GIST recent advances and Differential diagnosis

Dr. Indira Shastry.K Kasturba medical college

Manipal university, Manipal.

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.

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

Malignant Benign

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)

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

Pathophysiology

1. C-kit,PDGFRA mutations- chromosome 4q11-21, Type III tyrosine kinase protein receptor

2. Loss of potential suppressor genes

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.

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.

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

Colon Appendix Ano-rectum Extragastrointerstinal 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

GIST

Spindle shaped (70%)

Sclerosing spindle shaped

Palisading vacuolated cell subtype

Hypercellular

Sarcomatous spindle shaped

Epithelioid (20%)

Slerosing

Dyscohesive

Hypercellular

Sarcomatous Mixed type

(10%)

Cellular spindle cell GIST

vacuolated spindle cell GIST

Sclerosing spindle cell GIST Pallisaded – vacuolated spindle cell

GIST

Sclerosing epithelioid varient Epitheliod GIST

Dyscohesive epithelioid GIST Bizarre tumor cells with giant forms

Skeinoid fibers

Amorphous Elongated PAS positive eosinophilic

aggregates of extracellular collagen

  Heredity Mean Age M/F Associated Lesions Mutations GIST

Location Behaviour

Familial AD 45 M&FMast cell lesions, achalasia

GL KIT /PDGFRA

Small intestine

Frequently aggressive

Carney – stratakis AD 23 M&F Paragangliom

aGL SDH, No KIT / PDGFRA

Stomach epithelioid

GIST mets but protracted, Paragang. aggressive

Carney triad None <30 >95%FLung chondroma, paraganglioma

No KIT / PDGFRA or SDH

Stomach epithelioid

Mets (LN)but protracted course

NF 1 AD 40-50 M&F Neurofibromatosis

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

stomachMost are benign

GIST syndromes

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.

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.

Mixed spindle cell and epithelioid CD117 negative DOG 1 Pos CD34 pos

Epithelioid GIST Heterogeneous

membranous positivity Cytoplasmic &

membraneous DOG 1 pos

West et al

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.

• 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

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.

Mixed spindle cell and epithelioid PKCT pos

Grading (2003 WHO and 2012 Tan CB et al)

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.

The new TNM risk stratification system

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

• Spindled malignant GIST DDx• Leiomyosarcoma• Malignant fibrous

histiocytoma• Dedifferentiated liposarcoma

• Epithelioid GIST DDx• Poorly differentiated

carcinoma• Melanoma/clear cell sarcoma• Glomus tumor• Gangliocytic paraganglioma• GI endocrine carcinoma• Extramedullary myeloid

tumor• GI mucosal benign epithelioid

nerve sheath tumor

GI Leiomyoma GIST  (spindled, bland)

Usually arises in muscularis mucosaeNearly always arises in muscularis propria

Cytoplasm usually distinct, eosinophilic

Cytoplasm frequently indistinct

CD117- negative CD117 - 74-95%

CD34- negative CD34 -70%

DOG1 -negative DOG1 -87-94%

Desmin -100%Desmin -1-2% overall but 20% in oesophagus

GI leiomyoma

Desmin pos CD 117 pos in stellate cells DOG 1 positive GI leiomyoma

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%

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- negativeLow to moderate cellularity Moderate to high cellularityCytologically bland May be cytologically atypicalProminent thin walled dilated veins Lacks prominent veinsInfiltrative margin Usually circumscribed, pushing marginNo cystic degeneration or necrosis May have cystic degeneration or necrosis

Sclerosing Mesenteritis GIST (spindled, bland)

Lobulated paucicellular fibrosisNot typically lobulated, usually cellular rather than fibrotic

Prominent chronic inflammatory infiltrate

Inflammation not typical

Entrapped fat and fat necrosisLobules of entrapped fat and fat necrosis unusual

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 focalCD34 is usually positive in both

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

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%

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 stromaStroma occasionally sclerotic but not usually hyalinized

Spindled cytologicaly malignant GIST

GI leiomyosarco

ma

Dedifferentiated

liposarcoma

Malignant Fibrous

Histiocytoma

GIST (spindled,

cytologically malignant)

Frequently markedly pleomorphic

Frequently markedly pleomorphic

Markedly pleomorphicPleomorphism infrequent, even in malignant lesions

Frequently brightly eosinophilic cytoplasm

CD117, DOG1 negative

CD117, DOG1, CD34 - negative

CD117, DOG1, CD34 - positive

Epithelioid GIST

Poorly Differentiated Carcinoma

GIST 

May have a mucosal component or form glands

No mucosal component or true glands

Frequently markedly pleomorphicPleomorphism 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%%

Poorly differentiated carcinoma of duodenum positive for CD117

Negative for DOG 1 CK positive

GI mucosal benign

epithelial nerve sheeth

tumor

Extramedullary Myeloid

TumorGI Endocrine Carcinoma

Gangliocytic Paragangliom

aGlomus Tumor

GIST(epithelio

id)

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 positiveEosinophilic myelocytes frequently present

Stippled (salt and pepper) chromatin

Synaptophysin and chromogranin positive

Distinct cell borders

Cell borders may be indistinct

CD117 negativeInfiltration along collagen fibers

Keratin positive cells

Keratin positive epithelioid cells

Mitotic rate usually <1/50 HPF

Mitotic rate can be higher

CD34 negativeCD45, CD43, myeloperoxidase positive

Synaptophysin and chromogranin positive

CD117 negative CD117 negative CD117 74-95%

Restricted to colon

Extramedullary Myeloid Tumor CD117 negative Gangliocytic

ParagangliomaSmooth muscle actin positive

Smooth muscle actin frequently negative

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.

Thank you