P16, Cyclin D1, Ki-67, and AMACR as markers for dysplasia in Barrett esophagus
Division of Anatomical Pathology, Hunter Area of Pathology Service, Newcastle, Australia.Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry (Impact Factor: 2.01). 07/2008; 16(5):447-52. DOI: 10.1097/PAI.0b013e318168598b
Barrett esophagus (BE) is an established precursor of esophageal adenocarcinoma (AdenoCa). One hundred and one cases of BE diagnosed by esophageal biopsy and resections were examined morphologically for dysplasia. These were categorized as BE without dysplasia (n=25), indefinite for dysplasia (IND, n=17), low-grade dysplasia (LGD, n=18), high-grade dysplasia (HGD, n=15), and AdenoCa (n=26). Immunostaining for p16 (INK4A/CDKN2A), Cyclin D1 (CCND1), Ki-67, and alpha-methylacyl-CoA racemase (AMACR) was employed to assess their potential as diagnostic discriminators. Abnormal p16 expression (negative, cytoplasmic, or combined cytoplasmic and nuclear staining) was present in all categories, rising from 68% in BE without dysplasia to 100% in AdenoCa, with cytoplasmic staining only showing a significant correlation with the severity of dysplasia. Cyclin D1 expression was present in almost all cases, but high expression (>50% cells positive) was displayed mostly in HGD and AdenoCa (46.7% and 42.3%, respectively). Ki-67 index increased with the severity of dysplasia and labeling extended from the lower third of the crypts to the superficial epithelium. The frequency of AMACR-positivity was 12% in BE, 47.1% in IND, 44.4% in LGD, 93.3% in HGD, and 96.2% in AdenoCa. The intensity and extent of AMACR staining also increased with the severity of dysplasia. Aberrant p16 and high-cyclin D1 expression may reflect early genetic events during the progression of Barrett-associated carcinogenesis. Cytoplasmic staining of p16 is specific. It may represent a different pathway of p16 dysfunction. The pattern and extent of Ki-67 staining and AMACR overexpression are useful additional parameters for identifying dysplasia in BE.
Chapter: Upper Gastrointestinal Tract[Show abstract] [Hide abstract]
ABSTRACT: The application of immunohistochemistry in the diagnostic gastrointestinal pathology is similar to many other organ systems. The most commonly used markers are epithelial cell markers such as cytokeratin AE1/3, cytokeratin 7 and cytokeratin 20, and markers for common mesenchymal tumors such as CD117, CD34, S100, desmin, etc. Tumors of neuroendocrine origin are probably more commonly seen in the digestive and pulmonary systems. A synaptophysin and chromogranin immunostain generally can confirm their neuroendocrine nature. Use of immunohistochemical studies to evaluate dysplasia in Barrett’s esophagus is still investigational, although many have found p53 overexpression helpful in confirming dysplasia, particularly in high-grade dysplasia. The use of immunohistochemical studies in nonneoplastic diseases of the gastrointestinal tract is limited. Finally, immunohistochemistry, like GCDFP-15 immunostain, may play a critical role in differentiating certain metastases, such as lobular carcinoma of the breast, from primary tumors, including gastric signet ring cell carcinoma. KeywordsDysplasia-Carcinoma-GIST-Neuroendocrine-Metastasis-Keratin-CD117-SynaptophysinHandbook of Practical Immunohistochemistry, 01/1970: pages 409-422;
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