60 David M. Luesley1,2 1 Division of Reproductive and Child Health, University of Birmingham, Birmingham, UK 2 Birmingham Women’s Healthcare NHS Trust, Birmingham, UK Vulval carcinoma is uncommon. In 2013, just over 1300 cases were registered in the UK, making it the twentieth most common malignancy (Table 60.1). The lifetime risk of developing vulval cancer is now estimated at 1 in 275. Age‐specific incidence rates rise gradually from around age 35–39, and more sharply from around age 65–69, reaching the highest rates in the 90+ age group [1]. The age‐standardized incidence of vulval squamous cell carcinoma is 2.5 per 100 000 women per year in England and 2.4 per 100 000 in the USA [2]. Table 60.1 Vulval cancer (C51), number of new cases, crude and European age‐standardized incidence rates per 100 000 population, females, UK, 2013 (Cancer Research UK). There appears to be an association between vulval cancer incidence and social deprivation. The estimated deprivation gradient in vulval cancer incidence between females living in the most and least deprived areas in England has widened in the period 1996–2010 [1]. It has been estimated that there would have been around 240 fewer cancer cases each year in England during 2006–2010 if all females experienced the same incidence rates as the least deprived [1]. Vulval cancer mortality rates have decreased in the UK, an observation noted since the early 1970s. European age‐standardized mortality rates decreased by 43% between 1971–1973 and 2010–2012, with most of this decline occurring before the late 1990s. This trend can mainly be attributed to improvements in treatment and earlier diagnosis [3,4]. Over the last decade (between 2001–2003 and 2010–2012), European age‐standardized mortality rates have remained stable [5]. The West Midlands Cancer Registry UK, which covers a population of 5.6 million, has reported rates for cases registered between 2001 and 2005, with a 5‐year relative survival of 80.5% in women aged under 65 at diagnosis and 61.6% in older women; the corresponding figures from the SEER programme for cases diagnosed in the USA in 2004 were 81.6% and 70.6% [6]. In neither dataset is there evidence of an increase in relative survival over time in these age groups. There has been a significant increase in rates of vulval cancer in younger women. The proportion of cases diagnosed in those under the age of 50 years rose from 6% in 1975 to 15% in 2006 [1]. A similar trend has been documented in other countries [7,8]. These tumours appear to be more frequently associated with vulval intraepithelial neoplasia (VIN), human papillomavirus (HPV) infection, and immunosuppression. In older women they are more frequently associated with non‐neoplastic epithelial disorders such as lichen sclerosus. This suggests that there are at least two oncogenic pathways for the development of this cancer. The overall increase in vulval cancer might be explained by the rise in the average age of the female population and possibly because of an increase in HPV infection in younger women. The following are recognized as risk factors for developing vulval cancer. The aetiology of vulval cancer remains unknown. However, oncogenic HPVs are strongly associated with some vulvar cancers [22] and non‐neoplastic epithelial disorders (lichen sclerosus) with others. Currently available data suggest two hypotheses. First is the classic de novo neoplasm in the elderly that is frequently seen in association with conditions such as lichen sclerosus. The second type is more often associated with VIN, particularly multifocal disease and disease elsewhere in the lower genital tract. This ‘infectious‐like’ type is presumed to be linked to HPV. Recently it has been suggested that non‐HPV VIN or differentiated VIN might be the precursor lesion associated with lichen sclerosus and therefore non‐HPV squamous cell cancers. Previously it had been thought that differentiated VIN was found only in association with established cancers, but it has now become clear that this type of VIN can and does occur without contemporaneous cancers but usually with lichen sclerosus. This observation provides additional support for the two oncogenic pathways hypotheses [22]. Recent studies have focused on the genetic, epigenetic and molecular changes in vulval squamous cell carcinoma and associated lichen sclerosus [23]. Many studies have reported significantly higher incidences of somatic mutations in HPV‐negative tumours compared with their positive counterparts, TP53 being the most frequent. Epigenetic changes have also been identified and hypermethylation appears to be a common event in lichen sclerosus [24]. An understanding of premalignant epigenetic changes offers the opportunity of either reducing or even reversing the dysplastic process in vulvar epithelium. The majority of vulvar cancers are squamous in origin. The various histotypes include: Verrucous cancer and basal cell cancer are variants of squamous cell carcinomas. Non‐squamous cancers of the vulva account for 10% of all vulval cancers. Histology does have a bearing on management, largely because of the different risks of nodal metastases and the predilection for distant spread (Fig. 60.1 and Table 60.2). Fig. 60.1 Histological variants of vulval cancer. Table 60.2 Summary of histological variants. Most squamous cancers primarily involve the medial aspects of the labia majora, with the labia minora being involved only one‐third as often. Other sites of predilection include the clitoral and periurethral areas. Small lesions may be asymptomatic and go unnoticed by the patient, and even now there would appear to be excessive delay in diagnosis for some women. A recent review of practice in the West Midlands suggests that up to one‐ third of patients apparently report symptoms for over a year. This may reflect patients’ attitudes in seeking medical attention or, as suggested by Stroup et al. [25], a lack of awareness of the disease in both patients and clinicians. This study also suggested that older patients were more likely to be diagnosed with advanced disease. A more recent US‐based study [26] came to similar conclusions, with advancing age and social deprivation both being associated with more advanced stage at diagnosis. As squamous cell carcinoma of the vulva often progresses slowly, early disease presentation should be feasible and could enable diagnosis to be made at a less advanced stage. Both younger patient age and early disease stage are associated with favourable disease outcome. Therefore, efforts should be considered that improve both patient and primary care awareness. This observation is not new – Monaghan reported that 32 of 335 patients delayed seeking medical attention for more than 24 months, and only 35 of 335 presented within 3 months of noticing symptoms [27]. Similar delays ranging from 1 to 36 months, with a mean of 10 months, were noted by Hacker et al. [28]. Whether this is due to fear or ignorance on the part of the patients or to delay in clinical examination by the primary carer is unknown. A recent study, based on the first English National Audit of Cancer Diagnosis in primary care, analysed the patient and primary care interval in 10 953 patients covering 28 different cancer sites, including vulval cancer. The mean patient referral interval (patient time to present to GP) was 59 days, the fifth longest for the study cohort. The mean interval from consulting a GP to referral was 16 days, the third shortest referral interval [29]. These data imply that a significant burden of the delay lies in women not presenting to their GPs and thus a fairly robust case can be made for improved lay education. The reasons for presenting have been analysed by Podratz et al. [30] (Table 60.3). Table 60.3 Presenting symptoms in vulval carcinoma. Other indications for suspecting malignancy include pigmentation disorders relating to potential melanoma and melanoma in situ. This appears to be increasing although evidence so far is only anecdotal, but could reflect the growing awareness by the public of moles and other pigmented skin lesions and their association with malignant melanoma. There are two phases of investigation. First, confirming the diagnosis and histotype. The initial disease assessment should also include the clinical and histopathological extent of disease (stage). Second, the patient’s fitness needs to be assessed, as does the possibility of concurrent disease, which might influence management. Although not disease focused the second phase is equally important, as the age range of patients with this disease makes comorbidity and frailty important variables when designing management strategies. The clinical assessment of a vulval malignancy should document both the size and location(s) of all the lesions and the characteristics of the adjacent skin. Care should be taken to assess any involvement of the vagina, urethra, and base of bladder or anus. Palpation is important with large tumours to determine whether the tumour is infiltrating deep to the pubic and ischial bone. The integrity of the anal sphincter can only be reliably assessed by a combined rectal and vaginal examination. Discomfort and tenderness are often associated with large tumours, necessitating examination under general anaesthesia. The presence or absence of groin lymphadenopathy or discrete skin metastases should also be noted. Diagnosis is based on a representative biopsy of the tumour that should include an area where there is a transition of normal to malignant tissue. Biopsies should be of a sufficient size to allow differentiation between superficially invasive and frankly invasive tumours and orientated to allow quality pathological interpretation. Occasionally an alternative strategy might be considered. In certain situations where the clinical diagnosis is apparent and the patient is very symptomatic (i.e. experiencing heavy bleeding and/or pain), definitive surgery to the vulval lesion may be performed. However, biopsy with frozen section is recommended before performing any radical procedure. Because of the potential for other genital tract malignancy, the vagina and cervix should also be thoroughly assessed and biopsied as necessary. The major histotype will determine, to a certain extent, how the tumour invades and metastasizes. The following comments relate to the most common squamous variant. The tumour spreads both locally and via the lymphatics to the regional lymph nodes. Local spread may involve the vagina, perineum and anal canal, urethra and clitoris and, in late disease, involvement of bone may occur. The sites and extent of spread as well as the involvement of structures where function may be impaired (anal sphincter, urethra, clitoris, etc.) are of extreme importance when planning treatment. Skin beyond the vulva may also become involved (Fig. 60.2), particularly over the mons onto the lower abdominal wall and laterally to involve the skin of the thighs. Lymphatic drainage of the vulva is initially to the superficial inguinal nodes, thence to the deep inguinofemoral chain and on to the pelvic (iliac) nodes. In general, central vulvar structures are believed to drain bilaterally whereas lateral structures drain to the ipsilateral nodes primarily. Deep pelvic node involvement in the absence of inguinal node disease is rare. Overall, about 30% of operable patients have nodal spread, 10–15% with tumours measuring 4 cm or less in diameter and more for higher‐stage tumours [31–33]. Haematogenous spread can also occur but is uncommon and tends to be associated with large tumours that have already involved the regional nodes. Fig. 60.2 Large anterior vulval cancer with satellite skin deposits. (See also colour plate 60.2) Premalignant and malignant change in the vagina and cervix is not infrequently seen in association with vulvar cancers. This is not necessarily a metastatic process but may indicate a common aetiological event such as oncogenic HPV infection that can render the whole lower genital tract vulnerable to neoplastic transformation. Vulval cancer is staged surgico‐pathologically using the FIGO staging system, last updated in 2009 [34]. FIGO staging employs the familiar four categories with substages but now takes into account the number of positive nodes and type of nodal positivity. It also recognizes that tumour size on its own has little discriminatory value in terms of survival, large node‐negative tumours having almost as good an outcome as small node‐negative tumours (Table 60.4). An alternative is the tumour node metastasis (TNM) system, which is a composite of primary tumour, nodal and metastatic status (Table 60.5). Both systems employ nodal status to allocate stage. Table 60.4 International Federation of Gynecology and Obstetrics (FIGO) staging of vulval cancer (2009). Table 60.5 TNM classification system. Given that most surgically managed vulval cancers will not have metastatic involvement of the lymph nodes and that surgical exploration of the groin will be associated with short‐ and long‐term morbidity, it is understandable that continuing efforts are being made to identify node‐positive and node‐negative cases prior to surgical intervention. The more accurate the prediction, the more that unwanted morbidity can be avoided. The last 10 years has seen considerable effort in this area, initially with imaging but also with selective node resection. Table 60.6 lists the various methodologies that have been assessed in this role. Table 60.6 Imaging techniques for groin node assessment and sensitivities. * With and without fine needle aspiration. This technique has quickly become the most adopted as an adjunct to surgical treatment, particularly in earlier cancers. The sentinel node is defined as the first node in the lymphatic chain draining an anatomical area. If the sentinel node from the suspected lesion is negative for disease, then the remainder of the nodes should also be free of the disease (Fig. 60.3). The sentinel node for vulval lesions can be identified by injecting methylene blue dye into the tumour edge and/or using immunoscintigraphy where a radiolabelled marker (technetium‐99) is injected into and around the margins of the lesion. A hand‐held gamma camera is used to identify the radioactive tracer uptake in the regional lymph nodes [42,43]. Identification during surgery is further enhanced by the use of blue dye, which, along with the raised radiation count, allows the sentinel node to be clearly seen (Fig. 60.4). Fig. 60.3 (a) Reccurence in the right groin after previous simple vulvectomy. (b) Anterior local recurrence after radical vulvectomy. (See also colour plate 60.3) Fig. 60.4 Schematic demonstrating the rationale of sentinel lymph node sampling. Three recent systematic reviews [44–46] all indicate that the sentinel node technique using the combined method (technetium‐99 and blue dye) is sufficiently sensitive and specific to be regarded as the standard of care for women with unifocal tumours measuring 4 cm or less where there is no evidence of clinically enlarged nodes. The technique may be enhanced using preoperative SPECT/CT imaging, which might also help in the identification of aberrant sentinel nodes [47]. Data are still required as to the effectiveness of the technique when the primary lesion has been removed (post excision biopsy). In one study of 32 women, slightly more sentinel nodes were identified when performed after diagnostic biopsy when compared with those following excision biopsy [48]. In a cohort of 106 patients in whom one‐third had undergone primary excision with a secondary resection of the nodes performed on average 30 days later, no compromise in accuracy was noted [49]. Our own data and those of others indicate that surgical morbidity is significantly reduced, with shortened length of hospital stay, reduced wound breakdown, and reduced lymphoedema and lymphocyst. Table 60.7 compares the most frequently seen complications in a routine audit comparing women who had complete lymphadenectomy versus sentinel node. Both groups had similar tumours in terms of size and stage. Importantly, patient‐reported outcomes are favourable as well [49] and the technique has been shown to be significantly cost‐effective when compared with complete lymphadenectomy [50]. Table 60.7 Complication rate by groin node dissection type. As with inguinofemoral lymphadenectomy, there is a risk of a false‐negative outcome (2–3%). However, the difference between the false‐negative rates is not significant and given the potential huge benefit in morbidity avoidance is a small risk outweighed by benefit. One observer has raised a potential negative effect of this technique: although based on the observation of only two patients, there was concern that in patients who are node positive, the technique might increase the risk of extranodal metastasis by a direct effect on the lymphatics [51]. The site, size and relation of the lesion to important functional structures will determine the most appropriate method for treating the vulvar lesion. Similarly, the clinical presence or absence of nodal or distant disease will affect the management strategies. It would, for instance, be illogical to embark upon radical local treatment for the primary cancer in the presence of distant untreatable metastases unless there was no other suitable form of palliation. Two broad categories of patient can be identified at the outset: For the purposes of further discussion, these will be termed as early and late disease, respectively. Radical vulvectomy is excessive treatment for the majority of unifocal and early cancers. Wide local excision is usually sufficient for the majority of lesions between 1 and 10 mm in depth. Until recently the general consensus was that the most important factor governing local recurrence was the margin of excision. Two publications have underpinned this management principle for 20 years [37,52]. Current guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) still endorses the principle of wide resection margins in order to guarantee a post‐fixation maximum clearance of 8 mm on all margins. One large single institution retrospective cohort has recently questioned this approach [53]. This cohort contained 102 consecutive patients and the authors did not find any significant increased risk of recurrence in relation to the margin of excision, as long as the tumour was completely excised. A similar but larger cohort from the West Midlands [54] has reached similar conclusions. The latter included over 200 patients followed up for over 5 years. In addition, the histopathology of the adjacent epithelium and HPV status was also included in the multivariate analysis. There would appear to be ample evidence to revisit the concept of wide excision margins as this could have a significant impact on local surgical morbidity. The excision should be taken to the depth of the fascia lata, which is coplanar with the fascia of the urogenital diaphragm. Even when adequate excision has been achieved, there may be other variables identified after examination of the specimen that some have suggested indicate a high risk of relapse. These include tumour thickness (or invasiveness) and capillary lymphatic space involvement, and perineural infiltration [55]. In addition the adjacent epithelium, which may reflect the underlying oncogenic process, may influence recurrence. Differentiated VIN appears to have a higher rate of recurrence than basaloid or warty VIN, although this is based on a very small case series [56]. As one would expect, the local recurrence rate for wide local excision compares favourably with that following radical vulvectomy. Hacker and van der Velden [52] have collated data from 12 published series including 530 patients, of whom 165 were treated by radical local excision and 365 by radical vulvectomy. The local recurrence rates were 7.2% and 6.3%, respectively. The reader should appreciate that ‘advanced’ in vulvar terms indicates that wide local excision would either be a radical vulvectomy and/or would compromise function. The same principles apply here as with the smaller unifocal lesions in that the objective is to obtain adequate clearance on all the resection margins. As subsequent function and cosmesis are more likely to be affected, consideration should also be given to adjunctive treatment. It is important to consider the woman and her feelings when constructing the management plan. An elderly woman with extensive or multifocal disease with an associated symptomatic non‐neoplastic epithelial disorder such as lichen sclerosus may well gain an overall benefit from radical vulvectomy with subsequent grafting. Conversely, a young woman with a clitoral cancer may be managed initially by radiotherapy, reserving surgery for failed local control. These types of cases form the basis for local management of advanced vulvar lesions. The prime objective is to maximize local control, closely followed by consideration of further function and cosmesis in that particular woman. Patients with superficially invasive vulval cancer are at minimal risk of nodal disease (Table 60.8). This is defined as a depth of invasion of less than 1 mm. Depth of invasion is closely related to the risk of nodal disease, and should be measured from the most superficial dermal papilla adjacent to the tumour. Table 60.8 Relationship of depth of invasion to risk of nodal disease. Source: Hacker et al. [28]. Overall, about 30% of vulval cancers will have inguinofemoral nodal disease and about one‐fifth of those with positive inguinofemoral nodes will have positive pelvic nodes (i.e. about 5% overall). It has been known for many years that pelvic nodes are rarely, if ever, involved if the inguinal nodes are negative. The low frequency of pelvic node involvement and the doubts surrounding the ability of surgery to control disease at this site have led most to conclude that the routine application of pelvic node dissection in vulval cancer should be discontinued. The following clinical factors can predict for the presence of lymph node disease, although clinical examination of the nodes themselves is unreliable: Other risk factors depend on histopathological assessment of the primary lesion. Not surprisingly, these are similar to the general prognostic factors for outcome, and include: The primary lymphatic drainage of the vulva and distal vagina is to the inguinal (superficial femoral) and the nodes lying along the femoral vein. Efferent vessels from the superficial inguinal nodes drain to the deep inguinal or femoral nodes. The most cephalad femoral lymph node is the node of Cloquet. This is not a constant anatomical finding and has been noted to be absent in 54% of cadavers. The femoral nodes also receive some direct afferents, particularly from the clitoris and anterior vulva, thus explaining the observation of involved femoral nodes with uninvolved inguinal nodes. One prospective study [58] has suggested that superficial lymphadenectomy alone may be associated with a higher risk of groin relapse, although the relatively low relapse rate in early disease renders any conclusion somewhat unreliable. Extensive crossover of lymphatic channels of the vulva may result in nodal involvement of the contralateral groins in addition to the ipsilateral groin nodes. Because of this, bilateral groin node dissection is usually required. However in small (<2 cm) lateral tumours, only an ipsilateral groin node dissection need initially be performed. A lateralized lesion, agreed by the European Organization for Research and Treatment of Cancer (EORTC) Vulva Group consensus, is defined as one in which wide excision, at least 1 cm beyond the visible tumour edge, would not impinge upon a midline structure. If the ipsilateral nodes are subsequently shown to be positive for cancer, the contralateral nodes should also be excised or irradiated, as the nodes are more likely to be positive in this scenario. Andrews et al. [59] noted that this was also the case for T2 lesions despite a relatively high ipsilateral positivity rate of 34%. However, exceptions have been reported. For larger lateralized lesions the picture is more confused and, until further data become available, bilateral node dissection (or selective sentinel node biopsies) would be advisable. The need for en bloc removal of the lymph nodes has received much attention, largely because it has been felt that this type of procedure accounts for a significant proportion of the morbidity (Fig. 60.5) and that the technique employing separate groin incisions (Fig. 60.6) results in a better cosmetic outcome. The triple incision technique was first described in 1965, although it only became popular in the 1980s. Those who have reported on its use have not shown any disadvantages in terms of survival or local relapse for early‐stage carcinomas, and there have been quite marked improvements in the morbidity. Fig. 60.5 En bloc dissection of the inguinofemoral lymph nodes. (See also colour plate 60.5) Fig. 60.6 Separate groin incisions. (See also colour plate 60.6) The anxiety relating to the triple incision is the possibility of relapse in the bridge of tissue left between the vulvectomy or local excision and the groin nodes. This tissue will contain lymphatic channels, but whether lymphatic metastasis is an intermittent or embolic event or a continuous or permeation event remains uncertain. Certainly if the lymphatic channels contain malignant cells at the time of resection, then recurrence would seem to be a real possibility. Current consensus would suggest that en bloc dissection of the nodes is probably best retained for large vulvar lesions and in situations where there is gross involvement of the groin nodes (Fig. 60.7). It would seem more logical to address the increased morbidity of the procedure with more attempts at reconstruction rather than undertreating with less than adequate primary surgery. Fig. 60.7 Clinically suspicious left groin nodes. (See also colour plate 60.7) Resection of the groin lymph nodes provides prognostic information and might also confer some survival benefit. There are varying degrees of positivity, from microscopic deposits in one of many nodes to gross extracapsular spread in the entire group of nodes. As with the overall stage, this spectrum is also associated with a spectrum of outcomes (Table 60.9) and requires different approaches to management. The most important variable influencing survival is extracapsular spread from the lymph nodes; for patients who have only one node involved, the most important prognostic factor is the greatest dimension of the metastasis within the node (Table 60.10). These observations explain and underpin the 2009 revisions in FIGO staging. Table 60.9 Survival in relation to nodal status and size of vulval lesion. Source: Homesley et al. [61]. Table 60.10 Management in relation to lymph node status. * In the situation where there is only one node involved but the node is either completely replaced by tumour or there is extracapsular spread, the author feels that adjuvant radiotherapy is justifiable. In the past, pelvic lymphadenectomy was considered to be appropriate if the inguinofemoral nodes were involved. This practice has become increasingly uncommon, as it has been well demonstrated in Gynecologic Oncology Group protocol 37 [60] that in this situation pelvic radiation confers a better outcome than pelvic node dissection. Interestingly, the survival difference appeared to reflect better control of disease in the groin than pelvic or distant disease. A final observation with regard to the lymph nodes is that all the available data are based on what is considered to be standard pathological evaluation of the groin nodes (standard sections stained with haematoxylin and eosin). In other tumour systems it has been possible to define a group of patients with micrometastases by using complete serial sectioning and immunohistochemical staining. These nodes positive for micrometastases would have been negative on standard assessment. There are no studies available as yet indicating what, if any, clinical significance of such findings might be in vulval cancer. The complications of vulval and groin surgery are listed in Table 60.11. Any major cancer procedure carries immediate morbidity risks such as haemorrhage, thromboembolism and infection, and vulvar procedures are no exception to this. Prophylactic antiembolic strategies are of value and should be used in all cases. Reducing the length of hospitalization and early mobilization indirectly enhances such prophylaxis and may result from modifications of the radical approach. Table 60.11 Complications of surgery. Radical en bloc dissection (radical vulvectomy and bilateral node dissection) results in lymphoedema in between 8 and 69% of cases. Wound breakdown is very common, occurring in 27–85% of cases, and can become secondarily infected, resulting in cellulitis. The average hospital stay for this radical procedure varies from 17 to 33 days. The triple incision technique has yielded significant improvements in operative blood loss and length of stay, although high breakdown rates continue to be reported (22–52%) [62,63]. The occurrence of lymphocyst (Fig. 60.7) and lymphoedema does not seem to be significantly less than that with the radical en bloc technique. Unilateral groin dissection does appear to lower the incidence of morbidity, but there is no significant difference in morbidity when superficial is compared with deep groin node dissection. Van der Zee et al. [64] have reported significant reductions in wound breakdown, cellulitis, length of hospital stay and lymphoedema when sentinel node sampling is compared with inguinofemoral lymphadenectomy. Less radical approaches to the vulva have certainly improved cosmesis and subsequent function. Other surgical modifications [65] to reduce morbidity include sparing the saphenous vein at the time of surgery to reduce wound and lower limb complications, although the data on outcome in terms of lymphoedema are inconclusive [66,67]. It has also been suggested that the tissues most lateral in the groin need not be resected. Sartorius transposition to cover the femoral vessels in thin and emaciated patients also helps to reduce wound morbidity [67]. Wound healing is also improved by avoiding undermining of the skin edges, performing tension‐free closures, using wound drainage and administering prophylactic antibiotics. Increasingly, surgeons have employed grafting techniques either at the time of initial surgery or as a second‐stage procedure. The grafts successfully employed have been the gracilis and rectus muscle myocutaneous flaps and rotational full‐thickness skin flaps taken from the inner thigh or buttock (Fig. 60.8). The use of these flaps to fill considerable defects and a more conservative approach to excision have resulted in less scarring and more functional vulvas. As yet it has not been possible to demonstrate that this translates into improved psychological well‐being, although the psychological trauma of radical excision without reconstruction is well documented [68]. Fig. 60.8 Rotation skin flap to fill a large defect. (See also colour plate 60.8) For lymphoedema, compression hosiery is prescribed along with rest and exercise, avoidance of trauma (skin care), simple gravity drainage and manual lymphatic drainage. For lymphocyst, a conservative approach is adopted and drainage under antibiotic cover is recommended only for symptomatic cases, but they tend to re‐form. Wound healing can be promoted with manuka honey dressing [69]. Recently, there have been anecdotal reports of using tissue sealant to promote healing in groin wounds that have broken down [70]. The role of radiotherapy and chemotherapy in the treatment of vulvar cancer is less defined than that for surgery. However, there are data quite clearly indicating that squamous vulvar cancers are sensitive to both radiotherapy and chemotherapy. Basal cell cancers are well recognized as being radiosensitive, and radiotherapy may be the treatment of choice if surgery is likely to result in either functional or cosmetic impairment. Melanomas have not been shown to respond and verrucous cancers have been reported as becoming much more aggressive as a result of radiotherapy. The factors influencing the need for adjuvant radiotherapy are (i) surgical margins and (ii) groin node positivity. There is insufficient evidence to recommend adjuvant local therapy routinely in patients with suboptimal surgical margins (<8 mm). Adjuvant treatment for positive margins is associated with improved survival when compared with observation alone [71]. A more recent multicentre retrospective study of 257 patients concluded that in patients with close or positive margins the addition of adjuvant radiotherapy improved overall survival from 29% to over 60% [72]. As with most retrospective studies, selection bias is a cause for concern. Adjuvant radiotherapy should be considered when two or more lymph nodes are involved with microscopic metastatic disease or there is complete replacement and/or extracapsular spread in any node [58,73,74]. Treatment should be to the groins and the pelvic nodes, although there is no evidence to show whether treatment should be directed at both sides or to the involved side only. The increasing use of the sentinel node technique may require a re‐evaluation of this strategy. A large multicentre retrospective cohort study from Germany evaluated 1618 patients of whom 1249 had surgical groin staging and known lymph node status. Node‐positive patients receiving adjuvant radiation (N = 189) fared better than 61 patients who did not receive adjuvant radiotherapy (progression‐free survival 39.6% vs. 25.9%). This difference is significant and the authors concluded that the addition of chemotherapy would be likely to improve outcome further given the incremental improvements seen with other squamous cancer [75]. A subsequent study appears to lend weight to this assumption where, in a large retrospective cohort of patients eligible for adjuvant treatment, the addition of chemotherapy resulted in a 38% reduction in the risk of death [76]. Radiotherapy with or without concurrent or sequential chemotherapy is being used more frequently in the management of advanced vulval cancer. Radiotherapy may, in certain circumstances, be the sole treatment, but more usually it is used preoperatively with a view to allowing for sphincter‐preserving surgery. Encouraging results were reported by Beriwal et al. [77] who were able to demonstrate a complete pathological response in 16 of 33 patients receiving preoperative chemoradiation. All but one remained disease‐free at 26 months. In the remaining 17 patients, who had only a partial response, eight developed recurrence locally within 8 months. Radiotherapy may also be of use in place of surgery for histologically proven involved groin lymph nodes. Whether such irradiated nodes require removal after treatment remains unknown. Radical treatment usually requires that a prophylactic dose (45–50 Gy) is delivered to the primary and nodal sites and the tumour is then boosted by a second phase of treatment using electrons, conformal radiotherapy or brachytherapy to a total dose of 65 Gy. The total prescribed dose is determined by the clinical context. A Cochrane review suggests that there is no evidence that prophylactic groin irradiation should be used in preference to surgery [78]. With regard to the use of concurrent chemotherapy and radiation therapy, there are no robust prospective data. Several retrospective studies have suggested that there may be some improvement in local control with regimens employing cisplatin and 5‐fluorouracil, mitomycin C and 5‐fluorouracil, and 5‐fluorouracil alone. When there is no obvious macroscopic disease and the sole intention is adjuvant treatment, the total dose is 45–50 Gy with no concurrent chemotherapy. The reason for the limited application of radiotherapy in this disease lies in the poor record of tolerance and high levels of complications reported in the older series. This almost certainly relates to the type of treatments and techniques available in these series. More modern equipment and a greater understanding of its potential and applications have resulted in a marked improvement in tolerance and morbidity [79]. Most women will note erythema and some moist desquamation as a result of radiotherapy. With appropriate care and attention to local hygiene, such problems rarely result in premature discontinuation of treatment. Radiation‐induced cystitis requires bladder irrigation and treatment of any infection. Proctitis is managed with prednisolone (Predfoam), Normacol and loperamide. More severe side effects include necrosis of bone (symphysis and femoral heads) and fistula formation. Careful planning of field sizes, dose and fractionation minimize such risks. Between 15 and 30% of cases will develop recurrence. The most common site is the residual vulva (70%), with the groin nodes accounting for almost 20% and the remainder of relapses occurring in the pelvis or as distant metastases. In a large prospective cohort of well‐characterized unifocal cancers in the Groins V2 study, local recurrence was 27.2% at 5 years and 39.5% at 10 years after primary treatment [80]. Most recurrences occur 2 years after primary treatment, and close surveillance every 3 months in the first 2 years is usually practised. This is reduced to 6‐monthly surveillance for a further 2–3 years and annually thereafter. Additionally, patients are encouraged to self‐inspect and report any symptoms of pain, bleeding or discharge. It should be stated that this schedule for follow‐up is empirical and not evidence based. Survival is poor following regional relapse, hence the efforts to prevent this at the outset. Skin bridge recurrence has been reported to be more likely to occur in patients with positive lymph nodes [81]. In vulval cancer, disease can recur several years following presumed adequate treatment of the primary cancer. Furthermore, some features of the original disease seem to be associated with this late type of recurrence, to such an extent that other terms employed include ‘re‐occurrence’ or ‘second field tumours’. Rouzier et al. [82] were the first to document this late recurrence potential with tumours associated with lichen sclerosus in the adjacent epithelium. In a large retrospective cohort [54] we have also documented this phenomenon. The Birmingham cohort comprised 201 patients extensively classified in terms of pathology, HPV status and treatment modality. Furthermore, the minimum follow‐up was 5 years. It appeared from an in‐depth analysis that both local recurrence and re‐occurrence were significantly more likely in women who had evidence of lichen sclerosus when compared with usual‐type VIN. Lymph node positivity was also a significant predictor for local relapse. As long as the primary tumour was completely excised, the excision margin was not a predictor of relapse. This hypothesis‐generating cohort study proposes that local relapse in completely excised tumours occurs as a result of persisting bio‐instability of the adjacent epithelium (second field tumour) or as a direct result of tumour emboli in the associated skin lymphatics. Further work is in progress to develop a clearer understanding of the bio‐instability of adjacent epithelium and with it the potential for prophylaxis to reduce local recurrence risk. The management of relapsed disease will depend on the site and extent of the recurrence [83]. Wide excision of local recurrences can result in a 5‐year survival rate of 56% if the inguinal nodes are negative [84]. If excision would risk sphincter function, radiotherapy should be considered as the first choice. If radiotherapy has already been given to maximum dose, then excision should be considered. Groin recurrence has a much poorer prognosis and is difficult to manage. In patients who have not been treated previously with groin irradiation, radiotherapy (with or without additional surgery) would be the preferred option. The options are much more limited in those who have already been irradiated and palliation, which may include surgery, should be considered. There is no standard chemotherapy or other systemic treatment effective in patients with metastatic disease.
Malignant Disease of the Vulva and the Vagina
Background
England
Wales
Scotland
Northern Ireland
UK
Cases
1061
78
142
32
1313
Rate per 100 000
3.9
5
5.2
3.4
4
Age‐standardized rate per 100 000
4 (3.7–4.2)
4.8 (3.7–5.8)
5.1 (4.3–5.9)
3.8 (2.5–5.2)
4.1 (3.9–4.3)
Risk factors
Aetiology
Histology
Histotype
Comments
Squamous cell carcinomas
Account for 90% of malignant vulval neoplasms
Metastasize to the local lymph nodes, primarily the superficial and deep inguinal nodes, and they may be involved bilaterally. The risk of nodal disease varies with location and degree of invasion
Usually present with a nodule or ulcer and may cause pruritus or soreness and pain. Bleeding and an offensive odour may be present with larger lesions
Veruccous and basal cell carcinomas
Squamous variants and rarely, if ever, metastasize locoregionally
Verrucous carcinomas present as slow‐growing wart‐like lesions with a tendency to recur locally after excision
Basal cell carcinomas usually present as an ulcerated nodule on the labia. They do not metastasize and can be managed by local excision or radiation. Up to 20% recur locally after treatment
Malignant melanoma
Has a poor prognosis and is generally managed as for cutaneous melanomas at other sites
The overall 5‐year survival ranges between 8 and 50% and appears to be worse than for cutaneous melanomas elsewhere
Three patterns of vulval melanoma are identified: mucosal lentinginous (commonest), superficial spreading and nodular. Breslow’s thickness of invasion (invasion >1.75 mm has a high risk of recurrence), ulceration and amelanosis are significant prognostic factors. Surgical excision of the lesion with wide margins remains the mainstay of treatment. c‐Kit expression another valuable predictor of prognosis and survival
Adenocarcinomas
Exceedingly rare and are more likely to represent metastases from another site. There is an association with vulval Paget’s disease
Carcinoma of Bartholin’s gland
Also rare and may be squamous, adenocarcinoma or an adenoid cystic carcinoma. They occur more often in younger premenopausal women and overall have a survival rate of about 35% at 5 years
They usually present as a solid mass in the region of Bartholin’s gland with intact overlying skin. Surgical management is similar to that for squamous cell carcinoma
Sarcomas
Very uncommon and in general are biologically similar to soft‐tissue sarcomas at other sites. Generally there is poor prognosis after the appearance of regional or distant relapse. Wide local excision appears to offer the best chance of preventing local recurrence. Elective treatment of the regional nodes is not indicated and there is no advantage in resecting metastatic nodes. The role of adjuvant radiation and chemoradiation has not been assessed, largely because of its rarity
Metastatic tumours
Rare and account for about 8% of all vulval neoplasms. Cervix, endometrium and renal carcinomas have been the most frequently documented primary sites
Paget’s disease
Presents as a crusty, erythematous, dark pink/red eczematous ‘glazed’ area on the vulva. It is an intraepithelial malignancy in 90%. Up to 10–15% of vulval Paget’s disease is associated with underlying adenocarcinoma, which may be of the breast, stomach, bowel and bladder. Fluorescein dye has been used to detect the lateral extent of disease spread. Wide local excision with closure of large defects with advancement flaps is required to manage this condition
Presentation
Symptoms
Frequency (%)
Pruritus
71
Vulval lump or swelling
58
Vulval ulceration
28
Bleeding
26
Pain or soreness
23
Urinary tract symptoms
14
Discharge
13
Assessment
Examination
Diagnosis
Spread
Staging
Stage 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
Stage II
Tumour of any size with extension to adjacent perineal structures (lower third of urethra; lower third of vagina; anus) with negative nodes
Stage III
Tumour of any size with or without extension to adjacent perineal structures (lower third of urethra; lower third of vagina; anus) with positive inguinofemoral nodes
IIIa
With one lymph node metastasis (≥5 mm), or one or two lymph node metastases (<5 mm)
IIIb
With two or more lymph node metastases (≥5 mm), or three or more lymph node metastases (<5 mm)
IIIc
With positive nodes with extracapsular spread
Stage IV
Tumour invades other regional (upper two‐thirds of urethra; upper two‐thirds of vagina) or distant structures
IVa
Tumour invades any of the following: upper urethral and/or vaginal mucosa; bladder mucosa; rectal mucosa or fixed to pelvic bone; or fixed or ulcerated inguinofemoral lymph nodes
IVb
Any distant metastasis including pelvic lymph nodes
Primary tumour (T)
Tis/0
Pre‐cancer stage: carcinoma in situ or vulval intraepithelial neoplasia (VIN)
T1
There is a tumour and it is confined to the vulva and/or perineum
T1a
Tumour has grown no more than 1 mm into underlying stromal tissue and no more than 2 cm wide
T1b
Tumour is >2 cm wide or it has grown more than 1 mm into stromal tissue
T2
Tumour is any size and is growing into the lower third of the vagina or urethra or anus
T3
Tumour is any size and cancer is spreading to the upper urethra, rectum, bladder or pubic bone
Regional lymph nodes (N)
N0
Cancer has not spread to lymph nodes
N1
One to two lymph nodes have become infected in the groin area. Either:
N1a
One or two lymph nodes affected and area of cancer spread in both <5 mm
N1b
One lymph node is affected and area of cancer spread >5 mm
N2
Cancer has spread to the lymph nodes in the groin with one of the following features:
N2a
Three or more lymph nodes affected but each area of spread <5 mm
N2b
Two or more lymph nodes affected, all with area of spread 5 mm or more
N2c
Cancer has spread to lymph nodes and has started to grow through the outer covering of a least one node (known as extracapsular spread)
N3
Cancer has spread to the lymph nodes causing the development of open sores (ulcerations). The lymph nodes become stuck to the tissue near it
Distant metastasis (M)
M0
Cancer has not spread to distant sites (no metastasis)
M1
Cancer has spread to distant sites, metastasis. This includes spread to pelvic lymph nodes
Groin node assessment
Technique
Sensitivity
Reference
Magnetic resonance imaging
40–50%
Barton et al. [35]
Magnetic resonance lymphography
55–89%
Sohaib & Moskovic [36]
Ultrasonography*
58%
Heaps et al. [37]; Moskovic et al. [38]
Computed tomography scan
Poor
Lin et al. [39]; Andersen et al. [40]
Positron emission tomography
Poor
Kamran et al. [41]
Sentinel lymph node biopsy
Sentinel lymph node only (N = 89)
Sentinel lymph node biopsy plus full groin node (N = 18)
Lymphocyst
5.5%
44%
Lymphoedema
2.7%
33%
Recurrence
2%
0%
Average length of stay
2 (1–17) days
7 (5–25) days
Surgical management of the primary vulvar lesion
Surgical management of early vulvar cancer
Surgical management of advanced vulvar lesions
Lymph node disease
Invasion depth (mm)
Per cent node positive
<1
0
1.1–2
7.7
2.1–3
8.3
3.1–5
26.7
>5
34.2
Management of the lymph nodes
Types of lymph node dissection
Laterality
En bloc and separate groin incisions
Management of involved lymph nodes
Nodal status
Primary size
Survival (%)
Negative (N = 385)
≤2 cm
97.9
2–3 cm
90.5
>3 cm
75–80
All
90.9
Positive (N = 203)
All
57.2
1 or 2 positive nodes
–
75
3 or 4
–
36
5 or 6
–
24
7 or more
–
0
Groin nodes negative
No further treatment
Groin nodes positive after surgery
–
One node only involved*
Observation only
Two or more nodes involved
Inguinal and pelvic radiation
Clinically positive before surgery
Resection followed by radiation
Radiation followed by resection
Radiation only
Complications of surgical treatment
Groin dissection
Wound breakdown/cellulitis
Lymphocyst
Lymphoedema
Vulval resection
Wound breakdown/cellulitis
Rectocele
Urinary problems
Psychological
Management of complications
Radiotherapy and chemotherapy
Adjuvant radiotherapy
Primary treatment
Radiotherapy and chemotherapy schedules
Complications of radiotherapy
Recurrent disease
Treatment
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