Obstetrics & Gynecology:
Prognostic Value of Lymph Node Ratio and Clinicopathologic Parameters in Patients Diagnosed With Stage IIIC Endometrial Cancer
Polterauer, Stephan MD; Khalil, Susan MD; Zivanovic, Oliver MD; Abu-Rustum, Nadeem R. MD; Hofstetter, Gerda MD; Concin, Nicole MD; Grimm, Christoph MD; Reinthaller, Alexander MD; Barakat, Richard R. MD; Leitao, Mario M. Jr MD
From the Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; the Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Comprehensive Cancer Center Vienna, Vienna, Austria; and the Department of Obstetrics and Gynecology, Medical University of Innsbruck, Tirol, Austria.
Corresponding author: Mario M. Leitao Jr, MD, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the prognostic significance of lymph node ratio with respect to clinicopathologic characteristics in stage IIIC endometrial cancer patients.
METHODS: Using data from medical records and surgery notes, we identified all consecutive patients with stage IIIC endometrial cancer who received primary surgical treatment between 1993 and 2008. Lymph node ratio is the number of metastatic lymph nodes to the total number of removed lymph nodes. Survival analyses were performed using Kaplan–Meier and Cox proportional hazard methods.
RESULTS: Two hundred sixteen patients with stage IIIC endometrial cancer were included in this multicenter study. Age, number of metastatic lymph nodes, lymph node ratio, grossly suspicious lymph nodes, histologic subtype, and cervical metastasis were associated with progression-free survival and overall survival, respectively. Patients with lymph node ratios 10% or less, more than 10–50%, and more than 50% had 5-year overall survival rates of 79.0%, 60.6%, and 35.8%, respectively (P<.001). In multivariable analysis, only lymph node ratio was associated with both progression-free survival and overall survival, respectively. Total number of removed lymph nodes and number of metastatic lymph nodes did not correlate with overall survival in the group with grossly suspicious lymph nodes, whereas lymph node ratio did. In the subgroup of 123 (56.9%) patients who had pelvic and aortic lymphadenectomies with a minimum of 10 lymph nodes removed, age and lymph node ratio were still associated with progression-free survival and overall survival, whereas total lymph nodes removed was not.
CONCLUSION: Stratification based on lymph node ratio is useful when comprehensive lymphadenectomy is routinely performed and likely reflects metastatic nodal tumor burden. These data provide another prognostic variable in the heterogenic group of women with stage IIIC endometrial cancer.
LEVEL OF EVIDENCE: II
Endometrial cancer is the most common gynecologic malignancy, accounting for 6% of all female cancers.1 One of the most important prognostic factors for endometrial cancer is the presence of extrauterine disease, particularly pelvic and para-aortic lymph node metastases.2 Nodal involvement, the most common site of metastatic disease, is a strong predictor of recurrence and survival in endometrial cancer, and its presence warrants upstaging to International Federation of Gynecology and Obstetrics (FIGO) stage IIIC disease.2 However, considerable heterogeneity exists in node-positive patients based on various clinicopathologic characteristics.3,4 The prognostic information of other factors, such as cervical or adnexal metastasis, positive peritoneal washings, or depth of myometrial invasion, are not considered in the FIGO staging system once patients have stage IIIC disease diagnosed.5
Several recent studies have focused on the clinical relevance of lymph node ratio in assessing prognosis in various malignancies.6–9 Lymph node ratio is defined as the number of metastatic lymph nodes to the total number of removed lymph nodes. This parameter incorporates not only the burden of nodal disease and cancer spread but also the extent and quality of surgical staging. Therefore, lymph node ratios are most meaningful when standardized comprehensive lymphadenectomy templates are utilized routinely in surgical practice. The purpose of this large multicenter study was to estimate the value of lymph node ratio as well as other prognostic factors, such as intraoperative findings and clinicopathological parameters, for estimating outcome in patients with stage IIIC disease.
MATERIALS AND METHODS
The Institutional Review Boards of Memorial Sloan-Kettering Cancer Center, the Medical University of Vienna, and the Medical University of Innsbruck approved this study. Data were abstracted from electronic medical records and surgery notes were reviewed. All consecutive patients with stage IIIC endometrial cancer who received primary surgical treatment at the aforementioned institutions between 1993 and 2008 were identified for analysis. Only patients with epithelial histologies were eligible for study inclusion.
Patients were treated with upfront surgery, including abdominal exploration, pelvic peritoneal cytology, hysterectomy, bilateral salpingo-oophorectomy, and pelvic or para-aortic lymphadenectomy. In selected cases, radical hysterectomy was performed. Lymphadenectomy was performed based on current standard international practices. However, the extent of lymphadenectomy in the setting of grossly metastatic nodal disease varied based on individual surgeon intraoperative decisions. Board-approved pathologists, specializing in gynecologic pathology, assessed the pathological specimens. The number of removed and metastatic pelvic and para-aortic lymph nodes was assessed. Histological staging and grading were performed according to the current FIGO classification system based on the final evaluation of pathological specimens.5 Adjuvant therapy was administered at the discretion of the physician.
Overall survival was calculated from the date of surgery to either the last follow-up or the date of death. Overall survival probabilities were estimated using the Kaplan-Meier method. Progression-free survival was calculated from the date of surgery to either the last follow-up or the date of recurrence or progression. Overall survival and progression-free survival estimates were captured using the log-rank test. The hazard ratios were obtained by applying the Cox proportional hazard model. To correct for possible confounders, all parameters found to have a P<.05 (except for number of removed and metastatic lymph nodes) in univariable analysis were included into a multivariable Cox regression model. To address differences of prognostic parameters in distinctive subgroups of patients with stage IIIC endometrial cancer, two subgroup analyses were performed. These analyses were planned at the start of this retrospective review based on the fact that grossly metastatic disease is thought to confer a worse prognosis and that some may limit the lymphadenectomy in these cases and in other work that suggested a lymph node count of 10 being prognostic.10 Subgroup survival analyses of patients with or without grossly suspicious lymph nodes (based on subjective intraoperative findings) were performed. An additional analysis was performed in patients with stage IIIC endometrial cancer who had at least 10 lymph nodes removed and detected on final pathology. P<.05 was considered statistically significant. We used the statistical software SPSS 19.0 for Windows for statistical analysis.
Two hundred sixteen patients with FIGO stage IIIC endometrial cancer were identified, 144 from Memorial Sloan-Kettering Cancer Center in New York and 72 from the Comprehensive Cancer Center Vienna and Medical University of Innsbruck in Austria. Patient characteristics are provided in Table 1. Lymph node ratios 10% or less, more than 10–50%, and more than 50% were found in 93 (43.1%), 95 (44.0%), and 28 (13.0%) cases, respectively. The median follow-up duration was 30.5 months (range 0.1–220.2 months). Lymphovascular space involvement was found in 151 (69.9%) patients, and 86 (39.8%) had cervical involvement. The majority of patients (91%) received some form of adjuvant therapy. The type of adjuvant therapies is described in Table 1. Patients with lymph node ratio 10% or less received similar types of adjuvant therapy as described for the overall cohort. The exact nature of adjuvant therapies used was not ascertainable from the medical records in 13 cases. At last follow-up, of the seven patients who received no adjuvant therapy, two had no evidence of disease, three had died of disease, and two had died of other disease.
In univariable survival analyses, age, number of metastatic lymph nodes, lymph node ratio, histology, and presence of cervical metastasis were significantly associated with both progression-free survival and overall survival (Table 2). Patients with lymph node ratio 10% or less, more than 10–50%, and more than 50% had 5-year overall survival rates of 79.0%, 60.6%, and 35.8%, respectively (P<.001). Kaplan-Meier curves for progression-free survival and overall survival according to lymph node ratio groups are provided in Figure 1A and B. In the entire cohort, patients with a higher number of removed lymph nodes showed improved overall survival (P=.02). After correcting for possible confounders using a multivariable model, only lymph node ratio remained associated with both progression-free survival and overall survival (Table 3).
A subgroup analysis revealed that the total number of removed or metastatic lymph nodes did not correlate with overall survival in the group with grossly suspicious lymph nodes, whereas increased lymph node ratio still was associated with impaired prognosis. Detailed results of this analysis are provided in Table 4. In the group of patients with stage IIIC endometrial cancer who had at least 10 lymph nodes examined by pathology (n=123), lymph node ratio was shown to be a significant prognostic parameter for progression-free survival and overall survival, whereas the number of removed lymph nodes was not (Table 5).
The role of lymph node dissection in endometrial cancer therapy is controversial.10,11 A Study in the Treatment of Endometrial Cancer trial showed no survival benefit of staging with pelvic lymphadenectomy in patients with apparent stage I disease.12 To avoid morbidity related to systemic lymphadenectomy, the concept of sentinel lymph node dissection recently was introduced for endometrial cancer staging.13 In contrast, reports demonstrated that the removal of an increasing absolute number of metastatic lymph nodes improved prognosis of patients with endometrial cancer. It was shown that a high number of metastatic nodes is associated with adverse outcome.11,14 Recently, the prognostic concept of lymph node ratio emerged, which incorporates the metastatic lymph node count in relation to the removed lymph node count.6,8
Patients with a high count of involved lymph nodes or with a low count of removed lymph nodes have a high lymph node ratio. Thus, this parameter reflects not only the burden of nodal disease but also the quality and extent of pelvic lymph node dissection. In our analysis, patients with 10% or less lymph node ratio had considerably favorable prognosis, with a 5-year overall survival rate of 79.0%. It seems that this distinct group of patients has comparable outcome with patients with stage II disease without lymph node metastasis.2 In contrast, patients with more than 10–50% and more than 50% lymph node ratio showed adverse outcome, with 5-year overall survival rates of 69.6% and 35.8%, respectively. In contrast to the number of removed or positive lymph nodes alone, lymph node ratio was associated with progression-free survival and overall survival in both subgroup analyses in patients with or without grossly involved lymph nodes and in patients with at least 10 lymph nodes removed.
Our findings are in concordance with previous reports.6,7 A recent study with data from the National Cancer Institute Registry showed an association between lymph node ratio and survival in patients with FIGO stage IIIC–IV endometrial cancer.6 Our study evaluates the prognostic value of lymph node ratio with respect to intraoperative findings and clinicopathologic characteristics. For our analysis, we applied previously determined prognostic subgroups in a large and independent set of patients.6 The prognostic value of lymph node ratio remained significant after correcting for possible confounders.
Presence of a high number of metastatic lymph nodes was associated with adverse outcome. This is in concordance with previously published reports.6,15 For patients with advanced disease and presence of lymph node metastasis, recent studies reported a survival benefit of resection of lymph node metastasis and extensive lymph node dissection.16–18 In the subset of our patients with grossly suspicious lymph nodes, this effect was only present for progression-free survival but not for overall survival. It is reasonable to accept that the presence of grossly bulky nodal disease reflects a sign of more aggressive tumor burden and advanced disease. Therefore, the number of metastatic lymph nodes alone does not add additional prognostic information. Recommendations for the extent of lymph node dissection in patients with known lymph node metastasis are controversial. The Gynecologic Oncology Group recommends that a positive pelvic or para-aortic node should indicate no further sampling from that area is necessary and that only palpably positive nodes must be sampled for histology.19 Thus, several academic institutions question the necessity of extensive lymph node dissection in patients with stage IIIC disease.10,20 In contrast, an analysis of the Surveillance, Epidemiology, and End Results database showed a prognostic benefit of the resection of more than 20 lymph nodes, even in patients with stage IIIC–IV endometrial cancer.14 It seems biologically plausible that a minimum number of lymph nodes needs to be removed to acquire representative information on lymph node status and to remove metastatic disease. It is unclear if this assumption remains valid at the moment of finding metastatic disease to the lymph nodes. It is important to consider that extensive lymph node dissection is associated with a notable rate of perioperative complications and increases morbidity.21,22 Future studies are needed to identify if patients with lymph node metastasis would benefit from extensive lymph node dissection, especially as sentinel lymph node dissection techniques are becoming an accepted alternative to complete lymph node dissection in selected patients.
Patient age was one of the most important predictors of survival in our analysis. Older patients showed remarkably worse outcome than younger patients independent of other prognostic factors. This is in accordance with previous reports, suggesting that endometrial cancer appears to be intrinsically more aggressive in older patients.23 In contrast, other studies reported that elderly patients with early-stage endometrioid endometrial cancers have similar progression-free survival compared with their younger counterparts and suggested that the lower overall survival in this patient population is likely because of coincident comorbidities rather than death attributable to endometrial cancer.24 According to recent changes to the FIGO staging system, positive peritoneal washings are no longer considered.5 These changes were made because of a lack of prognostic relevance of positive cytology. In our study and other recent studies, positive peritoneal washings were associated with impaired overall survival in multivariable analysis.25 One might argue that this parameter might be a surrogate parameter for adnexal metastasis or extrauterine spread, but adnexal metastasis was not associated with survival in our cohort. We also identified cervical involvement as a prognostic parameter. Previous reports have described similar findings on the prognostic effect of cervical involvement and positive peritoneal washings and suggested the incorporation of these additional parameters into a novel staging system to separate patients into different prognostic subgroups.15
Patients who received adjuvant radiotherapy experienced improved progression-free survival compared with patients treated with chemotherapy or hormone therapy alone. This is in accordance with a previous study reporting similar survival outcomes after adjuvant chemotherapy and radiotherapy for patients with high-risk endometrial cancer; chemotherapy seemed to prevent or delay distant relapses, whereas radiotherapy tended to prevent or delay local relapses.26
Our study is limited by the many inherent limitations of any retrospective review and analysis of data. These data are hypothesis-generating, and this must be kept in mind when assessing these data. The patients seen in the three tertiary centers may not reflect general patient cohorts. Adjuvant therapy was administered individually and was not standardized in our study because over the relatively long study period adjuvant treatment concepts changed. The optimal treatment regimen for node-positive endometrial cancer is still controversial and remains to be determined. The current review cannot compare outcomes between the various treatments used. Additionally, the extent of lymphadenectomy in the presence of grossly metastatic disease was based on individual surgeon intraoperative decisions and did not follow a standard requirement. These shortcomings of our study need to be kept in mind when interpreting our results. Nevertheless, our study investigated a remarkably high number of patients with stage IIIC endometrial cancer in a multicenter setting. We investigated the prognostic value of lymph node ratio and also focused on various clinicopathologic parameters. Therefore, we think that our findings are clinically applicable and add valuable information for patient counseling. If our findings can be validated in a prospective study, then useful information for individualized treatment of patients with endometrial cancer could be gained. Patients with high lymph node ratio showing high risk of recurrence and cancer-related death might be candidates for intense adjuvant therapy and close follow-up.
Patients with stage IIIC endometrial cancer show remarkable differences in outcome.3 In this multicenter study, we evaluated the prognostic significance of lymph node ratio and additional prognostic parameters. Our study provides evidence that lymph node ratio is the strongest independent prognostic parameter and is useful for stratifying patients with stage IIIC endometrial cancer into distinct prognostic groups. We did not observe a positive survival effect of extensive lymph node dissection in the presence of positive lymph nodes, especially not in the presence of grossly positive lymph nodes.
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