Giant cell tumors of bone are neoplasms of stromal cells that recruit a mononuclear population of hematopoietic origin [7
]. These monocytes and/or multinucleated giant cells may in turn produce factors that support growth of the stromal cells, but this has not been explored. The onocytederived component is highlighted in immunohistochemical stains for the lysosomal marker CD68 and for monocyte lineage specific markers. The lineage of the stromal cells is still poorly characterized, but a subset variably expresses alkaline phosphatase, similar to osteoblasts [8
]. Factors such as monocyte colony stimulating factor (m-CSF) and RANK ligand, which are important for osteoclastogenesis and for fusion of monocytes to form multinucleated giant cells, are expressed in giant cell tumors of bone[9
]. Presumably the stromal cells are the source of m-CSF, akin to the situation in localized and diffuse giant cell tumors of tendon sheath/synovium where m-CSF is overexpressed by the neoplastic cells, sometimes secondary to a recurrent translocation[10
]. Accordingly, cultured giant cell tumor stromal cells are chemoattractant to peripheral blood monocytes[12
In karyotypic analysis of giant cell tumors of bone, end-to-end fusions of various chromosomes, termed telomeric associations, are seen in most tumors in a subset of cells, and these have been localized by FISH studies to the CD68 negative spindled stromal component[13
]. At lower frequency than telomeric associations, clonal chromosome gains, deletions and translocations can also be found in GCT of bone[14
]. Translocations occur more frequently in tumors that have more telomeric associations, and they probably result from ensuing problems in separation of dicentric chromosomes during telophase[14
]. However, cells with chromosomal abnormalities do not have enough of a growth advantage to dominate the tumor population, and analyses of many metaphases is required to recognize that there are clonal subpopulations in the tumor[14
]. In Goronova's study[14
] there was no association between karyotype and prognosis. Also, no dominant recurrent cytogenetic abnormality was seen that might give clues to pathogenesis. Thus, this peculiar low level chromosome instability reflects an underlying defect in chromosome maintenance, though probably not due to a generalized defect in telomerase activity[15
]. The minor genomic instability seen in vitro is reflected by a low but definite probability of transformation clinically, as seen here. However, because of the current lack of a defined molecular or cytogenetic marker of GCT of bone, formal proof that the rare cases of malignant transformation are due to evolution of the spindle cells of GCT of bone is lacking. An alternative hypothesis would be that that GCT of bone predisposes to malignancy in an unrelated cell--akin to secondary malignancy in the setting of osteonecrosis or Paget's disease of bone. Notably, cases are considered secondary malignant giant cell tumors even if, on recurrence, only the malignant component is seen.
This case illustrates a sarcoma arising at the site of a locally recurrent GCT of bone, with concurrent non-sarcomatous metastases. Local recurrence of GCT of bone is common, occurring 10-20% of the time[16
], and depends on the aggressiveness of the initial surgery[19
]. Metastasis with "benign" morphology, most commonly to the lung, was reported in an average of 3% of cases (table ), and more than half occurred in patients who also had local recurrence.
Reported incidence of "benign" metastasis in giant cell tumor of bone.
Diagnosis of transformation relies on overt malignant cytological features, as necrosis and scattered mitoses can be seen in the usual "benign" giant cell tumor of bone. Immunohistochemical studies are not required for the diagnosis of transformation. Usually there is no evident lineage of maturation, but cases of osteosarcoma have been reported[9
]. The incidence of malignancy in GCT varies considerably among studies, with an overall rate of approximately 5% considering the largest series together (table ). About half were associated with prior irradiation (table ), but transformation was found in the initial resection in about one third of cases (table ). Secondary transformation had a latency of up to 28 years[20
] in a case that without radiotherapy. Given the wide range of reported incidence of malignancy in giant cell tumor of bone among studies, it is probable that this entity has been over diagnosed in the reported series. Of note, in the publications with the highest rates of malignancy, there was no pathological slide review. In Bertoni's study, pathological review was performed[20
], and as a result, the initial diagnosis was revised to something other than malignant transformation of giant cell tumor in 12 of 26 cases initially considered for which slides were available. Anract's study, which did not include pathological review, includes 5 cases with "well differentiated fibrosarcoma"[5
], which is much different from the more widely recognized high grade transformation. Likewise, in Domovitov's report, 57% of the cases had the curious diagnosis of "focally" malignant histology. Accordingly, the outcomes in their study were optimistic, with 80% of patients predicted to be recurrence free at 5 years based on their data, compared to the 10-50% overall survival estimated in most other series. Thus, excluding radiation-induced transformation cases, and considering only series with pathological review, the incidence of malignant transformation of giant cell tumor of bone is only about 1%, which is the rate cited in the WHO publication[25
Reported incidence of malignancy associated with giant cell tumor of bone in large published series