Article Text
PDF
Abstract
Objective The circumflex iliac nodes distal to the external iliac nodes are frequently removed when bilateral pelvic lymphadenectomy is performed in patients with cervical cancer. The objective of this systematic review was to assess the incidence of metastasis in the circumflex iliac nodes in patients with cervical cancer.
Methods PubMed/Medline, ClinicalTrials, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Ovid databases were searched from inception to May 2021. We included articles published in English language reporting all types of studies, except for case reports and commentaries. Abstracts and unpublished studies were excluded. The inclusion criteria were diagnosis of cervical cancer, FIGO 2009 stages IA–IIB, squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, and primary surgery including pelvic lymph node dissection.
Results A total of 3037 articles were identified. Overall, 1165 eligible patients from four studies were included in the analysis. A total of 696 (59.7%) patients had early-stage disease (FIGO 2009 stages IA, IB1, IIA1). The median number of extracted circumflex iliac nodes, which was reported in two studies, was one (range not reported) and three (range 1–13). The positive lymph node rate for the entire population and circumflex iliac node involvement were 26.9% and 3.1%, respectively. Isolated metastases were reported for 904 patients (three studies) and in one patient nodal spread was detected (0.11%).
Conclusion The rate of isolated metastases in circumflex iliac nodes is small and excision of these lymph nodes as part of routine lymphadenectomy should be avoided.
- cervical cancer
- surgery
- lymph nodes
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Statistics from Altmetric.com
HIGHLIGHTS
The rate of positive circumflex iliac lymph nodes in patients with cervical cancer was 11.5%.
Isolated circumflex iliac nodes in patients with cervical cancer was 0.11%.
Overall, 95% of patients with circumflex iliac node involvement have involvement of other pelvic lymph nodes.
Introduction
The first-line treatment for early-stage cervical cancer (FIGO 2018 IA1 with lymphovascular invasion to IB2) is abdominal radical hysterectomy with pelvic lymph node assessment.1 2 In some countries patients with FIGO IB3 and IIB stage also receive surgical management.3 Lymph node evaluation may be performed through systematic pelvic lymph node dissection or by sentinel lymph node (SLN) detection.1 2 4 There are numerous adverse events from routine lymphadenectomy, such as vascular or nerve injury, lymphocyst formation aor lower-extremity lymphedema.5–7 The incidence of lymph node metastases in early-stage cervical cancer ranges between 12.4% and 18.4%8 9 and most patients will not benefit from the procedure.
The circumflex iliac nodes, also known as distal external iliac lymph nodes, supra-femoral nodes, and supra-inguinal nodes,10–12 are located distal to the deep circumflex iliac vein and are often removed as part of the skeletonization of the distal external iliac vessels for a routine bilateral pelvic lymphadenectomy. This procedure has been abandoned in some centers due to lower limb lymphedema10 and dissection of the circumflex iliac nodes should be spared if these are not macroscopically suspicious.2 Nevertheless, the rate of pathological involvement of circumflex iliac nodes has not been extensively evaluated. The objective of this systematic review was to assess the incidence of metastasis in the circumflex iliac nodes in patients with cervical cancer that underwent primary surgery including lymph node dissection.
Methods
A systematic literature review was conducted following the Meta-analyses of Observational Studies in Epidemiology (MOOSE) checklist. PubMed/Medline, ClinicalTrials, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Ovid databases were searched from inception and to May 2021. The overall search strategy is included in the online supplemental material. In addition, we searched the reference lists of all eligible study reports and undertook forward citation tracking (using Google Scholar) to identify further eligible studies.
Supplemental material
We included articles published in English language that reported all types of studies, except for case reports and commentaries. Abstracts and unpublished studies were also excluded. The patients included were those with cervical cancer (FIGO 2009 stages IA1–IIB) who underwent surgery including pelvic lymph node dissection or concomitant para-aortic lymph node dissection. Most (>90%) included patients in each study were required to have histological subtype of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Studies had to report specifically the pelvic lymph node sites that were resected and include circumflex iliac nodes distal to the external iliac nodes as part of the procedure. Criteria for excluding studies for this review were the inclusion of patients under 18 years of age, FIGO 2009 stages IIIA or higher, pregnancy, the use of neoadjuvant chemotherapy or previous pelvic radiotherapy as part of the primary treatment, or those with evidence of lymph node involvement on preoperative images.
If two or more articles were published by the same author/institution or using the same primary data source, only the most recent article was included in the review. The measured outcomes were the incidence of metastasis in the circumflex iliac nodes, the incidence of isolated metastasis in the circumflex iliac nodes, and the rate of complications associated with the circumflex iliac node dissection.
Study Selection
Two authors (JR, DV-C) independently assessed all titles and abstracts of records retrieved from the search strategy for inclusion. The final selection of trials for inclusion was undertaken independently by three authors (RP, JR, DV-C) and any disagreement was resolved through discussion. We designed a form to extract data, which was pilot tested. For eligible studies, two authors (JR, DV-C) extracted the data independently using the form. Any disagreement about extracted data was resolved through discussion until a consensus was reached. If necessary, we tried to contact the main investigators of included studies by email for further information when not all the relevant information was available.
Data are presented as medians or means (according to normal distribution) and percentages with absolute counts depending on whether they are quantitative or qualitative variables, respectively. Descriptive statistics were calculated using SPSS 21.0. According to local regulation, no institutional review board agreement was required for this type of study. Ethical approval was not required as only data from previously published studies were retrieved and analyzed. No new data are presented.
Results
The search identified 3037 articles, and after duplicates were removed 2558 articles were evaluated. Title and abstract screening of these articles identified 11 further studies as potentially eligible for review. Full text screening excluded seven of these studies, and four finally met the selection criteria. Specifically, one study was excluded for duplication of the information,13 one because it was not published in English,14 one because it did not provide quantitative data for lymph node involvement,15 and another included the use of neoadjuvant chemotherapy and patients with metastatic disease.16 Three additional studies did not include circumflex iliac node details (Figure 1).17–19
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for study selection.
In total 1165 patients from four studies were considered for the analysis. Two studies20 21 included only patients with early-stage cervical cancer (IA2–IIA) and two studies22 23 included those with early and locally advanced disease (IA1–IIB). All studies included patients with squamous cell and adenocarcinoma histological subtypes, one study also included adenosquamous carcinoma,21 and two studies included other histological types in less than 10% of cases.22 23 Table 1 presents a detailed description of the included studies.
Major characteristics of studies included in the systematic review
All but seven patients underwent a radical hysterectomy and pelvic lymph node dissection.23 Those seven patients underwent a radical parametrectomy after an inadvertent hysterectomy due to an incidental cervical cancer, and none had metastases to the circumflex iliac nodes. One study23 included patients who underwent minimally invasive surgery (40/261) using either conventional laparoscopy or robotic surgery. For 696 patients, in two reports, the number of extracted circumflex iliac nodes was presented20 21: the median number was one (range not reported) and three (range 1–13).
For the entire population (1165 patients), 314 (26.9%) patients had positive pelvic lymph nodes, and of these, 36 (11.5%) patients had circumflex iliac node metastases (Table 2). Isolated involvement was reported in three studies, including 904 patients20–22; it was not possible to get the information for one study, although we tried to contact the corresponding author.23 Only one patient of the 1165 had isolated circumflex iliac nodal spread (0.11%).20 This patient had FIGO 2009 stage IIA1 disease with an enlarged left circumflex iliac node. An additional 16 pelvic lymph nodes were removed and were negative.
Lymph node compromise and complications of the procedure
A subgroup analysis was performed in studies that included only early-stage disease (FIGO 2009 stage IA–IIA).20 21 There were 696 patients and lymph node metastases were confirmed in 175 (25.2%) patients. Circumflex iliac node involvement was confirmed in 17 (9.7%) of these 175 patients, which means that of the 696 patients only 2.4% had metastases to the circumflex iliac nodes and only one patient (0.14%) had isolated circumflex iliac node metastases.
Intraoperative complications were not reported in three of the four studies. Hoffman et al 21 reported an intraoperative complication in eight (12.7%) of 63 patients; six minor vascular injuries and two nerve injuries of the genitofemoral nerve. In the same cohort of patients, two patients had clinically significant lymphocysts and two patients had lymphedema. Yin et al 20 reported only postoperative complications; symptomatic lymphocyst and lower-limb lymphedema were found in 48% and 31% of patients, respectively. In this study, 43.8% of patients received postoperative radiotherapy, and the incidence of lower-limb lymphedema in patients with or without pelvic radiotherapy was 35.7% and 27.2%, respectively (p=0.02). No details were given about the schema used for surveillance or the criteria for diagnosis of lymphedema.
Discussion
Summary of Main Results
In our study, the overall rate of positive circumflex iliac nodes was 11.5%. The rate of isolated metastases in the circumflex iliac nodes was 0.11% for all patients and 0.14% for patients with early-stage cervical cancer. When the circumflex iliac lymph nodes were involved, there were metastases to other pelvic lymph nodes in 95% of patients. This finding highlights previous theories proposing that circumflex iliac lymph node metastases might occur after spread of disease from other pelvic lymph nodes.24 25
Results in the Context of Published Literature
Previous studies on SLN evaluation in cervical cancer do not specifically describe the circumflex iliac nodes as possible sites of sentinel nodes.26–28 The bilateral detection of SLNs in two prospective trials was 76.5%9 and 91%,27 which means that at least between 9% and 23.5% of patients would need a systematic pelvic lymph node dissection. Also, according to the European Society of Gynecological Oncology (ESGO) cervical cancer guidelines, the standard lymph node staging recommended is sentinel node biopsy followed by pelvic lymphadenectomy in all patients with stage IB–IIA disease.2 A survey published in 2019 by the Gynecologic Cancer Intergroup evaluating the practice patterns among centers and physicians worldwide for SLN biopsies in patients with cervical cancer29 showed that only 60% of 161 institutions from around the world perform SLN mapping; of these, if the SLN was confirmed to have metastatic disease, 45% completed a pelvic and para-aortic lymph node dissection. When SLN biopsy was negative, 39% performed a systematic pelvic lymph node dissection.
In patients with endometrial cancer, the compromise of circumflex iliac nodes has also been also evaluated. In a retrospective study30 including 508 patients with intermediate and high-risk endometrial cancer, the reported incidence of circumflex iliac node metastasis was 2.8% with a global rate of lymph node spread of 27.2%. The isolated rate of circumflex iliac nodes compromise was 0.59%. As the resection of compromised lymph nodes in cervical cancer has not been proven to impact the prognosis in prospective trials,31 32 the resection of circumflex iliac nodes distal to the external iliac nodes would not bring benefits to patients.
One potential adverse impact on removal of circumflex iliac lymph nodes is the development of lymphedema and/or lymphocyst after surgery.33 34 Unfortunately, the methods used for lymphedema assessment are not standardized35 making the reported incidence variable. In our review, the methods for surveillance, detection and diagnosis of lymphedema were not described in most studies. Factors that have been associated with lymphedema and lymphocyst after surgery include the use of radiotherapy, the number of resected lymph nodes36 37 and the extension of lymph node dissection, particularly if the excision of circumflex iliac nodes is performed,10–12 37 38 which doubles the risk of developing lymphatic adverse events.
We report that the incidence of lymphedema and lymphocyst formation could be higher than 30% if the circumflex iliac nodes distal to the external iliac nodes are removed, as was reported in one of the included studes20; however, it should be noted that almost half of the patients received postoperative radiotherapy. The intraoperative complications reported were minor vascular or nerve injuries.21 A systematic review39 showed that the incidence of lymphedema varied between 0% and 69% in patients with cervical cancer and circumflex iliac node resection was a risk factor.
Strengths and Weaknesses
The strength of our review is that it is a large analysis specifically evaluating the rate of metastastic disease in circumflex iliac lymph nodes. We do recognize that our review has a number of limitations. Owing to the clinical heterogeneity of the studies, we decided not to perform a meta-analysis. As we limited the search to published data in English language, we could have missed some relevant references published in other languages. The retrospective nature of all studies included in the review, with potential selection and publication bias must be mentioned. Also given the fact that patients with locally advanced cervical cancer were included by some authors, the circumflex iliac node involvement rate may be overestimated; nevertheless, we performed a subgroup analysis for early cervical cancer as the most pertinent group for this intervention considering guidelines recommendations. As the studies were conducted over a long period there could be potential performance bias. The total number of patients included might be considered small; in particular, we did not have complete information for isolated circumflex iliac node compromise in one of the four studies. There was incomplete information for the predefined outcomes of intraoperative and postoperative complications because most studies did not report related complications. Additionally, standardized surveillance strategies and methods were not used for diagnosis of lymphedema and lymphocyst among the studies.
Implications for Practice and Future Research
This systematic review confirms that isolated metastasis to the circumflex iliac lymph nodes in patients with cervical cancer is exceedingly rare, and when involved the remaining pelvic nodes are frequently affected. Therefore, dissection of these lymph nodes should not be performed in patients undergoing surgery for cervical cancer.
Conclusions
Given the potential significant morbidity associated with resection of circumflex iliac nodes and the fact that these are rarely documented to have metastatic disease in patients with cervical cancer, dissection of these lymph nodes in routine practice as part of standard lymphadenectomy should be avoided. Future studies should continue to aim for further exploration into the concept of sentinel lymph node identification and whether continued lymphadenectomy has a role at all in patients with early cervical cancer.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors DV-C: conceptualization, investigation, methodology, writing - original draft, writing - review, and editing. JR: data curation, formal analysis, investigation, methodology, writing - review, and editing. RP: conceptualization, methodology, formal analysis, writing - review and editing, supervision.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.