and 18 or 16, 18, 6, and 11. The predominant HPV subtypes for vulvar cancer appear to be 16 and 33 and for vaginal cancer, 16 and 18 [21]. However, other oncogenic subtypes may be present. There are few adverse effects of vaccination. The decision of whether to vaccinate a patient with established vulvar or vaginal intraepithelial neoplasia must be based on whether the cost justifies the limited benefit.

Type-specific testing for HPV 16 and 18 is not useful for identifying patients who should not receive the vaccine, since HPV infection can be transient and it is not known if previous HPV infection is protective against reinfection. (See "Human papillomavirus vaccination", section on 'Pre-existing HPV-associated disease'.)

CLINICAL MANIFESTATIONS — Clinical manifestations of VIN and VaIN in patients with HIV infection are the same as for patients without HIV infection. Approximately 50 percent of patients with VIN are asymptomatic. In symptomatic patients, the most common complaint is vulvar pruritus; other presentations include perineal pain or burning, dysuria, a visible lesion, or a palpable abnormality. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Clinical presentation'.)

VaIN is nearly always asymptomatic, but some patients present with postcoital spotting or vaginal discharge. (See "Vaginal intraepithelial neoplasia", section on 'Diagnostic evaluation'.)

SURVEILLANCE — VIN and VaIN are rare conditions, and screening is not routinely performed in the general population. Although patients with HIV infection have an increased risk of these conditions, there are no data or guidelines regarding screening patients with HIV for vulvar or vaginal cancer.

By contrast, multiple expert groups have devised consensus guidelines for cervical cancer screening in patients with HIV; this is reviewed in detail elsewhere. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states", section on 'Our approach to screening'.)

Patients with HIV should, therefore, undergo a pelvic examination annually, at minimum. We suggest that patients with HIV undergo a careful vulvar and vaginal examination whenever a pelvic examination is performed for cervical cancer screening or for another indication (with the exception of focused examinations during which vulvar or vaginal examination for neoplasia would not be practical).

In our practice, we examine patients who are immunosuppressed (CD4 cell count <200/mm³) or have a viral load of ≥500 copies/mL at least every six months.

DIAGNOSTIC EVALUATION — VIN and VaIN are histologic diagnoses based upon vulvar or vaginal biopsy. Biopsy may be directed by gross visual examination of lesions or by examination under magnification with a colposcope or hand-held magnifying device.

Indications for a diagnostic evaluation are:

●Clinical manifestations of VIN or VaIN

●Vaginal or vulvar lesions that are suspicious for neoplasia

●Abnormal cervical cytology, if a cervical lesion is not identified

Aspects of evaluation for VIN and VaIN that are specific to patients with HIV infection are described here. General techniques for vulvar and vaginal examination and biopsy are discussed separately. (See "Vulvar lesions: Diagnostic evaluation", section on 'Basic examination' and "Vulvar lesions: Diagnostic evaluation", section on 'Additional procedures' and "Vaginal intraepithelial neoplasia", section on 'Diagnostic evaluation'.)

Vulvar neoplasia

Vulvar examination — A complete examination is performed of areas with potential squamous neoplasia. In patients with HIV, this includes examination of the vulva as well as the perineum and perianal areas.

VIN is highly variable in appearance and may be a subtle visual finding. In the general population, VIN is commonly located between the 3:00 and 9:00 positions along the labia minora and the introitus (mapping vulvar sites according to locations around a clock face). In patients with HIV, VIN may be more extensive and scattered. Lesions may involve the clitoris, urethra, anus, and intergluteal cleft and can easily be overlooked [22].

Characteristics of vulvar lesions and techniques for vulvar examination and evaluation of anal lesions are discussed separately. (See "Vulvar lesions: Diagnostic evaluation", section on 'Basic examination'.)

Vulvar colposcopy and biopsy — Colposcopy or examination using a hand-held magnifying glass may be useful for some vulvar lesions. We use magnification to examine any small lesion that is visible but is difficult to see with the unaided eye. Biopsy is performed of all lesions that are not obviously benign (eg, epidermoid cysts, often erroneously referred to as sebaceous cysts). (See "Vulvar lesions: Differential diagnosis of vesicles, bullae, erosions, and ulcers".)

The techniques for vulvar colposcopy and biopsy are reviewed elsewhere. (See "Colposcopy", section on 'Vulvar colposcopy' and "Vulvar lesions: Diagnostic evaluation", section on 'Use of biopsy'.)

Vaginal neoplasia

Vaginal examination — During the vaginal examination, attempts are made to visualize lesions while using a speculum and to palpate lesions with a manual examination. VaIN may be difficult to visualize without magnification, and is therefore usually detected with cytology. When it is visible, it is generally white in appearance, with sharp borders and a granular texture. VaIN may be multifocal, particularly in patients with HIV.

Vaginal cytology, colposcopy, and biopsy — Vaginal and cervical cytology is performed if these samples have not yet been obtained. Colposcopy is usually needed to visualize vaginal lesions. Biopsy is performed of all lesions that are suspicious for neoplasia. (See "Colposcopy", section on 'Vaginal colposcopy' and "Vaginal intraepithelial neoplasia", section on 'Biopsy technique'.)

MANAGEMENT — Management of patients with HIV infection with VIN or VaIN involves treatment of lesions as well as of the underlying HIV infection.

Aspects of treatment for VIN and VaIN that are specific to patients with HIV infection are described here. General principles of VIN and VaIN treatment are discussed separately. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Treatment' and "Vaginal intraepithelial neoplasia", section on 'Treatment'.)

Vulvar neoplasia — Conservative surgical excision and destruction of the lesions are the mainstays of therapy for VIN in patients with HIV, as they are in the general population. Total or even simple vulvectomy may be debilitating, particularly in immunosuppressed individuals, and is rarely required. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Treatment'.)

Medical therapy of VIN is reserved for patients in whom excision with negative margins would necessitate significant vulvar mutilation (eg, clitoral, periurethral, or perianal lesions). There are few data regarding medical therapy for VIN (eg, fluorouracil, imiquimod, interferon alfa, retinoids) in patients with HIV [23,24]. Patients who fail treatment with topical therapy should be treated with surgical excision.

Vaginal neoplasia — There are no data regarding treatment of VaIN in patients with HIV. The usual approach to treatment is the same as for the general population. Unifocal VaIN is treated with conservative surgical excision and destruction of the lesions. Multifocal or recurrent VaIN is best treated with topical fluorouracil. (See "Vaginal intraepithelial neoplasia", section on 'Treatment'.)

Highly active antiretroviral therapy — Highly active antiretroviral therapy (HAART) appears to decrease the incidence and recurrence of VIN [10,14]. The magnitude of this effect was illustrated in a multicenter prospective study of 1562 HIV-positive patients [14]. Current or former use of HAART compared with no HAART use was associated with a one-third decrease in the incidence of VIN, which was statistically significant in a multivariate analysis that controlled for CD4 count and HIV RNA level. Based upon these data, we suggest HAART rather than no antiretroviral therapy for patients with HIV who are candidates for antiretroviral therapy and who have VIN. There are few data regarding the effect of HAART on vulvar cancer in patients with HIV [14].

Theoretically, HAART use should also decrease the incidence of VaIN and vaginal cancer, but no studies have investigated this question. This is likely because a beneficial effect is seen for VIN and cervical intraepithelial neoplasia, which have the same HPV-mediated pathophysiology as VaIN. As a result, we suggest use of HAART for patients with HIV with VaIN. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection", section on 'Antiretroviral therapy'.)

PROGNOSIS — Information on the outcome of VIN and VaIN in patients with HIV infection is limited. In the general population, the risk of recurrence after treatment of VIN and VaIN ranges from 20 to 70 percent, and the risk of progression to invasive cancer ranges from 1 to 5 percent. The risk of recurrence of VIN/VaIN appears to be higher in patients with HIV than in other patients, as it is for cervical intraepithelial neoplasia [25,26]. As an example, in a study of patients with anogenital lesions, the recurrence rate after laser treatment was higher for patients with HIV compared with patients without HIV infection (26 versus 17 percent) [26]. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Disease recurrence' and "Vaginal intraepithelial neoplasia", section on 'Natural history'.)

Long-term data on lower genital tract neoplasia in patients with HIV are limited. While it has been reported that multiple concurrent human papillomavirus-associated neoplasias may not be uncommon in patients with HIV, even in those whose disease is well-controlled as measured by CD4 and viral loads [27], the same authors previously found that the overall outcomes were similar to those seen in patients not infected with HIV in the same population with 20-year follow-up [28].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vulvar cancer and vaginal cancer".)

SUMMARY AND RECOMMENDATIONS

●Patients with HIV infection are at an increased risk of vulvar and vaginal neoplasia. The incidence and severity of vulvar and vaginal neoplasia appears to be correlated with worsening immunosuppression. (See 'Incidence' above and 'Pathophysiology' above.)

●For patients with HIV, we suggest human papillomavirus (HPV) vaccination (Grade 2B). Either the quadrivalent (HPV types 6, 11, 16, 18) or bivalent (HPV types 16 and 18) formulation can be used, but the quadrivalent vaccine offers the additional potential benefit of prevention of anogenital warts. (See 'Prevention' above.)

●Most patients with vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN) are asymptomatic. In symptomatic patients with VIN, the most common complaint is vulvar pruritus. Patients with VaIN occasionally present with postcoital spotting or vaginal discharge. (See 'Clinical manifestations' above.)

●We suggest that patients with HIV undergo a careful vulvar and vaginal examination whenever a complete pelvic examination is performed (eg, for cervical cancer screening). (See 'Surveillance' above.)

●For patients with HIV with abnormal cervical cytology in whom a cervical lesion is not identified, we suggest that vaginal cytology and colposcopy be performed. (See 'Surveillance' above.)

●VIN and VaIN are histologic diagnoses made using vulvar or vaginal biopsy. Biopsy may be directed by gross visual examination of lesions or by examination under magnification with a colposcope or hand-held magnifying device. (See 'Diagnostic evaluation' above.)

●Patients with HIV with VIN or VaIN are treated the same as patients in the general population. Conservative surgical excision and destruction of lesions are the mainstays of therapy. Topical therapy is reserved for patients with multifocal disease. (See 'Management' above and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Treatment' and "Vaginal intraepithelial neoplasia", section on 'Treatment'.)

●For patients with HIV with VIN or VaIN, we suggest highly active antiretroviral therapy rather than no antiretroviral therapy (Grade 2C). (See 'Highly active antiretroviral therapy' above.)