The issue
Women with vulval cancer that has spread to the groin lymph nodes need additional treatment. The standard treatment usually involves surgical removal of as many groin nodes as possible (known as complete inguinofemoral lymphadenectomy (IFL)). However, only about 30% of women with vulval cancer in whom lymph nodes are not obviously enlarged will have groin involvement; therefore, in about 70% of these women additional surgery is not necessary. As groin surgery often causes later swelling of the legs and other unpleasant side effects, it would be preferable not to undergo the surgery if it is not required; therefore, accurate screening tests to determine who should have surgery are needed.
Sentinel node assessment involves identifying the main lymph node/s draining the tumour. After the main (sentinel) nodes are identified, they are removed and examined under a microscope to check for cancer cells. Additional surgery depends on the findings of the examination: if cancer cells are found in the nodes, additional surgery is necessary; if the nodes are cancer-free, additional surgery can be avoided.
Why is this review important?
Several studies have been done using dyes or traceable agents to identify sentinel nodes. From these studies, it is not clear whether all of these agents are sufficiently accurate to predict which women have cancerous spread to the groin. This review summarises the evidence and produces overall estimates of the relative accuracies of the available tests.
How was the review conducted?
We included all studies that tested the accuracy of tracer agent/s against the standard method of identifying cancer in the groin nodes (removing all groin nodes (IFL) and examining them under a microscope). Women in these studies had vulval cancer of Federation of Gynecology and Obstetrics (FIGO) stage IB or higher without obvious signs of cancer in the groin (enlarged or palpable nodes). We only included studies of at least 10 women, and noted any concerns about the quality of studies.
What are the findings?
We included 34 studies (1614 women) that evaluated three techniques: blue dye only, technetium (a radioactive substance) only, or blue dye and technetium combined. Ten studies used all three techniques during the course of the study (one technique per participant). There are two attributes to a test: the ability to identify or detect the sentinel node, and the ability to identify the cancer in the sentinel node. We found that all tests can identify cancer in the groin nodes with good accuracy (more than 90% of nodes with cancer will be accurately identified with any of the tests), although the combined test was the most accurate (95%). The ability of the tests to detect sentinel nodes varied, with the blue dye test only detecting sentinel nodes in 82% of women, compared with 98% for the combined test. If sentinel nodes are not detected, they cannot be examined for cancer cells; therefore, women in whom sentinel nodes are not detected will usually need to undergo IFL.
What does this mean?
The combined and technetium only tests are able to predict accurately which women have cancerous spread to the groin. For a group of 100 women undergoing assessment, the findings mean that approximately one or fewer women having the combined or technetium only tests will undergo an unnecessary IFL, compared with approximately 11 women having the blue dye only test. This is mainly because the blue dye only test is not as good as technetium in identifying sentinel nodes. Fewer women with spread to the groin will be missed with the combined or technetium only tests (1 to 3 out of 30) compared with the blue dye only test (1 to 8 out of 30). It is not clear whether women with negative sentinel nodes (i.e. no spread of cancer to the groin lymph nodes) who do not undergo IFL will live as long as those who undergo IFL. The current best data on survival come from a Dutch study that followed up 259 women with negative sentinel nodes and reported a three-year survival of 97%.
There is little difference in diagnostic test accuracy between the technetium and combined tests. The combined test may reduce the number of women with 'missed' groin node metastases compared with technetium only. Blue dye alone may be associated with more 'missed' cases compared with tests using technetium. Sentinel node assessment with technetium-based tests will reduce the need for IFL by 70% in women with early vulval cancer. It is not yet clear how the survival of women with negative sentinel nodes compares to those undergoing standard surgery (IFL). A randomised controlled trial of sentinel node dissection and IFL has methodological and ethical issues, therefore more observational data on the survival of women with early vulval cancer are needed.
Vulval cancer is usually treated by wide local excision with removal of groin lymph nodes (inguinofemoral lymphadenectomy) from one or both sides, depending on the tumour location. However, this procedure is associated with significant morbidity. As lymph node metastasis occurs in about 30% of women with early vulval cancer, accurate prediction of lymph node metastases could reduce the extent of surgery in many women, thereby reducing morbidity. Sentinel node assessment is a diagnostic technique that uses traceable agents to identify the spread of cancer cells to the lymph nodes draining affected tissue. Once the sentinel nodes are identified, they are removed and submitted to histological examination. This technique has been found to be useful in diagnosing the nodal involvement of other types of tumours. Sentinel node assessment in vulval cancer has been evaluated with various tracing agents. It is unclear which tracing agent or combination of agents is most accurate.
To assess the diagnostic test accuracy of various techniques using traceable agents for sentinel lymph node assessment to diagnose groin lymph node metastasis in women with FIGO stage IB or higher vulval cancer and to investigate sources of heterogeneity.
We searched MEDLINE (1946 to February 2013), EMBASE (1974 to March 2013) and the relevant Cochrane trial registers.
Studies that evaluated the diagnostic accuracy of traceable agents for sentinel node assessment (involving the identification of a sentinel node plus histological examination) compared with histological examination of removed groin lymph nodes following complete inguinofemoral lymphadenectomy (IFL) in women with vulval cancer, provided there were sufficient data for the construction of two-by-two tables.
Two authors (TAL, AP) independently screened titles and abstracts for relevance, classified studies for inclusion/exclusion and extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We used univariate meta-analytical methods to estimate pooled sensitivity estimates.
We included 34 studies evaluating 1614 women and approximately 2396 groins. The overall methodological quality of included studies was moderate. The studies included in this review used the following traceable techniques to identify sentinel nodes in their participants: blue dye only (three studies), technetium only (eight studies), blue dye plus technetium combined (combined tests; 13 studies) and various inconsistent combinations of these three techniques (mixed tests; 10 studies). For studies of mixed tests, we obtained separate test data where possible.
Most studies used haematoxylin and eosin (H&E) stains for the histological examination. Additionally an immunohistochemical (IHC) stain with and without ultrastaging was employed by 14 and eight studies, respectively. One study used reverse transcriptase polymerase chain reaction analysis (CA9 RT-PCR), whilst three studies did not describe the histological methods used.
The pooled sensitivity estimate for studies using blue dye only was 0.94 (68 women; 95% confidence interval (CI) 0.69 to 0.99), for mixed tests was 0.91 (679 women; 95% CI 0.71 to 0.98), for technetium only was 0.93 (149 women; 95% CI 0.89 to 0.96) and for combined tests was 0.95 (390 women; 95% CI 0.89 to 0.97). Negative predictive values (NPVs) for all index tests were > 95%. Most studies also reported sentinel node detection rates (the ability of the test to identify a sentinel node) of the index test. The mean detection rate for blue dye alone was 82%, compared with 95%, 96% and 98% for mixed tests, technetium only and combined tests, respectively. We estimated the clinical consequences of the various tests for 100 women undergoing the sentinel node procedure, assuming the prevalence of groin metastases to be 30%. For the combined or technetium only tests, one and two women with groin metastases might be 'missed', respectively (95% CI 1 to 3); and for mixed tests, three women with groin metastases might be 'missed' (95% CI 1 to 9). The wide CIs associated with the pooled sensitivity estimates for blue dye and mixed tests increased the potential for these tests to 'miss' women with groin metastases.