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Metastatic lymph node number in epithelial ovarian carcinoma: Does it have any clinical significance?
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Gynecologic Oncology 108 (2008) 428 – 432 www.elsevier.com/locate/ygyno
Metastatic lymph node number in epithelial ovarian carcinoma: Does it have any clinical significance? Ali Ayhan a , Murat Gultekin b,⁎, Polat Dursun a , Nasuh Utku Dogan c , Guldeniz Aksan c , Suleyman Guven d , Melih Velipasaoglu c , Kunter Yuce c a
c
Baskent University Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Sihhiye, Ankara, Turkey b Cankırı Government Hospital, Department of Obstetrics and Gynecology, Cankırı, Turkey Hacettepe University Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Sihhiye, Ankara, Turkey d Karadeniz Techniqual University Faculty of Medicine, Department of Obstetrics and Gynecology, Trabzon, Turkey Received 17 July 2007
Abstract Objective. To analyze the clinicopathological correlations of metastatic lymph node (LN) numbers in patients with epithelial ovarian carcinoma. Method. A total of 328 patients with epithelial ovarian carcinoma diagnosed and treated at Hacettepe University Hospital during 1982–2005 were retrospectively reviewed. Patients' age, number of resected lymph nodes, clinical disease stage, preoperative Ca-125 levels, peritoneal cytology, presence of ascites, tumor histology, tumor grade, maximal tumor diameter, cytoreductive success, overall and disease-free survivals were compared with respect to the number of metastatic lymph nodes (b 4 vs. ≥4). Results. The mean number of resected lymph nodes was 24.5 and mean number of metastatic lymph nodes was 6.2. About 47.3% (n = 155) of the patients had b 4 metastatic lymph nodes and the remaining 52.7% of patients (n = 173) had ≥ 4 metastatic lymph nodes. Univariate comparison of the two groups relived preoperative Ca-125 values, peritoneal cytology and clinical disease stage to be significantly different among the two groups. However, multivariate analysis revealed a high Ca-125 level (≥ 500 IU/l) to be unique factor significantly different among the groups. Survival analysis also could not find a significant difference with respect to overall and disease-free survival among the groups. Conclusion. The number of metastatic lymph nodes increases as the preoperative Ca-125 values increase. Other patient characteristics do not have a significant effect on the number of metastatic lymph nodes. Metastatic LN number does not have a prognostic significance in terms of either the overall or the disease-free survival. Prospective series are needed for a definitive conclusion. © 2008 Elsevier Inc. All rights reserved. Keywords: Epithelial ovarian carcinoma; Lymphatic metastasis; Number of metastatic lymph node; Survival estimate
Introduction Epithelial ovarian cancers (EOC) are the most lymphophilic tumors among the genital cancers. Lymph node metastasis ranges between 12% and 25% in early stage and between 46% and 76% in advanced stage diseases. Therefore, the lymphatic metastasis and the role of lymphadenectomy are among the most commonly analyzed subjects in epithelial ovarian cancers during the last two decades [1,2]. However, there are still some ⁎ Corresponding author. Naci Cakir Mah. 1. Cadde, Kubra Apt. 1/1, Dikmen, Ankara, Turkey. Fax: +90 312 4475303. E-mail address: [email protected] (M. Gultekin). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.09.014
issues that need to be clarified such as the number of metastatic lymph nodes. There is no any data that primarily analyzed the number of metastatic lymph nodes in epithelial ovarian cancer patients. Among the limited data available, most had discussed the subject in their subgroup analysis. Some authors even did not present their related data in the article. The heterogeneity of the data, the low number of patients, rather suspicious findings due to the pattern of lymphadenectomy performed (sampling vs. systematic) and some inadequate statistical analysis confounds the prognostic significance of the number of nodal metastases. Another interesting and unresolved issue was the prognostic importance of the number of metastatic lymph nodes. While some have found the number of metastatic groups to be an
A. Ayhan et al. / Gynecologic Oncology 108 (2008) 428–432
important prognosticator, some others had negated its role on the survival of patients [3–9]. As a result of these above mentioned problems seen in previous studies, the authors intended to analyze the clinicopathological variables that significantly correlate with the number of metastatic lymph nodes and also the prognostic role of the subject in a selected group of homogenous patient population, all of whom had systematic lymphadenectomy in the same institution by the same surgeons. Materials and methods A total of 831 patients with epithelial ovarian carcinoma diagnosed and treated at Hacettepe University Hospital during 1982–2005 were retrospectively evaluated. Clinicopathologic variables were gathered from hospital files and special oncology follow-up charts. Patients who had no lymphatic metastasis or who had incomplete surgeries, who received preoperative chemotherapy, who had operative difficulties rendering a systematic lymph node dissection were excluded from the final analysis. Any patient with incomplete or suspicious clinical data or with surgical stages I–II (n = 206) or stage IV (n = 60, of whom 44 had lymphadenectomy and remaining 16 did not have a lymphadenectomy procedure) disease was also excluded leaving finally 328 surgical stage IIIc (clinically stages I–III) patients eligible for the analysis. All the patients were subjected to the primary cytoreductive surgery including systematic pelvic and paraaortic lymphadenectomy. Pelvic lymphadenectomy was carried out along the external iliac, internal iliac, common iliac and obturator vessels on both sides, and the paraaortic node dissection was performed from the bifurcation of aorta to the origin of the renal vessels by a transperitoneal approach. Other than lymphadenectomy, all the patients had undergone total abdominal hysterectomy, bilateral salpingooophorectomy, total omentectomy, appendectomy and tumoral debulking. Patients with residual disease b1 cm were defined as optimally cytoreduced. Surgeries were undertaken by the same surgical team in all patients. Among 328 patients, 15 had rejected to receive adjuvant chemotherapy. Two hundred and ninety-nine (95.5%, 299/313) of these remaining 313 patients (95.5%, 299/313) had received platinum-based adjuvant chemotherapy while only 14 (14/313, 4.5%) patients had received non-platinum-based adjuvant chemotherapy. Beside platinum, 181 patients had received taxane-based regimen (57.8%), 86 received cyclophosphamide-based regimen (27.4%) and remaining 46 (14.8%) received other combinations. Patients' age, number of resected lymph nodes, clinical disease stage (I–II vs. III), preoperative Ca-125 levels (0–35, 36–500, ≥500 IU/L), peritoneal cytology (positive or negative), presence of ascites, tumor histology (serous, mucinous, endometrioid and others), tumor grade, maximal tumor diameter (b10 cm vs. ≥10 cm), cytoreductive success (optimal if residual tumor is b1 cm and suboptimal if otherwise) and the number of metastatic lymph nodes (b4 vs. ≥4) were the variables analyzed in this study. Survival estimates were calculated from the date of initial surgery to the date of death due to disease or the last follow-up for the overall survival and to the date of disease recurrence for the disease-free survival.
Statistical analysis Student's t test, chi-square test and Kaplan Meier tests were used for the univariate comparisons of the groups. Binary logistic regression test was used for the multivariate analysis. A P value of b0.05 was accepted to be significant upon these statistical evaluations.
Results Mean number of resected lymph nodes was 24.5 and mean number of metastatic lymph nodes was 6.2. When we analyzed these patients with respect to laterality of the lymphatic metastasis, 272 patients (82.9%) had bilateral tumors (totally
429
as gross and microscopically tumor positivity). Remaining patients were equally distributed (28 had unilateral right and 28 had unilateral left tumors). Among these unilateral tumors, of these 56 (n = 56), 37 had paraaortic metastasis (37/56, 66.1%). Of these remaining 19 patients with isolated pelvic metastasis and unilateral tumors, 10 had bilateral, 8 had unilateral and only one patient had contralateral pelvic nodal metastasis. About 47.3% (n = 155) of the patients had b 4 metastatic lymph nodes (group A) and the remaining 52.7% of patients (n = 173) had ≥ 4 metastatic lymph nodes (group B). This threshold was used to group the patients because it was the median metastatic lymph node number and the patients were almost equally distributed among the groups. There was no any previous report pointing a clinically significant threshold for the lymphatic metastasis and all had chosen their thresholds arbitrarily. Comparison of these two groups with respect to clinicopathologic variables is given in Table 1. Mean age of the patients was 55.4 (range, 18–88) without a significant difference among both Table 1 Comparison of clinicopathologic variables with respect to the number of metastatic lymph nodes (LN) Patients with metastatic LN
Number of patients Mean age Mean resected LN Clinical stage Stages I–II Stage III Histology Serous Mucinous Endometrioid Others Grade I II III Ascites Absent Present Cytology Negative Positive Not available Ca-125 ≤35 35–500 ≥500 Not available Tumoral size b10 cm ≥10 cm Cytoreduction Optimal Suboptimal
P value
Total, n (%)
b4 metastatic LN, ≥4 metastatic LN, n (%) n (%)
328
155 (47.3)
173 (52.7)
55.4 24.5
53.1 23.13
55.6 25.8
0.08 0.06
37 (11.3) 24 (64.9) 291 (88.7) 131 (45.0)
13 (35.1) 160 (55.0)
0.023
224 (68.2) 14 (4.3) 32 (9.8) 58 (17.7)
112 (64.6) 5 (2.9) 23 (13.3) 33 (19.1)
0.06
31 (9.5) 16 (10.3) 85 (25.9) 43 (27.8) 212 (64.6) 96 (61.9)
15 (8.7) 42 (24.2) 116 (67.1)
0.6
194 (59.1) 100 (64.5) 134 (40.9) 55 (35.5)
94 (54.3) 79 (45.7)
0.06
127 (38.7) 67 (50.0) 163 (49.7) 67 (50.0) 38 (11.6) –
60 (38.5) 96 (61.5) –
0.04
24 (7.3) 123 (37.5) 152 (46.4) 29 (8.8)
9 (5.8) 55 (35.2) 92 (59.0) –
0.01
216 (65.9) 104 (67.1) 112 (34.1) 51 (32.9)
112 (64.7) 61 (35.3)
0.6
236 (72.0) 110 (71.0) 92 (28.0) 45 (29.0)
126 (72.8) 47 (27.2)
0.7
112 (72.3) 9 (5.8) 9 (5.8) 25 (16.1)
15 (10.5) 68 (47.5) 60 (42.0) –
Number of cases and percentages are given in parentheses. LN, lymph node.
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groups (P = 0.08). All the patients had surgical stage III disease. However, 37 (11.3%) patients had clinical stages I–II disease while remaining 291 (88.7%) had clinical stage III disease. Thirteen of clinical stages I–II patients (35.1%) and 160 (55.0%) of clinical stage III patients had ≥ 4 metastatic lymph nodes (P = 0.023, Table 1). Of these 328 patients, 224 (68.2%) had serous, 14 (4.3%) had mucinous, 32 (9.8%) had endometrioid, 16 (4.9%) had undifferentiated, 10 (3.0%) had Brenner, 8 (2.5%) had clear cell and 24 (7.3%) had mixed cell type tumors. With respect to histopathological diagnosis, there was no significant difference among groups (P = 0.06). Overall 134 (40.9%) patients had ascites. This rate was 35.5% in patients with b4 and 45.7% in patients with ≥ 4 metastatic lymph nodes (P = 0.06). Thirty-one (9.5%) patients had grade I, 85 (25.9%) had grade II and the remaining 212 (64.6%) had grade III disease. Distribution of tumor grades was not significant among the groups (P = 0.6). Maximal primary tumor diameter was b 10 cm in 216 patients (65.9%) and ≥ 10 cm in 112 patients (34.1%). Tumor diameter was also non-significant among the groups (P = 0.023). Optimal cytoreduction was accomplished in 236 (72.0%) patients. This rate was 71.0% in patients with lesser metastatic lymph node number and 72.8% in the remaining patients with higher metastatic lymph node numbers. Preoperative Ca-125 levels were as follows: 24 (7.3%) had preoperative Ca-125 less than 35, 123 (37.5%) had Ca-125 level between 36– 500 while 152 (46.4%) had a ≥ 500 IU/l preoperative Ca-125 value. Patients with ≥ 4 metastatic lymph nodes had significantly higher preoperative Ca-125 levels (P = 0.01). Of these patients, 92 (59.0%) had ≥ 500 IU/l preoperative Ca-125 levels. This rate was 42% in patients with b4 metastatic lymph nodes (P = 0.01). Presence of malignant washings or ascites was significantly higher in patients with higher metastatic lymph node numbers (61.5% vs. 50.0%, P = 0.04). Multivariate comparisons of the factors found to be significant on univariate analysis (Ca-125 ≥ 500 IU/l, positive cytology and clinical disease stage) revealed a Ca-125 value higher than 500 IU/l to be the unique significant factor among the two groups (P = 0.003, OR = 2.0; 95% CI = 1.25–3.15). Median follow-up of patients was 2.2 years. Survival analysis of patients did not reveal a significant difference among both groups. Median and 5-year overall survival was respectively 2.62 years and 27.2% in patients with b4 metastatic lymph nodes while these figures were 2.29 years and 14.3% in patients with ≥ 4 metastatic lymph nodes, respectively (P = 0.09) (Fig. 1). Median disease-free survival rate was also non-significant among the two groups (P = 0.7; 1.66 years for b4 vs. 1.76 years for ≥ 4 metastatic lymph nodes). A large time interval (1982–2005) used in this study may cause some biases due to possible changes in the individual treatment modalities (surgical and medical treatments with chemotherapeutics) of patients. To avoid such biases, a subgroup analysis is also performed according to the diagnosis years. Of the 313 patients who accepted to receive adjuvant chemotherapy, 156 (49.8%) was diagnosed before 1998 and the remaining 157 (50.2%) patients were diagnosed between 1998 and 2005. Median number of total resected lymph nodes in these groups was 24.3 and 24.5, respectively (P = 0.9). Median
Fig. 1. Comparison of the patient survivals with respect to metastatic lymph node numbers (P N 0.05).
number of resected metastatic lymph nodes was also similar (6.2 vs. 6.1, respectively P = 0.9). Median number of resected metastatic lymph nodes was b 4 in 51.3% (80/313) and ≥ 4 in 48.7% (76/313) of patients diagnosed before 1998. These figures were 45.9% (72/157) and 54.1% (85/157), respectively, in patients diagnosed after 1998 (P = 0.3). Optimal cytoreduction rates were also similar among both groups (71.1% 111/156 before 1998 and 71.9% 113/157 diagnosed after 1998). Almost all patients had received platinum-based chemotherapy in both groups (94.2% vs. 96.8%, P = 0.3). As one might expect, taxanes were significantly used in the latter years (95.5% vs. 19.9%) and cyclophosphamide-based regimens were more frequently used in patients with earlier diagnosis (53.2% vs. 1.9%) (P b 0.001). Despite to the changes in the chemotherapeutics used (mainly taxanes after 1995), there was no significant difference among median overall survivals according to the year of diagnosis of patients (2.41 vs. 2.63 years, respectively, P = 0.9). A subgroup analysis of patients with optimal vs. suboptimal debulking with respect to median preoperative Ca-125 levels (500 vs. 499.9 IU/L, respectively) and mean resected metastatic lymph node number (6.18 vs. 6.23, respectively) could not find a significant difference among the groups (P = 0.9 for each). Preoperative Ca-125 levels were ≤ 35 IU/L in 21 (9.8%), 35–500 in 84 (39.1%) and ≥ 500 IU/L in 110 (51.1%) patients with optimal debulking. These figures were 3.3% (n = 3), 46.7% (n = 39) and 50.0% (n = 42) in patients with suboptimal debulking (P = 0.3). Resected metastatic lymph node number was b4 in 110 (46.6%) of optimally debulked and 45 (48.9%) of suboptimally debulked patients (P = 0.7). Another subgroup analysis is also performed among patients with advanced stages (291 clinical stage III patients) with respect to the similar clinicopathological characteristics seen in Table 1 on both univariate and multivariate analysis. These patients are similarly divided in to two groups: those with b4 and the remaining with ≥ 4 resected metastatic lymph nodes. Multivariate comparisons revealed two factors to be significantly different among the groups: preoperative Ca-125 levels and tumor histology. In stage III disease, patients with ≥ 500 IU/L
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preoperative Ca-125 level had significantly higher number of lymph nodal metastasis (62.9% had ≥ 4 nodal metastasis, P = 0.003). With respect to histology in advanced stages, endometrioid tumors had significantly higher number of lymphatic metastasis (80.8% has ≥ 4 lymph nodal metastasis). Opposite to this, mucinous tumors had significantly lower number of lymph nodal metastasis (66.7% had b 4 nodal metastasis, P = 0.01). However, the number of these histologies was not adequate (12 mucinous and 26 endometrioid) for a statistically valid comparison. With respect to survival analysis, median overall survival in these subset of patients was 2.58 years for b4 and 2.16 years for the ≥ 4 resected metastatic lymph nodes (P = 0.1). Discussion Epithelial ovarian cancers are the most lymphophilic tumors. Lymphatic metastasis rate varies between 46.9% and 76.6% in advanced staged diseases [1,2]. There are numerous published data evaluating the clinical predictors and importance of lymphatic metastasis [3–9]. However, few of the studies had previously analyzed the number of metastatic lymph nodes (Table 2). Some other reports revealed the clinical significance of number of resected and metastatic lymph nodes in endometrial cancers [10]. However, there are scarce data about the epithelial ovarian cancers. This is especially true for the clinicopathological correlations of metastatic lymph node numbers. Burghardt et al. [3] were the first authors who had analyzed this subject. They evaluated 91 patients and found that metastatic lymph node number was greater in advanced staged diseases and it also correlated with the residual tumor size following the cytoreductive operation [3]. Benedetti-Panici et al. [4] in a small number of patients (n = 35) had found that lymphatic metastasis was less frequently encountered in clinical stages I–II disease and was also usually confined to one or a few lymph node groups. Lymphatic metastasis increased parallel to the progressive increase in intraabdominal tumor load. Suzuki et al. [8] also found the metastatic lymph node numbers to correlate with clinical stages. In current study analysis, a significant correlation between clinical stage and the number of metastatic
Table 2 Review of the literature about the number of resected metastatic lymph nodes Author
Year
n
Threshold
Correlation
Prognostic value
Burghardt et al. [3] Benedetti-Panici et al. [4] Petru et al. [5] di Re et al. [6]
1991
91 1 vs. ≥1
Clinical stage, residual disease Clinical stage
Yes
1993
35 –
1994 9 1 vs. N1 1996 194 –
Yes No
Onda et al. [7] Suzuki et al. [8] Morice et al. [9] Current study
1998 38 2000 5 2000 122 2007 328
No – No No
– Clinical stage, residual disease 1–4 vs. N4 – – Clinical stage 1 vs. N1 – b4 vs. ≥4 High Ca-125 levels
–
431
lymph nodes was also found. However, a Ca-125 value greater than 500 IU/l was more significant than the clinical stage on multivariate analysis. Among the evaluated factors, preoperative Ca-125 level was the only significant factor associated with higher metastatic lymph node numbers. Ca-125 level was also previously found to correlate with tumoral load and predictability of optimal cytoreduction [11]. A high Ca-125 level had also been found to predict the lymphatic metastasis in patients with epithelial ovarian cancers in our previous report [1]. So a high Ca-125 level may not only show the presence of lymphatic metastasis, but also a higher number of metastatic lymph nodes. As the preoperative values increase, both the intraabdominal and retroperitoneal tumor load seems to increase in patients with epithelial ovarian cancers. Based on the previous reports, it may be concluded that metastatic lymph node number increase parallel to the preoperative Ca-125 levels, clinical stages, intraabdominal tumor load and residual tumor volume after the operation. There is only a little more known about the prognostic effect of metastatic lymph node numbers in the literature. Burghardt et al. [3] found 5-year survival rates as 68.7%, 58.2% and 28.0% for patients with no lymph node metastasis, with only one node involvement and with N1 lymph node metastasis, respectively. However, they did not use multivariate analysis and patient numbers were not adequate [3]. Petru et al. [5] suggested the number of metastatic lymph nodes (1 vs. N 1) to be prognostic in a small patient sample (n = 9). On the other hand, di Re et al. [6] in a larger patient population (n = 194) could not find a prognostic role for the metastatic lymph node numbers when compared patients with 1–2 vs. 3–10 and N 10 metastatic lymph node numbers. Onda et al. [7] also found that the number of metastatic lymph nodes was not a significant prognostic factor when they compared 1–4 vs. N4 metastatic lymph node numbers. However, both authors did not give the detailed patient data in their article. Final report came from Morrice et al. [9]. They also could not find a significant prognostic role for the metastatic lymph node number when compared one and N 1 metastatic lymph node numbers. This overview of the previous literature revealed that there were few reports analyzing this subject [3–9]. Almost all were in retrospective nature and included inadequate patient numbers. A detailed clinicopathologic analysis was available in limited reports. Grouping of metastatic lymph nodes (1 vs. N1 or 1–2 vs. 3–10 vs. N 10, etc.) was performed arbitrarily. Multivariate analysis was not used in reports where the number of metastatic lymph nodes was found to be significant on univariate survival analysis. Neither of the reports analyzed progression-free interval with respect to extend of lymphatic metastasis. Therefore, prognostic role of the metastatic lymph node number is still under debate. While some did not find any significance, some authors found a prognostic role and claimed that as the number of metastatic lymph node number increased, it may lead to subperitoneal lymphangiosis and intraperitoneal persistence resulting in a poor chemoresponsiveness and worse intrinsic tumor biology [3–9]. That might also be the reason for the parallel increase of metastatic lymph node numbers and the intraabdominal tumor load or residual tumor volume [3–9].
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Another possible explanation for high preoperative tumor marker level parallel to high number of metastatic lymph node metastasis may be related to the biologic property and aggressiveness of tumor cell. The highly aggressive tumor may tend to have high level of preoperative Ca-125, advanced stage and high number of metastatic lymph node metastasis, and also with lower survival estimates. One may suggest our results to be biased due to large time interval we used (1982–2005). However, subgroup analysis (patients with year of diagnosis 1982–1998 vs. 1998–2005) revealed no significant changes in the surgical treatment of the patients within years (optimal cytoreduction and number of resected lymph nodes). This may be attributed to our experienced and constant surgical team who had been the primary operators in each patient during this time. Maximal effort had been used for optimal cytoreduction in each patient and any visceral resections had been performed accordingly. With respect to combination adjuvant chemotherapeutics, almost all patients had received platinum-based chemotherapeutics during this time interval. The only difference was the taxanes (was almost standard after 1995) which could not make a difference with respect to the overall survivals within the following years. This might be attributed to the high optimal cytoreduction rates in these advanced staged diseases and also to the highly advanced staged disease these patients have (all are IIIc surgically staged) where we still try to find better combinations and regimens for a better outcome. The current study is the largest single-institutional report analyzing this issue up to now. All patients were in surgical stage III disease and had systematic lymph node dissection and were analyzed not only by univariate but also by multivariate analysis with respect to many different clinicopathologic factors including both the overall and the disease-free survivals together with detailed overview of the whole related previous literature. Metastatic lymph node numbers was not found to have a significant effect on either the overall or the disease-free survival in current study analysis. Although short median follow-up period compared to some other previous reports was observed as one of the limitation point of our study, this may be attributed to the referral center property of our center. The important point is the presence of lymphatic metastasis rather than its' extent [1].
However, any possible prognostic effect may also be underestimated in our analysis since all the metastatic lymph nodes were debulked systematically in these selected patient population. Therefore, for a definitive conclusion, larger prospective reports may be needed, especially in evaluating a clinically significant threshold number of metastatic lymph nodes for the prognostic role and the resection extent. References [1] Ayhan A, Gultekin M, Taskiran C, Celik NY, Usubutun A, Kucukali T, et al. Lymphatic metastasis in epithelial ovarian carcinoma with respect to clinicopathological variables. Gynecol Oncol May 2005;97(2):400–4. [2] Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst Apr 20 2005;97(8):560–6. [3] Burghardt E, Girardi F, Lahousen M, Tamussino K, Stettner H. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol Feb 1991;40(2):103–6. [4] Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol Nov 1993;51(2):150–4. [5] Petru E, Lahousen M, Tamussino K, Pickel H, Stranzl H, Stettner H, et al. Lymphadenectomy in stage I ovarian cancer. Am J Obstet Gynecol Feb 1994;170(2):656–62. [6] di Re F, Baiocchi G, Fontanelli R, Grosso G, Cobellis L, Raspagliesi F, et al. Systematic pelvic and paraaortic lymphadenectomy for advanced ovarian cancer: prognostic significance of node metastases. Gynecol Oncol Sep 1996;62(3):360–5. [7] Onda T, Yoshikawa H, Yasugi T, Mishima M, Nakagawa S, Yamada M, et al. Patients with ovarian carcinoma upstaged to stage III after systematic lymphadenectomy have similar survival to Stage I/II patients and superior survival to other Stage III patients. Cancer Oct 15 1998;83(8):1555–60. [8] Suzuki M, Ohwada M, Yamada T, Kohno T, Sekiguchi I, Sato I. Lymph node metastasis in stage I epithelial ovarian cancer. Gynecol Oncol Nov 2000;79(2):305–8. [9] Morice P, Joulie F, Camatte S, Atallah D, Rouzier R, Pautier P, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg Aug 2003;197(2):198–205. [10] Creutzberg CL. Lymphadenectomy in apparent early-stage endometrial carcinoma: do numbers count? J Clin Oncol Jun 1 2005;23(16):3653–5. [11] Chi DS, Venkatraman ES, Masson V, Hoskins WJ. The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol May 2000;77(2): 227–31.
Gynecologic Oncology 108 (2008) 428 – 432 www.elsevier.com/locate/ygyno
Metastatic lymph node number in epithelial ovarian carcinoma: Does it have any clinical significance? Ali Ayhan a , Murat Gultekin b,⁎, Polat Dursun a , Nasuh Utku Dogan c , Guldeniz Aksan c , Suleyman Guven d , Melih Velipasaoglu c , Kunter Yuce c a
c
Baskent University Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Sihhiye, Ankara, Turkey b Cankırı Government Hospital, Department of Obstetrics and Gynecology, Cankırı, Turkey Hacettepe University Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Sihhiye, Ankara, Turkey d Karadeniz Techniqual University Faculty of Medicine, Department of Obstetrics and Gynecology, Trabzon, Turkey Received 17 July 2007
Abstract Objective. To analyze the clinicopathological correlations of metastatic lymph node (LN) numbers in patients with epithelial ovarian carcinoma. Method. A total of 328 patients with epithelial ovarian carcinoma diagnosed and treated at Hacettepe University Hospital during 1982–2005 were retrospectively reviewed. Patients' age, number of resected lymph nodes, clinical disease stage, preoperative Ca-125 levels, peritoneal cytology, presence of ascites, tumor histology, tumor grade, maximal tumor diameter, cytoreductive success, overall and disease-free survivals were compared with respect to the number of metastatic lymph nodes (b 4 vs. ≥4). Results. The mean number of resected lymph nodes was 24.5 and mean number of metastatic lymph nodes was 6.2. About 47.3% (n = 155) of the patients had b 4 metastatic lymph nodes and the remaining 52.7% of patients (n = 173) had ≥ 4 metastatic lymph nodes. Univariate comparison of the two groups relived preoperative Ca-125 values, peritoneal cytology and clinical disease stage to be significantly different among the two groups. However, multivariate analysis revealed a high Ca-125 level (≥ 500 IU/l) to be unique factor significantly different among the groups. Survival analysis also could not find a significant difference with respect to overall and disease-free survival among the groups. Conclusion. The number of metastatic lymph nodes increases as the preoperative Ca-125 values increase. Other patient characteristics do not have a significant effect on the number of metastatic lymph nodes. Metastatic LN number does not have a prognostic significance in terms of either the overall or the disease-free survival. Prospective series are needed for a definitive conclusion. © 2008 Elsevier Inc. All rights reserved. Keywords: Epithelial ovarian carcinoma; Lymphatic metastasis; Number of metastatic lymph node; Survival estimate
Introduction Epithelial ovarian cancers (EOC) are the most lymphophilic tumors among the genital cancers. Lymph node metastasis ranges between 12% and 25% in early stage and between 46% and 76% in advanced stage diseases. Therefore, the lymphatic metastasis and the role of lymphadenectomy are among the most commonly analyzed subjects in epithelial ovarian cancers during the last two decades [1,2]. However, there are still some ⁎ Corresponding author. Naci Cakir Mah. 1. Cadde, Kubra Apt. 1/1, Dikmen, Ankara, Turkey. Fax: +90 312 4475303. E-mail address: [email protected] (M. Gultekin). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.09.014
issues that need to be clarified such as the number of metastatic lymph nodes. There is no any data that primarily analyzed the number of metastatic lymph nodes in epithelial ovarian cancer patients. Among the limited data available, most had discussed the subject in their subgroup analysis. Some authors even did not present their related data in the article. The heterogeneity of the data, the low number of patients, rather suspicious findings due to the pattern of lymphadenectomy performed (sampling vs. systematic) and some inadequate statistical analysis confounds the prognostic significance of the number of nodal metastases. Another interesting and unresolved issue was the prognostic importance of the number of metastatic lymph nodes. While some have found the number of metastatic groups to be an
A. Ayhan et al. / Gynecologic Oncology 108 (2008) 428–432
important prognosticator, some others had negated its role on the survival of patients [3–9]. As a result of these above mentioned problems seen in previous studies, the authors intended to analyze the clinicopathological variables that significantly correlate with the number of metastatic lymph nodes and also the prognostic role of the subject in a selected group of homogenous patient population, all of whom had systematic lymphadenectomy in the same institution by the same surgeons. Materials and methods A total of 831 patients with epithelial ovarian carcinoma diagnosed and treated at Hacettepe University Hospital during 1982–2005 were retrospectively evaluated. Clinicopathologic variables were gathered from hospital files and special oncology follow-up charts. Patients who had no lymphatic metastasis or who had incomplete surgeries, who received preoperative chemotherapy, who had operative difficulties rendering a systematic lymph node dissection were excluded from the final analysis. Any patient with incomplete or suspicious clinical data or with surgical stages I–II (n = 206) or stage IV (n = 60, of whom 44 had lymphadenectomy and remaining 16 did not have a lymphadenectomy procedure) disease was also excluded leaving finally 328 surgical stage IIIc (clinically stages I–III) patients eligible for the analysis. All the patients were subjected to the primary cytoreductive surgery including systematic pelvic and paraaortic lymphadenectomy. Pelvic lymphadenectomy was carried out along the external iliac, internal iliac, common iliac and obturator vessels on both sides, and the paraaortic node dissection was performed from the bifurcation of aorta to the origin of the renal vessels by a transperitoneal approach. Other than lymphadenectomy, all the patients had undergone total abdominal hysterectomy, bilateral salpingooophorectomy, total omentectomy, appendectomy and tumoral debulking. Patients with residual disease b1 cm were defined as optimally cytoreduced. Surgeries were undertaken by the same surgical team in all patients. Among 328 patients, 15 had rejected to receive adjuvant chemotherapy. Two hundred and ninety-nine (95.5%, 299/313) of these remaining 313 patients (95.5%, 299/313) had received platinum-based adjuvant chemotherapy while only 14 (14/313, 4.5%) patients had received non-platinum-based adjuvant chemotherapy. Beside platinum, 181 patients had received taxane-based regimen (57.8%), 86 received cyclophosphamide-based regimen (27.4%) and remaining 46 (14.8%) received other combinations. Patients' age, number of resected lymph nodes, clinical disease stage (I–II vs. III), preoperative Ca-125 levels (0–35, 36–500, ≥500 IU/L), peritoneal cytology (positive or negative), presence of ascites, tumor histology (serous, mucinous, endometrioid and others), tumor grade, maximal tumor diameter (b10 cm vs. ≥10 cm), cytoreductive success (optimal if residual tumor is b1 cm and suboptimal if otherwise) and the number of metastatic lymph nodes (b4 vs. ≥4) were the variables analyzed in this study. Survival estimates were calculated from the date of initial surgery to the date of death due to disease or the last follow-up for the overall survival and to the date of disease recurrence for the disease-free survival.
Statistical analysis Student's t test, chi-square test and Kaplan Meier tests were used for the univariate comparisons of the groups. Binary logistic regression test was used for the multivariate analysis. A P value of b0.05 was accepted to be significant upon these statistical evaluations.
Results Mean number of resected lymph nodes was 24.5 and mean number of metastatic lymph nodes was 6.2. When we analyzed these patients with respect to laterality of the lymphatic metastasis, 272 patients (82.9%) had bilateral tumors (totally
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as gross and microscopically tumor positivity). Remaining patients were equally distributed (28 had unilateral right and 28 had unilateral left tumors). Among these unilateral tumors, of these 56 (n = 56), 37 had paraaortic metastasis (37/56, 66.1%). Of these remaining 19 patients with isolated pelvic metastasis and unilateral tumors, 10 had bilateral, 8 had unilateral and only one patient had contralateral pelvic nodal metastasis. About 47.3% (n = 155) of the patients had b 4 metastatic lymph nodes (group A) and the remaining 52.7% of patients (n = 173) had ≥ 4 metastatic lymph nodes (group B). This threshold was used to group the patients because it was the median metastatic lymph node number and the patients were almost equally distributed among the groups. There was no any previous report pointing a clinically significant threshold for the lymphatic metastasis and all had chosen their thresholds arbitrarily. Comparison of these two groups with respect to clinicopathologic variables is given in Table 1. Mean age of the patients was 55.4 (range, 18–88) without a significant difference among both Table 1 Comparison of clinicopathologic variables with respect to the number of metastatic lymph nodes (LN) Patients with metastatic LN
Number of patients Mean age Mean resected LN Clinical stage Stages I–II Stage III Histology Serous Mucinous Endometrioid Others Grade I II III Ascites Absent Present Cytology Negative Positive Not available Ca-125 ≤35 35–500 ≥500 Not available Tumoral size b10 cm ≥10 cm Cytoreduction Optimal Suboptimal
P value
Total, n (%)
b4 metastatic LN, ≥4 metastatic LN, n (%) n (%)
328
155 (47.3)
173 (52.7)
55.4 24.5
53.1 23.13
55.6 25.8
0.08 0.06
37 (11.3) 24 (64.9) 291 (88.7) 131 (45.0)
13 (35.1) 160 (55.0)
0.023
224 (68.2) 14 (4.3) 32 (9.8) 58 (17.7)
112 (64.6) 5 (2.9) 23 (13.3) 33 (19.1)
0.06
31 (9.5) 16 (10.3) 85 (25.9) 43 (27.8) 212 (64.6) 96 (61.9)
15 (8.7) 42 (24.2) 116 (67.1)
0.6
194 (59.1) 100 (64.5) 134 (40.9) 55 (35.5)
94 (54.3) 79 (45.7)
0.06
127 (38.7) 67 (50.0) 163 (49.7) 67 (50.0) 38 (11.6) –
60 (38.5) 96 (61.5) –
0.04
24 (7.3) 123 (37.5) 152 (46.4) 29 (8.8)
9 (5.8) 55 (35.2) 92 (59.0) –
0.01
216 (65.9) 104 (67.1) 112 (34.1) 51 (32.9)
112 (64.7) 61 (35.3)
0.6
236 (72.0) 110 (71.0) 92 (28.0) 45 (29.0)
126 (72.8) 47 (27.2)
0.7
112 (72.3) 9 (5.8) 9 (5.8) 25 (16.1)
15 (10.5) 68 (47.5) 60 (42.0) –
Number of cases and percentages are given in parentheses. LN, lymph node.
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groups (P = 0.08). All the patients had surgical stage III disease. However, 37 (11.3%) patients had clinical stages I–II disease while remaining 291 (88.7%) had clinical stage III disease. Thirteen of clinical stages I–II patients (35.1%) and 160 (55.0%) of clinical stage III patients had ≥ 4 metastatic lymph nodes (P = 0.023, Table 1). Of these 328 patients, 224 (68.2%) had serous, 14 (4.3%) had mucinous, 32 (9.8%) had endometrioid, 16 (4.9%) had undifferentiated, 10 (3.0%) had Brenner, 8 (2.5%) had clear cell and 24 (7.3%) had mixed cell type tumors. With respect to histopathological diagnosis, there was no significant difference among groups (P = 0.06). Overall 134 (40.9%) patients had ascites. This rate was 35.5% in patients with b4 and 45.7% in patients with ≥ 4 metastatic lymph nodes (P = 0.06). Thirty-one (9.5%) patients had grade I, 85 (25.9%) had grade II and the remaining 212 (64.6%) had grade III disease. Distribution of tumor grades was not significant among the groups (P = 0.6). Maximal primary tumor diameter was b 10 cm in 216 patients (65.9%) and ≥ 10 cm in 112 patients (34.1%). Tumor diameter was also non-significant among the groups (P = 0.023). Optimal cytoreduction was accomplished in 236 (72.0%) patients. This rate was 71.0% in patients with lesser metastatic lymph node number and 72.8% in the remaining patients with higher metastatic lymph node numbers. Preoperative Ca-125 levels were as follows: 24 (7.3%) had preoperative Ca-125 less than 35, 123 (37.5%) had Ca-125 level between 36– 500 while 152 (46.4%) had a ≥ 500 IU/l preoperative Ca-125 value. Patients with ≥ 4 metastatic lymph nodes had significantly higher preoperative Ca-125 levels (P = 0.01). Of these patients, 92 (59.0%) had ≥ 500 IU/l preoperative Ca-125 levels. This rate was 42% in patients with b4 metastatic lymph nodes (P = 0.01). Presence of malignant washings or ascites was significantly higher in patients with higher metastatic lymph node numbers (61.5% vs. 50.0%, P = 0.04). Multivariate comparisons of the factors found to be significant on univariate analysis (Ca-125 ≥ 500 IU/l, positive cytology and clinical disease stage) revealed a Ca-125 value higher than 500 IU/l to be the unique significant factor among the two groups (P = 0.003, OR = 2.0; 95% CI = 1.25–3.15). Median follow-up of patients was 2.2 years. Survival analysis of patients did not reveal a significant difference among both groups. Median and 5-year overall survival was respectively 2.62 years and 27.2% in patients with b4 metastatic lymph nodes while these figures were 2.29 years and 14.3% in patients with ≥ 4 metastatic lymph nodes, respectively (P = 0.09) (Fig. 1). Median disease-free survival rate was also non-significant among the two groups (P = 0.7; 1.66 years for b4 vs. 1.76 years for ≥ 4 metastatic lymph nodes). A large time interval (1982–2005) used in this study may cause some biases due to possible changes in the individual treatment modalities (surgical and medical treatments with chemotherapeutics) of patients. To avoid such biases, a subgroup analysis is also performed according to the diagnosis years. Of the 313 patients who accepted to receive adjuvant chemotherapy, 156 (49.8%) was diagnosed before 1998 and the remaining 157 (50.2%) patients were diagnosed between 1998 and 2005. Median number of total resected lymph nodes in these groups was 24.3 and 24.5, respectively (P = 0.9). Median
Fig. 1. Comparison of the patient survivals with respect to metastatic lymph node numbers (P N 0.05).
number of resected metastatic lymph nodes was also similar (6.2 vs. 6.1, respectively P = 0.9). Median number of resected metastatic lymph nodes was b 4 in 51.3% (80/313) and ≥ 4 in 48.7% (76/313) of patients diagnosed before 1998. These figures were 45.9% (72/157) and 54.1% (85/157), respectively, in patients diagnosed after 1998 (P = 0.3). Optimal cytoreduction rates were also similar among both groups (71.1% 111/156 before 1998 and 71.9% 113/157 diagnosed after 1998). Almost all patients had received platinum-based chemotherapy in both groups (94.2% vs. 96.8%, P = 0.3). As one might expect, taxanes were significantly used in the latter years (95.5% vs. 19.9%) and cyclophosphamide-based regimens were more frequently used in patients with earlier diagnosis (53.2% vs. 1.9%) (P b 0.001). Despite to the changes in the chemotherapeutics used (mainly taxanes after 1995), there was no significant difference among median overall survivals according to the year of diagnosis of patients (2.41 vs. 2.63 years, respectively, P = 0.9). A subgroup analysis of patients with optimal vs. suboptimal debulking with respect to median preoperative Ca-125 levels (500 vs. 499.9 IU/L, respectively) and mean resected metastatic lymph node number (6.18 vs. 6.23, respectively) could not find a significant difference among the groups (P = 0.9 for each). Preoperative Ca-125 levels were ≤ 35 IU/L in 21 (9.8%), 35–500 in 84 (39.1%) and ≥ 500 IU/L in 110 (51.1%) patients with optimal debulking. These figures were 3.3% (n = 3), 46.7% (n = 39) and 50.0% (n = 42) in patients with suboptimal debulking (P = 0.3). Resected metastatic lymph node number was b4 in 110 (46.6%) of optimally debulked and 45 (48.9%) of suboptimally debulked patients (P = 0.7). Another subgroup analysis is also performed among patients with advanced stages (291 clinical stage III patients) with respect to the similar clinicopathological characteristics seen in Table 1 on both univariate and multivariate analysis. These patients are similarly divided in to two groups: those with b4 and the remaining with ≥ 4 resected metastatic lymph nodes. Multivariate comparisons revealed two factors to be significantly different among the groups: preoperative Ca-125 levels and tumor histology. In stage III disease, patients with ≥ 500 IU/L
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preoperative Ca-125 level had significantly higher number of lymph nodal metastasis (62.9% had ≥ 4 nodal metastasis, P = 0.003). With respect to histology in advanced stages, endometrioid tumors had significantly higher number of lymphatic metastasis (80.8% has ≥ 4 lymph nodal metastasis). Opposite to this, mucinous tumors had significantly lower number of lymph nodal metastasis (66.7% had b 4 nodal metastasis, P = 0.01). However, the number of these histologies was not adequate (12 mucinous and 26 endometrioid) for a statistically valid comparison. With respect to survival analysis, median overall survival in these subset of patients was 2.58 years for b4 and 2.16 years for the ≥ 4 resected metastatic lymph nodes (P = 0.1). Discussion Epithelial ovarian cancers are the most lymphophilic tumors. Lymphatic metastasis rate varies between 46.9% and 76.6% in advanced staged diseases [1,2]. There are numerous published data evaluating the clinical predictors and importance of lymphatic metastasis [3–9]. However, few of the studies had previously analyzed the number of metastatic lymph nodes (Table 2). Some other reports revealed the clinical significance of number of resected and metastatic lymph nodes in endometrial cancers [10]. However, there are scarce data about the epithelial ovarian cancers. This is especially true for the clinicopathological correlations of metastatic lymph node numbers. Burghardt et al. [3] were the first authors who had analyzed this subject. They evaluated 91 patients and found that metastatic lymph node number was greater in advanced staged diseases and it also correlated with the residual tumor size following the cytoreductive operation [3]. Benedetti-Panici et al. [4] in a small number of patients (n = 35) had found that lymphatic metastasis was less frequently encountered in clinical stages I–II disease and was also usually confined to one or a few lymph node groups. Lymphatic metastasis increased parallel to the progressive increase in intraabdominal tumor load. Suzuki et al. [8] also found the metastatic lymph node numbers to correlate with clinical stages. In current study analysis, a significant correlation between clinical stage and the number of metastatic
Table 2 Review of the literature about the number of resected metastatic lymph nodes Author
Year
n
Threshold
Correlation
Prognostic value
Burghardt et al. [3] Benedetti-Panici et al. [4] Petru et al. [5] di Re et al. [6]
1991
91 1 vs. ≥1
Clinical stage, residual disease Clinical stage
Yes
1993
35 –
1994 9 1 vs. N1 1996 194 –
Yes No
Onda et al. [7] Suzuki et al. [8] Morice et al. [9] Current study
1998 38 2000 5 2000 122 2007 328
No – No No
– Clinical stage, residual disease 1–4 vs. N4 – – Clinical stage 1 vs. N1 – b4 vs. ≥4 High Ca-125 levels
–
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lymph nodes was also found. However, a Ca-125 value greater than 500 IU/l was more significant than the clinical stage on multivariate analysis. Among the evaluated factors, preoperative Ca-125 level was the only significant factor associated with higher metastatic lymph node numbers. Ca-125 level was also previously found to correlate with tumoral load and predictability of optimal cytoreduction [11]. A high Ca-125 level had also been found to predict the lymphatic metastasis in patients with epithelial ovarian cancers in our previous report [1]. So a high Ca-125 level may not only show the presence of lymphatic metastasis, but also a higher number of metastatic lymph nodes. As the preoperative values increase, both the intraabdominal and retroperitoneal tumor load seems to increase in patients with epithelial ovarian cancers. Based on the previous reports, it may be concluded that metastatic lymph node number increase parallel to the preoperative Ca-125 levels, clinical stages, intraabdominal tumor load and residual tumor volume after the operation. There is only a little more known about the prognostic effect of metastatic lymph node numbers in the literature. Burghardt et al. [3] found 5-year survival rates as 68.7%, 58.2% and 28.0% for patients with no lymph node metastasis, with only one node involvement and with N1 lymph node metastasis, respectively. However, they did not use multivariate analysis and patient numbers were not adequate [3]. Petru et al. [5] suggested the number of metastatic lymph nodes (1 vs. N 1) to be prognostic in a small patient sample (n = 9). On the other hand, di Re et al. [6] in a larger patient population (n = 194) could not find a prognostic role for the metastatic lymph node numbers when compared patients with 1–2 vs. 3–10 and N 10 metastatic lymph node numbers. Onda et al. [7] also found that the number of metastatic lymph nodes was not a significant prognostic factor when they compared 1–4 vs. N4 metastatic lymph node numbers. However, both authors did not give the detailed patient data in their article. Final report came from Morrice et al. [9]. They also could not find a significant prognostic role for the metastatic lymph node number when compared one and N 1 metastatic lymph node numbers. This overview of the previous literature revealed that there were few reports analyzing this subject [3–9]. Almost all were in retrospective nature and included inadequate patient numbers. A detailed clinicopathologic analysis was available in limited reports. Grouping of metastatic lymph nodes (1 vs. N1 or 1–2 vs. 3–10 vs. N 10, etc.) was performed arbitrarily. Multivariate analysis was not used in reports where the number of metastatic lymph nodes was found to be significant on univariate survival analysis. Neither of the reports analyzed progression-free interval with respect to extend of lymphatic metastasis. Therefore, prognostic role of the metastatic lymph node number is still under debate. While some did not find any significance, some authors found a prognostic role and claimed that as the number of metastatic lymph node number increased, it may lead to subperitoneal lymphangiosis and intraperitoneal persistence resulting in a poor chemoresponsiveness and worse intrinsic tumor biology [3–9]. That might also be the reason for the parallel increase of metastatic lymph node numbers and the intraabdominal tumor load or residual tumor volume [3–9].
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Another possible explanation for high preoperative tumor marker level parallel to high number of metastatic lymph node metastasis may be related to the biologic property and aggressiveness of tumor cell. The highly aggressive tumor may tend to have high level of preoperative Ca-125, advanced stage and high number of metastatic lymph node metastasis, and also with lower survival estimates. One may suggest our results to be biased due to large time interval we used (1982–2005). However, subgroup analysis (patients with year of diagnosis 1982–1998 vs. 1998–2005) revealed no significant changes in the surgical treatment of the patients within years (optimal cytoreduction and number of resected lymph nodes). This may be attributed to our experienced and constant surgical team who had been the primary operators in each patient during this time. Maximal effort had been used for optimal cytoreduction in each patient and any visceral resections had been performed accordingly. With respect to combination adjuvant chemotherapeutics, almost all patients had received platinum-based chemotherapeutics during this time interval. The only difference was the taxanes (was almost standard after 1995) which could not make a difference with respect to the overall survivals within the following years. This might be attributed to the high optimal cytoreduction rates in these advanced staged diseases and also to the highly advanced staged disease these patients have (all are IIIc surgically staged) where we still try to find better combinations and regimens for a better outcome. The current study is the largest single-institutional report analyzing this issue up to now. All patients were in surgical stage III disease and had systematic lymph node dissection and were analyzed not only by univariate but also by multivariate analysis with respect to many different clinicopathologic factors including both the overall and the disease-free survivals together with detailed overview of the whole related previous literature. Metastatic lymph node numbers was not found to have a significant effect on either the overall or the disease-free survival in current study analysis. Although short median follow-up period compared to some other previous reports was observed as one of the limitation point of our study, this may be attributed to the referral center property of our center. The important point is the presence of lymphatic metastasis rather than its' extent [1].
However, any possible prognostic effect may also be underestimated in our analysis since all the metastatic lymph nodes were debulked systematically in these selected patient population. Therefore, for a definitive conclusion, larger prospective reports may be needed, especially in evaluating a clinically significant threshold number of metastatic lymph nodes for the prognostic role and the resection extent. References [1] Ayhan A, Gultekin M, Taskiran C, Celik NY, Usubutun A, Kucukali T, et al. Lymphatic metastasis in epithelial ovarian carcinoma with respect to clinicopathological variables. Gynecol Oncol May 2005;97(2):400–4. [2] Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst Apr 20 2005;97(8):560–6. [3] Burghardt E, Girardi F, Lahousen M, Tamussino K, Stettner H. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol Feb 1991;40(2):103–6. [4] Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol Nov 1993;51(2):150–4. [5] Petru E, Lahousen M, Tamussino K, Pickel H, Stranzl H, Stettner H, et al. Lymphadenectomy in stage I ovarian cancer. Am J Obstet Gynecol Feb 1994;170(2):656–62. [6] di Re F, Baiocchi G, Fontanelli R, Grosso G, Cobellis L, Raspagliesi F, et al. Systematic pelvic and paraaortic lymphadenectomy for advanced ovarian cancer: prognostic significance of node metastases. Gynecol Oncol Sep 1996;62(3):360–5. [7] Onda T, Yoshikawa H, Yasugi T, Mishima M, Nakagawa S, Yamada M, et al. Patients with ovarian carcinoma upstaged to stage III after systematic lymphadenectomy have similar survival to Stage I/II patients and superior survival to other Stage III patients. Cancer Oct 15 1998;83(8):1555–60. [8] Suzuki M, Ohwada M, Yamada T, Kohno T, Sekiguchi I, Sato I. Lymph node metastasis in stage I epithelial ovarian cancer. Gynecol Oncol Nov 2000;79(2):305–8. [9] Morice P, Joulie F, Camatte S, Atallah D, Rouzier R, Pautier P, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg Aug 2003;197(2):198–205. [10] Creutzberg CL. Lymphadenectomy in apparent early-stage endometrial carcinoma: do numbers count? J Clin Oncol Jun 1 2005;23(16):3653–5. [11] Chi DS, Venkatraman ES, Masson V, Hoskins WJ. The ability of preoperative serum CA-125 to predict optimal primary tumor cytoreduction in stage III epithelial ovarian carcinoma. Gynecol Oncol May 2000;77(2): 227–31.