ORIGINAL STUDY
Prediction of Para-aortic Spread by Gross Pelvic Lymph Node Findings in Patients With Endometrial Carcinoma Anna Luomaranta, MD,* Jouko Lohi, MD,Þ Ralf Bu¨tzow, MD,Þ Arto Leminen, MD,* and Mikko Loukovaara, MD*
Objective: Isolated para-aortic lymph node metastases are rare in patients with endometrial carcinoma. We wanted to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in these patients. Methods: We identified all women with surgically treated endometrial carcinoma at our institution between January 2008 and February 2013 (n = 854). One hundred seventeen patients received pelvic-aortic lymphadenectomy. Lymph nodes were considered grossly positive based on size and morphology. Results: In patients who underwent comprehensive lymphadenectomy, grossly positive pelvic nodes predicted para-aortic metastasis with a sensitivity of 52.4% and specificity of 93.8%. The positive and negative likelihood ratios were 8.4 and 0.51, respectively. The predictive power of grossly positive pelvic nodes remained significant (odds ratio, 18; 95% confidence interval, 4.1Y78; P G 0.0001) after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. The whole sample of 854 patients was used for Bayesian calculations. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. The negative predictive value of the test (ie, grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis) was 99.7% for patients with superficial grade 1 to 2 endometrioid carcinomas and 98.0% for patients with deeply invasive grade 1 to 2 endometrioid carcinomas. For patients with grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive values were 97.3% and 92.2%, respectively. For the whole study population, the value was 98.4%. Conclusions: When uterine factors are used for risk stratification of endometrial carcinomas, selective para-aortic lymphadenectomy, based on gross findings of pelvic nodes, is feasible for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. Similarly, gross findings of pelvic nodes can be used to evaluate the need for para-aortic lymphadenectomy in the strategy of routine pelvic lymphadenectomy. Key Words: Endometrial carcinoma, Lymphadenectomy, Lymph node metastasis, Surgical staging Received August 21, 2013, and in revised form January 20, 2014. Accepted for publication January 21, 2014. (Int J Gynecol Cancer 2014;24: 697Y702)
Departments of *Obstetrics and Gynecology and †Pathology, Helsinki University Central Hospital, Helsinki, Finland. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000113 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Anna Luomaranta, MD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, PO Box 140, FIN-00029 HUS, Helsinki, Finland. E-mail: [email protected]. The authors declare no conflicts of interest.
& Volume 24, Number 4, May 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
697
Luomaranta et al
International Journal of Gynecological Cancer
he mainstay of the initial treatment for endometrial carT cinoma is surgery with total hysterectomy and bilateral
salpingo-oophorectomy. Based on the 22% risk for extrauterine spread in clinical stage I carcinomas,1 surgical staging with retroperitoneal lymph node dissection has been recommended by the International Federation of Gynecology and Obstetrics since 1988.2 However, the anatomical extent of the procedure and the number of lymph nodes considered adequate for a reliable staging have not been agreed upon. In fact, 2 randomized trials questioned the value of surgical staging in endometrial carcinoma, as pelvic lymphadenectomy was without prognostic benefit in women with clinical stage I to II carcinomas.3,4 These findings have prompted many surgeons to omit lymphadenectomy in patients with a low risk for lymphatic spread. Various algorithms have been used to identify low-risk endometrial carcinomas and to decide whether to perform lymphadenectomy. These algorithms most commonly utilize serum tumor markers (CA125, HE4),5,6 the depth of myometrial invasion as assessed by imaging studies7 or frozen section analysis,8 other preoperative and intraoperative tumor characteristics (histological subtype, grade, size),9 and combinations thereof.10Y12 Risk stratification of endometrial carcinomas by these methods has been variably successful. Although clinically relevant discordance between preoperative endometrial biopsy and final pathology occurs rarely,13,14 findings on the reliability of frozen-section analysis for the determination of tumor grade intraoperatively have been inconsistent.15,16 The sensitivity of magnetic resonance imaging (87%), fludeoxyglucose positron emission tomography/ computed tomography (93%), or transvaginal ultrasound (71%) in assessing myometrial invasion is probably not high enough for a replacement of surgical staging.7 Proponents for systematic lymphadenectomy emphasize that omission of lymphadenectomy may expose many patients with presumed early-stage disease at risk for incomplete surgery and adjuvant therapy. Some authors have also reported that pelvic and para-aortic lymphadenectomy are associated with improved survival.17,18 The extent of lymphadenectomy for the staging of endometrial carcinoma ranges from dissection of pelvic nodes alone to both pelvic and para-aortic dissection, which should ideally be carried out up to the renal vessels. Minimally invasive surgery, performed either by conventional or robotassisted laparoscopy, may restrict the extent of para-aortic lymphadenectomy to the level of inferior mesenteric artery even among experienced surgeons.8 This may reduce the reliability of the procedure, as 77% of para-aortic metastases extend to the supramesenteric level.19 A comprehensive paraaortic lymphadenectomy may be especially challenging in obese subjects, an important notion given the high prevalence of obesity in women with endometrial carcinoma.20 Thus, if reliable methods for risk assessment were available, selective para-aortic lymphadenectomy would be a reasonable option for patients with endometrial carcinoma. Selective approach is also supported by the finding that para-aortic lymphadenectomy is a powerful independent predictor of grade 2 or higher postoperative complications in these patients.21 The risk for para-aortic metastasis in the absence of positive pelvic nodes has been reported to be about 1% in
698
& Volume 24, Number 4, May 2014
endometrial carcinoma.22,23 Because of the rarity of isolated para-aortic metastasis, individualized surgical staging could be planned if there were means to reliably evaluate pelvic nodal status at surgery. The aim of our study was to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in patients with endometrial carcinoma.
MATERIALS AND METHODS Institutional review board approval was obtained for the study. We identified all women with surgically treated endometrial carcinoma at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, between January 2008 and February 2013 (n = 854). Four hundred fifty-five patients (53.3%) received pelvic lymphadenectomy only. One hundred seventeen patients (13.7%) received both pelvic and para-aortic lymphadenectomy and were selected for the current analysis (Table 1). According to the protocol applied at our institution, comprehensive lymphadenectomy was recommended for patients at high risk for extrauterine spread, that is, those with deeply invasive grade 1 to 2 endometrioid carcinomas, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas. Pelvic lymphadenectomy only was initially recommended for patients with superficial grade 1 to 2 endometrioid carcinomas, the depth of myometrial invasion being assessed by gross visual inspection. As of January 2012, lymph node dissection was omitted in grade 1 to 2 endometrioid carcinomas if magnetic resonance imaging showed less than 50% myometrial invasion. Preoperative endometrial histology was assessed in tissue samples obtained by uterine curettage or biopsy. There was some variation in practice patterns because the decision to perform lymphadenectomy and the extent of the procedure depended on patient comorbidities and surgical risks. Of the TABLE 1. Clinicopathologic data on patients who underwent hysterectomy with pelvic-aortic lymphadenectomy (n = 117) Age, mean (SD), y Body mass index, mean (SD), kg/m2 Lymph node yield,* mean (SD) FIGO 2009 stage, n (%) IA IB II IIIA IIIB IIIC1 IIIC2 IVA IVB
64.1 (9.8) 26.4 (4.9) 27.4 (12.1) 35 (29.9) 27 (23.1) 11 (9.4) 10 (8.5) 2 (1.7) 10 (8.5) 18 (15.4) 0 (0) 4 (3.4)
*Number of cases 114 (lymph node yield was not available for 3 patients). FIGO, International Federation of Gynecology and Obstetrics.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 4, May 2014
TABLE 2. Tumor characteristics of patients who underwent hysterectomy with pelvic-aortic lymphadenectomy (n = 117)
Histology Grade 1Y2 endometrioid, myoinvasion G50% Grade 1Y2 endometrioid, myoinvasion Q50% Grade 3 endometrioid Nonendometrioid
No. Cases (%)
No. Cases (%) With Positive Para-aortic Nodes
16 (13.7)
1 (6.3)
30 (25.6)*
5 (16.7)
39 (33.3)
4 (10.3)*
32 (27.4)†
11 (34.4)‡
*Stage IVB, n = 1. †Clear cell, n = 17; serous, n = 6; undifferentiated, n = 9. ‡Stage IVB, n = 2.
117 patients who received comprehensive lymphadenectomy, 16 (13.7%) had low-risk tumors according to the pathologic evaluation after surgery, that is, grade 1 to 2 endometrioid carcinomas with less than 50% myometrial invasion. Others had tumors with a high risk for extrauterine spread (Table 2). Seventy-one patients (60.7%) underwent laparotomy, and 45 (38.5%) had a conventional or robot-assisted laparoscopic procedure. One patient (0.9%) had a vaginal hysterectomy and second operation by laparotomy for staging. Criteria for grossly positive pelvic lymph nodes were analogical to those used in imaging studies for pathologic lymph nodes; that is, nodes were considered positive when described as metastatic based on size and morphology.24 Specifically, confluent nodes with an irregular contour (n = 14 in the sample of 117 patients) and multiple dense nodes (n = 3) were considered positive. Macroscopic lymph node findings were extracted from operative reports without reference to pathology reports. Lymph nodes were evaluated histologically from hematoxylin-eosinYstained slides without ultrastaging. A 2 2 table was constructed to calculate the sensitivity and specificity of grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis. The power of the test was expressed by positive and negative
Endometrial Carcinoma Para-aortic Spread
likelihood ratios. Likelihood ratios summarize how many times more or less likely patients with the disease are to have the test result than patients without the disease. The further likelihood ratios are from 1, the stronger the evidence for the presence or absence of disease. Bayes’ nomogram was used to compute positive and negative predictive values of the test. The whole study population of 854 patients, divided into subgroups at various risks for stage IIIC2 disease (positive para-aortic nodes with or without positive pelvic nodes), was used for Bayesian calculations.
RESULTS In the study population of 117 women, there were 17 patients (14.5%) with grossly positive pelvic nodes at surgery (confirmed also by the pathologic evaluation). Of these 17 patients, 11 (64.7%) had a concomitant para-aortic metastasis. One hundred patients (85.5%) had grossly negative pelvic nodes at surgery. Four of them (4.0%) had histologically confirmed lymph node metastasis in the pelvis only. Ten patients (10.0%) had positive para-aortic nodes (including 1 patient with a micrometastasis only), and 4 of these also had positive pelvic nodes according to the pathologic evaluation. Thus, in the subset of patients with grossly negative pelvic nodes, positive para-aortic nodes occurred concomitantly with histologically positive pelvic nodes in 4 (50.0%) of 8 patients. The proportion of isolated para-aortic metastasis was 5.1% (6/117). Macroscopic pelvic lymph node findings predicted paraaortic metastasis with a moderate sensitivity and high specificity (Table 3). The positive and negative likelihood ratios of the test were 8.4 and 0.51, respectively (Table 3). According to a logistic regression model, grossly positive pelvic nodes and nonendometrioid tumor histology were the strongest predictors of para-aortic space involvement (Table 4). The effect of deep myometrial invasion on the occurrence of para-aortic space involvement was of a borderline significance, and grade 3 endometrioid histology had no independent effect in our sample of mainly high-risk cases (Table 4). Calculations for diagnostic indices were performed for the population who underwent complete lymphadenectomy, including patients with stage IV carcinoma (n = 4). Instead, patients with stage IIIC2 carcinoma in whom no lymphadenectomy (n = 5) or pelvic lymphadenectomy only (n = 3) was TABLE 4. Odds ratios in the logistic regression model with positive para-aortic lymph nodes as the dependent variable
TABLE 3. Diagnostic indices for predicting para-aortic lymph node metastasis by grossly positive pelvic nodes
Sensitivity Specificity Positive likelihood ratio Negative likelihood ratio
Value
95% Confidence Interval
52.4% 93.8% 8.4 0.51
31.0%Y73.7% 88.9%Y98.6% 3.5Y20 0.32Y0.80
Myoinvasion Q50% Grade 3 endometrioid carcinoma Nonendometrioid carcinoma Grossly positive pelvic lymph nodes
Odds Ratio (95% Confidence Interval)
P
4.0 (1.0Y16) 0.55 (0.11Y2.8)
0.051 0.469
7.8 (1.9Y32)
0.005
18 (4.1Y78)
G0.0001
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
699
International Journal of Gynecological Cancer
Luomaranta et al
performed were not included in the analyses. Two of the 8 patients had low-risk tumors according to uterine risk factors (superficial grade 1Y2 endometrioid carcinomas). For the 7 cases in which pelvic nodal status was reported, nodes were grossly positive in 4 and negative in 3. Thus, the proportion of grossly positive pelvic nodes in these patients was essentially the same as in those who received complete lymphadenectomy. The proportion of patients with stage IIIC2 carcinoma, including 8 patients who did not receive para-aortic lymphadenectomy, was 3.0% (26/854) at our institution during the study period. The complete study population was divided into 3 subgroups according to the risk for stage IIIC2 carcinoma. Positive and negative predictive values of the test for each subgroup and the complete sample were then determined by Bayesian calculations. Separate calculations were made with the result of the preoperative endometrial sample as the histological diagnosis. The negative predictive values varied between 92.2% and 99.7%, depending on the risk for stage IIIC2 carcinoma (Table 5). The positive predictive values varied between 4.8% and 58.4% (Table 5). In the whole study population, 489 patients had tumors with a low risk for extrauterine spread, that is, superficial grade 1 to 2 endometrioid carcinomas, for which lymphadenectomy is not indicated according to our current treatment protocol. Tumor stage was IIIC1 or higher in 10 (2.0%) of these cases. Based on this, the cutoff for a clinically useful test was set at the negative predictive value of 98.0%. With the
& Volume 24, Number 4, May 2014
exception of grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive value of the test was 98.0% or higher (Table 5). Predictive values were comparable regardless of whether the histological diagnosis was made from preoperative endometrial samples or primary tumors obtained at surgery (Table 5).
DISCUSSION Endometrial carcinoma is the most common gynecologic malignancy in Western Europe and North America.20 Despite vast research efforts and communication between authorities, a consensus regarding the indications for lymph node dissection in endometrial carcinoma has not been reached. This is largely due to the fact that the disease is confined to the uterine corpus in more than 3 quarters of women in whom prognosis is favorable with hysterectomy and bilateral salpingo-oophorectomy alone.1 To avoid surgical risks and complications in the majority of patients, many surgeons choose to perform lymphadenectomy only when the probability of extrauterine spread is considered high, most notably in deeply invasive grade 1 to 2 endometrioid carcinomas, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas.1,25,26 However, spread beyond the uterus can also occur in so-called low-risk carcinomas. For example, in our study population of 854 women, there were 137 stage III to IV carcinomas, 22 (16.1%) of which were identified as superficial grade 1 to 2 endometrioid carcinomas.
TABLE 5. Prediction of para-aortic lymph node metastasis by grossly positive pelvic nodes in endometrial carcinoma patients at various risks for stage IIIC2 disease Risk Level Preoperative low-risk histology Hyperplasia or grade 1Y2 endometrioid carcinoma Preoperative high-risk histology Grade 3 endometrioid or nonendometrioid carcinoma All combined† Final low-risk histology Grade 1Y2 endometrioid carcinoma, myoinvasion G50% Final intermediate-risk histology Grade 1Y2 endometrioid carcinoma, myoinvasion Q50% Grade 3 endometrioid carcinoma Final high-risk histology Nonendometrioid carcinoma‡ All combined§
Stage IIIC2 Tumors per All Cases (%)
Positive Predictive Value, %
Negative Predictive Value, %
Clinically Useful Test*
12/706 (1.7)
12.7
99.1
+
14/124 (11.3)
51.7
93.9
j
26/830 (3.1)
21.2
98.4
+
3/489 (0.6)
4.8
99.7
+
7/179 (3.9)
25.4
98.0
+
6/115 (5.2)
31.5
97.3
j
10/70 (14.3) 26/854 (3.0)
58.4 20.6
92.2 98.4
j +
*Cutoff was set at the negative predictive value of 98.0%. †Preoperative histology was not available for 24 patients. ‡Clear cell, n = 29; serous, n = 22; undifferentiated, n = 18; neuroendocrine, n = 1 §The risk level of 1 stage IVB grade 2 endometrioid carcinoma was not determined because the depth of myometrial invasion was unknown.
700
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 4, May 2014
With the recognition of problems associated with selective lymphadenectomy, an alternative strategy, recommended, for example, by the American College of Obstetricians and Gynecologists,27 is to perform pelvic and para-aortic lymphadenectomy as a prognostic procedure in most women with endometrial carcinoma. The International Federation of Gynecology and Obstetrics takes notice of comprehensive lymphadenectomy in its current surgical staging system, which recognizes the survival difference between patients with positive pelvic nodes alone (stage IIIC1) and those with positive para-aortic nodes with or without positive pelvic nodes (stage IIIC2).28 In favor of routine lymphadenectomy, this approach was recently found to be more cost-effective than selective lymphadenectomy based on intraoperative risk factors.29 Because of 2 previous observations, we hypothesized that macroscopic pelvic lymph node findings at surgery may help in predicting para-aortic space involvement in patients with endometrial carcinoma. First, concomitant para-aortic metastases are frequently found in patients with histologically positive pelvic nodes, that is, in 47% of cases.30 Second, isolated para-aortic metastases are uncommon in endometrial carcinoma; 2 studies verified that they are found in about 1% of patients.22,23 We observed concomitant para-aortic metastases in 60% of patients with positive pelvic nodes, which compares fairly well with the earlier finding.30 Although the rate of isolated para-aortic metastasis was somewhat higher than expected in our sample of mainly high-risk cases (5.1%), we assume that the rate was considerably lower in the whole study population of 854 patients. Namely, of the 455 patients who received pelvic lymphadenectomy only, 416 patients had stage IA-IIIB disease (no lymphatic spread), and a primary para-aortic relapse occurred in 11 (2.6%) of these patients during a median follow-up time of 33 months (range, 1Y64 months). One patient had a relapse exclusively in the para-aortic space. Of the 117 patients in whom para-aortic lymphadenectomy was performed, a primary para-aortic relapse occurred in 3 patients during follow-up. Only 1 of them had the failure exclusively in the para-aortic space, suggesting that para-aortic dissection was generally reliable with few falsenegative cases. It is noteworthy that the patient with the failure in the para-aortic space only had stage IIIC1 carcinoma, and her pelvic nodes were grossly positive. Grossly positive pelvic nodes predicted para-aortic space involvement with a moderate sensitivity and high specificity. The result can be highlighted by likelihood ratios, according to which grossly positive pelvic nodes increased the likelihood of para-aortic metastasis about 8-fold, whereas the likelihood was halved when pelvic nodes were grossly negative. The value of grossly positive pelvic nodes as a predictor of para-aortic space involvement remained significant after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. Although our data on macroscopic lymph node findings were based on retrospective analysis of operative reports, we believe that they are reliable. Lymph nodes were considered grossly positive by strict criteria, which explains the fact that all grossly positive findings of pelvic nodes were correct according to the pathologic evaluation. As concluded from
Endometrial Carcinoma Para-aortic Spread
the operative reports, pelvic nodes were thoroughly evaluated by the surgeons also when they were histologically positive but interpreted as grossly negative; a description of the nodes (typically ‘‘normal’’ or ‘‘unsuspicious’’) was given in all 8 such cases. Likelihood ratios are independent of disease prevalence (in this case, that of para-aortic metastasis). To evaluate the usefulness of pelvic node findings in predicting para-aortic metastasis in different clinical scenarios, we used Bayes’ nomogram to compute the predictive values of the test for patients at various risks for stage IIIC2 carcinoma. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. This level was chosen because the risk for stage IIIC1-IVB carcinoma was 2.0% in patients with superficial grade 1 to 2 endometrioid carcinomas, in whom it is generally considered safe to omit surgical staging. Logically, a similar or smaller risk for para-aortic metastasis should not be an indication for para-aortic lymphadenectomy. A negative predictive value of 98.0% or higher was found for the whole study population and for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. This suggests that routine para-aortic lymphadenectomy, in addition to pelvic lymphadenectomy, yields minimal diagnostic and therapeutic value in an unselected patient population with endometrial carcinoma. Similarly, patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion, are unlikely to benefit from routine para-aortic lymphadenectomy. Deeply invasive grade 1 to 2 carcinomas are more common (179 cases in our sample) than either grade 3 endometrioid carcinomas (115 cases) or nonendometrioid carcinomas (70 cases). Our findings could therefore have a major impact in planning surgical staging procedures when they are performed selectively based on uterine risk factors. Although risk calculations may vary between different institutions and patient populations, we believe that our data are clinically applicable and may provide an additional tool for stratification of patients with endometrial carcinoma to para-aortic lymphadenectomy.
REFERENCES 1. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987;60:2035Y2041. 2. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol. 1989;96:889Y892. 3. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707Y1716. 4. The Writing Committee on Behalf of the ASTEC Study Group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125Y136. 5. Yildiz A, Yetimalar H, Kasap B, et al. Preoperative serum CA 125 level in the prediction of the stage of disease in endometrial carcinoma. Eur J Obstet Gynecol Reprod Biol. 2012;164:191Y195.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
701
Luomaranta et al
International Journal of Gynecological Cancer
6. Kalogera E, Scholler N, Powless C, et al. Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer. Gynecol Oncol. 2012;124:270Y275. 7. Antonsen SL, Jensen LN, Loft A, et al. MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancerVa multicenter prospective comparative study. Gynecol Oncol. 2013;128:300Y308. 8. Soliman PT, Frumovitz M, Spannuth W, et al. Lymphadenectomy during endometrial cancer staging: practice patterns among gynecologic oncologists. Gynecol Oncol. 2010;119:291Y294. 9. Al Hilli MM, Podratz KC, Dowdy SC, et al. Preoperative biopsy and intraoperative tumor diameter predict lymph node dissemination in endometrial cancer. Gynecol Oncol. 2013;128:294Y299. 10. Lee J-Y, Jung D-C, Park S-H, et al. Preoperative prediction model of lymph node metastasis in endometrial cancer. Int J Gynecol Cancer. 2010;20:1350Y1355. 11. Milam MR, Java J, Walker JL, et al. for the Gynecologic Oncology Group. Nodal metastasis risk in endometrioid endometrial cancer. Obstet Gynecol. 2012;119:286Y292. 12. Kang S, Todo Y, Odagiri T, et al. A low-risk group for lymph node metastasis is accurately identified by Korean gynecologic oncology group criteria in two Japanese cohorts with endometrial cancer. Gynecol Oncol. 2013;129:33Y37. 13. Leitao MM Jr, Kehoe S, Barakat RR, et al. Comparison of D&C and office endometrial biopsy accuracy in patients with FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol. 2009;113:105Y108. 14. Neubauer NL, Havrilesky LJ, Calingaert B, et al. The role of lymphadenectomy in the management of preoperative grade 1 endometrial carcinoma. Gynecol Oncol. 2009;112:511Y516. 15. Case AS, Rocconi RP, Straughn JM Jr, et al. A prospective blinded evaluation of the accuracy of frozen section for the surgical management of endometrial cancer. Obstet Gynecol. 2006;108:1375Y1379. 16. Kumar S, Medeiros F, Dowdy SC, et al. A prospective assessment of the reliability of frozen section to direct intraoperative decision making in endometrial cancer. Gynecol Oncol. 2012;127:525Y531. 17. Kilgore LC, Partridge EE, Alvarez RD, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with
702
18.
19.
20. 21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
& Volume 24, Number 4, May 2014
and without pelvic node sampling. Gynecol Oncol. 1995;56:29Y33. Cragun JM, Havrilesky LJ, Calingaert B, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol. 2005;23:3668Y3675. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11Y18. Sorosky JI. Endometrial cancer. Obstet Gynecol. 2012;120:383Y397. Dowdy SC, Borah BJ, Bakkum-Gamez JN, et al. Factors predictive of postoperative morbidity and cost in patients with endometrial cancer. Obstet Gynecol. 2012;120:1419Y1427. Abu-Rustum NR, Gomez JD, Alektiar KM, et al. The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. Gynecol Oncol. 2009;115:236Y238. Chiang A-J, Yu K-J, Chao K-C, et al. The incidence of isolated para-aortic nodal metastasis in completely staged endometrial cancer patients. Gynecol Oncol. 2011;121:122Y125. Bell DJ, Pannu HK. Radiological assessment of gynecologic malignancies. Obstet Gynecol Clin N Am. 2011;38:45Y68. Kwon JS, Qiu F, Saskin R, et al. Are uterine risk factors more important than nodal status in predicting survival in endometrial cancer? Obstet Gynecol. 2009;114:736Y743. Barrena Medel NI, Herzog TJ, Deutsch I, et al. Comparison of the prognostic significance of uterine factors and nodal status for endometrial cancer. Am J Obstet Gynecol. 2011;204:248.e1Y248.e7. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 65. Management of endometrial cancer. Obstet Gynecol. 2005;106:413Y425. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105:103Y104. Clements AE, Tierney BJ, Cohn DE, et al. Is selective lymphadenectomy more cost-effective than routine lymphadenectomy in patients with endometrial cancer? Gynecol Oncol. 2013;128:166Y170. Mariani A, Keeney GL, Aletti G, et al. Endometrial carcinoma: paraaortic dissemination. Gynecol Oncol. 2004;92:833Y838.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Prediction of Para-aortic Spread by Gross Pelvic Lymph Node Findings in Patients With Endometrial Carcinoma Anna Luomaranta, MD,* Jouko Lohi, MD,Þ Ralf Bu¨tzow, MD,Þ Arto Leminen, MD,* and Mikko Loukovaara, MD*
Objective: Isolated para-aortic lymph node metastases are rare in patients with endometrial carcinoma. We wanted to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in these patients. Methods: We identified all women with surgically treated endometrial carcinoma at our institution between January 2008 and February 2013 (n = 854). One hundred seventeen patients received pelvic-aortic lymphadenectomy. Lymph nodes were considered grossly positive based on size and morphology. Results: In patients who underwent comprehensive lymphadenectomy, grossly positive pelvic nodes predicted para-aortic metastasis with a sensitivity of 52.4% and specificity of 93.8%. The positive and negative likelihood ratios were 8.4 and 0.51, respectively. The predictive power of grossly positive pelvic nodes remained significant (odds ratio, 18; 95% confidence interval, 4.1Y78; P G 0.0001) after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. The whole sample of 854 patients was used for Bayesian calculations. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. The negative predictive value of the test (ie, grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis) was 99.7% for patients with superficial grade 1 to 2 endometrioid carcinomas and 98.0% for patients with deeply invasive grade 1 to 2 endometrioid carcinomas. For patients with grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive values were 97.3% and 92.2%, respectively. For the whole study population, the value was 98.4%. Conclusions: When uterine factors are used for risk stratification of endometrial carcinomas, selective para-aortic lymphadenectomy, based on gross findings of pelvic nodes, is feasible for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. Similarly, gross findings of pelvic nodes can be used to evaluate the need for para-aortic lymphadenectomy in the strategy of routine pelvic lymphadenectomy. Key Words: Endometrial carcinoma, Lymphadenectomy, Lymph node metastasis, Surgical staging Received August 21, 2013, and in revised form January 20, 2014. Accepted for publication January 21, 2014. (Int J Gynecol Cancer 2014;24: 697Y702)
Departments of *Obstetrics and Gynecology and †Pathology, Helsinki University Central Hospital, Helsinki, Finland. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000113 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Anna Luomaranta, MD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, PO Box 140, FIN-00029 HUS, Helsinki, Finland. E-mail: [email protected]. The authors declare no conflicts of interest.
& Volume 24, Number 4, May 2014
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
697
Luomaranta et al
International Journal of Gynecological Cancer
he mainstay of the initial treatment for endometrial carT cinoma is surgery with total hysterectomy and bilateral
salpingo-oophorectomy. Based on the 22% risk for extrauterine spread in clinical stage I carcinomas,1 surgical staging with retroperitoneal lymph node dissection has been recommended by the International Federation of Gynecology and Obstetrics since 1988.2 However, the anatomical extent of the procedure and the number of lymph nodes considered adequate for a reliable staging have not been agreed upon. In fact, 2 randomized trials questioned the value of surgical staging in endometrial carcinoma, as pelvic lymphadenectomy was without prognostic benefit in women with clinical stage I to II carcinomas.3,4 These findings have prompted many surgeons to omit lymphadenectomy in patients with a low risk for lymphatic spread. Various algorithms have been used to identify low-risk endometrial carcinomas and to decide whether to perform lymphadenectomy. These algorithms most commonly utilize serum tumor markers (CA125, HE4),5,6 the depth of myometrial invasion as assessed by imaging studies7 or frozen section analysis,8 other preoperative and intraoperative tumor characteristics (histological subtype, grade, size),9 and combinations thereof.10Y12 Risk stratification of endometrial carcinomas by these methods has been variably successful. Although clinically relevant discordance between preoperative endometrial biopsy and final pathology occurs rarely,13,14 findings on the reliability of frozen-section analysis for the determination of tumor grade intraoperatively have been inconsistent.15,16 The sensitivity of magnetic resonance imaging (87%), fludeoxyglucose positron emission tomography/ computed tomography (93%), or transvaginal ultrasound (71%) in assessing myometrial invasion is probably not high enough for a replacement of surgical staging.7 Proponents for systematic lymphadenectomy emphasize that omission of lymphadenectomy may expose many patients with presumed early-stage disease at risk for incomplete surgery and adjuvant therapy. Some authors have also reported that pelvic and para-aortic lymphadenectomy are associated with improved survival.17,18 The extent of lymphadenectomy for the staging of endometrial carcinoma ranges from dissection of pelvic nodes alone to both pelvic and para-aortic dissection, which should ideally be carried out up to the renal vessels. Minimally invasive surgery, performed either by conventional or robotassisted laparoscopy, may restrict the extent of para-aortic lymphadenectomy to the level of inferior mesenteric artery even among experienced surgeons.8 This may reduce the reliability of the procedure, as 77% of para-aortic metastases extend to the supramesenteric level.19 A comprehensive paraaortic lymphadenectomy may be especially challenging in obese subjects, an important notion given the high prevalence of obesity in women with endometrial carcinoma.20 Thus, if reliable methods for risk assessment were available, selective para-aortic lymphadenectomy would be a reasonable option for patients with endometrial carcinoma. Selective approach is also supported by the finding that para-aortic lymphadenectomy is a powerful independent predictor of grade 2 or higher postoperative complications in these patients.21 The risk for para-aortic metastasis in the absence of positive pelvic nodes has been reported to be about 1% in
698
& Volume 24, Number 4, May 2014
endometrial carcinoma.22,23 Because of the rarity of isolated para-aortic metastasis, individualized surgical staging could be planned if there were means to reliably evaluate pelvic nodal status at surgery. The aim of our study was to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in patients with endometrial carcinoma.
MATERIALS AND METHODS Institutional review board approval was obtained for the study. We identified all women with surgically treated endometrial carcinoma at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, between January 2008 and February 2013 (n = 854). Four hundred fifty-five patients (53.3%) received pelvic lymphadenectomy only. One hundred seventeen patients (13.7%) received both pelvic and para-aortic lymphadenectomy and were selected for the current analysis (Table 1). According to the protocol applied at our institution, comprehensive lymphadenectomy was recommended for patients at high risk for extrauterine spread, that is, those with deeply invasive grade 1 to 2 endometrioid carcinomas, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas. Pelvic lymphadenectomy only was initially recommended for patients with superficial grade 1 to 2 endometrioid carcinomas, the depth of myometrial invasion being assessed by gross visual inspection. As of January 2012, lymph node dissection was omitted in grade 1 to 2 endometrioid carcinomas if magnetic resonance imaging showed less than 50% myometrial invasion. Preoperative endometrial histology was assessed in tissue samples obtained by uterine curettage or biopsy. There was some variation in practice patterns because the decision to perform lymphadenectomy and the extent of the procedure depended on patient comorbidities and surgical risks. Of the TABLE 1. Clinicopathologic data on patients who underwent hysterectomy with pelvic-aortic lymphadenectomy (n = 117) Age, mean (SD), y Body mass index, mean (SD), kg/m2 Lymph node yield,* mean (SD) FIGO 2009 stage, n (%) IA IB II IIIA IIIB IIIC1 IIIC2 IVA IVB
64.1 (9.8) 26.4 (4.9) 27.4 (12.1) 35 (29.9) 27 (23.1) 11 (9.4) 10 (8.5) 2 (1.7) 10 (8.5) 18 (15.4) 0 (0) 4 (3.4)
*Number of cases 114 (lymph node yield was not available for 3 patients). FIGO, International Federation of Gynecology and Obstetrics.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 4, May 2014
TABLE 2. Tumor characteristics of patients who underwent hysterectomy with pelvic-aortic lymphadenectomy (n = 117)
Histology Grade 1Y2 endometrioid, myoinvasion G50% Grade 1Y2 endometrioid, myoinvasion Q50% Grade 3 endometrioid Nonendometrioid
No. Cases (%)
No. Cases (%) With Positive Para-aortic Nodes
16 (13.7)
1 (6.3)
30 (25.6)*
5 (16.7)
39 (33.3)
4 (10.3)*
32 (27.4)†
11 (34.4)‡
*Stage IVB, n = 1. †Clear cell, n = 17; serous, n = 6; undifferentiated, n = 9. ‡Stage IVB, n = 2.
117 patients who received comprehensive lymphadenectomy, 16 (13.7%) had low-risk tumors according to the pathologic evaluation after surgery, that is, grade 1 to 2 endometrioid carcinomas with less than 50% myometrial invasion. Others had tumors with a high risk for extrauterine spread (Table 2). Seventy-one patients (60.7%) underwent laparotomy, and 45 (38.5%) had a conventional or robot-assisted laparoscopic procedure. One patient (0.9%) had a vaginal hysterectomy and second operation by laparotomy for staging. Criteria for grossly positive pelvic lymph nodes were analogical to those used in imaging studies for pathologic lymph nodes; that is, nodes were considered positive when described as metastatic based on size and morphology.24 Specifically, confluent nodes with an irregular contour (n = 14 in the sample of 117 patients) and multiple dense nodes (n = 3) were considered positive. Macroscopic lymph node findings were extracted from operative reports without reference to pathology reports. Lymph nodes were evaluated histologically from hematoxylin-eosinYstained slides without ultrastaging. A 2 2 table was constructed to calculate the sensitivity and specificity of grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis. The power of the test was expressed by positive and negative
Endometrial Carcinoma Para-aortic Spread
likelihood ratios. Likelihood ratios summarize how many times more or less likely patients with the disease are to have the test result than patients without the disease. The further likelihood ratios are from 1, the stronger the evidence for the presence or absence of disease. Bayes’ nomogram was used to compute positive and negative predictive values of the test. The whole study population of 854 patients, divided into subgroups at various risks for stage IIIC2 disease (positive para-aortic nodes with or without positive pelvic nodes), was used for Bayesian calculations.
RESULTS In the study population of 117 women, there were 17 patients (14.5%) with grossly positive pelvic nodes at surgery (confirmed also by the pathologic evaluation). Of these 17 patients, 11 (64.7%) had a concomitant para-aortic metastasis. One hundred patients (85.5%) had grossly negative pelvic nodes at surgery. Four of them (4.0%) had histologically confirmed lymph node metastasis in the pelvis only. Ten patients (10.0%) had positive para-aortic nodes (including 1 patient with a micrometastasis only), and 4 of these also had positive pelvic nodes according to the pathologic evaluation. Thus, in the subset of patients with grossly negative pelvic nodes, positive para-aortic nodes occurred concomitantly with histologically positive pelvic nodes in 4 (50.0%) of 8 patients. The proportion of isolated para-aortic metastasis was 5.1% (6/117). Macroscopic pelvic lymph node findings predicted paraaortic metastasis with a moderate sensitivity and high specificity (Table 3). The positive and negative likelihood ratios of the test were 8.4 and 0.51, respectively (Table 3). According to a logistic regression model, grossly positive pelvic nodes and nonendometrioid tumor histology were the strongest predictors of para-aortic space involvement (Table 4). The effect of deep myometrial invasion on the occurrence of para-aortic space involvement was of a borderline significance, and grade 3 endometrioid histology had no independent effect in our sample of mainly high-risk cases (Table 4). Calculations for diagnostic indices were performed for the population who underwent complete lymphadenectomy, including patients with stage IV carcinoma (n = 4). Instead, patients with stage IIIC2 carcinoma in whom no lymphadenectomy (n = 5) or pelvic lymphadenectomy only (n = 3) was TABLE 4. Odds ratios in the logistic regression model with positive para-aortic lymph nodes as the dependent variable
TABLE 3. Diagnostic indices for predicting para-aortic lymph node metastasis by grossly positive pelvic nodes
Sensitivity Specificity Positive likelihood ratio Negative likelihood ratio
Value
95% Confidence Interval
52.4% 93.8% 8.4 0.51
31.0%Y73.7% 88.9%Y98.6% 3.5Y20 0.32Y0.80
Myoinvasion Q50% Grade 3 endometrioid carcinoma Nonendometrioid carcinoma Grossly positive pelvic lymph nodes
Odds Ratio (95% Confidence Interval)
P
4.0 (1.0Y16) 0.55 (0.11Y2.8)
0.051 0.469
7.8 (1.9Y32)
0.005
18 (4.1Y78)
G0.0001
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
699
International Journal of Gynecological Cancer
Luomaranta et al
performed were not included in the analyses. Two of the 8 patients had low-risk tumors according to uterine risk factors (superficial grade 1Y2 endometrioid carcinomas). For the 7 cases in which pelvic nodal status was reported, nodes were grossly positive in 4 and negative in 3. Thus, the proportion of grossly positive pelvic nodes in these patients was essentially the same as in those who received complete lymphadenectomy. The proportion of patients with stage IIIC2 carcinoma, including 8 patients who did not receive para-aortic lymphadenectomy, was 3.0% (26/854) at our institution during the study period. The complete study population was divided into 3 subgroups according to the risk for stage IIIC2 carcinoma. Positive and negative predictive values of the test for each subgroup and the complete sample were then determined by Bayesian calculations. Separate calculations were made with the result of the preoperative endometrial sample as the histological diagnosis. The negative predictive values varied between 92.2% and 99.7%, depending on the risk for stage IIIC2 carcinoma (Table 5). The positive predictive values varied between 4.8% and 58.4% (Table 5). In the whole study population, 489 patients had tumors with a low risk for extrauterine spread, that is, superficial grade 1 to 2 endometrioid carcinomas, for which lymphadenectomy is not indicated according to our current treatment protocol. Tumor stage was IIIC1 or higher in 10 (2.0%) of these cases. Based on this, the cutoff for a clinically useful test was set at the negative predictive value of 98.0%. With the
& Volume 24, Number 4, May 2014
exception of grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive value of the test was 98.0% or higher (Table 5). Predictive values were comparable regardless of whether the histological diagnosis was made from preoperative endometrial samples or primary tumors obtained at surgery (Table 5).
DISCUSSION Endometrial carcinoma is the most common gynecologic malignancy in Western Europe and North America.20 Despite vast research efforts and communication between authorities, a consensus regarding the indications for lymph node dissection in endometrial carcinoma has not been reached. This is largely due to the fact that the disease is confined to the uterine corpus in more than 3 quarters of women in whom prognosis is favorable with hysterectomy and bilateral salpingo-oophorectomy alone.1 To avoid surgical risks and complications in the majority of patients, many surgeons choose to perform lymphadenectomy only when the probability of extrauterine spread is considered high, most notably in deeply invasive grade 1 to 2 endometrioid carcinomas, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas.1,25,26 However, spread beyond the uterus can also occur in so-called low-risk carcinomas. For example, in our study population of 854 women, there were 137 stage III to IV carcinomas, 22 (16.1%) of which were identified as superficial grade 1 to 2 endometrioid carcinomas.
TABLE 5. Prediction of para-aortic lymph node metastasis by grossly positive pelvic nodes in endometrial carcinoma patients at various risks for stage IIIC2 disease Risk Level Preoperative low-risk histology Hyperplasia or grade 1Y2 endometrioid carcinoma Preoperative high-risk histology Grade 3 endometrioid or nonendometrioid carcinoma All combined† Final low-risk histology Grade 1Y2 endometrioid carcinoma, myoinvasion G50% Final intermediate-risk histology Grade 1Y2 endometrioid carcinoma, myoinvasion Q50% Grade 3 endometrioid carcinoma Final high-risk histology Nonendometrioid carcinoma‡ All combined§
Stage IIIC2 Tumors per All Cases (%)
Positive Predictive Value, %
Negative Predictive Value, %
Clinically Useful Test*
12/706 (1.7)
12.7
99.1
+
14/124 (11.3)
51.7
93.9
j
26/830 (3.1)
21.2
98.4
+
3/489 (0.6)
4.8
99.7
+
7/179 (3.9)
25.4
98.0
+
6/115 (5.2)
31.5
97.3
j
10/70 (14.3) 26/854 (3.0)
58.4 20.6
92.2 98.4
j +
*Cutoff was set at the negative predictive value of 98.0%. †Preoperative histology was not available for 24 patients. ‡Clear cell, n = 29; serous, n = 22; undifferentiated, n = 18; neuroendocrine, n = 1 §The risk level of 1 stage IVB grade 2 endometrioid carcinoma was not determined because the depth of myometrial invasion was unknown.
700
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 24, Number 4, May 2014
With the recognition of problems associated with selective lymphadenectomy, an alternative strategy, recommended, for example, by the American College of Obstetricians and Gynecologists,27 is to perform pelvic and para-aortic lymphadenectomy as a prognostic procedure in most women with endometrial carcinoma. The International Federation of Gynecology and Obstetrics takes notice of comprehensive lymphadenectomy in its current surgical staging system, which recognizes the survival difference between patients with positive pelvic nodes alone (stage IIIC1) and those with positive para-aortic nodes with or without positive pelvic nodes (stage IIIC2).28 In favor of routine lymphadenectomy, this approach was recently found to be more cost-effective than selective lymphadenectomy based on intraoperative risk factors.29 Because of 2 previous observations, we hypothesized that macroscopic pelvic lymph node findings at surgery may help in predicting para-aortic space involvement in patients with endometrial carcinoma. First, concomitant para-aortic metastases are frequently found in patients with histologically positive pelvic nodes, that is, in 47% of cases.30 Second, isolated para-aortic metastases are uncommon in endometrial carcinoma; 2 studies verified that they are found in about 1% of patients.22,23 We observed concomitant para-aortic metastases in 60% of patients with positive pelvic nodes, which compares fairly well with the earlier finding.30 Although the rate of isolated para-aortic metastasis was somewhat higher than expected in our sample of mainly high-risk cases (5.1%), we assume that the rate was considerably lower in the whole study population of 854 patients. Namely, of the 455 patients who received pelvic lymphadenectomy only, 416 patients had stage IA-IIIB disease (no lymphatic spread), and a primary para-aortic relapse occurred in 11 (2.6%) of these patients during a median follow-up time of 33 months (range, 1Y64 months). One patient had a relapse exclusively in the para-aortic space. Of the 117 patients in whom para-aortic lymphadenectomy was performed, a primary para-aortic relapse occurred in 3 patients during follow-up. Only 1 of them had the failure exclusively in the para-aortic space, suggesting that para-aortic dissection was generally reliable with few falsenegative cases. It is noteworthy that the patient with the failure in the para-aortic space only had stage IIIC1 carcinoma, and her pelvic nodes were grossly positive. Grossly positive pelvic nodes predicted para-aortic space involvement with a moderate sensitivity and high specificity. The result can be highlighted by likelihood ratios, according to which grossly positive pelvic nodes increased the likelihood of para-aortic metastasis about 8-fold, whereas the likelihood was halved when pelvic nodes were grossly negative. The value of grossly positive pelvic nodes as a predictor of para-aortic space involvement remained significant after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. Although our data on macroscopic lymph node findings were based on retrospective analysis of operative reports, we believe that they are reliable. Lymph nodes were considered grossly positive by strict criteria, which explains the fact that all grossly positive findings of pelvic nodes were correct according to the pathologic evaluation. As concluded from
Endometrial Carcinoma Para-aortic Spread
the operative reports, pelvic nodes were thoroughly evaluated by the surgeons also when they were histologically positive but interpreted as grossly negative; a description of the nodes (typically ‘‘normal’’ or ‘‘unsuspicious’’) was given in all 8 such cases. Likelihood ratios are independent of disease prevalence (in this case, that of para-aortic metastasis). To evaluate the usefulness of pelvic node findings in predicting para-aortic metastasis in different clinical scenarios, we used Bayes’ nomogram to compute the predictive values of the test for patients at various risks for stage IIIC2 carcinoma. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. This level was chosen because the risk for stage IIIC1-IVB carcinoma was 2.0% in patients with superficial grade 1 to 2 endometrioid carcinomas, in whom it is generally considered safe to omit surgical staging. Logically, a similar or smaller risk for para-aortic metastasis should not be an indication for para-aortic lymphadenectomy. A negative predictive value of 98.0% or higher was found for the whole study population and for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. This suggests that routine para-aortic lymphadenectomy, in addition to pelvic lymphadenectomy, yields minimal diagnostic and therapeutic value in an unselected patient population with endometrial carcinoma. Similarly, patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion, are unlikely to benefit from routine para-aortic lymphadenectomy. Deeply invasive grade 1 to 2 carcinomas are more common (179 cases in our sample) than either grade 3 endometrioid carcinomas (115 cases) or nonendometrioid carcinomas (70 cases). Our findings could therefore have a major impact in planning surgical staging procedures when they are performed selectively based on uterine risk factors. Although risk calculations may vary between different institutions and patient populations, we believe that our data are clinically applicable and may provide an additional tool for stratification of patients with endometrial carcinoma to para-aortic lymphadenectomy.
REFERENCES 1. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987;60:2035Y2041. 2. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol. 1989;96:889Y892. 3. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707Y1716. 4. The Writing Committee on Behalf of the ASTEC Study Group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125Y136. 5. Yildiz A, Yetimalar H, Kasap B, et al. Preoperative serum CA 125 level in the prediction of the stage of disease in endometrial carcinoma. Eur J Obstet Gynecol Reprod Biol. 2012;164:191Y195.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
701
Luomaranta et al
International Journal of Gynecological Cancer
6. Kalogera E, Scholler N, Powless C, et al. Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer. Gynecol Oncol. 2012;124:270Y275. 7. Antonsen SL, Jensen LN, Loft A, et al. MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancerVa multicenter prospective comparative study. Gynecol Oncol. 2013;128:300Y308. 8. Soliman PT, Frumovitz M, Spannuth W, et al. Lymphadenectomy during endometrial cancer staging: practice patterns among gynecologic oncologists. Gynecol Oncol. 2010;119:291Y294. 9. Al Hilli MM, Podratz KC, Dowdy SC, et al. Preoperative biopsy and intraoperative tumor diameter predict lymph node dissemination in endometrial cancer. Gynecol Oncol. 2013;128:294Y299. 10. Lee J-Y, Jung D-C, Park S-H, et al. Preoperative prediction model of lymph node metastasis in endometrial cancer. Int J Gynecol Cancer. 2010;20:1350Y1355. 11. Milam MR, Java J, Walker JL, et al. for the Gynecologic Oncology Group. Nodal metastasis risk in endometrioid endometrial cancer. Obstet Gynecol. 2012;119:286Y292. 12. Kang S, Todo Y, Odagiri T, et al. A low-risk group for lymph node metastasis is accurately identified by Korean gynecologic oncology group criteria in two Japanese cohorts with endometrial cancer. Gynecol Oncol. 2013;129:33Y37. 13. Leitao MM Jr, Kehoe S, Barakat RR, et al. Comparison of D&C and office endometrial biopsy accuracy in patients with FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol. 2009;113:105Y108. 14. Neubauer NL, Havrilesky LJ, Calingaert B, et al. The role of lymphadenectomy in the management of preoperative grade 1 endometrial carcinoma. Gynecol Oncol. 2009;112:511Y516. 15. Case AS, Rocconi RP, Straughn JM Jr, et al. A prospective blinded evaluation of the accuracy of frozen section for the surgical management of endometrial cancer. Obstet Gynecol. 2006;108:1375Y1379. 16. Kumar S, Medeiros F, Dowdy SC, et al. A prospective assessment of the reliability of frozen section to direct intraoperative decision making in endometrial cancer. Gynecol Oncol. 2012;127:525Y531. 17. Kilgore LC, Partridge EE, Alvarez RD, et al. Adenocarcinoma of the endometrium: survival comparisons of patients with
702
18.
19.
20. 21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
& Volume 24, Number 4, May 2014
and without pelvic node sampling. Gynecol Oncol. 1995;56:29Y33. Cragun JM, Havrilesky LJ, Calingaert B, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol. 2005;23:3668Y3675. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11Y18. Sorosky JI. Endometrial cancer. Obstet Gynecol. 2012;120:383Y397. Dowdy SC, Borah BJ, Bakkum-Gamez JN, et al. Factors predictive of postoperative morbidity and cost in patients with endometrial cancer. Obstet Gynecol. 2012;120:1419Y1427. Abu-Rustum NR, Gomez JD, Alektiar KM, et al. The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes. Gynecol Oncol. 2009;115:236Y238. Chiang A-J, Yu K-J, Chao K-C, et al. The incidence of isolated para-aortic nodal metastasis in completely staged endometrial cancer patients. Gynecol Oncol. 2011;121:122Y125. Bell DJ, Pannu HK. Radiological assessment of gynecologic malignancies. Obstet Gynecol Clin N Am. 2011;38:45Y68. Kwon JS, Qiu F, Saskin R, et al. Are uterine risk factors more important than nodal status in predicting survival in endometrial cancer? Obstet Gynecol. 2009;114:736Y743. Barrena Medel NI, Herzog TJ, Deutsch I, et al. Comparison of the prognostic significance of uterine factors and nodal status for endometrial cancer. Am J Obstet Gynecol. 2011;204:248.e1Y248.e7. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 65. Management of endometrial cancer. Obstet Gynecol. 2005;106:413Y425. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105:103Y104. Clements AE, Tierney BJ, Cohn DE, et al. Is selective lymphadenectomy more cost-effective than routine lymphadenectomy in patients with endometrial cancer? Gynecol Oncol. 2013;128:166Y170. Mariani A, Keeney GL, Aletti G, et al. Endometrial carcinoma: paraaortic dissemination. Gynecol Oncol. 2004;92:833Y838.
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
