Cells of the monocyte macrophage lineage form multinucleated giant cells (GCs) by
fusion, which may express some cell cycle markers. By using a comprehensive marker
set, here we looked for potential replication activities in GCs, and investigated
whether these have diagnostic or clinical relevance in giant cell tumor of bone (GCTB).
GC rich regions of 10 primary and 10 first recurrence GCTB cases were tested using
immunohistochemistry in tissue microarrays. The nuclear positivity rate of the general
proliferation marker, replication licensing, G1/S-phase, S/G2/M-phase, mitosis promoter,
and cyclin dependent kinase (CDK) inhibitor reactions was analyzed in GCs. Concerning
Ki67, moderate SP6 reaction was seen in many GC nuclei, while B56 and Mib1 positivity
was rare, but the latter could be linked to more aggressive (p = 0.012) phenotype.
Regular MCM6 reaction, as opposed to uncommon MCM2, suggested an initial DNA unwinding.
Early replication course in GCs was also supported by widely detecting CDK4 and cyclin
E, for the first time, and confirming cyclin D1 upregulation. However, post-G1-phase
markers CDK2, cyclin A, geminin, topoisomerase-2a, aurora kinase A, and phospho-histone
H3 were rare or missing. These were likely silenced by upregulated CDK inhibitors
p15(INK4b), p16(INK4a), p27(KIP1), p53 through its effector p21(WAF1) and possibly
cyclin G1, consistent with the prevention of DNA replication. In conclusion, the upregulation
of known and several novel cell cycle progression markers detected here clearly verify
early replication activities in GCs, which are controlled by cell cycle arresting
CDK inhibitors at G1 phase, and support the functional maturation of GCs in GCTB.
