Creatine kinase subunits M and B as markers in the diagnosis of poorly differentiated rhabdomyosarcomas in children

Antibodies against the M and B subunits of creatine kinase were assessed for their usefulness in the diagnosis of poorly differentiated rhabdomyosarcoma. Routinely processed formaldehyde-fixed tissue and the avidin-biotin-peroxidase complex technique were used. The majority of the poorly differentiated and all of the moderately and well-differentiated rhabdomyosarcomas studied showed immunostaining for the M subunit. The rhabdomyoblastic component of malignant "triton" tumors was also positive. Staining, although weak compared with that of the rhabdomyosarcomas, was also observed in a few leiomyosarcomas, hemangioendotheliosarcomas, malignant fibrous histiocytomas, and ganglioneuroblastomas. On the other hand, staining for the B subunit was seen in many types of soft tissue tumors, including rhabdomyosarcoma, Ewing's sarcoma, and (ganglio)neuroblastoma. The results indicate that creatine kinase subunit M is a useful marker for distinguishing poorly differentiated rhabdomyosarcoma from other types of small round cell tumors in children, such as neuroblastoma, Ewing's sarcoma, and malignant lymphoma.     

Immunohistochemical study of alveolar and embryonal rhabdomyosarcoma

Paraffin-embedded sections of 11 alveolar and 12 embryonal rhabdomyosarcomas, 12 lymphomas, five neuroblastomas, five extraskeletal neoplasms resembling Ewing's sarcoma, and six epithelial tumors were tested for immunoreactivity against myosin, myoglobin, and isozymes BB and MM of creatine kinase with a peroxidase-antiperoxidase method. Of the 23 cases of rhabdomyosarcomas 17 were positive for at least three of the antigenic determinants. In contrast, the other investigated tumors were consistently negative for all markers, with the exception of breast and prostatic carcinomas. Our results establish that the presence of three or four of the above markers in a tumor is strongly suggestive of a rhabdomyosarcoma and helpful in the distinction of alveolar and embryonal rhabdomyosarcomas from lymphomas, neuroblastomas, and extraskeletal neoplasms resembling Ewing's sarcoma.     

Bone marrow involvement at presentation in pediatric non-haematological small round cell tumours

Pediatric small round cell tumors (SRCT) are a group of neoplasms occurring in children, which have in common a cytomorphology of groups of small round cells with scanty cytoplasm. The common SRCT encountered are neuroblastoma, retinoblastoma, Ewing's sarcoma/peripheral neuroectodermal tumor (PNET), rhabdomyosarcoma and lymphoma which show varying degrees of bone marrow involvement and bone marrow evaluation forms a part of the initial staging procedure. This study was undertaken to evaluate marrow involvement at presentation in pediatric non hematological SRCT. 7833 bone marrow aspirates done over a period of three years in different malignancies were analysed and of these 180 aspirates were performed in patients of pediatric non hematological SRCT at presentation. These cases were evaluated in detail for incidence of marrow involvement. Thirty two (17.7%) cases showed marrow involvement and these cases have been analysed with respect to the primary tumor. The SRCT showing involvement of bone marrow included neuroblastoma (48.8%), retinoblastoma (11.1%), Ewing's sarcoma/PNET (8.6%) and rhabdomyosarcoma (3.2%).These findings are discussed in the light of available world literature.     

Role of immunocytochemistry and DNA flow cytometry in the fine-needle aspiration diagnosis of malignant small round-cell tumors

In the present study, DNA flow cytometry (FCM) and immunocytochemistry (ICC) with a selected panel of antibodies were performed on 51 cases of malignant tumors which were referred for fine-needle aspiration biopsy (FNAB) to our Department of Cytology for the last 2 yr. Twelve cases were diagnosed as neuroblastoma, 16 as Ewing's sarcoma, 2 as retinoblastoma, 5 as non-Hodgkin's lymphoma (NHL), 5 as rhabdomyosarcoma, 2 as peripheral neuroectodermal tumors (PNETs), and 8 as Wilms' tumor. Eleven of 12 neuroblastomas were diploid by FCM, and 1 was aneuploid, with an S-phase fraction (SPF) of 8.3%. Neuron-specific enolase (NSE) was negative in 3 and positive in 8 cases of neuroblastoma, whereas neuroblastoma marker was positive in 3/11. Sixteen of 17 Ewing's sarcomas were diploid, and 1 showed tetraploid aneuploidy, with an SPF of 10.06%. Eight of 13 Ewing's sarcomas were positive for Mic-2 gene product (Ewing's marker). All 5 NHL were positive for leukocyte-common antigen (LCA). Three of 5 rhabdomyosarcomas were diploid, and 2 cases showed aneuploidy. Rhabdomyosarcoma showed muscle-specific actin positivity in 4 and desmin positivity in 3 cases. All 3 cases of PNET were diploid and positive for the Mic-2 gene product, whereas NSE and vimentin were positive in 2 cases. Both cases of retinoblastoma were diploid. Immunostaining was noncontributory in 1 case, and the other showed positivity for the retinoblastoma gene product, NSE, and chromogranin. Seven of 8 Wilms' tumors were diploid, and 1 showed aneuploid, with an SPF of 11.13%. Seven of 8 Wilms' tumors were positive for cytokeratin (CK), 5 were positive for NSE, 6 were positive for epithelial membrane antigen (EMA), and 5 were positive for vimentin. FNAB diagnosis of malignant round-cell tumors is difficult only by light microscopy. Due to the availability of specific markers for subgrouping tumors, ICC has proved to be more useful these days, while DNA FCM has little diagnostic value, as most of them are diploid. Further ancillary studies, e.g., electron microscopy, image analysis, and other molecular investigations, are required to further categorize these tumors more precisely for better clinical management of these cases.     

Congenital alveolar rhabdomyosarcoma with multiple skin metastases. Report of a case

A rare case of congenital alveolar rhabdomyosarcoma revealing multiple skin metastases in a female neonate is reported. At birth, a ping-pong ball-sized tumor on the neck and a tumor the size of a little finger end on the chin were noticed. Then, multiple skin tumors over the whole body occurred soon after birth. A biopsied small skin tumor was at first interpreted as being compatible with metastatic congenital neuroblastoma. However, immunohistochemical and electron microscopic findings revealed positive immunoreactivity for myoglobin in a few tumor cells and the presence of a few rhabdomyoblasts among poorly differentiated tumor cells, resulting in a final diagnosis of alveolar rhabdomyosarcoma. Therefore, it should be emphasized that in cases of round cell tumor, immunohistochemical and ultrastructural studies are imperative in order to identify the tumor and differentiate it from other forms, including rhabdomyoblastoma, neuroblastoma, Ewing's sarcoma, malignant lymphoma, and small cell carcinoma.     

CONGENITAL ALVEOLAR RHABDOMYOSARCOMA WITH MULTIPLE SKIN METASTASES: Report of a Case

A rare case of congenital alveolar rhabdomyosarcoma revealing multiple skin metastases in a female neonate is reported. At birth, a ping-pong ball-sized tumor on the neck and a tumor the size of a little finger end on the chin were noticed. Then, multiple skin tumors over the whole body occurred soon after birth. A biopsied small skin tumor was at first interpreted as being compatible with metastatic congenital neuroblastoma. However, immunohisto-chemical and electron microscopic findings revealed positive immunoreactivity for myoglobin in a few tumor cells and the presence of a few rhabdomyoblasts among poorly differentiated tumor cells, resulting in a final diagnosis of alveolar rhabdomyosarcoma. Therefore, it should be emphasized that in cases of round cell tumor, immunohistochemical and ultrastructural studies are imperative in order to identify the tumor and differentiate it from other forms, including rhabdomyoblastoma, neuroblastoma, Ewing's sarcoma, malignant lymphoma, and small cell carcinoma. ACTA PATHOL JPN 38: 241–248, 1988.     

Expression of myogenic regulatory proteins (myogenin and MyoD1) in small blue round cell tumors of childhood.

The distinction of rhabdomyosarcoma (RMS) from other small blue round cell tumors of childhood, such as Ewing's sarcoma/peripheral primitive neuroectodermal tumor (pPNET) and neuroblastoma, continues to present a diagnostic challenge to pathologists. The recent recognition of the master role of myogenic regulatory proteins in skeletal muscle commitment and differentiation, and the availability of monoclonal antibodies to two of them (myogenin and MyoD1), has prompted us to test their diagnostic utility in routinely processed, formalin-fixed, and deparaffinized tissue. Preliminary studies had demonstrated that, with the use of heat-induced epitope retrieval techniques, expression of myogenin and MyoD1 could be documented specifically in nuclei of fetal skeletal muscle by the respective antibodies. We performed a retrospective immunohistochemical analysis on 72 cases of small blue round cell tumors, including 33 RMSs, 1 metastatic myogenous Wilms' tumor, 26 Ewing's sarcomas/pPNETs, and 12 neuroblastomas. Nuclear expression of myogenin and MyoD1 were both found in 30/33 non-overlapping cases of RMS, with no significant differences in the sensitivity with respect to histological subtypes, and in 1/1 case of myogenous Wilms' tumor. None of the neuroblastomas or Ewing's sarcomas/pPNETs demonstrated positive nuclear staining with either antibody. However, most of the neuroblastomas, and occasional Ewing's sarcomas/pPNETs, showed variable fibrillary, cytoplasmic immunoreactivity with antibody to MyoD1. We conclude that, with the use of microwave-based epitope retrieval, antibodies to myogenin and MyoD1 are both useful markers for the identification of RMS among other small blue round cell tumors of childhood, but antibodies to myogenin have technical advantages over those to MyoD1, as the latter may cross-react with an unknown cytoplasmic antigen in non-muscle cells and tumors.     

Immunohistochemical analysis of Ewing''s sarcoma cell surface antigen p30/32MIC2.

Monoclonal antibody (MAb) HBA71, which was raised against Ewing's sarcoma cells, recognizes a cell-surface glycoprotein, p30/32MIC2, that is encoded by the MIC2 gene in the pseudoautosomal region of human chromosomes X and Y. This immunohistochemical study evaluates the specificity and sensitivity of MAb HBA71 for tumor diagnosis. Frozen and paraffin-embedded tissues of more than 300 tumors of diverse histologic type, including more than 100 small round cell tumors of childhood and adolescence, were tested with this MAb by the avidin-biotin immunoperoxidase procedure. The authors found HBA71 immunoreactivity in 61 of 63 Ewing's sarcomas studied and 9 of 11 primitive neuroectodermal tumors and peripheral neuroepitheliomas. HBA71-negative tumors included neuroblastomas (0 of 24), melanomas (0 of 13), an esthesioneuroblastoma, small cell osteosarcomas (0 of 2), a malignant ectomesenchymoma, desmoplastic SRCT (0 of 5), and medulloblastomas (0 of 5). Heterogeneous expression of HBA71 immunostaining was found in some embryonal rhabdomyosarcomas (3 of 14) and astrocytomas (4 of 7), and in a few neuroendocrine tumors (4 of 26), carcinomas (3 of 94), and lymphomas (6 of 30). Because Ewing's sarcomas are consistently HBA71 positive, the authors searched for antigen-positive normal cells that may represent precursors for these tumors; however, no obvious candidate for the elusive cell of origin for Ewing's sarcoma was identified in the normal fetal tissues tested. Their findings indicate that HBA71 is a highly restricted cell-surface antigen of Ewing's sarcomas and primitive neuroectodermal tumors, and immunohistochemistry employing this antibody may be of value in the differential diagnosis of selected small round cell tumors in childhood and adolescence.     

Fine-needle aspiration biopsy of pediatric neoplasms: correlation between electron microscopy and immunocytochemistry in diagnosis and classification.

A series of fine-needle aspiration biopsies performed in 635 children were reviewed. The diagnoses rendered in these patients included malignant lymphoma in 139 (21.9%); Hodgkin's disease, 25 (3.9%); neuroblastoma, 58 (9.1%); Wilms' Tumor, 37 (5.8%); Ewing's sarcoma, 32 (5.0%); rhabdomyosarcoma, 25 (3.9%); retinoblastoma, 22 (3.5%); leukemia infiltrate, 33 (5.2%); and miscellaneous tumors, 52 (8.2%). In 171 patients (26.9%), the biopsy was nondiagnostic. The cytomorphological characteristics of these lesions are briefly described and illustrated. Salient morphological features are further correlated with histological and ultrastructural appearances. Immunocytochemical patterns of these tumors are also discussed briefly.     

Pleomorphic rhabdomyosarcoma in adults: immunohistochemistry as a tool for its diagnosis

Pleomorphic rhabdomyosarcoma in adults over 30 years of age was a diagnosis frequently made in the 1960s and 1970s. Since the general acceptance of malignant fibrous histiocytoma (MFH) as a tumor entity at the end of the 1970s, however, it has become a very rare tumor in adults. Therefore, 21 cases originally diagnosed on the basis of histology and clinical data as pleomorphic rhabdomyosarcoma in the 1960s and 1970s were reexamined immunohistochemically. Other types of pleomorphic sarcomas involved in the differential diagnosis were also studied. Specific antibodies against vimentin, desmin, creatine kinase subunit M, skeletal muscle actin and myosin, and myoglobin, and the avidin-biotin-peroxidase complex technique were used. The immunohistochemical findings indicate that rhabdomyosarcoma occurs only rarely in adults over 30 years of age and that the majority of the tumors have to be reclassified as MFH or leiomyosarcoma. On the other hand, several pleomorphic sarcomas were found to be diagnosed incorrectly as MFH or liposarcoma by routine histologic stains and electron microscopy. The revised diagnosis was pleomorphic rhabdomyosarcoma for one case and pleomorphic leiomyosarcoma for the other cases. Thus, this study clearly shows the usefulness of immunohistochemistry as a technique in the diagnosis of pleomorphic sarcomas in adults.     

Cytogenetic characterization of selected small round cell tumors of childhood

Small, round, blue-cell tumors (SRCT), including rhabdomyosarcoma, Ewing's sarcoma of bone and soft tissue, mesenchymal chondrosarcoma, small cell osteosarcoma, hemangiopericytoma, neuroblastoma, peripheral neurectodermal tumor (peripheral neuroepithelioma of bone and soft tissue), and the malignant small cell tumor of the thoracopulmonary region described by Askin (Askin's tumor), are often difficult to distinguish by light microscopy. We have evaluated the cytogenetics of these tumors by studying 24 tumor explants in short-term culture and 22 tumor cell lines. In Ewing's sarcoma (a tumor of unknown histogenesis), and in peripheral neuroepithelioma and Askin's tumor (tumors with evidence of neural origin), we have observed an indistinguishable t(11;22) translocation.     

Cytogenetics in pediatric solid tumors

Chromosome abnormalities found in pediatric solid tumors include deletions, translocations, homogeneously staining regions (hsr)/double minutes (dms), and ploidy abnormalities. The discovery of a 13q14 deletion found in lymphocytes of patients with retinoblastoma and developmental delay has led to the cloning of the retinoblastoma gene. Likewise the discovery of an 11p13 deletion in lymphocytes of patients with Wilms' tumor and aniridia has led to the cloning of the Wilms' tumor gene. Chromosome deletions found in tumor cells are considered to play a role on the homologous deletion of cancer suppressor genes. Recently, various translocations have been found mostly in soft tissue sarcomas; i.e. t(11;22) in Ewing's sarcoma, t(2;13) in alveolar rhabdomyosarcoma, t(3;8) in pleomorphic adenoma, t(3;12) in lipoma, t(12;16) in liposarcoma, t(12;14) in leiomyosarcoma, and t(X;18) in synovial sarcoma. These translocations provide important information on the difficult diagnosis of soft tissue sarcomas, and on the selection of chemotherapy protocol. Tumor cells in advanced stage neuroblastomas often show hsr/dms, in which N-myc amplification occurs. While near triploidy was regularly found in early-stage neuroblastomas, near-diploidy or near-tetraploidy was usually found in advanced stage tumors. Among various prognostic factors, N-myc copy numbers and tumor cell ploidies had the largest influence on the prognosis of neuroblastoma patients. Cytogenetic and molecular genetic analyses on tumor cells are becoming increasingly important for the diagnosis of pediatric solid tumors, and the prediction of the patients' prognosis.     

Immunohistochemistry of small round-cell tumors

The term "small round-cell tumor" describes a group of highly aggressive malignant tumors composed of relatively small and monotonous undifferentiated cells with high nuclear to cytoplasmic ratios. This group includes Ewing's sarcoma (ES), peripheral neuroepithelioma (aka, primitive neuroectodermal tumor or extraskeletal ES), peripheral neuroblastoma ("classic-type"), rhabdomyosarcoma, desmoplastic small round-cell tumor, lymphoma, leukemia, small-cell osteosarcoma, small-cell carcinoma (either undifferentiated or neuroendocrine), olfactory neuroblastoma, cutaneous neuroendocrine carcinoma (aka, Merkel-cell carcinoma), small-cell melanoma, and mesenchymal chondrosarcoma. Their clinical presentations often overlap, thus making a definitive diagnosis problematic in some cases. Yet, a clear understanding of their clinicopathologic features usually allows for a confident diagnosis, especially if immunohistochemistry is used. The following is a review of the immunohistochemistry of this small round-cell tumor group.     

Expression of microtubule-associated proteins, MAP-1 and MAP-2, in human neuroblastomas and differential diagnosis of immature neuroblasts

The expression of microtubule-associated proteins, MAP-1 and MAP-2, was studied in human neuroblastomas at various developmental stages using the immuno-alkaline-phosphatase technique and immunofluorescence microscopy. Of 15 cases examined, including grade I, grade II, and grade III neuroblastomas (M. Hughes, H. B. Marsden, and M. K. Palmer, Cancer 34:1706, 1974), rabbit antibodies raised against individual MAP-1 and MAP-2 from mammalian brain showed strong reactions with the whole spectrum of tumor cells including the immature small neuroblasts, partially mature neuroblasts, neurofibrils, and ganglion cells. Antibodies to alpha- and beta-tubulin showed similar staining patterns. In contrast, antibodies to the Mr = 200.000 neurofilament protein were reactive only with the mature and partially mature tumor cells, as well as with neurofibrils, but not with immature "round-cell" neuroblasts. Other types of round-cell tumors examined, including several cases of Ewing's sarcoma, undifferentiated rhabdomyosarcoma, and malignant lymphoma, showed no reaction with antibodies to MAP-1 and MAP-2. These tumors were reactive, however, with antibodies to various other tumor-specific as well as nonspecific antigens. It is concluded that antibodies to neuronal MAPs provide a valuable new tool for the differential diagnosis of neuroblastomas.     

Differentiating Ewing's sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues.

Ewing's sarcoma is a common malignancy of bone and soft tissue that occurs most often in children and young adults. Differentiating Ewing's sarcoma from other round blue cell tumors can be a diagnostic challenge because of their similarity in histology and clinical presentation. Thus, ancillary molecular tests for detecting disease-defining translocations are important for confirming the diagnosis. We analyzed 65 round blue cell tumors, including 53 Ewing's sarcoma samples from 50 unique cases. Samples were processed for RNA from archived formalin-fixed paraffin-embedded tissue blocks. Real-time RT-PCR assays specific for Ewing's sarcoma (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-ETV4, and EWS-FEV), synovial sarcoma (SYT-SSX1 and SYT-SSX2), and rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR) were tested across the samples. The translocation panel had a sensitivity of 81% (43 out of 53 samples) for diagnosing Ewing's sarcoma when using the histological criteria as the 'gold' standard. None of the Ewing's specific translocations were found in the non-Ewing's samples (100% specificity). Of the 43 samples with translocations detected, 26 (60%) had an EWS-FLI1 type 1 translocation, 13 (30%) had an EWS-FLI1 type 2 translocation, 3 (7%) had an EWS-ERG translocation, 1 had an EWS-ETV1 translocation, and 1 sample had both an EWS-FLI1 type 1 and type 2 translocation. Our real-time RT-PCR assay for detecting sarcoma translocations has high sensitivity and specificity for Ewing's sarcoma and has clinical utility in differentiating small round blue cell tumors in the clinical lab.     

Extracellular matrix synthesis by undifferentiated childhood tumor cell lines.

The authors have examined extracellular matrix (ECM) biosynthesis by small round cell tumors of childhood. Basal lamina (laminin and Type IV collagen) and stroma (collagens I, III, and V and fibronectin) constituents were studied. It was found that these tumors synthesize ECM in characteristic patterns. Five Ewing's sarcomas variably synthesized small amounts of all ECM constituents except Type V collagen. All eight neural tumors (neuroblastoma and primitive neural tumors) synthesized fibronectin (unlike some Ewing's sarcomas), as well as laminin and Type IV collagen (2 cases lacked Type IV collagen synthesis). No stromal (I/III) collagen synthesis was observed by neural tumors. All soft tissue sarcomas except an embryonal rhabdomyosarcoma synthesized stromal collagens and often laminin or fibronectin as well. Lymphomas synthesized no ECM of any kind. The synthesis of stromal collagens by sarcomas but not neural tumors serves to distinguish these two tumor types, especially Ewing's sarcoma from neuroblastoma. The presence of any ECM synthesis excludes lymphoma from diagnostic consideration.     

Ewing's Sarcoma with Neuroblastoma-like Features

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.     

Flow and image cytometric DNA analysis in Ewing's sarcoma.

Ewing's sarcoma is the second most common bone tumor in childhood, with an overall 5-yr survival of 40%. It is one of the poorly differentiated small spherical cell tumors frequently requiring distinction from rhabdomyosarcoma, neuroblastoma, osteosarcoma, primitive neuroectodermal tumor, and lymphoma. The majority of rhabdomyosarcomas, neuroblastomas, and osteosarcomas are aneuploid, whereas Ewing's sarcomas are usually diploid. To determine whether there is any correlation between DNA content, morphology, site, and survival in Ewing's sarcoma and extraosseous Ewing's sarcoma, 21 tumor samples were studied retrospectively (3 extraosseous Ewing's and 18 Ewing's sarcomas). The DNA analysis was performed on disaggregated paraffin-embedded tissue nuclei by flow (FCM) and image (IC) cytometry and correlated with the histology and clinical history. The DNA ploidy by FCM on 17 of 18 Ewing's sarcoma samples was 12 diploid, 1 aneuploid, and 4 tetraploid. By IC, the DNA ploidy on 16 samples was 13 diploid, 1 aneuploid, and 2 tetraploid. Three samples were nonevaluable (1 by FCM and 2 by IC). The agreement between FCM and IC was 12 of 16 (75%). The extraosseous Ewing's sarcoma tumors were 2 diploid and 1 aneuploid by IC. In this study there was no correlation between the DNA ploidy and either the histology, site, or survival.     

Ultrastructure of the Ewing's sarcoma family of tumors

Specimens of 47 tumors diagnosed by routine light microscopy as Ewing's sarcoma of bone, and 5 similar soft tissue tumors (extraskeletal Ewing's sarcomas), were examined by transmission electron microscopy. Immunohistochemical stains were performed on all the tumors, and pre-therapy and post-therapy specimens from 5 of the patients were compared. Cell and nuclear areas were assessed in 41 cases by cytomorphometry by using low-magnification electron micrographs. DNA ploidy was determined by static cytometry on 51 of the tumors. None of the methods revealed differences between the bone and soft tissue tumors. The ultrastructural spectrum extended imperceptibly from the typical forms to markedly irregular variants, and was much broader than could be anticipated from the light microscopy. Neural features were observed but they were not common. Comparison of the Ewing's sarcomas with a group of other small round cell tumors (rhabdomyosarcoma, neuroblastoma, small cell carcinoma) using the same techniques showed that they have similar cell and nuclear areas despite the obvious differences in their immunophenotypes and ultrastructure. The collective findings are in keeping with the currently favored view that Ewing's sarcoma and peripheral primitive neuro-ectodermal tumor are the extremes in a morphologic continuum within which neural differentiation ranges from absent to prominent.     

Cytogenetic and pathologic aspects of Ewing's sarcoma and neuroectodermal tumors.

Diagnostic classification of poorly differentiated, round cell, primitive neuroectodermal neoplasms, including Ewing's sarcoma, peripheral neuroepithelioma, Askin's tumor, and esthesioneuroblastoma, is challenging to the surgical pathologist using conventional histopathologic approaches because of very similar and overlapping morphologic and cytologic features. Furthermore, distinguishing these neoplasms from neuroblastoma, embryonal rhabdomyosarcoma, small cell osteogenic sarcoma, and non-Hodgkin's lymphoma can be difficult. This paper describes and reviews the cytogenetic and molecular genetic changes in these tumors and demonstrates how the ability to detect these changes has enabled a greater understanding of the histogenesis, classification, diagnosis, and prognosis of these neoplasms.