The expression of NeuroD and mASH1 in the gastroenteropancreatic neuroendocrine tumors

Abstract

Gastroenteropancreatic neuroendocrine tumors are uncommon and their tumor biology has not been well elucidated to date. Currently the WHO classification is widely used for the diagnosis and distinction of this tumor entity, which is sometimes cumbersome. Although neuroendocrine tumor markers do exist (ie chromograninA, synaptopyhsin, etc), sensitive and specific markers that accurately predict tumor growth and tumor behavior are still absent. In the present study, we assessed the expression of transcription factors (NeuroD and mASH1) essential for the normal fetal neuronal development in 33 gastroenteropancreatic neuroendocrine tumor patients (12 well-differentiated neuroendocrine tumors, 7 well-differentiated neuroendocrine carcinomas, and 14 poorly differentiated neuroendocrine carcinomas). NeuroD was less expressed in poorly differentiated neuroendocrine carcinoma (small-cell type) compared to well-differentiated neuroendocrine tumor (carcinoid) by reverse transcription-polymerase chain reaction. Immunohistochemical staining revealed that mASH1 was highly (sensitivity of 71%) and specifically (specificity of 95%) expressed in poorly differentiated neuroendocrine carcinoma. High NeuroD expression was seen in all well-differentiated neuroendocrine carcinoma and tumor (carcinoid) patients. Low NeuroD expression was seen in 36% (5 of 14) of poorly differentiated neuroendocrine carcinoma patients, which was associated with significant shorter overall survival. The expression pattern of these transcription factors may represent the biological and pathophysiological difference of gastroenteropancreatic neuroendocrine tumors and may become a new marker for the distinction of gastroenteropancreatic neuroendocrine tumors. Keywords: NeuroD; mASH1; hASH1; gastroenteropancreatic; neuroendocrine tumor Neuroendocrine tumors are a group of tumors originating from cells of the diffuse endocrine system. The diffuse endocrine system includes a number of endocrine cells spreading throughout all the body with the ability to secrete bioactive peptides and amines. Gastroenteropancreatic neuroendocrine tumors are fairly rare, and the pathophysiology of this tumor entity has not been well documented to date. Moreover diagnosis and target treatment is limited and management is challenging because little is known about the cell biology and mechanistic regulation of these tumors.1 Gastroenteropancreatic neuroendocrine tumors are classified according to the WHO classification into welldifferentiated tumors and carcinomas or poorly differentiated carcinomas.2 The current WHO classification system uses both stage-related criteria (size and presence of metastases) and grade-related criteria (mitotic rate, perineural invasion, angioinvasion, and Ki-67 proliferative index) for classifying and predicting the outcome of gastroenteropancreatic neuroendocrine tumors. As this approach includes the majority of well-accepted pathologic

A Tissue Microarray-based Comparative Analysis of Novel and Traditional Immunohistochemical Markers in the Distinction Between Adrenal Cortical Lesions and Pheochromocytoma

“…MASH1, also known has human achaetescute homolog-1, is a transcription regulator that plays an important role in brain development and the diffuse neuroendocrine system including adrenal medullary chromaffin cells, thyroid parafollicular C cells, glomus chief cells, and pulmonary neuroendocrine cells. 11,21,45 Although immunohistochemical expression of MASH1 has been reported in pulmonary neuroendocrine neoplasms 9,12,13,29 and gastrointestinal endocrine neoplasms 27,37 consistent with the protein's biology, the immunoreactivity in neoplasms derived from adrenal medullary chromaffin cells (pheochromocytoma) and the adrenal cortex has not been previously explored. We hypothesized that MASH1 might be another useful marker of pheochromocytoms; however, despite strong nuclear positive control staining using a pulmonary small cell carcinoma, MASH1 expression was not seen in any pheochromocytoma (0 of 35) or adrenal cortical lesion (0 of 63).…”

Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas

“…Carcinoids/ NETs are said to be derived from neuroendocrine cells dispersed mainly in the bronchial and GI tracts. Several reports have revealed that some basic helix-loop-helix transcription factors, which are critical in neural differentiation, contribute to enteroendocrine cell differentiation and that NENs including carcinoids/NETs express these factors [28][29][30] . Our data support the relationship between neural differentiation and carcinoid/NET tumorigenesis.…”

A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets

“…High levels of Ascl1 expression have been observed in a wide range of neuroendocrine tumors, including small cell lung carcinomas (Ball 2004), prostate tumors (Vias et al 2008), medullary thyroid cancers (Chen et al 2005), and gastroenteropancreatic tumors (Shida et al 2008). A direct role of Ascl1 in neurodendocrine tumor formation is supported by experiments of overexpression of Ascl1 together with SV40 Large T Antigen in lung epithelium, which produce massive neuroendocrine tumors (Linnoila et al 2000), and Ascl1 knockdown experiments, which inhibit proliferation of lung cancer cells both in vitro and in vivo (Osada et al 2005;Jiang et al 2009).…”