Vulvar Cancer

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.

EPIDEMIOLOGY

Key Points

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 colleagues³ observed 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.⁶ Immunosuppression 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.⁷ Finally, 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

DIAGNOSIS

Key Points

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

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.

PATHOLOGY

Key Points

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

*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

Stay updated, free articles. Join our Telegram channel

Join