Prostate Cancer Immunohistochemistry Markers
Prostate cancer is the most common non-skin cancer in men, and the third leading cause of cancer
death after lung and colorectal cancer. Immunohistochemistry (IHC) is used to facilitate the diagnosis
of prostate carcinoma, to determine whether or not foci are invasive, and to determine if a patient’s
cancer will respond to androgen therapy (Pentyala, 2016).
Early detection of prostate carcinoma relies on both clinical detection (rectal exam or transrectal ultrasound)
and performing serum measurements of proteins such as prostate-specific antigen (PSA / KLK3)
a glycoprotein secreted by epithelial cells of the prostate gland. Prostein
used alongside PSA to increase sensitivity in identifying prostate metastases. IHC with antibodies to NKX3-1
are also useful in identifying prostate as a site of potential origin in a metastasis of unknown primary (Kandalaft, 2015). When prostate biopsies are taken,
IHC with markers such as high molecular weight cytokeratins
can determine whether the basal cell myoepithelial layer is intact
or has been infiltrated by the tumor. Furthermore, markers such as GalNac-T3 (GALNT3)
, hepsin (TMPRSS1)
and PCA3 have been useful to distinguish between prostate cancer and benign prostatic hyperplasia (BPH).
The genetics of prostate cancer:
The progression of genomic alterations that drives prostate cancer involves a number of well described pathways...
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ACPP (PSAP) is a dephosphorylating enzyme produced in prostatic glandular epithelium. Increased serum levels of ACPP were shown to be associated with prostate cancer in the 1930’s, particularly in patients with bone metastases. This enzyme was one of the first tumor serum markers, and it was the main prostate cancer biomarker until the discovery of PSA (Gutman, 1938; Muniyan, 2013; Rao, 2008). Higher ACPP expression in tumors has been correlated with increasing tumor stage (Gunia, 2009), although ACPP is thought to be a tumor suppressant by means of vitamin D-associated slowing of prostate growth (Lin, 1992). Lower expression in normal tissue is therefore thought to be a risk factor for the development of cancer (Stewart, 2005; Kong, 2013). Recently, this target has been used successfully to sensitize patient dendritic cells in order to stimulate an immune response to cancer (Fong, 2001). Although it is highly expressed in prostatic glandular epithelium, ACPP is not as specific as PSA, and has been occasionally associated with other tumors such as lung carcinoid tumors (Azumi, 1991).
ACPP is expected to have cytoplasmic staining in prostate tissue.
CDKN1B, commonly known as p27 (or KIP1), is an important nuclear regulator of cell cycle progression. p27 protein is specifically involved in g1 arrest, where it functions to stop or slow down the cell division cycle. Loss of p27 nuclear expression and/or translocation from the nucleus to cytoplasm has been associated with poor prognosis and potential disease progression in a variety of cancers, such as squamous carcinomas of head and neck, melanomas, and lung carcinomas (Hnit, 2015; Vallonthaiel, 2016; Dobashi, 2017; Chu, 2008; Denicourt, 2007; Tsihlias, 1998). This target may also be associated with hereditary cancers: mutations in CDKN1B have been linked to an increased risk of prostate cancer (Chang, 2004). Decreased expression of p27 has been associated with growth in pituitary adenomas, and circulating p27 autoantibodies (hence decreased p27 expression) have been correlated with poor prognosis in osteosarcoma (Li, 2016; Martins, 2016; Bamberger, 1999; Teixeira, 2000). Conversely, the indolent course of thyroid papillary carcinomas has been attributed to the presence of p27 (Garcia-Rendueles, 2017). Tumor cells that are quiescent (non-dividing) are protected from the cytotoxicity of many chemotherapeutic agents. Therefore, disrupting the normal nuclear expression of p27, which prevents cells from entering the mitotic pathway, may enhance response rates to chemotherapy, making this target important in the search for new cancer treatments (Becker, 2017; Barzegar, 2017).
CDKN1B is expected to have predominantly nuclear staining in normal prostate tissue and may have loss of expression or show cytoplasmic translocation in prostate tumors.
Folate Hydrolase 1 (FOLH1, also known as Prostate-Specific Membrane Antigen or PSMA) is a membrane-associated protein that is highly expressed in prostatic epithelium. It increases in expression progressively with increasing grade in prostatic intraepithelial neoplasia and prostatic carcinoma. Decreased expression is associated with poor survival in prostate cancer (Bostwick, 1998; Murphy, 1998). The function of FOLH1 is not well understood (Kaittanis, 2018). Recently, this target has been shown to be expressed in neovascular endothelium in a number of non-prostatic carcinomas, including lung, pancreatic, and renal cell carcinomas, and glioblastomas. Positive expression in endothelium may predict a positive response to chemotherapy (Baccala, 2007; Nguyen, 2016; Stock, 2017; Wang, 2015; Wernicke, 2011).
FOLH1 is expected to have membranous and cytoplasmic staining in prostate tissue.
Prostein (SLC45A3 / p501S)
Prostein (also known as prostate cancer-associated protein 6 / P501S / SLC45A3) is a protein present in the golgi apparatus of benign and malignant prostatic glandular epithelium, and shows perinuclear cytoplasmic localization in immunohistochemical experiments (Xu, 2001; Sheridan, 2007). Because it is highly specific for prostate glandular cells, this target is useful for differentiating extra-prostatic metastases from other carcinomas such as urothelial carcinomas or colorectal carcinomas (Xu, 2001; Lane, 2008; Chuang, 2007; Sheridan, 2007). Although it may show diminished expression in some aggressive prostate cancers, this target is sometimes expressed in PSA-negative prostate carcinomas, and these two targets used in combination can lead to increased sensitivity in the identification of prostate cancer metastases (Perner, 2013; Sheridan, 2007).
Prostein is expected to have cytoplasmic staining in prostate tissue.