Historically, radical vulvectomy and en bloc bilateral inguinal node dissection was the standard approach for the majority of patients, regardless of disease extent.⁵^–⁸ Consequent to the chronic, often debilitating physical and psychological sequelae of radical vulvectomy in long-term survivors, questions arose regarding the need for radical vulvectomy in patients with limited disease at diagnosis. Unsatisfactory rates of locoregional control in patients with advanced disease as well as the morbidities associated with exenterative surgery stimulated exploration of novel combinations of therapies. Increasing awareness of the sensitivity of squamous vulvar cancer to RT and chemoradiation further suggested management changes.

Although optimal therapy for many situations remains to be defined, directions of change include conservative surgery for selected patients with early disease and multimodality therapy (chemoirradiation alone or integrated with less extensive surgery) for patients with locally advanced disease. Chemoradiation is increasingly accepted as alternative therapy for patients with disease that would require partial or total exenteration if treated by initial surgery. Preoperative or postoperative adjuvant RT or chemoradiation is now commonly utilized to complement conservative surgery in patients with adverse clinical or histopathologic features.

Mature published results remain sparse for patients treated on the basis of the newer concepts of integrated multimodality management tailored to the site and extent of disease. Valuable information continues to accumulate from phase 2 study reports, most of which support the concept of integrated, multimodality therapy. Selecting the order in which therapies are employed, defining the intensity and scope of irradiation and the extent of surgery when these complementary modalities are used sequentially, and optimizing the choice and schedule of chemotherapy when combined with RT, represent ongoing challenges in therapy refinement that emphasize the need for close collaboration between gynecologic oncologists and radiation oncologists in planning and accomplishing a treatment plan.

Etiology and Epidemiology

No universal cause for vulvar cancer has been identified. The etiology is likely multifactorial, but some risk factors have been identified. Many patients with vulvar carcinoma have had previous malignant or premalignant lesions of the genital tract.⁹^–¹¹ Between 2% and 5% of vulvar intraepithelial neoplasia (VIN) 3 lesions (severe dysplasia or carcinoma in situ) will progress to invasive carcinoma.¹² The risk factors for progression to invasive cancer are poorly understood but do include advanced age. One study observed that the relative risk for vulvar or vaginal carcinoma after treatment of cervical carcinoma was 2.9% regardless of whether the patient received radiation for treatment of the cervical cancer. Compromised immune status, whether iatrogenic in the setting of organ transplantation, congenital, or acquired based on human immunodeficiency virus (HIV) infection, leads to an increased risk for cancers in the lower genital tract, including the vulva and vagina. Improvement in immune function with highly active antiretroviral therapy (HAART) may decrease the risk in HIV-infected patients,¹³^–²² although longer survival with HAART may permit emergence of papillomavirus-associated anogenital malignancies in long-term survivors of HIV infection.²³

The human papillomavirus (HPV) has been implicated as a cause of vulvar cancer. Brinton and colleagues ²⁴ established a relative risk of vulvar cancer of 14.6% when there is a history of condylomata acuminata. HPV has been detected widely in sexually active women. The type of HPV is related to the risk for benign versus malignant tumors of the vulva. In patients with condylomata acuminata, the detected HPV is usually type 6 or 11, whereas for vulvar in-situ neoplasia or vulvar carcinoma, HPV 16 and 18 are more common.^25,²⁶ Invasive vulvar cancer and condyloma may be present synchronously in the same patient, delaying diagnosis of malignancy in some patients. Multiple studies have investigated the presence of HPV in vulvar carcinoma.^27,²⁸ It may be detected in both primary tumors and nodal metastases. Review of published data²⁹ employing polymerase chain reaction or hybrid capture assays for HPV DNA detection in 2790 patients with invasive vulvar cancer—1320 patients with VIN 2 and 3, and 71 patients with VIN 1—reveals HPV prevalence in invasive cancer to be 40.1% in invasive lesions, 80.4% in VIN 2 and 3, and 77.7% in VIN 1. HPV 16 serotype was the most common, detected in 29.3% of invasive cancers and 71.2% of VIN 2 and 3 lesions.

Smoking is an additional risk factor for vulvar carcinoma as it is with cervical cancer, and the combination of smoking with a history of genital warts results in a strong increase in the relative risk for vulvar cancer.^11,³⁰ It is possible that smoking and HPV infection have a synergistic effect on the genesis of vulvar cancer, with smoking functioning as a promoter.^31,³²

Data are conflicting as to the etiologic role of vulvar dystrophies (lichen sclerosus and squamous cell hyperplasia) in the cause of vulvar cancer. These epithelial alterations may be seen in approximately half of patients with vulvar cancer.³³^–³⁵ Patients with vulvar cancer and associated lichen sclerosus are, on average, significantly older than patients with newly diagnosed lichen sclerosus with or without squamous hyperplasia.³⁶ However, less than 5% of patients with these epithelial alterations will progress to invasive vulvar malignancy.

It has been observed that there are two, broadly different groups of vulvar cancer patients. The first consists of younger patients who more frequently smoke and are at higher risk for HPV infection and whose invasive cancers are commonly associated with VIN. The second, and more common, group consists of elderly patients whose disease may be unrelated to smoking or HPV infection and in whom concurrent VIN is unusual but lichen sclerosus and squamous hyperplasia are common associated findings.³⁷

Investigators have examined a number of molecular and genetic parameters in an effort to define prognostic factors in patients with invasive cancer, as well as to identify patients with lichen sclerosus, squamous hyperplasia, or VIN who are at highest risk for development of invasive malignancy.38–45,46 However, at this time, the use of molecular markers has not become a part of routine clinical practice.

Prevention and Early Detection

Because most vulvar malignancies arise from cutaneous surfaces readily accessible to examination, both visibly and palpably, invasive lesions should be diagnosed when small and easily treated. Unfortunately, most advanced vulvar cancers are a result of patient delay or neglect or physician failure to diagnose. Some elderly patients may be mentally impaired. Modesty, anxiety, or frank denial may lead a patient to ignore or minimize symptoms of pruritus, oozing, bleeding, the presence of a mass, and pain. A physician should perform a thorough examination when patients have such symptoms.

No known measures to prevent invasive vulvar cancer exist except for the appropriate treatment of VIN when it is detected. Whether treatment of lichen sclerosus and squamous hyperplasia reduces the risk of subsequent development of invasive cancer is unknown. Pooled data from three prospective clinical trials with mean follow-up of 42 months after initiation of vaccination with quadrivalent HPV vaccine (HPV types 6/11/16/18) show 100% efficacy in prevention of VIN 2 and 3 and vaginal intraepithelial neoplasia (VAIN) 2 and 3 among patients treated per protocol and 79% in an intent-to-treat population (HPV exposed and unexposed).⁴⁷ Whether this will ultimately translate into a clinically meaningful reduction in the incidence of preinvasive and invasive vulvar and vaginal malignancies remains specultative.⁴⁸ At this time, the target population for whom efficacy would seem most likely consists of sexually naive/HPV unexposed adolescents.

A history of smoking tobacco products is associated both with VIN and invasive vulvar malignancy. Patients who smoke should be encouraged to quit, because the statistical risk of anogenital malignancy associated with former smoking is observed to be substantially less than that associated with current smoking and diminishes with increasing time since cessation of smoking.³² Additionally, women with vulvar or vaginal cancer appear to have a fourfold increased risk of subsequently developing a second primary cancer of the lung.⁴⁹

Because VIN 3 may be associated with an occult invasive lesion in as many as 20% of symptomatic patients,⁵⁰ care must be taken when employing treatment techniques that do not include full-thickness histologic evaluation. Excisional techniques, provided that there is minimal loss of functionality and cosmesis, are preferable to ablative techniques without histologic material for study. Core biopsy or excisional biopsy of smaller lesions is suggested for most vulvar abnormalities, if necessary under colposcopic guidance. In circumstances in which there exists a strong clinical suspicion of an invasive cancer, a core biopsy is preferable to an excisional biopsy, in order to preserve the diagnostic accuracy of a subsequent sentinel node procedure. Even if vulvar lesions appear to have a warty appearance and are believed to be benign, confluent warts should be sampled to exclude an underlying diagnosis of squamous cell carcinoma.

Because of the risk for multifocal disease throughout the lower genital tract and anus where vulvar carcinoma is detected, it is appropriate to perform colposcopy of the cervix, vagina, and vulva and digital rectal examination or anoscopy to evaluate for the presence of synchronous lesions at other sites.

Pathology and Pathways of Spread

Pathology

Squamous cancer is the most common malignant lesion of the vulva and constitutes 80% to 90% of vulvar tumors. It may be unifocal or multifocal. Variants of squamous cancer include cancers with discontiguous, infiltrative borders permeating lymphatic spaces with a so-called spray pattern of local invasion ^51,⁵² and verrucous cancers with broad, pushing borders^53,54,55,56 (Fig. 58-1). Sarcomatoid differentiation is seen in a minority of squamous cancers and can be associated with an aggressive course.

Figure 58-1 Variants of squamous cell cancer of the vulva. A, Infiltrative pattern of growth with discontinuous satellites of malignant cells, sometimes called a spray pattern of growth. B, Verrucous cancer with a bulbous, pushing front of invasion into the surrounding stroma.

Photomicrographs courtesy Dr. Richard Oi, Department of Pathology, University of California at Davis.

Poorly differentiated cancers with a trabecular growth pattern manifesting finger-like projections and an infiltrative border with discontiguous islands and nests of malignant cells may spread to regional nodes, even when small, and frequently recur beyond the margins of local excision within dermal lymphatic channels. Recognition of this pattern of growth should prompt consideration of adjuvant radiotherapy.

Verrucous cancers may clinically manifest a warty appearance resembling a cauliflower floret, with exuberant hyperkeratosis microscopically. Broad, bulbous borders characterize these tumors, which rarely metastasize to regional nodes. Morphologic and biologic studies on 10 cases of verrucous carcinoma of the vulva support the theory that verrucous cancers constitute a discrete clinicopathologic subset of vulvar cancer.⁵⁷ Treatment is radical local excision. Despite a tendency for these tumors to recur locally, the role of radiotherapy as adjuvant treatment for this variant remains controversial because of anecdotal reports of clinical radioresistance.

Other, much less common tumors found in the vulva include malignant melanoma, basal cell carcinoma, Merkel cell tumors, carcinoid, transitional cell carcinomas, adenoid cystic carcinoma, vulvar Paget’s disease, and a variety of sarcomas. Tumors metastasizing from other sites may become manifest in the vulva.⁵⁸

Melanomas constitute less than 10% of primary tumors but are the second most common malignancy of the vulva. Even clinicians at tertiary referral centers will see only one or two patients with melanoma of the vulva annually. Melanomas may arise de novo or from preexisting junctional or compound nevi. Rare, amelanotic vulvar melanomas may occur. Diagnostic assessments, staging, and treatment broadly parallel the that for cutaneous melanoma arising at other sites. Prognosis correlates with depth of invasion ⁵⁹^–⁶¹ and with the presence or absence of spread to regional nodes. Locoregional therapy is primarily surgical.

Primary malignant tumors of the vulva may arise in the Bartholin complex, and some of these are variants of adenocarcinomas. Adenoid cystic carcinomas uncommonly disseminate to regional nodes and may have an indolent natural history with late local and hematogenous relapse.⁶² Perineural invasion is common. Tumors in the Bartholin complex also may be squamous and are thought to arise in ductal squamous epithelium.

Bartholin’s tumors tend to be deeply infiltrative and solid, often with the overlying skin remaining intact. This clinical presentation may be confused with benign cysts or infection, causing delay in diagnosis and difficulty in accomplishing surgical clearance with wide, negative margins because of proximity to the anorectum and the ischial ramus. Observational outcomes data suggest that patients with Bartholin’s tumors that are more locally extensive are less likely to manifest local failure when postoperative adjuvant RT is administered compared with patients with more favorable disease treated with surgery as monotherapy.⁶²

The International Society for the Study of Vulvar Disease (ISSVD) recommended abandoning the term microinvasion when applied to carcinoma of the vulva and proposed the current use of stage IA, which incorporates criteria for both tumor size and depth. The depth of invasion is defined as the distance from the epithelial stromal junction of the most superficial adjacent dermal papillae to the deepest point of invasion. Stage IA is defined as a solitary squamous cancer of the vulva measuring less than 2 cm in diameter, with clinically negative nodes in which the depth of invasion is 1 mm or less.^63,⁶⁴ This definition encompasses the previous understanding of microinvasion, because the risk of nodal involvement with invasion less than 1 mm is close to 0%. In addition to tumor stage and depth, other pathologic features of the primary tumor should be noted, including presence or absence of vascular space invasion, tumor grade, and tumor growth pattern.⁶⁵

Pathways of Spread

Vulvar cancer spreads by direct extension to adjacent structures, including the vagina, urethra, perineum, anus, and ischial rami. Tumor may spread by embolization through the lymphatics to the regional nodes. Permeation of in-transit regional lymphatic vessels is uncommon but may account for the occasional patient with recurrence in the skin bridge conserved when vulvar cancer is treated surgically employing separate incisions for the primary tumor and the regional node dissection. This is rare in the absence of extensive groin node metastases.⁶⁶

The lymphatics of the vulva (Fig. 58-2) consist of a network that covers the entire labia minora, fourchette, prepuce, and distal vagina below the hymenal membrane. Lymphatics coalesce anteriorly, forming larger trunks, which run lateral to the clitoris to the mons veneris, acquiring tributaries from the lymphatics of the labia majora, which run in a parallel fashion anteriorly from the perineal body. At the mons veneris, the vulvar lymphatic trunks diverge laterally to the inguinal nodes. Study of the localization of dye or radiolabeled tracer in regional lymph nodes after focal injection of discrete sites in the vulva and on the perineum reveals that the lymphatic drainage of the perineum, clitoris, and anterior labia minora is often bilateral whereas the lymph flow from well-lateralized sites (>2 cm from midline structures) in the vulva is predominantly to the ipsilateral groin.⁶⁷

Figure 58-2 Lymphatic drainage of the vulva and perineum. Arrows indicate the flow patterns.

Adapted from Russell AH: Cancer of the vulva. In Leibel SA, Phillips TL (eds): Textbook of Radiation Oncology, 2nd ed. Philadelphia, WB Saunders, 2004, p 1179.

The vulvar lymphatics run through the vulva and do not traverse the labiocrural fold. Perineal lymphatics course lateral to the labiocrural fold through the superficial tissues of the upper medial thigh. In the radiation treatment of patients with advanced vulvar cancer that extends to the perineal skin, these lateral channels should be taken into consideration. Advanced vulvar cancer extending up the vagina proximal to the hymenal ring may spread through vaginal lymphatics directly to pelvic nodes.

Primary lymphatic drainage is usually to the superficial inguinal nodes with secondary lymphatic drainage through the cribriform fascia to the femoral nodes, with subsequent tertiary flow under the inguinal ligaments to the external iliac nodes. However, metastases have been reported to the femoral lymph nodes without involvement of the superficial inguinal lymph nodes,^68,⁶⁹ especially from carcinomas of the clitoris and Bartholin’s gland. Sentinel node studies have demonstrated primary lymphatic flow to deep nodes in as many as 16% of cases,⁷⁰ and a Gynecologic Oncology Group (GOG) study also found an unexpectedly high incidence of ipsilateral groin recurrences secondary to presumed involvement of lymph nodes deep to the cribriform fascia despite prior negative superficial inguinal lymphadenectomy.⁷¹ The actuarial risk of groin recurrence at 5 years was 16% (19/119) among patients with vulvar cancer treated with groin node dissection alone at M.D. Anderson Cancer Center, of whom 111 had superficial inguinal node dissections. Of these patients, 117 had groin specimens histopathologically negative for metastases.⁷² Groin recurrence after superficial and deep groin dissection retrieving histologically negative nodes is 2% or less.⁷³^–⁷⁵

Clinical assessment of groin node status by palpation is notoriously inaccurate, with approximately 20% of groins judged clinically nonsuspicious harboring occult node metastases and approximately 20% of groins considered clinically suspicious for metastases containing only reactive or inflammatory nodes * (Table 58-1). The frequency of lymph node metastases to the inguinal-femoral nodes is related to the depth of stromal invasion^52,⁸¹^–⁸⁵ (Table 58-2), defined as the distance from the epithelial stromal junction of the most superficial adjacent dermal papillae to the deepest point of invasion. In Table 58-3 the incidence of occult nodal involvement in clinically nonsuspicious groin nodes treated by complete lymphadenectomy is cross-tabulated by primary tumor size.⁸⁶

TABLE 58-1 Clinical Assessment of Inguinofemoral Nodes by Palpation

Node Status	Histologically Negative	Histologically Positive
Clinically negative (451 patients)	363 (80.5%)	88 (19.5%)
Clinically positive (243 patients)	53 (21.8%)	190 (78.2%)

Pooled data from six institutions; see references 7, 76, 77, 78, 79, 80.

TABLE 58-2 Incidence of Groin Node Metastasis Correlated with Depth of Invasion for Primary Tumors 2 cm or Smaller

TABLE 58-3 Probability of Clinically Occult Metastasis to Inguinofemoral Lymph Nodes Correlated with Primary Tumor Size in Operable Vulvar Cancer

With lateralized primary tumors, metastases to the contralateral groin in the absence of ipsilateral groin metastases may be seen in up to 15% of patients with very advanced primary disease.⁸⁷ Metastases to contralateral groin nodes in the setting of uninvolved ipsilateral groins have been reported in patients with Bartholin’s gland primary disease⁸⁸ and tumors of the anterior labia minora.⁸³ In the absence of spread to ipsilateral nodes, discrete (≤2 cm diameter), well-lateralized primary cancers limited to the vulva and not approaching midline structures manifest spread to contralateral groin nodes in less than 1% of patients undergoing bilateral lymphadenectomy.^{82–85,89–91} However, 5 patients (2.6%) of 192 pooled patients with T1 lateralized cancers managed with ipsilateral groin dissection with no evidence of nodal disease have manifested contralateral groin recurrence.^71,^85,⁹²^–⁹⁶ A theoretic explanation for this discrepancy is the possibility that dissection of negative groin nodes may be therapeutic in a small number of patients in whom routine sectioning of groin nodes (as opposed to pathologic ultrastaging) may fail to detect minute micrometastases consequent to undersampling.

The overall incidence of metastases to the pelvic lymph nodes is 5%. Lymphadenectomy will detect metastatic involvement in pelvic nodes in 15% to 28% of patients with metastases to inguinal nodes.* Pelvic node metastasis is extremely rare in the absence of groin node metastases and very uncommon in the context of occult, microscopic involvement of a single groin node.

Hematogenous spread, usually to lung and bone, is unusual in the absence of prior inguinofemoral lymph node involvement and generally occurs late in the course of the disease. Most patients who die of disease do so with uncontrolled locoregional disease. However, in patients with three or more positive lymph nodes the ultimate risk of hematogenous spread is 66%. In contrast, patients with fewer than three positive lymph nodes have only a 4% risk of hematogenous spread.^102,¹⁰³

Biology and prognostic factors

In multivariate analysis the presence or absence of lymph node involvement remains the single most important prognostic factor in outcomes of treatment for vulvar cancer.¹⁰⁴ For those with negative lymph nodes, the average 5-year overall survival (OS) from nine large literature series is 91% (range, 83% to 100%).† For those with involved lymph nodes treated with curative intent, the average 5-year OS is 52% (range, 38% to 61%).‡ Ninety-five percent of relapses after primary surgical treatment occur in the vulva, perineum, or groins.^73,^82,¹⁰⁹^–¹¹² The extent of lymphatic involvement is prognostic and includes volume of tumor in the involved nodes, extracapsular penetration, number of positive nodes, and level of metastatic disease in the nodal chain.^{3,4,28,105,113}

Because of the dominant negative impact of inguinal node metastasis, some investigators only examine primary tumor-related characteristics in relation to their correlation with nodal involvement rather than their impact on risk of recurrence of disease at the primary site.

A number of primary tumor-related characteristics, identified on multivariate analysis, predict for vulvar relapse regardless of nodal involvement, among them tumor size and depth of invasion.⁷⁷ The latter correlates not only with locoregional recurrence but also with the risk of node metastasis. Heaps and colleagues⁶⁵ identified stage, width of surgical margin, depth of invasion, tumor thickness, growth pattern (infiltrative as opposed to pushing), and presence of vascular space invasion as factors predictive of local recurrence after primary surgery.

Three publications ^65,^114,¹¹⁵ have reported a clear association between risk of vulvar recurrence and width of surgical resection margins. When microscopic margins are 8 mm or less in formalin-fixed tissue, local recurrence has been observed in 43 of 145 patients (30%)^65,^114,¹¹⁵ (Table 58-4). These findings have not, however, been consistently observed in all pathology laboratories.¹¹⁶ Allowing for estimated fixation shrinkage artifact between 25% and 45%, this 8-mm pathologic margin correlates with a minimal clinical free space of 1 cm of uninvolved normal tissue, providing a practical guideline for identifying patients who are likely to be advised to undergo postoperative local irradiation for inadequate margins if treated by initial surgery. Under such circumstances, preoperative chemoradiation may be preferable to secure better margins and possibly to reduce the scope of subsequent conservative surgery.

TABLE 58-4 Width of Surgical Margin and Risk of Local Recurrence

Clinical Manifestations, Patient Evaluation, and Staging

Clinical Manifestations

The virus-related cause of vulvar cancer in some patients, its association with preinvasive or invasive cancers in other parts of the lower genital tract, and its histologic features suggest that vulvar cancer may be one manifestation of a multifocal disease or “field cancerization.”^46,¹¹⁷ However, at the time of diagnosis only about 5% of vulvar cancers are multifocal. Patients usually present with a vulvar mass or ulcer often following a variable history of pruritus or vulvar pain. Depending on the location and size of the lesion within the vulva, the patient may also complain of dysuria, difficulty with defecation, bleeding, or discharge. Rarely, patients may present with advanced inguinal node involvement, occasionally with ulcerating masses in the groins or with lower extremity lymphedema resulting from obstruction.

Patient Evaluation

The diagnosis of vulvar cancer requires pathologic confirmation, usually by punch biopsy. For patients with small lesions who have access to treatment in tertiary care facilities skilled in the performance of sentinel node biopsy, excisional biopsy should be avoided because this can compromise the diagnostic accuracy of the subsequent sentinel node procedure. When vulvar dystrophy is present and the vulva is more difficult to assess visually, use of a colposcope may assist in identifying abnormal areas for appropriately directed biopsies. The remainder of the lower genital tract and anus should be examined, if necessary by colposcopy and anoscopy, to evaluate for the presence of synchronous preinvasive or invasive cancers.

Clinical evaluation of the groin nodes by palpation is inaccurate in approximately 20% of cases. Clinically negative nodes will harbor occult metastases in approximately 20% of cases, and approximately 20% of patients with clinically positive groin nodes will have negative nodes if surgically dissected, presumably because of the confounding presence of inflammatory or reactive changes (see Table 58-1). Assessment of groin nodes is particularly compromised in the obese patient, when even superficial inguinal nodes may be several centimeters below the skin. Because of the imprecision of clinical assessment, pathologic verification of nodal status is desirable, when feasible, and is required for assignment of FIGO stage.

Staging

In 1988, FIGO introduced a surgical staging system for vulvar cancer that has since undergone several revisions, most recently in 2009 (Table 58-5). Staging systems are intended to standardize reporting of treatment efficacy, allowing comparison of the outcomes of treatment from different institutions and comparison of results employing different treatment strategies. Ideally, stage should not be employed to determine therapy and should be assigned prior to any major therapeutic intervention such as surgery. Unfortunately, the current clinicopathologic system defines stage for many patients based, in part, on information derived subsequent to surgical treatment of the groin nodes. Because of the strong association between prognosis and the number and size of groin node metastases, the staging system appears to implicitly endorse surgical management of the groin nodes when this may not be prudent or feasible in all clinical circumstances. In a patient with a locally advanced primary tumor requiring preoperative chemoradiation in an effort to avoid compromise of functionally important midline structures, it may be medically sensible to electively include clinically negative groin nodes in the irradiated volume, provided that they appear grossly uninvolved by physical examination and diagnostic imaging. Without subsequent groin dissection and without sampling of groin nodes prior to treatment, such patients are reported to have a very low probability of treatment failure of groin disease if treatment is carried out with appropriate technique.^118,¹¹⁹ Such patients are, however, “unstaged.” Comprehensive pretreatment evaluation of disease extent may be less important when institutional treatment policy is to perform initial surgery in all patients with medically operable and technically resectable disease, even in the presence of limited node metastases. If the detection of nodal disease before treatment will impact the selection, sequencing, or intensity of treatment modalities, the diagnostic cascade illustrated in Figure 58-3 may help to guide therapy. No consensus standard exists for the pretreatment evaluation of disease extent. PET/CT may not be available in many locations, and lack of reimbursement may prove an additional obstacle even when the technology is available for other indications. Experience with sentinel node identification is not universal, and its routine use outside tertiary referral centers remains controversial. Thus the algorithm in Figure 58-3 may not be applicable in all venues.

TABLE 58-5 FIGO 2009 Staging of Cancer of the Vulva

Stage	Description
I	Tumor confined to the vulva
IA	Lesions ≤2 cm, confined to the vulva or perineum and with stromal invasion ≤1.0 mm*; no nodal metastasis
IB	Lesions >2 cm or with stromal invasion >1.0 mm,* confined to the vulva or perineum, with negative nodes
II	Tumor of any size with extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus) with negative nodes
III	Tumor of any size with or without extension to adjacent perineal structures (one third lower urethra, one third lower vagina, anus) with positive inguinofemoral lymph nodes.
IIIA	(i) With one lymph node metastasis (≥5 mm), or (ii) One to two lymph node metastasis(es) (<5 mm)

IIIB

(i) With two or more lymph node metastases (≥5 mm), or

(ii) Three or more lymph nodes metastases (<5 mm)

IIIC With positive nodes with extracapsular spread IV Tumor invades other regional (two thirds upper urethra, one third upper vagina), or distant structures IVA

Tumor invades any of the following:

(i) Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa or fixed to pelvic bone, or

(ii) Fixed or ulcerated inguinofemoral nodes

IVB Any distant metastasis including pelvic lymph nodes

* The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.

From Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105:103-104, 2009.

Figure 58-3 Diagnostic algorithm for vulvar cancer. CT, computed tomography; FDG-PET, ¹⁸F-fluorodeoxyglucose positron emission tomography; M, metastasis; N, node; SLN, sentinel lymph node; T, tumor; VIN, vulvar intraepithelial neoplasia.

Confirmation of node status is often accomplished by surgical exploration of the inguinal nodes. The most common surgical practice is to obtain histologic examination of the ipsilateral inguinal lymph nodes for lateralized lesions of the vulva and of bilateral nodes for lesions considered to be midline or where ipsilateral nodes are involved. Although there is no widely accepted definition of midline, a minimum of 1 cm of clinically involved tissue separating the border of the tumor from a structure that has bilateral lymphatic drainage should be mandatory before considering omission of contralateral node assessment or treatment, and many clinicians recommend 1.5 to 2.0 cm.

Because lymphatic drainage from the anterior labia minora may be bilateral,^67,¹²⁰ bilateral groin assessment should be considered for lesions arising in these areas even if otherwise apparently lateralized because contralateral groin metastases with negative ipsilateral groin nodes have been described with primary tumors in this location.⁸³ Possibly because precise tumor extent may be more difficult to appreciate on physical examination, contralateral groin node metastases with negative ipsilateral groin nodes have similarly been reported in patients with primary cancers of the Bartholin complex, suggesting consideration of bilateral histologic groin assessment in such patients as well.⁸⁸

Sentinel nodes (Fig. 58-4) may be identified for selective excisional biopsy by injection of blue dye and radiocolloid at the primary site.^70,¹²¹^–¹²⁶ It is increasingly clear that use of a blue dye alone is insufficient to identify sentinel nodes. Results are better when a radioactive tracer is used in combination with blue dye. Sentinel nodes should be both “hot and blue” for greatest accuracy. When sentinel nodes are enlarged or heavily infested with metastatic cancer, a sentinel node study may be falsely negative consequent to altered patterns of lymphatic flow. Imaging of the groins before identification of the sentinel node, with ultrasonography or CT, should reduce the probability of a false-negative sentinel node study by identifying grossly enlarged or suspicious nodes, which may or may not be palpable, whose status requires clarification regardless of the findings from a sentinel node study.

Figure 58-4 Inguinal dissection sentinel node technique. Blue dye identifies node to be harvested.

Pathologic ultrastaging of groin nodes has been used to increase the sensitivity of sentinel node excisional biopsy in the detection of microscopic groin node metastases.^124,¹²⁷ Ultrastaging may include thin step-sectioning of retrieved nodes with or without immunohistochemical staining. When nodal disease is advanced and initial surgery to the groin area is not planned, histologic confirmation of metastatic contamination may be obtained by fine-needle biopsy or aspiration cytology.

Noninvasive imaging with PET/CT, MRI, or ultrasonography may assist in assessing lymph node status, particularly in larger or obese patients in whom femoral nodes may be many centimeters below the skin and well beyond a depth where node palpation is feasible.¹²⁸^–¹³¹ Metabolic imaging may sometimes detect metastases in the absence of gross nodal enlargement. CT alone is less sensitive owing to the frequency with which groin nodes are nonspecifically enlarged due to inflammatory or reactive changes and/or fat replacement. Spatial imaging may identify nodes accessible for image-guided fine-needle biopsy. Although clinically useful in some patients, the results of imaging assessment, unless confirmed histologically, do not alter assignment of FIGO stage. Accurate measurement of the depth of femoral nodes below the anterior skin surface at the level of the femoral artery as it passes under the inguinal ligament is critical in the design and implementation of radiation-based therapy for undissected groins as well as in the context of adjuvant irradiation of the groins after superficial or total inguinal lymph node dissection.^132,¹³³ Axial imaging is probably the most precise means of making this measurement.