Anatomic Pathology / KIT IN SOFT TISSUE SARCOMAS
Immunohistochemical Staining for KIT (CD117) in Soft
Tissue Sarcomas Is Very Limited in Distribution
Jason L. Hornick, MD, PhD, and Christopher D.M. Fletcher, MD, FRCPath
Key Words: KIT; CD117; GIST; STI571; Sarcoma; Immunohistochemistry
Abstract
We performed immunohistochemical analysis for
KIT in 365 soft tissue sarcomas. Most tumors evaluated
were completely negative for KIT, including all cases of
leiomyosarcoma, rhabdomyosarcoma,
myxofibrosarcoma, liposarcoma, solitary fibrous tumor,
synovial sarcoma, dermatofibrosarcoma protuberans,
schwannoma, malignant peripheral nerve sheath tumor,
clear cell sarcoma, low-grade endometrial stromal
sarcoma, and follicular dendritic cell sarcoma. Tumors
showing occasional immunoreactivity for KIT included
extraskeletal myxoid chondrosarcoma (2/20), Ewing
sarcoma/malignant primitive peripheral
neuroectodermal tumor (4/20), melanotic schwannoma
(3/5), metastatic melanoma (4/20), and angiosarcoma
(5/20). In most cases, staining for KIT was focal. Rare
tumor cells showing KIT positivity were identified in a
small number of other tumors. This study demonstrates
very limited expression of KIT in soft tissue tumors
other than gastrointestinal stromal tumors and
underscores the discriminatory value of KIT
immunohistochemical analysis for differential
diagnosis. As some of these findings differ markedly
from previous reports, it is evident again that variations
in immunohistochemical technique can lead to major
discrepancies in positive staining. Since treatment
eligibility for selective tyrosine kinase inhibitors such as
STI571 hinges on positive immunostaining,
standardization and reproducibility of meaningful
results are critically important.
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c-kit encodes a membrane receptor tyrosine kinase that is
expressed in gastrointestinal stromal tumors (GISTs) but not
in smooth muscle or neural tumors of the gastrointestinal
tract.1-3 Immunohistochemical staining for KIT (CD117) is
therefore increasingly regarded as invaluable in the differential
diagnosis of intra-abdominal mesenchymal tumors. c-kit also
is expressed in limited normal tissue cell types, including mast
cells, germ cells, melanocytes, breast epithelium, and interstitial cells of Cajal,4-7 the pacemaker cells of the gastrointestinal
tract from which lineage GISTs are thought to originate.2,8
Mutations in c-kit leading to the constitutive activation of the
tyrosine kinase are believed to have a role in the tumorigenesis
of the overwhelming majority of GISTs.9-13 STI571, a small
molecule inhibitor of the bcr-abl fusion protein of chronic
myelogenous leukemia,14,15 also has been shown to be a selective inhibitor of the tyrosine kinase activity of KIT.16 A recent
report demonstrated the clinical potential of STI571 in a
patient with metastatic GIST.17 Results of phase 1 and 2 clinical trials establishing the safety and efficacy of STI571 in
patients with recurrent or metastatic GISTs were presented
recently.18,19 In the phase 2 study, 19 (54%) of 35 evaluable
patients showed partial responses and 12 (34%) showed stable
disease.18 The promise of this novel therapeutic strategy for
GISTs has stimulated considerable clinical (and indeed
patient) interest in the possible expression of KIT in other
tumors, particularly of the mesenchymal type.
There have been several reports of KIT immunostaining
in a limited number of soft tissue tumors other than GISTs,
including metastatic melanoma, clear cell sarcoma, angiosarcoma, extraskeletal Ewing sarcoma, and desmoid fibromatosis, at times with conflicting results.1,20-22 In the present
study, we sought to undertake a comprehensive examination
© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
❚Table 1❚
Summary of KIT Immunostaining in Soft Tissue Tumors
Tumor
Total No.
No. (%) of
of Cases Positive Cases
Leiomyosarcoma
Rhabdomyosarcoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma
Myxoid/round cell liposarcoma
Dedifferentiated liposarcoma
Solitary fibrous tumor
Synovial sarcoma
Dermatofibrosarcoma protuberans
Desmoid fibromatosis
Extraskeletal myxoid chondrosarcoma
Ewing sarcoma/malignant primitive
peripheral neuroectodermal tumor
Schwannoma
Melanotic schwannoma
Perineurioma
Malignant peripheral nerve sheath tumor
Metastatic melanoma
40
25
20
10
10
10
20
20
30
20
20
20
0
0
0
1
0
0
0
0
0
1
2
4
(0)
(0)
(0)
(10)
(0)
(0)
(0)
(0)
(0)
(5)
(10)
(20)
20
5
10
20
20
0
3
2
0
4
(0)
(60)
(20)
(0)
(20)
Clear cell sarcoma
Angiosarcoma
Low-grade endometrial stromal sarcoma
Follicular dendritic cell sarcoma
10
20
10
5
0
5
0
0
(0)
(25)
(0)
(0)
of KIT immunohistochemical staining in a large number of
soft tissue tumors, both to clarify the discriminant value of
KIT immunostaining for differential diagnosis and to
examine whether other mesenchymal malignant neoplasms
might be candidates for therapeutic strategies involving KIT
tyrosine kinase inhibitors such as STI571. We focused principally on sarcomas and other aggressive mesenchymal
lesions because of the new therapeutic relevance of KIT
expression, but we also included certain benign or locally
aggressive spindle cell lesions because they may enter the
differential diagnosis of GIST.
Materials and Methods
Cases were retrieved from the consultation files of one
of the authors (C.D.M.F.) or the routine surgical pathology
files of Brigham and Women’s Hospital, Boston, MA (10
cases) or St Thomas’s Hospital, London, England (3 cases).
All tumors studied had been formalin-fixed. All diagnoses
were based on standard and widely accepted criteria.23,24
Immunohistochemical staining for KIT (CD117) was
performed using a 1:250 dilution of the rabbit polyclonal
antibody A4502 (DAKO, Carpinteria, CA) with the EnVision detection system (DAKO). No antigen retrieval method
was used. In cases of melanotic schwannoma, the LSAB
detection system conjugated with alkaline phosphatase
(DAKO) was used to yield a red reaction product. Appropriate positive and negative controls were used throughout.
© American Society for Clinical Pathology
Comments
Very rare cells positive
Focal weak positivity
1 case with >50% of cells positive; 1 case with focal weak positivity
1 case with >50% of cells positive; 3 cases with focal positivity
2 cases with >50% of cells positive; 1 case with focal positivity
1 case with >50% of cells positive; 1 case with rare cells positive
2 cases with focal positivity; 1 case with focal weak positivity; 1 case
with rare cells positive
3 cases with focal positivity; 2 cases with focal weak positivity
Results
We examined 365 soft tissue tumors for KIT expression
by immunohistochemical staining ❚Table 1❚. The presence of
mast cells in virtually all cases served as an internal control.
There was no tumor staining for KIT in 40 cases of
leiomyosarcoma, including 10 cases each of uterine, cutaneous, vascular, and soft tissue tumors. KIT immunostaining
also was completely negative in 25 cases of rhabdomyosarcoma, including 10 cases of alveolar type, 10 cases of
embryonal or spindle cell type, and 5 cases of pleomorphic
type. In addition, 20 cases of myxofibrosarcoma were negative for KIT. One case of 10 low-grade fibromyxoid
sarcomas showed very rare tumor cells positive for KIT. All
liposarcomas evaluated were negative for KIT, including 10
cases each of myxoid/round cell liposarcoma and dedifferentiated liposarcoma.
A prominent mast cell infiltrate showing anticipated
KIT positivity was seen in several cases of solitary fibrous
tumor (SFT) and synovial sarcoma ❚Image 1❚; however, no
staining of tumor cells was observed in 20 cases each of
either synovial sarcoma or SFT. Rare stromal endothelial
cells showed KIT staining in a case of SFT. Thirty cases of
dermatofibrosarcoma protuberans were negative for KIT,
including 15 cases of the higher grade fibrosarcomatous
variant. One case of extra-abdominal desmoid fibromatosis
showed focal weak immunostaining for KIT, whereas the
remaining 19 cases of fibromatosis, both intra-abdominal
and extra-abdominal, were completely negative.
Am J Clin Pathol 2002;117:188-193
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Hornick and Fletcher / KIT IN SOFT TISSUE SARCOMAS
❚Image 1❚ A prominent mast cell infiltrate positive for KIT in a
case of monophasic synovial sarcoma (immunohistochemical stain, ×200).
❚Image 2❚ Diffuse immunoreactivity for KIT in a case of
extraskeletal myxoid chondrosarcoma (immunohistochemical
stain, ×200).
❚Image 3❚ A case of Ewing sarcoma/malignant primitive
peripheral neuroectodermal tumor showing positivity for KIT
(immunohistochemical stain, ×200).
❚Image 4❚ Cytoplasmic staining for KIT in a case of melanotic
schwannoma (immunohistochemical stain with alkaline
phosphatase, red reaction product, ×400).
Among 20 extraskeletal myxoid chondrosarcomas, 1
case showed diffuse membranous staining for KIT ❚Image
2❚, while a second case demonstrated focal weak positivity.
Four of 20 cases of Ewing sarcoma/malignant primitive
peripheral neuroectodermal tumor (MPNET) were positive
for KIT ❚Image 3❚; in 3 of these cases, staining was focal.
Whereas all 20 schwannomas examined were negative for
KIT, including 10 cases of cellular schwannoma and 4 cases
of gastrointestinal schwannoma, 3 of 5 melanotic schwannomas showed positive staining for KIT ❚Image 4❚. Two of
10 soft tissue perineuriomas were positive for KIT, with 1
case showing diffuse cytoplasmic staining; in the second
case, only rare tumor cells were positive. There was no
tumor staining for KIT in 20 cases of malignant peripheral
nerve sheath tumor.
Focal membranous tumor cell staining for KIT was seen
in 4 of 20 cases of metastatic melanoma ❚Image 5❚. All 10
clear cell sarcomas (malignant melanomas of soft tissue)
examined were completely negative for KIT. Of 20 cases of
angiosarcoma, 5 showed focal staining for KIT ❚Image 6❚.
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Am J Clin Pathol 2002;117:188-193
© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
❚Image 5❚ Focal membranous staining for KIT in a case of
metastatic melanoma (immunohistochemical stain, ×400).
❚Image 6❚ A case of epithelioid angiosarcoma showing focal
KIT positivity (immunohistochemical stain, ×400).
No staining for KIT was seen in either 10 low-grade
endometrial stromal sarcomas or 5 follicular dendritic cell
sarcomas.
and to reflect the majority view of daily clinical practice, this
seemed to us to be the most realistic choice. The precise
staining protocols recommended in the various trials of
STI571 have varied somewhat with regard to antigen
retrieval. However, it has been our consistent personal experience with this particular antibody (as with a few others)
that staining intensity is actually reduced after heat-induced
antigen retrieval; thus, the method used in our laboratory was
optimized without this step.
Our positive results are concordant with those reported
previously for several tumors, although we found fewer KITpositive cases. We observed focal KIT immunoreactivity in
25% of angiosarcomas, while in a previous report, more than
half of angiosarcomas were positive for KIT, with half of those
cases showing reactivity in more than 50% of tumor cells.20
We also confirmed focal KIT immunopositivity in metastatic
melanoma (20% of cases), which has been described at a
somewhat higher frequency by others.1,21 Another group
examining KIT expression in benign and malignant
melanocytic lesions found decreasing KIT staining with
melanoma progression and the lowest numbers of positive
cases in metastatic tumors.25 Studies in vitro and in mouse
models have shown that enforced KIT expression in
melanoma cell lines decreases both tumorigenicity and metastases.26,27 Since loss of KIT seems to be associated with malignancy in melanocytic neoplasia, tyrosine kinase inhibitors are
unlikely to be of therapeutic benefit in metastatic melanoma.
Interestingly, we found no KIT-positive cases of clear cell
sarcoma, although a previous study reported tumor staining for
KIT in nearly 50% of such cases.1 These discrepancies might
be attributable to the different commercially available
Discussion
In this study, we found immunohistochemical staining
for KIT in a very limited number of soft tissue tumors. In the
majority of positive cases, KIT staining was focal. In
contrast, GISTs typically show diffuse and generally strong
staining for KIT, usually in a cytoplasmic distribution with or
without dot-like accentuation. We used the rabbit polyclonal
antibody A4502 (DAKO), which has shown consistent
performance with low background in our hands. More than
35 consecutive GISTs found to overexpress KIT by immunohistochemical analysis in our laboratory using this antibody
have been confirmed to express KIT by immunoblotting
(J.A. Fletcher, MD, verbal communication, 2001), and, thus,
we have gained confidence with this antibody in more than
400 GISTs that we have examined during the past 3 years
(unpublished data). We have been unable to achieve reproducible or consistently interpretable immunohistochemical
results with commercially available KIT antibodies used in
some other laboratories, although we are aware that others
have had more success.1 However, for the purposes of this
study, we selected the A4502 polyclonal antibody based not
only on our personal experience but also because it seems to
be the most widely used KIT antibody and because it is the
antibody specified in the ongoing large cooperative clinical
trials of STI571. Therefore, in the interests of practicality
© American Society for Clinical Pathology
Am J Clin Pathol 2002;117:188-193
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polyclonal antibody used in these other series, which, in our
personal experience, is more often associated with high background (and, hence, false-positive) staining.
We found KIT immunostaining in 20% of Ewing
sarcoma/MPNET cases, which again is approximately half
the frequency reported in a recent series.21 The ligand for
KIT, stem cell factor, has previously been shown to protect
MPNET and Ewing sarcoma cell lines from apoptosis in
vitro.28 A recent study in a mouse model, however, reported
a decrease in the metastatic rate of Ewing sarcoma cells
following pretreatment with stem cell factor.29 These preliminary experiments suggest that KIT may have a role in the
malignant phenotype of these tumors. Whether KIT
inhibitors might provide therapeutic benefit to the subset of
patients with Ewing sarcoma/MPNET whose tumors show
immunoreactivity for KIT remains to be determined.
Despite a previous report of several cases of dermatofibrosarcoma protuberans that showed focal reactivity for
KIT,1 in our hands, no cases of dermatofibrosarcoma protuberans were positive for KIT, including higher grade
fibrosarcomatous cases. Of 20 cases of desmoid fibromatosis, we found focal weak KIT immunostaining in only 1
case. Our results differ strikingly from a recent report that
described KIT staining in 75% of intra-abdominal desmoid
tumors.22 Interestingly, we used the same antibody as these
authors; however, we used no pretreatment, whereas they
performed heat-induced antigen retrieval for KIT immunostaining. The pretreatment conditions used by these authors
may have caused nonspecific tumor cell staining. In a subsequent report, 14 cases of fibromatosis purportedly all showed
positive KIT staining in tumor cells using the identical antibody with or without heat-induced antigen retrieval.30 These
findings are difficult to reconcile with our data, particularly
since through daily clinical practice outside the present
study, we have stained at least 20 other cases with similarly
negative results. Furthermore, kit-activating mutations and
KIT expression by immunoblotting have never been identified in a desmoid fibromatosis (J.A. Fletcher, MD, verbal
communication, 2001). It is likely that technical differences
in experimental protocol led to this apparent nonspecific
staining in fibromatosis.
We identified several tumors that have not previously
been reported to show KIT immunoreactivity. Among nerve
sheath tumors, a subset of melanotic schwannomas and
perineuriomas were positive for KIT, although we found no
cases of conventional schwannoma or malignant peripheral
nerve sheath tumor showing KIT immunostaining. Finally,
occasional cases of extraskeletal myxoid chondrosarcoma
demonstrated KIT positivity. The significance, if any, of
these findings awaits further elucidation through the study of
additional cases and molecular genetic analysis. Importantly,
we have not seen KIT positivity (in the present study or in a
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large number of tumors studied in daily clinical practice) in
leiomyosarcomas, by far the most frequent differential diagnosis of GIST. For all tumor types examined in the present
study, the KIT-positive tumor cells were generally a small
minority (<5% in most cases) and, hence, unlikely to be of
therapeutic relevance. Because this was a retrospective study,
in none of the positive cases did we have suitable material
for c-kit sequencing. However, in other cases of Ewing
sarcoma and desmoid fibromatosis that have been sequenced
in our laboratory, none have shown kit mutation (J.A.
Fletcher, MD, verbal communication, 2001).
We found that immunostaining for KIT in soft tissue
tumors other than GISTs is very limited. As our results differ
substantially from those reported by some other laboratories,
it is evident that choice of antibody and experimental conditions have a striking effect on the apparent immunoreactivity
of tumors. Since treatment eligibility for tyrosine kinase
inhibitors such as STI571 hinges on the results of KIT
immunohistochemical staining results, reproducibility and
the elimination of nonspecific staining are critical. Given the
indisputable and widely recognized interlaboratory variability in immunohistochemical staining results in at least a
small proportion of human tumors examined in routine clinical practice, the ideal route to achieve consistency is unclear.
In our opinion, the notion of a federally approved or
mandated antibody or technique is both untenable and unrealistic and, as exemplified by tests for HER2/neu expression,
runs the risk of causing confusion with no discernible
benefit. In view of the relative ease with which c-kit mutational status can be determined nowadays, molecular genetic
corroboration through demonstration of kit-activating mutations in these other tumor types showing occasional KIT
positivity would seem desirable before pathologists inadvertently raise false hopes of treatment sensitivity among clinicians and patients.
From the Department of Pathology, Brigham and Women’s
Hospital and Harvard Medical School, Boston, MA.
Address reprint requests to Dr Fletcher: Dept of Pathology,
Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.
Acknowledgment: We are very grateful to Catherine Quigley
for expert technical assistance and supervision.
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