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PubMed1998

Small round-cell type of malignant peripheral nerve sheath tumor.

Five cases of primitive, small, round-cell tumor that are a type of hitherto unclassified neurogenic sarcoma are described. The tumors were located deep within the soft tissue of the trunks and limbs without association with major nerves. The histologic features consisted mainly of uniform, small, round, tumor cells with scanty cytoplasm. Foci of uniform, short, spindle-shaped tumor cells arranged in whorl-like patterns were observed in some areas. Although the immunoreactivity for the neural markers, Leu-7 and MIC-2, was not marked, cell processes and fragmentous basal laminae, which are ultrastructural neural features, were found in both spindle-shaped and round tumor cells. In four cases, EWS chimeric transcripts were analyzed by reverse-transcription polymerase chain reaction. EWS chimeric mRNA (EWS-FLI-1, EWS-ERG, EWS-E1AF, EWS-ETV1, EWS-FEV) was not detected in any cases. The tumors were not consistent with peripheral primitive neuroectodermal tumor. We propose them as a small round-cell type of MPNST that might differentiate toward the immature neural cells.

Adolescent↗
PubMed1984

Neuroectodermal tumor and monoclonal antibodies.

Antibody-producing clones were obtained by hybridization of spleen cells from mice immunized with whole cultured human tumor cells and mouse myeloma cells, P3UX59AG8. The tumor cells were derived from a peripheral primitive neuroectodermal tumor. One of the antibodies produced by these clones reacts with the original cell line, SK-PN-DW, and other more differentiated neuroectodermal tumors such as neuroblastomas and melanomas. The cell line SK-PN-DW contains antigenic determinants recognized by monoclonal antibodies raised against melanoma, neuroblastoma, and human fetal brain. These data indicate that this primitive neuroectodermal tumor is derived from the neuroectoderm.

Adolescent↗
PubMed1994

EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations.

We have determined the frequency of EWS fusion transcripts in a series of primary Ewing's sarcomas and peripheral primitive neuroectodermal tumors and cells lines. Type 1 and 2 EWS-Fli1 fusions were demonstrated in 8 cell lines and 14 patient samples. Five patients with cytogenetically characterized rearrangements of chromosome 22 that did not involve chromosome 11 were included in these studies. A novel EWS-Fli1 in-frame isoform fusing EWS to exon 8 of Fli1 was isolated from a tumor with a variant t(12;22;22)(q14;p1;q12) translocation. Three in-frame isoforms of a novel hybrid transcript derived from the fusion of EWS with the ETS domain of the human erg gene were identified in patient samples and a cell line with cytogenetically unidentified or cryptic translocations involving chromosomes 21 and 22. Interphase analysis by fluorescent in situ suppression hybridization using two overlapping erg yeast artificial chromosome clones demonstrated disruption of the erg gene on chromosome 21 in a patient sample with monosomy 22. Our results provide new information about the involvement of EWS in small round cell tumors involving exchange of its putative RNA-binding domain with DNA-binding domains derived from different members of the ETS family of transcription factors. These studies emphasize the utility of reverse transcriptase PCR analysis and fluorescent in situ hybridization as additional diagnostic tools for differential diagnosis among small round cell tumors.

Adolescent↗
PubMed1998

Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation.

EWS/ets-oncogene fusion transcripts can be detected in at least 98% of Ewing tumors [(ET) Ewing sarcoma and peripheral primitive neuroectodermal tumor] by reverse transcriptase-polymerase chain reaction (RT-PCR), thus confirming the histopathologic diagnosis. To detect minimal amounts of tumor cells in the bone marrow (BM), we used an RT-PCR assay with a high sensitivity, revealing one tumor cell in a background of 10(6) normal cells. We examined BM samples from 35 newly diagnosed ET patients (23 with localized and 12 with metastatic disease). At diagnosis, tumor cells in the BM were detected in 7/23 patients with localized disease (30%). Fifty percent of patients with isolated lung metastasis were RT-PCR positive (3/6), whereas 6/6 patients with bone metastases showed positive signals (100%). All patients with initial PCR positivity in the BM became negative during treatment. After a median follow-up of 30 months, relapses were observed in both groups of patients with localized disease (3/7 RT-PCR positive and 2/16 RT-PCR negative). The only recurrence in the group with isolated lung metastases occurred as progressive lung disease in 1 of the 2 RT-PCR-negative patients, whereas among the 6 patients with bone metastases 2 remain in complete remission. So far, RT-PCR screening for BM involvement did not allow prediction of early relapse in ET. To assess better the significance of this test in the evaluation of long-term prognosis and in monitoring the effectiveness of systemic therapy, long observation periods are warranted before it becomes a tool for treatment stratification.

Adolescent↗
PubMedDate not supplied

Molecular genetics in the diagnosis and prognosis of solid pediatric tumors.

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management.

Child↗
PubMed1998

Molecular diagnosis of Ewing tumors: improved detection of EWS-FLI-1 and EWS-ERG chimeric transcripts and rapid determination of exon combinations.

Most Ewing tumors (ET), including Ewing sarcomas, peripheral primitive neuroectodermal tumors (PNET), and Askin's tumors, can be defined according to the specific chromosomal translocations t(11;22)(q24;q12) (EWS-FLI-1) or t(21;22)(q21;q12) (EWS-ERG). Detection of the chimeric RNA transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR) has greatly facilitated the diagnosis of ET. Because of variable chromosomal breakpoint locations, however, the EWS gene fusions with FLI-1 and ERG genes are highly heterogenous, resulting in different sizes of the amplification products. To improve the diagnostic usefulness of the RT-PCR assay, we have developed an assay to detect chimeric mRNA transcripts by nested RT-PCR, followed by digestion of the PCR fragments with three different restriction endonucleases. This allows confirmation of the specificity of the PCR product and provides a rapid method to determine the combination of exons present in a transcript. In the 12 Ewing tumors tested, five different exon combinations were detected. In nine repeat biopsies of four patients, the case-specific translocation remained unchanged. One additional central PNET had no ET-specific translocation. In conclusion, the suggested combination of RT-PCR and restriction analysis of the PCR products allows a rapid and specific determination of ET-specific translocations.

Adolescent↗
PubMed1998

The evolution of the diagnosis and understanding of primitive and embryonic neoplasms in children: living through an epoch.

Approximately 30% of malignant neoplasms in children are dysontogenetic tumors whose pathologic features resemble or recapitulate those of the developing organ or tissue of origin. Archetypes include classic neuroblastoma, Wilms' tumor, and embryonal rhabdomyosarcoma. This review traces the history of the principal types of dysontogenetic neoplasms and the primitive round cell tumors, Ewing's sarcoma, and peripheral primitive neuroectodermal tumor. Retinoblastoma, neuroblastoma, and Wilms' tumor were first described in the 19th century but with several different appellations than those we use today. Although some progress was made in the surgical management of Wilms' tumor during the 1940s and 1950s, most of these unique solid neoplasms of childhood were seen as essentially untreatable and inevitably fatal; surgery and perhaps irradiation were the principal therapeutic offerings. The folic acid analogue, aminopterin, was reported in 1948 as inducing the first complete but temporary remission in acute childhood leukemia. The chemotherapeutic era began shortly thereafter with effective chemotherapy in the management of Wilms' tumor with the introduction of dactinomycin. Pathologists were no longer restricted to being purveyors of the death sentence; they were now responsible for differentiating one type of primitive and embryonic neoplasm from another by using a variety of ancillary techniques, including tissue culture, electron microscopy, immunohistochemistry, and cytogenetics. Favorable or unfavorable morphologic types and subtypes of tumors were defined and, together with the pathologic staging, became incorporated into the therapeutic plan and prognostic assessment. During the past 40 years, these tumors progressed from being virtually treatment resistant to having an overall 5-year survival of 70% or greater. Through the cooperative efforts of pediatric hematologists/oncologists, pediatric surgeons, radiation therapists, and pathologists, the primitive and embryonic neoplasms of childhood are now viewed as some of the most treatable and curable of cancers.

Child↗
PubMed2005

Ewing's sarcoma and primitive neuroectodermal family of tumors.

Ewing's sarcoma (ES) initially was believed to be of perivascular endothelial origin. The Ewing's sarcoma family of tumors (EFT) includes ES of bone (ESB), extraosseous ES (EES), peripheral primitive neuroectodermal tumor of bone (pPNET), and malignant small-cell tumor of the thoracopulmonary region, or Askin's tumor, all of which are now known to be neoplasms of neuroectodermal origin. The degree of neuronal differentiation has been used for histopathologic subclassification of the EFT as classical ES (ESB or EES), which is characterized by minimal evidence of neural differentiation, and pPNET, which displays evidence of neural differentiation by standard microscopy, electron microscopy, or immunohistochemistry. Because the behavior, prognosis, and treatment appear to be similar for all subsets of EFT, this histopathologic subclassification may not be clinically significant, though some debate remains whether neural differentiation predicts for inferior outcome.

Bone Neoplasms↗
PubMed1997

An intra-abdominal small round cell neoplasm with features of primitive neuroectodermal and desmoplastic round cell tumor and a EWS/FLI-1 fusion transcript.

We report an intra-abdominal round cell tumor in a young man which exhibited the light and electron microscopic appearance of a peripheral primitive neuroectodermal tumor (PNET), in addition to the clinical and topographic characteristics, desmoplasia and a complex immunophenotypic profile of the intra-abdominal desmoplastic round cell tumor (DSRCT). Reverse transcription polymerase chain reaction revealed a EWS/FLI-1 fusion transcript as in PNET/Ewing's sarcoma, instead of the EWS/WT1 transcript of DSRCT. The tumor was also strongly positive for the mic2 protein. This is a unique case of a hybrid tumor arising in the peritoneal cavity of a young male. The existence of such a hybrid tumor in this location suggests that DSRCT and PNET may be related and possibly share a common histogenesis.

Abdominal Neoplasms↗
PubMed2002

[Musculoskeletal lymphomas].

Primary lymphomas of bone or skeletal muscle are rare entities. The most frequent among these diseases are primary non-Hodgkin's lymphomas of bone. They account for 3-5% of all bone tumors and 5% of all primary extranodal non-Hodgkin's lymphomas. Primary manifestations of Hodgkin's disease in bone or skeletal muscle are rarities. Primary non-Hodgkin's lymphomas of skeletal muscle are rarities as well. Primary non-Hodgkin's lymphomas of bone can be found in any patient age. A preference exists for the 3.-6. decade of life. The radiographic appearance of these entities resembles other aggressive bone tumors. Their differential diagnosis includes -- depending on the patient's age -- Ewing's sarcoma,malignant fibrous histiocytoma,metastases of small cell tumors and osteomyelitis.Further differential diagnoses are the peripheral primitive neuroectodermal tumor (PNET), osteosarcoma, eosinophilic granuloma and fibrosarcoma. Treatment of primary non-Hodgkin's lymphomas uses combinations of chemotherapy and radiation therapy. Operative treatment is reserved for the treatment of complications. The prognosis of primary non-Hodgkin's lymphomas is reflected by 10-year-survival-rates without recurrence of more than 80% in unifocal manifestations.

Bone Neoplasms↗
PubMed2005

EWS-ETS oncoproteins: the linchpins of Ewing tumors.

Ewing tumors, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumors, are highly aggressive and mostly affect children and adolescents. Their molecular signature is a chromosomal translocation leading to the generation of EWS-ETS (or very rarely FUS-ETS) fusion proteins that are capable of transforming cells. These oncoproteins act as aberrant transcription factors due to the fusion of an ETS DNA binding domain to a highly potent EWS (or FUS) transactivation domain. Accordingly, many EWS-ETS target genes have been identified whose dysregulation could contribute to the development of tumor formation. Furthermore, EWS-ETS oncoproteins may impact on RNA splicing or affect other proteins through disturbing their ability to form functional complexes. The molecular knowledge gained so far from studying EWS-ETS oncoproteins has not only broadened our understanding of Ewing tumors but also improved the diagnosis of these highly undifferentiated tumors. In addition, several potential prognostic markers have been uncovered and novel therapies are suggested that may improve the still dismal survival rate of Ewing tumor patients.

Chromosomes, Human, Pair 16↗
PubMed1999

The Ewing family of tumors and the search for the Achilles' heel.

The ideal cancer therapy would accomodate the specific biology of a tumor and be based upon understanding the mechanisms of malignancy. This vision has been the driving force in cancer research. However, the story of success in clinical cancer management is a story of empirie largely independent from progress in basic research. For the Ewing family of tumors (EFT) comprising Ewing's sarcoma and peripheral primitive neuroectodermal tumor, significant insights into the molecular basis have appeared recently. Some of last year's discoveries may have taken us closer to the identification of the Achilles' heel in this disease. The first clue has been obtained to the mechanism of chromosomal translocation, which constitutes a rate-limiting step in EFT pathogenesis. Also, researchers have progressed in understanding the control of EFT cell proliferation, differentiation, and death. A major role in these processes has been attributed to the EWS-ets gene rearrangement. Specific growth factor circuits appear to be involved in deregulated tumor cell growth. By analogy to heterologous cellular systems, it is possible to postulate an important functional role for CD99(MIC2) as it contributes to the malignant phenotype of EFT. In vitro, as well as the first in vivo, experimental evidence suggests that tumor cell expansion and spread can be counteracted by breaking these physiological pathways. Still, we are far from a tailored biological therapy of EFT. Before this goal may be achieved, we must seek further improvements and diversification of today's standard and intensified treatment regimens.

Animals↗
PubMed2005

Primary Ewing's sarcoma family of tumors arising from the broad ligament.

We report a case of a primary Ewing's sarcoma family of tumors (ESFT) that was an incidental finding in the broad ligament of a 53-year-old woman. ESFT now includes tumors previously described as Askin tumor, neuroepithelioma, extraskeletal Ewing's sarcoma, and peripheral primitive neuroectodermal tumor. This is because of the discovery that all of the above tumors contain a specific gene rearrangement involving chromosome 22q12. On microscopic examination, the tumor was composed of small, round cells with mild nuclear pleomorphism and scant eosinophilic cytoplasm. There were large areas of tumor necrosis and numerous mitoses. Immunohistochemically, there was strong membrane staining for CD99 and weak focal staining for CD56 and neuron specific enolase. Fluorescence in situ hybridization revealed a separation of the breakapart probe on chromosome 22q12 consistent with the presence of a gene rearrangement, supporting the diagnosis of ESFT. We believe the importance of recognizing the existence of a primary ESFT in the broad ligament as some primary tumors of the gynecological tract and of other systems may resemble it histologically. To the best of our knowledge, our case is the second case of extraskeletal Ewings sarcoma arising from the broad ligament but the first case that is confirmed by strong CD99 positivity and supported by fluorescence in situ hybridization.

12E7 Antigen↗
PubMedDate not supplied

Recurrent intrapulmonary malignant small cell tumor of the thoracopulmonary region with metastasis to the oral cavity: review of literature and case report.

Malignant small cell tumor of the thoracopulmonary region (MSCT) was first described in 1979 and has been referred to as the Askin tumor. This malignant neoplasm is a member of the peripheral primitive neuroectodermal tumor (PPNET) family and typically involves the periosteum, soft tissue, and extrapulmonary tissue of the thoracic wall. MSCT may also involve the lung parenchyma by local extension or may arise de novo in peripheral lung tissue. Local recurrence, abdominal involvement by tumor extravasation across the diaphragm, and skeletal metastatic disease are relatively common. However, metastasis to the head and neck region and in particular to the oral cavity is extremely rare. We present a recurrent intrapulmonary MSCT with metastasis to the oral cavity in an adolescent Hispanic boy, and review the literature regarding this member of the PPNET family. Differentiation from neuroblastoma may be made based on immunoreactivity for beta 2 microglobulin and HBA71 and lack of immunoreactivity for chromogranin in PPNET and MSCT. Ultrastructural features commonly seen in MSCT and PPNET are round to ovoid tumor cells with occasional cytoplasmic processes with relatively few pleomorphic dense core granules. These tumors lack the gangliocytic and Schwann cell differentiation that is characteristic of neuroblastoma. MSCT and PPNET have a common reciprocal cytogenetic translocation [t(11;22)q(24;q12)], which is shared with Ewing's sarcoma. Prognosis in MSCT is quite dismal, with a 2-year survival of 38% and a 6-year survival of only 14%.

Adolescent↗
PubMed1980

Peripheral neuroepithelioma: a light and electron microscopic study.

A primitive neuroectodermal tumor of peripheral nerve origin was examined by light and electron microscopy. The lesion arose in association with the S1 nerve root of the lumbosacral plexus in a 22-year-old female. Following a surgical biopsy, the patient received systemic chemotherapy; however, approximately one-and-a-half years later, she suffered a clinical relapse with locally recurrent tumor. An excisional biopsy was performed, and pathologic examination revealed progressive neuroblastic differentiation. The ultrastructural features of neoplastic Homer-Wright rosettes will be illustrated, and the non-specificity of cytoplasmic glycogen in the evaluation of "small round cell neoplasms" will be emphasized.

Adult↗
PubMed1991

Atypical primitive neuroectodermal tumors. Comparative light and electron microscopic and immunohistochemical studies on peripheral neuroepitheliomas and Ewing's sarcomas.

Recently, primitive neuroectodermal tumors (PNETs) have been shown to cover a wide spectrum of small round cell sarcomas, probably including some Ewing's sarcomas (ESs) and extraskeletal Ewing's sarcomas (EESs), in addition to classical peripheral neuroepitheliomas (PNs). In studies of small cell sarcomas, we found a group of undifferentiated tumors resembling PNETs with some features of neuroectodermal differentiation, but possessing areas of relatively large, pleomorphic cells. To clarify the nature of these tumors and their relationship to PNETs, we examined the variety of histological, immunohistochemical and ultrastructural features of 11 small cell sarcomas. Five of these tumors were composed of uniform, small round cells and were classified as PNs because of the presence of definite Homer-Wright rosettes and fibrillary processes. The presence of well developed neurite-like processes containing neurosecretory granules and immunoreactivities for various neural markers suggested that these PNs showed more advanced neuronal differentiation. Two tumors, with the classical features of ES, showed no ultrastructural evidence of neuronal differentiation, although only gamma-gamma neuron-specific enolase (NSE) positivity was detected. Four undifferentiated tumors with atypical features, included in this study as an atypical PNET group, showed certain neuroectodermal characteristics, such as ganglion cell differentiation, perivascular pseudorosettes, and gamma-gamma NSE reactivity. It is concluded from this study that PNETs may include small round cell tumors showing different degrees of neuro-ectodermal differentiation and some histological variations.

Adolescent↗
PubMedDate not supplied

In vitro antiproliferative effects of albumin-doxorubicin conjugates against Ewing's sarcoma and peripheral neuroectodermal tumor cells.

The 3-5 year survival rates of patients with disseminated Ewing's sarcoma (ES) or the closely related peripheral primitive neuroectodermal tumors (PNET) remain low, even under aggressive treatment involving highly toxic multidrug chemotherapeutic regimens. ES and PNET are sensitive to doxorubicin, but may escape treatment by expression of the multidrug-resistant phenotype and/or other mechanisms. In this study, we have identified albumin as growth supporting factor for ES and PNET cells in IGF-I-supplemented serum-free tissue culture medium. To investigate the specificity and toxicity of albumin-based drug conjugates, doxorubicin was coupled to bovine serum albumin (BSA) by either a two step glutaraldehyde or carbodiimide-C4-spacer technique, yielding monomeric DOX-albumin conjugates with conjugation numbers ranging from 3-20 moles DOX/mole BSA. Cellular uptake of fluorescein-isothiocyanate-(FITC)-labeled albumin and DOX-albumin conjugates could be demonstrated by flow cytometric measurements of cell-associated fluorescence and confocal microscopy. The cytostatic activity of these conjugates against ES/PNET cell lines, a neuroblastoma (LAN-1) and prostate cancer carcinoma cell line (PC-3) and normal lymphoblasts was tested in short-term proliferation assays (48 h). The results show a high selectivity of the DOX-albumin conjugates for ES/PNET cell lines, with highest growth inhibition by conjugates with low DOX conjugation numbers (n = 3) in serum-supplemented medium (17-32 fold loss of activity compared to free DOX), followed by 20-DOX-C4-albumin in serum-free medium and low activity of the other conjugates. In conclusion, DOX-albumin conjugates inhibit the growth of ES/PNET cell lines selectively, showing low activity against the unrelated carcinoma line PC-3 and sparing normal lymphoblasts. The inverse correlation of activity and conjugation number demonstrates a low cytotoxic activity of DOX in acid-stable binding to monomeric albumin, pointing to a selective cytostatic activity of the modified albumin against ES and PNET cells, even in the presence of a 100 fold excess of unmodified serum albumin.

Carbodiimides↗
PubMed1995

Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing's sarcoma EWS/FLI1 fusion gene.

Accurate diagnosis of primitive childhood sarcomas continues to be a formidable problem because these malignancies generally demonstrate very little morphological evidence of their tissue of origin. One of these tumor classes, the Ewing's sarcoma family of peripheral primitive neuroectodermal tumors (pPNETs), are thought to have a neural histogenesis based on evidence of neuroectodermal differentiation. Greater than 95% of pPNETs carry t(11;22) or t(21;22) chromosomal translocations which fuse the EWS gene from chromosome 22q12 in-frame with either FLI1 from chromosome 11q24 or ERG from chromosome 21q22. The pPNETs are considered to be histogenetically distinct from rhabdomyosarcomas, myogenic tumors lacking these EWS gene fusions and hypothesized to derive from immature skeletal muscle precursors. In the present study, we describe a unique set of childhood soft tissue sarcomas that show both neural and myogenic differentiation. These biphenotypic tumors express myogenic regulatory factors and muscle-specific antigens and also show neuroectodermal differentiation with ultrastructural evidence of neurosecretory granules and expression of neural-associated genes. Northern analysis and reverse transcriptase PCR reveal expression of EWS/FLI1 gene fusions in all biphenotypic sarcomas analyzed. Chimeric EWS/FLI1 transcripts and fusion proteins in these tumors are identical to those described for pPNETs. Our results provide evidence for a class of biphenotypic childhood sarcomas with myogenic and neural differentiation and suggest that these tumors may be related to the Ewing's sarcoma family of pPNETs.

Adolescent↗