Sentinel node assessment for diagnosis of groin lymph node involvement in vulvar cancer

  • Protocol
  • Diagnostic

Authors


Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

To assess the diagnostic test accuracy of sentinel lymph node assessment in detecting groin lymph node metastasis in patients with FIGO stage 1B or higher vulvar cancer.

Background

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).

Table 1. FIGO staging for carcinoma of the vulva
  1. * The depth of invasion is defined as the measurement of the tumour from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.

Stage ITumour confined to the vulva
1ALesions ≤ 2 cm in size, confined to the vulva or perineum and with stromal invasion ≤ 1.0 mm*, no nodal metastasis
1BLesions > 2 cm in size or with stromal invasion > 1.0 mm*, confined to the vulva or perineum, with negative nodes
Stage IITumour of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
Stage IIITumour 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)
IIICWith positive nodes with extracapsular spread
Stage IVTumour 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
IVBAny 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.

Index test(s)

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).

Clinical pathway

Alternative test(s)

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.

Rationale

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.

Objectives

To assess the diagnostic test accuracy of sentinel lymph node assessment in detecting groin lymph node metastasis in patients with FIGO stage 1B or higher vulvar cancer.

Methods

Criteria for considering studies for this review

Types of studies

We will include all prospective or retrospective studies that compare and report diagnostic test accuracy statistics of sentinel node assessment with the reference standard of groin lymph node dissection. We expect that most studies will report the number of sentinel node procedures (each side counted separately) rather than the number of women or cases who underwent sentinel node procedure (with the possibility of bilateral sentinel node reported as one case). We will exclude studies that report the number of cases unless a two-by-two table can be constituted from the description of sentinel node procedures. We will exclude studies reporting less than 10 sentinel node procedures, as well as studies for which construction of a two-by-two table is not possible.

Participants

Women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage 1B or higher vulvar cancer on the bases of diagnostic or excisional biopsy of vulvar cancer. We will consider all ages, histological types of tumour and all techniques and settings of sentinel node detection and their histological analysis in this review.

Index tests

Sentinel lymph node detection and histological assessment.

Studies should specify accurately the technique used accurately and should include the following as a minimum:

  • Description of agent

  • Technique, amount, location and timing of injection of agent

  • Method used to trace and detect sentinel node

  • Definition of what is regarded as a sentinel node

  • Description of the histological method used to assess the sentinel node

A sentinel node should be defined as the first lymph node that shows adequate concentration of tracing agent (e.g. greatest radioactive signal in groin basin detected on hand-held gamma probe in case of radioactive tracer agent, or a node that appears visually blue intra-operatively) (de Hullu 1998). The sentinel node should then be removed and subjected to standard histological examination or by frozen section with at least hematoxylin and eosin (H&E) staining. If the sentinel node is found to be malignant, it is defined as a positive sentinel node. If a sentinel node did not show any malignancy, it is defined as a negative sentinel node. If a sentinel node cannot be identified then it is defined as 'failure to detect sentinel node'. Details of reason for failure to detect sentinel node should also be reported where possible, along with the outcome of lymph node status on reference standard. All cases of positive lymph node involvement on reference standard (total groin lymph node removal) should be able to be correlated with sentinel node status of the same side, including failure to detect the sentinel node.

A groin lymph node dissection would include the sentinel node in the specimen, thus creating a situation where the index test result becomes part of the reference standard (incorporation). Realistically, therefore, false positive tests do not exist in this situation (see Figure 1B). In an event where the sentinel node is identified, assessed and deemed histologically positive but the remaining groin nodes are negative, the reference standard will still be regarded as a true positive (as described in Figure 1). We do not anticipate that false positive tests will be reported in the included studies, but if we encounter them, unless further information is available from the author to create a protocol-compliant two-by-two table, we will exclude such studies from the review.

Figure 1.

Possible outcomes of sentinel lymph node assessment followed by total groin lymph node removal (inguino-femoral lymphadenectomy). (A) Negative sentinel and rest of the groin nodes (True negative), (B) Positive sentinel node but negative rest of the groin nodes (True positive), (C) Positive sentinel and groin nodes (True positive) and (D) Negative sentinel but positive groin nodes (False negative)

We anticipate that many studies would report a combination of various sentinel node detection and analyses techniques. When analysing the diagnostic test accuracy of a single technique, we will only include these studies in the analyses if a separate two-by-two table for the technique in question can be constituted. Similarly, not all women may receive combined techniques in these studies. When analysing the diagnostic test accuracy of the combined technique, these studies will only be included in the analyses if all cases received the combined technique in question, or a separate two-by-two table for cases who received the combined technique in question can be constituted.

Target conditions

Groin (inguino-femoral) lymph node metastases in FIGO stage 1B or higher vulvar cancer

Reference standards

Histological assessment of systematic groin lymph node dissection will be used as a reference standard. The reference standard would be subjected to the standard histological assessment with at least H&E staining. If any of the removed nodes (including the sentinel node) show cancer metastasis histologically, the reference standard is considered positive. Studies should report the reference standard result by each side of groin node removal and not by patient/cases.

Systematic groin lymph node removal includes removal of inguinal and femoral lymph nodes. Traditionally this includes removal of lymph nodes above and parallel to the inguinal ligament up to the pubic tubercle medially and lymph nodes from the femoral triangle (parallel to femoral vessels and sapheno-femoral junction including cribriform fascia) up to and including the deep fascia of muscle forming the base of the femoral triangle. Dissection deeper to the deep fascia or into the adductor canal is usually not required. There still remains some uncertainty regarding the ideal extent and adequacy of surgical dissection for the groin lymph nodes (Hudson 2004). If heterogeneity exists in the surgical extent of reference standard in the included studies, we will explore it through heterogeneity analysis.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases:

  • MEDLINE (OvidSP) (1950 to current)

  • EMBASE (OvidSP) (1980 to current)

  • Cochrane Register of Diagnostic Test Accuracy Studies

  • The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (latest issue)

The search strategy for MEDLINE will reflect both subject headings (MeSH terms) and text words for the target condition (groin lymph node metastasis in vulvar cancer) and the diagnostic test under investigation (sentinel lymph node biopsy).

We will use the MEDLINE search strategy specified in Appendix 1. We will adapt the MEDLINE search strategy to search EMBASE. In particular, we will adapt the MEDLINE MeSH terms to the corresponding terms available in the EMTREE vocabulary.

We will not apply language restrictions to the electronic searches. Where possible, we will make arrangements to translate non-English articles, if relevant studies are found in languages other than English.

Searching other resources

We will also search the following databases:

  • DARE (Database of Abstracts of Reviews of Effects), www.york.ac.uk/inst/crd/crddatabases.htm#DARE

  • MEDION (Meta-Analyses van Diagnostisch Onderzoek), www.mediondatabase.nl

  • HTA Database (Health Technology Assessments Database), www.york.ac.uk/inst/crd/crddatabases.htm#HTA

  • ARIF (Aggressive Research Intelligence Facility), www.arif.bham.ac.uk

We will review the reference list of all relevant studies retrieved from electronic searches to identify additional potentially-relevant studies.

We will also use the relevant studies as seeds in the Science Citation Index (ISI Web of Knowledge) and Google Scholar (www.scholar.google.com) to determine whether articles citing these studies are also relevant. We will use all studies identified as relevant as seeds in PubMed to search for additional studies using the 'related articles' feature.

We will handsearch abstract books of meetings of the International Gynaecological Cancer Society (IGCS), the European Society of Gynaecological Oncology (ESGO), the Society of Gynaecologic Oncologists (SGO) and the American Society of Clinical Oncologist (ASCO) from 2000 to the present, to identify unpublished studies. Where necessary, we will contact main investigators of relevant ongoing studies for further information.

Data collection and analysis

Selection of studies

We will use the reference manager software Endnote® (Endnote 2012) to remove duplicates from all titles and abstracts retrieved from the literature search. AP and NR will independently examine all eligible references. We will exclude studies that clearly do not meet the inclusion criteria and will obtain full text articles of those that appear potentially relevant. AP and NR will independently assess the full text articles for their eligibility and in the event of disagreement will involve other authors (RN, KG, PMH and AB). We will document clearly the reasons for exclusion of potentially-relevant studies.

Data extraction and management

We will extract the following variables from each included study using a data extraction form:

  • Author, year of publication and journal (including language)

  • Country

  • Setting

  • Inclusion criteria

  • Exclusion criteria

  • Study design and flow of patient pathway

  • Population

  • Sample size

  • Details of diagnosis of vulvar cancer (diagnostic biopsy or radical excision)

  • Pathological parameters

    • Size of tumour

    • Histological type

    • Unifocal or multi-focal

    • Lympho-vascular invasion

    • Previous history of vulvar surgery

  • Were cases with suspected groin node involvement prior to sentinel node assessment included in the study?

  • Additional tests performed to assess groin lymph node status prior to the sentinel node assessment

  • Experience of the surgeons

  • Index test

    • Method(s)

      • Details of tracer agent used, amount, dilution

      • Method of application

      • Timing of application in relation to sentinel node excision

      • Method used to detect sentinel node

      • Method used for histological assessment of sentinel node

    • Results

      • Detection rate of sentinel node (total intended versus total detected)

      • False negative sentinel node test (categorise by negative sentinel node or failure to detect sentinel node)

      • Rate of adverse events associated with index test

  • Reference standard

    • Unilateral or bilateral

    • Is positive sentinel node (but negative remaining groin nodes) regarded as positive reference standard?

    • Average lymph node yield (quality marker for reference standard)

    • Extent of surgical dissection of groin lymph nodes

    • Method used for histological assessment

    • Rate of adverse effects associated with reference standard

  • QUADAS-2 items (see Assessment of methodological quality below)

  • Data for two-by-two table

AP and NR will independently abstract data using an Excel® spreadsheet designed specifically for this review. We will pilot the data abstraction spreadsheet including QUADAS-2 items using two included studies. Data between two authors will be matched and differences will be resolved by revisiting the original articles and, if necessary, involving other authors (RN, KG, PMH and AB).

Assessment of methodological quality

AP and NR will perform the assessment of methodological quality. In the event of disagreement, other co-authors will be involved (RN, KG, PMH and AB). We will assess patient pathway in detail for each included study. We will also assess the description of index and reference standard tests for each included study to determine if these are described in sufficient detail to a standard of reproducibility. We will assess study methodological quality using the QUADAS-2 tool (Whiting 2011) as described in Appendix 2, and report the results in detail in a tabular and graphical form. We will also summarise results in the text.

Statistical analysis and data synthesis

We will create two-by-two tables in Review Manager software (RevMan 2012) and calculate sensitivity (diagnostic accuracy statistic for proportion of women with the disease who are correctly identified from the test) for each included study. It is not necessary to calculate specificity as this will always be 100%; when the reference standard is negative, sentinel node will always be negative. We will present diagnostic accuracy statistics for each study in a paired forest plot (where specificity will always be 100%). As a result, sensitivity statistics will line up on y-axis (sensitivity) crossing x-axis at 0 (1-specificity) on receiver operating characteristic (ROC) space. Since there is no variability in specificity, we will consider a binary logistic regression model for sensitivity analyses (with random effects).

Investigations of heterogeneity

We anticipate that multiple factors can influence diagnostic accuracy statistics for sentinel node detection and analyses in vulvar cancer. These factors may lead to heterogeneity in the analyses. We will explore the effect of heterogeneity by investigating forest and ROC plots limited to relevant study level subgroup co-variables. As we expect that only sensitivity of sentinel node assessment would vary, whilst specificity remains static at 100%, a meta-regression analysis model will not be required to investigate heterogeneity or to estimate a summary ROC plot.

We will attempt to explore heterogeneity related to the following variables, if the number of eligible studies and accurate description of these variables in the studies allows us to do so:

  • Techniques used in sentinel node detection

  • Techniques used in sentinel node histological assessment

  • Commonly used combinations of techniques

  • Size, site and focality of tumour

  • Histological type

  • Previous surgery to vulva

  • Clinically suspected groin node involvement prior to sentinel node detection

  • Use of imaging techniques (US, CT, MRI, PET-CT) prior to sentinel node procedure

  • Reference standard: although not anticipated, if heterogeneity in reference standard exists, its effect will be explored

  • Experience of surgeon

  • Retrospective versus prospective study design

Sensitivity analyses

We will perform sensitivity analyses related to the remaining relevant methodological quality items (QUADAS-2). It is possible that during the review process we may come across variations related to population, methodology, index test, reference standard or data analysis aspects of individual studies which are not predicted at the protocol stage. In this situation we will perform sensitivity analyses to assess the effects of such variations. We will report all sensitivity analyses in a summary table and describe it in the review text.  

Assessment of reporting bias

Case withdrawals and dropouts from individual studies will be explored for more details. Our literature search also includes the abstract books of various conferences and meetings to minimise publication bias. We will contact authors to explore and retrieve unpublished data where relevant. We will also produce an effective sample size funnel plot and regression test of asymmetry if possible, as described by Deeks 2005 to evaluate publication bias.

Acknowledgements

We thank Jo Morrison for clinical expertise; Gail Quinn and Clare Jess for their contribution to the editorial process; and Anne Eisinga for designing the search strategy.

Appendices

Appendix 1. MEDLINE search strategy

MEDLINE (OvidSP)

 1. ((vulva* or clitoris or clitoral) adj5 (tumor* or tumour* or neoplas* or cancer* or carcinoma* or malignan* or metasta* or micrometasta* or carcinogen* or adenocarcinoma* or adenosquamous or growth*)).tw,ot.
2. Vulvar Neoplasms/
3. Neoplasm Invasiveness/ or Lymphatic Metastasis/ or Neoplasm Micrometastasis/ or Neoplasm Recurrence, Local/ or Neoplasm, Residual/
4. Neoplasm Staging/
5. Carcinoma, Squamous Cell/
6. ((lymphovascular or lympho-vascular) adj4 invasiv*).tw,ot.
7. (lymph* adj4 metasta*) or (detect* adj4 metasta*).tw,ot.
8. (vulva* or clitoris or clitoral or inguin* or groin).tw,ot.
9. Inguinal Canal/
10. Clitoris/
11. Vulva/
12. (3 or 4 or 5 or 6 or 7) and (8 or 9 or 10 or 11)
13. 1 or 2 or 12
14. Lymph Nodes/
15. Sentinel Lymph Node Biopsy/
16. ((groin or inguin*) adj3 (dissect* or status or node*1)).tw,ot.
17. Coloring Agents/
18. Technetium Tc 99m Sulfur Colloid/
19. Technetium Tc 99m Aggregated Albumin/
20. Radiopharmaceuticals/
21. Rosaniline Dyes/
22. Methylene Blue/
23. (technetium or tc 99m* or 99mtc* or blue dye*1 or patent blue or methylene blue or isosulfan or iso sulfan or lymphazurin blue or radiocolloid*).tw,ot,nm.
24. (sentin?l adj3 node*1).tw,ot.
25. (lymphoscintigraph* or lymphoscintigram*).tw,ot.
26. Lymphography/
27. (scintiphotograph* or scintigraph* or scintigram*).tw,ot.
28. (gamma adj3 (camera*1 or counter*1 or probe*1)).tw,ot.
29. radioisotope*.tw,ot.
30. (tracer or tracers).tw,ot.
31. ((trace or tracing or traceable) adj agent*1).tw,ot.
32. radiotracer*.tw,ot.
33. Fluorescence/
34. fluorescen*.tw,ot.
35. (microbubble or micro-bubble).tw,ot.
36. paraffin.tw,ot.
37. frozen section*.tw,ot.
38. (ultrastaging or ultra staging).tw,ot.
39. (microsection* or micro section*).tw,ot.
40. cytokeratin.tw,ot.
41. ((haematoxylin adj2 eosin) or (hematoxylin adj2 eosin)).tw,ot.
42. Gamma Cameras/
43. Frozen Sections/
44. (immuno-histo-chemistry or immunohistochemistry or immunohistochemical or immuno-histo-chemical).tw,ot.
45. (localisation or localization).tw,ot.
46. ((lymph node*1 or lymph nodal) adj3 (assess* or evaluat* or observ* or involve* or biopsy or biopsies)).tw,ot.
47. or/14-46
48. 13 and 47
49. exp animals/ not humans/
50. 48 not 49               

Appendix 2. Assessment of methodological quality criteria

We will consider the following core QUADAS-2 domains in the current review.

DOMAIN 1: PATIENT SELECTION

A. Risk of Bias

1. Was a consecutive or random sample of patients enrolled? Yes/No/Unclear

2. Did the study avoid inappropriate exclusions? Yes/No/Unclear

3. Was the spectrum of patients representative of the patients who will receive the test in practice?

  • Yes: at least 90% of patients had FIGO stage 1B or higher vulvar cancer

  • No: less than 90% of patients had FIGO stage 1B or higher vulvar cancer

  • Unclear: stage of disease was not reported or could not be clearly determine

OVERALL RISK OF BIAS: LOW/HIGH/UNCLEAR

B. Applicability

Is there concern that the included patients do not match the review question?

CONCERN: LOW/HIGH/UNCLEAR

DOMAIN 2: SENTINEL NODE ANALYSIS (INDEX TEST)

A. Risk of Bias

1. Were the index test results interpreted without knowledge of the results of the reference standard? (Reference standard results blinded)

  • Yes: histological analysis of sentinel node was carried out without the knowledge of the histological analysis of groin lymph node

  • No: histological analysis of sentinel node was carried out with the knowledge of the histological analysis of groin lymph node

  • Unclear: It is unclear whether histological analysis of sentinel node was carried out with or without the knowledge of the histological analysis of groin lymph node

OVERALL RISK OF BIAS: LOW/HIGH/UNCLEAR

 

B. Applicability

Is there concern that the index test, its conduct, or interpretation differ from the review question?

CONCERN: LOW /HIGH/UNCLEAR

 

DOMAIN 3: GROIN LYMPH NODE ANALYSIS (REFERENCE STANDARD)

A. Risk of Bias

1. Is the reference standard likely to correctly classify the target condition

  • Yes: all the patients received standard groin lymph node removal

  • No: only some patient received standard groin lymph node removal

  • Unclear: surgical extent of lymph node removal is not reported or could not be clearly distinguished

2. Were the reference standard results interpreted without knowledge of the results of the index test? (Index test results blinded)

  • Yes: histological analysis of groin lymph node removal was carried out without the knowledge of the histological analysis of sentinel node

  • No: histological analysis of groin lymph node removal was carried out with the knowledge of the histological analysis of sentinel node

  • Unclear: It is unclear whether the histological analysis of groin lymph node removal was carried out with or without the knowledge of histological analysis of sentinel node

OVERALL RISK OF BIAS: LOW/HIGH/UNCLEAR

B. Applicability

Is there concern that the target condition as defined by the reference standard does not match the review question?

CONCERN: LOW /HIGH/UNCLEAR

DOMAIN 4: FLOW AND TIMING

A. Risk of Bias

1. Was there an appropriate interval between index test and reference standard?

  • Yes: less than or equal to 4 weeks between index test and reference standard

  • No: more than 4 weeks between index test and reference standard

  • Unclear: not reported, variable or could not be clearly determined

2. Were other imaging tests performed prior to sentinel node test to rule out groin lymph node metastasis?

  • Yes: participants underwent US, CT, MRI or PET-CT to detect groin metastasis prior to sentinel node procedure

  • No: US, CT, MRI or PET-CT was not carried out prior to sentinel node procedure

  • Unclear: insufficient information as to whether US, CT, MRI or PET-CT was carried out to detect groin metastasis prior to sentinel node procedure

3. Did all patients receive a reference standard?

  • Yes: whole population received reference standard

  • No: reference standard not carried out in the whole population

  • Unclear: no clear information on what proportion of population received reference standard

4. Did patients receive the same reference standard?

  • Yes: all the patients received same reference standard regardless of index test results

  • No: not all the patients received same reference standard regardless of index test results

  • Unclear: it is unclear whether all the patients received same reference standard regardless of index test results

5. Were un-interpretable/intermediate test results reported?

  • Yes: all un-interpretable results (sentinel node detection and its histological analysis) were reported

  • No: not all un-interpretable results were reported

  • Unclear: it is not possible to determine if all un-interpretable results were reported

6. Were withdrawals from the study explained?

  • Yes: all withdrawals from study were explained

  • No: not all withdrawals from study were explained

  • Unclear: insufficient information to determine if all withdrawals were explained

7. Had test operators had appropriate training?

  • Yes: at least experience of 10 sentinel node procedures prior to taking part in the study

  • No: experience of less than 10 sentinel node procedures prior to taking part in the study

  • Unclear: insufficient information on training of surgeon taking part in the study

OVERALL RISK OF BIAS: LOW/HIGH/UNCLEAR

What's new

DateEventDescription
31 January 2013AmendedContact detail updated

Contributions of authors

Guarantor of the review: AP
Conceiving the idea: AP
Designing and coordinating the review: AP
Data collection for the review; Designing search strategies; Undertaking searches; Screening search results: AP, NR
Organising retrieval of papers: AP, NR
Screening retrieved papers against inclusion criteria: AP, NR
Appraising quality of papers: AP, NR
Extracting data from papers: AP, NR
Writing to authors of papers for additional information: AP, NR
Providing additional data about papers: AP, NR
Obtaining and screening data on unpublished studies: AP, NR
Data management of the review: AP
Entering data into RevMan 5: AP, NR
Analysis and interpretation of data: AP, NR, AB
Providing a methodological perspective; Providing a clinical perspective; Providing a policy perspective; Providing a consumer perspective: AP, NR, AB, AR, PMH, RN
Writing the review: AP
Providing general advice on the review: AP, NR, AR, PMH, RN,
Secure funding for the review: AP, NR, RN

Declarations of interest

None known

Sources of support

Internal sources

  • NIHR Cochrane Programme Grant support from 'Optimising care, diagnosis and treatment pathways to ensure cost effectiveness and best practice in gynaecological cancer. Improving the evidence for the NHS., UK.

External sources

  • No sources of support supplied

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