Regulators of skeletal development: a cluster analysis of 206 bone tumors reveals diagnostically useful markers

Abstract

The molecules Indian hedgehog (IHH), SP7 (also known as osterix), sex-determining region Y-box 9 (SOX9), runt-related transcription factor 2 (RUNX2) and TWIST1 regulate the normal differentiation of osteo-and chondrogenic cells from precursors during skeletal development and remodeling. The aberrant function of the same molecules has been implicated in the pathogenesis of bone tumors. Preliminary studies suggest that antibodies against these molecules have practical, diagnostic or prognostic utility in tumors. However, a comprehensive analysis of the expression of these molecules in a large, diverse set of bone tumors has yet to be reported. The goals of this study were to compare the immunohistochemical profiles of IHH, SP7, SOX9, RUNX2 and TWIST1 among bone tumors and to determine the optimum panel for diagnostic utility. Tissue microarrays prepared from 206 undecalcified tumors (71 osteosarcomas, 26 osteoblastomas/osteoid osteomas, 50 giant cell tumors, 5 chondromyxoid fibromas and 54 chondroblastomas) were stained with antibodies to IHH, SP7, SOX9, RUNX2 and TWIST1. The stains were scored for intensity (0À3 þ ) and distribution. The results were analyzed by cluster analysis. Optimum antibody panels for diagnostic sensitivity and specificity were calculated. Analysis revealed six main clusters that corresponded well to tumor types and suggested a close relationship between the stromal cells of giant cell tumor and the osteoblasts of osteosarcoma. The expression profile of chondromyxoid fibroma and chondroblastoma also suggested related differentiation. The distribution of osteoblastomas and osteoid osteomas was more heterogeneous. RUNX2, SOX9 and TWIST1 represented the most sensitive and specific immunohistochemical panel to distinguish among these diagnoses with the limitation that no result could discriminate between chondroblastoma and chondromyxoid fibroma. IHH and SP7 did not yield additional utility.

Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series

“…In order to assess whether denosumab treatment induces differentiation of the neoplastic cells of GCTB along the osteoblastic lineage, we examined the expression of RUNX2 and SATB2 in pretreatment and post-treatment tumour specimens. In agreement with previous studies,15 16 we observed that GCTB stains for both markers, although the staining for SATB2 tended to be less diffuse and presented in small groups of neoplastic cells, often associated with osteoid matrix production, whereas RUNX2 was expressed in most neoplastic cells. While RUNX2 expression remained unchanged after treatment, SATB2 was detected only in a subset of cells in areas of mature bone formation, and was not detected in cellular areas or in association with collagen matrix production.…”

Special AT‐rich sequence‐binding protein 2 (SATB2) expression is sensitive but may not be specific for osteosarcoma as compared with other high‐grade primary bone sarcomas

“…Mutation of SATB2 , in both mouse models and cases of human germline deletion, leads to a similar phenotype of craniofacial malformations and osteoblastic dysregulation . SATB2 knock‐out mice have skeletal anomalies, supporting the idea that SATB2 plays a vital role in skeletal development and osteoblastic differentiation, probably through interaction with runt‐related transcription factor‐2 (RUNX2, also known as CBFA1) …”

“…SATB2 IHC was performed on 26 cases stained as whole slides and on 22 cases on previously constructed tissue microarrays (TMAs). The construction of the TMAs has been previously reported …”

“…Osteosarcomas are genetically heterogeneous, with complex chromosomal abnormalities, and no reproducible genetic change . Therefore, an antibody targeted at a specific genetic aberration is not possible for confirming a diagnosis of osteosarcoma; however, osteoblastic lineage‐specific markers have potential for aiding the diagnosis . Given the role of SATB2 in osteoblastic differentiation, immunohistochemistry (IHC) for SATB2 has shown promise as a highly sensitive and fairly specific marker of osteoblasts .…”

SATB2 is a Novel Marker of Osteoblastic Differentiation and Colorectal Adenocarcinoma

“…9 Although it has been suggested that SP7 could be a useful marker for assisting in the differential diagnosis of bone tumors, the number of immunohistochemical studies on the expression of this marker in these neoplasms is limited. 20,21 At present, there is insufficient information available to determine whether SP7 has any practical use as an osteoblastic differentiation marker in the diagnosis of bone and soft-tissue tumors.…”