p16, cyclin D1, Ki-67, and AMACR as markers for dysplasia in Barrett esophagus

Appl Immunohistochem Mol Morphol. 2008 Oct;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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Barrett Esophagus / diagnosis
  • Barrett Esophagus / enzymology
  • Barrett Esophagus / metabolism*
  • Barrett Esophagus / pathology*
  • Biomarkers, Tumor / biosynthesis*
  • Biomarkers, Tumor / genetics
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16
  • Esophageal Neoplasms / diagnosis
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / pathology
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / biosynthesis*
  • Ki-67 Antigen / genetics
  • Male
  • Middle Aged
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Racemases and Epimerases / metabolism*


  • Biomarkers, Tumor
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen
  • Neoplasm Proteins
  • Cyclin D1
  • Racemases and Epimerases
  • alpha-methylacyl-CoA racemase