Abstract
OBJECTIVE To evaluate the feasibility of intra-operative detection of sentinel lymph nodes (SLN) in the patient with endometrial cancer (EC).
METHODS Thirty-one patients with Stage I and II endometrial cancer, who underwent a hysterectomy and a lymphadenectomy, were enrolled in the study. At laparotomy, methylene blue dye tracer was injected into the subserosal myometrium of corpus uteri at multiple sites, and dye uptake into the lymphatic channels was observed. The blue nodes which were identified as SLNs were traced and excised. The other nodes were then removed. All of the excised nodes were submitted for pathological hematoxylin and eosin (H&E) staining examination.
RESULTS Failure of dye uptake occurred in 4 of the 31 cases (12.9%) because of spillage, and no lymphatic coloration was observed there. Lymphatic staining was clearly observable as blue dye diffused to the lymphatic channels of the uterine surface and the infundibulopelvic ligaments in 27 (87.1%) cases. Concurrent coloration in the pelvic lymphatic vessels was also observed in 22 of the 27 patients. The SLNs were identified in 23 of the 27 (85.2%) cases with a lymphatic staining, with a total number of 90 SLNs, and a mean of 3.9 in each case (range, 1-10). Besides one SLN (1.1%) in the para-aortic area, the other 89 (98.9%) were in the nodes of the pelvis. The most dense locations of SLNs included obturator in 38 (42.2%) and interiliac in 19 (21.1%) cases. In our group, pelvic lymphadenectomy was conducted in 27 (87.1%) patients and pelvic nodal sampling in 4 (12.9%). Of the 31 cases, a concurrent abdominal para-aortic lymph node sampling was conducted in 7. A total of 926 nodes were harvested, with an average of 39.8 in each case (range, 14-55). Nodal metastases occurred in 3 patients (9.7%), 2 of them with SLN involvement and the other without SLN involvement. Adverse reactions or injury related to the study was not found.
CONCLUSION Application of methylene blue dye is feasible in an intra-operative SLN identification of endometrial cancer. The technology is convenient, safe, and worth further investigation.
keywords
Introduction
Retroperitoneal lymph node metastases are key factors in treatment and prognosis of endometrial cancer, however, the lymph node metastatic rate only reaches the 10% level in Stage I and II EC patients who account for a vast majority of the total EC patients[1] with diverse metastatic sites. A timely intra-operative discovery of a lymphatic metastasis is very important for determining the necessity of lymphadenectomy, and an introduction of the sentinel lymph node (SLN) identification technology provides a new approach in the study. In our study, the technology of methylene blue dye staining was used for a preliminary study on the SLN identification of EC.
Materials and Methods
Source of data
A total 31 EC patients who underwent surgery in our hospital, during a period from September 2004 to February 2007, were enrolled. The median age of the patients was 53 (range, 33-65). The histological types of the disease were in the following: endometrioid adenocarcinoma in 28 cases (90.3%), adenosquamous carcinoma in 2 (6.5%) and clear-cell carcinoma in 1 (3.2%). The differentiation grades included G1 in 13 cases (41.9%), G2 in 12 (38.7%), and G3 in 6 (19.4%). Preoperative segmented curettage for diagnosis and clinical staging were conducted in all patients based on the 1971 International Federation of Gynecology and Obstetrics (FIGO) standards, and the number of cases in Stage I amounted to 19 of the total cases (61.3%) and the cases in Stage II were 12 (38.7%) (Table 1). Postoperative surgical pathological staging was based on the standards of FIGO 1988, the number of cases in different stages showed in the following: 5 in Stage IA (16.1%), 8 in Stage IB (25.8%), 4 in Stage IC (12.9%), 5 in Stage IIA (16.1%), 4 in Stage IIB (12.9%), 2 in Stage IIIA (6.5%), and 3 in Stage IIIC (9.7%) (Table 2).
Preoperative Pathological Staging
Postoperative Surgical Pathological Staging
Mode of surgery
Of the 31 patients, a total hysterectomy and bilateral salpingo-oophorectomy, was performed in 7 (22.6%), subradical hysterectomy in 18 (58.1%), and radical hysterectomy in 6 (19.4%). A concurrent pelvic lymphadenectomy was performed in 27 patients (87.1%) and a pelvic node sampling in 4 (12.9%). In 7 of the 31 patients (22.6%), a para-aortic lymph node sampling was performed.
SLN identification
At the time of explorative laparotomy, the uterus was exposed and the fallopian tubes were occluded with hemoclips and 1% methylene blue dye (MB) was injected into the subserosal myometrium of corpus uteri (Fig. 1). As the 19 patients in Stage I having limited lesion confined to the uterus, the injection sites were at the most superior portion, the anterior midline and the posterior midline of the fundus. Four milliliters methylene blue dye was entirely injected into the 3 sites mentioned above. For the 12 patients in Stage II with cervical involvement, 2 ml of dye was injected into the bilateral uterus isthmus. Local compression and electronic coagulation were used to prevent dye spillage. The retroperitoneal spaces were opened right after dye injection to expose the lymph drainage region. Blue lymphatic channels were dissected to identify the dye-contained lymph nodes (SLN), these nodes were removed and sent to the pathology as individual specimens. The number and position of the SLN were recorded carefully. After this procedure, the formerly planned surgery was performed.
Methylene blue dye was subserously injected during the operation. In the figure the arrow on surface of the womb denotes the blue flash (blue stain) that emerged in the vessels around the injection site.
Pathological examination
Routine H&E staining examination for the SLN and other nodal samples was conducted separately, and the results were compared.
Results
No dye-contained lymphatics were found in the first 4 patients (12.9%) for the spillage of methylene blue. Thereafter, slow bolus injection, locally pressing and electronic coagulation were used to help preventing dye spillage. In the other 27 patients (87.1%), the blue “flash” initially occurred on the uterus surface (Fig. 1). and then the blue dye diffused to the infundibulopelvic ligaments. The lymphatic vessels in the infundibulopelvic ligaments were stained In 22 of the 27 cases mentioned above, there were blue-stained lymphatic vessels in the parametrial tissues (Fig. 2). The blue-stained vessels were also seen on the surface of the round ligament in 17 of the total patients.
After the MB injection, apparent blue-stained lymphatic vessels could be seen in the parametrial tissues beside the uterine artery, and the extending upwards along the course of the iliac blood vessels, see the arrow 1. The arrow 2 denotes the blue-stained SLN.
SLN was not found in 4 of the 27 patients with dye uptake in lymphatic vessel (14.8%), and para-aortic nodal sampling was not performed in these 4 patients. SLNs were identified in the other 23 patients (85.2%). Except for 1 patient whose SLN was located at the right inferior para-aortic area (between the inferior mesenteric artery and the aortic bifurcation), all SLNs of the other 22 patients were distributed to the pelvic cavity, and were connected with the blue-dyed lymphatics (Fig. 2). Of the 22 cases, the SLNs in 8 were from the unilateral pelvis, and 14 from bilateral pelvis. A total of 90 SLNs were obtained in our study, with an average of 3.9 per case (range, 1-10). Distribution of the SLNs was in the following, 38 in the obturator fossa (42.2%), 19 in the internal iliac area (21.1%), 18 in the external iliac area (20.0%), 12 in the common iliac area (13.3%), 2 in the deep inguinal node group (2.2%) and 1 in para-abdominal aortic area (1.1%). In the 31 cases of our group, the total number of lymph nodes dissected amounted to 926, with an average of 29.8 per case (14-55).
Pelvic lymphatic metastasis occurred in 3 patients (9.7%). Five metastatatic nodes located in the bilateral obturator and external iliac area, and 1 of 5 was SLN. Another patient was found positive nodes only in the left obturator and regarded to be SLN (Fig. 3). Two positive nodes were found in the right internal iliac area of the third patient, without SLN being found. No false negative occurred and no paraaortic lymph node metastasis was found in our group.
Metastasized cancer cell groups can be seen in the SLN
The SLNs procedures prolonged the operation time for 20 to 30 min. The urine of the patients was blue for 24 h aftersurgery. No adverse reactions were attributed to the study.
Discussion
In 1977, Canbanas et al.[2] first put forward the new concept of SLN, which defined the First Station nodes drained from the tumor site as the SLN. Therefore, the earliest tumor metastasis occurs in SLN. Before surgery, the blue dye and (or) tracer nuclide are injected around the tumor, and an identifying biopsy of the SLN is conducted by discovering a high concentration of tracer agent in SLN, thus deciding the possibility of tumor metastasis in the whole lymphatic drainage area. For those without a SLN metastasis, lymphadenectomy which can cause complications should be avoided, The SLN procedure in cervical cancer has been proven feasible[3], and researchers are encouraged to conduct trials in the surgery of EC.
There is indeterminacy in the lymphatic drainage of the corpus uteri, so it results in a lack of the regularity in lymph node metastasis of the EC. However, this provides an ideal model for the SLN procedure, enabling the SLN identification in EC with clinical significance. This kind of study is now at its primary stage, which is quite different in technique compared to several other studies[4-11]. As for choice of the tracer, the methylene blue dye was chosen as the tracer in our study, which is not only because its safety is superior to other dyes such as isosulfan blue etc.[12], but also because the result of MB is confirmative in the SLN identification of cervical cancer[3]. At the moment there is no criterion for choosing the dosage of the tracer dye. In our study, the total amount of MB was 4 ml, mainly referring to the amount in our studies on the SLN identification of cervical cancer[3]. There were miscellaneous injection methods of the tracers in previous reports. The intra-operative subserous injection was one of the most direct and convenient ways, and the course of dye drainage was in full agreement with that of the lymphatic metastasis in tumor infiltration of the deep myometrium[4,7,9,10]. In our study, this method has been utilized and improved. A dye injection in the uterine was intra-operatively conducted in 19 patients in Stage I, and for the other 12 patients in Stage II with a suspected cervical involvement, an intraoperative dye injection into the isthmic portion was added, in order to guide the cervical lymphatic drainage. There was a big difference among the results reported from several studies from overseas, and the identification rate of SLN ranged from 0 to 100% in these reports[4-11], among those the identifying rate of SLN by the dye method ranged from 0 to 92%[4,7,9,10], and that by the dye-nuclide combination method was at a range from 48% to 100%[5,6,8,11]. A final conclusion has not yet been made on whether or not the combined use of nuclide can raise the identifying rate. The dye method was used in our study. Since a dye leakage resulting in the failure of SLN identification occurred in 4 of the 31 cases in the initial stage, the researchers improved the injection method to solve this problem, indicating that a period of time was necessary to master the technique. Similar cases were also reported by other authors[11]. No dye leakage was found in the other 27 cases. However, failure of SLN identification still occurred in 4 of the 27 cases, and the rate of SLN identification achieved to 85.2%.
As for the lymphatic drainage of corpus uteri, a classical description of the process includes the following 3 routes: i) from the nodes of internal iliac area and obturator fossa to the common iliac lymph nodes; ii) from the round ligament to the inguinal lymph nodes; iii) from infundibulopelvic ligament to the paraaortic lymph nodes[1]. In our study, besides 1 SLN at paraaorta, all the other 89 were distributed in all pelvic sites, mostly including obturator and internal iliac nodes, and also including the deep inguinal nodes. These conditions were in accordance with the route i) and ii). The SLNs reported by other authors also were distributed in pelvis[4-11]. In fact, the main routes of the lymphatic metastasis of EC are the lymph nodes at obturator fossa and internal iliac area, a straight metastasis to the paraaortic nodes is rare[13,14]. In our study, one single SLN located at the paraaortic area was found in only 1 patient, without any SLN in the patient’s pelvis. In the studies of similar cases, the proportion of the paraaortic SLN accounted for 2.5%-42.2% in the involved sites[4,5,8-11], In Burke et al study, all the para-aortic SLNs were located at the superior portion of aorta between the inferior mesenteric artery and renal artery[4]. In our study, there was also a blue diffusion to the epigastria via lymphatic vessels in the infundibulopelvic ligament following the dye injection. However, since only 7 patients received the para-aortic lymph node sampling, and the range was restrained to the level of inferior mesenteric artery, it is impossible to know the condition of the para-aortic SLN of superior position. Frumovitz et al.[11] also suggested that the para-aortic SLN was covert, and identification failure was common owing to a difficulty of the intraoperative exposure.
Retroperitoneal lymph node metastasis was listed as the Stage IIIC disease in the 1988 FIGO Surgical Pathological Staging on Endometrial Cancer. As the key index for appraising the prognosis and selecting the postoperative treatment method, the lymphadenectomy has become an important part of the staging operation. However there is no the unified mode of lymphadenectomy which includes systematic excision and random sampling. The systematic lymph node excision involves an extensive scope because of a complicated mode of the lymphatic drainage in EC. The international gynecology and obstetrics group has suggested that the lymph nodes in the abdominopelvic cavity, from the renal artery on the top to the obturator foramen fossa at the bottom, should be included in the scope of excision[1]. For most of the patients without a lymphatic metastasis, to undergo such a wide-ranging lymphadenectomy is obviously unnecessary. A very high ratio of the obesity and the medicinal complication risk in the patients further decreases the surgical toleration. Employment of the lymph node random sampling may reduce the operation wound, nevertheless only 10% of metastasis nodes in EC can be palpable during the surgery, resulting in a big gap in the random sampling[1]. The management of the lymph node remains the key clinical problem. It would be undoubtedly an ideal option if an intra-operative identification of the SLN could be conducted, with a timely biopsy of the affected region. The result of our study confirmed that the intra-operative identification of SLN is feasible, and the average number of SLNs found in the identification is 3.9 per case, slightly higher than that in the same kind of other studies[4-11]. Duncan et al.[15] believed that there was a positive correlation between the number of the SLNs identified and the accuracy of the prediction. In our group, lymphatic metastasis occurred in only 3 cases, of which failure of the SLN identification occurred in 1. In the other 2 cases, SLN was found positive, which preliminarily showed that the SLN improved lymph node metastasis predictability. It is worth noting that, in similar studies, where there was a failure of the SLN identification there was an obvious lymphatic metastasis, or a false negative condition. This is most probably because obstruction of tumor emboli in the lymph vessels changed the lymphatic drainage[10]. Other authors suggested that the routine H&E staining examination might also omit some micro-metastases in the SLN, thus causing the false negative. Serial sections of the SLN combined with immunohistochemical examination can avoid occurrence of the false negative result[5]. Although there are still various problems to be further discussed. This technology is safe, worthy of further trial, and has a promising prospect of clinical application. The next step in the study is to focus on an improvement of the method, and to accumulate experience in treatment of a larger quantity of patients.
- Received November 17, 2008.
- Accepted March 14, 2009.
- Copyright © 2009 by Tianjin Medical University Cancer Institute & Hospital and Springer
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