Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma.
BACKGROUND
Synovial sarcomas are high-grade soft tissue neoplasms often characterized by a biphasic spindle and epithelioid cell morphology. The majority of synovial sarcomas harbor a specific chromosomal translocation in which the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes (most notably SSX1 and SSX2) at chromosome Xp11. SYT/SSX1 translocations are seen in nearly three times as many synovial sarcomas as SYT/SSX2 translocations. Although the SYT/SSX2 fusion is usually associated with the monophasic disease pattern, the SYT/SSX1 fusion is present in tumors with biphasic or monophasic patterns. The SYT/SSX1 fusion gene is associated with more aggressive tumor growth and poor outcome. Despite advances in the therapy of local disease, distant metastasis remains the predominant cause of death. Accordingly, there is a need for alternate therapies, such as those recently developed against the receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and HER-2/neu.


METHODS
Archival specimens of synovial sarcoma (n=38) representing 30 patients were assessed for EGFR and HER-2/neu protein expression by standard immunohistochemical techniques. To validate the immunohistochemistry results, quantitative real-time polymerase chain reaction (Q-PCR) assays using either fresh and/or archival material was performed. The presence of gene amplification was determined by chromogenic in-situ hybridization.


RESULTS
EGFR and HER-2/neu protein were detected by immunohistochemistry in 21 of 38 (55.3%) and 20 of 38 (52.6%) synovial specimens, respectively. EGFR immunoreactivity showed a granular and membranous pattern, whereas HER-2/neu immunoreactivity demonstrated only a membrane pattern. Coexpression was observed in 13 of 38 specimens (34.2%). HER-2/neu expression by immunohistochemistry in synovial sarcomas was restricted to tumors with the SYT/SSX1 translocations. Of 6 specimens with SSX2 translocation, none (0%) showed HER-2/neu immunoreactivity and 1 (17%) demonstrated EGFR expression. Q-PCR demonstrated the presence of mRNA for EGFR and HER-2/neu in 19 of 30 specimens (63.3%) and 22 of 30 specimens (73.3%), respectively. EGFR and HER-2/neu were expressed at low concentrations compared with the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No evidence of gene amplification was observed.


CONCLUSIONS
EGFR and HER-2/neu are expressed in the majority of patients with SYT/SSX1 synovial sarcomas, albeit at low levels. Treatment with tyrosine kinase inhibitors may represent appropriate alternate therapy for these patients.
Thomas
Dafydd G
DG
Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan 48109-0602, USA. Thomasda@med.umich.edu
Giordano
Thomas J
TJ
Sanders
Donita
D
Biermann
Sybil
S
Sondak
Vernon K
VK
Trent
Jonathan C
JC
Yu
Dihua
D
Pollock
Raphael E
RE
Baker
Laurence
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D066246:ErbB Receptors; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases