Lawrie Theresa A, Patel Amit, Martin-Hirsch Pierre P L, Bryant Andrew, Ratnavelu Nithya D G, Naik Raj, Ralte Angela
Cochrane Gynaecological Cancer Group, Royal United Hospital, Education Centre, Bath, UK, BA13NG.
Cochrane Database Syst Rev. 2014 Jun 27;2014(6):CD010409. doi: 10.1002/14651858.CD010409.pub2.
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.
AUTHORS' CONCLUSIONS: 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.
外阴癌通常采用广泛局部切除术，并根据肿瘤位置切除一侧或双侧腹股沟淋巴结（腹股沟股淋巴结清扫术）。然而，该手术会带来显著的发病率。由于约30%的早期外阴癌女性会发生淋巴结转移，准确预测淋巴结转移可减少许多女性的手术范围，从而降低发病率。前哨淋巴结评估是一种诊断技术，它使用可追踪的试剂来识别癌细胞向引流受影响组织的淋巴结扩散。一旦识别出前哨淋巴结，就将其切除并进行组织学检查。已发现该技术在诊断其他类型肿瘤的淋巴结受累情况时很有用。已使用各种追踪试剂对外阴癌的前哨淋巴结评估进行了评价。目前尚不清楚哪种追踪试剂或试剂组合最为准确。
评估使用可追踪试剂的各种技术在前哨淋巴结评估中诊断国际妇产科联盟（FIGO）IB期或更高分期外阴癌女性腹股沟淋巴结转移的诊断试验准确性，并调查异质性来源。
我们检索了MEDLINE（1946年至2013年2月）、EMBASE（1974年至2013年3月）以及相关的Cochrane试验注册库。
评估可追踪试剂在前哨淋巴结评估中的诊断准确性（包括识别前哨淋巴结和组织学检查）的研究，与外阴癌女性在完成腹股沟股淋巴结清扫术（IFL）后对切除的腹股沟淋巴结进行组织学检查相比较，前提是有足够的数据构建四格表。
两位作者（TAL、AP）独立筛选标题和摘要以确定相关性，对研究进行纳入/排除分类并提取数据。我们使用QUADAS - 2工具评估研究的方法学质量。我们使用单变量荟萃分析方法估计合并敏感度估计值。
我们纳入了34项研究，评估了1614名女性和约2396个腹股沟。纳入研究的总体方法学质量中等。本综述纳入的研究在其参与者中使用以下可追踪技术识别前哨淋巴结：仅使用蓝色染料（3项研究）、仅使用锝（8项研究）、蓝色染料加锝联合使用（联合试验；13项研究）以及这三种技术的各种不一致组合（混合试验；10项研究）。对于混合试验的研究，我们尽可能获取单独的试验数据。大多数研究使用苏木精和伊红（H&E）染色进行组织学检查。此外，分别有14项和8项研究采用了有或无超分期的免疫组织化学（IHC）染色。1项研究使用逆转录聚合酶链反应分析（CA9 RT - PCR），而3项研究未描述所使用的组织学方法。仅使用蓝色染料的研究的合并敏感度估计值为0.94（68名女性；95%置信区间（CI）0.69至0.99），混合试验为0.91（679名女性；95%CI 0.71至0.98），仅使用锝为0.93（149名女性；95%CI 0.89至0.96），联合试验为0.95（390名女性；95%CI 0.89至0.97）。所有指标试验的阴性预测值（NPV）均>95%。大多数研究还报告了指标试验的前哨淋巴结检测率（试验识别前哨淋巴结的能力）。仅使用蓝色染料的平均检测率为82%，混合试验、仅使用锝和联合试验分别为95%、96%和98%。假设腹股沟转移的患病率为30%，我们估计了100名接受前哨淋巴结手术的女性进行各种试验的临床后果。对于联合试验或仅使用锝的试验，分别可能有1名和2名腹股沟转移的女性被“漏诊”（95%CI 1至3）；对于混合试验，可能有3名腹股沟转移的女性被“漏诊”（95%CI 1至9）。与蓝色染料和混合试验的合并敏感度估计值相关的宽置信区间增加了这些试验“漏诊”腹股沟转移女性的可能性。
锝试验和联合试验在诊断试验准确性方面差异不大。与仅使用锝相比，联合试验可能会减少腹股沟淋巴结转移“漏诊”的女性数量。与使用锝的试验相比，仅使用蓝色染料可能会导致更多“漏诊”病例。对于早期外阴癌女性，基于锝的试验进行前哨淋巴结评估将使IFL的需求减少70%。目前尚不清楚前哨淋巴结阴性的女性与接受标准手术（IFL）的女性的生存率相比如何。前哨淋巴结清扫术和IFL的随机对照试验存在方法学和伦理问题，因此需要更多关于早期外阴癌女性生存率的观察性数据。
