A landscape effect in tenosynovial giant-cell tumor
from activation of CSF1 expression by a translocation
in a minority of tumor cells
Robert B. West*, Brian P. Rubin†, Melinda A. Miller‡, Subbaya Subramanian*, Gulsah Kaygusuz*, Kelli Montgomery*,
Shirley Zhu*, Robert J. Marinelli§, Alessandro De Luca‡, Erinn Downs-Kelly¶, John R. Goldblum¶, Christopher L. Corless?,
Patrick O. Brown§, C. Blake Gilks‡, Torsten O. Nielsen‡, David Huntsman‡**††, and Matt van de Rijn*,**‡‡
Departments of *Pathology and§Biochemistry, Stanford University Medical Center, Stanford, CA 94305;†Department of Anatomical Pathology, University
of Washington Medical Center, Seattle, WA 98195;‡Department of Pathology and Genetic Pathology Evaluation Centre, British Columbia Cancer Agency,
Vancouver, BC, Canada V5Z 3X7;¶Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH 44195; and?Department of Pathology,
Oregon Health and Science University Cancer Institute, Portland, OR 97239-3098
Edited by Bert Vogelstein, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, and approved November 22, 2005
(received for review August 23, 2005)
Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular
synovitis (PVNS) are related conditions with features of both
reactive inflammatory disorders and clonal neoplastic prolifera-
tions. Chromosomal translocations involving chromosome 1p13
have been reported in both TGCT and PVNS. We confirm that
translocations involving 1p13 are present in a majority of cases of
TGCT and PVNS and show that CSF1 is the gene at the chromosome
1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is
fused to COL6A3 (2q35). The CSF1 translocations result in overex-
pression of CSF1. In cases of TGCT and PVNS carrying this translo-
cation, it is present in a minority of the intratumoral cells, leading
to CSF1 expression only in these cells, whereas the majority of cells
abnormal accumulation of nonneoplastic cells that form a tumor-
pigmented villonodular synovitis ? receptor tyrosine kinase ?
macrophage ? COL6A3
Kinome’’) have been identified, including 90 potential tyrosine
kinases (1). Receptor tyrosine kinases (RTKs) relay external
signals to regulate diverse cellular processes including growth,
cell migration, differentiation, and survival. Genes encoding
RTK genes or their ligands are frequently altered by transloca-
tion or mutation in neoplastic cells, including carcinomas (e.g.,
EGFR in lung adenocarcinoma), germ-cell tumors (e.g., KIT in
seminoma), leukemias (e.g., ABL in chronic myelogenous leu-
kemia), and soft tissue tumors [e.g., KIT or PDGFRA in gastro-
intestinal stromal tumor (GIST); PDGFB in dermatofibrosar-
coma protuberans (DFSP)]. Several of these RTKs can now be
targeted with small-molecule inhibitors (2, 3), and clinical trials
suggest that tumors harboring mutations involving these genes
are particularly susceptible to small-molecule inhibitors because
the tumors are ‘‘addicted’’ to oncogenic signaling through these
One such inhibitor [imatinib mesylate (Gleevec)] is active
PDGFRA, and PDGFRB and has been used successfully in the
treatment of GIST and DFSP (1, 3, 4). GISTs are sarcomas of
the intestinal tract that have activating mutations of either KIT
or PDGFRA. DFSP, a sarcoma of the dermis, has a translocation
involving PDGFB, the ligand for PDGFRB. A different inhibitor
(SU11248) has been reported to be active against another
member of this group, CSF1R (5).
The tissue microarray (TMA) technique, by arraying repre-
sentative cores of tissue in a single paraffin block, is useful in
hrough the human genome project, many genes with the
protein kinase sequence (collectively referred to as ‘‘the
evaluating protein and RNA expression levels in large series of
tumors (6–8). The intention of our study was to test the
feasibility and potential of systematically analyzing expression of
mRNAs encoding tyrosine receptor kinases in large numbers of
soft-tissue tumors by in situ hybridization (ISH) on TMAs. We
confirmed high expression of KIT?PDGFRA in GIST and PDG-
FRB in DFSP. In addition, we observed that tenosynovial
giant-cell tumors (TGCT) showed exceptionally high expression
TGCT are benign tumors, but whether they are reactive or
neoplastic remains controversial, and the cell of origin is un-
known. They were suggested to be reactive by Jaffe (9) in the
initial classification of TGCT and related lesions. There have
subsequently been reports of clonal cytogenetic abnormalities,
most commonly involving 1p11, in TGCT, supporting a neoplas-
tic origin with activation of a growth-promoting gene through a
balanced translocation (10–15). The finding that the cells of
TGCT are polyclonal, by analysis of X-chromosome inactivation
(16), and the identification of similar chromosomal transloca-
tions in hemorrhagic synovitis or rheumatoid synovitis (11) has
cast doubt on the neoplastic nature of TGCT.
TGCT and the morphologically similar but more clinically
composed of mononuclear and multinucleated cells. Here, we
show by ISH, that both cell types express high levels of CSF1R.
In addition, we found that CSF1, encoding the ligand of CSF1R,
only a minority of tumor cells (2–16%) carry the translocation
and express CSF1. These data suggest that only a minority of
cells in TGCT and PVNS are neoplastic and that the majority of
cells in these tumors are nonneoplastic cells that are recruited by
the local overexpression of CSF1. Although tumors in which the
neoplastic clone constitutes a small minority of the cells present
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Freely available online through the PNAS open access option.
Abbreviations: BAC, bacterial artificial chromosome; DFSP, dermatofibrosarcoma protu-
berans; DTF, desmoid-type fibromatosis; GIST, gastrointestinal stromal tumor; ISH, in situ
hybridization; PVNS, pigmented villonodular synovitis; RTK, receptor tyrosine kinase; SFT,
solitary fibrous tumor; TGCT, tenosynovial giant-cell tumor; TMA, tissue microarray.
**D.H. and M.v.d.R. contributed equally to this work.
††To whom correspondence may be addressed at: Genetic Pathology Evaluation Centre,
Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6. E-mail:
‡‡To whom correspondence may be addressed at: Department of Pathology, Stanford
University Medical Center, 300 Pasteur Drive, Stanford, CA 94305. E-mail: mrijn@
© 2006 by The National Academy of Sciences of the USA
January 17, 2006 ?
vol. 103 ?
are well recognized in the case of some lymphomas, this phe-
nomenon has not been described for a mesenchymal tumor.
Results and Discussion
We conducted a survey to determine which other soft-tissue
tumors could potentially respond to small-molecule inhibitors by
examining type III RTK family expression in 507 soft-tissue
tumors represented on TMAs of paraffin-embedded tissue (Fig.
1) (17). mRNA levels of four RTKs were studied by ISH: KIT,
CSF1R, PDGFRA, and PDGFRB. As reported in ref. 8, KIT
mRNA expression was largely confined to GISTs. PDGFRA
mRNA expression was also seen in GIST but in a smaller subset
(8). DFSP, which has a translocation involving the ligand
PDGFB (18), demonstrated high levels of expression of PDG-
FRB in the vast majority of cases, correlating with our prior
gene-array findings (19). Several tumors showed expression of
more than one RTK: KIT and PDGFRA were often coexpressed,
whereas CSF1R was more frequently found to be coexpressed
with PDGFRB (see Fig. 8, which is published as supporting
information on the PNAS web site).
CSF1R was very strongly expressed in all nine cases of TGCT
(Fig. 2A), with expression evident in the majority of both the
mononuclear cells and the multinucleated giant cells of the
tumor. Our observation of high CSF1R expression in TGCT led
us to study the expression of the ligand (CSF1) in this lesion. As
shown in Fig. 2B, only a small subset of mononuclear cells in
TGCT highly expressed CSF1 mRNA. Each TGCT case dem-
onstrated this pattern of CSF1 expression (Fig. 1). Similar results
were obtained in stains of the related lesion PVNS (data not
TGCT and PVNS are both composed of a mixture of giant
cells, mononuclear cells, and inflammatory cells, the origin and
neoplastic nature of which is controversial (16). TGCT has been
analyzed by G-banding, and a breakpoint in the region 1p11–13
has been observed in the majority of cases (10–15). FISH probe
analysis showed that the breakpoints clustered to one region
located in 1p13.2 in 18 of 21 cases (12). The gene(s) involved in
these chromosomal abnormalities have not been identified, but
CSF1 is localized to this region. Using a bacterial artificial
chromosome (BAC) probe RP11–19F3 containing the CSF1
gene, we performed FISH on a metaphase spread of a TGCT
case (ST-143) and observed that the CSF1 locus is divided
between abnormal chromosomes 1 and 2 (Fig. 3A) (for a
description of FISH probes see Fig. 9, which is published as
supporting information on the PNAS web site). Examining
additional cases in a TMA format with probes RP11–354C7
(centromeric to CSF1) and RP11–96F24 (telomeric to CSF1), we
found that 87% (20 of 23 scorable cases) of TGCT, 35% (9 of 26
scorable cases) of PVNS, and no (0 of 4 scorable cases) giant-cell
tumors of bone show evidence for translocation involving the
CSF1 locus (see Fig. 10, which is published as supporting
information on the PNAS web site). Interestingly, only a small
percentage of cells in each lesion (range 2–16%) demonstrated
the split-probe signal. This finding correlated with the low
number of CSF1-expressing cells in TGCT and PVNS, as assayed
by ISH for CSF1 mRNA. Thus, the majority of cells that
comprise the tumor do not express CSF1 and do not have a
translocation involving CSF1.
Prior studies noted that the most common fusion partner of
chromosome 1 in TGCT is chromosome 2; G-banding showed
involvement of 2q35–37 in 8 of 26 cases (12). A metaphase
spread from the same TGCT case (case ST-143) described above
showed that FISH BAC probes RP11–354C7 (1p13) and RP11–
497D24 (2q37) came together in TCGT, indicating that the
translocation involves chromosomes 1p13 and 2q37. The BAC
probes, CTD-2344F21, RP11–96F24, RP11–354C7, and RP11–
25803 identify COL6A3 as the gene on 2q37 involved in the
translocation (Fig. 3 B and C). FISH on interphase nuclei in
TMA showed similar findings (Fig. 3 D–F). Combined inter-
phase FISH and CSF1 immunohistochemistry demonstrated
that only the cells with the translocation expressed CSF1 (Fig.
3G). Of the scorable cases with translocations at the CSF1 locus,
3 of 10 TGCT and two of five PVNS cases also involved the
the y axis by diagnosis. Results of ISH using four RTK antisense probes: CSF1R,
KIT, PDGFRA, and PDGFRB and one ligand, CSF1, are shown on the x axis.
Bright red, strong expression; dark red, weak expression; green, no expres-
sion; white, no data as a result of tissue loss.
RTK expression in 507 soft-tissue tumors. Tumors are grouped along
denote sites of hybridization. All scorable TGCT and PVNS were positive for
CSF1R mRNA expression in the vast majority of cells. (B) CSF1 ISH in TGCT. All
CSF1-positive cases of TGCT and PVNS showed similar low numbers of cells
CSF1 and CSF1R ISH in TGCT. (A) CSF1R ISH in TGCT; dark granules
West et al.
January 17, 2006 ?
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no. 3 ?
COL6A3 locus. Our data confirm earlier findings that the
majority of TGCT cases have a translocation involving chromo-
some 1 and that a subset of these cases show fusion with
chromosome 2 and identify CSF1 and COL6A3, respectively, as
the specific genes involved in these translocations.
Only a low percentage of cells in TGCT and PVNS express
CSF1 and have the translocation, whereas the majority express
CSF1R, suggesting that the majority of cells in these lesions are
reactive, their presence presumably a consequence of CSF1
production by the neoplastic cells. To investigate the nature of
the presumed CSF1-responsive cell population in TGCT and
PVNS, we compared the RNA-expression profiles of six TGCT
and seven PVNS against two other previously studied bland
soft-tissue tumors [six cases of solitary fibrous tumor (SFT) and
seven cases of desmoid-type fibromatosis (DTF)] by using DNA
microarrays. Because only a minority of cells in the tumor had
the translocation, we anticipated that expression profiles would
primarily reflect the biology of the nonneoplastic cells respond-
ing to expressed CSF1 rather than the neoplastic cells. Hierar-
chical clustering of the tumors based on similarities in their gene
expression patterns separated the tumors according to patho-
logic type (Fig. 4). PVNS and TCGT clustered together on a
main branch. Although the data confirmed that PVNS and
TGCT consistently expressed CSF1R, CSF1 expression did not
express CSF1 as seen by ISH. Among the genes most consistently
highly expressed in TGCT and PVNS relative to SFT or DTF,
many were associated with macrophage function and biology.
This finding was supported by a significance analysis of microar-
rays (SAM)-generated list of TGCT and PVNS genes. Gene-
Ontology analysis of this list found a significant representation
of genes involved in immune response, including CD163. An
immunostain for CD163, one of the highly expressed macro-
phage markers (20), confirmed that many cells in the tumor have
a macrophage phenotype (Fig. 5A). In double stains for CD163
and CSF1, there was little overlap, indicating that the CSF1-
expressing cells differ from the more abundant macrophages
(Fig. 5 B and C). It has been reported that synovial-lining cells
stain with the macrophage marker CD68 (21). Doubling staining
finding and the lack of CD163 coexpression suggest that the
CSF1-expressing neoplastic cells are derived from synovial-
lining cells (Fig. 5 D–F). Only synovial-lining cells in reactive
synovitis express CSF1, providing additional support for this
hypothesis (Fig. 6).
The CSF1–COL6A3 translocation in TGCT and PVNS is
reminiscent of the translocation that defines DFSP. In this
malignancy, t(17;22) brings PDGF-B under control of the strong
COL1A1 promoter. The posttranslationally processed form of
the fusion protein is a fully functional PDGF-B protein that may
stimulate oncogenesis through its receptor, PDGFRB. The
PDGFRB receptor is also up-regulated in DFSP, suggesting an
autocrine loop (19). However, TGCT differs from DFSP and
other soft-tissue tumors in that only a minority of cells in the
tumor contain the translocation and express CSF1 RNA, but
most of the cells within the tumor express CSF1R RNA.
Three conclusions are supported by our findings. First, TGCT
and PVNS are neoplasms. Although cytogenetic studies had
identified a variety of translocations in TGCT cases (10–15),
other studies using human androgen receptor (HUMARA)
assays failed to demonstrate clonality (16). Our finding that the
CSF1 gene is translocated in only a small percentage of the
Second, the neoplastic cells in TGCT constitute only a small
minority of the tumor-cell population; the majority of the cells
are apparently reactive, nonneoplastic cells. These conclusions
are consistent with the biology of CSF1. CSF1 mediates the
proliferation, differentiation, and function of macrophages and
their precursors (22). The cells with the CSF1 translocation most
likely recruit CSF1R-expressing macrophages (23) and may
induce the formation of multinucleated giant cells (Fig. 7). Thus,
the neoplastic cells create a tumor ‘‘landscape’’ comprised of
nonneoplastic cells responding to secreted CSF1. These tumors
may be a prototype for a unique form of tumor landscaping (24).
Third, the translocation involving COL6A3 and CSF1 results
in high levels of CSF1 expression in TGCT and PVNS. TGCT
The fusion of CSF1 and COL6A3 was confirmed by FISH. The COL6A3 locus is represented by CTD-2344F21 (labeled in white), the region telomeric to CSF1 is
represented by RP11–96F24 (labeled in green), and the region centromeric to CSF1 is represented by RP11–354C7 (labeled in orange). (C) In metaphase TGCT,
FISH with BAC probe RP11–25803 that covers the region telomeric to COL6A3, which fails to split. (D and E) Two nuclei with the fusion of CSF1 and COL6A3
demonstrated by FISH on interphase TMA sample of TGCT. The COL6A3 locus is represented by CTD-2344F21 (labeled in white), the region telomeric to CSF1 is
represented by RP11–96F24 (labeled in green), and the region centromeric to CSF1 is represented by RP11–354C7 (labeled in orange). (F) Lack of translocation
in a nucleus from the same sample as D and E shows an intact CSF1 gene. (G) Combined interphase FISH with the region telomeric to CSF1 represented by
RP11–96F24 (labeled in green) and the region centromeric to CSF1 represented by RP11–354C7 (labeled in orange), and CSF1 immunohistochemistry (labeled
in red) demonstrated that only the cells with the translocation expressed CSF1.
FISH on TGCT. (A) FISH with the CSF1-spanning BAC probe RP11–19F3B on TGCT confirms that the CSF1 gene is split by the translocation in TGCT. (B)
www.pnas.org?cgi?doi?10.1073?pnas.0507321103 West et al.
is a small, localized tumor that usually occurs on the fingers
and is easily controlled by surgery. PVNS is a more aggressive
tumor in and around large joints that can recur and cause
significant morbidity. The evidence suggesting a central role
for CSF1 in the pathogenesis of these tumors suggests that they
might respond to treatment with specific inhibitors of this
pathway (e.g., SU11248) (5).
Materials and Methods
TMA Construction. TMAs were constructed by using a manual
tissue arrayer (Beecher Instruments, Silver Spring, MD) fol-
lowing techniques described in ref. 17. A previously con-
structed set of two TMAs (TA38 and TA39) that represented
?50 different soft-tissue-tumor entities by a total of 460
600-?M cores in duplicate (a total of 920 cores) formed the
initial target of ISH for the four RTKs studied. These cores
represent material from 421 patients, with several patients
having more than one specimen appearing on the arrays (8,
17). The cores were taken from soft-tissue-tumor samples
archived at the Stanford University Medical Center Depart-
ment of Pathology between 1995 and 2001. Three new TMAs
(TA117, TA137, and TA153) were constructed for the purpose
of this study, and the cases represented on them are shown in
Table 1, which is published as supporting information on the
PNAS web site. TA137 has nine cases of TGCT from TA38.
TA38, TA39, and TA117 were used for the initial RTK
screening, representing 507 cases of soft-tissue tumors. TA137
and TA153 were used for further FISH and ISH analysis of
based on expression profiling with DNA microarrays. In the heatmap, red
represents high expression, black represents median expression, green rep-
resents low expression, and gray represents no data.
Unsupervised hierarchical clustering of seven cases of PVNS (in red),
CSF1 ISH in reactive synovitis, showing strong reactivity in synovial-
Combined A and B; CSF1 ISH with fluorescence (red) and CD163 immunohistochemistry (DAB). (D) CD68 immunohistochemistry with fluorescence (red). (E) CSF1
ISH with fluorescence (green). (F) Combined D and E; CSF1 ISH with fluorescence (green) and CD68 immunohistochemistry with fluorescence (red).
Double staining for CSF1 mRNA and CD163 or CD68 protein in TGCT. (A) CD163 immunohistochemistry (DAB). (B) CSF1 ISH with fluorescence (red). (C)
West et al.
January 17, 2006 ?
vol. 103 ?
no. 3 ?
TGCT and PVNS. Digital images of all stains on all tumors in
searchable format were stored at the publicly available Stan-
ford Tissue Microarray Consortium.
RNA ISH. ISH of TMA sections was performed based on a
protocol published in ref. 8. More details are provided in the
supporting information, which is published on the PNAS web
site. The primer sequences are given in Table 2, which is
published as supporting information on the PNAS web site.
TA38, 39, 137, 153, and 117 were stained with oligodT to assess
preservation of tissue RNA by using the INFORM ISH
oligodT control probe (Ventana Medical Systems, Tuscon,
AZ). ISH scoring was based on recognizing a strong dot-like
staining pattern associated with cells. Only cores that had
RNA as detected by an oligodT probe were scored.
Castra, Newcastle Upon Tyne, U.K.) and CSF1 (GeneTex, San
Antonio, TX) were used. More details are provided in sup-
porting information, which is published on the PNAS web site.
Digital images of all cores stained by hematoxylin and eosin or
immunohistochemistry were collected by using the BLISS
system from Bacus Laboratories (Lombard, IL).
Combined ISH and Immunohistochemistry. For double staining,
ISH was performed first, followed by immunostaining. A
streptavidin Alexa Fluor 594 conjugate (S-32356, Invitrogen)
diluted at 1:500 was used to visualize the ISH probe for CSF1.
The slide was imaged by using a Nikon E1000 microscope with
UV-2E DAPI and Texas red HYQ filter cubes (Nikon) fitted
with a CoolSNAP K4 (Photometrics, Tucson, AZ) camera.
Subsequently, the coverslip was removed, and the slide was
restained with anti-CD163 antibody (NovoCastra, diluted
1:100) by using the DAKO EnVision? System and the Vector
VIP substrate kit and counterstained with hematoxylin. The
slide was imaged again by using bright-field and RGB color
filters. The fluorescence image was aligned to and superim-
posed on the bright-field image by selecting the DAPI channel
and using PHOTOSHOP CS Version 8 (Adobe Systems, San Jose,
CA). For the final image, the DAPI channel was removed,
leaving the Texas red channel superimposed on the bright-field
FISH. Sections (6-?m thick) of the TMA slides were pretreated as
described in ref. 25. Metaphases and metaphase slides were
produced by using standard methods. Locus-specific FISH anal-
ysis was performed by using the following BACs from the
Human BAC Library RPCI-11 (BACPAC Resources Centre,
Children’s Hospital Oakland Research Institute, Oakland, CA)
unless otherwise noted. Listed centromeric to telomeric: 354C7,
19F3 and 96F24 (chromosome 1), and 155J6, 205L13, 585E12,
97L10, CTD-2344F21 (CITB Human D BAC library, Invitro-
gen), 279M4, 258O3, and 497D24 (chromosome 2). BACs were
directly labeled with either Spectrum green or Spectrum orange
(Vysis, Downer’s Grove, IL). The chromosomal locations of all
BACs were validated by using normal metaphases (results not
shown). Probe labeling and FISH was performed by using Vysis
reagents according to the manufacturer’s protocols. Slides were
counterstained with DAPI for microscopy. For all slides, FISH
signals and patterns were identified on a Zeiss Axioplan epif-
luorescent microscope. Signals were interpreted manually, and
images were captured by using the ISIS FISH imaging software
(MetaSystems Group, Belmont, MA). A cutoff of ?2 breaks per
100 nuclei was selected for a positive score based on examining
230 other soft-tissue tumors. Efficiency of the break-apart FISH
probes on TMAs was demonstrated with the t(X;18) in synovial
Combined FISH and Immunohistochemistry. Combined FISH and
immunohistochemistry was performed by using the pretreat-
ment steps of the standard immunohistochemistry, followed by
application of the antibody, followed by hybridization with the
FISH probes. BACs were directly labeled with either Spectrum
green or Spectrum orange (Vysis). The immunohistochemistry
was labeled with Cy5.
Gene Array. Tumors were collected from three academic institu-
tions [Vancouver General Hospital (Vancouver), University of
Washington Medical Center, and Stanford University Medical
Center], with institutional review board approval. After resec-
tion, a representative sample was quickly frozen and stored at
?80°C. Before processing, frozen sections of the tissue were cut
and histologically examined to ensure that the tissue represented
the diagnostic entity. Only cases with classic histologic findings
were used. Eight cases of PVNS and seven cases of TGCT were
compared with six cases of SFT and seven cases of DFT. In the
cases of SFT and DTF, all cases except two (STT3237 and
STT3524) have been published in ref. 27. Spot cDNA microar-
rays (42,000) were used to measure the relative mRNA-
expression levels in the tumors. The details of isolating mRNA,
labeling, and hybridizing are described in ref. 28. The raw data
files are publicly available at Stanford Microarray Database.
Data were filtered by using the following criteria: Only cDNA
the Cy3 and the Cy5 channel were included, only cDNA spots
that fulfill these criteria on at least 70% of the arrays were
included, and only cDNAs were selected that had an absolute
value at least four times greater in at least two arrays than the
geometric mean. Data were evaluated with unsupervised hier-
archical clustering and significance analysis of microarrays
T.O.N. and D.H. are scholars of the Michael Smith Foundation for
Health Research, Vancouver.
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Autocrine and paracrine scheme for CSF1 landscaping effect. CSF1 is
www.pnas.org?cgi?doi?10.1073?pnas.0507321103West et al.