ESD for EGC with undifferentiated histology Jun Haeng Lee, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Biopsy: M/D adenocarcinoma ESD: SRC >> M/D, 1.8 cm, MM, L/V (-/-)
Would you ESD? - Detected during the screening endoscopy (F/60) Forcep biopsy: Tubular adenocarcinoma, poorly differentiated
1. Location : middle third center at body and greater curvature 2. Gross type : EGC type IIc 3. Histologic type : tubular adenocarcinoma, poorly differentiated 4. Histologic type by Lauren : diffuse 5. Size : 2x1.7x0.1 cm 6. Depth of invasion : extension to mucosa (muscularis mucosa) 7. Resection margin: free from carcinoma safety margin: distal 7.2 cm, proximal 6.8 cm 8. Lymph node: metastasis to 3 out of 52 regional LNs (pn1) 9. Lymphatic invasion : not identified 10.Venous invasion : not identified 11.Perineural invasion : not identified 12. Stage by AJCC : IB (T1a, N1, MX)
Outcome of endoscopic treatment of EGC with differentiated histology 1. ITT analysis (both curative and non-curative resection cases) Comparison with surgery (propensity score matched cohort) 2. PP analysis 1) Curative-resection cases: single-arm long-term data 2) Non-curative resection cases: comparison between surgery group and observation group
ITT analysis: comparison with surgery - Propensity score matching, differentiated type EGC Differentiated type EGC (2002-2012) (n = 3595) EGC meeting indication treated with curative intent (n = 2563 ) Excluded 1) LNM on CT or EUS (n=6) 2) Previous gastric cancer (n=20) 3) Cancer of other origin (n=150) 4) Follow up < 2 years (n=856) Endoscopic resection (n = 1290) Surgery (n =1273) Propensity score matching Endoscopic resection (n = 611 ) Surgery (n = 611 ) Pyo JH. Am J Gastroenterol 2016
ITT analysis: comparison with surgery - Baseline characteristics (1) Overall Propensity score matched Variables Endoscopic resection (n=1290) Surgery (n=1273) P-value* Endoscopic resection (n=611) Surgery (n=611) P -value* Age, median (IQR), years 61 (54-68) 59 (51-65) <0.001 60 (53-67) 60 (53-67) 0.655 Sex, n(%) Male Female 1020 (79.1) 270 (20.9) 947 (74.4) 326 (25.6) 0.005 485 (79.4) 126 (20.6) 487 (79.7) 124 (20.3) 0.885 Performance (ECOG), n(%) 0 1 2 or above 1270 (98.5) 5 (0.4) 15 (1.2) 1261 (99.1) 4 (0.3) 8 (0.6) 0.339 605 (99.0) 1 (0.2) 5 (0.8) 604 (98.9) 2 (0.0) 5 (0.8) 0.847 F/U duration, median (IQR), month 44 (32-60) 58 (38-72) <0.001 46 (32-61) 58 (38-73) 0.066 Criteria of indication, n(%) Absolute criterion Expanded criterion I Expanded criterion II Expanded criterion III Beyond indication 895 (69.4) 178 (13.8) 7 (0.5) 100 (7.8) 110 (8.5) 536 (42.1) 460 (36.1) 36 (2.8) 130 (10.2) 111 (8.7) <0.001 386 (63.2) 127 (20.8) 5 (0.8) 44 (7.2) 49 (8.0) 362 (59.2) 123 (20.1) 16 (2.6) 84 (13.7) 26 (4.3) <0.001 Pyo JH. Am J Gastroenterol 2016
ITT analysis: comparison with surgery - Baseline characteristics (2) Variables Endoscopic resection (n=1290) Overall Surgery (n=1273) P-value* Propensity score matched Endoscopic resection (n=611) Surgery (n=611) P -value* Tumor size, mean (SD), cm 1.4 (0.9) 2.6 (1.7) <0.001 1.7 (1.1) 1.7 (1.1) 0.021 Morphology of tumor, n(%) Elevated Flat or depressed 770 (59.7) 520 (40.3) 192 (15.1) 1081 (84.9) <0.001 131 (21.4) 480 (78.6) 140 (22.9) 471 (77.1) 0.384 Location of tumor, n(%) Upper third Middle third Lower third Histology of tumor, n(%) Well differentiated Moderately differentiated Depth of tumor invasion, n(%) Mucosa Submucosa Lymphovascular invasion Absent Present R0 resection No Yes 78 (6.1) 357 (27.7) 855 (66.3) 511 (39.6) 779 (60.4) 1076 (83.4) 214 (16.6) 1217 (94.3) 73 (5.7) 223 (17.3) 1067 (82.7) 89 (7.0) 331 (26.0) 853 (67.0) 429 (33.7) 844 (66.3) 1054 (82.8) 219 (17.2) 1226 (96.3) 47 (3.7) 46 (3.6) 1227 (96.4) 0.450 40 (6.6) 180 (29.5) 391 (64.0) 0.002 229 (37.5) 382 (62.5) 0.678 515 (84.3) 96 (15.7) 0.018 577(94.4) 34 (5.6) <0.001 109 (17.8) 502 (82.2) 45 (7.4) 170 (27.8) 396 (64.8) 224 (36.7) 387 (63.3) 504 (82.5) 107 (17.5) 588 (96.2) 23 (3.8) 23 (3.8) 588 (96.2) 0.721 0.770 0.377 0.124 <0.001 Pyo JH. Am J Gastroenterol 2016
Overall survival Disease free survival Endoscopic resection Surgery Disease specific survival Recurrence free survival Pyo JH. Am J Gastroenterol 2016
PP analysis (1): single-arm follow-up - differentiated, curative (n=1,306) EGCs treated by ESD at Samsung Medical Center 1,838 patients with 1,889 differentiated-type EGCs November 2003 May 2011 Censoring date: May 2014 Differentiated-type EGC Well or moderately differentiated or papillary EGC According to the quantitatively predominant histologic type Differentiated-type EGC > 50% Min BH. Endoscopy 2015
PP analysis (1): single-arm follow-up - differentiated, curative (n=1,306) Median follow-up: 61 months (range 17-122) Local recurrence: 0.08% (1/1,306) Metachronous recurrence: 3.6% (47/1,306) Definition of metachronous recurrence: at least 12 months after ER Extragastric recurrence: 0.15% (2/1,306) 5-year overall survival Absolute indication: 97.3% Expanded indication: 96.4% Min BH. Endoscopy 2015
Two extragastric recurrences (0.15%) Min BH. Endoscopy 2015
Overall-survival - 1,306 curative ESDs from December 2003 to May 2011 Min BH. Endoscopy 2015
PP analysis (2): non-curative resection - comparison between surgery and observation group Noncurative resection 341 Lateral margin positive 67 (19.6%) Risk of lymph node metastasis 274 (80.4%) Surgery 194 (70.8%) Lymph node 11 (5.6%) Local residual 10 (5.2%) Observation 80 (29.2%) Patients refusal : 64 High surgical risk : 8 (severe comorbidities) Concomitant advanced cancer in other organs : 8 Kim ER. Br J Surg 2015
Predictors of LN metastasis (5.7%) Kim ER. Br J Surg 2015
Progression into advanced cancer Observation group Surgery group 5 cases (6.3%) (21 to 40 months) 1 case (0.5%) (22 months) (P = 0.013) Kim ER. Br J Surg 2015
Overall survival - Median duration of follow-up after ER: 60.5 months (6-141) Kim ER. Br J Surg 2015
Evidence supporting ESD for D-type EGC is well established ITT overall PP curative PP non-curative
What about ESD for UD-type EGC? Jun Haeng Lee, Samsung Medical Center, SKKUSOM, Seoul
Issues in ESD for UD-type EGCs Are UD-type EGCs included among the expanded indications? Important point when reading the literatures about expanded indications. Representative outcome studies Limitations in the retrospective design Back to the basic: clinical simulation
Are UD-type EGCs included among expanded indications? Depth Histology M cancer SM cancer No ulceration Ulcerated SM1 SM2 20 mm > 20 mm 30 mm > 30 mm 30 mm Any size Differentiated Undifferentiated Modified from Soetikno. J Clin Oncol 2005
UD-type EGCs in the guidelines. Small UD-type mucosal cancers are included among the expanded indications in the Korean, the Japanese, and the European guidelines. J Gastric Cancer 2015 Gastric Cancer 2011 Endoscopy 2015
Many literatures about expanded indications do not include UD-type EGCs. Goto. Endoscopy 2009
ER for UD-type EGC - Early experience at Yonsei University Kim. Gastrointest Endosc 2009
Kim JH. Surg Endosc 2014
ER for UD-type EGCs (n=125) - curative resection 64.8% (n=81), noncurative resection 35.2% (n=44) Oka. Surg Endosc 2014;28:639
ER for UD-type EGCs (n=125) - curative resection 64.8% (n=81), noncurative resection 35.2% (n=44) - follow up data analysis in 84 (67.2%) Expanded criteria 52 (61.9%) Curative resection 41 Incomplete resection 11 Beyond expanded criteria 32 (38.1%) Complete resection 18 Incomplete resection 14 Surgery required 43 Surgery done 17 (39.5%) Surgery not done 26 (60.5%) Oka. Surg Endosc 2014;28:639
ESD for UD-type EGCs at SMC - October 2002 to June 2011 ESD for undifferentiated type by ESD pathology PD: 42 SRC: 17 Gastrectomy 44 No gasterctomy 15 No LN mets No recur : 12 F/U loss : 3
Dig Dis Sci 2014:59:2536-43
In many cases with UD-type histology in the ESD specimen, the initial biopsy was differentiated-type histology. No discrepancy: only 15.3% (9/59) Dig Dis Sci 2014:59:2536-43
Indications are different from criteria Indication Pre-treatment Selection of ESD candidates Criteria Post-treatment Additional surgery after ESD
Endoscopic resection of EGCs with undifferentiated-type histology in the forceps biopsy : a clinical simulation with unselected surgical cohort Jun Haeng Lee, Dong Shin Kwak, Jae J. Kim, Kyoung-Mee Kim, Tae Sung Sohn, Sung Kim Departments of Medicine, Pathology and Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Surgery for gastric cancer in 2014 (n=1,336) ESD candidate selection by EGD and CT findings (1) Suspected M cancer (2) No ulcer (3) 2 cm or less (4) No LN in CT PD (n=104, 37.1%) in forceps biopsy UD-type histolology in forceps biopsy (n=802) Suspected as EGC in EGD (n=537) ESD candidates Beyond ESD indication (n=280, 52.1%) (n=257) SRC (n=176, 62.8%) in forceps biopsy Curative Non-curative Curative Non-curative resection resection resection resection
Rate of curative resection for expanded indications in undifferentiated type EGCs 100 80 P<0.05 60 40 42% 31% 48% 20 0 Total PD SRC
Reasons of non-curative resection
Three cases with lymph node metastasis in the curative resection group F/46 Biopsy: PD Final pathology - PD with SRCs - 1.4 cm - mucosal F/64 Biopsy: PD Final pathology - PD with SRCs - 1.1 cm - mucosal F/58 Biopsy: SRC Final pathology - PD with SRCs - 1.5 cm - mucosal
Outcomes of simulated ESD for smaller EGCs SRC-type less than 1 cm in diameter is the best candidate for ESD
Proposed indications based on pathology database of surgery patients Shim. World J Gastroenterol 2014
Be careful about undifferentiated! ITT overall Only small studies PP curative PP non-curative Evidence ESD for EGC with undifferentiated histology is NOT sufficient.
Conclusion Evidence supporting ESD for UD-type EGC is not enough. Data from surgical pathology is inconsistent. Long-term outcome data is not enough. Most importantly, selection bias makes the interpretation difficult. I propose to start with safer indications such as tumor size < 1 cm with histology of SRC to achieve better outcomes.
Thank you for your attention.