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Gastrointerstinal stromal tumor (GIST) recent advances and differential diagnosis
1. GIST recent advances and
Differential diagnosis
Dr. Indira Shastry.K
Kasturba medical college
Manipal university, Manipal.
2. History
• Golden and Stout in 1941: described the mesenchymal tumors
arising in bowel as tumors arising from smooth muscle cells;
leiomyoblastoma, leiomyoma and leiomyosarcoma.
• Term GIST was 1st used by Mazur and Clark in 1983.
• In 1998 Japanese research workers (Hirota et al) discovered KIT
mutations in GIST that possibly distinguish GIST from other
tumors.
3. 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 :
Leiomyoma, Leiomyosarcoma, Neural tumors, hemangiomas, fibromas,
myofibroblastic tumors.
• Stromal tumors : GIST
MalignantBenign
4. Epidemiology &Incidence
• Age : 60-80 yrs / familial
(<30yrs)
• Gender: M=F.
• Most common benign non-
epithelial tumor of the GI
tract.
• 1% of primary GI cancers. 2.2%
primary gastric cancers (SEER
data).
• Oesophagus: 5%
• Stomach: 50-70%
• SI: 25-40%
• Duodenum – 10-20 %
• Jejunum – 27-37%
• Ileum : 27-53%
• Colorectal : 10%
• Extra - gastrointestinal GIST :
6.7% (AFIP)
5. Cell of origin c 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 (just like GIST) .
Kit positivity
7. Molecular biology
• C-KIT: (85-95%)
• Exon 11 (mutations / In-frame deletions): most
common type 70%. GIST with missense point
mutation at Exon 11 have better prognosis in Gastric
but not in other sites.
• Exon 9 : 2nd most common , commonly associated
with small bowel with known aggressive clinical
behaviour.
• Exon 13: involve missense mutations and associated
with more malignant potential.
8. Molecular biology
• 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.
• Wild type: (IGFR 1 mutation)
• 5-15 % of GIST do not harbour KIT / PDGFRA mutations
• Can be positive for CD117, less responsive to imatinib.
9. Sites Oesophagus Stomach Duodenum Jejunum and ileum
Incidence 5% 50-70% 10-20% 27-37% and 27-53%
respectively
Gender predilection Males Males, in young
females
M=F M=F
Site Lower 1/3rd or GE
junction
Antrum followed by
pylorus
2nd part of
duodenum
-
Gross (size of tumor) Usually >5cm in size
(Miettinen et al)
Variable Usually >4.5 cm Variable
Morphology Spindled or
epithelioid
MC-spindle (70%) Cellular, usually
>2mitosis/50 hpf
Variable
Behaviour and
prognosis
Aggressive •Good survival with
complete resection.
•73-81% behave in
benign fashion.
•30-50% are
malignant.
•Presence of
necrosis /
epithelioid change
lower the mitotic
threshold for
malignancy.
Worse outcome than
gastric GIST
GIST in various sites Recent advances -21
10. Colon Appendix Ano-rectum Extragastrointerstina
l GIST
Incidence 5% Very rare
(only 4 cases
reported till now )
5% 6.7%
Gender predilection M=F - - -
Site Ascending and
descending colon
- - Omentum, mesentry
and retroperitonium
Gross (size of tumor) Variable Variable Usually >5cm Omental GIST can be
large with low mitosis
Morphology Heterogeneous but
MC is spindle with
fascicles, pallisiding
or storiform pattern
•All 4 showed spindle
morphology, 3
contained skeinoid
fibers
•Low mitosis
(<1/50hpf)
Variable
>5mitosis /50hpf
Variable
Behaviour and
prognosis
Variable •Good prognosis.
•Mets to liver and
lung observed after
10-15 yrs
32-54% malignant Omental GIST
resemble stomach
GIST.
Mesentric GIST
resemble SI GIST
20. Heredity Mean Age M/F
Associated
Lesions
Mutations GIST Location Behaviour
Familial AD 45 M&F
Mast cell
lesions,
achalasia
GL KIT
/PDGFRA
Small intestine
Frequently
aggressive
Carney –
stratakis
AD 23 M&F Paraganglioma
GL SDH, No KIT
/ PDGFRA
Stomach
epithelioid
GIST mets but
protracted,
Paragang.
aggressive
Carney triad None <30 >95%F
Lung
chondroma,
paraganglioma
No KIT /
PDGFRA or SDH
Stomach
epithelioid
Mets (LN)but
protracted
course
NF 1 AD 40-50 M&F
Neurofibromato
sis
GL SDH, No KIT
/ PDGFRA
Small intestine
spindled
As for usual
Sporadic SDHB
deficient
(pediatric
type)
None
<16, rarely also
adults
>90%F None
No KIT /
PDGFRA or SDH
Stomach
epithelioid
Mets but
protracted
course, may go
to nodes
Sporadic
multiple
None 60 M&F None As for usual
Usually
stomach
Most are benign
GIST syndromes
21. IHC
• DOG 1 (discovered on GIST 1): 87-97.8%
• CD117 up to 95%
• Protein kinase C theta – 96%
• Heavy caldesmon -80%
• 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.
22. DOG1 (discovered on GIST1)
• Novel gene that encodes for protein called calcium regulated chloride
channel protein.
• In a study conducted by West et al immunoreactivity for DOG1 in GIST
samples was 97.8%. Espinosa et al showed 87% sensitivity and specificity.
• 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.
26. 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.
27. • Other metastatic abdominal tumors that test positive for CD117
include
• Metastatic melanoma
• Clear cell sarcoma (30-50%)
• Ewings sarcoma (50%)
• Childhood neuroblastoma (30%)
• Angiosarcoma (50%)
• Poorly differentiated carcinomas
28. Protein Kinase C Theta (PKCT)
• Downstream effector in Kit signaling system involved in T cell activation,
signal transduction and neuronal differentiation.
• Strongly over expressed in GIST but not in sarcomas
• In study done by Kim et al 96% GIST was positive for PKCT were as 98%
cases were positive for CD117.
• Some investigators believe PKCT signaling in weaker than KIT hence it is
less useful.
31. TNM staging
• The 7th ed of the international union against cancer (UICC) in 2010
published for the first time, a classification and staging system for GIST
using the TNM system.
• AIM : uniform and standardized analysis of malignant tumors based on
their stage of development and degree of spread.
• Joensuu et al (2011) concluded large tumor size, high mitotic count, non-
gastric location, presence of rupture, and male sex were the independent
prognostic factors for recurrent free survival.
37. Palisading is more accentuated in GIST; CD34 stains 0-33% of GI
schwannomas
GI schwannoma GIST (spindled, bland)
Peripheral lymphoid cuff common Lacks lymphoid cuff
Frequent cell size variation Generally uniform cell size
No skeinoid fibers May have skeinoid fibers
S100 -100% S100 -5% (20% in small intestine)
GFAP - 65-100% GFAP - negative
CD117 -negative CD117 -74-95%
38. Fibromatosis
(mesentric or retroperitonial and
pelvic)
GIST
CD34 - negative CD34- 60-70% positive
CD117 -frequently negative, variable reports of
focal/weak staining
CD117- 74-95% positive
DOG1 -negative DOG1- 87-94%
Beta-catenin positive -90% (nuclear) Beta-catenin- negative
Low to moderate cellularity Moderate to high cellularity
Cytologically bland May be cytologically atypical
Prominent thin walled dilated veins Lacks prominent veins
Infiltrative margin Usually circumscribed, pushing margin
No cystic degeneration or necrosis May have cystic degeneration or necrosis
39. Sclerosing Mesenteritis GIST (spindled, bland)
Lobulated paucicellular fibrosis
Not typically lobulated, usually
cellular rather than fibrotic
Prominent chronic inflammatory infiltrate Inflammation not typical
Entrapped fat and fat necrosis
Lobules of entrapped fat and fat
necrosis unusual
40. GIST Solitary fibrous tumor
Spindled or epithelioid cytoplasm Scant cytoplasm
Skeinoid fibers: are irregular, globular and
have prominent retraction
Ropy collagen
Hemangiopericytoma-like vessels uncommon HPC-like vessels common
CD117 (KIT) 74-95%, DOG1 87-95% positive CD117, DOG1 negative
Actin 30-50% positive Actin rare and focal
CD34 is usually positive in both
41.
42. Inflammatory myofibroblastic
tumor
GIST
Usually in children Rare in children
Frequently associated with systemic signs and
symptoms
Not associated with systemic signs and
symptoms
Prominent inflammatory cells Usually only scattered inflammatory cells
Positive - desmin, keratin and ALK Desmin (1-2%), keratin and ALK – negative
CD117, DOG1, CD34 - negative CD117, DOG1, CD34- positive
43. Endometrial Stromal
Sarcoma (Metastatic)
GIST (spindled, bland)
History of prior hysterectomy No such history
May arise in endometriosis Not associated with endometriosis
Prominent spiral arterioles Hyalinized larger vessels
CD10, ER and PR - positive ER and PR negative
DOG1 - negative DOG1 87-94%
44. Calcifying fibrous pseudo
tumor
GIST (spindled, bland)
Calcification frequently psammomatous
Calcification dystrophic, not
psammomatous
Patchy chronic inflammation Inflammation not typical
May form multinodular mass Not typically multinodular
Prominent hyalinized stroma
Stroma occasionally sclerotic but not
usually hyalinized
46. Epithelioid GIST
Poorly Differentiated
Carcinoma
GIST
May have a mucosal component or form
glands
No mucosal component or true glands
Frequently markedly pleomorphic
Pleomorphism infrequent, even in
malignant lesions
Mucin stain may be positive No mucin
Keratin positive Keratin 1-2%
CD34 negative CD34 70%
DOG1 negative DOG1 87-94%%
48. GI mucosal
benign epithelial
nerve sheeth
tumor
Extramedullary
Myeloid Tumor
GI Endocrine
Carcinoma
Gangliocytic
Paraganglioma
Glomus Tumor GIST(epithelioid)
Centered in
lamina propria or
submucosa
Frequent history
of leukemia
Nuclei round and
regular
Three cell types:
epithelioid,
ganglion, spindled
Nuclei round and
regular
Nuclei usually
oval or spindled
S100 positive
Eosinophilic
myelocytes
frequently
present
Stippled (salt and
pepper)
chromatin
Synaptophysin
and chromogranin
positive
Distinct cell
borders
Cell borders may
be indistinct
CD117 negative
Infiltration along
collagen fibers
Keratin positive
cells
Keratin positive
epithelioid cells
Mitotic rate
usually <1/50 HPF
Mitotic rate can
be higher
CD34 negative
CD45, CD43,
myeloperoxidase
positive
Synaptophysin
and chromogranin
positive
CD117 negative CD117 negative CD117 74-95%
Restricted to
colon
Extramedullary
Myeloid Tumor
CD117 negative
Gangliocytic
Paraganglioma
Smooth muscle
actin positive
Smooth muscle
actin frequently
negative
49. References
• Morson and Dawson’s GI pathology ; 5th ed.
• Recent advances in histopathology ; 21 vol
• Rosai and Akerman surgical pathology 10th ed
• WHO pathology and genetics of tumors of digestive system. 2003.
• Christopher B Tan et al ; Gastrointestinal Stromal Tumors: A Review of Case Reports, Diagnosis,
Treatment, and Future Directions. International Scholarly Research Network gastroenterology.
2012.
• Novelli M et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of
gastrointestinal stromal tumours. Histopathology 2010, 57.
• Hadi MA et al. Evaluation of the Novel Monoclonal Antibody Against DOG1 as a Diagnostic
Marker for Gastrointestinal Stromal Tumors. Journal of the Egyptian Nat. Cancer Inst. 2009,
Vol. 21.
• Stanford university website.
CD117 is NOT expressed by: smooth muscle tumours, neural tumours, yolk sac tumours
Joensuu et al compared the NIH criteria, the modified NIH criteria and the AFIP system for risk stratification for recurrence-free survival (RFS) in imatinib naive operable GISTs.
