Gastrointestinal Stromal Tumor GIST: An Update

1
Gastrointestinal Stromal Tumor (GIST) An Update

• Keni Gu, MD, PhD
• October 5th, 2006

2
Outline

• Introduction/Clinical features
• Pathology features
• Molecular pathogenesis
• Mutation detection
• Therapeutic consideration

3
Introduction

• GIST as described in the early literature
  consisted of a heterogeneous group of mesenchymal
  tumors, primarily involving the wall of the
  bowel.
• The lack of objective criteria encouraged the
  inclusion of virtually any mesenchymal lesion of
  the gastrointestinal tract under the rubric of
  GIST, including desmoid fibromatosis, Schwannoma
  and leiomyosarcoma, among others. This situation
  persisted until 1998.

4
The KIT revolution

• Hirota S, Isozaki K, Moriyama Y et al.
  Gain-of-function mutations of c-kit in human GIST
• After the initial findings by Hirota and
  colleagues in
• 1998, there has been a virtual explosion of data
  regarding GIST.

5
The KIT revolution

• c-KIT (CD117), a type III receptor tyrosine
  kinase (RTK) that is involved in the development
  and maintenance of RBC, mast cells, melanocytes,
  germ cells and interstitial cells of Cajal (ICC).
• Loss of function KIT mutations result in anemia,
  loss
• of mast cells, white coat spotting due to
  failure of
• migration of dermal melanocytes, sterility due to
  a
• block in gametogenesis and gastrointestinal
  abnormalities
• due to loss of ICC.

6
GIST

• GIST, the specific KIT- or platelet-derived
  growth factor receptor-alpha (PDGFRA)-signaling
  driven mesenchymal tumor, arising from
  interstitial cells of Cajal (ICC), or stem cells.
• Clinicopathological features

7
45006000 new cases in the USA alone each
year.A wide age range, from pediatric to
elderly patients, 75 of GISTs over the age of
50.
Clinical features
8

• 5 esophagus,
• 50 stomach,
• 25 in the small bowel and 10 in the colon and
  rectum.
• A small number of GISTs in the appendix,
  gallbladder and pancreas.
• 10 outside of the tubal gut, within the
  mesentery, omentum, retroperitoneum, or pelvis
  (extra-gastrointestinal GISTs)

9
Size lt 1 cm to gt35 cm
10
Outline

• Introduction/Clinical features
• Pathology features
• Molecular pathogenesis
• Mutation detection
• Therapeutic consideration

11
Usually fleshy and solid with hemorrhage or
cystic degeneration
12
A,B Sclerosing subtype
C,D Palisading-vacuolized subtype
13
E,F Hypercellular subtype, F, mild atypia
G,H Sarcomatoid subtype
14
Epithelioid GIST
15
C-KIT
CD-34
Desmin
SMA
16
Immunohistochemical features
95 of GISTs positive for KIT (CD117), 6070
positive for CD34, 3040 for (SMA), 5 for
S100 12 positive for desmin or keratin. KIT
positivity is usually diffuse and strong, with a
cytoplasmic, membranous or paranuclear
dotlike distribution
17
The main differential diagnosis of GIST includes
- True smooth muscle tumors (leiomyomas
and leiomyosarcomas), - Schwannoma, -
Inflammatory fibroid polyp - Desmoid
fibromatosis. - Gastrointestinal autonomic nerve
tumor (GANT) C-kit melanomas, germ cell
tumors, angiosarcomas, etc.
18
Defining risk of aggressive behavior in GIST
19
Outline

• Introduction/Clinical features
• Pathology features
• Molecular pathogenesis
• Mutation detection
• Therapeutic consideration

20
Molecular pathogenesis of GIST

• KIT contains a total of 21 exons, encoding a
  145-kDa transmembrane receptor KIT.
• KIT mutations are identified in 8590 of GISTs
  regardless of size. These mutations result in
  virtually full-length KIT proteins that exhibit
  ligand-independent activation.

21
Stem cell factor (SCF)
Gain-of-function
22
(No Transcript)
23
Exons involved in KIT mutation in GIST

• exon 9 encoding the extracellular transmembrane
  domain,
• exon 11 encoding the intracellular juxtamembrane
  domain,
• exon 13 encoding the first portion of the split
  kinase domain,
• exon 17 encoding the kinase activation loop

24
Familial GIST Syndromegerm-line mutation, AD
pattern of inheritance
25
DNA sequence analyses
26
Therapeutic considerations

• The finding that most GISTs harbor activating KIT
  mutations led to the hypothesis that targeting
  KIT might be useful in treating GISTs.
• GISTs did not respond to standard chemotherapy.

27
Therapeutic considerations

• Imatinib mesylate, a small molecule inhibitor
  formerly known as STI-571 and known commercially
  as Gleevec or Glivec (Novartis) had been
  developed to inhibit Abl-kinase and treat CML.
• Imatinib is an ATP analogue that binds to the
  intracellular portion of KIT and inhibits
  signaling.

28
Clinicopathological correlates of mutation
status in GIST patients
29

• Approximately 5 of GISTs have mutations within
  PDGFRA.
• PDGFRA is a member of the same family of receptor
  tyrosine kinases as KIT, and thus is structurally
  very similar.

30
Clinicopathological correlates of mutation
status in GIST patients
31
GIST KIT immunostain mutation analyses
KIT Mut 80-85
KIT ( 95)
PDGFRA Mut 5-10
WT 10
KIT Mut 16
KIT - (5)
PDGFRA Mut 72
WT 12
32

• DNA sequence analysis of GIST is certainly very
  helpful to predict the outcomes of treatment of
  Gleevec
• Proof of concept therapeutic implications for
  KIT negative GIST

33
References

• 1. Hirota S, Isozaki K, Moriyama Y et al.
  Gain-of-function mutations of c-kit in human
  gastrointestinal stromal tumors. Science 1998
  279 577580.
• 2. Miettinen M, Sobin LH, Lasota J.
  Gastrointestinal stromal tumors of the stomach a
  clinicopathologic, immunohistochemical, and
  molecular genetic study of 1765 cases with
  long-term follow-up. Am. J. Surg. Pathol. 2005
  29 5268.
• 3. Rubin BP. Gastrointestinal stromal tumours an
  update. Histopathology. 2006 Jan48(1)83-96.
  Review.
• 4. Medeiros F, Corless CL, Duensing A, et al.
  KIT-negative gastrointestinal stromal tumors
  proof of concept and therapeutic implications. Am
  J Surg Pathol. 2004 Jul28(7)889-94.
• 5. Tarn C, Merkel E, Canutescu AA, et al
  Analysis of KIT mutations in sporadic and
  familial gastrointestinal stromal tumors
  therapeutic implications through protein
  modeling.
• Clin Cancer Res. 2005 May 1511(10)3668-77.
• 6. Tarn C, Godwin AK. Molecular research
  directions in the management of gastrointestinal
  stromal tumors. Curr Treat Options Oncol. 2005
  Nov6(6)473-86. Review.

34
Acknowledgement

• Dr. Lee