Arch Gynecol Obstet DOI 10.1007/s00404-013-3078-3
GYNECOLOGIC ONCOLOGY
Lymph node metastasis in patients with epithelial ovarian cancer macroscopically confined to the ovary: review of a single-institution experience Volkan Ulker • Oguzhan Kuru • Ceyhun Numanoglu Ozgur Akbayır • Ibrahim Polat • Mehmet Uhri
•
Received: 29 July 2013 / Accepted: 29 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Background To evaluate the patterns of lymphatic spread in epithelial ovarian cancer (EOC) macroscopically confined to the ovary and to determine risk factors for lymph node metastasis. Materials and methods All patients with clinically apparent stage IA/B/C EOCs who underwent staging surgery between January 2003 and February 2013 were retrospectively identified. Results Two hundred and thirty-six (n = 236) consecutive patients were operated for primary epithelial ovarian carcinoma. Sixty-two of these patients (26.2 %) who underwent a comprehensive staging procedure including pelvic and paraaortic lymphadenectomy were diagnosed with tumors confined to one or two ovaries (stage IA/B/C). Of these 62 patients, 17 (27.4 %) had upstaged disease and 8 (12.9 %) had lymph node metastasis. Tumor histology was serous in 25 patients (40.3 %), mucinous in 23 patients (37 %), endometrioid in 9 patients (14.5 %), and clear cell in 5 patients (8 %). Positive lymph node status was found in 20 % (5/25) of those with serous histology while this rate was only 8.1 % (3/37) in those with non-serous disease. Although the presence of ascites was not associated V. Ulker C. Numanoglu O. Akbayır Oncology Unit, Department of Obstetrics and Gynecology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey O. Kuru (&) I. Polat Department of Obstetrics and Gynecology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey e-mail: [email protected] M. Uhri Department of Pathology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey
with an increased risk of lymph node involvement (p = 0.24), positive peritoneal cytology (p = 0.001) and grade 3 disease (p = 0.001) were significant predictors of lymph node involvement. Conclusion All patients diagnosed with EOC macroscopically confined to the ovary should be considered for comprehensive staging surgery including pelvic and paraaortic lymphadenectomy. Keywords Lymphadenectomy Early stage Epithelial ovarian cancer Staging
Introduction Despite recent improvements in the treatment of patients with epithelial ovarian cancer (EOC), this tumor remains the leading cause of death among gynecologic malignancies. Patients with EOC have advanced disease at diagnosis in more than two-thirds of cases, due to the fact that they are usually asymptomatic until the cancer has metastasized [1]. Only 30 % of cases are diagnosed in the early stages of the disease and some of these cases are initially operated on by gynecologist or other specialists. These patients often present to the gynecologic oncologists for a comprehensive restaging operation to determine the need for systemic adjuvant therapy. Identifying the risk factors for lymph node involvement in grossly apparent early stage disease would help in this decision-making process [2]. A major controversy exists in the surgical treatment of grossly apparent early stage EOC concerning the optimal management of retroperitoneal lymph nodes, while the surgical procedures and the requirements for intraperitoneal disease are well established [3, 4]. Approaches ranging from biopsy of only grossly enlarged nodes to
123
Arch Gynecol Obstet
systematic dissection of bilateral pelvic and paraaortic lymph nodes have been employed [5]. Retroperitoneal lymph node involvement is reported in 4–27 % of patients with apparent early stage disease at the time of primary surgery [6]. This large heterogeneity in the reported rates of metastatic lymph nodes is mainly related to the type of lymphadenectomy (sampling vs. systematic, only pelvic or isolated ipsilateral pelvic lymphadenectomy etc.) [4, 6–10]. Previous studies were also excessively heterogeneous concerning analyzed variables such as tumor histology, grading, and substages. In addition, the majority of previous studies have evaluated patterns of lymph node involvement in patients with disease apparently confined to the pelvis (stage I and II disease) [2, 11, 12], while limited information exists on patients with disease entirely confined to the ovary (stage IA, IB, and IC). Thus, in this study we performed a retrospective analysis to evaluate the role of lymphadenectomy at primary surgery in patients with EOC macroscopically confined to the ovary. Furthermore, we sought to investigate the underlying risk factors for lymph node metastasis in these patients.
nodes were subdivided as being right or left sided. However, paraaortic nodes could not be subdivided in this way due to the en bloc resection technique that was applied in the paraaortic region. A retrospective review of medical records was performed and data were abstracted including patient demographics (age, menopausal status, pre-operative CA125 and CA19-9 levels), intraoperative findings (tumor bilaterality, presence of ascites), tumor histology, grade, and the number of resected and metastatic lymph nodes. Patterns of lymph node positivity including laterality and potential risk factors associated with occult advanced disease were assessed (ipsilateral vs. bilateral ovarian disease, histology, grade, and cytology). Statistical analyses were performed using the Statistical Package for the Social Sciences software version 13.0 (SPSS Inc., Chicago, IL, USA). Pearson’s Chi-squared analysis or Fisher’s exact tests were used to analyze the evaluated variables. The results were considered statistically significant if the p value was \0.05.
Results Materials and methods After obtaining the approval of the institutional review board, a retrospective review of the Kanuni Sultan Su¨leyman Training and Research Hospital tumor registry databases identified all patients undergoing primary treatment for ovarian carcinoma between January 2003 and February 2013. Patients who had malignant ovarian germ cell and sex-cord stromal tumors, patients who did not undergo comprehensive surgical staging, and patients with synchronous gynecologic tumors were excluded. The patients who underwent fertility sparing surgery were also excluded from the study. The study population consisted of 236 patients who were operated on by gynecologic oncologists, and staging was performed according to the FIGO (The International Federation of Gynecology and Obstetrics) recommendations. The staging process involved obtaining peritoneal washings for cytology and multiple peritoneal biopsies from both suspicious and normal appearing areas, total abdominal hysterectomy and bilateral salpingo-oophorectomy. After the initial step of the surgery, pelvic and paraaortic lymphadenectomy, appendectomy and total omentectomy were also performed. Specifically, pelvic lymphadenectomy included removal of the common, external, internal and obturator node groups to the level of the inguinal ligament. The paraaortic area was exposed just above the bifurcation of the aorta. Paraaortic lymphadenectomy included removal of node bearing tissues along the aorta and vena cava to the level of the renal veins on both sides. Resected pelvic
123
Between January 2003 and February 2013, 236 consecutive patients were operated for primary epithelial ovarian carcinoma at Kanuni Sultan Suleyman Training and Research Hospital. Seventy-four of these patients (31.3 %) were diagnosed with tumors confined to one or two ovaries based on both pre-operative and intraoperative evaluations. Of the 74 patients, 62 (26.2 %) had a comprehensive surgical staging procedure including pelvic and paraaortic lymphadenectomy. The mean age of the patients was 47.6 ± 10.1 years (ranging from 28 to 73 years) and 29 patients (46.8 %) were postmenopausal. Serum CA 125 was used as a tumor marker for most patients (93.5 %) in this study. The pre-operative CA 125 level was B35 U/ml in 21 patients (33.8 %), between 35 and 200 U/ml in 25 patients (40.3 %) and C200 U/ml in the remaining 12 patients (19.3 %). Twenty-nine patients had right sided ovarian tumors, 26 patients had left sided tumors, and the remaining 7 had bilateral ovarian tumors. The mean lymph node counts overall within the cohort were 20.2 ± 5.3 for pelvic nodes, and 10.7 ± 2 for paraaortic lymph nodes. Patient and tumor characteristics are given in Table 1. Of the 62 patients who had a comprehensive surgical staging, 17 patients (27.4 %) were found to have microscopic metastasis after post-operative pathological evaluations and, therefore, had upstaged disease. Following the review of pathology results, the final stages were found as IA/B (43.5 %) in 27 patients, IC (29 %) in 18, IIA (4.8 %) in 3, IIC (1.6 %) in 1, IIIA (8.1 %) in 5, and IIIC (12.9 %)
Arch Gynecol Obstet
in 8. Of those patients who were upstaged, three patients had ipsilateral tubal involvement and were upstaged to stage IIA. One patient had contralateral microscopic tubal and ovarian surface involvement with positive peritoneal cytology and was upstaged to stage IIC. Five patients had microscopic omental metastasis with positive peritoneal cytology and were upstaged to stage IIIA. Of those patients who were upstaged to stage IIIA, three also had microscopic peritoneal implants outside the pelvis. The remaining eight upstaged patients had lymphatic metastasis and were classified as stage IIIC disease. Of these eight patients with lymph node metastasis, seven had unilateral ovarian Table 1 Clinico-pathological features of patients with apparent clinical stage IA/B/C epithelial ovarian cancer who underwent staging surgery (n = 62) Mean age ± SD (years)
47.6 ± 10.1
Histology, n (%) Serous
25 (40.3 %)
Mucinous
23 (37 %)
Endometrioid
9 (14.5 %)
Clear cell
5 (8 %)
Grade, n (%) 1
17 (27.4 %)
2
31 (50 %)
3
14 (22.5 %)
CA 125, n (%) B35 U/ml
21 (33.8 %)
35–200 U/ml [200 U/ml
25 (40.3 %) 12 (19.3 %)
Ascites
35 (56.4 %)
Positive cytology
21 (33.8 %)
Lymph node counts Pelvic (mean ± SD)
20.2 ± 5.3
Paraaortic (mean ± SD)
10.7 ± 2
tumor and one had bilateral ovarian tumors. Tumor characteristics of patients with apparent early stage EOC and lymph node involvement are given in Table 2. Patterns with lymph node involvement were largely independent of laterality of primary tumors. Among those with unilateral tumors and positive nodes (n = 7), three had ipsilateral pelvic lymph node involvement, one had bilateral pelvic lymph node involvement, and three had isolated paraaortic lymph node involvement. One patient with bilateral tumor had paraaortic and unilateral pelvic lymph node metastasis. Histological distribution showed serous tumor in 25 patients (40.3 %), mucinous in 23 patients (37 %), endometrioid in 9 patients (14.5 %), and clear cell in 5 patients (8 %). Among patients with serous histology, 20 % (5/25) had positive lymph node involvement compared with only 8.1 % (3/37) in those with nonserous disease. Seventeen patients (27.4 %) had grade 1 tumors while 31 patients (50 %) had grade 2 and 14 patients (22.5 %) had grade 3 tumors. Presence of ascites was not associated with an increased risk of lymph node involvement (p = 0.24); however, a significant correlation was found between the presence of ascites and upstaged disease (p = 0.02). Lymph node involvement together with ascites was noted in 6/35 (17.1 %) of patients, whereas lymph node metastasis without ascites was present in 2/27 (7.4 %). Positive cytology was associated with an increased risk of lymph node metastasis (p = 0.001). Lymph nodes were positive in 33.3 % (7/21) of those with positive cytology. Higher FIGO grade of the tumor was also found to be a risk factor for lymph node metastasis (p = 0.001). Among patients with grade 3 disease, 42.8 % (6/14) had positive lymph nodes compared with only 6.4 % (2/31) in patients with grade 2 disease. None of the patients with grade 1 disease had positive lymph nodes. Among patients with positive lymph nodes, pre-operative serum CA 125 levels
Table 2 Tumor characteristics of patients with epithelial ovarian cancer macroscopically confined to the ovary and lymph node involvement (n = 8) Case no.
Histologic type
FIGO grade
Ascites
Cytology
Laterality of adnexal mass left/right/bilateral
No. and distribution of involved lymph node PALN
PLN
1
Serous
2
?
?
?/-/-
–
2
2
Serous
2
?
–
-/?/-
–
1
3
Serous
3
–
?
?/-/-
1
–
4
Serous
3
?
?
?/-/-
–
3a
5
Serous
3
?
?
-/-/?
1
2
6 7
Mucinous Endometrioid
3 3
– ?
? ?
-/?/-/?/-
– 1
1 –
8
Clear cell
3
?
?
-/?/-
1
–
FIGO The International Federation of Gynecology and Obstetrics, PALN paraaortic lymph node, PLN pelvic lymph node a
Bilateral pelvic lymph node involvement
123
Arch Gynecol Obstet
were B35 IU/L in 1 patient, between 35 and 200 IU/L in 3 patients, and C200 IU/L in the remaining 4 patients. Adjuvant chemotherapy was offered to 59.6 % (37/62) of patients who had upstaged disease, high-risk cellular histologic subtypes such as clear cell, or grade 3 disease. They were subsequently treated with adjuvant platinumbased chemotherapy. Among patients with apparent early stage EOC (Stage IA/B/C), there were only 2 cases of (3.2 %) severe intraoperative complications (inferior vena cava and left common iliac vein injuries). Five patients (8 %) had post-operative morbidity; 3 (4.8 %) had lymphocysts, 1 (1.6 %) had adhesive small bowel obstruction and 1 (1.6 %) had a severe post-operative wound infection. There were no surgery-related deaths.
Discussion Lymphadenectomy is an integral part of surgical staging and the presence of lymph node metastases is thought to be one of the most significant prognostic factors in EOC. Patients with positive regional lymph nodes unassociated with distant metastasis are classified as stage IIIC, even if intraperitoneal tumor spread is limited to the ovary. However, there is debate on the extent of lymphadenectomy that should be performed, particularly in early stage EOC. Issues regarding lymphadenectomy include: the extent to which the lymphadenectomy should be performed, whether or not a unilateral pelvic lymphadenectomy is sufficient and the necessity of paraaortic lymphadenectomy [6]. These issues are particularly important if one also considers the morbidity of lymphadenectomy and extensive staging laparotomy. The FIGO recommendations state staging should include ‘‘selected lymphadenectomy of pelvic and paraaortic nodes’’ [3]. On the contrary, a multicenter randomized trial comparing systematic pelvic and paraaortic lymphadenectomy versus removal of only the suspicious nodes in apparent early stage EOC (stage I and II disease) reported an approximately 13 % higher incidence of positive nodes who received systematic lymphadenectomy [4]. These authors revealed that systematic lymphadenectomy was associated with an improvement in both progression-free disease and overall survival; however, neither were statistically significant. The investigators stated that this trial lacked the power to detect a significant difference between the two groups. In a recent study, Powless et al. [2] assessed the patterns of lymphatic spread in apparent early stage EOC (stage I and II disease) and risk factors for lymph node metastasis. They found that bilateral ovarian lesions, presence of ascites, the FIGO grade, and serous histology were independent predictors of nodal involvement on multivariate analysis. In their study population,
123
even in patients with unilateral lesions, lymph node metastases were found to be commonly bilateral. Furthermore, among patients with serous histology 27.9 % had positive lymph nodes while none of the patients with mucinous EOCs had positive lymph nodes. Therefore, authors suggested that complete surgical staging in EOC patients with clinical stage I–II disease should include bilateral pelvic and paraaortic lymphadenectomy. At the same time, they concluded that these data are helpful for surgeons faced with patients referred for completion of staging procedures or intraoperatively among patients who are high-risk surgical candidates. While the majority of previous studies included patients with clinical stage I and II disease, there are limited numbers of published reports evaluating the role of lymphadenectomy in EOC apparently confined to one or two ovaries (stage IA/B/C) [6, 12, 13]. Desteli et al. reported lymph node involvement in two of a series of 33 patients (6 %) with intact ovarian capsules (clinical stage IA). According to their data, twelve patients (36.2 %) were found to have microscopic metastasis after post-operative pathological evaluations and, therefore, had upstaged disease. One of the two lymph node metastasis was solely in the paraaortic node and the other metastasis was in the ipsilateral pelvic lymph node. The tumor histologies in these two patients were serous and transitional cell. In another study conducted on a sample of 96 patients, Cass et al. [12] found that 15 % of patients with clinical stage I disease had positive lymph nodes and 39 (40.6 %) patients had upstaged disease. In our study, 62 EOC patients with clinical stage IA/B/C underwent comprehensive surgical staging and 8 (12.9 %) were positive for lymph node metastasis. Despite the similar rate of lymph node metastasis, our data revealed a lower overall upstaging rate (27.4 %) than those of previous studies [4, 6]. This difference in our study population may be explained by the presence of a much higher number of patients with mucinous histologies compared with serous histologies. These findings are consistent with previous studies showing an increased risk of upstaging during comprehensive surgery for serous histology when compared with mucinous histology [2, 14]. Serous tumors account for 67 % of all epithelial ovarian cancers and more commonly present at advanced stages [15]. In comparison to serous tumors, mucinous tumors are usually diagnosed at early stages [16– 18]. Furthermore, mucinous tumors are usually larger and have an expansile growth pattern. Symptoms such as abdominal or pelvic pain and discomfort caused by larger tumor volumes may be the reason for the detection of mucinous adenocarcinomas at earlier stages. When a mucinous tumor is grossly limited to the ovary, there is also a small possibility of occult lymph node metastasis. Cho et al. [19] reviewed 26 cases of mucinous
Arch Gynecol Obstet
ovarian cancer noted to be grossly stage I intraoperatively. All of these patients underwent lymphadenectomy as part of their staging procedures, and none were found to have lymph node metastasis. Suzuki et al. [20] described a subset of patients with presumed early mucinous and apparently low-grade stage I tumors who felt unlikely to have nodal dissemination based on risk factors. In our series, of the 23 patients with mucinous histology only two (8.6 %) had upstaged disease; one patient had lymph node involvement (stage IIIC) along with ipsilateral tubal involvement and grade 3 disease; one patient had microscopic ovarian capsule invasion with ipsilateral tubal involvement (stage IIA) and grade 2 disease. In contrast, none of the patients with grade I disease were found to have upstaged disease. According to these data, comprehensive staging is mandatory in all patients with mucinous histology. With the limited number of patients in this study, it is difficult to determine whether lymphadenectomy may be omitted especially for patients with mucinous histology and grade 1–2 disease. But, surgical staging procedure should include comprehensive lymphadenectomy in that sub-group of early stage mucinous grade 3 patients. Although a significant correlation was found between the presence of ascites and upstaged disease, we did not find a significant association between the presence of ascites and lymph node involvement. On the contrary, positive peritoneal cytology and grade 3 disease were found to be significant risk factors for lymph node involvement. Among patients with upstaged disease, 87.5 % (7/8) had positive peritoneal cytology and 75 % (6/ 8) had grade 3 disease. Although the overall incidences for serous and mucinous tumors were nearly equal, serous histology was detected nearly six times as much as mucinous histology in patients with upstaged disease. Laparoscopic surgery has been used diagnostically to predict resectability of ovarian cancer and therapeutically for cytoreduction. It is usually undertaken in young women with adnexal disease that is initially believed to be benign, but found to be malignant at exploration. A major concern with laparoscopic cancer surgery is that intact removal of the ovarian mass is often not possible; ovarian cyst rupture occurs in 12–25 % of adnexal masses managed laparoscopically [21, 22]. The potential risk of intraoperative spillage of malignant cells is that it may result in rapid intraabdominal dissemination via the peritoneal circulation, thus worsening the prognosis [23, 24]. However, the clinical effect of the rupture of an ovarian cancer, which can occur even at open procedures, is controversial [25, 26]. Many oncologists administer adjuvant chemotherapy to these patients unless the tumor is well differentiated. Another question regarding laparoscopic initial surgery for EOC is whether the pelvis and abdomen can be inspected as thoroughly as with an open surgical approach. Certainly,
surfaces cannot be directly palpated laparoscopically. However, data from small studies suggest that staging via laparoscopy is as accurate as via laparotomy [27, 28]. However, laparoscopic EOC staging is still under investigation, and is not for routine clinical use. Previous studies have shown that incomplete staging of apparently early stage disease, with subsequent treatment recommendations based on risk factors, leads to undertreatment in patients with occult advanced stage disease [2, 29]. However, the value of comprehensive staging including systematic retroperitoneal lymph node dissection may be associated with the upstaging of patients with clinical stage I EOC, which directs them to further treatment with chemotherapy. Chan et al. [13] evaluated the survival impact of lymphadenectomy in 6,686 women diagnosed with clinical stage I ovarian cancer. They found that lymphadenectomy improved the survival in those with non-clear cell epithelial ovarian cancer and the extent of lymphadenectomy (0 nodes, \10 nodes, and 10 or more nodes) increased the survival rates to 87.0, 91.9 and 93.8 %, respectively. In their study population, despite the lack of information on which patients received adjuvant chemotherapy, the benefit of the extent of lymphadenectomy was evident even in the subgroups of patients with grade 3 disease, with a non-statistical improvement in grade 1 and 2 tumors. Accordingly, authors concluded that if it is to be assumed that all women with grade 3 disease received chemotherapy based on recommended guidelines, the survival advantage in those who underwent lymphadenectomy persists. In the present study, factors as grade 3 disease or positive cytology were found to be potential predictors of pelvic lymph node status. Furthermore according to the findings in this study, approximately one-third of patients with EOC apparently confined to one or both ovaries (stage IA/B/C) with microscopic extraovarian metastases would have been missed if a staging operation similar to that employed for advanced stage ovarian cancer had not been performed. Conflict of interest We declare that we have no conflicts of interest.
References 1. Kwon YS, Hahn HS, Kim TJ, Lee IH, Lim KT, Lee KH et al (2009) Fertility preservation in patients with early epithelial ovarian cancer. J Gynecol Oncol 20(1):44–47 2. Powless CA, Aletti GD, Bakkum-Gamez JN, Cliby WA (2011) Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging. Gynecol Oncol 122(3):536–540 3. Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S (2000) FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70:209–262
123
Arch Gynecol Obstet 4. Maggioni A, Benedetti Panici P, Dell’Anna T, Landoni F, Lissoni A, Pellegrino A et al (2006) Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer 95(6):699–704 5. Chan JK, Urban R, Hu JM, Shin JY, Husain A, Teng NN et al (2007) The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients. Br J Cancer 96(12):1817–1822 6. Desteli GA, Gultekin M, Usubutun A, Yuce K, Ayhan A (2010) Lymph node metastasis in grossly apparent clinical stage Ia epithelial ovarian cancer: hacettepe experience and review of literature. World J Surg Oncol 30(8):106 7. Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C et al (1993) Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol 51(2):150–154 8. Onda T, Yoshikava H, Yokota H, Yasugi T, Taketani Y (1996) Assessment of metastases to aortic and pelvic lymph nodes in epithelial ovarian carcinoma. A proposal for essential sites for lymph node biopsy. Cancer 78(4):803–808 9. Chen SS, Lee L (1983) Incidence of para-aortic and pelvic lymph-node metastases in epithelial carcinoma of the ovary. Gynecol Oncol 16(1):95–100 10. Carnino F, Fuda G, Ciccone G, Iskra L, Guercio E, Dadone D et al (1997) Significance of lymph nodes sampling in epithelial carcinoma of the ovary. Gynecol Oncol 65(3):467–472 11. Petru E, Lahousen M, Tamussino K, Pickel H, Stranzl H, Stettner H et al (1994) Lymphadenectomy in stage I ovarian cancer. Am J Obstet Gynecol 170(2):656–662 12. Cass I, Runowicz CD, Fields AL, Goldberg GL, Leuchter RS, Lagasse LD, Karlan BY (2001) Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas. Gynecol Oncol 80(1):56–61 13. Chan JK, Munro EG, Cheung MK, Husain A, Teng NN, Berek JS, Osann K (2007) Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstet Gynecol 109(1):12–19 14. Ayhan A, Gultekin M, Taskiran C, Celik NY, Usubutun A, Kucukali T, Yuce K (2005) Lymphatic metastasis in epithelial ovarian carcinoma with espect to clinicopathological variables. Gynecol Oncol 97(2):400–404 15. Aletti GD, Dowdy S, Podratz KC, Cliby WA (2006) Role of lymphadenectomy in the management of grossly apparent advanced stage epithelial ovarian cancer. Am J Obstet Gynecol 195(6):1862–1868 16. Ditto A, Martinelli F, Reato C, Kusamura S, Solima E, Fontanelli R et al (2012) Systematic para-aortic and pelvic lymphadenectomy in
123
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
early stage epithelial ovarian cancer: a prospective study. Ann Surg Oncol 19(12):3849–3855 Frumovitz M, Schmeler KM, Malpica A, Sood AK, Gershenson DM (2010) Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol 117(3):491–496 Ji J, Fo¨rsti A, Sundquist J, Lenner P, Hemminki K (2008) Survival in ovarian cancer patients by histology and family history. Acta Oncol 47(6):1133–1139 Cho YH, Kim DY, Kim JH, Kim YM, Kim KR, Kim YT et al (2006) Is complete surgical staging necessary in patients with stage I mucinous epithelial ovarian tumors? Gynecol Oncol 103(3):878–882 Suzuki M, Ohwada M, Yamada T, Kohno T, Sekiguchi I, Sato I (2000) Lymph node metastasis in stage I epithelial ovarian cancer. Gynecol Oncol 79(2):305–308 Havrilesky LJ, Peterson BL, Dryden DK, Soper JT, ClarkePearson DL, Berchuck A (2003) Predictors of clinical outcomes in the laparoscopic management of adnexal masses. Obstet Gynecol 102(2):243 Canis M, Botchorishvili R, Manhes H, Wattiez A, Mage G, Pouly JL et al (2000) Management of adnexal masses: role and risk of laparoscopy. Semin Surg Oncol 19(1):28–35 Canis M, Rabischong B, Botchorishvili R, Tamburro S, Wattiez A, Mage G et al (2001) Risk of spread of ovarian cancer after laparoscopic surgery. Curr Opin Obstet Gynecol 13(1):9–14 Leminen A, Lehtovirta P (1999) Spread of ovarian cancer after laparoscopic surgery: report of eight cases. Gynecol Oncol 75(3):387–390 Sainz de la Cuesta R, Goff BA, Fuller AF Jr, Nikrui N, Eichhorn JH, Rice LW (1994) Prognostic importance of intraoperative rupture of malignant ovarian epithelial neoplasms. Obstet Gynecol 84(1):1–7 Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P et al (2001) Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357(9251):176–182 Nezhat FR, Ezzati M, Chuang L, Shamshirsaz AA, Rahaman J, Gretz H (2009) Laparoscopic management of early ovarian and fallopian tube cancers: surgical and survival outcome. Am J Obstet Gynecol 200(1):83 Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT et al (2008) Comparison of laparoscopy and laparotomy in surgical staging of early-stage ovarian and fallopian tubal cancer. Ann Surg Oncol 15(7):2012–2019 Le T, Adolph A, Krepart GV, Lotocki R, Heywood MS (2002) The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma. Gynecol Oncol 85(2):351–355
GYNECOLOGIC ONCOLOGY
Lymph node metastasis in patients with epithelial ovarian cancer macroscopically confined to the ovary: review of a single-institution experience Volkan Ulker • Oguzhan Kuru • Ceyhun Numanoglu Ozgur Akbayır • Ibrahim Polat • Mehmet Uhri
•
Received: 29 July 2013 / Accepted: 29 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Background To evaluate the patterns of lymphatic spread in epithelial ovarian cancer (EOC) macroscopically confined to the ovary and to determine risk factors for lymph node metastasis. Materials and methods All patients with clinically apparent stage IA/B/C EOCs who underwent staging surgery between January 2003 and February 2013 were retrospectively identified. Results Two hundred and thirty-six (n = 236) consecutive patients were operated for primary epithelial ovarian carcinoma. Sixty-two of these patients (26.2 %) who underwent a comprehensive staging procedure including pelvic and paraaortic lymphadenectomy were diagnosed with tumors confined to one or two ovaries (stage IA/B/C). Of these 62 patients, 17 (27.4 %) had upstaged disease and 8 (12.9 %) had lymph node metastasis. Tumor histology was serous in 25 patients (40.3 %), mucinous in 23 patients (37 %), endometrioid in 9 patients (14.5 %), and clear cell in 5 patients (8 %). Positive lymph node status was found in 20 % (5/25) of those with serous histology while this rate was only 8.1 % (3/37) in those with non-serous disease. Although the presence of ascites was not associated V. Ulker C. Numanoglu O. Akbayır Oncology Unit, Department of Obstetrics and Gynecology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey O. Kuru (&) I. Polat Department of Obstetrics and Gynecology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey e-mail: [email protected] M. Uhri Department of Pathology, Kanuni Sultan Su¨leyman Training and Research Hospital, Istanbul, Turkey
with an increased risk of lymph node involvement (p = 0.24), positive peritoneal cytology (p = 0.001) and grade 3 disease (p = 0.001) were significant predictors of lymph node involvement. Conclusion All patients diagnosed with EOC macroscopically confined to the ovary should be considered for comprehensive staging surgery including pelvic and paraaortic lymphadenectomy. Keywords Lymphadenectomy Early stage Epithelial ovarian cancer Staging
Introduction Despite recent improvements in the treatment of patients with epithelial ovarian cancer (EOC), this tumor remains the leading cause of death among gynecologic malignancies. Patients with EOC have advanced disease at diagnosis in more than two-thirds of cases, due to the fact that they are usually asymptomatic until the cancer has metastasized [1]. Only 30 % of cases are diagnosed in the early stages of the disease and some of these cases are initially operated on by gynecologist or other specialists. These patients often present to the gynecologic oncologists for a comprehensive restaging operation to determine the need for systemic adjuvant therapy. Identifying the risk factors for lymph node involvement in grossly apparent early stage disease would help in this decision-making process [2]. A major controversy exists in the surgical treatment of grossly apparent early stage EOC concerning the optimal management of retroperitoneal lymph nodes, while the surgical procedures and the requirements for intraperitoneal disease are well established [3, 4]. Approaches ranging from biopsy of only grossly enlarged nodes to
123
Arch Gynecol Obstet
systematic dissection of bilateral pelvic and paraaortic lymph nodes have been employed [5]. Retroperitoneal lymph node involvement is reported in 4–27 % of patients with apparent early stage disease at the time of primary surgery [6]. This large heterogeneity in the reported rates of metastatic lymph nodes is mainly related to the type of lymphadenectomy (sampling vs. systematic, only pelvic or isolated ipsilateral pelvic lymphadenectomy etc.) [4, 6–10]. Previous studies were also excessively heterogeneous concerning analyzed variables such as tumor histology, grading, and substages. In addition, the majority of previous studies have evaluated patterns of lymph node involvement in patients with disease apparently confined to the pelvis (stage I and II disease) [2, 11, 12], while limited information exists on patients with disease entirely confined to the ovary (stage IA, IB, and IC). Thus, in this study we performed a retrospective analysis to evaluate the role of lymphadenectomy at primary surgery in patients with EOC macroscopically confined to the ovary. Furthermore, we sought to investigate the underlying risk factors for lymph node metastasis in these patients.
nodes were subdivided as being right or left sided. However, paraaortic nodes could not be subdivided in this way due to the en bloc resection technique that was applied in the paraaortic region. A retrospective review of medical records was performed and data were abstracted including patient demographics (age, menopausal status, pre-operative CA125 and CA19-9 levels), intraoperative findings (tumor bilaterality, presence of ascites), tumor histology, grade, and the number of resected and metastatic lymph nodes. Patterns of lymph node positivity including laterality and potential risk factors associated with occult advanced disease were assessed (ipsilateral vs. bilateral ovarian disease, histology, grade, and cytology). Statistical analyses were performed using the Statistical Package for the Social Sciences software version 13.0 (SPSS Inc., Chicago, IL, USA). Pearson’s Chi-squared analysis or Fisher’s exact tests were used to analyze the evaluated variables. The results were considered statistically significant if the p value was \0.05.
Results Materials and methods After obtaining the approval of the institutional review board, a retrospective review of the Kanuni Sultan Su¨leyman Training and Research Hospital tumor registry databases identified all patients undergoing primary treatment for ovarian carcinoma between January 2003 and February 2013. Patients who had malignant ovarian germ cell and sex-cord stromal tumors, patients who did not undergo comprehensive surgical staging, and patients with synchronous gynecologic tumors were excluded. The patients who underwent fertility sparing surgery were also excluded from the study. The study population consisted of 236 patients who were operated on by gynecologic oncologists, and staging was performed according to the FIGO (The International Federation of Gynecology and Obstetrics) recommendations. The staging process involved obtaining peritoneal washings for cytology and multiple peritoneal biopsies from both suspicious and normal appearing areas, total abdominal hysterectomy and bilateral salpingo-oophorectomy. After the initial step of the surgery, pelvic and paraaortic lymphadenectomy, appendectomy and total omentectomy were also performed. Specifically, pelvic lymphadenectomy included removal of the common, external, internal and obturator node groups to the level of the inguinal ligament. The paraaortic area was exposed just above the bifurcation of the aorta. Paraaortic lymphadenectomy included removal of node bearing tissues along the aorta and vena cava to the level of the renal veins on both sides. Resected pelvic
123
Between January 2003 and February 2013, 236 consecutive patients were operated for primary epithelial ovarian carcinoma at Kanuni Sultan Suleyman Training and Research Hospital. Seventy-four of these patients (31.3 %) were diagnosed with tumors confined to one or two ovaries based on both pre-operative and intraoperative evaluations. Of the 74 patients, 62 (26.2 %) had a comprehensive surgical staging procedure including pelvic and paraaortic lymphadenectomy. The mean age of the patients was 47.6 ± 10.1 years (ranging from 28 to 73 years) and 29 patients (46.8 %) were postmenopausal. Serum CA 125 was used as a tumor marker for most patients (93.5 %) in this study. The pre-operative CA 125 level was B35 U/ml in 21 patients (33.8 %), between 35 and 200 U/ml in 25 patients (40.3 %) and C200 U/ml in the remaining 12 patients (19.3 %). Twenty-nine patients had right sided ovarian tumors, 26 patients had left sided tumors, and the remaining 7 had bilateral ovarian tumors. The mean lymph node counts overall within the cohort were 20.2 ± 5.3 for pelvic nodes, and 10.7 ± 2 for paraaortic lymph nodes. Patient and tumor characteristics are given in Table 1. Of the 62 patients who had a comprehensive surgical staging, 17 patients (27.4 %) were found to have microscopic metastasis after post-operative pathological evaluations and, therefore, had upstaged disease. Following the review of pathology results, the final stages were found as IA/B (43.5 %) in 27 patients, IC (29 %) in 18, IIA (4.8 %) in 3, IIC (1.6 %) in 1, IIIA (8.1 %) in 5, and IIIC (12.9 %)
Arch Gynecol Obstet
in 8. Of those patients who were upstaged, three patients had ipsilateral tubal involvement and were upstaged to stage IIA. One patient had contralateral microscopic tubal and ovarian surface involvement with positive peritoneal cytology and was upstaged to stage IIC. Five patients had microscopic omental metastasis with positive peritoneal cytology and were upstaged to stage IIIA. Of those patients who were upstaged to stage IIIA, three also had microscopic peritoneal implants outside the pelvis. The remaining eight upstaged patients had lymphatic metastasis and were classified as stage IIIC disease. Of these eight patients with lymph node metastasis, seven had unilateral ovarian Table 1 Clinico-pathological features of patients with apparent clinical stage IA/B/C epithelial ovarian cancer who underwent staging surgery (n = 62) Mean age ± SD (years)
47.6 ± 10.1
Histology, n (%) Serous
25 (40.3 %)
Mucinous
23 (37 %)
Endometrioid
9 (14.5 %)
Clear cell
5 (8 %)
Grade, n (%) 1
17 (27.4 %)
2
31 (50 %)
3
14 (22.5 %)
CA 125, n (%) B35 U/ml
21 (33.8 %)
35–200 U/ml [200 U/ml
25 (40.3 %) 12 (19.3 %)
Ascites
35 (56.4 %)
Positive cytology
21 (33.8 %)
Lymph node counts Pelvic (mean ± SD)
20.2 ± 5.3
Paraaortic (mean ± SD)
10.7 ± 2
tumor and one had bilateral ovarian tumors. Tumor characteristics of patients with apparent early stage EOC and lymph node involvement are given in Table 2. Patterns with lymph node involvement were largely independent of laterality of primary tumors. Among those with unilateral tumors and positive nodes (n = 7), three had ipsilateral pelvic lymph node involvement, one had bilateral pelvic lymph node involvement, and three had isolated paraaortic lymph node involvement. One patient with bilateral tumor had paraaortic and unilateral pelvic lymph node metastasis. Histological distribution showed serous tumor in 25 patients (40.3 %), mucinous in 23 patients (37 %), endometrioid in 9 patients (14.5 %), and clear cell in 5 patients (8 %). Among patients with serous histology, 20 % (5/25) had positive lymph node involvement compared with only 8.1 % (3/37) in those with nonserous disease. Seventeen patients (27.4 %) had grade 1 tumors while 31 patients (50 %) had grade 2 and 14 patients (22.5 %) had grade 3 tumors. Presence of ascites was not associated with an increased risk of lymph node involvement (p = 0.24); however, a significant correlation was found between the presence of ascites and upstaged disease (p = 0.02). Lymph node involvement together with ascites was noted in 6/35 (17.1 %) of patients, whereas lymph node metastasis without ascites was present in 2/27 (7.4 %). Positive cytology was associated with an increased risk of lymph node metastasis (p = 0.001). Lymph nodes were positive in 33.3 % (7/21) of those with positive cytology. Higher FIGO grade of the tumor was also found to be a risk factor for lymph node metastasis (p = 0.001). Among patients with grade 3 disease, 42.8 % (6/14) had positive lymph nodes compared with only 6.4 % (2/31) in patients with grade 2 disease. None of the patients with grade 1 disease had positive lymph nodes. Among patients with positive lymph nodes, pre-operative serum CA 125 levels
Table 2 Tumor characteristics of patients with epithelial ovarian cancer macroscopically confined to the ovary and lymph node involvement (n = 8) Case no.
Histologic type
FIGO grade
Ascites
Cytology
Laterality of adnexal mass left/right/bilateral
No. and distribution of involved lymph node PALN
PLN
1
Serous
2
?
?
?/-/-
–
2
2
Serous
2
?
–
-/?/-
–
1
3
Serous
3
–
?
?/-/-
1
–
4
Serous
3
?
?
?/-/-
–
3a
5
Serous
3
?
?
-/-/?
1
2
6 7
Mucinous Endometrioid
3 3
– ?
? ?
-/?/-/?/-
– 1
1 –
8
Clear cell
3
?
?
-/?/-
1
–
FIGO The International Federation of Gynecology and Obstetrics, PALN paraaortic lymph node, PLN pelvic lymph node a
Bilateral pelvic lymph node involvement
123
Arch Gynecol Obstet
were B35 IU/L in 1 patient, between 35 and 200 IU/L in 3 patients, and C200 IU/L in the remaining 4 patients. Adjuvant chemotherapy was offered to 59.6 % (37/62) of patients who had upstaged disease, high-risk cellular histologic subtypes such as clear cell, or grade 3 disease. They were subsequently treated with adjuvant platinumbased chemotherapy. Among patients with apparent early stage EOC (Stage IA/B/C), there were only 2 cases of (3.2 %) severe intraoperative complications (inferior vena cava and left common iliac vein injuries). Five patients (8 %) had post-operative morbidity; 3 (4.8 %) had lymphocysts, 1 (1.6 %) had adhesive small bowel obstruction and 1 (1.6 %) had a severe post-operative wound infection. There were no surgery-related deaths.
Discussion Lymphadenectomy is an integral part of surgical staging and the presence of lymph node metastases is thought to be one of the most significant prognostic factors in EOC. Patients with positive regional lymph nodes unassociated with distant metastasis are classified as stage IIIC, even if intraperitoneal tumor spread is limited to the ovary. However, there is debate on the extent of lymphadenectomy that should be performed, particularly in early stage EOC. Issues regarding lymphadenectomy include: the extent to which the lymphadenectomy should be performed, whether or not a unilateral pelvic lymphadenectomy is sufficient and the necessity of paraaortic lymphadenectomy [6]. These issues are particularly important if one also considers the morbidity of lymphadenectomy and extensive staging laparotomy. The FIGO recommendations state staging should include ‘‘selected lymphadenectomy of pelvic and paraaortic nodes’’ [3]. On the contrary, a multicenter randomized trial comparing systematic pelvic and paraaortic lymphadenectomy versus removal of only the suspicious nodes in apparent early stage EOC (stage I and II disease) reported an approximately 13 % higher incidence of positive nodes who received systematic lymphadenectomy [4]. These authors revealed that systematic lymphadenectomy was associated with an improvement in both progression-free disease and overall survival; however, neither were statistically significant. The investigators stated that this trial lacked the power to detect a significant difference between the two groups. In a recent study, Powless et al. [2] assessed the patterns of lymphatic spread in apparent early stage EOC (stage I and II disease) and risk factors for lymph node metastasis. They found that bilateral ovarian lesions, presence of ascites, the FIGO grade, and serous histology were independent predictors of nodal involvement on multivariate analysis. In their study population,
123
even in patients with unilateral lesions, lymph node metastases were found to be commonly bilateral. Furthermore, among patients with serous histology 27.9 % had positive lymph nodes while none of the patients with mucinous EOCs had positive lymph nodes. Therefore, authors suggested that complete surgical staging in EOC patients with clinical stage I–II disease should include bilateral pelvic and paraaortic lymphadenectomy. At the same time, they concluded that these data are helpful for surgeons faced with patients referred for completion of staging procedures or intraoperatively among patients who are high-risk surgical candidates. While the majority of previous studies included patients with clinical stage I and II disease, there are limited numbers of published reports evaluating the role of lymphadenectomy in EOC apparently confined to one or two ovaries (stage IA/B/C) [6, 12, 13]. Desteli et al. reported lymph node involvement in two of a series of 33 patients (6 %) with intact ovarian capsules (clinical stage IA). According to their data, twelve patients (36.2 %) were found to have microscopic metastasis after post-operative pathological evaluations and, therefore, had upstaged disease. One of the two lymph node metastasis was solely in the paraaortic node and the other metastasis was in the ipsilateral pelvic lymph node. The tumor histologies in these two patients were serous and transitional cell. In another study conducted on a sample of 96 patients, Cass et al. [12] found that 15 % of patients with clinical stage I disease had positive lymph nodes and 39 (40.6 %) patients had upstaged disease. In our study, 62 EOC patients with clinical stage IA/B/C underwent comprehensive surgical staging and 8 (12.9 %) were positive for lymph node metastasis. Despite the similar rate of lymph node metastasis, our data revealed a lower overall upstaging rate (27.4 %) than those of previous studies [4, 6]. This difference in our study population may be explained by the presence of a much higher number of patients with mucinous histologies compared with serous histologies. These findings are consistent with previous studies showing an increased risk of upstaging during comprehensive surgery for serous histology when compared with mucinous histology [2, 14]. Serous tumors account for 67 % of all epithelial ovarian cancers and more commonly present at advanced stages [15]. In comparison to serous tumors, mucinous tumors are usually diagnosed at early stages [16– 18]. Furthermore, mucinous tumors are usually larger and have an expansile growth pattern. Symptoms such as abdominal or pelvic pain and discomfort caused by larger tumor volumes may be the reason for the detection of mucinous adenocarcinomas at earlier stages. When a mucinous tumor is grossly limited to the ovary, there is also a small possibility of occult lymph node metastasis. Cho et al. [19] reviewed 26 cases of mucinous
Arch Gynecol Obstet
ovarian cancer noted to be grossly stage I intraoperatively. All of these patients underwent lymphadenectomy as part of their staging procedures, and none were found to have lymph node metastasis. Suzuki et al. [20] described a subset of patients with presumed early mucinous and apparently low-grade stage I tumors who felt unlikely to have nodal dissemination based on risk factors. In our series, of the 23 patients with mucinous histology only two (8.6 %) had upstaged disease; one patient had lymph node involvement (stage IIIC) along with ipsilateral tubal involvement and grade 3 disease; one patient had microscopic ovarian capsule invasion with ipsilateral tubal involvement (stage IIA) and grade 2 disease. In contrast, none of the patients with grade I disease were found to have upstaged disease. According to these data, comprehensive staging is mandatory in all patients with mucinous histology. With the limited number of patients in this study, it is difficult to determine whether lymphadenectomy may be omitted especially for patients with mucinous histology and grade 1–2 disease. But, surgical staging procedure should include comprehensive lymphadenectomy in that sub-group of early stage mucinous grade 3 patients. Although a significant correlation was found between the presence of ascites and upstaged disease, we did not find a significant association between the presence of ascites and lymph node involvement. On the contrary, positive peritoneal cytology and grade 3 disease were found to be significant risk factors for lymph node involvement. Among patients with upstaged disease, 87.5 % (7/8) had positive peritoneal cytology and 75 % (6/ 8) had grade 3 disease. Although the overall incidences for serous and mucinous tumors were nearly equal, serous histology was detected nearly six times as much as mucinous histology in patients with upstaged disease. Laparoscopic surgery has been used diagnostically to predict resectability of ovarian cancer and therapeutically for cytoreduction. It is usually undertaken in young women with adnexal disease that is initially believed to be benign, but found to be malignant at exploration. A major concern with laparoscopic cancer surgery is that intact removal of the ovarian mass is often not possible; ovarian cyst rupture occurs in 12–25 % of adnexal masses managed laparoscopically [21, 22]. The potential risk of intraoperative spillage of malignant cells is that it may result in rapid intraabdominal dissemination via the peritoneal circulation, thus worsening the prognosis [23, 24]. However, the clinical effect of the rupture of an ovarian cancer, which can occur even at open procedures, is controversial [25, 26]. Many oncologists administer adjuvant chemotherapy to these patients unless the tumor is well differentiated. Another question regarding laparoscopic initial surgery for EOC is whether the pelvis and abdomen can be inspected as thoroughly as with an open surgical approach. Certainly,
surfaces cannot be directly palpated laparoscopically. However, data from small studies suggest that staging via laparoscopy is as accurate as via laparotomy [27, 28]. However, laparoscopic EOC staging is still under investigation, and is not for routine clinical use. Previous studies have shown that incomplete staging of apparently early stage disease, with subsequent treatment recommendations based on risk factors, leads to undertreatment in patients with occult advanced stage disease [2, 29]. However, the value of comprehensive staging including systematic retroperitoneal lymph node dissection may be associated with the upstaging of patients with clinical stage I EOC, which directs them to further treatment with chemotherapy. Chan et al. [13] evaluated the survival impact of lymphadenectomy in 6,686 women diagnosed with clinical stage I ovarian cancer. They found that lymphadenectomy improved the survival in those with non-clear cell epithelial ovarian cancer and the extent of lymphadenectomy (0 nodes, \10 nodes, and 10 or more nodes) increased the survival rates to 87.0, 91.9 and 93.8 %, respectively. In their study population, despite the lack of information on which patients received adjuvant chemotherapy, the benefit of the extent of lymphadenectomy was evident even in the subgroups of patients with grade 3 disease, with a non-statistical improvement in grade 1 and 2 tumors. Accordingly, authors concluded that if it is to be assumed that all women with grade 3 disease received chemotherapy based on recommended guidelines, the survival advantage in those who underwent lymphadenectomy persists. In the present study, factors as grade 3 disease or positive cytology were found to be potential predictors of pelvic lymph node status. Furthermore according to the findings in this study, approximately one-third of patients with EOC apparently confined to one or both ovaries (stage IA/B/C) with microscopic extraovarian metastases would have been missed if a staging operation similar to that employed for advanced stage ovarian cancer had not been performed. Conflict of interest We declare that we have no conflicts of interest.
References 1. Kwon YS, Hahn HS, Kim TJ, Lee IH, Lim KT, Lee KH et al (2009) Fertility preservation in patients with early epithelial ovarian cancer. J Gynecol Oncol 20(1):44–47 2. Powless CA, Aletti GD, Bakkum-Gamez JN, Cliby WA (2011) Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging. Gynecol Oncol 122(3):536–540 3. Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S (2000) FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70:209–262
123
Arch Gynecol Obstet 4. Maggioni A, Benedetti Panici P, Dell’Anna T, Landoni F, Lissoni A, Pellegrino A et al (2006) Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer 95(6):699–704 5. Chan JK, Urban R, Hu JM, Shin JY, Husain A, Teng NN et al (2007) The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients. Br J Cancer 96(12):1817–1822 6. Desteli GA, Gultekin M, Usubutun A, Yuce K, Ayhan A (2010) Lymph node metastasis in grossly apparent clinical stage Ia epithelial ovarian cancer: hacettepe experience and review of literature. World J Surg Oncol 30(8):106 7. Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C et al (1993) Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol 51(2):150–154 8. Onda T, Yoshikava H, Yokota H, Yasugi T, Taketani Y (1996) Assessment of metastases to aortic and pelvic lymph nodes in epithelial ovarian carcinoma. A proposal for essential sites for lymph node biopsy. Cancer 78(4):803–808 9. Chen SS, Lee L (1983) Incidence of para-aortic and pelvic lymph-node metastases in epithelial carcinoma of the ovary. Gynecol Oncol 16(1):95–100 10. Carnino F, Fuda G, Ciccone G, Iskra L, Guercio E, Dadone D et al (1997) Significance of lymph nodes sampling in epithelial carcinoma of the ovary. Gynecol Oncol 65(3):467–472 11. Petru E, Lahousen M, Tamussino K, Pickel H, Stranzl H, Stettner H et al (1994) Lymphadenectomy in stage I ovarian cancer. Am J Obstet Gynecol 170(2):656–662 12. Cass I, Runowicz CD, Fields AL, Goldberg GL, Leuchter RS, Lagasse LD, Karlan BY (2001) Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas. Gynecol Oncol 80(1):56–61 13. Chan JK, Munro EG, Cheung MK, Husain A, Teng NN, Berek JS, Osann K (2007) Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstet Gynecol 109(1):12–19 14. Ayhan A, Gultekin M, Taskiran C, Celik NY, Usubutun A, Kucukali T, Yuce K (2005) Lymphatic metastasis in epithelial ovarian carcinoma with espect to clinicopathological variables. Gynecol Oncol 97(2):400–404 15. Aletti GD, Dowdy S, Podratz KC, Cliby WA (2006) Role of lymphadenectomy in the management of grossly apparent advanced stage epithelial ovarian cancer. Am J Obstet Gynecol 195(6):1862–1868 16. Ditto A, Martinelli F, Reato C, Kusamura S, Solima E, Fontanelli R et al (2012) Systematic para-aortic and pelvic lymphadenectomy in
123
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
early stage epithelial ovarian cancer: a prospective study. Ann Surg Oncol 19(12):3849–3855 Frumovitz M, Schmeler KM, Malpica A, Sood AK, Gershenson DM (2010) Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol 117(3):491–496 Ji J, Fo¨rsti A, Sundquist J, Lenner P, Hemminki K (2008) Survival in ovarian cancer patients by histology and family history. Acta Oncol 47(6):1133–1139 Cho YH, Kim DY, Kim JH, Kim YM, Kim KR, Kim YT et al (2006) Is complete surgical staging necessary in patients with stage I mucinous epithelial ovarian tumors? Gynecol Oncol 103(3):878–882 Suzuki M, Ohwada M, Yamada T, Kohno T, Sekiguchi I, Sato I (2000) Lymph node metastasis in stage I epithelial ovarian cancer. Gynecol Oncol 79(2):305–308 Havrilesky LJ, Peterson BL, Dryden DK, Soper JT, ClarkePearson DL, Berchuck A (2003) Predictors of clinical outcomes in the laparoscopic management of adnexal masses. Obstet Gynecol 102(2):243 Canis M, Botchorishvili R, Manhes H, Wattiez A, Mage G, Pouly JL et al (2000) Management of adnexal masses: role and risk of laparoscopy. Semin Surg Oncol 19(1):28–35 Canis M, Rabischong B, Botchorishvili R, Tamburro S, Wattiez A, Mage G et al (2001) Risk of spread of ovarian cancer after laparoscopic surgery. Curr Opin Obstet Gynecol 13(1):9–14 Leminen A, Lehtovirta P (1999) Spread of ovarian cancer after laparoscopic surgery: report of eight cases. Gynecol Oncol 75(3):387–390 Sainz de la Cuesta R, Goff BA, Fuller AF Jr, Nikrui N, Eichhorn JH, Rice LW (1994) Prognostic importance of intraoperative rupture of malignant ovarian epithelial neoplasms. Obstet Gynecol 84(1):1–7 Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P et al (2001) Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 357(9251):176–182 Nezhat FR, Ezzati M, Chuang L, Shamshirsaz AA, Rahaman J, Gretz H (2009) Laparoscopic management of early ovarian and fallopian tube cancers: surgical and survival outcome. Am J Obstet Gynecol 200(1):83 Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT et al (2008) Comparison of laparoscopy and laparotomy in surgical staging of early-stage ovarian and fallopian tubal cancer. Ann Surg Oncol 15(7):2012–2019 Le T, Adolph A, Krepart GV, Lotocki R, Heywood MS (2002) The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma. Gynecol Oncol 85(2):351–355
