Prostate Cancer Risk Factors Detection Diagnosis and Imaging with PET-CT Scan

Prostate cancer is the second most common cancer in men worldwide, and is often described as a disease of the elderly since its peak age of incidence is 80 years. In India, data regarding the incidence rate of prostate cancer is limited because this disease is not notifiable and the number of community based studies on this type of cancer are limited. However, due to environmental factors and lifestyle changes, the incidence of prostate cancer in India is expected to rise. One study carried out in the following cities of India: Ahmedabad, Bangalore, Chennai, Delhi, Mumbai, Karunagappalli, Nagpur, Pune, and Thiruvananthapuram, estimated that the age adjusted incidence rates of prostate cancer in India as a whole to be 3.7 per 1 lakh persons in the year 2008.

These rates clearly show a marked increase in reported cases of prostate cancer incidence in our country. However, this could also be due to greater awareness regarding this cancer which leads to more cases being reported over time and documented.

What is Prostate Cancer?
The prostate is a small reproductive gland located in males between the base of the penis and the bladder, just in front of the rectum. It secretes fluid, that nourishes and hydrates sperm and is excreted with it as semen. There are several types of cells in the prostate; cancers most commonly develop in the glandular cells. Prostate is absent in females, although they do have similar structure known as Skene's gland.

What are some risk factors of prostate cancer?
Some of the risk factors for developing prostate cancer are:
Age-Aging is the most significant risk factor of prostate cancer. Being over 50 years old, increases the chances of developing prostate cancer.

Ethnicity- Asian-American and Hispanic men are less at risk while African descent, including African American men have a greater risk of prostate cancer.

Family history- Prostate cancer is reported to run in families and therefore has probable genetic origins. The BRCA1 and BRCA2 genes that are involved in breast cancer in women, as well as HOXB13 gene are also reported to play a role in prostate cancer in men.

What is the main cause of prostate cancer?
Prostate cancer has a largely variable natural history, with some tumors being slow growing while others are highly aggressive. Tumors which grow slowly do not show significant symptoms until they reach more advanced stages. As the tumor enlarges, it may lead to certain signs ta symptoms like frequent urge for urination, difficulty in urinating, blood in urine or semen, and painful ejaculation. Early stage prostate cancer can be treated successfully in some cases. However, in other cases, prostate cancer can be very aggressive and can even be life threatening especially if it undergoes metastasis to other locations. Metastasis to the bone is more common, hence advanced prostate cancer also presents with bone pain and fractures.

How to Detect and Diagnose Prostate Cancer?
It is important to correctly diagnose prostate cancer even before its symptoms appear, since appearance of symptoms is a characteristic of advanced disease The most common detection techniques are digital rectal exam, transrectal ultrasound, and biomarkers.

Some of the common biomarkers used in prostate cancer testing are:
Prostatic Acid Phosphatase (PAP): PAP was the first biomarker to be used in diagnosis and staging of prostate cancer. It is secreted by the prostate epithelial cells and can be measured by immunoassay or enzymatic assay.
Prostate Specific Antigen (PSA test): PSA is produced by the prostate and secreted into the seminal fluid. In case of hyperplasia and neoplasia in the prostate gland, the physiological barriers are disrupted leading to the presence of PSA in circulation. It is one of the most widely used biomarkers for prostate cancer screening.
hK2: hK2 is a biomarker from the same family as PSA. While PSA is found in higher amounts in the bound state, hk2 mostly exists in free, unbound form in the serum.

How accurate is PET scan for prostate cancer?
PET-CT scan is one of the most advanced modalities for cancer imaging it combines the morphological information provided by CT with the metabolic data given, by PET. PET-CT uses "F-Fluoro-Deoxyglucose ("F-FDG) as a radiotracer to locate and characterize the tumor. While effective in most cancers, F-FDG in prostate cancer are not as good due to low glucose metabolic activity of prostate cancer. F-FDG is therefore only useful in those prostate cancer patients with high grade, hormone resistant cancers or lesions which are poorly differentiated. Bone Scan (BS) with Tc Methyl Diphosphonate (MDP) or other radiolabeled phosphonates are also presently used either in staging or in restaging to detect skeletal metastases. However, high uptake of this radiolabel can also occur due to non-malignant changes in the bones like trauma and degenerative bone disease, leading to false positive results. Due to these reasons, the development of new radiotracers for prostate cancer detection has become critical

What is the difference between Prostate Specific Membrane Antigen (PSMA) and PSA?
PSMA is a transmembrane protein (as opposed to PSA which is secretory protein), whose levels are elevated 100 to 1000 times more than normal cells in case of prostate cancer. It is involved in prostate cancer by supporting cellular growth and proliferation by increasing folate level in these cells, as it functions as a folate hydrolase. PMSA is selectively overexpressed in prostate cancer lesions as well as in bone and lymph node metastases. Since it is a transmembrane protein, detection of PSMA is done either by using anti-PSMA, monoclonal antibodies, or other radiolabeled ligands specific to PSMA, which bind to PSMA present on the surface of prostate cancer cells.

What is Prostate Specific Membrane Antigen (PSMA)?
PSMA expression is directly correlated with cancer aggressiveness, cancer progression, metastasis, and can serve as an independent indicator of poor prognosis. Earlier detection of prostate lesions through PSMA based tracers allows alteration in follow-up treatments. It is also reported to be a predictor of cancer recurrence in prostate cancer patients, and for cancer staging since PSMA expression is reported to increase with the stage and grade of the tumor. Due to these reasons, PSMA has gained popularity as a target for imaging and treatment of prostate cancer.

Several PSMA targeted PET tracers have been developed that have shown good results in staging and restaging of prostate cancer, even when PSA levels are found to be low. PMSA has both diagnostic and therapeutic value because this ligand is internalized into the cell via clathrin mediated endocytosis, which can be used as a mode to transport anticancer therapeutic agents into the cancer cell. Some of the most widely used PSMA agents are therefore theranostic (therapeutic and diagnostic) agents, such as PSMA-617 labeled with either "Ga or "Lu, and "GaPSMA-11.

In addition to diagnostic and therapeutic applications, PSMA can also be used in radio-guided surgery since PSMA-based tracers could provide real-time information to the surgeon regarding resection margins and extent of the disease. This is especially effective in cases when residual disease or micrometastases could not be completely removed during surgery as they are harder to identify

Future Perspectives of PSMA in Cancer Imaging the future of PMSA based cancer imaging is in the development of new tracers that target PSMA. One example of a promising radiotracer is 2-5-1-carboxy 5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)ureido)- pentanedioic acid) ("F-DCFPyL). This agent has higher tumor to background uptake which helps in detection of metastasis better than conventional modalities. Aside from its greatest application in patients with recurrent prostate cancer with low PSA levels, PSMA appears promising in the detection and characterization of primary tumors, local staging of regional lymph nodes, and the identification of metastatic disease for targeted treatment.

This modality is yet to be established in assessing treatment response, hence development of novel imaging response criteria is needed. Considering the promising results of PSMA based therapy for prostate cancer, individualization of therapy based on tumor characteristics can also be explored.