PSA Test for Prostate Cancer: From Raised PSA to PSMA PET CT

A PSA test for prostate cancer, a blood test for prostate-specific antigen, is a useful first signal, not a diagnosis. PSA is specific to the prostate rather than to cancer, so a normal value does not exclude cancer and a raised one does not confirm it. Diagnosis rests on rectal examination, PSA refinements and biopsy; staging rests on MRI and PSMA PET CT.

Where organised screening does not exist, prostate cancer is found late, and survival falls accordingly. Dr. Shafiq Ahmed, Senior Director - Urology, Andrology & Renal Transplant, BLK-Max Super Speciality Hospital, New Delhi, India, built his approach to diagnosis for that reality: a sequence of simple tests that any clinician can apply, a clear sense of where each test misleads, and a defined point at which a man should be referred for biopsy and advanced imaging. Staging then decides what treatment is possible. This article follows that sequence, from the first rectal examination to the PSMA PET CT scan.

What a digital rectal examination can detect

The digital rectal examination is the first step in screening, and in experienced hands it can detect a hard nodule suspicious of carcinoma. Its value depends on the clinician who performs it: an experienced examiner can feel a nodule that is not like normal prostate tissue, hard in consistency. A man with such a nodule goes on to needle biopsy.

Prostate cancer usually arises in the peripheral zone of the gland, the part that lies against the rectal wall, which is why the finger can reach many tumours.

How reliable is the PSA test for prostate cancer?

The PSA test is widely available but not specific to cancer, so on its own it can neither rule prostate cancer in nor rule it out. Prostate-specific antigen is a protein made by the prostate, a surrogate marker available almost everywhere. Its weakness is that it is specific to the prostate, not to prostate cancer. It rises in many other conditions, which makes the picture confusing for clinicians and patients alike.

Where PSA is most effective is after treatment. Following radical prostatectomy it is the surrogate marker of choice for follow-up, because with the gland removed any measurable PSA carries meaning.

As a screening test it misleads in both directions.

A normal PSA does not exclude cancer

A normal PSA does not rule out early prostate cancer. In Dr. Ahmad's view, men in African countries may harbour prostate cancer at a PSA as low as 2.5 ng/mL, whereas in his part of the world suspicion usually begins only when PSA rises above 4 ng/mL.

A raised PSA does not confirm it

False positives are common. PSA secretion into the blood rises after:

• prostatic massage or a vigorous rectal examination;
• instrumentation of the urinary tract;
• a prostate biopsy;
• infection of the prostate;
• benign prostatic hyperplasia (BPH).

In any of these settings, a high reading can be a false positive.

PSA velocity and the free-to-total PSA ratio

PSA velocity and the free-to-total PSA ratio are the two refinements that reduce false positives. Dr. Ahmad uses these two measures to separate a cancer from the many benign causes of a raised PSA.

PSA velocity. A rapidly proliferating glandular cancer pushes PSA up faster than benign tissue does. Where serial PSA values are available, a rise of more than 0.75 ng/mL per year should raise a strong suspicion of cancer.

The free-to-total PSA ratio. In the grey zone, a PSA between 2.5 and 10 ng/mL in his practice, the ratio of free to total PSA should always be checked. A ratio below 25 per cent is a reason to evaluate the man further, so that a cancer is not missed.

What to do about a high PSA when biopsy is not available

When biopsy is unavailable, a man with a raised PSA is checked and treated for infection, retested at six weeks, and followed with the free-to-total ratio and PSA velocity, with referral if suspicion rises. A participant in the live discussion asked how to manage a man with a total PSA above 10, a rectal examination without any nodule, and no access to biopsy. Dr. Ahmad's answer is a practical protocol for exactly the setting many district hospitals face.

1. Look for infection first. If the man has a prostatic infection, treat it with a course of antibiotics.
2. Repeat the PSA at six weeks. If the raised PSA was caused by infection, it should be trending down six weeks after antibiotics. If it is not, despite treatment, the suspicion of prostate cancer should be very high.
3. Check the free-to-total ratio. A ratio below 25 per cent adds weight to the diagnosis.
4. Follow the velocity. If the rectal examination is normal and biopsy is unavailable, the man can be followed for a year with serial PSA. A rise of more than 0.75 per year is the signal to refer him to a centre with transrectal ultrasound-guided biopsy or MRI.

His principle is that a man in this situation is followed regularly, and that once other causes have been ruled out, a PSA in this range must be treated as suspected prostate cancer and investigated further.

Transrectal ultrasound and Doppler in prostate cancer

Transrectal ultrasound (TRUS), an ultrasound probe placed in the rectum, images the peripheral zone, where most cancers arise, but greyscale appearances alone cannot confirm or exclude cancer. The difficulty is that a cancer can look like almost anything on ultrasound. Lesions may be hypoechoic, hyperechoic or isoechoic, and a substantial share of cancers are isoechoic and cannot be distinguished from normal tissue on greyscale imaging. A hypoechoic lesion raises suspicion, but it is not proof of malignancy.

Doppler adds information that greyscale imaging lacks. In the case Dr. Ahmad showed, a nodule visible on two-dimensional ultrasound displayed high vascularity on Doppler study of the same patient. A nodule with high vascularity is suspicious of cancer, and it becomes the target for biopsy.

Chronic prostatitis or prostate cancer?

Doppler also helps to separate chronic prostatitis from prostate cancer, because both can show increased blood flow. The pattern differs:

• In chronic prostatitis, vascularity is increased uniformly across the whole prostate.
• In prostate cancer, increased vascularity is confined to one specific point, such as a nodule.

Dr. Ahmad is clear, however, that ultrasound is not used on its own to decide between the two. The decision rests on clinical judgement, the PSA value and the man's age. Chronic prostatitis is a disease of young, sexually active men, typically in their forties and early fifties. Prostate cancer is a disease of old age. He is therefore hesitant to diagnose chronic prostatitis in an older man: when a man of 60 to 65 arrives with a PSA of 10 and urinary symptoms, he diagnoses BPH, keeps prostate cancer firmly in mind and evaluates him accordingly.

Is prostatic calcification a cause for concern?

In Dr. Ahmad's account, calcification seen on imaging is a sign of chronic prostatitis, and on its own it does the patient no harm. In a chronically infected prostate, secretions within the glandular part become impacted, and calcium is slowly deposited in them. Asked about a 60-year-old man with calcification, no obstructive symptoms, a normal PSA of 2.8 and a prostate of normal size, Dr. Ahmad's advice was that there is no need for concern. A symptomatic man should first be treated medically, and surgery considered only if medical management fails. Calcification itself does the patient no harm. It is a telltale sign of chronic infection in the gland.

Prostate biopsy and MRI fusion biopsy

Transrectal ultrasound-guided biopsy is the definitive test when PSA is high, and MRI fusion biopsy improves its aim. It is not infallible. In Dr. Ahmad's account, around 20 per cent of men with prostate cancer need more than two sets of biopsies before the diagnosis is confirmed, because even a well-performed biopsy can miss the target lesion.

That limitation is what MRI fusion biopsy addresses. MRI images are fused with real-time ultrasound through a dedicated machine. Nodules identified on MRI are localised on the live ultrasound image, and the needle is directed into them. Instead of sampling the gland and hoping to strike the cancer, the urologist targets the lesion the MRI has already found.

How prostate cancer is staged: MRI and PSMA PET CT

Once cancer is confirmed, staging needs two investigations: multiparametric MRI for spread within the pelvis, and PSMA PET CT, a scan that tracks prostate-specific membrane antigen (a protein on prostate cancer cells), for spread through the body.

Local staging with multiparametric MRI

Treatment planning depends on how far the cancer has spread within the pelvis. The questions are specific: whether the tumour has reached the seminal vesicles, the bladder, the sphincter or the rectum, and whether it has broken through the prostatic capsule. Extracapsular extension changes the operation, as it determines whether the nerves alongside the prostate can safely be preserved.

Multiparametric MRI answers these questions best. It is called multiparametric because several sequences are read together, typically T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging, to describe the size and activity of a lesion. It is the standard investigation for detecting extracapsular disease before any treatment is chosen, although it can miss microscopic extension beyond the capsule.

Distant staging: bone scan and PSMA PET CT

The conventional test for distant spread is a bone scan using a technetium-99m tracer, which shows skeletal metastases as areas of tracer uptake. A bone scan is indicated when:

• PSA is above 20 ng/mL;
• the tumour is T3 or T4;
• the biopsy shows a Gleason score (the grade of how abnormal the cells look under the microscope) of 8 to 10, a highly aggressive cancer likely to have spread beyond the pelvis.

In the present era, in Dr. Ahmad's experience, PSMA PET CT has become the most commonly used staging scan, and his team performs it routinely. Its advantage is breadth: it picks up bony metastases as well as spread to soft tissue and solid organs, which a bone scan cannot show.

The scan also identifies oligometastatic disease, a small number of bone deposits, which in selected men he still treats with surgery as part of multimodality treatment. How stage drives the choice of treatment is set out in the complete guide to the diagnosis and management of prostate cancer, and the operation itself in robotic radical prostatectomy, step by step.