Dr. med. R. Frei Leitender Arzt Gastroenterologie und Hepatologie KSSG GIST-Tumore Gastroenterologische Diagnostik Dr. med. R. Frei Leitender Arzt Gastroenterologie und Hepatologie KSSG

GIST-Tumor: Gastrointestinale Stroma Tumore 1 % aller GI-Tumore Potentiell maligne Inzidenz 1.5/100‘000/Jahr 60-65 Jahre Metastasierung Peritoneal Hepatisch Keine Lymphogene Metastasierung Fletcher et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002; 33: 459 Tran et al. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1458 cases from 1992 to 2000-. Am J Gastroenterol 2005; 100: 162. Kit-Rezeptor oder PDGFRA positiv

TNM Klassifikation nicht verwendet Tumorstaging TNM Klassifikation nicht verwendet Wesentliche prognostische Faktoren nicht einbezogen 3 wesentliche prognostische Faktoren Tumorgrösse Mitoserate Lokalisation Gastrische GIST bessere Prognose

Symptome 20 % asymptomatisch Symptome: GI-Blutung 25-50% Bauchschmerzen 20-50% Passagestörung 10-30% Eisenmangelanämie 15% palpabler Tumor 8% Int J Cancer 107:2003, Ann Surg 231:2000, Ann Chie Gynaecol 1998. Muccarini et al: Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population based study. BMC cancer 2007

GIST Lokalisation Lokalisation 60% im Magen 30% Dünndarm Kolon, Rectum, Ösophagus unter 5%

Gastroenterologsicher Approach Nicht selten asymptomatisch Zufallsbefundlich Mukosa intakt SET (subepithelialer Tumor)

Diagnostischer Approach: EUS 5 Schichtung des Magen Darm Traktes 1° Mucosa 2° Musc mucosae 3° Submukosa 4° musc propria 5° Serosa

Differential-Diagnose aufgrund der Ursprungschicht Mukosal Polypen Duplication cyst GIST (ex musc mucosae) Submukosal Lipome Ektopes Pankreas Varizen GIST Muscularis propria GIST Leiomyome Extrinsische Kompression Leber Milz Pseudozysten

52 jähriger Mann, Oberbauchschmerzen Ektopes Pankreas

Mann 75 jährig, Gewichtsverlust Lipom

47jährige Frau, Refluxsymptome Duplikaturzyste

Frau 56 jährig: Sodbrennen Extrinsische Kompression

Frau A.R. 44 jährig: Schmerzen, Emesis Neuroendokriner Tumor !

Mann H.E. 79 jährig, Bauchschmerzen GIST

EUS bei 226 Gastrischen subepithelialen Tumoren EUS Sensitivität EUS Spezifität GIST 76% 85% Ektopes Pankreas 73% Lipoma 92% 97% Dig Dis. 2013 Aug 29. doi: Accuracy of a scoring system for the differential diagnosis of common gastric subepithelial tumors based on endoscopic ultrasonography

GIST Tumore: EUS-Morphologie Hypoechogen Inhomogen Teils zystisch Hyperechogene Foci Ausgehend von der M. propria Frank Gress: Endoscopic ultrasonography,

EUS Features mit Malignität assoziiert* Gösse über 4cm Irreguläre Grenzen Echogene foci über 3mm Zystische Anteile über 4mm Hohe inter-observer Variabilität * Gastrointest endoscopy 1997

Diagnostisch wie weiter Knoten über 2cm biopsieren/excidieren* Direkt Biopsieren ? Bite on bite Biopsien (Knopflochbiopsien) ? Diagnostisch ca 38% ** EUS- FNA ? Biopsien aus der Tiefe ? «De-Roofing» * ESMO Guidelines 2012 ** Ji et al: diagnostic yield using a bite on bite technique. Korean J Intern Med 2009

Herr H. E. 79 jährig, Unwohlsein: EUS-FNA Fragmente eines gastro-intestinalen Stromatumors.

Gewebe Gewinnung: EUS-FNA (22G) 141 Pat. accuracy overall: 43.3%

Eus FNA: Wertigkeit für GIST overall accuracy für GIST 85%.

EUS FNA: Wertigkeit für GIST EUS-FNA performance characteristics for diagnosing GISTs (65 Pat) sensitivity of 82% specificity of 100%, and an overall accuracy of 86%. Dig Dis Sci. 2011 Jun;56(6):1757-62. doi: 10.1007/s10620-011-1646-6. Epub 2011 Mar 1. Yield and performance characteristics of endoscopic ultrasound-guided fine needle aspiration for diagnosing upper GI tract stromal tumors.

«single incision needle knife biopsy » «De-roofing» «Un-roofing» «Mucosal incision biopsy»

SINK-Biopsy: single incision needle knife biospy diagnostic yield 92.8% De la Sera et al: GI Endoscopy 2013

Weitere Staging Untersuchungen* CT- Thoraco-Abdomino-pelvin mit KM MRI Becken Rectaler GIST PET-CT Tumorantwort auf molekulare Therapie * ESMO Guidelines 2012

Diagnose subepithelialer Läsionen THM Diagnose subepithelialer Läsionen Befunde über 2cm müssen geklärt werden 1. Abklärung: EUS 2. Histologische Klärung EUS-FNA SINK-Biopsy

Risikostratifizierung nach AFIP The high-risk category: > 5 cm >5/50 high power fields (HPFs). Non-gastric > 5cm oder >5/50 HPF are also considered high risk, 2 grosse retrospektive Studien von AFIP: alle GISTS sind potentiell maligne, Lokalisation des Tumors für prognostisch relevant. Magen 1765 Pat.: Tumormortalität 17%, low risk 2% <10 cm/< 5/50 HPF, high risk 86% > 10cm/> 5/50HPF, intermediate 11-15% - Dünndarm 906 Pat.: Tumormortalität 39%, analog Magen low risk 3%, 86% high risk, intermediate risk (<5 cm/>5/50HPF/>10cm/<5/50HPF) > 50%!!! Details: analyzed 1869 cases originally classified as smooth muscle tumors of the stomach and found that 1765 (94%) of these were GISTs. Outcome was strongly dependent on tumor size and mitotic activity:  Only 2% to 3% of tumors<10 cm and<5 mitoses/50 HPFs metastasized  86% of tumors>10 cm and>5 mitoses/50 HPFs metastasized.  However, tumors>10 cm with mitotic activity<5/50 HPFs and those<5 cm with mitoses>5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were unfavorable factors (P<0.001), whereas tumor location in antrum was favorable (P<0.001). KIT expression was detected in 91% of the cases, CD34 in 82%, smooth muscle actin in 18%, and desmin in 5%; the latter two were favorable (P<0.001). KIT exon 11 mutations were detected in 119 cases; patients with point mutations fared better than those with deletions (P<0.01). PDGFRA exon 18 mutations (total 86 cases) were common in epithelioid GISTs and most commonly represented a D842V point mutation; none of these was prognostically significant. The above results may be helpful for setting the criteria for adjuvant treatment such as Gleevec. Darm: Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only <3% of tumors <5 cm and < or = 5 mitoses/50 HPF metastasized, - whereas 86% of tumors >10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity < or = 5/50 HPF and those < or = 5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.

Biopsieren

Diagnosestellung < 2cm Raumforderung < 2 cm Ösophagus/ Magen/Duodenum häufig low risk Endosonographie jährlicher follow-up Exzision bei Grössenzunahme oder Symptomen Raumforderung < 2 cm Rektum Komplikationsrisiko aufgrund der Lokalisation höher Endosonographie und Exzision Annals of Oncology 23 (Supplement 7) 2012. Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up ESMO: European Society for Medical Oncology

Diagnosestellung > 2cm Raumforderung >2 cm alle Lokalisationen Higher risk Exzision zur Biopsieanalyse: Endoskopie/Laparoskopie/Laparotomie US/CT gesteuerte FNP bei schwieriger Lokalisation Bei Vd.a. metastasierenden Tumor  Biopsie Annals of Oncology 23 (Supplement 7) 2012. Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Prognostisches Nomogram* Recurrence free survival after complete surgical resection Jason et al: Lancet Oncology 2009

GIST Tumore: Allgemein GIST: Gastro-intestinale Stroma Tumore Spindelzellige Tumore Früher als Leiomyome, Leiomyoblastome, Leiomyosarcome, Schwannome bezeichnet Seit 1998 als eigene Tumorentität verstanden Mutation im c-KIT Proto-Oncogen Interstitial cell of cajal

GIST-Tumor: Allgemein Pädiatrische GIST * Weibliche Prädominanz Keine KIT/PDGFR Mutationen Gastrisch multizentrisch und mit lymphogener Metastasierung Syndrome mit GIST assoziiert Carney Traid Recklinghausen * Pappo: pediatric GIST. Hematol Oncol Clin North Am 2009