1. Management of Esophageal Gastrointestinal Stromal Tumor Joint Hospital Surgical Grand Round 17th Jan 2015 KC Wong

2. Management of esophageal GIST What is the radiological study of choice? Should we perform routine biopsy? Treatment: Surgery vs Medication? Surgical approach: Enucleation vs Esophagectomy?

3. 58/M Non-progressive dysphagia x 6 months Upper endoscopy 32cm from incisors What is the diagnosis?

4. GIST ?? GIST ??

5. Differential Diagnosis Gastrointestinal Stromal Tumor (GIST) (17-25%) True smooth muscle tumors – Leiomyoma (75%) – Leiomyosarcoma (rare) Nerve sheath and melanocytic tumor – GI schwannoma – Metastatic melanoma – Primary GI clear cell sarcoma Fibroblastic tumor – Desmoid – Inflammatory myofibroblastic tumor – Inflammatory fibroid polyp – Undifferentiated sarcoma Miettinen M. Am J Surg Pathol. 2000 Gregory A. GI Endo. 1991

6. What is the role of imaging in esophageal GIST? CT vs MRI vs EUS – No comparative studies AJ Winant. Gastrointestinal Imaging 2014

7. CT scan Most popular Features well described AJ Winant. Gastrointestinal Imaging 2014 Esophageal GISTs tend to be more distal, larger, heterogenous and more contrast enhancing than leiomyomas

8. Endoscopic ultrasound Tumor size Layer of involvement High risk features EUS guided biopsy Gregory A. GI Endo. 1991 NCCN guideline. 2014 Irregular border Cystic spaces Ulceration Echogenic foci Heterogeneity

9. PET CT Monitor treatment response Detect secondary treatment resistance Esophageal GISTs are more markedly FDG avid then leiomyomas Van den Abbeele. The Oncologist 2008

10. What is the role of imaging in esophageal GIST? CT and EUS provide information for risk assessment Limited role on definitive diagnosis PET-CT helpful for treatment response monitoring

11. Should we perform biopsy? NCCN guidelines for soft tissue sarcoma Version 2.2014

12. Should we perform biopsy? No! Needle tract seedling Tumor bleeding Adhesion to mucosa Yes! Definitive diagnosis Special considerations for Esophageal GIST Small proportion of submucosal tumors High risk of resection

13. Biopsy? High risk for esophageal surgery vs other parts of GI tract Not the most common ddx Need to rule out more sinister diagnosis like SCC or adenoCA Most of the case series have confirmed diagnosis with biopsy, so it is important

14. Management NCCN guidelines for soft tissue sarcoma Version 2.2014

15. Management Risk stratification – Tumor size, mitotic index NCCN guidelines for soft tissue sarcoma Version 2.2014

16. Esophageal GIST ?

17. Case series and reports on esophageal GIST Case seriesCase reports Miettinen. 200017 casesLee. 2002Al-Salam. 2006 Blum. 20074 casesErtem. 2004Markakis. 2013 Peng. 20108 casesGouveia. 2005Masuda. 2007 Shinagare. 20124 casesFeakins. 2005Milman. 2009 Winant. 20148 casesChang. 2005Imai. 2010 Manu. 2005Ozan. 2010 Padula. 2005Takeno. 2014 Basoglu. 2006Yanagawa. 2014 Huang.2006

18. TKI: tyrosine kinase inhibitors Prognostic factorsSignificance (Log-rank test) Gender0.853 Tumor location0.438 Tumor size ( 5cm)0.144 Tumor size ( 7cm)0.044 Tumor size ( 10cm)0.014 Mucosal Ulceration0.018 Histology pattern0.054 Necrosis0.004 Mitotic count0.038 Adjuvant TKI0.190 Enucleation0.056 Disease Specific Survival

19. Esophageal GIST - 0% 8.3% 40% - 20% 22.2% 88.9%

20. Blum, Ann Thorac Surg. 2007 Primary Treatment – Surgery vs Medication

21. No available comparative study

23. OT or not? Yes if possible Only management that showed long term survival benefit

24. Surgical approach- esophagectomy vs enucleation No comparative studies currently available Overall survival Enucleation Survival (months) Esophagectomy/ esophagogastrectomy Enucleation Log-rank test p= 0.04

25. What OT to do ? Both acceptable for selected patients Both have long term survival

26. Summary Both EUS and CT scan are essential in assessment of prognostic factors but not in confirmation of diagnosis Biopsy provides important information to guide management of esophageal submucosal lesions Only surgery has demonstrated long-term survival benefit Both enucleation and oesophagectomy demonstrated long-term survival

27. Thank you!

28. Why esophageal GIST? Incidence 1.5/100000/year (1-3% of all GIST, 25% of esophageal mesenchymal tumors) probably under-reported More prone to clinical symptoms More difficult to treat Management guidelines not well established Miettinen M. Eur J Cancer. 2002

29. Gheorghe M. J Med Life. 2014

31. Post-resection management <2cm EUS guided FNA Contrast CT **High risk Low risk Complete resection Contrast CT Q3-6m x 3-5yrs, then annually Endoscopic surveillance Q6-12m History +Physical examination endoscopy >2cm Localised/ potentially resectable Unresectable/ metastatic With significant morbidity Without significant morbidity Biopsy Consider PET CT imatinib Contrast CT within 3m Response/ stable disease Progressive disease If feasible High risk features: irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity

32. Gross residual disease Complete resection Post-resection Metastatic disease Intermediate/ high risk of recurrence Pre-op imatinib with response Low risk of recurrence Consider imatinib Clincial exam.+ Contrast CT Q3-6m x 3-5yrs, then annually Recurrence Imatinib Consider re-resection Clincial exam.+Contrast CT Q3-6m Progressive disease

33. Consider: Salvage surgery RFA/ embolization/ chemoembolization Palliative RT for bone metastasis Dose escalation as tolerated Change to sunitinib Reassessment CT Consider: Regorafenib Clinical trial Best supportive care Consider: Dose escalation as tolerated Change to sunitinib Favourable performance status Reassessment CT GeneralisedLimited Progressive disease

34. Considerations of Management Risk stratification- location, size, mitotic index M Fletcher. Int J Surg Pathol. 2002

36. Miettinen M. Am J Surg Pathol. 2005 Miettinen M. Am J Surg Pathol. 2006 Considerations of Management Risk stratification- location, size, mitotic index

37. Considerations of Management Risk stratification Molecular genetic study Miettinen M. Arch Pathol Lab Med. 2006 Gheorghe M. J Med Life. 2014 KIT (75-80%) PDGFRA (5-7%) Exon11 (60-70%) Exon9 (5-13%) Exon13 Exon17 2-4% Exon12 (10%) Exon18 (90%) Exon14 (rare) Wild type (10-15%) Miettinen M. Semin Diagn Pathol. 2006 Lasota J, Semin Diagn Pathol. 2006 Responders

38. Gheorghe M. J Med Life. 2014

39. Other significant pathologic findings in evaluation of malignant potential Peritoneal nodules/ invasion to peritoneal fat Attachment or involvement or surrounding organs Mucosal invasion/ ulceation Tumor rupture/ positive resection margin Tumor necrosis Proliferation markers (Ki-67 analogs) : not been proven superior to mitotic counting. 92,93 Loss of p16 cell cycle regulator 94

40. Demographics % Age in years (range)Mean 60 (33-87) GenderF2439.3 M3760.7 Location of tumor in esophagusLower4187.2 Tumor size (cm; greatest dimention)Median 7.85 (2.3-25) Presenting symptomsany 73.7 Dysphagia 49.1 GIB 8.8 Mucosal ulceration1144 Distant metastasis at diagnosis46.6 Histological patternspindle3175.6 epithelioid614.6 mixed49.8 Necrosis2749.1 Mitotic count (/50 HPF)Median 5 (0-79) Immunohistochemical stainingCD3439/39100 c-kit (CD117)42/4397.7 Gene mutationKIT exon 1111/11 Others9 (5 co-exist with KIT exon11)

41. Treatment Primary TKI711.5 Neo-adjuvant TKI4/547.4 Surgery 5488.5 Enucleation1425.9 Esophagectomy59.3 Esophagogastrectomy1527.8 Unspecified2037 Surgical approach Thoracoscopic28.7 Thoracotomy1773.9 Thoraco-abdominal28.7 Trans-abdominal28.7 Adjuvant TKI10/5418.5 Follow-up time (months)Median 35 (2-202) TKI: tyrosine kinase inhibitors

42. Overall SurvivalMedian 63 months 3-month98% 6-month98% 12-month98% 2-year87.2% 3-year77.1% 5-year46.2% 10-year10.5% Recurrence 12 (26.7%) Time to recurrence (months) Median 33 (3-108)

43. Prognostic factors on survival Prognostic factors Significance (Log-rank test) Gender0.772 Tumor size ( 5cm)0.342 Location of tumor0.353 Mucosal ulceration0.070 Metastasis at diagnosis0.102 Histology pattern0.018 Necrosis0.010 Mitostic count ( 10/50 HPF) 0.034 Primary TKI vs surgery0.607 TKI: tyrosine kinase inhibitors

44. Overall survival Histological pattern Survival (months) Spindle Epithelioid Log-rank test p= 0.018

45. Overall survival Necrosis Survival (months) Absent Present Log-rank test p= 0.01

46. Overall survival Mitotic Count (/50 HPF) Survival (months) <10 >/=10 Log-rank test p= 0.034

47. Prognostic factors on survival Surgically treated cases Prognostic factors Significance (Log-rank test) Tumor size ( 10cm)0.211 Location of tumor0.363 Histology pattern0.019 Necrosis0.012 Mitotic count ( 10/50 HPF) 0.041 Adjuvant TKI0.214 Thoracoscopy0.782 Enucleation0.04 TKI: tyrosine kinase inhibitors

48. Disease specific survival Prognostic factorsSignificance (Log-rank test) Gender0.989 Tumor location0.592 Tumor size ( 5cm)0.269 Tumor size ( 7cm)0.043 Tumor size ( 10cm)0.012 Mucosal Ulceration0.116 Metastasis at diagnosis0.157 Histology pattern0.087 Necrosis0.011 Mitotic count0.013 Primary TKI0.666 TKI: tyrosine kinase inhibitors

49. Surgically treated cases TKI: tyrosine kinase inhibitors Prognostic factorsSignificance (Log-rank test) Gender0.853 Tumor location0.438 Tumor size ( 5cm)0.144 Tumor size ( 7cm)0.044 Tumor size ( 10cm)0.014 Mucosal Ulceration0.018 Histology pattern0.054 Necrosis0.004 Mitotic count0.038 Adjuvant TKI0.190 Enucleation0.056 Disease specific survival

50. Disease progression Time to event (months) </=10 >10 Log-rank test p= 0.014 Tumor size

51. Absent Present Log-rank test p= 0.018 Mucosal ulceration Disease progression Time to event (months)

52. EUS guided FNA Contrast CT *High risk features: Size>2cm, ulceration, necrosis Low risk Complete resection- consider enucleation if negative margin can be achieved Contrast CT Q3-6m x 3-5yrs, then annually Endoscopic+CT surveillance Q6-12m History +Physical examination endoscopy Localised/ potentially resectable Unresectable/ metastatic With significant morbidity Without significant morbidity Biopsy Consider PET CT imatinib Contrast CT within 3m Response/ stable disease Progressive disease If feasible High risk* Other mesenchymal tumors: treat accordingly

53. Stromal tumors arising in the GI tract- regarded as smooth-muscle neoplasms (“leiomyoma,” “leiomyosarcoma,” “leiomyoblastoma” ) 1940s Introduction of immunohistochemistry: many of these lesions lacked the immunophenotypic features of smooth- muscle differentiation 1980s Mazur and Clark introduced the more generic designation “stromal tumor” Histological origin of interstitial cells of Cajal- GI pacemaker cells CD34 immunopositivity up to 60-70% KIT immunoreactivity 90% TK receptor genes mutations 1983

54. TNM

55. GIST1

56. GIST2

57. GIST3

58. GIST4

59. GIST5

60. GIST6

61. GIST7

62. Principle of biopsy

63. Objectives of surgery

64. Resection

65. Follow-up