Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Vulva is the name of the female external genitalia. Which is found in the anterior triangle of the perineum that includes the inner and outer lips (labias), vagina opening, vestibular glands (Bartholin and Skene) and clitoris. Vulvar cancer mostly affects the labia (predominantly labia majora). Less commonly, it can originate from the clitoris or Bartholin's glands. When cells in these areas start to grow out of control, they can develop into vulvar cancer and spread to other parts of the body.

Most vulvar tumors originate from the skin and its appendages. Squamous cell carcinoma accounts for most (more than 90%) of vulvar cancers. There are fundamentally three subtypes: keratinized (not associated with HPV and mostly seen in older women), basaloid and warty. If the basaloid and warty ones are considered as non-keratinized, then we can consider as two basic types. Vulvar melanomas constitute about 5% of vulvar cancers. They are mucosal melanomas that are usually located on the inner lips and clitoris which are generally aggressive tumors. Vulvar adenocarcinoma originates from gland cells in the vulva (mostly in the Bartholin gland, rarely in the sweat glands of the skin) and accounts for about 3% of vulvar cancers. Rarely, sarcoma and basal cell carcinoma may develop in the vulva.

Vulvar cancer is a rare type of cancer, accounting for about 0.5% of all female cancers. 3 out of every 1000 women develop vulvar cancer. It is mostly seen in the postmenopausal period (half of the cases are after the age of 70, the mean age is 65). However, the age distribution is wide and can be seen at very young ages. Recently, there has been an increase in the incidence of vulvar cancer before the age of 60 due to the growing HPV infection prevalence.

Various risk factors of vulvar cancer have been identified, however, as in other cancers, the development process of this cancer is not known with all its clarity. Up to 50% of vulvar squamous cell carcinoma cases are due to human papillomavirus (HPV) infection (HPV-dependent). HPV-associated squamous cell cancers are particularly basaloid and warty types. They often also have accompanying or precursor SIL (squamous intraepithelial lesion) areas which usually occur in women who are young and smokes cigarettes. HIV infection and other types of immunosuppressive conditions are also risk factors. There is usually a multifocal lesion and besides the vulva, LSIL (low-grade SIL; aka VIN1) or HSIL (high-grade SIL; as known as usual VIN or VIN2/3) can also be found on the cervix, vagina and anus. The remaining half of vulvar squamous cell carcinoma cases occur in a process unrelated to HPV infection (HPV-independent). These tumors are in the keratinized subtype of vulvar squamous cancer and usually affect older women. Mostly associated with lichen sclerosus or dVIN (differentiated VIN). The keratinized subtype often has mutations of the p53 tumor suppressor gene, unlike in HPV-associated vulvar cancer. Unlike squamous cell cancers, little is known about how vulvar melanoma and adenocarcinomas develop. The following risk factors can be stated for vulvar cancer:

• Advanced age – Vulvar cancer is rare under the age of 50.
• Human papillomavirus (HPV) infection – More than half of vulvar cancers (especially vulvar cancers in young women) are linked to high-risk HPV types (HPV 16, 18, 26*, 31, 33, 34, 35, 39, 45, 51, 52, 53*, 56, 58, 59, 66*, 68*, 70*, 73*, 82).
• History of genital warts or abnormal Pap smears
• Multiple sexual partners
• Smoking
• Cervical (or vaginal) precancer/history of cancer
• Vulvar intraepithelial neoplasia (VIN) – Vulva squamous cell carcinoma develops gradually over the years. Usually, precancerous changes occur first and can last for several years. The most commonly used medical term for this precancerous condition is vulvar intraepithelial neoplasia (VIN). The term “intraepithelial” means that the abnormal cells are found only in the surface (epithelial) layer of the vulvar skin. Today, precancerous cellular changes are classified as LSIL (corresponding to VIN1), HSIL (corresponding to VIN2/3 or ordinary/usual VIN) and dVIN (differentiated VIN). LSIL (VIN1) and HSIL (VIN2/3 or usual VIN) are associated with HPV, while persistent HPV infection in dVIN is a very rare incidence (less than 2%). Among these, dVIN has the highest risk of cancer progression.
• Immunodeficiency/suppression
• Lichen sclerosis - A disease in which genetic, autoimmune and hormonal factors play a role. It causes the vulvar skin to become very thin and itchy that usually occurs in advanced ages. The risk of vulvar cancer appears to be slightly increasing (approximately 3% of cases of lichen sclerosis develop vulvar cancer).
• Melanoma or atypical moles – Women who have melanoma or dysplastic (atypical) moles elsewhere on their body have a higher risk of developing melanoma on the vulva.
• Family history of melanoma – Causes an increased risk of vulvar melanoma.

SYMPTOMS, DIAGNOSIS & STAGES

Almost all women with invasive vulvar cancer will have one or more of the following symptoms:

• An area on the vulva that looks different than normal – Squamous carcinoma may be paler or darker than the surrounding normal skin or may appear red/pink. Or there may be a thickening of the skin. Most vulvar melanomas are black or dark brown, but they can also be white, pink, red or other colors.
• Mass/swelling
• Ulcer (open sore)
• Itching or burning – Persistent itching without visible lesions may indicate Vulvar intraepithelial neoplasia (VIN) rather than invasive cancer. Although numerous women with VIN have no symptoms, the most common symptom is itching that persists or does not improve over time. There may also be changes in the skin appearance of the vulva. The VIN area is usually thicker in texture and lighter in color than the surrounding normal skin. However, could also appear darker or redder or pinker than the skin around.
• Pain, soreness or tenderness
• Redness and scaling – in Paget's disease
• Swelling or wound in the groin area – Visible or palpable
• Bleeding or discharge
• Changes in moles

Your doctor will do a physical examination, including a pelvic exam as a first step. In some cases, could need a detailed pelvic exam under anesthesia. Then, biopsy is used for definitive diagnosis; after finalizing the diagnosis, various tests are used to understand the extent of the disease (staging).

• Biopsy – A biopsy is the only way that insures the presence of cancer.
• Imaging tests – CT scan, MRI, and PET/CT scan are the most commonly used tests.  
• Cystoscopy – A lighted tube is used to check the bladder’s inner surface in cases where vulvar cancer spread to the bladder has been suspected.
• Proctoscopy (rectoscopy) – When the cancer has been suspected to progressed to the rectum.

Vulvar cancer spreads mostly through lymph and approximately one third of cases have groin lymph node involvement. Regional lymph nodes; includes superficial inguinal lymph nodes, deep inguinal (femoral) lymph nodes, and pelvic lymph nodes (external iliac, obturator, internal iliac, and common iliac lymph nodes). Pelvic lymph nodes are almost never positive unless there is inguinofemoral lymph node metastasis. Stages of non-melanoma vulvar cancer according to the FIGO/TNM staging system (last updated in 2021):

• Stage I– Tumor confined to the vulva or perineum, no nodal metastasis. This stage has two substages: Stagı IA (Lesion ≤ 2cm in size, and with stromal invasion <1mm ), Stage IB ( Lesion >2cm in size -or- with stromal invasion >1mm)
• Stage II– Tumor of any size with extension to lower one-third of the urethra, lower one-third of the vagina, lower one-third of the anus with negative nodes
• Stage III– Tumor of any size with extension to upper part of adjacent perineal structures (upper two-thirds of the urethra, upper two-thirds of the vagina, bladder mucosa, rectal mucosa) -or- with any number of non-fixed/non-ulcerated positive regional (inguinofemoral) nodes. This stage has three substages: Stage IIIA, Stage IIIB, Stage IIIC
• Stage IV– Tumor of any size fixed to bone, or fixed, ulcerated lymph node metastases, or distant metastases. Stage IV has two substages: Stage IVA, Stage IVB (distant metastasis)

In vulvar melanomas, other (Clark, Breslow, TNM, etc.) staging systems are used. The most widely used is the Clark scale, which was modified by Chung to evaluate mucosal melanomas and in this system, 5 levels are defined according to the depth of the tumor. Chung’s (modified Clark) classification:

• Level I – Tumor confined to the epithelium (i.e., Clark’s level I)
• Level II – Tumor penetrates basement membrane and invades depth of ≤1 mm
• Level III – Tumor invades depth of 1-2 mm
• Level IV – Tumor invades depth of >2 mm, but not subcutaneous fat
• Level V – Tumor penetrates subcutaneous fat (i.e., Clark’s level V)

TREATMENT & PROGNOSIS

Treatment in Stage IA (Microinvasive) Vulvar Cancer

If there is no other area of cancer or VIN, the cancer is surgically removed (radical local excision) along with 1-2 cm surrounding normal skin tissue and at a certain depth. There is no need for lymph node dissection.

Treatment in Stage IB-II (Early) Vulvar Cancer

Treatment for stage IB-II cancers, depending on the size of the tumor includes partial or total radical vulvectomy and inguinal lymph node dissection. Lymph node dissection can be unilateral or bilateral depending on the location of the primary tumor in the vulva. In suitable cases, sentinel lymph node biopsy (SLNB) can also be performed instead of complete lymph node dissection.

The following are the cases that require adjuvant radiotherapy (+/- chemotherapy) after surgery (radical local excision & inguinal lymph dissection or SLNB) in Stage IB and operable Stage II cases:

• Micrometastasis in two or more lymph nodes (<5mm)
• Macrometastasis in at least one lymph node (≥5 mm)
• Extracapsular spread in the metastatic lymph node
• Close (<5 mm) surgical margin
• Depth of invasion or tumor thickness >5mm

In patients who will receive radiotherapy due to lymph node involvement, the therapy is applied to include the pelvic lymph nodes. Radiation therapy can also be used as the main treatment (with or without chemotherapy) for women who are not healthy enough to have surgery.

Treatment in Stage III-IVA (Locally Advanced) Vulvar Cancer

Although the treatment varies according to the localization and extent of the disease, a multi-modal approach (combining surgery, radiotherapy and chemotherapy) is usually used. The options are:

• Partial or total radical vulvectomy and removal of lymph nodes – cancers with only inguinal lymph node metastases without spread to neighboring organs and structures can usually be treated with radical vulvectomy and removal of the inguinal lymph nodes (bilateral). A similar approach can be made by extending the vulvar phase of the surgery (radical vulvectomy) to allow the excision of the related structures, even when there is limited spread to neighboring structures. This is followed by radiation therapy (with or without chemotherapy).
• Neoadjuvant radiation (with or without chemo) followed by surgery – This strategy usually preserves normal structures such as the vagina, urethra and anus, furthermore, reduces the extent of surgery (and thus the risk of postoperative complications).
• Pelvic exenteration (ultraradical surgery) – This option is rarely used. Exenteration can be considered, especially if anorectal or bladder fistula is present.
• Lymph node debulking – A palliative surgery to remove bulky, fixed or ulcerated lymph nodes.
• Primary chemoradiation – For cases that cannot be operated.

Primary radiochemotherapy can be used as the main treatment in patients who cannot undergo surgery due to other medical problems. In this case, lymph node involvement can be confirmed via needle biopsy prior to radiation therapy application to the inguinal regions.

Treatment in Stage IVB (Metastatic) Vulvar Cancer

Surgery is not expected to cure these cancers but could be helpful in relieving symptoms such as bowel or bladder blockages. Radiation can be helpful in shrinking cancer and improving symptoms. Chemotherapy could also be an option. Women with vulvar cancer are recommended to participate in a clinical trial by most experts.

Treatment for Recurrent Vulvar Cancer

If the recurrence is local, it could still be possible to treat the cancer with surgery or a combination of chemoradiation therapy and surgery. Sometimes chemotherapy and/or radiation therapy (neoadjuvant radiochemotherapy) can be used to shrink the tumor. Surgery could become an option, following neoadjuvant radiochemotherapy.

If the cancer is not amenable to surgical removal (unresectable) or there is distant metastasis, radiochemotherapy or chemotherapy may be given to relieve symptoms such as pain and bleeding (palliative). These patients could be encouraged to participate in a clinical trial where new treatments have been experimented.

Vulvar Melanoma Treatment

Partial radical vulvectomy (radical local excision) is the preferred treatment. Removal of lymph nodes is also recommended, although its effect on survival is controversial. Lymphadenectomy was found to be more effective in younger women (<60), 1-2 mm tumor thickness and absence of ulcer. Since SLNB gives 15% false negative results in vulvar melanomas, currently this approach is not recommended as it increases the likelihood of regional recurrence. In some cases, radiation therapy, chemotherapy, and/or immunotherapy (e.g., Nivolumab) can also be used. Vulvar melanomas should be tested for c-kit and BRAF mutations to determine whether an immunotherapy option is available.

Vulvar Adenocarcinoma Treatment

If there is an invasive adenocarcinoma of a Bartholin's gland or vulvar skin sweat glands, partial radical vulvectomy with removal of unilateral or bilateral inguinal lymph nodes is recommended depending on the location of the primary tumor. Advanced vulvar adenocarcinoma is usually treated with chemotherapy or radiation.

Treatment Success & Prognosis (outlook)

The 5-year overall survival rate for vulvar cancer is around 70%. According to the prevalence of the disease:

• In localized disease (Stage I-II): 85% (90% in Stage 1, 80% in Stage 2)
• In locally advanced disease (Stage III-IVA): 50%
• In case of distant metastasis (Stage IVB): 15%

These rates are given for vulvar squamous cell cancers. The prognosis could be worse in melanoma and adenocarcinomas. Local or distant late recurrences are common in melanomas.

In squamous cell carcinoma of the vulva, the dominant prognostic factors are stage of the disease and condition of the inguinal lymph nodes. Criteria such as the presence of lymph node involvement, the number of involved lymph nodes, the size of the metastasis in the lymph node and whether there is extracapsular spread in the involved lymph node are important (which are also criteria that affect the stage of the disease). Other major prognostically important factors are depth of invasion (or tumor thickness), tumor diameter, tumor differentiation (grade), lymphovascular space involvement (LVSI), margin status (presence of an invasive tumor or VIN at or near the surgical margin) and patient's general health condition.

In our multicenter European study (100 different centers, 2453 patients), following factors were found to be associated with recurrence and survival rate (Reference: Prognostic factors in patients with vulvar cancer: the VULCAN study. Int J Gynecol Cancer 2020; 30: 1285-1291):

• Stage
• Number of positive inguinal lymph nodes
• Whether adjuvant treatment was applied or not
• Stromal invasion depth
• Surgical margin status
• Volume
• Patient age

You can visit our current website “oncosurgery.com.tr” for further information about vulvar cancer and its surgery.