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General Considerations
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Cancer of the vulva may arise from the skin, subcutaneous tissues, or glandular elements of the vulva. Approximately 90% of these tumors are squamous cell carcinomas. Less common tumors are EMPD with underlying adenocarcinoma, carcinoma of Bartholin's gland, basal cell carcinoma, melanoma, sarcoma, and metastatic cancers from other sites.
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Cancer of the vulva is uncommon, accounting for approximately 4% of gynecologic cancers. Vulvar cancer is more common in the poor and elderly in most parts of the world, and no race or culture is spared. Vulvar cancer is primarily a disease of postmenopausal women, with a peak incidence in women ages 60–70 years. The average age at the time of diagnosis is 65 years, and 75% of patients are older than age 50 years. In general, the mean age of patients with carcinoma in situ is approximately 10 years less than that for patients with invasive cancer. Intraepithelial cancer of the vulva in women ages 20–40 years has increased remarkably in recent years. Two independent pathways for the development of vulvar carcinoma are thought to exist. HPV infection is strongly associated in younger women with vulvar cancer, whereas in older women, vulvar dystrophy and chronic inflammation are thought to be the prevailing carcinogenic pathways. Older women are more likely to have squamous hyperplasia in the tissue adjacent to the tumor.
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Considering that cancer of the vulva is a disease of a body surface readily accessible to diagnostic procedures, early diagnosis should be the rule. This is not the case, however, and a 6- to 12-month delay in reporting symptoms of discovery of a tumor is common. Despite the advanced age of many of these patients and the frequent finding of a moderately large tumor, the disease is usually amenable to surgical therapy. In stage I and II disease, the corrected 5-year survival rate is >90%. A 75% corrected 5-year survival rate for all stages of vulvar cancer is reported by most institutions.
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Risk factor most frequently associated with carcinoma of the vulva are cigarette smoking, immunodeficiency syndromes, a history of cervical carcinoma or dysplasia, HPV infection, and chronic vulvar irritation secondary to diabetes mellitus, granulomatous venereal disease, or vulvar dystrophy.
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The gross appearance of vulvar cancer depends on the origin and histologic type. These tumors spread by local extension and, with few exceptions, by lymphatic embolization. The primary route of lymphatic spread is by way of the superficial inguinal, deep femoral, and external iliac lymph nodes (Fig. 47–5). Contralateral spread may occur as a result of the rich intercommunicating lymphatic system of the vulvar skin. Direct extension to the deep pelvic lymph nodes, primarily the obturator nodes, occurs in approximately 3% of patients and seems to be related to midline involvement around the clitoris, urethra, or rectum, or to cancer of a vestibular (Bartholin's) gland. Extension of the tumor to the lower and middle thirds of the vagina may also allow access of tumor cells to lymph channels leading to the deep pelvic lymph nodes.
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The following sections describe the gross and histologic appearance of the various types of vulvar cancers.
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Squamous Cell Carcinoma
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Squamous cell carcinoma is by far the most common type of tumor and most frequently involves the anterior half of the vulva. In approximately 65% of patients, the tumor arises in the labia majora and minora, and in 25%, the clitoris or perineum is involved. More than one-third of tumors involve the vulva bilaterally or are midline tumors. These tumors are most frequently associated with nodal spread, particularly bilateral nodal metastases. Midline tumors that involve the perineum do not worsen the outlook unless they extend into the vagina or to the anus and rectum.
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Squamous cell carcinoma of the vulva varies in appearance from a large, exophytic, cauliflowerlike lesion to a small ulcer crater superimposed on a dystrophic lesion of the vulvar skin (Figs. 47–6 and 47–7). Ulcerative lesions may begin as a raised, flat, white area of hypertrophic skin that subsequently undergoes ulceration. Exophytic lesions may become extremely large, undergo necrosis, and become secondarily infected and malodorous. A third variety arises as a slightly elevated, red, velvety tumor that gradually spreads over the vulvar skin. There does not appear to be a positive correlation between the gross appearance of the tumor and either histologic grade or frequency of nodal metastases. The primary determinant of nodal metastases is tumor size.
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Squamous cell cancers may be graded histologically from I to III. Grade I tumors are well differentiated, often forming keratin pearls; grade II tumors are moderately well differentiated; grade III tumors are composed of poorly differentiated cells. The extent of underlying inflammatory cell infiltration into the stroma surrounding the invasive tumor is variable. The histologic grade of the tumor may be of some significance in tumors <2 cm in diameter.
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A variant of squamous cell carcinoma, verrucous carcinoma, is a locally invasive tumor that seldom metastasizes to regional lymph nodes. Grossly, the tumor looks like a mature condylomatous growth. It is distinguished from squamous cell cancer by histopathology of the tumor base, which reveals papillary fronds without a central core. Local recurrence is common if a wide vulvectomy is not performed; lymphadenectomy is usually not recommended unless suspicious nodes are encountered. Radiation therapy is usually contraindicated as it can induce an anaplastic transformation increasing the risk of metastases.
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Depth of stromal penetration has proved to be the key factor in determining invasive potential of the tumor. The ISSVD, International Federation of Gynecology and Obstetrics (FIGO), and Tumor, Node, Metastasis (TNM) staging defined stage IA carcinoma of the vulva as a single lesion measuring 2 cm or less in diameter and exhibiting 1 focus of invasion to a depth of 1 mm or less. The depth of invasion was measured from the epidermal–stromal junction of the most superficial dermal papilla to the deepest point of tumor invasion.
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Carcinoma of Bartholin's Gland
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Carcinoma of Bartholin's gland accounts for approximately 1% of vulvar cancers and, although rare, is the most common site for vulvar adenocarcinoma. Approximately 50% of Bartholin's gland tumors are squamous cell carcinomas. Other types of tumors arising in the Bartholin's glands are adenocarcinoma, adenoid cystic, adenosquamous, and transitional cell carcinomas.
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Because inflammatory disease of the Bartholin's gland is uncommon after age 40, older women with a mass in this location undergo biopsy to rule out cancer. Because of its location deep in the substance of the labium, a tumor may impinge on the rectum and directly spread into the ischiorectal fossa. Consequently, these tumors have access to lymphatic channels draining directly to the deep pelvic lymph nodes as well as to the superficial channels draining to the inguinal lymph nodes.
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Basal cell carcinomas account for 1–2% of vulvar cancers. Most tumors are small elevated lesions with an ulcerated center and rolled edges, so-called “rodent” ulcers. Some are described as pigmented tumors, moles, or simply pruritic maculopapular eruptions. These tumors arise almost exclusively in the skin of the labia majora, although occasionally a tumor can be found elsewhere in the vulva. The tumor is derived from primordial basal cells in the epidermis or hair follicles and is characterized by slow growth, local infiltration, and a tendency to recur if not totally excised.
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On microscopic examination, the typical tumor consists of nodular masses and lobules of closely packed, uniform-appearing basaloid cells with scant cytoplasm and spherical or oval dark nuclei. Peripheral margination by columnar cells is usually prominent. In larger tumor nodules, there may be areas of central degeneration and necrosis.
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If a sufficiently wide local excision is not performed, there is a tendency for local recurrence, estimated to be approximately 20%. A lymphadenectomy is rarely indicated as these tumors, although sometimes locally aggressive, rarely metastasize.
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Approximately 5% of vulvar cancers are malignant melanomas, the second most common vulvar cancer. Because only 0.1% of all nevi in women are on vulvar skin, the disproportionate frequency of occurrence of melanoma in this area may be a result of the fact that nearly all vulvar nevi are of the junctional variety. Malignant melanoma most commonly arises in the region of the labia minora and clitoris, and there is a tendency for superficial spread toward the urethra and vagina. A nonpigmented melanoma may closely resemble squamous cell carcinoma on clinical examination. A darkly pigmented, raised lesion at the mucocutaneous junction is a characteristic finding; however, the degree of melanin pigmentation is variable, and amelanotic lesions do occur. The lesion spreads primarily through lymphatic channels and tends to metastasize early in the course of the disease; local or remote cutaneous satellite lesions may be found. In contrast to squamous cell cancers, melanoma is staged according to depth of invasion. All small pigmented lesions of the vulva are suspect and should be removed by excision biopsy with a 0.5- to 1-cm margin of normal skin. In the case of large tumors, the diagnosis should be confirmed by a generous biopsy.
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The patient with vulvar cancer characteristically has had infrequent medical examinations. Approximately 10% are diabetic, and 30–50% are obese or hypertensive or demonstrate other evidence of cardiovascular disease. The incidence of complicating medical illness exceeds that expected in the age group under consideration.
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Invasive squamous cell cancer is a disease mainly of the seventh and eighth decades of life, although approximately 15% of patients are age 40 years or younger. Approximately 20% of patients have a second primary cancer that was diagnosed prior to, at the time of, or subsequent to the diagnosis of vulvar cancer; 75% of these second primary cancers are in the cervix.
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Vulvar pruritus and/or a vulvar mass are frequent complaints and are present in more than 50% of patients with vulvar cancer. Other patients complain of bleeding or vulvar pain, whereas approximately 20% of patients have no complaints, and the tumor is found incidentally during routine pelvic examination. Approximately 25% of patients have seen a physician and received various medical treatments without benefit of a biopsy of the tumor. The importance of performing a biopsy of any vulvar lesion cannot be overemphasized. A biopsy should be taken from the area that appears to be the most abnormal, and multiple biopsies may be necessary in the event of multifocal disease.
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Differential Diagnosis
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The differential diagnosis includes epidermal inclusion cysts, acrochordons, seborrheic dermatoses, lichen sclerosus and other vulvar dystrophies, condyloma acuminate, granulomatous venereal diseases (eg, syphilis, herpes, or granuloma inguinale), pyogenic infections, or benign tumor, such as a granular cell myoblastoma.
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Unusual Vulvar Malignancies
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Sarcomas of the vulva constitute a variety of malignant neoplasms that account for 1–2% of vulvar cancers. The most common is leiomyosarcoma, followed in frequency of occurrence by the fibrous histiocytoma group and an array of other sarcomas. Clinically, sarcoma may present as a subcutaneous nodule or may be exophytic and fleshy. Prognosis is usually poor and depends on histologic type, extent of local invasion, and treatment. In general, radical vulvectomy and regional lymphadenectomy are indicated, with the exception of tumors such as dermatofibrosarcoma protuberans, which is a locally aggressive tumor that tends to recur locally but does not metastasize.
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Adenocarcinoma of the vulva is exceptionally rare unless it arises from the Bartholin's gland or the urethra. Primary cancer of the breast from ectopic breast tissue has been reported. Rarely, a malignant tumor will arise from a vulvar sweat gland.
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Metastatic cancers of the vulva constitute 8% of all vulvar tumors. They usually originate from a genital tract tumor, and 18% arise from the kidney or urethra. Advanced cervical cancer is the most common primary tumor. Other primary tumors have been reported, including malignant melanoma, choriocarcinoma, and adenocarcinoma of the rectum or breast. Cloacogenic carcinoma is primarily an anorectal neoplasm, occurring twice as often in women than in men; it may arise in anal ducts and present as a submucosal mass.
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Metastatic epidermoid cancer tends to form nests of cells within the dermis. Adenocarcinoma, regardless of the primary site, invades the surface squamous epithelium. Because these tumors are a manifestation of advanced disease, the prognosis is uniformly grave.
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Operative Morbidity & Mortality
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The most frequently encountered complication is wound breakdown, which occurs in well over 50% of patients undergoing radical vulvectomy and bilateral inguinal dissection. This complication is related to the amount of skin removed during the procedure, particularly at the groin areas. Separate groin incisions and careful handling of skin flaps have reduced the incidence of wound breakdown. Vigorous wound care with debridement almost always results in adequate healing.
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Lymphedema occurs in up to 65% of patients who have had inguinofemoral lymph node dissection. Hemorrhage, lymphocyst formation, thromboembolic disease, urinary tract infections, and sexual dysfunction are other commonly associated morbidities.
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Staging and treatment for vulvar cancer are surgical (Table 47–1). The primary treatment for invasive vulvar cancer is complete surgical removal of all tumor whenever possible. The recent trend is toward a more conservative surgical approach, departing from traditional en bloc resections.
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The number of preoperative studies ordered prior to surgery depends on the extent of disease and the general condition of the patient. A complete history and a thorough physical examination that includes cytologic study of the cervix and vulvoscopy should be performed. A large tumor may interfere with adequate pelvic examination. Bleeding may be caused by a lesion higher in the genital tract rather than the obvious vulvar tumor. In that case, the pelvic examination may be performed under anesthesia, and endometrial biopsy or dilatation and curettage (D&C) may be considered.
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Chest radiography and other studies such as proctoscopy, pyelography, barium enema, and computed tomography (CT) scans are ordered on an individual basis, especially in the event of locally advanced disease or suspected metastases. Enlarged lymph nodes do not require biopsy; they will be excised by lymphadenectomy or thoroughly sampled at the time of operation.
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Historically, the basic operation was radical vulvectomy and regional lymphadenectomy. The trend, however, is shifting away from standard en bloc radical vulvectomy and bilateral lymph node dissection toward wide radical local excision of the primary tumor with inguinal lymph node dissection. For a unifocal stage I lesion with <1 mm stromal invasion, wide radical local excision with surgical margins of at least 1–2 cm should be performed. Patients with unilateral lesions with a depth of invasion ≥1 mm should undergo ipsilateral groin dissection in addition to the above to determine nodal status. For patients with bilateral lesions, lesions impinging on or crossing the midline, or stage II or greater disease or if lymph node metastases are discovered at the time of unilateral lymphadenectomy, bilateral inguinal femoral lymphadenectomy can be performed. When disease has spread to lymph nodes, adjuvant radiation therapy is generally recommended; pelvic lymph node dissection is not required for staging or therapy. In general, lymphatic spread occurs in a sequential manner from the superficial to the deep inguinal lymph nodes. Consequently, if the superficial nodes harbor no metastatic disease, there is reasonable assurance that the deeper nodes are not involved. The role of sentinel node mapping is also being evaluated for patients with squamous vulvar carcinoma and melanomas and should be reserved for investigational use.
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Postoperative radiation therapy is usually reserved for patients with more than 1 microscopically involved lymph node or if 1 of more lymph nodes are macroscopically involved. Radiation therapy can also be considered for patients with negative lymph nodes who are at high risk of local recurrence (tumors measuring >4 cm, positive or close margins, lymphovascular invasion).
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When the disease involves the anus, rectum, rectovaginal septum, proximal urethra, or bladder, an adequate surgical resection is only possible with pelvic exenteration combined with radical vulvectomy. Operative mortality is high for these procedures, and the postoperative psychological impact is significant. In addition, with advanced-stage disease where ulcerated or fixed lymph nodes are palpated, attempts at lymphadenectomy have yielded very poor results. Based on data from the Gynecologic Oncology Group, this group of patients may benefit from preoperative chemoradiation, resulting in higher rates of successful resection and reduced need for more radical surgery. Chemotherapeutic agents such as cisplatin and 5-FU have been combined with radiation therapy. These chemotherapeutic agents are used as radiation sensitizers in large necrotic tumor beds, enhancing the radiation effects.
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There is controversy concerning the extent of surgery required for treatment of malignant melanoma of the vulva. For some years, standard treatment consisted of vulvectomy with superficial and deep inguinal and pelvic lymphadenectomy. It is also generally treated with a more conservative surgical approach. If depth of the vulvar lesion is <1 mm, vulvar melanoma may be adequately treated with local incision using a 1-cm margin. However, if the depth of invasion is between 1 and 4 mm, excision requires a 2-cm margin in addition to a bilateral groin node dissection. Advanced or recurrent melanoma may be best treated with chemotherapy, radiation, or immunotherapy.
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Radical wide local resection with wide surgical margins is the standard treatment for most vulvar sarcomas. Inguinofemoral lymphadenectomy should be performed for suspected metastases because the risk of lymphatic spread is low. The primary determinant of cure appears to be adequate wide removal of the primary lesion.
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After the immediate postoperative period, patients should be examined every 3 months for 2 years and every 6 months thereafter to detect recurrent disease or a second primary cancer. Nearly 80% of recurrent vulvar cancer occurs in the first 2 years. Treatment modalities depend on the location of recurrence. Malignant melanomas and sarcomas may recur locally or metastasize to the liver or lungs.
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The principal prognostic factors in cancer of the vulva are the presence or absence of regional lymph node metastases, size and location of the lesion, and the histologic type.
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A 5-year survival rate of 75% and a 10-year survival rate of approximately 58% should be expected after complete surgical treatment of primary invasive squamous vulvar cancer. Lymph node status is the most important prognostic variable. Overall, the survival rate for patients with vulvar cancer and negative inguinal femoral nodes is 90%, whereas rates drop to almost 40% with nodal metastasis. Several authors have reported no deaths from cancer among patients who were found to have negative lymph nodes. With tumors <2 cm in diameter, the incidence of nodal metastases is 10–15%. In general, approximately 30% of patients undergoing surgery will have positive lymph nodes. With nodal metastases, the approximate 5-year cure rates are as follows: 1 node, 94%; 2 nodes, 80%; and 3 nodes or more, <15%. Patients who have 3 or more positive lymph nodes in the groin usually demonstrate palpably suspicious nodes preoperatively. These patients have a high incidence of metastases to the pelvic lymph nodes; however, pelvic lymphadenectomy does not improve survival rates. Involvement of contiguous organs such as the bladder or rectum increases the incidence of nodal metastases and worsens the prognosis accordingly.
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The cure rate for adequately treated cancer of Bartholin's gland has not been established. There is a propensity for unresectable local recurrences under the pubic ramus despite a thorough primary operation.
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Wide local excision of basal cell carcinoma should be curative. Some authors have reported an approximately 20% recurrence rate after local excision that may represent cases of incomplete excision.
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Results of treatment of malignant melanoma are related to the level of penetration of the tumor into the dermis of the vulvar skin or the lamina propria of the vaginal mucosa and to the presence or absence of nodal metastases. The 5-year survival rate ranges from 24 to 70%. The prognosis of patients with metastases to groin lymph nodes is generally poor. Amelanotic cutaneous melanomas are particularly virulent tumors. The survival rate for patients with superficial spreading melanomas is much better than for those with the nodular variety, which tend to have a smaller diameter and exhibit aggressive vertical invasion, increased incidence of nodal metastases, treatment failures, and distant recurrences. The most common site of recurrence is at the site of resection or the groin lymph nodes (if not previously resected).
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Sarcomas of the vulva tend to recur locally, particularly if the initial resection is not extensive, and metastasize to the liver and lungs.
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