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1 RADIATION-IND UCED EXTRASKELETAL OSTEOSARCOMA LAURENCE 1. ALPERT, MD," IBRAHIM F. ABACI, MD,+ AND SEYMOUR WERTHAMER, M D ~ A case history is presented of a 41-year-old woman who developed an extraskeletal osteosarcoma of the upper chest wall at the site of therapeutic irradiation for breast carcinoma 8 years previously. The relation of the sarcoma to the irradiation was supported by the coexistence of a profound radiation angiitis. The development of this neoplasm, despite the relatively low total radiation dosage, is distinctly unusual. ARCOMAS ARE THE RAREST OF THE NEOPLASMS S known to occur as a complication of therapeutic irradiation. In 1970, Hatfield and Schulz6 described 11 cases of post-irradiation sarcomas presenting over a period of 15 years at the Massachusetts General Hospital, 5 of which developed following treatment for breast carcinoma. Of these, two were soft tissue fibrosarcomas, and two were osteosarcomas arising, respectively, in the scapula and humerus. We wish to report the very unusual development of an extraskeletal osteosarcoma developing in the soft tissue of the upper chest wall of a woman who had received a relatively small dosage of radiation for breast carcinoma 8 years previously. CASE REPORT '4 41-year-old Negro woman was admitted to the Methodist Hospital of Brooklyn, in June 1971, because of a lump in the upper anterolateral chest wall, which she had first noted approximately 4 months prior to admission. Physical examination revealed a freely movable indurated, non-tender subcutaneous From the Methodist Hospital of Brooklyn, Brooklyn, N.Y. Department of Pathology, Methodist Hospital of Biooklyn; Assistant Professor, Department of Pathology, Mt. Sinai School of Medicine, New York, N.Y. t Senior Fellow, Department of Pathology, Methodist Hospital of Brooklyn. t Department of Pathology, Methodist Hospital of Brooklyn; Associate Clinical Professor, Department of Pathology, Downstate Medical Center (SUNY), Brooklyn, N.Y. The authors are grateful to Drs. Howard Dorfman and Frani Enzinger for reviewing the histologic sections of the tumor, and to Frederico Capozzi, MD, for permitting use of the clinical material. Received for publication January 15, nodule, approximately 3 cm in diameter, in the upper portion of the right anterior axillary fold. The overlying skin showed mild thickening and telangiectasia. There was no associated lymphadenopathy. The ipsilateral breast showed a well-healed scar without underlying nodularity. There were no other abnormal physical or laboratory findings. A skeletal roentgenographic survey was negative. Past history disclosed that, in December 1964, she had undergone a local resection of an infiltrating duct carcinoma of the right breast, immediately followed by a course of radiation therapy at the Queen Elizabeth Hospital, Barbadoes, W. I., consisting of two portals: one anterior field 20 x 15 cm and an axillary field 8 >( 10 cm. A total dose of 2400 rads was administered to each field as eight fractionations using 200 kv. An excisional biopsy of the nodule, whose location corresponded to the mid portion of the axillary field of irradiation, was performed. It was observed to be well circumscribed and located within the pectoralis major muscle. Histologic examination disclosed a bony tumor surrounded by a dense skeletal muscle and connective tissue capsule. The central portion of the tumor showed mature, partially mineralized bony trabeculae. Towards the periphery of the tumor the trabeculae were irregular and poorly formed (Fig. 1). The tumor was densely cellular consisting of pleomorphic hyperchromatic bizarre osteoblastic cells, both plump and spindly, which exhibited numerous abnormal mitoses and were associated with tumor osteoid (Figs. 2 a, b). Occasional giant cells were also noted. Within the dense connective tissue and skeletal muscle capsule were occasional giant fibroblasts. Several arterioles and small arteries demonstrated prominent intimal cell proliferation with atypism, changes interpreted as consisent with radiation effect (Fig. 3).

2 1360 CANCER June 1973 Vol. 31 FIG. 1. Low-power photomicrograph of a histologic cross-section of the tumor nodule, showing a central arrangement of mature partly mineralized bony trabeculae. The peripheral portion of the tumor is densely cellular with immature or absent bone formation. The capsule is comprised of dense fibrous tissue (Masson s aniline blue, x12). The patient was discharged shortly after surgery. She has since remained asymptomatic without evidence of tumor recurrence for approximately one year following the initial appearance of the tumor. DISCUSSION In 1971, Allan and Soulel described 26 cases of osteosarcoma arising in the somatic soft tissues, bringing the total cases described in the world literature to 94. They estimated that the ratio of extraskeletal to skeletal osteosarcomas was approximately 1:25. This tumor, which presumably arises in the soft tissues from pluripotential fibroblastic cells, must be carefully differentiated from other ossifying soft tissue lesions, in particular myositis ossificans, pseudosarcomatous fasciitis with osseous metaplasia, and malignant mesenchymoma. The first condition is best distinguished by the absence of malignant cytologic features and its tendency to display a central area of osteoblastic activity with distinct peripheral maturation of the proliferating bony trabeculae. Ossifying pseudosarcomatous fasciitis may closely resemble soft tissue osteosarcoma, the distinction depending primarily on the lack of true cellular anaplasia. The diagnosis of malignant mixed mesenchymoma depends on the demonstration of two or more distinct malignant elements, exclusive of fibrosarcoma.3 The extraskeletal osteosarcomas have a somewhat longer survival period from the time of diagnosis than the osseous variety. Nevertheless, in the series of extraskeletal tumors described by Allan and Soule, 21 of their their 26 cases had succumbed as a result of recurrence at the time of the report. A distinct clinical difference lies in the age of onset. While the skeletal variety has a peak incidence in the second decade unless superimposed on Paget s disease of bone, extraskeletal osteosarcomas rarely occur prior to the fourth decade. The development of this lesion as a late effect of therapeutic irradiation is an especially

3 No. 6 EXTRASKELETAL OSTEOSARCOMA - Alpeyt et al FIG. 2a. High-power photomicrograph of a cellular portion of the periphery, demonstrating extreme pleomorphism and hyperchromatism of the proliferating cells, with occasional mitoses (H and E, ~400). FIG. 2b. Section from a more central portion of the tumor showing bizarre spindle cells forming osteoid (H and E, x400). unusual event, the present case constituting the sixth such reported case. The details of the five previous cases are summarized in Table 1. Boyer and Navin? who in 1965 reported two cases of radiation-induced extraskeletal osteosarcomas, suggested that the criteria for inclusion in this category should include, in addition to the strict histologic criteria for osteosarcoma, accompanying evidence of overlying chronic radiodermatitis. The present case satisfies this requirement not only by the clinical observation of skin thickening and telangiectasia but by the histologic evidence of severe radiation type of angiitis within the muscle and fibrous tissue comprising the tumor capsule. The degree and persistence of the bizarre intimal cell proliferation after a radiation-free interlude of 8 years is noteworthy in itself. The relatively long latent interval is consistent with that described in the previous cases of extraskeletal sarcomas and, in fact, with the long latency associated with skeletal osteosarcomar following radiation therapy. In their recent report of seven radiation-induced sarcomas involving bones of the head and neck, Arlen et al.2 observed a latent period of 7-23 years. The prognosis of radiation-induced extra-

4 1362 CANCER June 1973 Vol. 31 FIG. 3. An arteriole within the fibrous capsule of the tumor displays prominence of the endothelial cells, disruption of the elastica interna, and proliferation and swelling of the medial muscle cells. This pattern of injury is compatible with radiation angiitis (Elastica van Cieson s, xl00). skeletal osteosarcomas in the five previously reported cases was uniformly bad, all patients developing extensive recurrence with death, usually within one year. The benign course to date observed in the present case may be related to the presence of an extensive, histolog ically mature element in the lesion. No correlation between degree of histologic anaplasia and clinical prognosis was observed in previousiy described cases. FinalIy, the present case is unique in that tumor induction appeared to have been possible despite original radiation dosage that was relatively small. This contrasts with the 11 cases of post-irradiation bone sarcomas reported by Hatfield,6 of which three developed following megavoltage therapy. If the recorded dosage in this case was in fact that which the patient received, it suggests that other factors than dosage alone play a role in tumor induction. Auerbach et al.a Seminoma (1951) Kauffman et al.e (1963) Boyer and Navin (1965) Allan and Soulel (1971) Present case TABLE 1. Interval between Age at radiation to Primary tumor time of radiation Radiation dosage tumor diagnosis Tumor location Clinical course Retinoblastoma 1. Seminoma 2. Malignant teratoma?melanoma Breast ca rads rads tissue dose, 3 courses in 7 mos rads rads 26 Described only as extensive rads 8 fractions 4 yrs. Lumbar 11 yrs. Orbital soft tissue 4 yrs. Lumbar soft tissue 10 yrs. Anterior abdominal wall 27 yrs. Shoulder 8 yrs. Chest wall Local and metastatic recurrence; death in 3 yrs. Death-3 mos. due to local recurrence Extensive local recurrence with 2.5% paraplegia Death in 13 mos. due to local recurrence Alive 2 yrs. after forequarter amputation No recurrence 6 mos. post local resection

5 No Allan, C., and Soule, E.: Osteogenic sarcoma of the somatic soft tissues. Cancer 27: , Arlen, M., Shah, I., Heginbotham, A., and Huvos, A.: Osteogenic sarcoma of head and neck induced by radiation therapy. N.Y. State I. Med. 72: , EXTRASKELETAL OSTEOSARCOMA - Alpert et al. REFERENCES 3. Auerbach, O., Friedman, M., Weiss, L., and Cancer 16: , 1g63. Amory, H. I.: Extraskeletal osteogenic sarcoma rising 7. Stout, A. P.: Mesenchymoma, the mixed tumor of in irradiated tissue. Cancer 4: , mesenchymal deratives. Ann. Surg. 127: , Boyer, C., and Navin, J.: Extraskeletal osteogenic sarcoma. Cancer 18: , Hatfield, P., and Schulz, M.: Postirradiation sarcoma. Radiology 96: , Kauffman, S. L., and Stout, A. P.: Extraskeletal osteogenic sarcomas and chondrosarcomas in children.

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