Sign and symptom of cervical cancer

In 1998, approximately 3,200 women in the United States developed cancer of the vulva, and 800 women died of the disease. (1) Over the past decade, an increase in vulvar intraepithelial neoplasia (VIN) and VIN-related invasive vulvar cancer has been noted in women younger than 50 years. (2) Overall, vulvar cancer is relatively uncommon, accounting for 3 to 5 percent of female genital-tract malignancies.

Approximately 90 percent of vulvar tumors are squamous cell carcinomas. When such tumors are found early, the prognosis is quite good. Despite its infrequency, vulvar cancer remains an important female disease, because of its significant impact on sexuality. Over the past decade, numerous advances have been made in the management of vulvar cancer, with a trend toward more conservative surgery and improved psychosexual outcomes. Early detection and biopsy of any abnormal vulvar lesions by primary care physicians are imperative to achieve diagnosis of vulvar cancer in the early stages and improve subsequent morbidity and mortality.

Epidemiology

It has been suggested that vulvar cancer exists as two separate diseases. The first type involves human papillomavirus (HPV) infection, which leads to VIN and predisposes the patient to vulvar cancer. The second type involves vulvar non-neoplastic epithelial disorders (VNED) and advanced age, leading to cellular atypia and cancer (Table 1). (3)

Vulvar cancer most frequently occurs in women 65 to 75 years of age. (1) It can develop in younger patients, and a recent review (4) noted that approximately 15 percent of all vulvar cancers occur in women younger than 40 years of age. One study (5) noted that in women younger than 50 years of age, the incidence of vulvar cancer has increased from 2 to 21 percent over the past 20 years.

Most of the vulvar cancers appearing in young women arise in a field of warty or basaloid VIN. An estimated 80 percent of untreated women with warty VIN develop invasive disease. (5) Thirty percent of patients with vulvar cancer present at 70 years or older, and the rate increases with age, reaching a peak of 20 per 100,000 women by 75 years of age. (3) This rate equals lifetime risks of acquiring vulvar carcinoma and dying as a result of it of 0.3 and 0.1, respectively. (6)

No specific medical factors have been clearly identified as causative. Hypertension, diabetes mellitus, and obesity have been found to coexist in up to 25 percent of patients, although they are not considered independent risk factors. (7) In the past, syphilis and other granulomatous diseases have been associated with vulvar cancer. (7) However, this association is not likely, given the significant decline in the incidence of syphilis since 1992.

Over the past decade, the prevalence of VIN in young women has increased significantly. (2) VIN is clearly a premalignant finding (Figure 1) and is associated with HPV infection, particularly subtypes 16 and 18. (8) One study (8) evaluated tissue samples from 48 patients with vulvar cancer. These patients ranged in age from 45 to 88 years. HPV DNA was detected by polymerase chain reaction in 48 percent of the specimens, of which 96 percent were from subtypes 16 and 18. HPV detection was not associated with age, but 71 percent were associated with coexisting severe (grade 3) VIN.

A retrospective review (90 of women with vulvar cancer found a statistically significant correlation between patients younger than 45 years and HPV (relative risk [RR], 11.34), cigarette smoking (RR, 2.83), having more than two sexual partners (RR, 2.87), sexual initiation before age 19 years (RR, 2.43), and low economic status (RR, 1.77). In patients older than 45 years, there was a statistically significant correlation between VIN and vulvar cancer and VNED (RR, 23.6), residence in a rural area (RR, 2.17), low economic status (RR, 1.89), menopause before age 45 (RR, 1.84), poor hygiene (RR, 1.76), endocrine disorders (RR, 1.94), and low serum vitamin A levels (RR, 1.78).

Another study (10) of women with vulvar cancer identified an odds ratio for vulvar cancer of 18.8 (confidence interval, 11.9 to 29.8) among current smokers who were HPV-16 seropositive, compared with women who had never smoked and were HPV-16 seronegative.

Lichen sclerosus, a type of VNED, is thought to be a predisposing factor in the development of HPV-negative vulvar cancer. According to the "itch-scratch-lichen sclerosus hypothesis," lichen sclerosus, by causing a severe pruritus, sets up an itch-scratch cycle that over time causes the development of squamous cell hyperplasia. (11) Further progression results in atypia formation, followed by VIN and eventual invasive squamous cell cancer. (10) This hypothesis suggests that treatment of lichen sclerosus with topical steroids would prevent vulvar cancer in these patients, and some early research supports this suggestion. (11) Aggressive evaluation and treatment of VNEDs could have a dramatic impact on the incidence of vulvar cancer in this subgroup of patients.

Clinical Features

The most frequently reported symptom of vulvar cancer is a long history of pruritus. Less common presenting symptoms include vulvar bleeding, discharge, dysuria, and pain. The most common presenting sign of vulvar cancer is a vulvar lump or mass. Rarely, patients present with a large, fungating mass.

On physical examination, the vulvar lesion is usually raised and may be fleshy, ulcerated, leukoplakic, or warty in appearance (7) (Figure 2). Most squamous cell carcinomas are unifocal and occur on the labia majora. Approximately 5 percent of cases are multifocal, and the labia minora, clitoris, or perineum may be involved as primary sites.

Screening

Any patient who reports or is found to have a vulvar lesion must be thoroughly evaluated to rule out malignancy. Both patients and physicians contribute to the delay in early and accurate diagnosis of vulvar cancer. According to one study, (12) patients fail to seek treatment for symptomatic lesions or chronic pruritus for two to 16 months, while physicians often provide medical treatment of vulvar lesions for up to 12 months before obtaining a biopsy or considering referral.

Primary care physicians can identify women at risk and prevent serious, advanced disease by properly educating their peers and patients. Although there are no supporting data, expert opinion recommends routine annual visual inspection of the external genitalia, even if the patient is no longer receiving annual Papanicolaou smears. (3) Teaching female patients about vulvar self-examination as part of their preventive health care regimen has also been advocated. (3)

Histologic Diagnosis

No gross features are diagnostic of vulvar cancer; diagnosis is based on biopsy alone. Therefore, biopsy must be performed on any suspicious lesions of the vulva, asymptomatic or symptomatic. Indications for biopsy include any grossly suspicious lesion such as a confluent, wartlike mass; persistent ulceration or itchy area; or change in the color, elevation, or surface of a lesion. (12,13) Biopsy can be performed in the office under local anesthesia using excisional or punch biopsy. (7) Patients with large or highly suspicious lesions can be referred to a gynecologist for biopsy, depending on the physician's level of comfort.

A punch biopsy down to the dermis is sufficient for pathologic evaluation. The biopsy should include surrounding skin with underlying dermis and connective tissue so that the pathologist can evaluate the depth of stromal invasion. Cutting down to the subcutaneous fat layer assures that the proper depth has been reached. This can be accomplished with a cervical punch biopsy instrument or a toothed pick-up and iris scissors. A small amount of local anesthetic with epinephrine will provide good analgesia and hemostasis. If additional hemostasis is needed, Monsel's solution or silver nitrate can be applied, although they may discolor the area. In rare cases, a single 3-0 or 4-0 absorbable suture may be necessary.

Delaying biopsy is the most common mistake made by clinicians. Although there are no data available to establish this standard, expert opinion recommends that any lesion increasing in size or with an unusual warty appearance be biopsied. (7,12) Any typical condyloma that does not respond to therapy should be biopsied. The clinician must be diligent in observing any vulvar lesions and use biopsy aggressively on any lesion of concern to the clinician or patient.