Prostate-specific antigen (PSA) is a single-chain 34-kd glycoprotein of 237 amino acids containing approximately 8% carbohydrate. It is a serine protease produced almost exclusively by prostatic epithelial cells. PSA has chymotrypsin-like, trypsin-like and esterase-like activity. From the epithelial cells of the prostate, PSA is secreted via the prostatic ductal system into seminal plasma, where it catalyses the liquefaction of the seminal coagulum after ejaculation. The PSA gene, which belongs to the kallikrein gene family, is located on chromosome 19, region 13q. With immunohistochemical techniques, PSA can be demonstrated uniformly in normal prostate in the secretory epithelial cells of prostatic acini. The apical portion of the epithelial cell cytoplasm shows more intense staining than the lower part. Basal cells, transitional epithelium or stromal cells don not express PSA. Similarly, metaplastic squamous epithelium is negative for PSA. PSA is highly specific for prostate glandular epithelium. A few normal tissues at extraprostatic sites do, however, express PSA. These include scattered cells in the prostatic urethra and cloaca-derived tissues such as periurethral glands in males and females, anal glands and urachus. Seminal vesicles do not express PSA. In the urinary bladder, no PSA is seen in urothelium or in von Brunn’s nests, whereas PSA immunoreactivity has been described in bladder epithelium in cystitis cystica and cystitis glandularis.
PSA is readily demonstrated in adenocarcinomas of the prostate in about 99% of the cases. There is a correlation between malignancy grade and intensity of staining, high grade carcinomas displaying weaker expression. About 1% of poorly differentiated carcinomas have been negative for PSA. Radiation has not been shown to influence immunohistochemical PSA detection but reduction of staining intensity has been described following hormonal treatment. Different types of prostatic carcinoma, including ductal adenocarcinoma, mucinous, signet ring and small cell carcinoma, have been described to express PSA, whereas rare carcinoma with squamous differentiation as well as adenoid cystic carcinoma have been negative for PSA. Prostatic adenocarcinomas metastatic to lymph nodes or bones are, equally to primary carcinoma, identifiable by staining for PSA. PSA has been found in rare urethral papillomas and in some extraprostatic neoplasms, such as female and male breast carcinoma, as well as salivary and sweat gland tumours.
Due to the high specificity of PSA for prostatic glandular epithelium, it is very useful in identifying prostatic carcinoma in the prostate and in the adjacent organs often affected by epithelial malignancies, i.e. rectum and urinary bladder. Rectal adenocarcinoma, urothelial carcinoma or adenocarcinoma of the urinary bladder no not express PSA. Lack of PSA immunoreactivity in a very poorly differentiated malignancy does not, however, exclude the diagnosis of prostate cancer. Differential diagnosis of metastasis, especially in lymph nodes or bone, with unknown primary malignancy is another useful application for PSA immunohistochemistry. Metastasis of a PSA-expressing male breast carcinoma or of a PSA negative prostate carcinoma are rare exceptions for usually easy identification of prostate carcinoma as the source of metastasis. PSA may be used in a panel together with NKX3.1 and Prostein, which are at least as sensitive and slightly more specific than PSA.
Prostate hyperplasia and kidney/appendix is found to be recommendable positive and negative tissue controls for PSA. The epithelial cells of the prostate glands must show an as strong as possible cytoplasmic staining reaction. Due to leakage of the antigen in vicinity of the prostate glands, the stromal cells display a weak to moderate staining reaction. This staining pattern has to be accepted, otherwise the sensitivity of the assay is too low causing a general weak staining reaction of prostate carcinomas. Kidney and appendix can be used as negative tissue controls. No staining reaction should be seen in these tissues. If a positive staining reaction in the epithelial cells and/or a diffuse background staining is seen, the protocol must be recalibrated.
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