A comprehensive guide for patients: what it is, how it is diagnosed, risk classes and treatment options.
The prostate is a gland found only in men, roughly the size of a walnut, situated below the bladder and in front of the rectum. Its main function is to produce the bulk of the seminal fluid — the medium in which spermatozoa live.
Anatomically, the prostate is divided into zones with distinct characteristics. Think of it as an orange: the peel corresponds to the peripheral zone, where almost all cancers arise. The pulp corresponds to the central or transition zone, where benign prostatic hyperplasia develops — a completely separate condition, very common in men over 50.
Important: benign prostatic hyperplasia and prostate cancer are two different diseases affecting the same organ but originating from anatomically distinct zones, with separate causes and requiring different treatments. It is possible to have both simultaneously.
Prostate cancer is the most common malignancy in men in Western countries. In Italy, approximately 40,000 new cases are diagnosed each year and around 8,000 deaths occur: a 1-in-5 ratio between deaths and diagnoses which, while seemingly reassuring, represents very significant absolute numbers. It is the second leading cause of cancer-related death in men, after lung cancer. At present, an estimated 500,000 Italians have an active prostate cancer diagnosis and are under follow-up or treatment.
It is predominantly a disease of older age: men over 70 have an incidence rate nearly three times higher than men in their fifties. As the population ages, these numbers will continue to rise.
A key concept — competing risk: unlike many other cancers, prostate cancer survival is not measured at 5 years but at 15–20 years, because the natural history of the disease is often very slow. Many elderly patients with prostate cancer die from other causes before the tumour can cause harm — a phenomenon clinicians call "competing risk mortality". This means that treatment decisions must always take into account the patient's age, general condition, and life expectancy, not just the oncological disease.
As with many cancers, there is no single cause. Several factors are, however, associated with an increased risk.
Testosterone is necessary for prostate cancer to develop: those who do not produce it (for instance due to certain hormonal disorders) do not develop the disease. However, it is not the amount of circulating testosterone that determines risk — having higher levels does not mean having greater risk.
Men of African origin have a significantly higher risk of developing the disease and of developing a more aggressive form. Studies of Japanese migrants to California and Brazil demonstrated that within two generations the risk approached that of the local population, confirming the importance of environmental and dietary factors.
A diet high in red meat is associated with greater risk. Asian populations whose diet is based on rice and soya have historically had a much lower risk, although this tends to increase in generations that adopt a Western dietary pattern.
"True" familial history is defined by the presence of cases across three consecutive generations, or at least three cases across two generations. Having a single relative with prostate cancer does not constitute high-risk familial history — the disease is so common that almost everyone would be classified at risk under a broader definition. In families with genuine familial clustering, the BRCA1 and BRCA2 genes have been identified, the same genes implicated in breast cancer in women.
Localised prostate cancer is in the vast majority of cases completely asymptomatic. Many patients are diagnosed exclusively through PSA testing, in the absence of any symptoms whatsoever.
Some patients attend the urologist for urinary symptoms such as difficulty urinating, a weak stream, nocturia, or a sensation of incomplete emptying. These symptoms, however, are not caused by the cancer, but by concurrent benign prostatic hyperplasia — a separate condition that can coexist with cancer but is not a consequence of it.
True symptoms of prostate cancer appear in patients with metastatic disease. Prostate cancer metastases are almost invariably skeletal and present with:
The paradox of prostate cancer: when the disease is localised and perfectly curable, the patient has no symptoms whatsoever. When symptoms appear, the disease is already metastatic — treatable, but no longer definitively curable. This is why PSA screening is so important.
Through digital rectal examination the physician can palpate the posterior surface of the prostate, assessing its consistency and regularity. It is a very crude instrument — its sensitivity is approximately 50% and its positive predictive value around 20% — but it remains useful when the finding is frankly irregular or suspicious, and can initiate the diagnostic pathway even in the absence of an elevated PSA.
PSA (prostate-specific antigen) is a protein produced by the prostate, measurable with a simple blood test. It is not a cancer-specific marker, but a marker of prostatic pathology in general: it rises in the presence of cancer, but also with infection, inflammation, or benign hyperplasia. Its sensitivity is approximately 72% and the positive predictive value around 25%: even with an elevated PSA, only one in four patients actually has cancer.
The reference value of 4 ng/mL is a statistical convention, not a real biological threshold. The PCPT (Prostate Cancer Prevention Trial) demonstrated that even with very low PSA a probability of cancer exists: approximately 27% of patients with PSA between 3 and 4 have cancer, and even those with PSA below 1 have about a 6% probability. There is therefore no value below which the risk is zero: risk increases gradually with PSA, without a sharp cut-off.
Several factors can raise PSA even in the absence of cancer: urinary tract infections, prostatic inflammation (prostatitis), benign hyperplasia, intense physical activity, instrumental procedures on the urinary tract. Some medications (5-alpha reductase inhibitors) artificially lower it. For this reason the urologist never makes decisions based on a single measurement, but always requests confirmation from a second blood sample.
Important studies have demonstrated that PSA around the age of 40 is predictive of the risk of developing metastatic prostate cancer over the subsequent 25 years. A 40-year-old man with PSA below 1 ng/mL has a virtually negligible long-term risk of metastases; those with higher values merit more attentive follow-up in subsequent years. This allows the intensity of monitoring to be personalised according to individual risk, without unnecessarily burdening those at low risk.
Italy does not yet have an organised national screening programme for prostate cancer (unlike those for breast or colorectal cancer). The European ERSPC study, with 23 years of follow-up, demonstrated a growing survival benefit over time: 12 patients needed to be treated to prevent one death. Two regions (Lombardia and Basilicata) have already launched pilot programmes. Pending a national programme, so-called opportunistic screening — carried out on the initiative of the patient or physician — remains the most widespread approach, with all the heterogeneity this entails.
Today, when PSA is elevated or the rectal finding is suspicious, the first diagnostic step is no longer biopsy but multiparametric MRI of the prostate. It is a non-invasive examination, without ionising radiation, that identifies suspicious areas within the gland. On MRI, cancer appears as a dark (hypointense) area on T2 sequences, retaining this characteristic on diffusion-weighted sequences and showing enhancement with contrast medium.
Lesions are classified using the PI-RADS score from 1 to 5: lesions 1 and 2 are not suspicious; 3 is equivocal; 4 and 5 are the most suspicious for clinically significant cancer. The radiologist indicates the exact position of the lesion on a prostate map, which is essential for guiding subsequent biopsy.
The diagnosis of prostate cancer is always histological: small tissue cores must be obtained and examined under the microscope. With MRI available, it is now possible to perform a fusion biopsy: MRI images are "overlaid" on real-time ultrasound through dedicated software, which shows the surgeon exactly where to position the needle on the suspicious lesion. At Padova, both targeted cores on the MRI-visible lesion and systematic cores throughout the rest of the gland are obtained: this combined approach maximises the detection of clinically significant (high-grade) cancers.
Biopsy is now performed via the transperineal route (through the perineum, not through the rectum). This approach virtually eliminates the risk of post-biopsy sepsis — the most feared complication — without the need for prophylactic antibiotics. The EAU Guidelines now exclusively recommend this technique. The procedure is longer and requires more anaesthesia than the old transrectal technique, but the safety profile is markedly superior.
A negative MRI significantly reduces the risk of clinically significant cancer, but does not eliminate it entirely. Based on the residual risk calculated with dedicated tools (nomograms), the physician will decide whether to proceed with a systematic biopsy or limit management to close follow-up with repeat PSA testing.
When biopsy cores reach the pathology laboratory, the pathologist may find normal prostatic tissue (benign hyperplasia) or cancer. 99% of prostate cancers are acinar adenocarcinoma — a very uniform histological type.
In addition to diagnosis, the pathologist assigns a grade of differentiation according to the Gleason system. The pathologist Donald Gleason observed that tumours with different microscopic characteristics had different clinical courses, and devised a predictive score. A score (from 1 to 5) is assigned to the most represented tumour area and to the area with the highest grade; the sum gives a total Gleason score from 2 to 10. Today Grade Groups 1 to 5 are used:
Gleason score is the most powerful prognostic factor in prostate cancer. The higher it is, the greater the risk of progression, metastasis and death. Today biopsy aims above all at precisely identifying the grade of the tumour — not merely its presence — because this is the basis for almost all treatment decisions.
Based on PSA, rectal findings, and Gleason score, each patient is classified according to the D'Amico risk classes. This classification guides the choice of the most appropriate treatment.
PSA <10, negative rectal examination, Gleason score 6 (Grade Group 1). Fewer than 3 positive cores with <50% involvement. Approximately 20–25% of cases at diagnosis.
A single intermediate risk factor: PSA 10–20, marginally positive rectal examination, or Gleason 7 (3+4, Grade Group 2). Fewer than 50% of positive cores.
Two or more intermediate risk factors, Gleason 7 (4+3, Grade Group 3), or more than 50% of biopsy cores positive.
PSA >20, Gleason 8–10 (Grade Group 4–5), or disease extending beyond the prostatic capsule. Approximately 30% of cases at diagnosis.
Patients at very low and low risk do not require staging (active search for metastases), because the risk of disseminated disease is virtually nil. From unfavourable intermediate risk onwards, staging investigations are performed.
Prostate cancer metastasises predominantly to the pelvic lymph nodes (those adjacent to the prostate: common iliac, external iliac, obturator) and to the skeleton. Bone metastases are characteristically osteoblastic — they tend to increase bone density, unlike almost all other tumours — and localise predominantly to the vertebrae, pelvis and ribs.
CT of the abdomen and pelvis evaluates the lymph nodes. Bone scintigraphy with technetium identifies areas of the skeleton with abnormal metabolic activity, indicating where targeted supplementary imaging (plain X-ray, CT, or MRI) should be performed. In the presence of isolated lesions, these targeted investigations confirm or exclude a metastatic nature.
In recent years, PSMA PET-CT has entered clinical practice — an examination that uses a radioactively labelled monoclonal antibody capable of selectively binding to prostatic tumour cells wherever they are in the body. It is far more accurate than CT and bone scintigraphy and can detect metastases that conventional methods miss — including lymph nodes of just a few millimetres or minimal bone lesions.
This technique has, however, created a new category of patients — PET-oligometastatic — with few lesions visible only on this advanced modality. How to manage these patients is the subject of active research, since all prior treatment studies were conducted using conventional imaging. The current tendency is to treat the identified lesions, but the long-term benefit remains to be fully established.
The choice of the most appropriate treatment depends on two fundamental factors: the risk class of the tumour (as described above) and the patient's life expectancy. There is no one-size-fits-all treatment — two patients with the same disease may receive completely different recommendations if their general condition and age differ substantially.
The key concept: in elderly patients or those with multiple comorbidities, the probability of dying from another cause before the tumour can cause harm may be very high. In such cases, aggressive treatments may do more harm than good.
In patients with a life expectancy of less than 10 years, regardless of risk class, no treatment is often given. The patient is monitored and intervention occurs only if symptoms develop. This differs from active surveillance: here the goal is not cure, but the avoidance of unnecessary treatment in patients who would not benefit from it.
For very low and low risk tumours (Gleason 6, Grade Group 1), active surveillance is now the preferred option in international guidelines. The concept derives from a landmark study by Prof. Peter Albertson, who followed patients with prostate cancer not treated with curative intent for 24 years: in those with a low Gleason score, the probability of death from prostate cancer was negligible, while the vast majority died from other causes.
Active surveillance is not a renunciation of care. It is a structured protocol comprising:
The patient exits surveillance and is referred for curative treatment if biopsy reveals a higher grade (so-called "upgrading"), or if the patient wishes to proceed. Studies with up to 25 years of follow-up show disease-specific survival exceeding 94%, and approximately 50–60% of patients are never treated because the disease never progresses.
A reassuring datum: in very low and low risk patients on active surveillance, prostate cancer mortality at 25 years is around 3–6%. The vast majority die from causes unrelated to prostate cancer.
Radical prostatectomy — the surgical removal of the entire prostate — is one of the main options for localised intermediate and high risk tumours. At our centre, as in all referral centres, it has been performed exclusively using robotic technology (da Vinci system) since 2006. The open (laparotomy) technique is now considered obsolete.
The surgeon operates through 4 small incisions (approximately 7–8 mm each), controlling the robot's arms from a console. The robot provides a magnified three-dimensional view and millimetre-precision movements impossible with the naked hand. At Padova, a particular approach called Retzius-sparing is used, which preserves the anatomical support mechanisms of the bladder, with important benefits for the recovery of urinary continence.
The operation lasts approximately 2 hours. The patient is discharged after 24–48 hours. The urinary catheter is removed approximately 7 days later, and many patients return to light activities within 2–3 weeks.
In the immediate post-operative period, approximately half of patients experience some urinary leakage, which tends to resolve over the following months. With the Retzius-sparing technique, approximately half of patients are already continent at the time of catheter removal. Complete continence is recovered in 90% of patients within the first year, often with the assistance of pelvic floor physiotherapy.
The nerves responsible for erection run along the lateral surface of the prostate. In patients with limited, well-differentiated disease it is possible to perform nerve-sparing surgery, which maximises the probability of recovering erectile function. Whether this technique can be applied depends on the extent of disease, the surgeon's skill, and the patient's pre-operative erectile function. It should be noted that patients undergoing radiotherapy also experience progressive erectile difficulties over time, so in the long term the differences between the two techniques tend to diminish.
Overall complications occur in approximately 10% of cases. Serious complications requiring re-intervention occur in approximately 3% and almost always involve small lymphatic collections (lymphoceles). Perioperative mortality is virtually zero in modern series. All patients receive anti-thrombotic prophylaxis for 4 weeks after surgery.
After removal of the prostate, PSA must fall to zero (technically "undetectable"). A first check is performed approximately one month after surgery. If PSA rises again above 0.2 ng/mL, this is termed biochemical recurrence: it does not necessarily mean the disease has spread, but that closer monitoring is required and, in appropriate cases, salvage radiotherapy should be considered.
External beam radiotherapy is the main alternative to surgery for curative treatment of localised prostate cancer. It is administered by radiation oncologists and involves, in the standard schedule, approximately 39 sessions (5 per week for 8 weeks), each lasting a few minutes. Hypofractionated schedules (20–25 sessions) with equivalent results are also available.
In intermediate and high risk disease, radiotherapy is almost always combined with hormonal therapy for 6–36 months depending on risk: this significantly enhances the effectiveness of radiotherapy.
The only large randomised trial that compared the two options (the ProtecT study) demonstrated that, in terms of oncological efficacy, surgery and radiotherapy are equivalent in the majority of cases. The difference lies in the side effect profile:
In younger patients surgery tends to be preferred (to avoid the long-term effects of radiotherapy on tissue); in older patients or those with surgical contraindications radiotherapy is preferred. For many patients of intermediate age both options are valid, and the choice is shared with the patient based on their preferences regarding side effects.
Prostate cancer depends on testosterone to grow. Hormonal therapy (or androgen deprivation therapy, ADT) aims to eliminate testosterone levels, thereby blocking tumour growth. In the past, orchiectomy (surgical removal of the testes) was used; today so-called chemical castration is employed, with drugs that block testosterone production without surgical intervention.
In patients with metastases, hormonal therapy alone is no longer the standard: in recent years large randomised trials have demonstrated that adding agents such as abiraterone (an inhibitor of adrenal testosterone production) or the newer androgen receptor inhibitors (enzalutamide, apalutamide, darolutamide) to classical hormonal therapy significantly improves survival. In some patients with high-volume disease, chemotherapy with docetaxel is also added. Today almost no metastatic patient receives classical hormonal therapy alone.
Eliminating testosterone causes a form of "male menopause" (andropause) with important consequences that must be actively managed:
For this reason, patients on hormonal therapy require close metabolic monitoring (blood glucose, lipids, blood pressure), regular physical activity, and often medications to protect bone (bisphosphonates or denosumab).
For information or to book a urological appointment at the Urological Clinic of the University of Padova.
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