Summary Dermatofibrosarcoma protuberans (DFSP) is a cutaneous, locally aggressive spindle cell tumor of intermediate malignancy. Tumor cells are reactive for CD34 and characterized by a t(17;22) ...translocation or a supernumerary ring chromosome that results in the fusion of exon 2 of PDGFB to various exons of the COL1A1 gene. We developed a multiplex reverse transcription polymerase chain reaction (RT-PCR) assay to detect fusion transcripts for all possible COL1A1 breakpoints. Twenty-seven formalin-fixed, paraffin-embedded DFSP cases were analyzed using 18 COL1A1 forward primers and 1 exon 2 PDGFB reverse primer. Sequence analysis was performed to definitively characterize breakpoints. Results were correlated with histology, immunohistochemistry, PDGFB break-apart fluorescence in situ hybridization analysis, and cytogenetics when available. Fusion transcripts were detected by RT-PCR in all but one DFSP case. Sequencing revealed a PDGFB exon 2 breakpoint in all cases. COL1A1 breakpoints were in exons 7 (1 patient), 10 (1), 29 (2), 40 (1), 46 (3), and 49 (2), and intronic between exons 13:14 (1), 26:27 (2), 30:31 (1) 33:34 (1), 43:44 (7), 45:46 (1), and 46:47 (1). Three novel COL1A1 breakpoints were identified, intronic between exons 13:14 (1), 30:31 (1) and in exon 49 (2). There was no correlation found between breakpoints and age, sex, or histologic variants. Using this sensitive multiplex RT-PCR assay in combination with fluorescence in situ hybridization, we found COL1A1-PDGFB rearrangements appear more prevalent in DFSP than previously reported. Its detection may be particularly helpful in the differential diagnosis of atypical, fibrosarcomatous, and metastatic DFSP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary We hereby report an unusual gastric tumor arising from the pyloric wall of the stomach in a 9-year old child harboring the exceptionally rare translocation t(7;12) resulting in ACTB-GLI1 gene ...fusion. This tumor has been previously classified as pericytoma with t(7;12) and described in 6 patients, two of them children. We discuss the challenges in recognizing this rare entity and the importance of the molecular studies in establishing the correct diagnosis. Our case is the first report of this type arising in the stomach of a child.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Hepatoblastoma is characterized by a diversity of differentiation patterns, some resembling stages of liver development, and occasionally associated with clinical behavior. Our hypothesis is ...that histologic microheterogeneity in hepatoblastoma correlates with molecular heterogeneity and reflects different stages of developmental arrest. We studied the activation status of the Wnt and Notch pathways and the differential expression of hepatocyte nuclear factor 4 α , EGFR, and IGF2 genes, relevant to liver development and malignant transformation in histologic variants of hepatoblastoma. Eighty-seven percent of 32 hepatoblastoma cases studied carried CTNNB1 mutations within the ubiquitination domain. Large deletions were seen only in pure fetal cases, also characterized by CCND1 and GLUL (GS) overexpression. Hepatoblastomas with small-cell type appeared clearly distinct and were the only ones with negative GLUL expression. HES1 expression and HES1/AXIN2 used to measure Notch versus Wnt activation ratio were particularly elevated in pure fetal cases and were lowest in hepatoblastomas with small-cell component. Hepatocyte nuclear factor 4 α was relatively elevated only in embryonal hepatoblastomas. DLK1, DKK, AXIN2 , IGF2 , and EGFR were increased in all subtypes. Our results support the hypothesis that hepatoblastoma microheterogeneity correlates with molecular heterogeneity. DLK1 , a marker of bipotential oval cells, is consistently up-regulated in hepatoblastoma. Therefore, we speculate that hepatoblastomas may arise from a proliferating bipotential precursor. Wnt activation is prevalent in hepatoblastomas, most significantly in predominantly embryonal and mixed types, whereas Notch activation, needed for cholangiocytic differentiation at a more differentiated state, is highest in pure fetal hepatoblastomas. The relative Wnt versus Notch activation appears useful in stratifying different subtypes.
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Hep G2 is a hepatoblastoma-derived cell line López-Terrada, Dolores, MD, PhD; Cheung, Sau Wai, PhD, MBA; Finegold, Milton J., MD ...
Human pathology,
10/2009, Volume:
40, Issue:
10
Journal Article
Peer reviewed
...Hep G2 has been listed on the ATCC repository (American Type Culture Collection, Rockville, MD, USA) as a human cell line (HB 8065) "derived from the liver tissue of a 15-year-old white male with ...a well-differentiated hepatocellular carcinoma.âeuro The mistaken classification of the Hep G2 tumor of origin has created confusion between investigators and a divided body of scientific literature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Dermatofibrosarcoma protuberans (DFSP) is a rare malignant skin tumor associated with a characteristic chromosomal translocation (t17;22q22;q13) resulting in the COL1A1 -platelet-derived ...growth factor β (PDGFB) fusion gene. This malignancy is rarely diagnosed in childhood. Objective We observed an unexpected high incidence of this DFSP in children affected with adenosine deaminase–deficient severe combined immunodeficiency (ADA-SCID) and set out to evaluate the association of these 2 clinical entities. Methods Twelve patients with ADA-SCID were evaluated with a complete dermatologic examination and skin biopsy when indicated. Conventional cytogenetic and molecular analyses (fluorescence in situ hybridization, RT-PCR, or both) were performed when possible. Results Eight patients were found to have DFSP. Six patients had multicentric involvement (4-15 lesions), primarily of the trunk and extremities. Most lesions presented as 2- to 15-mm, round atrophic plaques. Nodular lesions were present in 3 patients. In all cases CD34 expression was diffusely positive, and diagnosis was confirmed either by means of cytogenetic analysis, molecular testing, or both. The characteristic DFSP-associated translocation, t(17;22)(q22;q13), was identified in 6 patients; results of fluorescence in situ hybridization were positive for fusion of the COL1A1 and PDGFB loci in 7 patients; and RT-PCR showed the COL1A1 - PDGFB fusion transcript in 6 patients. Conclusions We describe a previously unrecognized association between ADA-SCID and DFSP with unique features, such as multicentricity and occurrence in early age. We hypothesize that the t(17;22)(q22;q13) translocation that results in dermal overexpression of PDGFB and favors the development of fibrotic tumors might arise because of the known DNA repair defect in patients with ADA-SCID. Although the natural course of DFSP in the setting of ADA-SCID is unknown, this observation should prompt regular screening for DFSP in patients with ADA-SCID.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Hepatoblastoma is the most common malignant tumor of the liver of children worldwide. Histologically, hepatoblastomas show marked variation in the type and proportion of epithelial (fetal, ...embryonal, or small cell) and mesenchymal components with differing prognosis and response to therapy. The pure fetal–type hepatoblastoma, presenting as stage 1 and resectable, has the best prognosis, whereas the small cell histology has been associated with unfavorable outcome. Using gene expression profiling, we demonstrate that in addition to Wnt pathway deregulation, cell growth and survival pathways are also globally deregulated in hepatoblastomas. Furthermore, the different histologic subtypes are characterized by specific gene expression and pathway signatures that give insight into the degree of molecular heterogeneity that is present among these tumors. Although Wnt signaling pathway upregulation is common to all histologic types of hepatoblastoma, this pathway is even more significantly deregulated in aggressive hepatoblastomas. In addition, deregulation of MAPK signaling pathway and antiapoptotic signaling is preferentially upregulated in aggressive epithelial hepatoblastomas with a small cell component. The gene expression signatures reported here provide possible prognostic and diagnostic markers as well as therapeutic targets for this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Ewing sarcoma (ES) is an aggressive malignant small round cell tumor that arises in bone or soft tissue of adolescents and young adults. A characteristic molecular finding in ES is EWSR1 gene ...fusion with ETS (erythroblast transformation-specific) family genes including FLI1 (~90%) and ERG (>5%). Here we report our experience using integrated clinicopathologic, cytogenetic, fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR) analyses of 32 pediatric patients with ES diagnosed in a single institution between 2005 and 2011. Diagnostic EWSR1 rearrangements were detected in 30 (93.8%) of 32 patients. Cytogenetics detected t(11;22) (n = 14) and t(21;22) (n = 1) in 15 (46.9%) patients. FISH detected EWSR1 rearrangements in 27 (96.4%) of 28 patients tested. RT-PCR was positive in 27 (84.4%) of 32 patients, including 24 EWSR1 - FLI1 and 3 EWSR1 - ERG . RT-PCR defined breakpoints and fusion partners in 7 cases with EWSR1 rearrangements detected by FISH. Sanger sequencing further delineated breakpoints in 21 (77.8%) of 27 RT-PCR positive cases. In summary, conventional cytogenetic analysis provided a global view but had a lower detection rate and longer turnaround time than other methods. FISH is a rapid method and theoretically can detect all EWSR1 rearrangements, but it cannot identify all partners and is not completely specific for ES. RT-PCR and sequencing are more sensitive and useful in identifying fusion partners and refining breakpoints; however, these methods can be compromised by poor RNA preservation and primer design. In conclusion, an integrated approach that uses all methods capable of detecting EWSR1 rearrangements has value in the workup of suspected cases of ES.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the ...four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. Methods The CHIC steering committee—consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)—created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3–7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101–1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. Results Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. Interpretation We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). Funding European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission ( grant number 261474 ); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
FOXG1 is overexpressed in hepatoblastoma Adesina, Adekunle Michael, MD, PhD; Nguyen, Yummy, MS; Guanaratne, Preethi, PhD ...
Human pathology,
03/2007, Volume:
38, Issue:
3
Journal Article
Peer reviewed
Summary Bacterial artificial chromosome array comparative genomic hybridization analysis of hepatoblastomas reveals a deletion in the 14q12 locus in 12 of 16 cases. A high frequency of copy gain is ...seen on chromosomes 1q, 2, 5p, 8, and 20. Frequent deletions are also seen at 6q, 17q, and 1p with less frequent gains on 4p, 6p, and 19p. 14q12 deletion locus analyses using quantitative real-time polymerase chain reaction reveals copy number gain/amplification in the region immediately telomeric to the deleted locus, including copy number gain (2- to 4-fold) of FOXG1 in 13 out of 16 tumors. This is associated with up-regulation (∼87-fold) of FOXG1 gene transcripts and increased protein expression. Immunostaining reveals an inverse relationship between FOXG1 expression and p21cip1 expression in all histologic subtypes. However, FOXG1 transcript levels were significantly higher (∼75-fold) in tumors with embryonal and small cell components when compared with pure fetal hepatoblastomas. FOXG1 has been implicated in the repression of transforming growth factor β –induced expression of p21cip1 and cytostasis. Our findings are consistent with such a role for FOXG1. We propose that FOXG1 overexpression may contribute to the maintenance of the undifferentiated state in hepatoblastomas and could be a potential target for molecular therapeutics. This is the first report of a possible role for FOXG1 in hepatoblastoma and pediatric neoplasia.
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