YGYNO-976192; No. of pages: 5; 4C: Gynecologic Oncology xxx (2016) xxx–xxx
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A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer Yukiharu Todo ⁎, Kazuhira Okamoto, Sho Takeshita, Satoko Sudo, Hidenori Kato Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, 4-2 Kikusui, Shiroishi-ku, Sapporo 003-0804, Japan
H I G H L I G H T S • Risk of PAN metastasis can be preoperatively assessed in endometrial cancer. • A group at negligible risk of PAN metastasis can be preoperatively identified. • PAN searching is not needed in the group at negligible risk of PAN metastasis.
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Article history: Received 6 December 2015 Received in revised form 18 January 2016 Accepted 25 January 2016 Available online xxxx Keywords: Endometrial cancer Para-aortic lymph node metastasis Lymphadenectomy Preoperative risk assessment
a b s t r a c t Objective. The objective of this study was to identify a group at negligible risk of para-aortic lymph node metastasis (LNM) in endometrial cancer and its presumed prognosis. Methods. We enrolled 555 patients with endometrial cancer who underwent preoperative endometrial biopsy, pelvic magnetic resonance imaging, and determination of serum cancer antigen (CA)125, and surgical treatment including lymphadenectomy. Three risk factors for LNM confirmed in previous reports were grade 3/non-endometrioid histology, large tumor volume, and a high CA125 value. Pelvic LNM rate, para-aortic LNM rate, and 5-year overall survival rate were assessed in four groups according to the number of these risk factors. Results. LNM was noted in medical records of 74 patients (13.3%). Of 226 patients in the no risk factor group, pelvic LNM was noted in the medical records of five (2.2%), but no para-aortic LNM was noted. The 3-year/5-year survival rates in the no risk factor group were 97.2/96.6%, with a median follow-up period of 65.5 months. Of 186 patients in the one risk factor group, 21 (11.2%) had pelvic LNM. Of 113 patients undergoing para-aortic LN dissection in the one risk factor group, six (5.3%) had para-aortic LNM. Conclusion. Patients with grade 1/2 histology based on endometrial biopsy, small tumor volume assessed by magnetic resonance imaging, and low CA125 value are supposed to have negligible risk of para-aortic LNM. In such patients, the para-aortic region might not be considered as a target to be assessed by staging procedure. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Para-aortic lymph nodes (LNs) are widely known as regional LNs in endometrial cancer, through earlier surgicopathologic studies [1–6]. Randomized controlled trials have shown that pelvic lymphadenectomy does not have therapeutic significance and increases complication rates for clinical stage I endometrial cancer [7, 8]. In contrast, full lymphadenectomy with para-aortic lymphadenectomy might be efficacious in selected cases of endometrial cancer, especially in high-risk cases [9]. Clinical stage I endometrial cancer includes high-risk as well as lowrisk patients. However, no consensus exists for identifying low-risk patients with LN metastasis (LNM) in a preoperative setting. Therefore, decisions about whether to perform lymphadenectomy in clinical stage I patients are not easy. ⁎ Corresponding author. E-mail address: [email protected] (Y. Todo).
Alternatively, sentinel LN (SLN) biopsy is expected to offer a tradeoff between systematic lymphadenectomy and no dissection at all in clinical stage I endometrial cancer patients. SLN mapping in endometrial cancer is increasingly credible [10]. Although previous studies showed sufficient feasibility of SLN mapping as a staging procedure for endometrial cancer [11–18], there is a concern over detection of SLNs in the para-aortic area. This issue is closely related to the site of tracer injection. Merits and demerits of SLN mapping have been evaluated according to the following three injection sites: (1) subserosal injection into the uterine corpus at the time of surgery; (2) hysteroscopic injection into the endometrium; and (3) transvaginal injection into the uterine cervix. Cervical injection is the least technically demanding and has been favored in previous large studies of SLN mapping in endometrial cancer. The detection rate of SLNs, negative predictive value, and sensitivity were reported to be 81–92%, 97–99%, and 84–89%, respectively, in previous large studies of SLN mapping in endometrial cancer [11–13]. However, this procedure lacks the ability to assess para-aortic LNs
http://dx.doi.org/10.1016/j.ygyno.2016.01.024 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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Y. Todo et al. / Gynecologic Oncology xxx (2016) xxx–xxx
systematically [11–15]. If a patient group at negligible risk of para-aortic LNM can be preoperatively identified, assessment of the para-aortic region is not needed for systematic staging. The relevant patients might safely undergo SLN biopsy with the use of cervical tracer injection for appropriate staging. We previously confirmed the following three independent risk factors for LNM: (1) unfavorable histological results by endometrial biopsy; (2) high tumor volume by magnetic resonance imaging (MRI); and (3) high serum cancer antigen (CA)125 level [19, 20]. Similar results were confirmed in a Japan–Korea cooperative study [21]. We formulated a scoring system for predicting LNM that consisted of these three factors and reported that the para-aortic LNM rate was 0.5% in patients with none of these factors [20]. In the present study, we verified the predictive effects of this system regarding the para-aortic LNM rate and provided information on survival outcome in patients with favorable histology based on endometrial biopsy, small tumor volume, and low serum CA125 level. These patients could be proxies for hypothetical subjects who would have surgical staging by SLN biopsy with the use of cervical tracer injection and without concurrently using subserosal/hysteroscopic injection. 2. Methods 2.1. Patients A total of 926 patients with uterine corpus malignancies were treated in the National Hospital Organization, Hokkaido Cancer Center, Japan from January 1995 to December 2014. Of these patients, 46 who did not undergo surgery and 242 who underwent surgery without lymphadenectomy were excluded from the present study. Patients with lack of data from endometrial biopsy, pelvic MRI, and blood sampling for serum CA125, and patients in whom sarcoma/carcinosarcoma was diagnosed by preoperative endometrial biopsy were also excluded. Consequently, this study was carried out using data of 555 patients with endometrial carcinoma for whom tumor grade/histology, myometrial invasion, tumor volume, and serum CA125 level were preoperatively confirmed and extensive surgical staging was performed. We previously conducted a pilot study to confirm preoperative risk factors for LNM in endometrial cancer [19, 20]. However, there was no duplication of cases in the present study because Hokkaido Cancer Center did not participate in the previous studies. All included patients underwent lymphadenectomy in addition to hysterectomy and bilateral salpingo-oophorectomy. Some aspects of the management of endometrial cancer at Hokkaido Cancer Center changed during 2004. Prior to 2004, pelvic lymphadenectomy was performed without para-aortic lymphadenectomy. After 2004, both pelvic and para-aortic lymphadenectomy were performed. Para-aortic lymphadenectomy involves dissection of the para-aortic LNs from the level of the bifurcation of the aorta to the level of the renal veins. Adjuvant therapy also varied during the study period. Patients with extrauterine disease were considered to have a high risk of recurrence; patients with b50% depth of myoinvasion and grade 1/2 tumor without lymphovascular invasion were considered to have a low risk of recurrence; and other patients were considered to have an intermediate risk of recurrence. Before 2004, patients in the intermediate- and high-risk categories received adjuvant radiotherapy (whole-pelvic external-beam radiation, 50 Gy/25 Fr) or chemotherapy (platinum-based, 4–6 cycles), depending on patient preference and physician discretion. After 2004, patients in the intermediate- and high-risk categories received adjuvant chemotherapy. The study protocol was approved by the local Institutional Review Board and the hospital Ethics Committee. 2.2. Preoperative risk assessment The LNM score was formulated based upon the data in previous papers [20]. This scoring system comprised three risk factors for predicting
LNM: histological examination (grade 1/2 vs grade 3/others) based on biopsy, tumor volume (small vs large) assessed by MRI, and serum CA125 level (low vs high) (Table 1). LNM score was determined by the number of corresponding risk factors, which resulted in the score being classified into four categories: no risk factor, one risk factor, two risk factors, and three risk factors. A gynecologic oncologist (T.Y.) interpreted the MRI data. The data were evaluated in either T2weighted MR images or gadolinium-enhanced T1-weighted images. Tumor volume was substituted by volume index. Volume index was defined as the product of the maximum longitudinal diameter along the uterine axis, the maximum anteroposterior diameter (thickness) on a sagittal section image, and the maximum horizontal diameter on a horizontal section image (Fig. 1). The cutoff levels of volume index and CA125 were determined on the basis of data in a previous paper [20]. Large volume index was defined as ≥36. High CA125 level was defined as ≥ 70 U/ml for patients b50 years of age and ≥28 U/ml for patients ≥50 years of age. 2.3. Statistical analysis Variables were compared between groups using the χ2 test. Overall survival (OS) was used as a survival outcome measure. We compared the survival rates among every category in the respective assessment. Survival rates were estimated by the Kaplan–Meier method. The logrank test was used to compare survival curves. The statistical significance level was set at 0.05. Statistical analyses were performed with StatView J version 5.0 (SAS Institute, Cary, NC, USA). 3. Results The clinicopathologic characteristics of patients are shown in Table 2. The ages of the patients ranged from 27 to 85 years (median age, 58 years). Four hundred and twenty patients (75.7%) were in FIGO stage I, 31 (5.6%) were in stage II, 86 (15.5%) were in stage III, and 18 (3.2%) were in stage IV. The median number of LNs retrieved was 46 (mean ± SD, 47.4 ± 23.8). Three hundred and seven (55.3%) patients underwent para-aortic lymphadenectomy. Para-aortic lymphadenectomy was more frequently performed in patients with FIGO stage III (70.9%) or stage IV (61.1%) than in patients with FIGO stage I (52.1%) and stage II (51.6%) (P = 0.0015). Seventy-four (13.3%) patients had LNM and 30 (9.8%) had para-aortic LNM. Of the 30 patients with para-aortic LNM, 24 (80.0%) had pelvic LNM and 6 (20.0%) had no pelvic LNM. Twenty-one (70.0%) had para-aortic LNM above the inferior mesenteric artery and 9 (30.0%) had no LNM in the upper para-aortic region (Supplementary Table 1). Two hundred and ninety-nine (53.9%) patients received adjuvant treatment. The median follow-up period of the patients was 64 months (range: 1–173 months). Results of preoperative risk assessment are shown in Table 3. Two hundred and twenty-six (40.7%) patients were in the no risk factor group, 186 (33.5%) in the one risk factor group, 115 (20.7%) in the two risk factors group, and 28 (5.0%) in the three risk factors group. LNM frequencies according to the LNM score are shown in Table 4. The four groups significantly differed in LNM rates (P b 0.0001), pelvic LNM rates (P b 0.0001), para-aortic LNM rates (P b 0.0001), and OS rates (log-rank test; P b 0.0001). The rates of LNM were 2.2% (5/226) Table 1 Risk factors for predicting lymph node metastasis confirmed in the previous literature [20]. Factor
High-risk criteria
Tumor grade/histology Volume index assessed by MRI Serum CA125
Endometrioid grade 3/non-endometrioid 36 or more ≥70 U/ml for patients b50 years of age and ≥28 U/ml for patients ≥50 years of age
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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Table 2 Clinical background of patients with endometrial cancer who underwent extensive surgical staging including lymphadenectomy.
Age (years old) Median (range) Tumor grade/histology (final pathology) Endometrioid adenocarcinoma G1 G2 G3 Non-endometrioid carcinoma FIGO stage (2008) I II III IV Number of harvested lymph nodes Median (range) Number of harvested pelvic lymph nodes Median (range) Number of harvested para-aortic lymph nodes Median (range) Type of lymphadenectomy PLX + PALX PLX Lymph node metastasis Negative Positive Pelvic lymph node metastasis Para-aortic lymph node metastasisa Adjuvant treatment Not done Done Follow-up period (months) Median (range) Total (N)
Fig. 1. Volume index, defined as the product of maximum longitudinal diameter (a: 3.6 cm) along uterine axis, maximum anteroposterior diameter (b: 3.2 cm) in sagittal section image, and maximum horizontal diameter (c: 3.5 cm) in horizontal section image. Volume index of upper image was 40.3.
in the no risk factor group, 12.4% (23/186) in the one risk factor group, 25.2% (29/115) in the two risk factors group, and 60.7% (17/28) in the three risk factors group. The rates of para-aortic LNM were 0% (0/93) in the no risk factor group, 5.3% (6/113) in the one risk factor group, 18.4% (14/76) in the two risk factors group, and 40.0% (10/25) in the three risk factors group. Three-year OS rates were 97.2% in the no risk factor group, 96.1% in the one risk factor group, 87.4% were in the two risk factors group, and 69.6% in the three risk factors group. Five-year OS rates were 96.6% in the no risk factor group, 92.3% in the one risk factor group, 84.6% in the two risk factors group, and 57.1% in the three risk factors group. 4. Discussion In terms of SLN mapping procedure, cervical injection is the least technically demanding and its detection rate of pelvic SLN and negative predictive value/sensitivity for pelvic LNM are, on the whole, satisfactory [11–15]. However, this procedure has poor ability to detect paraaortic SLNs. While hysteroscopic injection reportedly achieved a paraaortic SLN detection rate of 18–56% [14–16], cervical injection resulted in a rate of 0–16% [11–15]. Additionally, although it is reported that subserosal injection [6] and hysteroscopic injection [15, 18] can detect para-aortic SLNs above the inferior mesenteric artery, as far as we know, SLNs in the upper para-aortic region have not been detected by cervical injection. Obviously, cervical injection lacks the ability to detect para-aortic SLNs above the inferior mesenteric artery, which is the weakest part of this procedure. Therefore, for patients with endometrial
Previous study [20]
Present study
56 (23–80)
58 (27–85)
54.4% (231) 27.1% (115) 13.6% (58) 5.0% (21)
53.2% (295) 20.2% (112) 12.6% (70) 14.0% (78)
75.5% (321) 5.4% (23) 17.4% (74) 1.6% (7)
75.7% (420) 5.6% (31) 15.5% (86) 3.2% (18)
75 (1–190)
46 (1–128)
52 (1–129)
37 (1−100)
22 (0–85)
5 (0–56)
99.1% (421) 0.9% (4)
55.3% (307) 44.7% (248)
84.2% (358) 15.8% (67) 14.6% (62) 10.5% (44)
86.7% (481) 13.3% (74) 12.3% (68) 9.8% (30)
50.8% (216) 49.2% (209)
46.1% (256) 53.9% (299)
75 (1–173) 425
64 (1–173) 555
FIGO: the International Federation of Gynecology and Obstetrics, PLX: pelvic lymphadenectomy, PALX: para-aortic lymphadenectomy. a The number of patients with para-aortic node metastasis/ the number of patients who underwent PALX.
cancer, SLN mapping with cervical injection should be limited to those at negligible risk of para-aortic LNM. In our previous study, only one patient (0.5%) had para-aortic LNM among 211 endometrial cancer patients with favorable histology, small tumor volume, and low serum CA125 level [20]. Para-aortic LNs above the inferior mesenteric artery were surgically removed and pathologically investigated. Consequently, a median 75 LNs were harvested, which gave a good value for para-aortic LNM rate. In the present study, no patient had para-aortic LNM in 93 patients corresponding to the Table 3 Results of preoperative assessment for predicting lymph node metastasis. Previous study [20] Present study LNM score Risk factor = 0 Risk factor = 1 Risk factor = 2 Risk factor = 3 Tumor grade/histology (preoperative biopsy) Endometrioid adenocarcinoma G1 G2 G3 Non-endometrioid carcinoma Volume index Small Large Serum CA 125 Low High Total (N)
49.6% (211) 26.1% (111) 18.6% (79) 5.6% (24)
40.7% (226) 33.5% (186) 20.7% (115) 5.0% (28)
60.7% (258) 24.9% (106) 11.3% (48) 3.1% (13)
60.4% (335) 14.8% (188) 12.1% (115) 12.8% (84)
68.2% (290) 31.8% (135)
64.5% (358) 34.5% (197)
65.9% (280) 34.1% (145) 425
70.3% (390) 29.7% (165) 555
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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Table 4 Actual rates of lymph node metastasis and overall survival according to the number of risk factors for lymph node metastasis. Previous study [20]
LNM rate LNM PLNM PANMa Survival rate 3 year-OS 5 year-OS 7 year-OS Patients who had PAN retrieved (N) Total (N)
Present study
RF = 0
RF = 1
RF = 2
RF = 3
RF = 0
RF = 1
RF = 2
RF = 3
3.3% (n = 7) 3.3% (n = 7) 0.5% (n = 1)
11.7% (n = 13) 11.7% (n = 13) 9.0% (n = 10)
36.7% (n = 29) 30.3% (n = 24) 27.6% (n = 21)
75.0% (n = 18) 70.8% (n = 17) 54.2% (n = 13)
2.2% (n = 5) 2.2% (n = 5) 0.0% (n = 0)
12.4% (n = 23) 11.3% (n = 21) 5.3% (n = 6)
25.2% (n = 29) 22.6% (n = 26) 18.4% (n = 14)
60.7% (n = 17) 57.1% (n = 16) 40.0% (n = 10)
97.1% 96.1% 94.8% 211 211
97.2% 93.3% 93.3% 111 111
90.9% 85.3% 78.4% 76 79
61.8% 57.4% 57.4% 24 24
97.2% 96.6% 94.8% 93 226
96.1% 92.3% 88.6% 113 186
87.4% 84.6% 71.5% 76 115
69.6% 57.1% 57.1% 25 28
LNM: lymph node metastasis, PLNM: pelvic lymph node metastasis, PANM, para-aortic lymph node metastasis, OS: overall survival, PAN: para-aortic lymph node, RF: risk factor. a The number of patients with PANM/the number of patients who had PAN retrieved.
above-mentioned group. Although 44.7% of the included patients did not undergo para-aortic LN dissection, the upper para-aortic LNs were routinely removed and investigated when para-aortic LN dissection was performed. Given the results of the previous and present studies collectively, actual para-aortic LNM rate in the relevant group, namely, patients with favorable histology, small tumor volume, and low serum CA125 level, was 0.33%. This is sufficiently negligible. This result justifies our conclusion that SLN mapping with the exclusive use of cervical tracer injection, that is, without concurrent use of subserosal/hysteroscopic injection, can be safely performed in endometrial cancer patients with the above characteristics. A limitation of the present study was its retrospective, observational design. Especially problematic was MRI assessment, namely, intraobserver inconsistency and/or inter-observer variability. Unfortunately, we have no data regarding such variability of volume indices assessment. One may ponder whether myoinvasion is better for predicting LNM than tumor volume is. We previously conducted a Japan–Korea cooperative study using a Korean cohort to evaluate whether LNM score functions in a different country from Japan [21]. In that study, highgrade histology assessed by endometrial biopsy, large volume index, and high serum CA125 level were significantly and independently related to LNM. When volume index was excluded from the analysis,
myoinvasion assessed by MRI was an independent risk factor for LNM as well as high-grade histology and high serum CA125 level. These results were compatible with our previous study [20]. It seems that myoinvasion assessed by MRI may be more intuitive to clinicians than tumor volume. However, myoinvasion assessed by MRI has the problem of interobserver inconsistency or variability. There would be some occasions when attending physicians would have difficulty in judging myometrial invasion using MRI. We do not intend to state that volume index is superior to myoinvasion assessed by MRI in predicting LNM. However, there would be fewer cases than expected with data for tumor size, which appears to be in a gray zone. Distributions of volume index values were similar despite the fact that they were evaluated in two different cohorts (Fig. 2). In the previous study [20], 4.9% of the patients had volume indexes of 30–40; and 9.0% in the present study had volume indexes in the same range. Less than 10% of the patients had a volume index close to 36, which has been determined as a cut-off for predicting LNM in endometrial cancer. We believe that volume index can be a substitute for predicting LNM when it is difficult to judge myometrial invasion using MRI. In conclusion, patients with grade 1/2 cancer based on endometrial biopsy, small tumor volume assessed by MRI, and low CA125 value are supposed to have negligible risk of para-aortic LNM. Prognosis of
Fig. 2. Distributions of volume index measurements.
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
Y. Todo et al. / Gynecologic Oncology xxx (2016) xxx–xxx
this group is excellent when appropriate surgical staging is performed. SLN mapping with the use of exclusive cervical tracer injection might be safely performed in this group of patients. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.01.024. Conflict of interest statement The authors have no conflict of interest to report regarding the research content, conclusions, and significance of this study.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer Yukiharu Todo ⁎, Kazuhira Okamoto, Sho Takeshita, Satoko Sudo, Hidenori Kato Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, 4-2 Kikusui, Shiroishi-ku, Sapporo 003-0804, Japan
H I G H L I G H T S • Risk of PAN metastasis can be preoperatively assessed in endometrial cancer. • A group at negligible risk of PAN metastasis can be preoperatively identified. • PAN searching is not needed in the group at negligible risk of PAN metastasis.
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Article history: Received 6 December 2015 Received in revised form 18 January 2016 Accepted 25 January 2016 Available online xxxx Keywords: Endometrial cancer Para-aortic lymph node metastasis Lymphadenectomy Preoperative risk assessment
a b s t r a c t Objective. The objective of this study was to identify a group at negligible risk of para-aortic lymph node metastasis (LNM) in endometrial cancer and its presumed prognosis. Methods. We enrolled 555 patients with endometrial cancer who underwent preoperative endometrial biopsy, pelvic magnetic resonance imaging, and determination of serum cancer antigen (CA)125, and surgical treatment including lymphadenectomy. Three risk factors for LNM confirmed in previous reports were grade 3/non-endometrioid histology, large tumor volume, and a high CA125 value. Pelvic LNM rate, para-aortic LNM rate, and 5-year overall survival rate were assessed in four groups according to the number of these risk factors. Results. LNM was noted in medical records of 74 patients (13.3%). Of 226 patients in the no risk factor group, pelvic LNM was noted in the medical records of five (2.2%), but no para-aortic LNM was noted. The 3-year/5-year survival rates in the no risk factor group were 97.2/96.6%, with a median follow-up period of 65.5 months. Of 186 patients in the one risk factor group, 21 (11.2%) had pelvic LNM. Of 113 patients undergoing para-aortic LN dissection in the one risk factor group, six (5.3%) had para-aortic LNM. Conclusion. Patients with grade 1/2 histology based on endometrial biopsy, small tumor volume assessed by magnetic resonance imaging, and low CA125 value are supposed to have negligible risk of para-aortic LNM. In such patients, the para-aortic region might not be considered as a target to be assessed by staging procedure. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Para-aortic lymph nodes (LNs) are widely known as regional LNs in endometrial cancer, through earlier surgicopathologic studies [1–6]. Randomized controlled trials have shown that pelvic lymphadenectomy does not have therapeutic significance and increases complication rates for clinical stage I endometrial cancer [7, 8]. In contrast, full lymphadenectomy with para-aortic lymphadenectomy might be efficacious in selected cases of endometrial cancer, especially in high-risk cases [9]. Clinical stage I endometrial cancer includes high-risk as well as lowrisk patients. However, no consensus exists for identifying low-risk patients with LN metastasis (LNM) in a preoperative setting. Therefore, decisions about whether to perform lymphadenectomy in clinical stage I patients are not easy. ⁎ Corresponding author. E-mail address: [email protected] (Y. Todo).
Alternatively, sentinel LN (SLN) biopsy is expected to offer a tradeoff between systematic lymphadenectomy and no dissection at all in clinical stage I endometrial cancer patients. SLN mapping in endometrial cancer is increasingly credible [10]. Although previous studies showed sufficient feasibility of SLN mapping as a staging procedure for endometrial cancer [11–18], there is a concern over detection of SLNs in the para-aortic area. This issue is closely related to the site of tracer injection. Merits and demerits of SLN mapping have been evaluated according to the following three injection sites: (1) subserosal injection into the uterine corpus at the time of surgery; (2) hysteroscopic injection into the endometrium; and (3) transvaginal injection into the uterine cervix. Cervical injection is the least technically demanding and has been favored in previous large studies of SLN mapping in endometrial cancer. The detection rate of SLNs, negative predictive value, and sensitivity were reported to be 81–92%, 97–99%, and 84–89%, respectively, in previous large studies of SLN mapping in endometrial cancer [11–13]. However, this procedure lacks the ability to assess para-aortic LNs
http://dx.doi.org/10.1016/j.ygyno.2016.01.024 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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systematically [11–15]. If a patient group at negligible risk of para-aortic LNM can be preoperatively identified, assessment of the para-aortic region is not needed for systematic staging. The relevant patients might safely undergo SLN biopsy with the use of cervical tracer injection for appropriate staging. We previously confirmed the following three independent risk factors for LNM: (1) unfavorable histological results by endometrial biopsy; (2) high tumor volume by magnetic resonance imaging (MRI); and (3) high serum cancer antigen (CA)125 level [19, 20]. Similar results were confirmed in a Japan–Korea cooperative study [21]. We formulated a scoring system for predicting LNM that consisted of these three factors and reported that the para-aortic LNM rate was 0.5% in patients with none of these factors [20]. In the present study, we verified the predictive effects of this system regarding the para-aortic LNM rate and provided information on survival outcome in patients with favorable histology based on endometrial biopsy, small tumor volume, and low serum CA125 level. These patients could be proxies for hypothetical subjects who would have surgical staging by SLN biopsy with the use of cervical tracer injection and without concurrently using subserosal/hysteroscopic injection. 2. Methods 2.1. Patients A total of 926 patients with uterine corpus malignancies were treated in the National Hospital Organization, Hokkaido Cancer Center, Japan from January 1995 to December 2014. Of these patients, 46 who did not undergo surgery and 242 who underwent surgery without lymphadenectomy were excluded from the present study. Patients with lack of data from endometrial biopsy, pelvic MRI, and blood sampling for serum CA125, and patients in whom sarcoma/carcinosarcoma was diagnosed by preoperative endometrial biopsy were also excluded. Consequently, this study was carried out using data of 555 patients with endometrial carcinoma for whom tumor grade/histology, myometrial invasion, tumor volume, and serum CA125 level were preoperatively confirmed and extensive surgical staging was performed. We previously conducted a pilot study to confirm preoperative risk factors for LNM in endometrial cancer [19, 20]. However, there was no duplication of cases in the present study because Hokkaido Cancer Center did not participate in the previous studies. All included patients underwent lymphadenectomy in addition to hysterectomy and bilateral salpingo-oophorectomy. Some aspects of the management of endometrial cancer at Hokkaido Cancer Center changed during 2004. Prior to 2004, pelvic lymphadenectomy was performed without para-aortic lymphadenectomy. After 2004, both pelvic and para-aortic lymphadenectomy were performed. Para-aortic lymphadenectomy involves dissection of the para-aortic LNs from the level of the bifurcation of the aorta to the level of the renal veins. Adjuvant therapy also varied during the study period. Patients with extrauterine disease were considered to have a high risk of recurrence; patients with b50% depth of myoinvasion and grade 1/2 tumor without lymphovascular invasion were considered to have a low risk of recurrence; and other patients were considered to have an intermediate risk of recurrence. Before 2004, patients in the intermediate- and high-risk categories received adjuvant radiotherapy (whole-pelvic external-beam radiation, 50 Gy/25 Fr) or chemotherapy (platinum-based, 4–6 cycles), depending on patient preference and physician discretion. After 2004, patients in the intermediate- and high-risk categories received adjuvant chemotherapy. The study protocol was approved by the local Institutional Review Board and the hospital Ethics Committee. 2.2. Preoperative risk assessment The LNM score was formulated based upon the data in previous papers [20]. This scoring system comprised three risk factors for predicting
LNM: histological examination (grade 1/2 vs grade 3/others) based on biopsy, tumor volume (small vs large) assessed by MRI, and serum CA125 level (low vs high) (Table 1). LNM score was determined by the number of corresponding risk factors, which resulted in the score being classified into four categories: no risk factor, one risk factor, two risk factors, and three risk factors. A gynecologic oncologist (T.Y.) interpreted the MRI data. The data were evaluated in either T2weighted MR images or gadolinium-enhanced T1-weighted images. Tumor volume was substituted by volume index. Volume index was defined as the product of the maximum longitudinal diameter along the uterine axis, the maximum anteroposterior diameter (thickness) on a sagittal section image, and the maximum horizontal diameter on a horizontal section image (Fig. 1). The cutoff levels of volume index and CA125 were determined on the basis of data in a previous paper [20]. Large volume index was defined as ≥36. High CA125 level was defined as ≥ 70 U/ml for patients b50 years of age and ≥28 U/ml for patients ≥50 years of age. 2.3. Statistical analysis Variables were compared between groups using the χ2 test. Overall survival (OS) was used as a survival outcome measure. We compared the survival rates among every category in the respective assessment. Survival rates were estimated by the Kaplan–Meier method. The logrank test was used to compare survival curves. The statistical significance level was set at 0.05. Statistical analyses were performed with StatView J version 5.0 (SAS Institute, Cary, NC, USA). 3. Results The clinicopathologic characteristics of patients are shown in Table 2. The ages of the patients ranged from 27 to 85 years (median age, 58 years). Four hundred and twenty patients (75.7%) were in FIGO stage I, 31 (5.6%) were in stage II, 86 (15.5%) were in stage III, and 18 (3.2%) were in stage IV. The median number of LNs retrieved was 46 (mean ± SD, 47.4 ± 23.8). Three hundred and seven (55.3%) patients underwent para-aortic lymphadenectomy. Para-aortic lymphadenectomy was more frequently performed in patients with FIGO stage III (70.9%) or stage IV (61.1%) than in patients with FIGO stage I (52.1%) and stage II (51.6%) (P = 0.0015). Seventy-four (13.3%) patients had LNM and 30 (9.8%) had para-aortic LNM. Of the 30 patients with para-aortic LNM, 24 (80.0%) had pelvic LNM and 6 (20.0%) had no pelvic LNM. Twenty-one (70.0%) had para-aortic LNM above the inferior mesenteric artery and 9 (30.0%) had no LNM in the upper para-aortic region (Supplementary Table 1). Two hundred and ninety-nine (53.9%) patients received adjuvant treatment. The median follow-up period of the patients was 64 months (range: 1–173 months). Results of preoperative risk assessment are shown in Table 3. Two hundred and twenty-six (40.7%) patients were in the no risk factor group, 186 (33.5%) in the one risk factor group, 115 (20.7%) in the two risk factors group, and 28 (5.0%) in the three risk factors group. LNM frequencies according to the LNM score are shown in Table 4. The four groups significantly differed in LNM rates (P b 0.0001), pelvic LNM rates (P b 0.0001), para-aortic LNM rates (P b 0.0001), and OS rates (log-rank test; P b 0.0001). The rates of LNM were 2.2% (5/226) Table 1 Risk factors for predicting lymph node metastasis confirmed in the previous literature [20]. Factor
High-risk criteria
Tumor grade/histology Volume index assessed by MRI Serum CA125
Endometrioid grade 3/non-endometrioid 36 or more ≥70 U/ml for patients b50 years of age and ≥28 U/ml for patients ≥50 years of age
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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Table 2 Clinical background of patients with endometrial cancer who underwent extensive surgical staging including lymphadenectomy.
Age (years old) Median (range) Tumor grade/histology (final pathology) Endometrioid adenocarcinoma G1 G2 G3 Non-endometrioid carcinoma FIGO stage (2008) I II III IV Number of harvested lymph nodes Median (range) Number of harvested pelvic lymph nodes Median (range) Number of harvested para-aortic lymph nodes Median (range) Type of lymphadenectomy PLX + PALX PLX Lymph node metastasis Negative Positive Pelvic lymph node metastasis Para-aortic lymph node metastasisa Adjuvant treatment Not done Done Follow-up period (months) Median (range) Total (N)
Fig. 1. Volume index, defined as the product of maximum longitudinal diameter (a: 3.6 cm) along uterine axis, maximum anteroposterior diameter (b: 3.2 cm) in sagittal section image, and maximum horizontal diameter (c: 3.5 cm) in horizontal section image. Volume index of upper image was 40.3.
in the no risk factor group, 12.4% (23/186) in the one risk factor group, 25.2% (29/115) in the two risk factors group, and 60.7% (17/28) in the three risk factors group. The rates of para-aortic LNM were 0% (0/93) in the no risk factor group, 5.3% (6/113) in the one risk factor group, 18.4% (14/76) in the two risk factors group, and 40.0% (10/25) in the three risk factors group. Three-year OS rates were 97.2% in the no risk factor group, 96.1% in the one risk factor group, 87.4% were in the two risk factors group, and 69.6% in the three risk factors group. Five-year OS rates were 96.6% in the no risk factor group, 92.3% in the one risk factor group, 84.6% in the two risk factors group, and 57.1% in the three risk factors group. 4. Discussion In terms of SLN mapping procedure, cervical injection is the least technically demanding and its detection rate of pelvic SLN and negative predictive value/sensitivity for pelvic LNM are, on the whole, satisfactory [11–15]. However, this procedure has poor ability to detect paraaortic SLNs. While hysteroscopic injection reportedly achieved a paraaortic SLN detection rate of 18–56% [14–16], cervical injection resulted in a rate of 0–16% [11–15]. Additionally, although it is reported that subserosal injection [6] and hysteroscopic injection [15, 18] can detect para-aortic SLNs above the inferior mesenteric artery, as far as we know, SLNs in the upper para-aortic region have not been detected by cervical injection. Obviously, cervical injection lacks the ability to detect para-aortic SLNs above the inferior mesenteric artery, which is the weakest part of this procedure. Therefore, for patients with endometrial
Previous study [20]
Present study
56 (23–80)
58 (27–85)
54.4% (231) 27.1% (115) 13.6% (58) 5.0% (21)
53.2% (295) 20.2% (112) 12.6% (70) 14.0% (78)
75.5% (321) 5.4% (23) 17.4% (74) 1.6% (7)
75.7% (420) 5.6% (31) 15.5% (86) 3.2% (18)
75 (1–190)
46 (1–128)
52 (1–129)
37 (1−100)
22 (0–85)
5 (0–56)
99.1% (421) 0.9% (4)
55.3% (307) 44.7% (248)
84.2% (358) 15.8% (67) 14.6% (62) 10.5% (44)
86.7% (481) 13.3% (74) 12.3% (68) 9.8% (30)
50.8% (216) 49.2% (209)
46.1% (256) 53.9% (299)
75 (1–173) 425
64 (1–173) 555
FIGO: the International Federation of Gynecology and Obstetrics, PLX: pelvic lymphadenectomy, PALX: para-aortic lymphadenectomy. a The number of patients with para-aortic node metastasis/ the number of patients who underwent PALX.
cancer, SLN mapping with cervical injection should be limited to those at negligible risk of para-aortic LNM. In our previous study, only one patient (0.5%) had para-aortic LNM among 211 endometrial cancer patients with favorable histology, small tumor volume, and low serum CA125 level [20]. Para-aortic LNs above the inferior mesenteric artery were surgically removed and pathologically investigated. Consequently, a median 75 LNs were harvested, which gave a good value for para-aortic LNM rate. In the present study, no patient had para-aortic LNM in 93 patients corresponding to the Table 3 Results of preoperative assessment for predicting lymph node metastasis. Previous study [20] Present study LNM score Risk factor = 0 Risk factor = 1 Risk factor = 2 Risk factor = 3 Tumor grade/histology (preoperative biopsy) Endometrioid adenocarcinoma G1 G2 G3 Non-endometrioid carcinoma Volume index Small Large Serum CA 125 Low High Total (N)
49.6% (211) 26.1% (111) 18.6% (79) 5.6% (24)
40.7% (226) 33.5% (186) 20.7% (115) 5.0% (28)
60.7% (258) 24.9% (106) 11.3% (48) 3.1% (13)
60.4% (335) 14.8% (188) 12.1% (115) 12.8% (84)
68.2% (290) 31.8% (135)
64.5% (358) 34.5% (197)
65.9% (280) 34.1% (145) 425
70.3% (390) 29.7% (165) 555
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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Table 4 Actual rates of lymph node metastasis and overall survival according to the number of risk factors for lymph node metastasis. Previous study [20]
LNM rate LNM PLNM PANMa Survival rate 3 year-OS 5 year-OS 7 year-OS Patients who had PAN retrieved (N) Total (N)
Present study
RF = 0
RF = 1
RF = 2
RF = 3
RF = 0
RF = 1
RF = 2
RF = 3
3.3% (n = 7) 3.3% (n = 7) 0.5% (n = 1)
11.7% (n = 13) 11.7% (n = 13) 9.0% (n = 10)
36.7% (n = 29) 30.3% (n = 24) 27.6% (n = 21)
75.0% (n = 18) 70.8% (n = 17) 54.2% (n = 13)
2.2% (n = 5) 2.2% (n = 5) 0.0% (n = 0)
12.4% (n = 23) 11.3% (n = 21) 5.3% (n = 6)
25.2% (n = 29) 22.6% (n = 26) 18.4% (n = 14)
60.7% (n = 17) 57.1% (n = 16) 40.0% (n = 10)
97.1% 96.1% 94.8% 211 211
97.2% 93.3% 93.3% 111 111
90.9% 85.3% 78.4% 76 79
61.8% 57.4% 57.4% 24 24
97.2% 96.6% 94.8% 93 226
96.1% 92.3% 88.6% 113 186
87.4% 84.6% 71.5% 76 115
69.6% 57.1% 57.1% 25 28
LNM: lymph node metastasis, PLNM: pelvic lymph node metastasis, PANM, para-aortic lymph node metastasis, OS: overall survival, PAN: para-aortic lymph node, RF: risk factor. a The number of patients with PANM/the number of patients who had PAN retrieved.
above-mentioned group. Although 44.7% of the included patients did not undergo para-aortic LN dissection, the upper para-aortic LNs were routinely removed and investigated when para-aortic LN dissection was performed. Given the results of the previous and present studies collectively, actual para-aortic LNM rate in the relevant group, namely, patients with favorable histology, small tumor volume, and low serum CA125 level, was 0.33%. This is sufficiently negligible. This result justifies our conclusion that SLN mapping with the exclusive use of cervical tracer injection, that is, without concurrent use of subserosal/hysteroscopic injection, can be safely performed in endometrial cancer patients with the above characteristics. A limitation of the present study was its retrospective, observational design. Especially problematic was MRI assessment, namely, intraobserver inconsistency and/or inter-observer variability. Unfortunately, we have no data regarding such variability of volume indices assessment. One may ponder whether myoinvasion is better for predicting LNM than tumor volume is. We previously conducted a Japan–Korea cooperative study using a Korean cohort to evaluate whether LNM score functions in a different country from Japan [21]. In that study, highgrade histology assessed by endometrial biopsy, large volume index, and high serum CA125 level were significantly and independently related to LNM. When volume index was excluded from the analysis,
myoinvasion assessed by MRI was an independent risk factor for LNM as well as high-grade histology and high serum CA125 level. These results were compatible with our previous study [20]. It seems that myoinvasion assessed by MRI may be more intuitive to clinicians than tumor volume. However, myoinvasion assessed by MRI has the problem of interobserver inconsistency or variability. There would be some occasions when attending physicians would have difficulty in judging myometrial invasion using MRI. We do not intend to state that volume index is superior to myoinvasion assessed by MRI in predicting LNM. However, there would be fewer cases than expected with data for tumor size, which appears to be in a gray zone. Distributions of volume index values were similar despite the fact that they were evaluated in two different cohorts (Fig. 2). In the previous study [20], 4.9% of the patients had volume indexes of 30–40; and 9.0% in the present study had volume indexes in the same range. Less than 10% of the patients had a volume index close to 36, which has been determined as a cut-off for predicting LNM in endometrial cancer. We believe that volume index can be a substitute for predicting LNM when it is difficult to judge myometrial invasion using MRI. In conclusion, patients with grade 1/2 cancer based on endometrial biopsy, small tumor volume assessed by MRI, and low CA125 value are supposed to have negligible risk of para-aortic LNM. Prognosis of
Fig. 2. Distributions of volume index measurements.
Please cite this article as: Y. Todo, et al., A patient group at negligible risk of para-aortic lymph node metastasis in endometrial cancer, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.01.024
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this group is excellent when appropriate surgical staging is performed. SLN mapping with the use of exclusive cervical tracer injection might be safely performed in this group of patients. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.01.024. Conflict of interest statement The authors have no conflict of interest to report regarding the research content, conclusions, and significance of this study.
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