85% of cancers of the vulva are squamous and the remaining are of various histological types, including melanomas. The labium majorum is the most common site of involvement and accounts for about 50% of cases. The labium minorum accounts for about 20% of cases.¹ The clitoris and Bartholin's glands are less frequently involved. Usually it spreads slowly, locally and metastasises to groin nodes and from there to pelvic nodes.

Epidemiology³

• Vulval cancer is rare and accounts for less than 1% of all cancer cases in the UK. It is extremely rare in women aged under 25. Rates in the UK are approximately 1 in 100,000 in women aged 25-44, 3 in 100,000 in those aged 45-64 and 13.2 per 100,000 in women aged 65 and above.
• The lifetime risk in the UK is 1 in 316 women.
• 1,603 new cases were diagnosed in the UK in 2006.
• The incidence dropped from 1975 to the mid-1980s but rose thereafter, particularly in younger women. This trend has been seen in other countries and is thought to be due to the increase in vulval intraepithelial neoplasia (VIN) associated with human papillomavirus (HPV) infection.
• North America has the highest incidence and Asia the lowest. This is thought to be due to lifestyle factors such as the interaction between smoking and HPV.¹
• 90% of vulval cancers are due to squamous cell carcinoma. The others comprise basal cell carcinomas, adenocarcinomas, sarcomas and melanomas.
• At least 10% of women with untreated carcinoma in situ go on to develop invasive vulval cancer.Treated, this figure drops to 2-5%.

Presentation⁴

• Vulval cancer may present with a vulval lump, vulval bleeding due to ulceration, pruritus or pain.
• The pattern of spread is influenced by the histology. Well-differentiated lesions tend to spread along the surface with minimal invasion, while anaplastic lesions are more likely to be deeply invasive.
• Spread beyond the vulva is either to adjacent organs such as the vagina, urethra and anus, or via the lymphatics to the inguinal and femoral lymph nodes, followed by the deep pelvic nodes.
• Approximately 5% of cases spread to distant sites.

Investigations⁴

• The diagnosis of vulval cancer is made by biopsy.
• Cystoscopy, proctoscopy, chest X-ray and intravenous urography are used for staging purposes.

Differential diagnosis⁴

• Lichen planus
• Ulcers: for example, herpes, Crohn's disease, Behçets disease, syphilis
• Dermatitis
• Fungal infection
• Other causes of swellings of the vulva include boils, sebaceous cysts, Bartholin's cyst or abscess and urethral caruncle

Staging

Stages are defined by the Fédération Intérnationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer's (AJCC) TNM classifications.²

TNM definitions

TNM Category/FIGO Stage

Primary tumour (T)

• TX: primary tumour cannot be assessed
• T0: no evidence of primary tumour
• Tis/0: carcinoma in situ (preinvasive carcinoma)
• T1/I: tumour confined to the vulva or vulva and perineum, 2 cm or less in greatest dimension
• T1a/IA: tumour confined to the vulva or vulva and perineum, 2 cm or less in greatest dimension and with stromal invasion no greater than 1 mm.
• T1b/IB: tumour confined to the vulva or vulva and perineum, 2 cm or less in greatest dimension and with stromal invasion greater than 1 mm.
• T2/II: tumour confined to the vulva or vulva and perineum, more than 2 cm in greatest dimension
• T3/III: tumour of any size with contiguous spread to the lower urethra and/or vagina or anus
• T4/IVA: tumour invades any of the following: upper urethra, bladder mucosa, rectal mucosa, or is fixed to the pubic bone

Regional lymph nodes (N)

• NX: regional lymph nodes cannot be assessed
• N0: no regional lymph node metastasis
• N1/III: unilateral regional lymph node metastasis
• N2/IVA: bilateral regional lymph node metastasis

Distant metastasis (M)

• MX: distant metastasis cannot be assessed
• M0: no distant metastasis
• M1/IVB: distant metastasis (including pelvic lymph node metastasis)

AJCC stage groupings

• Stage 0: Tis, N0, M0
• Stage I: T1, N0, M0
• Stage IA: T1a, N0, M0
• Stage IB: T1b, N0, M0
• Stage II: T2, N0, M0
• Stage III: T1, N1, M0; T2, N1, M0; T3, N0, M0; T3, N1, M0
• Stage IVA: T1, N2, M0; T2, N2, M0; T3, N2, M0; T4, any N, M0
• Stage IVB: any T, any N, M1

Management⁴

When to refer

• The National Institute for Health and Clinical Excellence (NICE) recommends that any woman presenting with an unexplained vulval lump and/or bleeding from ulcerated vulval skin should be referred for an urgent gynaecological opinion.⁵
• A 'treat, watch and wait' approach should be adopted with patients who have vulval pruritus or pain. Patients with persistent symptoms should be referred for a gynaecological opinion; this may be urgent or routine depending on the degree of patient/doctor concern about the possibility of cancer.⁶

Preinvasive carcinoma

• The trend is now to perform the least deforming procedure necessary and wide local excision is the treatment of choice for small (<2 cm) unilateral lesions.
• Vulval intraepithelial neoplasia occupying non-hairy areas can be considered an epithelial disease. With involvement of hairy sites, the pilosebaceous gland in usually involved and so requires a greater depth of destruction or excision.
• Irrespective of the procedure, a significant number of patients develop a recurrence with the most common sites being the perianal skin, presacral area and clitoris.
• Laser excision treatment is an alternative to surgery or an adjunct for those areas difficult to remove by surgery. Laser treatment is followed by a higher recurrence rate.
• Topical 5% fluorouracil cream is not a reliable first choice for treatment but is useful for women when complete surgical resection is not possible. Topical steroids may be used to relieve associated irritation but they are not a curative treatment.

Invasive carcinoma

• Standard treatment in vulval cancer is surgery. Simple vulvectomy gives a 5-year survival rate of essentially 100% but modified partial vulvectomy is often preferred due to the psychosexual implications of deformity. Total vulvectomy is however indicated in the presence of bilateral cancer. For most patients with stage III or IV disease, surgery is supplemented by external-beam radiation therapy.
• Large lesions (T1B or greater or >1 mm stromal invasion) are likely to have inguinal node involvement. Lymph node biopsy should be performed with removal of the nodes if possible. This may be unilateral or bilateral depending on histology findings.
• Newer strategies integrate possible therapeutic advantages of surgery, radiation therapy and chemotherapy.⁷
• Preoperative treatment with chemotherapy and radiotherapy reduces tumour size and improves the chances of surgical excision in women with initially inoperable primary tumours or fixed lymph nodes but side-effects (skin toxicity, wound breakdown, infection, lymphoedema and lymphoceles) are considerable.⁸
• In patients with large tumours, the complications of radiotherapy and chemotherapy followed by surgery might outweigh complications of surgery alone. Radiotherapy and chemotherapy treatment are not justified in patients with tumours that can be adequately treated with removal of the tumour by vulvectomy and bilateral groin node dissection alone.⁸
• Chemotherapy:
  • Preoperative chemoradiotherapy (using 5-fluorouracil and mitomycin) can reduce the size of large carcinomas and reduce the extent of surgery necessary.
  • Chemotherapy alone with bleomycin, methotrexate and CCNU® has been used successfully.⁹
  • However the results of chemotherapy for advanced and recurrent disease have overall been disappointing.²
• Invasive and preinvasive neoplasms of the vulva may be human papillomavirus (HPV)-induced and so close follow-up is required for early detection of recurrent or second tumours.

Prevention³

• Monthly self-inspection for vulval lesions is recommended for all women who have had anogenital cancer or vulval intraepithelial neoplasia (VIN) in the past.
• Immunotherapy for VIN may be beneficial in reducing subsequent development of vulval cancer but research is ongoing.
• The human papillomavirus (HPV) vaccine may make a significant difference in preventing vulval cancer in the future.

Prognosis⁴

• Vulval cancer is curable when diagnosed in an early stage.
• Operable disease without nodal involvement: the overall survival rate is 90%.
• Nodal involvement: the overall 5-year survival rate is approximately 50% to 60%.

Document references

1. National Cancer Institute (US); Vulvar cancer
2. Canavan T, Cohen D; Vulvar Cancer. American Family Physician; October 2002.
3. Cancerresearchuk.org; Vulval cancer - UK incidence statistics 2009.
4. Creasman WT; Malignant Vulvar Lesions, eMedicine, Nov 2009.
5. Referral for suspected cancer, NICE Clinical Guideline (2005)
6. Gynaecological cancer - suspected, Clinical Knowledge Summaries (2005)
7. Domingues AP, Mota F, Durao M, et al; Neoadjuvant chemotherapy in advanced vulvar cancer. Int J Gynecol Cancer. 2010 Feb;20(2):294-8. [abstract]
8. van Doorn HC, Ansink A, Verhaar-Langereis M, et al; Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev. 2006 Jul 19;3:CD003752. [abstract]
9. Wagenaar HC, Colombo N, Vergote I, et al; Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. European Organization for Research and Treatment of Cancer. Gynecol Oncol. 2001 Jun;81(3):348-54. [abstract]

Acknowledgements