INTRODUCTION —
Patients with human immunodeficiency virus (HIV) infection are at an increased risk of vulvar and vaginal neoplasia compared with patients without HIV infection. The incidence and severity of vulvar and vaginal premalignant and malignant disease also appear to correlate with worsening immunosuppression. Furthermore, despite standard therapy, patients with HIV with vulvar or vaginal neoplasia have higher rates of persistence and recurrence than patients without HIV.
Screening, diagnosis, and treatment for vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) in patients with HIV infection will be reviewed here. Cervical neoplasia in patients with HIV, as well as vulvar and vaginal neoplasia in patients without HIV are discussed separately.
●(See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)".)
●(See "Vaginal intraepithelial neoplasia".)
●(See "Preinvasive and invasive cervical neoplasia in patients with HIV infection".)
TERMINOLOGY —
Terminology for VIN and VaIN is as follows:
•Low-grade squamous intraepithelial lesion (LSIL) of the vulva (also referred to as VIN 1)
•High-grade squamous intraepithelial lesion (HSIL) of the vulva (also referred to as VIN 2 and VIN 3)
•Differentiated VIN
●VaIN [2,3]:
•LSIL of the vagina (also referred to as VaIN 1)
•HSIL of the vagina (also referred to as VaIN 2 or 3)
This is discussed in detail separately. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Terminology and epidemiology' and "Vaginal intraepithelial neoplasia", section on 'Classification'.)
INCIDENCE —
VIN and VaIN are precursors to vulvar and vaginal cancer and are more common in patients with HIV compared with patients without HIV [4-11]. (See "Vaginal intraepithelial neoplasia", section on 'Epidemiology' and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Epidemiology'.)
While the incidence of VIN and VaIN in patients with HIV infection has not been extensively studied, available data are consistent with increased risk:
●In a prospective study of 726 patients evaluating the risk of VIN and VaIN, those with HIV (53 percent) compared with patients without HIV had higher rates of developing a new high-grade vulvar/perianal intraepithelial neoplasia (five versus no patients) during the 3.2-year (median) follow-up period [9].
●In a subsequent prospective study of 280 patients, those with (69 percent) versus without HIV had higher rates of VIN and VaIN at baseline (1.6 versus 0 percent) and during the six years of follow-up (8.5 versus 1.1 percent, respectively) [10]. This study also included findings of perianal intraepithelial neoplasia.
●In another prospective study of 410 patients who had undergone hysterectomy, patients with versus without HIV infection had an increased rate of VaIN 2 or vaginal cancer (0.2 versus 0.01 per 100 person-years) [12].
PATHOGENESIS AND PREVENTION
Pathophysiology — Human papillomavirus (HPV) infection is the primary etiology of vulvar and vaginal neoplasia [13]. HPV and HIV interact in several ways that are relevant to VIN and VaIN:
●HPV and HIV infection share a sexual route of transmission.
●HIV-mediated immunosuppression results in exacerbation of HPV infection and an increased incidence and severity of high-grade vulvar and vaginal lesions [14-18].
●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].
In patients with HIV, the predominant HPV subtypes for vulvar cancer (16 and 33) and vaginal cancer (16 and 18) are the same as those without HIV infection [20]. However, other oncogenic subtypes are also often present. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Risk factors and prevention' and "Vaginal intraepithelial neoplasia", section on 'Human papillomavirus'.)
Prevention
HPV vaccination — Patients with HIV who meet age criteria for human papilloma virus (HPV) vaccination should be vaccinated as HPV vaccination decreases the incidence of vulvar and vaginal neoplasia. However, the vaccine may be less effective in patients with versus without HIV. (See "Human papillomavirus vaccination", section on 'Efficacy' and "Human papillomavirus vaccination", section on 'Patients with HIV or immunocompromising conditions'.)
Preexisting lower genital neoplasia is also 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. The decision of whether to vaccinate a patient with established VIN or VaIN is often based on whether the cost justifies the limited benefit. Type-specific testing 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'.)
Role of screening — For patients with HIV, we screen for VIN and VaIN as such patients are at an increased risk of these conditions (see 'Incidence' above). This is different than in patients without HIV, in whom screening is not routinely performed.
To screen for VIN and VaIN in patients with HIV, we perform a pelvic examination with a careful vulvar, vaginal, and perianal examination at least annually. In patients who are immunosuppressed (CD4 cell count <200/mm3) or have a viral load of ≥500 copies/mL, we perform this examination more frequently (eg, every six months). This can be performed during an examination for cervical cancer screening or another indication (except for focused examinations during which vulvar or vaginal examination for neoplasia would not be practical). Screening is also performed in patients without a cervix (eg, prior history of hysterectomy for benign disease).
However, there are no data nor guidelines to support routine screening or this schedule, though multiple expert groups have devised consensus guidelines for related conditions (eg, cervical cancer screening) in patients with HIV. This is reviewed in detail separately. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states", section on 'Our approach to screening'.)
CLINICAL MANIFESTATIONS —
Clinical manifestations of VIN and VaIN in patients with HIV infection are the same as for patients without HIV infection.
For patients with VIN, approximately 50 percent 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'.)
By contrast, VaIN is nearly always asymptomatic, but some patients present with postcoital spotting or vaginal discharge. (See "Vaginal intraepithelial neoplasia", section on 'Clinical presentation'.)
DIAGNOSTIC EVALUATION —
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 intraepithelial 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 patients without HIV, VIN is commonly located between the three o'clock and nine o'clock 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 (picture 1). Lesions may involve the clitoris, urethra, anus, and intergluteal cleft and can easily be overlooked [21].
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 intraepithelial neoplasia
Vaginal examination — During 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'.)
DIAGNOSIS —
VIN and VaIN are histologic diagnoses based upon vulvar or vaginal biopsy. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Diagnosis and histopathology' and "Vaginal intraepithelial neoplasia", section on 'Diagnosis'.)
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 intraepithelial neoplasia — Wide local excision or ablation of the lesions are the mainstays of therapy for VIN in patients with HIV, as they are in patients without HIV. Total or even simple vulvectomy may be performed in select patients (picture 2), but 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 [22,23]. Patients who fail treatment with topical therapy should be treated with surgical excision.
Vaginal intraepithelial neoplasia — There are no data regarding treatment of VaIN in patients with HIV. The usual approach to treatment is the same as for patients without HIV; unifocal VaIN is typically treated with surgical excision or ablative therapy, while multifocal or recurrent VaIN is typically treated with topical therapies. (See "Vaginal intraepithelial neoplasia", section on 'Treatment'.)
Role of antiretroviral therapy — Antiretroviral therapy (ART) appears to decrease the incidence and recurrence of VIN [11,24]. The magnitude of this effect was illustrated in a multicenter prospective study of 1562 HIV-positive patients [11]. Current or former use of ART compared with no ART 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. There are few data regarding the effect of ART on vulvar cancer in patients with HIV [11].
Theoretically, ART 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. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection", section on 'Antiretroviral therapy'.)
ART in patients with HIV is discussed separately. (See "When to initiate antiretroviral therapy in persons with HIV" and "Overview of antiretroviral agents used to treat HIV".)
POSTTREATMENT SURVEILLANCE AND PROGNOSIS —
After treatment has been completed, long-term surveillance of the entire genital tract is performed given the risk of disease recurrence. In our practice, we perform a clinical examination every six months for five years and then annually thereafter, and more frequently in those with immunosuppression (eg, CD4 cell count <200/mm3, viral load of ≥500 copies/mL). However, practice varies, and other experts may perform surveillance less often.
The risk of recurrence of VIN/VaIN appears to be higher in patients with HIV compared with patients without HIV, as it is for cervical intraepithelial neoplasia [24-27]. In one retrospective study of 106 patients with condylomatous or neoplastic anogenital lesions, patients with HIV compared with patients without HIV infection had higher rates of recurrence after laser treatment (26 versus 17 percent) during the six-month follow-up period [27]. Long-term data on lower genital tract neoplasia in patients with HIV are even more limited. While it has been reported that multiple concurrent human papillomavirus (HPV)-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) [28], 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 [29].
Disease recurrence and prognosis in patients with VIN and VaIN is discussed in more detail separately. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Disease recurrence' and "Vaginal intraepithelial neoplasia", section on 'Natural history'.)
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
●Incidence – Vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) are precursors to vulvar and vaginal cancer and are more common in patients with HIV compared with patients without HIV. (See 'Incidence' above.)
●Prevention
•HPV vaccination – Human papillomavirus (HPV) infection is the primary etiology of VIN/VaIN. Patients with HIV who meet age criteria for HPV vaccination should be vaccinated. This is discussed separately. (See 'Pathogenesis and prevention' above and "Human papillomavirus vaccination", section on 'Patients with HIV or immunocompromising conditions'.)
•Role of screening – We perform a pelvic examination with a careful vulvar, vaginal, and perianal examination at least annually, and more frequently (eg, every six months) for patients who are immunosuppressed (CD4 cell count <200/mm3) or have a viral load of ≥500 copies/mL. However, there are no guidelines to support routine screening or this schedule. This is also different than in patients without HIV, in whom screening is not routinely performed. (See 'Role of screening' above.)
●Clinical manifestations – Many patients with VIN or 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.)
●Diagnostic evaluation
•Diagnostic evaluation should be performed in patients with clinical manifestations of VIN or VaIN, vaginal or vulvar lesions that are suspicious for neoplasia (picture 1), or abnormal cervical cytology in whom a cervical lesion is not identified. (See 'Diagnostic evaluation' above.)
•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.)
●Diagnosis – VIN and VaIN are histologic diagnoses made using vulvar or vaginal biopsy. (See "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Diagnosis and histopathology' and "Vaginal intraepithelial neoplasia", section on 'Diagnosis'.)
●Management
•In general, patients with HIV with VIN or VaIN are treated the same as patients without HIV. Wide local excision and ablative treatment are the mainstays of therapy. Vulvectomy may be performed in select patients (picture 2), but is rarely required. Medical therapy is generally reserved for patients with multifocal disease. This is discussed in detail separately. (See 'Management' above and "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Treatment' and "Vaginal intraepithelial neoplasia", section on 'Treatment'.)
•Role of antiretroviral therapy – Use of antiretroviral therapy in patients with HIV is associated with a lower risk of VIN; antiretroviral therapy also likely lowers the risk of VaIN and vaginal cancer. ART is discussed in detail separately. (See 'Role of antiretroviral therapy' above and "When to initiate antiretroviral therapy in persons with HIV" and "Overview of antiretroviral agents used to treat HIV".)
●Posttreatment surveillance – After treatment (eg, excision, ablation) has been completed, long-term surveillance of the entire genital tract is performed given the risk of disease recurrence. In our practice, we perform a clinical examination every six months for five years and then annually thereafter, and more frequently in those with immunosuppression. However, other experts may perform surveillance less often. (See 'Posttreatment surveillance and prognosis' above.)