Molecular Pathobiology of Gastrointestinal Stromal ... - ResearchGate

Molecular Pathobiology of Gastrointestinal Stromal ... - ResearchGate

Annu. Rev. Pathol. Mech. Dis. 2008.3:557-586. Downloaded from

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line KIT exon 11 mutation. The remaining

five patients each had two synchronous tumors;

in four cases the tumors had matching

KIT mutations that were not germ line,

suggesting a clonal relationship. In the fifth

case the tumors had different mutations. Our

experience is similar. In addition to observing

multiple GISTs in familial GIST patients

and NF1 patients, we have analyzed

GISTs arising at different anatomic sites in

three nonsyndromic patients. In one case a

metachronous tumor had a mutation identical

to the first tumor and most likely represented

an abdominal recurrence. In the other two

cases (1 synchronous, 1 metachronous) the tumors

had differing genotypes (C.L. Corless

& M.C. Heinrich, unpublished information).

From the series by Kang et al. and our own

experience, it is apparent that patients can develop

more than one GIST without an identifiable

germ line risk factor (kinase gene or

NF1 mutation). This suggests that there are

other genes yet to be discovered that predispose

to GIST development.

KIT-Negative GISTs

In approximately 5% of GISTs, staining for

CD117 is completely negative or, at most,

equivocally positive, which leaves the morphologic

diagnosis somewhat in question. A

common misconception is that all these tumors

harbor PDGFRA mutations, but the actual

figure is more in the range of 30% (48,

50, 51). Over half of CD117-negative tumors

have KIT gene mutations, usually in exon

11, which has significant therapeutic implications

(see Treatment of GIST, below). It appears

that immunohistochemistry lacks sufficient

sensitivity to detect the small amounts

of mutant kinase that may sustain the tumor

cells in these cases. Whether a GIST can be

negative for CD117 staining and wild type for

KIT and PDGFRA is not entirely clear, as the

diagnosis must then be based strictly on exclusion.

It is likely that future studies will reveal

additional interesting variants in the stromal

tumor family.

568 Corless·Heinrich



In patients with a germ line KIT gene mutation,

multifocal proliferations of morphologically

benign, CD117-positive ICC cells are

commonly observed. These likely represent

the earliest stage of GIST development. Intriguingly,

minute growths (1 to 10 mm) of

ICC/GIST-like cells are present in 22% to

35% of thoroughly examined stomachs from

the adult population (76–78). The frequency

of KIT mutations in such incidental lesions

was reportedly low in one study, but ranged

from 46% to 85% in two other studies. A

single, subcentimeter GIST with a PDGFRA

mutation has also been reported (76). These

observations indicate that oncogenic kinase

mutations can contribute to the early development

of GISTs.

The prognostic impact of kinase mutations

has been examined in a number of retrospective

studies. Many groups have noted that KIT

exon 11 mutations are a negative prognostic

factor in clinically detected GISTs (79–

86). In particular, deletions involving codons

557 and 558 have been associated with malignant

behavior (59, 87, 88). It is possible that

mutant forms of KIT lacking these codons

generate stronger proliferative signaling than

other KIT mutations, but this remains to be

proven and the available data are insufficient

to be incorporated into routine clinical risk


As a group, PDGFRA mutant GISTs appear

to be less aggressive than KIT mutant

GISTs (89, 90), yet PDGFRA mutant

tumors can still progress and kill patients.

Once GISTs become metastatic, kinase genotype

does not factor into overall survival (91).

Thus, although a particular kinase mutation

may set the initial course of a GIST, the prognosis

at the time of clinical presentation is

clearly influenced by other genetic events.

Unfortunately, our knowledge of these additional

mutations remains limited, and current

recommendations for assessing the risk

of progression of a newly diagnosed primary

GIST are based on three simple parameters:

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