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.

Distinctive protein pattern in two-dimensional electrophoretograms of cancerous prostatic tissues.

In this report, we describe methods used to analyze the protein composition of sectioned frozen prostatic tissues by two-dimensional gel electrophoresis. Our results show a high degree of homology in two-dimensional electrophoretograms of proteins extracted from frozen sections of malignant prostate glands. Such homology was not apparent in protein patterns of benign hypertrophic prostatic tissue sections. Typically, 600 discrete proteins were resolved on two-dimensional electrophoretograms and 9 proteins were present in all patterns of prostate adenocarcinomatous tissues. These nine proteins were not observed in any of the protein electrophoretograms developed from nonmalignant prostate tissue. Three proteins were found common to nonmalignant prostate glands but were not present in prostatic adenocarcinoma.

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.

Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience.

Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I, II, and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF), Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH), and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.

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.

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.

"Dedifferentiated" chordoma. A clinicopathologic and immunohistochemical study of three cases.

Three cases of "dedifferentiated" chordoma arising in the sacrococcygeal region are presented. In all three cases, the "dedifferentiated" component arose de novo in conjunction with conventional chordoma. Two of these patients, whose tumors had a prominent malignant fibrous histiocytoma (MFH) component, died within 6 months of diagnosis. Both patients had lung metastases, one of which was histologically documented to be MFH. The third patient, whose initial tumor contained osteosarcoma, died 76 months after diagnosis and multiple recurrences. Most notable in this case was the absence of the "dedifferentiated" component (in this instance, osteosarcoma) in all of the local recurrences as well as the lung metastases. These were composed exclusively of conventional chordoma. None of the patients had a previous history of radiation therapy. The immunohistochemical staining pattern of conventional chordoma was similar to that of previous reports, where the epithelial-like cells stained for cytokeratin and epithelial membrane antigen. In addition, they stained for alpha-1-anti-chymotrypsin and vimentin. These latter two markers were also identified in the "dedifferentiated" component. As with "dedifferentiated" chondrosarcomas and liposarcomas, "dedifferentiation" in a chordoma usually portends an accelerated clinical course.

Sclerosing adenosis of the prostate gland. A lesion showing myoepithelial differentiation.

Sclerosing adenosis of the prostate is a rare lesion characterized by the proliferation of variably sized glands in a cellular stroma. We report light microscopic, immunohistochemical, and ultrastructural studies in 22 examples from 15 patients. Two cases were identified in 100 consecutive prostates embedded by a whole organ method, giving a prevalence of 2%. Antibodies directed against the following antigens were used: high-molecular-weight cytokeratin (CKH; 34 beta E12); cytokeratin (CK; AE1/AE3), prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), S-100 protein, muscle-specific actin (HHF35), and vimentin (Vim). Cells within the glandular component demonstrated positive reactivity for CK, CHH, PSA, and PAP, indicating a prostatic epithelial origin. In addition, a distinct population of cells reacting for muscle-specific actin and S-100 protein was identified within this glandular element. Adequate material for ultrastructural study was available in five cases; all showed the presence of flattened cells located between the basement membrane and secretory epithelial cells, which had features typical for myoepithelial differentiation. Although the prostate gland does not normally contain myoepithelial cells, we have documented their consistent presence in this unusual lesion; we believe these cells arise by a metaplastic process from the prostatic basal cells.

The pathologist's role in the diagnosis and treatment of osteosarcoma in children.

Tumor specimens from 24 children under 15 years of age were studied. The children had osteosarcoma and received intra-arterial infusions of cis-platinum before resection or amputation. There were 13 boys and 11 girls, and the median age was 12 years. Fifteen lesions were located in the femur, four in the humerus, three in the tibia, one in the pubis, and one in the radius. Sixteen patients underwent diagnostic needle biopsies and the remainder, open biopsies. Eleven patients had excellent tumor response, with over 90 per cent tumor destruction in six and 65 to 75 per cent in five. One patient had 50 per cent tumor destruction, and in nine patients the response was insignificant. Two patients had good clinical responses to treatment and refused limb amputation; one additional patient died of the disease without amputation or resection. The systematic study of pathology specimens is being undertaken to determine the utility of such a study as a guide to the selection of adjuvant chemotherapy. Patients in whom no responses are obtained should receive alternative treatment, and those in whom responses are optimal should retain the original agent in their adjuvant chemotherapy regimen.

Argentaffin endocrine carcinoma (carcinoid) of the pancreas with concomitant breast metastasis: an immunohistochemical and electron microscopic study.

A pancreatic carcinoid tumor that metastasized to the breast is reported. The breast tumor was originally diagnosed as adenocarcinoma of the breast. Silver impregnation revealed the presence of argentaffin cytoplasmic granules. Immunocytochemical studies demonstrated immunoreactivity for serotonin but not for lactalbumin, a marker for breast epithelial cells. These features, together with the electron microscopic observation of pleomorphic secretory granules, permitted recognition of the tumor as metastatic carcinoid. This report illustrates the importance of the combined histochemical, immunocytochemical, and electron microscopic studies of breast tumors with a carcinoid pattern.

Esophageal-atrial perforation due to recurrent esophagitis 18 years after esophageal bypass surgery.

A 62-year-old man presented with a grand mal seizure, progressive abdominal distention, and refractory hypotension 18 years after colonic bypass of a benign stricture of the low middle third of the esophagus. He died 3 hours after admission to the hospital. The patient had a history of liniment ingestion in childhood plus a long history of dysphagia and substernal pain. Autopsy disclosed a large ulcer of the anterior wall of the distal esophagus, which had eroded through the posterior wall of the left atrium. Histologic examination revealed chronic esophagitis with fibrous obliteration of the esophageal wall, pericardium, and left atrial myocardium near the site of perforation. Foreign material was present within small arteries of multiple viscera, and in several of these fragments transverse striations were demonstrated. Esophageal-atrial perforation is a rare but fatal complication of chronic esophageal ulceration. The clinical and pathological features of this and previously reported cases of nontraumatic esophageal-atrial perforation are reviewed.

Collagenous colitis.

Collagenous colitis is a newly described entity that clinically manifests itself as watery diarrhea of long-standing duration. The main histopathologic characteristic is the presence of a collagen band immediately beneath the colonic surface epithelium. Ultrastructurally, the collagen is deposited beneath the basement membrane, which is intact. Pathogenetically, an aberrant function of the pericryptal fibroblastic sheath may be involved.

Primary renal malignant fibrous histiocytoma.

The ninth case of a primary renal malignant fibrous histiocytoma to appear in the English literature is described. The patient underwent preoperative renal artery embolization followed by radical nephrectomy and adjuvant chemotherapy. While adjuvant chemotherapy has prolonged the disease-free interval and improved the survival rates for patients with tumor arising at other sites, its use in our patient did not prevent the development of metastasis and the patient's early death.

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.

The pathology of head and neck tumors: papillomas of the upper aerodigestive tracts, Part 18.

The human papillomavirus class of DNA viruses are more than circumstantially related to oral and airway papillomas. Whether they are fully oncogenic, in the malignant sense, without other agents is questionable. Recent advances in molecular virology and the use of genus-specific (common) antigen-antibody reactions have identified papillomavirus in laryngeal and oral papillomas. Laryngeal and oral papillomas could be precancerous lesions, but they show a low-risk and long-time interval leading to malignancy unless significant iatrogenic or host variables--such as radiotherapy or immuno-incompetence--are added. Two different papillomas in the larynx can be recognized; a nonkeratinizing, papillomavirus-related lesion, and a keratinizing, usually solitary papilloma, which may or may not be related to a virus genesis and may be equated with a keratosis or clinical leukoplakia.

Intracranial dural chondrosarcoma.

Three cases of intracranial dural chondrosarcoma are reported. The radiologic appearance of this slow-growing, extraaxial malignant tumor is different from the more familiar skull-base chondrosarcoma and may mimic an atypical meningioma. Dural chondrosarcoma tends to be less calcified or even to lack matrix calcification; it is associated with bone erosion but not with bone destruction or hyperostosis; and it usually appears avascular at arteriography.

Osteoid-osteoma: intraoperative tetracycline-fluorescence demonstration of the nidus.

Nine patients with a clinical and radiographic diagnosis of osteoid-osteoma received 750 to 4,000 milligrams of tetracycline preoperatively. Immediate examination of the surgically removed specimens under ultraviolet light demonstrated fluorescence of the nidus in all nine patients. Reactive and normal bone did not fluoresce. This simple technique permits quick, easy, economical, and sure verification that the nidus has been excised.

Estrogen receptors in normal salivary gland and salivary gland carcinoma.

To access for possible hormone dependence, 19 samples of normal salivary gland tissue and 14 samples of salivary gland carcinoma were quantitatively analyzed for estrogen receptor (ER) content. A receptor protein content of greater than or equal to 1 fmol/mg of cytosol protein was considered positive. Ten (77%) of 13 histologically normal samples, and four (80%) of five tumor samples obtained from male patients contained ER by this criterion, as did five (83%) of six normal samples and eight (88%) of nine tumor samples obtained from female patients. Mean ER concentrations plus or minus SE in male-derived samples were 2.02 +/- .42 fmol/mg of cytosol protein for normal tissue and 4.35 +/- 1.5 fmol/mg of cytosol protein for tumor tissue; mean ER concentrations in female-derived samples were 3.48 +/- 1.1 fmol/mg of cytosol protein for normal tissue and 12.64 +/- 6.4 fmol/mg of cytosol protein for tumor tissue. Four of eight tumors in women had levels considered to be "hormonally dependent" in breast carcinoma. These findings indicate that salivary gland carcinomas may be hormone-dependent.

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.