Target condition being diagnosed
Vulvar cancer is a rare gynaecological cancer with an incidence of 1 to 3 per 100,000 women per year (ONS 2009b; Sankaranarayanan 2006; Saraiya 2008). At the time of diagnosis more than half of patients are aged 70 years or above, and incidence peaks at the age of 75 years and above (ONS 2009b; Sankaranarayanan 2006). Seventy five per cent to 90% of vulvar cancers are squamous cell carcinomas (Saraiya 2008; Stehman 2007). The vulvar cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) classification (Table 1). Overall prognosis and outcomes in vulvar cancer are dependent on tumour size, presence of cancer cells in local lymphatic or blood vessels (lympho-vascular space involvement), and presence, number, size and surface involvement (capsular breach) of lymph node metastasis (Andreasson 1985; Boyce 1985; Homesley 1991; Parker 1975; Podratz 1983; Smyczek-Gargya 1997; van der Velden 1995). The vulvar cancer usually spreads (metastasises) to groin (inguino-femoral) lymph nodes through the lymph fluid channels (Curry 1980; Podratz 1983). The overall risk of lymph node spread depends on the type, size and location of the tumour (Curry 1980; Podratz 1983) and reported incidence varies from 25% to 50% (Sutton 1991; Simonsen 1984; Creasman 1997).
|Stage I||Tumour confined to the vulva|
|1A||Lesions ≤ 2 cm in size, confined to the vulva or perineum and with stromal invasion ≤ 1.0 mm*, no nodal metastasis|
|1B||Lesions > 2 cm in size or with stromal invasion > 1.0 mm*, confined to the vulva or perineum, with negative nodes|
|Stage II||Tumour of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes|
|Stage III||Tumour of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive groin lymph nodes|
|IIIA||(i) With 1 lymph node metastasis (≥ 5 mm), or|
|(ii) 1–2 lymph node metastasis(es) (b5 mm)|
|IIIB||(i) With 2 or more lymph node metastases (≥ 5 mm), or|
|(ii) 3 or more lymph node metastases (b5 mm)|
|IIIC||With positive nodes with extracapsular spread|
|Stage IV||Tumour invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures|
|IVA||(i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or|
|(ii) fixed or ulcerated groin lymph nodes|
|IVB||Any distant metastasis including pelvic lymph nodes|
Vulvar cancer is treated by wide local excision of vulvar tumour. Tumours smaller than two cm and depth of invasion less than one mm (FIGO stage 1A) do not require removal of lymph nodes (lymphadenectomy) from groin due to the extremely low risk (less than 1%) of metastasis (Hacker 1993). However in all other cases (FIGO stage 1B and higher) removal of all groin lymph nodes has been a traditional gold standard treatment. Vulvar tumours away from midline (lateralised) require removal of groin lymph nodes from the same side, whilst midline tumours require removal of lymph nodes from both sides (Iversen 1981; Hacker 1993). Most women with positive groin lymph node will require further treatment with radiation with its risk of additional morbidity. This treatment approach is highly effective, with a low groin tumour recurrence rate of 1% to 10% (Burger 1995; de Hullu 2002; Hacker 1981; Homesley 1991; Katz 2003). Vulvar cancer mortality has halved over the last three decades (ONS 2009a). This treatment approach, however, is associated with significant morbidity related to the wound and lymph drainage in up to 70% of cases (Fotiou 1996; Gaarenstroom 2003; Rouzier 2003; Stehman 1992; Van der Zee 2008). Short-term morbidities include wound infection, wound disruption, groin lymph collection (lymphocyst) and longer hospital stay, and long-term risks include chronic leg swelling (lymphedema), chronic and recurrent skin infection (erysipelas) and reduced mobility.
The lymphatic fluid from the vulvar skin is drained by lymphatic channels to the groin lymph nodes. The first lymph node to receive these lymphatic channels on each side is considered to be the sentinel node. Cancer cells from vulvar tumour spread via lymph fluid through lymphatic channels usually to the sentinel node, before spreading to other nodes. A diagnostic test can therefore be employed to detect, excise and examine the sentinel node(s) histologically for cancer cells. This is usually achieved by injecting a traceable agent subcutaneously around the vulvar tumour (usually at four quadrants). This agent spreads via the lymphatic channels to the lymph node, which can be traced using an appropriate tracing method. The first lymph node in each groin region to concentrate the traceable agent is considered the sentinel lymph node.
Various traceable agents and their detection techniques can be employed on their own or in combination. For instance, the most commonly-used technique involves a combination of radioactive 99m Technetium and patent blue dye. Radioactive 99m Technetium is injected at four quadrants of the vulvar tumour a day before, or on the day of, surgery followed by a scan to detect the sentinel node(s) (lymphoscintigraphy) which are marked on the overlying skin. Patent blue dye is injected around the tumour immediately before surgery. A hand-held gamma camera probe to detect the concentration of 99m Technetium and the visual discolouration of patent blue dye guides the surgeon during the operation to detect the sentinel node. Other techniques to detect the sentinel node, such as absorption and emission of specific light (infrared fluorescence) by tumour, and injection of air around tumour and detection by ultrasound (micro-bubble), are also being evaluated.
Once excised, the sentinel node is sent either for an immediate frozen section examination or for routine paraffin histology (which takes a few days to report). If the sentinel node is found to have cancer cells (positive sentinel node), further surgery to remove all remaining groin nodes (at the same time if reported on frozen section, or at a later date if on paraffin section) will be required. If the sentinel node is reported to be free of cancer cells (negative sentinel node), total removal of groin lymph node and its associated morbidity can be avoided. Ultra-staging techniques such as serial micro-sectioning (at 200 to 250 μm) and immuno-histo-chemistry staining (usually for cytokeratin) are used to detect micro-metastasis (< 2 mm size) in the sentinel node if initial haematoxylin and eosin (H&E) section is negative ( Knopp 2005; Terada 2000). This has proven to increase the detection rate of lymph node metastasis, but its significance in the overall prognosis in vulvar cancer remains unclear. It is anticipated that use of ultra-staging will have a significant effect on the diagnostic accuracy of sentinel node analysis.
Sentinel node detection and analysis has been pioneered and has become the standard of care in the surgical management of melanoma and breast cancer (Canavese 2010; Krag 2007; Morton 1990; Morton 2006; Rodier 2007; Thompson 2007; Wang 2011). Success rates of sentinel node detection in vulvar cancer with the combined use of 99mTechnetium ad patent blue dye approach have been reported to be between 89% and 100% (de Hullu 2000; Tavares 2001). Failure to detect the sentinel node could be due to the agent failing to reach to a sentinel node, too low concentration of agent in the lymph node, or the surgeon not being able to identify the sentinel node. In this situation it is advisable to undergo standard groin lymph node dissection. In those where sentinel node(s) are identified it is important that the false negative rate of groin lymph node metastasis (i.e. negative sentinel lymph node but presence of positive non-sentinel lymph nodes) is extremely low. A high false negative sentinel node rate will lead to poor outcomes due to avoidance of groin lymph node removal and radiation treatment in cases that would have actually benefited from these therapies.
Sentinel node detection is usually only used in cases where the vulvar tumour size is less than four cm in maximum diameter with more than one mm depth of invasion, and in cases where groin lymph node metastasis is clinically not suspected. The maximum tumour dimension of four cm, although arbitrarily chosen, is based on a relatively lower risk of lymph node metastasis and low failure rate to detect sentinel nodes. It is not clear at this time if the sentinel node detection success rate or false negative prediction rate differs in tumours larger than four cm in size. Similarly it is expected but remains unknown if these rates are affected in situations where the tumour has already been excised (where agents are injected around the scar), in multi-focal tumours and in women with a previous history of vulvar surgery (e.g. recurrent vulvar cancer).
Currently there are no diagnostic tests that predict groin lymph node metastases in vulvar cancer with reasonable test accuracy. Various imaging techniques including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography - computed tomography (PET-CT) have been used to evaluate groin lymph node status before definitive surgery. Although they have the advantage of being non-invasive, their ability to confirm (sensitivity) or exclude metastasis (specificity) is limited (Abang Mohammed 2000; Cohn 2002; de Hullu 1999; Hall 2003; Hawnaur 2002; Land 2006; Makela 1993; Moskovic 1999; Sohaib 2002) and therefore they are not routinely used in clinical practice.
Surgical excision of tumour and lymphatic staging remains a cornerstone of the management in vulvar cancer. For very early stage disease (FIGO IA), wide local excision of tumour without lymphatic staging is an accepted method of treatment due to the low risk (< 1%) of lymph node metastasis (Hacker 1993). For FIGO stage IB disease or above, a wide local excision of vulvar tumour along with the removal of groin lymph node from one or both sides (depending on the tumour location) is the traditional treatment of choice (Hacker 1993; Iversen 1981). This treatment, however, is associated with significant morbidity related to wound and lymph drainage in up to 70% of cases (Gaarenstroom 2003; Rouzier 2003; Stehman 1992; Van der Zee 2008). The overall rate of lymph node metastasis in vulvar cancer is reported to be 25% to 50% (Creasman 1997; Simonsen 1984; Sutton 1991). The node negative cases are unlikely to benefit from removal of groin lymph nodes and many will suffer from unnecessary associated surgical morbidity. Most women with positive groin lymph nodes will require further treatment with radiation, with its risk of additional associated morbidity.
The concept of sentinel node detection and analysis has been successfully applied to guide the management of melanoma and breast cancer (Canavese 2010; Krag 2007; Morton 1990; Morton 2006; Rodier 2007; Thompson 2007). The surgical morbidity of axillary lymph node dissection has been reduced without adverse effect on breast cancer outcomes (Canavese 2010; Krag 2007; Rodier 2007; Wang 2011). A similar concept in the research setting is being applied in vulvar cancer as well. The sentinel lymph node is the first lymph node in the groin region to which the vulvar cancer cells would spread via the lymphatic channels. The histological analysis of the sentinel groin node is considered to be representative of all other remaining non-sentinel groin lymph nodes draining to the same anatomical side. The use of sentinel node assessment will therefore triage only those women with positive sentinel node for further groin node dissection, avoiding surgical morbidity in the remaining sentinel node negative women. If sentinel node detection and analysis has very high sensitivity with an extremely low false negative rate in predicting groin lymph node metastasis, its use in routine clinical practice can be envisaged. This review aims to analyse the diagnostic accuracy of sentinel node assessment in vulvar cancer.