Expression of cSrc and comparison of cytologic features in cherubism , central giant cell granuloma and giant cell tumors

Cherubism (CBM) and central giant cell granuloma (CGCG) of the jaw and giant cell tumor (GCT) of the long bone are clinically different diseases. Histologically, they are all multinucleated giant cell (MGC)-containing lesions. This study aims to evaluate the expression of c-Src and cytologic features in CBM, CGCG and GCT and to clarify whether there is a common mechanism underlying the formation of multi-nucleated giant cells (MGCs) in these lesions. Specimens and paraffin blocks were collected from patients with CBM (12 cases), CGCG (24 cases) and GCT (37 cases). Histomorpho-metric differences in MGCs were compared among the three types of lesions. The expression of c-Src by immunohistochemistry and in situ hybridization and the expression of TRAP by enzyme histochemical staining were examined. Expression of c-Src mRNA and protein, as well as TRAP staining, was detected in both MGCs and a fraction of mononuclear cells in all investigated lesions. There are no quantitative differences for cytologic features and c-Src expression among the lesions. The results suggested that CBM, CGCG and GCT have overlapping cytological features at the histological level, and c-Src may be involved in the formation of MGCs in the three different diseases. Introduction Cherubism (CBM) is a non-neoplastic bone disease characterized by obvious bilateral, painless enlargement of the jaw in children and young adults (1,2). It is generally inherited as an autosomal dominant trait with a penetrance of 80% and variable expressivity (3), however, sporadic cases were also reported (4,5). Histologically, the lesions contain numerous multinuclear giant cells (MGCs) scattered throughout a fibrous connective tissue stroma (6). The pathogenesis and nature of CBM is uncertain. Similar areas with giant cell accumulation can also be seen in central giant cell granuloma (CGCG) and giant cell tumors (GCT) of bone (7,8). CGCG is usually considered a benign solitary osteolytic lesion of the jaw, which often involves the anterior mandible and crosses the midline. It is primarily diagnosed in patients aged between 10 and 30 years with a predilection for females. GCT, as a true neoplasm, commonly presents as a painful, slow-growing, expansile unilocular or multilocular benign lesion located in the metaphyseal end of a long bone or is adjacent to the ossified epiphyseal line, occasionally with metastasis and malignant transformation (9). Most patients are aged between 20 and 40 years, and women are more frequently affected. GCT rarely involves the jaw bone, and little is known about the appearance of GCT in the jaw (6,10). Although defined as different entities, the three lesions histologically contain multinucleated giant cells within a cellular and fibrous connective tissue stroma. Previous investigations demonstrated that MGCs in CBM, CGCG and GCT exhibit phenotypic characteristics of osteoclasts, including expression of tartrate-resistant acid phosphatase (TRAP) and the receptor activator of nuclear factor κB (RANK) (11,12). RANK signaling is essential for the differentiation and activation of osteoclasts (13). The Src protein, which is required for osteoclast activation in vitro, has been shown to bind to TRAF6 and allow RANK-mediated signaling pathways to induce cell survival, cytoskeletal rearrangements and motility (14). The crucial role of the RANK/TRAF6-Src pathway in osteoclastogenesis prompted us to hypothesize ONCOLOGY REPORTS 15: 589-594, 2006 589 Expression of c-Src and comparison of cytologic features in cherubism, central giant cell granuloma and giant cell tumors CHANGNING WANG1,2*, YALING SONG1,2*, BIN PENG2, MINGWEN FAN2, JIANG LI3, SHENGRONG ZHU4 and ZHUAN BIAN1,2 1Key Laboratory of Oral Biomedical Engineering, Ministry of Education of China, 2Department of Endodontics, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079; 3Department of Oral Pathology, School and Hospital of Stomatology, Shanghai Second Medical University, 639 Zhizaoju Road, Shanghai 200011; 4Department of Oral Maxillofacial Surgery, Tongji Hospital, Huazhong Science and Technology University, 1095 Jiefang Road, Wuhan 430030, P.R. China Received September 13, 2005; Accepted November 16, 2005 _________________________________________ Correspondence to: Professor Zhuan Bian, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079,