Squamous cell carcinoma of the vulva is a rare but significant cancer affecting the external female genital area, representing about 90% of all vulvar cancers. This condition most commonly affects older women, with the majority of diagnoses occurring after age 65, though cases are increasingly seen in younger women due to certain viral infections.

Epidemiology

Vulvar cancer, particularly squamous cell carcinoma, is considered rare among cancers affecting women. According to data from the United States, there are approximately 6,500 to 7,500 new cases of vulvar cancer diagnosed each year in the country^[1][2]. This represents only about 0.3% of all new cancer cases annually, occurring at a rate of roughly 2.6 per 100,000 women per year^[2].

The disease shows a clear pattern related to age. Most cases are diagnosed in women between ages 65 and 74, with the median age at diagnosis being around 68 to 69 years^[2][4]. Nearly 80% of people diagnosed are over age 50, and more than half of all diagnoses occur in people over age 70^[4]. This makes squamous cell carcinoma of the vulva predominantly a disease of older, post-menopausal women.

The incidence increases dramatically with age. While the overall worldwide incidence is approximately 1.8 per 100,000 women, this rate jumps to 20 per 100,000 after the age of 75 years^[3]. This steep increase underscores how closely linked this cancer is to aging.

However, there is an emerging trend that’s changing this traditional picture. An increase in human papillomavirus infections worldwide has led to more cases of vulvar squamous carcinoma in younger women^[9]. This shift means that while the disease remains most common in older women, healthcare providers are seeing more cases in younger age groups than in previous decades.

When diagnosed early, the outlook is generally favorable. About 60% of vulvar cancer cases are localized at diagnosis, meaning the cancer hasn’t spread beyond the vulva, and these cases have an 85% five-year survival rate^[2]. Squamous cell carcinoma accounts for approximately 90% of all vulvar cancers, making it by far the most common type^[2][5].

Causes

Squamous cell carcinoma of the vulva develops through specific biological pathways. The cancer forms when cells on the surface of the vulvar skin begin to grow out of control^[4]. Unlike many cancers that have a single clear cause, vulvar squamous cell carcinoma can develop through two distinct pathways, each with different underlying mechanisms.

The first pathway involves infection with human papillomavirus, commonly known as HPV, which is a virus that can be passed from person to person through sexual contact. About 30% to 40% of vulvar cancer cases are associated with high-risk HPV^[2]. This virus is known to have special proteins called E6 and E7 oncoproteins (cancer-causing proteins) that interfere with important protective mechanisms in cells. Specifically, these viral proteins inactivate two crucial proteins in cells called p53 and RB, which normally act as tumor suppressors by preventing uncontrolled cell growth. When these protective proteins are disabled, cells can begin to multiply without proper regulation, eventually leading to cancer^[2].

The second pathway is not related to HPV infection. Instead, it typically occurs in older women and is often associated with chronic inflammatory conditions of the vulvar skin, particularly a condition called lichen sclerosus^[4][9]. These non-HPV-associated cancers may also be connected to well-differentiated vulvar intraepithelial neoplasia, which is an abnormal change in cells that can precede cancer. This pathway represents the majority of cases in elderly post-menopausal women and tends to develop more slowly over time.

Squamous cell carcinoma of the vulva most commonly forms in specific areas. About 50% of vulvar carcinomas arise in the labia majora, which are the outer lips of the vulva. The labia minora, or inner lips, are the site of 15% to 20% of cases. The clitoris and Bartholin glands (small glands that produce lubricating fluid) are less frequently involved^[11]. In about 5% of cases, lesions appear in multiple locations^[11].

Risk Factors

Several factors have been identified that increase a woman’s likelihood of developing squamous cell carcinoma of the vulva. Understanding these risk factors can help women and their healthcare providers stay vigilant about potential warning signs.

Advancing age is the most important risk factor for most cancers, including vulvar squamous cell carcinoma^[11]. As women get older, particularly after menopause, their risk increases substantially. This is partly why the median age at diagnosis is in the late 60s.

Infection with human papillomavirus is a major risk factor, particularly with high-risk strains of the virus^[2][4]. HPV infection is typically transmitted through sexual contact, which means that certain sexual behaviors can influence risk. Women who have had many sexual partners or who began having sexual intercourse at an early age have a higher risk^[11]. The virus can persist in the body for years and may eventually lead to cellular changes that progress to cancer.

Smoking is another significant risk factor^[2]. The harmful chemicals in tobacco can damage cells throughout the body, including those in the vulvar area, making them more vulnerable to cancerous changes. Women who smoke and have HPV infection may face an especially elevated risk.

Inflammatory conditions of the vulva, particularly lichen sclerosus, represent an important risk factor^[2][4]. This chronic skin condition causes patches of white, thin skin in the genital area and can lead to itching and discomfort. Over many years, the chronic inflammation and cellular changes associated with lichen sclerosus can increase cancer risk.

Women who have had prior pelvic radiation therapy for other cancers face increased risk^[2]. Radiation, while effective at treating cancer, can damage healthy cells and potentially lead to new cancers years later.

Having a compromised immune system, whether from HIV infection, organ transplant medications, or other immunodeficiency conditions, increases vulnerability to vulvar cancer^[2]. A healthy immune system helps eliminate abnormal cells before they become cancerous, so when the immune system is weakened, this protective function is diminished.

Women with precursor lesions called vulvar intraepithelial neoplasia are at increased risk^[2]. These are areas of abnormal cell growth that haven’t yet become cancer but could progress to cancer if left untreated. Similarly, women with a history of genital warts, which are caused by certain HPV types, have elevated risk^[11].

A history of abnormal Pap smears or other gynecological abnormalities may also indicate increased risk^[11]. This connection likely reflects shared risk factors, particularly HPV infection, which can affect multiple areas of the genital tract.

Symptoms

Recognizing the symptoms of squamous cell carcinoma of the vulva is crucial for early detection. However, it’s important to understand that in the early stages, this cancer may not cause any noticeable symptoms at all^[4]. This is why regular gynecological check-ups are so important, especially for women with risk factors.

The most common initial sign is usually a visible change in the appearance of the vulvar skin. This might appear as a lump, wartlike bump, or an open sore on the vulva^[1][4]. The lesion most commonly develops on the labia majora or labia minora, though it can appear anywhere on the vulva^[7]. These growths might look like bumps or lumps and may sometimes resemble warts. They can also appear as ulcers, which are open sores that don’t heal^[7].

Changes in skin color are another important warning sign. The affected area may look darker or lighter than usual, or there may be patches of white skin^[4]. Sometimes the skin becomes thickened or develops rough patches^[1][4]. In the case described in one medical report, an 82-year-old woman presented with redness and swelling of the entire labia majora, along with an ulcerative nodule approximately 1.7 centimeters in diameter in the region of the labia minora^[3].

Persistent itching of the vulva that doesn’t respond to usual treatments is a very common symptom^[1][4]. This itching may be intense and bothersome, interfering with daily activities and sleep. Some women also experience a burning sensation in the vulvar area^[4][7].

Pain and tenderness affecting the vulva can occur, potentially becoming worse during sexual intercourse or when urinating^[1][4]. This discomfort can significantly impact quality of life and intimate relationships.

Unusual bleeding from the genital area that is not related to menstrual periods should always be evaluated^[1][4]. This might include bleeding after sex or spontaneous bleeding from the vulvar area.

It’s worth noting that squamous cell carcinoma of the vulva typically presents as a solitary nodule or ulcer on the labia majora or minora. Associated symptoms may include pain, bleeding, itching, odor, or discharge^[3]. Some women may not experience symptoms beyond the visible lesion, particularly in the earliest stages.

Prevention

While not all cases of squamous cell carcinoma of the vulva can be prevented, there are several steps women can take to reduce their risk of developing this cancer.

Vaccination against human papillomavirus is one of the most effective preventive measures available. The HPV vaccine protects against the high-risk strains of the virus that are most commonly associated with vulvar and other genital cancers. While the vaccine is most effective when given before a person becomes sexually active, it can still provide benefits even for those who have already been exposed to some HPV types.

Avoiding tobacco use or quitting smoking if you currently smoke is crucial^[2]. Smoking not only increases the risk of vulvar cancer directly but also appears to work synergistically with HPV infection to further elevate risk. Quitting smoking can reduce this risk and provides numerous other health benefits as well.

Practicing safer sex can reduce the risk of HPV infection. This includes limiting the number of sexual partners and using barrier protection methods, though it’s important to note that HPV can be transmitted even with condom use, as the virus can be present on skin not covered by a condom.

Regular gynecological check-ups are essential for early detection of precancerous changes. During these examinations, healthcare providers can identify vulvar intraepithelial neoplasia or other abnormalities before they progress to cancer. Women should not hesitate to discuss any vulvar symptoms or concerns with their healthcare provider, even if they seem minor or embarrassing.

For women with lichen sclerosus or other chronic inflammatory conditions of the vulva, proper management and regular monitoring are important. These conditions should be treated appropriately, and women with these diagnoses should have more frequent examinations to watch for any concerning changes.

Women who are immunocompromised should work closely with their healthcare team to optimize their immune function as much as possible and should have regular screening examinations.

Being aware of your own body and performing self-examinations can help detect changes early. Using a hand mirror, women can periodically examine their vulvar area for any new lumps, bumps, color changes, or other abnormalities. Any persistent changes should prompt a visit to a healthcare provider.

Pathophysiology

Understanding how squamous cell carcinoma of the vulva develops at the cellular and molecular level helps explain why certain treatments work and why the disease behaves as it does.

The vulva is composed of several types of tissue, but the most superficial layer consists of squamous cells. These are flat cells that form the outer surface of the skin. In squamous cell carcinoma, these cells undergo transformation and begin to multiply in an uncontrolled manner^[2].

As mentioned earlier, there are two main pathways through which vulvar squamous cell carcinoma develops. In the HPV-associated pathway, which accounts for 30% to 40% of cases, the process follows what scientists call the “two-hit hypothesis” for cancer development^[2]. This means that multiple genetic changes must occur for cancer to develop. The HPV virus carries genetic material that produces E6 and E7 oncoproteins. These proteins specifically target and inactivate two critical tumor suppressor proteins in human cells: p53 and RB^[2].

Under normal circumstances, p53 and RB act as cellular brakes, preventing cells from dividing when they shouldn’t and triggering damaged cells to self-destruct. When HPV’s E6 and E7 proteins disable these tumor suppressors, cells lose this critical regulation. The loss of these protective mechanisms leads to unregulated hyperproliferation, meaning cells multiply rapidly and without the normal checks and balances. Over time, these proliferating cells accumulate additional genetic mutations, eventually progressing from precancerous changes to invasive cancer.

The morphological variants associated with HPV infection include basaloid and warty subtypes of squamous cell carcinoma. These subtypes are found to harbor HPV infection in about 75% to 100% of cases^[2]. These types are more common in younger women and share many risk factors with cervical cancer, including multiple sexual partners and early age at first sexual intercourse.

The non-HPV-associated pathway operates through different mechanisms. This pathway is more common in older women and typically involves long-standing inflammatory conditions. Chronic inflammation can lead to repeated cycles of tissue damage and repair. Over many years, this process can result in genetic mutations that accumulate in cells. Women with lichen sclerosus and other epithelial conditions of the vulvar skin may develop well-differentiated vulvar intraepithelial neoplasia, which can progress to keratinizing variants of squamous cell carcinoma^[3]. These keratinizing variants tend to be HPV-negative and occur more frequently in elderly women.

As the cancer develops, it begins as changes in the outermost layer of cells. Initially, these abnormal cells remain confined to the surface epithelium—this is the precancerous stage called vulvar intraepithelial neoplasia. If left untreated, these abnormal cells can break through the basement membrane (a thin layer that separates the epithelium from deeper tissues) and invade into the underlying connective tissue. Once this invasion occurs, the condition is classified as invasive squamous cell carcinoma.

The cancer cells can then spread in several ways. They may grow locally, extending into surrounding structures such as the vagina, urethra, or anus. They can also spread through the lymphatic system, traveling to nearby lymph nodes in the groin area (inguinofemoral lymph nodes). The status of these lymph nodes—whether they contain cancer cells—is one of the most important factors affecting prognosis^[2]. In more advanced cases, cancer cells can enter the bloodstream and spread to distant organs, though this is less common at initial diagnosis.

The physical changes caused by the growing tumor explain many of the symptoms patients experience. The uncontrolled cell growth creates visible lumps or masses. As the tumor expands, it can outgrow its blood supply, leading to areas of tissue death that appear as ulcers. The presence of the tumor triggers inflammation, which causes redness, swelling, and itching. If the tumor erodes blood vessels, it causes bleeding. When the tumor involves nerve endings, it produces pain.

These pathophysiological processes underscore why early detection is so crucial. When the disease is caught at the precancerous or early invasive stage, before significant spread has occurred, treatment is much more likely to be successful and less extensive surgery may be required.