Thanks to the combination of surgery and adjuvant or neoadjuvant chemotherapy, the outcome for patients with nonmetastatic osteosarcoma of an extremity has improved dramatically over the last twenty years. For this group of patients, the five-year overall rate of survival increased from less than 15% in the 1970s1,2 to more than 65% as of the time of writing3,4. Patients with osteosarcoma of the extremity who present with lung metastasis (about 20% of all cases) have a poorer prognosis than those without metastases. Nonetheless, with the combination of chemotherapy and complete surgical removal of primary and secondary lesions, the survival of patients with metastases has improved from less than 5% to more than 20%5,6. However, when complete excision of all of the secondary lesions is impossible, the five-year survival rate becomes extremely low and almost all of these patients die within three years from the time of diagnosis5.
We report an unusual case of a patient with osteosarcoma of the extremity and with multiple bilateral nonresectable lung metastatic lesions at the time of presentation, who was treated with chemotherapy and surgery of only the primary tumor and who appears to have stable lung metastatic disease twelve years after the initial diagnosis. The parents of the patient were informed that data concerning the case would be submitted for publication and they consented.
A seven-year-old girl was admitted to our hospital in January 1995 with a three-week history of pain in the left upper arm. Physical examination revealed a hard and tender swelling in the proximal part of the humerus. The only abnormal result of laboratory tests was a very high level of alkaline phosphatase (1600 U/L; normal values, 190-490 U/L).
A radiograph showed a large osteolytic lesion at the proximal meta-diaphysis of the left humerus, extending toward the growth plate and into the surrounding soft tissues (Fig. 1). The lesion was characterized by inhomogeneous bone formation, cortical destruction with a periosteal sunburst appearance, and a Codman triangle. These findings were very suggestive of an osteogenic sarcoma. The computed tomography scan and magnetic resonance imaging scan of the left upper arm confirmed the described aspects of the lesion.
The staging was completed with a total-body technetium-99 bone scan and a computed tomography scan of the chest. The bone scan showed increased uptake in the proximal part of the left humerus, and the computed tomography scan of the chest showed ten pulmonary nodules with indistinct margins (Fig. 2). Three nodules were located in the left lung and seven nodules in the right lung. All nodules had diameters of between 0.2 cm and 0.35 cm.
A core-needle biopsy of the bone lesion demonstrated a grade-4 osteoblastic osteosarcoma according to the carcinoma grading system of Broders et al.7 (Fig. 3). The patient underwent a nine-week preoperative chemotherapy regimen with high-dose methotrexate, Adriamycin (doxorubicin), and ifosfamide according to the Istituto Ortopedico Rizzoli/Osteosarcoma-4 (IOR/OS-4) protocol, as previously reported5. After the preoperative treatment, the pain disappeared completely, the soft-tissue swelling decreased, and the serum alkaline phosphatase level returned to normal.
At the end of the preoperative chemotherapy regimen, a radiograph of the left upper arm showed marked ossification of both the intramedullary and extraosseous components. A computed tomography scan of the upper arm confirmed these findings, showing almost complete ossification of the tumor. However, the computed tomography scan of the chest (Fig. 4) showed that the lung nodules had increased in size and that there were three more lesions in the left lung.
According to the protocol in use at the time5, the treatment of patients with metastatic osteosarcoma consisted of induction chemotherapy, resection of both the primary lesion and all metastatic lesions, and postoperative chemotherapy. However, since surgical removal of all of the lung lesions was not feasible, only the primary tumor was excised. Surgery consisted of a wide resection of the proximal part of the left humerus and reconstruction with a custom-made megaprosthesis. The surgical margins of the humeral resection were wide and the histological response of the tumor to the preoperative chemotherapy was "poor" according to the protocol (necrosis of less than 90% of the tumor)5. After surgery, the patient completed the postoperative chemotherapy protocol without major violations. No major local or systemic complications were registered.
At the end of the postoperative chemotherapy regimen, a computed tomography scan of the chest showed no change. The patient was discharged and follow-up computed tomography scans of the chest were performed at two, four, eight, and twelve months. Since the computed tomographic appearance of the lung nodules at the follow-up intervals was unchanged with regard to number and size in comparison with their appearance at the end of the preoperative treatment, a biopsy of the lung lesions was planned to confirm their true metastatic nature. The patient therefore underwent a left thoracotomy, during which five nodules were excised. The remaining metastases were not resectable due to their diffuse distribution throughout the various lung segments and the central location of these nodules. Histological examination of all five excised nodules showed viable high-grade osteoblastic osteosarcoma cells, without any sign of necrosis or fibrosis (Fig. 5).
After excision of the nodules, the patient underwent follow-up computed tomography scans of the chest, radiographs of the humerus, and laboratory tests at six-month intervals and did not undergo any other treatment for the remaining lung nodules. As of the time of the last follow-up examination, in May 2007 (twelve years after the initial diagnosis), computed tomography scans of the chest showed that the nodules were completely stable (Fig. 6).
Computed tomography scans of the chest are routinely performed in the diagnostic workup and follow-up of patients with osteosarcoma. Because of the high sensitivity and low specificity of computed tomography scans of the chest for the detection of lung lesions, false-positive results are frequent. It has been suggested that 25% of the lung nodules seen in new patients with osteosarcoma who present with between one and three lung nodules on the initial computed tomography scan of the chest turn out to be nonmetastatic on histological examination8.
Occasionally, patients with other types of cancer have shown stabilization of histologically proven pulmonary metastases for many years after adequate chemotherapy9, and follow-up biopsies have shown necrosis without signs of viable tumor cells9. These "sterilized" nodules are radiographically indistinguishable from residual viable tumor. It must be noted that in all previously reported cases of stable ("sterilized") metastatic lung nodules, the number of nodules has been small (from one to four)9.
The case presented here is unique for two reasons: First, there were more than ten bilateral pulmonary nodules. Second, the histological examination of five of these, performed one year after the end of treatment, showed viable osteosarcoma cells in all nodules.
Spontaneous regression of a single, biopsy-proven metastatic lesion of the lung from osteosarcoma has been previously reported10,11, but, to our knowledge, this is the first description of a patient who had multiple bilateral metastatic lesions of the lung from osteosarcoma and in whom the condition was stable twelve years after the initial diagnosis.
The spontaneous regression or stability of multiple metastatic malignant lesions as documented on computed tomography scans has been described in a wide variety of cancers12, but never before in osteosarcoma, to our knowledge. The reason for this stability is not clear. Stimulation of the cellular and/or humoral immune system, triggered for example by infections or surgery, may activate natural cytotoxic defenses. Cole and Everson13 observed that eight of 176 cases of spontaneous tumor regression reported in the literature were associated with infection. However, in our patient there were no signs of infection. Therefore we are not able to give any explanation of the uncommon outcome of this case to date.
In a recent review on molecular mechanisms of metastasis, the authors reported that metastasis suppressor genes have a role in controlling proliferation of cancer cells in a lung environment14. We believe that further studies on the mechanisms of the metastatic process will aid in the treatment of metastatic osteosarcoma and other malignant tumors. 