Clinical Significance of Lymph Node Sampling in Endometrial Carcinoma

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1 Chinese Journal of Clinical Oncology [SpringerLink] DOI /s Jun. 2007, Vol. 4, No. 3 P 179~184 Ping Bai et al. 179 Clinical Significance of Lymph Node Sampling in Endometrial Carcinoma Ping Bai Min Cheng Shumin Li Wenhua Zhang Ying Ma Department of Gynecological Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing , China Correspondence to: Ping Bai baiping2627@.sina.com Received April 2, 2007; accepted April 12, OBJECTIVE To study the clinical significance of pelvic and para-aortic lymph node sampling in endometrial carcinoma. METHODS Data were analyzed from 311 patients who received surgical treatment in our hospital during the period from January 1995 to December Among the patients, 197 underwent lymph node sampling or lymphadenectomy. The patients were divided into 2 groups based on the nature of their lymph node dissection, i.e. a) The sampling group included 114 patients with an extrafascial hysterectomy or modified radical hysterectomy plus pelvic or paraaortic lymph node sampling of the abdominal aorta; b) The dissection group, included 83 patients with a radical or modified radical hysterectomy plus systemic pelvic lymph node clearance or paraaortic lymph node dissection of the abdominal aorta. RESULTS The median of the sampling sites for lymph node removal was 5 in the sampling group, and the median of the lymph nodes removed was 15 per case. Lymph node metastasis was found in 8 cases. In the dissection group, the median of the cases for lymph node removal was 8, and the median of the lymph nodes removed was 27 per case. Lymph node metastasis was found in 6 cases. The 5-year survival rates were 90.2% and 90.9% in the 2 groups, respectively. CONCLUSION Lymph node sampling of endometrial cancer is a good way of precisely finding lymphatic metastases, and is suitable for surgical staging without causing immoderate surgical treatment and without affecting the survival rate. KEYWORDS: endometrial carcinoma, lymph node sampling, lymphadenectomy. In 1988, surgical pathologic staging of endometrial carcinoma, based on the lymphatic metastasis status, was advocated by the International Federation of Gynecology and Obstetrics (FIGO) [1]. However in endometrial cancer there is the characteristic of a multidirectional lymphatic drainage, and an overall understanding of the lymph nodes inevitably leads to an extension of the operative scope. Moreover, in endometrial cancers, there are few lymph node metastasis. Problems such as extent of surgical intervention exist during surgery, and enlargement of the surgical scope fails to improve the survival rate [2]. Therefore, there is no agreement at present on how to deal with the lymph nodes at surgery for endometrial cancer, and lymph node sampling has replaced systemic lymph node dissection. Many surgeons have adopted lymph node sampling as a substitute for lymph node dissection [3-5], but no reports of cases have been published in China. In this study, our experience of lymph node sampling was summed up and analyzed. CJCO cocr@eyou.com Tel(Fax):

2 180 Chinese Journal of Clinical Oncology Jun. 2007, Vol. 4, No. 3 P 179~184 Ping Bai et al. MATERIALS AND METHODS Clinical data There were 311 patients with endometrial cancer who received surgical intervention in our hospital, during the period from January 1995 to December Lymph node sampling or lymph node dissection was performed on 197 of the patients. The patients ranged from 30 to 73 years of age. They were divided into 2 groups based on the condition of lymph node excisions. a) 114 cases in the sampling group: radical hysterectomy /modified radical hysterectomy plus pelvic/ paraaortic lymph node sampling of the abdominal aorta; b) 83 cases in the dissection group: radical or modified radical hysterectomy plus pelvic lymph node dissection / paraaortic lymph node dissection of abdominal aorta (Table 1). The median age of patients in the sampling group was 56 years and in the dissection group 51. For the surgical pathological conditions, see Table2. Postoperative adjuvant radiotherapy A postoperative pelvic or abdominal paraaortal irradiation was performed on 72 patients with high-risk factors, with a midplanar dose of 40 to 50 Gy. The factors included the following: the cell differentiation of grade-2 or 3 with an invasion of one half of the myometrium, vascular tumor embolus, lymph node metastasis, with an invasion of the parametrium or adnexa etc. Postoperative adjuvant radiotherapy was conducted for 42 patients (37.2%) of the sampling group and for 34 patients (41.0 %) of the dissection group. Statistical methods SPSS10.0 and the chi-square tests were used for analyzing the data. The life table method and log-rank test were employed for calculating the survival rate. The value of p <0.05 was regarded as a significant difference. Table 1. Surgical pathological staging of the 197 cases with endometrial cancer. Surgical pathological taging Sampling group (114 Cases) Dissection group (83 Cases) χ 2 P Ia Ib Ic IIa IIb IIIa IIIb IIIc IV Table 2. Pathological conditions of the 197 cases with endometrial cancer (%). Pathological condition Number of specimens Number of cases receiving dissection χ 2 P Pathological types Endomembraniform adenocarcinoma 95(83.3) 65(78.3) Adenosquamous carcinoma 13(11.4) 15(18.1) - - Serous mammilloid carcinoma 3(2.6) 1(1.2) - Clear-cell carcinoma 3(2.6) 2(2.4) - Histological classification G1 46(40.4) 30(36.2) G2 47(41.2) 31(37.3) - - G3 21(18.4) 22(26.5) - - Myometrial infiltration No 15(13.2) 14(16.9) <1/2 67(58.8) 48(57.8) - - 1/2 32(28.0) 21(25.3) - - Lymph node metastasis No 106(93.0) 77(92.8) Yes 8(7.0) 6(7.2) - -

3 Chinese Journal of Clinical Oncology Jun. 2007, Vol. 4, No. 3 P 179~184 Ping Bai et al. 181 RESULTS Lymph node resection and the metastatic rate In 114 cases of the sampling group, the median sampling sites of the subgroups was 5. The total number of dissected lymph nodes was 1,631, with a median of 15 per case. Lymph node metastasis occurred in 8 cases (7.0%). Among the 114 cases, abdominal paraaortal lymph node sampling was conducted in 11 cases, with a dissection of 45 lymph nodes. Lymph node metastasis was found in 1 case. In 83 cases of the dissection group, lymph node dissection reached to 2,272, with a median of 27 per case. Lymph node metastasis occurred in 6 cases (7.2%). Among the 83 cases, abdominal paraaortal lymph node dissection was conducted in 12, without lymph node metastasis. Pathologic grading and lymph node metastasis Our study showed that no lymphatic metastases were found in cases with well-differentiated endometrioid adenocarcinoma and adenosquamous carcinoma. Lymph node metastasis of moderately-differentiated endometrioid adenocarcinoma and adenosquamous carcinoma amounted to 2.6%, while that of the poorly-differentiated reached 11.9% (Table 4). Pathological types and lymph node metastasis The lymph-node metastasis rate of endometrioid adenocarcinoma was 3.8% and that of the adenosquamous carcinoma, clear-cell carcinoma and serous papilary adenocarcinoma was 10.7%, 40% and 75%, respectively. Sites of lymph node metastasis Among the 8 cases with lymph node metastasis of the sampling group, pelvic lymph node metastasis occurred in 7, including 6 in the external iliac zone (6/7), 4 in the obturator foramen (4/7), 2 in the common iliac zone (2/7) and 1 in the external iliac zone (1/7). Some patients even suffered several metastases. A single abdominal paraaortal lymph node metastasis occurred in 1 case. There were 6 cases with lymph node metastasis in the dissection group, including 3 in the external iliac zone (3/6), 3 in the obturator zone (3/6), 2 in the common iliac zone (2/6), and 1 in the internal iliac zone (1/6). Factors relating to lymph node metastasis Concerning uterine muscular invasion and lymph node metastasis, the rate of lymph node metastasis significantly increased in the deep muscular invasion of the uterus(table 3). Invasion of the cer vix and lymph node metastasis In the 197 cases, endometrial or mesenchymal invasion of the cervical canals occurred in 61, lymph node metastasis in 10, with a metastatic rate of 16.4%. The tumorous invasion of the cervical canals was absent in 135 cases, while lymphatic metastasis was seen in 4, accounting for 3.0%. Follow-up Loss of visits occurred in 13 of the 197 patients. A 2 to 90-month follow-up was conducted in 184 patients (93.4%), with a deadline of March Eleven patients died in the sampling group, with a 5-year survival rate of 90.2%, and in the dissection group the 5-year survival rate was 90.9% (life table method). Table 3. Uterine muscular invasion and lymphatic metastasis of 188 cases with endometrioid adenocarcinoma and adenosquamous carcinoma. Depth of infiltration myometrial Cases Pelvic lymph node metastasis % Myometrial infiltration = Myometrial infiltration <1/ Myometrial infiltration 1/ Table 4. Pathologic grading and lymph node metastasis of endometrioid adenocarcinoma and adenosquamous carcinoma. Depth of myometrial infiltration Case Well- differentiated Moderately- differentiated Poorly- differentiated Myometrial infiltration = Myometrial infiltration <1/ Myometrial infiltration 1/

4 182 Chinese Journal of Clinical Oncology Jun. 2007, Vol. 4, No. 3 P 179~184 Ping Bai et al. DISCUSSION Concept Three methods of lymph node treatment have been suggested [6], among which lymph node biopsy can be used for extirpation of the visible or palpable tumescent lymph nodes. However this method has limitations in it that fails to reflect the whole condition of the retroperitoneal lymph nodes, especially of the non-tumescent lymph nodes resulting in missed diagnosis or a missed microscopic micrometastasis. It was reported that only 30% of the metastasized lymph nodes could be detected by palpation. The examination failed to determine if there was a lymph node metastasis, since 50% of the positive lymph nodes were less than 1 cm [3,7]. So lymph node palpation is an inadequate method for surgical pathological staging. A second method, lymph node sampling, involves a vascular-orientated dissection of the lymph node chains with potential metastasis of the endometrial cancer involving the fatty tissue around the lymph nodes, such as the tissue of the external and common iliac zone, and the abdominal paraaortal lymph node zone, etc. In general, at least 4 subgroups are needed for sampling. However, the number of sampling sites are less compared to systemic lymphatic dissection, and the length and integrity of the sampling lymph node chain are usually less than that of the systemic dissection [8]. The third method, lymph node dissection, involves pelvic and abdominal paraaortal lymph node dissection. Pelvic lymphadenectomy means a systemic removal of the lymph nodes in the bilateral common iliac zone, external and internal iliac zone, and the groin involving to the obturator foramen. The lymph nodes in the group of presacral tissue sometimes are included in the excision. Clearance of the abdominal paraaortal lymph nodes includes the bilateral abdominal aortal lymphatic fatty tissue, with its upper edge to the level of the renal vein or inferior mesenteric artery and the lower margin to the vascular crotch of the left and right common iliac zone. Advantage of lymph node sampling The results of lymph node sampling can indicate the state of lymph node metastasis. The lymph node metastatic rate of the endometrial cancers ranged from 3.9% to 18.2% [9,10]. In our study, lymph node sampling was adopted in 114 cases, and lymph node dissection was employed in 83. Comparison of the two operative techniques showed that the median of the lymph nodes dissected in each case in the sampling group was 15, while the median in the lymphadenectomy subgroups was 5. In the dissection group, the median of the dissected lymph nodes in each case was 27, and the median of the subgroups ranged from 8 to 11 (including the subgroup of the bilateral common, external and internal iliac zone, the obturator foramen and groin, and of the abdominal paraaortal lymph node, etc.). Lymph node metastasis was found in 8 cases of the sampling group (7.0%) and 6 of the dissection group (7.2%). It follows that though the lymph node sampling may be imperfect, it can correctly determine the state of lymph node metastasis. As far as the surgical pathological staging is concerned, sampling can be used in place of lymph node dissection. Moreover, the procedure of lymph node sampling has a narrower scope compared to dissection, and complications during the operation or the adjuvant radiotherapy after operation can be minimized. It is worth noting that dissection of only several nodes may result in a missed diagnosis [11,12]. Lymph node sampling is suitable for surgical pathological staging Based on the regularity of lymph node metastasis, an implementation of multi-regional lymph node sampling may reveal the lymph node state better, thus providing a correct pathological staging. Based on reports from the literature, [13-15] the lymph node group of the external iliac zone was the site most commonly involved, accounting for 61 to 78%. In our study, invasion of the external iliac zone was found in 9 of the 14 cases with lymph node metastasis (64.3%). And the invasion was also seen in the lymph nodes of the external and common iliac zone and obturator foramen. It was shown that the rate of abdominal paraaortal lymph node metastasis in these endometrial cancers was 1.8~14%, [16-18] and a straight metastasis might occur there without passing through the pelvic lymph nodes. A total of 607 cases with endometrial cancer have been reported by McMeckin et al. [12] among which 47 were in Stage-IIIc. Pelvic lymph node metastasis occurred in 20 of the 47 cases (43%), pelvic plus abdominal paraaortal lymph node metastasis in 19 (40%), and a simple abdominal paraaortal lymph node metastasis, without pelvic lymph node metastasis, in 8 (17%) [11]. The metastatic rate was higher than that reported by the No. 33 document of the gynecologic oncology group (GOG). This finding is because, based on the GOG document, endometrial serous papillary carcinoma and clear-cell carcinoma were ruled out, and usually lymph node metastasis in these patients was very high. Moreover, simple dissection of the right abdominal paraaortal lymph nodes was conducted based on GOG regulations. However, a bilateral exci-

5 Chinese Journal of Clinical Oncology Jun. 2007, Vol. 4, No. 3 P 179~184 Ping Bai et al. 183 sion was performed by McMeckin et al. [12] and they thought that the lymph node metastases were commonly seen. Therefore they suggested that a bilateral abdominal paraaortal lymph node sampling could enhance the positive detection rate. In our study, abdominal paraaortal lymph node metastasis was found in 1 case, without complicating the pelvic lymph node metastasis. According to suggestions from the GOG, the information considered should be within the scope of abdominal paraaortal lymph nodes sampling, including the positive pelvic lymph node and metastasis of the annex, as well as the depth of the myometrial infiltration of over than 1/3. Lymph node sampling as the important basis for selecting the methods of postoperative treatment Lymph node metastasis is an important prognostic factor. It was found in this study that the invasive depth of the myometrium was less than 1/3 in Stage-G2 cancer cases, with lymph node metastasis of 2.6%. A postoperative adjuvant treatment of the patients was reasonable. It was noted that lymph node metastasis might also occur in Stage-G1 cases. Ben- Shachar et al. [9] reported that surgical pathological staging was conducted in 181 patients with Stage-G1 endometrial cancer, finding a lymphatic metastasis rate of 3.9%. Incorrect postoperative treatment might result if these patients failed to receive lymph node dissection. It also has been reported that the lymph node sampling had some merits, e.g., it could reduce the complications such as vascular and ureteral injury, etc., and it might minimize a pelvic relapse, etc. [3] Correlation factor of lymph node metastasis Based on analysis of our data, the rate of lymph node metastasis was very high when the cancer was poolydifferentiated and there was deep invasion of the myometrium and of the cervical canals. The lymph node metastasis rate was higher in cancers of various pathological types, such as clear-cell carcinoma, serous papilary adenocarcinoma and adenosquamous carcinoma, compared to endometrioid adenocarcinoma. These findings suggest that these patients should undergo either lymph node dissection, or lymph node sampling. Postoperative irradiation can be performed if there are lymph node metastases. Effect of lymph node dissection on survival The 197 cases with endometrial cancer were followed-up for 2 to 90 months, with a follow-up rate of 93.4%. Seven patients died in the sampling group, and 2 survived with a cancerous recurrence. The overall 5-year survival rate was 90.2%, reaching a satisfactory therapeutic effect. Four patients died in the dissection group and the 5-year survival rate was 90.9%. With regard to the effect of lymph node sampling on the survival rate, Chuang et al. [3] suggested that lymph node sampling could improve the survival rate. Gao et al. [2] reported that Stage-I endometrial cancers related neither to the survivals and the mode of surgical operation, nor to the clearance of lymph nodes. It was reported by Trimble et al. [19] that in 10,066 cases of Stage-I and II endometrial cancer, lymph node sampling increased the survival rate of the patients with stage-i G3. However, it failed to enhance the survival rate of the patients in Stage-I G1 and G2, which might have a low correlation with the number of lymph node specimens (with a median of 7 samples). Based on some reports of successful simple surgical treatment, the number of the dissected lymph nodes would at least amount to 20 [20, 21]. In summary, whether or not the lymph node sampling can replace lymph node dissection during a surgical operation for endometrial cancer, still depends on prospective observation of a large number of cases. REFERENCES 1 FIGO. Stages-1988 revision. Gynecol Oncol. 1989, 35: Gao JS, Shen J, Lang JH, et al. Effect of various modes of operation on survival and recurrence of the stage-i endometrial cancer. Chin J Obst Gyn. 2002; 37: Chuang L, Burke TW, Tornos C, et al. Staging laparotomy for endometrial carcinoma: assessment of retroperitoneal lymph nodes. Gynecol Oncol. 1995; 58: Sun JH. Questions on concept change and clinial treatment of endometrial cancer. Prog Obst Gyn. 2001; 13: Zhou CX, Sun JH. Clinical significance of abdominopelvic lymph node dissection on early endometrial cancer. Chin J Obst Gyn. 1998; 33: Chin Med Asso. Endometrial Cancer. 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