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
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5. Murray, L. J., Abrams, T. J., Long, K. R., Ngai, T. J., Olson, L. M., Hong, W.,
Keast, P. K., Brassard, J. A., O’Farrell, A. M., Cherrington, J. M. & Pryer, N. K.
(2003) Clin. Exp. Metastasis 20, 757–766.
6. Kononen, J., Bubendorf, L., Kallioniemi, A., Barlund, M., Schraml, P.,
Leighton, S., Torhorst, J., Mihatsch, M. J., Sauter, G. & Kallioniemi, O. P.
(1998) Nat. Med. 4, 844–847.
7. Subramanian, S., West, R. B., Marinelli, R. J., Nielsen, T. O., Rubin, B. P., Goldblum,
J. R., Patel, R. M., Zhu, S., Montgomery, K., Ng, T. L., et al. (2005) J. Pathol.
8. West, R. B., Corless, C. L., Chen, X., Rubin, B. P., Subramanian, S.,
Montgomery, K., Zhu, S., Ball, C. A., Nielsen, T. O., Patel, R., et al. (2004)
Am. J. Pathol. 165, 107–113.
9. Jaffe, H., Lichtenstein, L. & Sutro, C. (1941) Arch. Pathol. 31, 731.
10. Dal Cin, P., Sciot, R., Samson, I., De Smet, L., De Wever, I., Van Damme, B.
& Van den Berghe, H. (1994) Cancer Res. 54, 3986–3987.
11. Mertens, F., Orndal, C., Mandahl, N., Heim, S., Bauer, H. F., Rydholm, A.,
Tufvesson, A., Willen, H. & Mitelman, F. (1993) Genes Chromosomes Cancer
12. Nilsson, M., Hoglund, M., Panagopoulos, I., Sciot, R., Dal Cin, P., Debiec-
Rychter, M., Mertens, F. & Mandahl, N. (2002) Virchows Arch. 441,
13. Ohjimi, Y., Iwasaki, H., Ishiguro, M., Kaneko, Y., Tashiro, H., Emoto, G.,
Ogata, K. & Kikuchi, M. (1996) Cancer Genet. Cytogenet. 90, 80–85.
14. Rowlands, C. G., Roland, B., Hwang, W. S. & Sevick, R. J. (1994) Hum. Pathol.
15. Sciot, R., Rosai, J., Dal Cin, P., de Wever, I., Fletcher, C. D., Mandahl, N.,
Mertens, F., Mitelman, F., Rydholm, A., Tallini, G., et al. (1999) Mod. Pathol.
16. Vogrincic, G. S., O’Connell, J. X. & Gilks, C. B. (1997) Hum. Pathol. 28,
17. West, R. B., Harvell, J., Linn, S. C., Liu, C. L., Prapong, W., Hernandez-
Boussard, T., Montgomery, K., Nielsen, T. O., Rubin, B. P., Patel, R., et al.
(2004) Am. J. Surg. Pathol. 28, 1063–1069.
18. Simon, M. P., Pedeutour, F., Sirvent, N., Grosgeorge, J., Minoletti, F., Coindre,
Nat. Genet. 15, 95–98.
19. Linn, S. C., West, R. B., Pollack, J. R., Zhu, S., Hernandez-Boussard, T.,
Nielsen, T. O., Rubin, B. P., Patel, R., Goldblum, J. R., Siegmund, D., et al.
(2003) Am. J. Pathol. 163, 2383–2395.
20. Nguyen, T. T., Schwartz, E. J., West, R. B., Warnke, R. A., Arber, D. A. &
Natkunam, Y. (2005) Am. J. Surg. Pathol. 29, 617–624.
21. O’Connell, J. X., Fanburg, J. C. & Rosenberg, A. E. (1995) Hum. Pathol. 26,
22. Barreda, D. R., Hanington, P. C. & Belosevic, M. (2004) Dev. Comp. Immunol.
23. Guilbert, L. J. & Stanley, E. R. (1980) J. Cell Biol. 85, 153–159.
24. Kinzler, K. W. & Vogelstein, B. (1998) Science 280, 1036–1037.
25. Makretsov, N., He, M., Hayes, M., Chia, S., Horsman, D. E., Sorensen, P. H.
& Huntsman, D. G. (2004) Genes Chromosomes Cancer 40, 152–157.
26. Terry, J., Barry, T. S., Horsman, D. E., Hsu, F. D., Gown, A. M., Huntsman,
D. G. & Nielsen, T. O. (2005) Diagn. Mol. Pathol. 14, 77–82.
27. West, R. B., Nuyten, D. S., Subramanian, S., Nielsen, T. O., Corless, C. L.,
Rubin, B. P., Montgomery, K., Zhu, S., Patel, R., Hernandez-Boussard, T., et
al. (2005) PLoS Biol. 3, e187.
28. Nielsen, T. O., West, R. B., Linn, S. C., Alter, O., Knowling, M. A., O’Connell,
J. X., Zhu, S., Fero, M., Sherlock, G., Pollack, J. R., et al. (2002) Lancet 359,
29. Tusher, V. G., Tibshirani, R. & Chu, G. (2001) Proc. Natl. Acad. Sci. USA 98,
West et al.
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vol. 103 ?
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