Abstract
Surgical staging remains the standard primary treatment of endometrial cancer. Lymph node metastasis is the most important prognostic factor which helps in deciding adjuvant treatment. Extensive lymphadenectomy is associated with increased incidence of morbidity. The role of lymphadenectomy in surgical staging is still controversial especially in early stage disease. The surgico-pathological pattern of 155 patients with apparently stage 1 cancer endometrium who had undergone pelvic alone or pelvic and para-aortic lymph node dissection and its correlation to the grade of the tumour, myometrial infiltration and presence of peritoneal disease and incidence of peri-operative morbidity are analysed and described.
Keywords: Cancer endometrium, Lymphadenectomy, Sentinel lymph node mapping, Isolated para-aortic node metastasis, Complications
Introduction
Endometrial cancer is the sixth common cancer among females in India and the incidence shows an increasing trend. Surgical staging remains the standard primary treatment for endometrial cancer and lymph node metastasis is the most important prognostic factor for deciding on adjuvant treatment [1, 2]. The role of pelvic and para-aortic lymphadenectomy during surgical staging is controversial especially in early stages of the disease [3, 4]. Risk of advanced stage disease by surgical staging of clinical stage 1 disease ranges from 17.6 to 26.7% [5]. Various practices of lymph node evaluation have been described and include complete pelvic and para-aortic lymphadenectomy, intraoperative palpation and debulking of enlarged nodes, selective lymphadenectomy and sentinel lymph node dissection, and some authors have even advised no lymphadenectomy in early stages [6]. The potential complications as thromboembolic events are not so common except in one report [7]. Incidence of lymph node metastasis is related to grade of the tumour, depth of myometrial infiltration and peritoneal disease. [8] Various scoring systems have been developed using these factors for deciding on lymph node dissection and adjuvant treatment. [9] We analysed the patterns of pelvic and para-aortic lymph node involvement among our patients with early endometrial cancers.
Objective
To find out the incidence of lymph node metastasis in clinical stage 1 endometrial cancer and its relation to grade of the tumour, myometrial infiltration and peritoneal disease.
Materials and Methods
All patients with stage I endometrial cancer (clinical and radiological) who had undergone surgical staging at our institute during 2010–2015 were included in the study. Surgical and pathological data of these patients were collected and analysed retrospectively. Preoperatively, all patients had clinical evaluation to rule out intra-abdominal, cervical, vaginal and parametrial extension of the tumour. Magnetic resonance image (MRI) of abdomen and pelvis was done as an institutional protocol for all patients preoperatively to assess extent of disease in the pelvis and abdomen including retroperitoneal lymph nodes. Surgical staging included total abdominal hysterectomy, bilateral salpingooophorectomy and bilateral pelvic lymphadenectomy with or without para-aortic lymphadenectomy. Prophylactic antibiotics was given with first generation cephalosporin (cefazolin) and metronidazole one dose 30 min before incision (just before induction of anaesthesia) and one dose 6 h later. Pelvic lymphadenectomy included removal of bilateral iliac and obturator group of lymph nodes. Para-aortic node dissection included removal of nodal tissue anterior to aorta and inferior vena cava up to inferior mesenteric artery. If during surgery, enlarged nodes were detected, para-aortic area node dissection was extended up to the level of left renal vein. Postoperatively, pelvic drain was removed on second postoperative day irrespective of the quantity of drain if it is not chylous. Thromboembolic prophylaxis was given with thromboembolic device (TED) stockings from 1 day prior to surgery and was continued till date of discharge. In addition, low molecular weight heparin (LMWH) injection was started 12 h after surgery, followed by daily once injection till discharge and early ambulation. Incidence of lymph node metastasis and its relation to grade of the tumour, extent of myometrial infiltration and presence of peritoneal disease were calculated.
Statistical Analysis
Continuous variables were expressed as mean and standard deviation and categorical variables as counts and percentage. Chi-square test was used to find out the significance of the factors related to frequency of positive lymph nodes. A p value < 0.05 was set for statistical significance. Statistical analysis was performed using SPSS ver. 11.0 (SPSS Inc., Chicago, IL, USA).
Results
A total of 155 patients were included in the study. Mean age of the patients was 56 years (25–77 years). Clinicopathological factors are given in Table 1. Endometrioid carcinoma was the commonest histological type (136 patients, 88%). Other histological cell types were clear cell carcinoma (14 patients, 9%), papillary serous carcinoma (3 patients, 1.9%) and adenosquamous carcinoma (2 pts, 1.2%). A total of 153 patients had preoperative positive endometrial biopsy report. Two patients did not have preoperative biopsy diagnosis but had radiological evidence of tumour in the endometrium and hence underwent hysterectomy and intraoperative frozen examination of hysterectomy specimen before performing lymphadenectomy.
Table 1.
Clinico pathological characteristics
| Total number of patients | 155 |
| Mean age (years) | 56 (25–77 years) |
| Menopausal status | |
| Pre-menopausal | 22 (14%) |
| Post-menopausal | 133 (86%) |
| Histology | |
| Endometrioid carcinoma | 136 (88%) |
| Low-grade disease | |
| Endometrioid grade 1 | 8 (5%) |
| Endometrioid grade 2 | 84 (54%) |
| High-grade disease | |
| Endometrioid grade 3 | 44 (28%) |
| Clear cell carcinoma | 14 (9%) |
| Papillary serous carcinoma | 3 (1.9%) |
| Adenosquamous carcinoma | 2 (1.2%) |
| Myometrial infiltration | |
| Nil | 13 (8%) |
| < 50% | 68 (44%) |
| > 50% | 74(48%) |
| Peritoneal disease | |
| Nil | 142 (92%) |
| Yes | 13 (8%) |
Majority of patients (92 pts, 59%) had low-grade disease (endometrioid carcinoma grades 1 and 2) and 63 (41%) had high-grade disease (included endometrioid carcinoma grade 3, clear cell carcinoma, uterine papillary serous carcinoma and adenosquamous carcinoma).
Grade was not mentioned in preoperative biopsy report of 6 patients. Upgrading in the final histopathology report was noted in 12/147 (8%) and degrading in 5/147 (3%) of the patients.
A total of 129 (83%) patients had undergone pelvic and para-aortic lymphadenectomy and the rest 26 (17%) patients underwent pelvic lymphadenectomy alone. Mean number of lymph nodes removed was 14 (range 7–26). On final histology, 26 patients (17%) had nodal metastases of which 21 (13.5%) patients had pelvic lymph node metastasis alone, 4 (2.6%) patients both pelvic and para-aortic lymph node metastasis and 5 (3.2%) patients had isolated para-aortic node metastasis.
Pattern of lymph node metastasis was correlated with grade of the tumour (Table 2), myometrial infiltration (Table 3) and presence of peritoneal disease (Table 4). The incidence of lymph node metastasis in high-grade disease was 20% (13 out of 63 patients) and 14% (13 out of 92 patients) in low-grade disease. Among the patients with > 50% myometrial invasion, lymph node involvement was noted in 18 (24.3%) and in patient with < 50% myometrial infiltration, lymph node involvement was 5.8% (4/68)(P value 0.001). Among 142 patients without peritoneal disease, 17% (24 patients) had lymph node metastasis, whereas among 13 patients with peritoneal disease, 46% (6/13) had lymph node metastasis (P value 0.05). Isolated para-aortic lymph nodal metastases were noted in 5 (3.2%).
Table 2.
Frequency of lymph node metastasis and histological grade
| Histology | Number of patients (n) | No metastasis | Pelvic node metastasis | Pelvic + para-aortic node metastasis | Isolated para-aortic metastasis |
|---|---|---|---|---|---|
| Endometrioid | |||||
| Grade 1 | 8 | 6 | 0 | 0 | 2 |
| Grade 2 | 84 | 74 | 9 | 1 | 2 |
| Grade 3 | 44 | 32 | 9 | 2 | 1 |
| Papillary serous carcinoma | 3 | 2 | 1 | 0 | 0 |
| Clear cell carcinoma | 14 | 12 | 1 | 1 | 0 |
| Adenosquamous carcinoma | 2 | 1 | 1 | 0 | 0 |
P value: 0.455
Table 3.
Frequency of lymph node metastasis with respect to myometrial infiltration
| Myometrial infiltration (MI) | No metastasis | Pelvic node metastasis | Pelvic + para-aortic node metastasis | Isolated para-aortic node metastasis | Total |
|---|---|---|---|---|---|
| Nil | 11 | 0 | 0 | 2 (15.3%) | 13 |
| < 50% | 64 | 3 (4.41%) | 1 (1.5%) | 0 | 68 |
| > 50% | 50 | 18 (24.3%) | 3 (4%) | 3 (4%) | 74 |
P value 0.001
Table 4.
Lymph node metastasis with respect to peritoneal disease
| Peritoneal disease | N | No metastasis | Pelvic metastasis | Pelvic + para-aortic | Para-aortic |
|---|---|---|---|---|---|
| Absent | 142 | 118 | 17 | 3 | 4 |
| Present | 13 | 7 | 4 | 1 | 1 |
P value 0.05
Intraoperative and post-operative complications during the hospital stay are given in Table 5. Major intraoperative vascular injury was noted in 5 (3.2%) patients and obturator nerve injury in 2 (1.2%). Two patients had developed pulmonary embolism on first post-operative day before starting LMWH, and one of these two patients expired on fifth postoperative day due to massive embolism. Other main peri-operative complications included pneumonitis in four patients, paralytic ileus in five patients and lymphatic leak in four patients. The median hospital stay was 7 days.
Table 5.
Perioperative complications
| Total number of patients | 155 |
| Complications | 30 (19.2%) |
| Mortality | 1 (0.6%) |
| Intraoperative complications | 11 (7%) |
| Major vessel injury | |
| Inferior vena cava | 3 (1.9%) |
| External iliac vein | 2 (1.2%) |
| Nerve injury | |
| Obturator nerve | 2 (1.2%) |
| Chyle leak | 4 (2.5%) |
| Postoperative complications | 18 (11.6%) |
| Pelvic abscess | 1 (0.6%) |
| Vault cellulitis | 1 (0.6%) |
| Hematoma evacuation (pelvic) | 2 (1.2%) |
| Pneumonitis | 4 (2.5%) |
| Febrile morbidity | 2 (1.2%) |
| Pulmonary embolism | 2 (1.2%) |
| Paralytic ileus | 5 (3%) |
| Myocardial infarction | 1 (0.6%) |
Discussion
The therapeutic benefit of lymph node dissection in early endometrial cancer still remains controversial. Assessment of nodal involvement will help in accurate staging and to decide on adjuvant treatment. Preoperative MRI will help to assess degree of myometrial invasion and select out patients at low risk for nodal disease along with the grade of the tumour assessed on the biopsy. Contrast-enhanced MRI seems to be best radiological investigation to detect myometrial invasion, cervical involvement and lymph node evaluation [10].
The accuracy rate of preoperative biopsy and final pathology of hysterectomy specimen in our study was 88% and is comparable with other published literature [11, 12]. The rate of upgrading (8%) and degrading (5%) was very low compared with the other published data 21% and 25%, respectively, which could be explained by availability of the services of dedicated gynaecologic pathologist in our institute.
The overall incidence of lymph node metastasis was 17% (26/155) in our study in par with the reported incidence ranging from 3 to 5% for well-differentiated tumour with superficial myometrial infiltration to 20% in poorly differentiated deep myometrial invasion [4, 13, 14]. Our data also shows a higher incidence lymph node metastasis of 20% (13/63) in high-grade tumours. The incidence of isolated para-aortic metastasis was 3.2% as in other studies 2–6% [15]. Significant correlation of lymph node metastasis was found with depth of myometrial infiltration (p value 0.001) and presence of peritoneal disease (p value 0.05). Grade of the tumour alone was not significantly associated with lymph node metastasis (P value 0.455). Many of the centres practice selective lymph node dissection in endometrial cancer by risk stratification. Preoperative tumour grade in endometrial biopsy and myometrial infiltration by imaging are being used for risk stratification, and lymphadenectomy is done only in high-risk groups (patients with > 50% myometrial infiltration and high-grade disease). This practice can cause missing of lymph node metastasis in some patients with low-risk disease though it is rare. In GOG, 33 incidences of lymph node metastasis were 0% in grade 1 tumour limited to endometrium. In our data, two patients with grade 1 disease confined to endometrium had isolated para-aortic node metastasis. Both patients had bulk of tumour at the fundus of uterus. These patients would have been considered as low risk based on preoperative evaluation, and hence, not doing a lymphadenectomy in these patients might have resulted in understaging.
In our study group, complications were observed in 19.2% (30/155) of patients. Major intra-operative and post-operative complications were noted in 7% (11/155) and 11.6% (18/155) of patients, respectively. One mortality was due to massive pulmonary embolism. Patient expired on fifth postoperative day. Complication rates are similar to the other reports in the published literature [10]. Median hospital stay of patients was 6 days. The major postoperative complication needed increased hospital stay to 10–14 days. Two out of 155 patients developed pulmonary embolism on first postoperative day before starting LMWH. Our practice was to start LMWH 12 h after surgery. Now, the practice changed to start thromboprophylaxis with LMWH also on preoperative day itself as a part of ERAS (enhanced recovery after surgery) protocol.
The concept of sentinel lymph node mapping (SLNM) is the upcoming approach for lymph node evaluation to decrease the morbidities associated with lymphadenectomy. In SLNM, cervical injection alone may be associated with chance of missing the para-aortic node metastasis. Studies have shown that injecting dye into cervix and fundus improves detection rate of sentinel para-aortic nodes [16]. But at centres where sentinel lymph node mapping is not available, omitting lymphadenectomy by risk stratification should be done carefully. Even in low-risk patients, nodal basins should be evaluated intraoperative and any suspicious nodes should be biopsied.
Two major trials which addressed the question of the role of lymphadenectomy have shown no therapeutic benefit with pelvic lymphadenectomy, but questions have been raised regarding the methodological issues of these trials and the question remains unanswered [3, 4]. The result of STATEC (Selective Targeting of Adjuvant Therapy for Endometrial Cancer) may give a final answer regarding therapeutic benefit of lymphadenectomy in early endometrial cancer. Till further developments in preoperative assessment of the lymph node status based on biological factors, it is better to have an assessment of the lymph nodes for all patients with endometrial cancer depending on the available resources to prevent understaging and under treatment.
Footnotes
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References
- 1.Lutman CV, et al. Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecol Oncol. 2006;102(1):92–97. doi: 10.1016/j.ygyno.2005.11.032. [DOI] [PubMed] [Google Scholar]
- 2.Chan JK, Cheung MK, Huh WK, Osann K, Husain A, Teng NN, Kapp DS. Therapeutic role of lymph node resection in Endometrioid corpus cancer: a study of 12,333 patients. Cancer. 2006;107(8):1823–1830. doi: 10.1002/cncr.22185. [DOI] [PubMed] [Google Scholar]
- 3.Benedetti Panici P, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100(23):1707–1716. doi: 10.1093/jnci/djn397. [DOI] [PubMed] [Google Scholar]
- 4.Kitchener H, et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized study. Lancet. 2009;373:125–136. doi: 10.1016/S0140-6736(09)60678-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Orr JW., Jr Surgical staging of endometrial cancer: does the patient benefit? Gynecol Oncol. 1998;71:335–339. doi: 10.1006/gyno.1998.5296. [DOI] [PubMed] [Google Scholar]
- 6.Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO, Podratz KC. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109(1):11–18. doi: 10.1016/j.ygyno.2008.01.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Cliby WA, Clarke-Pearson DL, Dodge R, Kohler M, Rodriguez G, et al. Acute morbidity and mortality associated with selective pelvic and para-aortic lymphadenectomy in the surgical staging of endometrial adenocarcinoma. Gynecol Technol. 1995;1:19–26. [Google Scholar]
- 8.Rungruang B, Olawaiye AB. Comprehensive surgical staging for endometrial cancer. Rev Obstet Gynecol. 2012;5(1):28–34. [PMC free article] [PubMed] [Google Scholar]
- 9.ASTEC study group. Kitchener H, Swart AM, et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomized study. Lancet. 2009;373:125–136. doi: 10.1016/S0140-6736(08)61766-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Park JY, Kim EN, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT, Nam JH. Comparison of the validity of magnetic resonance imaging and positron emission tomography/computed tomography in the preoperative evaluation of patients with uterine corpus cancer. Gynecol Oncol. 2008;108:486–492. doi: 10.1016/j.ygyno.2007.11.044. [DOI] [PubMed] [Google Scholar]
- 11.Lago V, Martín B, Ballesteros E, Cárdenas-Rebollo JM, Minig L. Tumor grade correlation between preoperative biopsy and final surgical specimen in endometrial cancer: the use of different diagnostic methods and analysis of associated factors. Int J Gynecol Cancer. 2018;28(7):1258–1263. doi: 10.1097/IGC.0000000000001304. [DOI] [PubMed] [Google Scholar]
- 12.Visser NCM, Reijnen C, Massuger LFAG, Nagtegaal ID, Bulten J, Pijnenborg JMA. Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and meta-analysis. Obstet Gynecol. 2017;130(4):803–813. doi: 10.1097/AOG.0000000000002261. [DOI] [PubMed] [Google Scholar]
- 13.Boronow RC, Morrow CP, Creasman WT, Disaia PJ, Silverberg SG, Miller A, Blessing JA. Surgical staging in endometrial cancer: clinical-pathologic findings of a prospective study. Obstet Gynecol. 1984;63(6):825–832. [PubMed] [Google Scholar]
- 14.Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987;60:2035. doi: 10.1002/1097-0142(19901015)60:8+<2035::AID-CNCR2820601515>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
- 15.Dowdy SC, et al. Extra-peritoneal laparoscopic para-aortic lymphadenectomy—a prospective cohort study of 293 patients with endometrial cancer. Gynecol Oncol. 2008;111(3):418–424. doi: 10.1016/j.ygyno.2008.08.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kim Y, Eoh KJ, Lee J, et al. Comparison of outcomes between the one-step and two-step sentinel lymph node mapping techniques in endometrial cancer. Int J Gynecol Cancer. 2020;30:318–324. doi: 10.1136/ijgc-2019-000962. [DOI] [PubMed] [Google Scholar]