Gastrointestinal Stromal Tumours

Dr Priyageet Kaur

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

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

• 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

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)

• Incidence of GISTs (location-wise)- 5% esophageal- 50-70% stomach- 25-40% small intestine10-20% duodenum27-37% jejunum27-53% ileum- <10% colorectal----------– 50% colonic;

50% rectal - Rare omentum, peritoneum,

retroperitoneum

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

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.

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

Polypoid mass with a large central scar

• Extramural component

-may be attached to the stomach by a thin isthmus

• Both endophytic & exophytic components can also be present- dumbbell shape

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.

GIST in the stomach

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.

An ulcerated GIST originating in the muscle layer

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

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

GIST: Major Morphologic Patterns

Spindle Cell (70%) Epithelioid (9%)

Courtesy of Dr. C. Corless. Other-> mixed 21%

Spindle cell GIST with short fascicles & whorls

Spindle cell GIST with longer fascicles in bundles

• 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

• 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

Spindle cell GIST with prominent nuclear palisading

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

Epithelioid GIST with more pleomorphic nuclei & deeply acidophilic cytoplasm

Epithelioid GIST with round cells, clear cytoplasm & well defined cell borders

Epithelioid GIST with pleomorphic nuclei & clear vacuolated cytoplasm

Epithelioid GIST with rhabdoid features

• 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

GIST with abundant myxoid matrix separating the individual tumour cells

GIST with numerous multinucleated giant cells

• Criteria for malignancy is based on proliferative indices, tumour size & infiltrative pattern

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).

• 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.

• 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.

• 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)

Alternative receptor tyrosine kinase mutationsin PDGFRAApproximately 35% of GISTs negative for KIT mutationswere recently shown to have activating mutations in thePDGFRA gene encoding the platelet derived growth factor

alpha leading to similar signaling consequences as KIT mutations did.

Notably, tyrosine kinase inhibitor Imanitib also inhibitsPDGFR kinase.

Behaviour –general

• 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 fashion2. very small GISTs in some locations have been recorded

to metastasize3. even the blandest looking tumours can recur esp wen

large even after 20-30 years

Gross appearance of liver metastasis from GIST

Esophagus

• GISTs account for 25% of esophageal stromal tumours

• Lower third or GEJ• Pred in males• Spindled or epithelioid• Majority are aggressive

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

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

Extragastrointestinal GISTs

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 GISTCourtesy of Dr. C. Corless.Miettinen and Lasota. Virchows Arch. 2001;438:1.

GIST with strong and diffuse cytoplasmic staining of CD117 (c-kit)

• 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.

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)

Epithelioid cell GIST with strong cytoplasmic stainingof CD117 (×100)

Epithelioid cell GIST with patchy and heterogeneous staining of CD34 (×400)

Epithelioid cell GIST with punctate staining of h-Caldesmon (×100)

Epithelioid cell GIST with patchy mambrane staining of h-Caldesmon (×400)

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.

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

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

• 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.

• 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

• Leiomyosarcoma

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

• Histologically usually composed of well-differentiated smooth muscle cells, but may be focally pleomorphic.

• Immunohistochemically typically positive for smooth muscle actins and desmin.

• 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.

• 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

• 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

• Glomus tumour1. 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.

• Immunohistochemically positive for smooth muscle actin and negative for desmin.

• Variably CD34-positive,but is KIT-negative

• Fibromatosis/mesenteric 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

• 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

• Spindle cell carcinoma

• Follicular dendritic cell sarcoma

• PEComas

• Mesothelioma

• Dedifferentiated liposarcoma

Thank you!