Cytogenetic and Immunohistochemical Analyses of c-Met in Peripheral Nerve Sheath Tumors
T Motoi, A Kumagai, H Nitta, TM Grogan, A Yoshida, T Fukusato. Teikyo Universtiy School of Medicine, Tokyo, Japan; Ventana Medical Systems Inc., Tuscon, AZ; University of Tokyo, Tokyo, Japan
Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with only limited treatment options. It often develops from neurofibroma (NF) either sporadically or in the setting of neurofibromatosis type 1 (NF1). c-Met proto-oncogene (c-Met) is a tyrosine kinase receptor, whose amplification and overexpression is known to be associated with tumor progression of several types of neoplasms. Recent array-based comparative genomic hybridization analysis revealed c-Met amplification in MPNSTs. In order to clarify the role of c-Met in the development of MPNST, benign peripheral nerve sheath tumors and MPNSTs were examined by brightfield double in situ hybridization (BDISH) for c-Met gene status, and by immunohistochemistry for the protein expression.
Design: Formalin-fixed paraffin-embedded tissue samples (FFPEs) from 8 cases of MPNST (3 NF1-associated, 5 sporadic), 5 cases each of NF1-associated- and unassociated-NF, and 3 cases of schwannoma (SCH) were studied. The BDISH assay was performed with c-Met and chromosome 7 centromere (CEN7) probes, visualized respectively by fast red and silver acetate. The c-Met and CEN7 signals in 60 nuclei were counted per sample. Immunohistochemistry was performed using anti-c-Met monoclonal antibody; c-Met overexpression was defined as definite cytoplasmic staining over 50% of tumor cells.
Results: MPNSTs frequently showed amplified signals of both c-Met and CEN7 with a range of 1.9-4.3 signals/nuclei (mean 2.6) for c-Met and 1.8-4.2 (mean 2.6) for CEN7, which indicated the polysomy of chromosome 7. No selective c-Met amplification was identified in MPNSTs (c-Met/CEN7; 0.9-1.1, mean 1.0). The polysomy 7 was also seen in SCHs (3/3 cases, c-Met; mean 2.3, CEN7; mean 2.1); but it was seldom observed in NFs (c-Met; 1.6-1.8, mean 1.7, CEN7; 1.5-1.9, mean 1.7) regardless of NF1 status. Immunohistochemically, most MPNSTs overexpressed c-Met protein (7/8 cases), whereas the overexpression was rarely seen in NFs and SCHs (1/13 cases).
Conclusions: Our result suggests that polysomy 7 be acquired during malignant transformation of NF. The detection of this cytogenetic abnormality by BDISH may thus be a useful adjunct in differentiating between NF and MPNST in morphologically challenging cases. Although no c-Met amplification was found in MPNST, polysomy 7 may be one of the genetic mechanisms by which c-Met overexpression is induced in this sarcoma.
Category: Bone & Soft Tissue
Monday, March 22, 2010 1:00 PM
Poster Session II # 21, Monday Afternoon