Sentinel Lymph Node in Endometrial Cancer. Reem Abdallah, MD American University of Beirut Medical Center

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1 Sentinel Lymph Node in Endometrial Cancer Reem Abdallah, MD American University of Beirut Medical Center

2 No disclosures

3 Percent of Cases by Stage 8% 4% 21% 67% Localized (confined to primary site) Regional (spread to regional LN) Distant (metastatic) year Relative Survival 95,3 68,2 48,5 16,9 (Accessed on January 31, 2016).

4 LN status: Prognostic value, guide adjuvant trt Role of Lymphadenectomy controversial Systematic LND not widely adopted around 30% Selective, systematic, none.

5 No LND 65% Low-risk Pelvic LN mets 9% ASTEC trial, Panici et al: no therapeutic benefit Morbidity of comprehensive LND

6 Selective Risk of nodal mets size, DOI, grade, LVSI As low as 2% in low risk and Up to 35% in high-risk

7 Comprehensive FS variable accuracy 25% with preop grade 1 will be upgraded on final path Avoid unnecessary adj trt Therapeutic value? SEPAL study, Chan 2006 SEER

8 Risk of nodal mets size, DOI, grade, LVSI As low as 2% in low risk and Up to 35% in high-risk FS variable accuracy 25% with preop grade 1 will be upgraded on final path Understaging vs overtrt

9 Understaging vs overtrt SLN mid option Node most likely to harbor mets SLN endometrial ca first introduced by Burke,1996 Advantages: avoid unecessary extensive LND of neg LN, associated morbidity, guide the need of adjuvant trt, detecting micromets, ultrastaging prognostic significance? No RCT re role of SLNB, no long-term survival data

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11 Common Lymphatic Drainage 3% 36% 8% 30% 23%

12 Classical mapping

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15 Techniques Radioactive tracer +/- Green or blue dye Sites of injection: Cervical (combined superficial (submucosal, 1 3 mm) and deep (stroma, 1 2cm)) Fundal subserosal Peritumoral hysteroscopic Courtesy of Abu-Rustum NR, Levine DA, Barakat RR, eds. Atlas of Procedures in Gynecologic Oncology, 3rd ed. London: Informa Healthcare; c2013, Memorial Sloan-Kettering Cancer Center.

16 Cervical Subserosal fundal Peritumoral Pros 1. Main lymphatic drainage: parametria 2. Easy, accessible 3. Rarely distorted 1. Better reflection of PA drainage (Detection of PASLN: 39% But Isolated PALN mets in literature <5%) Cons Detection Rates 1. Low PA detection (Superficial injection: DR 2%, Deep: DR 17%) 1. Not reflective of main lymphatic drainage 2. Rarely infiltrating fundal serosa % 45-75% One study 92%: 8 sites 1. More complicated 2. Disseminating malignant cells through tubes? % Studies including >100 cases had detection rate >80%

17 Pros 1. Main lymphatic drainage: parametria 2. Easy, accessible 3. Rarely distorted Cervical Subserosal fundal Peritumoral 1. Better reflection of PA drainage (Detection of PASLN: 39%) Cons 1. Low PA detection (Superficial injection: DR 2%, Deep: DR 17%) 1. Not reflective of main lymphatic drainage 2. Rarely infiltrating fundal serosa 1. More complicated 2. Disseminating malignant cells through tubes? Detection Rates % 45-75% One study 92%: 8 sites % Isolated PALN mets in literature <5% Studies including >100 cases had detection rate >80% Most recent studies, DR >92%

18 Metaanalysis (26 studies, 1101 SLN procedures) Mean SLN detected 2.6 (1-4.7) Bilaterality of SLN 61% (20%-81%) Detection Rate 78% (95% CI=73%--84%) Sensitivity 93% (95% CI=85% 100%) False Negative Rate 7% (0-14%) Pericervical injection Increase in detection rate (p 0.031) Hysteroscopic only injection Decrease in detection rate (p 0.045) Subserosal only injection Decrease in sensitivity (p 0.049) Kang S, Yoo HJ, Hwang JH, et al. Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies. Gynecol Oncol 2011;123:

19 Metaanalysis Studies>30pts SLN procedures 1572 Bilaterality of SLN (Range) 52% (19%-100%) Detection Rate (Range) 83% (62%-100%) Sensitivity (Range) 81% (43%-100%) Algorithm Sensitivity 95% (83%-100%) Pericervical injection DR 62%-100% Corporeal injection DR 73%-95% DR in studies >100 pts >80% Cormier et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015 Aug;138(2):

20 Algorithm Peritoneal and serosal evaluation and washings Retroperitoneal evaluation Excision of all mapped SLNs with ultrastaging Any suspicious nodes must be removed regardless of mapping If no mapping on a hemi-pelvis, side-specific LND Para-aortic LND at the physician s discretion Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125:533

21 SLN alone Algorithm Sensitivity 85.1% 98.1% Negative Predictive Value 98.1% 99.8% False Negative Rate 14.9% 1.9% Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125:533

22 Algorithm Overall false false negative rate negative rate Overall Algorithm Author N (%) (%) sensitivity (%) sensitivity (%) Barlin (7/54) 2 (1/54) Ballester (3/20) 5 (1/20) How (3/11) 9 (1/11) Niikura (3/18) 6 (1/18) Torné 74 8 (1/13) 8 (1/13) Sawicki (1/2) 0 (0/2) Vidal (4/7) 14 (1/7) Delaloye (1/9) 0 (0/9) Solima (1/10) 0 (0/10) Lopez-de la 50 0 (0/3) 0 (0/3) Manzanara Bats (2/10) 0 (0/10) Lopes (6/11) 9 (1/11) Holloway (1/10) 10 (1/10) Mais (3/6) 17 (1/6) Mucke (1/6) 0 (0/6) Total (37/190) 5 (9/190) Cormier et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015 Aug;138(2):

23 Dual Labelling Standard has been: Isotope+Blue Dye Detection rates: % Bilateral detection: 40-80% Combination was not shown to be significantly higher in metaanalysis

24 Radiolabeled Colloid-Tc99 Short Protocol: mci, 2-4 hrs preop Long Protocol: 2-4 mci, hrs preop Maximum accumulation in SLN: 1.5hrs Lymphoscintigram (2 hrs after injection, then every 30 min to detect SLN) Gamma probes

25 LSG- Long vs Short Protocol Whole (N=118) Short (N=44) Long (n=66) P Detection Rate 88 (74.6%) 30 (68.2%) 53 (80.3%) 0.22 Bilateral detection 44 (37.3%) 12 (27.3%) 29 (43.9%) 0.29 Preop LSG Paraaortic SLN Common iliac SLN Median number of SLN detected per patient Number of SLN detected 0 10 (22.7%) 8 (12.1%) 23 (34.8%) Detection Rate 102 (86.4%) 36 (81.8%) 59 (89.4%) 0.62 Bilateral detection 62 (52.5%) 21 (47.4%) 36 (54.5%) 0.89 Intraop Paraaortic SLN Common iliac SLN 1 (2.3%) 12 (27.3%) 2 (3%) 16 (24.2%) Number of SLN detected Frati et al. Contribution of Lymphoscintigraphy for Sentinel Lymph Node Biopsy in Women with Early Stage Endometrial Cancer: Results of the SENTI-ENDO Study. Ann Surg Oncol (2015) 22:

26 LSG Short (N=44) Long (n=66) P Paraaortic SLN Common iliac SLN 0 10 (22.7%) 8 (12.1%) 23 (34.8%) % Number of SLN detected Preop LSG Number of PA SLN detected Number of common SLN iliac detected Paraaortic SLN Common iliac SLN 0 14 (9.5%) (27%) 34 (23%) (2.3%) 12 (27.3%) 2 (3%) 16 (24.2%) % 31% 3% Number of SLN detected Intraop Number of PA SLN detected 3 (3.3%) 4 (2.2%) % Number of common SLN iliac detected 13 (14.1%) 23 (12.5%) % Frati et al. Contribution of Lymphoscintigraphy for Sentinel Lymph Node Biopsy in Women with Early Stage Endometrial Cancer: Results of the SENTI-ENDO Study. Ann Surg Oncol (2015) 22:

27 Colored Dye Isosulfan blue 1% (Lymphazurin), Methylene blue 1%, Patent blue 2.5% Under anesthesia in the OR 2-4 ml Slowly, 5-10 sec/quadrant Time to reach LN: 5 min Median stain time in the SLN: 21 min Allergic reactions < 5%

28 Indocyanine Green (ICG) Near-infrared fluorescence imaging 2-4 ml Main contraindication: iodine allergy DR in literature: % Bilateral mapping: 65-85% vs Blue dye: Higher overall detection rate (87% vs 71%; p = 0.005) Higher bilateral detection (65% vs 43%; p = 0.002) In particular, obese vs Tc99: Similar overall (87% vs 88%, p = 0.83) and bilateral (65% vs 71%,p = 0.36) detection

29 Combination ICG+Tc99 probably yields the best results

30 Pathology H&E If neg, Ultrastaging: Two 5 μm sections, at each of two levels 50 μm apart from each paraffin block H&E and IHC 4 slides/block +3-7% micromets Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrialcancer staging. Int J Gynecol Cancer 2013;23:968;

31 Terminology Definition Significance Macromets tumor clusters >2 mm Positive Micromets tumor clusters mm Positive Isolated tumor cells single tumor cells or clusters 0.2 mm Positive value and trt still controversial Isolated cytokeratinpositive cells only Rare isolated cytokeratin-positive cells not identified on corresponding H&Estained sections or do not demonstrate morphologic features of invasive ca Negative

32 DMI Grade 1 Grade 2 Grade 3 Total No Invasion < 50% invasion 50% invasion Total MM 1 ITC 1 n = 165 MM 2 ITC 4 n = 80 MM 0 ITC 2 n = 16 10/261= 3.8% MM 0 ITC 0 n = 39 MM 0 ITC 4 n = 62 MM 0 ITC 0 n = 15 4/116= 3.4% MM 0 ITC 0 n = 38 MM 0 ITC 6 n = 56 MM 1 ITC 2 n = 37 9/131 = 6.9% 2/242 = 0.8% 16/198 = 8.0% 5/68 = 7.4% 23/508 = 4.5% Maybe omit ultrastaging if no myometrial invasion Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrialcancer staging. Int J Gynecol Cancer 2013;23:968;

33 No MI DMI<50% Preop grade 1 H&E 0 MMs 1 ITCs 1 N=193 H&E 8 MMs 2 ITCs 7 N=130 Preop grade 2 H&E 1 MMs 0 ITCs 0 N=48 H&E 4 MMs 0 ITCs 1 N=56 Total 19/323 (5.9%) 6/104 (6.9%) Total 3/241 (1.2%) 22/184 (12.0%) 25/425 (5.9%) Low volume mets detected by ultrastaging: 10/184 (5.4%) Final grade 1 Final grade 2 Final grade 3 Total No MI DMI<50% Total H&E 0 MMs 1 ITCs 1 N=194 H&E 8 MMs 2 ITCs 4 N=108 16/302 (5.3%) 21/174 (12.0%) H&E 1 MMs 0 ITCs 0 N=42 H&E 4 MMs 0 ITCs 3 N=66 8/108 (7.4%) H&E 0 MMs 0 ITCs 0 N=5 H&E 0 MMs 0 ITCs 1 N=10 1/15 (6.7%) 3/241 (1.2%) 22/184 (12.0%) 25/425 (5.9%) Low volume mets detected by ultrastaging: 9/174 (5.2%) Kim et al.sentinel Lymph Node Mapping with Pathologic Ultrastaging: A Valuable Tool for Assessing Nodal Metastasis in Low-Grade Endometrial Cancer with Superficial Myoinvasion. Gynecol Oncol December ; 131(3)

34 Author N Proportion of metastatic patients detected only by ultrastaging (%) Micrometastases Isolated tumor cells Kim (23/64) 4 19 Ballester (9/20) 7 1 Desai (5/10) 5 Niikura (8/18) 5 3 Solima (6/10) 3 3 Bats (1/10) 1 Holloway (4/10) 2 2 Total (56/142) Cormier et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015 Aug;138(2):

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36 Are these low-volume mets true mets? Frimer et al. Micrometastasis of endometrial cancer to sentinel lymph nodes: Is it an artifact of uterine manipulation? Gynecologic Oncology 119 (2010)

37 MM/ITC (n=19) (%) No MM/ITC (n=145) (%) P value LVSI <0.001 Present 12 (63.2%) 22 (15.2) Absent 7 (36.8) 123 (84.8) Depth of myometrial invasion 0.01 None 4 (21) 83 (57.2) <50% 12 (63.2) 47 (32.4) 79% 50% 3 (15.8) 15 (10.3) Low-volume SLN mets (N=23) Routine H&E SLN mets (N=35) Routine H&E non-sln mets (N=35) LVSI + LVSI - 20 (87%) 3 (13%) 31 (89%) 4 (11%) 5 (83%) 1 (17%) Negative SLN (N=444) 76 (17%) 368 (83%) Frimer et al. Micrometastasis of endometrial cancer to sentinel lymph nodes: Is it an artifact of uterine manipulation? Gynecologic Oncology 119 (2010) Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrialcancer staging. Int J Gynecol Cancer 2013;23:968;

38 25 pts with SLN+

39 High Risk Pts Retrospective multicenter French study: L/IR (N=141, 78%) HR (N=39, 22%) p Detection Rate 88% 88% NS Bilaterality 64% 60% NS False Negative Rate, Overall 2.3% 20% % excluding unilateral detection Senti-Endo: False Negative Rate, Overall L/IR (N=90) HR (N=16) 0% 18% All were type II Naoura I et al. Relevance of sentinel lymph node procedure for patients with high-risk endometrial cancer. Gynecol Oncol Jan;136(1):60-4. Ballester, M. et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). Lancet Oncol. mai 2011; 12:

40 Prospective, MD Anderson, early results Soliman SGO 2015: 60 patients, high risk Detection rate: 92.3% Bilaterality: 60.7% False Negative Rate: 0%

41 Algorithm Peritoneal and serosal evaluation and washings Retroperitoneal evaluation Excision of all mapped SLNs with ultrastaging Any suspicious nodes must be removed regardless of mapping If no mapping on a hemi-pelvis, side-specific LND Para-aortic LND at the physician s discretion Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125:533

42 SLN alone Algorithm Sensitivity 85.1% 98.1% Negative Predictive Value 98.1% 99.8% False Negative Rate 14.9% 1.9% Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 2012;125:533

43 Algorithm Overall false false negative rate negative rate Overall Algorithm Author N (%) (%) sensitivity (%) sensitivity (%) Barlin (7/54) 2 (1/54) Ballester (3/20) 5 (1/20) How (3/11) 9 (1/11) Niikura (3/18) 6 (1/18) Torné 74 8 (1/13) 8 (1/13) Sawicki (1/2) 0 (0/2) Vidal (4/7) 14 (1/7) Delaloye (1/9) 0 (0/9) Solima (1/10) 0 (0/10) Lopez-de la 50 0 (0/3) 0 (0/3) Manzanara Bats (2/10) 0 (0/10) Lopes (6/11) 9 (1/11) Holloway (1/10) 10 (1/10) Mais (3/6) 17 (1/6) Mucke (1/6) 0 (0/6) Total (37/190) 5 (9/190) Cormier et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015 Aug;138(2):

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46 Non-SLN if SLN positive? Positive non-sln, n (%) Negative non-sln, n (%) Total, n (%) SLN negative 0.6% All SLN mets 15 (34.8%) 28 (65.2%) 43 SLN metastasis >2 mm SLN metastasis 2 mm 14 (60.8%) 9 (39.2%) 23 (100%) 1 (5%) 19 (95%) 20 (100%) P < Touhami et al. Predictors of non-sentinel lymph node (non-sln) metastasis in patients with sentinel lymph node (SLN) metastasis in endometrial cancer. Gynecologic Oncology 138 (2015) 41 45

47 Frozen Section on SLN? 87/111 (78.5%) pts had intraop eval of SLN Intraop exam Technique used for intraop exam Frozen section (37) Final histology Positive Negative Positive 9 0 Negative 7 71 Final histology Positive Positive 6 0 Negative 1 30 Negative Sensitivity: 56.3 % (95 % CI, %) NPV: 91 % (95 % CI, %) Accuracy: 92 % (95 % CI, %) Sensitivity Macromets: 100% Sensitivity Micro/ITC:12.5% (7 FN/8) Sensitivity: 85.7 % (95 % CI, ), NPV:96.8 % (95 % CI: ) Accuracy:97.3 % (95 % CI: ) Imprint cytolog y Positive 3 0 Negative 6 41 Sensitivity: 33.3 % (95 % CI, ) NPV: 87.2 % (95 % CI, ) Accuracy: 88 % (95 % CI, %) Ballester M et al. Comparison of diagnostic accuracy of frozen section with imprint cytology for intraoperative examination of sentinel lymph node in early-stage endometrial cancer: results of Senti-Endo study. Ann Surg Oncol Oct;19(11):

48 46/268 (18.2%) pts had SLN sent for frozen Final histology of SLN (ultra-staging) Positive Negative Frozen section of SLN Positive 12 0 Negative 2 (1 macromet, 1 ITC) 35 Sensitivity: 85.7% (95% CI: 57.16%-97.80%) FNR: 14.3% Sensitivity for detecting macromets: 92.3% (95% CI: 63.90%-98.72%) Touhami et al. Predictors of non-sentinel lymph node (non-sln) metastasis in patients with sentinel lymph node (SLN) metastasis in endometrial cancer. Gynecologic Oncology 138 (2015) 41 45

49 Touhami et al. Predictors of non-sentinel lymph node (non-sln) metastasis in patients with sentinel lymph node (SLN) metastasis in endometrial cancer. Gynecologic Oncology 138 (2015) 41 45

50 Long-term outcomes , 507 MIS EC cases P<0.001 P<0.001 P 1.0 Leitao et al. Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer. Gynecol Oncol Apr;129(1):38-41.

51 Prior to SLN Since SLN Rate of Full Lymphadenectomy 65% 23% Median Operative Time 1 hr 40 min Median Lymph nodes removed 20 7

52 SLN algorithm vs comprehensive LND Intermediate Risk: Endometrioid MI>50% High-Risk; Clear cell, Serous Intermediate-risk High-risk Pelvic LN removed, median PALN removed, median LND (N=107) SLN (N=82) p LND (N=103) SLN (N=120) 35 (27-45) 10 (4-14) < (26-41) 11 (5-16) < (12-23) 5 (2-9) < (11-23) 4 (3-8) <0.001 p Stage IIIC 28% 35.4% % 22.5% 0.57 Ducie SGO 2015

53 SLN Algorithm vs Selective LND (1135 low risk cases E<50%MI): SLN (N=642) LND (N=493) p Pelvic Nodes removed 93% 58% <0.001 Pelvic Nodes + 5.1% 2.6% of the 31 SLN+ were ITC PALN + 0.8% 1% 0.75 Significance? Same Survival but more trt? Stage IIIC 5.6% 2.8% 0.02 Adjuvant EBRT and/or Chemo +/- Brachy 8.2% 4.6% < y PFS 94.9% 96.8% y Nodal-Free Recurrence 99.6% 99.6% y DSS 100% 98.8% 0.03 Erikkson SGO 2015 Comparison of a sentinel lymph node and a selective lymphadenectomy algorithm in patients with endometrioid endometrial carcinoma and limited myometrial invasion Article in press. Online dec 2015 gynecol oncol

54 Senti-Endo SLN - SLN+ P value EBRT 30% 78.5% Chemotherapy 12.5% 50% /16 SLN+ detected by ultrastaging 50- mo RFS 84.7% % adj trt 36% adj trt Daraï E, Dubernard G, Bats AS, Heitz D, Mathevet P, Marret H, Querleu D, Golfier F, Leblanc E, Rouzier R, Ballester M. Sentinel node biopsy for the management of early stage endometrial cancer: long-term results of thesenti-endo study. Gynecol Oncol Jan;136(1):54-9

55 Proficiency Preferred detection rate >80-90% Acceptable FNR <5% ~30 cases/surgeon Detection rate increased from 77% to 94% (p 0.033) Khoury-Collado F, Glaser GE, Zivanovic O, et al. Improvingsentinel lymph node detection rates in endometrial cancer: how many cases are needed? Gynecol Oncol 2009;115:

56 SGO statement November 2015 SLN mapping with adherence to a surgical algorithm and pathologic ultrastaging is a reasonable staging strategy that provides information on nodal metastasis and potentially reduces morbidity in patients with apparent uterine confined endometrial cancer gynecologic oncologists should consider continuing to perform full lymphadenectomy while their individual experience with SLN mapping is accrued (at least cases), and possibly until their detection rate for metastasis can be documented within the suggested breast SLN guidelines

57 insufficient data to suggest that the upper aortic lymph nodes (above the inferior mesenteric artery) can be reliably mapped using current cervical injection techniques. Decisions regarding the performance of paraaortic lymphadenectomy should continue to be determined by the tumor histology, intraoperative analysis of the primary tumor, and status of pelvic lymph nodes at surgery

58 NCCN SLN staging can be considered for the surgical staging of apparent uterine-confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extrauterine disease by exploration

59 What to do with a SLN+ Frozen on SLN? Missing micromets and ITC Complete LND? Or just Adjuvant trt? What to do with Micromets and ITCs? PALND? All high risk or only pelvic SLN+

60 Thank you