p504S

Synonyms: AMACR, α-methylacyl-CoA racemase

by Assia Bassarova

Background

P504s is a 382-amino-acid protein, which had been identified as human α-methylacyl coenzyme A racemase (AMACR). AMACR has a role in the β-oxidation of branched-chain fatty acids and fatty acid derivatives, ibuprofen and related drugs. AMACR is found in mitochondria and peroxisomes of numerous tissues such as prostate, liver, biliary tract, kidney and lung. The importance of AMACR in metabolism of branched-chain fatty acids is underlined by the observation that severe reduction of AMACR activity in humans results in a neurological disorder due to the accumulation of R-2-methyl fatty acids. Patients deficient in AMACR exhibit neurological symptoms with some similarities to adult Refsum’s disease, but with later onset and a more peripheral than central neurological phenotype. They exhibit the expected biochemical profile, with accumulation of bile acids and dietary (2R)-branched acids. The AMACR enzyme is highly conserved in mammalian species, with homologous proteins identified in invertebrates and bacteria.

Staining in normal cells/tissues

Epithelial cells of the proximal tubules.  Non-neoplastic prostate tissue shows very weak and focal immunohistochemical expression in about 20% of the cases.  AMACR positive glands in a prostate biopsy may represent seminal vesicle or periurethral glands.

Staining in tumors

AMACR is an androgen-independent growth modifier in prostate cancer cells. Concentrations of the AMACR protein are increased in all prostate cancers (with levels of up to 9-fold higher than in non-malignant cells reported, a subset of colon cancers and a variety of other cancers, like breast, renal and endometrial clear cell carcinoma, although there is considerable heterogeneity in the degree of overproduction. A diffuse staining pattern for AMACR has been found in more than 90% of prostate carcinomas irrespective of Gleason score. It is important to note that foamy, pseudohyperplastic and atrophic variants of carcinoma may be negative. In prostatic intraepithelial neoplasia (PIN), the positive rate of AMACR ranges from 13% to 72%.

Staining pattern

Moderate to strong granular cytoplasmic staining.

Control tissue

Kidney is recommended as positive tissue control for AMACR where virtually all epithelial cells of the proximal tubules must show a strong and distinct granular cytoplasmic staining, whereas epithelial cells of the distal tubules must display a weak granular cytoplasmic staining reaction. Normal prostate is recommended as negative tissue control for AMACR: The epithelial cells must be negative or only show a focal weak cytoplasmic reaction.

Application

  • AMACR is mainly used as an ancillary tool in prostate biopsy diagnostics. A combination of high molecular weight cytokeratin (CK 34bE12), p63 and p16 might help to detect small foci of prostate cancer, especially on needle biopsies. AMACR should always be used in conjunction with (HMW-CK) and/or p63. A double or triple staining is recommended.
  • Recently P504S expression has been investigated and shown to be positive in about one-third of metastatic colorectal carcinomas and none of an almost identical number of primary ovarian carcinomas.
  • Some other carcinomas of non-prostatic origin may be also positive.

Selected references

  1. Evans AJ. Alpha-methylacyl CoA racemase (P504S): overview and potential uses in diagnostic pathology as applied to prostate needle biopsies. J Clin Pathol. 2003 Dec;56(12):892-7. doi: 10.1136/jcp.56.12.892. PMID: 14645345; PMCID: PMC1770134.
  2. Fadare O, Parkash V, Gwin K, et al. Utility of α-methylacyl-coenzyme-A racemase (p504s) immunohistochemistry in distinguishing endometrial clear cell carcinomas from serous and endometrioid carcinomas. Hum Pathol. 2013 Dec;44(12):2814-21. doi: 10.1016/j.humpath.2013.07.033. Epub 2013 Oct 10. PMID: 24119561; PMCID: PMC3865867.
  3. Jiang, Z., Woda, B. A., Wu, C-L.,et al. (2004). Discovery and Clinical Application of a Novel Prostate Cancer Marker a-Methylacyl CoA Racemase (P504S). American Journal of Clinical Pathology, 122(2), 275–289.doi:10.1309/ejuy-uqpe-x1mg-68mk
  4. Lloyd MD, Darley DJ, Wierzbicki AS, et al. Alpha-methylacyl-CoA racemase–an ‘obscure’ metabolic enzyme takes centre stage. FEBS J. 2008 Mar;275(6):1089-102. doi: 10.1111/j.1742-4658.2008.06290.x. Epub 2008 Feb 12. PMID: 18279392.
  5. Lloyd, M. D., Yevglevskis, M., Lee, G. L., et al. (2013). α-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S. Progress in Lipid Research, 52(2), 220–230.doi:10.1016/j.plipres.2013.01.001
  6. Logani S, Oliva E, Arnell PM, et al. Use of novel immunohistochemical markers expressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma. Mod Pathol. 2005 Jan;18(1):19-25. doi: 10.1038/modpathol.3800260. PMID: 15389251.
  7. Remo A, Pancione M, Zanella C, et al. p16 Expression in Prostate Cancer and Nonmalignant Lesions: Novel Findings and Review of the Literature. Appl Immunohistochem Mol Morphol. 2016 Mar;24(3):201-6. doi: 10.1097/PAI.0000000000000171. PMID: 25906117.