The distinct clinical features of giant cell tumor of bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences

Abstract

Giant Cell Tumor of Bone (GCT) is a tumor characterized by neoplastic mesenchymal stromal cells and a high number of osteoclast-like multinucleated giant cells. Rarely, GCT could arise in bones affected by Paget's disease of bone (GCT/PDB). Although it is already known that GCT/PDB and GCT show a different clinical profile regarding the age-onset and skeletal localization, our deep clinical comparison between the two GCT/PDB and GCT cohorts, permitted us to identify additional differences (e.g. focality, ALP serum levels, the 5-year survival rate and the familial recurrence), strongly suggesting a different molecular basis. Accordingly, driver somatic mutations in H3F3A and IDH2 were described in GCT patients, while we recently identified a germline mutation in ZNF687 as the genetic defect of GCT/PDB patients.Here, we detected H3F3A mutations in our GCT cohort, confirming its molecular screening as the elected diagnostic tool, and then we excluded the two-hit in H3F3A and IDH2 as the trigger event for the GCT/PDB development. Importantly, we also identified an alternative biochemical profile with GCT/PDB not exhibiting the up-regulation of the GCT marker FGFR2IIIc. Finally, our histological analysis also showed a different appearance of the two forms of the tumor, with GCT/PDB showing a higher number of osteoclast-like giant cells (twice), with an abnormal number of nuclei per cell, corroborating its different behaviour in terms of neoplastic properties.We demonstrated that the distinct clinical features of pagetic and conventional GCT are associated with different genetic background, resulting in a specific biochemical and histological behaviour of the tumour.

ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone

“…Of interest, a preferential involvement of the skull, spine and pelvis remarkably characterized the familial cases, resembling the skeletal sites that we frequently observed as involved by GCT/PDB …”

“…Of interest, a preferential involvement of the skull, spine and pelvis remarkably characterized the familial cases, resembling the skeletal sites that we frequently observed as involved by GCT/PDB. 13,14 The patients carrying the p.Pro665Leu and p.Gln784Glu mutations were sporadic cases and, although showing a polyostotic PDB, their phenotype was milder than that of patients with the p.…”

ZNF687 Mutations in an Extended Cohort of Neoplastic Transformations in Paget's Disease of Bone: Implications for Clinical Pathology

“…Our recent publications highlighted that the founder P937R mutation in ZNF687 underlies GCT/PDB in Italian patients (15/15 cases). (15,16) Herein, we searched for this mutation in the remarkable "extraskeletal osteoclastomas" of a 45-year-old black American woman with neurofibromatosis 1 and polyostotic PDB (18) who is now deceased. PDB was widespread in her skeleton and involved the skull, clavicles, ribs, pelvis, femurs, and tibias ( Fig.…”

“…Although the germline ZNF687 mutation is responsible for GCT/PDB, highly recurrent somatic mutations (G34W, G34R, G34V and G34L) in the H3F3A gene cause conventional GCT. (12,15) During this study, we investigated a family with aggressive PDB that affected three family members (Fig. 4B).…”

“…In contrast, GCT/PDB is often a multifocal tumor associated with a 5-year survival rate <50%. (15) Furthermore, it has a different genetic basis, as we demonstrated previously, which involves the founder germline mutation (P937R) in the ZNF687 gene. (16) We have also reported that all such GCT/PDB patients are representatives of a "hot spot" geographic area in Southern Italy.…”