Role of pelvic and para-aortic lymphadenectomy in endometrial cancer: Current evidence

Abstract

The aim of the present review is to summarize the current evidence on the role of pelvic and para-aortic lymphadenectomy in endometrial cancer. In 1988, the International Federation of Obstetrics and Gynecology recommended surgical staging for endometrial cancer patients. However, 25 years later, the role of lymph node dissection remains controversial. Although the findings of two large independent randomized trials suggested that pelvic lymphadenectomy provides only adjunctive morbidity with no clear influence on survival outcomes, the studies have many pitfalls that limit interpretation of the results. Theoretically, lymphadenectomy may help identify patients with metastatic dissemination, who may benefit from adjuvant therapy, thus reducing radiation-related morbidity. Also, lymphadenectomy may eradicate metastatic disease. Because lymphatic spread is relatively uncommon, our main effort should be directed at identifying patients who may potentially benefit from lymph node dissection, thus reducing the rate of unnecessary treatment and associated morbidity. This review will discuss the role of lymphadenectomy in endometrial cancer, focusing on patient selection, extension of the surgical procedure, postoperative outcomes, quality of life and costs. The need for new surgical studies and efficacious systemic drugs is recommended.

Introduction

Endometrial cancer (EC) represents the most common gynecologic cancer in developed countries, accounting for approximately 6% of all malignancies.¹ It is estimated that the number of new EC diagnosed every year in the USA has increased from 40 100 to 49 560 between 2003 and 2013.^1,2 Despite the high incidence of EC, many features of its management remain unresolved. The main controversial topic in EC treatment concerns the therapeutic role of lymphadenectomy.³ Definitions of the adequacy and extent of lymphadenectomy have not been fully established.

In 1988, the International Federation of Gynecology and Obstetrics (FIGO) introduced the concept of surgical staging of EC,⁴ and in 2005, the American College of Obstetricians and Gynecologists (ACOG) recommended surgical staging as an important part of EC management. The ACOG committee suggested that ‘adjuvant therapy’ should be limited to patients with positive nodes, while ‘the use of adjuvant radiation therapy in women with disease limited to the uterus based on systematic surgical staging is controversial’.⁵ Theoretically, the removal of lymph nodes has several potential advantages. Complete surgical staging may allow the identification of patients with documented lymphatic dissemination, thus targeting postoperative treatment and potentially reducing the morbidity related to unnecessary radiation therapy. Moreover, lymph node dissection may eradicate metastatic lymphatic disease.

The major criticisms of lymphadenectomy are based on the results of two independent randomized trials that evaluated the role of pelvic and limited para-aortic lymph node dissection in early-stage EC.^6,7 Overall, a total of 1922 patients were randomly assigned to evaluate whether the addition of pelvic (and para-aortic, in selected cases) lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy may improve survival outcomes. The cumulative results of these studies reported that lymphadenectomy did not improve disease-free survival (pooled hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.96–1.58) and overall survival (pooled HR, 1.07; 95% CI, 0.81–1.43).^6,7

These findings should be interpreted with caution, however, because of several pitfalls in the study design of both trials. First, they included a large proportion of low-risk women, which diluted the possible therapeutic effects of lymphadenectomy. Given the low rate of lymphatic spread in the early stage of disease (9%– 13%), it is not surprising that the two trials failed to find any therapeutic role for pelvic lymphadenectomy in the low-risk population. Second, no clear indication was given for postoperative adjuvant therapy. One of the main goals of lymphadenectomy is to tailor adjuvant treatment to decrease radiation-related morbidity in patients with negative nodes. However, the adjuvant therapy administration rate was similar in both study arms; this result obviously influenced postoperative outcomes. Third, neither trial evaluated appropriately the role of para-aortic lymphadenectomy. In patients with lymphatic spread, para-aortic node involvement occurs in 60% of patients with endometrioid EC and 70% of those with non-endometrioid EC.⁸ Therefore, the performance of pelvic lymphadenectomy alone represents an incomplete surgical effort because of the partial removal of metastatic nodes.

Additionally, in the ASTEC trial,⁷ the number of pelvic nodes yielded was low in many of the patients. The median number of pelvic nodes harvested was 12 (range, 1–59); moreover, in the lymphadenectomy arm, 241 women (35%) had nine or fewer nodes and 72 women (12%) had four or fewer nodes.

Recently, in response to the current evidence that pelvic lymphadenectomy alone did not provide any significant benefit on EC, Todo et al.⁹ designed a retrospective cohort analysis (the SEPAL study) aimed at assessing the role of para-aortic lymphadenectomy. The authors compared outcomes of patients undergoing systematic pelvic lymphadenectomy or combined pelvic and para-aortic lymphadenectomy in intermediate- and high-risk EC patients. The SEPAL study showed that high-risk patients who had pelvic and para-aortic lymph node dissection experienced a longer overall survival than patients who had pelvic lymphadenectomy alone (HR, 0.53; 95% CI, 0.38–0.76; P < 0.001). Interestingly, in accordance with our previous comments, the authors found that survival was not influenced by the performance of para-aortic lymphadenectomy in the low-risk group (grade 1 and 2 endometrioid tumor limited to the inner half of the myometrium, without lymphovascular space invasion), while it was an independent prognostic factor in intermediate-risk EC patients (grade 1 and 2 tumor limited to the inner half of the myometrium with lymphovascular space invasion, grade 3 and/or nonendometrioid stage IA and IB tumor, stage IC and II) and high-risk EC patients (stage III and IV) (P < 0.001).⁹ However, only 8% of patients in the SEPAL trial had non-endometrioid EC (13.5% of the intermediate- and high-risk group). Therefore, results of the SEPAL trial may not be fully applicable to patients with nonendometrioid EC. Also, the median age of patients in the SEPAL trial was relatively young (56 years), and those results may not be applicable to elderly patients.⁹

Clinical Considerations

In light of the current evidence, it is not possible to draft definitive conclusions regarding the role of lymphadenectomy in EC patients. In this article, we will address the most important questions regarding the role of lymphadenectomy in EC:

1. Which is the population at risk of lymphatic spread?

2. How can we select patients at risk of lymphatic spread?

3. Which are the patterns of para-aortic lymphatic spread?

4. What is the role of sentinel lymph node (SLN) mapping?

5. How does lymphadenectomy impact morbidity, quality of life (QOL) and costs?

6. If lymph node metastases are identified, do we have adequate treatment?

7. How can we design a study to test the diagnostic and therapeutic role of lymphadenectomy?

1. Which is the population at risk of lymphatic spread?

According to a risk stratification system in use at Mayo Clinic, Rochester, Minnesota, USA (Table 1), low-risk patients can be adequately treated with removal of the uterus and adnexa alone, without significantly compromising survival. In this subgroup, lymphadenectomy carries only potential adjunctive morbidity.^10,11 In fact, we previously demonstrated that tumor diameter significantly influences the risk of lymph node dissemination. In an analysis of more than 300 endometrioid EC patients with FIGO grade 1 or 2 and myometrial invasion limited to the inner half, we found that no patients with tumor diameter of 2 cm or less had positive lymph nodes or lymph node recurrences or died of disease.¹¹ This finding has been recently prospectively validated by our group¹⁰ and others.^12,13

Table 1.

Endometrical cancer risk stratification

Low risk

Endometrioid, grade 1 and 2, MI <50%, PTD ≤2 cm

Endometrioid, MI 0%, any grade or PTD

Low-intermediate risk

Endometrioid, grade 1 and 2, MI <50%, PTD >2 cm (or unknown)

High-intermediate risk

Endometrioid, grade 1 and 2, 50% < MI ≤ 66%

Endometrioid, grade 3, MI <50%

High risk

Non-endometrioid

Endometrioid, grade 1 and 2, MI >66%

Endometrioid, grade 3, MI >50%

Adnexal metastasis

Ultra-high risk (IP and EA spread)

Grade 3 EC, USC, and CCC subcohorts

CCC, clear cell carcinoma; EA, extra-abdominal; EC, endometrial cancer; IP, intra-peritoneal; MI, myometrial invasion; PTD, primary tumor diameter; USC, uterine serous cell carcinoma.

Based on the surgical protocol currently in use at Mayo Clinic, all patients with primary epithelial EC undergo hysterectomy with or without bilateral salpingo-oophorectomy. The need to perform lymphadenectomy is based on the tumor characteristics (histological type, FIGO grade, tumor diameter and depth of myometrial invasion) determined at frozen-section analysis. Systematic pelvic and para-aortic lymphadenectomy is performed when patients have myometrial invasion greater than 50%, nonendometrioid histology or both. If patients do not match these characteristics, the choice to perform pelvic node dissection (with para-aortic lymphadenectomy only in those patients with documented pelvic lymph node metastases) is based on cervical involvement, FIGO grade and tumor diameter (Figs 1,2).^14–16 Para-aortic lymphadenectomy is therefore limited to patients with at least one of the following: (i) positive pelvic nodes (assessed at frozen section); (ii) type 2 EC; or (iii) deep myometrial invasion (>50%) (Fig. 1).¹⁵ In fact, we have recently observed that isolated para-aortic dissemination (in the absence of pelvic lymph node involvement) is generally very uncommon (≤5%), with the exception of patients with endometrioid grade 2 or 3 cancer and myometrial invasion greater than 50%.¹⁶ Also, para-aortic metastases are uncommon in patients with endometrioid grade 3 cancer with early myome-trial invasion (≤50%).¹⁵

Figure 1.

Algorithm for surgical management of endometrial cancer at our institution. In the case of type 2 endometrial cancer, omentectomy is required. No lymphadenectomy is done in the patients with stage IV cancer. BSO, bilateral salpingo-oophorectomy.

Figure 2.

Risk of lymph node metastasis and lymph node recurrence according to preoperative and operative findings. LN, lymph node; mts, metastases; TD, tumor diameter. (Data from AlHilli et al.¹⁴.)

In the presence of type II EC, omentectomy is performed (Fig. 1). However, random peritoneal biopsies, in the absence of macroscopic visible disease, are of limited diagnostic benefit.¹⁷

Interestingly, in a large analysis among high-risk and ultra-high-risk (grade 3 endometrioid, serous and clear cell) uterine cancers, we showed that lymphadenectomy as well as extensive surgery did not provide survival advantages in patients with advanced-stage disease.¹⁸

In light of these findings, patients with a preoperative diagnosis of FIGO grade 1 or 2 endometrioid EC confined to the endometrium or with myometrial invasion less than 50% and tumor diameter of 2 cm or less do not undergo lymph node dissection at our institution. Moreover, from a practical standpoint, lymphadenectomy may be omitted also in ultra-high-risk patients with stage IV disease (Fig. 1).

2. How can we select patients at risk of lymphatic spread?

A scoring system based on preoperative and operative parameters should be used to tailor surgery and reduce the rate of unnecessary lymphadenectomy. Several models have been described.^14,19–24 Decision-making at Mayo Clinic is traditionally based on four variables during intraoperative frozen-section analysis: (i) primary tumor diameter; (ii) FIGO grade; (iii) histo-logical type; and (iv) depth of myometrial invasion. An investigation by our group, aimed at determining the reliability of frozen-section analysis, suggested a high rate of clinical accordance (98.7%), with definitive pathological findings (permanent paraffin sections). Among 784 patients included, 10 women (1.3%) had a potential change in operation plan due to deviation in pathological results from frozen-section to permanent-paraffin analysis. This included changes in histological subtypes (n = 6, 0.7%), FIGO grade (n = 1, 0.12%) and myometrial invasion (n = 3, 0.38%).¹⁹ Although different studies from other institutions report a similarly high accuracy rate of intraoperative frozen section,^25,26 a survey of the Society of Gynecologic Oncologists revealed that only 31% of gynecologic surgeons use frozen section in their decision making for EC management.²⁷ For this reason, we recently showed that, in the absence of an accurate frozen section, preoperative biopsy (which is consistently available) and intraoperative tumor diameter (easily measured on fresh tissue and unchanged on final pathology) may reliably predict lymph node tumor spread. We observed that low-risk women (patients with preoperative diagnosis of grade 1 or 2, endometrioid EC and tumor diameter ≤2.0 cm) have less than 1% risk of lymphatic spread, while patients with tumor diameter greater than 2.0 cm or with preoperative diagnosis of endometrioid grade 3 or non-endometrioid EC had a substantial risk of lymphatic involvement greater than 10% (Fig. 2).¹⁴

Other authors have used preoperative imaging and serum markers, suggesting that tumor volume (measured with magnetic resonance imaging), positron emission tomographic scan findings,²⁸ and preoperative cancer antigen 125 or human epididymis protein 4 levels may be useful in tailoring the indications for lymphadenectomy.^20,21,29

Our experience suggests that frozen-section analysis may represent a safe and effective method to direct the operative plan in selected medical centers. However, if frozen-section analysis is not available or if it is not reliable, findings of preoperative endometrial sampling associated with intraoperative tumor size, imaging studies and serum markers are alternative methods to identify patients who may benefit from comprehensive surgical staging.

3. Which are the patterns of para-aortic lymphatic spread?

Traditional imaging, node palpation through the peritoneum and node sampling are inaccurate in predicting lymph node positivity.⁵ In 2005, ACOG recommended that ‘retroperitoneal lymph node assessment is a critical component of surgical staging’ because it ‘is prognostic and facilitates targeted therapy to maximize survival and to minimize the effect of undertreatment and potential morbidity associated with overtreatment’.⁵ Nevertheless, in clinical practice a high variation of procedures reflects the lack of standardization of lymphadenectomy: techniques vary from elective omission to simple lymph node sampling, to systematic pelvic lymphadenectomy with or without paraaortic lymphadenectomy.

One investigation at Mayo Clinic illustrated the prevalence and site of pelvic and para-aortic lymphatic metastases. We reported that, among patients with lymphatic spread, 84% and 62% had pelvic and para-aortic node metastases, respectively. In particular, 46%, 38% and 16% had involvement of both pelvic and aortic nodes, pelvic nodes only and aortic nodes only, respectively.⁸

Para-aortic lymph nodes can be classified based on their location above and below the inferior mesenteric artery (IMA). At Mayo Clinic, we evaluated paraaortic metastatic site frequency relative to the IMA and found that aortic nodes above the IMA were involved in 77% of cases.^8,30 Fotopoulou and coworkers³¹ corroborated these results; they reported that metastatic disease above the IMA was recorded in 54% and 70% patients with stage IIIC and IIIC2 EC, respectively. Recently, a prospective study by our department suggested that, considering patients with aortic node involvement, high para-aortic lymph node metastases were detected in 88% of them, with no discernible difference between endometrioid (89%) and non-endometrioid (88%) histological subtypes. Interestingly, 35% of patients with high para-aortic lymph node metastases had negative nodes below the IMA (39% endometrioid; 31% non-endometrioid). Furthermore, in the rare cases with para-aortic lymph node metastases and negative pelvic nodes, cancer dissemination is most commonly confined to the high paraaortic area (67%).¹⁶

Also, patients with pelvic node metastases may have occult aortic node involvement, with a rate of paraaortic dissemination higher than commonly reported. Todo et al.³² investigated the occurrence of occult metastases (i.e. micrometastases and isolated tumor cells) in the para-aortic area in patients with stage IIIC1 EC who underwent pelvic and para-aortic lymphadenectomy. Ultra-staging was performed by multiple slicing, staining and microscopic inspection of the specimens. The authors found that 73% of these patients had occult aortic node involvement. Although the role of micrometastases is not fully understood, the presence of microscopic occult disease in the paraaortic area should be considered even in stage IIIC1 EC or in those patients with documented pelvic lymph node invasion and no known information regarding the para-aortic area.

These findings indicate that para-aortic lymph node invasion is very common when pelvic lymph node metastases are demonstrated. Also, in the majority of patients with para-aortic lymph node invasion, the area above the IMA is involved. Table 2 shows the overall risk of para-aortic and high para-aortic lymph node metastasis in EC.

Table 2.

Prevalence of para-aortic lymph node metastasis (LNM) in endometrial cancer^†

Population	Para-aortic LNM	High para-aortic LNM	High para-aortic LNM with negative low para-aortic nodes
Total 'at-risk' population	12%	9%	4%
Patients with negative pelvic nodes	3%	3%	2%
Patients with positive pelvic nodes	51%	46%	12%
Patients with positive para-aortic nodes	100%	88%	35%

^†Values shown are the percentage of the population with the specific form of LNM. (Adapted from Kumar et at.,¹⁶ with permission.)

4. What is the role of SLN mapping?

Sentinel lymph node mapping is an accepted way to assess lymphatic spread in several solid tumors (i.e. breast cancer, vulval cancer and melanoma) and is gaining ground in cervical cancer and EC.^33–35 SLN biopsy can be considered a compromise between comprehensive surgical staging and the complete omission of lymphadenectomy. In an ideal world, SLN mapping should be as good as a systematic lymphadenectomy in the identification of patients with lymph node dissemination, while reducing the morbidity associated with an extensive surgical procedure.

Although the complexity of uterine lymphatic drainage may discourage use of this procedure, the estimated accuracy rate is, in general, reasonably good.^36–39 The prospective multi-institutional SENTI-ENDO study suggested that in stage I and II EC patients, SLN biopsy has a sensitivity of 84%.⁴⁰ Moreover, ultra-staging of the SLN may be even more sensitive than a full lymphadenectomy, with lymph nodes evaluated by conventional pathology.^35,41 However, we still do not know the clinical importance of isolated tumor cells discovered in a lymph node that is negative by traditional histological analysis. Recently, a paper from the Memorial Sloan-Kettering Cancer Center, describing one of the largest prospective single-institution cohorts, showed that applying an SLN mapping algorithm may be a safe and effective alternative to systematic lymphadenectomy.³⁸ The study pointed out that satisfactory SLN mapping requires adherence to a surgical algorithm and the removal of any ‘suspicious node’.³⁸ However, the definition of a suspicious node was unclear. Also, identification of suspicious lymph nodes without fully opening the retroperitoneal spaces and without palpation (not possible with the minimally invasive approach) is limited and unreliable.

Like every effort aimed at decreasing the amount of surgery and the morbidity of EC treatment, we look at the experimental results on the use of SLN sampling with great interest. Ideally, SLN biopsy could be an effective alternative to systematic lymphadenectomy. However, available data are still insufficient to define its role in clinical practice.

5. How does lymphadenectomy impact morbidity, QOL and costs?

Patients undergoing systematic pelvic and para-aortic lymphadenectomy experience longer operative times and are exposed to greater risk of intraoperative and postoperative complications than patients who have hysterectomy and bilateral salpingo-oophorectomy alone.⁶ While some investigations showed that lymph node dissection did not significantly influence complication rates among EC patients,^42,43 at Mayo Clinic, we observed that retroperitoneal staging, including para-aortic lymphadenectomy, increases morbidity in patients with EC.⁴⁴ Similarly, results from the ASTEC trial and the Italian collaborative trial indicated that women who underwent lymphadenectomy had a significantly higher risk of surgically related morbidity and lymphatic complications than those who had hysterectomy plus bilateral salpingo-oophorectomy alone (relative risk [RR], 3.72; 95% CI, 1.04–13.27; and RR, 8.39; 95% CI, 4.06–17.33, for risk of surgical and lymphatic complications, respectively).^6,7,45 However, it is important to note that the introduction of minimally invasive lymph node dissection may have reduced the complication rate of lymphadenectomy.^46–48

The impact of lymphadenectomy on long-term QOL in EC patients is not clear. Recently, a Dutch population-based analysis⁴⁹ evaluated the health-related QOL and symptoms following pelvic lymphadenectomy and radiation therapy (alone or in combination) versus no adjuvant therapy in patients with FIGO stage I and II EC. Lymphedema, gastrointestinal tract symptoms, diarrhea, back and pelvic pain, and muscular joint pain were the most commonly reported symptoms. The authors showed that, despite different symptom patterns, in patients who had pelvic lymphadenectomy (e.g. lymphedema), radiotherapy (e.g. diarrhea) or both, no clinical differences in overall QOL were observed compared with women not receiving adjuvant therapy, lymphadenectomy or both.⁴⁹

At Mayo Clinic, we analyzed the related surgical costs of lymphadenectomy in our low-risk EC population and reported that lymphadenectomy increased the median 30-day cost of care by approximately $US 4500 per patient.¹⁰

In conclusion, patients undergoing lymphadenectomy experience longer operative times and higher complication rates than patients who have hysterectomy plus adnexectomy alone. Also, the overall cost of surgical care is higher. The influence of lymphadenectomy on long-term QOL is less clear. For the above reasons, it is important to limit the performance and the extent of lymphadenectomy to patients who may potentially benefit from it.

6. When lymph node metastases are identified, is adequate treatment available?

Although lymphadenectomy is aimed at documenting the presence of lymphatic metastases, there is still no consensus about the best adjuvant approach in EC patients with positive lymph nodes. The Gynecologic Oncology Group 122 trial⁵⁰ suggested that chemo-therapy (doxorubicin and cisplatin) provides better survival than radiotherapy (whole abdominal irradiation) in stage III or IV and with 2 cm or less of residual disease. However, chemotherapy decreased the distant recurrence rate (from 19% to 10%) at the cost of a higher pelvic recurrence rate (from 13% to 18%). Interestingly, the authors reported that chemotherapy was not significantly better than abdominal radiation in patients with non-endometrioid tumors.⁵⁰ Similarly, the results of two randomized studies (NGSO/ERTC and MaNGO ILIADE-III), including high-risk EC patients (stage I to III), indicated that the addition of adjuvant chemotherapy to radiation improved disease-free survival overall, especially in the subgroup with grade 1 and 2 endometrioid EC. Chemotherapy was less likely to be beneficial in patients with endometrioid grade 3 and type 2 EC.⁵¹ In agreement with the above results, we recently demonstrated that chemotherapy did not significantly impact prognosis in stage III patients with high-risk histology (endometrioid grade 3 and type 2 EC).¹⁸ Although in our study radiotherapy (with or without chemotherapy) independently influenced survival in patients with stage III poorly differentiated cancer, the treatment failure rates remained extremely high, with a 67% recurrence rate at 3 years in patients with stage III and lymphovascular invasion.¹⁸

Similarly, Sutton et al.,⁵² in another Gynecologic Oncology Group study, reported that patients with stage III and IV high-risk histology (serous and clear cell) experienced 3-year recurrence-free and overall survival of 27% and 35%, respectively, when treated with whole abdominal radiotherapy.

Owing to the fact that radiotherapy seems to provide adequate locoregional protection of the targeted tissues but not systemic control, several authors suggested that combining radiotherapy and chemotherapy may guarantee better locoregional and systemic protection.^53,54 Secord et al.,⁵⁵ in a multi-institutional series of 265 stage IIIC EC (type 1 and type 2), reported that patients undergoing chemotherapy alone had a 2.2-and 4.0-fold increased risk of recurrence and death than patients who had chemotherapy plus radio-therapy. In contrast, there was no difference in survival between patients undergoing radiotherapy alone versus chemotherapy plus radiotherapy. Interestingly, the authors showed that among patients undergoing the combined regimen, overall survival for a ‘sandwich’ regimen of chemotherapy plus radiotherapy plus chemotherapy was 98% versus 90% for radio-therapy plus chemotherapy and 82% for chemo-therapy plus radiotherapy. However, no difference in disease-free survival was recorded among these three combination regimens.⁵⁵

In conclusion, in stage IIIC EC, the therapeutic role of chemotherapy remains unproven, especially in type II and more aggressive endometrioid tumor (grade 3).⁵⁶ Lymphadenectomy, like radiotherapy, is a locoregional treatment and likely has limited ability to prevent distant recurrences outside the surgical field, which in turn can be prevented only by an effective systemic treatment. It has been suggested that systemic cytotoxic chemotherapy may be more effective in advanced endometrioid grade 1 and 2 EC and less effective in advanced poorly differentiated EC.^18,46,51 For this reason, aggressive locoregional treatment (systematic lymphadenectomy and external radiotherapy) is more likely to improve the overall patient prognosis in tumors that are responsive to systemic adjuvant therapy.

7. How can we design a study to test the diagnostic and therapeutic role of lymphadenectomy?

While the role of lymphadenectomy in the identification of patients with lymphatic dissemination is well established, its role in patient selection for targeting postoperative treatment, and therefore decreasing postoperative morbidity and improving QOL, is less clear. Similarly, the available data do not allow us to draw definitive conclusions on the therapeutic value of lymphadenectomy in EC patients. We believe that a trial aimed at demonstrating a therapeutic benefit of lymphadenectomy should focus on patients at signifi-cant risk (>15%) of lymph node dissemination.⁵⁷ Two main questions should be addressed in the trial: (i) is lymphadenectomy therapeutic or mainly diagnostic for directing postoperative adjuvant treatment?; and (ii) is lymphadenectomy increasing or decreasing the cumulative treatment-related (surgery with or without adjuvant therapy) morbidity, costs and QOL? Although it is intuitive that a prospective, randomized controlled trial will best answer these questions, a well-designed prospective cohort study is potentially more feasible and more likely to provide a definitive answer.⁵⁸

Conclusions

The diagnostic role of lymphadenectomy in documenting areas of lymphatic dissemination is well recognized in EC. The identification of sites of tumor dissemination allows patient selection and targeting of postoperative treatment.

Based on our data on patterns of lymphatic dissemination in EC, we recently reported that isolated paraaortic dissemination (with negative pelvic nodes) is rare (usually <5%), with the exception of patients with deeply invasive endometrioid grade 2 and 3 cancer, in whom this percentage is higher than 10%.¹⁶ For this reason, from a purely diagnostic perspective (i.e. if lymphadenectomy is aimed only at identifying those patients with extrauterine disease), pelvic lymphadenectomy is usually sufficient (with the above exceptions, which include only 6% of the overall EC population).¹⁴ However, if lymphadenectomy is therapeutic, as suggested by the SEPAL trial, the para-aortic area needs to be targeted by surgery, radiation or both in most (if not all) patients with documented lymphatic dissemination in the pelvis.^9,32 In these cases, we need also to be aware that paraaortic disease is usually present in the anatomical area above the IMA.¹⁶

After many decades of debate, there are still no convincing data demonstrating a therapeutic role of lymphadenectomy in EC. Why is that? First, lymphadenectomy, like radiotherapy, is a locoregional treatment. For this reason, if lymphadenectomy is therapeutic, it is more likely to improve locoregional control and less likely to affect systemic disease. However, as overall patient survival is mainly driven by the presence of occult systemic disease, in the absence of an efficacious adjuvant systemic treatment, it is unlikely that lymphadenectomy will demonstrate any survival benefits.¹⁸ We are therefore in a difficult situation. Patients with poorly differentiated EC (grade 3 or type II) are more likely to present with occult lymphatic dissemination,¹⁶ but are also more likely to die of systemic disease.¹⁸ But patients with endometrioid grade 1 and 2 cancer are less likely to die of systemic disease and more likely to respond to systemic treatment⁵¹ and to be cured at the time of lymphatic recurrence.¹⁵ However, in these patients, lymphatic dissemination is rare (Fig. 3),^15,16 making it very difficult to demonstrate a therapeutic role of lymphadenectomy. Perhaps use of SLN mapping will be helpful for adequate patient selection in patients with low-risk tumor.^38–41 The continuing debate about the role of lymphadenectomy will probably end only when molecularly guided imaging or new biologic therapy becomes available to identify and treat systemic metastatic disease.

Figure 3.

Risk of lymph node metastasis. *Para-aortic lymph node metastases may be associated with lymphovascular space invasion. EC, endometrial cancer; LN, lymph node; MI, myometrial invasion; mts, metastases; PA, para-aortic; PL, pelvic. (Adapted from Kumar et al.,^15,16 with permission.)