Vulvar Cancer PDF

# Chapter 78 Carcinoma of the Vulva ## Anatomy ### Vulva The vulva is composed of the mons pubis, clitoris, labia majora and minora, vaginal vestibule, and their supporting subcutaneous tissues. The vulva blends with the urinary meatus anteriorly and with the perineum and anus posteriorly. The...

# Chapter 78 Carcinoma of the Vulva ## Anatomy ### Vulva The vulva is composed of the mons pubis, clitoris, labia majora and minora, vaginal vestibule, and their supporting subcutaneous tissues. The vulva blends with the urinary meatus anteriorly and with the perineum and anus posteriorly. The mons pubis consists of prominent tissue located anteriorly to the pubic symphysis. The labia majora are two elongated skin folds that course posteriorly from the mons pubis and blend into the perineal body. The skin of the labia majora is pigmented and contains hair follicles and sebaceous glands. The labia minora are a smaller pair of skin folds located between the labia majora. Anteriorly, the labia minora separates into two components that course above and below the clitoris, fusing with those of the opposite side to form the prepuce and frenulum, respectively. The skin of the labia minora contains numerous sebaceous glands but no hair follicles and has no underlying adipose tissue. The clitoris is 2 to 3 cm anterior to the urethral meatus and is supported externally by the fusion of the labia minora. The vaginal introitus is demarcated laterally by the labia minora and posteriorly by the perineal body. Anteriorly, numerous small vestibular glands are located beneath the mucosa and open onto its surface adjacent to the urethral meatus. The Bartholin glands (or greater vestibular glands) are two small mucus-secreting glands situated within the subcutaneous tissue in the posterior aspect of the labia majora. The ducts of the Bartholin glands open onto the posterolateral portion of the introitus. The Skene glands (or paraurethral glands) open in the anterior aspect of the introitus but can be variable in location. The perineal body is a 3- to 4-cm band of skin that separates the vaginal introitus from the anus and forms the posterior margin of the vulva with the fusion of the labia minora, the fourchette. ### Lymphatic Drainage The inguinofemoral nodes are located within the triangle formed by the inguinal ligament superiorly, the border of the sartorius muscle laterally, and the border of the adductor longus muscle medially. There are superficial inguinal lymph nodes that lie along the saphenous vein and its branches between Camper fascia and the cribriform fascia overlying the femoral vessels. There are usually three to five deep nodes, the most superior of which, Cloquet node, is located under the inguinal ligament. Lymph drains from these nodes into the external and common iliac pelvic lymph nodes. Lymphatic drainage is specific to the location of a vulvar lesion. Labial lesions drain into the superficial inguinal and femoral lymph nodes, and then penetrate the cribriform fascia and reach the deep femoral nodes. Lesions of the fourchette and perineum follow the lymphatics of the labia. Lymphatic drainage from the glans clitoris or perineal body enters either unilateral or bilateral superficial femoral nodes or the deep femoral and pelvic lymph nodes. Some lymphatics originating in the clitoris enter the pelvis directly, bypassing the femoral nodes to connect with the obturator and external iliac lymph nodes, though, in practice, the pelvic lymph nodes are rarely involved without synchronous involvement of the inguinal nodes (Fig. 78.1). ## Epidemiology Vulvar cancer is a rare malignancy that represents <1% of all the cancers diagnosed in women and <5% of all gynecologic neoplasms. In the United States, it is estimated that there were 6,020 new cases in 2017, with 1,150 deaths due to the disease.¹ The incidence is 2.5 cases per 100,000 women; however, this incidence increases to 15.5 per 100,000 in women of age >75 years. The incidence is slightly lower in black women (2.1 per 100,000) compared with whites (2.8 per 100,000). There are two primary mechanisms believed to be involved in the carcinogenesis of this disease: human papillomavirus (HPV) and vulvar dystrophy, including lichen sclerosus (LS) and squamous hyperplasia. HPV DNA can be identified in between 30% and 40% of invasive vulvar cancers, with 16, 18, and 33 being the predominant subtypes. This is in contrast to vulvar intraepithelial neoplasia (VIN), from which HPV can be isolated in 70% to 90% of lesions. Because HPV infection is related to numerous other cancers of the anogenital region (e.g., cervical cancer and anal canal cancer), the risk factors are similar: previous diagnosis of genital warts, multiple sexual partners, smoking history, previous abnormal Papanicolaou test, and immune suppression. LS is often associated with the remaining HPV-negative cancers, although there is no histopathologic evidence of direct transformation.5 Women with existing LS have a 5% to 7% risk of developing invasive disease, with risk increasing with older age and concurrent VIN (up to 19% risk of invasive cancer at 10 years).6,7 The evidence for VIN as an obligate precursor to invasive vulvar disease, however, is less compelling than that established between cervical intraepithelial neoplasia and cervical cancer. Only one-third of vulvar cancers have an associated VIN-3 lesion, and only 5% to 7% of women with an existing VIN lesion will subsequently be diagnosed with invasive disease.8 VIN may in fact be divisible into two general types, depending on the lesion dependence (or independence) from HPV. Usual-type VIN (uVIN) is often HPV driven and occurs in younger women with HPV risk factors. Differentiated-type VIN (dVIN) arises in the setting of LS and other chronic inflammatory processes and is associated with older age. These differing precursor lesions may then transform into two distinct classifications of squamous carcinoma: keratinizing squamous carcinomas (KSCs) arising from dVIN and basaloid squamous carcinomas (BSCs) arising from UVIN. 10 KSC is more common (80% of cases), and p53 mutations may play a role in pathogenesis in a subset of these neoplasms, whereas p16 is rarely positive indicating a lack of association with HPV.11,12 BSC, in contrast, is less common (20% of cases), and staining for p53 is often negative, whereas p16 is often positive because of its association with HPV. Similar to findings related to HPV-related cancers in other sites, HPV-driven lesions (uVIN and BSC) portend a better prognosis. 13 Overexpression of p16 may also be associated with an improved prognosis, even when high-risk HPV DNA is not detected. 14 ## Pathology ### Squamous Carcinoma Eighty to ninety percent of invasive disease of the vulva is squamous cell carcinoma (Fig. 78.2), 15 arising within squamous epithelium, within or adjacent to areas of epithelial abnormalities or of premalignant conditions such as LS, erythroplasia of Queyrat, and Bowen disease. 16 The depth of invasion, critical for appropriate staging and management, is defined as the distance from the epithelial stromal junction of the most superficial adjacent dermal papillae to the deepest point of invasion. Tumor thickness is measured from the overlying surface epithelium, or the bottom of the granular layer if the surface is keratinized, to the deepest point of invasion as specified by the International Society of Gynecological Pathologists.17 There are three recognizable types of growth pattern of squamous carcinoma: confluent, compact, and spray or finger-like growth. Confluent growth is defined as a tumor mass composed of interconnected tumor >1 mm in dimension. This type of growth is characteristic for being deeply invasive with associated stromal desmoplasia. Compact growth is associated with well-differentiated tumors, which maintain continuity with the overlying epithelium, infiltrating as a well-defined and circumscribed tumor mass, which rarely invades the vascular space. Histologically, the tumor cells resemble squamous cells of adjacent and overlaying epithelium. The spray or finger-like growth pattern is characterized by a trabecular appearance with small islands of poorly differentiated tumor cells found within the dermis or submucosa, deeper than the main tumor mass. This growth pattern is often associated with desmoplastic stromal response and a lymphocytic inflammatory infiltrate. Vascular space involvement is seen more commonly with this growth pattern than with tumors with a compact pattern. 18 ## Uncommon Histologic Types and Management ### Melanoma Malignant melanoma of the vulva accounts for approximately 10% of all primary tumors of the vulva, with a peak incidence in the sixth and seventh decades (Fig. 78.3). 19,20 Sometimes, the tumor arises in a preexisting pigmented lesion, and in these cases, the differential diagnosis includes benign vulvar melanosis and pigmented VIN. Vulvar melanomas can be subclassified into three specific categories: superficial spreading malignant melanoma, nodular melanoma, and acral lentiginous melanoma. As is the case for melanomas arising in other mucosal sites, the level of invasion, tumor thickness, and nodal evaluations dictate the therapy and determine the prognosis.21 Compared to nongynecologic melanomas, BRAF and KIT mutations are more frequently detected in vulvar and vaginal melanomas, and PD-L1 and PD-1 may be more frequently expressed, having implications for targeted therapies and immunmodulation.22 The prognosis is poor, with a 5-year overall survival of approximately 35%, and is worse in patients who have one or more of the following features: deep invasion, ulceration, nodular growth pattern, epithelioid cell type, and high mitotic rate. 23-25 The prognosis is also worse in older patients. Primary surgical excision with nodal evaluation is preferred if possible, with adjuvant radiotherapy for nodal disease or close margins at the primary site. In a study of 32 patients treated at the Royal Marsden Hospital in London, there was no difference in the outcome between patients treated with wide local excision and those treated with more radical surgical procedures. 26 Radiation may be considered for patients with positive margins or positive lymph nodes or for palliation of symptoms. As with melanomas of other sites, the prognosis is guarded because of a propensity for distant metastasis. ### Adenocarcinoma Adenocarcinomas of the vulva arise predominantly in the Bartholin glands, although apocrine, eccrine, and Skene glands can also be the site of origin. In the rare instances when adenocarcinomas arise in the absence of glandular tissue, they may be of cloacogenic origin. Carcinoma of the Bartholin gland is seen more frequently in older women and is often solid and deeply infiltrative. The overlying epidermis or mucosa may remain intact, leading to misinterpretation as a benign process. Other histopathologic types are mucinous, papillary, mucoepidermoid, adenosquamous, and transitional. The transition from normal to malignant glandular tissue can be recognized in some cases. Adenocarcinomas often present with more locally advanced disease and metastases to the inguinofemoral lymph nodes. The general approach to treatment, however, follows squamous cell carcinomas, with initial surgery with tailored adjuvant radiation therapy for resectable disease, and multimodality therapies for advanced stages. Survival after treatment is comparable to stage-matched squamous cell cancers. 27 The role of radiation for Bartholin gland carcinoma has been studied by Copeland et al. and Leuchter et al. 28,29 These two studies suggest that adjuvant radiation to the vulva and regional nodes after conservative surgery may decrease local recurrence, with 7% recurrence with radiation and 27% recurrence without it in the Copeland et al. study. Five-year survival of 67% was reported by Cardosi et al. in patients who were found to have close margins and were treated with primary surgery and adjuvant radiation. 30 ### Paget Disease of the Vulva Paget disease of the vulva (intraepithelial adenocarcinoma) is seen most often in postmenopausal, older white women. The disease varies in appearance, but most often, it presents as an eczematoid, red can, or weeping lesion, and it can be mistakenly diagnosed as eczema or contact dermatitis (Fig. 78.4). The lesion may be flat, raised, or ulcerated and may appear whitish (leukoplakia), red (erythroplastic), or hyperpigmented. This condition has a typical histologic pattern and often stains positive for carcinoembryonic antigen. Vulvar Paget disease is associated with invasive carcinoma in 10% to 20% of the cases. 31,32 The invasive disease may be an underlying adenocarcinoma of the apocrine or Bartholin glands, or it may be an adenocarcinoma arising elsewhere in the anogenital region. Management is generally focused on maximal safe resection, though radiotherapy is an effective therapy for recurrent or unresectable disease. 33 Topical imiquimod also shows promise as an effective nonoperative therapy. 34 ### Verrucous Carcinoma Verrucous carcinomas of the vulva are uncommon, usually diagnosed in the fifth or sixth decade of life. They are locally invasive tumors that present as fungating, ulcerative masses. Histologically, these tumors are often well differentiated and have a low incidence of metastasis to lymph nodes. In instances when the lesion is in early stage, excellent results are obtained with radical wide excision. 35 Inguinofemoral dissections are not recommended routinely because of the rarity of nodal metastases. The literature regarding vulvar verrucous carcinomas consists largely of case reports, with the exception of the series by Japaze et al.36 This study was based on 24 patients, 17 of whom were treated with surgery only and 7 of whom were treated with surgery and radiation. In the surgery group, only 1 patient developed recurrence and died as a result of it. In the radiation group, 4 patients developed recurrence, and all died from the disease. Although it is difficult to draw conclusions from this small series, there are no convincing data to recommend the routine use of radiotherapy for this disease. In addition, there is no sufficient evidence to support the notion that radiation induces anaplastic transformation.37 ### Other Histologies Other vulvar malignancies arising from epidermal cell types are rare. Merkel cell tumors (neuroendocrine carcinomas) are aggressive locally, have a high incidence of distant metastasis, and carry a poor prognosis. Basal cell carcinomas, on the other hand, seldom spread to lymph nodes and are appropriately treated with wide excision alone. 38 Transitional cell carcinomas may arise from the Bartholin glands or may also represent metastasis from the bladder and/or lower urinary tract. Leiomyosarcomas are the most common subtypes of vulvar sarcoma followed by malignant fibrous histiocytomas, epithelioid sarcomas, and rhabdomyosarcomas. Rhabdomyosarcomas of the vulva require combination therapy, chemotherapy, and radiation, as per rhabdomyosarcoma protocols of other sites. Results of treatment with other sarcomas of the vulva are unpredictable, and wide resection and/or radical radiotherapy should be considered, given the relative inactivity of chemotherapy. ## Clinical Presentation Vulvar pruritus is the most common presenting symptom, often associated with bleeding, pain, or discharge. If there is a visible lesion on physical examination, a biopsy is required to distinguish it from other vulvar lesions such as dystrophia, benign condylomata, and VIN. Unfortunately, many women have a long delay in diagnosis due to denial or minimization of symptoms and may present with a locally advanced tumor by the time of initial evaluation. These lesions may also present with symptoms related to the invasion of regional structures, including difficulty with urination or defecation. Metastatic disease is an uncommon presenting symptom because the primary lesion is usually much more problematic, although consequences of groin and distant disease may also be seen at presentation. ## Patterns of Disease and Spread ### Primary Site Approximately 70% of vulvar malignancies arise in the labia majora and minora, 15% in the clitoris, 5% in the perineum and fourchette, 5% in the prepuce Bartholin glands and urethra, and 5% are too extensive at presentation to classify.39 ### Lymphatic Spread High-grade tumors with "spray" growth pattern and lymphatic space invasion have a proclivity to spread to the regional lymphatic nodes. The superficial inguinofemoral lymph nodes are the first echelon, followed by the deep inguinofemoral nodes. For well-lateralized lesions, metastasis to the contralateral inguinal or pelvic lymph nodes is unusual in the absence of ipsilateral inguinofemoral node involvement. Lesions of the clitoris or urethra can spread directly to pelvic lymph nodes, although this is rare without inguinal node involvement.40,41 The frequency of inguinal lymph node metastasis in surgically staged patients ranges from 6% to 50%, depending on tumor invasion and extent of disease (Table 78.1).42-46 Physical examination alone is inaccurate to assess lymph node involvement: Plentl and Friedman reported a 62% incidence of lymph node metastases in patients with clinically palpable adenopathy and 35% involvement in patients without clinically palpable adenopathy.39 In the Gynecologic Oncology Group (GOG) protocol 36, Homesley reported that 24% of the patients with clinically negative inguinal nodes were found to have nodal metastasis on final pathology. When the lymph nodes were clinically suspicious, 76% of the patients had histologically positive nodes. Multiple clinical and histologic features of the primary tumor are associated with nodal metastasis, including tumor thickness, histologic grade, capillary-like space involvement, depth of invasion, location of the tumor, and tumor size. 47,48 Rutledge et al. 48 also described the adverse effect on local control and survival of tumor size, clinical stage, positive inguinal or pelvic nodes, and positive margins at the primary site. When the tumor thickness is ≤1 mm, the probability of nodal metastasis is ≤3%, but with a tumor thickness ≥ 5 mm, the probability increases to 33.3%. Depth of invasion of 1, 2, and 3 mm corresponds to a 4.3%, 7.8%, and 17% incidence of nodal involvement, respectively. It should be noted that thickness of the epithelium in the vulva varies significantly from one area to another, in some areas being >0.8 mm thick, which can influence the relative value given to tumor thickness and depth of invasion. Measuring tumor thickness in superficially ulcerated tumors can be misleading and may lead to underestimating the depth of invasion. Perineural invasion correlates strongly with lymph node metastasis.49 In analysis of the GOG database on carcinoma of the vulva, several clinical and histologic tumor characteristics were identified as predictors of nodal involvement. In order of importance, these are clinical node status (palpable vs. nonpalpable), grade, capillary lymphatic space involvement, tumor thickness, and patient's age.47,50,51 There is also a correlation between the size of the primary tumor and involvement of the lymph nodes. In Donaldson et al.'s series of 66 patients, the probability of having positive inguinal nodes rose from 18.9% for patients with lesions <3 cm to 72.4% for patients with primary tumors ≥3 cm.43 In a GOG study of 267 patients with superficial vulvar cancer reported by Sedlis et al.47, the frequency of positive inguinal nodes was 18.1% for patients with lesions up to 3 cm in size and 29.3% for patients with lesions ≥3 cm. Extension of the primary tumor to the urethra, vagina, and anal area is associated with an increased incidence of nodal involvement and worse prognosis. Inguinal nodal involvement is a strong predictor for pelvic nodal disease. In the GOG study reported by Homesley et al. of patients with positive inguinal nodes, the incidence of pelvic node involvement was 28%.52 Because of the rarity of isolated pelvic nodal metastasis, the status of the inguinal nodes determines the management of the pelvic nodes. Although deep pelvic node involvement is an ominous sign, and is currently staged as metastatic disease, one-fourth to one-third of the patients are still potentially curable, and aggressive local therapy is indicated. In a series from MD Anderson, 5-year overall survival for women with involved pelvic nodes was 43% when treated with aggressive local therapy. 53 ### Distant Metastases Hematogenous dissemination generally occurs late in the natural history of the disease, with the most common sites being the lungs, liver, and bones. The overall survival is limited in these cases to a median of approximately 6 months. 54 ## Prognostic Factors Lymph node metastasis is the most important prognostic factor in patients with vulvar cancer. The presence of inguinal node metastases is accompanied by a 50% reduction in long-term survival. 55 Lymph node extracapsular tumor extension has been noted in several series, and it is known to have a negative effect on prognosis. Origoni et al.5" evaluated the significance of the size of the metastases in the lymph nodes, the number of positive lymph nodes, and the extracapsular extension (ECE) of the disease and found that the presence of any one of these factors worsened the prognosis. Extracapsular tumor extension as an independent adverse prognostic factor on survival was also described by van der Velden et al.57 Pelvic nodal metastasis has an even more profound negative effect on survival.58 Although deep pelvic node involvement is an ominous sign, and is currently staged as metastatic disease, one-fourth to one-third of the patients are still potentially curable, and aggressive local therapy is indicated. In a series from MD Anderson, 5-year overall survival for women with involved pelvic nodes was 43% when treated with aggressive local therapy. 53 In an analysis of formalin-fixed tissue specimens, Heaps et al.59 demonstrated a sharp rise in the incidence of local recurrence for tumors with microscopic, surgical margins <8 mm. This corresponds to a margin of 1 cm in fresh, unfixed tissue. Although the frequency of local recurrences correlates with the adequacy of the margins of the surgical resection, when dealing with larger or thicker tumors or when they involve midline structures, adequate surgical margins may be difficult to obtain. Kurzl and Masserer analyzed 124 patients with various stages of vulvar carcinoma treated with simple vulvectomy alone and local/inguinal irradiation. They found that age, disassociated growth, lymphatic spread, thickness, and ulceration of the primary tumor were important prognostic factors. In a detailed analysis of a GOG clinicopathologic study of 558 women with vulvar cancer, two significant risk factors were identified that predispose for recurrence in the vulva: tumor size >4 cm and capillary lymphatic space involvement. 50 If either of these factors was present, the risk of local recurrence after radical vulvectomy was 21%, but if neither factor was present, the risk of local recurrence was only 9%. In this study, the depth of invasion did not predict for vulvar failure. HPV-positive or p16-positive cancers may have a better prognosis, as described above in the epidemiology section. ## Initial Evaluation A thorough examination of the genitourinary system is warranted in all women with vulvar cancer because the disease may be multifocal. Examination of the vagina, cervix, perianal skin, and anal canal is of particular importance in order to delineate the extent of disease and to identify synchronous lesions. Special attention as well is paid to the inguinofemoral basins for clinical detection of lymphatic spread. Imaging studies may not be necessary in early lesions that may be approached with surgery as the first treatment modality. However, imaging in women with locally advanced disease or with clinically suspicious lymph nodes helps the clinician select the most appropriate treatment. Computed tomography (CT) scans can identify suspicious lymphadenopathy in the inguinofemoral chains, pelvis, or para-aortic regions. 61 Contrast-enhanced magnetic resonance imaging (MRI) is also helpful to delineate the primary lesion and contributes to the evaluation of inguinal lymph nodes, with a sensitivity of 80% and a specificity of 88%.62 Clinically or radiographically detected inguinal nodes may be evaluated with ultrasound-guided fine needle aspiration, though a negative result does not rule out involvement. 63 Fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used to evaluate the groin prior to surgical evaluation, with a sensitivity of 67% and a specificity of 95%.64 FDG-PET at diagnosis may change the prior clinical impression in up to 50% of cases. 65 It should be noted that the sensitivities of all imaging modalities available are insufficient to omit surgical evaluation in women with a high risk of nodal involvement. ## Staging The staging system first adopted in 1983 was based entirely on clinical findings. The system was modified in 1988 to give the clinical status of the nodes more importance. In 1997, the staging was revised again to create a separate category for minimally invasive lesions, stage IA, emphasizing the need for histologic assessment of the inguinal nodes in all patients presenting with primary tumors with >1 mm depth of invasion. The most recent Federation of Gynecology and Obstetrics (FIGO) staging revision was performed in 2009 and contains significant changes from the 1988 framework (Table 78.2).17,66 Stage IB now includes primary lesions >2 cm in size (previously stage II), and stage II includes lesions with involvement of adjacent perineal structures (previously stage III). Stage III is now divided into three substages, reflecting the importance of the number and size of inguinal nodes involved and the prognostic significance of ECE. Presence of pelvic nodal metastases remains stage IVB disease. ## Management Overview Many factors make the treatment of carcinoma of the vulva challenging. Many women with this disease are older and have comorbidities. The tumor, by virtue of its location, can easily involve adjacent organs such as the bladder and the rectum, and the frequency of nodal involvement is high. Because of its relatively low incidence, most published reports consist of small and heterogeneous groups of patients. Management of carcinoma of the vulva is further complicated by the major psychosexual impact that the disease itself and its treatment can have on patients. For the aforementioned reasons, it has been difficult to study this disease and to develop general treatment guidelines. The management of vulvar carcinoma has undergone very significant changes in the last few decades. En bloc resection of the primary tumor and a full inguinal node dissection used to be the standard of care, but this is no longer the case. Extensive surgery has been replaced by multimodality therapy, with the surgery being more tailored to the extent of the disease. This change is in large measure due to the recognition of the morbidity associated with radical surgery, the improved results achieved with multimodality therapy, and the recognition of the negative impact that radical surgery can have on sexual function and body image. 67-69 Although radical surgery retains a very important place in the management of vulvar cancer, it is no longer the initial and main stay of treatment. The likelihood of controlling the primary tumor with surgery largely depends on the adequacy of the margins of resection, and it is not necessary to remove the entire vulva. A clear margin of 28 mm in all directions is sufficient to achieve a high rate of local control of the primary tumor. 59 There have been refinements in the surgical technique that have made the procedures more tolerable. Examples of such improvements include primary closure of the perineal wound, the use of myocutaneous flaps to close the surgical defect in the inguinal area, and the use of separate incisions for the resection of the primary tumor and the inguinal nodes. These developments have resulted in a decrease in operative mortality and morbidity. In recent decades, there have been also significant advances in all aspects of radiation therapy that apply to the treatment of carcinoma of the vulva. The technical resources available now make it possible to deliver effective doses of radiation to the vulvovaginal and inguinal regions with less acute and late morbidity. With high-photon energy units, well-collimated fields, multileaf collimators, electron beams of different energies, and intensity-modulated radiation therapy (IMRT), radiation is now delivered to the primary disease and lymph nodes with precise account of the differences in contour, tissue thickness, and extent of the disease. It is possible to tailor the treatment to the specified treatment volume while keeping the dose to the normal tissues within acceptable limits of tolerance. Brachytherapy may also be used as primary treatment in very selected cases or in combination with external beam to bring the dose higher to limited volumes. Perhaps the most significant advance of recent decades in the management of cancer patients is the use of more than one treatment modality concurrently or sequentially. Chemotherapy, radiation, and surgery in sequence and/or in combination lessen the impact of any one modality and can lead to functional organ preservation with comparable or improved local tumor control and survival (Fig. 78.5). ## Surgery ### Wide Local Excision, Radical Vulvectomy, and Exenteration In the past, even patients with early-stage IB disease were considered to have diffuse disease, and a radical vulvectomy was considered the standard of care, yielding 90% survival rates but with considerable physical and emotional sequelae. Although there is a lack of prospective data comparing radical local excisions versus more extensive radical vulvectomies, several retrospective studies reveal no difference in recurrence or survival outcomes. 70 For T1 and smaller T2 lesions (<4 cm) with ≤ 1 -mm invasion, a wide local excision is recommended without inguinofemoral node evaluation given the risk of nodal involvement in these cases is <1%.71 For tumors with >1-mm invasion, a more radical excision with an inguinofemoral groin node evaluation is recommended. If these tumors are well lateralized (>2 cm from the midline), only an ipsilateral groin evaluation is necessary; however, for midline lesions, bilateral groin node evaluation is recommended.72 At surgical resection, the depth of the excision should be to the deep perineal fascia or periosteum of the pubis for more anterior lesions. Excision of 2-cm margins of grossly ### Radical Wide Excision - <1 mm invasion, negative margins, negative risk factors* Observe - Node negative Observe or radiotherapy - 1 node positive Unilateral vs. bilateral - >1 mm invasion or clinically node positive Nodal evaluation sentinel vs. full dissection unilateral vs. bilateral - Positive/close margins, positive risk factors* Re-excise (for margins) or radiotherapy +/- chemotherapy - 2+ nodes positive Radiotherapy +/- chemoradiotherapy *Risk factors for local recurrence: margins < 8 mm, >10 mm thickness, inflitrative pattern, LVI, high mitotic activity, increased keratin ### Surgical Evaluation of Inguinofemoral Lymph Nodes Attention to risk factors for nodal involvement is critical as inguinal recurrences are very difficult to treat and a full inguinofemoral node dissection can be quite morbid. The main complications of groin surgery are wound breakdown, infection, and lower extremity lymphedema. Although wound breakdown will often heal successfully by secondary intention, chronic lower extremity edema is very difficult to deal with and can lead to significant long-term disability. To reduce the frequency and the severity of these complications, an effort is made to identify patients in whom the extent of the node dissection can be decreased or eliminated altogether without compromising the likelihood of control of the disease. As mentioned previously, patients with small (<2-cm diameter) superficial squamous cell carcinomas with a depth of invasion 1 mm or less and no lymph vascular invasion have a very low risk of nodal involvement, and the groin dissection may be omitted.77 For lesions with >1-mm invasion, groin node assessment should be performed in the form of superficial inguinal lymphadenectomy or sentinel node procedure. Small (<4 cm), lateralized lesions (>2 cm from the midline) may be treated by unilateral groin evaluation, whereas for midline and clitoral lesions, both groins should be assessed. For patients undergoing primary surgery, palpable inguinal nodes should be removed if present. The need to perform bilateral inguinal node dissection in patients with unilateral vulvar lesions, as well as the need to dissect the deep nodes whenever a superficial node dissection is carried out, has been re-examined in light of the additive morbidity of each procedure. When bilateral superficial and deep inguinal node dissections are performed, the potential for wound breakdown and lower extremity lymphedema increases. When a unilateral dissection is indicated and nodes are found to be negative, a contralateral node dissection is not required because of the low likelihood of contralateral metastasis.78,79 The deep inguinal node dissection is usually omitted, based on the fact that if the superficial nodes are free of tumor, the deep nodes are rarely involved. 80 However, control of the disease in the lymph nodes is of utmost importance because many women who develop groin recurrences will die as a result of the recurrence. 81 Women with fixed or ulcerated inguinal nodes are rarely curable with surgery alone. These patients should have a biopsy to document the nodal involvement and should be treated with combined radiation and chemotherapy, either primarily or in a preoperative fashion as discussed below. ### Sentinel Lymph Node Dissection Assessment of the groin nodes may be accomplished via full superficial inguinal dissection or alternatively via a sentinel lymph node procedure alone if performed by groups experienced with this technique. In the multicenter Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V), a sentinel node procedure using radioactive tracer and blue dye was performed in 623 groins and resulted in a 2.3% groin recurrence rate following a negative sentinel node. 82 This compares favorably to the 5% ipsilateral groin recurrence rate following negative full superficial inguinal dissection in a prospective GOG study of low-risk vulvar cancer. 81 Patients who underwent a sentinel but not a full node dissection had significantly lower groin wound breakdown (12% vs. 34%) compared to those who went on to a full inguinofemoral dissection following the sentinel procedure. Long-term follow-up of the GROINSS-V trial demonstrated 5- and 10-year recurrence rates of 24.6% and 36.4% for sentinel node-negative patients versus 33.2% and 46.4% in patients who had positive sentinel nodes with subsequent completion inguinofemoral node dissection.83 Optimal lesions for sentinel node procedures are those with small (<4 cm), unifocal lesions with surgeons who have performed at least 10 prior sentinel procedures under supervision. If a sentinel node approach is undertaken, it is recommended that the sentinel nodes be evaluated prior to vulvar resection to avoid disruption of lymphatic channels emanating from the tumor. If no sentinel node is found, a full inguinofemoral lymphadenectomy is recommended. The GOG 88 protocol tested whether radiation therapy alone could supplant nodal dissections after vulvectomy. 84 Women with clinically negative nodes after radical vulvectomy were randomized between 50 Gy to the bilateral inguinal regions or a lymph node dissection with selective radiation delivered to those with positive nodes. The radiation-alone arm had increased recurrences within the inguinal regions (at 2 years: 32% RT alone vs. 6% nodal dissection, P = .033), with an associated decrement in overall survival as well (59% RT alone vs. 90% nodal dissection, P = .035). Although the depth of the inguinal nodes to which the radiation dose was prescribed may account for the difference in local control and survival, surgical management of the lymph nodes remains the standard of care. 85 Intraoperative diagnosis of inguinal node metastasis necessitates further diagnostic or therapeutic procedures. Because there is no established sentinel node metastasis size cutoff below which withholding further treatment of the groin can be considered safe, all women in whom a sentinel node is found to be positive a full ipsilateral groin dissection and/or radiotherapy to the groin should be considered. 86 The GROINSS-VII/GOG 270 study is ongoing and evaluates groin radiotherapy versus completion inguinofemoral lymphadenectomy in this population.87 In an interim analysis of this study, excessive recurrences were found in sentinel nodes with macrometastases (>2 mm) or ECE (20%), compared to those without either factor (2%), causing these subjects to be excluded from radiation alone. Particular care should be taken therefore with these risk factors, and completion dissection should be considered. In the case of a non-sentinel node metastasis that is diagnosed intraoperatively, the options are to dissect the deep nodes as well as the opposite groin or to cover both groins with adjuvant radiotherapy. Standard adjuvant treatment for inguinal node metastasis consists of both inguinal and pelvic radiotherapies. 52 In the situation where an ipsilateral inguinal node is found to be positive for metastatic disease, nodal assessment of the contralateral groin versus radiation should be considered. ### Pelvic Lymph Nodes Patients with clinically or pathologically positive groin nodes are at risk for having contralateral groin and pelvic nodal involvement. Thus, the status of the groin nodes is to be taken into consideration when determining the management of the pelvic nodes. The randomized GOG trial of pelvic node dissection versus pelvic node radiation showed that control of the disease in the pelvis could be achieved with either form of therapy. 52 Radiation to the pelvic nodes is generally preferred over surgery as women in need of treatment to the pelvis often also require radiation to the primary and/or inguinal nodes. ## Adjuvant Radiation Therapy In the setting of early invasive disease treated with wide local excision, radiation to the tumor bed may be advised to prevent local recurrence. As noted previously, pathologic features associated with higher risk of local recurrence at the primary site include lymphatic-vascular invasion (LVI), depth of invasion >5 mm, margins <8 mm, and microscopically positive margins.59 Faul et al.s reported a retrospective study of 62 patients with close (≤8 mm) or positive surgical margins that found that local recurrence was significantly reduced from 58% with observation to 16% with postoperative radiation. Although postoperative