Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series.
OBJECTIVE
Denosumab, a fully human monoclonal antibody directed against RANKL, has recently been introduced in the treatment strategy of giant cell tumour of bone (GCTB). Aim of this study was to investigate the phenotypical modifications induced by denosumab treatment in a series of 15 GCTB.


METHODS
The tumours were characterised for histone 3.3 mutations, and studied immunohistochemically for the modifications of RANKL, RANK, SATB2 and RUNX2 expression, as well as of tumour proliferative activity and angiogenesis.


RESULTS
Nine of 11 tumours investigated presented a histone 3.3 mutation in H3F3A, and 2 of these for which the analysis was carried out in pretreatment and post-treatment specimens showed the same mutation in both. Denosumab induced the disappearance of osteoclast-like giant cells, leaving residual spindle neoplastic cells arranged in a storiform pattern, with deposition of trabecular collagen matrix and osteoid, which tended to maturation in the peripheral portions of the lesion. RANK and RANKL expression was variable, with no significant variation after treatment. Moreover, we did not observe any significant modification of the expression of the osteoblastic markers SATB2 and RUNX2. Denosumab treatment determined a significant reduction of the proliferative index and of tumour angiogenesis (p=0.001, Wilcoxon rank-sum test).


CONCLUSIONS
These results indicate that denosumab induces a partial maturation towards the osteoblastic phenotype of the neoplastic cells of GCTB, with production of fibrous and osteoid matrix, but with minor immunophenotypical changes. Finally, we first report an antiangiogenic activity of denosumab in GCTB, possibly mediated by a RANKL-dependent pathway.
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Ilaria
I
Girolami
Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy.
Irene
I
Mancini
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Antonella
A
Simoni
"Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Italy.
Giacomo Giulio
GG
Baldi
Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy.
Lisa
L
Simi
Department of Orthopaedic Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Domenico
D
Campanacci
Department of Orthopaedic Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Giovanni
G
Beltrami
Department of Orthopaedic Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Guido
G
Scoccianti
Department of Orthopaedic Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Antonio
A
D'Arienzo
Department of Orthopaedic Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Rodolfo
R
Capanna
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Alessandro
A
Franchi
D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004252:DNA Mutational Analysis; D000069448:Denosumab / Q000627:therapeutic use*; D005260:Female; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009389:Neovascularization, Pathologic; D011237:Predictive Value of Tests; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D050659:Core Binding Factor Alpha 1 Subunit; D006657:Histones; D036961:Matrix Attachment Region Binding Proteins; D053245:RANK Ligand; C493709:RUNX2 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; C521297:SATB2 protein, human; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D000069448:Denosumab
BONE TUMOURS; CANCER GENETICS; IMMUNOCYTOCHEMISTRY