[Biosynthesis of serotonin in the peripheral tissues].
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OBJECTIVES: Oat cell carcinoma of the urinary bladder is extremely uncommon. To date, 87 cases have been reported in the literature. Histologically, these tumors are similar to oat cell carcinoma of the lung and in slightly more than half of the cases the tumor is associated with another carcinomatous component: urothelial, squamous carcinoma, adenocarcinoma or, more rarely, sarcomatoid carcinoma. A case of sarcomatoid small cell carcinoma is described herein. METHODS/RESULTS: We report a case of sarcomatoid small cell carcinoma of the urinary bladder in a 79-year-old female patient. The tumor was in the advanced stages and was unamenable to resection. The patient was treated with multi-drug systemic chemotherapy, but she died five months after diagnosis. Light microscopy disclosed a carcinomatous component similar to oat cell carcinoma of the lung that stained with epithelial and neuroendocrine markers. The sarcomatoid component was histologically nondescript and showed extensive immunoreactivity to mesenchymal and epithelial markers. CONCLUSIONS: Sarcomatoid small cell carcinoma of the bladder is rare. To our knowledge, only five cases have been previously reported. It is aggressive, metastasizes early and has a poor diagnosis. Surgical resection with adjuvant multidrug systemic chemotherapy is currently the best available treatment.
The local effect of an implanted foreign body (polyvinyl chloride film) on the growth of transplanted syngeneic sarcoma cells was studied. Two cell lines derived from CBA mouse sarcomas induced by subcutaneously implanted polymer films were used. Small numbers of tumour cells were subcutaneously transplanted to CBA mice in several ways (1) as a suspension into normal tissue (control group); (2) as a suspension into the capsules around previously implanted polymer films; (3) attached to the surface of polymer films, and implanted with these films. The incidence of tumours was significantly increased and the time of their appearance was decreased in groups (2) and (3) as compared with the control group (1). Removal of the film from the capsule 24 h after the transplantation of sarcoma cells did not abolish the stimulation of tumor growth. It is concluded that the local environment of the implanted foreign body promotes the growth of sarcoma cells; similar promoting effects may play some role in the course of foreign body tumorigenesis.
Small numbers of virus-like particles were observed by electron microscopy in each of two cloned lines of 3T3 cells transformed by murine sarcoma virus, even though these lines were free of detectable quantities of infectious leukemia and sarcoma virus. The morphology and occurrence of the particles were identical to those of the murine leukemia-sarcoma group. Moreover, the particles incorporated uridine and had a buoyant density of 1.16 g/ml in sucrose gradients. No evidence of sarcoma or leukemia virus infectivity was associated with the particles in cells of several susceptible species under various conditions, including both cosedimentation with leukemia virus and infection in the presence of inactivated Sendai virus. The particles may represent a form of murine sarcoma virus deficient in one or more of the viral components necessary for infectivity.
Clear cell sarcoma is a rare soft tissue tumour, constituting approximately 1% of all soft tissue sarcomas. Prognosis is reported to be poor due to the great propensity to metastasise regionally and distantly. In this paper, we report the surgical experience of two university hospitals. Both disease-free and overall survival after resection of clear cell sarcoma in this limited study were excellent, which may be explained by relatively small tumour size in seven out of eight patients and adjuvant radiation treatment. The current treatment for clear cell sarcoma is wide local tumour excision, with adjuvant radiation therapy for resection margins of less than 1 mm.
In conclusion, the group of peripheral primitive neuroectodermal tumors has been redefined in recent years on the basis of cytogenetic, molecular genetic and more precisely defined histopathologic characteristics. Although in the past, many tumors has been called Ewing's sarcoma, currently this diagnosis is limited to tumors which cannot be more specifically classified on the basis of their ultrastructural and immunophenotypic characteristics. Most small round cell tumors previously classified as Ewing's sarcoma are now classified as peripheral PNET. The consistent cytogenetic abnormality in Ewing's sarcoma and peripheral PNET and patterns of neurotransmitter enzymes have supported a common neuroectodermal origin. The precise characterization of soft tissue Ewing's sarcoma is further complicated by the several primitive rhabdomyosarcomas that may exhibit a similar light microscopic appearance. The importance of histopathologic distinction among these various round cell tumors of childhood is well recognized. Furthermore, primitive tumors with overlapping neural and mesenchymal features, known as malignant ectomesenchymoma, are now identified more often than previously. Finally, molecular biologic and cytogenetic differences between peripheral PNET and neuroblastoma have confirmed their clinical and biologic differences, in spite of their morphologic similarities. Molecular genetic and flow cytometric evaluation have contributed to the distinction of groups with prognostic significance and offer possibilities for new clinical trials.
BACKGROUND: Paraneoplastic neurological syndromes (PNS) are inflammatory disorders that probably depend on autoimmune processes. Several autoantibodies (anti-Hu, anti-Ri, and anti-Yo) have been characterised in PNS and proved to be helpful in the diagnosis. However, these do not account for all the cases and the possibility that other types of antibodies could be detected was investigated. METHODS AND RESULTS: Of 45 patients with PNS whose serum was probed on paraformaldehyde fixed rat brain sections, 11 patients were identified whose serum samples recognised a cytoplasmic antigen in a subpopulation of glial cells in the white matter of adult rat brainstem, cerebellum, and spinal cord that were double labelled with a monoclonal antibody specific for oligodendrocytes. All serum samples reacted with a 66 kDa protein of newborn rat brain on western blot analysis. These antibodies were designated as anti-CV2 antibodies. Only one of the 11 patients had one of the well characterised autoantibodies (anti-Hu). Five patients had cerebellar degeneration, three had limbic encephalitis, two had encephalomyelitis, and one had Lambert-Eaton myasthenic syndrome. The tumours were small cell lung cancer or undifferentiated mediastinal cancer in seven patients, uterine sarcoma in two, and malignant thymoma in two. Among 1061 control serum samples, only two patients had anti-CV2 antibodies. One had small cell lung cancer and the other malignant thymoma. CONCLUSIONS: The detection of anti-CV2 antibodies in patients with neurological disorders should be considered as an indication of the presence of an occult cancer.
A neuroectodermal tumor of bone (NTB) is a small round cell tumor with Homer Wright rosettes. The differences in the nuclear profiles, proliferating activities, and biologic behavior between NTB and Ewing's sarcoma of bone (ESB) are still controversial. In this study, 11 cases of NTB and 12 cases of ESB were compared by a nuclear morphometrical approach using an image analyzer. In addition, the proliferative activity was also evaluated between the two groups by an immunohistochemical study using proliferating cell nuclear antigen (PCNA). The nuclei of NTB were found to be significantly more elliptical (Form Ell: NTB = 0.725, ESB = 0.743, P = 0.017) and irregular (Form Ar: NTB = 0.908, ESB = 0.933, P = 0.046) than those of ESB. The maximum diameter of the nuclei in NTB was larger than those of ESB (NTB = 6.92 micron, ESB = 6.33 micron, P = 0.017), however, there were no significant differences in the nuclear area between the two groups. Immunohistochemically, the mean PCNA score of the NTB (10 cases) were significantly higher than those of ESB (7 cases) (NTB = 25.9, ESB = 11.6, P = 0.005). The mitotic activities of NTB (17/10HPF) were also higher than ESB (6/10HPF) (P = 0.0008). There were no significant differences between the two groups in survival (log-rank test: P = 0.324) according to our small series. Our results suggest that these two tumors should be separated because their proliferating activity is different and they can be separated by some nuclear profiles.
Malignant soft tissue tumors are classified and named according to cellular differentiation and thus the non-neoplastic soft tissue they imitate. The topical WHO classification already comprises more than 140 entities and tumor subtypes, but the process of defining new tumor variants will go on. Questions of nomenclature are discussed briefly with laying special emphasis on the non-undisputed concept of malignant fibrous histiocytomas. Without doubt, this diagnosis is made too frequently by which it has become to a collective name for unclassifiable pleomorphic sarcomas. For the time being nobody is able to say whether or not the malignant fibrous histiocytoma will remain an entity. Likely, fibrosarcomas and hemangiopericytomas are defined as exclusion diagnosis, as well. The diagnosis of malignant soft tissue tumors is based on recognizing the cellular line of differentiation. This is frequently possible at light microscopic level, sometimes additional diagnostic methods are required. The most important adjunct method is immunohistochemistry. Because aberrant differentiations and unexpected immunohistochemical reactions are known the use of a panel of antibodies is necessary. In the last years soft tissue tumors has increasingly been characterized by molecular biological methods. The results are of significance for understanding sarcoma pathogenesis and may be used for diagnosis, as well. Chromosome translocations are explained and rhabdomyosarcomas are taken as example for demonstrating the diagnostic significance of molecular biological/cytogenetic findings. Molecular biology may also aid in defining the histopathologic features of an entity as shown for intraabdominal desmoplastic small cell tumors. Eventually, heterogeneity in soft tissue sarcomas is addressed and discussed in view of its importance for diagnosis, classification and therapy as well as for development of sarcoma progression.
Pleuropulmonary blastoma (PPB) is an unusual pleural-based blastoma presenting in childhood composed by undifferentiated sarcomatous tissue with divergent differentiation and occasional benign epithelial-lined structures. We are presenting the cytologic features of PPB as diagnosed by fine-needle aspiration cytology (FNAC) of the lower lobe of the right lung in a 4-year-old girl. The smears showed highly malignant cells with hyperchromatic oval or multilobulated pleomorphic nuclei strongly suggesting an aggressive sarcoma. Histology of the aspirated material also revealed small fragments of a myxoid sarcoma with some pleomorphic anaplastic cells. Lobectomy and surgical pathologic investigation confirmed the diagnosis. PPB seems to be another tumor in which accurate diagnosis may be achieved by FNAC.
Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.
Murine sarcoma virus induces foci of morphologically altered cells in BALB/3T3 cultures. Focus formation in mouse cells has been thought to require the presence of a helper, murine leukemia virus, which is present in murine sarcoma virus stocks but by itself does not induce any morphological transformation of mouse cells. The present studies show that early after infection, the titration pattern for murine sarcoma virus in BALB/3T3 cells is "two-hit" since only foci produced by virus spread can be detected. Such foci require the presence of both viruses in the initially infected cell. By seven days the titration pattern is "one-hit" under culture conditions which allow the growth and detection of small foci of transformed cells induced by murine sarcoma virus alone. The "two-hit" titration pattern results from the inability to detect these foci. We conclude that murine sarcoma virus is able to transform mouse cells without requiring murine leukemia virus.
Synovial sarcoma (SS) is a neoplasm that poses diagnostic problems, due to its histologic heterogeneity. The poorly differentiated variant, in particular, may be histologically indistinguishable from other small round cell tumors. Detection of the synovial sarcoma-associated t(X;18) or SYT-SSX fusion transcripts may be necessary to confirm the diagnosis of SS in difficult cases. Most of SS carry a t(X;18) in about one third of cases as the sole cytogenetic abnormality. We evaluated a case of poorly differentiated synovial sarcoma and their derived tumors in nude mice xenografts and cell cultures. We used a panel of antibodies (including those to intermediate filament, nerve-sheath associated markers, and neuronal and neuroectodermal related antigens) to better establish the immunophenotype, supported by the ultrastructural evaluation. The tumor exhibited the distinctive cytogenetic abnormality t(X;18), together with a der(1)t(1;22)(p36;q12). Present results show that this poorly differentiated synovial sarcoma not only expresses conventional biologic and genetical markers for SS but also neuroectodermal features when transplanted into nude mice and cultured in vitro.
Four tumors with the clinical and light microscopic features of Ewing's sarcoma contained cells that possessed to varying degrees ultrastructural features suggestive of neuroblastoma. These neoplasms were considered to be Ewing's sarcoma of bone by radiologic examination and on clinical grounds, and light microscopy was consistent with the diagnosis in every case. It is suggested that the ultrastructural morphology of Ewing's sarcoma is broader than had been supposed and that the presence of dendritic processes in a small cell tumor of bone should not exclude the diagnosis of Ewing's sarcoma.
At the present time there is still a group of soft tissue sarcomas with an unknown origin. These occur most frequently in the extremities and include the following sarcomas: clear cell, alveolar, synovial, epithelioid, chordoid and small round cell. Most of the studies directed to find their histogenesis are based on finding similarities between normal embryonic or mature tissues of the tenosynovial region and these tumors at the ultrastructural and immunohistochemical level searching for specific markers. In this sense, the results are confusing and the common or different cells responsible for these sarcomas have not yet been isolated. In the present hypothesis it is proposed that the common progenitor of these malignancies is an ectomesenchymal derived tissue related to the tendons, aponeuroses, synovia and menisci called chondroid tissue or pseudocartilage; the evolutionary reasons that support this hypothesis are also discussed here. This also emphasizes the possibility that these sarcomas originate in phylogenetic mature remains and not in the reactivation of embryological cellular groups (Cohnheim's theory).
Söderström bodies, also termed lymphoglandular bodies (LGB) and detectable in fine-needle aspiration cytology smears, have long been accepted as indicative of lymphoid tissues. To investigate the validity of this association, we examined 588 cytologic smears from high-grade non-Hodgkin's lymphoma (NHL), carcinoma, and sarcoma. Slides with lymphocytes in the vicinity of carcinoma and sarcoma cells had been excluded. Two independent observers scored smears to number, size, color, form, and smear background of the LGB. In 68 of 359 (19%) nonlymphoid malignancies rare (defined as < 1 LGB per high-power field) or occasional LGB (defined as 1-20 LGB per high-power field) were detectable. Half of these tumors consisted of melanomas, small cell lung carcinomas, and teratomas; the other half encompassed undifferentiated sarcomas. However, none of the smears obtained from carcinoma or sarcoma tissue had abundant LGB (defined as > 20 LGB per high-power field). When number of LGB was estimated to be abundant, the sensitivity for diagnosing a lymphoma was 54%; however, specificity was 100%. The difference in showing LGB between high-grade NHL and carcinoma/sarcoma was highly significant (p = 0.0001). The presence of abundant LGB in cytologic smears strongly suggests the diagnosis of lymphoma, while the absence of LGB nearly excludes this diagnosis. No trends were observed with the other criteria which were tested. LGB in aspiration cytology smears from malignant tumors thus represent a useful tool to distinguish high-grade NHL from carcinoma and sarcoma.
The HBA71 antigen is an M(r) 30,000/32,000 cell surface glycoprotein (p30/32MIC2), encoded by the pseudoautosomal MIC2 gene on chromosomes X and Y, that is expressed in Ewing's sarcomas. Immunohistochemical studies demonstrate a striking specificity for HBA71 among neoplasms of diverse histologic types. In the present study, 43 cases of Ewing's sarcoma of bone were tested for HBA71 expression and six additional immunohistochemical markers regularly used in the differential diagnosis of small round-cell tumors of childhood and adolescence (neuron-specific enolase, vimentin, leukocyte common antigen, cytokeratins, muscle-specific actin, desmin). The study design included (a) random selection of Ewing's sarcoma cases from the files of Memorial Hospital beginning in 1968, (b) blind review of the original histopathologic diagnoses of ES, (c) side-by-side immunohistochemical study of recut histologic specimens, and (d) statistical analysis of immunohistochemical findings in view of clinical outcome. Of the seven antigens studied, only HBA71, neuron-specific enolase and vimentin were expressed in a significant proportion of cases. Forty-one of the 43 cases were HBA71+ (95% sensitivity); of these, 21 were neuron-specific enolase+, 29 were vimentin+, and 15 were both neuron-specific enolase+ and vimentin+. One tumor lacked all antigens, and one was vimentin+ only. Comparison of tumor tissues in five patients obtained before and after cytostatic chemotherapy showed no change in HBA71 expression or in the other antigens tested. Product-limit survival analysis (median disease-free survival was 27.3 months for the study cohort) revealed no significance of neuron-specific enolase or vimentin marker status. These results raise doubts about the usefulness of neuron-specific enolase and vimentin immunohistochemistry to distinguish Ewing's sarcoma from other small round-cell tumors of childhood and adolescence or as prognostic indicators in Ewing's sarcoma. The positive identification of Ewing's sarcoma of bone now becomes a reality using HBA71 immunohistochemistry, either as a sole method or in combination with chromosomal breakpoint analysis. This may result in achieving uniform diagnostic criteria for evaluating the biologic, therapeutic, and prognostic aspects of Ewing's sarcoma and related neoplasms.
To search for the biochemical prerequisites for morphological transformation by p60v-src, we examined the effect of herbimycin A, a potent inhibitor of cell transformation, on chicken embryonic fibroblasts transformed by Rous sarcoma virus. A small dose of herbimycin (0.1-0.3 micrograms ml-1) was enough to convert the cell morphology to a normal phenotype with a concomitant reassembly of microfilament bundles. In the cells treated with the drug, the majority of the substrates for p60v-src remained phosphorylated and p60v-src was myristylated, membrane associated and fairly active as a protein kinase. Under the same conditions, however, the association of p60v-src with the cytoskeletal structure and with phosphatidylinositol 3' kinase was strongly inhibited, suggesting that the interactions of p60v-src with the cellular structure and the enzyme were indispensable for morphological transformation.