Abstract
Background/Aim: Little is known about the clinical characteristics in older patients of ≥75 years of age with primary osteosarcoma due to its rarity. We aimed to understand the clinical characteristics in these patients in order to make an appropriate diagnosis and provide treatment. Patients and Methods: The medical records of eight patients of ≥75 years of age with primary osteosarcoma were retrospectively reviewed. We investigated their clinical features, imaging findings, histopathological findings, treatment methods, and oncological outcomes. Results: There were two male and six female patients, with a mean age of 80 years. The mean follow-up period was 44 months. The initial symptom was pain in five, swelling in two, and a mass in one. The initial diagnosis was osteoarthritis in two, lumbar canal stenosis in two, benign bone tumor in four. The mean period from the first time the patient noticed symptoms to referral was 25 months. Two patients had a history of surgical curettage at their previous hospital for bone tumor that was considered benign. Lung metastasis was observed at presentation in three patients. The mean tumor size was 129 mm in its greatest dimension. Surgical treatment was performed on six patients, including frozen autograft reconstruction in one. Carbon-ion radiotherapy was conducted in one patient due to an unresectable pelvic lesion. Conclusion: Diagnosis requires care because the radiological and histological findings of primary osteosarcoma in patients ≥75 years of age are often non-specific, in addition to their delayed consultation. Individualized treatment including surgical procedure and radiotherapy is essential for older patients to maintain a good quality of their lives.
- Primary osteosarcoma
- older patients
- delayed consultation
- advanced-stage disease
- frozen autograft reconstruction
- carbon ion radiotherapy
- individualized treatment
Osteosarcoma is a rare cancer, and is the most common type of primary bone sarcoma in children, adolescents and young adults. However, osteosarcoma has a bimodal distribution of incidence, and a second smaller peak exists in adults over 40 years of age. Older patients are usually considered to develop secondary osteosarcoma due to Paget’s disease or irradiated bone lesions. Primary osteosarcoma is uncommon in older patients (1-4).
In recent years, the increase in lifespan through advances in medicine has led to the development of super-aged societies in Japan and other countries. In Japan, people of 65 years and older account for approximately 30% of the total population (5). Thus, the rate of older patients with primary osteosarcoma might be expected to increase accordingly. In order to make an appropriate diagnosis and provide treatment, it is necessary to understand the clinical characteristics of primary osteosarcoma in these patients. Previous studies have reported that the prognosis of patients with primary osteosarcoma worsens with increasing age (6, 7). However, little is known about the prognosis and clinical characteristics, including the imaging and pathological findings, in older patients with primary osteosarcoma, especially those ≥75 years of age, with the exception of a few case reports (8).
The standard treatment for osteosarcoma is usually a combination of surgery and chemotherapy; however, older patients often receive surgical treatment alone. They infrequently undergo chemotherapy due to their higher risk of adverse events, in comparison to younger patients (9-13). Adverse events tend to occur in older patients due to their reduced renal function, cardiac dysfunction, and reduced bone marrow tolerance.
Surgical treatment for malignant bone tumors usually consists of wide excision and reconstruction, as limb salvage surgery. Reconstruction using a prosthesis is commonly performed, however, biological reconstruction using a recycled autograft is also available for patients of any age, and has been reported to be associated with numerous advantages: the autograft can fit perfectly with the original site, and the retracted tendon or muscles can be reattached, and thus, the original joint function can be retained (14-18). Older patients who opt to retain traditional practices in daily living, such as sitting in the seiza position (a traditional Japanese sitting position), would be good candidates for such procedures.
From 1999 to 2018, a total of 131 patients were diagnosed with osteosarcoma, and received treatment at the Department of Orthopaedic surgery, Kanazawa University Hospital (Kanazawa City, Japan). The histological diagnosis of all patients was confirmed using the pathological database of the Department of Pathology, Kanazawa University Hospital. Among them, eight patients (6%) were ≥75 years of age. Thus, in the present study, we describe the cases of these eight patients with primary osteosarcoma patients, with their clinical characteristics, imaging and pathological findings, treatment methods and oncological outcomes. We also present a review of the relevant literature.
Patients and Methods
We retrospectively reviewed the medical records of eight patients aged ≥75 years who were histopathologically diagnosed with primary osteosarcoma. All diagnoses were confirmed according to the latest World Health Organization criteria (1). Clinical features such as age, sex, past history, tumor site, tumor size, stage (American Joint Committee on Cancer (eighth edition) (19), pathological fracture, symptoms, initial diagnosis at the previous hospital, and the period from initial symptoms to referral to our Department, were investigated using medical records. In addition, we examined their radiological imaging findings [X-ray, computed tomography (CT), and magnetic resonance imaging (MRI)], histopathological findings, treatment methods, and oncological outcomes. All patients provided their informed consent for the publication of their case information.
This retrospective study of patient specimens was approved by the Ethics Committee of Kanazawa University Hospital [Institutional Review Board Number 2019-61(3094)] in compliance with the guidelines of the 1975 Declaration of Helsinki, and written informed consent was obtained from all study participants.
Results
Clinical features. The present series of eight cases included two male and six female patients with a mean age of 80 years (range=75-92 years) (Table I). No patient had a history of Paget’s disease or radiotherapy for cancer. The initial symptom was pain in five, swelling in two, and a mass in one. The initial diagnosis at the previous hospital was osteoarthritis in two, lumbar canal stenosis in two, benign bone tumor in four. Two patients had a history of surgical curettage for bone tumor that was considered benign at their previous hospital (cases 2 and 4). The mean period from the first time the patient noticed symptoms to referral to our Department was 25 months (range=3-72 months). Normal alkaline phosphatase levels were observed for two patients (case 5 and case 8). The tumor sites were the distal femur in three, pelvic bone in two, proximal femur in two, and proximal tibia in one. The mean tumor size was 129 mm in its greatest dimension (range=45-380 mm). Two patients had a pathological fracture at the time of their diagnosis (cases 2 and 7). Staging was performed according to the eighth edition of the American Joint Committee on Cancer. and assigned as follows: Stage IIA in one, stage IIB in three, stage III in one, and stage IVA in three.
Clinical features of older patients with primary osteosarcoma.
Radiological imaging findings. The radiological imaging findings are presented in Table II. Nonspecific radiological imaging findings are shown in Figure 1. No periosteal reaction was observed on X-ray films in five patients, namely cases 1, 2, 4, 7, and 8 (Figure 1A, C, F and I, respectively). A lytic lesion with little or no calcification was observed on X-ray or CT in these same five patients. A septum was observed in two patients, cases 4 (Figure 1F) and 8 (Figure 1I and J), and no cortical destruction was observed on X-ray or CT in cases 2, 4, and 8 (Figure 1).
Radiological imaging findings of study patients.
Radiological imaging findings. Case 1: A lytic lesion with marginal sclerosis was detected on the medial side of the left distal femur (A). The patient had been observed at another hospital conservatively as having osteoarthritis, with no consideration of the possibility of a malignant bone tumor. After 44 months, calcification and periosteal reaction was observed in the lytic lesion (B), and thus, a malignant bone tumor was suspected, and the patient was referred to our Department. Case 2: A lytic bone lesion with little calcification and no cortical disruption was observed on the right femoral neck. A nearby doctor considered a benign bone tumor (C). The intraosseous lesion exhibited iso-intensity on T1-weighted magnetic resonance imaging (MRI) (D). The intraosseous lesion also exhibited iso- to hyperintensity with a sign of fluid-fluid level on T2-weighted MRI (E). Case 4: An intraosseous lesion with several septa but no cortical disruption was observed at the epiphysis to metaphysis of the right distal femur. At earlier consultation with another doctor, the lesion had been considered a benign bone tumor, including giant cell tumor of bone (F). Case 7: A bone lesion exhibited homogeneously hyperintensity on T2 fat-suppressed MRI (G). Peripheral enhancement was observed on contrast enhanced MRI (H). Case 8: An intraosseous lesion with little calcification and no cortical destruction was observed at the diaphysis of the right proximal tibia (I). A previous doctor considered it to be a benign bone tumor, including simple bone cyst, or fibrous dysplasia. A few septa were observed on axial computed tomography images (J).
On T1-weighted MRI, the lesions were homogeneously isointense in cases 2 (Figure 1D), 3, 4, 6, and 8, and heterogeneously iso-intense to hyperintense in the remaining three. On T2-weighted MRI, the lesions were homogeneously hyperintense in cases 4 (Figure 1G) and 8, and heterogeneously iso-intense to hyperintense in six patients [Cases 1 (Figure 1E), 2, 3, 5, 6, and 7]. Extraosseous lesions were not observed in cases 2 (Figure 1D and E), 4 (Figure 1G and H), and 8. A cystic area and a sign of fluid-fluid level was observed in cases 1, 2 (Figure 1E), 3, 4, and 8. Enhancement on contrast MRI was diffuse in cases 2, 5, and 6; peripheral in cases 3, 4 (Figure 1H), and 8; and slight in case 7.
Histopathological findings. The histopathological findings are presented in Table III. Non-specific histopathological findings are shown in Figure 2. Curetted specimens obtained at a previous hospital in cases 2 and 4, and core-needle biopsy specimens in cases 1 and 7 did not show osteosarcoma due to a lack of osteoid production and small amounts of neoplastic cells with nuclear atypia. These four cases were initially misdiagnosed as other bone tumors (Figure 2); the diagnoses included benign bone tumors [aneurysmal bone cyst (ABC) and giant cell tumor of bone], and malignant bone tumors (low-grade sarcoma and undifferentiated pleomorphic sarcoma). The diagnoses of ABC (case 2) and the low-grade sarcoma with ABC change (case 4) were amended to primary osteosarcoma after pathological review at our Department. Two cases were correctly diagnosed as primary osteosarcoma based on the examination of the excised specimen (cases 1 and 7). Evaluation of all other resected specimens (cases 2, 4, 5, and 8) also led to a diagnosis of primary osteosarcoma. ABC-like features were observed in the resected specimen in all six of these patients.
Histopathological findings, treatment methods, and oncological outcomes.
Histopathological findings. Case 1: The diagnosis of undifferentiated pleomorphic sarcoma was made based on anaplastic proliferation of pleomorphic tumor cells with no osteoid production in the biopsy specimen (A). Case 2: The diagnosis of aneurysmal bone cyst was made based on the histopathological findings of a curetted specimen at a previous hospital, which contained bleeding, osteoclast clusters, and reactive bone formation (B). Case 4: Tumor cells had a little nuclear atypia, and bleeding, osteoclast clusters, and hemosiderin deposit was observed in curetted specimen, and the diagnosis of low-grade bone tumor with aneurysmal bone cyst change was made at previous hospital (C). Case 7: Proliferation of spindle cells with little atypia and multiple osteoclasts were observed in the biopsy specimen, and thus the diagnosis of giant-cell tumor of bone was made (D). Scale bars=100 µm.
Treatment methods and oncological outcomes. The treatment methods and oncological outcomes are presented in Table III. Neoadjuvant chemotherapy was only administered to one patient, case 6; however, the tumor progressed due to the poor efficacy of chemotherapy, and no further treatment was provided; the patient opted to receive best supportive care at a local clinic near his home. Cases 2 and 4 had undergone curettage and artificial bone augmentation at their previous hospitals. After referral to our Department, additional wide excision of the tumor with prosthetic reconstruction was performed. No local recurrence or distant metastasis was observed at the final follow-up examinations at 10 and 120 months, respectively. Cases 1, 5, and 7 underwent wide excision of the tumor with prosthetic reconstruction. Two patients (cases 1 and 7) remained disease-free at the final follow-up examination at 14 and 81 months, respectively, while the other patient died of disease at 13 months after surgery. Case 8 underwent wide excision and pedicled frozen autograft reconstruction after treatment of the bone tumor with liquid nitrogen (Figure 3). At 96 months after surgery, she was disease-free, and retained her traditional practice of sitting in the seiza position, and lived a normal life with an excellent lower extremity function (Musculoskeletal Tumor Society score=30/30 points). CIRT was conducted for case 3 due to an unresectable pelvic lesion. No adverse events of radiotherapy were observed. The patient was able to walk with a cane, and there was no progression of the tumor or metastasis at 6 months after CIRT. However, at 9 months after CIRT, the patient suffered a fall, which caused a subtrochanteric fracture of the left femur, after which she was bedridden. This patient died of pneumonia 10 months after CIRT.
A case of wide excision and pedicled frozen autograft reconstruction after treatment of the bone tumor with liquid nitrogen. A: Computed tomography revealed a bone tumor with small amount of calcification on the right tibial shaft, and no bone cortical destruction or extraosseous lesion was observed. B: magnetic resonance imaging (MRI) showed that the bone tumor was isointense on T1-weighted MRI. C: The tumor was isointense to hyperintense with a sign of fluid-fluid level on T2-fat suppression MRI. D: The tumor was peripherally enhanced on contrast MRI. E: Osteotomy was performed 3 cm from the edge of the tumor, and the tibial shaft with tumor lesion was elevated. F: The tibial shaft with tumor lesion was covered by several sheets, and isolated from soft tissues in the distal lower leg including her ankle joint. G: The tibial shaft was immersed into liquid nitrogen for 20 minutes 3 cm distal from the edge of the tumor lesion, after curettage of tumors. H: The frozen bone was thawed at room temperature for 15 minutes. I: The frozen bone was washed using 0.35% iodine distilled-water for 15 minutes. J: Fixation using dual plates between the frozen bone and host bone was performed. K: Histological diagnosis of the excised specimen revealed primary osteosarcoma. L: At 96 months after surgery, bone union between host bone and frozen bone was confirmed by X-ray. M: The patient was able to continue her life without limitations, and was able to sit in the seiza position. N: The patient was able to completely extend her right knee joint. Scale bar = 100 µm.
The mean follow-up period was 44 months (range=4-120 months). At the final follow-up examination, the oncological outcomes were clinically disease-free in three, no evidence of diseases in two, alive with disease in one, dead due to other disease in one, and dead due to disease in one.
Discussion
Previous studies on the diagnosis and treatment of osteosarcoma have mostly focused on children, adolescents, and young adults. Osteosarcoma in older patients is rarely discussed, with the exception of osteosarcoma secondary to Paget’s disease or after radiotherapy (20-22). The clinical outcomes of older patients (≥60 years of age) with primary osteosarcoma have been discussed in some studies (6, 11, 20, 23-25). There are differences in the clinical characteristics, including the treatment methods and prognosis of patients of 60-75 years of age and those of ≥75 years of age; however, the clinical in studies, the outcomes of patients ≥75 years of age have been included with those aged ≥60 years (Table IV). Consequently, little is known about the specific clinical characteristics, including the imaging and pathological findings, of primary osteosarcoma in older patients (≥75 years of age), with the exception of a few case reports (8). In the present study, the medical records of eight primary osteosarcoma patients aged 75 years or more were reviewed in order to demonstrate the clinical characteristics (Table I).
Previous studies on older patients with osteosarcoma.
The diagnosis of osteosarcoma is made based on the combination of clinical, radiographic, and pathological findings. Pathological confirmation of the existence of woven bone or osteoid production by anaplastic tumor cells is the most important finding for the diagnosis of osteosarcoma. However, a nonspecific area of bleeding was histologically observed in the tumor in six of the patients in the present study. Among these patients, two had undergone curettage and bone grafting at a previous hospital, based on the assumption that it was a benign or low-grade bone tumor (e.g., ABC or low-grade tumor of bone with ABC change), and the possibility of a malignant bone tumor was not suspected until the patient developed local recurrence after surgery, when they were referred to our Institution. It has been reported that older patients with osteosarcoma are more frequently immunohistochemically positive for markers of angiogenesis; however, evidence to support this is not standardized and remains controversial (26). Thus, it is sometimes difficult to make an early diagnosis of primary osteosarcoma in older patients, and misdiagnoses are relatively common because of the nonspecific radiological and histological findings (27). Furthermore, the incidence of primary osteosarcoma in older individuals is very low, and the findings can resemble hypertrophic osteoarthropathy, metastasis from carcinoma, or other primary bone tumors that occur more commonly in older individuals, including chondrosarcoma and undifferentiated pleomorphic sarcoma.
Older people usually have differing degrees of osteoarthritis or lumbar degenerative disease and often complain of nonspecific symptoms including pain, numbness, or swelling around their joints. They are often followed-up conservatively with the administration of painkillers or the injection of local anesthetic by general practitioners. Plain roentgenography is necessary to determine whether or not a bone lesion is present; however, some general practitioners do not perform any examinations, particularly for older patients. On the other hand, older patients may not immediately consult a nearby doctor even though they notice pain or swelling around a joint because they manage their symptoms at home or due to economic problems. In the present study, the mean period from the first time the patient noticed symptoms to referral to our Department was 27 months (range=3-72 months) (Table I). The delayed detection of a malignant bone tumor may be associated with progression of the tumor, leading to growth to a huge size or metastasis (27, 28). Lung metastasis was seen at presentation in three patients, and the mean tumor size was approximately 156 mm in its greatest diameter. Among the six patients of our study, two patients died within approximately 1 year of diagnosis. Thus, older patients should consult a doctor as soon as they notice continuous pain or swelling involving the bone or joint, and general practitioners should refer a patient to a specialized institution for orthopedic oncology when a bone tumor is suspected based on roentgenography, or which proves refractory to conservative treatment.
The standard treatment for osteosarcoma is a combination of chemotherapy and surgery. However, older patients with osteosarcoma often undergo surgical treatment without chemotherapy. In previous studies, only 50-60% of patients ≥65 years of age received chemotherapy; this was much lower than the rate of chemotherapy in patients of 40-65 years of age (90-100%) (6, 11, 20, 23-25). Chemotherapy is usually effective for reducing micrometastases and reducing the size of the tumor, and may also contribute to good clinical outcomes. However, in many cases, older patients were unable not undergo chemotherapy due to cardiac dysfunction, reduced renal function, or reduced bone marrow tolerance. In the present study, only one patient underwent neoadjuvant chemotherapy, with a regimen of doxorubicin and cisplatin; however, the patient showed tumor progression and a poor response to chemotherapy. Thus, surgical treatment is still a reliable treatment method for older patients with osteosarcoma (Table IV) (6, 11, 20, 23-25). Surgical treatment for malignant bone tumors consists of wide excision and reconstruction. Reconstruction using a prosthesis is commonly performed; however, limited joint function or impairment of daily living sometimes remains (29-31). Biological reconstruction using a recycled autograft has also become available in recent years, and has been reported to be associated with numerous advantages: the autograft can fit perfectly with the original site, and the retracted tendon or muscles can be reattached, and thus, the original joint function can be retained (14-18). Older patients who wish to retain traditional practices in daily living, including sitting in the seiza position (e.g., case 8 in the present study), are optimal candidates for biological reconstruction. In case 8, several procedures could have been considered for reconstruction of the bone defect of the proximal tibia or tibial shaft after the excision of the malignant bone tumor (32-36). Reconstruction of the proximal tibia with a prosthesis or replacement of the diaphyseal segment with an endoprosthesis for the tibial shaft are often selected for this purpose. However, these procedures are associated with some problems, such as aseptic loosening and limitation of the extension function (32-35). Limb lengthening using an external fixator after the excision of a malignant bone tumor is a good option; however, limb-lengthening typically requires a long time, and is not appropriate for older patients due to the fragility of their bone (36). In addition to removing malignant bone tumors, maintaining a good quality of life is an essential aim of surgical treatment for older patients; thus biological reconstruction is an optimal procedure for achieving this.
Radiotherapy is also available for patients with malignant bone tumors. In recent years, CIRT has often been applied in the treatment of unresectable malignant bone tumors, including tumors located in the vertebrae or pelvic bone (37, 38). The efficacy and clinical outcomes were reported to be similar to those of surgical treatment. In the present study, one patient, case 3 (Figure 4), had a huge tumor that involved the neurovascular bundles, including the femoral artery and vein, femoral nerve, and sciatic nerve. Thus, radical surgery would have required an external hemipelvectomy. However, the patient was of advanced age, and it was expected that this would have a negative impact on their activities of daily life; therefore CIRT was selected. Considering an individualized treatment strategy is also important for maintaining a good quality of life in older patients.
A case of carbon-ion radiotherapy conducted for an unresectable pelvic lesion. A: An X-ray revealed that the tumor was located around the left sacropelvic joint with calcification. B: The bone tumor showed a low to iso signal intensity on T1-weighted magnetic resonance imaging. C: The tumor showed heterogeneous signal intensity, including low to high signals, with a sign of fluid-fluid level on T2-fat suppressed MRI. D: The tumor was unevenly enhanced on contrast MRI. E: Computed tomography revealed that the bone tumor was located around the left pelvis and included large and small calcifications. F: After open biopsy, the histological diagnosis was primary osteosarcoma (scale bar=100 µm). G: There was no progression of the tumor at 6 months after carbon-ion radiotherapy.
In conclusion, it is important to consider the possibility of primary osteosarcoma even in older patients with bone tumors. Care is required in the diagnosis because the radiological and histological findings of primary osteosarcoma in older patients are non-specific, and because patients may delay consultation. Surgery is a mainstay treatment, however, individualized treatment – including frozen autograft reconstruction or CIRT – is essential for older patients to maintain a good quality of their lives.
Acknowledgements
The Authors thank the other past and the present members of our Department for their work.
Footnotes
Authors’ Contributions
HT, NY, and YAr contributed to the concept and design of the study. HT, NY, KH, AT, SM, and KI managed all the patients for appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. TH, KA, YT, HY, SM, and YAs assisted in data acquisition. TN performed histological examination of all the specimens. YAr analyzed all the patient data and wrote the article. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received July 5, 2022.
- Revision received August 1, 2022.
- Accepted August 10, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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