The Prostate Gland
The prostate gland is a solid, chestnut-shaped organ that surrounds the first part of the male urethra. The prostate gland is situated just underneath the bladder. It produces secretions that form part of the seminal fluid during ejaculation. The prostate gland consists of two distinct zones: an inner zone, which produces secretions that keep the lining of the urethra moist, and an outer zone, which produces seminal secretions. Two ejaculatory ducts pass from the seminal vesicles through the prostate gland to enter the urethra; the ducts carry fluid and nutrients from the vesicles to be added to the semen. The prostate gland weighs only a few grams at birth. At puberty, androgen hormones cause the gland to enlarge, and it reaches adult size at around age 20. In most men, the prostate begins to enlarge further after the age of 50. There are a number of disorders that affect the prostate gland. These include benign prostatic hypertrophy, cancer, and prostatitis.
Benign prostatic hypertrophy
An increase in size of the prostate gland, which is most common in men over the age of 50. The cause is unknown.
The enlarging prostate compresses and distorts the urethra, impeding the flow of urine from the bladder (known as outflow obstruction). This causes symptoms of prostatism, such as frequent urination and dribbling at the end of the urine stream. There may also be incontinence (see incontinence, urinary). Eventually the bladder is unable to expel all the urine (see urinary retention) and becomes distended, causing swelling, which may be painful. The bladder’s inability to empty completely each time urine is passed may lead to urinary tract infections. Kidney failure may occur as a complication of outflow obstruction.
Diagnosis and treatment
Prostate enlargement is detected by a rectal examination. Tests may include blood tests, ultrasound scanning, and recording the strength of urine flow. Tests to exclude prostate cancer as a cause of enlargement may be needed. Mild cases do not require treatment, but severe abdominal pain due to blockage of the urine flow needs immediate treatment. Men with a severely enlarged prostate usually require prostatectomy (surgical removal of the prostate gland). Alternatively, alpha-blocker drugs may be given to improve the flow of urine or antiandrogen drugs may be used to counteract the effects of testosterone.
Prostate cancer is a cancerous growth in the prostate gland that is one of the most common types of cancer in men. The cause of the cancer is unknown, but the male sex hormone testosterone has been found to influence the growth rate and spread of the tumour. Men who have a family history of prostate cancer are at an increased risk of developing cancer of the prostate and the condition most commonly affects elderly men.
An enlarged prostate may cause symptoms that include difficulty in starting to pass urine, poor urine flow, and increased frequency of urination. If a tumour blocks the urethra (the passage from the bladder to the outside of the body) or the cancer spreads to the ureters (the tubes linking each kidney to the bladder), urine flow may eventually cease altogether. In some cases, there are no urinary symptoms and the first signs may only appear once secondary cancers have arisen. Such signs may include pain in the bones, enlarged lymph nodes, shortness of breath (due to tumours in the lungs), and weight loss.
Screening and diagnosis
Some older men and men suspected of having prostate cancer may be screened for the disorder. This procedure involves tests to detect blood levels of a protein called prostate-specific antigen (PSA), as well as a rectal examination. If blood levels of PSA are above a certain level, this may be an early sign of prostate cancer; rectal examination allows a doctor to assess the size and hardness of the gland. Transrectal ultrasound (a procedure in which an ultrasound probe is inserted into the rectum) and a biopsy (removal of a tissue sample for analysis) are used to confirm a diagnosis. Blood tests and a bone scan (see radionuclide scanning) may also be carried out.
Medical opinions vary regarding the appropriate treatment for localized prostate cancer. If the man is elderly and has a small prostate cancer that has not spread, no treatment may be recommended; the man’ s condition will be monitored. For younger men, prostatectomy (removal of the prostate gland) or radiotherapy may be performed. In many cases, widespread disease is controllable for some years with the use of drugs or with orchidectomy (removal of part or all of the testes). See below for an article about prostate cancer in detail.
Inflammation of the prostate gland, usually affecting men aged between 30 and 50. It is often caused by a bacterial infection that has spread from the urethra. The presence of a urinary catheter increases the risk of prostatitis. The main symptoms of prostatitis are fever, flulike symptoms, and pain in the lower back. There may also be pain around the rectum, which is particularly troublesome on passing faeces. Diagnosis is made by rectal examination and tests on urine samples. Treatment is with antibiotic drugs. The condition may be slow to clear up and tends to recur.
Prostatitis in more detail - technical
Prostatitis is a common cause of visits in primary care and of urological referrals. It can cause considerable morbidity, and patients may remain symptomatic for years. The National Institutes of Health (NIH) consensus classification of prostatitis syndromes is summarized in Bullet list 1
Bullet list 1 National Institutes of Health classification of prostatitis syndromes
- ◆ Acute bacterial prostatitis
- ◆ Chronic bacterial prostatitis
- ◆ Chronic prostatitis/chronic pelvic pain syndrome
- A Inflammatory
- B Noninflammatory
- ◆ Asymptomatic inflammatory prostatitis
Adapted from National Institutes of Health classification of prostatitis syndromes.
Acute bacterial prostatitis
Acute bacterial prostatitis causes fever, rigors, backache, and dysuria, and may result in acute urinary retention. Symptoms and signs of epididymitis may also be present. Rectal examination reveals an enlarged, tender prostate. Bacteriuria and pyuria are related to the prostate and bladder. Untreated, acute prostatitis may culminate in prostatic abscess formation. The causative organism (commonly E. coli) can be identified on urine culture. An antibiotic which has good tissue penetration (e.g. trimethoprim, a tetracycline, or a quinolone) should be used and continued for 4 weeks, as it is thought that this reduces the risk of chronic prostatitis.
Chronic bacterial prostatitis
This is an uncommon syndrome caused by the persistence of a uropathogen (usually Gram-negative organisms or enterococcus) within the prostate, with repeated episodes of acute infection caused by the same organism on each occasion, and few if any symptoms between episodes. Obtaining bacteriological proof that the infecting organism is ‘hiding’ in the prostate gland between acute episodes is difficult. The ‘textbook’ method described by Stamey and Mears involves culture of four specimens obtained during voiding of the bladder: the first 10 ml voided and a midstream sample are collected; the patient then interrupts the flow of urine, bends forward, and digital prostatic massage is performed, resulting (sometimes) in the collection of a few drops of ‘expressed prostatic secretions’; finally, voiding is completed and a fourth sample collected. Prostatitis is diagnosed when bacterial counts are highest in the expressed prostatic secretions and the final voided urine sample; urethritis, by contrast, results in high counts in the first sample. Because of its complexity and the unpleasantness of performing digital prostatic massage per rectum during interrupted micturition, this test is very rarely performed in practice, and many patients are simply treated with a prolonged course of a quinolone antibiotic. α-Blockers have been shown to reduce recurrence rate, possibly by reducing reflux of urine into prostatic ducts during micturition.
Acute and chronic bacterial prostatitis are the best understood but least common of the prostatitis syndromes. More than 90% of symptomatic patients have chronic prostatitis/chronic pelvic pain syndrome.
Chronic prostatitis/chronic pelvic pain syndrome
Chronic urological pain is the primary component of this disorder. Patients may also complain of dysuria, strangury, urinary frequency, and pain during sexual intercourse, but have no evidence of bacterial infection on cultures of prostatic secretions, semen, or postmassage urine specimens. Certain conditions must be excluded, including active urethritis, urological cancer, significant urethral stricture, or neurological disease affecting the bladder.
Patients with this symptom complex may be further subclassified as having inflammatory or noninflammatory pelvic pain syndrome according to the presence or absence of leucocytes in semen. Occasionally, patients are found to have evidence of prostatic inflammation on biopsy, or to have leucocytes in prostatic fluid in the absence of symptoms, in which case they are regarded as having asymptomatic inflammatory prostatitis.
Treatment of chronic prostatitis/chronic pelvic pain syndrome
There is no gold standard for diagnosis, nor a clear understanding of the pathophysiology, no correlation between symptoms and prostatic histology, and no satisfactory treatment for this ill-understood group of conditions. As in the urethral syndrome in women, some cases may be caused by persistent infection by fastidious bacteria, such as chlamydia or mycoplasma; a prolonged trial of a tetracycline is therefore often used. Other treatments include regular prostatic massage, NSAIDs, α-blockers, and 5-α reductase inhibitors. α-Blockers have been shown to be of some benefit in all types of symptomatic chronic prostatitis in one randomized study.
Prostate cancer in detail - technical
Prostate cancer is the commonest malignancy in men in the United Kingdom and the United States of America. Diagnosis and treatment is not straightforward because some prostate cancers are indolent and very unlikely to progress, whereas others are highly aggressive.
Diagnosis, grading, and staging—early prostate cancer is asymptomatic: diagnosis is made by combining a digital rectal examination (DRE) with serum prostate-specific antigen (PSA) measurement linked to transrectal ultrasound scanning and biopsy. Symptomatic presentation of more advanced disease is typically with lower urinary tract symptoms, or with evidence of metastatic disease. Histologically graded by the Gleason score (well differentiated, 6 or less; moderately differentiated, 7; poorly differentiated, 8–10), and staged according to the TNM classification.
Management—(1) Disease localized to the prostate may be treated with curative intent, either with surgery or radiotherapy, or by ‘active monitoring’ (regular PSA testing and DRE, with treatment if there is evidence of progression). (2) Locally advanced disease can be managed using a combination of radiotherapy and neo-adjuvant hormone therapy. (3) Metastatic prostate cancer is incurable but dramatically responsive to androgen blockade, which is most commonly achieved with luteinizing hormone-releasing hormone (LHRH) agonists, although eventually the cancer develops into a hormone-independent state.
Prostate cancer is an important health problem: it is the commonest malignancy in men in the United Kingdom and the United States of America and is second only to lung cancer as a cause of death from malignancy. In England and Wales it results in over 10 000 deaths annually. In the United States the recognized incidence of prostate cancer rose sharply after the introduction of prostate-specific antigen (PSA) testing in the early 1990s, but despite this the mortality from the condition has remained relatively static over the same time period, recently demonstrating a small decrease which has been ascribed to treatment for early-stage disease. However, in the United Kingdom, where PSA testing is not routine, there has also been a small decrease in mortality from prostate cancer, making it unlikely that changes in death rates are solely due to aggressive treatment of early cancers.
The diagnosis and treatment of prostate cancer is more complex than it immediately appears. Difficulties arise because some prostate cancers are rather indolent, have long latent periods, and are highly unlikely to progress and cause metastatic disease in a given individual; by contrast, other prostate cancers are highly aggressive, and some have an intermediate risk. The challenge is to diagnose prostate cancer while it is localized and to treat those people who have clinically significant disease that is likely to threaten longevity. This is difficult because there are no biomarkers that predict accurately whether a man is likely to die from prostate cancer. The natural history of untreated prostate cancer is also poorly defined: autopsy studies reveal microscopic foci of prostate cancer in up to 60% of 60-year-olds, yet only 3% of these men will eventually die of the disease.
Increasing age is a strong risk factor, but genetic risk factors are also important. Some men with first degree relatives affected by prostate cancer have a two- to threefold higher risk, the risk being higher if the first-degree relative is a brother as opposed to a father. Ethnicity also influences the risk of prostate cancer, with African-Americans having the highest risk and Asian men the lowest risk. Dietary factors may play a role: lycopene (found in tomatoes), selenium, and vitamin E are potentially protective; a Western-style high-fat diet is associated with a high risk for prostate cancer in the developed world, and probably plays a role in the increasing risk of such cancer in Japanese men who migrate to the United States of America. As for many cancers, it is likely that there is an interaction between environmental factors and an inherited genetic predisposition leading to prostate cancer.
Around 5 to 10% of all prostate cancer is thought to be related to a highly penetrant genetic predisposition, and genetic factors may be responsible for as many as 40% of those prostate cancers appearing at an early age (diagnosed prior to age 50 years). Several different putative prostate cancer genes are under evaluation, including HPC1 (chromosome 1), HPC2 (chromosome 17), MSR1 (macrophage scavenging receptor 1—chromosome 8), and RNASEl. Men from families harbouring a BRAC2 mutation have a fivefold increase in risk of prostate cancer. Recent genome wide scans have found more than 30 predisposition alleles known as single nucleotide polymorphisms [SNPs]. Many prostate cancers demonstrate a translocation between the androgen-regulated TMPRS2 gene and the ETS transcription factor, putting the latter under the control of an androgen-regulated promoter.
The androgen receptor plays an important role in cell signalling, progression, and metastases in prostate cancer, and androgen blockade (antitestosterone agents) can produce clinical regression of local and metastatic disease. Mutations in the androgen receptor leading to overexpression or altered ligand binding are associated with the development of later hormone independence.
Diagnosis, staging, and grading
The prostate is divided into different zones (peripheral, central, transitional, periurethral, and fibromuscular) based on different embryological origins, with most prostate cancers (75%) arising in the peripheral zone. Early prostate cancer does not give rise to any symptoms, whereas locally advanced disease may cause lower urinary tract symptoms or haematuria, and metastatic disease may present with bone pain from sclerotic metastases. As early prostate cancer is asymptomatic, diagnosis is currently achieved by combining a digital rectal examination (DRE) with a PSA measurement linked to transrectal ultrasound scanning and biopsy of the prostate (TRUSP).
PSA is a serum protease that is secreted by prostatic epithelium. It is not a specific marker for cancer as there are many nonmalignant processes that also elevate PSA, such as benign prostatic hyperplasia (BPH), urinary tract infection, urinary tract instrumentation, ejaculation, and traumatic catheterization. Age-adjusted norms for PSA are available to improve the sensitivity and specificity of the measurement in clinical practice, an alternative approach being to set a predetermined cut-off above which further evaluation is recommended. PSA kinetics may be more valuable in making treatment decisions than a single value: a rapidly rising PSA with a short doubling time (even if starting at a very low number) indicates that a man is likely to have high-risk prostate cancer.
If a man has an elevated PSA or an abnormal DRE and there is no evidence of urinary or prostatic infection which might explain the elevation, then it is recommended that the patient undergoes a transrectal ultrasound-guided needle biopsy of the prostate under local anaesthesia, taking about 10 separate biopsies which will detect 80 to 85% of clinically significant prostate cancers.
Histological analysis is carried out by Gleason grading. The architecture is graded into five categories (1–5) for the most prominent pattern, the second most prominent pattern is assigned a secondary Gleason score, and the two scores are added together to give a Gleason sum (e.g. 3 + 4 = 7). Well-differentiated disease has a Gleason sum of 6 or less, moderately differentiated disease is 7, and poorly differentiated disease 8 to 10. It is unusual to diagnose a Gleason sum of less than 6 on needle biopsy; very well differentiated prostate cancers (Gleason <5) may be diagnosed following a transurethral resection of prostate and are usually indolent. The Gleason score is predictive of outcome: large observational studies show that men with poorly differentiated disease have a 60 to 80% chance of dying from prostate cancer within 15 years of diagnosis. The biggest problem is predicting outcome in the individual with Gleason 6 or 7 disease.
Prostate cancer is staged using the AJCC system (Table 1). When prostate cancer metastasizes it frequently goes to the pelvis, to non-regional lymph nodes, other bones (sclerotic metastases), and also local pelvic structures. It rarely invades the rectum, with Denonvillier’s fascia providing a natural barrier. Digital rectal examination provides clinical T stage. Endorectal MRI may allow for improved pre-operative staging when interpreted by experienced radiologists. A bone scan is performed to evaluate for metastatic disease.
|Table 1 TNM classification of prostate cancer|
|Prostate cancer stage||TNM Descriptor|
|Primary tumour (T stage)|
|T1a||<5% of TURP chips, Gleason score <7|
|T1b||>5% of chips or high grade prostate cancer|
|T1c||Biopsy detected in benign feeling gland|
|T2a||Nodule <50% one lobe of prostate|
|T2b||Nodule >50% of one lobe|
|T2c||Nodules both lobes|
|T3||Disease extends outside prostate|
|T4||Invades other local organs/structures|
|N0||No metastatic disease to lymph nodes|
|N1||Single node <2 cm|
|N2||Single node 2–5 cm or multiple nodes|
|N3||Node >5 cm|
|M1a||Nonregional lymph node metastases|
Screening for prostate cancer is a controversial issue. There are several large trials currently evaluating whether prostate cancer screening should be recommended. In the United Kingdom screening is not recommended as it does not fulfil World Health Organization or United Kingdom national screening guidelines. There is no doubt that prostate cancer is an important health problem, but with PSA screening most cancers currently detected are low volume, well differentiated, often indolent, and do not threaten an individual’s life expectancy.
Several large observational studies have aided our understanding of the risk of prostate cancer death following diagnosis. Screening with a PSA and DRE is imperfect as there are many nonmalignant reasons for PSA elevation, thus subjecting many men to a potentially morbid prostate biopsy (with complications including sepsis, haemorrhage, pain, and urinary symptoms). Assigning age-derived normal PSA values with a cut-off point does not detect all clinically relevant prostate cancer, as shown in the prostate cancer prevention trial where a significant number of Gleason 3 + 4 cancers were found with a PSA between 0 and 2.5 ng/ml (normal).
Although there are well-established treatment options for screen-detected prostate cancer, there are no robust randomized trials demonstrating efficacy of treatment or revealing which option provides the best outcome. One important clinical trial randomized patients in a pre-PSA era to watchful waiting or radical prostatectomy, showing an improvement in overall and prostate cancer specific survival for patients treated with radical prostatectomy. The ProtecT (United Kingdom) and PIVOT (United States of America) trials should provide useful further information, but it must be remembered that treatments for prostate cancer are not without significant morbidity, including impotence and incontinence (discussed below). One recent large randomized trial of screening, the European Randomized Study of Screening for prostate cancer (ERSPC) has shown a 20% reduction in prostate cancer deaths. However, this was at the price of considerable overdiagnosis and over treatment, with 50 men required to be treated to save one life. A recent meta-analysis of randomized controlled trials concluded that screening for prostate cancer does not have a significant impact on overall mortality or mortality specific to prostate cancer, but this will not be the last word on the issue.
Treatment options for prostate cancer are dependent on many factors, including patient age, life expectancy, stage, Gleason grade, PSA kinetics, and tumour volume. For practical purposes patients are classified into having localized disease, locally advanced disease, or metastatic disease. One very important factor in the choice of treatment for a man with low- or intermediate-risk localized prostate cancer is the patient’s view of the risks and benefits of treatment.
Disease localized to the prostate may be treated with curative intent, with either surgery or radiotherapy. Patients are eligible for radical treatment if they have a life expectancy greater than 10 years, reflecting the fact that because prostate cancer is generally slow growing, the benefit from treatment of early-stage prostate cancer is not gained unless the patient lives at least another decade. More conservative approaches such as ‘active monitoring’ are very reasonable options for patients with low volume localized disease and favourable Gleason grade. This form of management involves regular PSA testing and rectal examination and aims to treat prostate cancer once there is evidence of progression (increasing PSA or increases in local stage on rectal examination), but before there is metastatic disease.
Radical prostatectomy involves removal of the prostate gland and seminal vesicles, plus or minus a pelvic lymph node dissection, followed by anastomosis of the bladder to the urethra. This can be performed by open or laparoscopic surgery, and the latter can be performed using a robotic three-dimensional system with superior instruments and vision over standard laparoscopy.
The neurovascular bundles which produce penile erection and a sense of orgasm run very close to the prostate and are at risk during the operation. Their preservation depends on the skill of the surgeon, and whether the stage and grade of the tumour argue for a more radical excision of periprostatic tissue. The seminal vesicles are removed with the prostate, hence ejaculation is invariably absent. The risks of urinary incontinence also depend on the skill of the surgeon. The best outcomes from surgery are achieved in centres where surgeons perform a large number of operations. After surgery there should be no detectable PSA in the serum, with PSA recurrence (rising PSA after surgery) indicating either local recurrence or metastatic disease. The long-term outcomes for screen-detected prostate cancer are good, with 80 to 90% 5-year biochemical-free survival (undetectable PSA). Local recurrent disease may follow where there are positive margins on the radical prostatectomy specimens, the chances of which can be reduced by low-dose radiotherapy in men at high risk of this complication.
Radical radiotherapy may be delivered using either external beam treatment or internally via brachytherapy (radioactive seeds implanted into the prostate). The cancer cure rates for surgery and radiotherapy are similar, with patient choice being the most important factor in deciding which treatment option is preferred. Overall there is slightly less urinary morbidity from radiotherapy, but at the expense of a small risk of bowel dysfunction (bloody diarrhoea). There also appears to be an increase in the risk of secondary cancers following pelvic radiotherapy, including rectal carcinoma.
Locally advanced disease
Locally advanced disease is described as cT3 or cT4 using the TNM classification. The definition of T3 disease is that it has either invaded the seminal vesicles or has spread beyond the prostate capsule as suggested by MRI or DRE. T4 disease invades the bladder base, urethral sphincter, or pelvic side wall. This is therefore a relatively heterogeneous group of patients, including some with early T3 disease and others with significant locally advanced disease. Some T3 patients can be managed using a combination of radiotherapy and neo-adjuvant hormone therapy. Patients with T4 disease are treated similarly, but also offered palliative radiotherapy as there is a high likelihood of both local recurrence and undetected micrometastatic disease. In the future multimodality treatment with chemoradiation and hormonal treatments, or combinations with radical surgery are likely to be tested in trials.
Metastatic prostate cancer
Metastatic prostate cancer is incurable but is dramatically hormone responsive. Androgens (testosterone, dihydrotestosterone, and dihydroepiandrostenedione—DHEA) drive prostate cancer growth via the androgen receptor. Androgen blockade at any point along the hypothalamic–pituitary axis results in tumour control, with temporary regression of local and metastatic disease in most men. Various forms of androgen blockade are available, including luteinizing hormone releasing hormone (LHRH) agonists, which work by providing a constant level of LHRH that prevents the physiological release of LH that is triggered by pulsatile gonadotropin releasing hormone (GnRH). Other options include orchidectomy or the use of antiandrogens. The most reliable forms of androgen blockade are LHRH agonists and orchidectomy. Patients are sometimes opposed to the latter for body image and psychological reasons, making LHRH agonists the most widely used form of castration.
Advanced prostate cancer treated by androgen ablation eventually develops into a hormone-independent state through selection of androgen-insensitive clones, or via further dedifferentiation of prostate cancer. Once a state of hormone independence is reached the median survival is less than 18 to 24 months. Second-line hormonal manipulations may result in PSA decline: these include the addition of an antiandrogen, or the use of oestrogens or ketaconazole, the latter being quite toxic. There is no proven survival benefit for such measures, but a decline in PSA may correlate with delayed progression. Chemotherapy with taxanes can result in modest improvements in overall survival in men with hormone-unresponsive disease and is now being trialled as an adjuvant treatment for high-risk early-stage prostate cancer. Vaccination against a prostate tumour antigen has been reported to produce modest improvement in overall survival in men with advanced hormone-refractory disease, although (surprisingly) in the absence of any measurable antitumour effect. Many novel agents are in clinical trials.
Haematuria, lower urinary tract symptoms, and distal ureteric obstruction are common manifestations in patients with hormone-independent prostate cancer. Haematuria may be treated with palliative radiotherapy to the prostate bed, and symptoms suggestive of bladder outflow obstruction can be treated with a channel transurethral prostatic resection if the patient’s performance status allows. Distal ureteric obstruction results in obstructive renal failure and may be treated with ureteric stenting in selected cases, but such intervention should not be pursued in a patient who is obviously terminally ill.
Bone metastases may cause pain, pathological fractures, or spinal cord compression. Radiotherapy in single fractions is useful in alleviating painful bone disease. Zoledronic acid, a potent bisphosphonate, can be used to reduce skeletal-related events.