gist for internist

GIST FOR INTERNISTSDr. Napa ParinyanitikulMedical Oncology unit Department of MedicineFaculty of MedicineKing Chulalongkorn Memorial Hospital

Introduction

Gastrointestinal-Stromal tumor (GIST) is a most common mesenchymal neoplasm of gastrointestinal organ.

Not difference in sex.

75% found in patients older than 50 years.

These tumors can arise anywhere in the GI tract.

Clinical Manifestation

GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum.

Emory et al. Am J Surg Pathol. 1999;23:82.

50%Stomach

25%Small

intestine

10%15%

Colon Other ( rectum, esophagus, mesentery, retroperitoneum)

Clinical Manifestation

Clinical feature : non-specific symptoms: asymptomatic: UGIB, abdominal mass, vague abdominal pain

and discomfort: Anemia, Anorexia, weight loss, nausea, fatigue: Acute intraperitoneal bleeding or perforation

Small, insignificant lesions may be found incidentally at endoscopy or at the time of surgery for other cancers as gastric cancer.

Clinical Manifestation

Average duration of presenting symptoms is 4-6 months.

Most GISTs arise from the bowel wall grow into the mucosa and cause ulceration or protrude towards the serosal side -> submucosal lesion

LN metastasis is rare presentation. But in advance GISTs may found lung or bone

metastasis.

EGD finding : submucosal lesion

Historical Classification as Other Soft-Tissue Sarcomas

A retrospective Swedish study determined that 72% of GI tumors now identified as GIST had been originally classified as other tumors

GIST

Leiomyoma

Leiomyosarcoma

Leiomyoblastoma

Other

Kindblom et al. Ann Oncol. 2002;13:157. Abstract 577O. Kindblom. At: www.peerviewpress.com/asco2003c.

7%

13%

18%

34%

28%

N=600

Leiomyoma Leiomyosarcoma

Low-Grade GIST High-Grade GIST

Pathology : Morphologic Similarity To Smooth Muscle Tumors

Courtesy of Dr. C. Corless.

Pathogenesis

Originally arised from interstitial cell of Cajal. (ICC)

KIT-positive fibroblast-like cells

Pacemaker cells of the gut

Intercalated between intramural neurons and smooth muscle cells

Generate electrical slow waves

Loss of ICC function has been implicated in diabetic gastroenteropathy, gastroenteric arrhythmia, and Hirschsprung’s disease

Pathogenesis

GIST and ICC may arise from a common mesenchymal stem cell associated with enteric neural plexus.

GIST shares several characteristics with ICC.

ICC hyperplasia is evidence in GI tracts of pateints with familial GIST.

Takayama et al. Arch Histol cytol 2002, 65 :1-26

Wang et al. Arch Pathol Lab Med 2000, 124:1471-1475

KIT ligand : stem cell growth factor

Heinrich et al. Hum Pathol. 2002;33:484.Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.

KIT and PDGFRA Mutations in GIST

Membrane

Cytoplasm

Exon 11 (67.5%)

Exon 9 (11%)

Exon 13 (0.9%)

Exon 17 (0.5%)

Exon 12 (0.9%)

Exon 18 (6.3%)

KIT (70-75%) PDGFRA 7%

Overall mutation frequency: 87.4%Wild type 10-15%

Exon 14 (0.3%)

GIST : Diagnosis

Depend on - Hx+PE - Radiology (CT scan , MRI whole abdomen,

PET/CT)- Pathology (FNA or Biopsy)

GIST : Staging

Evaluate symptoms or extend of mass

Detect metastasis

Assess tumor resectability

GIST : Biopsy

Preoperative biopsy in a resectable mass is commonly performed but may not be necessary and is associated with risks.

GISTs may be soft and fragile.

Biopsy may cause hemorrhage ad increase the risk of tumor dissemination.

GIST: Major Morphologic Patterns

Spindle Cell (70%) Epithelioid (9%)

Courtesy of Dr. C. Corless. Other-> mixed 21%

Immunohistochemistry

~95% of reported cases of GIST are positive for KIT (CD117)

Other markers often positive in GIST CD34

(mesenchymal/hematopoietic precursor cell marker) Positive in 60%-70%

Smooth-muscle actin Positive in 15%-60%

S-100 Positive in 10%

GIST rarely express desmin.Different KIT staining

patterns in GISTCourtesy of Dr. C. Corless.Miettinen and Lasota. Virchows Arch. 2001;438:1.

GIST : Management

Primary GIST Resectable GIST -> surgery (only curative Rx)

Locally advanced or Advanced GIST Neoadjuvant imatinib then surgery Palliative imatinib

Risk for tumor recurrence

Risk for tumor recurrence

SCIENTIFIC RATIONALE FOR IMATINIB IN THE TREATMENT OF ADVANCED GIST

Median OS of historical control 12 months

GIST : Imatinib resistance

Identify early tumor progression / late tumor progression

Increase dose imatinib 400 mg/d -> 800 mg/d Second-line treatment -> Sunitinib Many investigated drugs

The nodule within nodule

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