Practical Gynecologic Oncology
4th Edition

Vulva and Perianal Area
Since approximately 1970, there has been a marked increase in the incidence of high-grade preinvasive vulvar disease and a decrease in the modal age of diagnosis. There has not been an associated increase in the incidence of invasive vulvar cancer, presumably because the preinvasive disease is actively treated.
Classification
Preinvasive neoplasia of the vulva has been recognized for more than 75 years, but the descriptive terminology has been confusing. Vulvar carcinoma in situ has been described as Bowen’s disease, erythroplasia of Queyrat, carcinoma in situ simplex, bowenoid papulosis, kraurosis vulvae, and leukoplakia (339). This confusion was compounded by the use of similar terms to describe a group of nonneoplastic vulvar diseases to which Jeffcoate (340) in 1966 assigned the term chronic vulvar dystrophy. In 1989, the International Society for the Study of Vulvar Disease (341) agreed on a new classification of vulvar epithelial disorders (Table 8.8).
Table 8.8 Classification of Epithelial Vulvar Disorders

Nonneoplastic epithelial disorders of skin and mucosa

Lichen sclerosis (formerly lichen sclerosis et atrophicus)
Squamous hyperplasia (formerly hyperplastic dystrophy)
Other dermatoses (e.g., psoriasis)

Intraepithelial neoplasia

Squamous intraepithelial neoplasia
   VIN I (mild dysplasia)
   VIN 2 (moderate dysplasia)
   VIN 3 (severe dysplasia/carcinoma in situ)
Nonsquamous intraepithelial neoplasia
   Paget’s disease
   Tumors of the melanocytes, noninvasive (melanoma in situ)

Mixed nonneoplastic and neoplastic epithelial disorders

Invasive tumors

VIN, vulvar intraepithelial neoplasia.
From Committee on Terminology, International Society for the Study of Vulvar Disease. New nomenclature for vulvar disease. Int J Gynecol Pathol 1989;8:83.
Although this classification represented a significant advance in rationalizing previously confusing terminology, significant shortcomings exist. The vulvar intraepithelial neoplasia (VIN) terminology was introduced for uniformity and consistency with the grade classification for CIN. Although this seems logical, there exists an established biologic continuum from CIN 1 to CIN 3. The neoplastic biologic continuum from VIN 1 through VIN 3 to invasive cancer has not been established.
Although the progression rate of VIN 3 to invasive cancer remains controversial, the malignant potential is undisputed. By contrast, there is no evidence that VIN 1 has any malignant potential. The inclusion of such lesions in the neoplastic continuum creates pressure for a more aggressive therapeutic approach to low-grade vulvar lesions than can be justified.
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VIN is best classified into two clinically meaningful categories: low-grade VIN (subclinical HPV infection and VIN 1/mild dysplasia) and high-grade VIN (VIN 2–3/moderate to severe dysplasia/carcinoma in situ). There also exists a compelling argument for excluding low-grade VIN from the “intraepithelial neoplasia” category until biologic data justifying its inclusion have evolved. When mild squamous atypia is seen, usually limited to the lower epidermis, the lesion is more likely to be nonneoplastic reactive atypia. If a genuine VIN 1 lesion exists, it is almost always associated with high-grade VIN, either in the same lesion or in other coexisting lesions.
Although more than 95% of cervical malignancies are HPV-associated cancers, HPV DNA is detected only in approximately 50% of vulvar cancers (342). Many of the HPV-negative cancers, particularly in older women, are associated with lichen sclerosus (343,344,345,346,347,348).
Careful histologic and molecular review in the 1990s, particularly by Kurman and associates, has led to a reclassification of VIN 3 into three histologic subtypes, namely, basaloid, warty (or bowenoid), and differentiated (or carcinoma simplex) (349,350,351). Differentiated VIN is frequently found adjacent to invasive squamous cell carcinoma in older patients and is often associated with “chronic vulvar dystrophy,” particularly lichen sclerosus, but including lichen simplex chronicus and erosive lichen planus. Clinically, these lesions are difficult to distinguish against a dystrophic background. A keratotic nodule or shallow ulcer may be the only clinical indicator.
Paget’s Disease
Paget’s disease of the vulva is an uncommon intraepithelial lesion. It is sometimes associated with underlying invasive carcinoma. These conditions are discussed in Chapter 13.
Clinical Profile of High-Grade Vulvar Intraepithelial Neoplasia
The increased incidence of VIN 3 in recent decades reflects increased clinical awareness, improved diagnostic accuracy, and an absolute increase in disease incidence. Specific genital HPV types, in particular HPV 16, are strongly implicated in the causation of high-grade VIN (352,353,354). Other vulvar HPV-induced lesions, including condylomata acuminata and subclinical HPV infection, frequently either coexist with or predate the diagnosis of VIN 3. Cigarette smoking, nutritional deficiency, poor personal hygiene, granulomatous vulvar diseases, endogenous and exogenous systemic immune suppression, and pregnancy have been implicated as cofactors in the pathogenesis of
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VIN 3 (355,356,357). There is a strong association between VIN 3 and sexually transmitted disease, with rates varying from 20% to 60%.
Distribution
High-grade VIN lesions tend to be localized and unifocal in the older patient. A higher malignant potential is presumed for such lesions because invasive vulvar cancer occurs predominantly in the older age groups. However, many of the invasive cancers in elderly women occur against a background of lichen sclerosis and without a prior history of VIN 3 or coexisting histologic evidence of VIN 3 (344,345,346,347).
In younger patients, high-grade VIN lesions are frequently multifocal and extensive. Lesions may remain discrete or coalesce to develop a large field of disease. Lesions may extend laterally from the inner aspect of the mucous membranes of the labia minora to the hair-bearing skin of the labia majora and from the clitoris, periclitoral area, and mons pubis anteriorly to the perineum and perianal area posteriorly. Difficult-to-access sanctuary sites, such as the urethra, clitoris, vagina, and anal canal, need to be carefully inspected.
Symptoms
More than 30% of women with VIN 3 experience vulvar symptomatology. The most common symptoms are pruritus, burning, pain, and dysuria (357). Vulvar symptoms are often exacerbated by voiding. Patients may present reporting a localized lump or thickening in the vulvar skin, or they may notice an area of increased or decreased pigmentation. The patient may present with a history of recalcitrant vulvar condylomata acuminata.
Delay in diagnosis of high-grade VIN, even in symptomatic patients, is common (357,358,359). Opportunistic inspection of the vulva, particularly at the time of colposcopy for abnormal cervical cytology, is recommended.
Clinical Appearance
The clinical appearance of VIN 3 lesions varies according to patient age and skin color, as well as the location of the lesions in the vulva and perianal region (Fig. 8.18, Fig. 8.19). In both the hair-bearing and non–hair-bearing keratinized vulvar skin, lesions tend to be raised
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or papular. They may be white, red, or brown in color. White lesions are due to hyperkeratosis or dehydration of the outer keratinized layer. Red lesions result from increased vascularity, reflecting either an inflammatory response or increased blood vessel formation secondary to angiogenic factors of neoplasia. Brown or pigmented lesions, which occur in more than 10% of patients, result from melanin incontinence, usually in the keratinized squamous epithelium. On the mucosal surfaces and less frequently on the keratinized surfaces, VIN 3 lesions may be flat or macular. Occasionally, such macular lesions are evident through associated erythema or pigmentation. Usually, macular lesions are subclinical and are detected on colposcopic examination after application of 5% acetic acid solution.
Figure 8.18 Clinical appearance of vulvar intraepithelial neoplasia showing hyperkeratotic papular lesions.
Figure 8.19 Left: A multifocal VIN 3 lesion with multiple small hyperpigmented lesions on the labia major. Right: VIN 3 with more confluent hyperpigmented areas on the posterior fourchette with extensive perianal involvement.
The clinical appearance of VIN 3 in dark-skinned women is similar when detected on mucosal surfaces but may differ in keratinized and hair-bearing areas. Relative hypopigmentation may occur, producing pink or erythematous plaques. Such lesions may blanch densely acetowhite after application of acetic acid solution. Unifocal, localized lesions in older women less frequently involve the mucous membranes. Care must be taken in the assessment of suspicious vulvar lesions in older women because of the increased risk of undisclosed invasive cancer. Warning signs of an occult invasive lesion include yellow discoloration, nodularity, ulceration, thick scale, and abnormal vascularity.
Vulvar intraepithelial neoplasia grade 3 is often found on biopsy of recalcitrant and abnormal appearing condylomata acuminata. VIN 3 is reported in biopsies from 30% of patients with large, persistent condylomatous lesions, particularly if the lesions are pigmented or coalescent and sessile with a micropapilliferous surface. Condylomatous lesions exhibiting a severely dysplastic morphology on biopsy frequently harbor high-risk HPV types, with HPV 16 and 18 detected in more than 70% of such lesions (360).
Diagnosis
Colposcopy is now an accepted standard in the diagnostic assessment of preinvasive vulvar disease. After application of 5% acetic acid solution and colposcopic assessment
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using a magnification of at least 7, lesions appear as clearly demarcated, dense acetowhite areas. The multifocal distribution is usually evident. The acetic acid reaction is best seen in lesions that are nonpigmented or red. Pigmented lesions often develop an acetowhite hue or a rim of acetowhitening. Initial clinical examination may identify clinically apparent lesions. Colposcopy may permit identification of previously unidentified, subclinical lesions and better define the distribution of clinically evident disease.
In high-grade vulvar preinvasive lesions, vascular patterns are often inconspicuous or absent, particularly in the presence of hyperkeratosis. Macular lesions on the mucous membranes may reveal a capillary punctation pattern, and a fine punctation is sometimes observed in papular lesions. Marked vascular abnormalities characterized by a varicose, widely spaced punctation and, rarely, mosaicism represent a definite warning sign of invasive cancer, and the lesion must be excised. Colposcopic warning signs of vulvar cancer occur late in the neoplastic process, limiting the sensitivity of colposcopy for the identification of early invasive cancer. Histologic evidence of VIN 3 may be seen outside colposcopically identified margins of disease, particularly laterally in the hair-bearing areas.
Diagnosis ultimately depends on liberal use of directed biopsy. This is particularly the case if ablative treatment is being considered, either alone or in combination with excisional procedures. Biopsies are best taken with a Keyes biopsy instrument under local anesthetic in the office setting.
Natural History of High-Grade Vulvar Intraepithelial Neoplasia
Vulvar intraepithelial neoplasia grade 3 coexists with invasive cancer in 30% to 50% of cases. Vulvar dystrophy occurs in up to 50% of specimens, with lichen sclerosus and squamous hyperplasia equally represented. There is no coexistent disease in 10% to 15% of specimens (357,358,359).
Few studies have examined the natural history of untreated VIN. Jones and Rowan (361) reported in 1994 on the follow-up of 113 women with VIN 3 diagnosed between 1961 and 1993. Of 105 women whose disease was treated, 4 (3.8%) developed invasive cancer 7 to 18 years after treatment. Of eight untreated cases of VIN 3, progression to invasive cancer was reported in seven patients (87.5%) within 8 years, and the disease regressed spontaneously in the remaining patient. This very high incidence of progression within a reasonably short time is troubling.
A more recent review from the same authors studied women who experienced spontaneous regression of CIN 2–3 (362). These women had a median age of 19 years, an initial presentation through a sexual health clinic, and a previous history of condylomata acuminata. Most had multifocal, pigmented lesions. Median time to regression was 9.5 months.
The occurrence, usually in younger women, of multifocal, pigmented, papular vulvar lesions reported histologically as VIN 3 is well recognized and has been described as “bowenoid papulosis” (363). Reports of spontaneous regression, especially associated with pregnancy, suggested distinctive epidemiologic features for bowenoid papulosis, but the term has been abandoned by the International Society for the Study of Vulvar Disease and the International Society for Gynecologic Pathologists. High-grade VIN is a disease with a varied and individual clinical profile and histologic appearance. This range encompasses the entity previously described as “bowenoid papulosis.”
Treatment of High-Grade Vulvar Intraepithelial Neoplasia
Treatment is aimed at control of symptoms and prevention of progression to invasive cancer. Many treatment modalities have been used and, historically, vulvar carcinoma in situ was managed by simple vulvectomy (364). Such a radical approach is unjustified and is associated with significant morbidity, particularly for young women, including scarring, dyspareunia, urinary stream difficulties, loss of elasticity for vaginal delivery, and a “castrationlike” self-image.
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Since the 1970s, there has been a trend toward more conservative therapy, initially using excisional approaches and more recently, ablative modalities (357,358,365).
The risk of occult malignancy occurring in association with VIN 3 is too low to mandate complete excision of disease in all patients but too high to allow routine ablation. Women undergoing excisional treatment for VIN 3 are reported to have a 15% to 23% incidence of unsuspected invasive squamous cell carcinoma on histology of the excised specimens (357,358,359,366,367).
The clinical profile of VIN, including a broad age range and marked variability in extent, distribution, and symptomatology, demands individualization of the therapeutic approach for each patient. A period of close prospective follow-up without treatment may be appropriate for young, immunocompetent women with multifocal disease, particularly if they are pregnant. The patient must comply with close follow-up and understand and accept the risks of treatment delay.
Wide Local Excision and Superficial (Skinning) Vulvectomy
Localized high-grade VIN lesions are best managed by local, superficial excision. The lesion should be excised with a disease-free margin of at least 5 mm. Wide, local excision is ideal for unifocal and lateral lesions or for hemorrhoids involved with high-grade intraepithelial neoplasia. It is mandatory if a lesion has warning signs of possible invasive cancer. Primary closure of the defect usually achieves uncomplicated healing and a very satisfactory cosmetic and functional outcome. The elasticity of the vulvar skin permits preservation of sexual and reproductive functions, of particular importance in the young patient.
The surgical specimen should be submitted to careful histologic evaluation to exclude invasive disease and to ensure clear margins of excision. Wide local excision with disease-free surgical margins achieves a 90% cure rate for localized disease. If the margins of excision are involved with disease, the cure rate falls to 50%, demanding very close follow-up. As long as all macroscopic disease has been removed, reexcision is not justified for positive margins of excision. Most recurrences occur within 3 years of treatment, although late recurrence and progression to cancer can occur. Development of symptoms should prompt urgent review.
Large, confluent lesions or extensive multifocal disease, particularly in the presence of colposcopic warning signs of early invasion, require more extensive excisional procedures with rotational flaps to fill the defect or superficial (skinning) vulvectomy with a split-thickness skin graft. “Skinning” vulvectomy was introduced by Rutledge and Sinclair (368) for extensive VIN lesions, particularly in the hair-bearing skin where the skin appendages may be involved. Lesions are carefully mapped and a shallow layer of vulvar skin is excised, preserving the subcutaneous tissues. The vulvar skin at risk is replaced with epidermis from a donor site on the inner aspect of the thigh or buttock. The clitoris is preserved, with lesions on the prepuce or glans being superficially excised or laser ablated. The epithelium regenerates without loss of sensation.
DiSaia (369) reported a 39% recurrence rate in patients with VIN 3 treated by skinning vulvectomy with split-thickness skin grafting. There were no recurrences in grafted areas, although such recurrence has been reported. Although this procedure has been largely outmoded by CO2 laser treatment for many patients with extensive disease, it remains an important therapeutic option when there is an increased risk of occult invasive cancer.
CO2 Laser Surgery
Vulvar intraepithelial neoplasia is occurring more frequently in young women, and the disease may be very extensive, involving the hair-bearing area of the labia majora in more than 30% of cases. Excision of such wide areas, even with skin grafting,
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can cause significant scarring and anatomic distortion. With careful, expert colposcopy and liberal use of directed biopsy, the undisclosed cancer risk in selected patients is low.
An ablative procedure in these patients using the CO2 laser is the treatment of choice (370,371,372,373,374). The morbidity associated with ablation of large areas of VIN 3 has been found to be unacceptable in some studies. The initial 2 weeks following more extensive laser ablative procedures will be associated with significant pain, particularly with micturition. The use of appropriate laser technology and settings, advanced surgical expertise with careful control of depth of ablation, and appropriate postoperative care will mitigate much of the potential morbidity. The preservation of anatomy and function is a substantial benefit, particularly for younger women.
Physical Principles Governing Vulvar Laser Surgery
  • Choice of appropriate laser wavelength: The CO2 laser is the only laser proven to be safe and effective for the management of high-grade VIN.
  • Rapid delivery of the required energy dose: Vulvar laser surgery demands minimization of lateral thermal injury to prevent scarring and morbidity. The surgeon must be able to control higher powers to permit precise, rapid ablation. For ablative procedures, powers of less than 50 W in continuous mode are associated with an increased risk of thermal injury and should be avoided.
  • Choice of appropriate temporal mode: The option of choosing rapid superpulse or the newer ultrapulse technology affords a definite therapeutic advantage in CO2 laser ablation of vulvar lesions. The ability precisely to vaporize diseased tissue under visual control with minimal heat propagation to adjacent tissue is the key to nonmorbid laser surgery.
  • Choice of appropriate power density: CO2 laser ablation requires power densities in the range of 800 to 1,400 W/cm2.
  • Choice of appropriate beam geometry: The incident laser beam produces a conical impact crater with marked variation in intensity of the beam from point to point in the focal spot. The clinical importance of the concept of beam geometry is that the crater shape mirrors the intensity profile of the incident energy (Fig. 8.20). When the incident laser beam is highly focused, the vaporization crater is a narrow, deep “drill-hole.” This reflects the high power density and is arbitrarily designated as the X-beam geometry. The X-beam geometry is for cutting or for excisional procedures. If the incident laser beam is flattened completely, it will simply coagulate a broad zone of tissue at the impact site but will not have sufficient power to vaporize tissue. The wide, flattened spot size produces the Z-beam geometry. In contrast, defocusing the laser beam to an intermediate, round beam geometry produces a round, shallow vaporization crater at the impact site. This is designated the Y-beam geometry and permits controlled tissue vaporization to a relatively uniform and predictable depth.
    Figure 8.20 Diagrammatic representation of CO2 laser beam geometry.
    For ablative treatment of VIN, a high-power laser setting is selected. The spot diameter is progressively enlarged by defocusing the beam using the micromanipulator until a point is found where the impact crater is hemispherical. This permits controlled tissue vaporization with minimal lateral heat conduction. The laser should be first tested on a moistened tongue blade to defocus the beam to the hemispherical Y-beam geometry before use on the skin.
  • Intermittent gated pulsing: CO2 laser surgery to the vulvar skin requires training and skill in the use of the foot pedal to deliver the laser energy in short bursts to control the depth of ablation.
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Surgical Strategies Governing Vulvar CO2 Laser Surgery
  • Choice of appropriate beam delivery system: For ablative procedures, the laser must be controlled using a micromanipulator through a colposcope or operating microscope with a 300-mm objective to produce a relatively large spot size with excellent depth of field. The angle of impact of the laser is controlled by traction on the skin. A handheld mirror may occasionally be required to reflect the beam to difficult-to-access sites.
  • Minimization of thermal injury: Thermal injury can be further minimized by chilling the vulvar skin, before and during surgery, with laparotomy packs soaked in iced saline solution. This simple strategy diminishes postoperative pain and swelling and promotes healing.
  • Accurate delineation of treatment margins: The laser is used under colposcopic control. The possible extension of high-grade VIN beyond areas that are colposcopically evident indicates the need for treatment margins of several spot sizes. The laser can be used initially to circumscribe the distribution of the lesions before the acetic acid reaction fades.
  • Accurate depth control: Determination of depth of ablation is best achieved by a precise understanding of the visual landmarks of the surgical planes of the vulva as described by Reid et al. (371,372).
First surgical plane
Destruction to the first surgical plane removes the surface epithelium to the level of the basement membrane. The laser beam is rapidly oscillated across the target tissue with the spot describing a series of roughly parallel lines. When the impact debris is wiped away with a moistened swab, the moist “sand-grain” appearance of the papillary dermis will be evident.
Second surgical plane
Ablation to the second plane removes the epidermis and the superficial papillary dermis. This plane is achieved by a slightly slower oscillation of the laser beam across the first surgical plane, scorching but not penetrating the papillary dermis. The visual effect is a shrinking of the target tissue because of dehydration, and a finely roughened, yellowish surface similar in appearance to chamois cloth is produced. Ablation extends to the deep papillary dermis with minimal thermal injury to the underlying
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reticular dermis. The second surgical plane is the preferred depth of ablation for condylomata acuminata treated with the CO2 laser.
Third surgical plane
Destruction to the third surgical plane removes the epidermis, papillary dermis, and superficial reticular dermis containing the upper portions of the skin appendages, specifically the pilosebaceous ducts and hair follicles. This is achieved by a slower, purposeful movement of the laser beam across the second surgical plane. The tissue is seen to relax and separate as the midreticular dermis is exposed as moistened gray-white fibers representing coarse collagen bundles. Healing occurs from the base of the skin appendages, and scarring is absent or minimal. Ablative procedures for VIN 3 should be carried to the depth of the third surgical plane (Fig. 8.21).
Figure 8.21 Diagrammatic representation of three surgical planes.
The skin appendages are involved with the VIN process in more than 50% of cases (372). Depth of hair follicle involvement is usually less than 1 mm but may extend to 2 mm. Measured sweat gland involvement has been more than 3 mm in depth. Beyond 3 mm, the equivalent of a third-degree thermal defect is created, resulting in delayed healing, scarring, and alopecia. The implications of residual disease after treatment of VIN are different from those of residual CIN, which may be buried and escape detection. Although the surgeon should be aware of vulvar skin appendage involvement, this is not an indication to destroy beyond the midreticular dermis.
Fourth surgical plane
Destruction of the reticular dermis creates a thermal injury extending to the subcutaneous tissues and must be avoided.
6. Control of intraoperative and postoperative pain and bleeding: CO2 laser procedures for high-grade VIN are performed under general or regional anesthesia unless the disease is localized. Subcutaneous injection of a long-acting
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local anesthetic on completion of the procedure diminishes pain in the immediate postoperative period.
Narcotic analgesia is usually required in the immediate postoperative period or, alternatively, prolonged epidural analgesia can be used. Regular sitz baths followed by topical application of a mixture of equal parts 1% lidocaine and 2% silver sulfadiazine creams to the surgical site aid in pain relief. The postoperative discomfort is often most severe on the third to the sixth postoperative days. Patients should have available appropriate oral narcotic analgesics to provide relief after discharge from hospital.
Long-Term Follow-up
Regardless of treatment modality, recurrence of VIN is common. Lifelong vigilance is an important component of the management of high-grade VIN.
Immune Response Modifiers: Imiquimod
The discovery that VIN 2–3 lesions, particularly multifocal lesions in younger women, are strongly HPV associated, argues for the possible efficacy of immune response modifiers in treatment of high-grade VIN (375,376).
Imiquimod (Aldara) is an imidazoquinoline, a novel synthetic compound that is a topical immune response stimulator, enhancing both the innate and acquired immune pathways, particularly T helper cell type 1–mediated immune response, resulting in antiviral, antitumor, and immunoregulatory activities (376,377). Imiquimod causes cytokine induction in the skin which up-regulates the host immune system to recognize the presence of a viral infection or tumor, theoretically leading to eradication of the lesion. It also stimulates activation, maturation, and migration of Langerhans cells, the major antigen-presenting cells of the skin, which are depleted by HPV infection (376,377).
A patient-applied topical 5% imiquimod cream is clinically efficacious and safe in the management of condylomata acuminata (378,379,380). It was licensed in 1997 for the treatment of anogenital condylomata acuminata and is recommended for this application in sexually transmitted disease guidelines from the U.S. Centers for Disease Control and Prevention, as well as guidelines from Europe, Latin America, and Australia.
The beneficial effects, patient acceptability, and low morbidity of imiquimod in the treatment of genital condylomata acuminata led to its recent evaluation in the treatment of VIN 2–3. Case reports demonstrated efficacy against VIN 2–3, including in an immune-suppressed lung transplant patient (381). Pilot studies, applying imiquimod one to three times a week at night, indicate a 30% complete response rate and 60% partial response after 6 to 30 weeks of treatment (382,383). In contrast to surgical treatment, imiquimod focuses on the cause of many VIN cases and preserves the anatomy and function of the vulva. Exclusion of invasive cancer is an extremely important aspect of pretreatment assessment.
No treatment modality is ideal for every woman. Treatment should be individualized according to age, distribution, severity, associated disease, and previous treatment.