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Surgical staging in endometrial cancer
International Congress Series 1279 (2005) 158 – 161
www.ics-elsevier.com
Surgical staging in endometrial cancer Marian J. Mourits*, Jan G. Aalders Department of Gynaecologic Oncology, University Medical Centre, Hanzeplein 1 9713 GZ, Groningen, The Netherlands
Abstract. Endometrial cancer is the most prevalent cancer of the female genital tract. No randomised study exists to prove that pelvic and para-aortic lymphadenectomy increases survival, either by dissecting micrometastases or by altering the adjuvant treatment in all early stage (stage I grade 1 and 2) endometrial cancer patients. For lymph node metastases, adverse histology, deep myometrial invasion and cervical involvement are independent prognostic factors. We discuss the indication for full surgical staging in early endometrial cancer. In case a lymphadenectomy is indicated, this should always include a full pelvic and para-aortic lymphadenectomy. Lymphadenectomy does not replace adjuvant radiotherapy. D 2005 Elsevier B.V. All rights reserved. Keywords: Endometrial cancer; Surgical staging; Lymphadenectomy; Pelvic; Para-aortic
1. Introduction Endometrial cancer is the most prevalent cancer of the female genital tract. Due to the early declaration of the disease by vaginal bleeding, approximately 80% of endometrial cancers are diagnosed at an early stage. Total abdominal hysterectomy and bilateral salpingo-oophorectomy after peritoneal cytology remains the cornerstone of treatment. Tumor stage, histologic grade and depth of myometrial invasion are the most important prognostic factors. Surgical staging including pelvic and para-aortic lymphadenectomy has been advocated since 1988 when FIGO redefined stage of disease on the basis of surgical–pathological criteria. However, no randomised study exists to prove that pelvic and para-aortic lymphadenectomy increases survival, either by dissecting micrometastases or by altering the adjuvant treatment in early stage (stage I grade 1 and 2) endometrial cancer patients.
* Corresponding author. Tel.: +31 50 361 3152; fax: +31 50 361 1806. E-mail address: [email protected] (M.J. Mourits). 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.12.051
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
159
On the other hand, morbidity by extensive surgery performed on often elderly and obese women must be weighted against the potential gains. 2. Daily practice of lymphadenectomy in endometrial cancer Because of a lack of evidence of efficacy, the practice of full surgical staging including lymphadenectomy in clinical stage I endometrial cancer patients differs all over the world. In daily practice, the majority of patients with early stage endometrial cancer are treated in local hospitals by a generalist obstetrician–gynecologist. Staging by full pelvic and paraaortic lymphadenectomy is not usually part of the surgical experience of the generalist obstetrician–gynecologist which leads to a wide variation in clinical practice. Only 24% of the gynecologic oncology centers in Western Europe perform routine lymph node dissection in endometrial cancer patients, while 54% of the gynecologic oncology centers in North America do so. [1,2]. 3. Does a lymphadenectomy favour prognosis in early stage endometrial cancer? Randomised studies in early stage endometrial cancer patients, to compare survival and recurrence rate between total abdominal hysterectomy including full lymphadenectomy or not, are not available. Only retrospective studies have been performed in comparing patients after full surgical staging with historical controls. The survival rate for patients with stage I endometrial cancer submitted to lymphadenectomy was the same as patients without lymphadenectomy [3,4]. The advantage of accurate staging on survival cannot be measured in studies with a retrospective design. 4. Can a lymphadenectomy replace radiotherapy? In the randomised GOG 99 study after a pelvic and para-aortic lymphadenectomy, patients with a negative node status were randomised between locoregional radiotherapy and no further treatment [5]. After 2 years of follow-up, in the group without further treatment 18/200 developed a recurrence, versus 3/190 after adjuvant radiotherapy. Hence the recurrence free survival (RFS) was 85% in the group without further treatment and 93% in the group after adjuvant locoregional radiotherapy. The authors concluded that even in patients with histologically proven negative nodes, adjuvant radiotherapy stays mandatory in women with adverse histopathological features. 5. Is it possible to detect lymph node metastases preoperatively in endometrial cancer patients? 5.1. Grade or myometrial invasion In a surgical–pathological study from the US Gynaecologic Oncology Group, a close correlation was found between tumor grade, myometrial invasion and lymph node metastases [6]. In case of a clinical stage I disease, 12% of the patients had positive lymph nodes, of which 6% only in the pelvic nodes, 4% in pelvic as well as para-aortic nodes and in 2% in the para-aortic nodes only. In patients with a grade 3 tumor, 18% showed positive nodes and in case of deep myometrial invasion 22%. For some institutes, these data are
160
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
indicative of performing a lymphadenectomy in preoperatively defined grade 3 tumors, and/or preoperatively found deep myometrial invasion. However, dependent on the amount of tissue collected by D & C or microcurettage, preoperatively defined tumor grade can be different in up to 40% of cases from the definite uterine sample and depth of myometrial invasion can be hard to define macroscopically. Even MRI will predict only 70–80% of patients with deep myometrial invasion. 5.2. Detection of lymph node metastases preoperatively? In a study by Creasman et al. [7], less than 10% of all node metastases were found in grossly enlarged nodes. In case of histologically proven metastases, 47% of the nodes were b1 cm and 37% of the nodes were b2 mm. Preoperative palpation to detect enlarged nodes will miss 30–50% of all metastatic lymph nodes and is not a sensitive test to detect lymph node metastases [8]. CT scan and transvaginal sonography are only moderately reliable in predicting depth of myometrial invasion in endometrial cancer patients. Schmidt [9] showed that sensitivity of whole-body MRI in the prediction of lymph node metastases is limited (sensitivity 83%, specificity 85%). 5.3. Is PET scan of help? The sensitivity and specificity of positron emission tomography (PET) with 2[(18)F]fluoro-2-deoxy-d-glucose (FDG) for detecting pelvic and para-aortic lymph node metastasis in patients with uterine corpus carcinoma before surgical staging was recently performed by Horowitz et al. Patients with newly diagnosed FIGO grade 2 or 3 endometrioid, papillary serous, or clear cell adenocarcinoma or uterine corpus sarcoma scheduled for surgical staging, including bilateral pelvic and para-aortic lymphadenectomy, were eligible. Analyzed by lymph node regions, FDG-PET had 60% sensitivity and 98% specificity. The sensitivity and specificity by individual patient were 67% and 94%, respectively. The authors conclude that FDG-PET is only moderately sensitive in predicting lymph node metastasis preoperatively in patients with endometrial cancer [10]. 6. Which patient with endometrial cancer should have a lymphadenectomy? The balance stays between the risk for node involvement and the expected benefit of the lymphadenectomy and the complications rate of the procedure. Lymphadenectomy is advised in patients with clinical suspicious lymph nodes and whenever there is a nonnegligible risk of node metastasis, i.e., in patients with high risk factors for lymph node involvement [6,7]: – – – –
Histology: grade 3 endometrioid carcinoma; clear cell carcinoma; serous papillary carcinoma. Deep (N50%) myometrial invasion. Cervical involvement. Lymph vascular space involvement (LVSI).
7. If we decide to perform a lymphadenectomy, how radical should we be? In a retrospective study by Chuang et al. 4/51 (8%) of the patients with bnegativeQ palpation (no lymph node biopsies) developed retroperitoneal recurrences, 9/173 (5%) in
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
161
patients with limited node biopsies while no patients (0/38) developed a retroperitoneal recurrence after total selective pelvic and para-aortic lymphadenectomy [11]. In another retrospective study in 649 patients, surgical staging was divided into 3 groups (no node sampling, limited node sampling, multiple site (N4) node sampling). A significant survival advantage was found for patients receiving multiple-site node sampling, irrespective of low or high-risk factors and the use of adjuvant radiotherapy [12]. Because of the fact that 47–57% of the patients with positive pelvic nodes have para-aortic node metastases, and that 3–17% of the patients with negative pelvic nodes have bisolatedQ para-aortic node metastases, not only a pelvic but also a para-aortic lymphadenectomy should be performed in all patients with an indication to do a lymphadenectomy [7,13,14]. Even in patients with para-aortic lymph node metastases, survival was not different from patients with only pelvic positive nodes, suggesting that lymphadenectomy may have a therapeutic role [13]. 8. Conclusion In endometrial cancer patients, a lymphadenectomy should be performed in all patients with adverse histology (grade 3 endometrioid carcinoma; clear cell carcinoma; serous papillary carcinoma), deep myometrial invasion (N50%), and cervical involvement. A lymphadenectomy should always include a full pelvic and para-aortic lymphadenectomy by a skilled surgeon. Lymphadenectomy does not replace adjuvant radiotherapy. References [1] T. Maggino, et al., An analysis of approaches to the treatment of endometrial cancer in Western Europe : a CTF study, Eur. J. Cancer 31A (1995) 1993 – 1997. [2] T. Maggino, et al., An analysis of approaches to the management of endometrial cancer in North America: a CTF study, Gynecol. Oncol. 68 (1998) 274 – 279. [3] M. Ceccaroni, et al., Prognostic value of pelvic lymphadenectomy in surgical treatment of apparent stage I endometrial cancer, Anticancer Res. 24 (3b) (2004) 2073 – 2078. [4] E. Vizza, et al., Role of pelvic lymphadenectomy in the management of stage I endometrial cancer: our experience, Eur. J. Gynaecol. Oncol. 24 (2) (2003) 126 – 128. [5] H.M. Keys, et al., Gynecologic Oncology Group, A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol. Oncol. 92 (3) (2004) 744 – 751. [6] COSA-NZ-UK endometrial cancer study group, Pelvic lymphadenectomy in high risk endometrial cancer, Int. J. Gynecol. Cancer 6 (1996) 102 – 107. [7] W.T. Creasman, et al., Surgical Pathologic spread patterns of endometrial cancer. A gynecologic oncology group study, Cancer 60 (1987) 2035 – 2041. [8] K.W. Lo, et al., The value of pelvic and para-aortic lymphadenectomy in endometrial cancer to avoid unnecessary radiotherapy, Int. J. Gynecol. Cancer 13 (2003) 863 – 869. [9] G.P. Schmidt, et al., Comparison of high-resolution whole-body MRI using parallel imaging and PET-CT. First experiences with a 32-channel MRI system, Radiologe 44 (9) (2004) 889 – 898. [10] N.S. Horowitz, et al., Prospective evaluation of FDG-PET for detecting pelvic and para-aortic lymph node metastasis in uterine corpus cancer, Gynecol. Oncol. 95 (3) (2004) 546 – 551. [11] L. Chuang, et al., Staging laparotomy for endometrial carcinoma: assessment of retroperitoneal lymph nodes, Gynecol. Oncol. 58 (2) (1995) 189 – 193. [12] L.C. Killgore, et al., Adenocarcinoma of the endometrium: survival comparison of patients with and without pelvic node sampling, Gynecol. Oncol. 56 (1) (1995) 29 – 33. [13] D.S. McMeekin, et al., Nodal distribution and its significance in FIGO stage IIIc endometrial cancer, Gynecol. Oncol. 82 (2) (2001) 375 – 379. [14] A. Mariani, et al., Endometrial carcinoma: paraaortic dissemination, Gynecol. Oncol. 92 (3) (2004) 833 – 838.
www.ics-elsevier.com
Surgical staging in endometrial cancer Marian J. Mourits*, Jan G. Aalders Department of Gynaecologic Oncology, University Medical Centre, Hanzeplein 1 9713 GZ, Groningen, The Netherlands
Abstract. Endometrial cancer is the most prevalent cancer of the female genital tract. No randomised study exists to prove that pelvic and para-aortic lymphadenectomy increases survival, either by dissecting micrometastases or by altering the adjuvant treatment in all early stage (stage I grade 1 and 2) endometrial cancer patients. For lymph node metastases, adverse histology, deep myometrial invasion and cervical involvement are independent prognostic factors. We discuss the indication for full surgical staging in early endometrial cancer. In case a lymphadenectomy is indicated, this should always include a full pelvic and para-aortic lymphadenectomy. Lymphadenectomy does not replace adjuvant radiotherapy. D 2005 Elsevier B.V. All rights reserved. Keywords: Endometrial cancer; Surgical staging; Lymphadenectomy; Pelvic; Para-aortic
1. Introduction Endometrial cancer is the most prevalent cancer of the female genital tract. Due to the early declaration of the disease by vaginal bleeding, approximately 80% of endometrial cancers are diagnosed at an early stage. Total abdominal hysterectomy and bilateral salpingo-oophorectomy after peritoneal cytology remains the cornerstone of treatment. Tumor stage, histologic grade and depth of myometrial invasion are the most important prognostic factors. Surgical staging including pelvic and para-aortic lymphadenectomy has been advocated since 1988 when FIGO redefined stage of disease on the basis of surgical–pathological criteria. However, no randomised study exists to prove that pelvic and para-aortic lymphadenectomy increases survival, either by dissecting micrometastases or by altering the adjuvant treatment in early stage (stage I grade 1 and 2) endometrial cancer patients.
* Corresponding author. Tel.: +31 50 361 3152; fax: +31 50 361 1806. E-mail address: [email protected] (M.J. Mourits). 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.12.051
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
159
On the other hand, morbidity by extensive surgery performed on often elderly and obese women must be weighted against the potential gains. 2. Daily practice of lymphadenectomy in endometrial cancer Because of a lack of evidence of efficacy, the practice of full surgical staging including lymphadenectomy in clinical stage I endometrial cancer patients differs all over the world. In daily practice, the majority of patients with early stage endometrial cancer are treated in local hospitals by a generalist obstetrician–gynecologist. Staging by full pelvic and paraaortic lymphadenectomy is not usually part of the surgical experience of the generalist obstetrician–gynecologist which leads to a wide variation in clinical practice. Only 24% of the gynecologic oncology centers in Western Europe perform routine lymph node dissection in endometrial cancer patients, while 54% of the gynecologic oncology centers in North America do so. [1,2]. 3. Does a lymphadenectomy favour prognosis in early stage endometrial cancer? Randomised studies in early stage endometrial cancer patients, to compare survival and recurrence rate between total abdominal hysterectomy including full lymphadenectomy or not, are not available. Only retrospective studies have been performed in comparing patients after full surgical staging with historical controls. The survival rate for patients with stage I endometrial cancer submitted to lymphadenectomy was the same as patients without lymphadenectomy [3,4]. The advantage of accurate staging on survival cannot be measured in studies with a retrospective design. 4. Can a lymphadenectomy replace radiotherapy? In the randomised GOG 99 study after a pelvic and para-aortic lymphadenectomy, patients with a negative node status were randomised between locoregional radiotherapy and no further treatment [5]. After 2 years of follow-up, in the group without further treatment 18/200 developed a recurrence, versus 3/190 after adjuvant radiotherapy. Hence the recurrence free survival (RFS) was 85% in the group without further treatment and 93% in the group after adjuvant locoregional radiotherapy. The authors concluded that even in patients with histologically proven negative nodes, adjuvant radiotherapy stays mandatory in women with adverse histopathological features. 5. Is it possible to detect lymph node metastases preoperatively in endometrial cancer patients? 5.1. Grade or myometrial invasion In a surgical–pathological study from the US Gynaecologic Oncology Group, a close correlation was found between tumor grade, myometrial invasion and lymph node metastases [6]. In case of a clinical stage I disease, 12% of the patients had positive lymph nodes, of which 6% only in the pelvic nodes, 4% in pelvic as well as para-aortic nodes and in 2% in the para-aortic nodes only. In patients with a grade 3 tumor, 18% showed positive nodes and in case of deep myometrial invasion 22%. For some institutes, these data are
160
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
indicative of performing a lymphadenectomy in preoperatively defined grade 3 tumors, and/or preoperatively found deep myometrial invasion. However, dependent on the amount of tissue collected by D & C or microcurettage, preoperatively defined tumor grade can be different in up to 40% of cases from the definite uterine sample and depth of myometrial invasion can be hard to define macroscopically. Even MRI will predict only 70–80% of patients with deep myometrial invasion. 5.2. Detection of lymph node metastases preoperatively? In a study by Creasman et al. [7], less than 10% of all node metastases were found in grossly enlarged nodes. In case of histologically proven metastases, 47% of the nodes were b1 cm and 37% of the nodes were b2 mm. Preoperative palpation to detect enlarged nodes will miss 30–50% of all metastatic lymph nodes and is not a sensitive test to detect lymph node metastases [8]. CT scan and transvaginal sonography are only moderately reliable in predicting depth of myometrial invasion in endometrial cancer patients. Schmidt [9] showed that sensitivity of whole-body MRI in the prediction of lymph node metastases is limited (sensitivity 83%, specificity 85%). 5.3. Is PET scan of help? The sensitivity and specificity of positron emission tomography (PET) with 2[(18)F]fluoro-2-deoxy-d-glucose (FDG) for detecting pelvic and para-aortic lymph node metastasis in patients with uterine corpus carcinoma before surgical staging was recently performed by Horowitz et al. Patients with newly diagnosed FIGO grade 2 or 3 endometrioid, papillary serous, or clear cell adenocarcinoma or uterine corpus sarcoma scheduled for surgical staging, including bilateral pelvic and para-aortic lymphadenectomy, were eligible. Analyzed by lymph node regions, FDG-PET had 60% sensitivity and 98% specificity. The sensitivity and specificity by individual patient were 67% and 94%, respectively. The authors conclude that FDG-PET is only moderately sensitive in predicting lymph node metastasis preoperatively in patients with endometrial cancer [10]. 6. Which patient with endometrial cancer should have a lymphadenectomy? The balance stays between the risk for node involvement and the expected benefit of the lymphadenectomy and the complications rate of the procedure. Lymphadenectomy is advised in patients with clinical suspicious lymph nodes and whenever there is a nonnegligible risk of node metastasis, i.e., in patients with high risk factors for lymph node involvement [6,7]: – – – –
Histology: grade 3 endometrioid carcinoma; clear cell carcinoma; serous papillary carcinoma. Deep (N50%) myometrial invasion. Cervical involvement. Lymph vascular space involvement (LVSI).
7. If we decide to perform a lymphadenectomy, how radical should we be? In a retrospective study by Chuang et al. 4/51 (8%) of the patients with bnegativeQ palpation (no lymph node biopsies) developed retroperitoneal recurrences, 9/173 (5%) in
M.J. Mourits, J.G. Aalders / International Congress Series 1279 (2005) 158–161
161
patients with limited node biopsies while no patients (0/38) developed a retroperitoneal recurrence after total selective pelvic and para-aortic lymphadenectomy [11]. In another retrospective study in 649 patients, surgical staging was divided into 3 groups (no node sampling, limited node sampling, multiple site (N4) node sampling). A significant survival advantage was found for patients receiving multiple-site node sampling, irrespective of low or high-risk factors and the use of adjuvant radiotherapy [12]. Because of the fact that 47–57% of the patients with positive pelvic nodes have para-aortic node metastases, and that 3–17% of the patients with negative pelvic nodes have bisolatedQ para-aortic node metastases, not only a pelvic but also a para-aortic lymphadenectomy should be performed in all patients with an indication to do a lymphadenectomy [7,13,14]. Even in patients with para-aortic lymph node metastases, survival was not different from patients with only pelvic positive nodes, suggesting that lymphadenectomy may have a therapeutic role [13]. 8. Conclusion In endometrial cancer patients, a lymphadenectomy should be performed in all patients with adverse histology (grade 3 endometrioid carcinoma; clear cell carcinoma; serous papillary carcinoma), deep myometrial invasion (N50%), and cervical involvement. A lymphadenectomy should always include a full pelvic and para-aortic lymphadenectomy by a skilled surgeon. Lymphadenectomy does not replace adjuvant radiotherapy. References [1] T. Maggino, et al., An analysis of approaches to the treatment of endometrial cancer in Western Europe : a CTF study, Eur. J. Cancer 31A (1995) 1993 – 1997. [2] T. Maggino, et al., An analysis of approaches to the management of endometrial cancer in North America: a CTF study, Gynecol. Oncol. 68 (1998) 274 – 279. [3] M. Ceccaroni, et al., Prognostic value of pelvic lymphadenectomy in surgical treatment of apparent stage I endometrial cancer, Anticancer Res. 24 (3b) (2004) 2073 – 2078. [4] E. Vizza, et al., Role of pelvic lymphadenectomy in the management of stage I endometrial cancer: our experience, Eur. J. Gynaecol. Oncol. 24 (2) (2003) 126 – 128. [5] H.M. Keys, et al., Gynecologic Oncology Group, A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study, Gynecol. Oncol. 92 (3) (2004) 744 – 751. [6] COSA-NZ-UK endometrial cancer study group, Pelvic lymphadenectomy in high risk endometrial cancer, Int. J. Gynecol. Cancer 6 (1996) 102 – 107. [7] W.T. Creasman, et al., Surgical Pathologic spread patterns of endometrial cancer. A gynecologic oncology group study, Cancer 60 (1987) 2035 – 2041. [8] K.W. Lo, et al., The value of pelvic and para-aortic lymphadenectomy in endometrial cancer to avoid unnecessary radiotherapy, Int. J. Gynecol. Cancer 13 (2003) 863 – 869. [9] G.P. Schmidt, et al., Comparison of high-resolution whole-body MRI using parallel imaging and PET-CT. First experiences with a 32-channel MRI system, Radiologe 44 (9) (2004) 889 – 898. [10] N.S. Horowitz, et al., Prospective evaluation of FDG-PET for detecting pelvic and para-aortic lymph node metastasis in uterine corpus cancer, Gynecol. Oncol. 95 (3) (2004) 546 – 551. [11] L. Chuang, et al., Staging laparotomy for endometrial carcinoma: assessment of retroperitoneal lymph nodes, Gynecol. Oncol. 58 (2) (1995) 189 – 193. [12] L.C. Killgore, et al., Adenocarcinoma of the endometrium: survival comparison of patients with and without pelvic node sampling, Gynecol. Oncol. 56 (1) (1995) 29 – 33. [13] D.S. McMeekin, et al., Nodal distribution and its significance in FIGO stage IIIc endometrial cancer, Gynecol. Oncol. 82 (2) (2001) 375 – 379. [14] A. Mariani, et al., Endometrial carcinoma: paraaortic dissemination, Gynecol. Oncol. 92 (3) (2004) 833 – 838.