Vulvar cancer is relatively rare, accounting for about 4% of all malignant tumors of the female reproductive system. It mainly occurs in postmenopausal women, and the incidence rate increases with age. Ninety percent of primary vulvar cancers are squamous cell carcinomas, as well as malignant melanoma, adenocarcinoma, basal cell carcinoma, verrucous carcinoma, sarcoma, and other rare vulvar malignancies. Most squamous cell carcinomas occur in the labia majora, but can also occur in the labia minora.
However, it can also occur in the labia minora, clitoris and perineum.
Vulvar intraepithelial neoplasia (VIN), a precancerous lesion, occurs in young women and may be associated with similar lesions of the cervix and vagina. there are 2 types of VIN.
1. common type VIN: verrucous, basal cell-like and mixed type, associated with human papillomavirus (HPV) infection in most cases.
2. Differential VIN: mainly seen in older women, often associated with sclerosing tinea and/or squamous epithelial hyperplasia.
The best option for treating VIN is to perform superficial excision of the affected skin, which can be combined (or not) with laser treatment. Vulvar cancer used to be treated primarily with surgery, and radiation therapy and the relatively infrequent use of chemotherapy have evolved over the past 20 years. The trend of vulvar cancer treatment has become individualized with multidisciplinary involvement, and patients should concentrate on visiting a gynecologic cancer center with experts with relevant treatment experience.
I. Diagnosis and staging
Vulvar cancer means that the primary lesion of tumor is located in vulva. Secondary tumors in the vulva originating from the genitalia or outside the genitalia must be excluded, and histological evidence of tumor must be available for diagnosis. Involvement of inguinal lymph nodes and femoral lymph nodes is the site of regional spread of tumor. Involvement of pelvic lymph nodes (external iliac, internal iliac, foramen occulta and common iliac lymph nodes) should be considered as distant metastasis. The diagnosis must be confirmed by pathological biopsy before determining the treatment. A wedge or Keyes biopsy is performed under local anesthesia in an outpatient setting (Keyes
biopsy refers to the use of a pen-shaped chisel with a sharp ring tip to biopsy tissue by rotating the chisel, mainly for lesions requiring a certain depth of tissue biopsy) is usually sufficient. The biopsy should include some of the subcutaneous interstitial tissue, but it is preferable not to remove the entire lesion, otherwise it is difficult to determine the extent of excision when developing a treatment plan. If the wedge biopsy lesion is ≤2 cm in diameter and the depth of interstitial infiltration is <1 mm, the entire lesion must be excised for serial sectioning to determine the depth of infiltration.
Other tests include.
1, Pap smear is required if present in the cervix.
Colposcopy of the cervix and vagina is required because squamous epithelial lesions usually involve other areas.
CT scans of the pelvis and inguinal region are useful to detect enlarged lymph nodes in the appropriate areas.
4. Preoperative complete blood count, biochemistry and chest X-ray are routinely performed.
II. Treatment
(A) Treatment of VIN: There are various treatment methods for VIN. The first step is to identify the lesion as an intraepithelial lesion by multi-point biopsy. Patients with multicentric lesions require multiple biopsies. Once lesions on both sides of the vulva are diagnosed, superficial local excision of the vulvar epithelium should be performed, with the margin of excision extending 0.5-1.0 cm beyond the swelling. Local excision is also possible for lesions involving the labia minora, but laser vaporization is more effective. Laser treatment often damages the hair follicles, causing the vulva to lose its covering pubic hair and the pubic hair to stop growing. Laser treatment is also indicated for clitoral lesions. Large lesions can be treated with superficial vulvectomy (vulvar skin peeling) and thin skin slice implants.
(b) Infiltrative squamous carcinoma of vulva: Treatment of vulvar cancer must be individualized. There is no standard surgery, and the most conservative surgery is used as much as possible under the premise of ensuring the treatment effect.
1. Microinvasive vulvar cancer (stage IA): wide local excision is performed in stage IA. If local excision shows poor prognosis (infiltration of nerve or vascular area), more extensive excision is necessary. Usually, inguinal lymph nodes do not need to be removed.
2.Early stage vulvar cancer (stage IB-II).
(1) Treatment of primary lesion: In order to reduce the impact of treatment on the patient’s physical, mental and sexual life, a more conservative wide local excision than wide vulvectomy is usually chosen. This procedure is as effective as wide vulvectomy in preventing local recurrence. The surgical margin should extend at least 1 cm beyond the margin of the lesion to a depth below the genitourinary septum, i.e., at the level of the broad fascia and covering the fascial layer of the pubic symphysis. If the lesion is close to the urethra, the distal 1 cm of the urethra can be excised if it is not expected to cause incontinence. If VIN is also present, the superficial skin tissue at the site of the VIN lesion should be excised to control symptoms, exclude superficial infiltrates at other sites and prevent the lesion from progressing to invasive carcinoma.
(2) Management of inguinal lymph nodes: The mortality rate of patients with recurrence in the inguinal region is very high; therefore, proper management of inguinal lymph nodes is an important factor in reducing the mortality rate of early vulvar cancer. All patients with stage IB and II and interstitial infiltration of more than 1 mm should undergo at least ipsilateral inguinal lymph node dissection. The probability of contralateral lymph node metastasis in stage IB tumors confined to one vulva is less than 1%, so unilateral inguinal lymph node dissection is appropriate. Tumors located in the midline and involving the anterior labia minora should undergo bilateral inguinal lymphadenectomy. Bilateral inguinal lymphadenectomy is also feasible for large one-sided tumors, especially in those with positive ipsilateral lymph nodes. Studies related to anterior lymph nodes are ongoing. Because of the high recurrence rate in the inguinal region after inguinal lymph node resection alone, simultaneous resection of both inguinal and femoral lymph nodes is recommended. The femoral lymph nodes are located around the femoral vein within the fossa ovalis, so it is not necessary to remove the fascial layer when removing the femoral lymph nodes. Postoperative wound healing is better with the three-incision technique. Whole excision (of vulvar and inguinal lymph nodes) is also an option, especially for lesions located in and around the clitoris. To avoid skin necrosis, the entire subcutaneous superficial fascial tissue should be preserved. Pathology after inguinal lymph node dissection reveals positive lymph nodes, and the results are better in those with postoperative radiation therapy to the pelvic and inguinal regions than in those with pelvic lymph node dissection. Those with 1 (possibly 2) micrometastases (<5 mm) do not require adjuvant radiotherapy and have a good prognosis after surgery alone. Bilateral pelvic and inguinal radiotherapy should be performed in those with the following indications.
(i) There is a large metastasis (>5mm in diameter) in one inguinal lymph node.
(ii) Extracapsular spread of the metastatic lymph nodes.
③There are 2 (possibly 3) or more inguinal lymph nodes with micrometastases (<5mm). For most cases, the radiotherapy site should include the inguinal lymph node area and at least the lower pelvic lymph nodes, including the bifurcation of the common iliac vessels. In case of extensive inguinal lymph node involvement or suspected pelvic lymph node metastasis, the upper part of the radiotherapy field must be extended. One of the radiotherapy techniques is chosen according to the patient's physical condition and the extent of the lesion. Radiation therapy should be designed in three dimensions with high-quality computed tomography (CT) or magnetic resonance imaging (MRI) techniques. In combination with photoelectric techniques commonly used to treat regional lymph nodes and avoid over-irradiation of the apical femur, all superficial and deep inguinal lymph nodes should be included. In patients with a thin body type, over-irradiation of the superficial inguinal lymph nodes due to high-energy photon beam irradiation needs to be avoided. Once electron beam irradiation is chosen, an adequate dose of radiation to the femoral lymph node area needs to be ensured. In recent years, the application of modulated intensity modulated radiation therapy (IMRT) or other inverse design computational systems for the treatment of vulvar cancer has begun. Although these techniques can help reduce acute radiotherapy adverse effects in the surrounding skin and soft tissues, the treatment plan design and dose calculation are more complicated, and the accidental incidence of excessive dose in the target area is higher, so it is best to be performed by physicians with considerable expertise. The dose of radiotherapy should be determined according to the extent of the primary lesion and residual lesions. For microscopically detected metastases after inguinal lymph node dissection, a total of 50 Gy with a split dose of 1.8-2.0 Gy is usually sufficient. If there are multiple positive lymph nodes or evidence of extracapsular spread, a dose of up to 60 Gy may be given to reduce the tumor load. The role of concurrent radiotherapy in the treatment of inguinal and pelvic lymph nodes is not known.
3.Advanced vulvar cancer (stage III-IV): multidisciplinary comprehensive treatment is very important.
(1) Lymph node management: the groin should be clarified before determining the overall treatment plan.
The status of inguinal lymph nodes should be clarified before determining the overall treatment plan. Preoperative pelvic CT or MRI should be performed to help determine the extent of pelvic or inguinal lymph node lesions. Pelvic MRI is also useful to understand the anatomical extent of the primary lesion, but is not a routine procedure. If no suspicious lymph nodes are found on CT, bilateral inguinal lymph node dissection is performed. If the final histological examination is positive for lymph nodes, inguinal and pelvic radiotherapy should be added postoperatively, referring to the guidelines for the management of early lesions. If the lymph nodes are negative, inguinal and pelvic radiation therapy is not required. If the patient is not suitable for surgical treatment, radiotherapy is also indicated to treat the primary tumor and inguinal and pelvic lymph nodes. In patients with positive lymph nodes, systematic lymph node dissection is best avoided because systematic lymph node dissection combined with postoperative radiation therapy may lead to severe lymphedema. It is recommended that only the enlarged inguinal and pelvic lymph nodes be removed and postoperative radiotherapy to the inguinal and pelvic cavity be given. If inguinal lymph nodes are ulcerated or fixed and imaging does not show muscle or femoral vascular invasion, lymph node dissection should be performed. If resection is not possible, the diagnosis should be confirmed by biopsy before radiation therapy, combined (or not) with chemotherapy. In some cases, inguinal lymph node dissection may be required after the completion of radiotherapy.
(2) Treatment of primary tumor: Usually inguinal lymph nodes are removed first and primary tumor is treated later. If surgical excision of the primary tumor can achieve negative margins and does not damage the sphincter and cause fecal incontinence, the surgery is worthwhile. If surgery requires an artificial anus or diversion of urinary flow, it is best to treat the tumor with radiotherapy or chemotherapy before surgery to narrow the scope of surgery to remove the tumor or any residual lesions visible to the naked eye. Concurrent radiotherapy has been widely used in patients with large lesions whose surgical excision may damage the central structures of the perineum (anus and urethra), and complete remission without surgery has been reported after radiotherapy and chemotherapy. The need for concurrent radiotherapy of inguinal and pelvic lymph nodes is determined based on the status of inguinal lymph nodes determined prior to treatment. Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in patients with advanced vulvar cancer involving the urethra and anus can help preserve the anal sphincter and/or urethra. 5-fluorouracil and mitomycin C are commonly used as concurrent chemotherapy during radiotherapy for advanced lesions.
(3) Radiotherapy procedures: If inguinal lymph nodes are positive and appropriate radiotherapy equipment is available, adjuvant radiotherapy should be administered as early as possible. initial radiotherapy should cover the pelvis, inguinal lymph nodes and primary site with a total dose of at least 50 Gy. the inguinal lymph node area must be completely covered. Some physicians prefer a thigh-split position, but vulva shielding should be provided to avoid skin radiation overload. Large or particularly high-risk areas are usually selected for juxtaposition of the electron fields to achieve adequate radiation dose to both the surface and deeper layers. Large vulvar lesions may require 60-70 Gy to achieve local control, and although various radiotherapy procedures have been reported recently, the quantitative relationship between dose and local lesion control is uncertain. If the lesion is close to the surgical margin (<5 mm) and the margin cannot be resected further, postoperative radiotherapy may be added. Although postoperative radiotherapy may improve local control in high-risk patients, since the vast majority of local recurrences can be remedied by reoperation or radiotherapy.
Therefore, the significance for overall survival improvement is unclear. Brachytherapy may be used in some cases to treat positive margins, but this technique requires experience to avoid necrosis. Alternatively, juxtaposed electron field therapy or conformal external irradiation can be chosen for the surgical field.
III. Treatment of rare vulvar malignancies
1. Vulvar melanoma: Vulvar melanoma is the second most common vulvar malignant tumor after vulvar squamous cell carcinoma. Most of them are located in the clitoris or labia minora. A modified microscopic staging system by Clark or Breslow is recommended. Except for pigmented vulvar lesions that are found very early and have not changed for many years, all should be excised for biopsy. Treatment of cutaneous melanoma now tends to be more conservative, and vulvar melanoma also tends to be treated more conservatively surgically. The primary lesion should be extensively excised locally with the margin at least 1 cm away from the lesion. The role of lymph node dissection is controversial. A prospective, multicenter clinical randomized controlled trial divided the treatment of patients with moderately deep melanoma (1-4 mm deep) into an elective lymph node dissection group and a control group. A total of 740 patients were included, and survival rates were higher for patients aged ≤60 years with 1-2 mm depth of infiltration and no ulceration on the surface of the tumor with selective lymph node dissection than for the control group.
2. Bartholin’s adenocarcinoma: Malignant tumors occurring in the Bartholin’s gland can be metastatic cell carcinoma or squamous cell carcinoma, which can occur in the ducts, or in the gland itself. Adenoid cystic carcinoma and adenosquamous carcinoma have also been reported. Overall, adenocarcinoma of the vulva usually develops more than 10 years earlier than invasive squamous carcinoma. The diagnosis is usually made after the removal of a Bartholin’s gland cyst that already has a long history of disease. Extensive vulvectomy and bilateral inguinal lymph node dissection are the standard treatment for adenocarcinoma of the Bartholin’s gland. Ipsilateral inguinal lymph node dissection and subextensive episiotomy are equally effective for early lesions. Because the lesion is located in the sciatic rectal fossa and is deep, the incision margin may be close to the tumor and postoperative radiation therapy may reduce the possibility of local recurrence, especially for larger tumors. If the ipsilateral inguinal lymph nodes are positive, radiotherapy to the bilateral inguinal and pelvic lymph node areas may reduce local recurrence.
For adenoid cystic lesions, extensive local excision is also a treatment option. Postoperative adjuvant local radiotherapy is recommended for those with positive cut margins or nerve bundle infiltration.
Vulvar Paired’s disease: The majority of vulvar Paired’s disease are intraepithelial lesions, occasionally manifesting as invasive adenocarcinoma. It mainly occurs in menopausal or postmenopausal women. Most patients complain of vulvar discomfort and pruritus, and the physical examination often has an eczema-like appearance. Definitive diagnosis often relies on biopsy and is usually associated with intraepithelial lesions or invasive carcinoma. Intraepithelial Paijer’s disease requires superficial local excision. It is often difficult to obtain a clear surgical margin because the underlying histologic changes often exceed the extent of the clinically visible lesion. Extensive resection of intraepithelial lesions has recently been narrowed, and subsequent surgical resection may be performed if symptoms or clinically visible lesions develop later. Those with tumor invasion or spread to the urethra or anus are very difficult to manage and may require laser treatment. In the case of basal adenocarcinoma, the infiltrating portion must be extensively localized with the incision margin at least 1 cm away from the lesion margin. Unilateral lesions should be treated with at least ipsilateral inguino-femoral lymph node dissection and adjuvant radiotherapy with reference to the indications for radiotherapy for squamous carcinoma.