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National Cancer Institute
Ultima Vez Modificado: 9 de noviembre del 2012
Vulvar cancer accounts for about 5% of cancers of the female genital system in the United States.
Estimated new cases and deaths from vulvar cancer in the United States in 2012: 1
The vulva is the area immediately external to the vagina, including the mons pubis, labia, clitoris, Bartholin glands, and perineum. The labia majora are the most common site of vulvar carcinoma involvement and account for about 50% of cases. The labia minora account for 15% to 20% of vulvar carcinoma cases. The clitoris and Bartholin glands are less frequently involved. 2 Lesions are multifocal in about 5% of cases. About 90% of vulvar carcinomas are squamous cell cancers. 3 This evidence summary covers squamous cell cancers and vulvar intraepithelial neoplasias (VIN), some of which are thought to be precursors to invasive squamous cell cancers.
Survival is dependent on the pathologic status of the inguinal nodes and whether spread to adjacent structures has occurred. The size of the primary tumor is less important in defining prognosis. 4 In patients with operable disease without nodal involvement, the overall survival (OS) rate is 90%; however, in patients with nodal involvement, the 5-year OS rate is approximately 50% to 60%. 5
Overall, about 30% of patients with operable disease have lymph nodal spread.
In many cases, the development of vulvar cancer is preceded by condyloma or squamous dysplasia. The prevailing evidence favors human papillomavirus (HPV) as a causative factor in many genital tract carcinomas. 10 The HPV-related basaloid and warty types are associated with VIN. About 75% to 100% of basaloid and warty carcinomas harbor HPV infection. In addition to the much higher prevalence of HPV in these subtypes than in the keratinizing subtypes, the basaloid and warty subtypes also share many common risk factors with cervical cancers, including multiplicity of sex partners, early age at initiation of sexual intercourse, and history of abnormal Pap smears. 11 HPV-associated VIN (termed usual-type VIN when high-grade 2 and 3) is most common in women younger than 50 years, whereas non-HPV VIN (termed differentiated-type VIN when high-grade 3) is most common in older women. The former lesion-type VIN grade 1 is no longer classified as a true VIN. 12 13
The pattern of spread is influenced by the histology. Well-differentiated lesions tend to spread along the surface with minimal invasion, whereas anaplastic lesions are more likely to be deeply invasive. Spread beyond the vulva is either to adjacent organs such as the vagina, urethra, and anus, or via the lymphatics to the inguinal and femoral lymph nodes, followed by the deep pelvic nodes. Hematogenous spread appears to be uncommon.
Presented below is an adaptation of the histologic classification of vulvar disease and precursor lesions of cancer of the vulva developed by the International Society for the Study of Vulvar Disease. 1 This evidence summary deals with vulvar intraepithelial neoplasias (VIN) and invasive carcinomas.
The diagnosis of vulvar cancer is made by biopsy. The patient may be examined under anesthesia. Cystoscopy, proctoscopy, x-ray examination of the lungs, and intravenous urography (as needed), are used for staging purposes. Suspected bladder or rectal involvement must be confirmed by biopsy. The staging system does not apply to malignant melanoma of the vulva, which is staged like melanoma of the skin. 1
The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define vulvar cancer; the FIGO system is most commonly used. 1 2 Stage is based upon pathology staging at the time of surgery or prior to any radiation or chemotherapy, if they are the initial treatment modalities. 3
|Stage I||Tumor confined to the vulva.|
|IA||Lesions 2 cm in size, confined to the vulva or perineum and with stromal invasion 1.0 mmb, no nodal metastasis.|
|IB||Lesions >2 cm in size or with stromal invasion >1.0 mmb, confined to the vulva or perineum, with negative nodes.|
|Stage II||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||(i) With 1 lymph node metastasis (5 mm), or|
|(ii) 12 lymph node metastasis(es) (<5 mm).|
|IIIB||(i) With 2 or more lymph node metastases (5 mm), or|
|(ii) 3 or more lymph node metastases (<5 mm).|
|IIIC||With positive nodes with extracapsular spread.|
|Stage IV||Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures.|
|IVA||Tumor invades any of the following:|
|(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or|
|(ii) fixed or ulcerated inguino-femoral lymph nodes.|
|IVB||Any distant metastasis including pelvic lymph nodes.|
Grade is reported in registry systems. A two-, three-, or four-grade system may be used. If not specified, the following system is generally used: 1
Standard primary treatment for vulvar cancer is surgery. Radiation is usually added to surgery in patients with stage III or IV disease. 1 2 3 Newer strategies have integrated surgery, radiation therapy, and chemotherapy and tailor the treatment to the extent of clinical and pathologic disease. Patterns of practice in combining these treatments vary. 4
Since invasive and preinvasive neoplasms of the vulva may be HPV-induced and the carcinogenic effect may be widespread in the vulvar epithelium, patients should be followed regularly for symptoms or signs of recurrence. Because there are few patients with advanced disease (stages III and IV), only limited data are available on treatment efficacy in this setting, and there is no standard chemotherapy regimen for these patients. Physicians should offer eligible patients with stage III or IV disease participation in clinical trials.
Information about ongoing clinical trials is available on the NCI Web site.
Until the 1980s, the standard therapeutic approach to therapy for invasive locoregional vulvar carcinomas was radical surgery, including complete en bloc resection of the vulva and regional lymph nodes. Because of the high attendant complication rates, wound healing problems, lymphedema, and functional deficits, the trend since then has been toward more limited surgery, often combined with radiation therapy. 5 (Refer to the Role of Radiation Therapy section of this summary for more information.)
In tumors clinically confined to the vulva or perineum, radical local excision with a margin of at least 1 cm has generally replaced radical vulvectomy; separate incision has replaced en bloc inguinal node dissection; ipsilateral inguinal node dissection has replaced bilateral dissection for laterally localized tumors; and femoral lymph node dissection has been omitted in many cases. However, the different surgical techniques have not been directly compared in randomized controlled trials. In addition, even the nonrandomized studies suffer from lack of uniform staging definitions and clear descriptions of lymph node dissection or ancillary radiation. 6[Levels of evidence: 3iiiDii, 3iiiDiv] The evidence base is therefore limited.
Another strategy to minimize the morbidity incurred by groin-node dissection in patients with early clinical-stage disease is sentinel node dissection, reserving groin dissection for those with metastases to the sentinel node(s).
In a multicenter case series, 403 patients with primary vulvar squamous cell cancers smaller than 4 cm and clinically negative groin nodes underwent 623 sentinel node dissections using radioactive tracer and blue dye for sentinel node identification. 7 All patients had radical resection of the primary tumor. Node metastases were identified in 26% of sentinel node procedures, and these patients went on to full inguinofemoral lymphadenectomy. The patients with negative sentinel nodes were followed with no further therapy.
Local morbidity was much lower in patients who underwent sentinel node dissection than in patients with positive sentinel nodes who also underwent inguinofemoral lymphadenectomy: wound breakdown 11.7% vs. 34.0%; cellulitis 4.5% vs. 21.3%; chronic lymphedema 1.9% vs. 25.2%, respectively (P < .0001 for all comparisons). Mean hospital stay was also shorter: 8.4 vs. 13.7 days (P < .0001). After two local recurrences in 17 patients with multifocal primary tumors, the protocol was amended to only allow patients with unifocal tumors into the study. Actuarial groin recurrence for all patients with negative sentinel node dissections at 2 years was 3% (95% confidence interval [CI], 1%6%) and 2% (95% CI, 1%5%) for those with unifocal primary tumors. 7[Level of evidence: 3iiiDiv]
Therefore, sentinel node dissection may be useful when performed by a surgeon experienced in the procedure, and it may avoid the need for full groin node dissection or radiation in patients with clinically nonsuspicious lymph nodes. (Refer to the Role of Radiation Therapy section of this summary for more information.)
Groin lymph node metastases are present in approximately 20% to 35% of patients with tumors clinically confined to the vulva and with clinically negative nodes. 7 8 Lymph node dissection is traditionally part of the primary surgical therapy in all but the smallest tumors. However, a major cause of morbidity after surgery is groin node dissection, which is associated with high rates of wound breakdown, lymphocele formation, and chronic lymphedema. Some investigators recommend radiation therapy as a means to avoid the morbidity of lymph node dissection, but it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early stage disease.
A randomized trial to address the radiation therapy issue in patients with clinically localized vulvar cancer has been reported. 8 9 In that study, women with disease clinically confined to the vulva, who did not have groin lymph nodes clinically suspicious for metastases, underwent radical vulvectomy followed by either groin radiation (50 Gy in 2 Gy fractions) or groin dissection (plus groin radiation if nodes were pathologically involved).
Although the planned accrual was 300 patients, the study was stopped after 58 women were randomly assigned to it because of worse outcomes in the radiation therapy arm. Five (18.5%) of 27 women in the radiation therapy arm and 0 of 25 women in the surgery arm had a groin recurrence, but this difference was not statistically significant (relative risk [RR], 10.21; 95% CI, 0.59175.78). There were ten deaths in the radiation therapy arm versus three deaths in the groin dissection study arm (RR, 4.31; 95% CI, 1.0318.15). Disease-specific mortality was not statistically significantly different between the two arms; however, there were eight versus two vulvar cancer-related deaths (including one related to groin dissection), in the radiation therapy arm and groin dissection arm, respectively (RR, 3.70; 95% CI, 0.8715.80). 8 9[Level of evidence 1iiA] There were fewer cases of lymphedema in the radiation therapy arm (0 vs. 7) and shorter hospital stays. The dose penetration of the radiation (3 cm for full dose) has been criticized as inadequate. 8 In summary, the trial was stopped prematurely, and little can be said about the relative efficacy of the two treatment approaches. 8
Pelvic radiation has been compared to pelvic node dissection in the setting of documented groin node-positive disease. Patients with clinical stage I to stage IV primary squamous cell carcinoma of the vulva in whom groin nodal metastases were found at radical vulvectomy and bilateral groin node dissection were randomly assigned during the surgical procedure to receive either ipsilateral pelvic node resection or pelvic radiation (45 Gy50 Gy at 1.8 Gy2.0 Gy per fraction). 10 Because of a perceived emerging benefit of radiation, the planned accrual of 152 was stopped after 114 patients were randomly assigned. However, the apparent benefit of radiation was subsequently attenuated with further follow-up.
After a median follow-up of 74 months, the 6-year overall survival (OS) rate was 51% in the radiation arm versus 41% in the pelvic node dissection arm (hazard ratio [HR], 0.61; 95% CI, 0.31.3; P = .18). Vulvar cancer-specific mortality was statistically significantly lower in the radiation study arm: 29% versus 51% in the pelvic node resection arm (HR, 0.49; 95% CI, 0.280.87; P = .015) However, there were 14 intercurrent deaths in the radiation therapy arm versus two deaths in the pelvic dissection study arm. Late chronic lymphedema was similar in the radiation therapy and pelvic dissection groups arms (16% vs. 22%), respectively. 10[Level of evidence: 1iiB]
There is no standard chemotherapy for vulvar cancer, and reports describing the use of this modality in the setting of metastatic or recurrent disease are anecdotal. 5 Extrapolating from regimens used for anal or cervical squamous cell cancers, chemotherapy has been studied in combination with radiation in the neoadjuvant setting or as primary therapy in advanced disease. Chemotherapy regimens have included various combinations of 5-fluorouracil (5-FU), cisplatin, mitomycin-C, or bleomycin. 5 There is no clear evidence of improvement in survival or palliation. Given the advanced age and comorbidity of many patients with advanced or recurrent vulvar cancer, patient tolerance is a major consideration in the use of these agents.
A systematic review of the use of neoadjuvant chemoradiation in patients who were considered inoperable or who would have required extensive surgery, such as pelvic exenteration, colostomy, or urinary diversion revealed no randomized trials. 15 Five nonrandomized studies that met the inclusion criteria of neoadjuvant chemoradiation administered in this population with an intent to permit curative surgery were reviewed. 16 17 18 19 20 The five studies used four different chemoradiation schedules and different radiation therapy dose-fractionation techniques. In the four studies using 5-FU + cisplatin or 5-FU + mitomycin-C, the operability rate after chemoradiation ranged from 63% to 92%. 16 17 18 19
In the one study using bleomycin, the operability rate was only 20%. 20 In summary, there is evidence that neoadjuvant chemoradiation with 5-FU plus either cisplatin or mitomycin-C may convert patients to more operable status, but the evidence base is limited by study design. In addition to a paucity of randomized trials, interpretation of these studies is complicated by the lack of a standard definition of inoperability. 4[Level of evidence: 3iiiDiv] Treatment-related toxicity is substantial.
There is also limited evidence regarding the use of neoadjuvant chemoradiation in advanced operable cases of vulvar cancer, but the available data do not suggest an advantage to this approach. A systematic review found only one randomized trial that addressed this issue, and it was published only in abstract form. 4 21 In that trial, 68 patients with advanced vulvar cancer (T2 >4 cm, T3, any case with positive lymph nodes) were randomly assigned to receive preoperative neoadjuvant radiation therapy (50 Gy) concomitantly with 5-FU plus mitomycin-C versus primary surgery. Neoadjuvant therapy-related serious toxicity was high (13 of 24 patients; 10 patients had wound diastasis). After a mean follow-up of 42 months, the 5-year OS rates in the neoadjuvant and primary surgery groups were 30% and 49%, respectively (RR of death, 1.39; 95% CI, 0.942.06; P = .19). 4 21[Level of evidence 1iiA]
Traditionally, there were three grades of vulvar intraepithelial neoplasia (VIN). However, there is little evidence that all three grades are part of the same biologic continuum or that Grade 1 is even a cancer precursor. In 2004, the International Society for the Study of Vulvar Disease changed its terminology, reserving the designation VIN for two categories of lesions based on morphologic appearance: 1
The term VIN 1 was eliminated. 1 Disease that was previously called VIN 1 (grade I) is generally observed without definitive treatment.
High-grade VIN is usually managed with active therapy because of a higher risk for progression to invasive disease. 2 Estimates of progression rates are imprecise. A systematic literature review that included 88 untreated patients with VIN 3 reported a 9% progression rate (8 of 88 patients) to invasive vulvar cancer during 12 to 96 months of observation. In the same review, the spontaneous regression rate was 1.2%, all of which occurred in women younger than 35 years. 3 However, in a single-center study, 10 of 63 (16%) untreated women with VIN 2 or VIN 3 progressed to invasive cancer after a mean of 3.9 years. 4
VIN lesions may be multifocal or confluent and extensive. It is important to perform multiple biopsies in treatment planning to exclude occult invasive disease. VIN located in nonhairy areas can be considered an epithelial disease; however, VIN occupying hairy sites usually involves the pilosebaceous apparatus and requires a greater depth of destruction or excision because it can track along hair roots.
The principal treatment approach is surgical, but there is no consensus on the optimal surgical procedure. The goal is to remove or destroy the entire VIN lesion while preserving vulvar anatomy and function. Simple vulvectomy yields a 5-year survival rate of essentially 100% but is seldom indicated. Other more-limited surgical procedures, including separate excision of multiple lesions, are less deforming. 5 The choice of treatment depends on the extent of the disease and the preference or experience of the treating physician. There are no reliable data comparing the efficacy and safety of the various surgical approaches.
A systematic literature review identified only a single randomized trial comparing any of the surgical approaches. 2 In that trial, 30 women with high-grade VIN were randomly assigned to receive carbon dioxide (CO2) laser ablation versus ultrasound surgical aspiration (USA). 6 There were no statistically significant differences in disease recurrence, painful dysuria or burning, adhesions, or eschar formation between the two treatments after 1 year of follow-up. Scarring was observed in 5 of 16 women treated with laser ablation and 0 of14 women treated with USA (P < .01), but consequences of the scarring on sexual function or quality of life were not reported. 6[Level of evidence 1iiDii] The trial was too small to draw reliable conclusions about the relative efficacy of these surgical techniques. The remainder of the surgical literature is derived from case series and is prone to important study biases.[Level of evidence 3iiiD]
Whatever procedure is used, patients are at substantial risk of recurrence, particularly when the lesions are high grade or multifocal. 7 The most common sites of recurrence are the perianal skin, presacral area, and clitoral hood. About 4% of patients treated for VIN subsequently develop invasive cancer. 8 9
Because of the physical and psychosexual morbidity associated with many vulvar surgical procedures, nonsurgical approaches have been studied. Some of these approaches, including topical 5-fluorouracil, gamma-interferon, bleomycin, and trinitrochlorobenzene, have been largely abandoned because of intolerable local side effects, such as pain, irritation, and ulceration, or high recurrence rates. 10 11 Photodynamic therapy, using topically applied 5-aminolevulinic acid as the sensitizing agent for 635 nm laser light, has also been studied. However, data are limited to small case series with variable response rates. 12 13[Level of evidence: 3iiiDiv]
More recently, among women with high-grade VIN, substantial response rates and acceptable tolerability were reported for topical imiquimod 5%, an immune-response modifier with activity in HPV 6/11-associated vulvar condylomata. Three randomized placebo-controlled trials (including a total of 104 patients) with clinical response as their primary endpoints.[Level of evidence: 1iDiv] have been reported in either peer-reviewed-journal or abstract format. 14 15 16 17 The results of these trials were summarized in a systematic review. 11 At 5 to 6 months, the complete and partial response rates in patients were 36 of 62 and 18 of 62 in the combined imiquimod arms versus 0 of 42 and 1 of 42 in the combined placebo arms (relative risk [RR], 11.95; 95% confidence interval [CI], 3.2144.51).
In the only trial reporting progression to cancer (at 12 months), there was no difference in progression rate, but the trial was severely underpowered because only 3 of the total 52 women included developed invasive disease by 12 months. 16 The only trial reporting quality of life 16 showed no difference between imiquimod and placebo. Local side effects of imiquimod included pain, edema, erythema, and a single case of erosion. However, no patients had to discontinue treatment as a result of toxicity.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 vulvar cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
(Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, lymph node dissection, and radiation therapy.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I vulvar cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
(Refer to the Treatment Option Overview section of this summary for a more detailed discussion of the roles of surgery, node dissection, and radiation therapy.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II vulvar cancer. The lis
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