PathologieStephan Dirnhofer

GIST: Pathologie

12. Treffen der GIST-Gruppe SchweizZürich, 26. April, 2015

Epidemiology

• Clinical GIST: – Incidence: 15/million – Prevalence 150/million

• (Incidental) Micro-GIST: – 2-10% of Population (500 000 in CH)– Incidentally detected– KIT/PDGFRA-mutation

Münst, 2011; Nilsson 2005; Mazzola 2008; Liang 2010

When and why clinically relevant?

GIST: role of pathology

Diagnostic

Prognostic

Predictive

Follow`up

GIST-Diagnosis

Kindblom, 2005

GIST

CD117 (Kit)

Kindblom, 2004GIST

ICC

GIST- Diagnosis

Prognostic factors

• Size

• Site

• Mitosis/50hpf

• Tumor rupture

• Mutational status

Fletcher (NCI 2002)

Risk stratification by NCI, NCCN

• about 50% locally advanced and/or metastasied

Extracellular domain

Cell membrane

Juxtamembrane domain

Tyrosine kinase domain

KIT and PDGFRA mutations in GIST

TK1 domain

TK2 domain

Kinase insert

Regulation of dimerization

Ligand-binding domain

KIT ex 9 (10%)

KIT ex11 (70%) / PDGFRA ex12 (1%)

KIT ex13 (1%) / PDGFRA ex14 (1%)

KIT ex17 (1%) / PDGFRA ex18 (6%)

80-82 % 5-8 %

Mutually exclusive

Genotype is diagnostic for GIST

Genotype is prognostic for tumor recurrence

Genotype predictive for TKI-response

Genotype identifies primary resistance (D842V)

Genotype determines dose selection

Genotype associated with TKI resistance

Genotype is cost-effective

Genotype is recommended (ESMO, NCCN, CH)

GIST- Genotyping: Why?

„wild-type“ GIST

Courtesy: Prof. E. Wardelmann, Münster

„wild-type“ GIST

AlterationHäufigkeit (in der wt-Gruppe)

Referenzen

BRAF Mutation < 7% Agaram et al. Genes Chromosomes Cancer. 2008;47(10):853-859

KRAS Mutation <1% Heinrich and Corless, unpublished

Erhöhte IGF1R Expression 50% Tarn et al. PNAS. 2008;105(24):8387-8392

SDHA, SDHB, SDHC or SDHD Keimbahnmutation*

~12%Janeway et al. PNAS. 2011;108(1):314-318Pantaleo et al. J Natl Cancer Inst. 2011;103(12):983-7

Verlust der SDHB Expression häufig Janeway et al. PNAS. 2011;108(1):314-318

NF1 Keimbahnmutation selten Andersson et al. Am J Surg Pathol. 2005; 29:1170-1176

Courtesy: Prof. E. Wardelmann, Münster

GIST-Immunophenotype

• CD117(KIT) 95 %• DOG1 90-95% (1/3 of CD117 neg cases)

• CD34 70 %• SMA 25%• S100 <10%• Desmin <5%

• Most sarcomas (and other tumors) CD117 negative!

Hornick, 2002, Dirnhofer 2006

DOG1

Gastrointestinal Stromal Tumours (GIST)

• Most common non-epithelial neoplasm of the GI-tract

• Similar male-to-female ratio

• Highest incidence in 5th to 7th decades

• Rare in children/young adults

• “Molecular” subtypes

• Tumorgenotype is diagnostic, prognostic and predicitive

• Model for targeted therapy in solid tumors

GIST: Involved Sites

Occur anywhere in GI tract/abdomen

Site Incidence

Gastric 60%–70%

Small Intestine 20%–30%

Colon <5%

Other (omentum, mesentery, oesophagus)

<5%

• 578 consecutive autopsies – 17 „Mikro-“ GIST (3%)– 11 KIT-, 1 PDGFRA-Mutation– all benign

• 69 GISTS (39 KIT-mut, 2 PDGFRA-mut, 28 wt)• BRAF and KRAS mutation

• BRAF (V600E) in 2/28 wt GIST (7%)• KRAS wt• BRAF-mut: rare alternative molecular pathway

J Clin Pathol 2009

Succinate dehydrogenase (SDH)-complex

• SDH-complex: 4 subunits (SDH-A, B, C, D)

• Kebs cycle

• Ubiquitously present in mitochondria

• Tumor suppressor function

• HIF-pathway

• Hypermethylation

• Loss of function of SDH-complex in subset of GIST

Succinate dehydrogenase (SDH)-deficient GIST

• Clinical features:

• Children & young adults

• Chronic course (metastasis after 40 yrs!)

• Low rate of mortality

• Associated with paraganglioma

• Carney-Stratakis-Syndrome (CSS): GIST, Paraganglioma

• Carney Triad (CT): GIST, Paraganglioma, Chondroma

Succinate dehydrogenase (SDH)-deficient GIST

• Pathologic features:•Subset of gastric GIST (7-8%)

•Multinodular/plexiform growth pattern

•Epitheloid cytology

•KIT & DOG1+ (CD34 +/-), SDH-negative

•KIT & PDGFRA wt

•SDH-mutations (germline and sporadic)

•Prognosis unpredictable by standard parameters

•Lymph node matastasis

Am J Surg Pathol 2011

Miettinen 2011

SDH-negative cases

SDH-positive cases

Miettinen 2011

Programm

• Introduction

• Epidemiology

• Pathology

• Genetics

• Mutational analysis

• Subtypes (BRAF, SDH)

• Summary

Summary• Clinical GIST rare, incidental GIST common

• Pathology central

• for accurate diagnosis

• for accurate risk assessment

• for accurate molecular status

• KIT & PDFRA- mutations

• first oncogenic event (“drivers“)

• prognostic for tumor recurrence

• predictive for TKI sensitivity

• causes for TKI resistance

• Molecular subtypes (BRAF, SDH)

• Molecular status before systemic therapy