GASTROINTESTINAL STROMAL TUMOR

(CLINICAL DIAGNOSIS)
PROF. IGN. RIWANTO SP.B.KBD

Seminar GIST, Semarang 14 September 2013

KASUS
Biarawati 54 tahun, 4 bulan yang lalu operasi pseudokista pankreas yang sangat besar (lihat CT Scan) dilakukan gastro -sistostomi dan biopsi dinding kista Dalam perawatan tumor mengecil. Saat ini datang dengan tumor membesar lagi.

CT-SCAN ABDOMEN BULAN PEBRUARI 2004

ABDOMEN & PA
Bekas insisi median atas
Abdomen bagian atas cembung, teraba masa tumor sebesar kepala, agak fixed bergerak sedikit pada pernafasan. PA : leiomyoma yang bisa berasal dari lambung

CT-SCAN BULAN JUNI

LAPARATOMI
Tumor capsulated mudah dibebaskan dari pankreas, lien dinding belakang abdomen tetapi melekat dengan dinding belakang korpus lambung sekitar 7 cm. Diputuskan dilakukan eksisi sekitar 2 cm dari batas perlekatan tumor.

PA : Gambaran spindel cell, curiga Leiomyosarcoma lambung

IHS: CD 117+ GIST

DEFINITION
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, resulting from activating mutations in one of the receptor protein tyrosine kinases, KIT (CD117) or platelet-derived growth factor receptor alpha (PDGFRA). KIT-positive : 80% , Mutations in the PDGFRA gene 5% to 10% no detectable KIT or PDGFRA mutations (wild-type GIST).: 10-15%

Soft Tissue Sarcoma, Version 2. 2012 Featured Updates to the NCCN Guidelines J Natl Compr Canc Netw . 2012;10:951-960

GIST ? MALIGNANT SCHWANOMA? LEIOMYOSARCOMA?

GIST : FROM ICC (Interstitial Cells of Cajal)

LEIOMYOSARCOMA From smooth muscle

KIT AND PDGFRA MUTATIONS: OVERALL MUTATION FREQUENCY 86%

KIT (~70%) PDGFRA (~6.5% total) (~30% of KIT-WT)

Exon 9 (9%) Exon 11 (67%) Exon 13 (1%) Exon 17 (1%)

Abbreviation: PDGFRA, platelet-derived growth factor receptor . Corless Cl, et al. Annu Rev Pathol. 2008;3:557-586.

Exon 12 (2%)

Exon 14 (rare)
Exon 18 (5.5%)

1 0

HISTOLOGIC FEATURES OF GISTS

spindle cell pattern : 60 70%, epithelioid cytology : 20 - 30% pleomorphic pattern : <5%

MICROSCOPIC APPEARANCE OF GASTRIC GIST

MICROSCOPIC APPEARANCE OF INTESTINAL GIST

IMMUNOHISTOC HEMICAL STAINING KIT POSITIF

HISTORY OF GIST
Early years- smooth muscle tumor (leiomyoma, leiomyosarcoma) 1970-1980s (electron microscope & immunohistochemistry): -Partial smooth muscle differentiation, neural, mixed or null phenotypes -GANT (gastrointestinal associated neural tumor) 1980s- term GIST widespread used
Hornick JL: Mesenchymal tumor of the GI tract: an update, 2011

HISTORY OF GIST
1998 : KIT activating mutations 1998: KIT immunoreactivity 2002: Imatinib mesylate (gleevec) RCT 2003: PDGFRA activating mutation 2006: sunitinib malate (sutent) RCT 2009: adjuvant imatinib after resection of

localized GIST RCT

2011: genotyping to guide TKI therapy

Hornick JL: Mesenchymal tumor of the GI tract: an update, 2011

EPIDEMIOLOGY OF GIST
United States: about 5000 new cases annually, providing 1520 cases per million per year, and the black race is a risk factor Data obtained from 14 different countries from all over the world participating in the EORTC study the incidence rate was calculated as approximately 45 cases per million per year Similar in men and women

The mean age at the diagnosis is 5563 years , rare before 40 and very rare in children
Metastatic disease is more common in younger patients
POLSKIE ARCHIWUM MEDYCYNY WEWNTRZNEJ 2008; 118 (4)

* EGIST: Extra Gastro Intestinal Stromal Tumor

FREQUENCY OF GIST
Less 1% of Gastrointestinal tumor
LOCATION STOMACH SMALL INTESTINE DUODENUM COLORECTAL ESOPHAGUS & APPENDIX PERCENTAGE 60% 30% 5% < 5% <1%

OUT SIDE OF GI TRACT

RARE

Behazin. Gastrointestinal Stromal Tumor. Medscape 2013

MUTATION SUBTYPES ACCORDING TO THE PRIMARY LOCATION

Stomach (n = 738)
65.2% 1.8% 61.4% 1.2% 0.8% 22.9% 3.1% 0.5% 19.3% 11.9% 79.7% 23% 54% 2.3% 0.4% 1.2% 0% 0.4% 0.8% 19.1%

Genotype
KIT mutation Exon 9 Exon 11 Exon 13 Exon 17 PDGFRA mutation Exon 12 Exon 14 Exon 18 Wild type

Small Bowel (n = 261)

Abbreviation: PDGFRA, platelet-derived growth factor receptor . Data from Wardelmann E, et al. Pathologe. 2010;31(3):195-198.

2 0

STAGING OF GIST

AMERICAN JOINT COMMITTEE ON CANCER (AJCC) T: The size of the primary tumor, and whether it has spread to nearby organ N: The extent of which the cancer has spread to nearby lymph nodes M: Whether the cancer has spread, or metastasized, to distant parts of the body Mitotic rate: The measure of how fast the cancer cells are growing and dividing

CLASSIFICATION OF GIST
In the SSGXVIII/AIO trial, risk stratification was based on:tumor size, site, mitotic count, and rupture; patients with high-risk of recurrence: - mitotic count > 5 mitoses/50 HPF; - size > 5 cm; - nongastric location; and - tumour rupture
Joensuu H, JAMA 2012;307:1265-7

POLSKIE ARCHIWUM MEDYCYNY WEWNTRZNEJ 2008; 118 (4) HUMAN PATHOLOGY Volume33, No. 5 (May 2002)

NIH CLASSIFICATION FOR RISK OF RECURRENCE

Very Low Risk
NIH consensus criteria1 Tumor size < 2 cm Mitotic index < 5

Low Risk
Tumor size 2-5 cm Mitotic index < 5

Intermediate Risk
Tumor size 5-10 cm Mitotic index < 5 OR Tumor size < 5 cm Mitotic index 6-10

High Risk
Tumor size > 5 cm Mitotic index > 5 OR Tumor size > 10 cm Mitotic index, any OR Tumor size, any Mitotic index > 10

Modified NIH consensus classification2

Any location: Tumor size < 2 cm Mitotic index 5

Any location: Tumor size 2.1-5 cm Mitotic index 5

Any location: Tumor size < 5 cm Mitotic index 6-10

Gastric: Tumor size 2.1-5 cm Mitotic index > 5 OR Tumor size 5.1-10 cm Mitotic index 5

Any location: Tumor rupture OR Tumor size > 10 cm OR Mitotic index > 10 OR Tumor size > 5 cm Mitotic index > 5
Nongastric: Tumor size 2.1-5 cm Mitotic index > 5 OR Tumor size 5.1-10 cm Mitotic index 5

Abbreviations: Mitotic index, number of mitoses per 50 high-power fields; NIH, National Institutes of health. 1. Fletcher CD, et al. Hum Pathol. 2002;33(5):459-465; 2. Joensuu H. Hum Pathol. 2008;39(10):1411-1419.

2 4

SPECIFIC KIT MUTATIONS HAVE PROGNOSTIC IMPORTANCE

RFS in 127 pts with completely resected localized GIST based on mutation type
1.0 Proportion Recurrence-Free

0.8
0.6 0.4 0.2 0.0 0 1 2

KIT exon 11 PM/INS (n = 32)

No mutation (n = 29)

KIT exon 9 mutation (n = 4)

P < .001
3 4 5 6 7 Time After Resection, y 8 9 10

Abbreviation: RFS, recurrence-free survival. Adapted from DeMatteo RP, et al. Cancer. 2008;112(3):608-615.

2 5

SYMPTOMS OF GIST
GIST is often asymptomatic until it reaches a certain location, grows to a certain size or bleeds. Not infrequently, GIST is discovered incidentally during radiologic imaging for an unrelated condition or as a secondary finding in a surgical resection, which is the removal of all or part of an organ.

At diagnosis, approximately half of malignant GIST are metastatic.

SYMPTOMS OF GIST (conts)

Smaller GISTs, may have no symptoms or vague, nonspecific abdominal pain or discomfort. Large, aggressive GISTs may cause some of the following symptoms: Pain or discomfort in the abdomen, the area of the body

that contains the stomach, intestines, and other organs

Nausea and vomiting Blood in the stool or vomiting blood Fatigue due to low red blood cell counts (anemia) Diarrhea Intestinal obstruction Weight loss Abdominal mass

RELATIONSHIP BETWEEN TUMOR SIZE AND TIME OF DETECTION

TIME OF TUMOR DETECTION

MEAN DIAMETER (CM)

Based on symptom Incidental finding During autopsy

8.9 2,7 3.4

Behazin. Gastrointestinal Stromal Tumor. Medscape 2013

SYMPTOMS OF ESOPHAGEAL GIST

Small GIST no symptom found incidentally

Moderate size GIST: dysphagia Large GIST: obstruction

SYMPTOMS OF GASTRIC GIST

Upper GI Bleeding (due to ulcer forming) :40-65% Epigastric pain Anorexia Nausea Vomiting Weight loss Epigastric fullness Early satiety

Epigastric mass

SYMPTOMS OF DUODENAL GIST

Symptom as in gastric GIST may present
Obstructive jaundice

SYMPTOMS OF SMALL BOWEL GIST

Diarrhea Bleeding Intestinal obstruction Abdominal mass

Some find during emergency surgery for perforated viscus

SYMPTOM COLORECTAL GIST

Hematoscezia
Diarrhea Constipation Intestinal obstruction Some find during emergency surgery for perforated viscus

DIAGNOSTIC MODALITY
Contras gastrointestinal imaging
Endoscopy & biopsy Imaging (CT with iv contras) Endoscopic ultrasonography

SPACE OCCUPAYING LESSION

SMOOTH ROUND NODULE WITH NICE

SMOOTH ROUND NODULE WITH NICHE

IMMUNOHITOCHEMISTRY STAINING cKIT (+)

ENDOSCOPIC ULTRASONOGRAPHY
Useful diagnostic method in the identification of malignant tumors Features associated with malignant GIST are independently: - size more than 40 mm, - an irregular outer margin, - the presence of cysts and - non-homogenous echo pattern
POLSKIE ARCHIWUM MEDYCYNY WEWNTRZNEJ 2008; 118 (4)

CONCLUSION
GIST IS ICC MALIGNANCY AND DIFFER FROM LYOMYOSARCOMA MUTATION OF KIT (70%) OR PDGFRA (20%) NO SYMPTOM IN SMALL GIST OR JUST VAGUE ABDOMINAL PAIN AND FOUND INCIDENTALLY DURING GASTROINTESTINAL SERIES OR ENDOSCOPY LARGE GIST GIVE SYMPTOM ACCORDING TO LOCATION: BLEEDING OR OBSTRUCTION OR JUST MASS INCREASE AWARRNESS FOR SUBMUCOSAL INTESTINAL TUMOR IHC FOR KIT