Lymph node dissection in endometrial cancer and clinical outcome: A population-based study in 5546 patients

https://doi.org/10.1016/j.ygyno.2019.04.002Get rights and content

Highlights

  • Although it is recommended, a high proportion of patients had no lymph node surgery.

  • The incidence of recurrence seems not to be related to lymph node dissection.

  • The comorbidity status should be considered in analyses of lymph node surgery.

  • The survival analysis challenges lymph node dissection in endometrial cancer.

Abstract

Background

According to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection (LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy.

Materials and methods

Data were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included.

Results

Of 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found.

Conclusions

The application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.

Introduction

Endometrial cancer is the most common carcinoma of the female genital tract with over 300,000 new cases diagnosed each year worldwide [1]. Projections show an increasing incidence of this disease related to the ageing population as well as the increasing prevalence of obesity and metabolic syndromes [2]. Nodal involvement is one of the most relevant prognostic factors. Therefore, lymph node status is important to determine tumor stage and to consider adjuvant radiotherapy, chemotherapy or both [3]. Imaging techniques showed unfavorable sensitivity and specificity, thus, the current “gold standard” in the assessment of lymph node status remains comprehensive surgical staging, i.e. systematic pelvic and para-aortic lymph node dissection (LND) [4,5]. Since two randomized studies on endometrial cancer could not show a benefit in recurrence free survival (RFS) or overall survival (OS) for patients who underwent at least systematic pelvic LND compared to patients without LND, the necessity of LND is an ongoing controversy [6,7].

According to treatment guidelines and international consensus statements, a risk adopted management strategy is applied in the current clinical concept: In patients classified as low risk for lymph node involvement and recurrence (risk stratification see Table 1), with a tumor confined to the uterus, no conspicuous intra-abdominal findings and the absence of risk factors, it includes a simple hysterectomy and bilateral salpingo-oophorectomy without lymph node assessment [8,9]. In patients with high risk factors a systematic LND is recommended due to a higher prevalence of nodal involvement. In cases of intermediate/high intermediate risk factors, the best practice remains controversial, resulting in the recommendation that LND “may be” performed or not [9]. The role of systematic lymph node dissections is becoming increasingly controversial in modern oncology [[10], [11], [12]].

Furthermore, stratification criteria in endometrial cancer are often not valid pre- or intraoperatively: grading may change after final histopathologic examination, and the depth of myometrial invasion can differ compared to initial findings of preoperative imaging or fresh frozen section during surgery. The decision for adequate lymph node assessment therefore poses a fundamental challenge in the clinical management of these patients: is a “one stop” surgical approach justified or is a secondary lymph node operation after final histopathologic assessment more reliable?

Longer operative times are necessary for a systematic lymph node dissection and can be associated with considerable short- and long-time morbidity. Increased blood loss, thromboembolic complications and impairment of wound healing are more common after LND, and lymphocele formation or edema of the limb with a leg volume change over 10% in up to 34% of patients are long-term adverse events [13,14]. Therefore, the extent of surgical staging is a consideration of its associated risks: the benefit of the knowledge about nodal involvement has to be balanced against the adverse events of comprehensive surgical staging. Today, there is a wide range of surgical staging practices in endometrial cancer. The spectrum of lymph node assessment may consist of sentinel lymph node mapping, systematic pelvic or pelvic and paraaortic lymph node dissection [9,15].

Even though measurable criteria for omitting LND are lacking, it is likely that comprehensive surgical staging is rarely performed in patients with severe comorbidities. In addition to limited life expectancy, the restricted surgical treatment may also be due to a lack of adjuvant treatment. Therefore, the cohort of patients with LND may have an intrinsically favorable health status and better access to the recommended adjuvant treatment.

The aim of this study was to determine the status quo of surgical management of endometrial cancer in this large patient population. How many patients were surgically treated in accordance to the risk adopted algorithm consisting of the avoidance of an unnecessary LND in low risk patients and the performance of a reliable lymph node assessment in high risk patients. Also, how many patients with and without LND were diagnosed with loco-regional relapse or distant failure? And what is the correlation of LND and survival once the comorbidity status is considered?

Section snippets

Data collection

The Munich Cancer Registry (MCR) is a population-based clinical cancer registry representing Upper Bavaria and a region of Lower Bavaria in southern Germany [16]. The registry catchment area has grown to 4.8 million inhabitants over time. Pathology reports of solid tumors from all pathology laboratories in the catchment area are available and provide the total number of patients in the region as well as primary prognostic factors associated with the patients' disease. The clinicians provide

Results

The overall detection rate of lymph node involvement in the entire cohort of pT1 tumors was 170 of 5446 patients (3.1%). Out of all LND (n = 1906) the vast majority of 91.1% (n = 1736) had no nodal involvement and lymph node metastases were found in 8.9% (n = 170). Median lymph node count was 29 (Range 10 to ≤99). In 3188 patients with low risk factors, a LND was performed in 20.2% (n = 643). Within these patients, 1.7% (n = 11) were node-positive. In 1639 patients with intermediate/high

Discussion

This population-based cohort study presents a valid indication for the limitation of the current risk-adopted algorithm and the surgical intervention of a systematic lymph node dissection in early stage endometrial cancer. It suggests that the current concept is potentially associated with a high proportion of surgical over- and under-treatment. In 29% of the entire cohort, surgical staging differed from guideline recommendations. Treatment recommendations do not include an LND in the low risk

Abbreviations

    95%-CI

    95% Confidence interval

    DCO

    Death certificate only

    ESGO

    European Society of Gynecologic Oncology

    ESMO

    European Society of Medical Oncology

    ESTRO

    European Society for Radiotherapy and Oncology

    HR

    Hazard ratio

    LND

    Lymph node dissection

    MCR

    Munich Cancer Registry

    NCCN

    National Comprehensive Cancer Network

    OS

    Overall survival

    SEER

    Surveillance, Epidemiology, and End Results Program

    SLND

    Sentinel Lymph Node Dissection

Conflict of interest

The authors have no conflict of interest concerning this paper.

General conflict of interest

MP reports personal fees for serving on advisory boards and lecture honoraria from AstraZeneca, Teva and Roche. SM reports grants and personal fees from Astra Zeneca, personal fees from Clovis, grants and personal fees from Medac, grants and personal fees from MSD, personal fees from Novartis, grants and personal fees from PharmaMar, grants and personal fees from Roche, personal fees from Sensor Kinesis, grants and personal fees from Tesaro, grants and personal fees from Teva, outside the

Acknowledgements

We thank all the hospitals, departments, and practitioners that participated in the documentation of the data of the Munich Cancer Registry.

Contributors

MP and MR drafting of the manuscript, MR and JE planned, performed and wrote the statistical analyses, all other authors were responsible for patient recruitment, documentation and wrote and approved the final article.

References (38)

  • E.C. Rossi et al.

    A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study

    Lancet Oncol.

    (2017)
  • WHO. GLOBOCAN

    Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012

    (2012)
  • M.A. Sheikh et al.

    USA endometrial cancer projections to 2030: should we be concerned?

    Future Oncol.

    (2014)
  • J. Zhou et al.

    Prognostic value of lymph node ratio in stage IIIC epithelial ovarian cancer with node-positive in a SEER population-based study

    Oncotarget

    (2016)
  • T.J. Selman et al.

    A systematic review of tests for lymph node status in primary endometrial cancer

    BMC Womens Health

    (2008)
  • P. Benedetti Panici et al.

    Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial

    J. Natl. Cancer Inst.

    (2008)
  • H. Kitchener et al.

    Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study

    Lancet

    (2009)
  • N. Colombo et al.

    ESMO-ESGO-ESTRO consensus conference on endometrial Cancer: diagnosis, treatment and follow-up

    Int. J. Gynecol. Cancer

    (2016)
  • Leitlinienprogramm Onkologie

    (Deutsche Krebsgesellschaft DK, AWMF). Diagnostik, Therapie und Nachsorge der Patientinnen mit Endometriumkarzinom

  • Cited by (28)

    • Diagnostic accuracy of sentinel node biopsy in non-endometrioid, high-grade and/or deep myoinvasive endometrial cancer: A Turkish gynecologic oncology group study (TRSGO-SLN-006)

      2022, Gynecologic Oncology
      Citation Excerpt :

      Systematic lymph node dissection is suggested in patients with high-risk uterine features, but lymph node metastasis risk is approximately 20% in these patients as most of them don't have lymphatic metastasis. However, it is also important to determine nodal status for guiding the adjuvant treatment and surgical removal of lymph nodes seems like the gold standard to reveal the definitive status of lymphatic metastasis [1]. But complete lymphadenectomy is associated with many comorbidities such as neurovascular injuries and lymphedema which many patients face unnecessarily [2].

    • The 10-year results after national introduction of pelvic lymph node staging in Danish intermediate-risk endometrial cancer patients not given postoperative radiotherapy

      2021, European Journal of Obstetrics and Gynecology and Reproductive Biology
      Citation Excerpt :

      If a survival effect of pelvic and paraaortic lymphadenectomy is demonstrated, patients with sentinel node metastasis could then be offered reoperation with pelvic and pararaortic lymphadenectomy, thereby still offering an advantage of introducing sentinel node staging in the population of intermediate risk endometrial cancer patients. A large German cohort study examined 1639 stage I intermediate-risk patients and demonstrated that lymphadenectomy did not alter survival or recurrence rates in agreement with the present study, an earlier retrospective study [26–31], and two randomized studies [3,4]. The authors found lymph node metastasis in 9.6% of intermediate-risk patients in line with the results of the present study.

    • Effect of surgical approach on risk of recurrence after vaginal brachytherapy in early-stage high-intermediate risk endometrial cancer

      2021, Gynecologic Oncology
      Citation Excerpt :

      While the overall rate of lymph node sampling was different between our surgical groups (p < 0.001), the number of patients who did not receive lymph node sampling in both groups was small (Table 2). The risk of lymph node metastases in this cohort will vary depending on individual uterine risk factors [23] however it has been estimated to be approximately 10% in a large study of over 5500 women [24]. Thus, although the risk of undiagnosed stage 3 disease in our unstaged patients is small, our results must be interpreted in the context of these differing rates of staging.

    • Sentinel Node Mapping in Gynecologic Cancers: A Comprehensive Review

      2019, Seminars in Nuclear Medicine
      Citation Excerpt :

      In this study, the detection rates for ICG for pelvic SLN, bilateral pelvic SLN, and para-aortic SLN were 96%, 80%, and 55%, respectively, with sensitivity of 91% and NPV of 99%. To conclude, LN assessment is still controversial for early-stage endometrial cancer despite several studies and a last paper with a cohort of 5546 patients published in 2019, showed that routine systematic lymphadenectomy does not improve disease-free or overall survival compared to SLN biopsy (for all histopathologic grades, including high-risk grade) and is responsible of more frequent comorbidities.136 In this context, several studies showed that SLN is a feasible procedure with accurate detection rates especially when a pericervical injection of combined [99mTc]-labeled colloids (with preoperative SPECT/CT) and ICG is performed.

    View all citing articles on Scopus
    1

    The authors equally contributed to the paper.

    View full text