Amer Karam, MD
PREINVASIVE DISEASE OF THE VULVA
ESSENTIALS OF DIAGNOSIS
Possibly 1–2% of young women with cervical dysplasia have multifocal disease that tends to involve the upper third of the vagina and the vulva, perineum, and perianal areas—these surfaces arising from a common cloacogenic origin.
A spectrum of disease may be found ranging from mild dysplasia to carcinoma in situ. Involvement may not be appreciated without careful inspection with and without the green colposcopy filter. Clinically, the appearance of vulvar intraepithelial neoplasia can be quite variable.
Lesions are typically white and hyperkeratotic, but may also appear gray, pink, or brown.
Colposcopy and biopsy of any suspicious lesion should be performed and is considered the gold standard for diagnosis.
An abnormal vascular pattern is most frequently associated with a severe degree of dysplasia, carcinoma in situ, or early invasive disease.
General Considerations
The vulvar skin is 1 component of the anogenital epithelium, extending from the distal vagina to the perineum and perianal skin. The lower genital tract epithelium is of common cloacogenic origin. Neoplasia of the vulvar skin is often associated with multiple foci of dysplasia in the lower genital tract. A strong association exists between sexually transmitted diseases and vulvar intraepithelial neoplasia (VIN), primarily human papillomavirus (HPV), but also human immunodeficiency virus (HIV). Approximately 90% of VIN lesions are positive for HPV; multicentric VIN is primarily associated with high oncogenic risk HPV subtypes such as types 16, 18, and 31, whereas vulvar condylomata and low-grade VIN are frequently associated with low-risk HPV sub-types 6 and 11. Other risk factors include smoking and other genital precancers or cancers. VIN can also be classified into viral and nonviral etiologies. Younger women are more commonly affected by viral VIN than older women and are also more likely to exhibit multifocal disease. The incidence of VIN has increased over the past decade due to the increased incidence of HPV infections in young women. The incidence of vulvar carcinoma has increased as well but at a relatively slower rate. The long-term risk of malignant transformation of treated VIN III has been estimated at 3.4–7%, and the risk for progression of untreated VIN is thought to be higher.
Premalignant lesions of the vulva occur in both premenopausal and postmenopausal women, with the median age being approximately 40 years. The average age is shifting toward younger women, with 75% of lesions occurring during the premenopausal period. There is no racial predisposition to VIN, and the disease process is often asymptomatic. The most common presenting symptom is pruritus, which is seen in more than 60% of patients with VIN. The diagnosis is made by careful inspection of the vulvar area followed by biopsy of suspicious lesions.
Pathogenesis
Previously, the standard for reporting of vulvar dysplastic lesions was to classify VIN according to the degree of epithelial cellular maturation, with VIN I defined as immature cells occurring in the lower one-third of the epithelium and VIN III as complete loss of cellular maturation in the full thickness of epithelium, which is synonymous with carcinoma in situ of the vulva or Bowen’s disease. VIN II was designated as intermediate between VIN I and VIN III. In 2004, the International Congress of the International Society for the Study of Vulvar Disease (ISSVD) recommended that the designation of VIN be reserved for high-grade lesions such as VIN II and III, which are at higher risk of progression to invasive disease.
In contrast to intraepithelial carcinoma of the cervix, which seems to arise from a single point of origin, dysplasia of the vulva is often multicentric. These lesions may be discrete or diffuse, single or multiple, and flat or raised. They even form papules and vary in color from the white appearance of hyperkeratotic tumors to a velvety red or black.
The microscopic appearance of dysplastic vulvar lesions is characterized by cellular disorganization and loss of stratification that involves essentially the full thickness of the epithelium. Cellular density is increased, and individual cells vary greatly in size, with giant and multinucleated cells, numerous mitotic figures, and hyperchromatism (Fig. 47–1). HPV cytopathic changes, such as perinuclear halos with displacement of nuclei, are also common.
Figure 47–1. Carcinoma in situ demonstrating hyperkeratosis, acanthosis, and parakeratosis. The rete ridges are elongated and thickened, and individual cells are atypical.
Treatment
Treatment options for VIN are individualized based on biopsy results and include wide local excision, laser ablation, topical application of 5-fluorouracil (5-FU) or imiquimod, or superficial vulvectomy with or without split-thickness skin grafting. Untreated VIN has the potential for progression to invasive carcinoma. This risk may be high for women older than age 40 years. In younger patients, spontaneous regression may occur.
Treatment modality depends on the extent of involvement of the vulva, perineum, and perianal skin, which is defined by colposcopy. Wide local excision of small foci of VIN is preferred. For unifocal lesions, a 1-cm margin of uninvolved skin is usually curative. Carbon dioxide laser may be used for multifocal disease. Disadvantages of the laser include painful recovery and lack of pathology specimens. The incidence of foci of microinvasion in VIN III has been reported to range from 10 to 22% in different series. Extensive disease may be best treated by superficial vulvectomy. The surgical goal is to preserve as much of the normal anatomy as possible. In the superficial “skinning” vulvectomy procedure, the excised vulvar skin can be closed with fine suture or may need to be replaced with a split-thickness skin graft (Figs. 47–2 and 47–3) if the defect is too large.
Figure 47–2. Diffuse, hypertrophic carcinoma in situ of the vulva and perianal skin. A skinning vulvectomy was performed.
Figure 47–3. Appearance after skinning vulvectomy and split-thickness skin grafting of the lesion shown in Figure 47–2.
Topical application of imiquimod cream, which stimulates local cytokine release and enhances cell-mediated immunity, can be attempted in order to preserve vulvar anatomy, particularly in younger patients or around sensitive areas such as the clitoris. A recent review of published trials looking at topical imiquimod therapy for high-grade VIN reported a complete response rate of 51% with an additional 25% partial response rate. The use of 5-FU has fallen out of favor due to poor tolerance, with a significant proportion of patients reporting significant burning, pain, and ulcerations. Cryotherapy, photodynamic therapy, and ultrasonic surgical aspiration have each historically been proven useful in the treatment of some lesions, but remain investigational.
Follow-Up
Intraepithelial carcinoma of the vulva is often one manifestation of multifocal disease. For this reason, affected patients must be examined periodically for a number of years. Recommended follow-up includes thorough pelvic examinations with colposcopy every 3–4 months until the patient is disease free for 2 years. If the patient is disease free for a 2-year period, examinations can be done every 6 months.
EXTRAMAMMARY PAGET DISEASE
ESSENTIALS OF DIAGNOSIS
Pruritus and vulvar soreness are the most frequent symptoms.
These symptoms may persist for years before the patient seeks medical attention.
The lesion may be localized to 1 labium or involve the entire vulvar area.
The lesion usually has an eczematoid appearance macroscopically and usually begins on the hair-bearing portions of the vulva.
It is not unusual for the disease process to extend beyond the vulva to involve the perirectal area, buttocks, thighs, inguinal area, and mons.
Intraepithelial extramammary Paget’s disease presents as a lesion with hyperemic areas associated with a superficial white coating to give the impression of “cake icing.”
Although these lesions can be very extensive, most are confined to the epithelial layer.
The diagnosis is made by vulvar biopsy. It is important to palpate the lesion in its entirety.
A generous biopsy should be taken of any area that appears to be thickened to rule out an underlying adenocarcinoma.
General Considerations
Paget’s disease of the skin is an intraepithelial neoplasia, or adenocarcinoma in situ, and accounts for <1% of all vulvar malignancies occurring mostly in Caucasian patients in their 60s and 70s. Reports of long-term survival suggest that the in situ stage of the disease persists for a long time or that invasive disease is a different clinicopathologic entity. At present, most experts posit that extramammary Paget’s disease (EMPD) arises as either an intraepithelial neoplasia that may progress to a dermally invasive carcinoma (primary EMPD) or epidermal infiltration of malignant cells from an underlying or distant carcinoma (secondary EMPD) such as primary adenocarcinoma of an underlying apocrine gland, Bartholin’s gland, or anorectum. Unlike mammary Paget’s disease, <20% of vulvar Paget’s disease is associated with an underlying adenocarcinoma. Paget’s disease with an underlying adenocarcinoma metastasizes frequently to regional lymph nodes and distally. Paget’s disease without an underlying adenocarcinoma behaves like an intraepithelial neoplasia and can be treated as such. However, patients with Paget’s disease should be carefully examined for the presence of synchronous primaries elsewhere; 20–30% of these patients will be found to have carcinomas at other sites, including the breast, rectum, bladder, cervix, ovary, and urethra.
Pathogenesis
The initial lesion may be confused with a number of benign forms of chronic vulvar pruritus. It is a pruritic, slowly spreading, velvety-red discoloration of the skin that eventually becomes eczematoid in appearance with secondary maceration and development of white plaques; it may spread to involve the skin of the perineum, the perianal area, and the adjacent skin of the thigh. Grossly, the lesion gives the impression of “cake icing.” Because of the serpiginous growth pattern of Paget cells in the basal layer of the epidermis, the true extent of disease is difficult to assess.
Paget’s disease of the vulvar skin is an intraepithelial disease. The typical Paget cell, pathognomonic of the disease process, apparently arises from abnormal differentiation of the cells of the basal layer of the epithelium (Fig. 47–4). The appearance of malignant cells varies from that of the clear cell of the apocrine gland epithelium to a totally undifferentiated basal cell. It has been suggested that there may be both an intraepithelial and an invasive variety of the disease. The intraepithelial stage of the disease persists for years without evidence of an underlying adenocarcinoma.
Figure 47–4. Paget’s disease with typical cells in the basal layer of the epidermis.
Treatment
Wide local excision is the primary treatment modality for this disease process. The lesion needs to be excised in its entirety; however, wide margins need to be removed around the primary lesion as disease often extends beyond the clinically visible erythematous area. The underlying dermis should be removed for adequate histologic evaluation. Often such a resection involves a complete vulvectomy. Careful histologic examination of the entire operative specimen is necessary to delineate the true extent of disease, ensure free surgical margins, and detect the remote possibility of underlying adenocarcinoma. For this reason, laser therapy is unsatisfactory. Patients who have Paget’s disease with underlying adenocarcinoma should be treated with radical local excision of the vulva and bilateral inguinal lymph node dissection as they would for any other invasive tumor involving the vulvar area.
Prognosis
Paget’s disease of the vulva has a great propensity for local recurrence even with negative resection margins, which may represent persistence of the disease or development of new disease in the remaining vulvar skin. EMPD characteristically requires repeated local excisions of recurrent disease after treatment of the primary disease by total vulvectomy. Invasive disease without evidence of lymph node metastases has a favorable prognosis; however, with nodal metastases, the disease is almost invariably fatal.
Black D, Tornos C, Soslow RA, Awtrey CS, Barakat RR, Chi DS. The outcomes of patients with positive margins after excision for intraepithelial Paget’s disease of the vulva. Gynecol Oncol 2007;104:547–550. PMID: 17067662.
Kanitakis J. Mammary and extramammary Paget’s disease. J Eur Acad Dermatol Venereol 2007;21:581–590. PMID: 17447970.
McCarter MD, Quan SH, Busam K, Paty PP, Wong D, Guillem JG. Long-term outcome of perianal Paget’s disease. Dis Colon Rectum 2003;46:612–616. PMID: 12792436.
Parker LP, Parker JR, Bodurka-Bevers D, et al. Paget’s disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol 2000;77:183–189. PMID: 10739709.
Pierie JP, Choudry U, Muzikansky A, Finkelstein DM, Ott MJ. Prognosis and management of extramammary Paget’s disease and the association with secondary malignancies. J Am Coll Surg 2003;196:45–50. PMID: 12517548.
Shepherd V, Davidson EJ, Davies-Humphreys J. Extramammary Paget’s disease. BJOG 2005;112:273–279. PMID: 15713139.
CANCER OF THE VULVA
ESSENTIALS OF DIAGNOSIS
Typically occurs in postmenopausal women
Long history of vulvar irritation with pruritus, local discomfort, and bloody discharge
Appearance of early lesions like that of chronic vulvar dermatitis
Appearance of late lesions like that of a large cauliflower or a hard ulcerated area in the vulva
Biopsy necessary for diagnosis
General Considerations
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.
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.
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.
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.
Pathogenesis
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.
Figure 47–5. Lymphatic spread of cancer of the vulva.
The following sections describe the gross and histologic appearance of the various types of vulvar cancers.
A. Squamous Cell Carcinoma
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.
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.
Figure 47–6. Large, exophytic, squamous cell carcinoma of the vulva, which was treated by radical vulvectomy and regional lymphadenectomy.
Figure 47–7. Ulcerative squamous cell carcinoma of the vulva.
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.
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.
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.
B. Carcinoma of Bartholin’s Gland
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.
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.
C. Basal Cell Carcinoma
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.
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.
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.
D. Malignant Melanoma
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.
Clinical Findings
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.
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.
A. Symptoms & Signs
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.
B. Differential Diagnosis
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.
C. Unusual Vulvar Malignancies
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.
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.
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.
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.
Complications
A. Operative Morbidity & Mortality
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.
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.
Treatment
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.
Table 47–1. International Federation of Gynecology and Obstetrics (FIGO) staging of vulvar cancer.
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.
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.
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.
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).
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.
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.
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.
Follow-Up
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.
Prognosis
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. 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.
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.
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.
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).
Sarcomas of the vulva tend to recur locally, particularly if the initial resection is not extensive, and metastasize to the liver and lungs.
Al-Ghamdi A, Freedman D, Miller D, et al. Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases. Gynecol Oncol 2002;84:94–101. PMID: 11748983.
American Joint Committee on Cancer. Vulva. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
Beller U, Quinn MA, Benedet JL, et al. Carcinoma of the vulva. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006;95 (Suppl 1):S7–27. PMID: 17161169.
Beller U, Sideri M, Maisonneuve P, et al. Carcinoma of the vagina. J Epidemiol Biostat 2001;6:141–152. PMID: 11385774.
Gadducci A, Cionini L, Romanini A, Fanucchi A, Genazzani AR. Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer. Crit Rev Oncol Hematol2006;60:227–241. PMID: 16945551.
Gonzalez Bosquet J, Kinney WK, Russell AH, Gaffey TA, Magrina JF, Podratz KC. Risk of occult inguinofemoral lymph node metastasis from squamous carcinoma of the vulva. Int J Radiat Oncol Biol Phys2003;57:419–424. PMID: 12957253.
Gonzalez Bosquet J, Magrina JF, Gaffey TA, et al. Long-term survival and disease recurrence in patients with primary squamous cell carcinoma of the vulva. Gynecol Oncol 2005;97:828–833. PMID: 15896831.
Hillemanns P, Wang X, Staehle S, Michels W, Dannecker C. Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photo-dynamic therapy, excision and vulvectomy. Gynecol Oncol 2006;100:271–275. PMID: 16169064.
Joura EA, Losch A, Haider-Angeler MG, Breitenecker G, Leodolter S. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women. J Reprod Med. 2000;45:613–615. PMID: 10986677.
Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018–1022. PMID: 16648405.
Kunos C, Simpkins F, Gibbons H, Tian C, Homesley H. Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol 2009;114:537–546. PMID: 19701032.
Leminen A, Forss M, Paavonen J. Wound complications in patients with carcinoma of the vulva. Comparison between radical and modified vulvectomies. Eur J Obstet Gynecol Reprod Biol 2000;93:193–197. PMID: 11074142.
Montana GS, Thomas GM, Moore DH, et al. Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2000;48:1007–1013. PMID: 11072157.
Rodolakis A, Diakomanolis E, Vlachos G, et al. Vulvar intraepithelial neoplasia (VIN)—diagnostic and therapeutic challenges. Eur J Gynaecol Oncol 2003;24:317–322. PMID: 12807248.
Rouzier R, Haddad B, Atallah D, Dubois P, Paniel BJ. Surgery for vulvar cancer. Clin Obstet Gynecol 2005;48:869–878. PMID: 16286833.
Selman TJ, Luesley DM, Acheson N, Khan KS, Mann CH. A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer. Gynecol Oncol 2005;99:206–214. PMID: 16081147.
Sideri M, Jones RW, Wilkinson EJ, et al. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med 2005;50: 807–810. PMID: 16419625.
Stang A, Streller B, Eisinger B, Jockel KH. Population-based incidence rates of malignant melanoma of the vulva in Germany. Gynecol Oncol 2005;96:216–221. PMID: 15589604.
Sugiyama VE, Chan JK, Shin JY, Berek JS, Osann K, Kapp DS. Vulvar melanoma: a multivariable analysis of 644 patients. Obstet Gynecol 2007;110:296–301. PMID: 17666603.
van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit Rev Oncol Hematol 2008;68:131–156. PMID: 18406622.
van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol2005;97:645–651. PMID: 15863172.
PREINVASIVE DISEASE OF THE VAGINA
ESSENTIALS OF DIAGNOSIS
Almost all lesions of vaginal intraepithelial neoplasia are asymptomatic.
Lesions often accompany HPV infection, so patients may complain of vulvar warts. An abnormal Papanicolaou (Pap) smear is usually the first sign of disease.
The diagnosis is made by colposcopic examination of the vagina with a directed biopsy.
Colposcopic examination of the vagina can be difficult to perform, particularly if a hysterectomy has already been done, because lesions can lay hidden within the recesses of the vaginal cuff.
Techniques similar to those used for colposcopic examination of the cervix are used for examination of the vagina.
After application of 3–5% acetic acid to the vagina, a lesion under the colposcope may appear as white epithelium and may have mosaicism or punctuation.
Lugol’s iodine may also help to identify the borders of a lesion.
Lesions are often located along the vaginal ridges; they may appear to be raised or have spicules.
Because the disease process tends to be multifocal, a thorough examination of the vagina from the introitus to the apex must be conducted.
General Considerations
Vaginal intraepithelial neoplasia (VAIN) can occur as an isolated lesion, but multifocal disease is more common. Although little is known regarding the natural history of VAIN, it is thought to be similar to that of cervical intraepithelial neoplasia (CIN). Many patients may have similar intraepithelial neoplastic lesions involving the cervix or vulva. At least one-half to two-thirds of patients with VAIN have been treated for similar disease in either the cervix or the vulva. In addition, VAIN can reappear several years later, necessitating long-term follow-up in these patients. Several investigators have recognized a “field effect” involving the squamous epithelium of the lower genital tract including the cervix, vagina, and vulva to be affected simultaneously by the same carcinogenic agent. The vagina lacks a transformation zone, whereas in the cervix, immature epithelial cells are infected with HPV. The upper third of the vagina is where the majority of these lesions are diagnosed. As in cervical and vulvar intraepithelial neoplasia, several investigators have found that smoking is associated with an increased risk of high-grade VAIN. Controversy still exists regarding the role of prior irradiation in the pathogenesis of vaginal neoplasia.
Condylomatous lesions of the lower genital tract often demonstrate associated dysplasias. For this reason, a biopsy should be made of condylomatous growth of the vagina prior to treatment.
Pathogenesis
As with other intraepithelial neoplasias occurring in the lower genital tract, VAIN is characterized by a loss of epithelial cell maturation. This is associated with nuclear hyper-chromatosis and pleomorphism with cellular crowding. The thickness of the epithelial abnormality designates the various lesions as VAIN I, II, or III. VAIN III is synonymous with carcinoma in situ of the vagina.
Treatment
The primary treatment modality for VAIN is surgical excision or carbon dioxide laser ablation. VAIN I lesions usually do not require treatment, as lesions typically regress, and usually close clinical observation is sufficient. VAIN II and III can be treated by laser ablation or excision. VAIN III lesions are more often associated with an early invasive lesion; therefore, adequate sampling should be performed before any ablative procedure is employed. If the lesion is focal, it is best removed in its entirety with local excision. When carcinoma in situ of the cervix extends to the upper vagina, the upper third of the vagina can be removed at the time of hysterectomy. If multifocal disease is present, a total vaginectomy may be performed with a split-thickness skin graft vaginal reconstruction. Topical 5-FU may also be used in treating multifocal VAIN. Approximately 80% of patients can expect to have evidence of regression of disease after 1 to 2 courses of treatment. Several small series have also reported success in using topical application of imiquimod for the treatment of high-grade VAIN, although the treatment remains investigational.
Follow-Up
VAIN tends to be multifocal, with involvement of the cervix and vulva in many cases. These lesions can be difficult to eradicate with only 1 treatment modality or treatment session. This group of patients must be monitored closely every 4–6 months with cytologic smears and HPV testing and close examination of not only the vagina but also the entire lower genital tract.
CANCER OF THE VAGINA
ESSENTIALS OF DIAGNOSIS
Asymptomatic: abnormal vaginal cytology
Early: painless bleeding from ulcerated tumor
Late: bleeding, pain, weight loss, swelling
General Considerations
Primary cancers of the vagina are rare, representing approximately 0.3% of gynecologic cancers. Approximately 85% are squamous cell cancers, and the remainder, in decreasing order of frequency, are adenocarcinomas, sarcomas, and melanomas. A tumor should not be considered a primary vaginal cancer unless the cervix is uninvolved or only minimally involved by a tumor obviously arising in the vagina. By convention, any malignancy involving both cervix and vagina that is histologically compatible with an origin in either organ is classified as cervical cancer. Secondary carcinoma of the vagina is seen more frequently than primary vaginal cancers. Secondary, or metastatic, tumors may arise from cervical, endometrial, or ovarian cancer, breast cancer, gestational trophoblastic disease, colorectal cancer, or urogenital or vulvar cancer. Extension of cervical cancer to the vagina is probably the most common malignancy involving the vagina. In general, invasive vaginal carcinoma shares the same risk factors as cervical neoplasia such as smoking, HPV infection, multiple sexual partners, and a history of lower genital tract neoplasia. In addition, in utero diethylstilbestrol (DES) exposure is associated with an increased risk of primary vaginal adenocarcinoma, namely the clear cell variant.
Pathogenesis
Squamous cell carcinoma may be ulcerative or exophytic. It usually involves the posterior wall of the upper third of the vagina, but may be multicentric. Direct invasion of the bladder or rectum may occur. The incidence of lymph node metastases is directly related to the size of the tumor. The route of nodal metastases depends on the location of the tumor in the vagina. Tumors in the lower third metastasize like cancer of the vulva, primarily to the inguinal lymph nodes (Fig. 47–8). Cancers of the upper vagina, which is the most common site, metastasize in a manner similar to cancer of the cervix. The lymphatic drainage of the vagina consists of a fine capillary meshwork in the mucosa and submucosa with multiple anastomoses. As a consequence, lesions in the middle third of the vagina may metastasize to the inguinal lymph nodes or directly to the deep pelvic lymph nodes.
Figure 47–8. An ulcerated epidermoid cancer of the lower third of the vagina.
Adenocarcinomas account for the great majority of primary vaginal malignancies in young patients and may arise in areas of vaginal adenosis, endometriosis, wolffian duct remnants, or periurethral glands. In addition, the clear cell variant has been associated with a history of exposure to DES in utero (Fig. 47–9) with a mean age at diagnosis of 19 years. The risk of developing clear cell adenocarcinoma by age 24 years has been calculated to be 0.14–1.4 per 1000 exposed female fetuses.
Figure 47–9. A clear cell adenocarcinoma of the vagina in a 19-year-old patient. The lesion is on the posterior wall of the upper third of the vagina.
Melanomas of the vagina are rare and most frequently arise from the anterior surface and lower half of the vagina and almost always occur in Caucasian patients. Nevi rarely occur in the vagina; therefore, any pigmented lesion of the vagina should be excised or biopsied. Primary vaginal melanomas behave aggressively and tend to recur locally with distant spread and generally poor long-term survival.
The most common primary vaginal sarcoma is embryonal rhabdomyosarcomas or sarcoma botryoides, a highly aggressive tumor that occurs in infancy or early childhood replacing the vaginal mucosa with polypoid, edematous, “grapelike” masses that may protrude from the vaginal introitus. The outcome of these patients has improved with advent of multimodality treatment with chemotherapy, surgery, and radiation therapy. Leiomyosarcomas, endometrial stromal sarcomas, and carcinosarcomas occur in older women. The upper anterior vaginal wall is the most common site of origin. The appearance of these tumors depends on the size and the extent of disease at the time of diagnosis. In general, melanomas and sarcomas spread like squamous cell cancer, although hematogenous spread with liver and pulmonary metastases is more common.
Metastatic adenocarcinoma to the vagina may arise from the urethra, Bartholin’s gland, the rectum or bladder, the endometrial cavity, the endocervix, or an ovary, or it may be metastatic from a distant site. Hypernephroma of the kidney characteristically metastasizes to the lower third of the anterior wall of the vagina.
Clinical Findings
Vaginal cancer is often asymptomatic, discovered by routine vaginal cytologic examination, and confirmed by biopsy after delineation of the location and extent of the tumor by colposcopy.
Postmenopausal vaginal and/or postcoital bleeding are the most common presenting symptoms. Other common symptoms include vaginal discharge, a vaginal mass, or urinary symptoms. Approximately 50% of patients with invasive vaginal cancer report for examination within 6 months after symptoms are noted. Less commonly, advanced tumors may impinge upon the rectum or bladder or extend to the pelvic wall, causing pain or leg edema.
A diagnosis of primary cancer of the vagina cannot be established unless metastasis from another source is eliminated. A complete history and physical examination should be performed, including a thorough pelvic examination, cervical cytologic examination, endometrial biopsy when indicated, complete inspection of the vagina, including colposcopy, and biopsy of the vaginal tumor. Careful bimanual examination with palpation of the entire length of the vagina can detect small submucosal nodules not visualized during the examination. Biopsy should be performed to establish a histologic diagnosis.
The staging system for cancer of the vagina is clinical and not surgical (Table 47–2).
Table 47–2. International Federation of Gynecology and Obstetrics (FIGO) staging of carcinoma of the vagina.
Differential Diagnosis
Benign tumors of the vagina are uncommon, are usually cystic, arise from the mesonephric (wolffian) or paramesonephric ducts, and are usually an incidental finding on examination of the anterolateral wall of the vagina (Gartner’s duct cyst).
An ulcerative lesion may occur at the site of direct trauma, following an inflammatory reaction caused by prolonged retention of a pessary or other foreign body, or, occasionally, following a chemical burn. Granulomatous venereal diseases seldom affect the vagina but may be diagnosed with appropriate laboratory studies and a biopsy.
Endometriosis that penetrates the cul-de-sac of Douglas into the upper vagina cannot be differentiated from cancer except by biopsy.
Treatment
Following biopsy confirmation of disease, all patients should undergo a thorough physical examination and evaluation of the extent of local and metastatic disease. Pretreatment evaluation may include the following studies: chest radiography, intravenous pyelogram, cystoscopy, proctosigmoidoscopy, and CT scan of the abdomen and pelvis. The optimal treatment of patients with invasive vaginal cancer is still controversial and should take into account the proximity of adjacent structures that preclude a proper surgical margin and the desire to preserve a functional vagina. In general, surgery is reserved for those patients with stage I lesions affecting the upper vagina incorporating a radical hysterectomy with an upper vaginectomy and a bilateral pelvic lymphadenectomy if a hysterectomy had not been previously performed. Otherwise the treatment consists of primary radiotherapy with brachytherapy for small superficial lesions and external beam radiotherapy with or without intracavitary radiotherapy for larger lesions. Interstitial therapy is commonly used unless there exists a small vault lesion, which may be adequately managed by a tandem and ovoid implant.
For locally advanced cancers, because of the poor outcomes associated with radiation therapy alone, concurrent chemotherapy sensitization has been proposed, although the data are still lacking. An exenterative procedure with removal of the vagina, uterus, tubes, ovaries, rectum, pelvis, and/or bladder and urethra with or without vaginal reconstruction may be considered for patients with a central recurrence after radiation therapy or select patients with stage IVA tumors, especially if a rectovaginal or vesicovaginal fistula is present.
The principles of treatment of primary adenocarcinoma of the vagina are the same as those for squamous cell cancer. However, preferred therapy for clear cell carcinoma of the vagina and cervix in young women has not been established. Approximately 60% of tumors occur in the upper half of the vagina, and the remainder occur in the cervix. The incidence of nodal metastases is approximately 18% in stage I and 30% or more in stage II disease. If the disease is found sufficiently early and is confined to the upper vagina and cervix, radical abdominal hysterectomy, upper vaginectomy, and pelvic lymphadenectomy with ovarian preservation can be performed. More advanced lesions are treated with irradiation.
For sarcoma botryoides, primary radiation therapy and local excision have historically yielded poor results. Primary chemotherapy with vincristine, dactinomycin, and cyclophosphamide plus radiation has led to excellent results in treating patients with this disease. Melanoma of the vagina may be treated with radiation, conservative excision, and/or radical surgery.
Prognosis
The size and stage of the disease at the time of diagnosis are the most important prognostic indicators in squamous cell cancers. The 5-year survival rate is approximately 77% in patients with stage I disease, 45% in patients with stage II disease, 31% in patients with stage III disease, and 18% in patients with stage IV disease.
Melanomas—even small ones—are very malignant, and few respond to therapy. The tumor recurs locally and metastasizes to the liver and lungs. Chemotherapy and immuno therapy have been used as adjunctive treatment.
Too few sarcomas of the vagina have been reported to generate survival data. Except for sarcoma botryoides, these tumors have a propensity for local recurrence and distant metastases, and the prognosis is usually poor.
Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2000;70:209–262. PMID: 11041682.
Cardosi RJ, Speights A, Fiorica JV, Grendys EC Jr, Hakam A, Hoffman MS. Bartholin’s gland carcinoma: a 15-year experience. Gynecol Oncol 2001;82:247–251. PMID: 11531274.
Conley LJ, Ellerbrock TV, Bush TJ, Chiasson MA, Sawo D, Wright TC. HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet2002;359:108–113. PMID: 11809252.
Daling JR, Madeleine MM, Schwartz SM, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002;84:263–270. PMID: 11812085.
de Koning MN, Waddell K, Magyezi J, et al. Genital and cutaneous human papillomavirus (HPV) types in relation to conjunctival squamous cell neoplasia: a case-control study in Uganda. Infect Agent Cancer 2008;3:12. PMID: 18783604.
Frank SJ, Jhingran A, Levenback C, Eifel PJ. Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 2005;62:138–147. PMID: 15850914.
Frega A, French D, Piazze J, Cerekja A, Vetrano G, Moscarini M. Prediction of persistent vaginal intraepithelial neoplasia in previously hysterectomized women by high-risk HPV DNA detection. Cancer Lett2007;249:235–241. PMID: 17070990.
Hellman K, Lundell M, Silfversward C, Nilsson B, Hellstrom AC, Frankendal B. Clinical and histopathologic factors related to prognosis in primary squamous cell carcinoma of the vagina. Int J Gynecol Cancer2006;16:1201–1211. PMID: 16803507.
Iavazzo C, Pitsouni E, Athanasiou S, Falagas ME. Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. Int J Gynaecol Obstet 2008;101:3–10. PMID: 18222451.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. PMID: 20610543.
Samant R, Lau B, E C, Le T, Tam T. Primary vaginal cancer treated with concurrent chemoradiation using cis-platinum. Int J Radiat Oncol Biol Phys 2007;69:746–750. PMID: 17512130.
Sherman JF, Mount SL, Evans MF, Skelly J, Simmons-Arnold L, Eltabbakh GH. Smoking increases the risk of high-grade vaginal intraepithelial neoplasia in women with oncogenic human papillomavirus. Gynecol Oncol2008;110:396–401. PMID: 18586314.
Srodon M, Stoler MH, Baber GB, Kurman RJ. The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). Am J Surg Pathol 2006;30:1513–1518. PMID: 17122506.
Tjalma WA, Monaghan JM, de Barros Lopes A, Naik R, Nordin AJ, Weyler JJ. The role of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol 2001;81:360–365. PMID: 11371123.
Troisi R, Hatch EE, Titus-Ernstoff L, et al. Cancer risk in women prenatally exposed to diethylstilbestrol. Int J Cancer 2007;121:356–360. PMID: 17390375.
Vinokurova S, Wentzensen N, Einenkel J, et al. Clonal history of papillomavirus-induced dysplasia in the female lower genital tract. J Natl Cancer Inst 2005;97:1816–1821. PMID: 16368943.
von Gruenigen VE, Gibbons HE, Gibbins K, Jenison EL, Hopkins MP. Surgical treatments for vulvar and vaginal dysplasia: a randomized controlled trial. Obstet Gynecol 2007;109:942–947. PMID: 17400858.