CD99

Gene Summary

Gene:CD99; CD99 molecule
Aliases: MIC2, HBA71, MIC2X, MIC2Y, MSK5X
Location:Xp22.32 and Yp11.3
Summary:The protein encoded by this gene is a cell surface glycoprotein involved in leukocyte migration, T-cell adhesion, ganglioside GM1 and transmembrane protein transport, and T-cell death by a caspase-independent pathway. In addition, the encoded protein may have the ability to rearrange the actin cytoskeleton and may also act as an oncosuppressor in osteosarcoma. Cyclophilin A binds to CD99 and may act as a signaling regulator of CD99. This gene is found in the pseudoautosomal region of chromosomes X and Y and escapes X-chromosome inactivation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:CD99 antigen
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
-CD99 and Neuroectodermal Tumors, Primitive View Publications65
Bone Cancer (primary)CD99 and Bone Cancer View Publications50
Soft Tissue SarcomaCD99 and Soft Tissue Cancers View Publications32
Kidney CancerCD99 and Kidney Cancer View Publications26
Vulvar CancerCD99 and Vulvar Cancer View Publications9
Wilms TumourCD99 and Wilms Tumour View Publications7
Ewing's SarcomaMIC2 expression in the Differential Diagnosis of Ewing's Sarcoma
Unlike most other small blue cell tumors of childhood, Ewing's sarcoma and pPNET strongly express the MIC2(CD99) antigen. Therefore MIC2 analysis can be a useful part of the panel of tests used in the differential diagnosis of Ewing's sarcoma / pPNET.
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Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

MIC2 expression in the Differential Diagnosis of Ewing's Sarcoma

Unlike most other small blue cell tumors of childhood, Ewing's sarcoma and pPNET strongly express the MIC2(CD99) antigen. Therefore MIC2 analysis can be a useful part of the panel of tests used in the differential diagnosis of Ewing's sarcoma / pPNET.

See also: Ewing's Sarcoma - Clinical and Research information

Latest Publications

Sugita S, Arai Y, Tonooka A, et al.
A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.
Am J Surg Pathol. 2014; 38(11):1571-6 [PubMed] Related Publications
Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.

Specht K, Sung YS, Zhang L, et al.
Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities.
Genes Chromosomes Cancer. 2014; 53(7):622-33 [PubMed] Free Access to Full Article Related Publications
Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as ES-like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1, and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1 rearrangement. © 2014 Wiley Periodicals, Inc.

Amaral AT, Manara MC, Berghuis D, et al.
Characterization of human mesenchymal stem cells from ewing sarcoma patients. Pathogenetic implications.
PLoS One. 2014; 9(2):e85814 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin.
MATERIALS AND METHODS: In an initial study regarding a deep characterization of MSC obtained specifically from EWS patients (MSC-P), we compared them with MSC derived from healthy donors (MSC-HD) and EWS cell lines. We evaluated the presence of the EWS-FLI1 gene fusion and EWSR1 gene rearrangements in MSC-P. The presence of the EWS transcript was confirmed by q-RT-PCR. In order to determine early events possibly involved in malignant transformation, we used a multiparameter quantitative strategy that included both MSC immunophenotypic negative/positive markers, and EWS intrinsic phenotypical features. Markers CD105, CD90, CD34 and CD45 were confirmed in EWS samples.
RESULTS: We determined that MSC-P lack the most prevalent gene fusion, EWSR1-FLI1 as well as EWSR1 gene rearrangements. Our study also revealed that MSC-P are more alike to MSC-HD than to EWS cells. Nonetheless, we also observed that EWS cells had a few overlapping features with MSC. As a relevant example, also MSC showed CD99 expression, hallmark of EWS diagnosis. However, we observed that, in contrast to EWS cells, MSC were not sensitive to the inhibition of CD99.
CONCLUSIONS: In conclusion, our results suggest that MSC from EWS patients behave like MSC-HD and are phenotypically different from EWS cells, thus raising important questions regarding MSC role in sarcomagenesis.

White JC, Halligan GE, de Chadarévian JP, et al.
Unusual genetic aberrations including a deletion of KLF6 tumor suppressor gene revealed by integrated cytogenetic approaches in a pediatric ewing sarcoma.
J Pediatr Hematol Oncol. 2015; 37(1):e51-4 [PubMed] Related Publications
Ewing sarcoma is the third most common sarcoma in children and young adults. Its characteristic chromosomal rearrangement results in a chimerical EWSR1-ETS transcription factor. Secondary genetic alterations are very common. Membranous expression of CD99 is seen in almost all tumors. We report 2 unusual cytogenetic findings in a pediatric Ewing sarcoma, an insertion of the MIC2 gene encoding CD99 from Xp to 10p and a submicroscopic deletion of the well-known tumor supressor gene KLF6. The latter has not been described previously in pediatric neoplasms. Molecular pathways in tumorigenesis and genetic complexity in cancer are discussed.

Rekhi B, Vogel U, Basak R, et al.
Clinicopathological and molecular spectrum of ewing sarcomas/PNETs, including validation of EWSR1 rearrangement by conventional and array FISH technique in certain cases.
Pathol Oncol Res. 2014; 20(3):503-16 [PubMed] Related Publications
Over the years, a wide clinicopathological spectrum has been identified within Ewing family of tumors (EFTs). As these tumors are chemosensitive, their correct and timely identification is necessary. The aims of this study were (1) to present the diverse clinicopathological and molecular profile of EFTs in our settings, (2) to identify a pragmatic approach for diagnosing EFTs, especially for application of ancillary techniques, namely RT-PCR for specific transcripts (EWS-FLI1, EWS-ERG) and FISH for EWSR1 gene rearrangement, in certain cases and (3) to show the utility of tissue microarray in establishing a new FISH test. Fifty-eight EFTs were identified in 38 males and 20 females within an age-range of 1-65 years (median, 16), mostly in lower extremities (14) (24.1 %). Therapeutically, most patients underwent neoadjuvant chemotherapy with subsequent surgery. Histopathologically, diagnosis of EFTs was initially offered in 41/58 (70.6 %) tumors. On review, 59 % tumors showed diffuse pattern, while 41 % displayed rosettes. Immunohistochemically, tumor cells were mostly diffusely positive for CD99 (48/52) (92.3 %); FLI-1 (17/18) (94.4 %); variably for BCL2 (16/18) (88.8 %), synaptophysin (6/20) (35 %), S100-P (2/7) (28.5 %), CD56 (2/5) (40 %), NSE (2/5) (40 %), calponin (3/4) (75 %), EMA (5/24) (20.8 %) and CK (3/24) (12.5 %), the latter two mostly focally. Fifty five tumors were EWS-FLI1 positive, while a single tumor was EWS-ERG positive. Sensitivity for PCR was 61 %. EWSR1 rearrangement was detected by FISH in 12/13 Ewing sarcomas/PNETs. Sensitivity for EWSR1 test was 92.3 % and specificity was 100 %. Thirty-eight tumors, including 14 molecular confirmed EFTs and 21 other tumors were tested for EWSR1 rearrangement. Among 21 unrelated tumors, EWSR1 rearrangement was detected in few myoepithelial tumors, occasional desmoplastic small round cell tumor and an extraskeletal myxoid chondrosarcoma. Further, a tissue microarray with a separate set of 8 EFTs, confirmed at another laboratory was analysed for validation of EWSR1 rearrangement test. 23/28 (82.1 %) tissue cores of the tissue microarray, stained by FISH were interpretable, including EWSR1 rearrangement, detected in 20/28 tissue cores; not detected in 3 liver cores and uninterpretable in 5 (17.8 %) cores. Classical EFTs can be diagnosed with diffuse, membranous CD99 positivity, intranuclear FLI1 positivity and LCA negativity in malignant round cells. In unconventional cases, it is indispensable to reveal the concomitant fusion m-RNA by RT-PCR. In case of negative molecular results, it is necessary to prove EWSR1 rearrangement by FISH. These tests should be interpreted with clinicopathological correlation. Tissue microarrays for FISH are useful during validation of a new test, especially when sarcomas like EFTs show less genetic heterogeneity within tumor cells.

Franzetti GA, Laud-Duval K, Bellanger D, et al.
MiR-30a-5p connects EWS-FLI1 and CD99, two major therapeutic targets in Ewing tumor.
Oncogene. 2013; 32(33):3915-21 [PubMed] Related Publications
Ewing sarcoma is a pediatric bone tumor characterized in 85% of cases by the fusion between EWS and FLI1 genes that results in the expression of the EWS-FLI1 aberrant transcription factor. Histologically, the Ewing tumor expresses high levels of the CD99 membrane glycoprotein. It has been recently described that CD99 expression contributes to the Ewing tumor oncogenesis by modulating growth and differentiation of tumor cells. Different studies have also shown that overexpression of EWS-FLI1 induces CD99 expression in non-Ewing cells. At the opposite, the knockdown of EWS-FLI1 expression by siRNA approaches has no significant effect on CD99 mRNA level in Ewing cells. Here, by in vivo and in vitro studies, we show that while EWS-FLI1 inhibition has only slight effects on the amount of CD99 transcript, it induces a dramatic decrease of the CD99 protein expression level, hence suggesting post-transcriptional regulations, possibly mediated by microRNAs. To further investigate this issue, we identified a set of 91 miRNAs that demonstrate EWS-FLI1 modulation, three of them being predicted to bind CD99 3' untranslated region (30'UTR). Among these, we show that miR-30a-5p has the ability to interact with the 30'UTR region of CD99 and to regulate its expression. Moreover, the re-expression of miRNA-30a-5p in Ewing cell line induces decreased cell proliferation and invasion. In this study, we therefore show that miR-30a-5p constitutes a major functional link between EWS-FLI1 and CD99, two critical biomarkers and therapeutic targets in Ewing sarcoma.

Vural C, Uluoğlu O, Akyürek N, et al.
The evaluation of CD99 immunoreactivity and EWS/FLI1 translocation by fluorescence in situ hybridization in central PNETs and Ewing's sarcoma family of tumors.
Pathol Oncol Res. 2011; 17(3):619-25 [PubMed] Related Publications
Ewing's sarcoma family of tumors (ESFTs) are indicated by malignant, small, round and blue cell tumors of the bone and soft tissue. Gene rearrangements between EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to ESFTs. Another defining characteristic of ESFTs is their membranous expression of the CD99. In contrast, such translocations and immunoreactivity are not found in central primitive neuroectodermal tumors (cPNETs). The aim of this study was to investigate the detection of EWS/FLI1 translocations and CD99 immunoreactivity in order to evaluate their clinicopathological features and their roles in the differential diagnosis of these tumors. In this study, we investigated CD99 immunoreactivity using immunohistochemistry and Ewing's sarcoma / Friend leukaemia virus integration 1 (EWS/FLI1) translocation using the fluorescence in situ hybridization (FISH) method in 23 cases. CD99 expression was detected in 10/11 (90%) ESFT cases and 2/7 cPNET cases. In 18 cases EWS/FLI1 translocation was examined using the FISH method. The EWS/FLI1 translocations were detected in 7/8 (87.5%) ESFTs cases, whereas non of 8 cPNET cases were detected with this translocation. One case could not be classified as either central or peripheral, showed EWS/FLI1 translocation. There was a statistically significant difference in CD99 expression (p = 0.0013) and EWS/FLI1 translocation (p = 0,002) between cPNETs and ESFTs cases. In conclusion, CD99 expression and EWS/FLI1 translocation are specific and sensitive markers in the diagnosis of ESFTs. However, these were often not found in cases of cPNET. Therefore, in the diagnosis of ESFTs, clinical, radiological, histopathological and immunohistochemical parameters should always be evaluated together.

Angel JR, Alfred A, Sakhuja A, et al.
Ewing's sarcoma of the kidney.
Int J Clin Oncol. 2010; 15(3):314-8 [PubMed] Related Publications
Primitive neuroectodermal tumors (PNETs) are small, round-cell tumors of neural crest origin classically found in the central nervous system (CNS) but more recently characterized in the periphery. Peripherally located PNETs (pPNETs) are members of the Ewing's sarcoma family of tumors (EFTs). Renal localization of pPNETs is very rare, is found in young adults, and is characterized by an aggressive clinical course and poor prognosis. We present the case of a young man with renal pPNET characterized by psuedorosette formation, cluster of differentiation 99 (CD 99+), focally positive for neuron-specific enolase (NSE), with cytogenetic findings of the translocation t(11;22)(q24;q12) and the unique abnormality of trisomy 7. To our knowledge, we report the first case of trisomy 7 and PNET.

Manduch M, Dexter DF, Ellis PM, et al.
Extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor of the posterior mediastinum with t(11;22)(q24;q12).
Tumori. 2008 Nov-Dec; 94(6):888-91 [PubMed] Related Publications
Ewing's sarcoma/primitive neuroectodermal tumor family of tumors is part of a rare group of malignant neoplasms with small round-cell morphology. We describe a 24-year-old woman who presented with non-specific back pain. A chest radiograph and magnetic resonance imaging demonstrated an extraosseous, dumbbell-shaped mass of the posterior mediastinum with extension into the spinal canal. The patient underwent a left posterolateral thoracotomy and a T3-5 laminectomy with subsequent multi-agent chemotherapy. Histopathologic examination of the tumor demonstrated sheets of primitive small round malignant cells that showed no visible differentiation. Neoplastic cells were strongly immunoreactive for CD99 and vimentin and were negative for chromogranin, synaptophysin, CD31, CD34, calcitonin, desmin, low-molecular weight cytokeratins, wide-spectrum cytokeratins, leukocyte common antigen, S-100 protein, and thyroid transcription factor-1. The neoplasm was diagnosed as a Ewing's sarcoma/primitive neuroectodermal tumor, and cytogenetic studies confirmed a t(11;22)(q24;q12) chromosomal translocation and an associated trisomy of chromosome 2, supporting the histologic diagnosis. Extraskeletal Ewing's sarcoma/primitive neuroectodermal tumors are rare neoplasms that should be distinguished from other small round-cell tumors by morphology and ancillary laboratory techniques. Although rare, they need to be considered in the differential diagnosis of primary mediastinal tumors.

Terrier-Lacombe MJ, Guillou L, Chibon F, et al.
Superficial primitive Ewing's sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases.
Mod Pathol. 2009; 22(1):87-94 [PubMed] Related Publications
Superficial primitive Ewing's sarcomas are rare and have been reported to be of favorable prognosis compared to conventional deep-seated tumors. In the skin and subcutis, the diagnosis is often difficult, and performing molecular cytogenetic techniques may be helpful. We performed a retrospective analysis of 14 cases of superficial Ewing's sarcomas, all confirmed by molecular cytogenetics. Clinical, histological, immunohistochemical, molecular cytogenetic, therapeutic, and follow-up data are reported. There were 11 female and 3 male patients aged from 12 to 77 years (median: 17 years). Seven tumors occurred in the extremities, five in the trunk wall, and two in the head. Tumor size ranged from 1 to 5 cm (median, 3 cm). They were all small round-cell proliferations with a strong membranous positivity for CD99. Ewing's sarcoma translocations/fusion gene transcripts were detected in eight cases, both by FISH and reverse transcriptase (RT)-PCR. Four tumors were positive by RT-PCR alone (FISH not done in three cases and not interpretable in one case), and two cases were positive by FISH alone (RT-PCR not done). Surgical resection was performed in all patients. Chemotherapy was given in ten patients and radiotherapy in six. At last medical examination (median follow-up, 47 months), two patients who underwent surgical resection alone had died from the tumor. Our results confirm that superficial Ewing's sarcomas are of good prognosis. Given the difficulty of the diagnosis and the importance of an adapted treatment, a confirmation of the diagnosis by molecular or cytogenetic techniques is recommended when dealing with a superficial tumor.

Wang H, Zheng J, Wang YP, et al.
Molecular detection of EWS-Ets fusion transcripts and their clinicopathologic significance in Ewing's sarcoma/peripheral primitive neuroectodermal tumor.
Chin Med J (Engl). 2005; 118(16):1323-9 [PubMed] Related Publications
BACKGROUND: Ewing's sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is often difficult to distinguish from other small round cell tumors. The EWS-Ets gene fusions that result from chromosomal translocations in this tumor provide potential molecular diagnostic markers. To apply these molecular markers to commonly available archival materials, we evaluated the feasibility of detecting EWS-Ets including EWS-Fli1 and EWS-ERG fusion transcripts in paraffin-embedded tissues and its diagnostic value for detecting ES/pPNET.
METHODS: Thirteen paraffin-embedded samples of ES/pPNETs were retrieved from archives. Thirteen cases of other tumors with small round cell features (including rhabdomyosarcoma, neuroblastoma, lymphoma, small cell carcinoma, and desmoplastic small round cell tumor) were used as negative controls. Beta-actin and beta2-microglobulin were used as internal controls. A nested reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay was performed to detect the EWS-Fli1 and EWS-ERG fusion transcripts.
RESULTS: Beta-actin and beta2-microglobulin were detected in 10/13 and 13/13 ES/pPNETs, respectively. EWS-Fli1 fusion transcripts were detected in 11 of 13 (85%) ES/pPNETs. Three chimeric transcripts, all EWS-Fli1, were detected in ES/pPNET samples. Among 11 EWS-Fli1-positive cases, 7 cases had a type I fusion transcript involving fusion of EWS exon 7 with Fli1 exon 6, 2 cases had a type II fusion transcript involving EWS exon 7 with Fli1 exon 5, and 2 cases expressed fusion transcripts involving EWS exon 7 and Fli1 exon 8. Type I EWS-Fli1 fusion predominated over other types. Fusion types could not be distinguished in the remaining 2 cases. Thirteen negative controls did not show detectable chimeric messages. There was a significant relationship between EWS-Fli1 fusion transcripts and CD99 expression.
CONCLUSIONS: Molecular detection of EWS-Fli1 fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs.

Khoury JD
Ewing sarcoma family of tumors.
Adv Anat Pathol. 2005; 12(4):212-20 [PubMed] Related Publications
The Ewing sarcoma family of tumors (ESFT) comprises morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene and one of several members of the ETS family of transcription factors. The translocation t(11;22)(q24;q12) is the most common and leads to the formation of the EWS-FLI1 fusion protein, which contributes to ESFT pathogenesis by modulating the expression of target genes. Tumors may be composed of small uniform cells with minimal morphologic evidence of differentiation, or they may be composed of larger, less uniform cells with varying degrees of neuroectodermal differentiation. CD99 expression is identified in nearly all ESFT and constitutes a useful positive marker when used as part of a panel of immunostains that can help rule out other differential diagnostic considerations. Molecular diagnostic tests commonly used to detect the presence of ESFT-specific translocations include RT-PCR and fluorescence in situ hybridization. Current therapy for patients with ESFT includes chemotherapy and surgery with or without radiation therapy. At present, the most significant prognostic factor for patients with ESFT is whether the disease is localized or metastatic.

Bismar TA, Basturk O, Gerald WL, et al.
Desmoplastic small cell tumor in the pancreas.
Am J Surg Pathol. 2004; 28(6):808-12 [PubMed] Related Publications
Desmoplastic small cell tumor (DSCT) is a distinct type of small blue cell tumors and is characterized by the unique karyotypic aberration involving the fusion of the Ewing's sarcoma (EWS) gene and Wilms' tumor (WT1) gene. Typically, it grows along serosal surfaces; however, in some cases, the tumor presents as a dominant mass in an internal organ. Examples of DSCT forming a primary mass in ovary, testes, and brain have been described, but its presentation as a primary pancreatic mass has not been reported previously. The case reported here is a 31-year-old woman who presented with a 14-cm mass in the pancreas. There were smaller nodules on the peritoneal surfaces that were regarded clinically as metastasis from a primary pancreatic tumor. During the frozen section, the diagnosis of a poorly differentiated endocrine carcinoma of pancreatic origin was rendered and patient underwent subtotal pancreatectomy. On microscopic examination, the tumor was composed of large nests and broad bands of small blue cells, separated by fibrous stroma. Immunohistochemical stains showed positivity of the tumor cells for cytokeratins (AE1:AE3 and CAM5.2), neuron specific enolase, desmin and WT1, whereas chromogranin, S-100, and CD99 were negative. Since this immunoprofile is characteristic of DSCT, molecular analysis was performed which revealed the presence of EWS-WT1 gene fusion characteristic of DSCT. This case shows that in addition to primary pancreatic tumors characterized by prominent cellularity such as solid pseudopapillary tumors, acinar cell carcinoma, pancreatoblastoma, endocrine tumors, and other small blue cell tumors, the differential diagnosis of cellular, stroma-poor neoplasia in the pancreas also includes DSCT. This case is also another demonstrative example of how DSCT may form a dominant mass in intraabdominal organs.

Sezer O, Jugovic D, Blohmer JU, et al.
CD99 positivity and EWS-FLI1 gene rearrangement identify a breast tumor in a 60-year-old patient with attributes of the Ewing family of neoplasms.
Diagn Mol Pathol. 1999; 8(3):120-4 [PubMed] Related Publications
Rearrangements of the EWS gene with ETS transcription factor genes as a result of chromosomal translocation and high expression levels of CD99MIC2 characterize the Ewing family of tumors (EFT). This group of rather undifferentiated neoplasms affects bone and soft tissue in children and young adults mostly between 5 and 30 years of age (median, 15 years). This study reports a case of a CD99MIC2 positive small round cell tumor in the breast of a 60-year-old woman in whom a t(11;22)(q24;q12) chromosomal aberration was identified by cytogenetic analysis. Reverse transcriptase (RT)-polymerase chain reaction (PCR) followed by sequence analysis revealed expression of a chimera transcript in which EWS exon 10 was fused to FLI1 exon 6. Previously, this gene fusion has been reported to occur in approximately 3% of EFT. The specific gene rearrangement of EWS intron 10 was confirmed on Southern blot of genomic DNA. This study further contributes to the growing list of unusual neoplasms in adults that carry genotypic and phenotypic traits of the EFT.

Hattinger CM, Rumpler S, Strehl S, et al.
Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors.
Genes Chromosomes Cancer. 1999; 24(3):243-54 [PubMed] Related Publications
Ewing's sarcoma, peripheral primitive neuroectodermal tumors, and Askin tumors are referred to as Ewing tumors (ETs), and are characterized by high MIC2 expression and a t(11;22)(q24;q12) or other rearrangements involving 22q12. In addition to these constant aberrations, facultative numerical and structural aberrations have been reported: gains of chromosomes 8 and 12, the unbalanced translocation t(1;16), and deletions at the short arm of chromosome 1. To evaluate the frequency and to study the biological impact of these facultative aberrations, we analyzed tumor specimens from 58 ET patients by classical cytogenetics and/or in situ hybridization techniques and compared these data with clinical parameters. Gains of chromosomes 8 and 12 were detected in 55% (32/58) and 24% (14/58) of the cases, respectively. Loss of chromosome 16 or der (16)t(1;16) chromosomes were found in 20% (10/51); deletions at 1p36 were observed in 18% (9/51) of the cases evaluated. The presence of these aberrations did not correlate with age and sex of the patients, with the location of the primary tumor or with the extent of disease at diagnosis by chi-square analysis and Fisher's exact test. Patients with tumors harboring gains of chromosome 8 showed a slightly better clinical outcome (n = 14/30, P = 0.17), whereas gains of chromosome 12 did not influence the clinical outcome (n = 7/30, P = 0.63). However, Kaplan and Meier analysis revealed that deletions at the short arm of chromosome 1 were associated with an unfavorable outcome in patients with localized disease (n = 6/22; P = 0.004).

Hasegawa SL, Davison JM, Rutten A, et al.
Primary cutaneous Ewing's sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases.
Am J Surg Pathol. 1998; 22(3):310-8 [PubMed] Related Publications
Cutaneous small blue cell tumors are relatively uncommon and include primary lesions of either adnexal or neuroendocrine differentiation, as well as metastatic disease. Extraosseous Ewing's sarcoma/malignant primitive neuroectodermal tumor (MPNET) rarely may occur as a primary, superficially based neoplasm in children and young adults. We describe a series of five cases of Ewing's sarcoma/malignant primitive neuroectodermal tumor occurring as a primary cutaneous malignancy supported diagnostically both by immunohistochemical stains and fluorescence in situ hybridization (FISH). All five cases occurred as a solitary dermal nodule and were located in the lower extremities (3 cases), the axilla (1 case), and the flank (1 case). Three of the cases were clinically polypoid. Four of the five patients were female, and age at presentation ranged form 8 to 50 years of age (median, 18 years). All five tumors consisted of nodular proliferations of monomorphous, small blue cells with round, vesicular nuclei, and scant to moderate cytoplasm that were uniformly immunoreactive for the CD99 cell surface glycoprotein in a characteristic membranous pattern. Fluorescence in situ hybridization analysis of paraffin-embedded tissue revealed that three of four tumors were positive for a chromosomal translocation involving the EWS locus at 22q12, seen in more than 90% of cases of Ewing's sarcoma/malignant primitive neuroectodermal tumor. One case was not analyzable. All five patients were treated using local excision, and two patients additionally received postoperative chemotherapy and radiotherapy. Clinical follow-up is available in three cases (median duration, 33 months) and to date none has shown evidence of either local recurrence or metastasis. Because similar cases reported in the literature have likewise had favorable clinical courses after excision, primary cutaneous Ewing's sarcoma/malignant primitive neuroectodermal tumor may represent a clinically favorable subset of this otherwise highly aggressive neoplasm.

Nagao K, Ito H, Yoshida H, et al.
Chromosomal rearrangement t(11;22) in extraskeletal Ewing's sarcoma and primitive neuroectodermal tumour analysed by fluorescence in situ hybridization using paraffin-embedded tissue.
J Pathol. 1997; 181(1):62-6 [PubMed] Related Publications
The clonal chromosomal rearrangement t(11;22) has been reported by karyotypic analysis to be specific for Ewing's sarcoma of bone and soft tissue origin as well as primitive neuroectodermal tumour. In this report, immunohistological analysis of MIC 2 expression and fluorescence in situ hybridization (FISH) were performed using paraffin-embedded tissues. We examined t(11;22) in the nuclei isolated from two Ewing's sarcomas, four primitive neuroectodermal tumours, and three neuroblastomas, which served as negative controls by FISH with an alpha-satellite DNA probe for chromosome 11, a chromosome 22 marker probe, and whole chromosome painting probes for both chromosomes 11 and 22. Both cases of Ewing's sarcoma and the four primitive neuroectodermal tumour specimens were immunoreactive for MIC 2. Both Ewing's sarcomas and three of the four primitive neuroectodermal tumours contained the tumour-specific t(11;22), but the three neuroblastomas did not show this translocation. Based on the cytogenetic results and on the immunohistological investigation of MIC 2 expression, Ewing's sarcoma is suggested to be related closely to primitive neuroectodermal tumour. FISH is a useful aid in determining the tumour type of Ewing's sarcoma and putative related tumours.

Lee CS, Southey MC, Waters K, et al.
EWS/FLI-1 fusion transcript detection and MIC2 immunohistochemical staining in the diagnosis of Ewing's sarcoma.
Pediatr Pathol Lab Med. 1996 May-Jun; 16(3):379-92 [PubMed] Related Publications
Ewing's sarcoma (ES) and other primitive peripheral neuroectodermal tumors (pPNETs) can present a significant diagnostic problem, as they may morphologically resemble other small round cell tumors (SRCTs) of childhood. However, ES/pPNET is known to carry a characteristic t(11;22)(q24;q12), the detection of which may aid diagnosis. The recent identification of the EWS and FLI-1 genes flanking the translocation break point has enabled reverse transcriptase-polymerase chain reaction (RT-PCR) to be used to detect the putative chimeric transcription factor mRNA produced by the fusion gene. We have assessed the RT-PCR method of detection by examining 40 cases of ES for the presence of EWS/FLI-1 transcripts. Twenty-six (76%) of the 34 cases with intact mRNA yielded fusion transcripts. Four different transcript sizes were detected and two tumors contained two transcripts of different size. No transcripts were detected in a control group of non-ES/pPNET SRCTs. Eight cases with intact mRNA were transcript negative. The MIC2 cell surface antigen, which is reported to be present in over 95% of ES/pPNETs, was present in 32 of 33 tumors (97%), including all 24 EWS/FLI-1 transcript-positive cases examined. Hence MIC2 is a useful screen for ES, with RT-PCR detection of t(11;22) being the optimal method for confirming the diagnosis.

Thorner P, Squire J, Chilton-MacNeil S, et al.
Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types.
Am J Pathol. 1996; 148(4):1125-38 [PubMed] Free Access to Full Article Related Publications
The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor. We report four cases, all of which possessed this translocation as detected by reverse transcriptase polymerase chain reaction and confirmed by sequencing with or without fluorescent in situ hybridization, but none of which were Ewing sarcoma or peripheral primitive neuroectodermal tumor by histological criteria. Two were polyphenotypic tumors and two were mixed embryonal and alveolar rhabdomyosarcomas. Only one case was positive for MIC2 by immunohistochemistry and only in a rare cell. Two cases (one polyphenotypic tumor and one rhabdomyosarcoma) had double minute chromosomes with > 100 copies of the MDM2 gene. The presence of the t(11;22)(q24;ql2) translocation should probably not be considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor in the absence of supporting histological evidence. The presence of this translocation in Ewing sarcoma and peripheral primitive neuroectodermal tumor has been taken as evidence that these two tumors are related. Extending this relationship to include some polyphenotypic tumors and some rhabdomyosarcomas may not be justified unless additional evidence is gathered. Pathologists and oncologists will need to decide whether treatment regimens for tumors are better based on phenotype rather than genotype when these two profiles are seemingly in conflict.

Thorner P
Intra-abdominal polyphenotypic tumor.
Pediatr Pathol Lab Med. 1996 Jan-Feb; 16(1):161-9 [PubMed] Related Publications
The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET). We report a case of a polyphenotypic tumor that possessed this translocation as detected by reverse transcriptase polymerase chain reaction (RT-PCR). This tumor was positive for vimentin, desmin, low-molecular-weight keratin, neuron-specific enolase, S-100 protein, and CD57 by immunohistochemistry. Of note, the tumor was negative for MIC2. The tumor had double-minute chromosomes with > 100 copies of the MDM2 gene. Thus, the presence of the t(11;22)(q24;q12) translocation should not be considered diagnostic of Ewing sarcoma and pPNET in the absence of supporting histologic evidence such as positive staining for MIC2. The presence of this translocation in Ewing sarcoma and pPNET has been taken as evidence that these two tumors are related. Rather than extending this relationship to include some polyphenotypic tumors, other tumors may acquire this genetic change during tumor progression. Treatment regimens for tumors may be better based on phenotype rather than genotype when these two profiles are seemingly in conflict.

Latest Publications: CD99 (cancer-related)

Righi A, Gambarotti M, Longo S, et al.
Small cell osteosarcoma: clinicopathologic, immunohistochemical, and molecular analysis of 36 cases.
Am J Surg Pathol. 2015; 39(5):691-9 [PubMed] Related Publications
Small round cell osteosarcoma is a very rare type of osteosarcoma, histologically mimicking other small round cell malignancies of bone, most notably Ewing sarcoma. To distinguish small cell osteosarcoma from other primary small cell malignancies of bone, we evaluated the immunohistochemical (IHC) expression of CD99 and SATB2, a marker of osteoblastic differentiation. Second, we analyzed EWSR1 and FUS gene aberrations using fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR) techniques to assess whether small cell osteosarcoma and Ewing sarcoma share the same genetic alteration analysis. Thirty-six cases of primitive small cell osteosarcoma of bone were included in this study. All the cases of small cell osteosarcoma showed strong nuclear expression of SATB2 associated with negativity for CD99 antibody or weak, cytoplasmic staining in few neoplastic cells. Reverse transcription-polymerase chain reaction was negative for EWS-FLI1 type 1-2, EWS-ERG type 1, and CIC-DUX4 in the 10 available cases of small cell osteosarcoma analyzed. Fluorescence in situ hybridization analysis was feasible with a readable signal in 13 cases of small cell osteosarcoma, and none of these cases showed any EWSR1 and FUS gene rearrangements. In conclusion, it appears extremely useful to combine IHC analysis of SATB2 and CD99 with molecular analysis of Ewing sarcoma-associated genetic aberrations, to differentiate small cell osteosarcoma from other small round cell malignancies of bone. The strong IHC expression of SATB2 associated with CD99 immunonegativity and the absence of EWSR1 and FUS gene rearrangements in small cell osteosarcoma argues against the existence of a morphologic/genetic continuum with Ewing sarcoma.

Ud Din N, Pekmezci M, Javed G, et al.
Low-grade small round cell tumor of the cauda equina with EWSR1-WT1 fusion and indolent clinical course.
Hum Pathol. 2015; 46(1):153-8 [PubMed] Related Publications
We report a case of a longstanding, large tumor involving spinal nerve roots of the cauda equina. The tumor showed small round cells arranged in nests and cords and immunophenotypic features of a glomus tumor, along with infrequent mitoses and a low Ki-67 labeling index, but exhibited some rosette-like structures, with focal CD99 and Neu-N expression. Subsequent molecular analysis showed the presence of an EWSR1-WT1 gene fusion by fluorescence in situ hybridization, which was confirmed by reverse- transcriptase polymerase chain reaction. To our knowledge, this is the first case reported with EWSR1-WT1 fusion in a small round blue cell tumor with smooth muscle differentiation and an indolent course.

Shimada C, Todo Y, Okamoto K, et al.
Central type primitive neuroectodermal tumor/neuroblastoma of the uterus: a case report.
J Obstet Gynaecol Res. 2014; 40(10):2118-22 [PubMed] Related Publications
We encountered a 63-year-old woman who had a uterine tumor with peritoneal dissemination and para-aortic lymph node metastasis. Microscopic specimens of the tumor showed a small blue round-cell tumor. Immunohistochemistry showed cells to be negative for cytokeratin AE1/3, desmin, myogenin, CD10, CD34, and CD99, focal positive for vimentin, and positive for muscle-specific actin (HHF-35), neurofilament, synaptophysin and CD56. Fluorescence in situ hybridization revealed no split signal showing Ewing sarcoma breakpoint region 1 gene translocation. Deletion of 1p36 was identified in 30% of the tumor cells. These findings are thought to be equivalent to central type primitive neuroectodermal tumors/neuroblastoma. Cytoreductive debulking surgery followed by chemotherapy, including cyclophosphamide, vincristine and adriamycin, resulted in complete remission. She has no evidence of disease at 24 months after surgery.

Moore DD, Haydon RC
Ewing's sarcoma of bone.
Cancer Treat Res. 2014; 162:93-115 [PubMed] Related Publications
Ewing's sarcoma of bone is a primary bone sarcoma found predominantly in patients during their second decade of life. It is a high-grade aggressive small round blue cell tumor that is part of the Ewing's family of tumors. Its exact eitiology is unknown but it commonly demonstrates reproducible staining of CD99 and translocations of the EWS gene. Historically, this diagnosis was associated with near certain metastasis and subsequent mortality. However, current management consists of extensive chemotherapy in addition to local control with surgical resection and/or radiation. As a result, survival has improved to the 55-75% range in those patients who present without known metastases. Current research aims to continue this improvement by looking further into the associated gene abnormalities and possibly targeted therapies.

Shibuya R, Matsuyama A, Nakamoto M, et al.
The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma.
Virchows Arch. 2014; 465(5):599-605 [PubMed] Related Publications
Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs.

Sugita S, Arai Y, Tonooka A, et al.
A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.
Am J Surg Pathol. 2014; 38(11):1571-6 [PubMed] Related Publications
Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS.

Milione M, Gasparini P, Sozzi G, et al.
Ewing sarcoma of the small bowel: a study of seven cases, including one with the uncommonly reported EWSR1-FEV translocation.
Histopathology. 2014; 64(7):1014-26 [PubMed] Related Publications
AIMS: Primary Ewing sarcoma of the ileum has rarely been documented. Little is known about its pathogenesis and clinical implications, and it would be helpful to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in Ewing sarcoma, as FEV expression is restricted to prostate, brain and serotonin neuroendocrine cells (NE) and related tumours.
METHODS AND RESULTS: Paraffin sections or snap-frozen material were used in this investigation. Tumours were investigated by means of immunohistochemistry, RT-PCR (EWSR1-FLI1, EWSR1-ERG and EWSR1-FEV transcripts), FISH analysis (EWSR1 break-apart and specific EWSR1-FEV translocation) and spectral karyotyping (SKY). Ten ileal neuroendocrine tumours (INET) made up the control group for EWSR1-FEV translocation. Among 445 Ewing sarcomas cases spanning a period of 20 years, seven (1.6%) arose in the ileum. All tumours were immunoreactive for synaptophysin, CD99, FLI1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumour showing the uncommon EWSR1-FEV rearrangement, with SKY, RT-PCR and FISH confirmation. The mean survival of EWSR1-FLI1 patients was 14 months, whereas the EWSR1-FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation.
CONCLUSIONS: Most primary Ewing sarcomas of the ileum show the common EWSR1-FLI1 translocation, but EWSR1-FEV could be specific for tumours arising in the ileum and showing better prognosis.

Puls F, Niblett A, Marland G, et al.
BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma.
Am J Surg Pathol. 2014; 38(10):1307-18 [PubMed] Related Publications
BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis.

Specht K, Sung YS, Zhang L, et al.
Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities.
Genes Chromosomes Cancer. 2014; 53(7):622-33 [PubMed] Free Access to Full Article Related Publications
Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as ES-like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1, and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1 rearrangement. © 2014 Wiley Periodicals, Inc.

Conzo G, Tartaglia E, Gambardella C, et al.
Suprarenal solitary fibrous tumor associated with a NF1 gene mutation mimicking a kidney neoplasm: implications for surgical management.
World J Surg Oncol. 2014; 12:87 [PubMed] Free Access to Full Article Related Publications
Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm, usually occurring in the pleura. Pararenal SFT, mimicking an adrenal gland or renal tumor, as here described, is extremely rare. We report a case of a right suprarenal SFT, incidentally discovered by abdominal ultrasound in a 54-year-old woman carrying a point neurofibromatosis 1 (NF1) gene mutation. Preoperative diagnostic work-up was ineffective in evaluating its origin, and an open radical right nephrectomy was therefore undertaken. Immunohistochemical assay showed a positivity for CD34, CD99 and Bcl-2, so suggesting a diagnosis of SFT. According to our knowledge, the association between this type of tumor and NF1 gene mutation has never been described. In cases of pararenal tumors, a more detailed preoperative diagnosis could be useful to better plan the extension of resection, allowing, in selected cases, nephron-sparing surgery. More studies are needed to better analyze the relationship between NF1 gene mutation and SFT.

Ohzeki M, Fujita S, Miyazaki H, et al.
A patient with primary pericardial synovial sarcoma who presented with cardiac tamponade: a case report and review of the literature.
Intern Med. 2014; 53(6):595-601 [PubMed] Related Publications
A 36-year-old man presented with near-syncope. He was found to have massive pericardial effusion with a giant pericardial tumorous lesion. The pericardial effusion exhibited a bloody nature; however, neither malignant cells nor infectious organisms were detected. (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed an increased uptake of FDG in the pericardial tumor only. Although the tumor was not resectable, thoracotomy and tissue sampling were performed. A histological analysis showed CD99 positivity and SYT gene rearrangement, leading to a diagnosis of synovial sarcoma arising from the left lateral pericardial surface. The patient is now receiving chemotherapy.

Amaral AT, Manara MC, Berghuis D, et al.
Characterization of human mesenchymal stem cells from ewing sarcoma patients. Pathogenetic implications.
PLoS One. 2014; 9(2):e85814 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin.
MATERIALS AND METHODS: In an initial study regarding a deep characterization of MSC obtained specifically from EWS patients (MSC-P), we compared them with MSC derived from healthy donors (MSC-HD) and EWS cell lines. We evaluated the presence of the EWS-FLI1 gene fusion and EWSR1 gene rearrangements in MSC-P. The presence of the EWS transcript was confirmed by q-RT-PCR. In order to determine early events possibly involved in malignant transformation, we used a multiparameter quantitative strategy that included both MSC immunophenotypic negative/positive markers, and EWS intrinsic phenotypical features. Markers CD105, CD90, CD34 and CD45 were confirmed in EWS samples.
RESULTS: We determined that MSC-P lack the most prevalent gene fusion, EWSR1-FLI1 as well as EWSR1 gene rearrangements. Our study also revealed that MSC-P are more alike to MSC-HD than to EWS cells. Nonetheless, we also observed that EWS cells had a few overlapping features with MSC. As a relevant example, also MSC showed CD99 expression, hallmark of EWS diagnosis. However, we observed that, in contrast to EWS cells, MSC were not sensitive to the inhibition of CD99.
CONCLUSIONS: In conclusion, our results suggest that MSC from EWS patients behave like MSC-HD and are phenotypically different from EWS cells, thus raising important questions regarding MSC role in sarcomagenesis.

Clevenger JA, Saxena R, Idrees MT
A de novo unclassified malignant spindle cell neoplasm of liver allograft.
Arch Pathol Lab Med. 2014; 138(2):274-7 [PubMed] Related Publications
Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with Epstein-Barr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft.

Ahn S, Kang SY, Suh YL
Supratentorial ependymoma with glial component of two different histologies and neuropil-like islands: a case report.
Clin Neuropathol. 2014 Mar-Apr; 33(2):128-34 [PubMed] Related Publications
Glioneuronal tumors with neuropil-like islands (GTNIs) are a basically infiltrating astrocytoma or mixed oligoastrocytoma, containing large neuropil-like islands (NIs). Recently, we experienced a peculiar case of supratentorial ependymoma with NIs. A 29-month-old girl presented with seizure and a brain magnetic resonance image revealed a huge heterogeneous mass in the left lateral ventricle. Histologically, glial components of the tumor showed two different histologies: anaplastic ependymoma and myxopapillary ependymomatous features. The latter was admixed with numerous NIs. Immunohistochemically, the glial components expressed GFAP and a paranuclear dot pattern of EMA and CD99, whereas the NIs were positive for synaptophysin and MAP2. KI-67 was high in the anaplastic ependymoma, but very low in the fascicles of spindle cells and NIs. Quantitative PCR confirmed mRNA expression of five genes related to neuronal differentiation in both the glial and neuronal components of this tumor. Our case suggests that ependymoma with NIs may be in a spectrum of GTNIs.

Sabater-Marco V, Zapater Latorre E, Martorell Cebollada M
Postradiation cutaneous pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers.
J Cutan Pathol. 2014; 41(3):316-21 [PubMed] Related Publications
Rhabdomyosarcoma is a malignant mesenchymal neoplasm that rarely presents as primary skin tumor. So-called amianthoid fibers are hyalinized collagen mats that have been described in myofibroblastic tumors but not in rhabdomyosarcoma. A 65-year-old male developed a submandibular nodule 9 years after an oral squamous cell carcinoma, which had been treated with chemotherapy and radiotherapy. Histological examination of the nodule revealed a pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers. By immunohistochemistry, the tumor cells were positive for vimentin, desmin, smooth muscle actin (SMA), muscle-specific actin (MSA), CD10, CD56, CD99, β-catenin and D2-40. However, only 15-20% of the tumor cells were positive for myoglobin, MyoD1 and myf-4/myogenin. We describe first so-called amianthoid fibers harboring blood capillaries in a rhabdomyosarcoma, suggesting that they are rigid collagen structures that lead to tumor vascularization. The low expression for myogenic regulatory proteins and strong expression for other markers may be misleading and do not contribute to the diagnosis of rhabdomyosarcoma.

Zahir MN, Ansari TZ, Moatter T, et al.
Ewing's sarcoma arising from the adrenal gland in a young male: a case report.
BMC Res Notes. 2013; 6:533 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing's sarcoma uncommonly arises from extraosseous soft tissue or parenchymal organs. Primary adrenal Ewing's Sarcoma, although very rare, is extremely aggressive and commonly fatal.
CASE PRESENTATION: A 17 year old Pakistani male was referred to the outpatient oncology clinic at our center with a three month history of concomitant pain, swelling and dragging sensation in the right hypochondrium. Abdominal examination revealed a large, firm mass in the right hypochondrium extending into the right lumbar region and epigastrium. His genital exam was unremarkable and there were no stigmata of hepatic or adrenal disease.Computed tomography scans revealed a large peripherally enhancing mass in the hepatorenal area, biopsy of which showed a neoplastic lesion composed of small round blue cells which exhibited abundance of glycogen and stained diffusely positive for CD99 (MIC2 antigen). Fluorescence in situ hybridization demonstrated gene rearrangement at chromosome 22q12 which confirmed the diagnosis of Ewing's sarcoma. Staging scans revealed pulmonary metastasis and hence he was commenced on systemic chemotherapy.
CONCLUSION: This case report highlights the importance of keeping Ewing's sarcoma in mind when a young patient presents with a large non-functional adrenal mass.

White JC, Halligan GE, de Chadarévian JP, et al.
Unusual genetic aberrations including a deletion of KLF6 tumor suppressor gene revealed by integrated cytogenetic approaches in a pediatric ewing sarcoma.
J Pediatr Hematol Oncol. 2015; 37(1):e51-4 [PubMed] Related Publications
Ewing sarcoma is the third most common sarcoma in children and young adults. Its characteristic chromosomal rearrangement results in a chimerical EWSR1-ETS transcription factor. Secondary genetic alterations are very common. Membranous expression of CD99 is seen in almost all tumors. We report 2 unusual cytogenetic findings in a pediatric Ewing sarcoma, an insertion of the MIC2 gene encoding CD99 from Xp to 10p and a submicroscopic deletion of the well-known tumor supressor gene KLF6. The latter has not been described previously in pediatric neoplasms. Molecular pathways in tumorigenesis and genetic complexity in cancer are discussed.

Rekhi B, Vogel U, Basak R, et al.
Clinicopathological and molecular spectrum of ewing sarcomas/PNETs, including validation of EWSR1 rearrangement by conventional and array FISH technique in certain cases.
Pathol Oncol Res. 2014; 20(3):503-16 [PubMed] Related Publications
Over the years, a wide clinicopathological spectrum has been identified within Ewing family of tumors (EFTs). As these tumors are chemosensitive, their correct and timely identification is necessary. The aims of this study were (1) to present the diverse clinicopathological and molecular profile of EFTs in our settings, (2) to identify a pragmatic approach for diagnosing EFTs, especially for application of ancillary techniques, namely RT-PCR for specific transcripts (EWS-FLI1, EWS-ERG) and FISH for EWSR1 gene rearrangement, in certain cases and (3) to show the utility of tissue microarray in establishing a new FISH test. Fifty-eight EFTs were identified in 38 males and 20 females within an age-range of 1-65 years (median, 16), mostly in lower extremities (14) (24.1 %). Therapeutically, most patients underwent neoadjuvant chemotherapy with subsequent surgery. Histopathologically, diagnosis of EFTs was initially offered in 41/58 (70.6 %) tumors. On review, 59 % tumors showed diffuse pattern, while 41 % displayed rosettes. Immunohistochemically, tumor cells were mostly diffusely positive for CD99 (48/52) (92.3 %); FLI-1 (17/18) (94.4 %); variably for BCL2 (16/18) (88.8 %), synaptophysin (6/20) (35 %), S100-P (2/7) (28.5 %), CD56 (2/5) (40 %), NSE (2/5) (40 %), calponin (3/4) (75 %), EMA (5/24) (20.8 %) and CK (3/24) (12.5 %), the latter two mostly focally. Fifty five tumors were EWS-FLI1 positive, while a single tumor was EWS-ERG positive. Sensitivity for PCR was 61 %. EWSR1 rearrangement was detected by FISH in 12/13 Ewing sarcomas/PNETs. Sensitivity for EWSR1 test was 92.3 % and specificity was 100 %. Thirty-eight tumors, including 14 molecular confirmed EFTs and 21 other tumors were tested for EWSR1 rearrangement. Among 21 unrelated tumors, EWSR1 rearrangement was detected in few myoepithelial tumors, occasional desmoplastic small round cell tumor and an extraskeletal myxoid chondrosarcoma. Further, a tissue microarray with a separate set of 8 EFTs, confirmed at another laboratory was analysed for validation of EWSR1 rearrangement test. 23/28 (82.1 %) tissue cores of the tissue microarray, stained by FISH were interpretable, including EWSR1 rearrangement, detected in 20/28 tissue cores; not detected in 3 liver cores and uninterpretable in 5 (17.8 %) cores. Classical EFTs can be diagnosed with diffuse, membranous CD99 positivity, intranuclear FLI1 positivity and LCA negativity in malignant round cells. In unconventional cases, it is indispensable to reveal the concomitant fusion m-RNA by RT-PCR. In case of negative molecular results, it is necessary to prove EWSR1 rearrangement by FISH. These tests should be interpreted with clinicopathological correlation. Tissue microarrays for FISH are useful during validation of a new test, especially when sarcomas like EFTs show less genetic heterogeneity within tumor cells.

Sasaki T, Onishi T, Yabana T, Hoshina A
Ewing's sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review.
Tumori. 2013 May-Jun; 99(3):e104-6 [PubMed] Related Publications
We report a rare case of Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) arising from the adrenal gland. A 17-year-old Japanese woman presented with left upper abdominal pain and high fever. Computed tomography and magnetic resonance imaging revealed a 15 × 10 cm tumor replacing the adrenal gland. Preoperative diagnosis was an adrenocortical carcinoma. Resection of the tumor was performed. We obtained the final diagnosis of ES/PNET by immunohistochemical molecular study with positive staining for the MIC2 gene product (CD99) and a Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Local recurrence was observed one month after the surgery. The patient was then treated with systemic chemotherapy and localized radiotherapy.

Blandamura S, Alaggio R, Bettini G, et al.
Four cases of solitary fibrous tumour of the eye and orbit: one with sarcomatous transformation after radiotherapy and one in a 5-year-old child's eyelid.
J Clin Pathol. 2014; 67(3):263-7 [PubMed] Related Publications
BACKGROUND: Solitary fibrous tumour (SFT) is quite a rare neoplasm involving the eye and the orbit. It is described as showing benign behaviour in adults, but malignant cases are exceptionally reported in this location. This report describes four new cases of SFT/giant cell angiofibroma (GCA) of the eyelid and orbit, one in a 5-year-old child, and one with sarcomatous dedifferentiated transformation occurring 9 years after radiotherapy.
METHODS: Four cases of ocular SFT/GCA were retrieved from the database of the Pathological Anatomy Unit, University of Padova; immunohistochemistry and RT-PCR were used to identify COL1A1-PDBGF fusion gene transcripts in all cases.
RESULTS: In case 1, late relapse 9 years later was characterised by abrupt transition into a high-grade component, associated with a non-distinctive high-grade sarcomatous area. The latter component was CD34, CD99 and Bcl2 negative and smooth muscle actin positive. Molecular characterisation showed the absence of COL1A1-PDGFB fusion transcripts in cases 1, 3 and 4, excluded diagnosis of giant cell fibroblastoma in all cases. Analysis could not be performed in case 2.
CONCLUSIONS: An eyelid SFT/GCA in a 5-year-old child is the youngest case reported in the literature, indicating that the tumour is not exclusive to adults. The case with sarcomatous transformation, with dedifferentiated features occurring 9 years after radiotherapy, raises some questions about the choice of treatment for ocular SFT, in which excision is sometimes difficult without devastating surgery.

Kao YC, Lan J, Tai HC, et al.
Angiomatoid fibrous histiocytoma: clinicopathological and molecular characterisation with emphasis on variant histomorphology.
J Clin Pathol. 2014; 67(3):210-5 [PubMed] Related Publications
AIMS: Angiomatoid fibrous histiocytoma (AFH) is histologically typified by nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules and lymphocytic cuffs. The principal goal was to expand the spectrum of AFHs through clinicopathological and molecular characterisation.
METHODS: Thirteen AFHs, including 11 with confirmed hallmark translocation, were reappraised for classic features, reactive osteoclasts, mitoses and stromal, architectural and cytomorphological variations, with CD99, desmin and EMA stained in available cases.
RESULTS: Seven male and six female patients ranged in age from 4 to 63 years (median, 13), including 4 older than 20 years. Tumours were located on the extremities (n=6), trunk (n=4) and scalp (n=3). Although fibrous pseudocapsules were observed in all cases, four showed solid histology without pseudoangiomatoid spaces and another one lacked peripheral lymphoid infiltrates. Nuclear pleomorphism was striking in two cases, moderate in seven and absent in four, with osteoclasts seen in two cases. In three AFHs with sclerotic matrix, one exhibited perivascular hyalinisation and nuclear palisading, reminiscent of a schwannoma. In three varyingly myxoid tumours, one closely resembled a myoepithelioma with prominent reticular arrangement of spindle cells in an abundant myxoid stroma. Besides EWSR1 gene rearrangement detected in four cases by fluorescence in situ hybridisation (FISH), EWSR1-CREB1 fusion was confirmed in nine cases, including a schwannoma-like AFH, and EWSR1-ATF1 fusion detected in a myoepithelioma-like AFH. Immunohistochemically, 56% of AFHs were positive for EMA, 78% for desmin and 100% for CD99.
CONCLUSIONS: Molecular testing is diagnostic of variant AFHs displaying diverse histomorphological alterations in the architectural patterns, cytomorphology and extracellular matrix.

Sahara S, Otsuki Y, Egawa Y, et al.
Primary synovial sarcoma of the stomach--a case report and review of the literature.
Pathol Res Pract. 2013; 209(11):745-50 [PubMed] Related Publications
Synovial sarcoma (SS) is a mesenchymal spindle cell tumor which displays variable epithelial differentiation. It commonly arises around the major joints or tendon sheaths in young adults, but is not commonly seen in the stomach. We experienced a case of primary gastric SS. The patient is a 22-year-old male, who presented with epigastric pain. Upper endoscopy showed an ulcer of 25 mm in diameter with marginal elevation on the posterior mid-gastric body. Biopsy of the ulcer base showed monotonous proliferation of small spindle-shaped cells on HE-stain. On immunohistochemical staining, these cells were positively stained with vimentin, cytokeratin, epithelial membrane antigen, and CD99, but were negative for KIT, CD34, desmin, and S-100 protein. These findings were compatible with SS of monophasic type. Diagnosis of primary gastric SS was made because there were no other primary lesions, nor metastatic lesions. The wedge resection was performed. Reverse transcriptase polymerase chain reaction (RT-PCR), using the RNA from frozen neoplastic tissue of the resected specimen, detected a fusion gene called SYT-SSX1, specific for SS. Though SS arising in the stomach is rare, it should be considered in the differential diagnosis of KIT-negative gastric spindle cell tumor.

Choi EY, Thomas DG, McHugh JB, et al.
Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology.
Am J Surg Pathol. 2013; 37(9):1379-86 [PubMed] Related Publications
A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Lin Z, Chen B, Xu X, et al.
Analysis of clinical characteristics of 516 patients with non-Hodgkin's lymphoma in Shanghai area.
Hematology. 2014; 19(2):99-106 [PubMed] Related Publications
The aim was to determine the clinical and cytogenetic characteristics of non-Hodgkin's lymphoma (NHL) in Shanghai. A retrospective analysis was conducted in 516 patients with NHL. Patient clinical data, including age, sex, diagnosis, immunophenotypes, and karyotypes, were collected. The median age was 58 years. There was a male predominance in all NHL, except extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Patients with B cell NHL (1.5%) expressed CD3. T cell NHL patients (11.5%) expressed CD20. Epstein-Barr virus latent integral membrane protein 1, BCL6, CD10, Bcl-2, CD68, myeloperoxidase, CD99, CD30, CD15, and CD43 were present in various types of NHL. Complex karyotypes accounted for 92.3% of the 73.7% patients with abnormal karyotypes. Immunoglobin heavy chain gene translocation was present in 60.3% of B cell and 23.7% of T/NK cell neoplasms. Understanding the complex clinicopathological and molecular features of NHL may help with prognosis and serve as targets for treatments.

Jung TY, Choi YD, Kim YH, et al.
Immunological characterization of glioblastoma cells for immunotherapy.
Anticancer Res. 2013; 33(6):2525-33 [PubMed] Related Publications
The aim of this study was the immunological characterization of glioblastoma cells. Glioblastoma cell lines were cultured in serum and serum-free neurobasal (NBE) medium conditions. These cell lines were characterized by flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blot and natural killer (NK) cell-cytotoxicity assays. A previously described NK cell expansion method that uses K562 cells expressing interleukin (IL)-15 and 4-1 BB Ligand (BBL) (K562-mb15-41BBL) was used. RT-PCR and western blots for the expression of tumor-associated antigens (TAAs), were carried out in 32 glioblastoma and seven normal brain tissues. U87 and U343 tumor cell lines showed increased expression for major histocompatibility complex (MHC)-I and -II molecules. No significant differences in the levels of CD133, MHC class I/II, MHC class I-related chain A (MICA), MICB, UL16 binding protein 1-3 (ULBP 1-3) expression in these cell lines and in NK cell cytotoxicity were observed between serum and NBE conditions. Regardless of culture conditions, U87 and U343 cell lines were sensitive to expanded NK cells, with median cytotoxicities at 4:1 effector/target ratio of 43.2% and 46.5%, respectively. In RT-PCR, U343 and U87 showed the expression of most TAAs at a high ratio compared with U251. Western blots demonstrated positive expression for BIRC5, CD99 and ERBB2 in U251, U87 and U343 cell lines and tissues. These highly-expressed TAAs such as BIRC5, CD99 and ERBB2 in glioblastoma tissue could be the targets for immunotherapy. U87 and U343 cell lines could be useful for studying the efficacy of immunotherapy related to various TAAs and NK cell immunotherapy.

Kunkle BW, Yoo C, Roy D
Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.
PLoS One. 2013; 8(5):e64140 [PubMed] Free Access to Full Article Related Publications
In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors.

Tomlins SA, Palanisamy N, Brenner JC, et al.
Usefulness of a monoclonal ERG/FLI1 antibody for immunohistochemical discrimination of Ewing family tumors.
Am J Clin Pathol. 2013; 139(6):771-9 [PubMed] Free Access to Full Article Related Publications
Ewing family tumors (EFTs) and prostate carcinomas are characterized by rearrangement of ETS genes, most commonly FLI1 (EFTs) and ERG (prostate carcinomas). Previously, we characterized an antibody against ERG (EPR3864) for detecting ERG-rearranged prostate carcinoma. Because EPR3864 also cross-reacts with FLI1, we evaluated the usefulness of EPR3864 for discriminating EFTs from other small round blue cell tumors (SRBCTs) with immunohistochemistry. Of 57 evaluable EFTs, 47 (82%) demonstrated at least moderate, diffuse, nuclear ERG/FLI1 staining (including 89% and 100% of cases with confirmed EWSR1:FLI1 and EWSR1:ERG fusions, respectively), of which 1, 3, and 43 showed negative, cytoplasmic, or membranous CD99 staining, respectively. Among other SRBCTs (61 cases, 7 types), at least moderate, diffuse, nuclear EPR3864 staining was seen in all precursor B-lymphoblastic lymphomas/leukemias and subsets of Burkitt lymphomas (10%) and synovial sarcomas (45%). In summary, EPR3864 may be useful in detecting EWSR1:FLI1 and EWSR1:ERG rearranged EFTs in addition to prostate carcinomas.

Ramon AL, Bertrand JR, de Martimprey H, et al.
siRNA associated with immunonanoparticles directed against cd99 antigen improves gene expression inhibition in vivo in Ewing's sarcoma.
J Mol Recognit. 2013; 26(7):318-29 [PubMed] Related Publications
Ewing's sarcoma is a rare, mostly pediatric bone cancer that presents a chromosome abnormality called EWS/Fli-1, responsible for the development of the tumor. In vivo, tumor growth can be inhibited specifically by delivering small interfering RNA (siRNA) associated with nanoparticles. The aim of the work was to design targeted nanoparticles against the cell membrane glycoprotein cd99, which is overexpressed in Ewing's sarcoma cells to improve siRNA delivery to tumor cells. Biotinylated poly(isobutylcyanoacrylate) nanoparticles were conceived as a platform to design targeted nanoparticles with biotinylated ligands and using the biotin-streptavidin coupling method. The targeted nanoparticles were validated in vivo for the targeted delivery of siRNA after systemic administration to mice bearing a tumor model of the Ewing's sarcoma. The expression of the gene responsible of Ewing's sarcoma was inhibited at 78% ± 6% by associating the siRNA with the cd99-targeted nanoparticles compared with an inhibition of only 41% ± 9% achieved with the nontargeted nanoparticles.

Zucchini C, Manara MC, Pinca RS, et al.
CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity.
Oncogene. 2014; 33(15):1912-21 [PubMed] Related Publications
CD99, a transmembrane protein encoded by MIC2 gene is involved in multiple cellular events including cell adhesion and migration, apoptosis, cell differentiation and regulation of protein trafficking either in physiological or pathological conditions. In osteosarcoma, CD99 is expressed at low levels and functions as a tumour suppressor. The full-length protein (CD99wt) and the short-form harbouring a deletion in the intracytoplasmic domain (CD99sh) have been associated with distinct functional outcomes with respect to tumour malignancy. In this study, we especially evaluated modulation of cell-cell contacts, reorganisation of the actin cytoskeleton and modulation of signalling pathways by comparing osteosarcoma cells characterised by different metastasis capabilities and CD99 expression, to identify molecular mechanisms responsible for metastasis. Our data indicate that forced expression of CD99wt induces recruitment of N-cadherin and β-catenin to adherens junctions. In addition, transfection of CD99wt inhibits the expression of several molecules crucial to the remodelling of the actin cytoskeleton, such as ACTR2, ARPC1A, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) as well as ezrin, an ezrin/radixin/moesin family member that has been clearly associated with tumour progression and metastatic spread in osteosarcoma. Functional studies point to ROCK2 as a crucial intracellular mediator regulating osteosarcoma migration. By maintaining c-Src in an inactive conformation, CD99wt inhibits ROCK2 signalling and this leads to ezrin decrease at cell membrane while N-cadherin and β-catenin translocate to the plasma membrane and function as main molecular bridges for actin cytoskeleton. Taken together, we propose that the re-expression of CD99wt, which is generally present in osteoblasts but lost in osteosarcoma, through inhibition of c-Src and ROCK2 activity, manages to increase contact strength and reactivate stop-migration signals that counteract the otherwise dominant promigratory action of ezrin in osteosarcoma cells.

Terada T
Primary cutaneous neuroendocrine tumor (atypical carcinoid) expressing KIT and PDGFRA with myoepithelial differentiation: a case report with immunohistochemical and molecular genetic studies.
Int J Clin Exp Pathol. 2013; 6(4):802-9 [PubMed] Free Access to Full Article Related Publications
Primary cutaneous neuroendocrine tumors (NET) except for Merkel cell carcinoma have rarely been reported. Herein reported is a very unique case of primary cutaneous NET with immunohistochemical markers of myoepitheliomas. A 47-year-old woman presented a tumor measuring 0.8x0.9x0.6 cm of the face. The tumor was excised completely with wide margins. Morphologically, the tumor was located in the dermis, and the tumor was composed of epithelioid cells arranged in trabecular, sinusoidal, rosette, ribbon-like, and cord-like patterns. Focal areas show tubular formations. The tumor cells were homogenous, and their nuclei showed hyperchromasia but no apparent histological features of malignancy were seen. The stroma was very scant. No invasive features were seen. Immunohistochemically, the tumor cells were strongly positive for cytokeratin (CK) 34BE12, CD5/6, CK14, NCAM (CD56), p63, and KIT (CD117), and moderately positive for CK AE1/3, p53, chromogranin, synaptophysin, neuron-specific enolase (NSE), PDGFRA, CA19-9, and Ki-67 antigen (labeling index=23%). The tumor cells were negative for CK CAM5.2, CK7, CK8, CK18,CK19,CK20, EMA, vimentin, CEA, HMB45, S100 protein, α-smooth muscle antigen, desmin, CD34, GFAP, neurofilaments, CD99 (MIC2), CD45, CD57, ErbB2, TTF-1, MUC1, MUC2, MUC5AC, and MUC6. Mucins examined by d-PAS and Alcian blue techniques were negative. A genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Imaging modalities including CT and MRI identified no tumor in the body. The clinicians thought that the tumor was cured. She was a sailor and immediately visited other countries; therefore the follow-up could not be done.

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