Benign osteogenic tumors were the second most common benign tumor (355; 14.0%) (Table III) and occurred in the skull and face (48.5%) as well as mandible (14.9%) (Fig. 3). The number of patients with osteogenic tumors peaked at 10 to 19 years of age for both males and females, with an apparent secondary peak at 50 to 59 years of age among women (Fig. 1).
Intermediate Bone Tumors
We observed 272 intermediate bone tumors, including 212 giant cell tumors (77.9%) and 43 chondrogenic tumors (osteochondromatosis) (15.8%). The registration rates for intermediate bone tumors were 2.9 for males and 2.3 for females and remained stable over the observation periods (Table III). A primary peak of giant cell tumor was seen in patients 20 to 29 years of age, whereas a secondary peak was observed in patients 50 to 59 years of age (Fig. 1). Among the giant cell tumors, 64.6% of cases occurred in the long bones of the lower limb (Fig. 3).
Malignant Bone Tumors
We observed 506 malignant bone tumors over a period of 40 years. The registration rates from the first to the fourth decade were 3.5, 5.6, 4.6, and 5.5 for males and 3.0, 3.1, 3.2, and 4.8 for females, respectively (Table III). Malignant bone tumors occurred in the long bones of the lower limb (41.7%); in the pelvis, sacrum, and coccyx (16.2%); in the skull and face (10.7%); and in the rib, sternum, and clavicle (7.7%) (Table II). The numbers of malignant bone tumors were 287 for males and 219 for females, and the male:female ratio was 1.31:1. A primary peak in malignant bone tumors occurred in patients 10 to 19 years of age and then rapidly decreased. A plateau was observed in patients 20 to 50 years of age, with a secondary peak observed for patients 60 to 69 years of age and a decline observed in elderly individuals.
Tumor distributions by age were similar for both sexes. Among malignant bone tumors, the most frequent tumor types were osteogenic tumors (201; 39.7%) and chondrogenic tumors (135; 26.7%) (Table III). These 2 major histological groups covered approximately two-thirds of all malignant bone tumors. There was only a peak in teens for malignant osteogenic tumors, which occurred in the long bones of the lower limb (58.7%) (Figs. 1 and 3). There was a primary peak in teenagers and a secondary peak in middle-aged patients for malignant chondrogenic tumors, which were distributed in the long bones of lower limb (25.9%); in the bones of the trunk of the body such as the rib, sternum, and clavicle (20.0%); and around the pelvis (20.0%) (Figs. 1 and 3).
Time trends of the number of cases and registration rates were stable for entire period, particularly for female patients (Table III). However, in the last decade, the number of malignant cases increased because of an increase in the number of notochordal tumors in subjects aged 50 to 79 years.
Among the 51 miscellaneous tumors, 25 Ewing sarcomas were observed (14 in males and 11 in females) (Table I). Most cases of Ewing sarcoma occurred in children and adolescents (including 2 in patients 0 to 9 years of age and 13 in patients 10 to 19 years of age), and the other 10 cases occurred in patients 20 to 39 years of age.
We presented the statistics—by sex, skeletal site, and histological type—on bone tumors of all behavior types that were diagnosed between 1973 and 2012. We confirmed that 81.6% of benign bone tumors were chondrogenic tumors, primarily consisting of osteochondromas and enchondromas. The most dominant types of malignant tumors were osteogenic tumors and chondrogenic tumors. Approximately 40% of the malignant bone tumors occurred in the long bones of the lower limb, with different age peaks at the time of diagnosis for each major histological type. A similar distribution of histological types was seen during the 40-year observation period. We observed only 25 cases of Ewing sarcoma over 40 years.
Few cancer registries routinely collect data on both benign and malignant tumors. The Bone and Soft Tissue Tumor (BSTT) Registry in Japan, which is a nationwide and organ-specific registry, collects data on both benign and malignant bone tumors6. A recent report from that registry11 demonstrated that 8,979 benign bone tumors were registered between 2006 and 2013. With the exclusion of lesions that were not recognized as benign bone tumors in the present study (i.e., giant cell tumors [1,187], neurilemmomas , neurofibromas , and tumors of an unknown histological type ), the number of benign bone tumors decreased to 7,589. Of those, the most dominant type was chondrogenic tumors (80.4%; 6,100 of 7,589) and the second most common type was osteogenic tumors (10.1%; 768 of 7,589). The distribution of histological types among benign tumor cases reported by the BSTT Registry was consistent with the benign tumors in the present study. The BSTT Registry also showed that a primary peak of osteochondroma occurred in teenagers and that a primary peak of enchondroma occurred among men 30 to 34 years of age and among women 35 to 44 years of age11. The age distributions of osteochondroma and enchondroma were in accordance with our results.
The Swedish Cancer Registry, the Bone Tumor Registry of Western Australia, and the BSTT Registry collect information on giant cell tumor, which is recognized as an intermediate tumor. Liede et al. reported that the giant cell tumor-to-osteosarcoma ratio, based on the data from the BSTT registry in Japan as well as the registries of Sweden and Mexico, ranged from 0.49 to 0.7912. The giant cell tumor-to-osteosarcoma ratio from the Hiroshima Tumor Tissue Registry was 1.05, which was slightly higher than that reported in other registries.
Osteochondromatosis has a risk of malignant transformation into secondary chondrosarcoma, particularly in cases with multiple exostoses13. We observed 43 cases of osteochondromatosis, which has been reported to have a probability of malignant transformation of 1% to 5% among all primary osteochondromas14 , 15. As the patients with osteochondromatosis in the Hiroshima Tumor Tissue Registry had had tissue resected during biopsy or surgery, we carefully reviewed their data individually to determine whether there were any cases in which osteochondromatosis had transformed into malignant chondrosarcoma, but we did not find any cases of malignant transformation. We will continue to consider the possibility of malignant transformation among patients with osteochondromatosis who are registered in the Hiroshima Tumor Tissue Registry.
A peak in the incidence of osteosarcoma has been observed in elderly Caucasian individuals as a result of the relatively high prevalence of osteosarcoma in patients with Paget disease4. In addition, Ogura et al., in a report from the BSTT Registry, reported an increasing proportion of osteosarcoma cases among the elderly in Japan6. However, we found neither a peak of osteosarcoma in the elderly nor any case of osteosarcoma with Paget disease. These findings are attributed to the lower prevalence of osteosarcoma with Paget disease. Hashimoto et al.16, on the basis of a mail survey, reported that the prevalence of Paget disease was 2.8 per million in Japan during the period between 1990 and 2002. This prevalence was extremely low when compared with the prevalence of 0.1% to 5% among individuals in high-prevalence countries17. Furthermore, Hashimoto et al. reported that half of the cases in their report were not confirmed by histological diagnosis16. Therefore, osteosarcoma in patients with Paget disease may not have been registered in the Hiroshima Tumor Tissue Registry.
We found that giant cell tumor represented a considerable proportion of bone tumors. Giant cell tumors primarily appeared in the long bones of the lower limb in patients 10 to 40 years of age. Giant cell tumor previously was considered to be benign, but recurrence after excision has been reported in 20% to 50% of patients, with 10% of cases becoming malignant upon recurrence18 , 19. Histologically benign giant cell tumor rarely occurs in cases of lung metastases20. Therefore, giant cell tumor has been classified as intermediate since the latest WHO 2013 classification10. Although the first choice of treatment is curettage followed by filling with bone cement21 , 22 and additional treatment with adjuvants, the rate of recurrence is still high1 , 18. Chemotherapy with denosumab, a monoclonal antibody that inhibits the osteoclastic activity of giant cell tumor, recently has emerged as another choice of treatment21. Active treatments are necessary in cases of giant cell tumor because of the risk of recurrence and malignant metastasis; however, the safety of long-term denosumab use has not yet been reported23, although it was approved for use in giant cell tumor treatment in Japan in May 201424. We will continue to carefully observe the cases of giant cell tumor and the associated characteristics.
The present study had several limitations. First, our data were based on patients with tumors that had been resected during surgery or biopsy and registered in the Hiroshima Tumor Tissue Registry. Patients who did not undergo therapeutic or diagnostic resection were not registered in the database. According to Cancer Incidence in Five Continents, the incidence of malignant bone tumors in Hiroshima City from 1978 to 1999 and the rate in Hiroshima Prefecture per 100,000 population in the period 2003 to 2007 were reported to be 0.5 to 0.8 for males and 0.4 to 0.6 for females9 , 25 - 29; in comparison, the registration rates per 100,000 population for malignant bone tumor in the Hiroshima Tumor Tissue Registry were 0.35 to 0.56 for males and 0.30 to 0.48 for females. Second, we observed 2,542 benign bone tumors over a period of 40 years; however, this number is most likely an underestimation because the majority of benign bone tumors are asymptomatic30 and are not usually detected or resected for diagnosis. Conventional radiology such as radiographs, computed tomography, and magnetic resonance imaging are used to diagnose chondroid tumors1. Among the benign bone tumors registered in the Hiroshima Tumor Tissue Registry and diagnosed after 1993, 95.6% were in patients who underwent surgery.
The Hiroshima Tumor Tissue Registry is a population-based tumor tissue registry that collects information on all tumors that are diagnosed pathologically in hospitals and clinical laboratories in Hiroshima Prefecture. In 2012, 88 institutions, including all designated cancer care hospitals, hospitals, clinics, and clinical laboratories, reported their tumor diagnoses to the Hiroshima Tumor Tissue Registry. Of the cancer cases registered in the Hiroshima Prefecture Cancer Registry, which is a regional cancer registry, 75% of the cases were also covered by the Hiroshima Tumor Tissue Registry31. Moreover, at the time of registration, all patients reported by local pathologists to the Hiroshima Tumor Tissue Registry are confirmed to not already be registered in the database with use of personal identifying information such as name, date of birth, address, etc. Therefore, there is no duplication of patients, even if the tumor information is reported by different hospitals (e.g., following biopsy and surgical diagnosis). The diagnoses associated with all tumors registered in the Hiroshima Tumor Tissue Registry are confirmed histologically. If a patient with a benign bone tumor needed medical treatment, the diagnosis should be confirmed pathologically and the tumor information is registered in the Hiroshima Tumor Tissue Registry. Despite these limitations, we believe that the information on all benign, intermediate, and malignant bone tumors in the present study is valuable, and we have been able to show the variation of histological type and age distribution of bone tumors by behavior in Hiroshima Prefecture.
This report described characteristics of benign, intermediate, and malignant bone tumors with regard to frequency of cases, registration rate, age distribution, and skeletal site by pathological type. There were differences between osteochondroma and enchondroma in terms of the number of patients and skeletal sites where the tumor most frequently occurred, although both tumor types were originated from chondrogenic tumors. Giant cell tumor has a high frequency and was the most dominant type of intermediate bone tumor. These findings shed light on the epidemiological and pathological features of bone tumors.
NOTE: All authors are members of the Hiroshima Tumor Tissue Registry Working Committee. This study was administrated by the Committee. The tabulated numbers in this paper were based on the annual report of Hiroshima Tumor Tissue Registry No. 41, published in March 2017. The authors thank all pathologists who cooperated and submitted the pathological information and specimens to the Hiroshima Tumor Tissue Registry. They also thank the staff of the Hiroshima Prefecture Medical Association, the staff of the Tumor and Tissue Registry Office, the Radiation Effects Research Foundation, and Ms. Mikiko Hayashi for their help with data collection and analysis. The Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan, is a public interest incorporated foundation funded by the Japanese Ministry of Health, Labour and Welfare (MHLW) and the U.S. Department of Energy (DOE). This publication was supported by Radiation Effects Research Foundation Research Protocol 18-61. The views of the authors do not necessarily reflect those of the 2 governments.
Investigation performed at the Hiroshima Prefecture Medical Association and the Radiation Effects Research Foundation, Hiroshima, Japan
Disclosure: This study was conducted by the Hiroshima Tumor Tissue Registry Working Committee, which was operated by the Hiroshima Prefecture Medical Association with cooperation and financial support of Hiroshima Prefecture and the Radiation Effects Research Foundation. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A47).
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