Gastrointestinal Stromal Tumor GIST M. Regli Universittsklinik fr - - PowerPoint PPT Presentation

Gastrointestinal Stromal Tumor GIST

• M. Regli

Universitätsklinik für Viszerale Medizin – Gastroenterologie

Gastrointestinal Stromal Tumor GIST 25.07.2012 2 Universitätsklinik für Viszerale Medizin – Gastroenterologie

(746 vs. 946 patients)

Gastrointestinal Stromal Tumor GIST 25.07.2012 3 Universitätsklinik für Viszerale Medizin – Gastroenterologie

GIST - Introduction

• Epidemiology: • Incidence approx. 15 / 1'000'000 /y
• Prevalence 129 / 1'000'000
• 0.1 – 3% of all GI-malignoma
• mean age 50-70y
• Localization:

[Kindblom LG et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST) – A population-based study of 600

• cases. Ann Oncol 2002;13(Suppl 5):157]

[Nilsson B et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era - a population- based study in western Sweden. Cancer 2005;103:821] [Miettinen M et al. Gastrointestinal stromal tumors - definition, clinical, histological, immunohistochemical, and molecular genetic features and differential

• diagnosis. Virchows Arch 2001;438:1]

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Etiology - Pathogenesis

• Originate from ICC (interstitial cells of Cajal)
• pluripotent mesenchymal stem cells
• smooth muscular and neuronal properties
• autonomous pacemaker of intestinal contractions

[Hirota S et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577]

• 1998 gain-of-function Mutation of c-kit described
• KIT 80-85% of GIST
• PDGFRA 5-8% of GIST

uncontrolled activation of tyrosine kinase uncontrolled growth / proliferation

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Molecular genetics – c-Kit-mutation analysis

• c-Kit-Mutation1)

1) [Heinrich MC et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342] 2) [Tarn C et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A 2008;105:8387]

• No known mutation: 'wild type' GIST, poor prognosis

IGF1R probably plays a role2)

• Exon 9: poorer response to Imatinib, poorer prognosis
• Exon 11: better response to Imatinib, better prognosis

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Clinical presentation

• No symptoms 15 – 30%
• Symptomatic GIST ~75%

[Mucciarini C et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer 2007;7:230]

• Incidental findings e.g. on endoscopy, radiology, resections for other

reasons

• GI bleeding 25 – 53% (overt bleeding 34%)
• Abdominal pain 20 – 50%
• Passage 10 – 30%: N/V, early satiety, ileus, pain
• Palpable mass 8 – 13%

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Diagnostic workup

1) [Demetri GD et al. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma V.2.2010. www.nccn.org] 2) [Demetri GD et al. NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors. J Natl Compr Canc Netw 2010;8:S-1]

• Diagnostic modalities:
• Endoscopy
• Endosonography
• Radiology (CT, PET-CT, MRI)
• Histology / immunohistochemistry
• EUS-guided biopsy / FNA (if feasible)
• In some situations biopsy may not be necessary (ie classic EUS

findings, tumor easily resectable, preoperative therapy not required)2) Is biopsy mandatory?

• Diagnostic modality of choice: 1)

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Diagnostic workup

Endoscopy

• Drawback of Endoscopy w/ biopsy (stacked / bite-on-bite):
• Risk of bleeding / tumor perforation
• Poor diagnostic yield (17-42%)

[Hunt GC et al. Yield of tissue sampling for submucosal lesions evaluated by EUS. Gastrointest Endosc 2003;57:68] [Cantor MJ et al. Yield of tissue sampling for subepithelial lesions evaluated by EUS: a comparison between forceps biopsies and endoscopic submucosal resection. Gastrointest Endosc 2006;64:29]

• Endoscopic features of GIST:

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Diagnostic workup

EUS

• Classic EUS features of GIST:
• fourth wall layer (muscularis propria)
• round to oval shape
• hypoechoic

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Diagnostic workup

EUS +/- biopsy/FNA – Advantages:

• Tissue sampling
• Helps assessing malignant potential
• Sufficient specimen for cytologic diagnosis and immunohistochemistry
• Overall tissue yield of EUS-FNA in sampling subepithelial tumors: 91.8%
• Calculated sensitivity for diagnosis of GIST: 95%

[Ando N et al. The diagnosis of Gi stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis. Gastrointest Endosc 2002;55:37]

• Diameter (ie >3-4cm)
• Echogenic foci
• Irregular borders
• Cystic spaces
• Lymph nodes

[Chak A et al. Endosonographic differentiation of benign and malignant stromal cell tumors. Gastrointest Endosc 1997;45:468]

≥ 2 criteria met: sensitivity 80-100% ≥ 1 criteria met: sensitivity 91%, specifity 88%, PPV 83%

[Palazzo L et al. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours. Gut 2000;46:88]

Most accurate and reliable method to secure a diagnosis of GIST

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Diagnostic workup

18FDG-PET

• GIST highly metabolically active
• May not detect GIST <2cm

[Kamiyama Y et al. 18F-fluorodeoxyglucose positron emission tomography: useful technique for predicting malignant potential of gastrointestinal stromal tumors. World J Surg 2005;29:1429]

• Possible correlation between 18FDG-Uptake & mitotic index
• Monitoring tumor response to therapy:

predicting tumor response on imatinib therapy

• after 1mo in 85%
• after 3mo in 100%

[Stroobants S et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 2003;39:2012] [Antoch G et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004;45:357]

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Risk stratification

Normogram by Gold et al.3)

1) [Miettinen M et al. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002;33:478] 2) [Lasota J, Miettinen M et al. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006;23:91]

‘Staging’

Risk stratification by mitotic index, size and site (‘Miettinen’)1,2)

3) [Gold JS et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009;10:1045]

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Management localized GIST

• irregular border
• Cystic spaces
• Ulceration
• echogenic foci
• heterogenity
• Treatment strategies for localized GIST?

No large, prospective studies! Optimal frequency not defined! Low compliance for follow-up!

• Resection or serial follow-up

b) „after a thorough discussion with the patient regarding the risks and benefits“ a) Possible high-risk EUS features: * ESMO/NCCN; AGA >3cm *

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Management localized GIST

Principles of surgery?

1) [DeMatteo RP et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51]

• Complete tumor removal with clear resection margins
• Avoidance of tumor rupture
• Gastric GIST: lap. wedge resection when feasible
• Routine lymphadenectomy not necessary 1)

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Imatinib

[Demetri GD et al. NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors. J Natl Compr Canc Netw 2010;8:S-1]

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Imatinib

• Settings / Indications?

1) [DeMatteo RP et al. Lancet 2009;373:1097], [Kang B et al. J Clin Oncol 2009;27(Suppl):abstract #e21515]

• Adjuvant setting: effect of imatinib?
• Neoadjuvant setting:
• prolongs relapse-free survival RFS, overall survival not affected1)

At 1y RFS 98% vs. 83%, HR 0.35; best response for GIST >10cm with HR 0.28

• dose / duration? 400mg qd at least 1y

High risk GIST: better RFS / OS with therapy 3y2)

2) [Joensuu H et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). J Clin Oncol 2011;29(Suppl): ASCO 2011, #LBA1]

• Additive setting: incomplete resection (R1/2), intraoperative tumor

perforation Primarily unresectable / marginally resectable GIST (e.g. high operative risk for tumor bleeding or perforation)

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Follow up after complete resection

• Modality?
• Frequency?

[Demetri GD et al. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma V.2.2010. www.nccn.org]

• History, physical exam
• CT scan (abdominal / pelvic)
• q3-6mo for 3-5y
• Then q1y

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Therapeutic algorithm

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Prognosis

• Localized GIST: mean survival
• Incomplete Resection or metastatic GIST: 5y-survival

mean survival

• R0-Resected GIST: 5y-survival

5y overall 50-65% <35% <1y