Prognostic variables in osteosarcoma: a multi-institutional study.

This is a report of a multi-institutional study of all patients with osteosarcoma who were seen at 13 comprehensive cancer centers from July 1, 1977, to December 31, 1982. Follow-up extended to 9 years; a minimum of 3 years was obtained for greater than 90% of the patients. All patients with osteosarcoma were considered, but only those with tissue confirmation who had had at least part of their first course of treatment at one of the 13 institutions were included. There were 543 patients. In a search for prognostic indicators, 38 patient characteristics, three treatment categories, and an institutional variable were studied. A combination of nine of these constituted the best indicator of survival. They were morphology (two parts), site of primary cancer (two parts), spread of tumor, grade and size of tumor, duration of symptoms, weight loss of greater than 4.5 kg (10 lb), swelling at primary site, and lytic appearance. Unexpectedly, treatment was not one of the indicators of survival. A prognostic score was developed in which the coefficients were obtained from the Cox regression (step-down) method. Each patient had a score (S) and an observed survival time that together provided the expected risk of death for that patient. Although this was not a randomized study, treatments were compared before and after adjusting for characteristics identified as prognostic. Three treatments differed little: surgery alone, surgery plus chemotherapy and/or radiotherapy, and chemotherapy and/or radiotherapy followed in 1-4 months by surgery. Patients with amputations and those with resections had similar death rates, but the observed progression rates differed widely. However, when the rates were adjusted for prognostic characteristics, the difference disappeared. Complete surgery (if osteosarcoma existed within surgical margins) was no better than incomplete surgery (if osteosarcoma existed beyond surgical margins) with respect to death but, as would be expected, complete surgery was much better with respect to disease progression.

Sarcomas of calvarial bones: rare remote effect of radiation therapy for brain tumors.

After latent periods lasting from 7 to 23 years, sarcomas of the calvaria developed in four patients who had received radiation therapy for a brain tumor. There was no evidence of bony disease before radiation therapy, and the sarcoma (two fibrosarcomas and two osteosarcomas) developed in the field of radiation in all four patients. One of these four died during resection of the tumor, two survived for either 7 or 21 months after diagnosis of the sarcoma, and one was alive at 23 months after the clinical appearance of the sarcoma. The latter patient has had two resections and extensive chemotherapy. Distant metastases were not present in any of the patients. Sarcoma of the calvarial bones is a serious but rare remote effect of radiation therapy for brain tumors.

Treatment of stage IE primary lymphoma of bone.

PURPOSE: A retrospective analysis was performed to assess the efficacy of various treatments of Stage IE primary non-Hodgkins lymphoma of bone. METHODS AND MATERIALS: Sixty-three patients with Stage IE primary non-Hodgkins lymphoma of bone (single osseous focus) were seen at our institution between the years 1970 and 1989. Information was obtained regarding each patients' presentation and clinical course. The histology was reviewed in all patients. Modern immunohistochemical stains were performed on each case with available paraffin-embedded tissue. RESULTS: The histologic classification of the tumors was as follows: 43 diffuse large cell, 13 diffuse mixed cell, 3 small noncleaved, and 4 unclassified. The most common presenting symptom was pain (97%) and the following bony sites were involved: 36 long bone, 9 flat bone, 13 spine, and 5 pelvis. Of the 63 cases, 50 were treated with radiation alone, 10 with chemotherapy and radiation, 2 with chemotherapy alone, and 1 with surgery alone. Univariate analysis revealed a suggestion of an improved 5-year disease-free survival for patients treated with chemotherapy and radiation vs. radiation alone (90% vs. 57% respectively, p = .08). Multivariate analysis (controlling for extent of initial evaluation, extent of pathological evaluation and other potential prognostic factors) showed that neither treatment resulted in superior outcome with respect to disease-free survival, disease specific survival, or overall survival, however, doses of radiation greater than 4000 cGy resulted in improved overall survival compared to lower doses (p = 0.01). CONCLUSION: This study supports the use of primary RT (> 4000 cGy) for Stage IE PLB, however, the addition of chemotherapy to the radiotherapeutic management may decrease the initial relapse rate of some patients. Future studies should address this question.

Premalignant tumors and conditions of bone.

Most bone sarcomas arise in apparently normal bone. However, some sarcomas arise in preexisting benign bone tumors or in nonneoplastic conditions. Some of the lesions, such as multiple exostoses and Ollier's disease, have a propensity to develop chondrosarcoma. Rarely does a benign giant cell tumor become malignant without prior irradiation, malignant transformation of other benign tumors, such as osteoblastoma and chondroblastoma, is a medical curiosity. Among nonneoplastic conditions, radiation changes, long-standing chronic osteomyelitis, and Paget's disease have definite premalignant connotations. However, the risk of developing cancer in these conditions is still low.

Osteosarcoma of bone and its important recognizable varieties.

Osteosarcoma of bone is a recognizable entity if the histopathologist designates tumors as such when their malignatn cells produce osteoid substance even if only in small foci. Such definition distinguishes this lesion from other sarcomas that arise in bone, especially chondrosarcoma and fibrosarcoma. There is a general tendency to consider that osteosarcomas represent a stereotyped form of disease for which new modalities of treatment can be applied and assessed. The question of whether a given osseous lesion is actually malignant and not a benign neoplasm or even a reactive non-neoplastic condition simulating a malignant tumor may be difficult for the histopathologist. Pathologists without considerable experience in the diagnosis of bone tumors find this question especially vexing. The establishment of a valid diagnosis of osteosarcoma introduces the additional problem that the 11 varieties considered in this paper may pose significant recognizable variations in the clinical capability of the disease. It is apparent that the physician must recognize the known clinicopathologic and prognostic factors of these subtypes in his assessment of the overall problem.

Osteoblastoma with cartilaginous matrix. An unusual morphologic presentation in 18 cases.

By definition, the occurrence of cartilaginous matrix in a bone-forming tumor eliminates the diagnosis of osteoblastoma and suggests a possible diagnosis of osteosarcoma. However, this rule is not absolute, as demonstrated by 18 cases of osteoblastoma that produced cartilaginous matrix. Hyaline cartilage was detected in four cases, and chondro-osteoid material was detected in 14 cases. In all patients, the tumor was in the appropriate patient age range and location for an osteoblastoma. The radiographic features as well as the histology, with the exception of the cartilaginous components, were in keeping with diagnosis of osteoblastoma. Intralesional excision (curettage or debulking) was performed in 13 patients and wide resection in five patients. Persistent tumor in one patient required a further intralesional excision. There were four recurrences, and no metastases were reported after follow-up of 1 to 23 years. The presence of cartilaginous matrix in a bone-forming lesion does not exclude the diagnosis of osteoblastoma and, more importantly, it is not always an indication that the tumor is an osteosarcoma.

Fibrocartilagenous mesenchymoma of bone.

We studied 12 cases of a rare primary bone neoplasm--fibrocartilaginous mesenchymoma--including five from the original report on this condition. The seven male and five female patients were 9 to 25 years old. The metaphyses of the long bones were the most common site, with the fibula accounting for a third of all cases. Histologically, the lesion contained spindle cells, bone trabeculae, and islands of cartilage. At least some of the cartilage was in the form of plates that resembled epiphyseal plates. Intralesional excision led to a high rate of recurrence, but no metastasis or death was related to the tumor. Our results indicate that the entity described by Dahlin and co-authors is histologically distinct and that its behavior does not merit the term malignant.

Bizarre parosteal osteochondromatous proliferation of bone (Nora's lesion).

Bizarre parosteal osteochondromatous proliferation was first described in 1983, when Nora et al. reported 35 examples of a proliferative lesion involving the small bones of the hands and, less often, the feet. No examples involving the large bones were reported. We present 65 cases of this condition, five from the Mayo Clinic files and 60 from our consultation files, including 34 females and 31 males; patients' ages ranged from 8 to 73 years (average, 33.9 years). Thirty-six lesions involved the hands, 10 the feet, 17 the long bones, one the skull, and one an unknown site. The long bones involved were the radius (three lesions), ulna (six), fibula (two), femur (three), tibia (two), and humerus (one lesion). Roentgenograms typically showed a heavily calcific mass attached to the underlying cortex and having a broad base. Histologically, a large amount of hypercellular cartilage showed maturation to trabecular bone, which frequently contained spindle cells in the intertrabecular spaces, an appearance that could lead to a mistaken diagnosis of parosteal osteosarcoma. A helpful feature was the distinct blue tinctorial characteristic of the bone in the lesion. Follow-up information was available for 40 patients; approximately 55% had a recurrence. No metastasis had been reported in any of the 65 cases. Bizarre parosteal osteochondromatous proliferations are a form of heterotopic ossification and should not be mistaken for chondrosarcoma or osteosarcoma.

Malignant giant cell tumor of the tendon sheaths and joints (malignant pigmented villonodular synovitis).

Malignant pigmented villonodular synovitis (PVNS) is a rare lesion whose existence may be debatable. We studied eight cases that we consider to be examples of malignant PVNS. The three male and five female patients were aged 12 to 79 years. The knee was involved in three cases; the ankle in two; and the cheek, dorsum of the foot, and thigh in one each. Four patients had swelling for 6 months to 17 years before presentation. Three cases of malignant PVNS were secondary, arising in patients in whom PVNS had been documented previously, and five cases were primary, with histologic features similar to those of the secondary ones. Important histologic features of malignancy were (a) a nodular, solid infiltrative pattern of the lesion; (b) large, plump, round or oval cells with deep eosino philic cytoplasm and indistinct borders; (c) large nuclei with prominent nucleoli; and (d) necrotic areas. Atypical mitoses were occasionally seen. Four patients died with pulmonary metastasis (two also had metastasis to inguinal lymph nodes). Four patients are alive from 3 1/2 to 5 years after the last surgical treatment. The malignant nature of this lesion, the histologic architecture similar to that of PVNS, and the fibrohistiocytic appearance of the cells suggest that malignant PVNS is an entity.

Epithelioid hemangioendothelioma of bone.

Epithelioid hemangioendothelioma of bone is a rare tumor of vascular origin. A series of 40 cases from the Mayo Clinic files was studied to define the pathologic features of this disease and to evaluate any histologic or clinical factor influencing outcome. More than 50% of the tumors were multicentric, with a predilection for bones of a particular anatomical area. In this series, patients with multifocal tumors did not have a better prognosis than those with unicentric disease. We could not predict the outcome of cases on the basis of the histologic features. Visceral involvement was the most important criterion in predicting prognosis. Resection is still the primary treatment for these tumors. Radiotherapy may be useful for surgically inaccessible tumors. Too few patients have received adjuvant chemotherapy to evaluate its usefulness in this setting.

Periosteal chondroma and periosteal chondrosarcoma.

A clinicopathologic study of 46 patients with periosteal chondroma and 14 patients with periosteal chondrosarcoma revealed that periosteal chondroma tended to affect younger patients and that the lesion was usually smaller. Radiographically, the typical periosteal chondroma was a small, well-marginated tumor on the outer surface of a long bone. Erosion of the cortical surface and marginal buttresses were usually present. Periosteal chondrosarcoma had a more aggressive appearance and was seen as a large mass located superficially on the cortex; the margins of the mass were more irregular than those of chondroma. Histologically, periosteal chondroma frequently showed hypercellularity, plump nuclei, and binucleation. Thus, the differentiation of chondroma from chondrosarcoma is difficult and is based mainly on evidence of invasion. The prognosis in periosteal chondroma is good: only one patient had a local recurrence, none of the tumors underwent malignant change, and excision seems to be curative. However, the prognosis in periosteal chondrosarcoma is not as good: two patients died of metastasis to the lungs after local excision and two patients had recurrences after local resection. Periosteal chondrosarcoma should be treated more aggressively than periosteal chondroma.

Solitary congenital fibromatosis (infantile myofibromatosis) of bone.

Congenital fibromatosis is a rare and benign myofibroblastic tumor that may occur in either a solitary or multicentric form. The soft-tissue form of this entity is well recognized. This report analyzes the clinical and pathologic features of 14 cases of congenital fibromatosis in which the tumor existed as a solitary lesion in bone. Most of the tumors (71%) were in patients who were 2 years old or younger. All but one tumor involved the craniofacial bones. Radiographically, they were purely lucent lesions in which a sclerotic rim was visible in each skull lesion. The myofibroblastic appearance closely resembled the microscopic features seen in the soft-tissue counterpart. For appropriate surgical management, it is imperative to recognize that this tumor occurs as a solitary lesion in bone and that it is distinct from other, more aggressive fibrous lesions.

Clear cell chondrosarcoma of bone. Observations in 47 cases.

Clear cell chondrosarcoma of bone, a low-grade malignant tumor, frequently presents diagnostic difficulties. Its clinical, roentgenographic, and pathologic characteristics separate it from conventional chondrosarcoma and, more importantly, from several benign bone tumors with which it is often confused. This report analyzes 47 cases seen at the Mayo Clinic and in consultation. The lesion is more common in males than females (2.6:1) and has a predilection for the end of long bones, particularly the proximal femur. The age range is wide; most patients are in the third and fourth decades of life. Roentgenographically, the lesion most often is purely lytic and slightly expansile, with a sharp margin between the tumor and the adjacent normal bone. Pathologically, clear cells arranged in an indistinct lobular pattern characterize the tumor. Frequently, areas mimicking other primary bone tumors, benign and malignant, are present, often to such an extent as to obscure the true identity of the process. The overall mortality in the present series was 15%. En bloc resection, including a margin of normal bone and soft tissue, appears to be the treatment of choice.

High-grade surface osteosarcomas.

Nine patients (seven males and two females) had high-grade, ordinary-type osteosarcomas that were juxtacortically located. The ages of these patients ranged from 9 to 62 years at the time of diagnosis. The roentgenographic appearance of these tumors occasionally is similar to that of periosteal osteosarcomas. Histologically, these tumors were indistinguishable from ordinary high-grade intramedullary osteosarcomas. None of the nine tumors had histologic features of parosteal or periosteal osteosarcomas. All nine patients were treated by ablative surgery. Seven patients died of tumor. Because of its poorer prognosis, this tumor should be differentiated from other juxtacortical osteosarcomas.

Hemangiopericytoma of bone.

Hemangiopericytoma primary in bone is a rare tumor. A review of 15 cases (five from the Mayo Clinic files and 10 from the consultation files) revealed that all tumors were unifocal and that the most common location was the pelvis (three lesions in the sacrum and two in the ischium). The series involved seven male and eight female patients whose ages ranged from 14 to 74 years. Histologically, all of the tumors were composed of cells with round to oval nuclei arranged around vascular spaces. On the basis of cellularity, nuclear atypia, and mitotic activity, four tumors were benign, two intermediate, and nine malignant. Surgery was the primary treatment for the 15 patients. Of the 14 patients with adequate follow-up, eight died of disease, three were alive with recurrent disease, and three were alive and disease-free.

Langerhans' cell granulomatosis (histiocytosis X) of bone in adults.

Langerhans' cell granulomatosis (LCG) (histiocytosis X) of bone is generally considered a childhood disease. A series of 61 adult patients who presented with histologically confirmed skeletal disease was studied. The male-to-female ratio was 2.1, and 36 patients were more than 30 years old, the oldest being 71 years. Pain was the most frequent symptom. Forty-six patients has solitary lesions, six had two or three, and nine had more than three. The time interval between the development of lesions, although usually less than 2 years, ranged up to 32 years. Rib, skull, and pelvis were the most frequently involved sites. Eight patients had extraskeletal disease. Radiologically, a well-defined lytic lesion, either with no surrounding reaction or with sclerotic margins, was seen most often. The rare, poorly defined lesions tended to occur in the clavicle. Microscopically, typical Langerhans' cells were present in large numbers. Eosinophils were usually prominent. Benign giant cells, mitotic figures, and necrosis also were observed. There was no histologic difference between solitary and multiple lesions. Surgery, radiation therapy, or a combination of both usually provided adequate treatment. Only two of the solitary lesions recurred. Eleven patients suffered from chronic, progressive disease, which inconsistently responded to treatment. None of the patients in our series died of the disease.

Sarcomas of bone complicating osteitis deformans (Paget's disease): fifty years' experience.

Osteitis deformans (Paget's disease of bone) may be complicated by osseous cancer. Of 3964 patients between 1927 and 1977, 38 had primary malignant bone tumors. This represents an incidence of sarcomatous change of 0.95%. The bones of the pelvis were most often involved; the humerus and the femur were next in frequency. No region of the skeleton was spared, with the exception of the forearms and hands. Of the 38 tumors, six were fibrosarcomas and 32 were osteosarcomas. Irrespective of the site of involvement, the histopathologic extremely poor. The 5-year survival rate was 7.9%, with a mortality rate of 86.8% 36 months after diagnosis. The main cause of death was pulmonary metastasis or local extension of tumor growth. Three patients were long-term survivors, but no clinical or pathologic elements could be identified which differentiated these survivors from the other patients in the study.

Dedifferentiated clear cell chondrosarcoma.

Dedifferentiation, a change in the histologic character and clinical behavior of a tumor to a more immature and aggressive one, occurs in approximately 11% of all chondrosarcomas. The original lesion is usually a low-grade chondrosarcoma. Clear cell chondrosarcoma is a rare cartilaginous tumor of low-grade malignancy with a preference for the ends of long bones. It is usually curable by resection. Recurrence commonly follows inadequate surgery, and metastases to lung, brain, and bones can develop. However, dedifferentiation has not yet been described in association with clear cell chondrosarcoma. Three patients are described who were initially diagnosed as having clear cell chondrosarcoma of the femur. Two were treated with en bloc resection for a clear cell chondrosarcoma. One of these had an undifferentiated sarcoma in a local recurrence after 6 years. In the second, metastasis of the clear cell chondrosarcoma developed 5(1/2) years after surgery; autopsy revealed undifferentiated sarcoma in the lung, heart, and lumbar spine. The third patient had dedifferentiated clear cell chondrosarcoma at the time of resection following the biopsy diagnosis of clear cell chondrosarcoma. All three died with metastatic disease. These three patients represent three different manifestations of dedifferentiation-at initial diagnosis, at recurrence, and at metastasis. To our knowledge, this is the first description of dedifferentiation occurring in clear cell chondrosarcoma.

Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.

This article describes the clinical and pathologic features of four unusual bone tumors. Three were congenital or most likely so; the fourth, detected at age 1 year, was probably of considerable duration. The patients, three boys and one girl, each presented with a painless mass. Two had the Carney complex, a familial lentiginous and multiorgan tumorous syndrome; another probably had this disorder; the fourth did not show it, but his mother did. The tumors occurred in the nasal region (n = 2) and the diaphysis of the tibia and radius (n = 1 each). Roentgenographically, three had benign characteristics; the fourth, malignant features. Grossly, the tumors were gelatinous, cartilaginous. and bony. Microscopically, they featured benign-appearing polymorphic cells with few division figures arranged in sheets and lobules set in a myxomatous, cartilaginous, osseous, and hyaline fibrous matrix. Cellularity was low to moderate. The tumors eroded bone, one infiltrated between bony trabeculae, and three had soft tissue extension. Complete resection of one tumor was curative; incomplete excision of two tumors resulted in local recurrence (intracranial and fatal) in one and persistence in the other; the fourth tumor remains under observation after biopsy. No tumor metastasized.

Osteogenic melanoma. A rare variant of malignant melanoma.

Osteogenic melanoma is a rare variant of malignant melanoma; only eight cases have been reported. To characterize this unusual neoplasm further, we present four new cases. Two patients were men and two were women (average age, 56 years; range, 47-78 years). All tumors arose from acral lentiginous melanomas. Three were subungual finger lesions and one was on the sole of the foot. All four had been previously diagnosed as or were suspected to have been primary osseous lesions. The vertical growth components were high-grade, amelanotic sarcomatoid malignancies with abundant osteoid matrix. Two tumors also had chondroblastic differentiation. Cells with epithelioid features, including prominent eosinophilic nucleoli, were discernible in every tumor. Regional lymph node metastases in two cases retained osteocartilaginous differentiation, whereas metastatic cells in another case were purely epithelioid. Tumor cells in every case were immunoreactive for S-100 protein and vimentin, and non-reactive for cytokeratin. Two tumors also expressed HMB-45. Melanosomes were identified ultrastructurally in every tumor. Follow-up information was available on every patient. Three developed regional lymph node metastases and are currently alive and well after 14, 39, and 101 months. The fourth patient died of metastatic uterine carcinoma 20 months postoperatively. The differential diagnosis of osteogenic melanoma includes osteosarcoma as well as atypical fibro-osseous proliferations. Clinico-pathologic features that support a diagnosis of osteogenic melanoma include junctional activity, absence of primary bony involvement, regional nodal metastases, immunoreactivity for S-100 protein and/or HMB-45, lack of cytokeratin reactivity, and ultrastructural identification of melanosomes.