Prostate cancer: diagnosis, staging and treatment

Prostate cancer is the most frequently diagnosed cancer in men in Italy: according to AIOM-AIRTUM data, around 31,200 new cases are estimated each year, roughly 17% of all cancers in men. It is rare before the age of 40 and its incidence rises steadily with age. When diagnosed while still organ-confined — as it is in the large majority of cases today — the prospects of cure are excellent.

Three distinct entities that should not be confused

When discussing prostate cancer statistics, three entities must be kept apart:

• Clinical carcinoma: the cancer that makes itself known and is diagnosed in clinical practice. Epidemiological data refer to this
• Incidental carcinoma: found by chance during endoscopic resection or adenomectomy performed for benign prostatic hyperplasia
• Latent (biological) carcinoma: asymptomatic microcarcinomas found only on histology. These are extremely common: they are found in 80% of autopsies of men over 80 — men who died with the tumour, not because of it

Risk factors

Age is by far the most important risk factor; the other factors investigated have not yet been clearly demonstrated. Among those studied: family history, hormonal factors, diet, genetic and ethnic factors, and exposure to metals (zinc, cadmium).

Where it starts and how it spreads

Prostate carcinoma arises:

• in about 80% of cases from the peripheral zone of the gland — which is why digital rectal examination is so effective at detecting it
• in about 20% from the central zone
• in the remainder from the transition zone

The tumour initially grows within the gland; spread by contiguity, through the lymphatics and through the bloodstream comes later. The prostatic capsule acts as a barrier, but it has two weak points that are readily infiltrated: the apex, and the point where the ejaculatory ducts enter the gland.

• Spread by contiguity: periprostatic tissue, seminal vesicles, bladder neck, ureters, urethra. Rectal involvement occurs later, despite the anatomical proximity, thanks to the barrier of Denonvilliers' fascia
• Lymphatic spread: first to the regional nodes (obturator, hypogastric, presacral, pre-ischiatic), then to extraregional nodes (iliac, inguinal, para-aortic, mediastinal, supraclavicular)
• Haematogenous spread: generally follows lymph node involvement. Bone metastases are the most frequent, affecting the pelvis, spine, ribs and femur. Visceral metastases (lung, liver, adrenal, kidney) are usually late

Grading: the Gleason score

Grading is essential in estimating how aggressive the tumour is and how it is likely to progress. The most widely used system is the Gleason score, based on the degree of cellular differentiation.

How it is built: the pathologist assigns a score from 1 to 5 to each of the two histological patterns present in the specimen — the predominant one and the most aggressive one — where 1 indicates a poorly aggressive tumour and 5 a highly aggressive one. The sum of the two gives the Gleason score.

• Lower scores: less aggressive disease, slower progression
• Score 7: intermediate aggressiveness
• Scores 8–10: highly aggressive tumour cells

Symptoms: why they come late

Urinary symptoms in prostate cancer appear late. This is why diagnosis cannot rely on waiting for symptoms.

When they do appear, the voiding disturbances are both irritative and obstructive, and often rapidly worsening: frequency, strangury (painful urination) and dysuria (difficulty urinating). These symptoms are, however, highly non-specific: they are typical of every condition that obstructs the lower urinary tract, starting with benign prostatic hyperplasia.

Sometimes the tumour presents directly with the signs of advanced disease:

• Bone pain
• Perirenal pain
• Renal failure from ureteric obstruction
• Lower limb lymphoedema from infiltration of the inguinal nodes
• Palpable lymph node masses, abdominal or cervical

Diagnosis

The diagnosis of prostate carcinoma rests on four pillars:

• Digital rectal examination (DRE): the first objective assessment. Since 70–80% of carcinomas arise in the peripheral zone of the gland, many can be detected by this simple manoeuvre
• Transrectal prostate ultrasound: a hypoechoic area may raise suspicion
• PSA blood test
• Prostate biopsy: the only test that gives a definitive diagnosis

PSA: what it tells you and what it does not

PSA (prostate-specific antigen) is a glycoprotein produced by prostate cells and measurable in blood. It rises whenever the glandular structures are damaged: by prostate cancer, but also by infection and by benign prostatic hyperplasia.

It is extremely sensitive but not very specific: a raised PSA is not a diagnosis of cancer. To improve specificity, additional parameters are used, such as free PSA and the ratio of free to total PSA.

The risk of prostate cancer in relation to PSA level is broadly as follows:

• PSA up to 4.0 ng/ml: risk around 5%
• PSA between 4.1 and 9.9 ng/ml: risk around 25%
• PSA of 10 ng/ml or above: risk around 55%

PSA has one clear historical merit: today 70–80% of prostate cancers are diagnosed while the disease is still organ-confined, compared with only 20–30% in the pre-PSA era.

Treatment: how it is chosen

There is no single treatment. In choosing the right one, the specialist weighs factors relating:

• to the patient: age, general condition, personal preferences, expectations regarding preservation of sexual function
• to the disease: extent or stage of the tumour, any lymph node involvement, grade of aggressiveness

The options may be used alone or in combination: surgery, radiotherapy, brachytherapy, hormone therapy, chemotherapy and, for some slow-growing or non-aggressive forms, observation.

Radical prostatectomy

This is the gold standard for localised prostate cancer, given its high cure rates. The operation removes the prostate and seminal vesicles en bloc and restores the urethral channel. It is very different from surgery for benign disease, which removes only the central part of the gland.

• Indication: localised disease. The best results are obtained in stages T1–T2, with low PSA and a low Gleason grade
• Techniques: open, laparoscopic or robotic. Laparoscopic and robotic surgery involve no skin incision, only small ports. The choice depends on the surgeon's experience, the patient's condition and the size of the gland
• Results: biochemical progression-free survival (no PSA rise) after radical prostatectomy for localised disease is 83–94% at 5 years, 53–91% at 10 years and 40–57% at 15 years

Main complications:

• Erectile dysfunction: common, and more so with increasing age, because surgery may damage the nerves responsible for erection, which run very close to the prostate. The nerve-sparing technique has reduced its incidence. Erectile rehabilitation programmes exist after prostatectomy, and in non-responsive cases the penile prosthesis
• Urinary incontinence: uncommon, more likely with age, and in most cases mild or temporary
• Urethral stricture

It is precisely the frequency of these complications and their impact on quality of life that demand careful patient selection.

External beam radiotherapy

Radiotherapy induces necrosis of tumour cells through high-energy radiation from a linear accelerator. It is used:

• As an alternative to surgery in localised disease (radical radiotherapy)
• Together with hormone therapy in disease beginning to extend beyond the prostatic margins (stage T3)
• As palliative treatment in advanced stages, to reduce pain from bone metastases or spinal cord compression

Acute side effects: increased daytime and night-time urinary frequency (15% severe), burning and urgency, diarrhoea and faecal urgency, rectal bleeding (10–15% severe).

Chronic side effects: radiation cystitis with bladder contraction, chronic urinary retention (3%), urinary incontinence (2%), erectile dysfunction (40–70%), proctitis (6%), persistent rectal bleeding (<1%), femoral head necrosis (<1%).

Brachytherapy

Permanent prostate brachytherapy delivers a very high radiation dose to localised carcinoma without damaging adjacent structures. Small radioactive capsules (“seeds”) containing Palladium-103 or Iodine-125 are implanted into the prostate under ultrasound guidance.

• Procedure: minimally invasive, completed in a single session of around 90 minutes
• Precision: the narrow range of each seed spares the rectum, bladder and urethra compared with external beam radiotherapy
• Decay: Palladium (half-life 17 days) releases 90% of its energy in 2 months and is spent within 6; Iodine (half-life 60 days) takes 6 months and 1 year respectively. Thereafter the seeds remain inert in the prostate, entirely unnoticed by the patient
• Results: in specialist centres, superior to conventional external beam radiotherapy in terms of patients free from disease without a PSA rise

Hormone therapy

This is the treatment of choice in advanced disease or in relapse after surgery or radiotherapy. Since prostate growth depends on androgens, the aim is androgen deprivation, achieved through so-called “chemical castration”.

• LH-RH agonists: monthly or three-monthly injections. When used as monotherapy, an antiandrogen must be added for at least the first month to prevent the temporary worsening caused by the drug's mechanism of action (the flare phenomenon)
• Antiandrogens: taken as tablets. They may be combined with LH-RH agonists

Hormone therapy achieves disease control in 80–85% of cases. Some tumours, however, eventually escape hormonal control (androgen-independent disease): second-line hormone therapy is then attempted, to which 20–40% of patients respond, and if that fails, chemotherapy follows.

Side effects of LH-RH agonists: loss of libido, erectile dysfunction, hot flushes, osteoporosis, fatigue and muscle weakness, mood changes.

Side effects of antiandrogens alone: diarrhoea, nausea, breast tenderness or nipple pain (mastodynia), reduced desire and possible erectile dysfunction.

Chemotherapy

Used in patients whose tumour no longer responds to hormone therapy (hormone-refractory disease).

Observation

In highly selected cases the decision is taken not to intervene, but to monitor the disease over time. This applies to patients with localised tumours (T1–T2), non-aggressive low-to-intermediate grade forms, and low-to-intermediate PSA values. In these men the disease often does not progress.

Follow-up is mandatory: if evidence — or even a suspicion — of progression emerges, the decision not to treat must be reconsidered and treatment started.

Treatment of bone metastases

Bone is the most frequent site of metastasis in prostate cancer: spine, pelvis, ribs, and the proximal ends of the humerus and femur. In patients with bone metastases the approach is symptomatic, aimed at maintaining an acceptable quality of life, since pain is extremely debilitating.

• External beam radiotherapy: the first-choice treatment, being short, simple and effective. It achieves complete or partial pain remission in around 80% of patients, with reduction or withdrawal of analgesics, and offers good prophylaxis against pathological fracture
• Bone-seeking radioisotopes: usable alone, as an alternative to external beam radiotherapy in patients with diffuse bone involvement, or more rationally in combination with it. They carry a modest, dose-related bone marrow toxicity
• Bisphosphonates: pyrophosphate analogues that inhibit osteoclast activity — inhibiting osteoclastogenesis, inducing apoptosis of the mature osteoclast, and mechanically hindering osteolysis of the bone matrix. They have also proved useful in metastatic bone pain that does not respond to other treatments

Frequently asked questions about prostate cancer

Does a high PSA mean I have prostate cancer?

No. PSA is highly sensitive but not specific: it also rises with infection and benign prostatic hyperplasia. With a PSA up to 4 ng/ml the risk of cancer is around 5%; between 4.1 and 9.9 it rises to 25%; above 10 it reaches 55%. Only a prostate biopsy gives a definitive diagnosis.

Can benign prostatic hyperplasia turn into cancer?

No. They are two distinct diseases: they may coexist in the same patient, but benign prostatic hyperplasia does not progress to carcinoma.

Does prostate cancer cause symptoms?

Not in its early stages. Urinary symptoms appear late and are non-specific: the same complaints occur in benign prostatic hyperplasia. This is why diagnosis cannot rely on waiting for symptoms.

Will I lose my erections after surgery?

Erectile dysfunction is a common complication of radical prostatectomy, because the nerves responsible for erection run right alongside the prostate; the risk increases with age. The nerve-sparing technique has reduced its incidence. Post-operative erectile rehabilitation programmes exist and, in non-responsive cases, penile prosthesis implantation. This is a subject to raise with the specialist before surgery, not after.

Can prostate cancer be left untreated for a time?

In highly selected cases, yes: localised tumour, non-aggressive form, low-to-intermediate PSA. Observation with mandatory periodic follow-up is chosen. If follow-up shows progression, or even raises a suspicion of it, treatment begins.

Is prostate cancer always fatal?

No. When diagnosed while organ-confined — today 70–80% of cases — the prospects of cure are excellent. There is also a very large pool of latent microcarcinomas that never become clinically apparent: they are found in 80% of autopsies of men over 80, who died with the tumour rather than from it.

Do you have an abnormal PSA or a diagnosis you would like reviewed? Ask Prof. Natali for a consultation or book an appointment at his practices in Florence and Empoli, Italy.

The information on this page is provided for general educational purposes and does not replace a medical examination, which remains the only diagnostic tool for correct and effective treatment.