Endometrial cancer is the most common female pelvic malignancy in the western world. Endometrioid histology is thought to be a low-risk histology with a very good prognosis, especially if diagnosed early [15]. The five-year survival rate is dependent on stage, and is 87-93% for grade 1 and 2 and approximately 61% for poorly-differentiated endometrioid adenocarcinomas. In contrast, the five-year survival rate for clear-cell adenocarcinoma is approximately 42%, and only 24-34% for cases of serous-papillary histology [21].
Staging and therapeutic surgical intervention includes an explorative laparatomy with radical hysterectomy and bilateral salpingo-oophorectomy, peritoneal washing, and pelvic and para-aortic lymph node sampling [3]. However, no specifications regarding the type, extent and prognostic impact of pelvic lymph node dissection have been established, this being a controversial topic of ongoing debate.
In 1995, Kilgore and colleagues published a retrospective analysis of 649 patients with adenocarcinoma of the endometrium. Of these patients, 212 underwent multiple-side lymph node sampling and 205 patients had limited pelvic node sampling (less than four pelvic sites), while 208 patients were not sampled. Overall survival was significantly better in patients with multiple-site lymph node sampling. Adjuvant radiation or splitting into low- and high-risk groups did not affect this result [7].
In a 2007 analysis of the large SEER database from the United States, 42,814 patients with endometrial adenocarcinoma were analysed by multivariate Cox regression analysis [13], and the rate of lymphadenectomy was found to be only 46%. Lymphadenectomy was identified as an independent prognostic factor for overall survival, with hazard ratios of 0.74 for the subgroup with more than 11 lymph nodes dissected, and 0.89 for the subgroup with 1-11 nodes removed [13].
Although a very small number of studies have not shown that lymphadenectomy has an impact on survival [9], most studies have demonstrated increased survival and have established lymphadenectomy as an important prognostic factor. This is also supported by the results of a few authors who have detected an increasing frequency of lymphadenectomy in recent decades. For example, in a retrospective analysis of 1,312 patients, Barakat et al. demonstrated an increase from 28% in 1993 to 82% in 2004 [22]. For patients of the SEER program, the frequency has risen from 31% in 1988 to 53% in 2003 [13].
However, the relevance of overall survival is limited, because compared to other patients, the frequency of lymphadenectomy is low in older patients with comorbidities. For this reason, analysis of progression-free survival is a more meaningful approach. In our study, the results from the progression-free survival curve are not statistically significant. However, the results from multivariate analysis (p = 0.016) argue that lymphadenectomy does have a major influence on progression-free survival. Since patients with FIGO stage I also did not show increased survival, we assume that the usefulness of lymphadenectomy as an independent prognostic factor results from increased survival of patients in higher stages. In this study, the number of patients with grade 3 (11.2%) or higher (13.1%) FIGO stage cancer is very low, so it is not possible to perform adequate statistical analysis of survival. Nevertheless, we were able to demonstrate that lymphadenectomy had an impact on cause-specific and overall survival of patients with endometrioid histology, for patients of early-stage, and all stages.
The question of whether pelvic lymphadenectomy improves survival rates of high-risk patients has not yet been resolved. Lutman et al. demonstrated improved overall and progression-free survival in a group of patients with FIGO stage 1-2, high-risk histology (clear-cell, papillary serous or grade 3 endometrioid histology) and more than 12 lymph nodes dissected. For low-risk cases, the results were not significant [11]. Similarly, in another study no significant impact on overall survival was demonstrated for low risk-patients (grade 1 and 2, outer-half myometrial invasion, no serous-papillary or clear-cell differentiation) [12]. Further, in a recent prospective study, there was no evidence of benefit in terms of overall or recurrence-free survival arising from pelvic lymphadenectomy in women with early endometrial cancer [14].
A contribution to the survival of patients who undergo lymphadenectomy may be the identification of patients with nodes positive for disease, a significant prognostic parameter [5], and the administration of a suitable adjuvant therapy. However, the incidence of cases with nodal metastases is very low, which suggests that lymphadenectomy itself has a therapeutic benefit. A final possible explanation is the removal of occult small metastatic disease which was not detected by classical histopathological evaluation [23, 24].
There is a small number of unsolved issues. The extent of the lymphadenectomy would have a major impact on the benefit to patient survival, meaning that as more lymph nodes were removed, the probability would increase of identifying patients with nodes positive for disease. Also, the therapeutic effect of removing occult lymph node metastases would rise. For this analysis, we disregarded the extent and localisation of the removed lymph nodes. In the literature, the cut-off for splitting patients undergoing lymphadenectomy into a limited sampling and a multiple sampling group is around 10 to 12 lymph nodes. Although this number is essentially the median, it is basically a randomly-selected range, and exceeding the cut-off does not mean that a full dissection will be made. Of course, the regions sampled also play a decisive role in the patients' outcome. An impact on survival of para-aortic sampling in patients with high-risk adenocarcinoma of the endometrium was demonstrated by Chang and colleagues [25]. However, it is not yet known whether para-aortic lymph node dissection could play a substantial role in routine treatment of all patients. Furthermore the possibility of underestimating FIGO IIIC disease in non-surgically-staged patients remains, and this problem cannot be solved by any current imaging modality.
The main purpose of this analysis was to investigate the effect of lymphadenectomy only in patients with endometrioid histology. Our results show that lymphadenectomy improves patient survival, and so demonstrate the prognostic relevance of this intervention in treatment of patients with endometrioid adenocarcinoma. Therefore, a pelvic and/or para-aortal lymphadenectomy should be performed during surgery, even in endometrioid adenocarcinoma. In a recent prospective study, there was no evidence of benefit in terms of overall or recurrence-free survival from pelvic lymphadenectomy in women with early endometrial cancer [14]. However, these results remain to be confirmed in further studies.