10.1245/ASO.2004.03.004
Annals of Surgical Oncology 11:998-1004 (2004)
© 2004 Society of Surgical Oncology
Osteosarcomas after the Age of 50: A Clinicopathologic Study of 64 Cases—an Experience in Northern Japan
Kyoji Okada, MD,
Tadashi Hasegawa, MD,
Jun Nishida, MD,
Akira Ogose, MD,
Takahiro Tajino, MD,
Toshihisa Osanai, MD,
Michiro Yanagisawa, MD and
Masahito Hatori, MD
From the Tohoku Musculoskeletal Tumor Society (TMTS), Japan (KO, JN, AO, TT, TO, MH); National Cancer Center, Tokyo, Japan (TH); Department of Orthopedic Surgery, Akita University School of Medicine, Akita, Japan (KO); Pathology Division, National Cancer Center Research Institute, Tokyo, Japan (TH); Department of Orthopedic Surgery, Iwate Medical School, Morioka, Japan (JN); Niigata University School of Medicine, Niigata, Japan (AO); Fukushima Prefecture Medical School, Fukushima, Japan (TT); Yamagata University School of Medicine, Yamagata, Japan (TO); National Hirosaki Hospital, Hirosaki, Japan (MY); and Tohoku University School of Medicine, Sendai, Japan (MH).
Correspondence: Address correspondence and reprint requests to: Kyoji Okada, MD, Department of Orthopedic Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543 Japan; Fax: 81-18-836-2617; E-mail: cshokada{at}med.akita-u.ac.jp
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ABSTRACT
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Background: The clinicopathologic profile and prognostic factors of osteosarcomas after the age of 50 years have been obscure.
Methods: Clinicopathologic features were analyzed in 645 patients with osteosarcoma who were registered at the Tohoku Musculoskeletal Tumor Society and National Cancer Center in Tokyo between 1972 and 2002.
Results: Sixty-four patients (9.9%; 34 men and 30 women) were more than 50 years old. The most common location was the distal femur (n = 13), followed by the pelvis (n = 10), proximal femur (n = 9), and proximal fibula (n = 6). Seven (11%) patients had lung metastasis at initial presentation. On radiographs, an osteolytic appearance without periosteal reactions was a common and characteristic feature. Forty-eight tumors (75%) were classified as conventional osteosarcomas. Fourteen cases (22%) were secondary; postradiation osteosarcoma was most common in these patients, but there was no Paget’s sarcoma. At the initial presentation, misdiagnoses without biopsy were made in 15 (23%) of the 64 cases. Preoperative chemotherapy was given to 22 patients, but the effect was poor in 18 cases (82%). Fifty-four patients underwent surgery, whereas the other 10 patients were treated without surgery because of systemic or inoperable local conditions. The overall survival rate at 5 years was 55.5%. Multivariate analysis showed initial pulmonary metastasis, axial tumor location, and larger tumors as significant prognostic factors.
Conclusions: In northern Japan, most patients with osteosarcoma after the age of 50 had primary osteosarcoma. Careful radiological examination and biopsy are mandatory for correct diagnosis. Current systemic chemotherapy is not effective for this age group. Alternative treatment strategies should be considered.
Key Words: Osteosarcoma • Diagnosis • Elderly • Old
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INTRODUCTION
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Most osteosarcoma patients are adolescents, but there is a significant second peak in the seventh and eighth decades of life.1,2 In addition, it has already been described that the age of osteosarcoma patients is increasing.3 Therefore, analysis of a considerable number of older patients with osteosarcoma is increasingly valuable.
The clinical and histopathologic features of osteosarcoma in adolescent patients have been well described, but there are only a few reports of the clinical and radiographical features of osteosarcoma in elderly patients in the United States, Europe, and Japan.4–7 Reports from the United States and Europe indicate that most osteosarcomas in patients over the age of 50 years are secondary lesions and have generally been considered sarcomatous transformation of Paget’s disease of bone, some other benign bone lesion, or a complication of irradiation.4–6 This considerable predominance of Paget’s sarcoma is meaningful, because the poor prognosis of Paget’s sarcoma, including osteosarcoma, is well known.1,2,8 However, in Japan, Paget’s disease is uncommon.7 Therefore, most older patients with osteosarcoma in Japan are considered to have primary osteosarcoma. The recommendations for conventional osteosarcomas in the elderly may not be the same as the recommendations for secondary osteosarcoma.
We examined 645 cases of osteosarcoma registered in the Tohoku Musculoskeletal Tumor Society and National Cancer Center between 1972 and 2002. Sixty-four of these cases involved osteosarcoma in patients older than 50 years of age. In this article, we describe a clinicopathologic profile of osteosarcomas after the age of 50 in northern Japan, with special attention to prognostic factors and treatment strategies.
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MATERIALS AND METHODS
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We reviewed more than 800 cases of osteosarcoma involving the extremities or axial bones filed at the Tohoku Musculoskeletal Tumor Society and the National Cancer Center in Tokyo, Japan, between 1972 and 2002. Microscopic slides of the biopsied specimen and slides of the surgical specimen were reviewed. Patients with osteosarcoma in the jawbones or cranium, those with dedifferentiated chondrosarcoma with foci of osteosarcoma, and those who underwent surgery for metastatic foci only were excluded from this study. Consequently, 645 patients with osteosarcoma were reviewed in this study. Of these 645, 64 patients (9.9%) were more than 50 years old. All deceased patients died as a result of tumor progression or unrelated causes. All protocols were accepted by the institutional review boards at our institutions. Informed consent was obtained from all patients. One case of tumor in the patella after radiotherapy was previously reported.9
In 64 cases, clinical details and treatment information were obtained by reviewing all medical charts, and the histological subtype was determined in each case by using hematoxylin and eosin slides of the biopsy specimen. In surgical specimens after preoperative chemotherapy, the chemotherapy effect was evaluated by the percentage of tumor necrosis as follows: good, 
95%; moderate, 90% to 95%; and poor, <90%.
In 62 of the 64 patients whose follow-up information was available, the following clinicopathologic variables were analyzed for prognostic value by the Kaplan-Meier method, and the differences were compared by log-rank test: patient age and sex, tumor site and size, accuracy of the initial diagnosis, surgery, surgical margin, local recurrence, preoperative chemotherapy, preoperative and postoperative chemotherapy, cumulative dose of doxorubicin, secondary factors, and distant metastasis at presentation. Patients who underwent inadequate initial surgery because of misdiagnosis and patients who underwent conservative therapy because of misdiagnosis were classified as having an incorrect diagnosis. The relative risk of each variable was estimated by the Cox proportional hazards model. Multivariate analysis was conducted with variable selection by a stepwise forward procedure. Differences at P < .05 were considered significant.
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RESULTS
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The 64 patients ranged in age from 51 to 78 years (mean, 63 years). There was no apparent sex predominance; 34 patients were male, and 30 were female. Tumors were located on the bones of the extremities in 41 patients (upper extremities, n = 6; lower extremities, n = 35) and on the axial bones in 23 (Fig. 1). In the extremities, the most common location was the distal femur (n = 13), followed by the proximal humerus (n = 9), proximal fibula (n = 6), proximal tibia (n = 4), and proximal tibia (n = 3), and there was 1 each in the radius, ulna, patella, distal tibia, mid tibia, and foot. In the axial bones, the most common site was the pelvis (n = 10), followed by the sacrum (n = 4) and rib (n = 3), with 2 each in the scapula and spine and 1 each in the clavicle and sternum. Tumor size ranged from 4 to 22 cm in maximal diameter (mean, 9.7 cm). Information on symptoms was available in 60 patients; pain was the most common symptom and occurred in 54 (90%) of the 60. The duration of symptoms before consulting the institutes ranged from 1 to 276 months (mean, 18 months). Although the mean duration was relatively longer than that in typical adolescent patients, the duration was <1 year in 54 of the 60 patients. Radiological findings were not specific. In 59 tumors whose radiographs were available for review, 27 cases showed osteolytic and destructive lesions, 8 showed osteoblastic lesions, and 24 showed a mixed pattern. In 56 of the 59 cases, tumors destroyed cortical bones with a soft tissue extension, but in 3 cases, cortical bone expanded with thinning. In contrast to osteosarcomas in adolescents, 20 (74%) of the 27 tumors with an osteolytic appearance had no apparent periosteal reactions (Fig. 2). Seven (11%) patients had lung metastasis at the initial presentation.
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FIG. 2. Characteristic radiological features of osteosarcoma after the age of 50. An osteolytic pubic lesion without periosteal reaction is shown.
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Histologically, 48 (75%) of the 64 were conventional osteosarcomas. The rate of histological subtypes was similar to that of osteosarcomas in adolescents; 23 were osteoblastic, 17 were fibroblastic, and 6 were chondroblastic, depending on the predominant matrix production (Fig. 3). Six of the 17 fibroblastic osteosarcomas showed marked pleomorphism, and in 1 of the 17 tumors, giant cells were predominant, resembling giant cell tumors of bone. Fourteen (22%) of the 64 were secondary osteosarcoma; of these 14 patients, 10 had a history of radiotherapy, 3 had preexisting bone infarction, and the remaining 1 had a preexisting solitary osteochondroma. However, none of the patients had a history of Paget’s disease of bone. Of the 64 tumors, 2 each were parosteal osteosarcoma and telangiectatic osteosarcoma.
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FIG. 3. Photomicrograph of a fibroblastic osteosarcoma with foci of osteoid production (stain, hematoxylin and eosin; magnification, x200).
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Clinical or radiological misdiagnoses at the initial presentation were observed in 15 (23%) of the 64 cases. The length of time in delay of diagnosis ranged from 3 to 12 months (average, 6 months). Misdiagnoses included benign conditions in 10 patients and malignant tumors in 5; 8 patients (53%) underwent a definitive initial surgery without biopsy, and their surgical margins were inadequate (Table 1). Frequent anatomical sites of misdiagnosis were rib, sacrum, and proximal fibula; all three lesions arising in the rib, two (50%) of the four involving the sacrum, and three (50%) of six osteosarcomas in the proximal fibula were misdiagnosed. Two of the three lesions arising in the rib were misdiagnosed on biopsy, which identified fibrous dysplasia and chondrosarcoma. Although the tumors were resected with wide surgical margins, these patients died of metastasis. The most common incorrect diagnosis was giant cell tumor in the long bones (3 of the 15 cases); the lesions appeared as osteolytic, expansile lesions without any cortical disruption or periosteal reaction (Fig. 4). Two patients with low back pain were misdiagnosed as having sciatic neuralgia and received prolonged conservative treatment before they were accurately diagnosed.
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FIG. 4. Anteroposterior view of an osteolytic and expansile lesion without periosteal reaction of the distal femur. This lesion was misdiagnosed (without biopsy) as a giant cell tumor of bone.
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Preoperative chemotherapy was given to 22 patients but was not administered to 42 patients because of insufficient systemic conditions or misdiagnosis before the initial treatment. In the 22 patients who received preoperative chemotherapy, 17 were treated with combination chemotherapy—mainly high-dose methotrexate (6–10 g/m2 per course with leucovorin rescue), doxorubicin (40–75 mg/m2 per course), and cisplatinum (50–100 mg/m2 per course) with or without ifosfamide (4 to 10 g/m2 per course). Five other patients were treated with combination chemotherapy of methotrexate, cisplatinum, ifosfamide, and doxorubicin in varying combinations. Tumor necrosis rates in the surgical specimen were <90% in 18 (82%) of the 22 patients. In 6 (27%) of the 22 patients, chemotherapy schedules were not completed because of severe toxicity or patient intolerance; the necrosis rates were <90% in 5 of the 6 patients and <95% in 1 patient. In the other 16 patients, preoperative chemotherapy was performed according to protocol; the necrosis rates were >95% in 3 patients and <90% in 13 patients. Postoperative adjuvant chemotherapy of methotrexate, cisplatinum, ifosfamide, and doxorubicin in varying combinations was given in 21 patients. The most commonly used agent in preoperative and postoperative chemotherapy was doxorubicin. The cumulative dose of doxorubicin ranged from 30 to 590 mg (mean, 176 mg).
Fifty-two patients underwent surgery; 40 of the 54 underwent wide excision, and only one patient developed local recurrence after surgery. Fourteen underwent marginal or intralesional excision; 11 of the 14 patients developed local recurrence. The remaining 10 of the 64 patients were treated without surgery because of insufficient systemic conditions or inoperable local conditions for surgical treatment.
Follow-up information on 62 of the 64 patients was available and covered periods ranging from 4 to 300 months (mean, 48 months). The overall survival rate at 5 years was 55.5% (95% confidence interval, 40.9%–70.1%). Of the 15 patients who were misdiagnosed, the survival rate at 5 years was 54.2% (95% confidence interval, 22.5%–85.8%), and the rate at 10 years was 27.1% (95% confidence interval, 0%–58.0%). In 47 patients who were accurately diagnosed, the survival rate was 55.5% both at 5 and 10 years (95% confidence interval, 38.9%–72.1%; P = .46; Fig. 5). Univariate analysis showed that tumor site (axial bones: P < .001; relative risk, 5.7; 95% confidence interval, 2.4–13.5), size (10 cm: P < .001; relative risk, 4.2; 95% confidence interval, 1.8–9.7), surgery (no surgical treatment: P < .001; relative risk, 6.2; 95% confidence interval, 2.7–14.5), distant metastasis at initial presentation (P < .001; relative risk, 5.3; 95% confidence interval, 2.0–13.8), surgical margin (inadequate: P = .003; relative risk, 3.4; 95% confidence interval, 1.5–7.5), and local recurrence (present: P = .005; relative risk, 3.1; 95% confidence interval, 1.4–6.8) were significant (Table 2). Multivariate analysis showed that disease in axial bones (relative risk, 4.8; 95% confidence interval, 1.9 to 12.1), larger tumors (relative risk, 4.2; 95% confidence interval, 1.6–10.8), and distant metastasis at the initial presentation (relative risk, 5.2; 95% confidence interval, 1.8–15.1) were significant prognostic factorsin patients with osteosarcoma after the age of 50 (Table 3; Figs. 6–8
).
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FIG. 5. Kaplan-Meier curve according to the accuracy of the initial diagnosis. No significant difference was found (Ô = censored patients). However, please note that long-time survivors were found only after accurate diagnosis.
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TABLE 2. Patient and tumor characteristics and univariate analysis for overall survival in 62 cases of osteosarcoma after the age of 50
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FIG. 6. Kaplan-Meier curve according to the site of the lesion (Ô = censored patients). The patients with axial sites had a significantly worse prognosis.
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FIG. 7. Kaplan-Meier curve according to the size of the lesion (Ô = censored patients). The patients with larger tumors had a significantly worse prognosis.
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FIG. 8. Kaplan-Meier curve according to initial distant metastasis (Ô = censored patients). Patients with initial distant metastases had a significantly worse prognosis.
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DISCUSSION
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This study showed several demographic characteristics of osteosarcoma in elderly patients in Japan. In contrast to osteosarcomas in adolescents, occurrences in axial bone (23 of 64) such as the spine, pelvis, or rib were not uncommon. In the extremities, although the distal femur was the most common site, unusual sites including the proximal femur and proximal fibula were also common. Because proximal tumors tend to be larger than distal ones, this characteristic site distribution indicates that surgical treatment for osteosarcoma in elderly patients is technically more difficult. In previous reports from Europe and the United States regarding osteosarcoma in elderly patients, the percentage of osteosarcoma associated with Paget’s disease of the bone was considerable.4–6 Huvos et al.5 reported that 66% of osteosarcomas in patients older than age 60 arose in a preexisting lesion, such as Paget’s disease, or developed after radiotherapy. Several secondary osteosarcomas were included in the current study, but most cases (78%) in this series did not involve any previous bony condition. Therefore, this series demonstrates characteristic features of primary osteosarcoma in elderly patients.
Misdiagnoses were observed in 15 (23%) of the 64 cases, and 8 patients underwent inadequate surgery without biopsy. Radiographical characteristics of osteosarcoma in elderly patients are probably associated with these misdiagnoses. In three cases misdiagnosed as giant cell tumor, the radiographical features were quite similar to those of typical giant cell tumor of the bone, showing expansile and osteolytic lesions without cortical disruption. In two cases misdiagnosed as metastatic cancer, the lesion showed osteolytic lesions without periosteal reactions. Rare periosteal reactions in osteosarcoma in elderly patients were previously described.4 Although many factors are related to these misdiagnoses, radiological characteristics of osteosarcoma, such as expansile growth and an absence of periosteal reactions, in elderly people might promote inaccurate assessment.
Unusual sites of osteosarcoma in elderly patients may also cause confusion in the diagnosis. Two patients with lesions around the sacroiliac joints were initially treated for low back pain with sciatic neuralgia. In these patients, initial radiographs covered only the normal lumbar spine region, and the tumor was noted later. Osteosarcoma arising in the rib, sacrum, or proximal fibula may be easily misdiagnosed. Of 13 osteosarcomas that arose in these locations, 8 (62%) were misdiagnosed. A diagnosis of any symptomatic bony lesions, other than obvious cases such as those involving multiple bony lesions with a cancer history, should be confirmed by biopsy. Furthermore, we should remember the possibility of primary osteosarcoma for osteolytic bony lesions even in elderly patients, although metastatic cancer and multiple myeloma are common diagnoses for these conditions.10 It should be stressed that the 10-year survival rate of patients with incorrect diagnoses was much lower than that of patients with correct diagnoses, although statistical significance was not identified.
The importance of the effect of systemic chemotherapy has been widely accepted.11–15 Preoperative neoadjuvant chemotherapy was performed in 22 cases, but the effects were poor in 82% of the cases. The high rate of intolerance of the patients in this series (6 of 22) may be related to the poor effects of the systemic chemotherapy. In addition, it has already been reported that pharmacokinetics in patients with osteosarcoma are age related16 and that the side effects of antitumor agents are more prominent in elderly patients.17 Other alternatives, including molecular-targeting chemotherapy, should be investigated further. On multivariate analysis, a larger tumor, site in the axial bone, and initial distant metastasis were poor prognostic factors. Larger tumor and site in axial bones are closely related to local control of the primary disease site.10 Lack of local control has already been proven to be a poor prognostic factor in osteosarcomas in adolescents.15,18–20 In this series, however, 10 of the 64 patients had inoperable disease at the initial presentation; 5 of the 10 were inoperable because of systemic complications, and the other 5 were inoperable because of severe local extension of the tumor. Absence of surgery, inadequate surgical margin, and local recurrence were associated with poor prognosis on univariate analysis, although these factors were not significant on multivariate analysis. Radiation was selected as a therapeutic alternative in most of these patients, but all of the 10 patients without surgery died as a result of the tumor. Therefore, it should be stressed that local control by surgery with an adequate margin is essential to achieve long-term survival for osteosarcoma in elderly patients.
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FOOTNOTES
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In northern Japan, most patients with osteosarcoma after the age of 50 had primary osteosarcoma. Careful radiological examination and biopsy are mandatory for correct diagnosis. Current systemic chemotherapy is not effective for this age group.
Received for publication March 4, 2004.
Accepted for publication August 1, 2004.
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ABSTRACT
INTRODUCTION
