Obligatory—this is not medical advice
Giant cell tumor of bone (GCTB) is a rare, usually benign, condition for which have answers. If you’ve read other portions of this substack, you have likely come to realize that not all forms of treatment for sarcoma are so clearly recommended. This is not to say that medications or surgeries are given without forethought and careful consideration, but rather that, in the great spectrum of care that is offered to our patients with sarcomas, GCTB occupies a space where treatment efficacy and toxicity have a better balance. There is still much to discuss and I will highlight a few aspects of the care here.
History
Giant cell tumor of bone has been written about, or so we suspect, since the early 1800s. The picture below is an illustration from a surgical essay published in 1818. 1While the mechanism and pathologic aspects of its diagnosis were unknown, it was seen to be a disease that was locally recurrent.
Our understanding has evolved over time, with gradual recognition of its molecular drivers as well as visual characteristics. The diagnosis has become easier, and more consistent with incorporation of IHC and genetic testing in rare cases. Retrospective analyses have indicated that it represents approximately 10% of bone tumors in Sweden and possibly up to 20% in China.2 3 While such analyses are not as robust in the United States, this likely indicates hundreds of cases nationally, annually. The incidence of malignant giant cell tumor of bone is much less, at perhaps 1 in 10000000 annually. 4
There remain some questions about the true nature of giant cell tumor of bone and if it might accurately be characterized as a neoplasm. Nonetheless, it is well understood that a key molecular driver is Receptor activator of nuclear factor kappa B ligand (RANKL). This is required for formation of osteoclasts, cells that are utilized in catabolism of bone, to develop. Histone modifications, such as in H3 histone family 3A, are seen in over 90% of GCTBs. It is unknown how this might relate ultimately to the pathophysiology of this tumor. 5
Diagnosis
Initial imaging performed for extremity pain, or other symptoms may indicate a lucent, or lytic lesion (see x-ray below). 6
This is generally followed by a biopsy of curettage which culminates in something akin to the following picture under the microscope. 7
Treatment
For localized, resectable tumors, treatment involves extirpation of the tumor. The exact details and approach are highly contingent upon location. When this is not an option, there is a discussion about the role of systemic treatment. First line therapy for this is denosumab, which is a subcutaneous injection. There have been numerous studies, but we will focus on one primarily.
The design of this trial was complicated and integrated multiple cohorts to a convoluted Phase 2 design. This leads to some questions about the exact population of patients, nonetheless, the long term stability of the disease in the vast majority of patients was staggering. Let's focuse on one of the cohorts (see below).8
There was a low rate of progression or recurrence after administration of the medication out to over 6 years. 50% of patients within Cohort 1 (chart) discontinued denosumab without subsequent disease progression. Within this group, note that most patients discontinued denosumab, and only 10% of them had progression on the agent.
The medication was well tolerated. Rates of grade 3 or 4 adverse events were low. Approximately 5% of all patients on this trial had osteonecrosis of the jaw (ONJ). It appears that this effect occurred at a median of 43 denosumab doses in one of the cohorts, and 20 in another. ONJ was preceded by tooth extraction in 57% of cases, or an oral infection. Denosumab was discontinued in 14 patients, temporarily held in 9 patients, and continued in 5. The condition resolved in 15 of 28 cases.
Conclusions
Giant cell tumor of bone is a neoplastic disease that ranges from benign to malignant. For most patients, surgical resection of disease is appropriate. For those in whom surgery is not an option, denosumab may be considered. Careful discussion with patients about the long term side effects of denosumab should be had. In some instances, it may be appropriate to discontinue active therapy in favor of close surveillance. Early signs of ONJ should be recognized, and counseling regarding appropriate management of denosumab should be provided.
https://wellcomecollection.org/works/w9z2pf9s
https://pubmed.ncbi.nlm.nih.gov/29944971/
https://radiopaedia.org/cases/giant-cell-tumour-5
https://pubmed.ncbi.nlm.nih.gov/23016917/
https://pubmed.ncbi.nlm.nih.gov/31704134/