Mark Milam and Charles F. Levenback
Vulvar cancers are among the least common gynecologic malignancies. Radical surgery is the primary approach for most patients, and advances in neoadjuvant chemotherapy and radiation may decrease operative morbidity in those patients with locally advanced disease. This chapter focuses on the diagnosis and management of vulvar cancer, with special emphasis on changes in staging and sentinel lymph node biopsy (SLNB). Due to the recent modifications in International Federation of Gynecology and Obstetrics (FIGO) staging, the reported outcomes in this chapter reflect the older staging criteria.
1. Vulvar cancer is the fourth most common gynecologic malignancy, with approximately 3900 diagnoses in 2010.
2. Prevention strategies for cervical dysplasia using the human papillomavirus (HPV) vaccine may decrease the incidence of vulvar dysplasia and vulvar carcinoma.
3. The median age of patients with vulvar cancer is 68 years of age, with approximately 1 in 387 women at risk for a vulvar cancer diagnosis during their lifetime.
4. Risk factors for invasive vulvar cancer depend on age of diagnosis and may include HPV infection, smoking, immunosuppression, and potentially lichen sclerosis.
Vulvar cancer is the fourth most common gynecologic malignancy in the United States, with approximately 3900 diagnoses in 2010.1 The incidence of this disease increases with age and peaks in the seventh decade of life. The majority of vulvar cancers are of squamous histology, and many develop from progressively worsening dysplastic conditions known as vulvar intraepithelial neoplasia (VIN).
In the United States, the demographic characteristics of the 12 areas associated with the Surveillance, Epidemiology, and End Results (SEER) study demonstrate that the median age for patients with a diagnosis of vulvar cancer is 68 years.2 Only 26.6% of patients have a diagnosis at age younger than 55 years, with most women being in their 60s and 70s at diagnosis.2 Recently, Kumar and colleagues3observed that approximately 19% of women who have a diagnosis of vulvar cancer are younger than 50 years. These women appear to have an overall better prognosis because their tumors are characterized by lower stage and superficial invasion.
Vulvar cancer may arise through 2 distinct pathways, each with its respective risk factors. The first is characterized by nonkeratinizing carcinomas and is more commonly diagnosed in younger women with VIN and concurrent HPV infection. The second pathway results in keratinizing, well-differentiated carcinomas; these are more frequently diagnosed in older women with a background of vulvar dystrophies such as lichen sclerosus. HPV infection is rarely identified in these women.
HPV infection remains a significant risk factor for the development of vulvar dysplasia and subsequent malignant transformation in the first type of invasive vulvar carcinoma.4 Recent advances in immunization may decrease the incidence of VIN and vulvar cancer through prevention of HPV infection. A recent 4-year trial has demonstrated the benefit of the prophylactic HPV quadrivalent vaccine against low-grade vulvar lesions. These data indicate an efficacy of approximately 100% for vulvar epithelial lesions specifically associated with HPV subtypes 6, 11, 16, and 18 and an efficacy of approximately 75% for vulvar epithelial lesions associated with any HPV type.5 In the future, the current HPV vaccinations may reduce the overall burden of vulvar cancer. Because there is a prolonged interval between HPV infection and clinical manifestation of vulvar disease, it can potentially be decades before the clinical impact of HPV vaccination is fully appreciated.
Additional risk factors for the development of vulvar cancer include smoking, immunosuppression, and potentially lichen sclerosis. Tobacco smoking in particular promotes carcinogenesis in HPV-associated disease.6Immunosuppression is a risk factor likely due to HPV infection and persistence; women with human immunodeficiency virus infection, for example, have an increased incidence of vulvar cancers.7Finally, lichen sclerosis is a benign chronic inflammatory vulvar lesion that is associated with vulvar cancer, especially in older women. A causative relationship between lichen sclerosis and invasive vulvar cancer remains controversial, although recent evidence suggests that inactivation of the p53 tumor suppressor gene in these lesions promotes progression to malignancy.8
1. Vulvar cancer often presents with a pruritic or painful lesion.
2. Early biopsy of suspicious vulvar lesions is critical to diagnosis of malignant disease.
3. Clinical features of vulvar cancer are variable, and clinicians should have low thresholds to recommend biopsy of concerning lesions.
4. Physical examination of lymph nodes to determine metastatic disease is unreliable.
Early biopsy of suspicious vulvar lesions is critical to the diagnosis of vulvar cancer. Patients who present with concerns of pruritic or painful vulvar conditions should be evaluated for the possibility of vulvar cancer with a complete pelvic examination and office biopsy. Postmenopausal women who report pruritic vulvar pain that does not resolve with conservative measures are of special concern, as such symptoms may be an early sign of vulvar cancer. Vulvar cancer is a rare disease; hence patients and clinicians may not be aware of the possibility of development of this tumor, and treatment delay is possible. Reluctance in reporting gynecologic symptoms to clinicians may also make it difficult to articulate concern and lead some women to minimize their symptoms.
The clinician must consider several differential diagnoses when women present with a chief complaint of vulvar pruritus. These are often separated into acute and chronic conditions: Acute conditions may involve infectious processes and possible contact dermatitis; chronic conditions may involve dermatoses, including lichen sclerosis and general atrophy, and also HPV infections.9 The vulvar manifestation of systemic disease is possible, including but not limited to Crohn disease and other autoimmune conditions9 (Table 9-1).
Table 9-1 Differential Diagnoses of Pruritic Vulvar Conditions
Contact dermatitis (allergic or irritant)
Scabies and/or pediculosis
Atopic and contact dermatitis
Lichen sclerosis, lichen planus, lichen simplex
Vulvar intraepithelial neoplasia or vulvar cancer
Human papillomavirus infection
Vulvar manifestations of systemic disease
Human immunodeficiency virus
Modified from ACOG Practice Bulletin No. 93: diagnosis and management of vulvar skin disorders. Obstet Gynecol. 2008;111:1243-1253.
It must be underscored that the liberal use of biopsies when evaluating a concerning vulvar lesion will afford definitive pathologic identification of a benign or malignant etiology. Early diagnosis of a small vulvar cancer can result in a less aggressive surgical procedure, with minimal morbidity and decreased risk for potential adjuvant therapy (Figure 9-1). Conversely, a prolonged delay in diagnosis may lead to advancing stage of disease, with more extensive and radical surgical intervention and the potential need for adjuvant radiation therapy and potential chemotherapy (Figure 9-2). Rectal or urinary bleeding is suggestive of tumor involvement of the colorectal and/or urinary system, and such metastases will influence the treatment plan and lead to consideration of neoadjuvant chemotherapy and surgery for curative attempts.
FIGURE 9-1. Early-stage vulvar cancer.
FIGURE 9-2. Late-stage vulvar cancer.
The majority of vulvar cancer diagnoses appear to be localized without regional lymph node involvement. SEER data indicate that approximately 61% of all vulvar cancers are confined to the vulva without metastases to the inguinal-femoral lymph node basins.2 Lymph node metastasis confers worse prognosis, and therefore clear knowledge of nodal metastatic disease is critical for treatment planning. Physical examination of the inguinal/femoral nodes alone is poorly sensitive for the detection of metastases and should not be used as criteria for evaluation of patients with a known diagnosis of vulvar cancer.10
Imaging may assist in the preoperative diagnosis of metastatic disease to the regional lymph nodes and is more sensitive than physical examination and palpation alone. These modalities include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET),11 and lymphoscintigraphy12 (Figure 9-3). In general, MRI affords superior evaluation of soft tissues, and contrast-enhanced MRI techniques in particular provide improved visualization of lymph node involvement.13 PET testing, fused with CT images, can also identify potential metastatic lesions in the inguinal-femoral lymph nodes; limitations include potential false-positive findings due to inflammatory processes, with potential inappropriate adjuvant therapy if confirmatory lymphatic dissection is not performed.11 It is important to note that neither the 1988 nor 2009 FIGO staging criteria for vulvar cancer allow inclusion of preoperative imaging results.
FIGURE 9-3. Metastatic disease demonstrated in preoperative lymphoscintigraphy.
1. Squamous cell carcinoma is the most common histology in vulvar cancers, followed by melanoma and adenocarcinoma.
2. Depth of invasion is measured from the epithelial stromal junction of the most superficial dermal papillae to the deepest point of invasion.
3. FIGO staging has changed to reflect metastatic spread patterns that emphasize the prognostic significance of the number and morphology of nodal metastases.
The most common vulvar cancer is squamous cell (approximately 83% of diagnoses), followed by adeno-carcinoma (8% of diagnoses), and melanoma (6%).2, 3,14,15 Most vulvar cancers arise from the squamous epithelium of the labia majora and minora, clitoris, or the anterior and posterior fourchette. These areas are characterized by a junction between the keratinized stratified squamous epithelium and the nonkeratinized squamous mucosa of the vagina. Frequently, invasive squamous cell carcinomas of the vulva have adjacent VIN or lichen sclerosis.
Squamous cell carcinomas of the vulva may metasta-size via several routes: local expansion, with extension into adjacent tissues; lymphatic spread to the regional nodal tissues; and hematogenous metastases to distant sites. These patterns of metastases are reflected in the 2009 revised FIGO staging for vulvar carcinoma (Table 9-2). Local growth may involve extension of carcinoma to the urethra, vagina, and anus. Lymphatic embolization occurs first to the regional inguinal-femoral lymph nodes in the groin; further spread to the pelvic and/or para-aortic lymph nodes is considered as a distant metastasis. Finally, hematogenous dissemination to lung, bone, or liver is uncommon with initial presentation and may be observed with recurrent disease.
Table 9-2 Revised FIGO Surgical Staging Criteria for Carcinoma of the Vulva17
Stage I: Tumor confined to the vulva IA Lesions ≤ 2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm,a no nodal metastasis
IB Lesions > 2 cm in size or with stromal invasion > 1.0 mm,a confined to the vulva or perineum, with negative nodes
Stage II: Tumor of any size with extension to adjacent perineal structures (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 inguinofemoral lymph nodes
IIIA (i) With 1 lymph node metastasis (≥ 5 mm), or
(ii) 1-2 lymph node metastasis(es) (< 5 mm)
IIIB (i) With ≥ 2 lymph node metastases (< 5 mm), or
(ii) ≥ 3 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 inguinofemoral lymph nodes IVB Any distant metastasis, including pelvic lymph nodes
*The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.
Reprinted from International Journal of Gynecology & Obstetrics, Vol 105, Iss 2, Pecorelli S, Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. © 2009, with permission from Elsevier.
The revised staging criteria reflects several modifications over the initial surgical staging system proposed by the FIGO Committee on Gynecologic Oncology in 1988 (Table 9-3). The 1988 criteria changed the staging system from clinical to surgical to better reflect the prognostic significance of metastatic regional lymph nodes. However, this staging system included several heterogeneous populations within stage III. For example, patients were included with small tumors involving the vagina or urethra (but with negative nodes), as were patients with small primary tumors and 1 positive lymph node, and patients with large primary tumors with 2 positive lymph nodes; in a Gynecologic Oncology Group study, survival of these 3 groups ranged from 100%, 95%, and 34%.16 Furthermore, survival is dramatically worse for patients with increasing number and size of metastatic lymph nodes, as well as for those with extracapsular spread.
Table 9-3 1988 Surgical Staging Criteria for Carcinoma of the Vulva17
To better reflect the prognostic significance of these findings, the 2009 criteria has expanded stage III to include 3 subcategories. Stage IIIA includes patients with 1 lymph node metastasis (≥ 5 mm) or 1 to 2 lymph node metastases (< 5 mm). Stage IIIB includes patients with ≥ 2 lymph node metastases (≥ 5 mm) or ≥ 3 lymph node metastases (< 5 mm). Stage IIIC includes those patients with positive nodes with extracapsular spread. The revised criteria should afford improved prognostic discrimination between the different stages and limit the heterogeneity in regards to survival within stages.
Several studies have demonstrated the prognostic significance of the depth of invasion and lymphvascular space invasion in predicting the risk of nodal metastasis. Pathologists must apply strict criteria for assessment of the depth of invasion for all patients diagnosed with vulvar cancer; this includes measurement from the epithelial-stromal junction of the most superficial dermal papilla to the deepest point of invasion.17
The prospective Gynecologic Oncology Group (GOG) protocol that evaluated 637 patients with vulvar cancer found on multivariate analysis that factors involved in the risk for lymphatic metastasis in squamous cell vulvar tumors include lymphvascular space invasion (LVSI) and patient age (Table 9-4).10 They also reported that clinically fixed nodes and utilization of 5-step GOG criteria on grading were associated with nodal metastasis as well. The reproducibility of some of these clinicopathologic risk factors makes tumor depth of invasion and tumor size among the more utilized factors in evaluating the potential risk for nodal metastasis. Grading systems based on 3-tier criteria are not necessarily predictive of nodal metastasis, and LVSI is limited in the tumor beds, with only a small percentage of tumors identified with LVSI.10,18 This underscores the importance of using pathologists either formally trained or with a background in gynecologic pathology for review of these specimens.
Table 9-4 Risk Factors for Groin Node Metastasis in Squamous Vulvar Carcinoma10
Ultrastaging of lymph node tissue to detect microscopic disease in lymph nodes has demonstrated an increased detection rate for metastatic disease in cervical cancer and may play a role in vulvar cancer.19Caution must be advised, however, as some of these identified metastatic lesions may consist of microscopic disease (one report consisted of a single cell in the lymph node), and the clinical outcome may not be clear.19 Current management of patients identified with this technique is the same as for those with a positive lymph node by conventional techniques until further data are available.
1. Primary treatment of vulvar cancer involves radical surgery to excise the primary lesion with a clinical margin of 1 to 2 cm.
2. Microinvasive, or stage IA, vulvar cancers have a low risk of nodal metastases and may be managed with radical surgical excision alone.
3. Ipsilateral inguinal-femoral lymphadenectomy is recommended for all invasive squamous cell vulvar cancers; bilateral inguinal-femoral lymphadenectomy is recommended for patients with lesions less than 2 cm from the midline, with clinically suspicious inguinal lymph nodes, and with positive ipsi-lateral nodes.
4. Sentinel lymph node biopsies (SLNB) may identify lymph node–positive patients who require additional treatment and lymph node–negative patients who do not require full inguinal-femoral lymphadenectomy.
Treatment of Microinvasive Disease
Stage IA vulvar cancers are characterized by small primary tumors less than 2 cm in size, with clinically negative inguinal/femoral lymph nodes, and with the depth of invasion ≤ 1.0 mm. Similar to the microinvasive stage IA1 disease of cervical squamous cell cancers, the risk of nodal metastases is minimal, and patients may undergo radical local excision of the primary lesion with 1-cm clinical margins at the time of resection. Inguinal-femoral lymphadenectomy is not indicated for these very low-risk patients.
Treatment of Early-Stage Disease
Surgery is the primary approach for patients with vulvar cancers that do not demonstrate extension to adjacent perineal structures. Depending on the size of the primary tumor, patients may undergo total radical vulvectomy, partial radical vulvectomy, or radical local excision. As opposed to a skinning or simple vulvectomy, the radical nature of this procedure involves excision of the lesion with 1- to 2-cm clinical margins at the time of resection and dissection down to the level of the perineal membrane (previously considered as the deep fascia of the urogenital diaphragm).20 Resection of the regional inguinal and femoral lymph nodes is also indicated, both for prognostic reasons and adjuvant treatment planning. Patients may undergo ipsi-lateral inguinal-femoral lymphadenectomy if lesions are of squamous histology; the primary tumor is well lateralized and less than 2 cm in diameter, both groins are clinically negative for metastases, and the ipsilateral groin is pathologically negative for metastases.21
Historically, this surgical excision has evolved from a butterfly-shaped resection (removing the vulva, the inguinal and femoral lymph nodes, and the intervening skin and lymphatics in between). Application of 3 incisions has significantly improved morbidity and mortality from this procedure without a cost in survivorship. Attempts to reduce the extent of groin dissection, however, were abandoned when unexpected fatal recurrences in the groin occurred.22,23 Historic GOG data suggest that the risk of groin relapse after a radical en bloc dissection of the groin that included skeletonization of the femoral artery and vein and sartorius muscle transposition was less than 1%.24 In GOG-74, the relapse rate after negative superficial inguinal lymphadenectomy in a very-low-risk patient population was more than 7%. These groin relapses, even when they appear to be detected early, are difficult to treat and are associated with a high mortality rate.
To minimize the morbidity of complete inguinal-femoral lymphadenectomy without a cost in survival, several investigators defined lymphatic drainage patterns with injections of various compounds into the vulva.25,26 In 1992, the modern sentinel lymph node biopsy (SLNB) technique was described by Morton and colleagues27 as an alternative to regional lymphadenectomy for patients with cutaneous melanoma. This technique was easily applied to vulvar cancer patients, as the tumor is easy to inject and the lymphatic drainage is predictably to the groin.28 Multiple single-institution series confirmed the general concept of SLNB in vulvar cancer patients29 (Table 9-5).
Table 9-5 Levenback and GROINS-V Table30,31
Two recent multi-institution trials suggest that SLNB is an alternative to lymphadenectomy for selected patients with vulvar cancer. The first trial was a collaboration of Dutch investigators led by Van der Zee,30 who reported the results of the GROinigen International Sentinel Node for Vulvar Cancer trial. This trial had an observational design in which eligible patients with invasive vulvar cancer limited to the vulva and up to 4 cm in diameter were treated with SLNB and resection of the primary tumor. If the sentinel lymph node result was negative, the patients were observed every 2 months for signs of relapse. Of the 403 patients enrolled, 296 were sentinel lymph node negative and were observed. The relapse rate was 3%, within the predetermined statistically acceptable outcome range. Exclusion of patients with multifocal tumors would have reduced the relapse rate to just over 2%. The outcomes for the 8 patients with relapse were poor; however, the overall survival at 3 years was 97% with decreased perioperative morbidity, including lymphedema and wound breakdown, among the SLNB-only patients as compared with the node-positive patients who underwent lymphadenectomy.30
The second multi-institutional trial was conducted by the GOG and the study, GOG-173, has been presented in abstract form. This trial enrolled more than 500 patients who had invasive squamous carcinoma 2 to 6 cm in diameter limited to the vulva. The patients underwent SLNB followed by unilateral or bilateral lymphadenectomy depending on the location of the primary tumor. The success of sentinel lymph node identification was improved dramatically by the use of radiocolloid in addition to blue dye. There were 131 lymph node–positive patients. The sensitivity and false-negative predictive value in the study group met the predetermined statistical targets, with a sensitivity of approximately 90% and a false-negative predictive value of less than 5%. The false-negative predictive value is the statistical estimate of a false-negative sentinel lymph node when the status of the remaining lymph nodes is not known. Among the patients with tumors less than 4 cm, the false-negative predictive value was less than 3%.31
Implementation of SLNB strategy involves teamwork and communication between the gynecologic oncologist, diagnostic radiologist, pathologist, radiation oncologist, and patient. Case selection for best outcome is a patient with a unifocal tumor, less than 4 cm in size, without a history of prior radiotherapy or groin surgery (although prior wide local excision for diagnosis is acceptable). Patients with gross involvement of a lymph node on physical examination or imaging are not considered optimal candidates for SLNB due to alterations in lymphatic drainage. In fact, a solitary grossly involved lymph node is presumed to be the sentinel node, the first site of metastatic disease.
Candidates for SLNB may benefit from preoperative lymphoscintigraphy, which may help guide decisions regarding when to perform unilateral or bilateral groin dissection. Patients with direct tumor involvement of midline structures should have surgical evaluation of both groins, even if a sentinel lymph node is not imaged in one or both of the groins. If the tumor is close to but not involving the midline, and there is ipsi-lateral unilateral lymphatic drainage on the lymphoscintigram, then unilateral surgical groin evaluation is acceptable. Limitations of this technique include the potential use of painful injections with limited utility in a patient before any surgical intervention; recent data have suggested that use of perioperative Lymphazurin blue dye and technetium-99 during lymphatic mapping negates the need for this imaging technique.12
In the operating room, the radioactive tracer is injected intradermally before the patient is prepped, approximately 20 to 30 minutes before groin incision. The blue dye, which is a smaller molecule and travels more rapidly from the injection site to the lymph node than the radiocolloid, is injected after the patient is prepped and draped. It takes approximately 5 minutes for the blue dye to reach the sentinel lymph node. A single groin might have more than 1 sentinel lymph node, and therefore special care must be taken to ensure that all nodes that take up the blue dye or radio-colloid are removed. If a sentinel lymph node is not found, then lymphadenectomy should be performed.
Sentinel lymph nodes are then subjected to pathologic ultrastaging.32,33 The gross specimen is subjected to serial sectioning and routine hematoxylin and eosin examination. If no metastases are found, then deeper levels are subjected to cytokeratin immunohistochemical staining. Identification of metastatic disease increases 20% to 40% with this analysis.19,30 A prospective study of 723 sentinel lymph nodes with metastatic disease found that increased size was associated with poorer disease-specific survival (88% for patients with ≤ 2 mm in size vs. 70% with 2-5 mm in size vs. 69% for > 5 mm in size; P < .01).33Identification of those patients with micrometastatic disease is important for further treatment and also for identifying patients at risk for recurrence. In other disease sites, especially breast cancer, there are patients with micrometastases who may be treated the same as for lymph node–negative patients. With the current fund of knowledge, all patients with micrometastases in a sentinel lymph node should be considered as having metastatic disease and as candidates for further treatment, including lymphadenectomy or possibly radiotherapy.
Treatment of Advanced Disease
Patients with advanced disease with involvement and encroachment of the urethra and rectum may benefit from neoadjuvant chemotherapy and/or radiation. Preoperative radiotherapy may also benefit patients who would otherwise require a pelvic exenteration; shrinkage of the primary tumor may lead to preservation of bowel and bladder functions before more conservative surgical intervention.34 A combination of chemoradiation in a phase II study by the GOG evaluated this modality in patients with stage III to IV vulvar cancer before surgical intervention; they demonstrated that even in advanced-stage disease, bowel and bladder function can be preserved (2 of 71 patients or 2.8% had residual unresectable disease).35
A candid conversation with patients, regardless of age, before surgical intervention should include complete disclosure of unique risks and benefits. It is important to emphasize that besides the usual risks of bleeding, infection, and damage to bowel and bladder, patients must be made aware of the potential impact on sexuality and sexual function. Pretreatment counseling and decision making are critical to patients, especially younger patients who are diagnosed with vulvar cancer, as this dissection and excision may be viewed as a cosmetically mutilating procedure that may change patients’ view of self, result in loss of sexual function, and may change the way that they interact with their sexual partner.36
Treatment of Metastatic Lymph Nodes
Groin radiation is recommended for those patients with a positive nodal metastasis, with or without a formal full inguinal-femoral node dissection. Patients who undergo this treatment may have issues with vaginal and perivaginal dryness. Hormone replacement therapy for these patients with vaginal dryness with emphasis on quality of life and sexual function is not contraindicated with squamous cell carcinomas treated with surgery and radiation.37 Certainly, patients who require radiation after surgical resection may undergo early ovarian failure and are candidates for hormone replacement therapy. There is no contraindication for short-term hormone replacement therapy in patients with a history of vulvar cancer.
Treatment of Poor Surgical Candidates
Neoadjuvant chemoradiation may be considered for medically infirm patients, with the potential for decreased morbidity with extensive resection. Patients who have extensive medical issues including diabetes and poor functional status, chronic steroid use with a decrease in functional ability, and concern for bowel and bladder function may need a tailored approach that focuses on treatment cure and on limiting surgical and treatment morbidity.
Further treatment summaries are listed in the treatment box in Figure 9-4, and these underscore the importance of tailored treatment plans based on the patient’s clinical presentation. The important point is the potential of decreased lymph node dissection in patients with smaller tumors and with imaging/examination suggesting no lymph node involvement. Patients with positive lymph nodes (either by the traditional lymph node dissection or by SLNB) require further treatment (regardless or tumor size), until further data are available.33
FIGURE 9-4. Flowchart for management (lymphatic mapping with both radioactive tracer and blue dye). T1, ≤ 1.0 mm, a, without ulceration; T1 b, with ulceration or level IV or V; T2, 1.01 ro 2.0 mm, a, without ulceration; T2 b, with ulceration; T3, 2.01 to 4.0 mm, a, without ulceration; T3 b, with ulceration; T4, > 4.0 mm, a, without ulceration; T4 b, with ulceration.
SURVIVAL AND PROGNOSIS
1. The 5-year median survival of women with vulvar cancer (all histologies included) is approximately 76%.
2. Lymph node metastases remain the most significant prognostic factor in vulvar cancer. Patient age and tumor histology are also predictive of survivorship in vulvar cancer.
In general, survival rates for women with early-stage squamous cell carcinomas of the vulva are excellent, with 5-year survivorship of 80% to 90% for patients with stage I and II disease. Reflecting the significance of nodal metastases as a prognostic factor, patients with stage III disease, categorized by the 1988 FIGO criteria, demonstrate a 55% survival rate at 5 years, and those with stage IV disease are only at 28% (Table 9-6).15 As discussed previously, the range of survival within stage III disease (per the 1998 criteria) is between 34% and 100%, and prospective application of the 2009 revised staging criteria should limit the significant heterogeneity observed with the prior system.
Table 9-6 Five-Year Survival Based on Histology: Modified From SEER Survival Monograph15
In addition to stage, survival in this disease is associated with several additional prognostic features, including patient age and tumor histology. Patients with a diagnosis of vulvar cancer at a younger age have improved survival, with 5-year survival rates of 87.5% for younger women and 52.5% for older women.3 Older patients have also been demonstrated to have more advanced disease and risk for nodal metastasis; although age is not factored into the staging criteria, it should be considered during patient evaluation.10,38
Tumor histology is also associated with improved survival, with women with vulvar adenocarcinoma having improved 5-year survival rates compared with women with squamous and melanoma vulvar tumors15 (Table 9-6). As discussed later, vulvar adenocarcinomas are typically indolent in nature and have a decreased risk of advanced lymphatic spread. Melanomas are on the opposite side of the spectrum, with increased risk of metastatic disease despite pathologic evidence of local disease status. This is part of the reason that, based on histology, survival patterns favor adenocarcinoma, followed by squamous tumors, with melanoma having the worst prognosis.2,3,14,15
Groin relapse has been demonstrated to have a high mortality rate; patients with a potential for treatment with salvage therapy are often detected early. In the GROINS-V study, patients were followed every 2 months,30,33 with a reported higher mortality rate in patients with recurrence. At this time, we recommend surveillance every 2 to 3 months with use of imaging modalities based on clinical history, including ultrasound, CT, or MRI.
MANAGEMENT OF RECURRENT DISEASE
1. Local recurrence on the vulva may be successfully salvaged surgically with re-excision.
2. Recurrences in the groin are almost uniformly fatal, and chemotherapy remains only palliative.
3. Nonresectable recurrences should include local wound care to address potential erosive disease.
After completion of primary therapy, patients with vulvar cancer should be followed closely, with visits every 3 months for the first 2 to 3 years. These visits should include a detailed history and physical examination, including evaluation of the groin nodes and the vulva, pelvis, and rectum. Visits may be extended to 6-month intervals until 5 years after therapy, when patients may then be seen on an annual basis. If recurrence is suspected on the basis on symptoms or physical findings, biopsy and imaging (using CT, PET, or MRI) should be used. The application of routine imaging in vulvar cancer is not well established, but MRI in particular may have a role in postoperative imaging of this disease.13
In the event of recurrence, a detailed evaluation is necessary to characterize the extent of disease. Recurrences may be categorized as local (in the vulva alone), groin (in the inguinal-femoral lymph nodes), or distant (lung, liver, and/or brain). For local recurrences, surgery can be associated with a high morbidity, but can result in cure. Up to 75% of all patients with recurrence limited to the vulva may be successfully treated with salvaged therapy that includes radical wide excision; absence of carcinoma at the margins of resection are predictive of long-term survival. For those patients with groin recurrences, cure is rarely possible. In patients without prior groin radiation, surgical resection with radiation should be considered. In women who experience recurrence in a previously radiated groin or those who present with distant sites of recurrence, palliative treatment is recommended, usually with chemotherapy.
There are few palliative treatment options for women with recurrent disease, and these often involve platinum-based agents that are similar to those used for metastatic cervical cancer. The activity of platinum combination agents and/or taxanes is limited,39,40 and patients with recurrent disease may best be managed with enrollment in clinical trials. Recent data have demonstrated potential benefit with antagonism of the epidermal growth factor receptor pathway. These studies have shown impressive initial responses in small studies, but durable responses have yet to be seen.41,42
Additional palliative care treatment options should be discussed with patients with recurrent vulvar cancer, as this can lead to erosion along the skin surfaces and potentially into the large vessels along the femoral and groin regions. Involvement may also occur along the vaginal periurethral and perirectal areas, limiting the patient’s bowel and bladder function; this may require diverting ostomies for palliative benefit.
SPECIAL MANAGEMENT PROBLEMS
There are significant postoperative management considerations in patients who have vulvar cancer and undergo surgery and radiation. Approximately 50% of patients will have complications involving wound breakdown at the groin and/or vulvar incisions, and lymphedema (Figure 9-5).43 Lymphedema, in particular, results from disruption of the normal lymphatic channels in the groin after inguinal-femoral lymph-adenectomy and can be compounded by radiation-induced fibrosis. This complication can be disfiguring, painful, and prone to chronic cellulitides. According to recent data, use of hemostatic agents has not affected the incidence of lymphedema and may worsen perioperative morbidity.43 In breast cancer, randomized placebo-controlled studies have suggested a potential benefit with α-tocopherol (vitamin E) and pentoxifylline in the reduction of radiation-induced fibrosis and arm lymphedema, although other studies failed to replicate any benefit.44,45 SLNBs can lessen the risks of these complications; in the prospective study by Van der Zee and colleagues,30 sentinel node dissection was associated with a significant decrease in wound breakdown, cellulitis, and lymphedema.
FIGURE 9-5. Severe lymphedema.
Melanoma is the second most common vulvar cancer and accounts for approximately 10% of all primary malignant neoplasms. This disease occurs predominantly in elderly white women, with the peak frequency between the sixth and seventh decades. Vulvar melanoma can develop on the labia minora, labia majora, or clitoris and can arise from both pigmented lesions and nonpigmented normal-appearing skin. Presenting signs of vulvar melanoma typically include pruritus, bleeding, and an ulcerated lesion. In general, these malignancies are highly aggressive, with a strong propensity for local and distant metastases and recurrences. The 5-year survival rate is 36% and is lower than the survival rate for both cutaneous melanoma and vulvar squamous cell carcinoma.46
There are 3 histologic subtypes of vulvar melanoma: superficial spreading melanoma and nodular melanoma are more common, and acral lentiginous melanoma is the rarest. Superficial spreading melanomas demonstrate radial growth of ≥ 4 retia lateral to the vertical or infiltrative growth. Nodular melanomas, in contrast, have no radial growth. Immununohistochemical staining for the S100 antigen is characteristic for most melanomas and can differentiate this tumor from squamous cell carcinomas.
Vulvar melanomas may be staged via several criteria. The American Joint Committee on Cancer (AJCC) frames its system on the tumor-nodes-metastases (TNM) classification, with tumor thickness (T), regional nodal involvement (N), and the presence or absence of distant metastases (M). The AJCC recently revised these criteria in 2010 to highlight several prognostic factors, including mitotic rate, presence of microtumor burden in lymph nodes, and levels of lactate dehydrogenase in patients with distant metastases.47 Similarly, the FIGO classification system described for squamous cell carcinomas may also be applied to vulvar melanomas, but criticisms of this staging system include limited assistance in guiding treatment decision making and a weak predictor of survival. As such, vulvar melanoma may be further staged via several microstaging systems for cutaneous melanoma. The Clark system is based on the depth of invasion into the dermis; the Breslow system focuses on tumor thickness (Figure 9-6). Finally, the Chung system is a modification of the Clark criteria specifically for vaginal and vulvar melanoma and reflects the absence of a keratin or granular layer in much of the vulvar vestibule.
FIGURE 9-6. Microstaging of melanoma according to depth of penetration. A. Superficial spreading melanoma. B. Nodular melanoma.
Surgery remains the initial treatment modality for most patients with vulvar melanoma. Gynecologic oncologists have traditionally advocated aggressive surgical resection, including radical vulvectomy or radical local excision; however, recent data have shown no differences in survival in patients undergoing radical vulvectomy, simple vulvectomy, partial vulvectomy, or wide local excision.48 As such, conservative management with less radical procedures, such as wide local excision, is recommended, with the caveat that a 1-cm deep surgical margin should be obtained. For tumors that are less than 1 mm thick, 1-cm lateral surgical margins are appropriate; 2-cm lateral margins are indicated for lesions thicker than 1 mm.
The role of elective inguinal-femoral lymphadenectomy remains controversial in the management of vulvar melanoma. Metastases to the regional groin nodes are rare with thin lesions less than 1 mm (< 5%) but significant with lesions greater than 4 mm (> 70%). SLNB may be an option for patients with tumors between 1 and 4 mm thick, but this modality remains to be confirmed as standard of care.
Vulvar melanomas carry a poor prognosis and have a high propensity toward hematogenous dissemination to distant sites. Prognostic factors for survival in specifically vulvar melanomas include younger age, localized disease, and negative lymph nodes.49 In high-risk, resected cutaneous melanomas, adjuvant treatment with high-dose α-interferon demonstrated strong evidence for improved recurrence-free survival and moderate improvement in overall survival in 2 randomized, prospective studies; in a pooled analysis of 4 randomized trials, interferon demonstrated only an improvement in recurrence-free survival.50
Paget Disease of the Vulva
Paget disease of the vulva is a rare lesion, characterized as a red, velvety, weeping lesion on the labia majora, posterior fourchette, or clitoris. Similar to melanoma, patients with Paget disease tend to be elderly white women. This disease is associated with an underlying invasive adenocarcinoma in 10% to 20% of cases; more recently, a large study of 100 patients with this disease found a 16% incidence of invasive adenocarcinoma or other associated vulvar cancer. In this study, the risk of recurrent Paget disease was reported in 34% of the patients approximately 3 years after primary treatment.51 Primary management remains surgical and frequently involves wide local excision in the absence of invasive features. Paget disease has a propensity for recurrence, despite negative margins; therefore, 1-cm surgical margins are typically advocated.
Significant progress has been made in the surgical management of women with invasive vulvar cancers. As discussed, the potential impact of SLNB may result in dramatically improved quality of life for survivors. Further study is needed in the management of women with groin and distant recurrences, and current treatment strategies remain only palliative in nature. As discussed earlier, the epidermal growth factor receptor pathway may have a role in management of advanced metastatic disease, either alone or in combination with cytotoxic chemotherapy. Similarly, additional study is warranted in patients found to have micrometastatic lymph node disease as a result of ultrastaging techniques. Historically, these patients were considered to have negative nodes; until further data are available, management of these patients should include radiotherapy with potential additive chemotherapy.52,53
Future studies should emphasize the transition period that is now underway in vulvar cancer in both staging and the sentinel lymph node technique. Vulvar cancers are rare tumors and require specialized treatment. Owing to the potential local nature of this disease, however, the goal of a cure is attainable at centers that manage this condition. The importance of a focused primary surgical treatment with the idea of curative intent cannot be overemphasized. Further management of metastatic disease may lead to multiple potential biologically plausible treatment pathways.
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