Definition & Terminology

GI tract associated stromal (mesenchymal) neoplasm

with activating mutations in c-KIT (CD117) or
PDGFR A, whose line of differentiation recapitulates
the interstitial cells of cajal and has broad spectrum of
biological behaviour.
Stromal/mesenchymal tumors of GIT can be divided in
to:

• Those identical to tumors arising from soft tissue in rest

of the body :
- Leiomyosarcoma
-Neural tumors
-Hemangiomas
-Fibromas
-Myofibroblastic tumors.

• Stromal tumors : GIST

 Cell of origin
GIST, the specific KIT- or platelet-derived growth factor
receptor-alpha (PDGFRA)-signal driven mesenchymal
tumor, arises from interstitial cells of cajal (ICC).

• ICC are KIT + fibroblast like cells located around the

myenteric plexus and in the muscularis propria throughout
the GI tract.

• ICC arise from precursor mesenchymal cells that ultra-

structural and immunophenotypic features of both
neuronal and smooth muscle differentiation
 Epidemiology &Incidence
Age : 60-80 yrs / familial (<30yrs)

 Gender: M=F.

Most common locations –

– Stomach (60%)
– Jejunum & ileum (30%)
– Duodenum (5%)
– Colorectum (< 5%)
• Rare cases have been reported in
• – oesophagus
• – appendix
• – gall bladder Extraintestinal GISTs
• – mesentery
• – omentum
• – retroperitoneum
 PATHOPHYSIOLOGY
 C-kit, PDGFRA Mutations
-C4q11-21,
-Type III tyrosine kinase protein receptor

 Dysfunction of SDH complex

 Mutation in NF1 (neurofibromin), BRAF, HRAS,

NRAS orPIK3CA
 MOLECULAR BIOLOGY

C-KIT: (85-95%)

Exon 11 (mutations / In-frame

deletions): most common type
70%.
•have better prognosis.
Exon 9 : 2nd most common
associated with small bowel
with aggressive clinical
behaviour.
Exon 13: involve missense
mutations and associated with
more malignant potential.
 PDGFR A:

• Close homologues to KIT. PDGFRA mutations seen

in 5-7% cases.

• Most PDGFRA mutant GIST are located in stomach

with aggressive behaviour.

• Epithelioid morphology with weak / negative

staining for CD117.

• These tumors are usually resistant to imatinib

treatment.
KIT and PDGFRA are receptor tyrosine kinases (RTKs)

Gain-of-function mutation of the KIT or PDGFRA

Gene plays a central role in the pathogenesis of GIST

Activation of KIT downstream signals

RAS-RAF, MAPK and PI3K-AKT-mTOR pathways

Dysfunction of SDH complex is another possible
pathogenetic mechanism of wild-type’ GISTs.

Gene mutation in a member of the SDH complex cause

destabilization of the SDH complex

Lead to accumulation of succinate, resulting in the

stabilization of HIF1-α

Activate the transcription of target oncogenes related with

cell proliferation and angiogenesis.
 Carney-Stratakis syndrome:
• GIST and paraganglioma
• Hereditary, autosomal dominant
• Germline mutations in SDHB, SDHC or SDHD
subunit

Neurofibromatosis (NF):
• 7% of patients with NF1 develop one or more GIST,
usually in small bowel
• Familial: germline mutations
• KIT or PDGFRα 
• Autosomal dominant
• Immunopositive for SDHB
Histologically three types of GISTs are seen:

The most common type -SPINDLE CELL TYPE (70%)

Followed by EPITHELIOID TYPE (20%)

Mixed SPINDLE CELL AND EPITHELIOID TYPE(10%)

Pathologic type and subtype of gastrointestinal
stromal tumors

Spindled cell type

-Diffuse hypercellularity subtype
-Palisade-vacuolated subtype
-Sclerosing subtype

Epithelioid cell type

-Diffuse hypercellularity subtype
-Pseudopapillary subtype

Mixed spindled and epithelioid cell type

-Diffuse hypercellularity subtype
-Palisade-vacuolated subtype
-Sclerosing subtype
 Sclerosing spindle
shaped
Spindle
shaped (70%) Palisading vacuolated
cell
subtype
Hypercellular

Sarcomatous spindle
GIST shaped

Epithelioid Slerosing
(20%)
Dyscohesive

Hypercellular
Mixed
type
Sarcomatous
(10%)
 SPINDLE CELL TYPE

Spindle cells with faintly eosinophilic cytoplasm in a syncytial

pattern; elongated nuclei with inconspicuous nucleoli; artifactual
paranuclear vacuoles
vacuolated spindle cell GIST
 EPITHELIOID TYPE

Round cells with clear to eosinophilic cytoplasm in sheets or nests

Sclerosing epithelioid
varient Epitheliod
GIST
Dyscohesive epithelioid
GISTBizarre tumor cells with
giant forms
 Amorphous Elongated
PAS positive
eosinophilic aggregates
of extracellular
collagen
SPINDLE CELL AND EPITHELIOID TYPE
 IHC
• DOG 1 (discovered on GIST 1): 87-97.8%
•• CD117 up to 95%
• Protein kinase C theta – 96%
•
• CD 34 -70%
• Nestin – non specific (pos in schwannoma, leiomyosarcoma and
melanoma)

• Smooth muscle actin 20-30%

• S100 – 5% ( 15-20% in SI GIST, more frequent in NF 1 associated

GIST)..

• Desmin & CK – 1-2%

• SDHB ( succinate dehydrogenase B) – loss of staining in

syndromic or paediatric GIST.
 DOG1
• Novel gene that encodes for protein called calcium
regulated chloride channel protein.
•
• DOG1 is highly expressed not only in typical GISTs
but also in kit mutation- negative GISTs.

• 5% of GIST that do not react with CD117, DOG 1 would

be essential tool for
more reliable diagnosis of GIST.

• DOG 1 +ty also identified in subset of mesenchymal

tumors – leiomyomas and synovial sarcomas.
 CD 117
• CD117/KIT : +ve in >95% tumors but no longer considered
absolute requirement.

• Other tumors show consistent positivity include:

• Mastocytoma
• Seminoma (membranous)
• Lung small cell carcinoma
• Extramedullary myleoid tumors.
 Metastatic melanoma
• Clear cell sarcoma (30-50%)
• Ewings sarcoma (50%)
• Childhood neuroblastoma (30%)
• Angiosarcoma (50%)
• Poorly differentiated carcinomas
CD117
DOG1
 PDGFRA

GIST. PDGFRA immunostaining. (A) Low power view showing fascicles of spindle cell
with intense cytoplasmic immunostaing. (B) Detail showing the cytoplasmic
immunostaining .
Immunohistochemistry for 5-hydroxymethylcytosine in succinate dehydrogenase (SDH)-
deficient gastrointestinal stromal tumors (GISTs). (a) SDH-deficient GIST with SDHA mutation
(a, H&E) showing loss of 5-hydroxymethylcytosine staining (b). SDH-deficient GIST (c, H&E)
showing weak staining for 5-hydroxymethylcytosine 
CD 34
 Prognostic factors
•GIST can have clinically malignant behavior
•25% of gastric GIST act malignant versus 35 - 40%
of small intestinal GIST
•Prognosis depends upon tumor size, mitotic rate and
site of origin
•Intraoperative tumor rupture is also associated with
poorer prognosis
•Compete surgical resection: improved local recurrence
rate and overall survival
•Incomplete resection particularly in the area of the
rectum, is associated with a higher risk of recurrence
•60 - 80% of patients with SDH deficient GIST
developed distant metastasis
 Differential diagnosis
• Spindled bland GIST
• Leiomyoma
• Schwannoma
• Fibromatosis
• Sclerosing mesenteritis
• Inflammatory fibroid polyp
• Gastric plexiform fibromyxoma
• Solitary fibrous tumor
• Inflammatory myofibroblastic tumor
• Endometrial stromal sarcoma
• Calcifying fibrous pseudotumor
 Epithelioid GIST DDx
Spindled malignant
• Poorly differentiated
GIST DDx carcinoma
•
• Melanoma/clear cell
Leiomyosarcoma
sarcoma
• Malignant
• Glomus tumor
fibrous
• Gangliocytic
histiocytoma
paraganglioma
•
• GI endocrine carcinoma
Dedifferentiated
liposarcoma • Extramedullary myeloid
tumor
• GI mucosal benign
epithelioid
nerve sheath tumor
GIST LEIOMYOMA schwannoma Solitory fibrous Fibromatosis
tumor
Nearly always Usually arises in Peripheral Scant cytoplasm CD34 - negative
arises in muscularis lymphoid cuff
muscularis mucosae common
propria
Cytoplasm Cytoplasm
frequently usually distinct,
indistinct eosinophilic
CD117 - 74-95% CD117- negative Frequent cell size CD117
variation Ropy collagen
-negative,
DOG1 -negative
CD34 -70% CD34- negative No skeinoid fibersHPC-like vessels
common
DOG1 -87-94% DOG1 -negative CD117, DOG1 Beta-catenin
S100 -100%
negative positive -90%
CD117 -negative (nuclear)

Desmin -1-2% Actin rare and Low to moderate

GFAP - 65-100%
overall but 20% in Desmin -100% focal cellularity
GI leiomyoma

CD 117
GI pos in
Desmin
leiomyoma pos DOG 1
stellate
positive
cells
 GI mucosal
benign Extramedulla GI Gangliocyti
epithelial ry Endocrine c Glomus GIST(epithelio
nerve sheeth Myeloid Carcinoma Paraganglio Tumor id)
tumor Tumor ma
Centered in Frequent history Nuclei round and Three cell types: Nuclei round and Nuclei usually
lamina propria or of leukemia regular epithelioid, regular oval or spindled
submucosa ganglion, spindled

Eosinophi
lic Stippled (salt and Synaptophysin Distinct Cell borders may
S100 positive pepper) and chromogranin cell
myelocyte be indistinct
s chromatin positive borders
frequently
present
Infiltration along Keratin positive Keratin positive Mitotic rate Mitotic rate can
CD117 negative
collagen fibers cells epithelioid usually <1/50 HPF be higher
cells

CD45, CD43, Synaptophysin

CD34 negative myeloperoxidase and chromogranin CD117 negative CD117 negative CD117 74-95%
positive positive

Smooth muscle
Restricted to Extramedullary CD117 negative Gangliocytic Smooth muscle actin frequently
colon Myeloid Tumor Paraganglioma actin positive negative
 Spindled cytologicaly malignant
GIST
GIST
GI Dedifferentiated Malignant Fibrous
(spindled,
leiomyosarcoma liposarcoma Histiocytoma
cytologically
malignant)

Pleomorphis
Frequently Frequently
Markedly m
markedly markedly pleomorphic
infrequent,
pleomorphic pleomorphic
even in
malignant
lesions

Frequently CD117, DOG1, CD117, DOG1,

brightly CD117, DOG1 CD34 - CD34 -
negative
eosinophilic negative positive
cytoplasm