β-Catenin mutations in 2 nested stromal epithelial tumors of the liver - A neoplasia with defective mesenchymal-epithelial transition
Institut für Pathologie, Ludwig-Maximilians-Universität, 80337 München, Germany.Human pathology (Impact Factor: 2.77). 06/2012; 43(11):1815-27. DOI: 10.1016/j.humpath.2012.03.018
Nested stromal epithelial tumor of the liver is a rare neoplasm of early childhood and adolescence with a characteristic nested morphology of spindle and epithelioid cells. Histogenesis and pathogenesis of this neoplasm are, however, still unclear. Because the characteristic nested morphology with spindle mesenchymal and epithelioid cells is suggestive of altered mesenchymal-epithelial transition and β-catenin mutations are rather common in other liver tumors such as hepatoblastomas, we investigated the β-catenin gene in 2 nested stromal epithelial tumors of the liver and analyzed additional factors involved in mesenchymal-epithelial transition, such as E-cadherin, vimentin, c-Met, TWIST, SNAIL, and SLUG by molecular genetic and immunohistochemical methods. Mutation analysis of both cases revealed large deletions in exon 3 of the β-catenin gene (155 and 228 base pairs), resulting in an accumulation of β-catenin in the cytoplasm and nuclei of tumor cells, as evidenced by immunohistochemistry. The expression of the mesenchymal-epithelial transition factors SNAIL, SLUG, TWIST, c-Met, vimentin, and β-catenin was generally increased, whereas E-cadherin was decreased. Morphological and immunohistochemical analysis, however, showed a variable expression pattern of various epithelial and mesenchymal markers both in the spindle and epithelioid cell compartments of the tumors, thus illustrating the transitional status of the tumor cells. In conclusion, our data clearly identify protein stabilizing mutations of the β-catenin gene as a common feature of nested stromal epithelial tumors of the liver, similarly as in hepatoblastomas. Therefore, nested stromal epithelial tumors of the liver may be regarded as a variant of hepatoblastoma, despite differing from it in clinical and morphological aspects. The characteristic epithelioid-spindle morphology along with the incomplete epithelial differentiation proposes impaired mesenchymal-epithelial transition as a possible pathogenetic mechanism of this rare tumor. However, because only 2 cases were studied, this hypothesis awaits further validation.
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ABSTRACT: Abstract Background: Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, congenital malformation and tumor predisposition. Children with BWS have a higher incidence of tumors, commonly intra-abdominal tumors such as Wilms tumor, hepatoblastoma and adrenal cortical carcinoma. Here, we describe the first case of a rare hepatic malignancy of nested stromal epithelial tumor (NSET) of the liver in a child with BWS. Case Report: A 22-month old girl with BWS had a new incidental liver mass. Her alpha-feto protein levels were normal. She underwent a liver segmentectomy. Results: Histopathological features combined with immunohistochemistry results (positivity for pan keratin (AE1/3), CD56, CK19, CD117 and CD99 (weak membranous pattern), β-catenin and WT1-COOH (focal)), were diagnostic of NSET of the liver. Conclusions: This is the first case of NSET of the liver associated with BWS. Its occurrence at such an early age is consistent with the tumor predisposition of BWS.
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ABSTRACT: Hepatoblastoma is the most common hepatic tumor in paediatric population with an increasing incidence. It occurs almost in patients younger than 3 years without history of liver disease. Even if the aetiology is unknown, it can be associated with a congenital abnormality or an APC mutation. Hepatoblastoma appears as a well-circumscribed liver mass with, in most cases, an abnormal elevation of alfa-foetoprotein level (AFP). The imaging characteristics of the tumor reflect its gross pathologic appearance and histological composition. A biopsy is mandatory to confirm the diagnosis and study biological markers of the tissue. The radiological characteristics and the histology have permitted to build a new classification and a stratification of the treatment. Cisplatinum associated with surgical resection is the mainstay of treatment. Tumors considered unresectable may be treated with liver donor transplantation. The intensification of the chemotherapy and the radical surgery have increased the complete resection rate and the overall survival (80%) even in the high risk stage.
Article: Hepatic Tumors in Childhood[Show abstract] [Hide abstract]
ABSTRACT: Great progress in the treatment of hepatoblastoma and some other tumors of the liver in children has been achieved in the past quarter century. Mostly, the benefits have derived from cis-platinum-based chemotherapy for neoplasms and propranolol for infantile hemangiomas. With the advances has come the recognition that thorough histopathologic characterization of HB has prognostic significance and should influence the choice of therapy. These advances have done less for disease that is all too often disseminated at presentation, including most hepatocellular carcinomas and the small undifferentiated cell and rhabdoid variants of HB. The rarity of the tumors has led to increasing international collaboration among all disciplines to address the outstanding issues. Molecular genetic research on pathways of gene expression is providing insights into carcinogenesis and will lead to therapies that avoid the toxicity of current regimens while more effectively attacking the neoplastic cells. But traditional morphologic diagnoses and complete surgical extirpation, including transplantation, remain essential. This chapter summarizes the current data on the antecedent and acquired genetic abnormalities in liver tumors while emphasizing those aspects of histopathology that are essential for diagnostic accuracy and prognosis.
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