AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in Barrett's Esophagus, Ulcerative Colitis, and Crohn's Disease

Abstract

Alpha-methylacyl-CoA racemase (AMACR) catalyzes the racemization of alpha-methyl, branched carboxylic coenzyme A thioesters, and is overexpressed in a variety of neoplasms, such as prostate and colon cancer. The aim of this study was to evaluate AMACR expression in the metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus (BE), ulcerative colitis (UC), and Crohn's disease (CD) and to determine whether its expression can be used to detect dysplastic epithelium in these conditions. One hundred thirty-four routinely processed biopsy and/or resection specimens from 134 patients with BE [M/F ratio: 5.7, mean age: 67 y (36 negative (intestinal metaplasia only), 14 indefinite for dysplasia (IND), 16 low-grade dysplasia (LGD), 32 high-grade dysplasia (HGD), and 36 invasive adenocarcinoma (ACA)] and 74 specimens from 74 patients with inflammatory bowel disease (IBD) [56 with ulcerative colitis, 18 with Crohn's disease, M/F ratio: 1.8, mean age: 55 y (17 negative, 7 IND, 26 LGD, 10 HGD, and 14 ACA)] were immunostained with a monoclonal AMACR antibody (p504S). The degree of cytoplasmic staining in all cases was evaluated in a blinded fashion according to the following grading system: 0, negative (0% cells positive); 1+, 1% to 10% cells positive; 2+, 10% to 50% cells positive; or 3+, >50% cells positive. In patients with BE, AMACR was not expressed in any negative foci (0%) but was significantly increased (P<0.0001) in foci of LGD (38%), HGD (81%), and ACA (72%). Three of 14 (21%) IND foci from 3 BE patients were only focally positive (grade 1: 7%, 2: 14%). However, 1 of these 3 patients had follow-up information available and had developed ACA subsequently. Similarly, in patients with IBD, AMACR was not expressed in any foci considered negative for dysplasia, but was significantly increased (P<0.0001) in foci of LGD (96%), HGD (80%), and ACA (71%). Only 1/7 (14%) IND focus from 1 patient was focally positive (grade 1). The sensitivity for the detection of LGD and HGD in BE and IBD was 38% and 81%, and 96% and 80%, respectively, for the 2 types of disorders. The specificity was 100% for both BE and IBD. AMACR is involved in the neoplastic progression in BE and IBD. The high degree of specificity of AMACR for dysplasia/carcinoma in BE and IBD suggests that it may be useful to detect neoplastic epithelium in these conditions.

Expression of α-methylacyl coenzyme A racemase in the dysplasia carcinoma sequence associated with Barrett’s esophagus

“…10 Previous studies demonstrated the expression of AMACR to be a highly specific marker in Barrett's neoplastic lesions. 7,8 Columnar epithelial cell changes indefinite for dysplasia were positive in 3/30 cases in these studies. Follow-up was available for 11 of these patients with columnar epithelial cell changes indefinite for dysplasia.…”

“…7,8 AMACR is known to be expressed in prostate and colon cancer. Both studies demonstrated the expression of AMACR as a highly specific marker in Barrett's neoplastic lesions.…”

“…The slides were stained with the monoclonal anti-AMACR antibody p504S (clone 13H4, 1:500 dilution; Bioprime, Germany; Dako Autostainer; LSAB Detection System, #K5005). Two different pathologists evaluated the immunohistochemical stainings for the presence and the extent of AMACR expression in a blinded fashion, designating samples according to Lisovsky et al, 7 as negative (0 to o5% cells positive), 1 þ (5-14% of cells positive), …”

“…6 Recently, two studies focused on a-methylacyl coenzyme A racemase (AMACR) in Barrett's neoplastic lesions, an enzyme known to be expressed in prostate and colon cancer. [7][8][9] AMACR catalyzes the racemization of a-methyl-branched carboxylic coenzyme A thioesters. This protein was originally identified in the mitochondria and peroxisomes of rat liver cells.…”

Anti-phosphorylated histone H3 expression in Barrett's esophagus, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma

“…Immunohistochemical markers, such as a-methyl coenzyme A racemase (AMACR), p53, caspase 3, and survivin, are promising as ancillary tests to facilitate the grading of dysplasia and to diagnose early adenocarcinoma in Barrett's esophagus. [8][9][10] Increased cell division with an expanded proliferation zone is consistently observed in gastrointestinal epithelial dysplastic lesions such as inflammatory bowel disease-associated dysplasia 11 and gastric dysplasia. 12 In Barrett's esophagus, dysplastic lesions have elevated proliferation index on Ki67 immunohistochemical staining.…”