Prostate Cancer Risk Stratification: PSA, Gleason and EAU

Prostate cancer risk stratification sorts a newly diagnosed man into a low, intermediate or high risk group using three findings: his prostate-specific antigen (PSA) level, the Gleason score from his biopsy, and the clinical stage felt on digital rectal examination. The group, together with MRI and PSMA PET staging, determines which treatments are appropriate and whether the intent is curative.

Dr. Anurag Puri, Additional Director Urology, Fortis Hospital, Shalimar Bagh, New Delhi, India, put it simply for the doctors on his masterclass: before planning any treatment, stratify the patient, and only three parameters are needed to do it. This article follows the diagnostic path he described from the first consultation to the risk group, with the reasoning behind each step. It is part of a series whose overview is the guide to prostate cancer diagnosis and latest treatment guidelines; how each risk group is then treated is covered in prostate cancer treatment by stage, age and fitness.

The first consultation: history and rectal examination

When a man with a suspected prostate cancer arrives in the outpatient clinic, the workup begins with a complete history and examination. Dr. Puri singled out two parts of the history: the family history, because a father or brother with prostate cancer raises the man's own risk, and the urinary history, because obstructive symptoms or blood in the urine or semen can signal locally advanced disease.

The examination must include a digital rectal examination (DRE), in which the doctor feels the back of the prostate with a gloved finger through the rectum. On its own, DRE has low sensitivity and specificity for prostate cancer. Its value lies in finding a nodule: an indurated, hard area in the gland. Dr. Puri noted that such a nodule proves cancerous about half the time, and his rule is unambiguous: every patient with a nodule should have a biopsy.

The three first-line tests

Dr. Puri recommends three tests for any man with urinary symptoms or a suspected prostate cancer:

1. A serum PSA. Prostate-specific antigen (PSA) is a protein made by prostate tissue and measured in a blood sample. A level above 4 ng/mL is suspicious for cancer. PSA is not specific to cancer: a urinary infection can also raise it, which is why the next test matters.
2. A complete urine analysis, to identify or exclude infection before a raised PSA is acted upon.
3. An ultrasound scan, to assess the prostate and the urinary tract.

How to read a borderline PSA: repeat it, then check free PSA

PSA has to be interpreted with caution, and Dr. Puri was firm that a single report should not drive the decision to biopsy. His sequence is:

1. Read the total PSA first.
2. If there is doubt, repeat the PSA two to three weeks after the first test.
3. If both total PSA readings are high, proceed to biopsy.
4. If the total PSA lies between 4 and 10 ng/mL and doubt remains, order a free PSA test.

Free PSA is the fraction of PSA circulating unbound in the blood, expressed as a percentage of the total. A free PSA below 10% of the total points towards malignancy. A free PSA above 25% of the total means a lower chance of malignancy. The result helps decide which men in the grey zone need a biopsy now and which can be followed.

Two further points on PSA came up in the discussion. First, PSA testing is not mandatory for every man with benign enlargement, but a baseline value should be recorded before starting a 5-alpha-reductase inhibitor such as dutasteride, because these drugs lower PSA and would otherwise mask a later rise. Second, thresholds are not fixed for every man: PSA rises with age and prostate size, a subject explored in detail in age-adjusted PSA levels, PSA density and PSA velocity.

When to do a prostate biopsy, and how

A biopsy is indicated in two situations, in Dr. Puri's practice:

• a PSA above 4 ng/mL in the absence of a urinary infection, confirmed as described above; or
• an abnormal nodule felt on digital rectal examination.

A prostate biopsy is not a scan. A fine needle is used to take small samples of prostate tissue for examination under the microscope. In the approach Dr. Puri described, the needle passes through the rectum under the guidance of a transrectal ultrasound probe, and 12 cores are usually taken so that all regions of the gland are sampled. Current European Association of Urology (EAU) guidance favours the transperineal route, through the skin between the scrotum and anus, where it is available, because it carries a lower risk of infection.

Who should perform the biopsy

Asked whether a urologist or an interventional radiologist should perform an ultrasound-guided prostate biopsy, Dr. Puri answered that both do. His preference is for the urologist, who is better trained to manage the complications if they occur, such as bleeding in the urine or bleeding from the rectum.

Staging: multiparametric MRI and PSMA PET

Once the biopsy confirms cancer, the next task is to establish how far it has spread. Current EAU guidance recommends that the multiparametric MRI be done before the biopsy where available, so that suspicious areas can be targeted and some men spared a biopsy. Dr. Puri divides staging into two questions.

• Local spread is assessed with a multiparametric MRI of the prostate. This MRI combines several imaging sequences to show the tumour within the gland and whether it has breached the capsule or reached the seminal vesicles.
• Distant spread is assessed with a PSMA PET scan. Prostate-specific membrane antigen (PSMA) is a protein present in large amounts on prostate cancer cells; a PET scan using a tracer that binds to it shows deposits in lymph nodes and bones.

Dr. Puri described the PSMA PET scan as the newest staging modality and very specific for prostate cancer metastasis. He also noted that PET facilities are very limited in much of Africa, which matters for referral: a man whose staging was done without a PSMA PET scan may need one before treatment is planned.

A case from the discussion

A doctor described a man in his fifties with an established adenocarcinoma of the prostate staged as T4 N0 M0, meaning a tumour invading neighbouring structures with no nodal or distant spread found on available imaging, who was planning to travel for treatment. Dr. Puri's answer showed why staging dominates prognosis. Prostate cancer is one of the slowest growing cancers in the body. With a very high PSA and T4 disease there may be foci of spread that conventional imaging misses, so the absence of metastasis has to be reconfirmed with a PSMA PET scan on arrival. If metastasis is present, the prognosis changes a great deal. If it is not, the man may have a very good life expectancy despite the extent of the local disease.

The Gleason score: how aggressive the cancer is

Prognosis and life expectancy depend on two things, Dr. Puri explained: the histological grade of the cancer and the extent of the disease. Grade is reported as the Gleason score.

The pathologist assigns a grade to the most common growth pattern in the biopsy and to the second most common pattern, each on a scale from 1 to 5, and adds them together. In contemporary practice only patterns 3 to 5 are reported, so the scores seen today range from 6 to 10. A score of 6 indicates a low-grade, less aggressive cancer; a score of 7 indicates intermediate grade; and scores of 8 to 10 indicate high-grade, more aggressive disease. The International Society of Urological Pathology (ISUP) translates these scores into Grade Groups 1 to 5, the format many pathology reports now use.

The four clinical stages Dr. Puri uses

For the purposes of planning, Dr. Puri described four stages based on what the examining finger and the investigations find:

1. Stage one: the cancer cannot be felt at all. It is detected only on pathological examination, either after a raised PSA leads to biopsy or incidentally in tissue removed during surgery for a benign condition such as transurethral resection of the prostate (TURP).
2. Stage two: a hard nodule can be felt on rectal examination, but the cancer is confined to the prostate gland.
3. Stages three and four: the cancer has extended beyond the prostate into the surrounding structures and outside the gland.

These stages correspond broadly to the T categories of the TNM system (T1 to T4), which the referring doctor will see on formal staging reports.

EAU risk groups: low, intermediate and high risk

The European Association of Urology divides localised prostate cancer into three risk groups. Each combines the three parameters Dr. Puri named: the PSA level, the Gleason score and the clinical stage on examination.

A man is low risk only if all three criteria are met. He moves into the intermediate group if any one criterion reaches the intermediate level, and into the high risk group if any one reaches the high level. Disease that has spread beyond the gland (cT3 to cT4) or to the pelvic lymph nodes is classed as locally advanced.

In plain terms, as Dr. Puri summarised it: in a low risk patient the PSA is low, the Gleason score is low and the cancer burden felt on examination is small. As each parameter rises, so does the risk group.

How prostate cancer risk stratification decides treatment

Stratification is not an academic exercise. It sets the range of reasonable treatment for each man:

• low risk disease opens the option of active surveillance, alongside robotic radical prostatectomy and radiotherapy;
• intermediate risk disease is generally treated with curative intent, by surgery or radiotherapy;
• high risk disease can still be treated surgically, with an extended lymph node dissection; in Dr. Puri's practice, surgery is reserved for men whose lymph nodes are negative.

Asked by a doctor from the Democratic Republic of the Congo which stages robotic surgery is used for, Dr. Puri answered along these lines: low and intermediate risk disease, and selected high risk disease with negative nodes. The full treatment map, including the role of age, fitness and hormone therapy, is set out in prostate cancer treatment by stage, age and fitness. A complementary view of biopsy technique and when to avoid biopsy is in when to do a prostate biopsy, and the full set of questions from this session is on the Live Discussion page.