Of mice and men: divergent risks of teriparatide-induced osteosarcoma.

SUMMARY: Since approval by the U.S. Food and Drug Administration (FDA) in December 2002, teriparatide (recombinant 1-34 PTH; Forteo) has been safely used by more than 430,000 patients. Prior to FDA approval, however, there was concern that teriparatide might increase the risk for patients to develop osteosarcoma, as almost 45% of the rats treated with this drug at the highest-tested dose level developed this aggressive form of bone cancer. Balancing the proven benefits of teriparatide shown by clinical trials with the theoretical risk for teriparatide-induced human osteosarcoma, the FDA mandated both a 'black-box' warning of this potential side-effect and a company-sponsored postmarketing surveillance program. As a participating institute of that surveillance program, we report upon the second person with potential teriparatide-induced osteosarcoma, in this case, complicated by a history of pelvic radiation. INTRODUCTION: Given the theoretic risk of the drug teriparatide and the known risk of radiation in inducing osteosarcoma, we raise the issue of whether teriparatide magnified the risk of radiation-induced osteosarcoma in our patient and try to determine which factor played the predominant role in the development of his disease. METHODS: We analyzed preclinical rat data, human clinical experience with teriparatide, and our patient's clinical history to assess the human risk of teriparatide and radiation exposure. RESULTS: After the first case of suspected osteosarcoma was reported in December 2005, we encountered a second possible teriparatide-induced osteosarcoma less than a year later. Review of the preclinical animal data would suggest that teriparatide is safe for human use when used as recommended by the manufacturer. Given the location of the sarcoma within the field of radiation and the limited exposure to teriparatide before diagnosis, it is unlikely that teriparatide played the predominant role in the emergence of this patient's osteosarcoma. We cannot, however, exclude the possibility that teriparatide magnified the carcinogenic effect of radiation therapy to induce the osteosarcoma. CONCLUSION: Of more than 430,000 persons who have received teriparatide for treatment of severe osteoporosis, we report the second patient to develop osteosarcoma. Although teriparatide reduces osteoporosis-related fractures in select patient populations, important contraindications, such as prior radiation exposure, should be considered before use.

Osteosarcoma of bone in apatient with primary hyperparathyroidism: a case report.

A 69-year-old woman was diagnosed with a malignant tumor of the right proximal femur. She had primary hyperparathyroidism and chronic elevation of parathyroid hormone levels (PTH > 1,000 pg/ml). She underwent resection of the bone lesion; histological analysis showed a high-grade fibroblastic osteosarcoma. In addition, she underwent curative resection of a large left superior parathyroid adenoma. To our knowledge, this is the third reported clinical case of osteosarcoma arising in association with hyperparathyroidism.

Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway.

Metastases from prostatic adenocarcinoma (prostate cancer) are characterized by their predilection for bone and typical osteoblastic features. An in vitro model of bone metastases from prostate cancer was developed using a bicompartment coculture system of mouse osteoblasts and human prostate cancer cells. In this model, the bone-derived prostate cancer cell lines MDA PCa 2a and MDA PCa 2b induced a specific and reproducible increase in osteoblast proliferation. Moreover, these cells were able to induce osteoblast differentiation, as assessed by increased alkaline phosphatase activity, Osteocalcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into severe combined immunodeficiency disease mice. In contrast, the highly undifferentiated, bone-derived human prostate cancer cell line PC3 did not produce an osteoblastic reaction in vitro and induced osteolytic lesions in vivo. The osteoblast differentiation induced by MDA PCa 2b cells was associated with up-regulation of the osteoblast-specific transcriptor factor Cbfa1. Moreover, treatment of osteoblasts with conditioned medium obtained from MDA PCa 2b cells resulted in up-regulation of Cbfa1 and Osteocalcin expression. In support of the differentiation studies, a microarray analysis showed that primary mouse osteoblasts grown in the presence of MDA PCa 2b cells showed a shift in the pattern of gene expression with an increase in mRNA-encoding Procollagen type I and Osteopontin and a decrease in mRNA-encoding proteins associated with myoblast differentiation, namely myoglobin and myosin light-chain 2. Taken together, these findings suggest that the bone-derived prostate cancer cells MDA PCa 2a and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent pathway. These results also established that soluble factors produced by prostate cancer cells can induce expression of osteoblast-specific genes. This in vitro model provides a valuable system to isolate molecules secreted by prostate cancer cells that favor osteoblast differentiation. Moreover, it allows to screen for therapeutic agents blocking the osteoblast response to prostate cancer.

Osteosarcoma in preadolescent patients.

The medical records of boys younger than 11 years and girls younger than 10 years of age with osteosarcoma of the pelvis or extremity were reviewed. Thirty patients were identified who were newly diagnosed but untreated for osteosarcoma. None of these patients had pulmonary metastases. The same four protocols were used to treat the patients in the current study as were used to treat adolescents. The event-free and overall survival was calculated and prognostic factors were assessed. The median followup time was 8 years (range, 6-14 years). The results were compared with the results of older patients treated with the same protocols and with published results. Fourteen patients had pulmonary metastases (47%); among these patients, four also had skeletal metastases (in two of the latter, skeletal metastases appeared before the pulmonary metastases). Event-free survival was 53% and overall survival was 57%. This result is comparable with current survival results in adolescent and older patients. Serum alkaline phosphatase and serum lactic dehydrogenase levels before treatment, height percentile greater than 50%, chemotherapy-induced tumor necrosis, surgical procedure, tumor site, tumor histologic features, and patient gender were not prognostic indicators. The prognosis for prepubertal patients with osteosarcoma is similar to the prognosis of their adolescent and older counterparts. There does not seem to be any indication to treat preadolescent patients with osteosarcoma using alternate therapies.

Protease expression in dedifferentiated parosteal osteosarcoma.

BACKGROUND: Parosteal osteosarcoma with dedifferentiation provides a useful model to study tumor progression from an indolent locally aggressive neoplasm to highly lethal metastasizing malignancy. Up-regulation of the proteolytic enzymes participating in stromal degradation is known to promote invasive growth and metastasis of several human and experimental tumors. METHODS: The expression patterns of urokinasase plasminogen activator (u-PA), its cell-surface receptor (u-PAR), and cathepsin B were analyzed by immunohistochemical techniques in 11 cases of parosteal osteosarcoma and in 4 cases of dedifferentiated parosteal osteosarcoma. RESULTS: Both enzymes and the receptor were coexpressed in most tumor cells of parosteal and dedifferentiated parosteal osteosarcoma. Their expression was strikingly enhanced in the dedifferentiated high-grade component of the tumors. Tumor cells involved in bone production (ie, those adjacent to tumor produced bone trabeculae) exhibited equally strong expression of u-PA, u-PAR, and cathepsin B, regardless of their histologic grade. Expression of u-PA, u-PAR, and cathepsin B was undetectable in the "normalized" cells embedded in the well-developed tumor bone trabeculae. CONCLUSION: These data indicate that u-PA and its interacting molecules, such as u-PAR and cathepsin B, may have some contributory effects on the metastatic potential of tumor cells in dedifferentiated parosteal osteosarcoma.

Phase II study of recombinant interleukin 1alpha and etoposide in patients with relapsed osteosarcoma.

A Phase II trial using interleukin 1alpha (IL-1alpha) and etoposide for patients with relapsed osteosarcoma (OS) was undertaken to assess the feasibility and tolerability of combination therapy with biotherapy and chemotherapy. Nine patients with histologically proven relapsed OS were treated with IL-1alpha immediately followed by etoposide daily for 5 days every 3 weeks. Surgical resection of lung metastasis or peripheral tumor was performed after two or three cycles. We observed three partial responses; disease was stable in another case. One case could not be evaluated. The side effects associated with combination therapy were as predicted from known side effects of the individual agents; however, more profound neutropenia was observed. Four patients exhibited clinical signs of capillary leak syndrome, i.e., hypotension, edema, and weight gain. The etiology of the capillary leak was unclear, because serum IL-1alpha, IL-2, tumor necrosis factor, and nitric oxide levels could not be used to predict which patients would develop capillary leak. Histological analysis of tumor specimens obtained after two or more courses of therapy showed changes consistent with a response to a biological response modifier: peripheral fibrosis surrounded the metastasis with infiltration of chronic and acute inflammatory cells. Because the response of relapsed OS to any type of salvage regimen has been poor, we interpret the clinical response of this therapy as good. However, the significant side effects associated with this therapy must also be taken into consideration before deciding to use this combination therapy. It is unfortunate that the study was stopped early due to halted production of IL-1alpha. If this agent is again manufactured for clinical use, we conclude that additional evaluation in patients with relapsed OS is warranted.

Conventional and dedifferentiated parosteal osteosarcoma. Diagnosis, treatment, and outcome.

BACKGROUND: Dedifferentiated parosteal osteosarcoma (dd-POS) designates high grade transformation, of conventional low grade parosteal osteosarcoma (c-POS). The paradigm of preoperative diagnosis, neoadjuvant chemotherapy, and wide local excision has not been adequately evaluated for dd-POS, as it has been for conventional high grade intramedullary osteosarcoma. METHODS: A retrospective review was conducted of 28 patients treated at the authors' institution between January 1980 and December 1992 for an osteosarcoma arising on the surface of the bone diagnosed as either c-POS or dd-POS. The clinicopathologic features, diagnosis, treatment, and patient outcome were analyzed. RESULTS: A dedifferentiated component was identified in 12 of 28 tumors (43%). Neither the presence of radiolucencies (77% in c-POS and 100% in dd-POS, P = 0.06) nor medullary invasion (42% in c-POS and 50% in dd-POS, P = 0.28) distinguished dd-POS from c-POS. However, all patients who presented with focal hypervascularity on an arteriogram defined the high grade component of dd-POS that was confirmed by selective needle biopsy. This differed significantly (P = 0.00003) from c-POS. None of the patients with c-POS died of the disease (median survival duration, 77 months; range, 16-152 months). Six patients (35%) developed a local recurrence, but five were treated successfully with further surgery. In the dd-POS group, 7 of the 12 patients died of the disease. Ten patients with dd-POS received preoperative chemotherapy (IA cis-diamminedichloroplatinum, IV doxorubicin), and a good response (> 90% necrosis of high grade component) was observed in four. Among patients whose disease was localized, continuous disease free survival was prolonged significantly (P = 0.03) in patients with a good response (median, 75 months) compared with those who responded poorly (median, 13 months). Five patients remained continuously disease free (median, 66 months, range, 29-95 months). CONCLUSIONS: Wide surgical excision alone is adequate treatment for patients with c-POS. Recognition of dedifferentiated areas with angiography and percutaneous biopsy of hypervascular areas should prompt the administration of chemotherapy and wide local excision to optimize patient outcome.

Osteosarcoma. Specimen management following primary chemotherapy.

The use of preoperative (i.e., primary) chemotherapy has been shown to be of direct and significant benefit to the osteosarcoma patient. There is virtually an immediate palliation of symptoms. Increasing numbers of patients with osteosarcoma involving bones of the appendicular skeleton are eligible for limb-salvage procedures secondary to the local effects of chemotherapy that result in a decrease in size and compaction (i.e., down-staging) of the tumors.

Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation.

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)

Giant solitary synovial chondromatosis.

The purpose of this report is to describe giant solitary synovial chondromatosis, a previously unrecognized feature of synovial chondromatosis that may histologically and radiographically mimic a malignant neoplasm. Giant solitary synovial chondroma is an intra- and/or extraarticular lesion measuring over 1 cm in size and sometimes as large as 20 cm. The radiographic appearance is that of a large, well-marginated mass either of irregular feathery calcification from coalescence of multiple small synovial chondromas, or a rounded calcified mass from the growth of a single synovial chondroma. Radiographically, giant solitary synovial chondromatosis may appear similar to chondrosarcoma and parosteal osteosarcoma.

Electron microscopy in the diagnosis of small round cell tumors of bone.

Small round cell tumors involving bone can present problems in differential diagnosis by light microscopy. In exploring the role of electron microscopy in this situation, seven small cell osteosarcomas and seven mesenchymal chondrosarcomas were examined by electron microscopy and compared with typical and atypical Ewing's sarcomas. There is much overlap in the ultrastructural features of these tumors, but electron microscopy is helpful to establish or confirm a diagnosis of typical Ewing's sarcoma and, if representative matrix is present, of small cell osteosarcoma.

Desmoplastic melanoma.

Desmoplastic melanoma is an uncommon type of malignant melanoma that has a predilection for the skin of the head and neck. Because of a progressive metaplasia of melanocytes and an accompanying desmoplasia, the neoplasm can be mistaken for benign or malignant soft tissue lesions. The neurotropism exhibited by many desmoplastic melanomas is a strong adverse factor for prognosis; otherwise, the biologic behavior is not unlike that of conventional melanomas.

Immediate free flap mandibular reconstruction: significance of adequate surgical margins.

The pathologic records of 182 consecutive patients who had mandible resections were reviewed to determine the incidence of positive margins in the bone specimens and the risk factors associated with positive margins. Of the 182 cases reviewed, 82 (45%) were found to have involvement of the mandible at the time of resection and four (2%) were found to have positive margins. The predominant tumor histology was squamous cell carcinoma, 148 of 182 (81%), followed in frequency by osteosarcoma 12 of 182 (7%), salivary gland tumors 13 of 182 (7%), and miscellaneous other tumors (nine of 182 (5%). Of the four tumors with positive margins, two (50%) were squamous cell carcinomas, one (25%) was an osteosarcoma, and one (25%) was a salivary gland tumor. All four tumors were large tumors that had failed to respond to previous therapy. All obviously involved the mandible at the time of presentation. This study demonstrates that the incidence of bone margin involvement after mandibulectomy is rare and predictable and that clinical selection of candidates for immediate reconstruction is reliable in preventing inappropriate use of free bone flaps in patients at risk for positive bone margins.

Diagnosis of eosinophilic granuloma of bone by fine-needle aspiration with concurrent institution of therapy: a cytologic, histologic, clinical, and radiologic study of 27 cases.

Twenty-seven patients with eosinophilic granuloma (EG) of bone seen at our institution between 1979 and 1991 underwent fine-needle aspiration (FNA) with or without concurrent Tru-Cut biopsy. The 16 males and 11 females ranged in age from 2 1/2 to 61 years (median, 10 yr). Twenty-four patients had monostotic lesions. The clinicoradiologic differential diagnosis included osteomyelitis and Ewing's sarcoma (young patients) and primary and metastatic malignancies (older patients). Twenty-four of 28 FNAs (one patient had two FNAs) were diagnostic of EG, and 10 cases were diagnosed by FNA alone. Smears in these cases showed histiocytes, often with grooved or infolded nuclei, and abundant eosinophils. Multinucleated giant cells, foamy histiocytes, neutrophils, lymphocytes, and plasma cells were present in variable numbers. Four FNAs were misdiagnosed: two as osteomyelitis where smears contained abundant neutrophils, sparse eosinophils, and histiocytes misinterpreted as foamy histiocytes, and two as metastatic carcinoma (in adults) where histiocytes in a scant specimen (one case) and skin appendiceal structures without lesional tissue (one case) were misinterpreted. These cases were correctly diagnosed on repeat FNA (one case), Tru-Cut (two cases), or excisional biopsy (one case); however, three cases diagnosed by FNA had nondiagnostic concurrent Tru-Cut biopsies. Treatment consisted of intralesional injection of 125 mg of methylprednisolone (22 cases). Progressive or complete healing of all lesions occurred. FNA is a rapid and useful technique for the immediate diagnosis of EG that allows concurrent institution of therapy.