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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 111Neoplasms of the Vulva and Vagina

, MD and , MD.

The Vulva

Cancer of the vulva accounts for 4% of malignant neoplasms in the lower genital tract. It is the fourth most frequent gynecologic cancer.1

Most vulvar carcinomas occur in older women, with more than 50% of the patients being 60 to 79 years of age. Invasive vulvar carcinomas are being seen with increasing frequency in younger patients, however, with 15% of vulvar cancers arising in women under the age of 40 years (Fig. 111.1).2 This increased frequency in younger patients may be attributed to an increase in the number of sexual partners or venereal viral infections within the population.

Figure 111.1. Age incidence curve for cancer of the vulva in Caucasian women in the United States.

Figure 111.1

Age incidence curve for cancer of the vulva in Caucasian women in the United States. Source: Menczer J, Voliovitch Y, Modan B, et al. Some epidemiologic aspects of carcinoma of the vulva in Israel. Am J Obstet Gynecol 1982;143:893.

Several epidemiologic studies suggest a sexually transmitted origin for carcinoma of the vulva. Condyloma acuminata associated with human papilloma virus (HPV) has been noted in many patients with premalignant and malignant vulvar disease. It has been estimated that over 1 million women per year in the United States develop perineal warts, and that as many as 10% are infected with HPV.3 Currently, HPV types 6 and 11 are most frequently found in benign vulvar warts while HPV types 16, 18, 31, 33, and 45 are more frequently associated with intraepithelial neoplasia or invasive carcinoma.3–5

Although epidemiologic evidence strongly suggests a viral cause, other associations have been implied as well. Factors such as granulomatous diseases of the vulva, diabetes, hypertension, and obesity also have been associated with vulvar carcinoma, but perhaps because of the usual age of patients. A case-control study by Mabuchi and colleagues6 found that domestic servants, or those working in laundry or cleaning plants, have an increased risk for vulvar carcinoma, thus suggesting an environmental component.

The association of carcinoma in situ with invasive carcinoma of the vulva indicates a continuum from preinvasive to invasive carcinoma. The progression of vulvar intraepithelial neoplasia to invasive carcinoma has been estimated to be on the order of 6%.7,8 Progression, however, may differ in younger and older patients. Some authors suggest that the multifocal carcinoma in situ of women in their thirties or forties may not be as likely to progress as that seen in older women.9–11

Vulvar Atypias

There has been a lack of uniformity in defining vulvar atypias. There is minimal data to support vulvar dystrophies being a cause of cancer. The International Society for the Study of Vulvar Disease has provided a standard nomenclature for these lesions, and this has been adopted by the International Society for Gynecologic Pathology (Table 111.1).12 The 1985 nomenclature has been replaced by the terms carcinoma in situ or vulvar intraepithelial neoplasia (VIN). In addition, the nonpremalignant squamous changes previously termed hyperplastic dystrophy are now considered under the classification of squamous hyperplasia.

Table 111.1. Classification of Vulvar Atypias.

Table 111.1

Classification of Vulvar Atypias.

Vulvar atypias can present with a variety of symptoms. The most common is irritation or itching; however, 20% of patients are asymptomatic.

Grossly, the lesions can be flat, raised (i.e., maculopapular), or verrucous. In color, they may be brown (i.e., hyperpigmented), red (i.e., erythroplastic), white, or discolored.

White lesions can appear to have a whitish, thickened keratin layer (i.e., leukoplakia) or a diffuse, white, brittle, paperlike appearance (i.e., lichen sclerosis) (Fig. 111.2). Areas of squamous hyperplasia (i.e., hyperplastic dystrophy) as well as dysplasia can also have a white appearance. Unlike lichen sclerosis, however, the tissue often is thickened, and the process tends to be focal or multifocal rather than diffuse.13

Figure 111.2. Lichen sclerosis of the vulva, with a basal cell carcinoma of the right lower portion of introitus.

Figure 111.2

Lichen sclerosis of the vulva, with a basal cell carcinoma of the right lower portion of introitus.

Microscopically, atypical changes in the vulvar epithelium consistent with preinvasive lesions usually are marked by loss of maturation of the squamous epithelium. There is increased mitotic activity and an increase in the nuclear cytoplasmic ratio. Mild dysplasia (VIN I) is diagnosed if changes involve the lower third of the epithelium. If there is moderate dysplasia (VIN II), then one-half to two-thirds of the epithelium is affected. If there is severe dysplasia (VIN III), then two-thirds of the epithelium is affected. For carcinoma in situ (also classified as VIN III) of the vulva, the full thickness of epithelium usually is abnormal.

It often is difficult to distinguish between benign squamous hyperplasia and intraepithelial neoplasia. Crum and colleagues14 suggested that nuclear size may be helpful in diagnosis because intraepithelial neoplasia of the vulva almost always contains nuclei that are fourfold or greater in size compared with benign condyloma or non-neoplastic epithelium.15

The best method of establishing a diagnosis is a high index of suspicion and early biopsy. Several methods also can be used to help assess these lesions. Cytology, colposcopy, and toluidine blue O can be used cautiously before biopsy. In general, however, cytologic evaluation of the vulva has not been helpful as a screening examination because the vulvar skin often is thickened and keratinized. Colposcopic examination of the vulva is difficult because unlike cervical lesions, the changes are difficult to recognize. Therefore, colposcopic examination is not used for routine vulvar examination; rather, it is primarily employed for patients who are being evaluated or followed for vulvar atypia or intraepithelial malignancies. The toluidine blue O test is nonspecific and stains nuclei in the superficial part of the epithelium. Colposcopy is performed after applying a 1% aqueous solution of toluidine blue O to the vulva for 1 minute and decolorizing the tissue with 1% acetic acid. Areas that retain the stain are biopsied. A positive test, however, does not always indicate a premalignant condition, because 20% of benign areas on the vulva stain positively.

To obtain the entire thickness of the skin for a definitive diagnosis, a biopsy of the vulva usually is done with a Keys dermal punch. Occasionally, a larger biopsy is needed, in which case a larger field can be locally anesthetized with xylocaine and a small scalpel or cervical punch biopsy used to obtain a specimen.

Once the correct diagnosis has been established by biopsy, appropriate therapy can be undertaken. For lichen sclerosis, 2% topical testosterone propionate in petrolatum, used twice daily, is an effective preparation to overcome the epithelial atrophy. The medication should be given continuously, or the atrophy returns. Side effects such as clitoral hypertrophy and increased hair growth can occur.

Local measures (e.g., cotton underclothes, avoidance of strong soaps and detergents) often are used to diminish irritation. Topical fluorinated corticosteroids applied twice daily for 1 to 2 weeks are helpful in controlling pruritus, but prolonged use of these steroid preparations can lead to vulvar atrophy or contracture. If long-term therapy is needed, a nonfluorinated compound (e.g., 1% hydrocortisone) is used. Some patients with lichen sclerosis have severe contracture in the area of the posterior fourchette. Treating these areas surgically with plastic repair of the fourchette has been suggested.16,17

Vulvar intraepithelial neoplasia can be treated by a variety of methods, and many authors have reported successful control of the disease by wide local excision.7,16 Buscema and colleagues7 reported that 68% of 62 patients had no evidence of recurrence when treated by wide excision. Adequate margins must be obtained with wide excision; however, this often may be difficult because of the multifocal nature of the disease. Friedrich and colleagues18 reported a 50% risk of recurrence if the margins were involved with neoplasia.

Other modalities also have been reported in the treatment of vulvar intraepithelial neoplasia. Carbon dioxide laser vaporization of the vulva to a depth of 3 mm has been used, and current evidence indicates that laser therapy is as effective as surgical excision for the control of this disease. Before lasering the vulva, however, it is necessary to ascertain by histologic confirmation that invasive disease does not exist. Leuchter and colleagues6 treated 142 patients with carcinoma in situ of the vulva. Of those treated by laser, 17% had a recurrence, a result that is similar to that in lesions treated by local excision.

5-Fluorouracil (5-FU) cream has been used successfully to treat carcinoma in situ of the vulva, and application of this has been reported to be successful in 75% of cases. With continuous application, however, this treatment causes edema and pain.

Paget’s Disease

Paget’s disease is a rare intraepithelial disorder of the vulvar skin that is seen in postmenopausal women.19–21 Unlike VIN, the intraepithelial neoplastic cells are glandular rather than squamous. The lesion primarily occurs in Caucasians of an average age of 65 years. Grossly, it appears as a reddish, eczematoid lesion. Microscopically, this type of lesion is characterized by large pale cells that often occur in nests and infiltrate through the epithelium. Once the diagnosis is made, it is important to rule out the presence of an underlying cancer. A review by Lee and colleagues20 reported a total of 75 cases of Paget’s disease of the vulva: 16 (22%) of the patients had underlying invasive carcinoma of the adnexal structures, and 7 (9%) had adnexal carcinoma in situ.

Paget’s disease of the vulva often spreads in an occult fashion, with margins extending beyond the normal appearance of the lesion.21 If there is no evidence of an underlying malignant neoplasm, a wide local excision or total vulvectomy usually is performed.22 If wide local excision is performed, a slightly deeper excision is needed to remove the epidermis down to the level of the underlying fat to ensure removal of adnexal skin structures. Because this lesion extends subepithelially, a frozen section in the operating room may assist in ensuring complete removal.

Bergen and colleagues22 evaluated 14 patients with Paget’s disease of the vulva that was treated by vulvectomy, skinning vulvectomy with a graft, or hemivulvectomy. With a median follow-up of 50 months, all patients were free of disease; however, 3 patients had had locally recurrent disease.

Other modalities (e.g., topical 5-FU cream, laser) have not been used for treatment of this disease. Because both local and distant recurrence is a major risk, close follow-up is required.

Invasive Vulvar Carcinomas

The International Federation of Gynecology and Obstetrics has defined four clinical stages of vulvar carcinoma.23 In addition, many centers use the tumor, nodes, metastasis (TNM) classification. In 1988, the International Federation of Gynecology and Obstetrics (FIGO) staging was modified to reflect lymph node status as well as the location of the tumor (Table 111.2). In this classification, a tumor that is located on the perineum is no longer is considered to be stage III. In 1995, FIGO instituted a subclassification of stage I into Ia and Ib, based on whether there is stromal invasion greater than 1 mm.

Table 111.2. Classification and Staging of Vulvar Carcinoma.

Table 111.2

Classification and Staging of Vulvar Carcinoma.

Squamous Cell Carcinoma

Squamous cell carcinomas comprise approximately 90% of primary vulvar malignancies. Grossly, these carcinomas usually appear as ulcerated or polyploid masses on the vulva. Biopsy reveals the characteristic histologic appearance: the tumor appears in nests and cords of squamous cells infiltrating the stroma, often with islands of keratin.

The pattern of spread for this carcinoma relates to the intricate lymphatic drainage of the vulva (Fig. 111.3).5 Tumors located in the middle of either labium initially drain to the ipsilateral inguinal femoral nodes whereas midline perineal tumors can spread either to the left or right side. Using technectium 99m colloid, Iverson and Aas24 showed that when radioactivity was injected to one side of the vulva, 98% of it localized in the ipsilateral nodes and less than 2% in the contralateral nodes. Tumors along the midline in the clitoral or urethral areas may spread to either groin. From the inguinal-femoral nodes, lymphatic spread continues to the deep pelvic iliac and obturator nodes. Although there has been concern in the past that tumors in the clitoral-urethral area could spread directly to the deep pelvic nodes, current evidence indicates this is rare.

Figure 111.3. Lymphatic drainage of the vulva.

Figure 111.3

Lymphatic drainage of the vulva.

Stage I Microinvasive Carcinoma

There is no uniformly accepted definition regarding microinvasive carcinoma of the vulva, and this may result from confusion in measuring the depth of invasion. Microinvasion has been defined by some as a small lesion of the vulva less than 2 cm in diameter and invading less than 3 mm.25 The International Society for the Study of Vulvar Diseases has recommended that the term microinvasive be dropped and that stage IA be used for tumors less than 2 cm in diameter and invading less than 1 mm from the epidermal-stromal junction (i.e., basement membrane).

Different clinical results have been reported with this definition. Spread to regional lymph nodes has varied from 0 to 10% in tumors with less than a 5 mm depth of invasion.26–30 For example, Hoffman and colleagues28 reported no nodal metastases in 43 patients whose tumor invaded less than 2 mm. Lesions that were at risk for spread to inguinal nodes included tumors with confluent tongues rather than those with individual tongues merely extending into the stroma. Hacker and colleagues,27 however, reported that 6 of 7 patients with invasion of less than 3 mm had regional node involvement.

The risk of nodal involvement may be decreased when carcinoma in situ is present in the lesion. Rowley and colleagues29 noted only 1 of 35 cases with adjacent carcinoma in situ had nodal metastases. By contrast, 5 of 27 had positive lymph nodes when superficial stage I lesions penetrating 2.1 to 5.0 mm did not have adjacent carcinoma in situ.

For stage IA lesions, therapy may be less extensive than with invasive vulvar carcinoma. Different treatments have been reported, including wide local excision with or without ipsilateral node dissection, simple vulvectomy without node dissection, and radical vulvectomy without node dissection.30–32 In younger patients, especially those with tumors located at a distance from the clitoris, an operation that spares the clitoris should be considered. DiSaia and colleagues31 have recommended an operative procedure in which the superficial inguinal lymph nodes are removed and sent for frozen section. If positive nodes are found, bilateral complete groin dissection and complete radical vulvectomy are performed; if the nodes are negative, wide local excision of the primary cancer is performed.

Iverson and colleagues32 have reported an alternative approach, recommending a hemivulvectomy with ipsilateral groin dissection for lesions involving the labia. For medial lesions, they suggest conventional radical vulvectomy with bilateral groin dissection. Boyce and colleagues recommend that conservative therapy can be used with minimal risk.33 This recommendation appears to be advisable if invasion is greater than 1 mm and the tumor diameter greater than 2 cm.

Stage I, II, and III Invasive Carcinoma

The prognosis of a patient with vulvar carcinoma relates to the stage of disease (Fig. 111.4) as well as the nodal status.34 Presence of carcinoma in the regional lymph nodes correlates with the size and thickness of the primary lesion, the degree of tumor differentiation, and the involvement of vascular spaces by the tumor (Table 111.3). In 272 women with invasive vulvar carcinoma reported by the Gynecologic Oncology Group (GOG), regional nodes were involved in 8.9% of stage I, 25.3% of stage II, and 31.1% of stage III lesions.35 If a lesion was less than 1 mm thick, there was a 3.1% incidence of positive nodes. With larger lesions, 4 mm or greater in thickness, 31% of nodes were positive. Hacker and colleagues36 reported an actuarial 5-year survival rate of 96% in those with negative nodes. Survival decreased to 94% with one positive node, 80% if two nodes were positive, and 12% if three or more nodes were involved by tumor.

Figure 111.4. Survival of patients with carcinoma of the vulva.

Figure 111.4

Survival of patients with carcinoma of the vulva. (Adapted from 20th Report on End Results of Therapy of Gynecologic Malignancies. Stockholm: International Federation of Gynecology and Obstetrics, 1988.)

Table 111.3. Prognostic Factors of Stage, Grade and Tumor Thickness Associated with Positive Regional Nodes.

Table 111.3

Prognostic Factors of Stage, Grade and Tumor Thickness Associated with Positive Regional Nodes.

Not only is the number of nodes important, but there appears to be a correlation with the size of the metastases. Hoffman and colleagues37 noted that 14 of 15 patients with inguinal lymph node metastases measuring less than 36 mm survived free of disease for 5 years compared with 12 of 29 patients whose tumor metastases measured greater than 100 mm.

The grade of tumor related to the percent of positive nodes in the GOG study. Patients with grade 1 lesions did not have positive nodes, yet patients with grade 4 lesions had 47.7% of nodes being positive.

Vascular space involvement also was prognostic because 72% with vascular invasion showed tumor in regional nodes compared with 34% of those without vascular invasion. Nodal involvement also correlated with the location of the primary lesion.38 Lesions on the labia are associated with 7.4% positive nodes whereas clitoral lesions have a higher incidence of positive nodes (27.4%).39 Boyce and colleagues33 reported that six tumors under 1 cm in diameter had no metastases to regional nodes, but that the fraction of tumors with positive nodes rose to 55% for 29 cases with lesions over 4 cm.

Therapy for stage I, II, and early stage III vulvar carcinoma is accomplished with radical vulvectomy and bilateral inguinal femoral node dissection. The deep pelvic nodes are rarely removed unless the inguinal nodes are involved. Most oncologists now remove only the inguinal and femoral nodes at the time of operation and treat the deep pelvic nodes with external radiation if superficial nodes are involved with tumor.

Different surgical approaches to invasive vulvar carcinoma have been evaluated. Classically, an en bloc dissection has been performed. Radical vulvectomy and groin dissection have been carried out through a single suprapubic incision that extends between the left and right anterior iliac spines (Fig. 111.5). This operation removed the entire vulva, including the clitoris, subcutaneous tissue, and inguinal femoral nodes. If the lesion involved the distal urethra, this has often been removed without the loss of urinary continence. In this procedure, the major complication has been wound breakdown and infection (occurring in 50% of the patients). Recently, modifications have been introduced to decrease the incidence of wound breakdown. These modifications include performing the inguinal femoral node dissection through separate inguinal incisions, then completing the radical vulvectomy. Tumor recurrences rarely occur in the skin bridge when separate groin incisions are used.40

Figure 111.5. Gross vulvectomy specimen showing a vulvar carcinoma.

Figure 111.5

Gross vulvectomy specimen showing a vulvar carcinoma.

Less-mutilating procedures also have been reported in stage I disease. Rowley and colleagues29 reported using wide local excision and superficial inguinal node dissection in 20 patients with stage I lesions invading to a depth of less than 5 mm. The superficial and contralateral inguinal femoral nodes were removed only if the superficial nodes contained tumor. This approach seems to be reasonable if a unilateral lesion is present; however, with a midline lesion, bilateral inguinal node dissection seems to be appropriate. In a recent update of a series of 50 patients initially reported by DiSaia, only one patient died because of recurrent carcinoma treated with the latter conservative approach.31 Six patients had only recurrent carcinoma in situ or minimally invasive carcinoma. Modifying the approach for these early-stage lesions appears to be effective and is associated with less morbidity than the standard radical vulvectomy. If the nodes are free from tumor in stage I and II carcinomas of the vulva, no further therapy is required. If the nodes (especially the femoral nodes) are involved, pelvic irradiation is required. Homesley and colleagues35 reported, from a randomized study, an improved survival rate in 118 patients with positive lymph nodes who received 4,500 to 5,000 cGy of radiation (Fig. 111.6).

Figure 111.6. Treatment of squamous cell carcinomas of the vulva.

Figure 111.6

Treatment of squamous cell carcinomas of the vulva.

Advanced Vulvar Tumor

Large tumors of the vulva encroaching on the anorectal area and the urethra require more extensive treatment than a radical vulvectomy. In addition to a radical vulvectomy, it usually is necessary to perform a diversion of the urinary or fecal stream. If the nodes are negative, a 5-year survival rate of 50% has been reported.

However, newer approaches that involve a combination of preoperative radiation and surgery have been reported in treating these lesions. External radiation often is given to reduce the size of the tumor before surgical removal by radical vulvectomy, with or without regional lymph node dissection. Approximately 4,000 to 4,500 cGy is delivered to the pelvis and inguinal nodes, the operation being performed 5 weeks after the completion of radiation. This approach may obviate a urinary or fecal diversion. Boronow and colleagues41,42 reported a 5-year survival rate of 80% in 26 patients with primary carcinoma of the vagina and vulva who were treated with this technique. Rotmensch and colleagues43 recently reported on 16 patients with advanced vulvar lesions who were treated with preoperative radiation to the vulva and achieved an overall 5-year survival rate of 45%. Recurrences were more likely if the resection margins were within 1 cm of the tumor. Complications have included stenosis of the introitus and urethra as well as rectovaginal fistula.

Because the vulvar skin is prone to radiation dermatitis, fibrosis, and ulceration, radiation as sole therapy has been less than desirable. If the patient is inoperable because of medical conditions, however, radiation can be used as the primary treatment of a vulvar carcinoma.44


Recurrences may be local or distant. More than 80% of recurrences occur in the first 2 years after therapy. The risk for recurrence of vulva carcinoma increases as the stage of disease increases. In an analysis of 224 patients with vulvar carcinoma, Podratz and colleagues45 reported a recurrence rate of 14% in stage I and 71% in stage IV disease. Local recurrences were the most common.

Different modalities have been used to treat local recurrences. Both radiation therapy and resection of local vulvar recurrence provide effective control and a 5-year survival rate of approximately 50%.

The combination of chemotherapy and radiation therapy has been used to treat recurrent disease and some large, primary vulvar carcinomas. Thomas and colleagues46 reported the use of 5-FU (1 g/m2) as a continuous intravenous infusion for 4 to 5 days every 4 weeks during radiation. This combined approach was the sole treatment in 9 patients, and 6 had a complete remission. Disseminated disease requires chemotherapy, but unfortunately, no chemotherapy has been successful in this situation.

Bartholin’s Gland Carcinoma

Primary carcinoma of Bartholin’s gland accounts for 5% of all vulvar cancers, and over 200 cases have been reported.47 Only approximately 50% of those tumors are non-epidermoid in nature. Bartholin’s gland carcinomas can be either squamous if they originate near the orifice of the duct, or papillary if they arise from transitional epithelium of the duct or they can be adenocarcinomas if they arise from the gland itself. An enlargement of Bartholin’s gland in a postmenopausal female should raise suspicion of malignancy. These tumors are treated similarly to primary squamous cell carcinomas of the vulva, by radical vulvectomy and bilateral inguinal femoral lymphadenectomy. The overall 5-year survival rate of approximately 70% is below that reported for all carcinomas of the vulva and probably relates to a delay in diagnosis.

The adenoid cystic variety of Bartholin’s gland carcinoma invades locally and rarely metastasizes. It usually requires only wide local excision for adequate therapy. Rosenberg and colleagues48 reported 5 cases of adenocystic carcinoma of Bartholin’s gland, with 4 patients alive and free of disease 28 to 57 months after treatment.

Basal Cell Carcinoma

Basal cell carcinoma rarely is encountered in the female genital tract. Such lesions are usually locally invasive, nonmetastatic tumors that are commonly found on the labium majus. Therapy consists of wide local excision of the lesion. If the surgical margins are free of tumor, the disease is cured.

Verrucous Carcinoma

Verrucous carcinoma of the vulva is a variant of epidermoid carcinoma. Clinically, it appears as large, condylomatous lesions. They are locally aggressive, nonmetastatic, fungating tumors that gradually increase in size, pushing into rather than invading the underlying structures. Histologically, they consist of mature squamous cells with extensive keratinization. To establish the diagnosis, adequate biopsy is important because biopsy of a large verrucous carcinoma often can lead to an incorrect diagnosis of condyloma acuminata.

These tumors tend to grow slowly and invade locally, rarely spreading to regional lymph nodes. In 24 cases of verrucous carcinoma, Japaze and colleagues49 found no lymph node metastases. Depending on the size and location of tumor, a wide local excision or simple vulvectomy is effective therapy; radical vulvectomy with inguinal node dissection or radiation therapy is not indicated as treatment for this entity. Radiation therapy is ineffective and can even worsen the prognosis, causing malignant changes within the tumor. The 17 cases treated surgically by Japaze and colleagues had an excellent 5-year survival rate of 94%. Close long-term follow-up is needed because disease can recur locally, especially if the tumor is large. If concurrent squamous cell carcinoma is found within the verrucous carcinoma, local excision is an inadequate therapy.50


Melanoma is the most frequent nonsquamous cell malignancy of the vulva and comprises approximately 5% of primary carcinomas of the vulva. Approximately 400 cases of melanoma of the vulva have been reported, with an overall 5-year survival rate of approximately 33% irrespective of the therapeutic modality used. Patients with malignant melanoma of the vulva vary widely in age, ranging from the late teens to the eighties, with an average age of approximately 50 years. These lesions most often affect the labia minora or the clitoris.

For vulvar melanomas, the FIGO classification usually has been used. This classification is not, however, as good a prognostic indicator as is the depth of invasion. A system for vulvar melanoma analogous to that used by Clark for cutaneous melanoma has been adopted (Table 111.4). Levels I to V have been identified, based on the Clark classification. The level of invasion correlates with survival, which varies from 100% for level II to 83% for level IV and 28% for level V.51

Table 111.4. Classification of Melanomas of the Vulva.

Table 111.4

Classification of Melanomas of the Vulva.

Two varieties of melanoma have been described: nodular and superficial spreading melanoma.52 The superficial spreading melanoma is more common and has a better prognosis, with a 5-year survival rate of 71%. Nodular melanoma has a worse prognosis, and this directly relates to its potential for vertical growth. The 5-year survival rate for nodular melanoma, which is more invasive, is only 38%.

The thickness of the tumor also may be useful in evaluating this lesion. Breslow53 reported a classification using depth of invasion as measured from the skin surface. In his classification, Breslow reported the overall prognosis as excellent and the spread to regional nodes as unlikely for melanomas whose thickness is less than 0.76 mm (measured from the surface to the deepest point of penetration).

Wide local excision for Clark’s level I and II disease when no palpable regional nodes are present has been recommended.54 In a report of 36 melanoma cases, Rose and colleagues55 noted that wide excision was as effective as radical vulvectomy. Prognosis was better for younger patients, presumably because most had superficial spreading rather than nodular melanomas.

A reasonable approach is to excise a melanoma with a 2-cm margin and without node dissection for cases that are less than 2 mm thick. An excision with a 2- to 3-cm margin combined with node dissection could be performed for more advanced melanomas. An alternative approach for lesions that have extended to Clark’s levels III, IV, and V is radical vulvectomy with groin and pelvic lymphadenectomy.

It has been reported that melanoma of the vulva can metastasize to pelvic nodes, bypassing the inguinal femoral nodes, but current evidence indicates that pelvic node involvement does not occur without prior inguinal node involvement. A further therapeutic consideration is that patients with melanoma whose pelvic nodes are involved with tumor usually do not survive their disease.

Long-term results generally are not available for large series of melanomas. Most series of malignant melanoma report an overall survival rate of approximately 50%.56 For lesions that correspond to Clark’s level I or II (i.e., lesions 0.76 mm thick) and treated by wide local excision, the 5-year survival rate is in the vicinity of 100%. Prognosis becomes poorer with melanomas more than 3 mm thick. If the regional nodes are negative, the survival rate is approximately 60%; if the regional nodes are involved with tumor, survival is only 30%.

The role of chemotherapy for distant metastasis has not been well established. Regressions but not cures have been reported with various multiagent cytotoxic programs, including chemotherapy and/or immunotherapy.


Sarcomas of the vulva are rare. Leiomyosarcomas appear to be the most frequently encountered sarcomas in this group of patients,57 and surgical removal by wide local excision is the recommended initial treatment of choice. The 5-year survival rate is reported to be approximately 100%. Locally recurrent lesions are similarly treated. Chemotherapeutic considerations are the same as for those sarcomas in other sites of the female genital tract.58

Carcinoma of the Vagina

Primary vaginal cancers are rare, constituting less than 2% of all gynecologic malignancies.59,60 Carcinoma of the vagina is defined as a primary carcinoma arising in the vagina and not involving the external os of the cervix superiorly or the vulva inferiorly.

The most common symptom of vaginal carcinoma is abnormal bleeding or discharge. With advanced tumors, pain or urinary frequency occasionally occurs, especially in cases of anterior wall tumors. Constipation or tenesmus has been seen with tumors involving the posterior vaginal wall. These tumors usually are diagnosed by direct biopsy of the tumor mass, and abnormal cytologic findings often will lead to diagnosis of a vaginal cancer.

Staging criteria for vaginal carcinomas according to the International Federation of Gynecology and Obstetrics (FIGO) are given in Table 111.5.

Table 111.5. FIGO Staging Classification for Vaginal Cancer.

Table 111.5

FIGO Staging Classification for Vaginal Cancer.

Premalignant Vaginal Disease

Premalignant disease of the vagina generally is detected on cytologic screening. Once an abnormal cytology is obtained, a biopsy directed by colposcopic examination is required to verify the severity of changes. Because vaginal intraepithelial neoplasia is often multifocal, it is necessary to inspect the entire vaginal canal.

Most lesions occur at the vaginal apex. Audet-Lapointe and colleagues61 noted that 61 of 66 cases of vaginal intraepithelial neoplasia occurred in the upper third of the vagina. These lesions usually can be excised locally. Other modalities often are preferred, however, because of the multifocal nature of this disease or the necessity of excising large areas, requiring skin grafting.62

Nonsurgical approaches for treating these lesions include laser ablation and 5-FU cream for widespread multifocal disease. Carbon dioxide laser frequently has been used and if carried to a depth of 2 to 4 mm, allows for vaporization of abnormal tissue. Preliminary results reported by Petrilli and colleagues63 with this modality have shown a success rate of approximately 90%. Radiation currently is not recommended for the treatment of noninvasive disease because of the proximity of the bladder and rectum and the availability of newer modalities.

Another approach to treating vaginal intraepithelial neoplasia is the use of 5% 5-FU cream for approximately 7 days, repeated every 3 to 4 weeks if the vaginal intraepithelial neoplasia persists. Hyperkeratotic lesions appear to be less sensitive to treatment because of their thickness and parakeratosis. Krebs64 reported on the use of 5% 5-FU daily for 10 days and noted that 17 of 20 patients with vaginal condylomas responded to this therapy. Ballon and colleagues65 and Petrilli and colleagues63 both have reported success rates of 80 to 90% for vaginal intraepithelial neoplasia after multiple cycles of therapy.

Invasive Carcinomas of the Vagina

Squamous cell carcinomas of the vagina may appear grossly as either ulcerated or fungating tumors, or they may be exophytic and protrude through the vaginal canal. They are the most common vaginal malignancy and account for 90% of primary vaginal cancers. The disease occurs primarily in women over 50 years of age. Most squamous cell carcinomas occur in the upper third of the vagina. In examining the patient, it is important to visualize the entire vagina because lesions on the posterior wall can be concealed by a speculum.

Microscopically, these tumors have the classic findings of invasive squamous cell carcinoma. They have pleomorphic squamous cells with occasional keratin pearls.

The location of the tumor determines the areas of lymphatic spread (Fig. 111.7).66 Lymphatics of the middle and upper vagina communicate superiorly with the lymphatics of the cervix and drain into the pelvic nodes of the obturator, internal, and external iliac chains. Lymphatics of the distal third of the vagina drain to the inguinal as well as the pelvic nodes, with a pattern of drainage similar to that of the vulva. The posterior wall lymphatics drain to the rectal lymphatic system.

Figure 111.7. Lymphatic drainage of the vagina.

Figure 111.7

Lymphatic drainage of the vagina.

Depending on the location, both radiation and surgery have been used effectively in treating these lesions (Table 111.6). Treatment is often individualized, depending on the size, stage, and location of the tumor.65

Table 111.6. Treatment Scheme for Vaginal Carcinoma.

Table 111.6

Treatment Scheme for Vaginal Carcinoma.

If the tumor is less than 2 cm thick, some investigators advocate using only local radiation.67 If the carcinoma is less than 0.5 cm thick, intracavitary irradiation with a vaginal cylinder to deliver 8,000 cGy to the mucosa will give over 90% tumor control.68 Spirtos and colleagues69 studied 23 stage I patients and noted only two local recurrences, and both of these had tumor doses of less than 7,500 cGy. For larger lesions, external radiation is used, with a concomitant reduction in the local vaginal component of primary tumor treatment.70 Implants, however, often cannot be used in patients with larger stage III or IV carcinomas. If such is the case, only external beam is used, and a central boost is given after an initial whole-pelvis dose of 5,000 cGy radiation.71

Small tumors located in the upper third of the vagina often can be excised.72 In patients with these, a radical hysterectomy, partial vaginectomy, or pelvic lymphadenectomy usually is effective. Surgery has been preferred in younger patients.

If distant metastasis occurs, effective chemotherapy for recurrent squamous cell carcinoma of the vagina has not been developed. For squamous cell carcinoma, a variety of regimens using multiagent chemotherapy similar to those for cervical carcinoma has been employed.

The overall survival rate for patients with primary carcinoma of the vagina has been reported as approximately 45% and is related to the stage of disease (Table 111.7).

Table 111.7. Stage and Survival of Squamous Cell Carcinoma of the Vagina.

Table 111.7

Stage and Survival of Squamous Cell Carcinoma of the Vagina.

Clear Cell Adenocarcinoma of the Vagina

Clear cell adenocarcinomas have been seen more frequently in young women since 1970 because of the association with intrauterine exposure to diethylstilbestrol.73,74 Three predominant histologic patterns are found with clear cell carcinoma, which have been described as tubulocystic, solid, and papillary patterns.75,76 Most clear cell carcinomas of the vagina are polypoid or nodular, with a reddish color.

Clear cell carcinomas can spread locally as well as by the lymphatic and hematogenous routes. Metastases to regional pelvic nodes have been found in approximately one-sixth of stage I cases. Spread to regional pelvic nodes becomes more frequent in higher-stage tumors. Clear cell adenocarcinomas are staged as other carcinomas of the vagina are by the International Federation of Gynecology and Obstetrics. Some 80% have been diagnosed as stage I or II.

Several prognostic factors have been identified. Older patients (i.e., > 19 years of age) have a more favorable prognosis than younger patients.77 This difference has been associated with the presence of a more favorable tubulocystic pattern of clear cell adenocarcinoma, which is the most frequent histologic pattern found in older patients. In addition, smaller tumor diameter and superficial depth of invasion correlate with improved patient survival.

Survival also depends on the stage of disease. In 547 patients treated for clear cell adenocarcinoma of the vagina, the survival for those in stage I, II, III, and IV has been 93, 83, 37, and 0%, respectively (Table 111.8).77

Table 111.8. Five- and 10-Year Survival for 547 Patients with Clear Cell Adenocarcinoma of the Vagina and Cervix.

Table 111.8

Five- and 10-Year Survival for 547 Patients with Clear Cell Adenocarcinoma of the Vagina and Cervix.

Because of the young age of these patients, surgery often is the primary therapy. For stage I and early stage II disease (Fig. 111.8), radical hysterectomy, partial or complete vaginectomy, pelvic lymphadenectomy, and replacement of the vagina with a split-thickness skin graft has been the approach most frequently used.78

Figure 111.8. Clear cell adenocarcinoma of the anterior wall, with vaginal adenosis on the posterior wall at edge of tumor.

Figure 111.8

Clear cell adenocarcinoma of the anterior wall, with vaginal adenosis on the posterior wall at edge of tumor.

In patients with small, stage I tumors of the vagina, efforts have been made to preserve fertility. The tumor has been excised with retroperitoneal lymph node dissection, followed by local radiation. Senekjian and colleagues reported that the survival rate of patients with small vaginal tumors treated with such an approach compares favorably with that of patients treated with conventional therapy.78 In their series, 8 pregnancies have been reported in 5 patients who were treated locally.

Larger tumors have been treated with whole-pelvic radiation in addition to intracavitary implant. For tumors greater than 2 cm, whole-pelvis radiation of 4,000 to 5,000 cGy has been given, with an additional implant of 3,000 to 4,000 cGy.79 In a few instances, exenterative surgery has been performed for larger tumors; however, this procedure usually has been applied to central recurrences following primary radiation therapy.80

If there is a recurrence, therapy consists of additional radical surgery, often requiring exenteration or extensive radiation localized to the pelvis. Systemic chemotherapy has been used in cases of metastatic disease. Cisplatin (75–100 mg/m2) with a continuous infusion of 5-FU (1 g/m2 for 3 to 5 days every 3 to 4 weeks) is currently recommended. However, no single agent or combination of chemotherapeutic agents has emerged as the most effective. Prolonged follow-up is necessary because recurrences, especially in the lungs and supraclavicular areas, have been reported as long as 19 years after primary therapy.

Vaginal Melanomas

Malignant melanomas of the vagina are rare; they constitute less than 1% of all melanomas occurring in females. Age distribution of the neoplasm has ranged from 22 to 83 years, with an average age of 55. Most patients are postmenopausal and present with vaginal bleeding, discharge, or a mass. Tumors may vary from 0.5 to 7.5 cm in diameter, with approximately 30% being 2 cm or less in diameter. Most of these tumors develop in the distal third of the vagina, commonly on the anterior wall. Primary vaginal melanomas presumably arise from vaginal melanocytes that are present in approximately 3% of normal females. Histologically, this neoplasm is similar to other melanomas found elsewhere and tends to be deeply invasive in the vagina.

The prognosis is worse than that of vulvar melanomas. Chung and colleagues81 reported a 5-year survival rate of only 21% in a series of 19 patients. Reid and colleagues82 reported a 5-year survival rate of 17.4% in 15 cases, but prognosis was improved for those tumors that were small and less than 3 cm in diameter. More recently, Borazjani and colleagues83 reported improved survival for cases in which there were less than six mitoses per 10 high-power fields.

Optimal treatment has not been established. Treatment usually consists of radical surgery or wide excision of the vagina and dissection of the regional lymph nodes, depending on the location of the lesion. Because of the poor prognosis, adjunctive radiation and chemotherapy have been used as local recurrences and distant metastases with this disease are common.

Other Rare Vaginal Tumors in Young Females

Endodermal sinus tumor is a rare germ cell malignancy that usually is found in the ovary.84 This tumor secretes alpha-fetoprotein, which often is a useful tumor marker for monitoring patients with this neoplasm. It usually is found in infants and children, and approximately 20 cases have been reported as occurring in the vaginas of infants who were under 2 years of age.85,86 Patients generally present with complaints of bleeding or spotting from the vagina. On physical examination, there is a friable red to pinkish-white polypoid tumor. This tumor is aggressive, and most patients have died. Therapy has involved surgery, radiation, and chemotherapy. Young and Scully87 reported six patients who were disease-free from 2 to 9 years after local therapy with operation, irradiation, or both, followed by systemic chemotherapy with vincristine, actinomycin-D, and cyclophosphamide (VAC). Copeland and colleagues88 reported similar results using the combination of chemotherapy and excision, and Collins and colleagues89 recently noted the regression of tumor with chemotherapy alone. In this report, a 5-month-old patient had regression of the tumor after VAC therapy.

Another rare tumor found in the vaginas of young females is sarcoma botryoides (i.e., embryonal rhabdomyosarcoma).90 This tumor usually is found in children under 8 years of age. As with endodermal sinus tumor, the most common symptom has been vaginal bleeding. In 58 cases reviewed by Hilgers,39 the average age at onset of symptoms was 38.3 months. This tumor resembles clusters of grapes and forms multiple polypoid masses that are believed to begin in the subepithelial layers of the vagina and to rapidly expand, filling the vagina. Histologically, these tumors are identified by the presence of rhabdomyoblasts that may contain cross-striations. Because of infiltration of the tumor under the vaginal epithelium, there is often a distinct subepithelial zone, called the cambium layer. The 5-year survival rate of these tumors in the past has ranged from 10 to 35%, and exenterative procedures often have been used.91 Hilgers39 reviewed the literature on pelvic exenterations in 21 cases of embryonal rhabdomyosarcoma and found that this form of therapy was ineffective in curing these patients. Effective control with less radical surgery has been achieved using multimodal treatment consisting of multiagent chemotherapy (VAC), combined with operation or radiation.

Hayes and colleagues92 recently reported 21 patients with vaginal rhabdomyosarcoma who received chemotherapy. In their series, 7 relapsed, with 5 of these 7 having had residual disease following incomplete resection. In 17 of 21 patients who received chemotherapy before surgery, a subsequent delayed excision could be performed. Data regarding the long-term survival of a large number of patients are not available, but such a combined approach appears to result in effective therapy with less mutilating surgery.

A rare, benign, fibroepithelial vaginal polyp that resembles sarcoma botryoides can be found in the vaginas of infants or pregnant women.93,94,52 Although large atypical cells are present microscopically, epithelial infiltration, a cambium layer, and strap cells are absent. Grossly, these polyps do not resemble the grape-like appearance of sarcoma botryoides. These hormonally stimulated hyperplastic lesions are called pseudosarcoma botryoides, and treatment by local excision is effective.


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