KIT-negative gastrointestinal stromal tumors: proo... - ResearchGate

Am J Surg Pathol • Volume 28, Number 7, July 2004
KIT-Negative GISTs
consistent negativity of these tumors for KIT by both immunohistochemistry
and immunoblotting. No tumors had mutations
involving KIT and PDGFRA concomitantly, corroborating
previous evidence that these are mutually exclusive transforming
equivalents in GIST oncogenesis. 9 Three tumors
otherwise indistinguishable from the others in this study had
no detectable KIT or PDGFRA mutations, suggesting that
some KIT-negative GISTs arise through alternative oncogenic
mechanisms.
The biologic basis for the absence of KIT expression, in
the subgroup of GISTs identified in our study, is unclear. Most
of the tumors contained PDGFRA mutations, and as discussed
above, such mutations appear to be alternate, or “either/or”
transforming mechanisms, compared with the more common
KIT oncogenic mutations in GISTs. In PDGFRA-mutant tumors,
KIT expression may simply be superfluous and therefore
down-regulated, as mutant PDGFRA appears to act as an
oncogenic substitute for KIT in these cases. It would have been
of interest, if feasible, to assess the PDGFRA-mutant cases immunohistochemically
for evidence of PDGFRA protein expression.
However, multiple trials using a variety of currently
available antibodies (in both our Boston and Portland laboratories)
have failed to identify any commercial antibody that
yields meaningful and reproducible results with a clean background.
Thus, we do not think that these presently available
antibodies have clinical utility. More puzzling are the four tumors
containing KIT gene mutations but in which KIT protein
expression was not demonstrated. It is counterintuitive that the
neoplastic GIST cells would select for a genomic KIT mutation
in the absence of the functional protein product of that gene.
One possibility is that these tumors originated through a KITactivated
pathway and then later became independent as a result
of additional secondary mutations. 6 Another possibility is
that these discordant genomic and protein findings could be
related to technical factors. For example, deletion of the KIT
C-terminus, containing the epitope against which the DAKO
KIT antibody was raised, could lead to false-negative immunostaining
results. On the other hand, C-terminal truncation
cannot account for the negative KIT immunohistochemistry in
all KIT-negative GISTs, because we corroborated absence of
KIT protein expression, using antibodies to a kinase domain
epitope, by immunoblotting in three PDGFRA-mutant or KITmutant
cases with available frozen tissue. Finally, it is conceivable
that routine immunohistochemistry is insufficiently sensitive
to detect the lowest biologically relevant levels of KIT
expression in all tumors. We recently reported a case of a KITmutant
GIST in which KIT expression was virtually absent,
excluding the patient from a clinical trial. The tumor became
PET negative and showed shrinkage on CT scan when the patient
was treated with imatinib off protocol. 1 Based on this anecdotal
example, it is possible that other KIT-mutant GISTs
that lack KIT expression, such as the 4 cases in the present
series, are imatinib sensitive.
In summary, we report that a small subset of GISTs lack
KIT expression but have otherwise typical clinical, histopathologic,
and cytogenetic features. Most of these tumors have at
least partly or totally epithelioid cytomorphology and harbor
PDGFRA mutations, but some examples have KIT mutations
despite the absence of demonstrable KIT protein expression.
Given that most KIT-negative GISTs contain PDGFRA or KIT
mutations, one might expect that patients with such tumors
could potentially respond to therapeutic PDGFRA and KIT inhibition
with imatinib. 8 Even acknowledging that the commonest
PDGFRA D842V mutation is intrinsically imatinib resistant,
8,11 approximately 30% of the PDGFRA mutations
identified are known to be potentially imatinib sensitive, 8 providing
a greater hope of treatment response than with any other
currently approved therapy. Therefore, it is important for pathologists
and oncologists to be aware that, in the context of
otherwise typical morphology, a GIST diagnosis should not be
precluded on the basis of negative immunohistochemical
staining for KIT and that such patients should not a priori be
denied imatinib therapy. Where testing is available, the finding
of KIT or PDGFRA mutations not only may help to confirm or
enable the diagnosis of a KIT-negative GIST, but can also provide
important prognostic information for patients in whom
imatinib therapy is being considered. 8
ACKNOWLEDGMENTS
The authors thank Troy Bainridge, Laura McGreevey,
Andrea Haley, Ajia Town, Maureen Thyne, and Catherine
Quigley for excellent technical assistance.
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