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

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?

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

GIST ?? GIST ??

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 Gregory A. GI Endo. 1991

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

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

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

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

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

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

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

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

Management NCCN guidelines for soft tissue sarcoma Version

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

Esophageal GIST ?

Case series and reports on esophageal GIST Case seriesCase reports Miettinen casesLee. 2002Al-Salam Blum casesErtem. 2004Markakis Peng casesGouveia. 2005Masuda Shinagare casesFeakins. 2005Milman Winant casesChang. 2005Imai Manu. 2005Ozan Padula. 2005Takeno Basoglu. 2006Yanagawa Huang.2006

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

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

Blum, Ann Thorac Surg Primary Treatment – Surgery vs Medication

No available comparative study

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

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

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

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

Thank you!

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

Gheorghe M. J Med Life. 2014

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

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

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

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

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

Considerations of Management Risk stratification Molecular genetic study Miettinen M. Arch Pathol Lab Med Gheorghe M. J Med Life 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 Lasota J, Semin Diagn Pathol Responders

Gheorghe M. J Med Life. 2014

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

Demographics % Age in years (range)Mean 60 (33-87) GenderF M Location of tumor in esophagusLower 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 patternspindle epithelioid614.6 mixed49.8 Necrosis Mitotic count (/50 HPF)Median 5 (0-79) Immunohistochemical stainingCD3439/39100 c-kit (CD117)42/ Gene mutationKIT exon 1111/11 Others9 (5 co-exist with KIT exon11)

Treatment Primary TKI711.5 Neo-adjuvant TKI4/547.4 Surgery Enucleation Esophagectomy59.3 Esophagogastrectomy Unspecified2037 Surgical approach Thoracoscopic28.7 Thoracotomy Thoraco-abdominal28.7 Trans-abdominal28.7 Adjuvant TKI10/ Follow-up time (months)Median 35 (2-202) TKI: tyrosine kinase inhibitors

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)

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) Primary TKI vs surgery0.607 TKI: tyrosine kinase inhibitors

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

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

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

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) Adjuvant TKI0.214 Thoracoscopy0.782 Enucleation0.04 TKI: tyrosine kinase inhibitors

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

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

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

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

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

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

TNM

GIST1

GIST2

GIST3

GIST4

GIST5

GIST6

GIST7

Principle of biopsy

Objectives of surgery

Resection

Follow-up