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PubMed1976

Influence of glucocorticoid, estrogen, and androgen hormones on transformation of human cells in vitro by feline sarcoma virus.

Infection of human foreskin cells (D-550) by the Snyder-Theilen strain of feline sarcoma virus produced small but countable foci and demonstrated "single-hit" dose-response kinetics. Significant quantitative and qualitative enhancement of focus formation was observed when the glucocorticoid hormones, dexamethasone, hydrocortisone, cortisol acetate, and prednisolone were added to cell cultures (1.0 mug/ml) 24 hr postinfection. However, aldosterone, while inducing qualitatively larger foci, did not bring about a quantitative enhancement in total foci number. By contrast, 17beta-estradiol, progesterone, cortisone acetate, methyltestosterone, and estrone elicited little or no effect on focus induction by Snyder-Theilen feline sarcoma virus. Evidence is suggestive of a posttranscriptional effect possibly modulating viral genome expression resulting in an increased efficiency of viral transformation, and an increased proliferation of transformed cells.

Aldosterone↗

PubMed2001

Differentiating lymphoblastic lymphoma and Ewing's sarcoma: lymphocyte markers and gene rearrangement.

We encountered a child with an intraosseous small round cell tumor that was negative for LCA, CD20 (L26), and CD3 and positive for vimentin, CD99 (MIC-2), and periodic acid-Schiff. The tumor exhibited rosette-like formations. This case was initially interpreted as Ewing's sarcoma (ES); however, additional studies revealed positivity for CD79a, CD43, and TdT expression, and an immunoglobulin heavy chain gene rearrangement (IgH-R) by polymerase chain reaction (PCR) established this to be a precursor B-lymphoblastic lymphoma. Because the differential diagnosis of ES and lymphoblastic lymphoma can be difficult and the differential diagnostic value of leukocyte antigens and immunoglobulin heavy chain gene rearrangement studies have not been fully evaluated, we conducted a more extensive investigation on 33 (21 soft tissue and 12 intraosseous) ES cases. Cases were retrieved from the files of the Department of Pathology at Georgetown University and from the Soft Tissue Registry of the Armed Forces Institute of Pathology. The cases were studied by light microscopy, immunohistochemistry, and PCR for IgH-R and T cell receptor gamma chain gene rearrangement (Tgamma-R). There were 17 females and 16 males; the mean age was 29.3 years. Locations included the extremities (n = 17) and trunk (n = 16). All cases fit the ES spectrum by light microscopy and immunohistochemistry, as previously determined, and were negative for lymphoid markers (LCA, CD3, CD20, CD43, CD79a, and TdT), CD10 and CD34. CD99 was positive in 31/33 and bcl-2 was weakly positive in 13/33 cases. All 21 cases studied for gene rearrangements by PCR were negative for IgH-R and Tgamma-R. Distinction of intraosseous lymphoblastic lymphoma from ES may be difficult because lymphomas may occasionally exhibit unexpected morphologic and immunophenotypic properties including LCA, CD3 and CD20 negativity and cytokeratin positivity. Additional analysis using CD79a, CD43, TdT, and PCR should be performed to avoid misdiagnosis. True ES is negative for lymphoid markers including CD79a, CD43, and TdT, as well as for IgH-R and Tgamma-R.

12E7 Antigen↗

PubMed1995

New entities, concepts, and questions in childhood tumor pathology.

There are major differences between tumors in children and adults, viz. the incidence of tumor types, the predisposition of certain organs and tissues (e.g. sympathetic nervous tissue, kidney, and soft tissues) to develop tumors, problems related to tumor classification, and the biologic behavior of childhood malignancies, which are usually characterized by high rates of proliferation activity. A large number of new entities, especially in soft tissue tumors, have been published over the past years, including nodular mesothelial hyperplasia, which is a tumor-like lesion derived from peritoneal macrophages; infantile myofibromatosis, which can mimic leiomyosarcoma; intermediate grade fibrohistiocytic tumors, like dermatofibrosarcoma protuberans-related giant-cell fibroblastoma, plexiform fibrohistiocytic tumor and angiomatoid malignant fibrous histiocytoma displaying evidence of myogeneous differentiation; finally, the high-grade intraabdominal desmoplastic small cell tumor. With modern methods we can gain better insights into the biology of tumors. For example, tumors of the Ewing's sarcoma family have in common a characteristic t(11; 22) chromosomal translocation, the Ewing's sarcoma (EWS) (22q12) gene rearrangement, and the MIC2 gene. The EWS gene rearrangement is not restricted to tumors of the Ewing's sarcoma family (classic Ewing's sarcoma and malignant peripheral neuroectodermal tumor), however, but occurs in malignant melanoma of the soft tissue and in intraabdominal desmoplastic small cell tumor. Rhabdomyosarcomas (RMS) can be divided into two basic types with different prognoses: embryonal RMS, including botryoid and spindle-cell variants, and alveolar RMS, including the solid variant. The prognosis of alveolar RMS is poorer than that of classic embryonal RMS, mainly due to early tumor dissemination in alveolar RMS. The prognosis of neuroblastoma is mainly based on chromosomal and molecular biologic findings. Structural chromosome 1 abnormalities, double minute chromosomes, homogeneously staining regions, N-myc amplifications, and DNA diploidy are indications for an unfavorable outcome. Despite progress in childhood solid tumor pathology, many questions remain open, including those relating to basic chromosomal defects in germ cell tumors and the obscure nature of tumor heterogeneity.

Child, Preschool↗

PubMed1998

Detection of the MyoD1 transcript in rhabdomyosarcoma cell lines and tumor samples by reverse transcription polymerase chain reaction.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Diagnosis of RMS can be difficult when it appears as a small round-cell tumor without evidence of differentiation. Recently, a set of regulatory proteins expressed during skeletal muscle development has been described. Among them, MyoD1 has been detected by Northern blot and immunohistochemical analyses in normal skeletal muscle and RMS. Given the relevance of this marker in the diagnosis of RMS, we developed an assay to evaluate the expression of MyoD1 mRNA in small tissue specimens by reverse transcription polymerase chain reaction. Specificity and sensitivity of the assay was determined in a series of 25 tumor cell lines and 39 pediatric tumor samples, including 35 RMSs. Subsequently, we studied the expression of MyoD1 in bone marrow and peripheral blood stem cell specimens. We detected the MyoD1 transcript in normal skeletal muscle and in almost all RMSs, whereas no expression was found in non-RMS samples or in normal hematopoietic tissues. This assay showed high sensitivity and specificity, and it could be a useful molecular tool for the diagnosis of RMS within small roundcell tumors of childhood and for the detection of minimal bone marrow and peripheral blood stem cell involvement in children with RMS, regardless of the histological subtype.

Bone Marrow↗

PubMed1987

Expression of c-src in cultured human neuroblastoma and small-cell lung carcinoma cell lines correlates with neurocrine differentiation.

Human cell lines with neuronal and neuroendocrine features were examined for their expression of pp60c-src, the cellular homolog of the transforming gene product pp60v-src of Rous sarcoma virus. Four neuroblastoma (LA-N-5, SH-SY5Y, Paju, and SK-N-MC) and three small-cell lung carcinoma (U-2020, U-1690, and U-1285) cell lines were selected on the basis of their stage of neurocrine differentiation, as determined by the expression of neuron-specific enolase. In an immune complex protein kinase assay, all seven cell lines displayed c-src kinase activity which was considerably higher than that found in nonneurocrine cells (human diploid fibroblasts, glioma, and non-small cell lung carcinoma cell lines). Furthermore, the c-src kinase activity, as determined by autophosphorylation or phosphorylation of an exogenous substrate, enolase, correlated with the stage of neurocrine differentiation. There was an approximately 30-fold difference in c-src kinase autophosphorylation activity between the cell lines representing the highest and lowest stages of neurocrine differentiation. A similar variation was found in the steady-state levels of the c-src protein of these cell lines. Highly differentiated neuroblastoma cells expressed two forms of the src protein. Digestion by Staphylococcus aureus V8 protease did reveal structural diversity in the amino-terminal ends of these c-src molecules. In summary, we found a clear correlation between c-src kinase activity and the stage of neuronal and neuroendocrine differentiation. Thus, the phenotypic similarity between neurons and neuroendocrine cells includes high c-src expression.

Carcinoma, Small Cell↗

PubMed1996

Immunostaining of the p30/32MIC2 antigen and molecular detection of EWS rearrangements for the diagnosis of Ewing's sarcoma and peripheral neuroectodermal tumor.

The identification of Ewing's sarcoma (ES) and peripheral neuroectodermal tumor (PNET) among other small round cell tumors (SRCTs) is a critical issue in musculoskeletal pathology because of the lack of clearly distinctive morphological features. In this study, the authors have compared advantages and limits of two procedures that were recently suggested as additional tools for the identification of ES/PNET, the analysis of p30/32MIC2 antigen by immunohistochemistry, and the evaluation of the fusion products of two specific chromosomal aberrations, the t(11;22)(q24;q12) and the t(21;22)(q22;q12), by reverse transcriptase-polymerase chain reaction (RT-PCR). The authors have analyzed the expression of p30/32MIC2 in 28 cell lines and in 90 tumor samples. p30/32MIC2 was highly expressed in ES/PNET but was also present in all the other cell types. The broad spectrum of positivity for p30/32MIC2 in SRCTs of bone was substantially confirmed by the analysis of tissue samples. In the same material, the authors have evaluated the presence of t(11;22) or t(21;22) transcripts (EWS/FLI-1 and EWS/ERG, respectively) by RT-PCR. These transcripts were found in all the cell lines and tissue samples of ES/PNET, but not in other tumors. The authors' results question the use of p30/32MIC2 immunostaining alone for the identification of ES/PNET and suggest the adoption of RT-PCR as an advantageous alternative. Molecular diagnosis of ES/PNET by RT-PCR is highly specific and can be applied to small amounts of tissue. Moreover, RNA extracted from paraffin-embedded specimens was shown to be suitable for RT-PCR analysis, thus enabling analysis of archival material.

Adolescent↗

PubMed2005

Cytokeratin-positive meningeal peripheral PNET/Ewing's sarcoma of the cervical spinal cord: diagnostic value of genetic analysis.

Peripheral primitive neuroectodermal tumor (PNET)/Ewing's sarcoma (ES) of the central nervous system is extremely rare and should be differentiated from central PNET and other small blue round cell tumors. We describe a case of a meningeal peripheral PNET/ES of the spinal cord in an 11-year-old boy. Immunohistochemically, the small blue round cell tumor showed expression of epithelial markers and of CD99, thus posing an important differential diagnostic problem with a poorly differentiated synovial sarcoma. Fluorescence in situ hybridization revealed rearrangement of the EWS gene, as seen in peripheral PNET/ES. Peripheral PNET/ES does occur in the central nervous system, but its diagnosis can be extremely difficult on morphologic and immunohistochemical grounds alone. Genetic analysis plays a key role in its distinction from other small blue round cell tumors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Does malignant small round cell tumor of the thoracopulmonary region (Askin tumor) constitute a clinicopathologic entity? An analysis of 30 cases with immunohistochemical and electron-microscopic support treated at the Institute Gustave Roussy.

The morphology and clinical outcome of 30 patients with malignant small round cell tumors located in the thoracopulmonary region (Askin tumor) are reported. Histologically, all tumors had similar patterns, with small round-to-oval cells and a lobulated stroma. Immunohistochemical analysis always resulted in positive staining for one or several neural markers. No significant differences were found compared with the immunomarkers in 26 typical Ewing's sarcomas located outside the thoracic wall. In three specimens, electron microscopy confirmed the presence of membrane-bound neurosecretory granules. It was confirmed that there is a remarkable similarity among all malignant small round cell tumors, including Askin tumor and Ewing's sarcoma. Overall survival was poor with a 2-year rate of 38% and a 6-year rate of 14%.

Adolescent↗

PubMed2001

Neuroectodermal and neuroendocrine tumors principally seen in children.

Neuroectodermal tumors comprise a large proportion of childhood neoplasms. Neuroblastic tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, are the most frequent extracranial solid cancers of childhood, occurring primarily in infants and toddlers. Primitive neuroectodermal tumors, including Ewing sarcoma and peripheral neuroepitheliomas, occur most frequently in older children and adolescents, and as pediatric sarcomas are second in frequency only to rhabdomyosarcomas. Rarer neuroectodermal tumors include desmoplastic small cell tumors, esthesioneuroblastomas, and melanotic neuroectodermal tumors, the first two entities occurring as rather site-specific lesions in the abdomen and nose, respectively. Diagnosis can be difficult due to the undifferentiated nature of many of these cancers, but ancillary studies, including electron microscopy, immunohistochemistry, cytogenetics, and molecular genetics, enhance their recognition. The molecular nature of childhood neuroectodermal tumors is as diverse as their histology, ranging from the fusion genes characterizing the Ewing sarcoma family of tumors to the proto-oncogene amplification seen in aggressive neuroblastomas.

Adolescent↗

PubMed1987

Nucleolar organizer regions in small cell tumours of childhood.

A silver colloid technique for nucleolar organizer regions (AgNORs) was applied to paraffin sections of 50 small cell tumours of childhood. These comprised 20 neuroblastomas, 10 Ewing's sarcoma, and 20 rhabdomyosarcomas, including spindle cell, myxoid, and round cell variants. On the basis of the number of AgNORs, one could differentiate between the three groups. The differences observed were statistically significant (P = 0.01-0.001). The subtypes of rhabdomyosarcoma could not be distinguished from one another on the basis of AgNOR counts. We suggest that this simple histochemical technique may be a useful adjunct to the range of special techniques now available to assist the pathologist in the diagnosis of small round cell tumours.

Adrenal Gland Neoplasms↗

PubMed1995

Docetaxel.

PURPOSE: We reviewed the preclinical and clinical profiles of the antineoplastic taxoid docetaxel (Taxotere, Rhône-Poulenc Rorer, Collegeville, PA). DESIGN: From the literature and manufacturer's data, we detail docetaxel's activity, tolerability, and pharmacokinetics in preclinical and phase I studies and its activity and side effects in phase II trials in various neoplasms. RESULTS: Docetaxel promotes the assembly of and stabilizes microtubules, preventing their depolymerization. In phase I studies in patients with solid tumors refractory to standard chemotherapy, docetaxel's major dose-limiting toxicity (DLT) was dose- but not schedule-dependent neutropenia; another major side effect was schedule-dependent grade 3 mucositis. Other, generally less severe effects included hypersensitivity reactions (HSRs), neurotoxicities, cutaneous reactions, alopecia, and asthenia. Responses were observed in breast, bronchial, and ovarian carcinomas. The recommended dose for phase II studies was 100 mg/m2 as a 1-hour intravenous (i.v.) infusion every 3 weeks. Preliminary phase II results confirmed docetaxel's activity against breast, non-small-cell and small-cell lung, ovarian, head and neck, and gastric cancers; melanoma; and soft tissue sarcomas. Neutropenia again was the principal dose-limiting side effect. Nonhematologic effects, usually grade 1 or 2, including HSRs, were common. HSRs were manageable with premedication. Corticosteroid premedication partially alleviated fluid retention seen after repeated docetaxel courses. Studies are evaluating docetaxel in various combination regimens in advanced breast cancer, non-small-cell lung cancer, and other solid tumors. CONCLUSION: Multicenter and single-institution studies have demonstrated docetaxel's consistent significant activity in various cancers. Phase III and combination therapy trials are ongoing. Work is in progress to understand and prevent/resolve some of this drug's side effects.

Adult↗

PubMed1977

Polyhistioma: a malignant tumor of bone and extraskeletal tissues.

Polyhistioma, a neoplasm whose basic cells are small and round like those of Ewing's sarcoma, but which differentiate into various mesenchymal structures, most often bone, is described. Those cases that produce cartilage have been called mesenchymal chondrosarcoma; the others therefore are mostly urecognized. The name "polyhistioma" is suggested in the hope that with this terminology more of these tumors will be diagnosed. Polyhistiomas are not excessively rare; they affect bone and soft tissue. Half the patients with polyhistiomas died within 2 years. Treatment has resulted in survival of over 20 years. Thirty-eight of the 144 patients with polyhistioma have survived 5 years or more following first definitive treatment. Thirty-seven cases of the disease are presented.

Adolescent↗

PubMedDate not supplied

Electron microscopy in the diagnosis of head and neck tumors.

Six patients with malignant head and neck tumors are shown to have required electron microscopy for accurate diagnosis. In all of these tumors, there were ultrastructural features of cytodifferentiation that were not discernible by light microscopy, such as neurosecretory granules, desmosomes, cytoplasmic processes, tonofibrils, and myofilaments. Electron microscopy is helpful in the differential diagnosis of tumors in general, but its effectiveness is particularly apparent in small-cell "undifferentiated" tumors such as neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, undifferentiated squamous-cell carcinoma of the lymphoepithelioma type, and malignant lymphoma. It has also been helpful in the identification of amelanotic melanoma and spindle-cell carcinoma.

Adult↗

PubMed1986

Pharmacokinetics of high-dose melphalan in children and adults.

Melphalan pharmacokinetics were studied in 20 children with stage IV neuroblastomas or Ewing's sarcomas and in 10 adults with AML, ALL, or small cell lung carcinomas, after IV administration of high doses (140 mg/m2 with furosemide-induced diuresis and 180 mg/m2 without induced diuresis) and high fluid intake (3000 ml/m2/day). Unchanged melphalan was assayed in plasma and cerebrospinal fluid by means of a high-performance liquid chromatographic procedure. The elimination half-life (t1/2 less than 80 min) allows autologous bone marrow transplantation 24 h after the drug administration. In some children we were able to detect melphalan in cerebrospinal fluid samples.

Adolescent↗

PubMed2005

Development and characterization of a novel Cremophor EL free liposome-based paclitaxel (LEP-ETU) formulation.

Taxol is a marketed product for the treatment of ovarian, breast, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma. It is thus far one of the most effective anticancer drugs available on the market. However, paclitaxel is only sparingly soluble in water and therefore, intravenous administration depends on the use of the non-ionic surfactant Cremophor EL (polyethoxylated castor oil) to achieve a clinically relevant concentrated solution. Unfortunately, Cremophor EL increases toxicity and leads to hypersensitivity reactions in certain individuals. We have developed a well characterized novel lyophilized liposome-based paclitaxel (LEP-ETU) formulation that is sterile, stable and easy-to-use. The mean particle size of the liposomes is about 150 nm before and after lyophilization, and the drug entrapment efficiency is greater than 90%. Stability data indicated that the lyophilized LEP-ETU was physically and chemically stable for at least 12 months at 2-8 and 25 degrees C. Moreover, the formulation can be diluted to about 0.25mg/ml without drug precipitation or change in particle size. In vitro drug release study in phosphate-buffered saline (PBS, pH 7.4) showed that less than 6% of the entrapped paclitaxel was released after 120 h, indicating that the drug is highly stable in an entrapped form at physiologic temperature.

Chemistry, Pharmaceutical↗

PubMed1985

Leukocyte common antigen--a diagnostic discriminant between hematopoietic and nonhematopoietic neoplasms in paraffin sections using monoclonal antibodies: correlation with immunologic studies and ultrastructural localization.

Immunohistochemical localization of human leukocyte common antigen (LCA), a major membrane glycoprotein restricted to leukocytes, was evaluated in paraffin sections of a wide variety of hematopoietic and nonhematopoietic tissues (294 specimens) with monoclonal antibodies (PD7/26 and 2B11). In nonneoplastic tissues, LCA was identified on B and T lymphocytes, with variable immunoreactivities for plasma cells and histiocytes. By light microscopy and ultrastructurally, LCA was localized predominantly to the cell membrane and was also present focally in the cytoplasm. Myeloid cells at all stages of maturation were non-reactive, as were erythroid cells, megakaryocytes, and all non-hematopoietic tissues. Monocytes and mast cells, however, revealed membrane staining for LCA. In nearly all non-Hodgkin's lymphomas of the B- and T-cell types (74 of 80; 93 per cent), the lymphoid infiltrate was immunoreactive for LCA. In specimens from patients with Hodgkin's disease (nodular sclerosis and mixed cellularity type), rare Reed-Sternberg cells stained for LCA. Neoplastic cells were consistently immunoreactive for LCA in specimens from patients with chronic lymphocytic leukemia of the B- or T-cell type, prolymphocyte leukemia, and hairy cell leukemia. However, tissues from only three of eight cases of acute lymphoblastic leukemia were LCA-positive, with most non-reactive specimens exhibiting CALLA (J5) positivity. In cases of multiple myeloma, only minor populations of plasmacytic cells exhibited membrane staining for LCA. Nonhematopoietic neoplasms (102 evaluated), including small cell anaplastic carcinomas, amelanotic melanomas, alveolar rhabdomyosarcomas, Ewing's sarcoma, and germ cell tumors, were uniformly non-reactive. Human LCA represents an excellent cell marker for paraffin sections, to distinguish hematopoietic neoplasms, particularly of the lymphoid type, from poorly differentiated tumors of epithelial, mesenchymal, or neural derivation.

Antibodies, Monoclonal↗

PubMed1986

Use of a monoclonal antibody (B72.3) as a novel immunohistochemical adjunct for the diagnosis of carcinomas in fine needle aspiration biopsy specimens.

Monoclonal antibody B72.3 has been shown to be reactive with a high-molecular-weight glycoprotein complex termed TAG(tumor-associated glycoprotein)-72. By the avidin-biotin immunoperoxidase method, fine needle aspirates and corresponding surgically excised tumor tissues from both malignant and benign tissues were analyzed for TAG-72 expression. Staining (range, 1 to 100 per cent of tumor cells) with monoclonal antibody B72.3 was observed in needle aspirates from 18 of 18 adenocarcinomas and adenosquamous carcinomas of the lung, 17 of 21 adenocarcinomas of the breast, and six of six adenocarcinomas of the colon, as well as adenocarcinomas from other body sites. In contrast, small cell carcinomas of the lung, malignant melanomas, lymphomas, and sarcomas did not stain with the antibody. Benign lesions from the breast, lung, pancreas, parotid, and thyroid also failed to stain. In 66 patients, tumor-bearing tissue had also been resected and was available for comparative examination with monoclonal antibody B72.3. In 62 of these 66 patients, the staining patterns in the aspirates were found to be predictive of the patterns of antibody reactivity in the comparable surgically resected tissues. From these studies it is concluded that monoclonal antibody B72.3 defines a tumor-associated antigen that is expressed in neoplastic cells but not in benign cells and is most selectively expressed in adenocarcinomas. This monoclonal antibody may be used as a novel adjunct for the diagnosis of carcinoma in fine needle aspiration biopsy specimens.

Antibodies, Monoclonal↗

PubMed1993

Carcinosarcoma of the prostate.

A unique case of carcinosarcoma of the prostate occurring in a 32 year old man is presented. This is the youngest case reported to date among nine well-documented examples. The patient underwent a total prostatectomy under the diagnosis of prostatic sarcoma. Despite adjuvant chemotherapy and full-dose radiotherapy being undertaken, the patient died from multiple lung metastases about 8 months after the operation. The surgically resected primary tumor was composed of two histologically distinct elements, these being an undifferentiated carcinoma and a sarcoma with various mesodermal components. These elements were intimately intermingled and transitional forms were often noticed. The sarcomatous portion contained myxoid areas, spindle cell sarcomas with nuclear palisading, areas of osteoid formation and small islands of chondromatous differentiation. The pathogenesis of this complex neoplasm is discussed, and it is suggested that vestigial embryologic Müllerian mesodermal tissue may be capable of diverse differentiation.

Adult↗