Chondromyxoid fibroma resembles in vitro chondrogenesis, but differs in expression of signalling molecules

Abstract

Chondromyxoid fibroma is a rare benign cartilaginous bone tumour characterized by morphological features that resemble different steps of chondrogenesis in terms of both cellular morphology, ranging from spindled to rounded cells, and the extracellular matrix formed, which ranges from fibrous to cartilaginous. The presence in chondromyxoid fibroma of signalling molecules that regulate the spatial expression of proteins involved in normal cartilage proliferation and differentiation was investigated in samples from 20 patients and compared with articular chondrocytes from 11 normal donors cultivated in 3D pellet culture. Sections were stained with safranin-O and H&E, and immunohistochemistry was performed for p16, cyclin D1, FGFR3, BCL2, p21, PTHLH, PTHR1 and N-cadherin. Expression patterns were analysed using hierarchical clustering. In chondromyxoid fibroma, specific morphological features correlated with a distinct pattern of expression. Comparison with normal chondrocytes in pellet culture showed a striking morphological resemblance, but with an unmistakably different pattern of expression. N-cadherin, PTHLH, and PTHR1 were expressed to a significantly higher level (p < 0.01) in articular chondrocyte pellets but, conversely, there was significantly lower expression of cyclin D1, p16 and BCL2 (p < 0.05) in these cells. Morphological similarities reflect common steps in cartilage differentiation, albeit driven by different molecular mechanisms. The proteins we have found to be differentially expressed seem crucial for neoplastic chondrogenesis.

The role of noncartilage‐specific molecules in differentiation of cartilaginous tumors

“…in cell cycle progression (although with an inhibitory action), 7,20 was significantly higher in CMF versus HGCCS (P < .05). Specifically, 67% of CMF samples versus 27.5% of HGCCS samples were positive for p16INK4A.…”

“…Scores that were generated with the same evaluation system for p16INK4A and cyclin D1 (CCND1) in CMF and HGCCS were available from previous studies. 7,19,20 A cut-off value >2 was applied for the sum of intensity and the number of positive cells for p16INK4A and CCCND1, and a cut-off value >3 was applied for activated leukocyte adhesion molecule (ALCAM/CD166). Cut-off selection was set as the minimal value for the sum of intensity and percentage that best discriminated CMF versus HGCCS.…”

“…A meta-analysis of CCND1 immunohistochemistry confirmed the significantly higher expression levels in CMF versus HGCCS: 67% of CMF samples versus 20% of HGCCS samples were positive for CCND1. 7,19 In addition, the expression of p16INK4A, a molecule that is involved FIGURE 2. (A) Genes that were expressed differentially in chondromyxoid fibroma (CMF) versus chondroblastoma (CB).…”

“…3 We demonstrated previously that, within the histology of CMF, the different steps of in vitro chondrogenesis are reflected by the presence of round cells that are more similar to mature chondrocytes and the presence of less differentiated spindle-cell precursors that show partial myofibroblastic transdifferentiation. 6,7 The polygonal-atypical cells in CMF sometimes closely resemble the cells of highgrade central chondrosarcoma (HGCCS). This can make the differential diagnosis difficult in clinical practice, especially in biopsy specimens.…”

Heterogeneous and Complex Rearrangements of Chromosome Arm 6q in Chondromyxoid Fibroma

“…as previously described in detail. 3 The cellular localization (nuclear, cytoplasmic, and membranous) of immunoreactivity was also noted.…”