Osteosarcoma in the Elderly: Clinical Features and Outcome

Study

Age

Total number (secondary/%)

Number of Paget’s disease of bone

Huvos [5]

60<

117 (66/56 %)

58 (50 %)

Grimer [11]

40<

481 (83^a/17 %)

42 (8.7 %)

Longhi [16]

65<

43 (14/33 %)

13 (30 %)

Okada [13]

50<

64 (14/22 %)

0 (0 %)

Nishida [14]

60<

95 (12/13 %)

0 (0 %)

^aPaget’s disease and radiation-induced osteosarcoma described in the study

In secondary osteosarcoma, previous studies indicated that the prognosis of elderly patients is dependent on the presence of preexisting conditions. Generally, osteosarcomas arising from a preexisting condition have a dismal prognosis, particularly from Paget’s disease of bone [2, 7]. However, little progress has been made in the treatment of Paget’s sarcoma in the last 60 years [8]. The proportion of Paget’s disease in secondary osteosarcoma as a preexisting condition has been differently reported even from Western countries (Table 5.1). Because osteosarcoma arising from Paget’s disease has been reported to be uncommon in Japan [9], two subsequent studies from Japan have reconfirmed the unlikelihood of this disease as an underlying pathological condition in this country. The significance of Paget’s disease of bone as a preexisting condition of osteosarcoma thus differs markedly among countries.

The carcinogenic effect of radiation is one of the crucial concerns in the treatment of patients with primary malignancy. Prior radiation of bone is a well-known risk factor for the development of secondary osteosarcoma [2, 6, 10]. The median latency period between radiotherapy for the primary cancer and the development of postradiation sarcoma ranges from 8 to 16 years. Grimer et al. reported that the time lag between radiotherapy and subsequent development of osteosarcoma ranged from 6 to 23 years [11]. Historically, radiotherapy was less used for patients with cancer in Japan than those in Western countries. However, comparing the past few decades, radiotherapy has recently assumed more prominent roles in the treatment of cancer. Thus it is likely that the number of secondary osteosarcomas, particularly radiation-induced osteosarcoma (Fig. 5.1), will increase in the near future. Grimer et al. reported that analyses of 41 patients with radiation-induced osteosarcoma confirmed that cure can be achieved even in the older (over 40 years) group of patients if treated aggressively with multidisciplinary treatment including surgery and chemotherapy [11], which is consistent with other previous studies [2, 6]. Contrary results have also been reported. Lewis et al. reported that despite multi-agent chemotherapy, postradiation osteosarcoma continues to have a poor prognosis. Possible contributing factors may include the advanced age and worsened performance status of this patient population [12].

Fig. 5.1

70-year-old male. He received 60 Gy of radiotherapy for the treatment of his prostate cancer 7 years before. He developed radiation-induced osteosarcoma in his right pubic bone (white arrows) (a). Axial sections of CT image (b) and MR images of T1 weighted (c) and T2 weighted (d) show extraosseously invading tumor (green arrows)

5.3 Delay in Diagnosis

Malignancies of bone are commonly metastases from other primary malignancies in elderly patients, possibly resulting in the misdiagnosis and/or delay in diagnosis of osteosarcoma. Okada et al. reported that the duration between development of symptoms and referral to a specialist ranged from 1 to 276 months (mean 18 months). Clinical and radiological misdiagnoses at the initial presentation were observed in 15 (23 %) of the 64 cases. The length of time in the delay of the diagnosis ranged from 3 to 12 months (average, 6 months) [13]. Nishida et al. reported that although the median duration from the initial presentation at any clinic to the definitive diagnosis of osteosarcoma at specialist centers was 2 months, the mean duration from presentation was 5.2 months. There were 23 cases in which it took more than 5 months between presentation and the making of the correct diagnosis. In many cases, the lesion was considered to be a bone metastasis from carcinoma at another site [14]. A possible reason for such a misdiagnosis is that rare periosteal reactions in osteosarcoma in elderly patients (Fig. 5.2) were previously reported [15], occasionally leading to the radiological diagnosis of metastatic disease of bone.

Fig. 5.2

78-year-old female. Primary osteosarcoma developed in her left shaft of femur. X-ray indicated permeative osteolytic lesion without obvious periosteal reaction (white arrows) (a and b). T2-weighted axial image (c) and STIR coronal image (d) demonstrated the extraosseously invading tumorous lesion (green arrows)

The results of these Japanese studies agree with those of another report in which the median time interval from onset of symptoms to diagnosis was 4 months [16]. In the younger population, the median time interval has been reported to be 10 weeks [17].

A major concern is the association between delay in diagnosis and patient prognosis. A previous report indicated that misdiagnosis is associated with a poor prognosis in elderly patients with osteosarcoma. The 10-year survival rate of patients with inadequate diagnoses was much lower than that of patients with adequate diagnoses, although the difference was not statistically significant [13]. In contrast, another study demonstrated that a prolonged latency period before the correct diagnosis was made was not an individual prognostic factor [14].

5.4 Site of Predilection

The knee region is affected in approximately 62 % of adolescents with osteosarcoma [18]. Several reports have shown a predilection for axial localization in elderly persons with osteosarcoma (Table 5.2), including Longhi’s report in which 4 (9.3 %) of 43 patients were noted to have had a primary tumor in the knee area and 10 (23 %) a tumor in the axial skeleton [16]. Grimer’s study based on 481 cases over 40 years revealed that 21 % of cases had tumor in the axial bones [11]. Other series including primary and secondary osteosarcoma reported higher rates (27–38 %) of axial skeleton as the site of involvement in elderly patients [5, 13, 14, 19]. Secondary osteosarcoma due to conditions such as postradiation sarcoma and Paget’s sarcoma often occurs in the pelvis [2, 7, 8], contributing to a higher tumor incidence in axial bone. However, Manoso et al. and Iwata et al.’s studies focusing on primary osteosarcoma in the elderly [20, 21] also demonstrated the predilection of primary osteosarcoma for axial bones (19 % and 49 %, respectively). Taking these results together, it may be that primary osteosarcoma in elderly patients is also more likely to involve axial bone (Fig. 5.3).

Table 5.2

Site of osteosarcoma in elderly patients

Study	Age	Number of patients	Axial bone, number (%)
Huvos^a [5]	60<	117	32 (27 %)
Carsi [19]	40<	47	18 (38 %)
Grimer [11]	40<	481	100 (21 %)
Okada [13]	50<	64	24 (38 %)
Longhi [16]	65<	43	10 (23 %)
Manoso^b [21]	40<	58	11 (19 %)
Nishida [14]	60<	95	31 (33 %)
Iwata^b [20]	40<	86	42 (49 %)

^aSite of craniofacial bone is included

^bSecondary osteosarcoma is not included. Site of craniofacial bone is included

Fig. 5.3

64-year-old male. Primary osteosarcoma occurred in his right first rib, an atypical site. CT axial (a) and coronal (b) images show extraosseously expanding lesion (white arrows)

5.5 Stage at Diagnosis

The Cooperative Osteosarcoma Study Group (COSS) had a uniform treatment protocol for two decades. The registration was not limited to the young patients with localized limb tumors, but included all patients with osteosarcoma. The results of this study [22] reflecting the long-term outcome of a wide spectrum of patients with high-grade osteosarcoma after the introduction of multi-agent chemotherapy may be representative of the whole osteosarcoma cohort, thereby facilitating comparison with those of elderly patients with osteosarcoma. In this study, of 1702 patients, 1491 (87.6 %) presented with localized disease, and 211 (12.4 %) had distant metastases.

Regarding the cohort of elderly patients with primary and secondary osteosarcoma, Longhi et al. reported the results of 43 osteosarcoma patients over 65 years of whom 13 had metastatic disease (30.2 %) and 30 (69.8 %) localized disease [16]. Nishida et al. reported that 12 (13 %) of 91 patients had distant metastases at diagnosis [14]. According to the results of Okada et al. who analyzed patients over 50 years, 11 % had lung metastasis at the initial presentation [13]. In the cohort of elderly patients with only primary osteosarcoma, Grimer et al. described that 48 (18 %) of 270 patients with high-grade primary osteosarcoma over 40 years had distant metastasis at diagnosis [11]. Manoso et al. noted a lower proportion of the cases with distant metastasis at diagnosis (5 %) in their cases over 40 years. Iwata et al. reported that 28 % of patients with primary osteosarcoma over 40 years had distant metastasis at diagnosis [20]. In this way the reported proportion of distant metastasis at diagnosis in the cohort of elderly patients has been reported to range from 5 to 30 %. Stage at diagnosis, particularly with distant metastasis, is slightly higher compared with the all-age cohort (12.4 %) [22]. It is likely that the feasibility of chemotherapy and/or surgical treatment and response to chemotherapy may be more important for elderly patients with osteosarcoma.

5.6 Treatment Modality

5.6.1 Surgery

As discussed later, “operability” has been reported as a significant good prognostic factor for elderly patients with osteosarcoma in several studies [14, 16, 20]. However, as was described above, the axial skeleton, in particular the pelvis, is significantly more often affected in elderly patients with osteosarcoma, which makes definitive surgery more difficult to achieve. A previous report, reflecting the whole osteosarcoma cohort based on 1702 cases, indicated that 113 (6.6 %) of 1702 cases retained macroscopic residual tumor at the primary tumor site [22]. Among the 113 patients with macroscopic residual tumor, 84 had not been surgically treated, while 29 had residual tumor after definitive surgery.

In their cohort of elderly patients over 40 years, Carsi et al. reported that 42 (89 %) of 47 cases were operable [19]. According to Grimer’s study of a cohort over 40 years, of 238 cases with high-grade nonmetastatic extremity primary osteosarcoma, 212 (92 %) underwent amputation or limb salvage surgery, while of elderly patients with pelvic osteosarcoma, 37 (51 %) of 72 cases underwent surgery [11]. Iwata et al. investigated elderly patients with primary osteosarcoma over 40 years, of whom 63 (73 %) of 86 received surgical treatment [20]. Nishida et al. noted that 81 (85 %) of 95 cases received surgical treatment in an analysis of patients over 60 years [14]. Of the cohort of aged over 65 years, 74.4 % underwent surgery [16]. Together, the predilection of osteosarcoma in the elderly for axial bone may be the main factor precluding the achievement of complete resection of primary tumors.

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