Malignant disease of the vulva and vagina

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CHAPTER 41 Malignant disease of the vulva and vagina

Shun N. Shingm Siu, David Luesley

Introduction

Vulval cancer is an uncommon condition that largely affects elderly women (Figure 41.1). The Office of National Statistics recorded 842 cases in 2005 (Office of National Statistics 2008). This incidence of 3.3 per 100,000 ranks vulvar cancer as the 20th most common cancer in women. The most recent mortality figures recorded 270 deaths for all age groups, giving a death rate of 1.05 per 100,000 women (0.53/105 persons), ranking it the 19th most common cause of cancer death in women.

Figure 41.1 Age distribution of vulval cancer.

Source: Office of National Statistics 2008 Cancer Statistics Registration, Registration of Cancer Diagnosed in 2005, England. Series MB1 No. 36. Her Majesty’s Stationery Office, London.

The changing population demographics will result in an increase in the incidence of the disease as a result of an ageing population, and an increase in the associated comorbidity, providing additional medical challenges to effective multimodality care.

The disease is potentially curable in most cases, even in the elderly and unfit. However, if the diagnosis is delayed or if managed inappropriately, the outcome is variable with the potential for a miserable, degrading death. Effective surgical treatment seems deceptively simple, but few gynaecologists and their nursing colleagues acquire sufficient experience of this disease to offer the highest quality of care for these women. This is a disease where there is a compelling case for centralized care, and where one might expect the reorganization of gynaecological cancer services to benefit women significantly.

Aetiology

There seem to be two distinct types of vulval carcinoma: the first type occurs predominantly in older women, is typically a well-differentiated keratinizing tumour that is not associated with usual-type vulvar intraepithelial neoplasia (VIN) or human papilloma virus (HPV) infection, but which often shows adjacent epithelial disorders such as lichen sclerosus and/or differentiated VIN; and a second type which mainly occurs in younger women, is associated with usual-type VIN, shows evidence of oncogenic HPV infection, and may be associated with synchronous or metachronous squamous preneoplastic or neoplastic lesions of the cervix, vagina and anal canal (Crum et al 1997, van der Avoort et al 2006). Smoking may be an important cofactor involved in the aetiology of HPV-related vulvar tumours (Hussain et al 2008).

Case-controlled studies have failed to confirm an association with diabetes mellitus, obesity, vascular disease and syphilis.

The following are recognized risk factors for all types of vulval cancer:

• immunosuppression;

• advanced age;

• history of cervical neoplasia (Ansink and Heintz 1993);

• lichen sclerosus (4–7% risk of developing cancer) (MacLean and Reid 1995, Meffert et al 1995);

• VIN and multifocal disease (5–90%) (Herod et al 1996, Jones et al 1997);

• Paget’s disease (Fishman et al 1995);

• melanoma in situ (Bradgate et al 1990, Ragnarsson-Olding et al 1993); and

• smoking (Hussain et al 2008).

Histology

The majority of vulvar cancers (90%) are squamous in origin (Figure 41.2). Verrucous and basal cell cancers are squamous cell variants.

Figure 41.2 The histological subtypes of vulval cancer.

Non-squamous cancers include Bartholin’s gland cancer and other adenocarcinomas, malignant melanoma, Paget’s disease and sarcomas. The vulva may also be a site for lymphoma and metastases from elsewhere (Finan 2003). Rarely, primary breast cancers have been reported (Piura et al 2002).

The histology has a bearing on management, largely because of the different risks of nodal metastases and the predilection for distant spread.

Lymphatic Drainage

An understanding of the lymphatic drainage is important as the regional nodes are a potential site of metastases.

Lymph drains from the vulva to the superficial inguinal glands and then to the deep femoral glands in the groin. Drainage continues to the external iliac glands. Drainage to both groins occurs from midline structures — the perineum and the clitoris — but some contralateral spread may take place from other parts of the vulva (Iversen and Aas 1983). Direct spread to the pelvic nodes along the internal pudendal vessels occurs very rarely, and no direct pathway from the clitoris to the pelvic nodes has been demonstrated consistently. An important aspect of the lymphatic drainage is the concept of sentinel nodes in each groin. This is the first node that draining lymph encounters as it drains bilaterally from the vulvar basin (Cabanas 1977). This anatomical concept has been exploited recently to develop selective lymphadenectomy in this disease.

Natural History of Squamous Cancers

Malignant transformation may occur in more than one site, and this appears to apply in both HPV-negative and -positive scenarios, although more commonly in the latter. The earliest recognizable phase of vulval cancer is termed ‘superficially invasive disease’ (stage Ia). The tumour is less than 2 cm in lateral dimension, and there is less than 1 mm invasion when measured from the base of an adjacent dermal papilla. Accurate identification and classification of this stage requires expert pathological interpretation, and is exceptionally important as the current consensus would suggest a virtually negligible risk of lymph node metastases. As the cancer gradually increases in size and progressively invades the deeper layers of the dermis, it spreads locally. The tumour will eventually involve the local lymphatics, hence the propensity for groin lymph node involvement (Table 41.1).

Table 41.1 Groin recurrences in women who did not undergo any form of groin node surgery. None had clinically suspicious lesions in the groin, and all were regarded as ‘low-risk cases’. In many, groin node surgery was omitted because of associated medical problems

Local progression will eventually lead to involvement of adjacent structures. The urethra, anus and vagina can all become involved. In advanced stages, there can be extensive local destruction and involvement (often with superadded infection), groin node metastases and potentially lymph node involvement in the pelvis, para-aortic and neck nodes. Metastases in adjacent skin may also be noted, and haematogenous spread can also occur in late disease.

If widespread disease is seen with small vulvar tumours, a more aggressive histotype may be present, such as a melanoma or sarcoma.

Presentation

The medial aspects of the labia majora are the most common sites for disease to develop (70%). The labia minora, clitoris, periurethral areas, posterior fourchette and perineum account for the remainder (30%). Small lesions may be asymptomatic and go unnoticed by the patient. However, both Hacker et al (1981) and Monaghan (1990) have commented that, in a significant minority of patients, there appears to be considerable delay in presentation. The intimate nature of the disease, fear and/or ignorance and the advanced age of many patients might partly explain this observation. The fact that the disease is uncommon may also be contributory, as primary carers may not recognize the significance of symptoms or fail to recognize the clinical signs. Whatever the cause, a significant number of cases continue to present in advanced stages.

The reasons for presenting have been analysed by Podratz et al (1983a). Pruritus is the most common presenting symptom (71%), and an ulcer or mass will have been noted in nearly 80% of cases. Surprisingly, pain is only a feature in 23% of cases. Bleeding (26%), discharge (13%) and urinary tract dysfunction (14%) are other common reasons for presentation.

Assessment

The assessment of these women should include confirmation of the diagnosis, an assessment of disease extent, and an holistic approach to the patient to assess relevant comorbidity and/or other factors that may impact on the management plan.

Examination

The character, size and location(s) of all lesions should be documented. Particular attention should be paid to assess any involvement of the vagina, urethra, bladder base or anus. Palpation is important to determine possible involvement of the surrounding bony structures. Discomfort and tenderness may necessitate an examination (and biopsies) under general anaesthesia. The groin should be examined, although a negative assessment cannot reliably exclude cancer. Hard, enlarged, fixed or ulcerated nodes (Figure 41.3) need to be documented as this will almost certainly influence management.

Figure 41.3 Enlarged fungating lymph node.

Due to the potential for other genital tract malignancies, the vagina and cervix should also be assessed thoroughly and biopsied as necessary.

Diagnosis

Diagnosis is based upon a representative biopsy of the tumour. The biopsy should include an area where there is a transition from normal to malignant tissue (Figure 41.4). Biopsies should be of a sufficient size to allow differentiation between superficially invasive tumours and frankly invasive tumours, and orientated to allow quality pathological interpretation. Radical excision should not be undertaken without prior biopsy confirmation of malignancy unless there are extenuating circumstances.

Figure 41.4 Diagnostic ‘wedge biopsy’ to include tumour and adjacent ‘normal’ epithelium.

The histopathological report should include:

• site;

• size (in three dimensions);

• associated features (such as the presence of VIN or condylomata);

• tumour type;

• depth of invasion;

• maximum horizontal measurement;

• whether the tumour is completely excised and tumour-free margin measurement;

• presence or absence of lymphovascular invasion; and

• nature of the adjacent non-malignant squamous epithelium.

The grading of the tumour is based on the percentage of undifferentiated cells, with grade 1 having no undifferentiated cells, grade 2 having less than half undifferentiated cells and grade 3 having more than half poorly differentiated cells.

Staging

There are two staging systems: the Tumour, Node, Metastasis system and the International Federation of Gynaecology and Obstetrics (FIGO) system. Most gynaecologists use the latter which, since its last update in 2000, is based upon clinical and surgical findings. Table 41.2 details both staging systems.

Table 41.2 FIGO staging of vulval cancer

FIGO stage	Description
I	Tumour confined to the vulva
Ia	Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1 mm. No nodal metastasis
Ib	Lesions >2 cm in size or with stromal invasion >1 mm confined to the vulva or perineum. No nodal metastasis
II	Tumour of any size with extension to adjacent perineal structures (lower 1/3 urethra; lower 1/3 vagina; anus) with negative nodes
III	Tumour of any size with or without extension to adjacent perineal structures (lower 1/3 urethra; lower 1/3 vagina; anus) with positive inguinofemoral nodes
IIIa	(i) With 1 lymph node metastasis (≥5 mm), or (ii) 1–2 lymph node metastasis(es) (<5 mm)

IIIb

(i) With 2 or more lymph node metastase (≥5 mm), or

(ii) 3 or more lymph node metastases (<5 mm)

IIIc With positive nodes with extracapsular spread IV Tumour invades other regional (upper 2/3 urethra; 2/3 vagina) or distant structures IVa 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 inguinofemoral lymph nodes

IVb Any distant metastasis including pelvic lymph nodes

FIGO, International Federation of Gynaecology and Obstetrics.

Prognostic Factors

The size of the primary tumour and the status of the regional lymph nodes are the only two factors that have been consistently associated with outcome (Homesley et al 1991). The 5-year survival rate in cases without lymph node involvement is in excess of 80%, falling to less than 50% if the inguinal nodes are involved and 10–15% if the iliac or other pelvic nodes are involved.

Tumour size

Tumours larger than 2 cm in diameter have a greater chance of being frankly invasive and metastasizing to lymph nodes.

Depth of invasion

Invasion less than 1 mm (superficially invasive or stage Ia) has a negligible risk of lymph node involvement, and groin node dissection may be omitted (Hacker et al 1984b). The risk of nodal metastasis rises to 8% for a depth of 1–2 mm, 11% for 2–3 mm, and over 25% for lesions with a depth greater than 3 mm (Morrow et al 1993) (Figure 41.5).

Figure 41.5 The relationship between depth of invasion and groin node metastases (squamous lesions).

Lymphovascular space permeation

This factor along with tumour border pattern (infiltrating vs pushing) and perineural invasion are not included in the surgicopathological staging of vulvar cancer, although they are associated with an increased risk of metastasis (Heaps et al 1990, Hopkins et al 1991).

Lymph node status

This is the most important prognostic variable. The number of lymph nodes involved and the nature of involvement influence the prognosis. Microscopic involvement of a single groin node, without extracapsular involvement, represents a low risk of recurrence, and adjuvant therapy is not necessary (Hacker et al 1983). Conversely, multiple nodal diseases and macroscopic and/or capsular involvement are indications for adjuvant radiotherapy in order to reduce the risk of groin recurrence, which is usually fatal (van der Velden et al 1995). It is well recognized that groin node dissection is associated with significant morbidity. Almost 50% of patients undergoing groin node dissection will suffer postoperative complications, most commonly wound infection, wound breakdown and lymphoedema (Gaarenstroom et al 2003). For these reasons, a presurgical investigation that could identify those at risk could have a significant therapeutic benefit. Assessment by clinical palpation of the groins is inadequate; of patients with clinically normal lymph nodes, 16–24% have metastases, while 24–41% of those with clinically involved nodes are negative when examined histologically (Sedlis et al 1987, Homesley et al 1993). Even though the majority of vulval cancers are still assessed clinically, there is increasing interest in utilizing additional imaging, particularly of the regional node groups. Ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography have all been assessed but lack the sensitivity to exclude microscopic disease reliably (Selman et al 2005). Sentinel node sampling (vide infra) has shown promise, and the collective experience of this technique now suggests that it is reliable, at least in early-stage disease.

Sentinel lymph node detection

The concept of the ‘sentinel lymph node’ (SLN) was introduced in 1977 by Cabanas (1977). He defined the SLN as the first node in the lymphatic basin that receives primary lymphatic flow. Subsequent studies have confirmed that a tumour-free SLN implies absence of lymph node metastases in the entire draining lymphatic basin (Balega and van Trappen 2006). The last two decades have seen the technique become established in the management of cutaneous melanoma and breast cancer. The concept (Figure 41.6) has now been introduced for the management of early vulval cancers, and the published performance data to date are promising (Table 41.3).

Figure 41.6 Diagramatic illustration of the sentinel node concept.

Table 41.3 Performance of the sentinel lymph node technique in early vulval cancer

There are two ways to detect the SLN: blue dyes and radioactive tracer. Both are injected around the edge of the tumour prior to surgery; they are complementary and combining these techniques achieves a higher sensitivity compared with a single tracer. Excised SLNs are subjected to frozen section analysis and ultrastaging. Full inguinofemoral lymphadenectomy is avoided if SLNs are negative. Since unrecognized groin disease is nearly always fatal, the negative predictive value of this method is of particular concern. Early studies included full inguinofemoral lymphadenectomy following the SLN procedure to provide a ‘gold standard’ for comparison. The results confirmed a negative predictive value approaching 100%.

A large-scale international trial, the Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V), was established to test the safety and clinical utility of SLN dissection in early-stage vulvar cancer. This was an observational study. Patients with stage I and II disease with tumour size less than 4 cm were recruited. Only patients found to have disease in either SLN underwent full inguinofemoral lymphadenectomy. Among 259 patients with unifocal vulvar cancer and a negative sentinel node, groin recurrences occurred in six (2.3%) women, and the 3-year survival rate was 97%. This result was comparable with similar historical groups of patients that had full inguinofemoral lymphadenectomy. However, both short- and long-term morbidity were significantly reduced, including shorter hospital stay and less wound breakdown and lymphoedema (van der Zee et al 2008). The authors thus proposed that sentinel node dissection should be the standard treatment for patients with unifocal early-stage vulvar cancer. In the second phase of the GROINSS-V study, investigators are evaluating radiotherapy, rather than complete inguinofemoral lymphadenectomy, in patients with metastatic SLNs. The objective is to further reduce morbidity by avoiding double-modality treatment.

Treatment

Factors influencing the management plan

Site of the tumour

Centrally located tumours lie close to midline structures such as the clitoris, urethra, vagina and anus, and are associated with a higher risk of bilateral inguinal nodal spread compared with more lateral tumours. If the medial margin lies within 1 cm of the midline, they should be defined as central (de Hullu and van der Zee 2006). Bilateral groin node dissection is recommended for central tumours, and ipsilateral groin node dissection is recommended for lateralized tumours (Figure 41.7). Furthermore, if central tumours approximate to the urethra or anal canal such that these structures would be sacrificed to achieve satisfactory clearance, urinary or bowel diversion may be necessary.

Figure 41.7 Laterality.

Surgery

Surgery is the mainstay of treatment. The traditional ‘butterfly’ incision en-bloc radical (Figure 41.8) vulvectomy introduced by Taussig (1940) and Way (1960) clearly improved survival. The excised tissues included the vulvar lesion, the inguinofemoral lymph nodes and the lymphatics in between. Large areas of normal tissue were frequently included, and primary wound closure was rarely achieved. Protracted postoperative recovery and severe wound complications and disfigurement were associated with this procedure. This postoperative morbidity has been the main driver for progress over the last two decades. Surgical treatment has become more individualized and conservative, aimed at reducing morbidity without compromising survival.

Figure 41.8 En-bloc radical vulvectomy.

Separate incisions

The use of three separate incisions for groin dissections and vulvectomy instead of the traditional ‘butterfly incision’ has improved wound healing and reduced the frequency of wound breakdown (Hacker et al 1981). The suggestion that this lesser approach might result in an increase in skin bridge recurrence was not born out in a Cochrane review, which showed a skin bridge recurrence rate of less than 1% (Ansink and van der Velden 2000). The hypothesis underpinning this strategy is based upon the belief that in early tumours, cells disseminate by embolization rather than in continuity (Willis 1973); therefore, there should be no residual tumour in the lymphatic channels between the tumour and the groin nodes. Reported cases of skin bridge recurrences were mainly seen in women with large groin node metastasis (Rose 1999). No prospective randomized controlled studies have been performed comparing the traditional radical vulvectomy with en-bloc inguinofemoral lymphadenectomy with the separate incision technique. However, de Hullu et al (2002) did undertake a retrospective comparison and noted a significant increase in groin and skin bridge recurrence with the less radical procedure (6.3% vs 1.3%, P=0.029). This, however, did not result in a difference in overall survival. They concluded that in view of the morbidity of the ‘butterfly incision’ and relatively low skin bridge recurrence rate, separate incisions were the preferable technique for stage I and II disease.

Modified radical vulvectomy or wide local excision

The main factor causing severe morbidity and disfigurement following radical vulvectomy is the extensive dissection and removal of normal tissue from the vulvar region. In the last two decades, less radical surgery, such as modified radical vulvectomy, hemivulvectomy and wide local excision, has been introduced to reduce morbidity without compromising survival. Tumour-free margins are the most important predictive factor for local recurrences. Both Heaps et al (1990) and de Hullu et al (2002) showed that a tumour-free margin of more than 8 mm was associated with significantly lower local recurrence rate. These studies found that suboptimal tumour-free margins (<8 mm) were more likely when the intentional macroscopic margin was 1 cm or less. A lesion might extend further than judged by macroscopic inspection, and tissues usually shrink during preparation for histological examination (Balega et al 2008). A macroscopic surgical margin of 2 cm is thus recommended. This may be difficult to achieve in some cases where the tumour is adjacent to the urethra and anus, but every effort should be made to maximize the margins. The tumour-free margins should be the same regardless of whether a radical vulvectomy or a wide local excision is performed.

Unilateral inguinofemoral lymphadenectomy

Lateralized vulvar tumours rarely metastasize to the contralateral inguinofemoral lymph nodes without the ipsilateral nodes being involved. van der Velden (1996) pooled 489 patients with unilateral vulvar cancers and found only 0.9% with isolated contralateral lymph node metastases in lateralized stage I disease. Similarly, Gonzalez Bosquet et al (2007) reviewed 320 patients who underwent bilateral groin lymph node dissection. Among 163 patients with unilateral vulvar lesions, only three (1.8%) had an isolated contralateral nodal metastasis. No patients with a tumour diameter equal to or less than 2 cm and depth of invasion less than 5 mm had bilateral groin lymph node involvement. Given the recognized higher morbidity and low numbers of patients with contralateral metastases, it is now a generally accepted practice to perform a unilateral inguinofemoral lymphadenectomy in patients with stage I and II lateralized tumours, without suspicious lymph nodes on palpitation. If nodal disease is found in one groin, the opposite groin should also be explored. Normal lymph flow may be disturbed in cases of ipsilateral groin node metastases with alternate channels developing, thus allowing contralateral spread.

Superficial inguinal lymphadenectomy

In order to reduce lymphoedema and wound breakdown associated with groin dissection, DiSaia et al (1979) proposed removing only the superficial inguinal lymph nodes lying anterior to the cribriform fascia, without exploration of the deeper femoral nodes. The rationale for this was that lymphatic drainage from the vulva passes first to the superficial inguinal nodes before subsequently draining to the femoral nodes. The superficial inguinal nodes were assessed by frozen section, and a deep dissection was performed if the superficial nodes were found to be positive. However, the results of subsequent studies have not been encouraging. Unexpected groin recurrences occurred in patients with early-stage disease and presumed negative inguinal nodes (Hacker et al 1984b, Kelley et al 1992, Stehman et al 1992a). The current practice is that a full inguinofemoral lymphadenectomy including all superficial inguinal lymph nodes and femoral lymph nodes medial to the femoral veins should be performed whenever there is an indication for node dissection.

Pelvic lymphadenectomy

Routine pelvic lymphadenectomy is no longer considered in the surgical management of vulvar carcinoma. The incidence of pelvic node metastases is approximately 5% and is very rare in the absence of inguinofemoral lymph node metastases (Gadducci et al 2006). One randomized trial (Homesley et al 1986) compared pelvic lymphadenectomy with pelvic radiotherapy in patients with inguinofemoral lymph node metastases after radical vulvectomy and bilateral inguinofemoral lymphadenectomy. The 2-year survival rate for the radiation group was significantly better than that for the pelvic lymphadenectomy group (68% vs 54%, P<0.03). The incidence of groin recurrence was less in the radiation group (5.1% vs 23.6%, P<0.02). However, the rate of pelvic recurrence was increased in patients who received pelvic irradiation. It was postulated that radiation may not be able to sterilize bulky pelvic metastatic nodes. Therefore, removal of enlarged pelvic nodes seen on CT scan via an extraperitoneal approach was suggested before starting radiotherapy.

Surgical morbidity

Incremental reduction in the radicality of treatment has resulted in less morbidity. Wound breakdown, wound infections, lymphocysts, lymphoedema, vulvar disfigurement and psychosexual disturbance remain problematic.

Vulvar morbidity

Primary wound closure was often difficult if not impossible when the traditional ‘butterfly incision’ was used. This is still the case when large excisions are required, but even in these instances, more frequent use of plastic reconstructive techniques results in improved healing and better cosmetic outcomes. In smaller vulvar tumours, wide local excision with separate groin wounds has decreased the wound breakdown rate significantly.

Problems with micturition (spraying, angulation of urine, urethral stenosis) are not uncommon if the distal third of the urethra is excised. Surgery for perineal and perianal lesions may give rise to problems with defaecation (constipation, tenesmus and faecal incontinence), localized pain when sitting and coital difficulties (Barton 2003). Occasionally, repeat surgery is needed to excise fibrotic tissue or to widen the stenotic introitus in order to facilitate coitus.

Groin morbidity

Lymphocysts and infection are the two most common short-term groin complications. Despite the routine use of drains and antibiotics, complications are still as high as 66% (Gaarenstroom et al 2003). More troublesome is the long-term complication of lower limb lymphoedema, which is often difficult to treat and can cause significant distress to patients. The incidence of lymphoedema is further increased if adjuvant radiotherapy is given after surgery (Barton 2003). The simplest approach to reduce groin morbidity is less radical surgery and avoidance of double treatment. SLN dissection goes some way to addressing this need without compromising disease control, at least in early vulval cancer. The incidence of wound breakdown, infection and lymphoedema decreased to 11.7%, 4.5% and 1.9%, respectively (van der Zee et al 2008).

Psychological morbidity

Vulvar disfigurement, coital difficulties and lower limb oedema are all chronic problems that continually remind patients of their past disease and treatment. This can impact adversely on relationships and self-esteem. Leg oedema is distressing as it is a visible disfigurement, can reduce mobility and impact on independent living. Such complications may eventually result in depression, low self-esteem and loss of confidence. Consideration should be given to provide psychological and psychosexual support for these patients.

Radiotherapy

Radiotherapy was traditionally considered to have a limited role in the management of vulvar cancer. Vulvar skin does not tolerate irradiation well, especially so when orthovoltage equipment was in use. Vulvar skin is thin, delicate, very sensitive and highly vascularized. Radiotherapy to this area frequently causes both acute and chronic reactions, making treatment difficult to tolerate, particularly in the elderly. Acute inflammation with both dry and moist desquamation is very painful, and may be exacerbated by associated urinary incontinence. Tolerance of radiotherapy has improved with megavoltage therapy. Late reactions include scarring, fibrosis and telangiectasia causing functional compromise and cosmetic impairment.

Postoperative adjuvant therapy

Patients with risk factors for local recurrence, such as a close surgical margin, lymphovascular space permeation, poorly differentiated tumour grade or diffuse infiltrative growth pattern, should be considered for adjuvant external beam radiation therapy to reduce the risk of recurrence (Perez et al 1998, Blake 2003).

With regard to the nodal status, no additional treatment is recommended if there is only one microscopically positive lymph node (Hacker et al 1983). However, if two or more metastatic nodes are present, or there is capsular involvement in a single metastatic node, postoperative adjuvant radiotherapy is usually recommended (van der Velden et al 1995). In a subgroup analysis of Homesley et al’s study, the survival advantage of radiotherapy was limited to those patients with clinically evident groin nodes or more than one positive groin node (Homesley et al 1986).

Neoadjuvant therapy

In order to achieve an adequate surgical margin with large tumours close to the urethra and/or anal canal, it may be necessary to compromise urethral and/or anal function with an associated diversion. In 1973, Boronow suggested a combined radiosurgical approach to shrink the tumour preoperatively, aiming to spare this group of patients from exenterative surgery. Subsequent reports (Hacker et al 1984a, Boronow et al 1987) confirmed the feasibility of this function-sparing approach. More recently, concurrent chemoradiation has been used with the same intent. Moore et al (1998) gave concurrent cisplatin/5-fluorouracil (5FU) and radiation therapy to 71 patients with stage III–IV disease. Thirty-three patients (46.5%) had no visible tumour after chemoradiation, and only three patients were not able to preserve urinary and/or gastrointestinal continence after surgery. van Doorn et al (2006) reviewed the available literature and concluded that preoperative chemoradiotherapy reduces tumour size and improves operability. However, complications are considerable, especially in delayed wound healing, and overall increased treatment-related morbidity.

Primary treatment

Radiotherapy alone as a treatment for vulvar cancer is not recommended in operable tumours, mainly because of the perceived intolerance of vulvar tissue. However, it is an option in patients who cannot undergo surgery because of advanced disease or comorbidity issues. In selected cases, primary radiotherapy can cure vulvar cancer with acceptable morbidity (Busch et al 1999). Chemotherapy can be added to the regimen, either as a neoadjuvant to reduce tumour bulk or as concomitant chemoradiotherapy to improve cure rates (Moore et al 1998).

Although the groin tolerates radiotherapy better than the vulva, primary radiotherapy to treat groin disease is not recommended. One study has reported a higher recurrence rate when comparing radiation therapy with inguinofemoral lymphadenectomy (Stehman et al 1992b). However, this study has been criticized on the basis of suboptimal radiotherapy technique, particularly that the maximum dose did not reach the deep inguinofemoral nodes. More recently, Katz et al (2003) re-evaluated the value of primary radiotherapy for groin disease. Comparable recurrence rates were observed when radiotherapy alone was compared with inguinofemoral lymphadenectomy (15% vs 16.6%). The authors concluded that radiotherapy alone was as effective as surgery in preventing groin recurrence. This study was criticized largely because of difficulties in interpreting the individualized treatment. There were also doubts about the radicality of lymphadenectomy.

Although the available data are somewhat confused, radiotherapy appears to be an effective treatment for microscopic (residual) disease in the groin, but less effective when gross disease is present.

Palliation

Patients with advanced disease and distant metastasis might not derive much overall benefit from radical surgery. Radiotherapy may offer a palliative option in some of these cases.

Chemotherapy

The role of chemotherapy in vulvar cancer is either as concomitant therapy with radiation or as a palliative manoeuvre in recurrent or metastatic disease. Several cytotoxic drugs (cisplatin, methotrexate, bleomycin, mitomycin C and 5FU) have been shown to have activity when used alone or in combination (Shimizu et al 1990, Benedetti Panici et al 1993). 5FU appears to be the most effective agent. In a series of 12 patients with advanced vulvar cancer involving either or both the anus and urethra, a combination of cisplatin and 5FU gave a 100% response rate. The anal sphincter and urethra were conserved in these patients during subsequent radical surgery. However, three patients receiving cisplatin alone showed no response or even progression (Geisler et al 2006). However, all of the studies were small and uncontrolled, and should be interpreted with caution.

Advanced Disease

Advanced vulvar cancer (T3/T4) is characterized by local extension to neighbouring structures (urethra, vagina, bladder and anus). Regional lymph node metastases are present in over 50% of these patients (Hacker et al 1983). Ultraradical surgery with urinary tract and/or bowel diversion is required for complete excision. Unfortunately, most of these patients are elderly and frail, having significant comorbidities rendering them unsuitable for such extensive surgery. Radiation therapy with or without chemotherapy can shrink some tumours before surgery, sparing them from stoma formation and reducing surgical morbidity (Hacker et al 1984a, Boronow et al 1987). Furthermore, preoperative chemoradiation can result in fixed groin nodes becoming resectable (Montana et al 2000). Radiation therapy with or without concurrent chemotherapy should be considered as an alternative option for patients with advanced vulvar cancer who would otherwise require exenterative surgery.

Recurrences

Rouzier et al (2002) identified three patterns of local recurrence:

• primary site recurrence, defined as within 2 cm of the vulvectomy scar (39%);

• recurrence remote from the primary tumour site, regarded as reoccurrence of cancer (39%); and

• skin bridge recurrence (22%).

Tumour size, surgical margins and depth of invasion (Rouzier et al 2002) are risk factors for primary site relapse. It is usually salvageable with repeat surgical excision or radiotherapy (Thomas et al 1989, Hopkins et al 1990). Local recurrence remote from the primary tumour site should be considered as a new primary lesion and is seen more frequently in patients with a background of lichen sclerosus or differentiated VIN. Again, surgical excision is the first choice of treatment. The prognosis is generally good, with more than 60% of patients surviving for more than 3 years. Patients with skin bridge recurrence seldom live for more than 1 year (Rouzier et al 2002).

Almost one-third of all recurrences occur in the groin. Groin recurrence is seen more often when previous node dissection was omitted, or when positive nodes were present at primary surgery. The prognosis is poor, with more than 90% of patients dying within 1 year (Hacker et al 1984b).

Malignant Melanoma

Malignant melanoma is the second most common vulvar malignancy, accounting for 5–10% of cases of vulvar cancer. The incidence is less than 0.2 per 100,000 women per year (Piura 2008). It is a disease of the elderly, occurring in the fifth to seventh decades, and is more common in Caucasians. They usually present with a vulvar mass, bleeding and pruritus. The labia minora, clitoris or inner aspects of the labia majora are the most common sites. A variety of pigmented lesions mimic vulvar melanoma, including vulvar melanosis, different types of nevi and acanthosis nigricans. Biopsy is essential for diagnosis. Three histological subtypes have been described (Ragnarsson-Olding et al 1999a):

• lentiginous melanoma;

• superficial spreading melanoma; and

• nodular melanoma.

Up to 25% of tumours are amelanotic.

Various staging systems have been proposed for vulvar melanoma. The most commonly used are the Clark et al (1969), Breslow (1970) and Chung et al (1975) systems. However, in 1994, a Gynecologic Oncology Group study showed that the American Joint Committee on Cancer melanoma staging system is more accurate in predicting outcome (Phillips et al 1994).

Radical vulvectomy has been recommended for vulvar melanoma in the past. However, the available literature suggests no survival difference in patients having a radical vulvectomy, simple vulvectomy or wide local excision (Rose et al 1988, Tasseron et al 1992). The current consensus is to aim for a tumour-free margin of at least 1 cm for tumour less than 1 mm thick, a tumour-free margin of 2 cm for tumours 1–4 mm thick, and a tumour-free margin of at least 1 cm at the subcutaneous layer for all cases. The role of elective regional node dissection is controversial for both cutaneous and vulvar melanoma. A prospective study by the Gynecologic Oncology Group in 1994 failed to find a definite survival benefit for elective lymph node dissection in patients with vulvar melanoma (Phillips et al 1994). The role of adjuvant therapy for treatment of vulvar melanoma is also unclear. Radiotherapy has been suggested for incomplete tumour resection or positive groin/pelvic lymph nodes (Piura 2008). Interferon α-2b seems to be a promising adjuvant therapy for cutaneous melanoma (Kirkwood et al 2001), but data in vulvar melanoma are lacking.

Vulvar melanoma is usually highly aggressive, with a tendency to recur locally and spread haematogenously to distant organs such as the liver, lung and brain. Reported 5-year survival rates range from 21% to 54% (Podratz et al 1983b, Blessing et al 1991, Ragnarsson-Olding et al 1999b, Verschraegen et al 2001). As with cutaneous melanoma, the survival rate correlates with depth of invasion.

Bartholin’s Gland Carcinoma

Primary carcinoma of Bartholin’s gland is rare, accounting for 0.1–7% of all vulvar carcinomas (Nasu et al 2005). Bartholin’s gland carcinomas may initially be confused with Bartholin’s cyst or an abscess. The tumour may arise from either the gland or the duct, thus various histological types may occur, including adenocarcinomas, squamous carcinomas, transitional cell carcinomas, adenosquamous carcinomas and adenoid cystic carcinomas. Since most of these lesions are located deep in the vulva, radical excision usually involves removing part of the vagina, levator muscles and the ischiorectal fat in order to achieve an adequate tumour-free margin. If regional groin or pelvic lymph nodes are positive, adjuvant radiotherapy is indicated to reduce the risk of recurrence (Copeland et al 1986). Adenoid cystic carcinoma is a rare variant, characterized by slow growth, with a marked tendency for perineural and local invasion. The tumour seldom metastasizes and carries a better prognosis (Nasu et al 2005).

Invasive Paget’s Disease

Paget’s disease of the vulva is a rare intraepithelial neoplasia, probably originating from the vulvar apocrine glands. Approximately 10% of cases are invasive and 4–8% are associated with adenocarcinoma (Fanning et al 1999). The disease predominantly affects postmenopausal Caucasian women, usually presenting with vulvar pruritus and soreness. The lesion is usually multifocal, well demarcated and characterized by red eczematous patches (Figure 41.9). These originate on the hair-bearing regions of the vulva. Notoriously, vulvar Paget’s disease extends beyond the macroscopic lesions, and recurrence frequently occurs despite a clear surgical margin obtained at wide local excision (MacLean et al 2004). Thus, it is not uncommon for patients to undergo multiple recurrences and re-excisions over years of surveillance. In the event of finding invasive carcinoma, the patient should be treated with radical vulvectomy and groin node dissection, as for squamous cell carcinoma.

Figure 41.9 Recurrent Paget’s disease after vulval excision.

An additional concern with extramammary Paget’s disease is its association with other malignancies, including breast, uterine, vagina, bladder, pancreas, lung and stomach. Appropriate management includes investigations to try and exclude other cancers.

Verrucous Carcinoma

Verrucous carcinoma is a rare variant of squamous cell carcinoma, characterized by local invasion without nodal or distant metastases. The gross appearance resembles a giant condyloma. Histologically, there is an exophytic papillary component of well-differentiated squamous epithelium with hyperparakeratosis and well-demarcated pushing borders. The treatment is modified radical vulvectomy. Lymphadenectomy is not indicated (Finan 2003).

Basal Cell Carcinoma

Basal cell carcinoma accounts for approximately 2–4% of all cases of vulvar cancer. It usually appears as a small (1–2 cm), raised, nodular lesion with well-defined edges. Wide local excision with a 1 cm margin is usually curative, and recurrence and metastases are rare (Mulayim et al 2002).

Sarcoma

Vulvar sarcoma is extremely rare and treatment options are derived from anecdotal case reports. Leiomyosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, dermatofibrosacroma protuberans and epithelioid sarcoma are all reported in the literature. The usual treatment is radical vulvectomy and groin node dissection (Aartsen and Albus-Lutter 1994, Hensley 2000).

Cancer of The Vagina

Introduction

Vaginal carcinoma accounts for less than 2% of gynaecological cancers (Kirkbride et al 1995). In 2005, 216 cases were registered in the UK, equivalent to 0.8/100,000 women (Office of National Statistics 2008). Seventy percent of these patients were 60 years of age or older. Squamous cell carcinoma was the most common variant (Grigsby 2002). The evidence base is drawn from case reports and retrospective reviews.

Aetiology

The exact aetiology for primary vaginal cancer is unknown. Up to one-third of patients have a history of a cervical lesion, either benign or malignant (Peters et al 1985). Stock et al (1995) reviewed 100 cases of vaginal cancer and found that patients who had a previous hysterectomy were more likely to develop a lesion in the upper third of the vagina compared with women who had not had an hysterectomy (62% vs 34%, P<0.005). Possible explanations for this are: occult residual disease from a cervical lesion, HPV as a persisting carcinogenic agent (Daling et al 2002), an effect of radiation therapy given for previous genital tract cancer may induce vaginal cancer, and the disease interval is usually more than 10 years (Chaturvedi et al 2007).

Similar to cervical cancer, there is a premalignant condition in the vagina, vaginal intraepithelial neoplasia (VAIN). However, the true malignant potential of VAIN is unclear. Vaginal cancer caused by chronic irritation, such as procidentia and vaginal pessaries, has been reported (Ghosh et al 2009) but the incidence is extremely low. Intrauterine exposure to diethylstilboestrol was thought to be a causative agent for clear cell adenocarcinoma of the vagina in the past (Herbst et al 1971). However, with the cessation of its use in the 1970s, it is rarely seen nowadays.

Pathology

More than 80% of primary vaginal tumours are squamous cell carcinomas; adenocarcinomas are the second most common, accounting for approximately 15% (Grigsby 2002). The remainder are sarcomas, malignant melanomas, small cell carcinomas, lymphomas and carcinoid tumours. Metastatic lesions from non-gynaecological sites have also been reported, including bladder, kidney, colon and rectum (Tarraza et al 1998, Parikh et al 2008).

Clinical assessment

The most common presenting symptoms are painless vaginal bleeding (81%) and abnormal discharge (33%) (Pingley et al 2000). Large, posteriorly sited tumours may cause tenesmus. When disease has spread beyond the vagina, patients may present with pelvic pain. Occasionally, vaginal cancer may be recognized after an abnormal Pap smear (Pride et al 1979).

The majority of lesions are located in the upper posterior vagina, usually in the form of an exophytic mass with contact bleeding (Pingley et al 2000). It is not uncommon to miss a small lower vaginal lesion at the initial examination, when it may be hidden by the blades of the speculum. If vaginal cancer is to be excluded, a full and thorough inspection of the entire vagina is required.

In order to make a diagnosis of vaginal cancer, apart from histological confirmation, certain criteria are to be met (Benedet et al 2000):

• the primary site has to be in the vagina;

• the lesion should not involve the uterine cervix, vulva or urethra, otherwise they should be considered as the likely primary cancer; and

• this is not a recurrence of genital tract cancer.

The diagnosis of vaginal cancer should only be made with a biopsy, which may be taken either in the office or under anaesthesia. The latter is preferable because it provides an opportunity to examine the patient in total relaxation, and a generous full-thickness excisional biopsy may be obtained. Cystoscopy and proctosigmoidoscopy are indicated when local spread is suspected. Chest radiography and an intravenous pyelogram are necessary to exclude lung metastasis and ureteric involvement. Cross-sectional imaging (CT scan or MRI) is useful in evaluate the extent of disease and intra-abdominal metastasis.

Staging

The FIGO staging system for vaginal cancer is shown in Table 41.4. It is a clinical staging system based on findings from physical examination, cystoscopy, proctoscopy and chest X-ray.

Table 41.4 International Federation of Gynaecology and Obstetrics (FIGO) staging for carcinoma of the vagina

FIGO stage	Description
Stage 0	Carcinoma in situ, intraepithelial carcinoma, high-grade vaginal intraepithelial neoplasia
Stage I	The carcinoma is limited to the vaginal wall
Stage II	The carcinoma has invaded the subvaginal tissues but has not extended on to the pelvic sidewall
Stage IIa	The carcinoma has invaded the subvaginal tissues but has not extended to the parametrium
Stage IIb	The carcinoma involves the parametrium but has not extended to the pelvic sidewall
Stage III	The carcinoma has extended to the pelvic sidewall
Stage IV	The carcinoma extends beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum. Bullous oedema as such does not permit a case to be allocated to stage IV
Stage IVa	The carcinoma has spread to adjacent organs and/or direct extension beyond the true pelvis
Stage IVb	The carcinoma has spread to distant organs

Pattern of spread

Vaginal cancer initially spreads by local invasion; it may infiltrate adjacent pelvic organs and the side walls by direct extension. Tumour in the upper vagina embolizes to the pelvic and para-aortic lymph nodes, while those in the lower vagina metastasize to the groin lymph nodes and secondarily to pelvic nodes. Haematogenous dissemination to distant organs is a late event.

Treatment

Due to the rarity of this disease, there is no consensus on the treatment, be it radiation or surgery. Patients should be managed in tertiary centres, and all treatment should be individualized according to stage and site of disease.

Radiotherapy is the most commonly used treatment modality for vaginal cancer. The close proximity of the bladder and rectum limit the ability of surgery to radically excise tumour without significant functional compromise. Exenterative surgery is often needed in order to achieve adequate margins, especially with lower vaginal tumours (Figure 41.10).

Figure 41.10 Primary tumour of the lower third of the vagina.

Both teletherapy and brachytherapy are used in managing these cancers. A number of reports have shown that sequential use of teletherapy followed by brachytherapy results in a better outcome (Perez et al 1999, Pingley et al 2000). External radiation is used to treat disease with lateral infiltration; the irradiation field is similar to that for cervical cancer. The pelvis receives 50 Gy, covering the side walls, pelvic nodes and the whole vagina (Grigsby 2002). The irradiation field should be extended to the groin if the tumour is located in the lower third of the vagina. External beam irradiation also results in shrinkage of large tumours, facilitating subsequent brachytherapy. Interstitial implants using premade templates may be indicated for deeply invasive tumours. Early-stage disease (stage I–II) may be treated by brachytherapy alone.

Although surgery has a limited role in the treatment of vaginal cancer, it is indicated in certain situations. Stage I–II upper vaginal lesions can be treated surgically. Upper vaginectomy in combination with radical hysterectomy and bilateral pelvic lymphadenectomy can be performed for patients with an intact uterus. If the patient has had a hysterectomy, radical upper vaginectomy and pelvic lymphadenectomy may be considered. In a retrospective study of 89 stage I and II patients, Davis et al (1991) reported no survival differences when comparing surgery and radiotherapy.

Pelvic exenteration can be considered for localized recurrent disease after radiotherapy. It should also be considered in medically fit patients with stage IVa disease, especially in those with symptomatic fistulae.

There is limited information in the literature regarding concurrent chemoradiation therapy for vaginal cancer. The use of this modality of treatment for vaginal cancer is a logical extension of its use in cervical cancer.

This rare tumour mainly affects children below 5 years of age. The polypoid tumour protrudes from the vagina, resembling a bunch of grapes. Treatment is based upon primary chemotherapy using vincristine, actinomycin D and cyclophosphamide plus doxorubicin, followed by conservative organ-sparing surgery or radiotherapy. Survival rates of over 80% are now achievable (Andrassy et al 1999, Harting et al 2004).

Clear cell adenocarcinoma

Approximately 15% of primary vaginal cancers are adenocarcinomas, predominantly affecting young women. In the main, they arise from vaginal adenosis, which is a consequence of disrupted Müllerian development. This malformation may or may not be related to in-utero diethylstilboestrol exposure (Herbst and Anderson 1990). The treatment is similar to that of squamous cell carcinoma of the vagina. However, every effort should be made to retain vaginal and ovarian function as most of these patients are still in their reproductive years.

Malignant melanoma

Primary malignant melanoma of the vagina constitutes less than 0.3% of all melanomas and less than 3% of malignant vaginal tumours (Siu et al 2004). It is highly malignant and is notoriously more aggressive than non-genital and vulvar melanoma. Most patients are diagnosed at an advanced stage with a deeply invasive tumour. The 5-year survival rate is 17%. Radical surgery does not appear any better than conservative surgery (wide local excision) in terms of survival (Reid et al 1989). Radiotherapy is mainly used as an adjuvant therapy to decrease recurrence.

KEY POINTS

1 Vulval cancer probably arises through two oncogenic pathways: one related to oncogenic HPVs and the other related to lichen sclerosus.

2 It is predominantly a disease of the elderly and comorbidity is common.

3 Surgery is the mainstay of treatment and has become progressively less radical over time.

4 Management must always address the possibility of regional disease in the groin lymph nodes.

5 Sentinel node detection is likely to further reduce treatment-related morbidity for early vulval cancer.

6 Multimodality treatment with reconstructive surgery should improve outcomes in more locally advanced disease.

7 Groin node dissection is not routinely required for vulval melanoma as the depth of invasion is the most potent prognostic indicator.

8 The squamous variants, basal cell and verrucous carcinoma, have a very low risk of regional spread, and therefore do not require groin lymphadenectomy.

References

Aartsen EJ, Albus-Lutter CE. Vulvar sarcoma: clinical implications. European Journal of Obstetrics and Gynecology and Reproductive Biology. 1994;56:181-189.

Andrassy RJ, Wiener ES, Raney RB, et al. Progress in the surgical management of vaginal rhabdomyosarcoma: a 25-year review from the Intergroup Rhabdomyosarcoma Study Group. Journal of Pediatric Surgery. 1999;34:731-735.