Pathology of GIST

1
Pathology of GIST

• Pancras C.W. Hogendoorn
• Department of Pathology
• Leiden University Medical Center
• The Netherlands

2
GIST

• Histopathological criteria
• Immunophenotype
• Epidemiology
• Risk assessment
• Recurrent GIST/GIST post treatment

3
Definition of GIST

• Diagnostic criteria
• Mesenchymal tumor
• Adjacent to / Vincity of the GI-tract
• Characteristic Histomorphology
• 95 Expression of the c-KIT receptor (CD-117)
  Previously often diagnosed as a type of soft
  tissue sarcoma
• -leiomyoma, leiomyosarcoma, leiomyoblastoma
• -schwannoma, dd liposarcoma, desmoid, carcinoid

4
GastroIntestinal Stromal Tumour definition

• Most frequent mesenchymal tumor of GI tract
• Equal male / female ratio
• Highest incidence 5th-7th decade
• Characteristic histomorphology

5
Where does the phenotype of GIST come from?

• Recapitulation of interstitial cells of Cajal
• Pacemaker Cells of the Gut wall
• Combines (incomplete) Myoid and Neural Phenotype

CD-117
CD-34
6
Tumor Location

• Stomach 40-50
• Small bowel 30
• Rectum/ Colon 10
• Omentum/Mesent 7
• Esophagus 1-2
• Peritoneum Rare
• Metastasis
• Liver, rarely to lymph nodes and almost never to
  the lungs

7
Symptoms at presentation

• Often asymptomatic
• Often non-specific symptoms
• At diagnosis gt 30 evident malignant due to
• Widespread intra-abdominal and liver Metastasis
• Tumor infiltration in surrounding organs

8
Macroscopy

• submucosal lesion
• normal overlying mucosa
• occasionally central ulcerwith bleeding
• biopsies often not sufficient tissue

9
Histological Spectrum of GIST

• Spindle Cell Type(70)
• Epithelioid Cell Type(20)
• Mixed Spindle and Epithelial Cell Type(10)

10
Spindle Cell GIST
11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
Epithelioid GIST
15
Immunohistochemistry

• CD117
• CD34
• SMA
• Desmine
• S-100

• gt 90
• 60 70
• 30 40
• Rare
• 5

16
Kit Staining Patterns

• Membranous, Cytoplasmic, or Dot-like
• Intensity
• Focal versus Diffuse

17
CD117
18
Antigen Retrieval and C-KIT

• With Retrieval a variety of unrelated tumors are
  getting positive without a therapeutic
  meaning(material a.o. from Eur J Cancer
  2003392006)
• Consensus No antigen retrieval!
• Kit sequence analysis useful for morphologic GIST
  which is KIT negative

19
J Clin Pathol 20015496-103
20
Pathology of GIST Differential Diagnosis

• Schwannoma - MPNST S100 , KIT-
• Smooth Muscle Tumors desmin , actin,
  KIT-
• Desmoid-type Fibromatosis actin, beta
  catenin(nuclear!) , KIT- /
  (disputed)
• Solitary Fibrous Tumor CD34, KIT- /
• (Metastatic) Melanoma S100 , KIT- / ,
  HMB45 , Melan-A
• Dedifferentiated Liposarcoma MDM2 , CDK4 ,
  KIT-
• Inflammatory Myofibroblastic Tumor actin ,
  KIT-
• Dendritic Reticulum Cell Sarcoma CD35 ,
  CD21 , KIT-
• Spindle cell carcinoma keratin, KIT-

21
EORTC Phase III GIST trial

• False positive (GIST) diagnosis in /- 6
• GIST misdiagnosed as
• melanoma, clear cell sarcoma, leiomyosarcoma,
  carcinoma, reticulum cell sarcoma, glomus tumor,
  intestinal desmoid, sarcoma nos

Lancet 20043641127J Clin Oncol 2005235795
22
Prognostication and GIST

• Correct Diagnosis
• Classic Histopathological Criteria for Assessment
  of Prognosis
• Molecular Genetics

Lancet 20043641127
23
Pathology of GIST Risk Assessment

• Any GIST is potentially malignant
• Metastatic likelyhood given by size, site, and
  mitotic activity (new risk classification
  Miettinen 2006)
• Prognosis worse in extragastric
• KIT 9 more in small bowel, PDGFRA more in stomach
  (epithelioid)

24
Pathology of GIST Prediction of Behaviour
Risk Assessment
NIH Consensus Conference
Hum Pathol 200233459Ann Oncol 200516566
25
Incidence of GIST

• Availability of immunohisto-chemistry
• Awareness of therapeutical options

• The Netherlands 12/millionPopulation based
  Study

Eur J Cancer 2005412868
26
Response to Imatinib

• Clinical response to imatinib in 80 of GIST
  patients
• Depends on exonic location of KIT mutation
• 10-20 of GIST patients are primary resistant
• Secondary resistance after 2 years (median)

27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
(No Transcript)
31
Diagnosis of GIST

• Based upon histology
• Histological spectrum
• Spectrum may change in time/during therapy
• Immuno is helpful to rule out other tumours/
  Confirm diagnosis