To our knowledge, this represents the first investigation of malignancy in GCT of bone conducted in the general U.S. population. Our results confirm that malignant GCT of bone is a rare occurrence in the United States (less than one case per million persons per year). While we observed a decrease in incidence over the decades from 2.2 cases per 10 million persons in the 1970’s to 1.0 case per 10 million persons in the 2000’s, the rarity of the tumor prevented any formal test of trend in incidence over time. Results reported in an analysis of 75 malignant GCT of bone cases from a Swedish population-based national cancer registry showed an average annual incidence of 0.63 per million from 1958 to 1968, a somewhat higher estimate than our own.15
However, based on the small number of cases identified in both the Swedish report and our current investigation, it is possible that the observed trends in incidence over time and/or difference in incidence rates between these reports may not be meaningful but merely a reflection of chance variability in the populations studied.
The current investigation is also the first to examine racial/ethnic differences in the incidence and survival associated with this rare disease. Our results suggest no significant racial difference in the incidence of malignant GCT of bone. Survival estimates suggest a reduction in risk of death among non-white compared with white patients, but the results were not statistically significant. And although a slightly greater proportion of cases diagnosed were females compared to males, there was no significant difference in the overall incidence of malignant GCT by gender. We found most malignant GCT cases are typically diagnosed in the third and fourth decades of life, a finding supported by most case-series.2,3,5,16–19
The average 5-year relative survival rate for patients with malignant GCT of the bone in our study was 84.2%. As seen with other cancer types, older age and metastatic disease at diagnosis were associated with poorer survival. However, we did not observe any significant difference in risk of death among patients diagnosed with regionally advanced disease. No significant differences in risk of death were detected by year of diagnosis, gender, race, or treatment. Our survival rates are improved over hospital-based case-series in malignant GCT, possibly reflecting advances in treatment of these tumors over time and/or geographic differences in referral patterns to specific institutions as well as availability and access to medical care for these patients. However, these are difficult theories to prove with existing data. The SEER registry records information on first line treatment, but no subsequent treatment information is collected on patients. Anract et al.
observed a 5-year relative survival rate of 50% in a case-series of 29 malignant GCT patients diagnosed between 1954 and 1993.3
Case ascertainment in this study began approximately twenty years prior to the establishment of the SEER registry and ended a decade prior to our patient follow-up. Bertoni et al.
showed that 59% of all patients diagnosed with malignancy in GCT at a single institution eventually died, most of metastatic disease.12
The authors also indicated a survival disparity between patients diagnosed with primary and secondary malignant GCT, though not formally tested because of the small number of patients in the series (n=17). Of notable importance, there was variability in the number of patients diagnosed with primary versus secondary malignant GCT in these studies as less than one-third of patients included in the Italian study12
were diagnosed with primary malignant GCT, while nearly 60% of patients in the French investigation were similarly diagnosed.3
A limitation of SEER with respect to this investigation is the inability to classify patients as having primary or secondary malignant GCT, as the SEER database does not record medical history of benign lesions. This information might have been useful in our evaluation of patient survival. If survival is improved among patients diagnosed with primary malignant GCT and the proportion of patients diagnosed with primary versus secondary malignant GCT is higher among patients in SEER, this might explain some of the variability in survival rates between studies. As our study demonstrates, surgery is the preferred treatment choice for most patients, particularly if the tumor appears indolent and confined to the bone. For biologically aggressive or recurrent tumors, curettage has been coupled with adjuvant chemotherapy or radiation.6
The typical treatment for patients with non-resectable GCT has been a course of moderate-dose radiation therapy.20,21
Reported rates of recurrence of benign, primary malignancy in GCT or secondary malignancy in GCT are variable and dependent on tumor characteristics and treatment.1,22
Wide resection and the adjuvant use of polymethymethacrylate following intralesional curettage have been associated with reduced recurrence rates.23,24
The use of intravenous and oral bisphosphonates may also reduce risk of local recurrence in patients with soft tissue extension of GCT.25
The treatment of recurrent and metastatic GCT has been mostly surgical. Metastasectomy of lung nodules may result in long-term survival.26–28
Chemotherapy is generally of marginal benefit in advanced GCT, but may provide palliative treatment of primary or secondary malignancy in GCT. Results of a phase II trial of the fully human monoclonal antibody to RANKL, denosumab, in patients with recurrent or unresectable giant cell tumor of bone indicate nearly 90% of cases had a positive response to the agent (either elimination of giant cells or no radiographic progression of the target lesion) and nearly 85% of patients reported reduced pain and/or improvement in functional status,29
suggesting that denosumab is a viable treatment approach for patients with advanced or metastatic GCT not amenable to surgery.
Our investigation does have a few limitations which necessitate some caution in evaluating our results. As previously mentioned, our sample size prohibits the detection of statistically significant differences in incidence across the study period and determinants of long term survival amonng various subgroups. Therefore, analyses relating demographic differences in malignant GCT incidence as well as demographic and clinical determinants of survival must be interpreted with prudence, particularly if the observed disparities between these subsets of the population are modest. Additionally, formal review of the histopathology of patients in this investigation was not possible because of the unavailability of historical medical records on all patients through the individual SEER registries.
Nevertheless, the current investigation represents the largest population-based and most comprehensive examination of the descriptive epidemiology of malignancy in GCT of bone and the first of its kind conducted in the United States. Based on the rare nature of malignancy in GCT, only a large cancer database such as NCI’s SEER has the ability to accrue an adequate number of cases to estimate rates of incidence and survival. An important strength of the SEER cancer registry is the active tracking of cases for vital status (over 97%) regardless of migration out of the registries catchment areas. Because losses to follow-up in our patient population are minimal, the calculated survival rates are an accurate representation of the survival experience of these patients. In the future, we would recommend that the SEER registries consistently and routinely collect information on cases of benign GCT of bone as well. Benign GCT of bone is unique in that it is considered to be a borderline neoplasm because of its potential to metastasize. Obtaining information on the diagnosis, treatment and follow-up of both benign and malignant GCT cases would enhance our understanding of the determinants of risk and survival among those diagnosed with this disease.