Hacker & Moore's Essentials of Obstetrics and Gynecology: With STUDENT CONSULT Online Access,5th ed.

Chapter 40

Vulvar and Vaginal Cancer

Neville F. Hacker

image Vulvar Neoplasms

Malignant tumors of the vulva are uncommon, representing about 4% of malignancies of the female genital tract. Most tumors are squamous cell carcinomas, with melanomas, adenocarcinomas, basal cell carcinomas, and sarcomas occurring much less frequently.

Squamous cell carcinoma of the vulva occurs mainly in postmenopausal women, and the mean age at diagnosis is 65 years. A history of chronic vulvar itching is common.

EPIDEMIOLOGY

Recent studies suggest two different etiologic types of vulvar cancer. One type is seen mainly in younger patients, is related to human papillomavirus (HPV) infection and smoking, and is commonly associated with vulvar intraepithelial neoplasia (VIN) of the basaloid or warty type. The more common type is seen mainly in elderly women and is unrelated to smoking or HPV infection; concurrent VIN is uncommon, but long-standing lichen sclerosus is common. When VIN is present, it is of the differentiated type. VIN III carries a significant risk for progression to invasive cancer if left untreated.

About 5% of patients have positive results on serologic testing for syphilis. In the latter group of patients, vulvar cancer occurs at an earlier age and carries a graver prognosis. Although rarely seen in the United States, vulvar cancer also occurs in association with lymphogranuloma venereum and granuloma inguinale.

image Intraepithelial Neoplasia

The International Society for the Study of Vulvar Disease recognizes two varieties of intraepithelial neoplasia: squamous cell carcinoma in situ (Bowen’s disease) or VIN III, and Paget’s disease. With the introduction of the HPV vaccines, there should be a significant reduction in the incidence of VIN and invasive vulvar cancer, particularly in young patients, in the future.

SQUAMOUS CELL CARCINOMA IN SITU: VULVAR INTRAEPITHELIAL NEOPLASIA TYPE III

During the past 25 years, the incidence of VIN has increased markedly. Younger patients are being affected, and the mean age is about 45 years.

Clinical Features

Itching is the most common symptom, although some patients present with palpable or visible abnormalities of the vulva. About half of patients are asymptomatic. There is no absolutely diagnostic appearance. Most lesions are elevated, but the color may be white, red, pink, gray, or brown (Figure 40-1). About 20% of the lesions have a “warty” appearance, and the lesions are multicentric in about two thirds of cases.

image

FIGURE 40-1 Vulvar intraepithelial neoplasia type III: carcinoma in situ of the vulva. Note the pigmented and multicentric nature of the lesions and the extensive perianal involvement in this patient.

Diagnosis

Careful inspection of the vulva in a bright light, with the aid of a magnifying glass if necessary, is the most useful technique for detecting abnormal areas. Colposcopic examination of the entire vulva after the application of 5% acetic acid will sometimes highlight additional acetowhite areas.

Management

The mainstay of treatment is local superficial surgical excision, with primary closure. The microscopic disease seldom extends significantly beyond the colposcopic lesion, so margins of about 5 mm are usually adequate. For extensive lesions involving most of the vulva, a “skinning” vulvectomy, in which the vulvar skin is removed and replaced by a split-thickness skin graft, may be used. Because the subcutaneous tissues are not excised, the cosmetic result is superior to that obtained with vulvectomy.

Laser therapy is also effective, particularly for multiple small lesions, or for lesions involving the clitoris, labia minora, or perianal area. No specimen is available for histologic study after laser ablation, so a liberal number of biopsies must be taken before treatment to exclude invasive cancer.

PAGET’S DISEASE

Paget’s disease of the vulva predominantly affects postmenopausal white women. Paget’s disease also occurs in the nipple areas of the breast.

Clinical Features

Itching and tenderness are common and may be long-standing. The affected area is usually well demarcated and eczematoid in appearance, with the presence of white plaquelike lesions. As growth progresses, extension beyond the vulva to the mons pubis, thighs, and buttocks may occur; rarely, it may extend to involve the mucosa of the rectum, vagina, or urinary tract. In 10% to 20% of cases, Paget’s disease is associated with an underlying adenocarcinoma.

Histologic Features

The disease is an adenocarcinoma in situ and is characterized by large, pale, pathognomonic Paget’s cells, which are seen within the epidermis and skin adnexa. They are rich in mucopolysaccharide, a diastase-resistant substance that stains positive with periodic acid–Schiff stain. The intracytoplasmic mucin may also be demonstrated by Mayer’s mucicarmine stain. The Paget’s cells are typically located adjacent to the basal layer, both in the epidermis and in the adnexal structures.

Management

The histologic extent of Paget’s disease is frequently far beyond the visible lesion. Local superficial excision with 5- to 10-mm margins is required to clear the gross lesion, exclude underlying invasive cancer, and relieve symptoms. Recurrences are common and may be treated by further excision or laser therapy. If an underlying invasive carcinoma is present, the treatment should be the same as for other invasive vulvar cancers.

image Invasive Vulvar Cancer

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma accounts for about 90% of vulvar cancers.

Clinical Features

Patients generally present with a vulvar lump, although long-standing pruritus is common. The lesions may be raised, ulcerated, pigmented, or warty in appearance, and definitive diagnosis requires biopsy under local anesthesia.Most lesions occur on the labia majora; the labia minora are the next most common sites. Less commonly, the clitoris or the perineum is involved (Figure 40-2). About 5% of cases are multifocal.

image

FIGURE 40-2 A small perineal carcinoma. Note that the remainder of the vulva is normal.

Methods of Spread

Vulvar cancer spreads by direct extension to adjacent structures, such as the vagina, urethra, and anus; by lymphatic embolization to regional lymph nodes; and by hematogenous spread to distant sites, including the lungs, liver, and bone. In most cases, the initial lymphatic metastases are to the inguinal lymph nodes, located between Camper’s fascia and the fascia lata. From these superficial nodes, spread occurs to the femoral nodes located medial to the femoral vein. Cloquet’s node, which is situated beneath the inguinal ligament, is the most cephalad of the femoral node group. From the inguinofemoral nodes, spread occurs to the pelvic nodes, particularly the external iliac group (Figure 40-3).

image

FIGURE 40-3 Lymphatic drainage of the vulva. Inguinal nodes are displayed on the right side of the groin, and femoral nodes are seen on the left side of the groin.

The incidence of lymph node metastases in vulvar cancer is about 30%. It is related to the size of the lesion (Table 40-1). About 5% of patients have metastases to pelvic lymph nodes. Such patients usually have three or more positive unilateral inguinofemoral lymph nodes. Hematogenous spread usually occurs late in the disease and rarely occurs in the absence of lymphatic metastases.

TABLE 40-1 INCIDENCE OF LYMPH NODE METASTASES IN RELATION TO LESION SIZE IN VULVAR CANCER

image

Staging

In 1989, the International Federation of Gynecology and Obstetrics (FIGO) Cancer Committee introduced a surgical staging system for vulvar cancer. This system was revised in 1994, and the present FIGO staging system is shown in Table 40-2.

TABLE 40-2 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING OF VULVAR CARCINOMA (1994)

Stage 0

Carcinoma in situ, intraepithelial carcinoma

Stage I

Tumor confined to the vulva or perineum, or both, and 2 cm or less in greatest dimension; no nodal metastasis

Stage Ia

As above with stromal invasion ≤1 mm

Stage Ib

As above with stromal invasion >1 mm

Stage II

Tumor confined to the vulva or perineum, or both, and more than 2 cm in greatest dimension; no nodal metastasis

Stage III

Tumor of any size with:

 

1. Adjacent spread to the urethra and/or vagina and/or anus

 

2. Unilateral regional lymph node metastasis, or a combination

Stage IV

 

Stage IVa

Tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa, pelvic bone or bilateral regional node metastasis, or a combination

Stage IVb

Any distant metastasis including pelvic lymph nodes

Management

In the past, en bloc radical vulvectomy and bilateral inguinofemoral lymphadenectomy, with or without pelvic lymphadenectomy, had been considered the standard treatment for invasive vulvar cancer. During the past 30 years, a more conservative approach has been used for the primary lesion, and the groin dissection has frequently been performed through a separate groin incision.

Using the separate incision technique, major wound breakdown is significantly reduced, so hospital stays are shorter. Groin seromas and cellulitis are common acute complications, whereas deep venous thrombosis and pulmonary embolism are uncommon. Chronic complications include lower leg lymphedema, genital prolapse, and urinary stress incontinence. Rarely, introital stenosis, pubic osteomyelitis, a femoral hernia, or a rectoperineal fistula may occur.

To decrease the morbidity associated with groin dissection, current research is focusing on identification of a sentinel node (or nodes). After the injection of a blue dye and a radiocolloid around the primary tumor, the sentinel nodes are identified and resected. They are subjected to thorough histopathologic analysis to detect any small micrometastases. Theoretically, patients with negative sentinel nodes should be at very low risk for disease in other nodes, so full groin dissection could be avoided. At the time of writing, this approach remains experimental.

EARLY VULVAR CANCER

During the past 30 years, much emphasis has been placed on vulvar conservation in an attempt to decrease psychological morbidity. With respect to the lymphadenectomy, patients with stage Ia disease(i.e., with T1 tumors and penetration depth of <1 mm from the overlying basement membrane) do not need groin dissection. All other patients require at least an ipsilateral inguinal-femoral lymphadenectomy. For patients with midline lesions invading more than 1 mm, bilateral groin dissection is necessary. For ipsilateral lesions, there is about a 1% risk for involvement of the contralateral nodes if the ipsilateral nodes are negative.

For patients with TI or T2 lesions (i.e., lesions confined to the vulva), a wide and deep local excision (radical local excision) is as effective as radical vulvectomy in preventing local recurrenceprovided that the remainder of the vulva is normal. For patients with stage I vulvar cancer, there is about a 10% risk for local recurrence, even with radical vulvectomy, and this incidence appears to be no higher with radical local excision. Surgical margins should be at least 1 cm.

ADVANCED VULVAR CANCER

If the cancer involves the proximal urethra, anus, or rectovaginal septum, radical surgery would necessitate a bowel or urinary stoma. For such patients, preoperative radiation or chemoradiation should be used to shrink the primary tumor, followed by more conservative surgical excision. Bilateral groin node dissection, or at least removal of any large, positive nodes, is usually performed before the radiation therapy. Most patients can be spared a stoma with this approach.

MANAGEMENT OF PATIENTS WITH POSITIVE NODES

Patients with more than one nodal micrometastasis (≤5 mm in diameter), one or more macrometastases, or evidence of extranodal spread should receive postoperative radiation to both groins and to the pelvis.

Prognosis

The overall survival rate for vulvar carcinoma is about 70%. Survival by FIGO stage is shown in Table 40-3. Survival also correlates significantly with lymph node status because patients with positive nodes have a 5-year survival rate of about 50%, whereas those with negative nodes have a 5-year survival rate of about 90%. Patients with one involved node have a good prognosis, regardless of stage, whereas those with three or more involved nodes do poorly, regardless of stage.

TABLE 40-3 SURVIVAL FOR VULVAR CANCER BY FIGO STAGE (EPIDERMOID INVASIVE CANCER ONLY)

Stage

No. of Patients

Five-Year Survival (%)

I

160

76.9

II

202

54.8

III

125

30.8

IV

44

8.3

Data from the Annual Report on the Results of Treatment in Gynecological Cancer. Patients treated 1996-1998. J Epidemiol Biostat 83:7-26, 2003.

MALIGNANT MELANOMA

Malignant melanoma is the second most common type of vulvar cancer. Melanomas may arise de novo or from a preexisting junctional or compound nevus. They occur predominantly in postmenopausal white women and most commonly involve the labia minora or clitoris (Figure 40-4).

image

FIGURE 40-4 Malignant melanoma arising from the right labium minus.

Diagnosis and Staging

Any pigmented lesion on the vulva requires excisional biopsy for histologic diagnosis. The FIGO staging of vulvar cancer does not apply well to melanomas, which are usually smaller lesions and tend to metastasize early. The prognosis correlates more closely with the depth of penetration into the dermis. Those lesions that penetrate to a depth of 1 mm or less from the granular layer of the epidermis rarely metastasize. Clark’s levels are not readily applicable to vulvar melanomas.

Management

For the superficial lesions referred to previously, radical local excision alone, with margins of at least 1 cm, is adequate therapy. For lesions with 1 mm or deeper invasion, radical local excision of the primary tumor is usually combined with at least ipsilateral inguinal-femoral lymphadenectomy. Adjuvant therapy with nonspecific immunostimulants or chemotherapeutic agents has been disappointing, although vaccines prepared from the patient’s own tumor have shown some promise.

Prognosis

The overall 5-year survival rate for vulvar melanomas is about 30%, which is comparable to that for cutaneous melanomas of nongenital origin.

VERRUCOUS CARCINOMA

Verrucous carcinoma is a variant of squamous cell carcinoma and was originally described in the oral cavity. The lesions, which are cauliflower-like in nature, may occur in the cervix, vulva, or vagina. Invasion occurs with a broad “pushing” front, and unless the base of the lesion is submitted for histologic examination, these tumors may be difficult to differentiate from condyloma acuminatum or squamous papilloma. Metastasis to regional lymph nodes is rare, but the tumors are locally aggressive and prone to local recurrence unless wide surgical margins are obtained. Radiation therapy may induce anaplastic transformation and is contraindicated.

BARTHOLIN’S GLAND CARCINOMA

Adenocarcinomas, squamous cell carcinomas, and rarely, transitional cell carcinomas may arise from the Bartholin’s gland and its duct. A history of preceding inflammation of Bartholin’s gland is present in about 10% of patients, and malignancies may be mistaken for benign cysts or abscesses. Current management consists of hemivulvectomy and ipsilateral inguinofemoral lymphadenectomy. Postoperative vulvar irradiation appears to decrease the local recurrence rate for patients with large lesions.

BASAL CELL CARCINOMA

Basal cell carcinomas of the vulva are rare. They commonly present as a rolled-edged “rodent” ulcer, although nodules and macules may occur. They are locally aggressive but nonmetastasizing, so wide local excision is adequate treatment.

Vulvar Sarcoma

Vulvar sarcomas represent 1% to 2% of vulvar malignancies. Many histologic types have been reported, including leiomyosarcomas, fibrosarcomas, neurofibrosarcomas, liposarcomas, rhabdomyosarcomas, angiosarcomas, and epithelioid sarcomas. Leiomyosarcomas are the most common, and recurrences are most likely with lesions larger than 5 cm, with infiltrating margins, and with five or more mitotic figures per 10 high-power fields.

image Vaginal Neoplasms

INTRAEPITHELIAL NEOPLASIA

Carcinoma in situ of the vagina, or vaginal intraepithelial neoplasia (VAIN), is much less common than its counterparts on the cervix or vulva. Most lesions occur in the upper third of the vagina, and the patients are usually asymptomatic.

Etiology

VAIN appears to be related to infection with the wart virus in many cases, and vaccination against HPV should decrease the incidence of VAIN and vaginal cancer in the future. Patients with a past history of in situ or invasive carcinoma of the cervix or vulva are at increased risk. Some lesions may occur after irradiation for cervical cancer.

Diagnosis

The diagnosis is usually considered because of an abnormal Papanicolaou smear in a woman who either has had a hysterectomy or has no demonstrable cervical abnormality. Definitive diagnosis requires vaginal biopsy, which should be directed by colposcopy or Lugol’s iodine staining. Colposcopic findings are similar to those seen with cervical lesions, although thorough colposcopy of all vaginal walls is technically more difficult. In postmenopausal patients, a 4-week course of topical estrogen before colposcopy is indicated to enhance the colposcopic features and eliminate those patients with Papanicolaou smear abnormalities because of inflammatory atypia.

Management

When the lesion involves the vaginal vault, surgical excision is indicated to treat the VAIN and to exclude invasive cancer. For multifocal disease, laser therapy or topical 5-fluorouracil may be used. Extensive disease may require total vaginectomy and creation of a neovagina using a split-thickness skin graft.

SQUAMOUS CELL CARCINOMA OF THE VAGINA

Squamous cell carcinoma of the vagina is uncommon. The mean age of patients at presentation is about 60 years. Up to 30% of patients with primary vaginal cancer have a history of in situ or invasive cervical cancer that was treated at least 5 years earlier. Symptoms consist of abnormal vaginal bleeding, vaginal discharge, and urinary symptoms. On physical examination, ulcerative, exophytic, and infiltrative growth patterns may be seen. About half of the lesions are in the upper third of the vagina, particularly on the posterior wall. Punch biopsy is required to confirm the diagnosis.

Patterns of Spread

Vaginal cancer spreads by direct invasion as well as by lymphatic and hematogenous dissemination. Direct tumor spread may result in involvement of the bladder, urethra, or rectum, or progressive lateral extension to the pelvic side wall. The lymphatic drainage from the upper vagina is to the obturator, hypogastric, and external iliac nodes, whereas the lower third of the vagina drains primarily to the inguinofemoral nodes. Hematogenous spread is uncommon until the disease is advanced.

Staging

The FIGO staging for vaginal cancer is clinical, as shown in Table 40-4. In practice, all patients should have at least a chest radiograph and pelvic and abdominal computed tomography or magnetic resonance imaging to detect evidence of metastatic spread, including bulky pelvic or para-aortic lymph nodes. Positron emission tomography is increasingly used to look for metastatic disease.

TABLE 40-4 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING OF VAGINAL CANCER

Stage I

Carcinoma limited to the vaginal wall

Stage II

Carcinoma has involved the subvaginal tissue but has not extended onto the pelvic side wall

Stage III

Carcinoma has extended to the pelvic side wall

Stage IV

Carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum

Stage IVa

Spread to bladder or rectum

Stage IVb

Spread to distant organs

Management

Radiotherapy or chemoradiation is the main method of treatment for primary vaginal cancer. Initial treatment usually consists of 4500 to 5000 cGy of externalirradiation to the pelvis to shrink the primary tumor and treat the pelvic lymph nodes and paravaginal tissues. Brachytherapy is then given, either with intracavitary vaginal applicators or by interstitial techniques. When the lower third of the vagina is involved, the groin nodes should either be included in the treatment field or surgically removed.

Radical surgery has a limited role in the management of vaginal cancer. Radical hysterectomy, partial vaginectomy, and pelvic lymphadenectomy may be performed for early lesions in the posterior fornix. Surgery should otherwise be reserved for medically fit patients in whom a central recurrence develops after irradiation. Pelvic exenteration with creation of a neovagina may be appropriate in such patients provided there are no lymph node metastases at the time of exploratory laparotomy and adequate surgical margins can be attained.

Prognosis

The overall 5-year survival rate for vaginal cancer is about 50%. When corrected for death from intercurrent disease, 5-year survival rates should be about 85% to 90% for stage I lesions, 55% to 65% for stage II lesions, 30% to 35% for stage III lesions, and 5% to 10% for stage IV lesions.

RARE VAGINAL CANCERS

Adenocarcinoma

Most adenocarcinomas of the vagina are metastatic, usually from the cervix, endometrium, or ovary, but occasionally from more distant sites such as the kidney, breast, or colon. Most primary vaginal adenocarcinomas are clear cell carcinomas in female offspring of women who ingested diethylstilbestrol (DES) during pregnancy (see later in this chapter). Primary adenocarcinomas of the vagina not related to DES are rare but may arise in residual glands of müllerian (paramesonephric) origin, Gartner’s duct (a remnant of the embryonic wolffian or mesonephric duct), or foci of endometriosis.

Malignant Melanoma

Vaginal melanomas account for fewer than 2% of vaginal malignancies. The mean age at diagnosis is 55 years. The carcinoma usually occurs on the distal anterior wall. Radical surgery has been the traditional treatment, but comparable local control and overall survival maybe obtained with conservative tumor resection and postoperative radiation therapy. The use of high-dose fractions (>400 cGy) may be beneficial. The prognosis is poor, with an overall 5-year survival rate of 5% to 10%.

Sarcoma

Vaginal sarcomas are rare. In adults, leiomyosarcomas are most common, whereas in infants and children, sarcoma botryoides predominates. The latter term comes from the Greek botrys (bunch of grapes), which these lesions usually grossly resemble. The mean age at diagnosis of sarcoma botryoides is 2 to 3 years, with a range of 6 months to 16 years. Histologically the tumor is an embryonal rhabdomyosarcoma. Treatment consists of conservative surgical resection followed by adjuvant chemotherapy, with or without radiation therapy.

image Diethylstilbestrol Exposure in Utero

In 1971, an association between in utero exposure to DES and the later development of clear cell adenocarcinoma of the vagina was reported. Since that time, numerous non-neoplastic uterine and vaginal anomalies have been reported in young women exposed in utero to DES. Vaginal adenosis (vaginal columnar epithelium) is the most common anomaly and is present in about 30% of exposed females.This tissue behaves similarly to the columnar epithelium of the cervix and is replaced initially by immature metaplastic squamous epithelium. With progressive squamous maturation, complete resolution of this anomaly usually occurs.

Structural changes of the cervix and vagina occur in about 25% of exposed females. Possible changes include a transverse vaginal septum, cervical collar, cockscomb (a raised ridge, usually on the anterior cervix), or cervical hypoplasia. Most of these changes tend to disappear as the individual matures. The risk is insignificant if the drug was given after the 22nd week of gestation.

In addition to these changes in the lower genital tract, upper genital tract anomalies occur in at least half of patients and may be associated with exposure later in pregnancy. The most common abnormalities are a T-shaped uterus and a small uterine cavity (<2.5 cm in length). Exposed individuals have an increased risk for miscarriage, premature delivery, or ectopic pregnancy, but most are able to deliver a viable infant successfully.

CLEAR CELL ADENOCARCINOMA

The risk for developing a clear cell adenocarcinoma following DES exposure in utero is somewhat less than 1 in 1000. The tumors are rare before age 14 years, and the mean age of patients at diagnosis is about 19 years. A few cases have been reported in women in their 40s and 50s. Not all patients with vaginal clear cell adenocarcinomas give a history of prior DES exposure in utero. For early tumors, radical hysterectomy and vaginectomy (with creation of a neovagina) or radiation therapy is effective. Overall, the 5-year survival rate is about 80%, which is considerably better than that for squamous cell cancer of the cervix or vagina.

SUGGESTED READING

Chan J.K., Sugiyama V., Pham H., et al. Margin distance and other clinico-pathologic factors in vulvar carcinoma: A multivariate analysis. Gynecol Oncol. 2007;104:636-641.

Hacker N.F. Vulvar cancer. In Berek J.S., Hacker N.F., editors: Practical Gynecologic Oncology, 5th ed, Philadelphia: Lippincott Williams & Wilkins, 2009.

Hakim A.A., Terada K.Y., et al. Sentinel node dissection in vulvar cancer: Current treatment options in oncology. 2006;7:85-91.

Jones R.W., Baranyai J., Stables S. Trends in squamous cell carcinoma of the vulva: The influence of vulvar intraepithelial neoplasia. Obstet Gynecol. 1997;90:448-452.

Landrum L.M., Lanneau G.S., Skaggs V.J., et al. Gynecologic Oncology Group risk groups for vulvar carcinoma: Improvement in survival in the modern era. Gynecol Oncol. 2007;106:521-525.

Tran P.T., Su Z., Lee P., Lavori P., et al. Prognostic factors for outcome and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol. 2007;105:641-649.