The landmark study GOG 33 described the patterns of spread in endometrial carcinoma and concluded that clinical staging is inaccurate as 22% of clinical stage I patients were assigned a higher surgical stage [
Multivariate analysis of GOG 33 indicated 3 uterine factors as independent predictors of nodal metastasis, including tumor grade, depth of myometrial invasion, and the presence of intraperitoneal disease [
We designed a study examining the role of para-aortic lymphadenectomy in the surgical staging of patients with intermediate and high-risk endometrial adenocarcinomas. Our objectives were to assess whether or not para-aortic lymphadenectomy impacts administration of adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS).
This a retrospective cohort study investigating patients who underwent surgical staging for newly diagnosed high-grade endometrioid, serous, or clear cell endometrial adenocarcinoma at Brigham and Women’s Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, between January 2000 and December 2010. Institutional review board (IRB) approval was obtained from the hospitals’ ethics board. Eligible patients were identified using the hospitals’ pathology data base and data points were obtained from the patients’ electronic medical records.
The first study group included patients who underwent primary surgical staging including total abdominal, laparoscopic or robotic hysterectomy, bilateral salpingooophorectomy, washings, and pelvic and para-aortic lymphadenectomy (PPALN group). The second study group included patients who underwent a similar staging procedure with the exception of the para-aortic lymphadenectomy (PLN group). Data were collected from the patients’ hospital charts and analyzed using appropriate statistical tests.
The primary outcome measure of this study was to compare overall survival (OS) between the two study groups to evaluate the impact that para-aortic lymphadenectomy has on OS. The secondary outcome measures were to examine whether the absence of a para-aortic lymphadenectomy impacts administration of adjuvant therapy, disease recurrence, or disease-free survival (DFS).
Chi-square, Fisher’s exact tests, and
Of all women diagnosed with endometrial carcinoma at Brigham and Women’s Hospital and Massachusetts General Hospital, Boston, MA, USA, between January 2000 and December 2010, 257 met our inclusion criteria and were subjected to our final analysis. The PPALN group was composed of 118 patients, while 139 patients underwent PLN. The mean age at time of diagnosis in the PPALN group was 63.1, and in the PLN group it was 67.1 (
Demographic and clinical characteristics of patients in the PPALN and the PLN groups.
PPALN* |
PLN** |
|
|
---|---|---|---|
Age | |||
Mean (SD) | 63.1 (10.7) | 67.1 (9.5) | 0.002 |
Histology | |||
Grade 3 endometrioid | 52 (44.4%) | 33 (23.7%) | 0.002 |
Papillary serous | 23 (19.7%) | 45 (32.4%) | |
Clear cell | 9 (7.7%) | 15 (10.8%) | |
Grade 2 endometrioid | 4 (3.4%) | 2 (1.4%) | |
Mixed | 25 (21.4%) | 43 (30.9%) | |
Stage | |||
I | 66 (55.9%) | 74 (53.2%) | 0.33 |
II | 7 (5.9%) | 12 (8.6%) | |
III | 35 (29.7%) | 33 (23.7%) | |
IV | 10 (8.5%) | 20 (14.4%) | |
Lymphovascular invasion | |||
No | 52 (47.7%) | 83 (64.8%) | 0.008 |
Yes | 57 (52.3%) | 45 (35.2%) | |
Myometrial invasion | |||
No | 60 (52.6%) | 88 (64.7%) | 0.05 |
Yes | 54 (47.4%) | 48 (35.3%) | |
Intraoperative complications | |||
None | 99 (86.1%) | 124 (89.9%) | 0.44 |
1 or more | 16 (13.9%) | 14 (10.1%) | |
Postoperative complications | |||
None | 54 (46.6%) | 79 (57.2%) | 0.09 |
1 or more | 62 (53.4%) | 59 (42.8%) |
**Pelvic lymph node group.
The surgical stages were similar between the PPALN group and the PLN group (Table
Disease-free survival analysis adjusting for the following variables: tumor histology, lymphovascular invasion, myometrial invasion, and number of para-aortic lymph nodes.
No recurrence |
Recurrence |
Age-adjusted |
Fully adjusted* |
| |
---|---|---|---|---|---|
Histology | |||||
Endometrioid/mixed | 112 (61.5%) | 52 (70.3%) | 1.00 | 1.00 | |
Clear cell | 17 (9.3%) | 7 (9.5%) | 0.95 (0.42, 2.14) | 1.33 (0.58, 3.05) | 0.50 |
Papillary serous | 53 (29.1%) | 15 (20.3%) | 0.64 (0.36, 1.15) | 0.68 (0.37, 1.26) | 0.23 |
Lymphovascular invasion | |||||
No | 112 (67.1%) | 23 (32.9%) | 1.00 | 1.00 | |
Yes | 55 (32.9%) | 47 (67.1%) | 2.99 (1.82, 4.93) | 1.67 (0.91, 3.07) | 0.10 |
Myometrial invasion | |||||
No | 121 (67.6%) | 27 (38.0%) | 1.00 | 1.00 | |
Yes | 58 (32.4%) | 44 (62.0%) | 2.76 (1.70, 4.45) | 1.69 (0.93, 3.06) | 0.08 |
Lymph nodes | |||||
PLN | 111 (60.7%) | 28 (37.8%) | 1.00 | 1.00 | |
PPALN |
56 (30.6%) | 42 (56.8%) | 2.16 (1.33, 3.52) | 2.34 (1.36, 4.02) | 0.002 |
PPALN |
16 (8.7%) | 4 (5.4%) | 1.06 (0.37, 3.01) | 1.36 (0.44, 4.24) | 0.59 |
**PPALN patients with 10 or more dissected para-aortic nodes.
(a) Number of positive lymph nodes in the PLN and PPALN groups. (b) Breakdown of pelvic and para-aortic nodal metastasis in the PPALN group.
PPALN | PLN | |||
---|---|---|---|---|
All | <10 | ≥10 | ||
Positive pelvic lymph nodes | ||||
None | 84 (71.2) | 68 (69.4) | 16 (80.0) | 98 (70.5) |
1 or more | 34 (28.8) | 30 (30.6) | 4 (20.0) | 41 (29.5) |
Mean (SD) | 1.0 (2.4) | 1.1 (2.6) | 0.4 (1.1) | 0.5 (1.1) |
Positive para-aortic lymph nodes | ||||
None | 92 (78.0) | 75 (76.5) | 17 (85.0) | — |
1 or more | 26 (22.0) | 23 (23.5) | 3 (15.0) | — |
Mean (SD) | 0.4 (0.9) | 0.4 (1.0) | 0.2 (0.4) | — |
PPALN |
Negative pelvic and para-aortic nodes | Positive pelvic and para-aortic nodes | Positive pelvic nodes only | Positive para-aortic nodes only |
---|---|---|---|---|
118 (100) | 78 (66.1) | 20 (16.9) | 14 (11.8) | 6 (5.08) |
Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5,
(a) Disease recurrence patterns in the PPALN and the PLN groups. (b) Overall survival analysis adjusting for recurrence site amongst patients who experienced a recurrence*.
PPALN |
PLN |
Chi-square |
|
---|---|---|---|
Vagina | |||
No | 39 (84.8%) | 24 (85.7%) | 0.91 |
Yes | 7 (15.2%) | 4 (14.3%) | |
Pelvic lymph node | |||
No | 38 (82.6%) | 24 (85.7%) | 0.72 |
Yes | 8 (17.4%) | 4 (14.3%) | |
Pelvis | |||
No | 34 (73.9%) | 22 (78.6%) | 0.65 |
Yes | 12 (26.1%) | 6 (21.4%) | |
Para-aortic lymph node | |||
No | 33 (71.7%) | 23 (82.1%) | 0.31 |
Yes | 13 (28.3%) | 5 (17.9%) | |
Extraperitoneal | |||
No | 21 (45.7%) | 12 (42.9%) | 0.81 |
Yes | 25 (54.3%) | 16 (57.1%) | |
Abdomen | |||
No | 33 (71.7%) | 13 (46.4%) | 0.03 |
Yes | 13 (28.3%) | 15 (53.6%) |
Alive |
Dead |
Age-adjusted HR |
Fully adjusted* HR (95% CI) |
| |
---|---|---|---|---|---|
Vagina | |||||
No | 52 (82.5%) | 11 (100.0%) | |||
Yes | 11 (17.5%) | 0 (0%) | |||
Pelvic lymph node | |||||
No | 53 (84.1%) | 9 (81.8%) | 1.00 | 1.00 | |
Yes | 10 (15.9%) | 2 (18.2%) | 0.64 (0.12, 3.31) | 0.22 (0.02, 2.43) | 0.22 |
Pelvis | |||||
No | 48 (76.2%) | 8 (72.7%) | 1.00 | 1.00 | |
Yes | 15 (23.8%) | 3 (27.3%) | 1.06 (0.28, 4.02) | 1.41 (0.15, 13.1) | 0.76 |
Para-aortic lymph node | |||||
No | 48 (76.2%) | 8 (72.7%) | 1.00 | 1.00 | |
Yes | 15 (23.8%) | 3 (27.3%) | 0.46 (0.11, 1.93) | 0.37 (0.04, 3.16) | 0.36 |
Extraperitoneal | |||||
No | 31 (49.2%) | 2 (18.2%) | 1.00 | 1.00 | |
Yes | 32 (50.8%) | 9 (81.8%) | 3.26 (0.69, 15.4) | 10.9 (0.42, 285) | 0.15 |
Abdomen | |||||
No | 39 (61.9%) | 7 (63.6%) | 1.00 | 1.00 | |
Yes | 24 (38.1%) | 4 (36.4%) | 1.46 (0.39, 5.43) | 1.19 (0.16, 8.87) | 0.86 |
Kaplan-Meier disease-free survival estimate. PPALN < 10* versus PLN† or PPALN+10** logrank test: HR 2.34, CI 1.36–4.02,
OS was similar between the PLN and the PPALN groups (
(a) Kaplan-Meier overall survival estimate. Logrank test PLN versus PPALN
Our study investigates the role and extent of retroperitoneal lymphadenectomy in the management of women with intermediate and high-risk endometrial adenocarcinomas. Women who underwent para-aortic lymph node dissections had an overrepresentation of deep myometrial invasion, lymphovascular invasion, and grade 3 endometrioid histology, and they were less likely to undergo postoperative multimodality adjuvant therapy. Cox proportional hazards models as well as multivariate analysis were adjusted for age, year of surgery, histology, lymphovascular invasion, myometrial invasion and adjuvant therapy to control for the variations within the groups. Multivariate analysis incorporating these significant variables along with the extent of lymphadenectomy confirmed that only para-aortic lymphadenectomy yielding less than 10 nodes was associated with an increased risk of recurrence and decreased PFS. No difference in OS was observed between the groups. These data suggest that limited para-aortic lymph node dissection may not obviate the need for aggressive, multimodality adjuvant therapy based on clinical risk factors.
The role of para-aortic lymph node dissection in the staging of endometrial carcinoma is debatable. At our center, the decision to perform systematic para-aortic nodal dissection is largely surgeon dependent. Moreover, the necessity of systematic para-aortic lymphadenectomy is being challenged by some surgeons as they believe it increases morbidity without added benefit. Notably, lymphatic drainage of uterine lesions confined to the corpus is primarily to the external iliac and the obturator lymph nodes [
The therapeutic effects of lymphadenectomy are an issue of great debate in the gynecologic oncology literature. Findings from two large prospective randomized trials of pelvic lymphadenectomy failed to demonstrate a clear therapeutic benefit [
Interestingly, our results indicate that patients in the PPALN group had an increased disease recurrence compared to patients in the PLN group. The number of para-aortic lymph nodes retrieved at dissection was a significant variable in predicting DFS. Abu-Rustum et al. showed that removal of 10 or more regional lymph nodes was indicative of adequate surgical staging [
Adjuvant treatment is an important consideration in the management of women with endometrial carcinoma. The SEPAL study indicated that adjuvant chemotherapy improves survival in intermediate and high-risk diseases [
Patients in the PPALN group experienced a decreased DFS than patients in the PLN group. Recurrences in the vagina, pelvis, pelvic lymph nodes, para-aortic lymph nodes, and extraperitoneal sites were similar between the groups. Interestingly, the absence of a para-aortic lymph node dissection in the PLN group did not impact the risk of para-aortic recurrence. Isolated para-aortic lymph node recurrence usually occurs in approximately 6% of women with endometrial carcinoma [
The limitations of this study are inherent to its retrospective nature. Patients underwent surgical staging with or without para-aortic lymph node dissection based on recommendations by the attending surgeon. This decision may have been influenced by preoperative biopsy results, medical or surgical co-morbidities, and surgeon preferences and practice. Patients in the PLN group were older, and tumors in that group were less likely to invade the outer myometrium or the lymphovascular space. To control for the heterogeneity between the groups, multivariate statistical analyses were preformed. Importantly, the heterogeneous variables had no impact on DFS or OS. As such, the results were statistically significant and consequently have clinical relevance.
In conclusion, patients in the PLN group had improved DFS than patients in the PPALN group. DFS was equivalent between patients in the PLN group and patients in the PALN group who had more than 10 para-aortic lymph nodes removed. Notably, intermediate and high-risk endometrial malignancies often exhibit aggressive tumor biology and may require adjuvant therapy to decrease the risk of recurrence. Importantly, patients in the PLN group were more likely to receive multimodality adjuvant therapy than patients in the PALN group, which may have contributed to their improved survival. Thus, operative staging with pelvic lymphadenectomy alone followed by adjuvant radiation and chemotherapy may represent a safe and effective treatment option for women with this disease. Alternatively, if systematic pelvic and para-aortic lymphadenectomy is performed, thorough nodal dissection is advocated with the goal of obtaining 10 or more nodes per lymphatic chain. If less than 10 para-aortic lymph nodes are sampled, the dissection may be an inadequate triage tool for adjuvant therapy. Hence, adjuvant radiation therapy and chemotherapy should be considered to improve DFS.
The authors have no conflict of interests to disclose.
The authors wish to thank Dr. Dan Cramer, Department of Obstetrics and Gynecology, Epidemiology Center, Brigham and Women’s Hospital, Boston, MA, USA, for his assistance in statistical analysis and for critically reviewing the paper.