Vulvar Intraepithelial Neoplasia

Etiology

There are 2 different types of VIN: uVIN, which is associated with HPV, and dVIN, which is associated with chronic inflammation. The classification of VIN is based on histology and does not involve HPV testing. 

dVIN

• Accounts for only 5% (approximately) of all VIN cases
• Correlates with a greater potential for progression to invasive SCC [3] 

uVIN 

• An HPV lesion
• Increases the likelihood of other anogenital cancers [3] 

Low-grade lesions are not considered premalignant and are treated as condyloma. HPV prevalence in VIN (HSIL) has been reported in 72% to 100% of cases. HPV-16 is the most common HPV type.[4]

Epidemiology

The incidence of VIN is higher in White women than non-White women, with the highest reported incidence occurring during the fourth decade of life.[3] uVIN is more common in younger women and can even occur in adolescent girls (average age at presentation, 40 years), whereas dVIN is more common in older women (average age at presentation, 60 years).[3][5][6] 

HPV DNA is present in most VIN and SCC; thus, VIN is considered an HPV-associated disease.[3] The 3 most common types of HPV found in VIN lesions are 16, 18, and 33.[3] Other risk factors for VIN include multiple sexual partners, cigarette smoking, and immunocompromised states such as those found in patients with HIV infection, autoimmune diseases, and organ transplants.[5][6][7] Risk factors for dVIN include vulvar dermatoses such as lichen sclerosis. 

A recent study from the Netherlands of 1100 patients with high-grade VIN showed an increased incidence of both HSIL and dVIN.[8] This change may be due to greater awareness of VIN, which may have led to increased vulvar biopsies.[8] The study also showed the 10-year cumulative risk of vulvar cancer, which was significantly greater for dVIN than for HSIL.[8] Another study put the risk of vulvar cancer in dVIN between 33% and 86%, with time to progression between 9 and 23 months.[9]

Table. Characteristics of uVIN and dVIN

Adapted from Kavitha A, Deeksha P.[10]

Pathophysiology

HPV is a single-stranded DNA virus. When the body fails to produce an effective immune response to high-risk HPV subtypes, uVIN occurs. The viral DNA integrates into host cells, producing oncoproteins E6 and E7, which interfere with normal cellular function.[3] Mutations in the tumor suppressor genes p53 and PTEN and microsatellite instability have also been demonstrated in HPV-independent carcinogenesis.[3][5][6] In contrast, dVIN appears to be related to chronic oxidative genetic damage that promotes similarly aberrant cellular function. Lichen sclerosis and lichen planus are examples of chronic, inflammatory changes in the normal epithelium that are associated with SCC of the vulva.[3][5] 

Histopathology

The histological feature necessary for diagnosing VIN is the proliferation of atypical basal cells. The 5 criteria for atypia are basal layer involvement, enlarged nuclei, hyperchromasia, pleomorphic cells, and increased numbers of mitotic figures.[3] Aside from atypia, both uVIN and dVIN have distinctive features.

In uVIN, proliferation begins at the basal layer and involves partial to full thickness of the squamous epithelium.[5] The uVIN lesions exhibit basal cells with large, dark nuclei and small amounts of basophilic cytoplasm.[3] However, approaching the surface epithelium, atypical basaloid cells may mature to develop an abundant eosinophilic cytoplasm.[3] The more mature squamous cells often display a cytopathic change termed koilocytosis.[3] Warty and basaloid subtypes of uVIN are described; both forms are premalignant and treated identically.[3]

A high oncogenic potential exists with dVIN, and dVIN characteristics are more subtle.[5] Key features of dVIN are a thickened epidermis, parakeratosis, basal nuclear atypia, and premature maturation above the basal layer. These premature cells possess eosinophilic cytoplasm, intracellular prickles, large nuclei, and prominent nucleoli.[3] The relatively high degree of differentiation often present in dVIN lesions can be mistakenly diagnosed as benign.[5]

Immunohistochemistry markers can be used to differentiate between uVIN and dVIN. P53 positivity and p16 negativity support a dVIN diagnosis, whereas the converse supports a uVIN diagnosis.[3][5][6] VIN with a TP53 mutation may be a significant risk factor for both VIN recurrence and the development of invasive disease.[10]

History and Physical

VIN is a clinical diagnosis.[3] There is no routine screening test for VIN; however, abnormal cytology or a positive high-risk HPV test used in cervical cancer screening warrants an independent visual assessment of the vulva.[3] Acetic acid alone is not recommended for diagnosis because the whitened color of observed lesions is not specific to vulvar intraepithelial neoplasia.[3] One should note the following on examination of the vulva for lesions seen: location, number, size, shape, color, and thickness.

VIN is generally multifocal. Lesions may be raised, verrucous, and white; however, they may also be red, gray, or pigmented. There is no pathognomic appearance, hence the need for a biopsy of any abnormal vulvar lesion. Different patterns may be present in the same patient.[11]

Evaluation

uVIN and dVIN are clinically dissimilar: uVIN is commonly multifocal and elevated, found around the introitus and labia majora;[3] dVIN lesions demonstrate poorly demarcated pink or white plaques (often associated with lichen sclerosis or lichen planus) and are refractory to medical therapy.[3][6] 

A colposcopic examination of the vulva can be performed to complement a visual exam; a hand lens with magnification can also be used. Toluidine solution to identify VIN (Collins test) has low specificity and is not recommended.[12] 

All portions of the vulva, including the labia majora and minora, vestibule, clitoris, terminal urethra, perineum, and perianal area, should be examined. If high-grade lesions are discovered, an examination and cytology of the anal canal may be necessary. Up to 18% of patients with vulvar HSIL may have anal lesions.[11] Any observed vulvar lesions require a biopsy to determine appropriate treatment.[3]

Treatment / Management

The ideal treatment of VIN involves the complete destruction of the lesion, symptom improvement, and preservation of vulvar function.[3] Treatment options include surgical, medical, or expectant management. Prevention has, and will ultimately continue to, decrease the disease burden.

uVIN

Excisional Treatment

Cold knife surgery and loop electrosurgical excision procedure (LEEP) are the preferred treatments for uVIN. The recommendations for negative surgical margins are a 5-mm peripheral margin and a 4-mm deep margin. However, margin status does not predict the risk of invasive or recurrent disease.[3]

An alternative treatment is CO₂ laser ablation, but vaporization of the diseased tissue precludes a pathologic specimen.[3] Although the advantage of laser ablation is the preservation of normal anatomy with less scarring, the cost is an increased risk of recurrence.[7](B2)

Medical Treatment

Imiquimod is an immune-modifying drug that induces proinflammatory cytokines with antiviral and antitumor properties and enhances innate and cell-mediated immunity against HPV.[3] Trials using Imiquimod have demonstrated efficacy comparable to surgical results, and it can be an adjunct to excision with positive margins or recurrent cases.[13] Local irritation, erythema, and erosions may occur. Complete response rates in database reviews were 51%, and partial response rates were 25%.[14](A1)

Other medical options for treatment are utilized less often. Cidofovir is an acyclic nucleoside analog with antiviral properties that promotes apoptosis of HPV-infected cells.[3] Photodynamic therapy is an option in conjunction with nonthermal light to generate oxygen-induced cellular death.[3] 

dVIN

Excisional Treatment

dVIN is associated with lichen sclerosis and invasive disease (specifically, SCC of the vulva).[15] Recurrence rates for dVIN are much higher than those for uVIN.[16] Treatment of these lesions should include surgical excision with a scalpel, LEEP, or laser. Wide local excision is preferable as the initial treatment.[17][18][19](A1)

Expectant Management

Spontaneous regression is reported in uVIN but is adversely influenced by the increasing age of the patient, clinical presentation with chronic immunosuppression and multifocal disease, and the longer duration of the lesion.[3] Close surveillance of these patients is required even after spontaneous regression occurs. Women younger than 35 years have a higher rate of regression. Pregnancy has been reported to increase both spontaneous regressions and the progression of premalignant vulvar lesions.[5]

Preventative Management

HPV vaccination has reduced the incidence of VIN in young women.[5] However, HPV vaccination is designed as a prophylactic measure, not a treatment for confirmed lesions.[6](B3)

Differential Diagnosis

Any observed lesion of the vulva requires a biopsy for diagnosis. Benign lesions include common dermatopathology such as lichen simplex, lichen sclerosis, or lichen planus. Vulvar lesions may also result from infections such as vestibulitis, candidiasis, or herpes. Genital warts, psoriasis, condyloma acuminata, and seborrheic keratosis are also included in the differential diagnosis. VIN is a preinvasive lesion that may appear similar to these more common skin changes or common malignancies such as basal cell carcinoma, SCC, Paget disease, or melanoma. Treatment without biopsy confirmation risks progression and delays the diagnosis of potential malignancy.[20]

Prognosis

The prognosis of biopsy-confirmed VIN that receives prompt treatment is uniformly good; there is rarely progression to invasive cancer unless treatment is declined or markedly delayed. Without treatment, uVIN can progress to invasive cancer in 6 to 7 years, whereas in untreated dVIN, vulvar cancer can result in 2 to 4 years.

Long-term surveillance is necessary, given the high recurrence rate after any treatment and the possibility of long-term recurrences. Follow-up is recommended every 6 to 12 months (for at least 5 years for uVIN, indefinitely for dVIN).

A third to one-half of patients may have a recurrence of their disease, and 25% of patients can experience late recurrences. Risk factors for recurrence include large lesion size, age (50 years and older), positive excision margins, multifocal disease, immunosuppression, and tobacco use.[21][10] 

Complications

The most severe complication of untreated VIN is progression to invasive carcinoma. Malignant disease of the vulva necessitates more involved radical resection, commonly associated with perioperative morbidities such as pain, infection, wound dehiscence, and altered vulvar appearance. Surgical resection complications depend on the treated lesions' location, distribution, and size. Topical therapies may result in irritation, burning, or ulceration.