Prostate cancer: risk factors and diagnosis

Prostate cancer is the second most common cancer in men worldwide^[1] and the most commonly diagnosed cancer in men in the UK^[2]. In the UK, a total of 41,700 men were diagnosed with prostate cancer in 2011 and there were a total of 10,800 deaths from metastatic prostate cancer in 2012 ^[2]. These figures equate to 110 new cases and 30 deaths every day. Risk of developing the disease increases with age, with more than a third of prostate cancers diagnosed in men aged over 75 years ^[2]. There is a lack of international consensus for the detection, diagnosis and management of prostate cancer, with the disease currently managed differently in the UK and United States. This article focuses on providing an overview of prostate cancer, including early detection and prevention, prostate-specific antigen (PSA) testing, diagnosis and staging.

Risk factors

Age is the most important risk factor for developing prostate cancer, with the risk generally increasing with age after 50 years, although the risk increases after the age of 40 years in patients with a first-degree relative with a history of prostate cancer^[3] . This approximately doubles the lifetime risk of developing prostate cancer; this risk is higher for men who have a brother with a history of prostate cancer than for those who have an affected father. Unlike other cancers, where increased understanding of the molecular biology of the disease at a cellular level has led to identification of risk factors, there are currently no common specific gene mutations that are associated with prostate cancer risk as the full range of prostate cancer genomic alterations are incompletely characterised^[4] . Ethnicity is a significant risk factor in prostate cancer, although the reason for racial variability is currently unknown. The highest incidence of prostate cancer worldwide is found in American black men, who have around a 9.8% lifetime risk of developing prostate cancer; 1.6 times that of white men^[3] . In the UK, black men also have a substantially greater risk of developing prostate cancer compared with white men. although this risk is lower than that of American black men^[5] . Japanese and Chinese men have the lowest rates of prostate cancer^[3] . Socioeconomic status appears to be unrelated to the risk of prostate cancer^[3] . Dietary factors were thought to play a part in prostate cancer risk, with high levels of dietary fat associated with an increased risk and cruciferous vegetables (e.g. broccoli) associated with a reduced risk. However, no study to date has proven that diet and nutrition are either causative or preventative factors for the development of prostate cancer. Vasectomy may increase the relative risk of prostate cancer, according to data from several large epidemiologic studies; however, these studies did not report an increased risk of dying from prostate cancer associated with vasectomy, so any link remains unproven^[3] . Regular ejaculation may reduce prostate cancer risk. A large prospective study of more than 29,000 men demonstrated an association between high ejaculatory frequency (more than 21 ejaculations/month) and a decreased risk of prostate cancer, with a lifetime relative risk of 0.67, compared with men who reported a lower ejaculatory frequency^[6] . The reliability of this study had previously been questioned because of its short follow-up, however, more recent follow-up data confirm the original findings and have provided the firmest evidence to date that men can decrease their risk of prostate cancer by ejaculating frequently^[7] . The Health Professionals Follow-up Study followed nearly 32,000 healthy men for 18 years, 3,839 of whom were later diagnosed with prostate cancer. All participating men were asked to report their average monthly frequency of ejaculation from the ages of 20–29 years, 40–49 years and for the previous year, which allowed calculation of a lifetime average. After potential confounders were controlled for, the risk of prostate cancer was 20% lower in men who ejaculated at least 21 times a month than in men who ejaculated between four and seven times a month (P<0.0001)^[7] .

Symptoms of prostate cancer

As men age, their prostate gland often enlarges, most commonly caused by benign prostatic hyperplasia (BPH). The exact cause of BPH is unknown, but it is likely to be a normal part of the ageing process in men, caused by changes in hormone balance and cell growth. There is no definite link between BPH and prostate cancer, as BPH does not usually develop into cancer and men can develop prostate cancer without having first experienced BPH. However, an enlarged prostate may sometimes contain areas of cancer cells, and men with BPH can develop prostate cancer. BPH commonly manifests as problems passing urine (more frequently, difficulty in passing and passing at night). Early stage prostate cancer is generally asymptomatic, as many prostate cancers start in the posterior peripheral zone (the outer part of the prostate away from the urethra). It is not until the tumour has grown large enough to put pressure on the urethra that symptoms are noticeable. Locally advanced prostate cancer will most commonly cause bladder outlet obstruction, with a small proportion of patients experiencing haematuria, urinary tract infections, irritation on passing urine or erectile dysfunction. Many of the symptoms of prostate cancer are also present in BPH, and there is a lack of symptoms to aid early detection and diagnosis. Prostate cancer is usually slow growing and can be present for a number of years before it is detected. Men with advanced disease can present with bone pain from bony metastases and occasionally bilateral lower leg oedema from bulky lymph node metastases.

Diagnosis

The UK National Institute for Health and Care Excellence (NICE) has issued guidance on diagnosis of prostate cancer^[8] . Patients presenting to their GP with symptoms that suggest prostate cancer (e.g. nocturia, urinary frequency, hesitancy, urgency, retention, erectile dysfunction or visible haematuria) are given a digital rectal examination (DRE) and prostate specific antigen (PSA) blood test^[9] . Urinary tract infections should be ruled out prior to performing a PSA test. Patients who have had a urine infection should not undergo a PSA test for at least a month after treatment finishes^[10] . There is no single PSA level that is considered ‘normal’ as it varies from man to man and the normal level increases with age. As a guide:

• 3ng/mL or less is normal for a man aged under 60 years;
• 4ng/mL or less is normal for a man aged 60–69 years;
• 5ng/mL or less is normal for a man aged over 70 years.

A reading higher than 10ng/mL can be an indication of a non-cancerous (benign) enlargement of the prostate gland. However, the higher the level of PSA, the more likely it is that the patient has prostate cancer^[10] . If the PSA test result is outside the age-specific reference range and a hard, irregular prostate is felt on DRE, the patient should be referred to a hospital urologist urgently and should be seen within two weeks. If the PSA test result is borderline normal and there is doubt about whether to refer, a second PSA test should be performed after an interval of six to eight weeks. If the second test indicates that the PSA level is rising, the patient should be referred urgently^[9] . Patients with lower urinary tract symptoms with high PSA levels should be referred urgently. In most cases, a positive test will lead to a biopsy, which often does not give a definitive diagnosis and may cause complications (see ‘Prostate cancer screening’). Biopsy is usually performed using transrectal ultrasonographic guidance under local anaesthesia and causes infection in one in every 200 cases^[9] . Haematuria is common for two to three days following the biopsy, as well as haematospermia for up to four to six weeks. If the biopsy result is negative, then patients are usually followed up with active surveillance.

Staging

Prostate cancer staging can be complex because various staging, grading and classification systems are used either alone or in combination. It is most usefully described as one of three stages:

• localised
• locally advanced
• metastatic

More detailed staging of prostate cancer is undertaken by evaluating the size and location of the tumour, regional lymph node involvement and presence of distant metastases, using the TNM system (see ‘TNM staging for prostate cancer’)^[16] . The tumour grade is determined by assessing the extent of tumour cell differentiation. Staging and grading of the prostate cancer are essential to determining optimal treatment and prognosis. Ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) scans and bone scans are all used at this stage to determine the extent of the tumour.   Loca lly advanced disease will, over time, progress to metastatic disease. Patients will also frequently present with distant bone metastases. Prognosis for advanced metastatic disease is poor, with 30% of men surviving for five years after diagnosis ^[2] . Localised prostate cancer, in comparison, has a much better five-year survival rate of 90%. This figure drops to 70–80% for locally advanced prostate cancer, but still remain s higher than for metastatic disease^[2] . The majority of prostate cancers are adenocarcinomas. The Gleason grading system is used to provide the pathological prognostic information based on the microscopic appearance of the cancer cells in addition to clinical stage ^[17]  (see ‘Gleason grading system’). The pathologist will rate the two most common (primary and secondary) tumour patterns seen under the microscope and score each on a scale of 1 to 5. The two scores are combined to give the final Gleason score. Treatment options and staging investigations for men with potentially localised prostate cancer are determined by patients’ D’Amico risk classification^[18] and provisional treatment intent (radical or non-radical). The D’Amico risk classification system uses PSA, Gleason score and T stage (size of the tumour on DRE or ultrasound) to group men into low, intermediate or high risk groups.



• Low-risk: PSA of less than or equal to 10ng/mL, Gleason score of less than or equal to 6, and clinical stage T1-2a
;
• Intermediate risk: PSA of between 10ng/mL and 20ng/mL, Gleason score of 7, or clinical stage T2b
;
• High-risk: PSA of more than 20ng/mL, Gleason score of equal to or larger than 8, or clinical stage T2c-3a;

The treatment strategy for a patient with prostate cancer also considers other prognostic factors, such as age, comorbidities and wishes of the patient^[8] . While traditional staging is still the mainstay of treatment decision making, biomarkers are being investigated that can provide both prognostic and predictive information. There are a number of biomarkers in development and early use in the United States, such as Oncotype DX, which is used in the diagnosis of breast cancer in the UK. However, these markers are still not accepted into routine practice^[19] .