Vulvar Cancer - Berek and Novak's Gynecology 15th Ed.

Berek and Novak's Gynecology 15th Ed.

38 Vulvar Cancer

Christine H. Holschneider

Jonathan S. Berek

• Vulvar lesions require biopsy to avoid delay in diagnosis.

• The modern approach to patients with vulvar cancer is multidisciplinary and individualized.

• Management of the primary lesion and groin nodes is determined separately.

• Most T₁, T₂, and early T₃ lesions can be managed with radical local excision.

• Large T₃ and T₄ primary tumors are best treated with chemoradiation followed by more limited surgical resection.

• When groin dissection is indicated, it should be a thorough inguinofemoral lymphadenectomy.

• The potential role of the sentinel lymph node procedure to eliminate the need of a complete inguinofemoral lymphadenectomy is being investigated.

• The single most important prognostic factor is lymph node status: 5-year survival without groin node metastases is greater than 90%; with groin node metastases 5-year survival is 50%.

• Postoperative radiation decreases the risk of groin recurrence in patients with multiple positive inguinofemoral lymph nodes.

• Recurrence in the groin is almost universally fatal.

With 3,900 new[MB1] cases and 920 deaths annually in the United States, vulvar cancer is uncommon, representing about 4% of malignancies of the female genital tract and 0.6% of all cancers in women (1,2). Squamous cell carcinomas account for about 90% of all primary vulvar malignancies, whereas melanomas, adenocarcinomas, basal cell carcinomas, and sarcomas are less common. The incidence of in situ vulvar cancer is increasing worldwide, primarily because of the increasing occurrence in young women, who account for 75% of the cases. The overall rate of invasive vulvar carcinoma is increasing, but at a much lower rate (3,4). In women younger than 50 years, there is a striking increase in the incidence of in situ and invasive squamous cell carcinoma of the vulva (5).

Following the reports of Taussig in the United States and Way in Great Britain, radical vulvectomy and en bloc groin dissection, with or without pelvic lymphadenectomy, was standard treatment for all patients with operable disease (6,7). Postoperative morbidity was high and prolonged hospitalization common. During the past 25 years, there were significant advances in the management of vulvar cancer, reflecting a paradigm shift toward a more conservative surgical approach without compromised survival and with markedly decreased physical and psychological morbidity:

1. Individualization of treatment for all patients with invasive disease

2. Vulvar conservation for patients with unifocal tumors and an otherwise normal vulva

3. Omission of the groin dissection for patients with microinvasive tumors (T1a, ≤2 cm diameter and ≤1 mm of stromal invasion)

4. Elimination of routine pelvic lymphadenectomy

5. The role of the sentinel lymph node procedure to eliminate requirement for complete inguinofemoral lymphadenectomy is being investigated

6. The use of separate incisions for the groin dissection to improve wound healing

7. Omission of the contralateral groin dissection in patients with lateral T₁ lesions and negative ipsilateral nodes

8. The use of preoperative radiation therapy to obviate the need for exenteration in patients with advanced disease

9. The use of postoperative radiation therapy to decrease the incidence of groin recurrence in patients with multiple positive groin nodes

Etiology

The etiology of vulvar cancer is only partially elucidated and likely to be multifactorial. Reported risk factors for vulvar cancer include human papillomavirus (HPV) infection, vulvar intraepithelial neoplasia (VIN), cervical intraepithelial neoplasia (CIN), lichen sclerosus, squamous hyperplasia, cigarette smoking, alcohol consumption, immunosuppression, a prior history of cervical cancer, and northern European ancestry (8,9). Based on histopathologic and environmental factors, there appear to be at least two distinct etiologic entities of squamous cell carcinoma of the vulva:

1. Basaloid or warty types, which tend to be multifocal, occur generally in younger patients and are related to HPV infection, VIN, and cigarette smoking.

2. Keratinizing, differentiated, or simplex types, which tend to be unifocal, occur predominantly in older patients, are not related to HPV, and often are found in areas adjacent to lichen sclerosus and squamous hyperplasia.

High-grade vulvar intraepithelial neoplasia (VIN 3) was closely studied as a potential precancerous lesion. The direct progression of VIN to cancer is difficult to document, but a review of 3,322 published patients with VIN 3 reports a 9% progression rate to cancer for untreated cases (10). VIN is found adjacent to basaloid or warty vulvar squamous cell carcinomas in more than 80% of cases and 10% to 20% of vulvar carcinoma in situ lesions harbor an occult invasive component (11,12). HPV DNA is documented in 89% of patients with VIN 3, in 60% of vulvar cancers overall, and in up to 86% of warty or basaloid type carcinomas of the vulva; but it occurs in less than 10% of the keratinizing type of carcinomas of the vulva (13). HPV 16 and 33 are the prevalent subtypes, accounting for 55.5% of all HPV-related vulvar cancers (14). Epidemiologic risk factors for the basaloid or warty type squamous cell carcinoma of the vulva are similar to those for cervical cancer and include a history of multiple lower genital tract neoplasias, immunosuppression, and smoking (13,15).

Frequently implied as an etiologic variable for the keratinizing carcinoma is the itch–scratch cycle associated with lichen sclerosus and squamous hyperplasia, with atypical changes occurring in the repaired epithelium. Differentiated (or simplex) VIN is a precursor to squamous cell carcinoma and is associated with lichen sclerosus. In keratinizing carcinoma, associated lichen sclerosus or squamous hyperplasia is found in more than 80% of patients(16,17). Women with vulvar lichen sclerosus are at increased risk of developing invasive squamous cell cancer of the vulva, reported at 2.5% to 7.2% with a median follow-up of 4.7 to 6.2 years (18–20). Supportive evidence that some of these lesions could be precancerous comes from molecular studies that demonstrate aneuploid DNA content, p53overexpression, high Ki67 expression, indicating high proliferation indices and monoclonal expansion of keratinocytes in lichen sclerosus and associated squamous hyperplasia (21–23). An area of active research explores whether treatment of lichen sclerosus with superpotent topical steroids can impact the malignancy risk (18–20). Some studies reported vulvar cancer to be more common in patients who are obese, have hypertension and diabetes mellitus, or are nulliparous, but a case-control study of vulvar cancer did not confirm any of these as risk factors (15,24,25).

Types of Invasive Vulvar Cancer

The histologic subtypes of invasive vulvar cancer are shown in Table 38.1.

Table 38.1 Types of Vulvar Cancer

*Type*	*Percent*
Squamous	92
Melanoma	2–4
Basal cell	2–3
Bartholin gland (adenocarcinoma, squamous cell, transitional cell, adenoid cystic)	1
Metastatic	1
Verrucous	<1
Sarcoma	<1
Appendage (e.g., hidradenocarcinoma)	Rare

Squamous Cell Carcinoma

Approximately 90% to 92% of all invasive vulvar cancers are of the squamous cell type. Squamous carcinomas of the vulva can be divided into distinct histologic subtypes designated as basaloid carcinoma, warty carcinoma, and keratinizing squamous carcinoma (16). Mitoses are noted in these malignancies, but atypical keratinization is the histologic hallmark of invasive vulvar cancer (26). Most vulvar squamous carcinomas reveal keratinization (Fig. 38.1). Histologic features that correlate with the occurrence of inguinal lymph node metastasis are lymph–vascular space invasion, tumor thickness, depth of stromal invasion, histologic pattern of invasion (spray and stellate versus broad and pushing), and increased amount of keratin (27–30).

Figure 38.1 Squamous cell carcinoma of the vulva, keratinizing type. The multiple pearl formations consist of laminated keratin.

Microinvasive carcinoma of the vulva (T_1a) is defined as a lesion 2 cm or less in diameter with 1 mm or less stromal invasion (31). Depth of stromal invasion is measured vertically from the epithelial–stromal junction (basement membrane) of the adjacent most superficial dermal papilla to the deepest point of tumor invasion (Fig. 38.2). When the tumor invades 1 mm or less, metastasis to the inguinal lymph nodes is extremely rare among reported series. When invasion is greater than 1 mm, there is a significant risk of inguinal lymph node metastasis.

Figure 38.2 Early invasive carcinoma of vulva originating from vulvar intraepithelial neoplasia. An irregular nest of malignant cells extend from the base of rete pegs. Desmoplastic stromal reaction and chronic inflammation are useful diagnostic signs of stromal invasion. The depth of stromal invasion is measured from the base of the most superficial dermal papilla vertically to the deepest tumor cells.

Clinical Features

Squamous cell carcinoma of the vulva is predominantly a disease of postmenopausal women. The mean age at diagnosis is about 65 years and 15% of patients who develop vulvar cancer do so before age 40. There may be a longstanding history of an associated vulvar intraepithelial disorder, such as lichen sclerosus, squamous hyperplasia, or VIN. As many as 27% of patients with vulvar cancer have a second primary malignancy (32–34). Based on data from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, patients with invasive vulvar cancer have an increased risk of 1.3% for developing a subsequent cancer. Most of the excess second cancers were smoking related (e.g., cancers of the lung, buccal cavity and pharynx, esophagus, nasal cavity, and larynx) or related to infection with human papillomavirus (e.g., cervix, vulva, vagina, and anus) (35).

Most patients are asymptomatic at the time of diagnosis. If symptoms exist, vulvar pruritus, a lump, or a mass are the most common findings. Less frequent symptoms include a bleeding or ulcerative lesion, discharge, pain, or dysuria. Occasionally, a large metastatic mass in the groin is the initial symptom.

A careful inspection of the vulva should be part of every gynecologic examination. On physical examination, vulvar carcinoma is usually raised and may be fleshy, ulcerated, plaquelike or warty in appearance. It may be pigmented, red or white, and tender or painless. The lesion may be clinically indistinct, especially in the presence of VIN or vulvar dystrophies (12). Any lesion of the vulva warrants a biopsy.

Most squamous carcinomas of the vulva occur on the labia majora and minora (60%), but the clitoris (15%) and perineum (10%) may be primary sites. Approximately 10% of the cases are too extensive to determine a site of origin, and about 5% of the cases are multifocal.

As part of the clinical evaluation, a careful assessment of the extent of the lesion, including whether it is unifocal or multifocal, should be performed. The groin lymph nodes should be evaluated carefully, and a complete pelvic examination should be performed. A cytologic sample should be taken from the cervix, and colposcopy of the cervix and vagina should be performed because of the common association with other squamous intraepithelial or invasive neoplasms of the lower genital tract.

Diagnosis

Diagnosis requires a Keys punch biopsy or wedge biopsy, which can be obtained in the office using local anesthesia. The biopsy must include sufficient underlying dermis to assess for microinvasion.

Physician delay is a common problem in the diagnosis of vulvar cancer, particularly if the lesion has a warty appearance. Any large or confluent warty lesion requires biopsy before medical or ablative therapy is initiated.

Routes of Spread

Vulvar cancer spreads by the following routes:

1. Direct extension, to involve adjacent structures such as the vagina, urethra, and anus

2. Lymphatic embolization to the regional inguinal and femoral lymph nodes

3. Hematogenous spread to distant sites, including the lungs, liver, and bone.

Lymphatic metastases may occur early in the disease. Twelve percent of tumors 2 cm in diameter or smaller have regional metastases (32,36). Initially, spread is usually to the inguinal lymph nodes, which are located between Camper’s fascia and the fascia lata (37). From these superficial groin nodes, the disease spreads to the deep femoral nodes, which are located medial to the femoral vessels (Fig. 38.3). Cloquet's or Rosenmüller’s node, situated beneath the inguinal ligament, is the most cephalad of the femoral node group. Metastases to the femoral nodes without involvement of the inguinal nodes is reported (38–41). A study from the M. D. Anderson Cancer Center reported a 9% groin recurrence rate in 104 patients with vulvar cancer who had negative nodes on superficial inguinal lymphadenectomy at initial surgery, and intraoperative lymphatic mapping studies found the sentinel node deep to the cribriform fascia in 5% to 16% of these cases (42–44).

Figure 38.3 Inguinal-femoral lymph nodes. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:541, with permission.)

From the inguinal-femoral nodes, the cancer spreads to the pelvic nodes, particularly the external iliac group. Although direct lymphatic pathways from the clitoris and Bartholin gland to the pelvic nodes were described, these channels seem to be of minimal clinical significance (45–47). The lymphatics from either side of the vulva form a rich network of anastomoses along the midline. Lymphatic drainage from the clitoris, anterior labia minora, and perineum is bilateral. Metastases to contralateral lymph nodes in the absence of ipsilateral nodal involvement is very rare (0% to 0.4%) for lateral vulvar tumors that are either 2 cm or less in diameter or with 5 mm or less invasion (36,48).

The overall incidence of inguinal-femoral lymph node metastases is reported to be about 32% (41,43,46–56) (Table 38.2). Metastases to pelvic nodes occur in about 12% of cases. Pelvic nodal metastases are rare (0.6%) in the absence of groin node involvement, but they occur in about 16% of cases with positive groin nodes (Table 38.2). The risk increases to 33% in the presence of clinically suspicious groin nodes and to 40% to 50% if there are three or more pathologically positive inguinal-femoral nodes (33,48,57–60). The incidence of lymph node metastases correlates positively with depth of invasion, as shown in Table 38.3. Hematogenous spread usually occurs late in the course of vulvar cancer and is rare in the absence of lymph node metastases.

Table 38.2 Incidence of Lymph Node Metastases in Squamous Cell Carcinoma of the Vulva

Table 38.3 Nodal Status in T1 Squamous Cell Carcinoma of the Vulva versus Depth of Stromal Invasion

Staging

Initially, vulvar carcinoma was staged clinically based on tumor size and location, palpable regional lymph node status, and a limited search for distant metastases. The prognostic importance of the lymph node status is significant, but clinical assessment of the lymph nodes has limited accuracy. This led the Cancer Committee of FIGO to introduce a surgical staging system for vulvar cancer in 1988, which underwent several revisions, most recently in 2009, to provide better prognostic discrimination between stages and less heterogeneity within stages (31,61,62) (Table 38.4). The main changes are:

Table 38.4 FIGO Staging and TNM classification for Vulvar Cancer (2008)

*FIGO Stage*	*TNM Classification*	*Clinical/Pathologic Findings*
Stage IA	T_1aN₀M₀	Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1 mm,^* no nodal metastasis
Stage IB	T_1bN₀M₀	Lesions >2 cm in size or with stromal invasion >1 mm,^b confined to the vulva or perineum, with negative nodes
Stage II	T₂N₀M₀	Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
Stage III		Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive inguino-femoral lymph nodes
IIIA	T_1or2 N_1b M₀ T_1or2 N_1a M₀	(i) with 1 lymph node metastasis (≥5 mm) or (ii) 1–2 lymph node metastasis(es) (<5 mm)
IIIB	T_1or2 N_2b M₀ T_1or2 N_2a M₀	(i) with 2 or more lymph node metastasis (≥5 mm) or (ii) 3 or more lymph node metastases (<5 mm)
IIIC	T_1or2 N_2c M₀	with positive nodes with extracapsular spread
Stage IV		Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures
Stage IVA	T₃N_any M₀ T_anyN₃	Tumor invades any of the following: (i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal musosa, or fixed to pelvic bone or (ii) fixed or ulcerated inguino-femoral lymph nodes
IVB	T_anyN_anyM₁	Any distant metastasis including pelvic lymph nodes
FIGO, International Federation of Gynecology and Obstetrics; TNM, tumor node metastasis.
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet 2009;105:103-104.
^*The depth of stromal invasion is measured from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. ^aTNM Classification: (This table needs to be replaced with the one on the middle of the page 545 in Berek & Hacker, 5th edition)

T	Primary tumor
T_x	Primary tumor cannot be assessed
T₀	No evidence of primary tumor
T_is	Carcinoma in situ (preinvasive carcinoma)
T_1a	Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1 mm
T_1b	Lesions >2 cm in size or any size with stromal invasion >1 mm, confined to the vulva or perineum
T₂	Tumor of any size with extension to adjacent perineal structures (lower 1/3 of urethra, lower of 1/3 vagina, anal involvement)
T₃	Tumor of any size with extension to any of the following: upper 2/3 of urethra, upper 2/3 of vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone
N	Regional lymph nodes (femoral and inguinal nodes)
N_x	Regional lymph nodes cannot be assessed
N₀	No regional lymph node metastases
N₁	One or two regional lymph node metastases with the following features:
N_1a	One or two lymph node metastases each <5 mm
N_1b	One lymph node metastasis ≥5 mm
N₂	Regional lymph node metastases with the following features
N_2a	≥3 lymph node metastases, each <5 mm in diameter
N_2b	≥2 lymph node metastases ≥5 mm
N[MB2][MB2]_2c	Lymph node metastases with extracapsular spread
N₃	Fixed or ulcerated regional lymph node metastasis
M	Distant metastasis
M₀	No distant metastasis
M₁	Distant metastasis (including pelvic lymph node metastasis)

1. While stage Ia remains unchanged as the only group of patients with a negligible risk of lymph node metastases, former stages I and II have been combined into stage Ib.

2. The new stage II segregates patients whose tumors involve the lower adjacent perineal structures from those with positive lymph nodes.

3. For stages III and IV, the number and morphology of the involved nodes are taken into account and the bilaterality of lymph nodes is discounted.

The new FIGO staging system was validated in 269 patients, 42% of whom were restaged (63). The number of positive nodes negatively correlated with survival, as did the presence of extracapsular growth. This study confirmed Gynecologic Oncology Group (GOG) and SEER data indicating that in patients with negative nodes, tumor size was not predictive of survival (62). This study confirmed reports demonstrating that, when corrected for the number of positive nodes, bilaterality of nodal metastases was not predictive of survival (64–67).

Paralleling the changes to the FIGO staging, the American Joint Committee on Cancer (AJCC) significantly modified the vulvar cancer tumor-node-metastasis (TNM) classification with the release of the 2009 edition of the AJCC Cancer Staging Manual (Table 38.4) (68).

Prognosis and Survival

Survival of patients with vulvar cancer correlates with FIGO stage (69). The prognosis for patients with early-stage disease is generally good (Table 38.5). The single most important prognostic factor is lymph node status (54–56,59,70,71). A report from the Mayo Clinic on 330 patients with primary squamous cell carcinoma of the vulva demonstrated a significant correlation between lymph node status and risk of treatment failure, especially in the first 2 years following initial therapy: 44.2% overall recurrence rate with positive versus 17.5% with negative lymph nodes. More than one-third of relapses presented 5 years or more after initial therapy (72). There is a strong negative correlation between the number of positive lymph nodes and survival (Table 38.6). Patients with negative lymph nodes have a 5-year survival rate of over 80%; for patients with positive nodes 5-year survival falls below 50%. The number of positive nodes is of critical importance: Patients with one microscopically positive lymph node have a prognosis similar to those with all negative lymph nodes, whereas patients with three or more positive nodes have a poor prognosis and a 2-year survival rate of 20% (73). The survival rate for patients with positive pelvic nodes is about 11% (74). In addition to the number of nodes involved, the morphology of the positive groin nodes is of prognostic significance. As demonstrated in several studies, significant negative predictors of survival are the size of the nodal metastasis, the proportion of the node replaced by tumor cells, and the presence of any extracapsular spread (62,70,75,76). Histologic grade, tumor thickness, depth of stromal invasion, and lymph–vascular space involvement contribute to the risk of lymph node involvement but are not independent predictors of survival (73).

Table 38.5 Five-Year Survival for Patients with Vulvar Carcinoma

*FIGO Stage*	*No. of Patients*	*5-Year Survival (%)*
I	286 (34%)	79
II	266 (32%)	59
III	216 (26%)	43
IV	71 (8%)	13
FIGO, International Federation of Gynecology and Obstetrics.
Modified from the FIGO Annual Report on the Results of Treatment in Gynecological Cancer using 1994 FIGO staging classification (69).

Table 38.6 Five-year Survival for Patients with Vulvar Squamous Cell Carcinoma by Number of Lymph Node Metastases

No. of Lymph Node Metastases	*No. of Patients*	*5-Year Survival (%)*
0	302 (61%)	81
1	66 (13%)	63
2	43 (9%)	30
3	24 (5%)	19
4 or more	62 (12%)	13
FIGO, International Federation of Gynecology and Obstetrics.
Modified from the FIGO Annual Report on the Results of Treatment in Gynecological Cancer (69).

Treatment

After the pioneering work of Taussig and Way, en bloc radical vulvectomy and bilateral dissection of the groin and pelvic nodes were the standard treatment for most patients with operable vulvar cancer (6,7). When the disease involved the anus, rectovaginal septum, or proximal urethra, some type of pelvic exenteration was combined with the dissection.

Although the survival rate improved markedly with this aggressive surgical approach, several factors led to modifications of this treatment plan. These factors are summarized as follows:

1. An increasing proportion of patients present with early-stage disease—up to 50% of patients in many centers have tumors 2 cm in diameter or smaller.

2. Concerns about the postoperative morbidity and associated long-term hospitalization common with the en bloc radical dissection.

3. Increasing awareness of the psychosexual consequences of radical vulvectomy.

To individualize the patient’s care and determine the appropriate therapy, it is necessary to independently manage the primary lesion and groin lymph nodes. Before initiation of therapy, all patients should undergo colposcopy of the cervix, vagina, and vulva. Preinvasive (and rarely invasive) lesions may be present at other sites along the lower genital tract.

Management of the Primary Lesion

Microinvasive Vulvar Cancer (T_1a)

Tumors 2 cm or less in diameter with 1 mm or less invasion are appropriately treated with a wide local excision, which is as effective as radical surgery for the prevention of vulvar recurrences for these tumors (77). The excision should go sufficiently deep into the dermis that depth of invasion is fully assessed.

Early Vulvar Cancer (T_1b)

The modern approach to the management of patients with T_1b carcinoma of the vulva should be individualized. There is no standard approach applicable to every patient, and emphasis is on performing the most conservative operation that is consistent with cure of the disease. Radical vulvectomy was considered the standard treatment for primary vulvar lesions, but this operation is associated with significant surgical morbidity and disturbances of sexual function and body image. Psychosexual sequelae are a major long-term morbidity associated with the treatment of vulvar cancer (37). One study reported that sexual arousal was reduced to the eighth percentile and body image was reduced to the fourth percentile for women who had undergone vulvectomy when compared with healthy adult women (66). Traditionally, the concern was that without an en bloc resection of vulva and groin nodes, intervening tissue left between the primary tumor and the regional lymph nodes contained microscopic tumor foci in draining lymphatics. Experience with a separate incision technique for node dissection confirmed that metastases rarely occur in the skin bridge in patients without clinically suspicious nodes in the groin (78).

During the past 20 years, several investigators advocated a radical local excision rather than a radical vulvectomy for the primary lesion for patients with T_1b tumors (37,49,79,80). Regardless of whether a radical vulvectomy or a radical local excision is performed, the surgical margins adjacent to the tumor are the same. An analysis of the literature indicates that the incidence of local invasive recurrence after radical local excision or radical hemivulvectomy is not higher than that after radical vulvectomy (36,49,74,81–83). This finding suggests that in the presence of an otherwise normal-appearing vulva, radical local excision is a safe surgical option, regardless of the size of the tumor or the depth of invasion. Based on cumulative data of 413 patients reported in four studies, an 8 mm or greater histopathological resection margin results in a high rate of local disease control (81,84–86). Of the 252 patients whose tumors were resected with margins of 8 mm or greater, 2.4% experienced a local recurrence, compared to 30.3% of the 161 patients whose margins were less than 8 mm. Neither clinical tumor size nor the presence of coexisting benign vulvar pathology correlated with local recurrence. It is important to bear in mind that paraffin-embedded tissue shrinks by about 25%. At the time of radical local excision, at least a 1-cm grossly negative margin, without putting the skin under tension, should be obtained and extended down to the level of the inferior fascia of the urogenital diaphragm.

When vulvar cancer arises in the presence of VIN, vulvar dystrophy, or some nonneoplastic epithelial disorder, treatment is influenced by the patient’s age. Elderly patients who often had many years of chronic itching may not be disturbed by the prospect of a vulvectomy. In younger women, it is desirable to conserve as much of the vulva as possible. Radical local excision should be performed for the invasive disease, and the associated intraepithelial disease should be treated in the manner most appropriate to the patient. For example, topical steroids may be required for lichen sclerosus or squamous hyperplasia, whereas VIN may require superficial local excision with primary closure or laser ablation.

Radical local excision is most appropriate for lesions on the lateral or posterior aspects of the vulva (Fig. 38.4). Midline lesions pose special challenges because of their proximity to clitoris, urethra, or anus. For anterior lesions, conservative clitoris-sparing surgery allows for excellent local control as long as pathological margins are at least 8 mm (87). For tumors that involve the clitoris or that are in close proximity to it, any type of surgical excision will have psychosexual consequences. In addition, marked edema of the posterior vulva may occur. For young patients with periclitoral lesions, the primary lesion can be treated with a small field of radiation therapy, possibly with concomitant sensitizing chemotherapy. Small vulvar lesions should respond very well to about 5,000 cGy external radiation, and biopsy can be performed after therapy to confirm the absence of any residual disease (61).

Figure 38.4 Small (T1) vulvar carcinoma at the posterior fourchette. (From Berek JS, Hacker NF. Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:547, with permission.)

Early T₂ Vulvar Cancer

The indications for vulvar conservation can be extended to selected patients with early T₂ tumors. The tumor-free margin should be the same, whether or not a radical vulvectomy or a radical local excision is performed. It seems both feasible and desirable to extend the indications for vulvar conservation, particularly for younger patients. Tumors that are suitable for a conservative resection are those involving the posterior vulva and lower vagina, where preservation of the anus, clitoris, and urethra is feasible.

For patients with more advanced T₂ lesions, management consists of radical vulvectomy and/or chemoradiation therapy, as discussed below. When the disease involves the distal urethra or anus, partial resection of these organs is required. Alternatively, it is often preferable to give preoperative radiation therapy with chemosensitization to allow for a less radical resection (see below).

Closure of Large Defects

After radical local excision, primary closure without tension can be accomplished for smaller defects. If an extensive dissection is required to treat a large primary lesion, a number of options are available to repair the defect:

1. An area may be left open to granulate, which it will usually do over a period of 6 to 8 weeks (88).

2. Full-thickness skin flaps may be devised (89–92). The rhomboid flap is best suited to covering large defects of the posterior vulva, whereas for lateral defects, a mons pubis pedicle flap is advocated (89,92).

3. Myocutaneous flaps may be developed to cover the defect. Unilateral or bilateral gracilis myocutaneous grafts are useful when an extensive area from the mons pubis to the perianal area was resected. Because the graft brings a new blood supply to the area, it is particularly applicable if the vulva is poorly vascularized from prior surgical resection or radiation (93).

4. If extensive defects exist in the groin and vulva, the tensor fascia lata myocutaneous graft may be the most applicable (94).

Advanced Disease: Large T₂ and T₃ Primary Tumors

To achieve primary surgical clearance for tumors involving the upper urethra, anus, rectum, or rectovaginal septum, pelvic exenteration is needed in addition to radical vulvectomy and inguinal-femoral lymphadenectomy, which carries an extremely high physical and psychological morbidity (95,96). Reported 5-year survival rates with this approach are about 50% (97–100). For many of these patients, a combined approach of surgery and radiation therapy offers improved survival and reduced morbidity and is the preferred treatment approach. Numerous small prospective and retrospective series report on the use of external beam radiation, often with concomitant chemotherapy to shrink the primary tumor. Reported initial response rates to chemoradiation are 80% to 90%, and operability is achieved in 63% to 92% of cases (101–108). It is important that this chemoradiation is followed by a more limited resection of the tumor bed on an individualized basis. About one-half of the specimens will contain residual tumor, and local relapse rates are as high as 50% to 79% with external radiation alone (with or without concomitant chemotherapy), emphasizing the need for a combined approach that involves radiation and surgery (109–112).

As experience with this combination therapy evolved, it appeared that external beam therapy is appropriate for most cases, with more selective use of brachytherapy. The extensiveness of the surgery is significantly modified. A limited vulvar resection is advocated, and bulky N2 and N3 nodes are resected without full groin lymphadenectomy to avoid the leg edema associated with groin lymphadenectomy and radiation. With this combined radiation-surgical approach, 5-year survival rates as high as 76% are reported (110). With the experience accrued, preoperative radiation, with or without concurrent chemotherapy, is regarded as the first treatment of choice for patients with advanced vulvar cancer who would otherwise require some type of pelvic exenteration or stoma. Neoadjuvant therapy is not justified in patients with tumors that can be adequately treated with primary radical vulvectomy and bilateral groin node dissection.

Management of the Lymph Nodes

Appropriate groin dissection is the single most important factor in decreasing the mortality from early vulvar cancer.

When assessing a patient for groin dissection, the following facts should to be kept in mind:

1. The only patients with virtually no risk of lymph node metastases are those whose tumor is small and invades the stroma to 1 mm or less (T_1a).

2. Patients who develop recurrent disease in an undissected groin have a greater than 90% mortality (113).

3. Based on the laterality of the vulvar lesions and the status of the ipsilateral groin, an ipsilateral or bilateral lymphadenectomy becomes necessary.

Groin dissection is associated with postoperative wound infection and breakdown. Although the incidence of wound breakdown is reduced significantly when separate incisions are used for the groin dissection, lymphocyst formation and chronic leg edema remain a major problem (Fig. 38.5) (78).

Figure 38.5 Skin incision for groin dissection through a separate incision. A line is drawn 1 cm above and parallel to the groin crease, and a narrow ellipse of skin is removed. (Revised from Berek JS, Hacker NF. Practical Gynecologic Oncology. 2nd ed. Baltimore, MD: Williams & Wilkins, 1994:418, with permission.)

All patients whose tumors demonstrate more than 1 mm of stromal invasion or whose tumors are larger than 2 cm (T_1b and above) require inguinal-femoral lymphadenectomy. If there is any question regarding the need for inguinofemoral lymphadenectomy, a Keys biopsy or wedge biopsy of the primary tumor should be obtained, and the depth of invasion should be determined. If it is smaller than 1 mm on the wedge biopsy specimen, the entire lesion should be locally excised and analyzed histologically to determine the depth of invasion. If the lesion is 2 cm in diameter or smaller and there is no invasive focus larger than 1 mm, groin dissection may be omitted, provided there is no lymph–vascular space invasion and there are no clinically suspicious groin lymph nodes. An occasional patient with less than 1 mm of stromal invasion has documented groin node metastases, but the incidence is so low that it is of no practical significance (114,115).

Inguinal-Femoral Lymphadenectomy

If groin dissection is indicated in patients with vulvar cancer, it should be a thorough inguinal-femoral lymphadenectomy. The GOG reported six groin recurrences among 121 patients with tumors 2 cm or less after a superficial (inguinal) dissection, although the removed inguinal nodes were negative, and a study from the M. D. Anderson Cancer Center reported a 9% groin recurrence rate in 104 patients with vulvar cancer and negative nodes on superficial inguinal lymphadenectomy (41,42). Whether all of these recurrences were in the femoral nodes is unclear, but both studies indicate that an incomplete groin dissection will increase the number of groin recurrences and mortality. GOG data indicate that radiation therapy cannot substitute for groin dissection followed by selective radiation as indicated, even in patients with clinically nonsuspicious lymph nodes (116). This GOG study was closed early because a significantly higher incidence of recurrences occurred in women who were receiving groin radiation therapy only (19% versus 0%). The dose of radiation was 5,000 cGy given in daily 200-cGy fractions to a depth of 3 cm below the anterior skin surface. Although the radiation regimen prescribed was criticized extensively, other uncontrolled studies give no evidence for better groin control with radiotherapy (117,118). Surgery remains the treatment of choice for the groin for women with vulvar cancer.

Unilateral versus Bilateral Groin Dissection

It is not necessary to perform a bilateral groin dissection if the primary lesion is unilateral and the ipsilateral lymph nodes are negative. In a patient with a unilateral lesion and negative ipsilateral groin nodes, the risk of contralateral lymph node metastasis is very low (36,48). In a study from the Mayo Clinic, 8 of 163 patients with unilateral vulvar cancers (4.8%) had bilateral lymph node metastases and only 3 (1.8%) had isolated contralateral lymph node metastases. None of the patients with unilateral vulvar lesions that were either 2 cm or less or had 5 mm or less depth of invasion had bilateral groin node involvement at diagnosis (48). There is an increase in the risk of contralateral nodal involvement proportional to the number of positive ipsilateral inguinal nodes (60,48). It is recommended that patients with any bulky or multiple microscopically positive ipsilateral groin lymph nodes undergo contralateral inguinal-femoral lymphadenectomy. Bilateral inguinal-femoral lymphadenectomy should be performed for midline lesions (clitoris, anterior labia minora, posterior fourchette) or those within 2 cm of the midline because of the more frequent contralateral lymph flow from these regions (119).

Management of Bulky Groin Nodes

All clinically or radiologically suspicious groin nodes should be resected. If nodal metastasis is confirmed by frozen section, the question arises whether a full inguinofemoral lymphadenectomy may be safely omitted to decrease morbidity without compromising survival. One small, retrospective, multi-institutional study suggests that targeted nodal debulking compared with full lymphadenectomy does not jeopardize survival when both are followed by groin and pelvic radiation (120). Patients with fixed, unresectable groin nodes should be treated with primary chemoradiation. If there is no other evidence of metastatic disease following chemoradiation, GOG data suggest that it may be appropriate to resect the residual nodes (121).

Management of Pelvic Lymph Nodes

In the past, pelvic lymphadenectomy was part of the routine surgery for invasive vulvar cancer. The incidence of pelvic lymph node metastasis is rare in the absence of groin node involvement, and a more selective approach is preferred (Table 38.2). Patients most prone to pelvic lymph node metastasis are those with three or more pathologically positive groin nodes (33,45,57,122). In addition to the number of nodes involved, the morphology of the positive groin nodes is of prognostic significance. As demonstrated in several studies, significant negative predictors of survival are the number of positive nodes, the size of the nodal metastasis, the proportion of the node replaced by tumor cells, and the presence of any extracapsular spread (65,70,75,76). In these patients, the pelvis requires treatment by radiation (discussed below). If a preoperative pelvic imaging study reveals bulky pelvic lymph nodes, resection of these nodes should be performed via an extraperitoneal approach prior to radiation because of the limited ability of external beam radiation therapy to sterilize bulky positive pelvic nodes.

Sentinel Lymph Node Studies

Considerable investigation was conducted regarding the use of intraoperative lymphatic mapping using lymphoscintigraphy with technetium-99m-labeled nanocolloid or isosulfan blue dye to identify a sentinel node that would predict the presence or absence of regional nodal metastases (43,123–125). A systematic review of 29 small studies of 961 groins found lymphoscintigraphy to be the most accurate technique, with a pooled sensitivity and negative likelihood ratio of 97% and 0.12, respectively (126). Studies suggested that a sentinel node could be identified in most patients (127–129). A GOG study of 403 evaluable patients in whom 697 groins were assessed demonstrated that a sentinel node was successfully identified in 78.8% (67 of 85) of patients using blue dye only and in 96.2% (306 of 318) using combination of radiolocalization and blue dye, demonstrating the superiority of the combination of blue dye and radiocolloid over blue dye alone for sentinel node identification (130). The sensitivity of the sentinel node assessment is enhanced by ultrastaging using serial sectioning or immunohistochemistry to detect micrometastases (129,131–133).

The strong interest in the sentinel node concept lies in the desire to reduce the significant lifelong morbidity of lymphedema associated with a thorough inguinofemoral lymphadenectomy. Reliable identification of the sentinel node and forgoing full lymphadenectomy in patients with clinically nonsuspicious groin lymph nodes and a negative sentinel node may significantly reduce the number of patients who undergo unnecessary, extensive lymphadenectomy in the absence of disease. This is contingent upon a negative sentinel lymph node reliably predicting the absence of any other nodal metastases given the greater than 90% mortality associated with a groin recurrence.

The largest study published to date on the safety of the sentinel node procedure in vulvar cancer, GROINSS-V, included 403 assessable patients with a sentinel node procedure performed in 623 groins (Table 38.2) (129). Metastatic sentinel nodes were found in 26% of patients. In eight of 276 patients (3%) groin recurrences were diagnosed at a median follow-up time of 35 months. At the time of groin recurrence these patients all underwent bilateral inguinofemoral lymphadenectomy followed by chemoradiotherapy; six of the eight patients died of disease.

False-negative sentinel nodes were reported by others, but were thought to occur with low incidence in patients with clinically nonsuspicious nodes (44,134,135). Two recent studies of sentinel nodes in vulvar cancer, one single institution study of 56 patients and one multi-institution study of 127 patients with inclusion criteria similar to those in GROINSS-V, showed an unexpectedly high false-negative rate (27% and 7.7%, respectively), some of which may be attributable to insufficient experience of low-volume providers (128,136). This highlights one of the key concerns that any wide implantation of the sentinel node procedure beyond select expert centers might carry with it an unjustifiable rise in the frequency of groin recurrences.

The 2008 International Sentinel Node Society’s expert panel statement stresses the importance of a well-informed patient treated by a skilled multidisciplinary team of a gynecologic oncologist, a nuclear medicine specialist, and a pathologist with expertise in the sentinel lymph node technique (137). They recommended the following eligibility criteria for the performance of the sentinel node procedure: unifocal primary tumor of 4 cm or less in diameter with greater than 1 mm invasion; and absence of any obvious metastatic disease on physical examination or imaging studies, including the absence of suspicious groin nodes. Until data from prospective randomized controlled trials document comparable survival for patients undergoing the sentinel node procedure compared to full inguinofemoral lymphadenectomy, complete inguinofemoral lymphadenectomy remains indicated in all but stage Ia disease, given the high mortality of recurrence in an undissected groin. The sentinel node technique should be limited to carefully selected patients in expert centers, ideally on research protocols.

Postoperative Management

Despite the age and general medical condition of many elderly patients with vulvar cancer, surgery is usually remarkably well tolerated. Patients should be able to commence eating a low-residue diet on the first postoperative day. In the past, bed rest was advised for 3 to 5 days postoperatively to allow for immobilization of the wounds and to foster healing. Because radical local excisions are being performed with increasing frequency and groin lymphadenectomy is done through separate incisions, patients begin ambulation on postoperative day 1 or 2. Pneumatic calf compression or subcutaneous heparinshould be given to help prevent deep venous thrombosis, and active leg movements are to be encouraged. Frequent dressing changes are performed to keep the vulvar wound dry. Meticulous perineal hygiene is maintained. Suction drainage of each side of the groin is continued until output is minimal to help decrease the incidence of groin seromas. It is not uncommon for suction drainage to continue for 10 or more days. The Foley catheter is removed when the patient is ambulatory. If there is significant periurethral swelling, prolonged bladder drainage may be advisable. If there is breakdown of the vulvar wound, sitz baths or whirlpool therapy is helpful, followed by drying of the perineum with a hair dryer.

Early Postoperative Complications

The major immediate morbidity is related to groin wound infection, necrosis, and breakdown. This complication is reported in as many as 53% to 85% of patients having an en bloc operation (32,33). With the separate-incision approach, the incidence of wound breakdown can be reduced to about 44%; major breakdown occurs in about 14% of patients (34,78,138,139). With appropriate antibiotics, debridement, and wound dressings, the area will granulate and re-epithelialize over several weeks and may be managed with home nursing. Whirlpool therapy is effective for areas of extensive breakdown. The most common complications with the separate incision approach continues to be wound infection requiring antibiotic therapy and lymphocyst formation, both reported in about 40% of cases (139). Symptomatic lymphocysts should be managed by periodic sterile aspiration.

Other early postoperative complications include urinary tract infection, seromas in the femoral triangle, deep venous thrombosis, pulmonary embolism, myocardial infarction, hemorrhage, and, rarely, osteitis pubis. Anesthesia of the anterior thigh resulting from femoral nerve injury is common and usually resolves slowly.

Late Complications

One major late complication is chronic lymphedema, which occurs in about 30% of patients (32–34,138–140). Recurrent lymphangitis or cellulitis of the leg develops in about 10% of patients and usually responds to oral antibiotics. Urinary stress incontinence, with or without genital prolapse, occurs in about 10% of patients after radical vulvectomy and may require corrective surgery. Introital stenosis can lead to dyspareunia and may require a vertical relaxing incision, which is sutured transversely. An uncommon late complication is femoral hernia, which can be prevented intraoperatively by closure of the femoral canal with a suture from the inguinal ligament to Cooper’s ligament. Pubic osteomyelitis and rectovaginal or rectoperineal fistulas are rare late complications.

Other major long-term treatment complications associated with the extent of vulvar surgery include depression, altered body image, and sexual dysfunction (96,97). Modifications in the radical extent of the surgical approach and appropriate preoperative and postoperative counseling may help lessen some of the psychological trauma.

Role of Radiation Therapy

Radiation therapy traditionally had a limited role in the management of patients with vulvar cancer. In the orthovoltage era, local tissue tolerance was poor and vulvar necrosis was common, but with megavoltage therapy, tolerance improved significantly. Radiation therapy, frequently with concurrent chemotherapy, has an increasingly important role in the management of patients with vulvar cancer. It is important to remember that, with a rare exception, radiation therapy alone has little place in the primary management of vulvar cancer. It is indicated in conjunction with surgery.

The indications for radiation therapy for patients with primary vulvar cancer are evolving. Radiation seems to be indicated in the following situations:

1. Preoperatively, in patients with advanced disease who would otherwise require pelvic exenteration or suffer loss of anal or urethral sphincteric function

2. Preoperatively, in patients with fixed, unresectable groin nodes (141)

3. Postoperatively, to treat the pelvic lymph nodes and groins of patients with multiple microscopically positive groin nodes, one or more macrometastasis (10 mm or larger), or any evidence of extracapsular spread.

Possible roles for radiation therapy include the following:

1. Postoperatively, to help prevent local recurrences in patients with involved or close surgical margins (141–143)

2. As primary therapy for patients with small primary tumors, particularly clitoral or periclitoral lesions in young and middle-aged women, for whom surgical resection would have significant psychological consequences (80).

No additional treatment is recommended if one microscopically positive groin node (5 mm or less tumor deposit) is found in a fully dissected groin. The prognosis for this group of patients is excellent, and only careful observation is required (57). If unilateral groin dissection was performed for a lateral lesion, there seems to be no indication for dissection of the other side, because contralateral lymph node involvement is likely only if there are multiple microscopic or any gross ipsilateral inguinal node metastases (57,60). For patients with a single groin node metastasis, a recent retrospective SEER database review suggests that adjuvant radiation may provide a therapeutic benefit, especially if the groin dissection was limited (144).

If clinically evident groin metastases (any extracapsular spread or two or more microscopically positive groin nodes) are found, the patient is at increased risk of groin and pelvic recurrence and should receive postoperative groin and pelvic irradiation. In 1977, the GOG initiated a prospective trial in which patients with positive groin nodes were randomized to either ipsilateral pelvic node dissection or bilateral pelvic plus groin irradiation (60). The survival rate for the radiation group (68% at 2 years) was significantly better than the survival rate for the pelvic lymphadenectomy group (54% at 2 years) (p = 0.03). The survival advantage was limited to patients with clinically evident groin nodes or more than one microscopically positive groin node. Groin recurrence occurred in 3 of 59 patients (5%) treated with radiation, compared with 13 of 55 (23.6%) patients treated with lymphadenectomy (p = 0.02). Four patients who received radiation had a pelvic recurrence, compared with one who had lymphadenectomy. These data indicate no benefit from pelvic irradiation compared with pelvic lymphadenectomy for the prevention of pelvic recurrence, but they do highlight the value of groin irradiation in preventing groin recurrence in patients with multiple positive groin nodes.

Recurrent Vulvar Cancer

Recurrence of vulvar cancer correlates closely with the number of positive groin nodes (57). Patients with fewer than three positive nodes, particularly if the nodes are only microscopically involved, have a low incidence of recurrence at any site, whereas patients with three or more positive nodes have a high incidence of local, regional, and systemic recurrences (57,60).

Most recurrences of vulvar cancer occur within the first 2 years from initial therapy, with groin recurrences occurring sooner (median time to recurrence 6 to 7 months) than vulvar recurrences (median time to recurrence 3 years) (72,145–147). About one-third of vulvar cancer relapses present 5 or more years after initial therapy (72). In a long-term follow-up study at the Mayo Clinic, nearly 1 in 10 patients with vulvar cancer had a late (longer than 5 years) reoccurrence of disease (72). Over 95% of those late relapses had local reoccurrences (same site recurrence or second primary vulvar site). Because of this propensity for late local reoccurrence, regular and long-term careful examinations of the vulva and groin constitute the cornerstone of posttreatment surveillance for these patients.

The published literature on the management and outcome of recurrent disease is limited. The timing and primary site of recurrence is critical to the prognosis postrecurrence. Although groin recurrences tend to occur early and are nearly always fatal, 5-year overall survival rates of 50% to 70% are reported for patients with surgically treated isolated vulvar recurrences and more than 60% of patients with local recurrence or reoccurrence were alive at 20 years in the Mayo Clinic long-term follow-up study (72,147,148).

Local Recurrence

Margin status at the time of radical resection of the vulvar cancer is the most powerful predictor of local vulvar recurrence, with an almost 50% recurrence risk with margins closer than 0.8 cm(84). Margin status does not predict survival (71). Local vulvar recurrences are likely in patients with primary lesions larger than 4 cm in diameter, especially if lymph–vascular space invasion is present, and in patients with deeply invasive tumors (141,149,150). When detected early, isolated local failure is usually treatable by additional surgical therapy, often with a myocutaneous graft to cover the defect (34,41,49,78,151). Radiation therapy, particularly a combination of external beam therapy plus interstitial needles, at times combined with chemotherapy, is used to treat vulvar recurrences (152).

Three distinct patterns of local recurrence were described: remote vulvar recurrence (greater than 2 cm of the primary tumor site), primary tumor site recurrence (within 2 cm of the primary tumor site), and skin bridge recurrence (81,150). Although reported treatment rates are excellent for remote site recurrences with 3-year survival rates of 67% to 100%, the literature is controversial as to the prognostic significance of primary tumor site recurrences, with one study reporting a 3-year survival rate of only 15% and the other a 5-year survival of 93% (81,150). Patients with skin bridge recurrence have a very poor prognosis, similar to those with groin recurrence.

Regional and Distant Recurrence

Regional and distant recurrences are difficult to manage and are associated with a poor prognosis (141,145,146). Radiation therapy may be used in conjunction with surgery for groin recurrence, whereas chemotherapeutic agents that have activity against squamous carcinomas may be offered for distant metastases. The literature on the use of chemotherapy for recurrent vulvar cancer consists mainly of small series. The most extensively studied regimens contain bleomycin, methotrexate, and lomustine (a nitrosourea); bleomycin and mitomycin C; or cisplatin, vinorelbine, and paclitaxel, but response rates are low and the duration of response is usually disappointing (153–157). Long-term survival is very uncommon with regional or distant recurrence. Symptom control and quality of life are important treatment goals, and early involvement of a multidisciplinary palliative care team is generally indicated.

Melanoma

Vulvar melanomas are rare, with an incidence of 0.1 to 0.19 per 100,000 women (158,159). They account for 4% to 10% of all cases and are the second most common form of vulvar malignancy.Most melanomas arise de novo, but they may arise from a preexisting junctional nevus (160). Vulvar melanomas occur most frequently in postmenopausal white women, but are commonly seen in individuals with darker pigmented skin. Contrary to cutaneous melanoma, based on SEER data, there are low racial differences in vulvar melanomas, the development of which appears to be determined by factors other than ultraviolet radiation exposure and the photoprotective effects of melanin seen in cutaneous melanoma (161). The incidence of cutaneous melanomas worldwide is increasing significantly, but not that of vulvar melanoma (161). Vulvar melanomas appear to behave in a manner similar to that of other truncal cutaneous melanomas (162–165).

Most patients with vulvar melanoma have no symptoms other than a pigmented lesion that may be enlarging. Some patients have itching or bleeding, and a few have a groin mass. Vulvar melanomas occur most frequently on the labia minora or the clitoris (Fig. 38.6), and extension into the urethra or vagina at discovery is not uncommon. Any pigmented lesion on the vulva should be excised or, if the lesion is large, sampled for biopsy unless it is known to have been present and unchanged for some years. Most vulvar nevi are junctional and may be precursor lesions to melanoma; any nevus of the vulva should be removed.

Figure 38.6 Melanoma of the vulva involving the right labium minus. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:564, with permission.)

Histopathology

There are three basic histologic types of vulvar melanoma (Fig. 38.7):

Figure 38.7 Vulvar melanoma. Spindle-shaped melanoma cells form interlacing bundles, and some contain melanin pigment (right upper corner). Epidermal invasion is evident in the form of Pagetoid migration (left upper corner).

1. The mucosal lentiginous melanoma is a flat freckle that may become quite extensive but tends to remain superficial.

2. The superficial spreading melanoma tends to remain relatively superficial early in its development.

3. The nodular melanoma, which is the most aggressive, is characterized by a raised lesion that penetrates deeply and may metastasize widely.

In one of the largest reported series, more than one-fourth of the cases of melanomas were macroscopically amelanotic (158). Vulvar melanoma tends to spread early, not only lymphatically but also hematogenously.

Staging

The FIGO staging used for squamous lesions is not applicable to melanomas because the lesions are usually much smaller and the prognosis is related to the depth of tumor invasion rather than to the diameter of the lesion (162,165,166). The leveling system established by Clark et al. for cutaneous melanomas is less readily applicable to vulvar lesions because of the different skin morphology (166). The vulvar skin lacks a well-defined papillary dermis. Breslow measured the thickest portion of the melanoma from the surface of intact epithelium to the deepest point of invasion (167). This system is more adequate for the vulva. Chung et al. proposed a modified system that retained Clark’s definitions for levels I and V but arbitrarily defined levels II, III, and IV, using measurements in millimeters (165). A comparison of these systems is shown in Table 38.7.

Table 38.7 Microstaging of Vulvar Melanoma

The revised 2009 AJCC staging for cutaneous melanoma indicates that tumor thickness remains the primary determinant of the T staging, but mitotic rate was integrated to subcategorize T₁ tumors in addition to the presence of ulcerations. Specific immunohistochemistry criteria for the detection of micrometastases were included. The number and volume of metastatic nodes, site(s) of distant metastatic disease, serum lactate dehydrogenase level, and sentinel node results remained part of the staging (168).

Treatment

With better understanding of the prognostic significance of the microstage, some individualization of treatment developed. Treatment of vulvar melanoma continues to be controversial, in part because of the lack of large prospective studies, which makes it difficult to draw conclusions regarding its behavior and best treatment. Treatments are guided by experience from cutaneous melanoma and squamous cell carcinomas of the vulva. Paralleling the trend toward more conservative surgical management of cutaneous melanoma, there is a shift toward more conservative management of vulvar melanoma (163,164,169–171).

It is accepted that lesions with less than 1 mm of invasion may be treated with radical local excision alone (165,172). With more invasive lesions, en bloc resection of the primary tumor and regional groin nodes was traditionally recommended. In the past 15 years, radical vulvectomy was performed less frequently and survival did not seem to be compromised (173). One study reported on 32 patients with vulvar melanoma who underwent local excision (n = 14), simple vulvectomy (n = 7), or radical resection (n = 11) (174). No group had a superior survival rate, although the overall survival rate at 5 years was only 25%. Another study reported on 59 patients who underwent radical vulvectomy and 19 who underwent more conservative resections (163). Survival was not improved by the more radical approach, and they recommended radical local excision for the primary tumor, with groin dissection for tumors with a thickness of more than 1 mm. A recent SEER data analysis of 644 patients with vulvar melanoma did not find a survival difference in patients with localized disease treated with more conservative versus radical surgery. Five-year disease specific survival rates for patients undergoing conservative surgery for localized disease were 75% versus 79% for those undergoing radical surgery (174). Literature on cutaneous melanoma suggests that a 1-cm margin of skin and subcutaneous tissue is sufficient for the treatment of superficial localized melanoma (Breslow tumor thickness <0.76 mm), whereas a 2-cm margin suffices for intermediate-thickness lesions (1 to 4 mm) (175,176). At least a 1-cm tumor-free deep surgical margin is recommended, irrespective of tumor thickness. Because melanomas commonly involve the clitoris and labia minora, the vaginourethral margin of resection is a common site of failure, and care should be taken to obtain an adequate “inner” resection margin (177). A 10-year survival rate of 61% was shown for lateral lesions, compared with 37% for medial lesions (p = 0.027) (149).

Controversy exists as to which patients may benefit from inguinal-femoral lymphadenectomy. A prospective study by the GOG demonstrated that the risk of inguinal-femoral lymph node metastasis correlated with the Breslow microstage (165). As with cutaneous melanoma, it appears that for superficial lesions (Breslow tumor thickness <0.76 mm), the risk for nodal spread is so low that routine lymphadenectomy is not indicated as long as the nodes appear clinically free of disease. For intermediate-thickness (1 to 4 mm) cutaneous melanoma, a randomized controlled trial of elective lymph node dissection versus observation showed a 5-year survival advantage for patients who underwent elective lymph node dissection, who were younger than 60 years, and whose tumors were characterized by 1- to 2-mm thickness and no ulcerations (178). Patients with deeply invasive cutaneous melanomas (>4-mm tumor thickness) have a high risk of regional and systemic metastases and are unlikely to benefit from regional lymphadenectomy (179). Given some of the epidemiologic, histologic, and prognostic differences between vulvar and cutaneous melanoma, extrapolation of these data to the vulva should be done with caution (180). Specific to patients with vulvar melanoma, there is a small body of literature to suggest that there may be a clinical benefit in elective groin lymphadenectomy and the resection of clinically positive nodes (162,163). The role of the sentinel lymph node procedure in vulvar melanoma is under investigation. In cutaneous melanoma, sentinel lymph node biopsy replaced elective lymph node dissection in patients with clinically negative nodes, as it provides the same prognostic information with reduced morbidity. Only patients with metastatic disease undergo completion lymphadenectomy. Results from an interim analysis of the Multicenter Selective Lymphadenectomy Trial confirmed the prognostic value of the sentinel node procedure. These data suggest that an immediate completion lymphadenectomy following detection of a positive sentinel lymph node improves survival in patients with regional nodal metastases (181). Studies on the sentinel lymph node procedure for vulvar melanoma are limited. A review of the literature estimates a false-negative rate of about 15% (182). Although the sentinel node procedure appears appropriate for select patients with vulvar melanoma, the importance of an expert team familiar with the procedure and consisting of a gynecologic oncologist, a nuclear medicine specialist, and a pathologist with expertise in microstaging cannot be overemphasized.

Pelvic node metastases do not occur in the absence of groin node metastases (177,183,184). The prognosis for patients with positive pelvic nodes is so poor that there seems to be no value in performing pelvic lymphadenectomy for this disease. Immunotherapy and chemotherapy have demonstrated modest results in cutaneous melanoma. Several randomized cooperative and Intergroup trials of high-risk melanoma patients demonstrated a small but significant improvement in disease-free and overall survival with adjuvant interferon alpha (185–187). Dacarbazine (DTIC) is considered the most active single-agent chemotherapy, with a response rate of 16%, and randomized controlled trials failed to demonstrate superiority of any multiagent regimen (188). Targeted therapy is an area of promising development as single agents, in combination, and combined with chemotherapy. A vaccine stimulating both antibody and T-cell responses against melanoma is a promising but experimental treatment that is under investigation (189). Estrogen receptors were demonstrated in human melanomas, and an occasional response to tamoxifenwas reported (190,191). Traditionally, melanomas were thought to be radiation resistant. There is a growing body of literature for advanced, high-risk, lymph node–metastatic cutaneous melanoma, demonstrating improved locoregional disease control compared to surgery with therapeutic lymphadenectomy alone (192,193).

Prognosis

The behavior of melanomas can be unpredictable, but the prognosis is poor. The reported 5-year overall survival rate for vulvar melanoma is in the range of 50% to 60% (158,159,171). A SEER database analysis showed disease-specific survival rates for patients with localized, regional, and distant disease of 76%, 39%, and 22%, respectively (171). Localized disease, negative lymph nodes, and younger age were significant independent prognostic factors for improved survival. Because vulvar melanoma has a propensity for late recurrences, 5-year survival may not reflect cure. Prognosis is best predicted by microstaging. Patients with lesions invading to 1 mm or less have a good prognosis, but as depth of invasion increases, the prognosis worsens (Table 38.8). Tumor volume is reported to correlate with prognosis; patients whose lesions have a volume less than 100 mm³ have an excellent prognosis (184). Additional prognostic factors are the patient’s age, AJCC stage, presence of multifocal or satellite lesions, tumor ulceration, central tumor location, histologic growth pattern, lymph–vascular space involvement, and aneuploidy (158,162–164,194–197).

Table 38.8 Prognosis for Patients with Vulvar Melanoma Stratified by Breslow Microstaging

*Breslow Tumor Thickness*	*No. of Patients*	*% DOD*
<0.76 mm	31 [19]	7 (23%) [1 (5%)]^a
0.76–1.5 mm	35	6 (17%)
1.51–3.0 mm	42	23 (55%)
>3.0 mm	195	131 (67%)
DOD, died of disease.
^aAll but one of these seven deaths were reported in one study with an unusually low 5-year survival of 48% for 12 patients with superficial melanomas of Breslow thickness <0.76 mm. If these 12 cases were excluded, 5% of patients with superficial melanoma of the vulva died of disease.
From references 160, 165, 174, 185, 186, 196–199.

Bartholin Gland Carcinoma

Epidemiology

Primary carcinoma of the Bartholin gland is a rare form of vulvar cancer, which accounts for about 2% to 7% of vulvar malignancies (198). Because of its rarity, individual experience with the tumor is limited, and recommendations for management must be based on the review of small published series. Only about 300 cases are reported (46,198,199). Bartholin gland carcinoma is five times more common in postmenopausal than in premenopausal women (200).

Histopathology

The bilateral Bartholin glands are greater vestibular glands situated posterolaterally in the vulva. Their main duct is lined with stratified squamous epithelium, which changes to transitional epithelium as the terminal ducts are reached. Because tumors may arise from the gland or the duct, a variety of histologic types occur, including adenocarcinomas, squamous carcinomas, and, rarely, transitional cell, adenosquamous, and adenoid cystic carcinomas.

Classification of a vulvar tumor as a Bartholin gland carcinoma typically required that it fulfill Honan’s criteria, which are as follows:

1. The tumor is in the correct anatomic position

2. The tumor is located deep in the labium majus

3. The overlying skin is intact

4. There is some recognizable normal gland present.

Strict adherence to these criteria results in underdiagnosis of some cases. Large tumors may ulcerate through the overlying skin and obliterate the residual normal gland. Although transition between normal and malignant tissue is the best criterion, some cases will be diagnosed on the basis of their histologic characteristics and anatomic location.

Signs and Symptoms

The most common initial symptom of Bartholin gland carcinoma is a vulvar mass or perineal pain. About 10% of patients have a history of inflammation of the Bartholin gland, and malignancies may be mistaken for benign cysts or abscesses. Delay of diagnosis is common, particularly for premenopausal patients. The differential diagnosis of any pararectovaginal neoplasm should include cloacogenic carcinoma and secondary neoplasm (199).

Treatment

Traditionally, treatment was radical vulvectomy with bilateral groin and pelvic node dissection (201). There seems to be no indication for dissection of the pelvic nodes in the absence of positive groin nodes, and good results were reported with hemivulvectomy or radical local excision for the primary tumor (199). Because these lesions are deep in the vulva, extensive dissection is required in the ischiorectal fossa; surgical margins are often close. Postoperative radiation to the vulva decreased the likelihood of local recurrence from 27% (6 of 22 patients) to 7% (1 of 14 patients) (199). If the ipsilateral groin nodes are positive, bilateral groin and pelvic irradiation may decrease regional recurrence. If the tumor is fixed to the inferior pubic ramus or involves adjacent structures, such as the anal sphincter or rectum, preoperative radiation and chemotherapy is preferable to avoid ultraradical surgery. A recent report of 10 consecutive patients with primary Bartholin gland carcinoma suggests that treatment with radiation or chemoradiation using teletherapy combined with a boost to the primary site or regional nodes and/or interstitial brachytherapy may offer an effective alternative to surgery with 3- and 5-year survival rates of 72% and 66%, respectively (202).

Prognosis

Because of the deep location of the gland, disease tends to be more advanced than squamous carcinomas at the time of diagnosis but, stage for stage, the prognosis is similar. Five-year disease-free survival rates by stage are summarized in Table 38.9.

Table 38.9 Survival of Patients with Bartholin Gland Carcinoma

Adenoid Cystic Carcinoma of the Bartholin Gland

The adenoid cystic variety accounts for 15% of Bartholin gland carcinomas. A review of 62 cases reported in the literature demonstrates that adenoid cystic carcinoma of the Bartholin gland is a slow growing tumor characterized by perineural infiltration and a marked propensity for local relapse preceding distant recurrences by years. It is less likely to metastasize to lymph nodes and carries a somewhat better prognosis (Fig. 38.8) (203–205). The slowly progressive nature of these tumors and the tendency for late recurrences is reflected in the disparity between progression-free interval and overall survival (204).

Figure 38.8 Adenoid cystic tumor of the Bartholin gland. Basaloid cells form cribriform, sievelike spaces containing mucinous material. The hyaline stroma is another distinct feature of this tumor.

Other Adenocarcinomas

Adenocarcinomas of the vulva usually arise in a Bartholin gland or occur in association with Paget disease. They may arise rarely from the skin appendages, paraurethral glands, minor vestibular glands, aberrant breast tissue, endometriosis, or a misplaced cloacal remnant (206).

Adenosquamous Carcinoma

A particularly aggressive type of carcinoma is the adenosquamous carcinoma. This tumor has a number of synonyms, including cylindroma, pseudoglandular squamous cell carcinoma, adenoid squamous cell carcinoma, and adenoacanthoma of the sweat gland of Lever. The tumor has a propensity for perineural invasion, early lymph node metastasis, and local recurrence. One study noted a crude 5-year survival rate of 5.5% (1 of 18) for adenosquamous carcinoma of the vulva, compared with 62.3% (48 of 77) for patients with squamous cell carcinoma (207). Treatment should be radical vulvectomy and bilateral groin dissection. Postoperative radiation therapy may be appropriate.

Basal Cell Carcinoma

Basal cell carcinomas represent about 2% of vulvar cancers. As with other basal cell carcinomas, vulvar lesions commonly appear as a “rodent ulcer” with rolled edges, although nodules and macules are other morphologic varieties that occur. Most lesions are smaller than 2 cm in diameter and are usually situated on the anterior labia majora. Giant lesions occasionally occur (208). Basal cell carcinoma usually affects postmenopausal white women and is locally aggressive. Symptoms are frequently present for a prolonged period and most often include pruritus, soreness, and irritation (209). It is diagnosed by biopsy, and radical local excision is adequate treatment (210). Metastasis to regional lymph nodes is reported but is rare (211–213). The local recurrence rate is about 10% to 20% (209,214). Basal cell carcinoma of the vulva is associated with a high incidence of antecedent or concomitant malignancies elsewhere (209). In a series of 28 women with vulvar basal cell carcinoma, 10 patients had other basal cell carcinomas, and 10 patients suffered from other primary malignancies (209).

About 3% to 5% of basal cell carcinomas contain a malignant squamous component, the so-called basosquamous carcinoma. These lesions are more aggressive and should be treated as squamous carcinomas (213). Another subtype of basal cell carcinoma is the adenoid basal cell carcinoma, which must be differentiated from the more aggressive adenoid cystic carcinoma arising in a Bartholin gland or the skin (213).

Verrucous Carcinoma

Verrucous carcinoma is a variant of squamous cell carcinoma and has distinctive clinical and pathologic characteristics (215). Although most commonly found in the oral cavity, verrucous lesions may be found on any moist membrane composed of squamous epithelium (216). In the female genital tract, these lesions may develop on the cervix, vulva, and vagina. The cause of the lesion in the female genital tract is not fully understood, but associated HPV-6 and HPV-11 were found in some studies, whereas others find it to have no association with HPV infection (217,218). Some studies found as many as one-third of the cases to have coexisting squamous carcinoma of the vulva, underscoring the importance of careful histopathologic assessment of these tumors (219).

Grossly, the tumors have a cauliflowerlike appearance; microscopically, they contain multiple papillary fronds that lack the central connective tissue core that characterizes condylomata acuminata (Fig. 38.9). The gross and microscopic features of a verrucous carcinoma are very similar to those of the giant condyloma of Buschke-Loewenstein, and they probably represent the same disease entity (206). Adequate biopsy from the base of the lesion is required to differentiate a verrucous carcinoma from a benign condyloma acuminatum or a squamous cell carcinoma with a verrucous growth pattern.

Figure 38.9 Verrucous carcinoma of the vulva. Note the exophytic hyperkeratotic papillary fronds and endophytic bulky rete pegs with smooth borders.

Verrucous carcinomas usually occur in postmenopausal women, and they are slow-growing but locally destructive lesions. Even bone may be invaded. Metastasis to regional lymph nodes is rare but was reported (220). Radical local excision is the basic treatment, although any palpably suspicious groin nodes should be evaluated with fine-needle aspiration cytology or excisional biopsy. Usually, enlarged nodes will be caused by inflammatory hypertrophy (221). If the nodes contain metastases, radical vulvectomy and bilateral inguinal-femoral lymphadenectomy are indicated.

Several small studies failed to document any therapeutic advantage with radiation therapy (221). There is concern that radiation may induce anaplastic transformation with subsequent regional and distant metastasis (222). One study reported a corrected 5-year survival rate of 94% for 17 patients treated with surgery alone, compared with 42% for 7 patients treated with surgery and radiation (221). The latter patients had more advanced disease. If there is a recurrence, further surgical excision is the treatment of choice, which occasionally may necessitate some type of exenteration.

Vulvar Sarcoma

Sarcomas represent 1.5% of vulvar malignancies and constitute a heterogenous group of tumors (223). Leiomyosarcomas are the most common, and other histologic types include fibrosarcomas, neurofibrosarcomas, liposarcomas, rhabdomyosarcomas, angiosarcomas, epithelioid sarcomas, and malignant schwannomas.

Leiomyosarcomas usually appear as enlarging, often painful masses, usually in the labium majus. Smooth muscle tumors of the vulva that show at least three of the following four criteria should be regarded as sarcomas: (i) diameter greater than 5 cm, (ii) infiltrating margins, (iii) 5 or more mitotic figures per 10 high-power fields, (iv) moderate-to-severe cytological atypia (224). The absence of one, or even all, of these features does not guarantee against recurrence (225). Lymphatic metastases are uncommon, and radical local excision is the usual treatment.

Epithelioid sarcomas characteristically develop in the soft tissues of the extremities of young adults but rarely may occur on the vulva. In a description of two cases and review of three other reports, the authors concluded that these tumors might mimic a Bartholin cyst, leading to inadequate initial treatment (226). They believed that vulvar epithelioid sarcomas behave more aggressively than their extragenital counterparts, with four of the five patients dying of metastatic disease. They suggested that early recognition and wide excision should improve the prognosis.

Rhabdomyosarcomas are the most common soft tissue sarcomas in childhood, and 20% involve the pelvis or genitourinary tract (227). Dramatic gains were made in the treatment of these tumors during the past 20 years. Previously, radical pelvic surgery was the standard approach, but results were poor. A multimodal approach evolved, and survival rates improved significantly, with a corresponding decrease in morbidity. In a report of the experience of the Intergroup Rhabdomyosarcoma Study I and II (1972 to 1984) with primary tumors of the female genital tract, nine patients aged 1 to 19 years had primary vulvar tumors, and these tumors were often regarded as a form of Bartholin gland infection before biopsy (228). They were all managed with chemotherapy (vincristine, or actinomycin D and cyclophosphamide and doxorubicin), with or without radiotherapy. Wide local excision of the tumor, with or without inguinal-femoral lymphadenectomy, was carried out before or after the chemotherapy. Seven of the nine patients were free of disease 4 or more years from diagnosis, one patient was free of disease when lost to follow-up at 5 years, and one patient was alive with disease.

Rare Vulvar Malignancies

In addition to the previously mentioned tumors, a number of malignancies more commonly seen in other areas of the body may rarely occur as isolated vulvar tumors.

Lymphomas

The genital tract may be involved primarily by malignant lymphomas but, more commonly, involvement is a manifestation of systemic disease. In the lower genital tract, the cervix is most often involved, followed by the vulva and the vagina (229). Most patients are in their third to sixth decades of life, and about three-fourths of the cases involve diffuse large cell or histiocytic non-Hodgkin’s lymphomas. The remainder are nodular or Burkitt’s lymphomas. Treatment is by surgical excision followed by chemotherapy and radiation or both, and the overall 5-year survival rate is about 70% (229).

Endodermal Sinus Tumor

There were four case reports of endodermal sinus tumor of the vulva, and three of the four patients died of distant metastases (230). All patients were in their third decade of life, but none was treated with modern chemotherapy.

Merkel Cell Carcinoma

Merkel cell carcinomas are primary small cell carcinomas of the skin that resemble oat cell carcinomas of the lung. They metastasize widely and have a very poor prognosis (231–233). They should be locally excised and treated with cisplatin-based chemotherapy.

Dermatofibrosarcoma Protuberans

This rare, low-grade cutaneous malignancy occasionally involves the vulva. It has a marked tendency for local recurrence but a low risk of systemic spread (234). Radical local excision should be sufficient treatment.

Metastatic Tumors of the Vulva

Eight percent of vulvar tumors are metastatic. The most common primary site is the cervix, followed by the endometrium, kidney, and urethra. Most patients in whom vulvar metastases develop have advanced primary tumors when diagnosed, and in about one-fourth of the patients, the primary lesion and the vulvar metastasis are diagnosed simultaneously (235).

References

1. American Cancer Society. Cancer facts and figures 2010. Atlanta: American Cancer Society 2010. Available online at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-026238.pdf

2. US Cancer Statistics Working Group. United States cancer statistics. Available online at: http://apps.nccd.cdc.gov/uscs/

3. Judson PL, Habermann EB, Baxter NN, et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018–1022.

4. Joura EA, Losch A, Haider-Angeler MG, et al. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women. J Reprod Med 2000;45:613–615.

5. Jones RW, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448–452.

6. Taussig FJ. Cancer of the vulva: an analysis of 155 cases. Am J Obstet Gynecol 1940;40:764–778.

7. Way S. Carcinoma of the vulva. Am J Obstet Gynecol 1960;79:692–697.

8. Madsen BS, Jensen HL, van den Brule AJ, et al. Risk factors for invasive squamous cell carcinoma of the vulva and vagina—population-based case-control study in Denmark. Int J Cancer 2008;122:2827—2834.

9. Ansink A. Vulvar squamous cell carcinoma. Semin Dermatol 1996;15:51–59.

10. van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 2005;97:645–651.

11. Hording U, Junge J, Poulsen H, et al. Vulvar intraepithelial neoplasia III: a viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276–279.

12. Modesitt SC, Waters AB, Walton L, et al. Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence. Obstet Gynecol 1998;92:962–966.

13. Trimble CL, Hildesheim A, Brinton LA, et al. Heterogeneous etiology of squamous carcinoma of the vulva. Obstet Gynecol 1996;87:59–64.

14. Insinga RP, Liaw KL, Johnson LG, et al. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev 2008;17:1611–1622.

15. Brinton LA, Nasco PC, Mallin K, et al. Case-control study of cancer of the vulva. Obstet Gynecol 1990;75:859–866.

16. Kurman RJ, Toki T, Schiffman MH. Basaloid and warty carcinomas of the vulva: distinctive types of squamous cell carcinoma frequently associated with human papillomaviruses. Am J Surg Pathol 1993;17:133–145.

17. Vilmer C, Cavelier-Balloy B, Nogues C, et al. Analysis of alterations adjacent to invasive vulvar carcinoma and their relationship with the associated carcinoma: a study of 67 cases. Eur J Gynaecol Oncol 1998;19:25–31.

18. Cooper SM, Gao XH, Powell JJ, et al. Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol 2004;140:702–706.

19. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, et al. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch Dermatol 2004;140:709–712.

20. Bradford J, Fischer G. Long-term management of vulval lichen sclerosus in adult women. Aust N Z J Obstet Gynaecol 2010;50:148–152.

21. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Hum Pathol1998;29:932–948.

22. Tate JE, Mutter GL, Boynton KA, et al. Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias. Am J Pathol 1997;150:315–322.

23. Raspollini MR, Asirelli G, Moncini D, et al. A comparative analysis of lichen sclerosus of the vulva and lichen sclerosus that evolves to vulvar squamous cell carcinoma. Am J Obstet Gynecol 2007;197:592.e1–e5.

24. Franklin EW, Rutledge FD. Epidemiology of epidermoid carcinoma of the vulva. Obstet Gynecol 1972;39:165–172.

25. Green TH Jr, Ulfelder H, Meigs JV. Epidermoid carcinoma of the vulva: an analysis of 238 cases. Parts I and II. Am J Obstet Gynecol 1958;73:834–864.

26. Woodruff JD. Early invasive carcinoma of the vulva. Clin Oncol 1982;1:349.

27. Binder SW, Huang I, Fu YS, et al. Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma. Gynecol Oncol 1990;37:9–16.

28. Boyce J, Fruchter RG, Kasambilides E, et al. Prognostic factors in carcinoma of the vulva. Gynecol Oncol 1985;20:364–377.

29. Donaldson ES, Powell DE, Hanson MB, et al. Prognostic parameters in invasive vulvar cancer. Gynecol Oncol 1981;11:184–190.

30. Buscema J, Woodruff JD. Progressive histobiologic alterations in the development of vulvar cancer. Am J Obstet Gynecol 1980;138:146–150.

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

32. Rutledge F, Smith JP, Franklin EW. Carcinoma of the vulva. Am J Obstet Gynecol 1970;106:1117–1130.

33. Podratz KC, Symmonds RE, Taylor WF, et al. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 1983;61:63–74.

34. Cavanagh D, Fiorica JV, Hoffman MS, et al. Invasive carcinoma of the vulva: changing trends in surgical management. Am J Obstet Gynecol 1990;163:1007–1115.

35. Sturgeon SR, Curtis RE, Johnson K, et al. Second primary cancers after vulvar and vaginal cancers. Am J Obstet Gynecol 1996;174:929–933.

36. Hacker NF, Van der Velden J. Conservative management of early vulvar cancer. Cancer 1993;71:1673–1677.

37. DiSaia PJ, Creasman WT, Rich WM. An alternative approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825–832.

38. Hacker NF, Nieberg RK, Berek JS, et al. Superficially invasive vulvar cancer with nodal metastases. Gynecol Oncol 1983;15:65–77.

39. Chu J, Tamimi HK, Figge DC. Femoral node metastases with negative superficial inguinal nodes in early vulvar cancer. Am J Obstet Gynecol 1981;140:337–339.

40. Podczaski E, Sexton M, Kaminski P, et al. Recurrent carcinoma of the vulva after conservative treatment for “microinvasive” disease. Gynecol Oncol 1990;39:65–68.

41. Stehman FB, Bundy BN, Dvoretsky PM, et al. Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 1992;79:490–497.

42. Gordinier ME, Malpica A, Burke TW, et al. Groin recurrence in patients with vulvar cancer with negative nodes on superficial inguinal lymphadenectomy. Gynecol Oncol 2003;90:625–628.

43. Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995;59:216–220.

44. Rob L, Robova H, Pluta M, et al. Further data on sentinel lymph node mapping in vulvar cancer by blue dye and radiocolloid Tc99. Int J Gynecol Cancer 2007;17:147–153.

45. Curry SL, Wharton JT, Rutledge F. Positive lymph nodes in vulvar squamous carcinoma. Gynecol Oncol 1980;9:63–67.

46. Leuchter RS, Hacker NF, Voet RL, et al. Primary carcinoma of the Bartholin gland: a report of 14 cases and a review of the literature. Obstet Gynecol 1982;60:361–368.

47. Piver MS, Xynos FP. Pelvic lymphadenectomy in women with carcinoma of the clitoris. Obstet Gynecol 1977;49:592–595.

48. Gonzalez Bosquet J, Magrina JF, Magtibay PM, et al. Patterns of inguinal groin metastases in squamous cell carcinoma of the vulva. Gynecol Oncol 2007;105:742–746.

49. Burke TW, Levenback C, Coleman RL, et al. Surgical therapy of T1 and T2 vulvar carcinoma: further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995;57:215–220.

50. Burrell MO, Franklin EW III, Campion MJ, et al. The modified radical vulvectomy with groin dissection: an eight-year experience. Am J Obstet Gynecol 1988;159:715–722.

51. Collins CG, Lee FY, Roman-Lopez JJ. Invasive carcinoma of the vulva with lymph node metastases. Am J Obstet Gynecol 1971;109:446–452.

52. Morley GW. Infiltrative carcinoma of the vulva: results of surgical treatment. Am J Obstet Gynecol 1976;124:874–888.

53. Krupp PJ, Bohm JW. Lymph gland metastases in invasive squamous cell cancer of the vulva. Am J Obstet Gynecol 1978;130:943–952.

54. Keys H. Gynecologic Oncology Group randomized trials of combined technique therapy of vulvar cancer. Cancer 1993;71:1691–1696.

55. Benedet JL, Turko M, Fairey RN, et al. Squamous carcinoma of the vulva: results of treatment, 1938 to 1976. Am J Obstet Gynecol 1979;134:201–207.

56. Iversen T, Aalders JG, Christensen A, et al. Squamous cell carcinoma of the vulva: a review of 424 patients, 1956–1974. Gynecol Oncol 1980;9:271–279.

57. Hacker NF, Berek JS, Lagasse LD, et al. Management of regional lymph nodes and their prognostic influence in vulvar cancer. Obstet Gynecol 1983;61:408–412.

58. Monaghan JM, Hammond IG. Pelvic node dissection in the treatment of vulvar carcinoma—is it necessary? BJOG 1984;91:270–274.

59. Hopkins MP, Reid CG, Vettrano I, et al. Squamous cell carcinoma of the vulva: prognostic factors influencing survival. Gynecol Oncol 1991;43:113–117.

60. Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 1986;68:733–740.

61. Hacker NF. Vulvar cancer. In: Berek JS, Hacker NF, eds. Gynecologic oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:536–575.

62. Hacker NF. Revised FIGO staging for carcinoma of the vulva. Int J Gynaecol Obstet 2009;105:105–106.

63. van der Steen S, de Nieuwenhof HP, Massuger L, et al. New FIGO staging system of vulvar cancer indeed provides a better reflection of prognosis. Gynecol Oncol 2010;119:520–525.

64. Hopkins MP, Reid GC, Johnston CM, et al. A comparison of staging systems for squamous cell carcinoma of the vulva. Gynecol Oncol 1992;47:34–37.

65. Raspagliesi F, Hanozet F, Ditto A, et al. Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva. Gynecol Oncol 2006;102:333–337.

66. Lataifeh I, Nascimento MC, Nicklin JL, et al. Patterns of recurrence and disease-free survival in advanced squamous cell carcinoma of the vulva. Gynecol Oncol 2004;95:701–705.

67. Fons G, Hyde SE, Buist MR, et al. Prognostic value of bilateral positive nodes in squamous cell cancer of the vulva. Int J Gynecol Cancer 2009;19:1276–1280.

68. College of American Pathologists. Protocol for the examination of specimens from patients with carcinoma of the vulva. October 2009. Available online at: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/Vulva_09protocol.pdf

69. Beller U, Quinn MA, Benedet JL, et al. 26th annual report on the results of treatment in gynecological cancer: carcinoma of the vulva. Int J Gynecol Obstet 2006;95:S7–S27.

70. Paladini D, Cross P, Lopes A, et al. Prognostic significance of lymph node variables in squamous cell carcinoma of the vulva. Cancer 1994;74:2491–2496.

71. Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1991;164:997–1003.

72. Gonzalez Bosquet J, Magrina JF, Gaffey TA, et al. Long-term survival and disease recurrence in patients with primary squamous cell carcinoma of the vulva. Gynecol Oncol 2005;97:828–833.

73. Homesley HD, Bundy BN, Sedlis A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group Study). Gynecol Oncol 1993;49:279–283.

74. van der Velden J, Hacker NF. Update on vulvar carcinoma. In: Rothenberg ML, ed. Gynecologic oncology: controversies and new developments. Boston, MA: Kluwer Academic Publishers, 1994:101–119.

75. Van der Velden J, van Lindert AC, Lammes FB, et al. Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer 1995;75:2885–2890.

76. Origoni M, Sideri M, Garsia S, et al. Prognostic value of pathological patterns of lymph node positivity in squamous cell carcinoma of the vulva stage III and IVA FIGO. Gynecol Oncol 1992;45:313–316.

77. Magrina JF, Gonzalez Bosquet J, Weaver AL, et al. Squamous cell carcinoma of the vulva stage IA: long-term results. Gynecol Oncol 2000;76:24–27.

78. Hacker NF, Leuchter RS, Berek JS, et al. Radical vulvectomy and bilateral inguinal lymphadenectomy through separate groin incisions. Obstet Gynecol 1981;58:574–579.

79. Iversen T, Abeler V, Aalders J. Individualized treatment of stage I carcinoma of the vulva. Obstet Gynecol 1981;57:85–89.

80. Hacker NF, Berek JS, Lagasse LD, et al. Individualization of treatment for stage I squamous cell vulvar carcinoma. Obstet Gynecol 1984;63:155–162.

81. Tantipalakorn C, Robertson G, Marsden DE, et al. Outcome and patterns of recurrence for International Federation of Gynecology and Obstetrics (FIGO) stages I and II squamous cell vulvar cancer. Obstet Gynecol 2009;113:895–901.

82. DeSimone CP, Van Ness JS, Cooper AL, et al. The treatment of lateral T1 and T2 squamous cell carcinomas of the vulva confined to the labium majus or minus. Gynecol Oncol 2007;104:390–395.

83. Farias-Eisner R, Cirisano FD, Grouse D, et al. Conservative and individualized surgery for early squamous carcinoma of the vulva: the treatment of choice for stages I and II (T1–2, N0–1, M0) disease. Gynecol Oncol 1994;53:33–38.

84. Heaps JM, Fu YS, Montz FJ, et al. Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990;38:309–314.

85. De Hullu JA, Hollema H, Lolkema S, et al. Vulvar carcinoma. The price of less radical surgery. Cancer 2002;95:2331–2338.

86. Chan JK, Sugiyama V, Pham H, et al. Margin distance and other clinico-pathologic prognostic factors in vulvar carcinoma: a multivariate analysis. Gynecol Oncol 2007;104:636–641.

87. Chan JK, Sugiyama V, Tajalli TR, et al. Conservative, clitoral preservation surgery in the treatment of vulvar squamous cell carcinoma. Gynecol Oncol 2004;95:152–156.

88. Simonsen E, Johnsson JE, Tropé C. Radical vulvectomy with warm-knife and open-wound techniques in vulvar malignancies. Gynecol Oncol 1984;17:22–31.

89. Potkul RK, Barnes WA, Barter JF, et al. Vulvar reconstruction using a mons pubis pedicle flap. Gynecol Oncol 1994;55:21–24.

90. Trelford JD, Deer DA, Ordorica E, et al. Ten-year prospective study in a management change of vulvar carcinoma. Am J Obstet Gynecol 1984;150:288–296.

91. Julian CG, Callison J, Woodruff JD. Plastic management of extensive vulvar defects. Obstet Gynecol 1971;38:193–198.

92. Barnhill DR, Hoskins WJ, Metz P. Use of the rhomboid flap after partial vulvectomy. Obstet Gynecol 1983;62:444–447.

93. Ballon SC, Donaldson RC, Roberts JA. Reconstruction of the vulva using a myocutaneous graft. Gynecol Oncol 1979;7:123–127.

94. Chafe W, Fowler WC, Walton LA, et al. Radical vulvectomy with use of tensor fascia lata myocutaneous flap. Am J Obstet Gynecol 1983;145:207–213.

95. Andersen BL, Hacker NF. Psychological adjustment after vulvar surgery. Obstet Gynecol 1983;62:457–462.

96. Andersen BL, Hacker NF. Psychosexual adjustment following pelvic exenteration. Obstet Gynecol 1983;61:457–462.

97. Kaplan AL, Kaufman RH. Management of advanced carcinoma of the vulva. Gynecol Oncol 1975;3:220–232.

98. Phillips B, Buchsbaum HJ, Lifshitz S. Pelvic exenteration for vulvovaginal carcinoma. Am J Obstet Gynecol 1981;141:1038–1044.

99. Cavanagh D, Shepherd JH. The place of pelvic exenteration in the primary management of advanced carcinoma of the vulva. Gynecol Oncol 1982;13:318–322.

100. Grimshaw RN, Aswad SG, Monaghan JM. The role of anovulvectomy in locally advanced carcinoma of the vulva. Int J Gynecol Cancer 1991;1:15.

101. Moore DH, Thomas GM, Montana GS, et al. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the GOG. Int J Radiat Oncol Biol Phys 1998;42:79–85.

102. Cunningham MJ, Goyer RP, Gibbons SK, et al. Primary radiation, cisplatin, and 5-fluorouracil for advanced squamous carcinoma of the vulva. Gynecol Oncol 1997;66:258–261.

103. Eifel PJ, Morris M, Burke TW, et al. Prolonged continuous infusion cisplatin and 5-fluorouracil for advanced squamous carcinoma of the vulva. Gynecol Oncol 1995;59:51–56.

104. Gerszten K, Selvaraj RN, Kelley J, et al. Preoperative chemoradiation for locally advanced carcinoma of the vulva. Gynecol Oncol 2005;99:640–644.

105. Lupi G, Raspagliesi F, Zucali R, et al. Combined preoperative chemoradiotherapy followed by radical surgery in locally advanced vulvar carcinoma. A pilot study. Cancer 1996;77:1472–1478.

106. Landoni F, Maneo A, Zanetta G, et al. Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma. Gynecol Oncol 1996;61:321–327.

107. Beriwal S, Coon D, Heron DE, et al. Preoperative intensity-modulated radiotherapy and chemotherapy for locally advanced vulvar carcinoma. Gynecol Oncol 2008;109:291–295.

108. van Doorn HC, Ansink A, Verhaar-Langereis M, et al. Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 2006;3:CD003752.

109. Hacker NF, Berek JS, Juillard GJF, et al. Preoperative radiation therapy for locally advanced vulvar cancer. Cancer 1984;54:2056–2061.

110. Boronow RC, Hickman BT, Reagan MT, et al. Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. II. Results, complications and dosimetric and surgical considerations. Am J Clin Oncol 1987;10:171–181.

111. Backstrom A, Edsmyr F, Wicklund H. Radiotherapy of carcinoma of the vulva. Acta Obstet Gynecol 1972;51:109–115.

112. Thomas G, Dembo A, DePetrillo A, et al. Concurrent radiation and chemotherapy in vulvar carcinoma. Gynecol Oncol 1989;34:263–267.

113. Marsden DE, Hacker NF. Contemporary management of primary carcinoma of the vulva. Surg Clin North Am 2001;81:799–813.

114. Atamdede F, Hoogerland D. Regional lymph node recurrence following local excision for microinvasive vulvar carcinoma. Gynecol Oncol 1989;34:125–128.

115. Vernooij F, Sie-Go DM, Heintz AP. Lymph node recurrence following stage IA vulvar carcinoma: two cases and a short overview of literature. Int J Gynecol Cancer 2007;17:517–520.

116. Stehman FB, Bundy BN, Thomas G, et al. Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1992;24:389–396.

117. van der Velden K, Ansink A. Primary groin irradiation vs primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev 2001;4:CD002224.

118. Hallak S, Ladi L, Sorbe B. Prophylactic inguinal-femoral irradiation as an alternative to primary lymphadenectomy in treatment of vulvar carcinoma. Int J Oncol 2003;31:1077–1085.

119. Iversen T, Aas M. Lymph drainage from the vulva. Gynecol Oncol 1983;16:179–189.

120. Hyde SE, Valmadre S, Hacker NF, et al. Squamous cell carcinoma of the vulva with bulky positive groin nodes-nodal debulking versus full groin dissection prior to radiation therapy. Int J Gynecol Cancer 2007;17:154–158.

121. Montana GS, Thomas GM, Moore DH, et al. Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2000;48:1007–1013.

122. Hoffman JS, Kumar NB, Morley GW. Prognostic significance of groin lymph node metastases in squamous carcinoma of the vulva. Obstet Gynecol 1985;66:402–405.

123. Terada K, Shimizu D, Wong J. Sentinel node dissection and ultrastaging in squamous cell carcinoma of the vulva. Gynecol Oncol 2000;76:40–44.

124. Ansink AC, Sie-Go DM, van der Velden J, et al. Identification of sentinel lymph nodes in vulvar carcinoma patients with the aid of a patent blue V injection: a multicenter study. Cancer 1999;86:652–656.

125. De Cicco C, Sideri M, Bartolomei M, et al. Sentinel node biopsy in early vulvar cancer. Br J Cancer 2000;82:295–299.

126. Selman TJ, Luesley DM, Acheson N, et al. A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer. Gynecol Oncol 2005;99:206–214.

127. Plante M, Renaud MC, Roy M. Sentinel node evaluation in gynecologic cancer. Oncology (Williston Park) 2004;18:75–87.

128. Hampl M, Hantschmann P, Michels W, et al. Validation of the accuracy of the sentinel lymph node procedure in patients with vulvar cancer: results of a multicenter study in Germany. Gynecol Oncol 2008;111:282–288.

129. Van der Zee AG, Oonk MH, de Hullu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008;26:884–889.

130. Levenback CF, Tian C, Coleman RL, et al. Sentinel node (SN) biopsy in patients with vulvar cancer: a Gynecologic Oncology Group (GOG) study. J Clin Oncol 2009;27(Suppl):abstr 5505.

131. Moore RG, Granai CO, Gajewski W, et al. Pathologic evaluation of inguinal sentinel lymph nodes in vulvar cancer patients: a comparison of immunohistochemical staining versus ultrastaging with hematoxylin and eosin staining. Gynecol Oncol 2003;91:378–382.

132. Hakam A, Nasir A, Raghuwanshi R, et al. Value of multilevel sectioning for improved detection of micrometastases in sentinel lymph nodes in invasive squamous cell carcinoma of the vulva. Anticancer Res 2004;24:1281–1286.

133. Narayansingh GV, Miller ID, Sharma M, et al. The prognostic significance of micrometastases in node-negative squamous cell carcinoma of the vulva. Br J Cancer 2005;92:222–224.

134. Merisio C, Berretta R, Gualdi M, et al. Radioguided sentinel lymph node detection in vulvar cancer. Int J Gynecol Cancer 2005;15:493–497.

135. Raspagliesi F, Ditto A, Fontanelli R, et al. False-negative sentinel node in patients with vulvar cancer: a case study. Int J Gynecol Cancer 2003;13:361–363.

136. Kowalewska M, Szkoda MT, Radziszewski J, et al. The frequency of human papillomavirus infection in polish patients with vulvar squamous cell carcinoma. Int J Gynecol Cancer 2010;20:434–437.

137. Levenback CF, van der Zee AG, Rob L, et al. Sentinel lymph node biopsy in patients with gynecologic cancers expert panel statement from the International Sentinel Node Society Meeting, February 21, 2008. Gynecol Oncol 2009;114:151–156.

138. Hopkins MP, Reid GC, Morley GW. Radical vulvectomy: the decision for the incision. Cancer 1993;72:799–803.

139. Gaarenstroom KN, Kenter GG, Trimbos JB, et al. Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gynecol Cancer 2003;13:522–527.

140. Gould N, Kamelle S, Tillmanns T, et al. Predictors of complications after inguinal lymphadenectomy. Gynecol Oncol 2001;82:329–332.

141. Podratz KC, Symmonds RE, Taylor WF. Carcinoma of the vulva: analysis of treatment failures. Am J Obstet Gynecol 1982;143:340–351.

142. Malfetano J, Piver MS, Tsukada Y. Stage III and IV squamous cell carcinoma of the vulva. Gynecol Oncol 1986;23:192–198.

143. Faul CM, Mirmow D, Huang Q, et al. Adjuvant radiation for vulvar carcinoma: improved local control. Int J Radiat Oncol Biol Phys 1997;38:381–389.

144. Parthasarathy A, Cheung MK, Osann K, et al. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. Gynecol Oncol 2006;103:1095–1099.

145. Oonk MHM, de Hullu JA, Hollema H, et al. The value of routine follow-up in patients treated for carcinoma of the vulva. Cancer 2003;98:2624–2629.

146. Stehman FB, Bundy BN, Ball H, et al. Sites of failure and time to failure in carcinoma of the vulva treated conservatively: a GOG study. Am J Obstet Gynecol 1996;174:1128–1133.

147. Cormio G, Loizzi V, Carriero C, et al. Groin recurrence in carcinoma of the vulva: management and outcome. Eur J Cancer Care 2010;19:302–307.

148. Crosbie EJ, Slade RJ, Ahmed AS. The management of vulval cancer. Cancer Treat Rev 2009;35:533–539.

149. Homesley HD. Management of vulvar cancer. Cancer 1995;76(Suppl 1):2159–2170.

150. Rouzier R, Haddad B, Plantier F, et al. Local relapse in patients treated for squamous cell vulvar carcinoma: incidence and prognostic values. Obstet Gynecol 2002;100:1159–1167.

151. Hopkins MP, Reid GC, Morley GW. The surgical management of recurrent squamous cell carcinoma of the vulva. Obstet Gynecol 1990;75:1001–1005.

152. Hruby G, MacLeod C, Firth I. Radiation treatment in recurrent squamous cell cancer of the vulva. Int J Radiat Oncol Biol Phys 2000;46:1193–1197.

153. Wagenaar HC, Colombo N, Vergote I, et al. Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. Gynecol Oncol 2001;81:348–354.

154. Durrant KR, Mangioni C, Lacave AJ, et al. Bleomycin, methotrexate, and CCNU in advanced inoperable squamous cell carcinoma of the vulva: a phase II study of the EORTC Gynaecological Cancer Cooperative Group (GCCG). Gynecol Oncol 1990;37:359–362.

155. Tropé C, Johnsson JE, Larsson G, et al. Bleomycin alone or combined with mitomycin C in treatment of advanced or recurrent squamous cell carcinoma of the vulva. Cancer Treat Rev 1980;64:639–642.

156. Cormio G, Loizzi V, Gissi F, et al. Cisplatin and vinorelbine chemotherapy in recurrent vulvar carcinoma. Oncology 2009;77:281–284.

157. Witteveen PO, van der Velden J, Vergote I, et al. Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer—Gynaecological Cancer Group). Ann Oncol 2009;20:1511–1516.

158. Ragnarsson-Olding BK, Nilsson BR, Kanter-Lewensohn LR, et al. Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features. Predictors of survival. Cancer 1999;86:1273–1293.

159. Weinstock MA. Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival. Am J Obstet Gynecol 1994;171:1225–1230.

160. Dunton CJ, Kautzky M, Hanau C. Malignant melanoma of the vulva: a review. Obstet Gynecol Surv 1995;50:739–746.

161. Hu DN, Yu GP, McCormick SA. Population-based incidence of vulvar and vaginal melanoma in various races and ethnic groups with comparisons to other site-specific melanomas. Melanoma Res 2010;20:153–158.

162. Podratz KC, Gaffey TA, Symmonds RE, et al. Melanoma of the vulva: an update. Gynecol Oncol 1983;16:153–168.

163. Trimble EL, Lewis JL Jr, Williams LL, et al. Management of vulvar melanoma. Gynecol Oncol 1992;45:254–258.

164. Phillips GL, Bundy BN, Okagaki T, et al. Malignant melanoma of the vulva treated by radical hemivulvectomy: a prospective study by the Gynecologic Oncology Group. Cancer 1994;73:2626–2632.

165. Chung AF, Woodruff JM, Lewis JL Jr. Malignant melanoma of the vulva: a report of 44 cases. Obstet Gynecol 1975;45:638–646.

166. Clark WH, From L, Bernardino EA, et al. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969;29:705–727.

167. Breslow A. Thickness, cross-sectional area and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970;172:902–908.

168. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–6206.

169. Aitken DR, Clausen K, Klein JP, et al. The extent of primary melanoma excision—a re-evaluation. How wide is wide? Ann Surg 1983;198:634–641.

170. Day CL, Mihm MC Jr, Sober AJ, et al. Narrower margins for clinical stage I malignant melanoma. N Engl J Med 1982;306:479–482.

171. Sugiyama VE, Chan JK, Shin JY, et al. Vulvar melanoma: a multivariable analysis of 644 patients. Obstet Gynecol 2007;110:296–301.

172. Phillips GL, Twiggs LB, Okagaki T. Vulvar melanoma: a microstaging study. Gynecol Oncol 1982;14:80–88.

173. Rose PG, Piver MS, Tsukada Y, et al. Conservative therapy for melanoma of the vulva. Am J Obstet Gynecol 1988;159:52–55.

174. Davidson T, Kissin M, Wesbury G. Vulvovaginal melanoma—should radical surgery be abandoned? Br J Obstet Gynaecol 1987;94:473–476.

175. Veronesi U, Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438–441.

176. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanoma (1–4 mm): results of a multi-institutional randomized surgical trial. Ann Surg 1993;218:262–269.

177. Morrow CP, Rutledge FN. Melanoma of the vulva. Obstet Gynecol 1972;39:745–752.

178. Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1–4 mm thick melanomas for patients 60 years of age or younger. Ann Surg 1996;224:255–263.

179. Balch CM, Soong SJ, Milton GW, et al. A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia. Ann Surg 1982;196:677–684.

180. Dunton JD, Berd D. Vulvar melanoma, biologically different from other cutaneous melanomas. Lancet 1999;354:2013–2014.

181. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307–1317.

182. Dhar KK, DAS N, Brinkman DA, et al. Utility of sentinel node biopsy in vulvar and vaginal melanoma: report of two cases and review of the literature. Int J Gynecol Cancer 2007;17:720–723.

183. Jaramillo BA, Ganjei P, Averette HE, et al. Malignant melanoma of the vulva. Obstet Gynecol 1985;66:398–401.

184. Beller U, Demopoulos RI, Beckman EM. Vulvovaginal melanoma: a clinicopathologic study. J Reprod Med 1986;31:315–319.

185. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.

186. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alpha-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000;18:2444–2458.

187. Kirkwood JM, Ibrahim J, Sosman JA, et al. High-dose interferon alpha-2b significantly prolongs relapse-free and overall compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB–III melanoma: results of Intergroup trial E1694/S9512/C509801. J Clin Oncol 2001;19:2370–2380.

188. Atallah E, Flaherty L. Treatment of metastatic malignant melanoma. Curr Treat Options Oncol 2005;6:185–193.

189. Bystryn JC, Reynolds SR. Melanoma vaccines: what we know so far. Oncology (Williston Park) 2005;19:97–108.

190. Masiel A, Buttrick P, Bitran J. Tamoxifen in the treatment of malignant melanoma. Cancer Treat Rep 1981;65:531–532.

191. Nesbit RA, Woods RL, Tattersall MH, et al. Tamoxifen in malignant melanoma. N Engl J Med 1979;301:1241–1242.

192. Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 2009;115:5836–5844.

193. Mendenhall WM, Amdur RJ, Grobmyer SR, et al. Adjuvant radiotherapy for cutaneous melanoma. Cancer 2008;112:1189–1196.

194. Scheistroen M, Tropé C, Kaern J, et al. Malignant melanoma of the vulva: evaluation of prognostic factors with emphasis on DNA ploidy in 75 patients. Cancer 1995;75:72–80.

195. Woolcott RJ, Henry RJW, Houghton CRS. Malignant melanoma of the vulva: Australian experience. J Reprod Med 1988;33:699–702.

196. Piura B, Egan M, Lopes A, et al. Malignant melanoma of the vulva: a clinicopathologic study of 18 cases. J Surg Oncol 1992;50:234–240.

197. Look KY, Roth LM, Sutton GP. Vulvar melanoma reconsidered. Cancer 1993;72:143–146.

198. Cardosi RJ, Speights A, Fiorica JV, et al. Bartholin’s gland carcinoma: a 15-year experience. Gynecol Oncol 2001;82:247–251.

199. Copeland LJ, Sneige N, Gershenson DM, et al. Bartholin gland carcinoma. Obstet Gynecol 1986;67:794–801.

200. Visco AG, Del Priore G. Postmenopausal Bartholin gland enlargement: a hospital-based cancer risk assessment. Obstet Gynecol 1996;87:286–290.

201. Barclay DL, Collins CG, Macey HB. Cancer of the Bartholin gland: a review and report of 8 cases. Obstet Gynecol 1964;24:329–336.

202. López-Varela E, Oliva E, McIntyre JF, et al. Primary treatment of Bartholin’s gland carcinoma with radiation and chemoradiation: a report on ten consecutive cases. Int J Gynecol Cancer 2007;17:661–667.

203. Wheelock JB, Goplerud DR, Dunn LJ, et al. Primary carcinoma of the Bartholin gland: a report of 10 cases. Obstet Gynecol 1984;63:820–824.

204. Copeland LJ, Sneige N, Gershenson DM, et al. Adenoid cystic carcinoma of Bartholin gland. Obstet Gynecol 1986;67:115–120.

205. Yang SY, Lee JW, Kim WS, Jung et al. Adenoid cystic carcinoma of the Bartholin’s gland: report of two cases and review of the literature. Gynecol Oncol 2006;100:422–425.

206. Fu YS, Reagan JW. Benign and malignant epithelial tumors of the vulva. In: Fu YS, Reagan JW, eds. Pathology of the uterine cervix, vagina, and vulva. Philadelphia, PA: WB Saunders, 1989:138–192.

207. Underwood JW, Adcock LL, Okagaki T. Adenosquamous carcinoma of skin appendages (adenoid squamous cell carcinoma, pseudoglandular squamous cell carcinoma, adenoacanthoma of sweat gland of Lever) of the vulva: a clinical and ultrastructural study. Cancer1978;42:1851–1858.

208. Dudzinski MR, Askin FB, Fowler WC. Giant basal cell carcinoma of the vulva. Obstet Gynecol 1984;63:57S–60S.

209. Benedet JL, Miller DM, Ehlen TG, et al. Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients. Obstet Gynecol 1997;90:765–768.

210. de Giorgi V, Salvini C, Massi D, et al. Vulvar basal cell carcinoma: retrospective study and review of literature. Gynecol Oncol 2005;97:192–194.

211. Jimenez HT, Fenoglio CM, Richart RM. Vulvar basal cell carcinoma with metastasis: a case report. Am J Obstet Gynecol 1975;121:285–286.

212. Sworn MJ, Hammond GT, Buchanan R. Metastatic basal cell carcinoma of the vulva: a case report. Br J Obstet Gynaecol 1979;86:332–334.

213. Hoffman MS, Roberts WS, Ruffolo EH. Basal cell carcinoma of the vulva with inguinal lymph node metastases. Gynecol Oncol 1988;29:113–119.

214. Palladino VS, Duffy JL, Bures GJ. Basal cell carcinoma of the vulva. Cancer 1969;24:460–470.

215. Isaacs JH. Verrucous carcinoma of the female genital tract. Gynecol Oncol 1976;4:259–269.

216. Partridge EE, Murad R, Shingleton HM, et al. Verrucous lesions of the female genitalia. II. Verrucous carcinoma. Am J Obstet Gynecol 1980;137:419–424.

217. Kondi-Paphitis A, Deligeorgi-Politi H, Liapis A, et al. Human papillomavirus in verrucous carcinoma of the vulva: an immunopathological study of three cases. Eur J Gynecol Obstet 1998;19:319–320.

218. Gualco M, Bonin S, Foglia G, et al. Morphologic and biologic studies on ten cases of verrucous carcinoma of the vulva supporting the theory of a discrete clinicopathologic entity. Int J Gynecol Cancer 2003;13:317–324.

219. Haidopoulos D, Diakomanolis E, Rodolakis A, et al. Coexistence of verrucous and squamous carcinoma of the vulva. Aust N Z J Obstet Gynaecol 2005;45:60–63.

220. Gallousis S. Verrucous carcinoma: report of three vulvar cases and a review of the literature. Obstet Gynecol 1972;40:502–507.

221. Japaze H, Van Dinh TV, Woodruff JD. Verrucous carcinoma of the vulva: study of 24 cases. Obstet Gynecol 1982;60:462–466.

222. Demian SDE, Bushkin FL, Echevarria RA. Perineural invasion and anaplastic transformation of verrucous carcinoma. Cancer 1973;32:395–401.

223. Ulutin HC, Zellars RC, Frassica D. Soft tissue sarcoma of the vulva: a clinical study. Int J Gynecol Cancer 2003;13:528–531.

224. Nielsen GP, Rosenberg AE, Koerner FC, et al. Smooth-muscle tumors of the vulva: a clinicopathological study of 25 cases and review of the literature. Am J Surg Pathol 1996;20:779–793.

225. Tavassoli FA, Norris HJ. Smooth muscle tumors of the vulva. Obstet Gynecol 1979;53:213–217.

226. Ulbright TM, Brokaw SA, Stehman FB, et al. Epithelioid sarcoma of the vulva. Cancer 1983;52:1462–1469.

227. Bell J, Averette H, Davis J, et al. Genital rhabdomyosarcoma: current management and review of the literature. Obstet Gynecol Surv 1986;41:257–263.

228. Hays DM, Shimada H, Raney RB Jr, et al. Clinical staging and treatment results in rhabdomyosarcoma of the female genital tract among children and adolescents. Cancer 1988;61:1893–1903.

229. Harris NL, Scully RE. Malignant lymphoma and granulocytic sarcoma of the uterus and vagina. Cancer 1984;53:2530–2545.

230. Dudley AG, Young RH, Lawrence WD, et al. Endodermal sinus tumor of the vulva in an infant. Obstet Gynecol 1983;61:76S–79S.

231. Bottles K, Lacy CG, Goldberg J, et al. Merkel cell carcinoma of the vulva. Obstet Gynecol 1984;63:61S–65S.

232. Husseinzadeh N, Wesseler T, Newman N, et al. Neuroendocrine (Merkel cell) carcinoma of the vulva. Gynecol Oncol 1988;29:105–112.

233. Khoury-Collado F, Elliott KS, Lee YC, et al. Merkel cell carcinoma of the Bartholin’s gland. Gynecol Oncol 2005;97:928–931.

234. Bock JE, Andreasson B, Thorn A, et al. Dermatofibromasarcoma protuberans of the vulva. Gynecol Oncol 1985;20:129–135.

235. Dehner LP. Metastatic and secondary tumors of the vulva. Obstet Gynecol 1973;42:47–57.

Page

Contents

If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!