cyclin-d1 and Appendiceal-Neoplasms

The Ras-association domain family 1A (RASSF1A) tumour suppressor gene is inactivated in a variety of solid tumours, usually by epigenetic silencing of the promoter and/or allelic loss of its locus at 3p21.3. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, 62 endocrine tumours from different sites in the gut were investigated for methylation of the RASSF1A promoter using the polymerase chain reaction, the presence of 3p21.3 deletions by loss of heterozygosity analysis, and cyclin D1 expression by immunohistochemistry. Methylation was found in 20/62 (32%) cases and was restricted to foregut tumours; deletion at 3p21.3 was found in 15/58 (26%) informative cases and restricted to malignant foregut tumours; cyclin D1 hyper-expression was found in 31/58 (53%) cases and correlated with RASSF1A methylation. Our data suggest that RASSF1A is involved in the development of endocrine tumours derived from the foregut only, and that the presence of both RASSF1A methylation and 3p21.3 deletion is associated with malignancy. These results may provide a rationale for foregut-targeted therapy for aggressive endocrine carcinomas entailing the use of demethylating agents.

Topics: Adult; Aged; Aged, 80 and over; Appendiceal Neoplasms; Carcinoma, Neuroendocrine; Cyclin D1; Duodenal Neoplasms; Female; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Ileal Neoplasms; Intestinal Neoplasms; Loss of Heterozygosity; Male; Methylation; Middle Aged; Pancreatic Neoplasms; Promoter Regions, Genetic; Rectal Neoplasms; Stomach Neoplasms; Tumor Suppressor Proteins

Goblet cell carcinoids of the appendix are rare neoplasms with uncertain biological behavior.. The aims of our study were to evaluate the immunophenotype of this neoplasm with cell cycle/cell proliferation markers and to understand their histogenesis with ultrastructural analysis using conventional carcinoids as a frame of reference.. Clinical data and archival pathologic material of all goblet cell carcinoids of the appendix recorded by the Saskatchewan Cancer Registry between 1970 and 1998 were reviewed and evaluated by light microscopy, histochemistry, immunohistochemistry, and electron microscopy.. Seven cases of goblet cell carcinoids were identified among 110 cases of conventional carcinoids of the appendix. Histopathology revealed widespread infiltration of the periappendiceal fat in all cases, with extensive perineural invasion. The cells stained strongly positive for mucicarmine, periodic acid-Schiff, periodic acid-Schiff diastase, Alcian blue, cytokeratin, and carcinoembryonic antigen. Most cases were positive for synaptophysin. Increased expression of cell proliferation markers and cell cycle markers was observed. Expression of p53 was strong in one case. Electron microscopy demonstrated the presence of mucinous vacuoles of varying sizes and occasional membrane-bound neuroendocrine granules.. Goblet cell carcinoids of the appendix arise from a pluripotent cell with divergent neuroendocrine and mucinous differentiation. These neoplasms are widely invasive; they demonstrate a high cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin D1 and p21, and down-regulation of p16. Complete removal of the tumor is recommended because of the unpredictable biological behavior of this tumor, which includes delayed local recurrences and lung metastases.

Topics: Adult; Aged; Aged, 80 and over; Appendiceal Neoplasms; Biomarkers, Tumor; Carcinoid Tumor; Cyclin D1; Cytoplasmic Granules; Female; Goblet Cells; Humans; Immunohistochemistry; Immunophenotyping; Ki-67 Antigen; Male; Middle Aged; Neoplasm Proteins; Neurosecretory Systems