Lymphadenectomy as a prognostic marker in uterine non-endometrioid carcinoma

Arch Gynecol Obstet (2012) 285:207–214 DOI 10.1007/s00404-011-1914-x

G Y N E CO L O G IC O N C O L O G Y

Lymphadenectomy as a prognostic marker in uterine non-endometrioid carcinoma Ioannis Mylonas · Christian Schindlbeck

Received: 19 October 2010 / Accepted: 19 April 2011 / Published online: 3 May 2011 © Springer-Verlag 2011

Abstract Introduction A pelvic lymphadenectomy with or without para-aortic lymphadenectomy is performed during surgery for endometrial cancer at least in high-risk patients for recurrence or progression. The question of whether pelvic and/or para-aortic lymphadenectomy improves survival rates of high-risk patients with uterine non-endometrioid carcinoma is still unclear. Therefore, the aim of this study was to evaluate the outcome of patients with uterine non-endometrioid cancer, with regard to the performance of a lymphadenectomy in a well-characterized cohort population. Materials and methods The prognostic value of a performed lymphadenectomy was examined in 55 patients with a histological diagnosis of a uterine non-endometrioid carcinoma. A performed lymphadenectomy was analyzed with respect to the surgical and pathological stage and characteristics. Results Of the 55 patients with an uterine non-endometrioid carcinoma, 38 (69.1%) and 2 (3.6%) patients were diagnosed in FIGO stage I and II, respectively, while 14 (25.5%) patients had FIGO stage III and 1 patient (1.8%) presented with metastatic disease (FIGO IV). 16 patients (29.1%) demonstrated a myometrial invasion of more than 50%, while a cervical and ovarian involvement could be observed in 7 (12.7%) and 9 (16.4%) cases, respectively. Pelvic and/or para-aortic lymph node sampling was I. Mylonas (&) 1st Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich, Maistrasse 11, 80337 Munich, Germany e-mail: [email protected] C. Schindlbeck Department of Obstetrics and Gynecology, Klinium Traunstein, Trostberg, Traunstein, Germany

performed for 42 patients (76.4%) while 7 patients (12.7%) demonstrated lymph node metastasis. Univariate survival analysis demonstrated no diVerences in progression-free survival, cause-speciWc survival or overall survival for a performed lymphadenectomy. Regression analysis led to a model containing only the FIGO surgical stage as an independent term that was predictive of progression-free survival, cause-speciWc survival and overall survival. Discussion Although a performed lymphadenectomy did not have any positive beneWt in the survival of patients with uterine non-endometrioid carcinomas in this study, it might provide important prognostic information with a subsequent adjuvant treatment. However, these results remain to be conWrmed in further larger and prospective studies. Keywords Endometrial cancer · Non-endometrioid carcinoma · Lymphadenectomy · Prognosis · Survival

Introduction Endometrial cancer is the seventh most common malignancy worldwide, being the most common cancer of the female genital tract in developed countries [1, 2]. The annual incidence is estimated to be 15–20 per 100,000 women. The lifetime risk of developing endometrial cancer is approximately 2.5%, while the lifetime probability of dying from this cancer is estimated to be 0.52% [1, 3]. More than 75% of patients with endometrial cancer are diagnosed at an early stage, resulting in a favorable prognosis with a 5-year overall survival rate of 80–85% and a cancer-speciWc survival rate of 90–95% [4, 5]. Meanwhile, endometrial cancer has been described as consisting of two diVerent subgroups [6–9]. Type I endometrial cancers are mostly well-diVerentiated endometrioid adenocarcinomas

123

208

with a more favorable outcome compared to endometrial cancer of the second group [2, 3, 6–8, 10]. On the contrary, type II endometrial cancers are often of the non-endometrioid type, poorly diVerentiated with a poor prognosis [8, 9, 11]. The 5-year survival rate for serous-papillary histology is 24–34%, whereas clear-cell adenocarcinoma is estimated to be approximately 42% [12]. A pattern analysis of spread in endometrial cancer revealed that pelvic lymph nodes are the most common site of extra-uterine disease in patients with clinically earlystage disease [13]. Therefore, the International Federation of Gynecology and Obstetrics (FIGO) established a pathological and surgical staging system that includes an explorative laparotomy with radical hysterectomy and bilateral salpingo-oophorectomy and pelvic and para-aortic lymph node sampling [14, 15]. In particular, the value of a performed lymphadenectomy in human endometrial cancer is still being controversially discussed [16–21]. Several studies have demonstrated an impact on survival for patients with a higher number of removed lymph nodes, especially in cases showing high-risk clear-cell or serous-papillary histology [22–24]. Meanwhile, several studies have addressed this issue, but the results and conclusions have been rather inconsistent. However, in two recent prospective studies, there was no evidence of a substantial beneWt from pelvic lymphadenectomy in terms of overall or recurrence-free survival in women with early endometrial cancer [25, 26]. The question of whether pelvic and/or para-aortic lymphadenectomy improves survival rates of high-risk patients with a uterine non-endometrioid carcinoma has still to be clariWed, since not many studies have focused on this issue. Therefore, the aim of this analysis was to evaluate the outcome of patients with uterine non-endometrioid cancer, with regard to performance of a lymphadenectomy in a well-characterized cohort population.

Materials and methods Tissue samples Pathological and surgical records of 55 patients who have been operated in the 1st Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich between 1990 and 2002 were reviewed for this retrospective analysis. Only specimens with a uterine non-endometrioid adenocarcinoma were included. The evaluated patient group has been previously well characterized and an evaluation for several prognostic markers has been performed [18, 27–30]. All hematoxylin and eosin-stained slides were rereviewed by a gynecological pathologist to verify the

123

Arch Gynecol Obstet (2012) 285:207–214

diagnosis, histological type, FIGO surgical stage, lymphovascular space invasion, adnexal or cervical involvement as previously described [28, 29]. Pathological stage and histological subtype were determined for each surgical specimen according to the 1988 FIGO criteria [15] that was updated to the FIGO classiWcation established in 2009 [14]. Patients with endometrial carcinoma received a modiWed radical hysterectomy, salpingo-oophorectomy or selective pelvic lymphadenectomy, with or without para-aortic lymphadenectomy. Lymph node sampling or dissection was generally performed in patients having tumors with deep myometrial invasion and/or high-grade or aggressive histological features. Obesity, advanced age and excessive comorbidity were factors against full surgical staging. Patient data were obtained from three sources: hospital tumor registry, automated database and chart review as previously described [27–29, 31]. All cases of recurrence had radiographic evidence of disease or biopsy-proven progression of disease. Only the records of patients who died of disease were considered to be uncensored; the records of all patients who were alive at follow-up or who did not die of disease (or a related cause) were considered to be censored. Additionally, censored cases were also considered as those cases where the exact cause of death was unknown but died within 2 years after the diagnosis of a metastatic lesion [28, 29]. Statistical analysis Pearson 2 and Fisher’s exact test were used for categorical variables where applicable. The outcome variables analyzed were progression-free survival, cause-speciWc survival and overall survival. Univariate analysis was performed with Kaplan–Meier life-table curves to estimate survival and was compared using the log-rank test [32]. Prognostic models used the Cox regression analysis for multivariate analyses of survival in a forward stepwise manner, as previously described [18, 27–29, 33, 34]. Data were adjusted for age (·65 vs. >65 years), histology (categorical variable), FIGO stage (FIGO I/II vs. FIGO III/IV), lymph node involvement (categorical variable), lymphovascular space invasion (positive vs. negative), cervical involvement (positive vs. negative), deep myometrial invasion (50%), ovarian metastasis (positive vs. negative), presence of positive lymph nodes (positive vs. negative), and lymphadenectomy (performed vs. not performed). Hazard ratios (HR), 95% conWdence intervals (CI) and p values are reported. SigniWcance of diVerences was assumed at p · 0.05 at the two-sided tests (SPSS, version 17.0; SPSS Inc., Munich, Germany).

Arch Gynecol Obstet (2012) 285:207–214

209

Results

Discussion

Clinicopathological characterization

Endometrial cancer has become the most frequent gynecologic malignancy in the Western World [2, 6, 10]. Several important prognostic factors in endometrial carcinoma, primarily age, race and endocrine status have been identiWed [13, 28, 35]. Uterine factors included histological cell type, tumor grade, depth of myometrial invasion, occult extension of the cervix and vascular space invasion. Additionally, extrauterine prognostic factors were deWned as adnexal metastasis, other extrauterine spread, positive peritoneal cytology, pelvic lymph node metastases, and paraaortic involvement [13, 35]. Interestingly, no speciWcations regarding the type and extent of pelvic lymph node dissection have been established and the extent and performance depend on the surgeon and the region [16, 17]. In particular, in patients with a low risk for lymph node metastases, a routine lymph node dissection is often not performed [16]. Although some studies have not shown that lymphadenectomy has an impact on survival [21], most studies have demonstrated increased survival and have established lymphadenectomy as an important prognostic factor [18, 34, 36, 37]. In an analysis of the large SEER database from the United States, 42,814 patients with endometrial adenocarcinoma were analyzed [37]. Lymphadenectomy was identiWed as an independent prognostic factor for overall survival, with hazard ratios of 0.74 for the subgroup with more than 11 lymph nodes dissected, and 0.89 for the subgroup with 65

30 (54.5)

10 (33.3)

22 (88)

n.s.

20 (66.7)

Adipositas Negative

36 (65.5)

8 (22.2)

28 (77.8)

Positive

19 (34.5)

5 (26.3)

14 (73.7)

Negative

51 (92.7)

10 (19.6)

41 (80.4)

Positive

4 (7.3)

3 (75)

1 (25)

n.s.

Diabetes 0.037

Hypertension Negative

32 (58.2)

6 (18.8)

26 (81.3)

Positive

23 (41.8)

7 (30.4)

16 (69.6)

FIGO I

38 (69.1)

10 (26.3)

28 (73.7)

FIGO IA

34 (61.8)

9 (26.5)

25 (73.5)

FIGO IB

4 (7.3)

1 (25)

FIGO II

2 (3.6)

1 (50)

FIGO III

14 (25.5)

n.s.

Surgical characteristics FIGO stage

2 (14.3)

n.s.

3 (75) 1 (50) 12 (85.7)

FIGO 3A

6 (10.9)

2 (33.3)

4 (66.7)

FIGO 3B

1 (1.8)

0 (0)

1 (100)

FIGO 3C1

7 (12.7)

0 (0)

7 (100)

FIGO 3C2

0 (0)

0 (0)

0 (0)

FIGO IV

1 (1.8)

0 (0)

1 (100)

Lymphadenectomy Not performed

13 (23.6)

Performed

42 (76.4)

Pathological characteristics Histology Serous/papillary

29 (52.7)

Clear cell

7 (12.7)

Mucinous

14 (25.5)

UndiVerentiated

7 (24.1) 0 (0) 4 (28.6)

22 (75.9)

n.s.

7 (100) 10 (71.4)

5 (9.1)

2 (40)

3 (60)

·50% myometrium

39 (70.9)

10 (25.6)

29 (74.4)

>50% myometrium

16 (29.1)

3 (18.8)

13 (81.3)

Myometrial invasion n.s.

Cervical Invasion Negative

48 (87.3)

Positive

7 (12.7)

12 (25) 1 (14.3)

36 (75) 6 (85.7)

Negative

46 (83.6)

11 (23.9)

35 (76.1)

Positive

9 (16.4)

2 (22.2)

7 (77.8)

n.s.

Ovarial invasion

LN status Negative

35 (63.6)

Positive

7 (12.7)

Unknown

123

13 (23.6)

n.s.

Arch Gynecol Obstet (2012) 285:207–214

211

Table 1 continued Total n = 55 (%)

No lymphadenectomy (%)

Performed lymphadenectomy (%)

2

LVSI Negative

48 (87.3)

10 (20.8)

38 (79.2)

Positive

7 (12.7)

3 (42.9)

4 (57.1)

n.s.

Therapeutic characteristics Radiotherapy Negative

31 (56.4)

8 (25.8)

23 (74.2)

Positive

23 (41.8)

4 (17.4)

19 (82.6)

Negative

53 (96.4)

13 (24.5)

40 (75.5)

Positive

2 (3.6)

n.s.

Denial Anti-hormonal therapy 0 (0)

n.s.

2 (100)

Chemotherapy Negative

54 (98.2)

Positive

1 (1.8)

13 (24.1) 0 (0)

41 (75.9)

n.s.

1 (100)

Denial LN lymph node, LVSI lymphovascular space invasion, n.s. not signiWcant

and more than 12 lymph nodes dissected. For low-risk cases, the results were not signiWcant [23]. Similarly, in another investigation no signiWcant impact on overall survival was demonstrated for low-risk patients (grade 1 and 2, outer-half myometrial invasion, no serous-papillary or clear-cell diVerentiation) [24]. Recently, in two recent prospective studies, there was no evidence of a substantial beneWt from pelvic lymphadenectomy in terms of overall or recurrence-free survival in women with early endometrial cancer [25, 26]. In a performed meta-analysis, no evidence exists that lymphadenectomy decreases the risk of death or disease recurrence compared with no lymphadenectomy in women with early-stage endometrial carcinoma [38]. However, surgical lymph node staging still continues to be controversial and an important subject of debate [39–41]. There are several unsolved aspects regarding the prognostic value of a performed pelvic and/or para-aortic lymphadenectomy in uterine cancer. First, the reason why such a procedure might have an impact on survival rate could be the identiWcation of patients with positive nodes, which constitutes by itself a signiWcant prognostic parameter [35]. An additional explanation for a survival beneWt could be the removal of occult small metastatic disease that was not detected by classical histopathological evaluation [42, 43]. Furthermore, the potential of underestimating FIGO IIIC disease in non-surgically staged patients is also possible. Unfortunately, no current imaging modalities have an impact on the prediction of lymph node metastasis and preoperative estimation of the extensiveness of the operation [44]. These assumptions have been rarely addressed and the

situation in non-endometrioid carcinomas remains still unclear. The extent of the lymphadenectomy would have a major impact on the beneWt of patient survival, since, by removing as more lymph nodes as possible, the probability would increase to identify patients with positive nodes. Also, the therapeutic eVect of removing occult lymph node metastases would increase. An impact on survival of para-aortic sampling in patients with high-risk adenocarcinoma of the endometrium was recently demonstrated [45]. Additionally, para-aortic lymphadenectomy in endometrial cancer has been demonstrated to have a positive survival beneWt for patients at intermediate or high risk of recurrence [46]. Moreover, pelvic lymphadenectomy alone might be an insuYcient surgical procedure for endometrial cancer in patients at risk of lymph node metastasis [46, 47]. However, it is not Wnally deWned yet whether para-aortic lymph node dissection could play a substantial role in routine treatment of patients with a non-endometrioid histology. This study provides and emphasizes the need of prospective studies regarding this entity of endometrial cancer. Additionally, it accentuates the fact that the value of lymphadenectomy in these patients might be diVerent from those observed for endometrioid adenocarcinomas. Although a performed lymphadenectomy did not reveal any positive beneWt on the survival of patients with uterine nonendometrioid carcinomas in this study, it might provide important prognostic information with a subsequent adjuvant treatment. However, these results remain to be conWrmed in further larger and prospective studies. Therefore,

123

212

Arch Gynecol Obstet (2012) 285:207–214

Fig. 1 Kaplan–Meier curves of the clinical outcome. Clinical outcome regarding a performed lymphadenectomy for progression-free

survival (a), cause-speciWc survival (b) and overall survival (c). Green, performed lymphadenectomy; blue, not performed lymphadenectomy

identiWcation of a subgroup of patients who beneWt from performing a lymphadenectomy remains still controversial and warrants further research.

References

Acknowledgments The author would like to thank Mrs. N. Bassarak, Dr. T. Blankenstein, Dr. A. Brüning, Dr. D. Dian, Dr. F. Bergauer and Prof. Dr. K. Friese for their help in conducting the primary study with endometrioid adenocarcinomas. Additionally, the author would like to thank Dr. N. Shabani (Department of Obstetrics and Gynecology, Klinikum Neuperlach, Munich, Germany) for re-evaluating the histological Wndings and Prof. D. Hölzel (Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich) as well as Mr. M. Schmidt of the Munich Tumor Registry for supplying the survival data. I. ConXict of interest I. Mylonas is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG BR 3641/3-1). The authors do not have any Wnancial, personal, political, intellectual or religious interests in publishing this article.

123

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249. doi:10.3322/ caac.20006 2. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I (2005) Endometrial cancer. Lancet 366:491–505 3. Gloeckler Ries LA, Reichman ME, Lewis DR, Hankey BF, Edwards BK (2003) Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) program. Oncologist 8:541–552 4. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van den Bergh AC, van de Steen-Banasik E, Beerman H, van Lent M (2000) Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355:1404–1411. doi:S0140673600021395

Arch Gynecol Obstet (2012) 285:207–214 5. Papanikolaou A, Kalogiannidis I, Goutzioulis M, Misailidou D, Makedos A, Vergote I, Makedos G (2006) Pelvic lymphadenectomy as alternative to postoperative radiotherapy in high risk early stage endometrial cancer. Arch Gynecol Obstet 274:91–96. doi:10.1007/s00404-006-0138-y 6. Prat J (2004) Prognostic parameters of endometrial carcinoma. Hum Pathol 35:649–662 7. Deligdisch L, Holinka CF (1987) Endometrial carcinoma: two diseases? Cancer Detect Prev 10:237–246 8. Bokhman JV (1983) Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15:10–17 9. Lax SF (2004) Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classiWcation. Virchows Arch 444:213–223 10. Jereczek-Fossa B, Badzio A, Jassem J (1999) Surgery followed by radiotherapy in endometrial cancer: analysis of survival and patterns of failure. Int J Gynecol Cancer 9:285–294 11. Faratian D, Stillie A, Busby-Earle RM, Cowie VJ, Monaghan H (2006) A review of the pathology and management of uterine papillary serous carcinoma and correlation with outcome. Int J Gynecol Cancer 16:972–978 12. Dallenbach-Hellweg G (1999) Histopathologie und Stadieneinteilung des Endometriumkarzinoms inklusive seiner Präkanzerosen. Onkologe 5:388–395 13. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB (1987) Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 60:2035–2041 14. Pecorelli S (2009) Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105:103–104 15. (1989) FIGO stages (announcements). Gynecol Oncol 35:125– 127 16. Soliman PT, Frumovitz M, Spannuth W, Greer MJ, Sharma S, Schmeler KM, Ramirez PT, Levenback CF, Ramondetta LM (2010) Lymphadenectomy during endometrial cancer staging: practice patterns among gynecologic oncologists. Gynecol Oncol 119:291–294. doi:10.1016/j.ygyno.2010.07.011 17. Sehouli J, Camara O, Stengel D, Kohler G, Lichtenegger W (2003) Multi-institutional survey on the value of lymphadenectomy in endometrial carcinoma in Germany. Gynakol GeburtshilXiche Rundsch 43:104–110 18. Bassarak N, Blankenstein T, Bruning A, Dian D, Bergauer F, Friese K, Mylonas I (2010) Is lymphadenectomy a prognostic marker in endometrioid adenocarcinoma of the human endometrium? BMC Cancer 10:224. doi:10.1186/1471-2407-10-224 19. Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton HM, Noojin F 3rd, Conner W (1995) Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 56:29–33 20. Orr JW Jr, Holimon JL, Orr PF (1997) Stage I corpus cancer: is teletherapy necessary? Am J Obstet Gynecol 176:777–788 (discussion 788-779) 21. Ceccaroni M, Savelli L, Bovicelli A, Alboni C, Ceccarini M, Farina A, Bovicelli L (2004) Prognostic value of pelvic lymphadenectomy in surgical treatment of apparent stage I endometrial cancer. Anticancer Res 24:2073–2078 22. Abu-Rustum NR, Chi DS, Leitao M, Oke EA, Hensley ML, Alektiar KM, Barakat RR (2008) What is the incidence of isolated paraaortic nodal recurrence in grade 1 endometrial carcinoma? Gynecol Oncol 111:46–48. doi:10.1016/j.ygyno.2008.06.010 23. Lutman CV, Havrilesky LJ, Cragun JM, Secord AA, Calingaert B, Berchuck A, Clarke-Pearson DL, Soper JT (2006) Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecol Oncol 102:92–97

213 24. Cragun JM, Havrilesky LJ, Calingaert B, Synan I, Secord AA, Soper JT, Clarke-Pearson DL, Berchuck A (2005) Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 23:3668–3675 25. Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK (2009) EYcacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 373:125– 136. doi:10.1016/S0140-6736(08)61766-3 26. Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, Angioli R, Tateo S, Mangili G, Katsaros D, Garozzo G, Campagnutta E, Donadello N, Greggi S, Melpignano M, Raspagliesi F, Ragni N, Cormio G, Grassi R, Franchi M, Giannarelli D, Fossati R, Torri V, Amoroso M, Croce C, Mangioni C (2008) Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 100:1707–1716. doi:10.1093/jnci/ djn397 27. Mylonas I (2010) Inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid carcinomas: Prognostic signiWcance and clinical implications. Eur J Cancer 46:2485–2493. doi:10.1016/ j.ejca.2010.06.001 28. Shabani N, Kuhn C, Kunze S, Schulze S, Mayr D, Dian D, Gingelmaier A, Schindlbeck C, Willgeroth F, Sommer H, Jeschke U, Friese K, Mylonas I (2007) Prognostic signiWcance of oestrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor A (PR-A) and B (PR-B) in endometrial carcinomas. Eur J Cancer 43:2434–2444. doi:10.1016/j.ejca.2007.08.014 29. Mylonas I, Worbs S, Shabani N, Kuhn C, Kunze S, Schulze S, Dian D, Gingelmaier A, Schindlbeck C, Bruning A, Sommer H, Jeschke U, Friese K (2009) Inhibin-alpha subunit is an independent prognostic parameter in human endometrial carcinomas: analysis of inhibin/activin-alpha, -betaA and -betaB subunits in 302 cases. Eur J Cancer 45:1304–1314. doi:10.1016/j.ejca.2009.01.008 30. KäuX SD, Kuhn C, Kunze S, Shabani N, Bruning A, Friese K, Mylonas I (2010) Inhibin/activin-betaC subunit does not represent a prognostic parameter in human endometrial cancer. Arch Gynecol Obstet. doi:10.1007/s00404-010-1614-y 31. Mylonas I (2010) Inhibin-betaA subunit immunolabeling as a prognostic factor in endometrioid adenocarcinomas: a matter of evaluation? Arch Gynecol Obstet. doi:10.1007/s00404-010-1680-1 32. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481 33. Cox DR (1972) Regression models and life tables. J R Stat Soc B 34:187–220 34. Mylonas I, Matsingou C, KäuX SD, Brüning A (2011) Inhibin/ activin betaE-subunit in uterine endometrioid adenocarcinoma and endometrial cancer cell lines: From immunohistochemistry to clinical testing? Gynecol Oncol. doi:10.1016/j.ygyno.2011.03.019 35. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, Graham JE (1991) Relationship between surgicalpathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 40:55–65 36. Barakat RR, Lev G, Hummer AJ, Sonoda Y, Chi DS, Alektiar KM, Abu-Rustum NR (2007) Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches. Gynecol Oncol 105:150–156. doi:10.1016/ j.ygyno.2006.11.007 37. Smith DC, Macdonald OK, Lee CM, GaVney DK (2008) Survival impact of lymph node dissection in endometrial adenocarcinoma: a surveillance, epidemiology, and end results analysis. Int J Gynecol Cancer 18:255–261. doi:10.1111/j.1525-1438.2007.01020.x 38. May K, Bryant A, Dickinson HO, Kehoe S, Morrison J (2010) Lymphadenectomy for the management of endometrial cancer.

123

214

39.

40.

41.

42.

43.

Arch Gynecol Obstet (2012) 285:207–214 Cochrane Database Syst Rev:CD007585. doi:10.1002/14651858. CD007585.pub2 Seracchioli R, Solfrini S, Mabrouk M, Facchini C, Di Donato N, Manuzzi L, Savelli L, Venturoli S (2010) Controversies in surgical staging of endometrial cancer. Obstet Gynecol Int 2010:181963. doi:10.1155/2010/181963 Delpech Y, Barranger E (2010) Management of lymph nodes in endometrioid uterine cancer. Curr Opin Oncol 22:487–491. doi:10.1097/CCO.0b013e32833b9b75 Vorgias G, Fotiou S (2010) The role of lymphadenectomy in uterine carcinosarcomas (malignant mixed mullerian tumours): a critical literature review. Arch Gynecol Obstet doi:10.1007/s00404010-1649-0 Yabushita H, Shimazu M, Yamada H, Sawaguchi K, Noguchi M, Nakanishi M, Kawai M (2001) Occult lymph node metastases detected by cytokeratin immunohistochemistry predict recurrence in node-negative endometrial cancer. Gynecol Oncol 80:139–144 Gonzalez Bosquet J, Keeney GL, Mariani A, Webb MJ, Cliby WA (2003) Cytokeratin staining of resected lymph nodes may improve

123

44.

45.

46.

47.

the sensitivity of surgical staging for endometrial cancer. Gynecol Oncol 91:518–525 Sayin NC, Varol FG, Yuce MA, Kaplan P, Ahmet N, Sut N, Gucer F (2009) Do routine preoperative imaging techniques facilitate the operation in endometrial cancer? Arch Gynecol Obstet 280:211– 215. doi:10.1007/s00404-008-0893-z Chang SJ, Kim WY, Yoon JH, Yoo SC, Chang KH, Ryu HS (2008) Para-aortic lymphadenectomy improves survival in patients with intermediate to high-risk endometrial carcinoma. Acta Obstet Gynecol Scand 87:1361–1369. doi:10.1080/ 00016340802503054 Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N (2010) Survival eVect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 375:1165–1172. doi:10.1016/S0140-6736(09)62002-X Yoon JH, Yoo SC, Kim WY, Chang SJ, Chang KH, Ryu HS (2010) Para-aortic Lymphadenectomy in the Management of Preoperative Grade 1 Endometrial Cancer ConWned to the Uterine Corpus. Ann Surg Oncol. doi:10.1245/s10434-010-1199-5