Vulvar carcinoma is an uncommon tumor that is seen most often in older women. Subtle symptoms such as pruritus should prompt examination and targeted biopsy in all women as this disease can be successfully treated even in elderly, frail individuals. Vulvar cancer has a bimodal age distribution and is seen in both young and older women with risk factors including human papillomavirus (HPV) infection, smoking, and vulvar skin diseases (i.e., lichen sclerosus). This cancer is staged surgically, with an update in 2009 incorporating prognostic factors. The treatment of vulvar carcinoma has evolved to include more conservative surgical techniques that provide improved cure rates with emphasis on minimizing morbidity. Advanced and metastatic lesions are now treated with chemoradiation which produces substantial cure rates with decreased morbidity. Promising areas of research in vulvar cancer include refinement of sentinel lymph node biopsy, prevention of lymphedema, and preservation of sexual function following treatment.
Introduction
Vulvar carcinoma is uncommon, representing only 5% of gynecologic malignancies and 1% of cancers in women. In 2013, there will be an estimated 4490 new cases of vulvar cancer and 950 deaths from this disease in the United States . Although this cancer is most often seen in postmenopausal women, there are increasing numbers of young women with this diagnosis . Human papillomavirus (HPV) infection and smoking increase risk for this cancer. Vulvar cancer can present with relatively subtle symptoms such as pruritus or dysuria. Awareness and recognition of this disease entity is particularly important because it can be successfully treated even in very frail individuals, and the success and morbidity of treatment is correlated with stage at diagnosis. Delay in the diagnosis of vulvar cancer can occur when lesions are not discussed secondary to patient embarrassment or when symptoms are treated without examination or histologic confirmation of the diagnosis.
Etiology
Over 90% of vulvar cancers are of squamous histology, although melanomas, basal cell cancers, sarcomas, and adenocarcinomas from Paget’s disease or originating in the Bartholin’s gland can also occur. Risk factors for the development of vulvar cancers include smoking, HPV infection, lichen sclerosus, immunosuppression, vulvar or cervical neoplasia, and northern European ancestry. Squamous cell carcinomas are the most common type of vulvar cancer and arise from one of two pathogenic mechanisms that correlate with age. Basaloid or warty type carcinomas are seen in younger women with HPV infection. Keratinizing squamous carcinomas are associated with inflammatory vulvar skin diseases such as lichen sclerosus and are generally found in older individuals. These keratinizing squamous carcinomas are not typically associated with HPV infection . Although the incidence of vulvar cancer is fairly stable at 1% lifetime risk, the incidence of vulvar intraepithelial neoplasia (VIN) is increasing, and one study found that rates had tripled in younger women over the last two decades .
Etiology
Over 90% of vulvar cancers are of squamous histology, although melanomas, basal cell cancers, sarcomas, and adenocarcinomas from Paget’s disease or originating in the Bartholin’s gland can also occur. Risk factors for the development of vulvar cancers include smoking, HPV infection, lichen sclerosus, immunosuppression, vulvar or cervical neoplasia, and northern European ancestry. Squamous cell carcinomas are the most common type of vulvar cancer and arise from one of two pathogenic mechanisms that correlate with age. Basaloid or warty type carcinomas are seen in younger women with HPV infection. Keratinizing squamous carcinomas are associated with inflammatory vulvar skin diseases such as lichen sclerosus and are generally found in older individuals. These keratinizing squamous carcinomas are not typically associated with HPV infection . Although the incidence of vulvar cancer is fairly stable at 1% lifetime risk, the incidence of vulvar intraepithelial neoplasia (VIN) is increasing, and one study found that rates had tripled in younger women over the last two decades .
Clinical presentation
Most vulvar cancers present as a palpable lump or visible mass on the vulva with or without associated pruritus, discharge, dysuria, or bleeding. The lesion may be difficult to visualize secondary to labial agglutination from surrounding dystrophy. Rarely, vulvar cancers are asymptomatic. As coexistent lower genital tract neoplasia is found in 13% of cases, initial evaluation should include examination of the entire vulva for multifocal lesions as well as the rest of the lower genital tract (cervix and vagina) including cervical cytology . Any suspicious lesion should be biopsied, and multiple biopsies of multiple sites or of the same suspicious lesions over time may be necessary to make the diagnosis. If the lesion is clinically suspicious and the pathology does not correlate with the clinical suspicion (for example, necrosis) then repeat biopsy may be warranted. The center of the lesion should be sampled for highest yield. If vulvar cancer is suspected, excision of the primary tumor prior to evaluation by an oncologist should be discouraged as it can preclude accurate estimation of tumor size, location, margin status, and make sentinel node evaluation difficult or impossible.
Evaluation prior to treatment
Evaluation of the patient prior to treatment must include a thorough assessment of the patient’s medical history, functional status, and physical exam. Vulvar cancers spread by direct extension onto surrounding tissues and also by tumor emboli with lymphatic spread first to inguinal lymph nodes. The primary tumor must be carefully evaluated for its size and proximity to adjacent structures such as the urethra, vagina, and anus and fixation to bone. The vagina, cervix, and perianal skin should be evaluated for coexistent neoplasia and the bilateral groins and supraclavicular (scalene) nodes carefully examined for palpable adenopathy. Patients with significant discomfort may benefit from an exam under anesthesia, and in advanced cases, cystoscopy or proctoscopy may be of benefit to determine the extent of disease. Vulvar cancers may be multifocal and arise in a background of intraepithelial neoplasia (VIN), HPV infection, or vulvar skin diseases and multiple biopsies may be necessary to determine the boundaries of resection and plan for treatment.
In cases with a large tumor burden or when pelvic node metastasis is suspected, tumor imaging may be indicated. Magnetic resonance imaging can be helpful in defining the anatomic extent of bulky tumors. Although significant evidence is not available for vulvar carcinoma, evaluation of the lymph nodes with preoperative positron emission tomography (PET) scan may be helpful in detecting distant spread including lymph node metastases .
Staging
The process of assigning a stage to a cancer defines both treatment options as well as prognosis. This allows the gynecologic oncologist to have a more meaningful conversation with the woman and her family. The last major change in staging for vulvar cancer occurred in 2009 when changes were initiated after evaluating the accumulating data regarding outcomes and issues with the prior staging system. Surgical staging includes histopathologic assessment of depth of invasion and the involvement of nodes. This is generally omitted in patients with metastatic or fixed disease at the time of diagnosis. Appendix I shows the present Staging system adopted by the International Federation of Gynecology and Obstetrics (FIGO), the American Joint Committee on Cancer (AJCC), and the International Union Against Cancer (UICC) . Among the changes were defining the depth of invasion as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion, which highlights the importance that depth of invasion holds in defining treatment options. Less than 1% of women with ≤1 mm invasion will have inguinal lymph node metastases, allowing more conservative surgery without inguinal node dissection . This entity is identified as Stage IA versus the group of patients with 1–5 mm of invasion who may have rates of nodal metastases up to 28%. Staging now is inclusive of the number of number of positive nodes as well as evidence of extracapsular spread. All are important in prognosis and treatment.
Surgical management of vulvar carcinoma
Treatment modalities for vulvar carcinoma have greatly improved over the last three decades by providing improved cure rates with more conservative surgery that carries decreased risk of morbidity (e.g., lymphedema, disfigurement, and sexual dysfunction). Surgical management of vulvar carcinoma must be individualized and tailored to the extent of disease. By optimizing care to the individual patient, psychological, sexual, and physical morbidity will be minimized.
Surgical resection of early vulvar cancers – clinical stage I/II
Early invasion
Small vulvar tumors that are <2 cm in diameter and have ≤1 mm of invasion with no vascular space involvement and can be treated with a wide deep excision with 1-cm margins around the tumor. This is the only group of patients who do not need lymph node evaluation as the risk of lymphatic dissemination is <1% .
Stage I tumors with invasion over 1 mm
For Stage I tumors with >1 mm of invasion, treatment can be accomplished by a radical wide excision and lymph node assessment. Radical wide excisions include a 2-cm margin around the tumor and excision of the tumor and subcutaneous fat down to the perineal fascial layer.
The extent of required lymph node assessment in these cases depends on the location of tumor and the presence of positive nodes. If the tumor is lateralized, meaning 2 cm or more lateral to midline structures such as the clitoris and urethra, unilateral node assessment is sufficient, assuming that the nodes removed are negative for tumor. In the case of midline disease or positive ipsilateral nodes, bilateral inguinal assessment should be done.
Larger stage I and II tumors
For cancers that are grossly >2 cm or any size tumor involving adjacent vulvar structures, the historic treatment was a radical vulvectomy and inguinal node dissection with a “butterfly” incision that included all tissue including skin over the inguinal area, the vulva to the perineal fascia, and adjacent areas as needed to remove the cancer en bloc, including at times the removal of the underlying pubic rami. This approach, while curing many individuals, resulted in significant morbidity including infections, wound breakdowns, and loss of sexual function. If the margins around the disease were not adequate, this radical approach also failed to control the disease. Comparisons of this en bloc approach to local radical resection, defined as a surgical excision of the lesion with at least 1 cm deep and lateral margins have been limited but have not shown a more favorable outcome in women treated by local radical resection . Because of this significant difference in morbidity, radical local resection including radical wide excision, partial or complete vulvectomy with secondary inguinal incisions for node dissection is favored as management.
Sentinel lymph node dissection
Inguinofemoral lymphadenectomy can be a highly morbid procedure with early wound breakdown or infection occurring in 30–40% of patients, and risk of chronic lymphedema as high as 30% . The probability of lymph node metastases in women with Stage I or II disease is 25–35%; however, as unrecognized groin metastases are typically fatal, complete inguinofemoral lymphadenectomy is widely regarded as the standard of care . A sensitive and specific surgical technique to detect lymph node metastases with less potential morbidity is therefore of great interest. For selected patients with a negative clinical groin exam, a sentinel lymph node biopsy may be a less morbid alternative to a full inguinofemoral lymph node dissection, if the center in which they are receiving treatment has the appropriate surgical and pathological resources.
Women who are ideal candidates for sentinel lymph node biopsy have lesions that are lateralized, unifocal, and between 2 and 4 cm. There should be no palpable groin nodes, no infection, and no history of vulvar surgery, or any other factors that may predispose to disrupted lymphatic drainage. Lymphatic mapping should be performed preoperatively with lymphoscintigraphy and intraoperatively with blue dye as well as radiolocalization to optimize sentinel lymph node detection .
In performing sentinel lymph node biopsies, the injections of blue dye and radionuclide are to be performed prior to resection of the primary tumor. Injection should be made into the dermis at the junction of tumor and normal vulvar skin at the border of the tumor closest to the groin. The half-life of radionuclide is approximately 6 h, depending on the agent chosen. Isosulfan blue dye is visible in the surgical field up to 30–45 min after injection. Sentinel lymph nodes may be identified as blue, hot, or by preoperative lymphoscintigraphy . Sentinel nodes must be pathologically evaluated by a pathologist experienced in this approach to rapid node assessment. In the case that either frozen section or final pathologic evaluation reveals lymph node metastases, a full inguinofemoral lymphadenectomy should be performed.
In a large observational study of sentinel lymph node biopsy in vulvar cancer, radioactive tracer and blue dye were used to identify sentinel nodes. In women in whom at least one sentinel node was detected and was negative, no further treatment was given. The groin recurrence rate was 3% at 35 months in this group. This is similar to the historically reported recurrence rate following full inguinofemoral lymphadenectomy . Gynecologic Oncology Group (GOG) 173 further compared sentinel lymph node biopsy with full lymphadenectomy and reported a sensitivity of 92% with a negative predictive value of 96% in women with unifocal, lateral tumors under 4 cm. Thus, in well-selected patients and in centers with appropriate expertise in sentinel lymph node biopsy, this procedure may be a less morbid alternative to full inguinal lymphadenectomy with a similar outcome.
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