Vulva

Normal Anatomy

The vulva is composed of the following anatomic structures: mons pubis, clitoris, labia minora, labia majora, vulvar vestibule and vestibulovaginal bulbs, urethral meatus, hymen, Bartholin and Skene glands and ducts, and vaginal introitus.

The labia majora are lined by keratinized skin containing all the cutaneous adnexa: hair follicles, sebaceous glands, apocrine glands, and sweat (eccrine) glands. The labia minora are covered by nonkeratinized stratified squamous epithelium on their vestibular surfaces but have a thin keratinized layer on their lateral side. Skin adnexa are usually absent in them, but on occasion, one encounters both sweat and sebaceous glands.

The Bartholin gland is the major vestibular gland and has a tubuloalveolar structure. It is made up of acini composed of mucus-secreting columnar cells and a duct lined with transitional epithelium. Minor vestibular glands are of simple tubular type and are lined with a mucus-secreting columnar epithelium that merges with the stratified squamous epithelium of the vestibule.

Skene or periurethral glands are analogous to the male prostate gland; they are lined by a pseudostratified mucus-secreting columnar epithelium that merges with the transitional-type epithelium of the ducts, which in turn joins with the stratified squamous epithelium of the vestibule.

The hymen is lined by nonkeratinized stratified squamous epithelium on both surfaces.

The clitoris contains erectile tissue similar to that present in the corpora cavernosa of the penis.

Most of the vulvar lymph vessels drain to the superficial inguinal nodes, but those in the clitoris empty directly into the deep chain.

Mammary-Like Glands of the Vulva and Related Lesions

Mammary-like glands of the vulva , formerly thought to be ectopic breast tissue related to the “milk line,” are now recognized as a normal finding in the vulva, and are found primarily in the sulcus between the labium minus and labium majus. These glands consist of ducts, variably with associated acini, lined by glandular epithelium identical to that of the breast. The ducts draining these glands empty through the skin. Clear cells (Toker cells) may be found singly or in clusters where these ducts traverse the epidermis. This tissue is subject to many of the physiologic and pathologic changes that occur in the normally situated breast and some that seem peculiar to this location. These include swelling and secretion of milk during pregnancy, cysts, peculiar hyperplastic changes, so-called pseudoangiomatous stromal hyperplasia (PASH; see Chapter 36 ), fibroadenoma (including the juvenile type), ( Fig. 30.1 ) phyllodes tumor, and carcinoma. Most of the latter have been of ductal type, but any histotype/molecular subtype, i.e. luminal, basal-like, HER2, may be encountered. In addition, it is likely that ectopic mammary tissue is the source of the common benign vulvar tumor known as papillary hidradenoma.

Inflammatory Diseases

Syphilis in women often manifests itself initially in the vulvar region. The fully developed syphilitic chancre is composed microscopically of plasma cells, lymphocytes, and histiocytes, and is covered by a zone of ulceration infiltrated by neutrophils and necrotic debris. The microscopic appearance is not specific, but the combination of numerous plasma cells and endarteritis should alert to the diagnosis. Your diagnostic report can suggest the possibility of syphilis, based on the histopathologic findings, indicating to the clinician the need to exclude this possibility with appropriate serologic testing on the patient. Additionally, immunostains for Treponema pallidum are now available and allow for easy confirmation of the causative organisms. Sometimes, the possibility of syphilis is first suggested on the basis of the microscopic examination of an enlarged inguinal lymph node if this node shows a combination of capsular and pericapsular fibrosis, follicular hyperplasia, plasma cell infiltration, and endarteritis. The latter feature, which represents the most useful clue to the diagnosis, is particularly well seen in or outside the nodal capsule (see Chapter 37 ).

Granuloma inguinale (donovanosis) is a chronic infection caused by Klebsiella ( Calymmatobacterium) granulomatis , a gram-negative, nonmotile, encapsulated bacillus. It begins as a soft elevated granulomatous area that enlarges very slowly by peripheral extension and ulcerates. Microscopically, there is a dense dermal inflammatory infiltrate composed of histiocytes and plasma cells, with a scattering of small abscesses. The diagnosis rests on the demonstration of Donovan bodies, which appear as small round encapsulated bodies inside the cytoplasm of the histiocytes. They can be seen in hematoxylin-eosin (H&E) sections but are best demonstrated with Giemsa or Warthin-Starry stains. Pronounced pseudoepitheliomatous hyperplasia, which may accompany chronic lesions, should be distinguished from the very rare squamous cell carcinoma that may arise in such areas. The infection can spread to the retroperitoneum and simulate a soft tissue neoplasm.

Lymphogranuloma venereum (LGV) is a venereal disease produced by Chlamydia trachomatis organisms (specifically l -serovars). It mainly affects lymph vessels and lymphoid tissue. The initial small ulcer at a site of venereal contact often goes unnoticed. The first clinical manifestation is swelling of inguinal lymph nodes caused by stellate abscesses surrounded by pale epithelioid cells. There is extensive scarring as the disease progresses, often leading to fistulas and strictures of the urethra, vagina, and rectum. It is increasing in incidence, especially in homosexual men. The diagnosis can be confirmed by submission of swabs for nucleic acid amplification, with LGV genotyping on samples positive for Chlamydia . Rainey reported 11 cases of squamous cell carcinoma or adenocarcinoma arising from lymphogranulomatous strictures. Most of the tumors were located in the anorectal area.

Crohn disease can involve the vulvar region. In some cases, the vulvar lesions are associated with perineal disease and fistula formation, whereas in others they are separated from the anal lesions by normal tissue. Grossly, erythematous areas appear that later ulcerate. Microscopically, noncaseating granulomas may be found. The process reported as vulvitis granulomatosa is probably related to Crohn disease, in that some of the patients have subsequently developed either intestinal Crohn disease or cheilitis granulomatosa.

Behçet disease can, rarely, involve the vulvar region, where it presents as a microscopically nonspecific ulceration.

Necrotizing fasciitis of the vulva may be seen in diabetic women. It is associated with a high mortality rate; wide excision of the diseased tissue is the treatment of choice.

Vulvar vestibulitis is a disorder characterized microscopically by a nonspecific chronic inflammatory infiltrate predominantly involving the mucosal lamina propria and the periglandular/periductal connective tissue of the vestibular region. It is unrelated to human papilloma virus (HPV).

Plasma cell vulvitis (of Zoon) is an uncommon condition of uncertain etiology. It typically presents as a solitary, asymptomatic, sharply defined red/brown patch. Microscopically, there is a dense band-like mononuclear inflammatory infiltrate in the superficial dermis, consisting predominantly (>50%) of plasma cells. The differential diagnosis includes secondary syphilis and lichenoid drug reaction, but neither of these conditions present as a solitary lesion resembling those of plasma cell vulvitis.

Spongiotic and Lichenoid Reactions of the Vulvar Skin

There exists a group of vulvar diseases that are pathogenetically unrelated but that have several features in common at the clinical level. They typically present as a long-standing lesion consisting of irregular areas of thickened skin, often accompanied by severe pruritus. The color is usually white, in which case the clinically descriptive term leukoplakia has been used (note that this is not an acceptable histopathologic diagnosis!). In other instances, the lesions are red or a mixture of both colors. They are easily traumatized and excoriated. In some of these lesions the vulvar soft tissues are atrophied and shrunken, in which case the clinical term kraurosis vulvae has been employed.

In the presence of a lesion with some of these clinical features, it is essential to reach a specific diagnosis, and this often necessitates the performance of a biopsy. Multiple biopsies may be necessary if the lesion is large or varies in appearance from place to place. Although a key function of the biopsy is to exclude neoplasia, it is important to reach a specific diagnosis as this will guide subsequent management, and the former practice of diagnosing benign “vulvar dystrophy” or “squamous hyperplasia” is not acceptable. What follows is a list of the most commonly encountered inflammatory conditions of the vulva; this list is by no means exhaustive but will be sufficient to handle most vulvar biopsies taken for a non-neoplastic inflammatory process that will be encountered in general surgical pathology practice, focusing on those entities that chiefly involve the vulva. The vulvar skin can be secondarily involved in a wide range of inflammatory dermatopathies and the reader is referred to Chapter 2 for a full discussion of these conditions.

Spongiotic dermatitis (eczematous reaction) is a nonspecific pattern of cutaneous inflammation, familiar to those whose practice includes a significant dermatopathology component. It is characterized histologically by intercellular edema in the epidermis (spongiosis) with intraepithelial lymphocytes, and less commonly neutrophils and/or eosinophils. Pure acute spongiotic reactions are rarely encountered in vulvar biopsies, but spongiotic dermatitis is not uncommonly seen admixed with a chronic process, especially lichen simplex chronicus (discussed below), so awareness of the histopathologic features is important. Eczematous reactions confined to the vulva are most commonly attributable to allergic or irritant contact reactions, with drug reaction and atopic reaction less common. In patients with allergic contact reaction, the precipitant may be difficult to identify, clinically, as the reaction can persist for variable periods of time after removal of the irritant. Management consists of scrupulous avoidance of irritants/allergens. When longstanding, there is progression to lichen simplex chronicus and it is our impression that many cases of lichen simplex chronicus start as an acute spongiotic dermatitis.

Lichen simplex chronicus is probably the most common diagnosis rendered on vulvar biopsies. It can affect nonvulvar sites or be limited to the vulva, where it manifests as pruritic scaly plaques. The microscopic findings reflect chronic irritation, and the diagnosis of lichen simplex chronicus does not indicate a single disease entity but instead reflects chronic irritation of vulvar skin from any cause. On histopathologic examination there is hyperkeratosis (predominantly orthokeratosis, with parakeratosis focally present, for example, as sites of excoriation) with epidermal hyperplasia and a patchy, predominantly lymphocytic inflammatory infiltrate in the superficial dermis ( Fig. 30.2 ). Because lichen simplex chronicus reflects trauma, and can appear secondary to many different primary dermatopathic conditions, it is important to search for an underlying disease process that has precipitated the lichen simplex chronicus. That being said, in most cases no underlying condition can be identified. Cutaneous fungal infections can result in changes of lichen simplex chronicus but can be ruled out with periodic acid–Schiff–diastase (PAS-D) stain. The differential diagnosis of lichen simplex chronicus, especially for the clinician, is vulvar intraepithelial neoplasia (VIN), but lichen simplex chronicus lacks the atypia of VIN (differential diagnosis discussed in more detail later, in the section on differentiated VIN [dVIN]).

Lichen planus is an idiopathic inflammatory dermatopathy characterized by pruritic red/purple papules. While there is usually extragenital involvement, vulvar lesions may be the only finding at presentation. The lesions resolve after 12–18 months in most patients. The histopathologic findings are a band-like infiltrate in the superficial dermis, with damage to basal keratinocytes, resulting in apoptotic keratinocytes (Civatte bodies). The inflammatory infiltrate does not extend into the suprabasal keratinocytes. Hyperkeratosis with wedge-shaped hypergranulosis is a common finding. Lichen planus is considerably less common than lichen simplex chronicus or lichen sclerosus. The absence of basal keratinocyte degenerative changes aids in the distinction of lichen simplex chronicus from lichen planus. Lichen planus involves mucosal membranes and other extragenital sites, which is a clinical finding that can also serve to distinguish lichen planus from lichen sclerosus. The histopathologic features useful in differential diagnosis between lichen planus and lichen sclerosus are discussed in the following paragraphs.

Lichen sclerosus (also spelled sclerosis) of the vulva may occur in any age group, including children ( Fig. 30.3 ). In the latter group, the vulvar region represents the most common location, and there is a high incidence of spontaneous involution at the time of puberty. The microscopic features are similar but not identical to those seen in this disorder when it occurs elsewhere in the skin (see Chapter 2 ) ( Fig. 30.4 ). It has been stated that the minimal histologic criteria for the microscopic diagnosis of lichen sclerosus (LS) are the presence of a vacuolar interface reaction pattern in conjunction with dermal sclerosis (homogenized and hyalinized eosinophilic collagen bundles) of any thickness in between the inflammatory infiltrate and the epithelium and/or vessel walls. In the early stages, LS may be difficult to diagnose as it may be indistinguishable from lichen planus. In such cases, the differential diagnosis should be noted, and it can be indicated in the pathology report that with follow-up it will declare itself to be either lichen planus or LS, as in LS the pathognomonic superficial hyalinized collagen will appear. The diagnostic alterations of early LS may be very subtle and often are more prominent in adnexal structures than in the interfollicular skin. The overlying epidermis is characteristically atrophic, but on occasion it may show foci of hyperplasia ; however, the presence of hyperplasia in LS, especially as a focal finding, forming a clinically recognizable discrete lesion with an abrupt change from the adjacent atrophic epithelium, should always raise the differential diagnosis of dVIN arising in LS. The presence of basal atypia and altered maturation (loss of the granular cell layer) in the hyperplastic focus is evidence supporting a diagnosis of dVIN.

It is now accepted that LS is a precancerous condition, associated with an increased risk of developing dVIN and HPV-independent squamous cell carcinoma. The risk, however, is relatively small. In one series, squamous cell carcinoma developed in only one of 92 patients, and in another it was found in 12 (4%) of 290 patients followed for a mean period of 12.5 years. In a large ( n = 507) prospective study of patients with LS, 0 of 357 patients who were compliant with treatment recommendations developed invasive squamous cell carcinoma or VIN, compared to 7 of 150 patients who were not fully compliant. While many invasive HPV-independent vulvar squamous cell carcinomas are seen in a background of LS at the time of diagnosis, newly diagnosed LS (in the absence of neoplasia) can be managed medically with a relatively low risk of progression. The designation “atypical LS” has been used for cases of LS where there is basal atypia of the atrophic epithelium, greater than would be expected in usual LS. Atypical LS has been reported to show overexpression of p53, and atypical LS may well be a step in the pathway towards development of dVIN, but we do not have the ability to render the diagnosis of atypical LS reproducibly, nor do we understand its clinical significance; therefore, it cannot be considered to be a robust clinically relevant diagnosis. In practice, the presence of basal atypia in LS should be documented in the Comment field of the surgical pathology diagnostic report, indicating that it may be associated with increased likelihood of malignant transformation, with recommendation for close follow-up.

Human Papilloma Virus and Vulvar Pathology

The role of HPV in vulvar pathology is analogous to the one it plays in the vagina and cervix, and is discussed in detail in connection with the latter (see Chapter 32 ). In the vulva, this includes condyloma (acuminatum and flat), as well as high-grade squamous intraepithelial lesion (HSIL) VIN2/3 and HPV-associated invasive squamous cell carcinoma. The vulva differs from the cervix in that there are a significant number of HPV-independent squamous cell carcinomas, unlike in cervix, where virtually all squamous cell carcinomas are HPV-associated. It is becoming apparent that the HPV-independent intraepithelial and invasive squamous cell neoplasms are more aggressive than their HPV-associated counterparts in the vulva. Accordingly, attention will be paid to the differences (histopathologic and natural history) between these two subtypes of vulvar squamous neoplasia, which are summarized in Table 30.1 . With respect to diagnosis, immunostaining for p16INK4a has emerged as a sensitive and specific surrogate for detection of HPV-associated versus HPV-independent vulvar squamous neoplasia, with sensitivity of 100% and specificity of 98%–99%. Staining is most reliably performed on intraepithelial lesions or early invasive carcinomas, as p16 expression can be lost during tumor progression. Polymerase chain reaction (PCR) for HPV DNA allows for viral genotyping and is highly sensitive, but lacks specificity. In situ hybridization for HPV is highly specific, but is more expensive than immunostaining and has a longer turnaround time; however, it can be valuable in establishing HPV status for those cases where the clinical, histomorphologic, and p16 immunostaining data are not concordant. Detection of mRNA of HPV oncogene E6 can be used to establish an etiologic role for HPV by demonstrating that the virus genome is being transcribed. However, such testing is not widely available, and p16 immunostaining is currently the most important surrogate test of HPV status.

Condyloma and Seborrheic Keratosis

Vulvar condyloma is a venereal disease caused by HPV, usually type 6. Although according to the 2012 Lower Anogenital Squamous Terminology (LAST) recommendations, these lesions should be diagnosed as (VIN1) (low-grade squamous intraepithelial lesion [LSIL]), the diagnosis of condyloma is well established, while a diagnosis of LSIL may lead to confusion. The diagnosis of VIN1 was not used for vulvar lesions for the 8 years prior to the LAST recommendations, as the 2004 International Society for the Study of Vulvar Diseases had dropped it from recommended terminology as it was generally accepted to not have a specific meaning. It was instead viewed as a collection of different conditions, including low-risk HPV infection. While we are able to endorse LSIL (CIN1) for cervical lesions, we do not recommend adopting this terminology for condylomatous vulvar lesions, and recommend, instead, the diagnosis of “condyloma.” The better-known form of condyloma is condyloma acuminatum, which is characterized grossly by one or several soft elevated masses of variable size ( Fig. 30.5 ). Microscopically there is a complicated papillary arrangement of well-differentiated undulating squamous epithelium supported by delicate, well-vascularized connective tissue stalks containing mononuclear inflammatory cells (mainly CD4+ and CD8+ cells) ( Figs. 30.6 and 30.7 ). The other form of condyloma, which is actually much more common, is the flat condyloma (not to be confused with the condyloma latum of syphilis). The cytologic features are similar in both forms. Koilocytosis of the malpighian epithelium and lymphocytic infiltration of the stroma are regular features ( Fig. 30.8 ). Koilocytosis refers to the combination of perinuclear cytoplasmic clearing and wrinkling of the nuclear membrane (nuclear “raisins”). As a rule, this change is not as florid in vulvar condylomas as it tends to be in condylomas of the cervix. A typical condyloma shows minimal basal or parabasal cell atypia, orderly maturation, and a smooth transition to koilocytotic intermediate and superficial cells; mitoses may be numerous but are all typical. In contrast, the lesions of VIN2/3 exhibit abnormal mitoses and nuclear pleomorphism, enlargement, and hyperchromasia in the basal and parabasal cell layers, as well as “block positivity” on p16 immunostaining, with strong nuclear and cytoplasmic immunoreactivity in all cells of at least the basal third of the epithelium, but with positivity usually extending into the upper half (see later section). The increased proliferative activity of condyloma (in contrast to fibroepithelial polyp and squamous papilloma) can be easily appreciated with the Ki-67 stain. The DNA content of condylomas is diploid and polyploid (including tetraploidy and octaploidy), in contrast to the aneuploid pattern seen in most cases of VIN2/3.

Sometimes one sees verrucopapillary vulvar lesions that lack the viral cytopathic effects (koilocytic change) of condyloma; these are often referred to as squamous papillomas and usually contain genital HPV types by PCR. Conversely, there may be multinucleated atypia of the epithelial squamous cells associated with reactive conditions in the absence of HPV infection. A final consideration in the diagnosis of condyloma in children is that verruca vulgaris, due to HPV2, can occur on the vulva of children and be morphologically indistinguishable from condyloma. It is therefore important to exercise caution in diagnosing condyloma in children (with the implication of a venereal infection/sexual abuse). We recommend that HPV testing to document genital-type HPV be required to support a diagnosis of condyloma in this setting. Another vulvar lesion which needs to be discussed here is the process morphologically indistinguishable from cutaneous seborrheic keratosis, which in this particular location is usually associated with HPV infection. The differential diagnosis of condyloma also includes a lesion characterized by epidermolytic hyperkeratosis , which could be related to Darier disease or represent a form of Hailey–Hailey disease. The acantholysis is usually suprabasal, but we have also seen it at the level of the granular layer. A final important differential diagnosis is verrucous carcinoma. Despite the name, verrucous carcinoma is not associated with HPV and is part of the spectrum of non-HPV-associated vulvar squamous neoplasia; it is distinguished from condyloma by examination of the epidermal/dermal junction. Verrucous carcinoma is characterized by a distinctive pattern of bulbous downgrowths with pushing margins, and will be discussed in greater detail later in this chapter.

The traditional therapy for condyloma consisted of podophyllin application. Microscopically, this results in epidermal pallor, necrosis of keratinocytes, and marked increase in mitosis; these changes wane after 72 hours and are essentially gone in 1 week. Occasionally, similar microscopic changes are seen in the absence of podophyllin therapy. The treatment of choice for these lesions at present is carbon dioxide laser.

Squamous Intraepithelial Lesions

It is now appreciated that squamous neoplasia of the vulva can be subclassified into HPV-associated and HPV-independent forms, which differ with respect to etiology, age at diagnosis, natural history, and morphology (i.e., they are different diseases). These differences are summarized in Table 30.1 . In North America, most preinvasive lesions (VIN) are HPV-associated (HSIL) (VIN2/3) rather than dVIN, while most invasive squamous cell carcinomas are HPV-independent; this is thought to reflect the more rapid progression of dVIN to invasive carcinoma. The presence of an admixture of HPV-associated and HPV-independent squamous neoplasia in the vulva is in contrast to the uterine cervix or vagina, where virtually all squamous neoplasia is HPV-associated. Because of the histopathologic differences between HPV-associated and HPV-independent squamous neoplasia (both intraepithelial and invasive), they will be considered separately in the following sections. It is important to acknowledge that clinical and morphologic features (based on examination of H&E stained slides) cannot distinguish between HPV-associated and HPV-independent squamous neoplasia in every case; however p16 immunostaining is a sensitive (100%) and specific (>98%) marker of HPV-associated squamous neoplasia in the vulva. Interpretation of p16 immunostaining, as for cervical lesions, is based on the presence or absence of “block” positivity, defined as intense nuclear and cytoplasmic staining of every cell in the basal third of the epithelium ( Fig. 30.9 ). p16 positivity, so defined, is evidence of HPV-associated VIN or invasive squamous cell carcinoma. Note that p16 staining intensity often decreases in the superficial layers of HSIL (VIN2/3), as the neoplastic squamous epithelium undergoes maturation.

Human Papilloma Virus-Associated Squamous Intraepithelial Neoplasia: High-Grade Squamous Intraepithelial Lesion (VIN2/3)

The in situ or pre-invasive lesion of HPV-associated vulvar squamous neoplasia is, as noted previously, referred to as HSIL or high-grade vulvar intraepithelial neoplasia (VIN2/3) and is entirely analogous to equivalent lesions in the vagina (VaIN2/3), cervix (CIN2/3), or anal mucosa (AIN2/3). The recommended terminology for preinvasive lesions associated with oncogenic HPV (most commonly HPV16 or 18, but a number of other oncogenic HPV genotypes have also been reported), according to the LAST recommendations, is HSIL (VIN2 or VIN3). In practice, it is not possible to reproducibly distinguish between VIN2 and VIN3, nor is the distinction clinically relevant. It has been proposed that VIN2 be used for cases where the “dysplasia” does not extend into the upper third of the squamous epithelium, while VIN3 be diagnosed in cases with full-thickness or near-full-thickness dysplasia; biologically this is a curious proposition, as all cells in VIN2/3 are neoplastic and transformed by oncogenic HPV (i.e., the full thickness of the epithelium is replaced by a clonal neoplastic proliferation, irrespective of whether there is some degree of flattening or maturation of the superficial cells). Any distinction between VIN2 and VIN3, accordingly, is arbitrary, and one may simply call all such cases VIN3 or VIN2/3, in practice. If this seems a touch iconoclastic, it is worth noting that according to the 2004 recommendations of the International Society for the Study of Vulvovaginal Disease, the diagnosis of “high-grade VIN” was used for all lesions that would be diagnosed as VIN2 or VIN3 according to the LAST criteria, and many of us used this simplified system for almost a decade and found it entirely satisfactory.

HSIL (VIN2/3) usually presents as a slightly elevated, plaque-like lesion with a red velvety appearance. It is typically centered in the labia majora, and it may extend to the perineum and anus. Microscopically, there is hyperkeratosis and parakeratosis, acanthosis, and a variable number of multinucleated dyskeratotic cells and abnormal mitoses involving the entire thickness of the epidermis ( Fig. 30.10 ). The acrotrichium (intraepidermal portion of the hair follicle) is often involved, whereas the acrosyringium (intraepidermal portion of the sweat gland) is usually spared. On occasion, the tumor cells are arranged in a nested pattern and/or have a clear cytoplasm, thus simulating Paget disease. The lesions of HSIL (VIN2/3) may be uniformly composed of cells with high N:C ratio (basaloid pattern VIN2/3) or there may be maturation as the cells move toward the surface, with epithelial hyperplasia and koilocytic change (warty pattern VIN2/3). This latter pattern can mimic condyloma but shows greater atypia, as well as block p16 positivity.

The type of HSIL (VIN2/3) that was, historically, designated as bowenoid papulosis presents as multiple, often pigmented, papules in or near the vulva of young patients. Clinically, they resemble verrucae, small condylomas, or nevi, but microscopically they show striking cytologic atypia, similar to that of Bowen disease/usual HSIL. It is important to note that the terms Bowen disease and Bowenoid papulosis may be used clinically but the pathologic diagnosis is HSIL (VIN2/3) for both, as there are no histopathologic features for reliably distinguishing between them. The designations of “warty” or “basaloid” VIN similarly are not routinely used in practice, as they are not of clinical significance.

It has been stated that, if left untreated, HSIL (VIN2/3) will progress into invasive carcinoma in approximately 10% of cases, but the rate of transformation varies widely among the different series. The therapy for HSIL (VIN2/3) depends on the age of the patient and the size, configuration, and distribution of the lesions. Localized lesions can be treated by wide local excision, skinning vulvectomy, laser, or topical therapy. Imiquimod, an immune-response modulator, can be used to treat HSIL (VIN2/3), with many lesions showing a response, sometimes a complete response.

It is anticipated that with increasingly widespread use of vaccination against HPV, cases of HSIL (VIN2/3) will start to decrease in the coming years. It has been increasing, especially in younger women. The frequent history of an abnormal cervical smear is important, and all patients with a past history of HSIL or HPV-associated squamous cell carcinoma elsewhere in the lower anogenital tract are at increased risk for vulvar disease.