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C-kit expression in renal oncocytomas and chromophoberenal cell carcinomas
Lei Huoa, Jun Sugimurab, Maria S. Tretiakovac, Kurt T. Pattona,Rohit Guptaa, Boris Popova, William B. Laskin MDa, Anjana Yeldandi MDa,Bin Tean Tehb, Ximing J. Yang MD, PhDa,*
aDepartment of Pathology, Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine,
Chicago, IL 60611, USAbLaboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USAcDepartment of Pathology, University of Chicago, Chicago, IL 60637, USA
Received 11 May 2004; accepted 3 January 2005
0046-8177/$ – see front matter D 2005
doi:10.1016/j.humpath.2005.01.011
T Corresponding author.
E-mail address: xyang@northwester
Keywords:C-kit;
Renal cell carcinoma;
Oncocytoma;
Angiomyolipoma
Summary C-kit encodes the membrane-bound tyrosine kinase KIT, whose expression has been
identified in several types of human neoplasms. Recently, KIT has been reported to be a marker for
chromophobe renal cell carcinoma (RCC) and renal angiomyolipoma. However, expression of this
molecule has not been adequately studied in other renal tumors, particularly oncocytoma, which may
morphologically resemble chromophobe RCC. In this study, we analyzed c-kit messenger RNA
(mRNA) levels in 17 chromophobe RCCs and 20 renal oncocytomas obtained from complementary
DNA (cDNA) microarrays. Furthermore, comprehensive immunohistochemical analysis of KIT protein
using a monoclonal antibody was performed in 226 renal tumors including chromophobe RCC (n = 40),
oncocytoma (n = 41), clear-cell RCC (n = 40), renal angiomyolipoma (n = 29), and papillary RCC (n =
21) on tissue microarrays (TMAs) and was compared with immunostaining results from
25 chromophobe RCCs and 30 oncocytomas using standard sections. The staining intensity was
semiquantitatively graded on a 3-tier scoring system. All chromophobe RCCs and oncocytomas showed
significant overexpression of c-kit mRNA. The average increase of mRNA compared with normal
kidney tissue was 7.4- fold for chromophobe RCCs and 7.4- fold for oncocytomas. Immunohisto-
chemical expression of KIT was found in most chromophobe RCCs (95% in TMAs and 96% in
conventional sections) and oncocytomas (88% in TMAs and 100% in conventional sections) but was
infrequently observed in renal angiomyolipomas (17%), papillary RCCs (5%), and clear-cell RCCs
(3%). Furthermore, the average KIT immunoreactivity in TMAs was stronger in chromophobe RCC
(1.93) and oncocytoma (2.07) than in other subtypes of renal tumors tested, including angiomyolipomas
(0.17), papillary RCCs (0.05), and clear-cell RCCs (0.03). In conclusion, we found a significant
elevation of c-kit mRNA by cDNA expression microarrays and overexpression of KIT protein by
immunohistochemistry not only in chromophobe RCCs but also in oncocytomas. In contrast,
immunohistochemical expression of KIT was not detected in most other types of renal cell tumors
Human Pathology (2005) 36, 262–268
Published by Elsevier Inc.
n.edu (X.J. Yang).
C-kit in oncocytoma and chromophobe renal cell carcinoma 263
evaluated. The differential expression of c-kit in these renal tumors may have diagnostic and
therapeutic implications.
D 2005 Published by Elsevier Inc.
1. Introduction
Chromophobe renal cell carcinoma (RCC) and renal
oncocytoma are presently considered histogenetically
related neoplasms with a purported origin from the
intercalated cell of the collecting duct [1,2]. Chromophobe
RCC accounts for approximately 5% to 8% of renal cell
neoplasms and has a better prognosis than the other
subtypes of RCC such as clear cell, papillary, and collecting
duct. In contrast, renal oncocytoma is a benign neoplasmwith
an incidence of 5% among renal epithelial tumors [3].
Because chromophobe RCC and oncocytoma share many
morphological features, their diagnosis sometimes may be a
challenge, especially when a tumor is composed of cells with
abundant eosinophilic cytoplasm. In addition, clear-cell RCC
and papillary RCC may occasionally demonstrate over-
lapping histological features with chromophobe RCC or
oncocytoma. As the prognosis and treatment of these
neoplastic entities differ, a correct diagnosis is essential.
Gene-expression microarray analysis has recently shed
light on the molecular pathogenesis of renal tumors, and it
has also contributed to the identification of new biomarkers
useful for histological diagnosis. For example, differential
expression of glutathione S-transferase a in clear-cell RCC,
a-methylacyl racemase in papillary RCC, carbonic anhy-
drase II in chromophobe RCC, and keratin 19 in transitional
cell carcinoma was initially demonstrated by complementa-
ry DNA (cDNA) microarray studies and later confirmed by
immunohistochemistry [4]. Analysis of gene expression
profiles has shown that chromophobe RCC and oncocytoma
cluster closely together, thereby supporting the notion of a
common histogenetic linkage and distinguishing them from
other renal tumors [4,5]. Thus, a search for novel markers
capable of distinguishing chromophobe RCC from oncocy-
toma has become a relevant diagnostic pursuit.
Expression of KIT, a membrane receptor tyrosine kinase
encoded by c-kit, has been demonstrated in several types of
neoplasms [6-10]. The therapeutic implication of KIT
overexpression in a tumor is the potential efficacious use
of Gleevec (Novartis Pharmaceuticals, East Hanover, NJ),
an anti–tyrosine kinase drug, in treatment because over-
expression of KIT correlates with gain-of- function muta-
tions of the gene [11,12].
Recently, with high-density oligonucleotide arrays,
overexpression of KIT was reported in chromophobe RCC
but not in other types of RCC tested. This result was verified
by immunohistochemistry on only a few examples of
chromophobe and clear-cell RCCs [13], and expression of
KIT in renal oncocytoma was not evaluated. In addition,
recent studies reported KIT immunoreactivity in renal
angiomyolipomas [14], oncocytomas [15-17], and other
types of RCCs [18-20].
Given the diagnostic value and potential therapeutic
implications of c-kit overexpression in tumor cells, we
decided to perform a comprehensive analysis of messen-
ger RNA (mRNA) and protein levels of c-kit on a large
number of renal tumors, particularly oncocytoma, chromo-
phobe RCC, and angiomyolipoma.
2. Materials and methods
2.1. C-kit cDNA expression microarray
cDNA microarrays of kidney tumors were performed as
previously described [4,21,22]. The 37 renal tumors ana-
lyzed by cDNA microarrays included oncocytomas (n = 20)
and chromophobe RCCs (n = 17). Briefly, total RNA was
isolated from renal tumor tissues using Trizol reagent.
Microarrays were performed using gene chips containing
21632 cDNA clones. Polymerase chain reaction–amplified
bacterial colonies were transferred into 384-well plates and
printed onto aminosilane-coated glass slides using a home-
built robotic microarrayer. Fifty micrograms of total RNA
from each tumor and reference were reverse transcribed with
oligo(deoxythymidine) primer and Superscript II (Invitro-
gen, Carlsbad, Calif) in the presence of Cy5-dCTP and Cy3-
dCTP (Amersham Pharmacia Biotech, Peapack, NJ). The
Cy5- and Cy3-labeled cDNA probes were mixed with probe
hybridization solution containing formamide and hybridized
to prewarmed (508C) slides for 20 hours at 508C. Afterhybridization and washing, slides were scanned using
ScanArray Lite (GSI Lumonics, Billerica, Mass) operating
at 532- and 635-nm wavelengths. Images were analyzed with
the GENEPIX PRO 3.0 software (Axon Instruments, Foster
City, Calif). The gene ratios were median centered before
hierarchical clustering by using CLUSTER and were then
visualized by using TREEVIEW (MB Eisen, http://rana.lbl.
gov). The CIT software was used to find genes that were
differentially expressed (using Student t test) between one
histological subtype and the others. To find significant
discriminating genes, 10000 t statistics were calculated by
randomly placing patients’ samples into 2 groups.
2.2. Clinical material and tissue microarray
Conventional formalin-fixed, paraffin-embedded sections
of chromophobe RCC (n = 25) and renal oncocytoma
(n = 30) accessioned to the Department of Pathology,
Northwestern Memorial Hospital, from 1996 to 2003 were
retrieved and formed the basis of this study.
Fig. 1 C-kit mRNA expression by cDNA microarrays. (A) Increased c-kit mRNA expression in 17 chromophobe RCCs over normal
kidney control indicated in fold increase. Each case was analyzed with 2 probes (N20798 and N24824) as described in Materials and
methods. (B) Increased c-kit mRNA expression in 20 oncocytomas analyzed in a similar fashion.
Table 1 C-kit mRNA expression measured by cDNA expression
microarrays
Tumor type C-kit mRNA
overexpression
Expression
(fold)
Chromophobe RCC 17/17 7.4 F 3.6
Oncocytoma 20/20 7.4 F 4.2
Expression are presented as mean F SD values (calculated after averaging
the 2 values obtained with the 2 probes for each case).
L. Huo et al.264
A total of 171 cases of primary kidney tumors from
nephrectomy specimens were selected from the Surgical
Pathology archives of Northwestern Memorial Hospital and
University of Chicago Hospitals. All paraffin-embedded
donor tissue blocks were sampled with 1.5-mm punchers
using a Beecher tissue microarray (TMA) instrument
(Beecher Instruments Inc, Sun Prairie, Wis). Four paraffin
TMA blocks containing arrayed core cylinders from 40
chromophobe RCCs, 41 oncocytomas, 40 clear-cell RCCs,
21 papillary RCCs, 29 renal angiomyolipomas, and 10
normal kidneys were subjected to routine hematoxylin and
eosin staining and immunohistochemical staining.
2.3. Immunohistochemistry
Standard tissue sections and TMA sections were sub-
jected to immunohistochemical staining using a monoclonal
antibody specific for c-kit protein (Dako, Carpinteria, Calif)
as previously described [23,24]. Briefly, endogenous per-
oxidase activity was blocked with 3% hydrogen peroxide.
Heat-induced epitope retrieval was carried out in citrate
buffer (10 mmol/L, pH 6) for 15 minutes at 1008C in a
microwave oven. A primary mouse monoclonal anti–c-kit
antibody (Dako) at 1:100 dilution was applied for 1 hour at
room temperature. A subsequent reaction was performed
with biotin-free, horseradish peroxidase enzyme–labeled
polymer of EnVision plus detection system (Dako). A
positive reaction was visualized with diaminobenzidine
solution followed by counterstaining with hematoxylin. A
gastrointestinal stromal tumor (GIST) was used as a positive
control. Appropriate negative controls for the immuno-
staining were prepared by using nonimmune mouse IgG.
C-kit in oncocytoma and chromophobe renal cell carcinoma 265
2.4. Evaluation of immunohistochemistry andstatistical analysis
C-kit immunostaining was semiquantitatively evaluated
for intensity (0, negative; 1, weak; 2, moderate; 3, strong
staining) and patterns of reactivity (membranous and/or
cytoplasmic). Statistical analysis was performed using
Student t test.
3. Results
3.1. C-kit mRNA expression
All 17 chromophobe RCCs and 20 oncocytomas showed
an increased level of c-kit mRNA by cDNA microarray
analysis using 2 v-kit probes N20798 and N24824 (Fig. 1
and Table 1) compared with paired nonneoplastic kidney
Fig. 2 KIT immunohistochemical staining on TMAs. (A) Normal kid
showing strong KIT staining (membranous and cytoplasmic). (C) Onco
angiomyolipoma demonstrating weak KIT expression. (E) Papillary RCC
negative staining. (Original magnification �200.)
tissues. As measured from cDNA microarrays, there is a
2.3- fold variation in c-kit mRNA levels of normal kidney
controls ranging from 0.56 to 1.29 (mean F SD, 1 F0.316). In chromophobe RCCs, c-kit was expressed 1.4- to
14.0-fold over the normal kidney control, with a mean of
7.4-fold increase (SD, 3.6). The levels in oncocytomas
ranged from 1.2- to 14.5-fold, with a mean of 7.4-fold
increase (SD, 4.2). The mRNA levels between the
chromophobe RCCs and oncocytomas were not significant-
ly different (P N .05).
3.2. KIT expression by immunohistochemistry
To confirm the above gene-expression microarray results
demonstrating c-kit overexpression in both chromophobe
RCC and oncocytoma at the mRNA level, immunohisto-
chemical analysis of the KIT protein was performed on
tissue sections with a monoclonal antibody specific for KIT.
ney tubules showing focal KIT staining. (B) Chromophobe RCC
cytoma showing strong KIT cytoplasmic staining. (D) A case of
showing negative to minimal staining. (F) Clear-cell RCC showing
Fig. 3 KIT immunohistochemical staining on conventional sections. (A) Chromophobe RCC (hematoxylin-eosin, original magnification
�200). (B) Chromophobe RCC showing combined membranous and cytoplasmic KIT staining. (C) Oncocytoma (hematoxylin-eosin,
original magnification �200). (D) Oncocytoma showing cytoplasmic KIT staining.
L. Huo et al.266
On TMAs, nonneoplastic renal tubules showed focal
positive staining (Fig. 2A), whereas 38 (95%) of 40
chromophobe RCCs and 36 (88%) of 41 oncocytomas
demonstrated strong KIT expression (Fig. 2B and C). In
contrast, only 5 (17%) of 29 angiomyolipomas (Fig. 2D),
1 (5%) of 21 papillary RCCs (Fig. 2E), and 1 (3%) of 40
clear-cell RCCs (Fig. 2F) showed KIT expression. The
average immunostaining intensity was significantly higher
in oncocytomas (2.07) and chromophobe RCCs (1.93) than
in other renal tumors (0.17 for angiomyolipomas, 0.05 for
papillary RCCs, and 0.03 for clear-cell RCCs). In conven-
tional sections, KIT expression was detected in 24 (96%) of
25 chromophobe RCCs (mean intensity, 1.76) (Fig. 3A and
B) with 13 demonstrating predominantly membranous
Table 2 KIT expression by immunohistochemistry in renal
tumors
Tumor type Total no.
of cases
Positivity Average
intensity
Oncocytoma
TMA 41 36 (88) 2.07
Conventional 30 30 (100) 2.58
Chromophobe RCC
TMA 40 38 (95) 1.93
Conventional 25 24 (96) 1.76
Angiomyolipoma 29 5 (17) 0.17
Papillary RCC 21 1 (5) 0.05
Clear-cell RCC 40 1 (3) 0.03
Positivity values are presented as n (%).
staining (mean intensity, 1.8), 4 showing predominantly
cytoplasmic staining (mean intensity, 2.3), and 7 displaying
combined cytoplasmic and membranous staining (mean
intensity, 1.6). All 30 (100%) oncocytomas (mean intensity,
2.58) (Fig. 3C and D) showed strong, predominantly
cytoplasmic staining. The immunohistochemistry results
are summarized in Table 2.
4. Discussion
KIT, a 145-kd membrane-bound tyrosine kinase receptor
for stem cell factor, is encoded by the protooncogene c-kit
[10], which is a homologue of v-kit. KIT activation plays an
important role in the normal development of certain
hematopoietic cells, including mast cells, gonadal germ
cells, melanocytes, and interstitial cells of Cajal of the
gastrointestinal tract, and it is overexpressed in some
neoplasms derived from these cell types [6-10].
Recently, Yamazaki et al [13] reported KIT overexpres-
sion in chromophobe RCCs but not conventional RCCs and
therefore proposed KIT as a marker for chromophobe RCC.
Their conclusions were based on a limited number of cases
and renal oncocytoma, a benign renal cell neoplasm that
shows not only a morphological overlap but also a genetic
relationship to chromophobe RCC [4,5], which was not
included in their study. Because chromophobe RCC and
oncocytomas are morphologically and genetically related
[23], a biomarker should be tested in both tumors before it
can be declared bspecific.Q The RON oncogene product was
C-kit in oncocytoma and chromophobe renal cell carcinoma 267
initially touted as boncocytoma specific.Q However, we haveshown convincing evidence that RON immunoreactivity in
both oncocytomas and chromophobe RCC [24].
Petit et al [15] and Pan et al [17] reported KIT
immunoreactivity in most chromophobe RCCs and renal
oncocytomas but not in other renal tumors. Other studies
reporting KIT immunoreactivity in renal angiomyolipomas
and papillary RCC [14,18,20] raised the question of
possible false-positive staining. Herein, we demonstrate
elevated levels of c-kit mRNA in all 17 chromophobe
RCCs and 20 oncocytomas evaluated by cDNA microarray
analysis, thus reducing the possibility of immunohisto-
chemical cross reactivity with other proteins and validating
the elevated c-kit expression in both oncocytomas chro-
mophobe RCC. In addition, the immunohistochemical
study of KIT expression in a large number of renal
neoplasms confirms our cDNA microarray results by
demonstrating that most chromophobe RCCs and oncocy-
tomas express KIT; in contrast, angiomyolipoma, papillary,
and clear-cell RCC show lower KIT expression. The results
of our study compare favorably with those by Petit et al
and Pan et al (Table 3).
We do not have an explanation for the discrepancy
between the KIT immunoreactivity in all papillary RCCs
reported by Lin et al [20] and negative or weak KIT staining
in other 4 studies including ours. With our staining condition,
a small percentage of papillary RCC and angiomyolipomas
displayed faint or weak (intensity score, 1-2) KIT immunos-
taining (Fig. 3D and E). In fact, in the study by Miliaras et al
[18], the KIT immunoreactivity in other renal tumors was also
weak, scored as 2 of 4, which was consistent with our finding.
Therefore, a small percent of papillary RCC (5%-26% Table
3) and angiomyolipomas (17%-21%, Table 3) may be
positive for KIT; however, their weaker KITstaining intensity
is different from the strong staining observed in chromophobe
RCC and oncocytomas.
Angiomyolipoma, a member of the perivascular epithe-
lioid cell tumor family [25], is an essentially benign
neoplasm composed of thick-walled blood vessels, smooth
muscle, and adipose tissue in varying proportions. Makhlouf
et al [14] reported KIT immunoexpression in all 21
angiomyolipomas they tested, including 15 examples from
Table 3 KIT immunoreactivities reported
Authors Ref CC Pap
Yamazaki et al [13]
Makhlouf et al [14]
Petit et al [15] 0/29 0/10
Pan et al [17] 0/256 0/25
Miliaras et al [18] 2/13 2/7
Lin et al [20] 0/28 18/18
Subtotal 2/326 (1%) 20/60 (33%)
This study 1/40 (3%) 1/21 (5%)
Total 2/366 (0.5%) 21/81 (26%)
CC indicates clear-cell RCC; Pap, papillary RCC; Chr, chromophobe RCC; Onc,
the liver and 6 tumors from the kidney. The authors
suggested that angiomyolipoma be included in the differ-
ential diagnosis of KIT-positive tumors because some
angiomyolipomas share morphological features with GIST
and melanoma, which are 2 other KIT-expressing tumors.
However, our study demonstrated that most (83%) of renal
angiomyolipomas showed little or no expression of KIT
when compared with the strong KIT immunoreactivity in
GIST (positive control), renal oncocytoma, and chromo-
phobe RCC. The discrepancy in these results may be
attributed to the use of different dilutions of antibodies that
react with different epitopes in the molecule, different
antigen- retrieval techniques used, or differences in inter-
pretation of staining patterns and intensity of reaction.
The recent use of TMAs has resulted in more efficient
immunohistochemical phenotyping of tissue. However,
technical issues regarding TMA testing of renal tumors
have not been adequately addressed. In this study, we found
that there is no difference of KIT immunoreactivity in
chromophobe RCC between TMA (95%) and conventional
sections (96%). However, TMA slightly underestimated
KIT expression in oncocytomas (88%) compared with
results from standard tissue sections (100%). This difference
is most likely caused by sampling nonimmunoreactive areas
of the tumor. Therefore, when TMA sections are used for
immunohistochemistry analysis, it is important to keep this
issue in mind.
KIT immunoexpression correlates with c-kit gain-
of-function mutations and thus makes it a potential target
for Gleevec, a competitive antagonist of the ATP binding
site within the tyrosine kinase domain of the molecule
[26,27]. The efficacy of Gleevec in the treatment of meta-
static and inoperable GISTs and related tumors has recently
been documented [11,12]. Surgical resection, the treatment
of choice for chromophobe RCC and oncocytomas, may not
be suitable for certain patients because of potential clinical
complications. Gleevec may provide an option for patients
with contraindications to nephrectomy, provided that the
radiological or pathological diagnosis can be established
preoperatively and the tumor shows c-kit mutations.
In conclusion, using a combination of cDNA expression
microarrays and immunohistochemistry on TMAs and
Chr Onc AML
4/4
6/6
22/25 10/14 0
24/29 5/7 0/23
4/7 7/7 2/4
20/20
74/85 (87%) 22/28 (78%) 8/33 (24%)
62/65 (95%) 66/71 (93%) 5/29 (17%)
136/150 (91%) 88/98 (90%) 13/62 (21%)
renal oncocytoma; AML, renal angiomyolipoma.
L. Huo et al.268
standard tissue sections, we confirmed KIT as a good
biomarker for chromophobe RCC and oncocytoma because
it exhibited a high degree of sensitivity and specificity.
Although KIT does not distinguish chromophobe RCCs
from benign renal oncocytomas, KIT immunoreactivity may
be useful in separating chromophobe RCC from potential
mimics featuring cells with abundant eosinophilic cyto-
plasm. Overexpression of KIT in defined subtypes of renal
tumors indicates a potential therapeutic role for tyrosine
kinase inhibitors in managing patients with these tumors.
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