Vulvar cancer is surgically staged and is categorized by the pathologic evaluation of the vulvar tumor and the inguinofemoral lymph nodes. All tumors more invasive than 1 mm and larger than 2 cm require pathologic assessment of inguinofemoral lymph nodes. Sentinel node biopsy is an alternative to inguinofemoral lymphadenectomy in many cases that require a lymphadenectomy. Radical local excision with inguinofemoral lymph node assessment is the preferred procedure for early-stage disease. Primary neoadjuvant chemoradiation is used for most advanced-stage tumors.
Vulvar cancer is the fourth most common gynecologic cancer and comprises 5% of the malignancies of the female genital tract. Squamous cell carcinoma of the vulva is predominantly a disease of postmenopausal women, with a mean age at diagnosis of approximately 65 years. The diagnosis is often made after years of symptoms of pruritus associated with vulvar dystrophy. The lesion is usually raised and may be fleshy, ulcerated, leukoplakic, or warty in appearance. Most squamous cell carcinomas of the vulva occur on the labia majora, but the labia minora, clitoris, and the perineum may be primary sites.
Vulvar cancer is surgically staged based on pathologic evaluation of a vulvar biopsy and of the inguinofemoral lymph nodes. A complete clinical assessment helps guide the surgical and medical approach to treatment. In particular, the diameter of the primary tumor should be measured, and the inguinal, axillary, and supraclavicular lymph nodes should be palpated. Because of the multifocal nature of squamous intraepithelial lesions, cervical cytology and colposcopy of the cervix, vagina, and vulva should be performed. Imaging, such as abdominal/pelvic computed tomography (CT) may be performed for women with tumors 2 cm or larger to detect suspected metastases to lymph node or other distant sites.
Diagnosis requires a biopsy specimen, which can be taken in the office. The biopsy specimen must include underlying dermis and connective tissue so that depth and stromal invasion can be evaluated. Staging and primary surgical treatment are typically performed as a single procedure. Staging should include the evaluation for factors related to prognosis: tumor size, depth of invasion, lymph node metastases, and distant metastases.
Staging
Historically, staging was based on clinical factors using the tumor, node, metastasis (TNM) classification adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1969. This staging was focused on a clinical evaluation of the primary tumor, the regional lymph nodes, and a limited search for distant metastases. However, clinical evaluation of inguinofemoral lymph nodes is inaccurate in approximately 25% to 30% of cases. The percentage of error in clinical staging compared with surgical staging increased from 18% for stage I disease to 44% for stage IV disease. In 1988, surgical staging for vulvar cancer was introduced, and updated FIGO staging occurred in 2008 ( Table 1 ). Surgical staging is preferable because the diagnosis of inguinofemoral lymph node metastasis is the most important predictor of overall prognosis.
| Stage I | Tumor confined to the vulva |
| IA | Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm a , no nodal metastasis |
| IB | Lesions >2 cm in size or with stromal invasion >1.0 mm a , confined to the vulva or perineum, with negative nodes |
| Stage II | Tumor of any size with extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus) with negative nodes |
| Stage 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 | (1) With 1 lymph node metastasis (≥5 mm), or (2) 1−2 lymph node metastases (<5 mm) |
| IIIB | (1) With 2 or more lymph node metastases (≥5 mm), or (2) 3 or more lymph node metastases (<5 mm) |
| IIIC | With positive nodes with extracapsular spread |
| Stage IV | Tumor invades other regional (two-thirds upper urethra, two-thirds upper vagina), of distant structures |
| IVA | Tumor invades any of the following: (1) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (2) fixed or ulcerated inguinofemoral lymph nodes |
| IVB | Any distant metastasis including pelvic lymph nodes |
a 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.
Pathology
Squamous cell carcinoma
More than 90% of vulvar malignancies are squamous cell carcinomas. There are 2 subtypes, both of which usually occur on the labia or vestibule. The keratinizing, differentiated, or simplex type is most common. This type occurs in older women and is not related to human papillomavirus (HPV) infection but is associated with vulvar dystrophies such as lichen sclerosus and, in developing countries, chronic venereal granulomatous disease. The classic, warty, or bowenoid type is predominantly associated with HPV 16, 18, and 33, and is found in younger women. These women tend to present with early-stage disease, although several cases of stage III/IV disease in HIV-infected women have been reported. Verrucous carcinoma is a variant of squamous cell carcinoma that has distinct features. Although cauliflowerlike in appearance, it is differentiated from squamous cell carcinoma with a verrucous configuration. The lesion grows slowly and rarely metastasizes to lymph nodes, but it may be locally destructive.
Melanoma
Melanoma is the second most common vulvar cancer histology, accounting for approximately 5% of primary vulvar neoplasms. Melanoma of the vulva occurs predominantly in postmenopausal, white, non-Hispanic women at a median age of 68 years. Vulvar melanoma is usually a pigmented lesion, but amelanotic lesions also occur. Most arise de novo on the clitoris or labia minora, but can also develop within preexisting junctional or compound nevi.
Basal cell carcinoma
Two percent of vulvar cancers are basal cell cancers and 2% of basal cell cancers occur on the vulva. They usually affect postmenopausal white women and may be locally invasive, although they are usually nonmetastasizing. The typical appearance is that of a rodent ulcer with rolled edges and central ulceration; the lesion may be pigmented or pearly and gray. They are often asymptomatic, but pruritus, bleeding, or pain may occur. Basal cell carcinomas are associated with a high incidence of antecedent or concomitant malignancy elsewhere in the body. A thorough search for primary malignancies should be performed.
Sarcoma
Soft tissue sarcomas such as leiomyosarcomas, rhabdomyosarcomas, liposarcomas, angiosarcomas, neurofibrosarcomas, fibrous histiocytomas, and epithelioid sarcomas constitute 1% to 2% of vulvar malignancies. As with soft tissue sarcomas located elsewhere on the extremities and trunk, high-grade lesions that are larger than 5 cm in diameter, with infiltrating margins and a high mitotic rate, are most likely to recur.
Adenocarcinoma
Most primary adenocarcinomas of the vulva occur in the Bartholin gland. This gland is composed of columnar epithelium; ducts are lined by stratified squamous epithelium that changes to transitional cell epithelium as the terminal ducts are reached. Cancers arising in the Bartholin gland are most often adenocarcinomas or squamous cell carcinomas, but transitional cell carcinomas, adenosquamous carcinomas, and adenoid cystic cell carcinomas may also develop. Median age is 57 years, and enlargement of the Bartholin gland in a postmenopausal woman is a concern for malignancy because benign inflammatory disease usually does not occur in this age group. The gland should be biopsied in older (>40 years of age) women with a mass in this location, even if the lesions appear cystic or abscessed. Metastatic disease is common in cancers of the Bartholin gland because of the rich vascular and lymphatic network.
Invasive adenocarcinoma may be present within or beneath the surface intraepithelial lesion, which is known as Paget disease. This is an uncommon malignancy. Most patients are in their 60s and 70s and white. Pruritus is the most common symptom, present in 70% of patients. The lesion has an eczematoid appearance; it is well demarcated and has slightly raised edges and a red background, often dotted with small, pale islands. It is usually multifocal and may occur anywhere on the vulva, mons, perineum/perianal area, or inner thigh. Vulvar biopsy should be performed in patients with suspicious lesions, including those with persistent pruritic eczematous lesions that fail to resolve within 6 weeks of appropriate antieczema therapy. Women with Paget disease should be evaluated for the possibility of synchronous neoplasms because approximately 4% to 5% of these patients have a noncontiguous carcinoma involving the breast, rectum, bladder, urethra, cervix, or ovary.
Surgical management
In the 1940s, Taussig in the United States and Way in Great Britain pioneered the historic standard treatment of operable vulvar cancer with en bloc radical vulvectomy and bilateral removal of the inguinofemoral and pelvic lymph nodes. This resection consists of removal of the entire vulva down to the level of the deep fascia of the thigh, to the periosteum of the pubis, and to the inferior fascia of the urogenital diaphragm. Traditionally, this procedure could be performed with 2 teams of surgeons, if appropriate, through a single incision that circumscribes the labia majora and extends to the inguinofemoral regions bilaterally. This approach has largely been abandoned because most of the vulvar cancers now treated are low stage and because neoadjuvant chemoradiation is used for most of the advanced cases.
Surgical management
In the 1940s, Taussig in the United States and Way in Great Britain pioneered the historic standard treatment of operable vulvar cancer with en bloc radical vulvectomy and bilateral removal of the inguinofemoral and pelvic lymph nodes. This resection consists of removal of the entire vulva down to the level of the deep fascia of the thigh, to the periosteum of the pubis, and to the inferior fascia of the urogenital diaphragm. Traditionally, this procedure could be performed with 2 teams of surgeons, if appropriate, through a single incision that circumscribes the labia majora and extends to the inguinofemoral regions bilaterally. This approach has largely been abandoned because most of the vulvar cancers now treated are low stage and because neoadjuvant chemoradiation is used for most of the advanced cases.
Management of stage I to II vulvar cancer
The modern approach to the management of patients with early-stage vulvar carcinoma should be individualized. In considering the appropriate operation, it is necessary to determine independently the appropriate management of the primary lesion and the inguinofemoral lymph nodes.
Management of the Primary Tumor
Several factors have led to modifications from the en bloc radical vulvectomy and bilateral inguinofemoral and pelvic lymphadenectomy. These factors include the more frequent presentation of smaller tumors at diagnosis in younger women, the concern of postoperative morbidity and associated long-term hospitalization, the psychosexual effects from distortion of the vulva, and the problem of lymphedema. Alternative and less radical surgical approaches that remove less of the vulva and the surrounding skin are most commonly performed.
Two factors should be taken into consideration: age and condition of the remainder of the vulva. Since the 1980s, several investigators have advocated a radical local excision rather than a radical vulvectomy for the primary lesion in patients with T1a (2 cm or less) or T1b (larger than 2 cm). It is desirable to conserve as much of the vulva as possible. For stage II disease, the most conservative excision technique should be used that results in at least a 1-cm tumor-free margin. Depending on the size, location, and depth of invasion of the lesion, this may necessitate radical local excision, or modified radical vulvectomy, and the separate incision technique of an inguinofemoral lymphadenectomy ( Table 2 ).
| Size of Lesion | Depth of Invasion (mm) | Location | Operation | Inguinal Femoral Lymphadenectomy or Sentinel Lymph Node Evaluation a , b |
|---|---|---|---|---|
| T1a | ≤1 | Lateral c or central | Radical local excision | No |
| >1 | Lateral c | Radical local excision | Ipsilateral | |
| T1a | >1 | Central | Radical local excision | Bilateral |
| T1b | Lateral | Radical local excision | Ipsilateral | |
| T2: Any size with extension to adjacent perineal structures (lower/distal one-third urethra, lower/distal one-third vagina, anal involvement) | — | — | Modified radical d and/or selected chemoradiation | Bilateral |
| Extensive T3–T4 disease (spread to the urethra, anus, bladder, rectum, or pelvic bone) | — | — | Neoadjuvant chemoradiation e and selected surgery | — |
a Sentinel node biopsy can be considered as an alternative to inguinofemoral lymphadenectomy in all cases that require a lymphadenectomy.
b Bilateral lymphadenectomy is performed if unilateral node is positive.
c Further than 1 cm from midline.
d Modified radical vulvectomy (terminology includes radical hemivulvectomy, anterior or posterior modified radical vulvectomy).
e Can consider chemoradiation as primary treatment or postoperative radiation for patients with high risk of local recurrence (those with stage IVA disease, positive or close margins, and a large number of groin nodes).
Radical Local Excision
Radical local excision or modified radical vulvectomy (removal of part or all of the vulva unilaterally, also called modified radical hemivulvectomy) is most appropriate for the lesions on the lateral or posterior aspects of the vulva where preservation of the clitoris is feasible ( Figs. 1 and 2 ). For anterior lesions, clitoral-sparing modified radical vulvectomy can be an option. However, the depth of the resection, from the skin to the urogenital diaphragm, is the same as in standard radical vulvectomy.
In a retrospective study including 41 patients with squamous carcinoma of the anterior vulva not involving the clitoris, 13 patients had clitoral-sparing modified radical vulvectomy and 28 had radical vulvectomy. The 13 patients who had clitoral-sparing surgery included 8 with stage I, 2 with stage II, 2 with stage III, and 1 with stage IV disease. After a median follow-up of 59 months, none of the 13 patients having conservative surgery had locoregional failure. In another study, 122 patients with lateral T1 and T2 lesions were studied: half of these patients had radical vulvectomy and the other half a radical hemivulvectomy. Disease-free survival at 5 years was 98% and 93%, respectively. Local or distant recurrence was not more common in patients treated by radical vulvectomy or radical hemivulvectomy. Another published experience at the Royal Hospital for Women in Sydney described 116 patients with FIGO stages I and II vulvar cancer who underwent radical local excision. The patients who had radical vulvectomy had multifocal tumors. With a median follow-up of 84 months, the overall 5-year survival of patients with radical local excision was 96.4%.
Technique for Radical Local Excision
Radical local excision implies a deep excision of the primary tumor. The surgical margins should be at least 1 cm and should be drawn using a marking pen with the vulva in its natural state. The incision should be carried down to the inferior fascia of the urogenital diaphragm, which is coplanar with the fascia lata and the fascia over the pubic symphysis. The surgical defect is closed in 2 layers. For perineal lesions, proximity to the anus may preclude adequate surgical margins, and consideration should be given to preoperative radiation. For periurethral lesions, the distal half of the urethra may be resected without loss of continence ( Fig. 3 ).
For all types of vulvar excisions, a tumor-free margin of at least 1 cm seems to decrease the risk of local recurrence. A retrospective case series (n = 135) reported a decrease in the rate of local recurrence in cases with normal tissue margins of 1 cm or greater compared with less than 8 mm (0% vs 50%). Therefore, a surgical margin of at least 1 cm accounts for the 20% tissue shrinkage with formalin fixation. Care should be taken to ensure that the skin incision is made without tension.
Management of Inguinofemoral Lymph Nodes
Appropriate management of the regional lymph nodes is the single most important factor in decreasing mortality from early vulvar cancer. The only patients who are not at significant risk of lymph node metastases are those with a T1a tumor that invades the stroma to a depth of no greater than 1 mm. If a tumor is less than 2 cm in diameter, the lesion should be locally excised and analyzed histologically to determine the depth of invasion. Depth of invasion is measured from the most superficial dermal papilla adjacent to the tumor to the deepest focus of invasion.
If recurrence occurs in the undissected inguinofemoral lymph nodes, there is a high mortality. Pelvic lymphadenectomy, removal of iliac and obturator nodes, is not required for staging or therapy and has not been shown to improve survival. The choice of approach for lymphadenectomy depends on the size and location of the lesion as well as the presence of bulky positive nodes.
Tumor thickness is also measured and the average difference between tumor thickness and depth of invasion has been found to be 0.3 mm. If the invasive focus is less than 1 mm, inguinofemoral lymphadenectomy may be omitted because the incidence of nodal metastases is essentially nil. All patients with a more deeply invasive T1a or T1b tumor require surgical removal of inguinofemoral lymph nodes or sentinel node evaluation (see later discussion). The Gynecologic Oncology Group (GOG) reported 6 inguinofemoral recurrences among 121 patients with T1N0 or T1N1 tumors after a superficial (inguinal) dissection, even though the inguinal nodes were reported as negative, although it is unclear whether all these recurrences were in femoral nodes. Therefore, this approach has been abandoned in favor of either a complete inguinofemoral lymphadenectomy or a sentinel lymph node assessment.
Separate incision technique
The separate incision technique allows for radical excision of the primary lesion and the unilateral or bilateral pathologic analysis of the inguinofemoral lymph nodes. This operation can be performed in a modified dorsal lithotomy position using Allen stirrups. In this manner, the surgeon can modify the degree of exposure for the vulvectomy and the inguinofemoral lymphadenectomy to maximize the exposure during each portion of the operation. The radical local excision is performed to remove the primary tumor with at least a 1-cm margin.
Ipsilateral inguinofemoral lymph node assessment
The surgical evaluation of the ipsilateral inguinofemoral lymph nodes is suitable for lateralized primary lesions, when there are no metastases in the ipsilateral inguinofemoral lymph nodes. A study of 163 patients with a unilateral vulvar cancer, of whom 48 had positive inguinofemoral lymph nodes, 3 of the patients with positive contralateral nodes had negative ipsilateral nodes. In this study, the only independent risk factor for contralateral lymph node involvement was the total number of positive ipsilateral inguinofemoral lymph nodes. With each positive lymph node, the possibility of having bilateral inguinofemoral lymph node involvement increased by 84%. Central, nonlateralized lesions should have bilateral surgical assessment. Ipsilateral lymphadenectomy was associated with less than a 1% risk of contralateral inguinofemoral node metastases for stage IB disease that are unifocal, lateral at least 1 cm from vulvar midline, not located in the anterior portion of the labia minora (area just posterior to the clitoris), have no palpable lymphadenopathy in either inguinofemoral region, and no lymph node metastases found at time of unilateral lymphadenectomy.
Bilateral lymphadenectomy is performed for midline tumors or if lymph node metastases are discovered at unilateral lymphadenectomy. The rate of bilateral inguinofemoral metastases in women with lesions with unilateral lesions with stromal invasion 3 mm or deeper is 2.8% or greater. If an inguinal lymphadenectomy is being performed, it should include the femoral lymph nodes because so-called superficial lymphadenectomy has been associated with a high rate of inguinofemoral recurrence.
Technique for Inguinofemoral Lymphadenectomy
The patient is placed in a modified dorsal lithotomy position. Flexion at the hip is minimized. The inguinofemoral dissection routinely includes removal of the lymph nodes superficial to the inguinal ligament, nodes within the proximal femoral triangle (borders formed by the sartorius muscle and the adductor longus muscle), and the lymph nodes deep to the cribriform fascia. A linear incision is made along the aspect of a line drawn between the anterior superior iliac spine and the pubic tubercle ranging from 6 to 10 cm long. The incision is best made about 1 cm above the inguinal crease ( Fig. 4 ). The incision is carried through the subcutaneous tissues to the superficial fascia.
