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© 1999 The Journal of Bone and Joint Surgery, Inc. Osteosarcoma Arising from Heterotopic Ossification After an Electrical Burn. A Case Report* , ATLANTA, GEORGIAInvestigation performed at the Departments of Orthopaedic Surgery and Pathology, Emory University School of Medicine, Atlanta
Extraskeletal bone formation (heterotopic ossification) may originate in tendons, fasciae, periosteum, subcutaneous fat, or organs such as the kidney or breast22. It is histologically similar to myositis ossificans, which refers more specifically to the formation of bone in muscle tissue. Because of the histological and clinical similarities between heterotopic ossification and osteosarcoma, the conditions can be easily misdiagnosed. Heterotopic ossification usually develops after a single traumatic injury or a series of minor injuries and is considered to be a benign, self-limiting condition. Thermal injury is one of the least common causes of extraskeletal bone formation. The reported prevalence of heterotopic ossification following thermal injury has ranged from less than 1 to 23 percent6,13,20,25. Boyd et al. retrospectively reviewed the cases of approximately 1000 patients who had been seen during a twenty-five-year period for the treatment of a burn and identified six patients (less than 1 percent) who had heterotopic ossification6. In a retrospective study of 1460 patients who had been hospitalized because of a burn during a twenty-four-year period, Evans identified twenty-nine patients (2 percent) who had heterotopic ossification13. In a prospective study, Munster et al. noted the formation of heterotopic bone in twelve (14 percent) of eighty-eight patients who were managed at the United States Army Institute of Surgical Research because of a burn injury20. In a similar study from the same institution, Schiele et al. reported heterotopic ossification in sixteen (23 percent) of seventy patients25. Heterotopic ossification following a burn injury most often develops about the elbow, where it leads to stiffness and contracture of the joint22,25. As far as we know, the only well documented report of osteosarcoma arising from heterotopic ossification involved a patient who had dermatomyositis11. We present the first report in the literature, to our knowledge, of an extremely unusual case of a patient in whom osteosarcoma developed from an area of heterotopic ossification that had formed after an electrical shock.
A forty-four-year-old man, who previously had been right-hand dominant, was referred to our institution in April 1996 for evaluation and treatment of a bleeding wound on the proximal part of the volar aspect of the right forearm. The patient reported that he had sustained an electrical injury of the involved extremity ten years earlier, when he was working on an electrical stove, and that the shock had bounced him across the room. He had not sought medical attention at that time. Approximately one month later, a flexion contracture began to develop in the right hand. Over the next few months, the contracture spread to the elbow, the wrist, and all of the digits of the right hand. The stiffness and contractures slowly worsened, and the patient sought medical attention in June 1987, approximately one year after the injury. At that time, he had fixed flexion contractures of the elbow, wrist, and hand, but sensation was intact. The forearm was described as rock-hard, but no areas of tenderness, pain, or swelling were discovered. The findings of serum-chemistry studies were within normal limits except for the alkaline phosphatase level, which was 143 units per liter (2.4 King-Armstrong units) (normal, twenty to ninety-five units per liter [0.3 to 1.5 King-Armstrong units]). Plain radiography and computed axial tomography revealed massive, diffuse heterotopic ossification of the forearm (Figs. 1-A and 1-B). A technetium bone scan revealed diffusely increased uptake in the soft tissues throughout the entire forearm. Because of the magnitude of the heterotopic ossification, no operative intervention or radiation therapy was recommended.
The condition of the patient remained stable for the next nine years. The size of the forearm did not increase, although the patient reported that it bruised easily. In February 1996, ten years after the initial injury and nine years after he had first sought medical attention, the patient reported that he had struck the right forearm on the door of a vehicle and an area of ecchymosis and blistering had developed over the proximal aspect of the affected extremity within twenty-four hours. The patient was evaluated by his primary-care physician, who noted a tender, soft mass measuring three by four centimeters, which the physician believed to be a hematoma. An orthopaedic consultation was obtained, and it was decided that the patient would be observed for two months. In April 1996, no improvement was noted, and the patient had an operation at another hospital. A soft-tissue mass with multiple areas of punctate arterial and venous bleeding was noted. No histological studies were performed. Postoperatively, the operative incision continued to bleed, and a wound dehiscence developed despite the local application of microfibrillar collagen (Avitene; MedChem Products, Woburn, Massachusetts) and a compression dressing. The patient was transferred to our institution seven days after exploration of the wound. A physical examination revealed fixed flexion contractures of the right wrist and elbow with less than 10 degrees of motion of the joints of the digits. The forearm was hard. With the exception of a chronically oozing operative wound that measured six by five centimeters on the proximal-medial aspect of the forearm, the skin appeared normal. A tender, firm, 5.5 by 7.0-centimeter mass was palpable under the wound. Sensation to light touch was intact, and brisk capillary refill was present in all digits. A digital subtraction arteriogram revealed a distinct tumor blush (Fig. 2). Plain radiographs (Fig. 3) and computed axial tomography (Figs. 4-A and 4-B) demonstrated a soft-tissue mass arising from an area of heterotopic ossification.
The results of an open biopsy performed the following day revealed a high-grade telangiectatic osteosarcoma arising from the site of heterotopic ossification. Because this was a unique presentation for osteosarcoma, three musculoskeletal pathologists from different institutions were asked to review the clinical history, radiographic studies, and histological specimens. All of them independently confirmed the original diagnosis. Staging studies, including a computed axial tomography scan of the chest and a bone scan, revealed negative findings. Limb salvage was not considered an option because of the extent of the tumor, the involvement of neurovascular structures, the inability to obtain a wide operative margin, and the functional status of the limb. A transhumeral amputation was performed. After the amputation, a program of alternating intravenous infusion of doxorubicin (Adriamycin) and cisplatin (Platinol-AQ) was begun. After the first course of chemotherapy, neutropenia and an infection associated with the central venous catheter developed. After the removal of the catheter and the resolution of the cytopenia, the patient refused to complete the course of chemotherapy. Twelve months after the amputation, the patient was seen by his primary-care physician because of shortness of breath. A radiograph of the chest demonstrated multiple pulmonary metastases bilaterally. The patient declined additional therapy and died of respiratory failure a month later. Gross examination of the specimen revealed large areas of hard, white, sclerotic tissue throughout the forearm, a finding that was consistent with massive heterotopic ossification. A protuberant area of hemorrhagic red soft tissue that measured 16.0 by 12.0 by 8.5 centimeters was present in the proximal part of the volar aspect of the forearm. Decalcified sections of tissue obtained from the volar aspect of the forearm and stained with hematoxylin and eosin revealed two distinct histological patterns with sharp zones of transition. Sections from hard areas subjacent to the lesion and those from other areas showed masses of mature heterotopic lamellar bone within skeletal muscle and fascia (Fig. 5-A). These areas were consistent with long-standing heterotopic ossification. Sections from the hemorrhagic lesion revealed a sharp transition from areas of mature heterotopic ossification to a highly vascular telangiectatic, disorganized, lacelike bone-forming tumor with hypercellularity and nuclear pleomorphism (Figs. 5-B, 5-C, and 5-D). Numerous mitotic figures, including atypical forms, were present in this area of woven bone as were occasional multinucleated giant cells. Several areas of hemorrhagic necrosis and ulceration as well as large blood-filled cystic areas separated by thin septae were also present.
It is difficult to establish a clear-cut relationship between osteosarcoma and underlying heterotopic ossification for several reasons. First, osteosarcoma arising from heterotopic ossification is extremely rare. Second, heterotopic ossification and extraskeletal osteosarcoma have similar histological and clinical findings, and misdiagnosis is possible. A causative role of other risk factors, such as radiation, for the development of a malignant lesion must be ruled out. Third, efforts to substantiate a relationship may be hampered because the full range of related radiographic and histological studies, which may have been carried out for years or even decades, may not be available. Extraskeletal osteosarcoma, a rare variant of osteosarcoma, accounts for approximately 1 percent of all soft-tissue sarcomas. Approximately 320 cases of extraskeletal osteosarcoma have been described in major series that have been reported in the English-language literature3,5,7,9,14,17,20,23,28,30. Most reports of extraskeletal osteosarcoma have come from large cancer centers, where the cases have been collected for a long period of time and the total number of soft-tissue tumors treated during that time was not recorded. Lee et al. reported on forty patients with extraskeletal osteosarcoma who had been managed at the Mayo Clinic during a seventy-three-year period17. They estimated that these patients represented about 1 percent of all patients who had been managed because of a soft-tissue sarcoma at that institution during the same time-period. In a review of the cases of more than 2100 patients who had been managed at the Mayo Clinic because of a soft-tissue sarcoma, it was found that twenty-six (1 percent) had an extraskeletal osteosarcoma3. These highly malignant neoplasms develop most commonly in patients who are more than thirty years old3,5,7,15,17,28,30. Osteosarcomas of bone, in contrast, develop primarily in younger patients. Extraskeletal osteosarcomas develop predominantly in the lower extremities, but the involvement of multiple anatomical sites has been reported3,5,7,17. The most common histological patterns include osteoblastic, chondroblastic, and pleomorphic malignant fibrous histiocytoma-like osteosarcomas; telangiectatic extraskeletal osteosarcomas are unusual4,5,17,24. We know of one report of three patients who had an extraskeletal telangiectatic osteosarcoma19. Secondary skeletal osteosarcomas have been known to develop in patients who have preexisting Paget disease and bone infarcts15,16, but little is known about secondary extraskeletal osteosarcoma. Traumatic injury has been theorized as an etiological factor; however, radiation therapy has been found to be a definite predisposing factor in the development of extraskeletal osteosarcoma3,26,30. Heterotopic ossification is a benign process that can occur after an operation, a neurological injury, and poliomyelitis as well as after a thermal or electrical burn6,13,20,29. It has been compared with a callus of the soft tissues18. Histologically, such ossification can mimic osteosarcoma. Clinical features such as pain and rapid expansion, which are shared by these entities, may contribute further to misdiagnoses12,18. Ackerman urged the use of zone phenomena to distinguish heterotopic ossification from osteosarcoma1. In heterotopic ossification, the central, undifferentiated, spindled zone merges into oriented osteoid formation, which merges into well formed bone at the periphery. In sarcoma, the reverse occurs; the well formed bone occupies the central zone, and the undifferentiated sarcomatous component is at the periphery1. Despite Ackerman's description1, heterotopic ossification continues to be misdiagnosed as extraskeletal osteosarcoma18. Although the use of aspiration biopsy for cytological diagnosis of heterotopic ossification has been reported2,10, such a procedure does not allow a pathologist to view a cross section of the lesion and thereby document the zone phenomena. We agree with Mirra et al.18 that, when a biopsy of a lesion is warranted, a large sample of tissue that preserves the architecture of the tumor is essential for an accurate diagnosis. Although there are several reports of osteosarcoma arising from heterotopic ossification, the diagnoses were based on a clinical history of heterotopic ossification before treatment and no attempts were made to determine the diagnosis radiographically or histologically8,14,21,26-28. In addition, the investigators did not explore the possibility of risk factors for malignant tumor. In 1956, Fine and Stout reported on twelve patients who had a documented extraskeletal osteosarcoma14. They believed that the extraskeletal osteosarcoma in two of their patients arose from preexisting heterotopic ossification. However, they did not specifically define the histological or radiographic relationship between the sarcoma and underlying heterotopic ossification. In 1967, Shanoff et al. reported on a patient who had had histological verification of osteogenic sarcoma evolving from heterotopic bone26. The patient had previously had multiple operations and radiation therapy for the treatment of a squamous-cell carcinoma of the lower lip, and later an osteosarcoma of the mandible was diagnosed after a biopsy specimen from the surrounding soft tissue showed areas of heterotopic ossification. Because the soft-tissue mass was histologically benign and the malignant tumor was confined to the mandible several years after radiation therapy, we believe that the patient had a radiation-induced osteosarcoma of the mandible in proximity to an area of benign heterotopic bone. To our knowledge, the only well documented case of malignant transformation of heterotopic bone was reported by Eckardt et al., in a thirty-two-year-old man with dermatomyositis and extensive calcinosis cutis who had been managed with corticosteroids when he was a child11. When the patient was eight years old, a large calcified mass had developed in the posterior aspect of the thigh. Ten years later, an unsuccessful attempt was made to excise the mass. Histological examination of the tumor revealed findings that were consistent with heterotopic ossification. Thirteen years after the attempted excision, the mass had rapidly increased in size and had become painful. Another subtotal resection was performed, and a diagnosis of high-grade osteosarcoma was made on the basis of histological examination. The patient had a hemipelvectomy, but pulmonary metastases developed later. A review of the radiographs and histological specimens from the original biopsy and subsequent subtotal excision provided clear evidence that the malignant tumor had arisen from the site of previously benign heterotopic bone. The authors noted a well documented association between dermatomyositis and malignant lesions. The case of our patient involved malignant transformation of heterotopic bone, which had developed after an electrical burn more than a decade earlier, into extraskeletal osteosarcoma. Although no biopsy had been performed before the identification of the malignant lesion, clinical and radiographic documentation of the lesion at the time of the injury was available, as were large areas of tissue after the open biopsy and amputation. Massive areas of mature lamellar bone, representing long-standing heterotopic ossification, were present throughout the forearm and were consistent with the history and the previous radiographic studies. The sharp zone of transformation into a highly vascular stroma with woven bone, marked cellular pleomorphism, and numerous mitoses was consistent with a diagnosis of telangiectatic osteosarcoma16,19. Considering the high grade of the tumor coupled with the known highly malignant behavior of extraskeletal osteosarcoma, it is highly unlikely that the tumor had been present for ten years. The absence of previous radiation therapy to this area further supports the conclusion that this extraskeletal osteosarcoma arose from heterotopic ossification secondary to an electrical burn.
NOTE: The authors thank Dr. Howard Dorfman and Dr. K. Krishnan Unni for consultation on this case.
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
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