2. Introduction
• Gastrointestinal stromal tumors (GISTs) constitute a
majority of mesenchymal neoplasms of the
gastrointestinal (GI) tract and abdomen.
• Pathologic activation of KIT signal transduction appears
to be a central event in GIST pathogenesis
3. How did the concept of GIST
evolve?
• Mazur and Clark introduced the term stromal tumour in
1983 after they failed to find ultrastructural evidence of
smooth muscle or nerve sheath differentiation
• Tumours with unequivocal smooth muscle derivation are
most commonly seen in esophagus and rectum
• The lack of unequivocal smooth muscle derivation +
presence of positivity for markers not indicative of
smooth muscle origingave rise to concept of GIST
4. • Formerly regarded as leiomyomas and
leiomyosarcomas based on morphology
• Subsequent IHC & ultrastructural study showed
that true e/o smooth muscle differentiation was
infrequent in gastric and small intestinal stromal
tumours- Desmin expression was unusual
• Thus GIST was introduced
5. Incidence and distribution
• GISTs represent about 1% of all GI
malignancies
• Malignant GISTs are rare with an
incidence of about 5 million of population
• Adults --- 50-60 years (mc age group)
7. Nature and differentiation
• Originally arised from interstitial cell of Cajal (ICC)
• KIT-positive & CD34 positive fibroblast-like cells
• Pacemaker cells of the gut--- Regulate GI motility
• Location-
– Auerbach’s plexus of stomach, SI & colon
– 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
8. Clinical features
-Gastrointestinal bleeding or vague ulcer-like pain
are the most common symptoms of GIST.
-Anemia due to chronic bleeding
-Those GISTs that do not cause ulceration
can grow into a large size with little symptoms.
-palpable abdominal masses
-intestinal perforation.
-disseminated intra-abdominal tumor.
9. Macroscopic features
• Usually present as
single intramural
tumours
- Ulceration seen more in
endophytic tumours often
with a central crater
- Ulceration can occur in
entirely benign tumours
and does not necessarily
suggest malignancy
11. • Extramural
component
-may be attached to the
stomach by a thin
isthmus
• Both endophytic &
exophytic components
can also be present-
dumbbell shape
12.
13. GIST in the mesentery of a 50 y/o female who presented with an abdominal
mass. The resected loop of small intestine measured 70 cm in length and
contained a 30 x 20 x 13 cm fleshy tumor with hemorrhagic surface.
15. Cut surface
• Characteristically grey in colour (without the
typical whorling pattern typical of leiomyomas)
• Granular or rubbery
• Circumscribed but not encapsulated
• Coursing bvs may be seen
• Malignant GISTs tend to be whiter in color-
increased cellularity & are more likely to show
areas of necrosis, hghe & myxoid degeneration.
19. Microscopic features
• Location:
1. submucosal
2. intramuscular– muscularis propria
Often the muscularis appears hypertrophic with
muscle bundles present within the tumour &
forming muscular septa that may divide the
tumour into lobules.
3. subserosal—predominantly in exophytic
tumours
20. Spindle shaped
• About 70% of gastric GISTs and majority of the
rest of the bowel are spindle- celled tumours.
• Oval uniform blunt-ended nuclei with
abundant amphophilic or eosinophilic
slightly fibrillary cytoplasm
• Pattern: cellular sheets or fascicles with whorled
storiform or palisaded patterns
24. Spindle cell GIST with short
fascicles & whorls
Spindle cell GIST with longer
fascicles in bundles
25. • Hyalinisation & myxoid
degeneration,
hemorrhage & even
necrosis may all occur in
varying proportions in
otherwise benign
tumours
• Mitotic activity is low &
usually behave in a
benign fashion
26. • Features s/o
smooth muscle
differentiation
such as
perinuclear
vacuoles may
be present but
should not invite
a diagnosis of
leiomyoma in
the absence of
IHC evidence Spindle cell GIST showing characteristic cytoplasmic
vacuoles indenting the nuclear poles
28. Epithelioid GISTs
• Most occur in the fundus of the stomach
• These are the commonest GISTs prominent in
the antrum
• Rounded cells with abundant prominent
cleared cytoplasm & well defined cell borders
• The tumour cells are arranged in sheets or
packets , rather than fascicles; & tend to be
oriented in a perivascular pattern
29. Epithelioid GIST with more
pleomorphic nuclei & deeply
acidophilic cytoplasm
Epithelioid GIST with round cells,
clear cytoplasm & well defined cell
borders
30. Epithelioid GIST with pleomorphic
nuclei & clear vacuolated
cytoplasm
Epithelioid GIST with rhabdoid
features
31. • Hyalinisation & myxoid change are common
• Cellular pleomorphism is characteristic -large
bizarre nuclei are often present this per se
does not indicate malignancy
• Malignant epithelioid GISTs tend to have smaller
cells with less vacuolated cytoplasm
• They have more monotonous nuclei- cells
appear clustered with an alveolar pattern
34. • Criteria for malignancy is based on
proliferative indices, tumour size &
infiltrative pattern
35.
36. Genetics-KIT Gene and Protein and
Their
Alterations in GIST
• KIT gene, mapped to 4q12, encodes a 145 -
160kDa protein, a transmembrane tyrosine
kinase receptor (RTK) for stem cell factor (SCF,
previously also called Steel factor).
• KIT displays extensive homology with other
members of RTK type III family, such as platelet-
derived growth factor receptors (PDGFR),
colony-stimulating factor-1 receptor (CSF1R)
and FMS-related tyrosine kinase 3 (FLT3).
37. • Activation of KIT leads to downstream
phosphorylation of substrate proteins and
subsequently activates networks of signal
transduction pathways which regulate
important cell functions including proliferation,
apoptosis, chemotaxis and adhesion.
• KIT expression is critical for the development
and maintenance of mast cells, hematopoietic
stem cells, melanocytes, gametocytes, and ICCs
in the GI tract.
38. • Structurally similar, constitutional, inheritable
germline mutations have been found in patients
with familial GISTs.
• In GISTs, the majority of KIT mutations have
been identified in the juxtamembrane
domain, exon 11.
• In addition, mutations in the extracellular (exon
9) and tyrosine kinase domains (exons 13, 14
and 17) have also been reported.
39. • Type of KIT mutation may have an impact of
Imatinib treatment.
• GISTs with KIT mutations affecting extracellular
(exon 9) and tyrosine kinase domains (exons 13
& 14) may not respond to tyrosine kinase
inhibitors equally well as do tumors with mutated
KIT juxtamembrane domain (exon 11)
40. Alternative receptor tyrosine kinase mutations
in PDGFRA
Approximately 35% of GISTs negative for KIT mutations
were recently shown to have activating mutations in the
PDGFRA gene encoding the platelet derived growth factor
alpha leading to similar signaling consequences as KIT
mutations did.
Notably, tyrosine kinase inhibitor Imanitib also inhibits
PDGFR kinase.
42. • Malignant GISTs recur locally and spread mainly to
adjacent organs, omentum or mesentery,
retroperitoneum & liver
• Less commonly 0-15% to LN or rarely bone
• Distinction between benign & malignant cannot be made
with certainty:
1. poorly differentiated tumours do not always behave in a
malignant fashion
2. very small GISTs in some locations have been recorded
to metastasize
3. even the blandest looking tumours can recur esp wen
large even after 20-30 years
44. Esophagus
• GISTs account for 25% of esophageal stromal
tumours
• Lower third or GEJ
• Pred in males
• Spindled or epithelioid
• Majority are aggressive
45. Stomach
• Gastric GISTs are more frequent in males
• Young patients esp females have a better
outcome
• Epithelioid GISTs – 11% of gastric GISTs, of
which 73- 81% behave in a benign fashion
• Large tumours in the fundus or cardiac area and
posterior wall are more likely to be aggressive
46. Duodenum
• Mc in the second part
• 35-50% are malignant
• Cellular, have more than 2 mitoses per hpf
• Greater than 45mm in diameter
Jejunum and ileum
• Worse outcomes than gastric GISTs
48. 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
• Focal-Positive in 25%-
40%
– S-100
• Positive in 10%
• GIST rarely express desmin.
Different KIT staining
patterns in GIST
Courtesy of Dr. C. Corless.
Miettinen and Lasota. Virchows Arch. 2001;438:1.
49. GIST with strong and diffuse cytoplasmic staining of CD117 (c-kit)
50. • The most convincing pattern of CD117 positivity
is one featuring a cell membrane component
in addition to a cytoplasmic one
• The presence of CD117 immunoreactivity in a
tumor does not necessarily indicate that a
mutation of the gene is present. Conversely, a
CD117 mutation can exist in the absence of the
immunohistochemically detectable marker.
51. A. Spindle cell GIST with strong and diffuse cytoplasmic staining
of CD117 (c-kit) (×400);
B. Spindle cell GIST with strong and diffuse membrane staining of
CD34 (×400)
56. Treatment
• The primary treatment of GIST consists of
surgical excision of the tumour with a good
margin of normal tissue
• Wide resection of LN areas is not indicated
because of the extreme rarity of LN metastasis.
• Gene product targeted therapy
• Imatinib (Glivec), a 2-phenylaminopyrimidine
derivative, a selective inhibitor of c-abl, c-kit &
PDGFR tyrosine kinases.
57. Prognostic indicators
• Mitotic activity & tumour size
• Site
• Proliferation markers ( Ki-67)
• Pattern of differentiation
• Loss of p16 regulator, loss of CD44 expression
& overexpression of HSPsunfavourable
factors
• Presence and type of KIT mutation
• Presence of PDGFR mutation
• Other molecular genetic features
58.
59. Differential diagnosis
• Intramural
leiomyoma
1. Most common in the
esophagus
2. Composed of well
differentiated smooth
muscle cells, and usually
much less cellular than
GIST; focal atypia may
occur.
3. Smooth muscle actin and
desmin-positive
4. CD117 and CD34-
negative
60. • Leiomyoma of
muscularis
mucosae
1. Usually endoscopically
diagnosed as an incidental
diminutive polyp in colon or
rectum of older adults.
2. Composed of well-
differentiated smooth
muscle cells merging with
muscularis mucosae and
usually covered by intact
mucosa.
3. Focal atypia may occur, but
behavior is benign.
61. • Retroperitoneal &
peri-intestinal
leiomyoma
1. Occurs nearly exclusively in
adult women, histologically
similar to uterine leiomyoma.
2. Can form a large
retroperitoneal tumor or
smaller nodule attached to
external aspect of intestines,
usually colon or rectum.
3. Positive for actins, desmin
and estrogen and
progesterone receptors
62. • Leiomyosarco
ma
1. Rare in stomach and
intestines (at most 5 -
10% of GISTs), but
retroperitoneum is a
common site.
2. Usually occurs in older
adults, with a significant
female predominance in
retroperitoneal tumors
63. • Histologically usually
composed of well-
differentiated smooth
muscle cells, but may
be focally pleomorphic.
• Immunohistochemically
typically positive for
smooth muscle actins
and desmin.
64. • Inflammatory
myofibroblastic
tumour
1. gastric or intestinal
mass simulating a
GIST.
2. More often omental or
mesenteric.
3. Spindled or slightly
epithelioid cells with
amphophilic cytoplasm
and cytoplasmic
processes.
4. Has ALKgene
expression and
rearrangements.
65. • Schwannomas
1. Usually a relatively small (<5
cm), yellow circumscribed
submucosal tumor, most
commonly in the stomach and
secondly in the colon.
2. Slender, often bundled S100-
protein positive spindle
cells.
3. GFAP-positivity is typical;
this is almost never seen in
GISTs
66. • Inflammatory
fibrous polyp
1. Spindle cell lesion, mc
seen in the small
intestine of adults as an
ulcerated intraluminal
polyp.
2. oval or slender spindle
cells in highly vascular
granulation tissue-like
stroma
3. Some examples are
CD34-positive, but all
are KIT-negative.
4. Smooth muscle actin
positivity is possible;
negative for desmin
67. • Glomus tumour
1. Conceptually identical
with glomus tumor of
peripheral soft tissue.
2. Occurs almost
exclusively in the
stomach in the GI-
tract, mostly in the
antrum.
3. Round tumor cells
arranged around
prominent, often
dilated vessels.
69. • Fibromatosis/mesenteri
c desmoid
1. Can be extraintestinal or have
GIST-like gastric or intestinal
wall involvement. Grossly very
firm and white.
2. Histologically composed of
fibroblasts and myofibroblasts in
collagenous, often focally
myxoid background.
3. CD34-negative; can be focally
smooth muscle actin and
desmin positive
70. • Solitary fibrous
tumour
1. May present on the
peritoneal surfaces, pelvis
or occasionally in the liver.
2. Collagenous spindle cell
tumor, often with a focal
hemangiopericytoma-like
pattern.
3. Nearly always CD34-
positive and negative for
smooth muscle actin and
desmin
The major histologic patterns of GIST are spindle cell and epithelioid. GIST with a spindle cell morphology often will appear syncytial while clear cell borders are common in epithelioid GIST.
Gastric GIST are often of spindle cell morphology, with the epithelioid GIST often historically misclassified as myoblastomas.
GIST of the small intestine are primarily of spindle cell morphology. A salient feature of small intestine GIST, especially those of lower risk, is the presence of aggregates of collagen fibers known as skeinoid fibers. In contrast, epithelioid GIST of the small intestine are generally of high risk.
Spindle cell morphologies dominate GIST at other sites.
GIST are often defined as KIT-positive mesenchymal tumors of the GI tract.
Over 90% of reported cases (but not all GIST) express KIT.
KIT is a type III transmembrane receptor tyrosine kinase, the protein product of the KIT proto-oncogene. KIT is the single most common tumor marker for GIST.
CD34 is a mesenchymal and hematopoietic precursor cell marker that is positive in many tumors of mesenchymal origin. It is expressed in 60% to 70% of GIST, making it a modestly sensitive and specific diagnostic GIST marker.
Vimentin and smooth-muscle actin are variably expressed by GIST.
Desmin is rarely present in GIST. In contrast, true smooth-muscle tumors often express high levels of desmin and smooth-muscle actin.
S-100 is used to distinguish tumors of neural crest origin, such as schwannomas and melanomas, and it is particularly useful for differentiating GIST with neural phenotype (formerly GANT) from primary schwannomas.
