EXTRAOSSEOUS OSTEOGENIC SARCOMA Clinicopathological Study of Eight Cases and Review of Literature

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1 EXTRAOSSEOUS OSTEOGENIC SARCOMA Clinicopathological Study of Eight Cases and Review of Literature UMA RAO, MD, ANTHONY CHENG, AND MUKUND S. DIDOLKAR, MD," MD, MS (SURG), ACS (ENG)* S Since 1963, eight patients with extraosseous osteogenic sarcoma were treated at Roswell Park Memorial Institute; these constituted 4.6% of all the osteogenic sarcoma patients during the period. The mean age of the patients was 58.7 years and a ratio of male to female was equal. Local swelling of insidious onset was the commonest symptom. All the tumors originated in extremities; the lower extremity was the more frequent site. At the time of diagnosis, seven patients had localized tumor and one had pulmonary metastases. Radiologically, a soft tissue mass with spotty calcification without any adjacent bone involvement, was the classical sign. Elevated alkaline phosphatase without liver metastases was observed in five of six patients when disease progressed. Ultrastructurally, the prominent cell type was a fibroblast-like cell intermingled with varying numbers of osteoblasts and undifferentiated mesenchymal cells. Extreme morphologic variability probably accounts for the difference in composition of this tumor. Radical soft part excision or amputation should be the treatment of choice. Local recurrence was not seen in four patients after radical surgery, but it was observed in three of the four patients who had simple excision. The lung was the commonest site of metastases. No objective responses were observed after chemo- or immunotherapy. The overall median survival was 20 and 5-year survival rate was 25%. Cancer 4 1 : , PONTANEOUS EXTRAOSSEOUS OSTEOGENIC SAR- coma of the somatic soft tissues is an extremely rare type of tumor. Since the first report by Wilson" in 1941, 104 cases have been reported in the English literature. 1-3,7,8,13 EXcluded from this entity are paraosteal osteogenic sarcoma, sarcomas originating from bone or cartilage invading the soft tissue, as well as osteogenic sarcoma arising in organs such as breast, kidney, and lung. To be classified as extraosseous osteogenic sarcoma, the tumor must not be in anatomical continuity with the skeletal structures. Extreme rarity of this tumor and lack of reports on larger number of patients with this sarcoma prompted us to review the literature in addition to describe the clinicopathological findings in 8 patients with this sarcoma treated at Roswell Park Memorial Institute from 1963 to 1976) (Table 1). During the period of the study, rom the Departments of Pathology and Surgical Oncology,* New York State Department of Health Roswell Park Xlemorial Institute, Buffalo, New York. Address for reprints: Uma Kao, M.D., Pathology Department, Roswell Park X4emorial Institute, 666 Elm Strret, Buffalo, New York The authors thank Soon Won Chai for technical help in Lhl. study. Accepted for publication July 22, cases of primary skeletal osteogenic sarcoma, were treated at this institute. Ultrastructural findings of this tumor are included in this report because they have not been previously reported. MATERIALS AND METHODS Clinical indings American Cancer Society 1488 Of the 11 cases of extraosseous osteogenic sarcoma confirmed histologically at Roswell Park Memorial Institute, three could not be included in this study because their tumors developed after immunotherapy consisting of irradiated osteogenic sarcoma cell injection into soft tissue. Only 8 cases could be included in this study. The age range of the patients was from 34 to 85 years, with a median value of 57 years; there was an equal number of men and women. The local swelling of insidious onset was the initial symptom in all the patients. In three, it was associated with pain. A history of previous trauma was conspicously absent. The duration of the swelling, prior to diagnosis was one and one-half in four patients, and five in another. The remaining patients had the swelling for approximately three, six, and eleven years

2 ~ No. 4 EXTRAOSSEOUS OSTEOGENIC SARCOMA Rao et al TABLE 1. Clinicopathological Data Age Symptoms Case _ Sex Duration Location Treatment 1 34 Thigh 2 64 M 3 ns M 6 53 pvl pain 1 month 36 pain 1 month 1 month Swelline; 120 pain 5 72 It * NEII-No Evidence of Disease Thigh Thigh Thigh Shoulder Scapular area Calf Excision (4), groin dissection, chemotherapy with Thio Tepa, Glucosamine, Adriamycin for lung metastasis Excison; hemipelvectomy for local recurrence. Irradiated Dalsis cell for lungmetastasis Biopsy; chemotherapy for lung metastasis Excision (2), Radiation therapy for local recurrence End Result Excision, thoracotomy & wedge resection for metastasis, radiation therapy for media-,4utopsy performed stinal metastasis, chemotherapy with Acetylenic Carbamate Wide excision and scapulectomy; adjuvant 15, died of BCG + Irradiated tumor cell thoracotomy & pulmonary & hepatic wedge resection for lung metastasis, chemotherapy with Adriamycin DTIC & Vincristine Soft part resection, adjuvant immunotherapy with DTIC + Adriamycin and C. Parvum Antecubital Above elbow amputation fossa 76, died of metastasis, autopsy performed 25, died of metastasis, 110 autopsy 6, died of disease 22, died of bronchopneumonia. NED* clinically, no autopsy 76, died of disease. metastasis 12, alive NED 20, died of lung metastasis, no autopsy prior to diagnosis. All the tumors were located in the extremities; the most common site was the thigh (4) shoulder area, (2) antecubital fossa (1) and calf (1). At the initial diagnosis, 7 patients had localized tumor; while one had pulmonary metastases as evidenced by roentgenological examination. The regional lymph nodes were not involved clinically. Roentgenological, Radioisotopic and Biochemical indings Roentgenological examination of the soft parts showed a spotty calcification in three patients. None of the patients had any radiological sign of bone involvement by the tumor. Arteriogram was done in one patient and showed abnormal tumor vessels. Bone scan examinations by T,99, were done in two patients and showed no abnormality. Of interest was the persistent elevation of serum alkaline phosphatase at the late stage of disease in six patients. Only one patient had liver metastases. This high value persisted until they died. Serum alkaline phosphatase was normal in the seven patients at the time of localized disease. PATHOLOGY These tumors formed well-circumscribed, unencapsulated masses of varying sizes with sharply defined margins in the subcutaneous tissue and muscles. The tumor size ranged from 3 X 3 cm to 20 X 20 cm; no histological evidence of attachment to the bone was noted. Microscopically, the tumors were of uniform appearance and showed fibrosarcomatous, osteoblastic, and chondroblastic components in varied amounts (igs. 1, 2). Osteoclast-type giant cells mingled with spindle cells, were seen in one case (ig. 3). Cellular areas were located at the periphery of the lesion and contained malignant osteoid. Osteoid formation and occasional areas of necrosis were seen at the center (ig. 1). Vascular and lymphatic invasion by the tumor was not observed. An ultrastructural study of non-calcified tumor areas was performed in three recent cases. Three types of tumor cells could be discerned in the same tumor mass. irst type of cell (ig. 4) had cell membranes showing interdigitating short processes. An incomplete basement mem-

3 1490 CANCER April 1978 Vol. 41 IL. 1. Extraosseous osteosarcorna in subcutaneous soft tissue demonstrating the reverse zoning- eft ect with central osteoid formation and necrosis, and peripheral proliferation of spindle cclls (H&E X 10). 1Iigher magnification of osteoid (X.50) (inset). brane was seen in one case only. Ilesmosomes, however, were not identified. The cytoplasm contained abundant filaments scattered in the cell body and occasionally extended into the cell processes. Moderate amounts of free polyribosomes were present; the rough endoplasmic reticulum was sparse. The mitochondria were globular with well-preserved cristae. The second type of cell (ig. 5) resembling fibroblasts, was predominant. Cell membrane did not show interdigitating processes, but was intimately related to collagen, suggestive of its synthesis. By these cells, the cytoplasm in marked contrast to the first type, had prominent golgi zone, sparse fibrils, and abundant distended rough endoplasmic reticulum. A striking feature was the presence of an electron dense material in the distorted mitochondrial cristae and the mitochondrial matrix (ig. 6). Some mitochondria were extremely distorted and identified only through the presence of a distinct outer wall. The third type of cell resembled osteoclasts (ig. 7). It had numerous short smooth surface endoplasmic reticulum, globular mitochondrian, and membrane-bound lysosomal bodies containing irregularly electron dense crystalline material. In all above cell types, the nuclei were extremely convoluted, with coarse chromatin clumped on nuclear membrane, and had bizarre nucleoli. In one patient, the tumor cells had numerous short cell processes. Lipid, glycogen, dilated cisternae, and structures representing phagosomes, were also present. In all three cell types, the extracellular matrix had variable amounts of typical collagen fibrils. These areas were close in proximity often blending with the cell membrane. This was seen prominently in Type I1 (fibroblast-like) cells. The collagen was often haphazardly arranged forming irregular dense intercellular condensations. TREATMENT AND RESULTS As an initial definitive surgical procedure, 4 patients had simple excision. Three of these de-

4 IG.2. Extraosseous osteogenic sarcoma showing malignant cartilagenous foci (H&E X 140).. ic, 3 Extraosseous osteogenic sarcoma showing stromal cells and osteoddst-like giant cells (H&E ~ X200) ~

5 1492 CANCER April 1978 Vol. 41 IG. 4. Electron micrograph of Type 1 mesenchymal cell with cell processes, abundant cytoplasmic fibrils, few globular mitochondria and free ribosome (original magnification X 10,500). veloped local recurrence; in 2 patients it was in six and in the third patient 23 following surgery. ollowing the local recurrence, three patients had wide excision or amputation; one patient had hemipelvectomy none of these developed local recurrence. One patient after radical surgery, is alive and free of disease for one year following soft part resection. Six patients developed metastases to the lungs from which they ultimately died. The metastases developed in 0, 1, 5, 12, 50 and 70 respectively following treatment of the primary tumor. Chemotherapy agents, including adriamycin, DTIC, vincristine, and actinomycin D, were administered for systemic metastases. No objective response was noted. Immunotherapy using BCG alone and BCG with irradiated tumor cells was given to two patients; it provided no benefit. SURVIVAL Of the 8 patients, one is alive and free of disease one year following the treatment. The overall survival period from the diagnosis of the primary tumor, ranged from 4 to 76, with the median value of 20. The 5-year survival rate was 25%. Almost twothirds of the patients died within the first three years. Of the 6 patients who developed pulmonary metastases, 5 died within one year. DISCUSSION Extraosseous osteogenic sarcoma arising from soft tissue, is a definite entity of the soft tissue sarcomas, constituting 1.2% of all the soft tissue sarcomas. ' At Rosewell Park Memorial Institute, 4.6% of all the osteogenic sarcomas were of soft tissue origin. A similar incidence has been reported by Allan and Soule, ' as well as Wurlitzer et al. l3 Due to the rare occurrence of this tumor, very few series of relatively small number of patients, have been reported in the literature; to date, approximately 104 cases of this tumor have been reported.

6 No. 4 EXTRAOSSEOUS OSTEOGENIC SARCOMA Rao et al In the absence of a report on a large series of patients, it is difficult to give generalizations about the biological behavior of this tumor. However, the clinicopathologic findings, treatment, and survival of our 8 patients, correspond to other series reporting on similar numbers of patients (Table 2). 1~9,13 The mean age of the patients in five large series, was 52.7 years; there was a slight preponderance of women with a ratio of 1.1 to 1. The lower extremity including the buttock area, was the most common site of origin, constituting almost 69% of the cases, followed by upper extremity 20%, trunk region including retroperitoneum 9.5%, and head and neck area 1.5%. The common mode of presentation of these patients, was a swelling of insidious onset. Pain was associated in approximately one-third of the patients. requently, these tumors grow to a large size before the patient seeks medical advise. In our series, the median duration of the symptoms before the diagnosis, was three. Most of the patients had localized disease at the time of diagnosis, although one patient had pulmonary metastases at the time of diagnosis. Roentgenological examination of the soft parts is essential to rule out any continuity of this tumor with the bone. If the adjacent bone shows radiological changes of involvement by the tumor, it is more likely to be a sarcoma originating from the bone rather than from the soft tissue. A soft tissue mass with spotty calcification without any adjacent bone involvement is one of the classical roentgenological appearances of this tumor. Arteriographic examination is useful to know the vascularity and sometimes the extent of the tumor. The association of elevated alkaline phosphatase in the absence of liver disease, is an interesting finding in soft tissue osteogenic sarcomas at the advanced stage. This information is im- IG. 5. Electron micrograph showing Type I1 fibroblast-like cell with abundant dilated endoplasmic reticulum and nonspecific cytoplasmic fibrils. Note the electron dense material on EK and within mitochondria (original magnification X21,OOO).

7 1494 CANCER April 1978 Vol. 41 IG. 6. Showing a higher magnification of distorted and calcified mitochondria (X41,OOO and 50,000). portant in the follow-up of the patients. In our series, 5 patients at the advanced stage of disease had increased alkaline phosphatase without any liver involvement. Similar findings have been stressed by Das Gupta et ul.'it appears that the osteoblasts secrete alkaline phosphatase and its levels are higher when there is more tumor present. Since the first most common site of metastases is lung, tomographic films of the chest are mandatory in these patients, before planning a major resection of the soft parts. The light as well as ultrastructural appearance of skeletal and extraosseous osteogenic sarcoma are similar. The single most important criteria for diagnosis of these tumors is the presence of malignant osteoid. Indeed, a variable amount of fibroblastic and chondroblastic components may also be present. To be classified extraosseous, the tumors must not be in anatomical continuity with the skeletal structures. All of our cases fulfilled these criteria. In addition, this tumor should be differentiated from myositis ossificans. In extraosseous TABLE 2. Clinical indings and Survival of Patients in ive Reports Author Sex Ymr No. M Sex No. Pts. Avg. Location of the Tumor Living Age LowerExt. Upper Trunk H&N 5 yrs. ine & Stout Das Gupta pt al.2 Allan & Soule' Wurlitzer ut al.13 Present Total Percent % % (mean) 63% 20% 9.5% 1.5% 13.6% - 1

8 No 4 EXTRAOSSEOUS OSTEOGENIC SARCOMA Rao et al IG. 7. Electron microqaph of Type I11 osteoblast-like cell with phagosomes containing dense crystalline material. The cells have abundant short smooth Eli and intact globular mitochondria ( x 2 1,000). osteogenic sarcoma, the active tumor cells forming osteoid, are in the periphery, while mature osteoid is present in the center. This is in contrast to the appearance of myositis ossificans. Ultrastructural variations of both spontaneous and radiation-induced skeletal osteogenic sarcomas, have been studied by Kay,6 Ghadiall~,~ and Lee.7 The basic cell type in the above reports and in three of our cases, appeared to be a fibroblast-like cell. Characterized by abundant dilated rough endoplasmic reticulum, prominent golgi apparatus, and pleomorphic lysosomal bodies; these cells, in addition, contained cytoplasmic fibrils which were also present extracellularly and seemed to blend with mature collagen fibrils. The latter in some areas, were in intimate contact with the cell membrane, indicating that they are being synthesized by these cells. Intermediate forms of cells, with features of both fibroblastic and osteoblastlike cells, were also recognized. However, transitions between the primitive mesenchymal cells (Type I) and the other types of cells were not seen. The lysosomal content in one case were not as frequent as those described by Lee et al.,7 in skeletal bone-forming sarcoma. Crystalline material was seen in extracellular collagen and phagosomes. In another case, osteoid did not appear mineralized by light microscopy in H&E or in plastic embedded thick sections used for ultrastructural examination. Perhaps this explains why we did not find hydroxyapatite crystals with greater frequency within collagen. The dense condensations of intercellular collagen which occur with such great frequency in osteogenic sarcoma, could perhaps, be used as a marker for these tumors, along with other cellular characteristics. Though we have seen it within benign fibrous tissue, it is possible that the differentiated fibroblast, osteoblasts are derived from the primitive mesenchymal cell. The type of cell described in one of our cases resembles the stromal cells described by Ha- naoka et ~ 1 in. giant ~ cell tumor of bone. Other glycogan filled cells resembled chondrocytes. This patient had neurofibromatosis and theoretically; it is possible that the original osteogenic sarcoma arose in a mesenchymoma. However, other than above described cells, no other mesenchymal cell types including Schwann cells, were identified in our material. The presence of mitochondria1 electron dense deposits, probably calcium, in an otherwise viable cell is intriguing. After establishing the histologic diagnosis,

9 1496 CANCER April 1978 Vol. 41 wide local excision with at least 5-10 cm margin of normal tissue, should be the first treatment of choice. If this is not feasible due to the anatomic location of the tumor, amputation should be done. Simple excision or enucleation of the tumor should not be done, because it is often followed by local recurrence and later, pulmonary metastases. The incidence of local recurrence following simple excision, has been reported to be very high and in our series it was 75%. In contrast, the patients in our series who had wide excision of the soft parts or amputation did not develop local recurrence. The occurrence of pulmonary metastases is common, and in most cases, it appears within two years of the first surgical excision. Biologically, these tumors are very malignant and they metastasize frequently. Their behavior is comparable to that of other poorly differentiated soft tissue sarcomas and that of classic type osteogenic sarcoma. The average 5-year survival rates from five series including the present one, was only 15.6%. Almost 80% of the patients died within 2-3 years. These survival rates are comparable to those of classic type osteogenic sarcoma and poorly differentiated soft tissue sarcomas. Since most of the recurrences occur within two years of the first treatment, the adjuvant chemotherapy and immunotherapy might benefit these patients. Due to the small number of patients in this series, no comment can be made about the choice of chemotherapeutic agents for the treatment of distant metastases. REERENCES 1. Allan, C. J., and Soule E. H.: Osteogenic sarcoma of the somatic soft tissues-a clinicopathologic study of 26 cases and review of the literature. Cancer 27: , Das Gupta, T. K., Hajdu, S. I., and oote,. W., Jr.: Extraosseous osteogrnic sarcoma. Ann. Surg. 168: , ine, G., and Stout, A. P.: Osteogenic sarcoma of the extraskeletal soft tissues. Cancer 9: , Ghadially,. N., and Mehta, P. N. : Ultrastructure of osteogenic sarcoma. Cancer 25: , i. Hanaoka, H., riedman, B., and Mack, R. P.: Ultrastructure and histogenesis of giant cell tumor of bone. Cancer 25: , Kay, S.: Ultrastructure of an osteoid type of osteogenic sarcoma. Cancer 28: Lee, W. R., Laurie, J., and Townsend, A. L.: ine structure of a radiation-indiced osteogenic sarcoma. Cancer 76: , Lewis, R. J., Lotz, M. J., and Beazley, R. M.: Extraosseous osteosarcoma: Case Report and approach to therapy. Ann. Surg. 40: , hliller, W. H., Wirman, J. A,, and McKinney, P.: Extraosseous osteogenic sarcoma of forearm. Arch. Pathol. 97: , Pack, G. T., and Braund, R. R.: The development of sarcoma in myositis ossificans. ]A.A4A 119: , Scranton, P. E., Jr., DeCicco,. A,, Totten, R. S., and Yunis, E. J.: Prognostic factors in osteosarcoma. A review of 20years experience at The University of Pittsburgh Health Center Hospitals. Cancer 36: , Wilson, H.: Extraskeletal ossifying tumors. Ann. Surg. 113:95-112, Wurlitzer,., Ayala, A,, and Komsdahl, M.: Extraosseous osteogenic sarcoma. Arch. Surg. 105: , 1972.