Squamous vulval cancer is a rare condition with a poorly understood aetiology. Two factors seem to have an important role; infection with human papilloma virus leading to vulva intraepithelial neoplasia and chronic inflammatory vulval dermatoses such as lichen sclerosus.
Diagnosis based on biopsy and management is complex. Consideration is given to site and size of lesion as well as the FIGO staging system.
Depending on the stage of cancer, other treatment modalities such as chemoradiation may play a role in the management of the condition.
To know how to perform an incisional biopsy of a suspicious vulval lesion.
To acknowledge that incisional biopsy is the preferred mode of diagnosis for vulval cancer and appreciate that the role of wide local excision is limited.
To be aware of the use of sentinel node biopsy in the management of vulval cancer.
To understand that reconstructive surgery has an important place in the management of these patients.
How can health professionals help women cope with the psychosexual sequelae after vulval surgery?
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Vulval cancer remains a relatively rare condition accounting for 3–5% of female genital cancers and historically affecting older women. Approximately 90% of tumours are squamous in origin. Evidence suggests that there are two separate aetiological factors leading to vulval cancer. First, tumours developing from vulval intraepithelial neoplasia (VIN) caused by human papilloma virus (HPV) infection. Secondly, the development of squamous cell hyperplasia and atypia from chronic inflammation and itch in non-neoplastic vulval dermatoses such as lichen sclerosus. This leads to HPV-negative VIN and eventually to invasive keratinising squamous cell carcinoma.
Recently, the prevalence of HPV associated VIN has significantly increased and consequently, the incidence of vulval cancer in young women is rising. One study demonstrated more than a 10-fold increased incidence of cases in women younger than 50 years of age over a 20-year period. Rates of progression to invasive cancer are imprecise but in one systematic review of 88 patients with untreated VIN 3, eight (9%), progressed to cancer during the 8 years of observation. HPV serotypes 16 and 18 are strongly associated with VIN. A study demonstrated a 5.3-fold increase in vulval neoplasia in subjects positive for HPV-16 antibodies and in those with high antibody levels this rose to a 20-fold increase. The vast majority of these carcinomas harbour warty or basaloid VIN and they share many common risk factors with cervical cancer including multiplicity of sexual partners, early age at initiation of sexual intercourse, cigarette smoking and low socio-economic status. It is, therefore, likely that the HPV vaccination programme to reduce cervical cancer will also provide protection against HPV-related vulval squamous cancer.
Presentation and diagnosis
Women with vulval cancer are rarely asymptomatic. The most common symptoms include pruritis, burning, soreness, bleeding, pain or a lump. Any woman presenting with such symptoms should be examined. Genital warts are not common in postmenopausal women and so this finding should raise the suspicion of cancer. Other concerning features are ulcers, a fungating mass, irregularity of skin contour, depigmentation or hyperpigmentation and groin lymphadenopathy. Most squamous cell carcinomas are unifocal and occur on the labia majora (Figure 2). Other sites include the clitoris and perineum.
Diagnosis is made by biopsy of a suspicious lesion. If the lesion is small and well circumscribed it may be possible to perform a wide local excisional biopsy. It is preferable to use clinical photography to have a precise record of the site of the lesion prior to performing the excision. A clearance margin of at least 1 cm, including depth, is required. If there is no wide margin of normal tissue then the lesion should be biopsied rather than excised. Caution must be exercised when performing excision biopsies. If further surgery is necessary, wide local excision can be extremely challenging when the initial lesion is no longer present.
For most lesions, it will be more appropriate to take one or multiple biopsies. The procedure can be performed with local anaesthetic using a Keye's biopsy blade (Figure 1). The site of biopsy is crucial; it should be taken from the edge of lesion and thus will include adjacent normal epithelium. Plain lignocaine with or without adrenaline is first instilled with a fine needle. A punch biopsy is then driven full thickness through the epithelial surface. The surrounding skin is pressed to release the desired tissue. A soluble suture is usually required to achieve haemostasis.
Pathological examination will confirm histological type of cancer and give details of depth of invasion and clearance margins. Depth of invasion is defined as the measurement from the epithelial junction of the most superficial adjacent dermal papillae to the deepest point of invasion. It directly correlates with lymph node involvement. Tumours with less than 1 mm invasion have a negligible (less than 1%) risk of lymph node metastasis thus the need for nodal resection is eliminated in these cases. These tumours are termed superficially invasive squamous carcinoma. All other squamous vulval cancers have a risk of nodal spread that is directly correlated to depth of invasion as shown in Table 1. The exception to the rule is verrucous carcinoma, a subtype of squamous carcinoma. These typically large condylomatous lesions are well differentiated, low grade fungating tumours and do not metastasise.
Table 1. Depth of stromal invasion versus nodal status in 578 patients with squamous cell carcinoma of the vulva
The natural history of vulval cancer is to grow by direct extension followed by lymphatic embolisation. Initially this is to local inguinal lymph nodes and later to femoral and the external iliac chain. Final spread to distant sites is haematogenous. Lymph node involvement can occur early in the disease process. This is reflected by the International Federation of Gynaecology and Obstetrics (FIGO) staging system for vulval cancer (Table 2).
Table 2. Staging of cancer of the vulva (adapted from FIGO Committee of Gynaecology Oncology), 2009.
Tumour confined to the vulva.
Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm, no nodal metastasis.
Lesions >2 cm in size or with stromal invasion >1.0 mm, confined to the vulva or perineum, with negative nodes.
Tumour of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes.
Tumour of any size, with or without extension to adjacent perineal structures, with positive inguino-femoral lymph nodes.
(i) With 1 lymph node metastasis (≥5 mm), or
(ii) 1–2 lymph node metastases (<5 mm).
(i) With 2 or more lymph node metastases (≥5 mm), or
(ii) 3 or more lymph node metastases (<5 mm).
Positive nodes with extracapsular spread.
Tumour invading other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures.
Tumour invades any of the following:
(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
(ii) fixed or ulcerated inguino-femoral lymph nodes.
Any distant metastasis including pelvic lymph nodes.
Staging of disease prior to surgery is unsatisfactory as palpation of groin nodes is notoriously difficult. More clinical information may be obtained through the use of imaging modalities and fine needle aspiration of enlarged nodes.
Mortality is directly related to stage of disease at presentation. Data from the National Cancer Institute shows a 5 year survival rate of 86% for stage I compared to 53% for stage III and 15% for those with distant metastases.
Vulval cancer should be managed by a multidisciplinary team in a cancer centre.
Surgery remains the gold standard of treatment for vulval cancer. Previously, women routinely underwent extensive and mutilating surgery in the form of radical vulvectomy with en bloc bilateral groin node resection. Although survival rates are impressive after a radical procedure, complication rates are high. As many patients are frail and elderly with significant co-morbidities they may be deemed unsuitable for extensive surgery. Treatment should be tailored to the individual and should take into consideration her age, fitness, sexual function, tumour size, tumour site and stage of disease. Although most commonly performed under general anaesthesia it should be remembered that for those women deemed unfavourable for this mode of anaesthetic, a combination of regional anaesthetic with conscious sedation has been shown to be an effective and safe alternative.
Treatment of early vulval cancer
The current trend of management of early vulval cancer (stage II or less) is to leave as much vulval tissue as possible. There are no randomised controlled trials to support this practice but a review of the data found no difference in local recurrence rates between radical wide local excision and radical vulvectomy. If the primary lesion is a superficially invasive squamous cell carcinoma then resection of lymph nodes is not necessary. For all other tumours management includes inguinofemoral lymphadenectomy. Lateral tumours, defined by their location of more than 1 cm from the midline, drain to the ipsilateral lymph nodes. For these tumours, performing an ipsilateral lymph node resection has the same outcome with regard to groin recurrence as a bilateral resection. If the lesion is central then both groins should be resected. Superficial lymph node resection results in a higher incidence of recurrence so both superficial inguinal and deep femoral lymph nodes should be resected. En bloc groin resection has been replaced with dissection through a separate incision.
Surgery related morbidity is a substantial problem and is mainly related to groin resection. An analysis of 164 patients that underwent inguinofemoral lymphadenectomy revealed that older age, diabetes, en bloc surgery and higher drain production on the last day of drain in situ gave a higher risk of developing short-term complications (wound breakdown, infection and lymphocele). Younger age and lymphocele gave an increased risk of suffering long-term sequelae (lymphoedema and cellulitis). One small randomised controlled trial compared lymph node resection with primary radiotherapy for patients with early vulval cancer. Morbidity from lymphoedema and life threatening cardiovascular complications was reduced in the radiotherapy group but groin recurrence rate increased (relative risk 10.21). Radiotherapy should, therefore, only be considered as first-line for early disease when a patient is not fit enough to withstand a surgical procedure.
Radiotherapy may be required as an adjuvant for early disease, for example in cases where margins are inadequate (less than 8 mm) or if multiple lymph nodes display microscopic involvement.
Treatment of advanced vulval cancer
For stage III and IV disease a combination of treatment modalities can be used according to the individual case. Surgery entails radical vulvectomy with en bloc resection of bilateral inguinofemoral lymph nodes. Most patients require post operative radiotherapy to the pelvis and groin. Pre operative neoadjuvant radiotherapy or chemoradiation can be used to improve operability and reduce extent of surgery required including those cases that would otherwise require a stoma. There are several small case series published that support the use of chemoradiation in cases of advanced disease that would otherwise warrant pelvic exenteration. The regime was found to have acceptable morbidity even in the elderly and in those achieving a complete response, the need for surgery was avoided. Overall, there does not appear to be a significant difference in survival or treatment-related adverse effects when chemoradiation is compared with primary surgery in cases of advanced disease. Data assessing quality of life issues with the different treatments is lacking.
A role for sentinel lymph node biopsy
The sentinel lymph node is the node to which the tumour first drains. For women with early disease, only 20% will have lymph node metastases. The majority of these patients are, therefore, undergoing an unnecessary lymph node resection and the associated complications. If the sentinel lymph node is isolated and resected, it can be examined by frozen section pathology. A sulphur colloid tagged with the radioactive technetium-99 m is injected near the tumour. By using scintigraphic imaging, the node or nodes that take up the radioactive substance can be identified. Similarly, blue dye can be injected intraoperatively about 15 minutes before biopsy. Visual inspection can then identify the sentinel node. A frozen section procedure takes less than 20 minutes enabling rapid microscopic analysis of the node. If there is no evidence of metastases then further resection can be avoided. One small study of 59 patients undergoing inguinofemoral lymphadenectomy evaluated the accuracy of the technique. Intraoperative sentinel node biopsy was performed in all cases prior to lymph node resection. Routine histopathological examination revealed 27 cases of lymph node metastases, all of which were identified at the time of sentinel lymph node biopsy. The negative predictive value for a negative sentinel lymph node was 100%.
The long-term outcome following sentinel lymph node biopsy has been evaluated in the Netherlands. Of 403 women undergoing surgical excision for early stage vulvar cancer, 276 had no sign of metastases in sentinel nodes and so did not have further lymphadenectomy. The women were followed for an average of 35 months after surgery. Women undergoing sentinel node biopsy suffered fewer short- and long-term complications compared to their lymph node resection counterparts. The rate of cancer recurrence in the groin was 3% which was deemed comparable to women treated with lymphadenectomy. Performing sentinel lymph node biopsy requires extensive clinical experience and it is not yet implemented into the routine treatment for early vulval cancer. The Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V) II is an observational multicentre trial currently recruiting patients to further evaluate the role of sentinel node biopsy.
Recurrence of disease
A large, multicentre trial of 502 patients with primary vulval carcinoma demonstrated a recurrence rate of 37%. More than half of the recurrences occurred at the perineum. Three statistically significant risk factors were identified; FIGO stage greater than II (P = 0.029), positive lymph nodes (P = 0.009) and vascular space invasion (P = 0.004). Site of recurrence correlated to survival with a 5 year survival rate of 60% for perineal recurrence, 27% for inguinal and pelvic recurrence and 15% for distant recurrences. Radical re-excision or radiation can be employed to manage local relapse.
Psychosexual issues following vulval cancer
It is essential to address the sexual impact that genital surgery can have. The issue should be raised pre operatively and ideally included in the consent process. Scarring and loss of genital architecture can cause narrowing of the introitus and, in turn, lead to dyspareunia. It can also leave a woman feeling defeminised. Arousal and sexual pleasure can be diminished and it may not be possible to achieve an orgasm. It is common for women to feel numbness in the genital area following vulvectomy although this may improve with time. An analysis of sexual function in 42 patients after radical wide local excision or vulvectomy demonstrated disruption to sexual excitement and orgasm but interestingly sexual desire was not diminished. More women became sexually inactive with time and there was a reluctance to initiate relationships with new sexual partners due to the genital changes. Sexual outcome correlated with degree of surgical intervention with more conservative excision better preserving sexual function.
A Cochrane review examined five interventions for psychosexual dysfunction in 413 women treated for gynaecological cancer. No benefit was found with clinical nurse specialist input, psychoeducational group therapy or couple coping intervention. Vaginal estrogen after radiotherapy was suggested to have short-term benefit but more robust studies are required in this area. A psychosexual counsellor and reconstructive plastic surgeon have an important role is managing sexual issues and should be part of the multidisciplinary team caring for women with vulvar cancer.
Reconstructive surgery plays an important role in the cosmetic and functional results of wide radical vulval surgery. Gynaecological oncologists will have experience in such surgery but input from a plastic reconstructive surgeon is often necessary. Surgical techniques range from simple procedures for introital stenosis to complicated procedures where large areas of skin and underlying tissue are used as flaps to cover defects caused by radical surgery. It is preferable to perform reconstruction at the same time as primary surgery. A variety of graft procedures, realignment of standard incisions and use of vascular pedicle flaps can be employed. A study of more than 60 women requiring reconstructive plastic surgery involving use of fasciocutaneous or and myocutaneous skin flaps for defects led to excellent wound healing and cosmetic results. Reconstruction can allow for more radical excisions and thus the achievement of sufficient clearance margins can be improved.
There can be a role for reconstructive surgery at a later stage. Cosmetic appearance of the vulva can be enhanced by procedures such as labial reconstruction.
Vulval cancer is rare and so should be managed in specialist cancer centres with a multidisciplinary approach. The principle of management is to eradicate disease whilst preserving as much function as possible. Morbidity may be reduced by the use of sentinel node biopsy although this treatment should be undertaken in the context of a clinical trial until further research data are available. Sexual dysfunction is an important and distressing consequence of vulvar surgery that needs to be recognised by health professionals and addressed with patients before surgery.