Chondrosarcoma is the second most frequent primary malignant bone tumor [1
]. Because of its recalcitrance to chemotherapy and radiotherapy, chondrosarcoma is primarily treated with surgery, and the clinical prognosis of chondrosarcoma has been correlated with the grading of the histological malignancy [3
For pathological consideration, distinguishing benign (enchondroma) from low-grade chondrosarcoma, or low-grade chondrosarcoma from high-grade chondrosarcoma, is one of the most frequent diagnostic dilemmas facing orthopedic oncologists.
Enchondroma is a very common and benign cartilaginous tissue tumor that occurs within bones. Approximately 69% of the patients are in the first and second decades of life [4
]. More than 49% of the tumors are in the small bones of the hands and feet, particularly in the phalanges. Unlike chondrosarcoma, enchondroma rarely develops in the pelvis or ribs. The pathological distinction between enchondroma and low-grade chondrosarcoma is, however, not always easy because of their similar cytology and cellularity. Chondrosarcoma has a broad array of presentations in pathology and clinical course. Chondrosarcoma is primarily a tumor of adulthood and old age. Approximately 62% of the patients are in the fourth to sixth decades. More than two-thirds of the tumors are in the trunk, including the pelvis, ribs, and shoulder girdle. The pathological grading of chondrosarcoma is based on cellularity, nuclear atypia, and pleomorphism [5
]; however, in some borderline cases, exact histological grading is difficult using only routine histopathological examinations because the criteria of the grading system are not necessarily definitive [6
]. Therefore, correlative interpretation of histopathological, imaging, and clinical information is currently used for making this distinction.
Several authors have reported supplementary methods, including the evaluation of DNA synthesis and content [7
], flow cytometry[9
], p53 [10
], MIB-1 [11
], COX-2 [6
], and p21 [3
], to assess the prognosis of patients with chondrosarcoma. These methods are, however, based on non-specific phenomena in chondrocytic differentiation.
Chondrogenesis, i.e., cartilage formation including chondrocyte differentiation and maturation, is a process that occurs during skeletal development. This process occurs in stages beginning with mesenchymal cell recruitment and migration, proliferation, and condensation, followed by chondroprogenitor cell determination and differentiation. Finally, chondrocyte differentiation is terminated by hypertrophy. Bone morphogenetic proteins (BMPs), which were originally identified as molecules that induce ectopic endochondral ossification [12
], set the stage for bone morphogenesis by initiating chondroprogenitor cell determination and differentiation and regulate the later stages of chondrocyte maturation and hypertrophic phenotype [13
We previously reported the growth arrest and DNA damage-inducible protein 45β (GADD45β) as an early responding gene to BMP-2 stimulation in the chondrocyte cell line [14
]. The expression of GADD45β gradually increased along with chondrocyte differentiation from the proliferation phase to hypertrophic phase. GADD45β stimulates MMP-13 (a marker of terminal differentiation of hypertrophic chondrocytes) promoter activity in chondrocytes through the JNK-mediated phosphorylation of JunD, partnered with Fra2 and in synergy with Runx2. These facts suggested that GADD45β plays an essential role during chondrocyte terminal differentiation.
In the present study, we investigated the immunohistochemical expression of GADD45β in enchondroma and chondrosarcoma of histological grades I, II, and III, to clarify the diagnostic significance of GADD45β in histological grading of chondrosarcoma.