CHAPTER 31: Vulvar Cancer

Vulvar cancers comprise only about 4 percent of all gynecologic malignancies. Most vulvar cancers are diagnosed at an early stage (I and II). Advanced disease is found mainly in older women, perhaps due to clinical and behavioral barriers that lead to diagnostic delays. Thus, biopsy of any abnormal vulvar lesion is imperative to help diagnose this cancer early.

In the United States, vulvar cancers carry a comparatively good prognosis with a 5-year relative survival rate of 78 percent (Stroup, 2008). For resectable disease, traditional therapy includes radical excision of the vulva plus inguinal lymphadenectomy or plus sentinel lymph node biopsy. For advanced stages, chemoradiation may be used either primarily or as an adjunct to surgery to aid tumor control. All of these treatments can result in extensive short- and long-term morbidity and dramatic anatomic and functional deformity. Accordingly, vulvar cancer management recently has trended toward more conservative surgery that preserves oncologic outcome, lessens morbidity, and improves psychosexual well-being.

The vulva includes the mons pubis, labia majora and minora, clitoris, vestibule, vestibular bulbs, Bartholin glands, lesser vestibular glands, paraurethral glands, and the urethral and vaginal openings. Lateral margins of the vulva are the labiocrural folds (Fig. 38-25). Vulvar cancer may involve any of these external structures and typically arises within the covering squamous epithelium. Unlike the cervix, the vulva lacks an identifiable transformation zone. That said, squamous neoplasia arises predominantly on the vestibule at the border between the vulvar keratinized stratified squamous epithelium, which lies laterally, and the nonkeratinized squamous mucosa, which lies medially. This demarcation line is termed Hart line.

Deep to the vulva are the superficial and deep urogenital triangle compartments. The superficial space lies between Colles fascia (superficial perineal fascia) and the perineal membrane (deep perineal fascia) (Fig. 38-26). Within this space lie the ischiocavernosus, bulbospongiosus, and transverse perineal muscles and the highly vascular vestibular bulb and clitoral crus. During radical vulvectomy, dissection is carried to the depth of the perineal membrane. As a result, contents of this superficial urogenital triangle compartment that lie beneath the mass are removed during tumor excision.

The lymphatics of the vulva and distal third of the vagina typically drain into the superficial inguinal node group (Fig. 38-29). From here, lymph travels through the deep femoral lymphatics and the node of Cloquet to the pelvic nodal groups. Importantly, lymph can also drain directly from the clitoris and upper labia to the deep femoral nodes (Way, 1948). Vulvar lymphatics cross at the mons pubis and the posterior fourchette but do not cross the labiocrural folds (Morley, 1976). Thus, lesions found within 2 cm of the midline may spread to lymph nodes on either side. In contrast, lateral lesions rarely send metastases to contralateral nodes. This anatomy point influences the decision for ipsilateral or bilateral node dissection, as discussed later.

The superficial inguinal nodes cluster within the femoral triangle formed by: the inguinal ligament, sartorius muscle, and adductor longus muscle. The deep femoral nodes lie within the borders of the fossa ovalis and just medial to the femoral vein. An inguinofemoral lymphadenectomy typically refers to removal of both superficial inguinal and deep femoral lymph nodes (Levenback, 1996).

In the United States, women have a 1 in 333 chance of developing this cancer at some point. In 2014, approximately 4850 new vulvar cancers and 1030 cancer deaths were predicted (National Cancer Institute, 2014). The age-adjusted incidence of invasive vulvar tumors in the United States has trended upward during the past three decades due to an aging population and greater longevity of human immunodeficiency virus (HIV)-infected women. This increase persists among all age groups and all geographic areas (Bodelon, 2009). Specifically, the age-adjusted incidence of vulvar carcinoma in situ (CIS) has increased by 3.5 percent per year, whereas that of invasive cancers has risen by 1 percent yearly (Jemal, 2010).

Of vulvar tumors, approximately 90 percent are squamous cell carcinoma (Fig. 31-1). Malignant melanoma is the second most common, but rare histologic subtypes may also be encountered (Table 31-1).

Age is a prominent factor and positively correlates with this cancer. Less than 20 percent of affected women are younger than 50 years, and more than half of cases develop in women older than 70. Survival rates also differ by age. Kumar and associates (2009) described a hazard ratio of nearly 4 for death in women older than 50 years compared with younger women. Last, vulvar cancer pathology can be divided into two distinct age-dependent profiles. Those that develop in younger women (<55 years) tend to have the same risk profile as other anogenital cancers. These cancers are usually described histologically as basaloid or warty and are linked with human papillomavirus (HPV) in 50 percent of cases. In contrast, older affected women typically are nonsmokers and lack a history of prior sexually transmitted infections. Their cancers are largely keratinizing, and HPV DNA is found in only 15 percent (Canavan, 2002; Madeleine, 1997). Such HPV-independent vulvar cancers have been associated with lichen sclerosus and with genetic alterations such as mutations in p53. This tumor suppressor gene normally modulates cell death, and its mutation can be carcinogenic.

Infection with high-risk HPV serotypes is another vulvar cancer risk. Serotype 16 predominates, although HPV serotypes 18, 31, 33, and 45 are also reported. Although HPV is implicated in many vulvar cancers, stronger correlations are noted between HPV infection and preinvasive vulvar lesions (Hildesheim, 1997). Specifically, HPV DNA is detected in 50 to 70 percent of invasive lesions but is seen in >90 percent of vulvar intraepithelial neoplasia (VIN) lesions (Gargano, 2012). HPV becomes a stronger contributor when combined with other cofactors such as smoking or herpes simplex virus (HSV) infection (Madeleine, 1997). Women who have smoked and have a history of HPV genital warts have a 35–fold increased risk for developing vulvar cancer compared with women without these predispositions (Brinton, 1990; Kirschner, 1995). For these reasons, prophylactic vaccination against high-risk HPV may ultimately reduce vulvar cancer incidence. A full discussion of HPV and VIN is found in Chapter 29

Herpes simplex virus infection is also linked with vulvar cancer in several studies (Hildesheim, 1997; Madeleine, 1997). As noted, the association is more prominent when coupled with other cofactors such as smoking. Thus, the causal link between HSV alone and vulvar cancer is not considered conclusive.

Chronic immunosuppression can predispose to vulvar cancer. For example, transplant patients have a high incidence. In this group, vulvar cancer develops at a much younger age than in the general population, and more than 50 percent have a prior history of condyloma acuminata (Penn, 2002). With HIV, vulvar cancer rates are also increased (Elit, 2005; Frisch, 2000). And, of the increased high-grade VIN and invasive vulvar carcinoma incidence noted in younger women, HIV-infected patients make up the majority (Casolati, 2003). A possible explanation for this is the association of HIV and high-risk HPV subtypes. However, vulvar cancer is not yet considered an acquired immunodeficiency syndrome (AIDS)-defining malignancy. Because of these links with vulvar cancer, we recommend that all immunocompromised women undergo thorough vulvar inspection and, when indicated, vulvoscopy and biopsy.

Lichen sclerosus is a chronic vulvar inflammatory disease and is related to vulvar cancer development. Keratinocytes affected by lichen sclerosus show a proliferative phenotype and can exhibit markers of neoplastic progression. As such, lichen sclerosus may be a precursor lesion in some invasive squamous vulvar cancers (Rolfe, 2001). Vulvar cancers coexistent with lichen sclerosus tend to develop in older women, predominate in near the clitoris, and lack association with VIN 3.

Last, progression from VIN 3 to invasive cancer is suspected. Several reports demonstrate that in a small percentage of women older than 30 years, untreated lesions can progress to invasive cancer within a mean of 4 years (Jones, 2005; van Seters, 2005). Although this progression cannot be conclusively validated, we recommend that patients with moderate and severe vulvar dysplasias receive early definitive treatment (Chap. 29).

Symptoms

Women with VIN and vulvar cancer commonly present with pruritus and a visible lesion (Fig. 31-2). However, pain, bleeding, ulceration, or inguinal mass may be other complaints (Fig. 31-3). Manifestations can persist for weeks or months before diagnosis, as many patients may be embarrassed or may not recognize the significance of their symptoms.

Lesion Evaluation

Lesions may be raised, ulcerated, pigmented, or warty, but in younger women with multifocal disease, a well-defined mass is not always present. Importantly, other clinical entities may present similarly and include preinvasive neoplasia (VIN), infection, chronic inflammatory disease, and granulomatous disease. Thus, the goal of evaluation is to obtain an accurate and definitive pathologic diagnosis.

For this, colposcopic examination of the vulva, termed vulvoscopy, can direct biopsy site selection. To begin, the vulva is soaked with 3-percent acetic acid for 5 minutes to allow adequate penetration into the keratin layer. This aids identification of acetowhite areas and abnormal vascular patterns, which are characteristics of vulvar neoplasia. The entire vulva and perianal skin are systematically examined. We recommend obtaining multiple biopsies, as illustrated in Figure 4-2, from the most suspicious raised or dyspigmented skin. Specimens removed with a Keyes punch should be approximately 4 mm thick to include the surface epithelial lesion and the underlying stroma. This permits evaluation for invasion and depth of invasion. Concurrent colposcopic examination of the cervix and vagina and careful evaluation of the perianal area are recommended to diagnose any synchronous lesions or associated neoplasm of the lower genital tract.

Cancer Patient Evaluation

Following histologic diagnosis, a patient with vulvar cancer is assessed for the clinical extent of disease and for comorbid conditions. Thus, detailed physical examination includes measurement of the primary tumor and evaluation of cancer extension into other genitourinary system compartments, the anal canal, the bony pelvis, and inguinal lymph nodes. At our institution, if a thorough physical examination is not possible because of patient discomfort or disease extent, an examination under anesthesia is performed. This may be coupled with cystourethroscopy, proctosigmoidoscopy, or both if suspicion of tumor invasion into the urethra, bladder, or anal canal is high (Fig. 31-4).

Women with small tumors and clinically negative groin nodes require few additional diagnostic studies other than those needed for surgical preparation (Chap. 39). Although not a formal part of surgical tumor staging, preoperative imaging may complement staging in those with larger tumors or with clinically suspected metastatic disease. In such cases, a chest radiograph and computed tomography (CT), positron emission tomography (PET), or magnetic resonance (MR) imaging of the abdomen and pelvis provide information regarding disease extent or metastases that may modify preoperative planning.

Staging Systems

The International Federation of Gynecology and Obstetrics (FIGO) advocates surgical staging of patients with vulvar cancer that is based on a tumor, nodal, metastatic (TNM) classification. Thus, staging involves: (1) primary tumor resection to obtain tumor dimensions and (2) dissection of superficial and deep inguinofemoral lymph nodes to evaluate tumor spread (Pecorelli, 2009). This system is used to direct treatment and predict prognosis (Van der Steen, 2010). Table 31-2 and Figure 31-5 describe FIGO staging and American Joint Committee on Cancer (AJCC) staging criteria for all vulvar cancer types except melanoma. This cancer’s staging is discussed separately on page 688. The general nuanced differences between FIGO and AJCC systems are described in Chapter 30.

Overall survival rates of women with squamous cell carcinoma of the vulva are relatively good. Five-year survival rates of 75 to 90 percent are routinely cited for stage I and II disease. As anticipated, 5-year survival rates for higher stages are poorer, and rates of 54 percent for stage III and 16 percent for stage IVB are reported (American Cancer Society, 2015). Apart from FIGO stage, other important prognostic factors include lymph node metastasis, lesion size, depth of invasion, resected-margin status, and lymphatic vascular space involvement (LVSI) (Table 31-3).

Of these, lymph node metastasis is the single most important vulvar cancer predictor, since inguinal node metastasis reduces long-term survival rates by 50 percent (Farias-Eisner, 1994; Figge, 1985). Nodal status is determined by surgical resection and histologic evaluation. Among patients with nodal metastasis, other factors further predict poor prognosis. These include a high number of involved lymph nodes, large nodal metastasis size, extracapsular invasion, and fixed or ulcerated nodes (Homesley, 1991; Origoni, 1992).

Tumor diameter also influences survival rates. But this stems mainly from the positive correlation between lesion size and nodal metastasis rates (Homesley, 1993).

Depth of invasion is another prognostic element. As shown in Figure 31-6, this depth is measured from the basement membrane to the deepest point of invasion (Kurman, 2014). Tumors with a depth of invasion <1 mm carry little or no risk of inguinal lymph node metastasis. However, increased nodal metastasis rates positively correlate with greater invasion rates.

Surgical margins that are tumor-free decrease local tumor recurrence rates, and traditionally a 1- to 2-cm tumor-free margin is desired. More specifically, two large retrospective series demonstrated that a tumor-free surgical margin ≥8 mm yielded a high rate of local control. In contrast, if tumor was found within this 8-mm margin, the recurrence rate was 23 to 48 percent (Chan, 2007; Heaps, 1990). Hence, when lesions are close to the clitoris, anus, urethra, or vagina, a 1-cm surgical tumor-free margin may be used to preserve important anatomy yet still provide optimal resection.

Lymphatic vascular space invasion (LVSI) describes histologic identification of tumor cells within lymphatic vessels and is a predictor of early disease recurrence (Preti, 2005). LVSI is also associated with a higher frequency of lymph node metastasis and a lower overall 5-year survival rate (Hoskins, 2000).

Surgery

For vulvar cancer treatment, surgery is often an integral part. Potential procedures, in increasing order of radicality, include wide local excision (WLE), radical partial vulvectomy, and radical complete vulvectomy.

Of these, wide local excision is appropriate only for microinvasive tumors (stage IA) of the vulva. With this excision, also termed simple partial vulvectomy, 1-cm surgical margins are obtained around the lesion. Deep surgical margins measuring 1 cm are also preferred. This deep margin usually corresponds to Colles fascia (Fig. 38-25).

With radical partial vulvectomy (Section 46-25), tumor-containing portions of the vulva are completely removed, wherever they are located. Skin margins are 1 to 2 cm, and excision extends deep to the perineal membrane (Fig. 31-7). Radical partial vulvectomy is typically reserved for unifocal lesions that are clinically confined to the labia majora, labia minora, mons, vestibule, and/or perineum and that have limited involvement of the adjacent urethra, vagina, and/or anus. Moreover, only patients with a solitary tumor that is not too large or too extensive and with an otherwise normal vulva are considered for this vulva-conserving surgery.

Radical total vulvectomy (Section 46-26) is a complete dissection of vulvar tissue to the level of the perineal membrane and the periosteum of the pubic rami or symphysis. Adequate margins will generally require an incision in the labiocrural fold that extends down to the fourchette and up over the mons pubis. All intervening subcutaneous tissue is excised. Lesions involving or adjacent to the clitoris may require wider margins cephalad to the mons. Such radical resections are performed for large midline or multifocal vulvar cancers. Flap reconstruction is occasionally needed and described in Section 46-28. Contraindications to a radical complete vulvectomy include poor surgical risk, poor patient compliance, and metastatic disease beyond regional lymph nodes.

Of the three procedures shown in Figure 31-8, the en bloc incision, colloquially termed the butterfly or longhorn incision, has largely been abandoned. It has survival rates equivalent to radical complete vulvectomy but carries significantly greater morbidity.

Inguinofemoral Lymphadenectomy

This procedure is usually an integral part of surgical cancer staging and accompanies radical partial or radical complete vulvectomy. It is recommended for all vulvar squamous carcinomas that invade deeper than 1 mm on initial biopsy or have a tumor diameter >2 cm regardless of invasion depth (stages IB-IVA). To maximize metastatic disease detection and staging accuracy, surgical evaluation of the groin nodes is recommended. Traditionally, both the superficial inguinal and deep femoral lymph nodes have been removed for evaluation of metastatic disease (Gordinier, 2003). Moreover, lymph nodes may be excised unilaterally or bilaterally. Traditionally, an ipsilateral inguinofemoral lymphadenectomy is performed for a “lateralized” vulvar lesion, namely, one that lies >2 cm beyond the midline. Bilateral node excision is recommended for all lesions within 2 cm of the midline. Aside from acquiring staging information, inguinofemoral lymphadenectomy may also be used to debulk large, cancerous lymph nodes.

Entire steps for lymphadenectomy are described and illustrated in Section 46-27. To summarize, the superficial inguinal lymph nodes lie within the fatty tissue caudal to the inguinal ligament and superficial to the thigh’s fascia lata. This node-containing tissue is dissected free to reach the fossa ovalis. Here, deep femoral nodes are excised from their location medial to and alongside the femoral vein. For these deep nodes, a modified approach preserves the cribriform fascia (portion of fascia lata overlying the fossa ovalis) by removing the deep femoral nodes through the cribriform fascia’s perforations. This modification yields cancer recurrence rates comparable to those obtained following classic inguinofemoral node dissection (Bell, 2000; Hacker, 1983). Advantageously, complication rates of wound breakdown, infection, and lymphedema are significantly decreased (Table 31-4). However, a classic inguinofemoral node dissection on occasion is required to reach these deep femoral lymph nodes. In such cases, the cribriform fascia is transected, lymph nodes are removed, and the sartorius muscle can then be transposed over the femoral vessels. This transposition may reduce the risk of postoperative erosion into the skeletonized femoral vessels if superficial wound dehiscence occurs. However, this transposition does not reduce overall postoperative wound morbidity rates (Judson, 2004; Rouzier, 2003).

Surgical evaluation of the groin nodes has been reported to confer a superior prognosis compared with primary groin irradiation. A phase III randomized controlled trial conducted by the Gynecologic Oncology Group (GOG) showed that patients undergoing primary groin dissection experienced significantly fewer groin recurrences and a better prognosis compared with women receiving groin irradiation (Stehman, 1992b). Furthermore, limiting node dissection to only the superficial inguinal nodes also confers a higher groin recurrence rate compared with historical controls undergoing removal of both superficial and deep nodes (Stehman, 1992a). Higher than acceptable groin recurrence rates have also been described for patients who received primary groin irradiation (Manavi, 1997; Perez, 1993). Thus, in general, both deep and superficial inguinal lymph node removal is recommended to allow for thorough evaluation for nodal metastasis. But, because of groin dissection morbidity, this advantage has been challenged for those with early-stage disease and clinically negative nodes. Namely, recent evidence supports the use of sentinel lymph node biopsy in vulvar lesions <4 cm in diameter and assures a low false-negative rate of undetected nodal metastasis.

Sentinel Lymph Node Biopsy

As another less morbid option, selective dissection of a solitary node or nodes, termed sentinel lymph node biopsy (SLNB), dramatically reduces surgical morbidity yet adequately assesses nodal involvement. Physiologically, the first lymph node to receive tumor lymphatic drainage is termed the sentinel lymph node. Thus, a sentinel lymph node devoid of disease implies absent lymph node metastases within the entire lymph node basin. SLNB is not performed if groin node metastases are clinically suspected.

Currently, both lymphoscintigraphy and isosulfan blue dye techniques are recommended when performing SLNB for vulvar cancer (Levenback, 2008). To begin, intraoperative lymphatic mapping is accomplished by injecting radionuclide intradermally at the tumor border that lies closest to the ipsilateral groin. For midline tumors, both sides of the tumor are injected. A handheld gamma counter aids attempts to identify the sentinel node subcutaneously, and the skin is marked by pen over the strongest signal. Next, isosulfan blue dye is injected at the same tumor border. Last, the groin skin over the prior pen mark is incised approximately 5 minutes later (Fig. 31-9). The tracer and dye are taken up by the specific node that drains the tumor site first. The handheld gamma counter signal may assist in localizing the sentinel node, and/or it can be visually identified by its blue color. Once identified, it is separated and excised from the other nodes within that regional group.

Several studies have confirmed the accuracy of SLNB to predict vulvar cancer metastasis in the inguinal lymph nodes. One multicenter trial by the GOG reported the sensitivity of this technique was >90 percent and the false negative rate was 2 percent for tumors measuring <4 cm. Patients with tumors measuring ≥2 cm and invading to a depth >1 mm and with clinically negative nodes were included in the study (Levenback, 2012). SLNB for patients with a vulvar lesion that does not involve midline structures but that also does not meet the definition of a lateralized lesion is appealing as it potentially avoids unnecessary groin exploration on one side (Coleman, 2013).

A second study, the GROningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V), evaluated SLNB for patients with squamous cell cancer of the vulva measuring <4 cm. It too confirmed the predictive value of SLNB. Moreover, this study concluded that the risk of metastasis to additional inguinal lymph nodes increases with sentinel-node metastasis size (Oonk, 2010; Van der Zee, 2008). Last, one ongoing prospective study (GROINSS-V-II) is observing early-stage vulvar cancer patients with a sentinel node metastasis measuring ≤2 mm to see if complete inguinofemoral lymphadenectomy can be safely replaced by adjuvant radiotherapy following vulvectomy.

Microinvasive Tumors (Stage IA)

Within the FIGO system, stage I vulvar cancers are divided into two categories. Stage IA lesions measure ≤2 cm in diameter, are confined to the vulva or perineum, and display stromal invasion ≤1 mm. These lesions, termed microinvasive cancers, reflect a subpopulation in which the risk of inguinal metastasis is negligible (Binder, 1990; Donaldson, 1981; Hacker, 1984). Women with microinvasive stage IA tumors tend to be younger and have multifocal disease associated with HPV. For probable cure, these patients can undergo wide local excision with a 1-cm margin. Lymphadenectomy is not indicated because associated lymph node metastasis is rare.

Stage IB–II

Patients with early-stage vulvar cancer typically present with T1B and T2 lesions (stage IB and II) of the vulva and clinically negative groin nodes. For stage IB lesions, radical resection of the primary tumor and inguinofemoral lymphadenectomy is recommended. If adequate margins and dissection to the perineal membranes can be achieved, then radical partial vulvectomy offers similar recurrence rates but less morbidity than radical complete vulvectomy (Tantipalakorn, 2009). Because 20 to 30 percent of women with T1 and T2 disease will have diseased nodes, SLNB and/or inguinofemoral lymphadenectomy is performed. As described on page 685, lesion laterality and clinical impression regarding groin involvement guides the decision to perform ipsilateral or bilateral groin dissection.

Stage II cancers are most often managed with a larger radical partial excision. For example, a 4-cm lesion involving the clitoral hood may be managed by an anterior hemivulvectomy and bilateral inguinofemoral lymphadenectomy. Again, reported experience with conservative surgery suggests identical local recurrence rates if 1- to 2-cm surgical margins are achieved (Burke, 1995; Farias–Eisner, 1994; Tantipalakorn, 2009). Occasionally, a radical complete vulvectomy may be required, depending on tumor size and location.

Stage III

By definition, stage III vulvar cancers include node-positive tumors. Affected patients have T1 or T2 vulvar lesions with regional nodal spread that is not fixed or ulcerated. Most patients with clinically negative nodes have typically undergone a radical partial or complete vulvectomy and inguinofemoral lymphadenectomy. However, in cases where groin nodes are grossly positive and resectable, “nodal debulking” is performed but further nodal dissection is forfeited. This allows adjuvant radiotherapy to treat any residual microscopic disease yet minimize additional groin dissection morbidity. In practice, most women with stage III vulvar cancer are treated with adjuvant radiation therapy directed to both groins and the pelvis.

Efficacy for this was shown in a randomized GOG trial of 114 patients with invasive squamous cell carcinoma of the vulva and diseased groin nodes. Adjuvant radiation to both groins and the pelvic midplane proved superior to extended pelvic node resection. However, 12 percent of women completing radiotherapy still relapsed in the groin and pelvis, and 8.5 percent at distant sites (Homesley, 1986; Kunos, 2009).

Nodal metastasis does not increase the risk of recurrence on the vulva. Hence, adjuvant radiation to the vulva is the treating physician’s decision and guided by margin status, tumor size, and LVSI.

The addition of platinum-based chemotherapy concurrent with radiation therapy stems from treatment of cervical cancer. Also, extrapolation of apparent efficacy in phase II trials of more locally advanced vulvar cancer suggests a role for this for postoperative patients with lymph node metastases (Moore, 1998, 2012). To improve control in both inguinal and pelvic lymph nodes and survival rates, a randomized phase III trial (GOG protocol #185) is currently comparing adjuvant radiation therapy and the combination of radiation plus weekly cisplatin chemo­therapy in vulvar cancer patients with positive nodes.

Stage IVA

These locally advanced vulvar cancers involve the proximal urethra, proximal vagina, bladder or rectal mucosa, or pelvic bone and may or may not have affected inguinal lymph nodes. With stage IVA vulvar cancers, women occasionally can be treated with radical primary surgery. Much more often, tumor size and location necessitate some form of exenterative surgical procedure to remove the entire lesion with adequate margins. Such unresectable, locally advanced vulvar cancers can be effectively treated with neoadjuvant chemoradiation to drastically minimize the surgical resection required. Two Phase II studies conducted by the GOG have demonstrated the feasibility of this approach using cisplatin regimens (Moore, 1998, 2012). An on-going Phase II trial is currently evaluating the efficacy of cisplatin, gemcitabine, and intensity-modulated radiation therapy (IMRT) for primary treatment of locally advanced squamous cell carcinoma of the vulva. As described in Chapter 28, IMRT offers greater sculpting of radiation delivery to minimize toxicity.

Our current practice is to offer preoperative cisplatin-based chemoradiation to women with inoperable primary tumors or with extensive lesions that would require pelvic exenteration. In cases without fixed groin nodes, pretreatment inguinofemoral lymphadenectomy is performed to determine the need for groin irradiation. If groin nodes are fixed or ulcerated, then primary chemoradiation is administered.

If residual disease remains on the vulva following chemoradiation, then local resection is indicated. If there has been complete clinical response, the primary tumor site undergoes excisional biopsy to confirm pathologic response. Unresected groins that are clinically or radiographically positive 8 weeks after surgery are biopsied by fine-needle aspiration (FNA). If the FNA is positive, a targeted excision of the groin is performed.

In contrast, for stage IVB vulvar cancer, treatment is individualized. A multimodality approach is used to achieve palliation.

After completing primary treatment, all patients receive thorough physical examination, including inguinal lymph node palpation and pelvic examination every 3 months for the first 2 to 3 years. Surveillance examinations are then scheduled every 6 months to complete a total of 5 years. Thereafter, disease-free women may be seen annually. Vulvoscopy and biopsies are performed if concerning areas are noted during history or physical examination. Radiologic imaging and biopsies to diagnose possible tumor recurrence are performed as indicated.

Vulvar Recurrences

In a woman with suspected recurrence, careful evaluation is completed to define the disease extent. Local vulvar recurrences are most common, and surgical reexcision is usually the best option. Radical partial vulvectomy is appropriate for smaller lesions. For large central recurrences involving the urethra, vagina, or rectum, a total pelvic exenteration with reconstructive surgery may be required (Section 46-4). With exenteration, to maintain sexual function, vaginal reconstruction can be completed at the time of surgery or after a short postoperative interval (Section 46-9). Radiated tissue often has a poor blood supply. Thus, vulvar recurrences in a previously radiated field typically require myocutaneous flaps for reconstruction after surgical resection. Last, for patients who are not surgical candidates and are radiation naïve to the vulva, external beam radiation combined with interstitial brachytherapy can be an option.

Distant Recurrences

Inguinal lymph node recurrences are virtually always associated with ultimately fatal disease, and few women are alive at the end of the first year following this diagnosis. Women with pelvic or distant metastases can be offered palliative chemotherapy. Combination platinum-based chemotherapy has modest activity in recurrent vulvar cancers (Cunningham, 1997; Moore, 1998). Platinum-based regimens (e.g., cisplatin/paclitaxel) as recommended for advanced cervical cancer might be considered for vulvar cancer if palliative chemotherapy is indicated.

Squamous cell cancer of the vulva diagnosed and surgically treated during pregnancy is rare, and an incidence of 1 per 20,000 deliveries has been reported (DiSaia, 1997). Nevertheless, any suspicious lesion is evaluated, even during pregnancy.

Radical complete or partial vulvectomy and inguinofemoral lymphadenectomy can be performed when indicated after the first trimester. During the third trimester, markedly increased genital vasculature can increase surgical morbidity. In general, if a diagnosis is made during the late third trimester, lesions may be removed by wide local excision, and definitive surgery completed postpartum. In cases diagnosed at delivery, definitive surgery is performed typically 2 to 3 weeks postpartum.

The mode of delivery following cancer surgery is heavily influenced by the state of the postsurgical vulva. In instances of vaginal stenosis, significant fibrosis, or tumor involvement, a cesarean delivery is recommended, otherwise vaginal delivery is appropriate.

This rare variant of squamous cell carcinoma constitutes less than 1 percent of all vulvar cancers. Its etiology is unknown, but HPV genome has been found in some of these tumors. Verrucous carcinomas are locally invasive and rarely metastasize. Most women have a cauliflower-shaped vulvar mass that usually elicits pruritus or pain. Surgery is preferred, and most tumors are excised by wide local excision that ensures a 1-cm surrounding margin. Inadequate margins risk local recurrence. Verrucous carcinomas are resistant to radiotherapy and may undergo anaplastic transformation to become more aggressive and invasive. Enlarged groin lymph nodes are evaluated preoperatively by FNA because they usually are inflammatory.

Clinical Presentation and Staging

Melanoma is the second most common vulvar cancer and accounts for 10 percent of all vulvar malignancies. Vulvar melanoma disproportionately affects the elderly and develops more commonly among whites than other races. Vulvar melanoma has an overall poor prognosis, and 5-year survival rates range from 8 to 55 percent (Evans, 1994; Piura, 1992).

Malignant vulvar melanomas most commonly arise from the labia minora, labia majora, or clitoris (Fig. 31-10) (Moore, 1998; Woolcott, 1988). Some benign pigmented lesions can also be found here and include lentigo simplex, vulvar melanosis, acanthosis nigricans, seborrheic keratosis, and nevi (Chap. 4). Last, pigmented vulvar neoplasia may be VIN, squamous cell carcinoma, or Paget disease. Thus, tissue sampling is mandatory, and immunohistochemical studies or electron microscopy can help clarify the diagnosis (Fig. 31-11). Three histologic subtypes of vulvar melanoma have been described: superficial spreading melanoma (SS), nodular melanoma (NM), and acral lentiginous melanoma (AL).

Vulvar melanomas have been staged by several microstaging systems that include the Chung, the Clark, and the Breslow systems and by the macroscopic systems published by FIGO and AJCC (Table 31-5). Of these, the AJCC stage and Breslow thickness are major predictors of overall survival and are used most often. Breslow thickness measures in millimeters the thickest portion of the lesion from the intact epithelium’s most superficial surface to the deepest point of invasion (Moxley, 2011; Verschraegen, 2001).

Treatment

Surgery

Vulvar melanoma has limited response to both chemotherapy and radiotherapy. Thus, excision is the single best definitive therapy. Conservative surgery, such as wide local excision or a radical partial vulvectomy, is preferred as radical surgery appears to offer no greater survival advantage (Irvin, 2001; Verschraegen, 2001).

Nodal metastasis is a major predictor of prognosis. The incidence of occult inguinal lymph node metastases is <5 percent for thin melanomas measuring <1 mm thickness, but >70 percent for lesions >4 mm (Hoskins, 2000). Women with clinically positive groin lymph nodes should undergo inguinofemoral lymphadenectomy if possible, as surgical removal of regional disease is the most effective method of control. In patients with clinically negative groins, the decision to perform inguinofemoral lymphadenectomy or SLNB is influenced by lesion thickness. Primary lesions that warrant inguinofemoral node evaluation are those that have a Breslow thickness >1 mm. Other high-risk candidate lesions are lesions <1 mm thick but showing ulceration, a mitotic rate >1 per mm², or LVSI, and those lesions with ambiguous thickness due to a biopsy’s positive deep margin (Lens, 2002b). At our institution, we encourage women with clinically negative groins to first undergo SLNB. If diseased nodes are detected, then an inguinofemoral lymphadenectomy can be considered.

Adjuvant Therapy

Women may be considered for adjuvant therapy if their primary vulvar melanoma poses a great risk for disease recurrence. Factors include lesions that are 2 to 4 mm thick and ulcerated, deep primary tumors, positive nodes, or other high-risk features.

Of options, in certain patients with regional cutaneous melanoma involving other body surfaces, adjuvant alpha interferon (IFN-α) increases both progression-free and overall survival rates (Lens, 2002a). At our institution, however, we strongly advocate enrollment in a trial for such patients, recognizing that interferon regimens have considerable toxicity and offer limited benefit.

Adjuvant radiation therapy also shows some promise to reduce locoregional recurrence rates (Ballo, 2005). The National Comprehensive Cancer Network (NCCN) guidelines for treatment of positive resection margins or macroscopically positive fully resected nodal basins include radiotherapy to the affected areas.

Metastatic Disease

Metastatic melanoma is challenging to treat, and 5-year survival rates are <20 percent (Sugiyama, 2007). Resection of distant metastases can be considered for selected patients in whom a survival benefit might be expected compared with medical treatment.

For systemic therapy, several options are available. Preferred regimens include ipilimumab, vemurafenib, or high-dose interleukin-2 (HD IL-2). Of these, HD IL-2 (Proleukin) was approved by the Food and Drug Administration (FDA) in 1998 for metastatic melanoma and benefits a small patient subset. Based on these findings, other novel immunotherapeutic approaches have subsequently been investigated.

One novel approach involves T-cell mechanisms that self-regulate T-cell activation through expression of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4, thereby increasing T-cell activity and promoting antitumor actions. Ipilimumab (Yervoy) received FDA approval for treatment of metastatic melanoma in March 2011. Although the response rate and overall survival rates with ipilimumab are modest, therapy toxicities, which include immune-related enterocolitis, hepatitis, and dermatitis, are manageable.

In addition, recognition of other key molecular mutations that drive melanoma tumorigenesis has led to promising agents that selectively inhibit the actions of these mutations. Namely, BRAF and c-KIT mutations may be found in these tumors, and women with melanoma often have their tumors tested for these mutations. Vemurafenib (Zelboraf), a BRAF inhibitor, was approved by the FDA for treatment of metastatic or unresectable melanoma that exhibits the BRAF mutation (Robert, 2011). Imatanib (Gleevec) may be used for tumors with the c-KIT mutation.

Last, biochemotherapy refers to regimens that combine cytotoxic agents with IFN-α and/or HD IL-2. Biochemotherapy may provide a palliative benefit in patients who are symptomatic and/or have rapidly progressive disease. However, the lack of survival benefit with biochemotherapy suggests that alternative therapies should be considered.

Basal cell carcinoma (BCC) of the vulva accounts for <2 percent of all vulvar cancers and is most commonly found in elderly women (DiSaia, 1997). Lesions typically arise on the labia majora, are characterized by poor pigmentation and pruritus, and often mimic eczema, psoriasis, or intertrigo. As a result, correct diagnosis is often delayed due to treatment for other presumed inflammatory or infectious dermatoses.

Although ultraviolet radiation is thought to be the primary risk factor for BCC on sun-exposed areas, its development on sun-protected areas raises the possibility of other, yet undefined, etiologies. Some suggest that local trauma and advancing age may contribute at these sites (LeSueur, 2003; Wermuth, 1970).

Basal cell carcinoma is removed by radical partial vulvectomy using a minimum surgical margin of 1 cm. Lymphatic or distant spread is rare, but inguinofemoral lymphadenectomy or SLNB is considered for clinically suspicious nodes. However, disease may locally recur, particularly in tumors removed with suboptimal margins. Most basal cell carcinomas of the vulva are indolent and locally invasive, but rarely metastatic. If surgery is contraindicated, then primary radiation therapy can be considered. Local immunomodulators such as imiquimod can be selected for patients who are inappropriate surgical candidates. Because surgery is the recommended treatment, any other treatment modalities will warrant close observation to detect cancer progression.

Sarcoma of the vulva is rare, and leiomyosarcoma, malignant fibrous histiocytoma, epithelioid sarcoma, and malignant rhabdoid tumor are the more frequently encountered histologic types. Of these, leiomyosarcoma appears to be most common. Tumors typically develop as isolated masses on labia majora, clitoris, or Bartholin gland (Fig. 31-12). Unlike squamous cell carcinoma, the age of affected women is significantly broader and varies between histologic types.

The outcome of vulvar sarcomas is influenced by size, degree of mitotic activity, and level of infiltration. That is, disease associated with lesions >5 cm in diameter, with infiltrating margins, with extensive necrosis, and with more than five mitoses per 10 high-power fields is most likely to recur after surgical resection (Magné, 2011).

Hematogenous metastasis is the most frequent route of tumor dissemination. Radical partial or complete vulvectomy or pelvic exenteration is recommended if total surgical resection is possible. Removal of inguinofemoral lymph nodes is performed if nodes are large and/or symptomatic. Adjuvant radiation, chemotherapy or both can be considered depending on risk factors for recurrence. Neoadjuvant chemotherapy and/or radiotherapy are considerations for unresectable vulvar sarcomas.

Primary malignant tumors arising from the Bartholin gland can be adenocarcinomas, squamous cell carcinomas, or transitional cell carcinomas. The incidence of Bartholin gland carcinomas peaks in women in their mid-60s. Soft, distensible tissue normally surrounds these glands, and tumors may reach considerable size before patients develop symptoms. Dyspareunia is a common first complaint. Bartholin gland enlargement in a woman older than 40 years and recurrent cysts or abscesses warrant a biopsy or excision. Similarly, all solid masses require FNA or biopsy to establish a definitive diagnosis.

Bartholin gland carcinomas tend to spread into the ischiorectal fossa and have a propensity for lymphatic spread into the inguinal and pelvic lymph nodes. Therapy for most early cancer stages includes a radical partial vulvectomy with inguinofemoral lymphadenectomy. Decisions to perform ipsilateral or bilateral groin dissection follow the same criteria as for squamous cell tumors. Postoperative chemoradiation has been shown to reduce the likelihood of local recurrence for all stages. If the initial lesion impinges on the rectum or anal sphincter, preoperative chemoradiation can be used to avoid extensive surgery.

Extramammary Paget disease is a heterogeneous group of intraepithelial neoplasias and when present on the vulva, appears as an eczematoid, red, weeping area (Fig. 31-13). These are often localized to the labia majora, perineal body, or clitoris. This disease typically develops in older white women and accounts for approximately 2 percent of all vulvar tumors. Vulvar Paget disease is accompanied by invasive Paget disease or adenocarcinoma of the vulva in 10 to 20 percent of cases (Hoskins, 2000). Moreover, 20 percent of patients with extramammary Paget disease will have a carcinoma at another nonvulvar location (Pang, 2010; Wilkinson, 2002).

A histologic classification proposed by Wilkinson and Brown (2002) includes: (1) primary vulvar cutaneous Paget disease, (2) Paget disease as an extension of transitional cell carcinoma of the bladder or urethra, and (3) Paget disease as an extension of an associated adjacent primary cancer such vulvar, anal, or rectal cancers. The histologic differentiation of these Paget disease types is important because the specific diagnosis significantly influences treatment selection.

Of these, primary cutaneous vulvar Paget disease displays slow growth. Diseased areas ideally are resected by wide local excision with a 1- to 2-cm margin. In contrast to VIN 3 treatment, margins are frequently positive, and disease recurrence is common regardless of the surgical margin status (Black, 2007). If invasive disease is suspected, radical partial vulvectomy is warranted by extending the deep margins to the perineal membrane. The latter is frequently accompanied with an ipsilateral or bilateral inguinofemoral lymphadenectomy.

Recurrent Paget disease is common, and long-term surveillance is prudent since repeat surgical excision is often necessary. Moreover, screening and surveillance for tumors at nongynecologic sites is considered and includes evaluation of the breasts and the gastrointestinal and genitourinary tracts. A detailed discussion of Paget disease of the breast is presented in Chapter 12.

Metastatic tumors make up approximately 8 percent of all vulvar cancers. Tumors may extend from primary cancers of the bladder, urethra, vagina, or rectum. Less proximate cancers include those from the breast, kidney, lung, stomach, and gestational choriocarcinoma (Wilkinson, 2011).