Gastrointestinal Stromal Tumor (GIST)

Definition

• Gastrointestinal tract associated mesenchymal neoplasm with activating mutation in KIT (CD117) or platelet derived growth factor A (PDGFRA)

Alternate/Historical Names

• Most gastric leiomyomas and leiomyosarcomas and virtually all  leiomyoblastomas in the older literature would now be considered GIST
• Gastrointestinal stroma tumor (GANT) is now considered to be GIST

Diagnostic Criteria

• Encompasses most mesenchymal lesions of the GI tract
• Smooth muscle, fibroblastic and nerve sheath tumors are excluded (see Differential Diagnosis)
• Principal patterns are spindled or epithelioid, may be mixed
• Spindled 2/3 of cases
• Uniform spindle cells
• Pale eosinophilic, indistinct cytoplasm
• Oval to short spindled nuclei
• Frequently palisades
• May have paranuclear vacuoles
• May have skeinoid fibers
• Brightly eosinophilic bundles/globules of collagen
• Distinct from surrounding stroma
• Frequent retraction
• PAS/d positive
• Most common in small intestine
• Epithelioid 1/3 of cases
• Round/polygonal cells
• Round to oval nuclei
• Frequent cytoplasmic retraction creates clearing artifact
• May be discohesive
• Occasional to rare patterns and variants (may be superimposed on spindled or epithelioid patterns)
• Blood vessel walls may be hyalinized
• Calcification is frequent
• Chondroid
• Glandular (mucin and keratin negative)
• Myxoid
• Osteoclast-like giant cells
• Paraganglioma-like pattern (chromogranin and synaptophysin negative)
• Rhabdoid or rhabdomyomatous
• Sclerosing
• Usually small and benign
• May calcify
• Signet ring (mucin and keratin negative)
• Rhabdomyosarcoma has been reported following Imatinib therapy
• CD117/KIT positive
• 95% sensitive
• Specific in the right pathological and clinical context
• May occur throughout the GI tract
• Nearly all GI cases involve muscularis propria
• Most common in stomach
• Rare in esophagus and large intestine
• Rare extra-GI cases reported
• Identical histology, immunohistology and genetic defects as usual GIST
• If metastasis is ruled out, these may be designated as extra-GI GIST
• Responses to Imatinib mesylate have been reported in such cases
• Most in omentum and mesentery
• Solitary omental GIST are generally considered to be detached gastric primaries
• Rarely in gall bladder, pancreas, liver, urinary bladder, vagina
• Gastrointestinal autonomic nerve tumor (GANT)
• Presently considered to fall within the spectrum of GIST
• We do not make this diagnosis
• Malignant cases typically exhibit peritoneal spread
• Metastases may be seen to liver, lungs, bone
• Lymph node metastases very rare except in pediatric (and adult pediatric-type) cases
• Size and mitotic rate are predictive of behavior (see Grading)
• Incidental microscopic (seedling) GIST
  • They can be found in up to 10% of esophagogastrectomies
  • Rarer in other sites
• Rare cases may be multiple or hereditary or pediatric
  • May be associated with other neoplasms
  • Pediatric type metastasizes to lymph nodes
    • One series of pediatric type occuring in adults (Rege 2011)
  • Does not include multiple incidental microscopic GIST

Original posting/last update : 12/2/09, 8/13/11, 12/4/11

Multiple/Familial/Pediatric/Syndromes

• AD = autosomal dominant, GL = germ line, SDH = succinate dehydrogenase, paragang = paraganglioma, mets = metastases
• Mutations entries refer to germ line and somatic unless indicated otherwise; “Most negative” indicates that while a minority of cases may have somatic mutations in KIT or PDFGRA, most do not, in spite of positive staining for KIT.
• Incidental microscopic (seedling) GIST do not apply to the definitions of any of these syndromes; they can be found in up to 10% of esophagogastrectomies but are rarer in other sites

Familial

• See left sidebar for detailed general criteria for GIST
  • Germ line KIT or PDGFRA mutation
  • Autosomal dominant
    • Incomplete penetrance
  • Mean age 45 years
  • Males and females affected
  • Usually small intestine
  • Frequently multiple
  • Occasional interstitial cell of Cajal (ICC) hyperplasia
  • Some cases with
    • Mucocutaneous hyperpigmentation
    • Mast cell lesions
    • Melanoma
    • Esophageal dysmotility/achalasia
  • Frequently aggressive, even if small and with low mitotic rate
• References (see left side bar for general GIST bibliography)
  • Robson ME, Glogowski E, Sommer G, Antonescu CR, Nafa K, Maki RG, Ellis N, Besmer P, Brennan M, Offit K. Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res. 2004 Feb 15;10(4):1250-4.
  • Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogatko Y, Heslin MJ, Eisenberg B, Birbe R, Patchefsky A, Dunbrack R, Arnoletti JP, von Mehren M, Godwin AK. Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clin Cancer Res. 2005 May 15;11(10):3668-77.
  • Lasota J, Miettinen M. A new familial GIST identified. Am J Surg Pathol. 2006 Oct;30(10):1342.
  • Kleinbaum EP, Lazar AJ, Tamborini E, Mcauliffe JC, Sylvestre PB, Sunnenberg TD, Strong L, Chen LL, Choi H, Benjamin RS, Zhang W, Trent JC. Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor. Int J Cancer. 2008 Feb 1;122(3):711-8.

Carney-Stratakis Syndrome

• See left sidebar for detailed general criteria for GIST
• Familial paraganglioma and GIST
• Autosomal dominant
• Germline mutations in succinate dehydrogenase genes SDHB, SDHC or SDHD
• No germline or somatic CKIT or PDGFRA mutations
• Mean age 23
  • Males and females affected
• Nearly all stomach
  • Frequently multiple and multinodular
• GIST may metastasize to lymph nodes
  • Usually protracted, indolent course (e.g. 15 years) in most cases even with metastasis or recurrence
• Paragangliomas frequently aggressive
• Presentation (except for the triad features), pathology and behavior are essentially the same as Carney Triad and sporadic SDHB deficient (pediatric type) GIST
  • Must exclude NF1 and Carney Triad
• References (see left side bar for general GIST bibliography)
• Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002 Mar 1;108(2):132-9.
• Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88.
• Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, Levy I, Xekouki P, van Nederveen FH, den Bakker MA, O'Sullivan M, Dinjens WN, de Krijger RR. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011 Jan;24(1):147-51.

Carney Triad

• GIST in Carney triad (see left sidebar for detailed criteria for GIST)
• Includes pulmonary chondroma and paraganglioma
• Few with identifiable CKIT or PDGFRA mutations
• CKIT stain is generally positive
• Succinate dehydrogenase subunit B (SDHB) deficient
• Not familial
• Most <age 30
• Female predominance (88%)
• Virtually all gastric and epithelioid (86%)
• Frequently multiple and multinodular
• High incidence of metastasis and recurrence but course is protracted
  • Reported 100% 10 year survival and 73% 40 year survival (Zhang)
• Presentation (except for the triad features), pathology and behavior are essentially the same as Carney-Stratakis syndrome and sporadic SDHB deficient (pediatric type) GIST
  • Rule out Carney-Stratakis syndrome
    • Familial, associated with paragangliomas but no chondromas
• References (see left side bar for general GIST bibliography)
  • Agaimy A, Pelz AF, Corless CL, Wünsch PH, Heinrich MC, Hofstaedter F, Dietmaier W, Blanke CD, Wieacker P, Roessner A, Hartmann A, Schneider-Stock R. Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep. 2007 Jul;18(1):9-15.
  • Zhang L, Smyrk TC, Young WF Jr, Stratakis CA, Carney JA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol. 2010 Jan;34(1):53-64.
  • Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, Levy I, Xekouki P, van Nederveen FH, den Bakker MA, O'Sullivan M, Dinjens WN, de Krijger RR. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011 Jan;24(1):147-51

NF1

• GIST in NF1 (neurofibromatosis) (see left sidebar for detailed criteria for GIST)
• Germ line NF1 mutation
• Autosomal dominant
• Associated with café au lait spots, neurofibromas, pheochromocytomas
• 0-15% with identifiable somatic CKIT or PDGFRA mutations in GIST
• CKIT and DOG1 positive in 90-100%
• Mean age 40-50
• Males and females affected
• Usually small intestine
• Frequently multiple
• Nearly all are spindled
  • Skeinoid fibers very common (80%)
• Interstitial cell of Cajal hyperplasia in most cases
• 35-65% of GIST are S100 positive
• May be patchy
• Usual GIST 5% positive
• Most are small and benign
• May be aggressive if large and mitotically active
• References (see left side bar for general GIST bibliography)
  • Takazawa Y, Sakurai S, Sakuma Y, Ikeda T, Yamaguchi J, Hashizume Y, Yokoyama S, Motegi A, Fukayama M. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease). Am J Surg Pathol. 2005 Jun;29(6):755-63.
  • Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol. 2005 Sep;29(9):1170-6.
  • Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006 Jan;30(1):90-6.
  • Wang JH, Lasota J, Miettinen M. Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists. J Cancer. 2011 Feb 16;2:90-3.

SDHB Deficient (Pediatric Type)

• SDHB deficient GIST include both sporadic tumors and two syndromes that are covered in more detail separately
• Carney triad
• Carney-Stratakis syndrome
• Sporadic tumors are predominantly pediatric
• SDHB deficient tumors make up virtually all tumors < age 20 and half of those age 20-30
• Infrequent adult cases have been reported (Rege 2011)
• Most are young adults but reported up to 63 years
• Same behavior and characteristics as pediatric cases
• On followup, some later fulfill criteria for syndromic GIST
• Both syndromic and sporadic SDHB deficient GISTs share features distinct from usual SDHD positive tumors

• Genetic basis of SDHB deficient GIST is not well understood
• CKIT and DOG1 stains positive >90%
• Lack CKIT or PDGFRA mutations
• Germline SDHB mutations in Carney-Stratakis syndrome
• No germline or somatic mutations have been found in Carney triad or sporadic cases
• NF1 associated cases do not fit well into the above dichotomy
• Although SDHB positive, they lack CKIT or PDGFRA mutations
• They are not imatinib sensitive
• Although frequently multiple, they are exclusively spindled and restricted to the intestines

• References (see left side bar for general GIST bibliography)
• Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol. 2005 Oct;29(10):1373-81.
• Prakash S, Sarran L, Socci N, DeMatteo RP, Eisenstat J, Greco AM, Maki RG, Wexler LH, LaQuaglia MP, Besmer P, Antonescu CR. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol. 2005 Apr;27(4):179-87.
• Agaram NP, Laquaglia MP, Ustun B, Guo T, Wong GC, Socci ND, Maki RG, DeMatteo RP, Besmer P, Antonescu CR. Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res. 2008 May 15;14(10):3204-15.
• Rege TA, Wagner AJ, Corless CL, Heinrich MC, Hornick JL. "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol. 2011 Apr;35(4):495-504.
• Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, Tobias V, Samra J, Goldstein D, Smith C, Sioson L, Parker N, Smith RC, Sywak M, Sidhu SB, Wyatt JM, Robinson BG, Eckstein RP, Benn DE, Clifton-Bligh RJ. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010 May;34(5):636-44.
  
• Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, Levy I, Xekouki P, van Nederveen FH, den Bakker MA, O'Sullivan M, Dinjens WN, de Krijger RR. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011 Jan;24(1):147-51.
  
• Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011 Nov;35(11):1712-21.
• Wang JH, Lasota J, Miettinen M. Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists. J Cancer. 2011 Feb 16;2:90-3.

Sporadic Multiple

• Multicentric sporadic GIST (see left sidebar for detailed criteria for GIST)
• Somatic CKIT or PDGFRA in 80%
• May have different mutations in different tumors from same patient
• Not familial
• Mean age 60
• Males and females affected
• Usually gastric
• Multiple small tumors in stomach accompanying one large one
• Multiple sites not involved
• Aggressive behavior is unusual
• Rule out all other syndromes of multiple GIST
• References (see left side bar for general GIST bibliography)
  • Haller F, Schulten HJ, Armbrust T, Langer C, Gunawan B, Füzesi L. Multicentric sporadic gastrointestinal stromal tumors (GISTs) of the stomach with distinct clonal origin: differential diagnosis to familial and syndromal GIST variants and peritoneal metastasis. Am J Surg Pathol. 2007 Jun;31(6):933-7.

Supplemental studies

Immunohistology

• DOG1 (Discovered On GIST) is a newly available monoclonal antibody that appears to be more sensitive and specific than CD117
  • The percent positive depends on case selection
    • Consult cases tend to have lower reactivity
    • Cases from treatment series tend to have high KIT reactivity
  • See side by side comparison below
• CD117 usually diffuse strong staining
• Frequently perinuclear dots
• Occasionally focal

• From Espinosa 2008
• Low percentage reactivities due to referral bias
  • Non-reactive cases more often sent for consultation
• DOG1 positive on 36-70% of KIT negative GIST (Liegl; Espinosa)
• Miettinen 2009 reports 6/37 synovial sarcomas reactive for DOG1

Molecular Studies

• Most have gain of function mutations in KIT
  • Actual percentage reported is highly variable, from 50-90%
    • May depend upon case selection or technical matters
    • From unselected or population based studies:
      • KIT 65-75%
      • PDGFRA 5-12%
    • In series of treated patients, KIT is frequently higher as it may be an inclusion criterion
    • In series of referral cases, KIT is frequently lower, as negative cases are more often referred
• About 1/3 of KIT mutation negative cases have mutations in PDGFRA instead
• Pediatric and NF1 associated GIST typically lack KIT and PDGFRA mutations
  • CD117 and DOG1 positive staining in nearly all cases
• Various mutations can be correlated to response to specific therapies (see Lasota 2008)
  • If further therapy is anticipated, identification of the precise mutation is worthwhile for determining therapy
• Secondary mutations may occur following therapy

Molecular Genetic Studies

• Frequency of KIT mutations

  KIT
  exon 9	18%
  exon 11	67%
  exon 13	2%
  exon 17	2%
  PDGFRA
  exon 12	1%
  exon 18	4%

• Screening for kinase mutations in suspectied GISTs can be clinically useful
  • Molecular confirmation of GIST
  • Clinical response to treatment with small molecular inhibitor Gleevec is predicted by mutation status
    • KIT exon 11 mutant GIST are sensitive to low doses
      • No increased response from higher dose
    • KIT exon 9 mutations predict drug dose sensitivity
      • High doses are more effective than low
    • KIT immunohistochemistry negative cases have a gain of function KIT mutation
      • Usually exon 11
      • Responsive to anti-KIT therapy
    • GIST with PDGFRa exon 18 D842 V mutations are resistant to Gleevec
• Secondary mutations may follow treatment with small molecule inhibitors
  • Typically clustered in KIT ATP binding pocket and kinase catalytic regions
    • Drugs effective against such mutations are in development
• Other tumors with KIT mutations
  • Acute myelogenous leukemia
  • Mastocytosis
  • Myeloproliferative disorders
  • Primary mediastinal germ cell tumor
  • Seminoma
• For more reading:
  • Heinrich 2003, 2008
  • Corless 2005

Differential Diagnosis

General differential diagnostic features of GIST reactive antibodies (see Supplemental Studies):

• CD117 stains very few other spindled lesions but stains many carcinomas and melanomas
• CD34 stains many spindled lesions but stains almost no carcinomas or melanomas
• DOG1 stains very few spindled lesions or melanomas or carcinomas

• Spindled, bland GIST DDx
  • 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
  • Poorly differentiated carcinoma
  • Melanoma/clear cell sarcoma
  • Glomus tumor
  • Gangliocytic paraganglioma
  • GI endocrine carcinoma
  • Extramedullary myeloid tumor
  • GI mucosal benign epithelioid nerve sheath tumo

Spindled, Bland GIST DDx

GIST (spindled, bland)	Gastric Plexiform Fibromyxoma
Usually solitary nodule	Multinodular, plexiform
Myxoid pattern rare	Myxoid pattern predominates
KIT and/or DOG1 74-95%	KIT and DOG1 negative
CD34 frequently positive	CD34 negative

Spindled, Malignant GIST DDx

Epithelioid GIST DDx

Clinical

• Mean age 55-60
• Spread is typically over peritoneal surface
  • Metastases may be seen to liver, lungs, bone
  • Lymph node metastases very rare except in SDHB deficient syndromic and pediatric-type cases
• Most cases responsive to Imatinib mesylate (tyrosine kinase inhibitor)
• Also known as Gleevec or Glivec
• CD117 negative cases may still respond
• If further therapy is anticipated, identification of the precise mutation is worthwhile for determining therapy
• SDHB deficient cases are poorly sensitive

Grading/Staging/Report

Grading

Staging

• See 7th edition AJCC manual for staging
  • Key cutoffs in size are 2, 5 and 10 cm
• Above grading scheme incorporates one element of staging, the tumor size
• Other relevant points should be included in report
  • Wider margins of soft tissue tumors are not required

Report should include:

• Epithelioid vs. spindle morphology
• Mitotic rate
• Presence or absence of coagulative tumor necrosis
• Results of immunohistologic stains and genetic studies, if performed
• Size
• Location
• Margin status
  • Any clear margin is sufficient
  • Wider margins of soft tissue tumors are not required
• Organs and tissues involved
• Sites of spread

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