Clinical Significance of Sentinel Lymph Nodes in Patients with Endometrial Cancer

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1 KSGO 2014 Clinical Significance of Sentinel Lymph Nodes in Patients with Endometrial Cancer Daisuke Aoki, M.D., Ph.D. Chairman and Professor, Department of Obstetrics and Gynecology, School of Medicine, Keio University

2 Contents 1. What is sentinel lymph node (SLN) and sentinel lymph node biopsy (SLNB)? 2. Procedures of SLN mapping for endometrial cancer 3. An on-going clinical study on SLN mapping for endometrial cancer in our Institute

3 Contents 1. What is sentinel lymph node (SLN) and sentinel lymph node biopsy (SLNB)? Para-aortic lymphadenectomy (PAN) Pelvic lymphadenectomy (PLA)

4 Lancet 2009 全生存 OS OS RFS No evidence of benefit in terms of OS or RFS for pelvic lymphadenectomy (PLA) in women with early endometrial cancer. PLA cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials

5 Lancet 2010, 375: A retrospective study comparing systematic pelvic lymphadenectomy (PLA) (n=325 patients) and combined pelvic and para-aortic lymphadenectomy (PAN) (n=346). Patients at intermediate or high risk of recurrence were offered adjuvant radiotherapy or chemotherapy. OS Low-risk Inter-mediate and high risk -PAN +PAN +PAN -PAN RFS Low-risk Intermediate and high risk +PAN -PAN +PAN +PAN

6 What is appropriate lymphadenectomy in endometrial cancer? Based on the results of these two studies, patients with endometrial cancer at low risk do not need lymphadenectomy, but those at more than intermediate risk should undergo the lymphadenectomy including paraaortic lymphadenectomy. It is not always easy to determine which the patients are classified into low or intermediate risk before operation. The sentinel lymph node concept may be applicable to determine the extent of lymphadenectomy.

7 Sentinel lymph node(sln)? Defined as the first lymph node to which cancer cells are most likely to spread from a primary tumor. Clinical significance of SLNs A negative sentinel lymph node biopsy (SLNB) result suggests that cancer has not developed the ability to spread to nearby lymph nodes (regional lymph node) or other organs. From Japan Society of Clinical Oncology regulations of lymph nodes A positive SLNB result indicates that cancer is present in the sentinel lymph node and may be present in other nearby lymph nodes and, possibly, other organs.

8 Contents 1. What is sentinel lymph node (SLN) and sentinel lymph node biopsy (SLNB)? 2. Procedures of SLN mapping for endometrial cancer 3. An on-going clinical study on SLN mapping for endometrial cancer in our Institute

9 RI Injection of 99m-Technetium ( 99m Tc)-labeled phytate

10 Combined RI and dye-guided method (intra-operative time table) 9:00 Ope started Subserosal injection of dye (ICG) Retroperitoneal incision and observation of ICG flow Detection of SLNs by macroscopic observation Marking of SLNs (green SLNs) Completed within 30 mins after injection of ICG 10:00 Detection of SLNs by gamma detection probe Marking of SLNs (hot SLNs) Sampling of green + hot SLNs Frozen sectioning + pathological diagnosis Back-up retroperitoneal lymphadenectomy

11 RI Detection of RI 1. pre-operative Lymphscintigraphy 2. Intra-operative detection by a gamma-detecting probe PAN326b1 lt PAN326b2 rt uterus Lt. ext. iliac LN Lymphoscintigraphy was performed 1hr before operation.

12 Dye Dye-guided method (subserosal injection of ICG) During operation, indocyanine green (ICG) is injected subserosally at 5 points, and sentinel green nodes are detected by macroscopic observation. After 6 miniutes, retroperitoneum is incised and retroperitoneal sentinel green nodes are detected macroscopically. Injection of green dye Para-vesical space uterus Uterus

13 Pathological examination After SLN detection by RI and dye-guided methods, 3 SLNs are applied to frozen section during operation. After operation, immunohistochemical staining using anti-cytokeratin antibody is performed to detect micrometastais and isolated tumor cells (ITCs).

14 EMB:Endometrioid adenocarcinoma Grade 3 MRI: myometrial invasion <1/2 Lymphoscintigraphy + ICG Dye Lt. Ext. iliac lymph node Total 4 hot nodes were detected. Para-aortic lymph nodes (3) Lt. Ext. iliac lymp hnode (1) Micrometastasis 1.1mm

15 EMB:Endometrioid adenocarcinoma Grade 2 MRI: myometrial invasion 1/2< Rt. ext. iliac lymph node ICG Dye only Lt. ext. iliac lymph node Three SLNs were detected. Frozen sections revealed no metastasis, however, paraffin sectons with IHC showed ITCs in 2 SLNs.

16 Contents 1. What is sentinel lymph node (SLN) and sentinel lymph node biopsy (SLNB)? 2. Procedures of SLN mapping for endometrial cancer 3. An on-going clinical study on SLN mapping for endometrial cancer in our Institute

17 Objectives of Sentinel Lymph Node Mapping for Endometrial Cancer in our Institute To investigate the following points by utilizing both radioisotope (RI) and dye-guided method in the patients who receive standard operations including systemic retroperitoneal lymphadenectomy. Detection rate of SLN Number and localization of SLNs detected Sensitivity, specificity, and negative predictive value for detecting metastasis in SLNs in frozen sections and in paraffin sections (including immunohistochemistry) Our goal is to investigate whether SLN concept would be applicable to surgery of endometrial cancer.

18 Surgical staging and pathological subtypes of 62 patients examined Surgical staging (FIGO2008) Pathological subtypes Ⅳ 0% clear 2% Ⅲ 31% EMG3 16% serous 8% EMG1 19% Ⅱ 6% Ⅰ 63% EMG2 55%

19 Detection rate and number of SLNs in 62 patients Detection rate : 100%(62/62) Number of detected SLNs: average: 5.5 ± 2.3 /patient (pelvic and para-aortic LNs: 341/ 62 patients) (detecting method) dye-guided method: 4.6±2.3 / patient RI method: 4.2±2.8 / patient (regional LNs) pelvic LN(PLN) : 3.7±1.9 /patient para-aortic LN(PAN) : 1.8±1.3 /patient

20 鼠径上 R 鼠径上 L 基靱帯 R 基靱帯 L 閉鎖 R 閉鎖 L 内腸骨 R 内腸骨 L 外腸骨 R 外腸骨 L 総腸骨 R 総腸骨 L 仙骨 PAN326b2R PAN326b2L PAN326b1R PAN326b1L Suprafemoral R Suprafemoral L parametrial R parametrial L Obturator R Obturator L Int. iliac R Int. iliac L Ext. iliac R Ext. iliac L Common Ext. iliac iliac L R Common iliac L Sacral Localization of detected SLNs 326b1 R PAN 326b1 L PAN 1.2 Per case 1 dye 色素法 RI RI 法 326b2 R PAN 326b2 L PAN From BAGGISH KARRAM Atlas of Pelvic Anatomy and Gynecologic Surgery The most frequent localization of SLNs are 326b2(rt.) region,obturator region and ext. iliac region. PAN326b1 SLNs could be detected more frequently by RI method than by dye-guided method.

21 Pathological diagnosis of SLNs and non-slns in frozen sections Paraffin with IHC frozen section pn1 pn0 total frozen positive frozen negative total detected only by IHC diameter of metastasis less than 2mm Including 4 cases having isolated tumor cells sensitivity :61.5%( 8/13) specificity :100.0%(48/48) negative predictive value :90.6%(48/53)

22 Application of SPECT in place of lymphoscintigaphy for detecting hot nodules in RI method 1 hour before operation ( 15 hrs after RI injection) Keio University Hospital SPECT: Single photon emission computed tomography

23 Near infrared camera system HyperEye Medical System (HEMS) Handy MNIRC-500

24 Summary : SLN mapping for endometrial cancer Still under investigation for endometrial cancer. Should be done as a clinical study. Combined use of RI method and dye-guided method is recommended for improving detection rate of SLNs, sensitivity and specificity for the metastasis-positive nodes. To identify SLNs in para-aortic region RI method is more advantageous than dye-guided method. Need to clarify the clinical significance of micrometastasis or ITC in SLNs. A multi-centric prospective randomized control study is needed to validate the SLN concept in patients with endometrial cancer.