Japanese Journal of Clinical Oncology 31:562-566 (2001)
© 2001 Foundation for Promotion of Cancer Research
Synchronous Multifocal Osteosarcoma with Lymphatic Spread in the Lung: an Autopsy Case Report
1Department of Orthopaedic Surgery and 2Department of Pathology, Tohoku University Graduate School of Medicine, Sendai and 3Department of Pathology, Iwate Medical College, Morioka, Japan
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ABSTRACT |
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Synchronous multifocal/multicentric osteosarcoma (MOS) is a rare variant of osteosarcoma. We report here an autopsy case of a 15-year-old boy with MOS. Radiological examinations showed multiple sclerotic lesions in the left distal femur and in the ipsilateral proximal tibia without pulmonary metastasis at the first examination. Histological examination showed osteoblastic-type osteosarcoma. Despite high-dose chemotherapy the patient died of multiple bone and lung involvements 6 months after the initial diagnosis. Autopsy examination revealed prominent invasion of the tumor cells into lymphatic vessels and pleural dissemination without the formation of bulky, nodular metastasis in the lungs. Metastases in pulmonary hilar lymph nodes were noted without metastasis in other organs. Immunohistochemistry revealed that p53 protein was positive in most of the tumor cells. In summary, the present case was characterized by multiple bone involvement and prominent lymphatic spread of sarcoma cells in the lungs.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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Most osteosarcomas (OSs) arise as a solitary lesion. More than one bone lesion of OS without pulmonary metastasis at the initial examination is designated as multicentric or multifocal osteosarcoma (MOS). Such a variant has been recognized since 1936 (1), accounting for 1–2% of all OS (2,3). The involvement of more than one bone naturally compounds therapists’ problems (4) and the prognosis in this rare disease remains poor. Parham et al. reported that the median survival of their series was 12 months despite multi-agent chemotherapy, mainly high-dose methotrexate and cisplastin–doxorubicin (5).
MOSs are classified into two types: synchronous and metachronous. The synchronous type is defined as multiple lesions that appear to develop within 6 months (3). It is controversial whether the tumors have a true multicentric origin or merely represent bone-to-bone metastasis without pulmonary metastasis (2,6,7–9). To analyze this further, postmortem autopsy analysis is of particular importance. However, to date only few detailed autopsy reports have been recorded on MOS (1,9). We report here a case of a 15-year-old boy with MOS, which showed prominent lymphatic vessel invasion by the sarcoma cells in the lung, to discuss the possible route of lung metastasis in this special case.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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A 15-year-old boy presented with left knee pain with a 4-week history. Radiographs showed multiple sclerotic and/or lytic lesions in the distal femur and the ipsilateral proximal tibia. The largest lesion was observed in the left distal metaphyseal femur, associated with periosteal reaction (Fig. 1). Magnetic resonance (MR) imaging revealed a small lesion in his right femur diaphysis and multiple lesions in the left lower extremity (Fig. 2). Bone scan further showed the presence of other lesions (Fig. 3). Radiological examination revealed no evidence of lung metastasis. Histological examination of a biopsy specimen from the left femur showed osteoblastic-type OS (Fig. 4). The lesion was diagnosed as MOS.
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The patient received high-dose chemotherapy with methotrexate, bleomycin, cyclophosphamide and actinomycin-D, according to the Rosen T-12 protocol (10), for 9 weeks. However, no response to this regimen was noted. Administration of ifosfamide for 12 weeks followed by epirubicin and carboplatin for 2 weeks did not improve the lesions. Bone scans revealed new lesions in the cervical and thoracic vertebrae after 2 months and in the skull after 3 months from the initial diagnosis. During the clinical course, the lesions enlarged, coalesced and began to expand the affected bone. Periosteal reaction was radiologically observed in the affected entire femur and ipsilateral tibial lesions. The value of alkaline phosphatase was elevated from 5545 IU/l (normal value: 112–330 IU/l) at the first laboratory examination to 17 060 IU/l 2 months after admission. Lung metastasis was detected 6 months after the initial diagnosis. The patient died of multiple bone and lung involvement 6 months after the initial diagnosis.
The present case was subclassified as Type 1 according to Amstutz (11) (Type 1, child adolescent multiple, simultaneous; Type 2, adult low-grade multiple malignancies; and Type 3, metastatic metachronous lesions) and also as group A by Mahoney’s classification (8) [group A, childhood–adolescent synchronous metaphyseal; group B, adult low-grade synchronous random; group C, early metachronous (up to 24 months); and group D, late metachronous (after 24 months)].
Autopsy was performed 2 h after death. On gross examination, multiple, ovoid and flat tumors were observed in the subpleural areas of bilateral lungs, on the bilateral parietal pleurae and on the bilateral pleural surfaces of the diaphragm, indicating pleural dissemination. Pleural effusion of 2600 ml was observed in the right lung cavity. On cut surfaces, the lungs were free of bulky, nodular metastasis. However, whitish thickening was noted along the peribronchial spaces on the bilateral sides (Fig. 5A and B). Lymph node metastasis, gray in color, was observed in the pulmonary hilar region, without metastasis in lymph nodes of other regions. The cut surface of vertebral bodies of the sixth thoracic and second, third, fourth and fifth lumbar vertebral bodies showed white and firm lesions. No metastatic lesions were detected in any other internal organs.
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Microscopic examination of the spine and lung metastasis uniformly showed osteoblastic OS; there was extensive proliferation of spindle-shaped or ovoid atypical cells with frequent formation of osteoid cells (Fig. 6A and B). Of particular interest, prominent invasion of lymphatic vessels by the tumor cells was observed around pulmonary arteries in the lung (Fig. 7). Infiltration of the lung parenchyma by the tumor cells was also observed, particularly in the subpleural region as a direct spread of the sarcoma cells from lymphatic vessel invasion. Lymph node metastasis in the pulmonary hilar region and bone lesions showed identical histopathologic features. Careful examination revealed only sporadic foci of tumor emboli in the medial-sized pulmonary arteries (Fig. 8). Immunohistochemistry revealed that p53 protein (clone DO-7, DAKO) was uniformly positive in the tumor cells (Fig. 9).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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In multifocal/multicentric osteosarcoma (MOS), the issue of whether the bone lesions are multifocal in origin or merely represent bone-to-bone metastases has been controversial. Initially, many authors proposed that MOS was caused by multiple primary tumors if the lungs were free of metastatic disease (12,13). Later, Mahoney et al. suggested that metachronous lesions that develop within a 24-month period are probably metastatic, whereas tumors that develop after longer intervals may be true multicentric (8). Daffner et al. stated that MOS represents one extreme of a continuous scale of metastatic OS rather than multiple synchronous primary tumors (7). Histology of the present case showed high-grade, sclerotic OS of osteoblastic type, consistent with the previous reports (2,5,14,15). To support the bone-to-bone metastasis theory, the following facts were noted: (a) one lesion was larger and more extensive than the other lesions in the majority of patients (11); (b) bone metastases were found in 41% of all OS at autopsy (16); and (c) an anatomical route was postulated in the vertebral venous plexus system connecting the extremities and spine without passage through the lungs to explain the absence of pulmonary metastasis (2,17). In the present case, a larger lesion was noted in the left lower femur than in the other locations, suggesting the primary focus. Other lesions could be metastatic.
In most patients with usual OS, hematogenous metastasis is observed primarily in the lungs as randomly distributed nodular lesions. The present case showed an unusual spread pattern to the lungs; lymphatic vessels were frequently invaded by sarcoma cells with metastasis to pulmonary hilar lymph nodes. This suggests an unusual spread of OS via the lymphatic route in MOS as Daffner et al. suggested (7). Tumor cell emboli rarely observed in the pulmonary arteries may have spread through the following pathway: pulmonary hilar lymph nodes, thoracic duct, left subclavian vein, right ventricle and pulmonary arteries. These features in the present case may explain multifocal lesions in bone tissue as increased bone-to-bone spread via the lymphogenous route.
There is a possibility that specific mutations in tumor-suppressor genes are associated with multifocal osteosarcoma, since p53 mutations were found in all four patients with multifocal osteosarcoma (18), higher in usual osteosarcoma (19). Consistent with this, most of the tumor cells in the present case were positive for p53 by immunohistochemistry. Papai et al. examined the correlation between p53 expression and clinical prognosis and also response to therapy for conventional osteosarcomas and found that all patients who showed any kind of positive p53 expression were non-responders to chemotherapy (20). Mutations of p53 gene may play an important part in pathogenesis and chemoresistance of MOS. We need further analyses including clarification of the route of metastasis (hematogenous or lymphogenous) and genetic alterations in MOS.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentsREFERENCES |
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We are grateful to Ms Fumiko Date, Miss Sonoko Miura and Mr Katsuyoshi Shoji for technical assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Masahito Hatori, Department of Orthopaedic Surgery, Tohoku University School of Medicine, 1–1 Seiryomachi, Aobaku, Sendai 980-8574, Japan. E-mail: mhato@mail.cc.tohoku.ac.jp
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REFERENCES |
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Received March 5, 2001; accepted July 27, 2001.
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