PATHOLOGY

The role of P501S and PSA in the diagnosis of metastatic adenocarcinoma of the prostate
Sheridan T, Herawi M, Epstein JI, Illei PB
Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
Am J Surg Pathol. 2007; 31: 1351-5

• Background: Adenocarcinoma of the prostate can present as metastatic carcinoma with no known primary. Prostatic origin can be confirmed in most of these cases by immunohistochemistry for prostate-specific antigen (PSA) and prostate-specific acid phosphatase. In a small subset of high-grade prostate carcinomas, both markers are negative and therefore are not helpful for confirming prostatic origin. Recently, novel marker proteins that are preferentially expressed in prostate tissue were identified. One such marker is P501S or prostein, a 553-amino acid protein that is localized to the Golgi complex. It is expressed in both benign and neoplastic prostate tissues, but not in any other normal or malignant tissue examined to date. Owing to its apparent specificity, prostein may be a good marker to demonstrate prostatic origin in metastatic prostate cancer.
• Design: Five-micron sections of a tissue microarray were subjected to immunohistochemistry with a monoclonal mouse anti-P501S (clone 10E3, Dako, Carpintera, CA) antibody and a monoclonal mouse anti-PSA (clone ER-PR8, Dako, Carpintera, CA) antibody. The tissue microarray contains 78 cases of metastatic prostatic adenocarcinoma, 20 cases of primary prostatic adenocarcinoma, and 20 cases of benign prostate tissue from the peripheral zone as well as samples of benign brain, pancreas, kidney, thyroid, testis, skeletal muscle, and fibroconnective tissue.
• Results: Similar staining (intensity and extent) was identified for both markers in the majority of metastatic tumors (11 distant sites, 42 pelvic lymph nodes), in all 20 primary tumors and in all benign prostate and nonprostate tissues. The P501S stain had perinuclear cytoplasmic (Golgi) distribution even in poorly differentiated tumors and metastases. Two distant metastases were negative for PSA but retained focal weak positivity for P501S. Two other distant metastases were weakly PSA positive, but strongly P501S positive. Metastases in the pelvic lymph nodes were positive for both markers in 53 cases and 1 lymph node metastasis was strongly PSA positive but P501S negative. In summary, 67 of the 69 cases (97%) of metastatic prostate carcinomas were PSA positive, whereas 68 of the 69 cases showed at least focal weak reactivity for P501S (99%). None of the tumors were negative for both markers.
• Conclusions: Immunohistochemistry for P501S is a sensitive and highly specific marker for identifying prostate tissue. The large majority of metastatic prostatic adenocarcinomas are P501S positive (99%). A small subset of metastatic prostatic adenocarcinoma shows significant differences in staining intensity and extent for PSA and P501S and, therefore, combined use of these markers may result in increased sensitivity for detecting prostatic origin.
  
  
• Editorial Comment
  In 2001 (1), Xu et al. identified P501S or prostein, a novel prostate-specific protein expressed in normal and malignant prostate tissues. Characterization of the prostein gene showed that prostein cDNA encodes a 553-amino acid protein. The protein is predicted to be a type IIIa plasma membrane protein with a cleavable signal peptide and 11 transmembrane-spanning regions. Prostein gene is located on chromosome 1 at the WI-9641 locus between q32 and q42. Prostein mRNA is shown to be uniquely expressed in normal and cancerous prostate tissues using Northern blot, eDNA microarray, and real-time PCR analysis. Furthermore, prostein mRNA expression does not appear to be prostate tumor grade related and is restricted exclusively to prostate cell lines. Immunohistochemical staining using a mouse monoclonal antibody generated against prostein demonstrates that this protein is specifically detected in prostate tissues both at the plasma membrane and in the cytoplasm.
  P501S or prostein should not be confounded with P504S (alpha-methylacyl coenzyme A racemase or AMACR). In 2000, Xu et al. (2) using cDNA library substraction in conjunction with high throughput microarray screening, identified 3 genes: P503S, P504S and P510S that showed differential expression in malignant and benign prostate glands. It was demonstrated AMACR (P504S) immunoreactivity in prostatic adenocarcinoma but not in benign prostatic glands, while P503S immunoreactivity was present in both malignant and benign glands. Furthermore, it was found AMACR overexpression in colorectal, ovarian, beast, bladder, lung, and renal cell carcinomas, as well as lymphomas and melanomas (3). This findings makes AMACR unsuitable for the diagnosis of metastatic adenocarcinoma of the prostate.
  In the study surveyed, P501S or prostein showed that is a good marker in metastatic adenocarcinoma of the prostate. The authors found that 67 of the 69 cases (97%) of metastatic prostate carcinomas were PSA positive, whereas 68 of the 69 cases showed at least focal weak reactivity for P501S (99%). None of the tumors were negative for both markers. They conclude that Immunohistochemistry for P501S or prostein is a sensitive and highly specific marker for identifying prostate tissue. The large majority of metastatic prostatic adenocarcinomas are P501S positive (99%).

References
1. Xu J, Kalos M, Stolk JA, Zasloff EJ, Zhang X, Houghton RL, et al.: Identification and characterization of prostein, a novel prostate-specific protein. Cancer Res. 2001; 61: 1563-8.
2. Xu J, Stolk JA, Zhang X, Silva SJ, Houghton RL, Matsumura M, et al.: Identification of differentially expressed genes in human prostate cancer using subtraction and microarray. Cancer Res. 2000; 60: 1677-82.
3. Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA: Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions. Am J Surg Pathol. 2002; 26: 926-31.

Dr. Athanase Billis
Full-Professor of Pathology
State University of Campinas, Unicamp
Campinas, São Paulo, Brazil