4267

CD99

HBA71|MIC2|MIC2X|MIC2Y|MSK5X;CD99 molecule;CD99;CD99 molecule

CD99 antigen|E2 antigen|MIC2 (monoclonal antibody 12E7)|T-cell surface glycoprotein E2|antigen identified by monoclonal 12E7, Y homolog|antigen identified by monoclonal antibodies 12E7, F21 and O13|surface antigen MIC2

Xp22.32 and Yp11.3

protein-coding

Ewing sarcoma/'peripheral' primitive neuroectodermal tumor (ES/pPNET) is the designation given to a family of small cell neoplasms that typically arise in bone or soft tissue and are unified by their common expression of the MIC2 antigen and specific translocations involving a gene on chromosome 22q12 [the most common being t(11;22)(q24;q12)]. ES/pPNET of intracranial origin is extraordinary. We report the case of a 6-year-old boy with a large left frontal region mass that adhered to dura and was extracerebral at surgery. Histologic study revealed a high-grade, undifferentiated-appearing neoplasm of small cell type that was negative on immunostudy for glial fibrillary acidic protein, synaptophysin, desmin, leukocyte common antigen, smooth muscle actin and epithelial membrane antigen, but positive for vimentin and neuron-specific enolase and diffusely labeled by antibody O13 (which recognizes the MIC2 gene product). RNA-based polymerase chain reaction assay confirmed the diagnosis of ES/pPNET by demonstrating fusion transcripts indicative of t(11;22) translocation. Bone scan, computerized tomography of the chest and bone marrow examination revealed no systemic tumor. The limited observations published to date suggest that primary intracranial ES/pPNET is most likely to present in childhood as a circumscribed, contrast-enhancing and dural-based extracerebral mass. It must be distinguished from a variety of small cell neoplasms, particularly PNETs of central neuroepithelial origin.

Retinoblastoma is the most common intraocular tumor of childhood and has served as a model for the understanding or tumorigenesis. This study retrospectively examines the clinicopathologic features of 19 retinoblastomas and defines the MIB-1 (cell proliferation marker), p53 (tumor suppression gene), and CD99 (HBA71or MIC2 antibody) immunoreactivity in 10 selected cases. Nineteen patients (11 boys), ranging in age from 6 to 47 months (mean, 20 months), were included for study. Clinical presentations included: leukocoria (n = 12), strabismus (n = 6),apparent decreased visual acuity (n = 5), and proptosis (n = 1). Five patients had bilateral tumors and one neoplasm arose in a patient with a known family history of retinoblastoma. ALL tumors were histologically characterized by a proliferation of small cells with high nuclear-to-cytoplasmic ratios. Commonly encountered histologic features included necrosis (n = 17, 89%), calcification (n = 16, 84%), fleurettes (n = 14, 74%), and Flexner-Wintersteiner rosettes (n = 11, 58%). Retinal involvement was noted in 18 tumors (95%) and optic nerve invasion in six cases (32%). The surgical optic nerve margin was positive in one case. Mitosis counts were evaluable in 18 cases and ranged from 1 to 42 mitotic figures/10 high power field (mean, 13 mitotic figures/10 high power field). Ten tumors were evaluated with MIB-1, p53, and CD99 antibodies by paraffin immunohistochemistry. MIB-1 labeling indices ranged from 31.4 to 77.1 (mean, 49.4). p53 immunostaining was observed in six tumors; less than 10% of tumor cells were noted to be p53 positive in each case. CD99 positivity was demonstrable focally in three tumors. Adjuvant chemotherapy and/or radiation therapy was administered in six patients. tumor recurrence was not observed in any of the patients with a mean follow-up of 8.9 years. Only one patient died (20 years after enucleation) because of metastatic osteosarcoma. In conclusion: (1) Fleurettes and Flexner-Wintersteiner rosettes are variable findings in retinoblastoma. (2) Retinoblastomas are characterized by marked cell proliferation as evidenced by generally high mitosis counts and extremely high MIB-1 labeling indices, but this does not appear to adversely impact on prognosis. (3) Unlike peripheral primitive neuroectodermal tumors, most retinoblastomas do not stain positively with antibody to CD99. (4) Limited p53 immunostaining was present in 60% of tumors studied. (5) Enucleation with negative optic nerve margin is potentially curative in patients with retinoblastoma.

In the present study we review ENT tumor pathology in childhood. Only the most salient aspects are emphasized and the variety of entities reviewed was restricted. Molecular biology techniques reveal infection by human papilloma virus (types 6 and 11) in 50 % of papillomas, while immunohistochemical techniques are less effective in papilloma virus detection. The myofibroblastic nature of nasal angiofibroma has been demonstrated and its incidence is 25 timesmore frequent in patients with familial polyposis of the colon. Overexpression of p53 occurs in the initial stages of nasopharyngeal carcinoma, while overexpression of c-myc is correlated with an unfavorable prognosis. Recently, olfactory neuroblastoma has been shown not to express the protein product of theMIC-2 gene (antibody 12E7), thus the hypothesis that it could be a member of theEwing tumor family (neuroectodermal peripheral tumors) has not been confirmed, although it is a primitive neural tumor. The head and neck rhabdomyosarcoma withthe best prognosis is that located in the orbit, and cytogenetic studies have shown chromosomic translocation t(2;13) in 50 % of these childhood tumors when they are of the alveolar-type, while trisomy of chromosome 2 or 20 is more characteristic of the embryonic-type. Currently, any classifying features of ENTlymphomas must be based on the Revised European-American Classification of Lymphoid Neoplasms (REAL). Papillary and medullary carcinomas are the most common histological types of thyroid carcinoma in childhood. Alterations in ret/PTC play a significant role in the pathogenesis of both.

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 astriking 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 changein 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.

Ewing's sarcoma is the second most frequent primary bone cancer, with approximately 225 new cases diagnosed each year in patients less than 20 years of age in North America. It is one of the pediatric small round blue cell tumors, characterized by strong membrane expression of CD99 in a chain-mail pattern and negativity for lymphoid (CD45), rhabdomyosarcoma (myogenin, desmin, actin) and neuroblastoma (neurofilament protein) markers. Pathognomonic translocations involving the ews gene on chromosome 22 and an ets-type gene, most commonly the fli1 gene on chromosome 11, are implicated in the great majority of cases. Clinical presentation is usually dominated by local bone pain and a mass. Imaging reveals a technetium pyrophosphate avid lesion that, on plain radiograph, is destructive, diaphyseal and classically causes layered periosteal calcification.Magnetic resonance best defines the extent of the lesion. Biopsy should be undertaken by an experienced orthopedic oncologist. Approximately three quartersof patients have initially localized disease. About two thirds survive disease-free. Management, preferably at a specialist center with a multi-disciplinary team, includes both local control-either surgery, radiation or a combination-and systemic chemotherapy. Chemotherapy includes cyclic combinations, incorporating vincristine, doxorubicin, cyclophosphamide, etoposide, ifosfamide and occasionally actinomycin D. Topotecan in combination with cyclophosphamide has shown preliminary activity. Patients with initially metastatic disease fare less well, with about one quarter surviving. Studies incorporating intensive therapy followed by stem cell infusion show no clear benefit. New approaches include anti-angiogenic therapy, particularly since vascular endothelial growth factor is an apparent downstream target of the ews-fli1 oncogene.

Ewing's Sarcoma (ES), the second most frequent bone tumor in childhood and adolescence, and the probably closely related peripheral primitive neuroectodermal tumor (pPNET) share a unique cytogenetic translocation between chromosomes 11 and 22. Both of them expose high amounts of a glycoprotein on their cell surface, which can be specifically detected by the mAb HBA-71. The cDNA coding for the HBA-71 antigen was isolated by screening a cDNA expression library constructed from a pPNET-derived cell line. Nucleotide sequencing revealed the HBA-71 antigen to be the product of the pseudoautosomal gene MIC2 previously identified by the mAb 12E7 in haematopoietic cells. This antigen is aglycoprotein with a molecular weight of about 29,000 and is expressed in low amounts in most human cell lines and probably normal tissues and tumors with only a few exceptions. In T-cells the antigen is involved in cell adhesion processes.In ES- and pPNET-derived cell lines MIC2 expression is significantly enhanced. No gross changes in posttranslational modification could be observed. The high expression results in easy and specific detection of the antigen in immunocytochemical analysis of paraffin embedded tissue sections making HBA-71 auseful tool in tumor diagnosis.

Ewing's Sarcoma (ES), the second most frequent bone tumor in childhood and adolescence, and the probably closely related peripheral primitive neuroectodermal tumor (pPNET) share a unique cytogenetic translocation between chromosomes 11 and 22. Both of them expose high amounts of a glycoprotein on their cell surface, which can be specifically detected by the mAb HBA-71. The cDNA coding for the HBA-71 antigen was isolated by screening a cDNA expression library constructed from a pPNET-derived cell line. Nucleotide sequencing revealed the HBA-71 antigen to be the product of the pseudoautosomal gene MIC2 previously identified by the mAb 12E7 in haematopoietic cells. This antigen is aglycoprotein with a molecular weight of about 29,000 and is expressed in low amounts in most human cell lines and probably normal tissues and tumors with only a few exceptions. In T-cells the antigen is involved in cell adhesion processes.In ES- and pPNET-derived cell lines MIC2 expression is significantly enhanced. No gross changes in posttranslational modification could be observed. The high expression results in easy and specific detection of the antigen in immunocytochemical analysis of paraffin embedded tissue sections making HBA-71 auseful tool in tumor diagnosis.

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 HBA71for 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 63Ewing'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 authorssearched 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.

Monoclonal antibody HBA71 detects a cell surface antigen of human Ewing's sarcomas and peripheral neuroepitheliomas that distinguishes these tumors from other small round cell tumors of childhood and adolescence. In the present study, we show that monoclonal antibody HBA71 reacts with polypeptides of Mr 32,000 and30,000 and that the HBA71-coding gene segregates with human chromosomes X and Y in rodent-human hybrids. Therefore, we compared HBA71 to the T-cell leukemia antigen 12E7, which is encoded by the pseudoautosomal region of chromosomes X and Y. We show that monoclonal antibodies HBA71 and 12E7 (a) detect polypeptides of identical size, (b) react with mouse cells transfected with complementary DNA corresponding to the 12E7-coding gene, MIC2, and (c) give similar patterns of reactivity with human tumor cell lines and small round cell tumor tissues. Thus,HBA71 and 12E7 are identical or closely related antigens and the available MIC2 probes will facilitate analysis of the molecular mechanisms that determine differential HBA71 expression in small round cell tumors of childhood and adolescence.

childhood cutaneous and subcutaneous malignancies are rare and include metastatic tumors of diverse histogenesis as well as primary lesions, such as sweat gland carcinomas. Some cutaneous malignancies exhibit a small round cell tumor morphology with few definitive differentiating features; they can thus pose a significant diagnostic problem. We describe two primary malignancies of the skinand superficial subcutis, which were originally diagnosed as sweat gland carcinomas on the basis of their morphological features. A cytogenetic analysis performed on one of these lesions showed the t(11;22)(q24;q12) rearrangement, believed to be unique to the Ewing's sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) group of neoplasms. In view of this unexpected result, reverse transcriptase-polymerase chain reaction analysis was performed on both lesions and showed that they expressed EWS/FLI-1 fusion gene mRNA transcripts, the molecular equivalent of t(11;22)(q24;q12). The two tumors also had an immunohistochemical profile suggesting ES/pPNET, including strong expression of the MIC2 antigen. Both patients were treated with wide local excision, and one was given a course of chemotherapy. Neither patient showed evidence of tumor elsewhere after follow-up periods of 2 years and 16 years. These findings suggest that these tumors are indeed a form of primary ES/pPNET arising in the skin or superficial subcutis, which may be of low-grade malignancy and curable by local surgery.

Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not.MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors ofchildhood, since it represents the first positive marker for Ewing's sarcoma andPNET. This study addresses the reliability of MIC2 analysis using the monoclonalantibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand ALL the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the resultsare interpreted in the total context with clinical and pathologic parameters.

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, havebeen 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-cellfibroblastoma, 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 neuroectodermaltumor), 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.