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As early as the tenth gestational week and under the influence of fetal androgens, solid epithelial buds form around the urogenital sinus just caudal to the bladder neck. The surrounding mesenchyme gives rise to the muscular and stromal components of the future prostate gland and has a major role in differentiation. The full development is not usually complete until puberty. Seminal vesicles develop similarly to but independently from the prostate. Skene’s tubules, which open on either side of the female urethra, are the homologue of the prostate.
The prostate gland is ovoid shaped and weighs around 18 g in the adult male; it is inferior to the urinary bladder and is traversed by the urethra. Laterally, it is cradled by the pelvic floor muscles and inferiorly by the urethral sphincter muscle. Posteriorly Denonvilliers’ fascia separates it from the rectum. The broadest part is referred to as the base and is near the bladder; the narrowest part is the apex near the sphincter muscle. The contemporary classification of the prostate into different zones was based on the work of McNeal (Figure S84.1). He showed that it is divided into the peripheral zone, which lies mainly posteriorly and from which most carcinomas arise, and a central zone, which lies posterior to the urethral lumen and above the ejaculatory ducts as they pass through the prostate; the two zones are rather like an egg in an eggcup. There is also a periurethral transitional zone, from which most benign prostatic hyperplasia (BPH) arises. Smooth muscle cells are found throughout the prostate but, in the upper part of the prostate and bladder neck, there is a separate sphincter muscle that subserves a sexual function, closing during ejaculation. Resection of this tissue during prostatectomy is responsible for retrograde ejaculation. The distal striated urethral sphincter muscle is found at the junction of the prostate and the membranous urethra; it is horseshoe shaped with the bulk lying anteriorly and is quite distinct from the muscle of the pelvic floor.
The glands of the peripheral zone (Figure S84.2), lined by columnar epithelium, lie in the fibromuscular stroma and their ducts, which are long and branched, open into posterolateral grooves on either side of the verumontanum. The glands of the central zone and transitional zone are shorter and unbranched. All these ducts, the common ejaculatory ducts and the prostatic utricle open into the prostatic urethra. BPH starts in the periurethral transitional zone and, as it increases in size, it compresses the outer peripheral zone of the prostate, which becomes the false capsule. There is also the outer true fibrous anatomical capsule and external to this lie condensations of endopelvic fascia known as the periprostatic sheath of endopelvic fascia. Between the anatomical capsule and the prostatic sheath lies the abundant prostatic venous plexus. The neurovascular bundles supplying autonomic innervation to the corpora of the penis are in very close relationship to the posterolateral aspect of the prostatic capsule and are at risk of damage during radical prostatectomy.
Sagittal diagram of the prostate just lateral to the urethra showing the division into the different zones described by McNeal. The transitional zone is the area from which most benign prostatic hyperplasia arises.
The prostate has a sexual function and may play a role in coagulation and liquefaction, but it is unclear how important its secretions are to human fertility. The normal adult prostate undergoes atrophy after castration.
Systemic hormonal influences (endocrine) and local growth factors (paracrine and autocrine)
The growth of the prostate is governed by many local and systemic hormones whose exact functions are not yet known. The main hormone acting on the prostate is testosterone, which is secreted by the Leydig cells of the testes under the control of luteinising hormone (LH), itself secreted from the anterior pituitary under the control of hypothalamic luteinising hormone-releasing hormone (LHRH). LHRH has a short halflife and is released in a pulsatile manner. The administration of LHRH analogues in a continuous, non-pulsatile manner exploits the concept of receptor desensitisation and forms the basis for androgen deprivation therapy in prostate cancer. Testosterone is converted to 1,5-dihydrotestosterone (DHT) by the enzyme 5α-reductase, which is found in high concentration in the prostate and the perigenital skin. Oestrogenic steroids are also secreted by the adrenal cortex and, in the ageing male, may play a part in disrupting the delicate balance between DHT and local peptide growth factors, and hence increase the risk of BPH. Other locally acting peptides are secreted by the prostatic epithelium and mesenchymal stromal cells in response to steroid hormones. These include epidermal growth factor, insulin-like growth factors, basic fibroblast growth factor and transforming growth factors alpha and beta. These undoubtedly play a part in normal and abnormal prostatic growth, but as yet their functions are unclear.
- Androgenic hormones, which drive prostate growth, are derived from several sources
- The majority of testosterone (90%) is secreted by the Leydig cells of the testes under the control of luteinising hormone, secreted from the anterior pituitary
- Metabolised adrenal androgen accounts for the remaining 5–10% of testosterone
- Testosterone is converted to DHT by the enzyme 5α-reductase type II, which is found in high concentration in the prostate and the perigenital skin
- DHT has five times the potency of testosterone
Elaboration and secretion of prostatespecific antigen
Prostate-specific antigen (PSA) is a serine protease glycoprotein. Its function may be to facilitate liquefaction of semen, but it is a marker for prostatic disease as it is uniquely secreted by prostatic epithelial cells. It is measured by an immunoassay and the normal range can differ a little from laboratory to laboratory. There is no real normal lower or upper limit. The levels increase with age, benign prostatic enlargement, urinary tract infections, prostatitis, instrumentation, catheterisation or prostate biopsy, and most importantly with prostate cancer. Historically, age-related normal values have been used, with an upper level of normal at 2.5 ng/mL for men aged 40–50 and the level increases one point to 3.5 ng/mL for the next decade of life; it is generally accepted that any level below 6.5 ng/mL is normal for men aged 70 years and older. PSA level in men with metastatic prostate cancer is usually increased to >20–30 ng/mL or higher (can run into >1000 ng/mL) and falls to low levels after successful androgen ablation. As PSA sensitivity and specificity are poor, PSA screening is diffi cult to establish. The National Institute for Health and Care Excellence (NICE) in the UK recommends offering PSA testing to men aged 50 and older who request the test after careful discussion about the risks of overdiagnosis. PSA testing should also be offered to men with urinary tract symptoms, erectile dysfunction, haematuria and unexplained symptoms that may indicate advanced disease (i.e. back pain, bone pain and weight loss). NICE does not recommend routine screening for asymptomatic men. Men with a family history of prostate and breast cancer are encouraged to undergo PSA testing.
Men with symptoms attending for elective treatment (excluding acute and chronic retention)
It is in men with relatively mild symptoms, reasonable flow rates (>10–15 mL/s) and good bladder emptying (residual urine <100 mL) that careful discussion over the merits and side effects of operative treatment is warranted. Waiting for a period of 6 months after careful discussion of the diagnosis is indicated. After this, a repeat assessment of symptoms and flow rates and an ultrasound scan are helpful; many men with stable symptoms will elect to leave matters be.
In men who are very concerned about the development of sexual dysfunction after TURP, the use of drugs may be helpful. Two classes of drug have been used in the treatment of men with BOO. α-adrenergic blocking agents inhibit the contraction of smooth muscle that is found in the prostate. The other class of drug is the 5α-reductase inhibitors, which inhibit the conversion of testosterone to 1,5-dihydrotestosterone (DHT), the most active form of androgen. These drugs, when taken for a year, result in a 25% reduction in the size of the prostate gland. Both groups of drugs are effective; however, α-blockers work more quickly and although the 5α-reductase inhibitors have fewer side effects they need to be taken for at least 6 months and their effect is greatest in patients with large (>40 g) glands. Drug therapy results in improvements in maximum flow rates by about 2 mL/s more than placebo and results in a mild (20%) improvement in symptom scores. Another drug class that has improved patients’ symptom scores but not their maximum flow rate are the phosphodiesterase 5 inhibitors, which reduce smooth muscle tone and possibly the inflammation in the prostate gland. These drugs are particularly useful if patients have concomitant erectile dysfunction. TURP, however, results in improvements in maximum flow rates from 9 to 18 mL/s and a 75% improvement in symptom scores. These drugs are expensive in comparison with their effectiveness, and a significant proportion of men who try these drugs will subsequently undergo surgical treatment.
Apart from the strong indications for operative treatment mentioned above, the most common reason for TURP is a combination of severe symptoms and a low flow rate of <12 mL/s. The key is to assess the symptoms carefully and to counsel men about side effects and likely outcome before advising operative treatment.
Retropubic prostatectomy (Millin)
This procedure is less frequently performed nowadays as it has been largely superseded by HOLEP, where it is available. However, where HOLEP is not available or where diverticulectomy or the removal of large stones are required, this open operation may be performed. Using a low, curved transverse suprapubic Pfannenstiel incision, which includes the rectus sheath, the recti are split in the midline and retracted to expose the bladder. With the patient in the Trendelenburg position, the surgeon separates the bladder and the prostate from the posterior aspect of the pubis. In the space thus obtained, the anterior capsule of the prostate is incised with diathermy below the bladder neck, care being taken to obtain complete control of bleeding from divided prostatic veins by suture ligation. The prostatic adenoma is exposed and a finger used to dissect along the avascular plane between the transitional and peripheral zones. A wedge is taken out of the posterior lip of the bladder neck to prevent secondary stricture in this region. The exposure of the inside of the prostatic cavity is good, and control of haemorrhage is achieved with diathermy and suture ligation of bleeding points before closure of the capsule over a Foley catheter (inserted through the urethra) draining the bladder.
This operation is very rarely performed nowadays but provides an alternative means by which to enucleate the prostate when BOO is combined with a large bladder stone. The bladder is opened and the prostate enucleated by putting a finger into the urethra, pushing forwards towards the pubes to separate the lateral lobes, and then working the finger between the adenoma and the false capsule (compressed peripheral zone). In Freyer’s operation (1901), the bladder was left open widely and drained by a suprapubic tube with a 16-mm lumen in order to allow free drainage of blood and urine. Harris (1934) advocated control of the prostatic arteries by lateral stitches inserted with his boomerang needle. The bladder wall was then closed and the wound drained.
Simple robotic prostatectomy
This is a minimally invasive procedure that is an emerging new modality for the large prostate. The procedure follows the same surgical steps of open transvesical prostatectomy except that it is performed using minimally invasive access and uses robotic instruments instead of the surgical hands. A robotic scissor creates a plane between the adenoma and the compressed capsule and all the bleeding blood vessels are controlled either with sutures or with coagulation. A catheter is placed at the end of the procedure for 2–3 days and the patient can be discharged 24–48 hours later.
This option is particularly appealing if the prostate is very large (>150–200 g) and if there is concomitant bladder stone to be treated at the same time.
Minimally invasive techniques
Prostate artery embolisation
PAE aims at reducing the size of the prostate by blocking the blood supply to the prostate adenoma. This technique is offered under local anaesthetic and does not involve any instrumentation of the urinary tracts. Injection of embolising substance is achieved through a vascular cannula that is inserted into the femoral artery and directed by the operating interventional radiologist to the prostatic arteries under radiographic guidance. It therefore has a high dose of radiation, but patients benefit from preserving ejaculation and have a reduced risk of erectile dysfunction.
Water vapour treatment (Rezūm)
This treatment is delivered via endoscopic insertion of a needle that infuses water vapour into the prostatic lobes. The high temperature (100°C) of the vapour induces cell death in the adenoma tissue and a gradual decrease in the size of the prostate. Patients are more likely to preserve their ejaculation and sexual function after this treatment compared with TURP. However, this treatment is not effective in large prostates and if the patient has bladder stones or recurrent infections.
Prostatic urethral lift (Urolift)
The urologist inserts a series of clips to the lateral lobes of the prostate in the shape of treasury tags that are used to keep office files together. The Urolift implant simply lifts the lateral lobe of the prostate, creating a wider prostatic urethra channel. The procedure does not involve any resection of the tissue. The success rate of improving voiding symptoms is high; however, symptoms tend to recur when the size of the prostate continues to increase. This method has the highest chance of preserving ejaculatory and erectile function among all other BPH procedures. However, patients with very small (<30 mL) or large (>70 mL) prostates and patients with a prominent middle lobe would not benefit from this procedure. This procedure does not appeal to patients who do not want to have a permanent implant in their prostates.
Image-guided waterjet ablation of benign prostatic hyperplasia (Aquablation)
This technique provides endoscopic treatment of BPH with heat-free resection of prostate tissue using a simple water jet. The water is passed through a tiny nozzle at high speed, the effect of which creates the power to cut. It is used to ablate prostatic adenomas. This is done under ultrasound guidance and using a completely automated system. Medium size (30 mL) to large (150 mL) prostates are suitable, including large middle lobes. The process protects the ejaculatory ducts, therefore patients are more likely to preserve their erectile function and their ejaculation compared with TURP. However, patients tend to have more bleeding afterwards.
iTIND (temporarily implanted nitinol device)
This is a minimally invasive treatment for BPH. It is deployed endoscopically in the urethra in an expanded configuration at the prostate level, and 5 days after deployment the device is removed by cystoscopy. The expanded nitinol device compresses the obstructing prostate tissue and causes ischaemic necrosis of the compressed area. It is an easy technique to use but requires a second visit to remove the device, which can be uncomfortable when it is in place.
Patients are counselled on their treatment options based on an estimated risk of a localised cancer spreading and causing death. The patient’s life expectancy and comorbidities should be taken into consideration. The strongest risk factors for metastasis are PSA level, Gleason grade and clinical stage. Tables and nomograms are available using these three parameters to predict lymph node involvement and risk of metastasis.
Curative treatment can only be offered to patients with early disease. Low-risk prostate cancer (low PSA, small foci of Gleason 6 disease) can be managed by active surveillance. Here, with 3-to 6-monthly digital rectal examination (DRE) and PSA measurement, mpMRI yearly or 2-yearly and repeated prostate biopsy, a proportion can safely avoid the toxicity of radical treatment. However, one-third of patients embarking on this approach will require radical treatment within a few years. The options available for T1, T2 or some T3 disease need to take into account the patient’s age, performance status and lifestyle preferences. The treatment of patients with advanced disease (T4 or any nodal or distant metastases) is only palliative.
Radical prostatectomy is suitable for localised disease and should be carried out only in men with a life expectancy of >10 years. A wide excision approach can give clear surgical margins in T3a disease. Exclusion of metastases would require a negative bone scan and MRI of the pelvis. It is a procedure that should be performed only by experienced surgeons when there is a high chance of cure. It results in a high incidence of impotence, but a low incidence of severe stress incontinence (<2%), which may require the fitting of an artificial urinary sphincter or urethral sling. It involves removal of the prostate down to the distal sphincter mechanism in addition to the seminal vesicles (Figure S84.3). The bladder neck is reconstituted and anastomosed to the urethra. Modifications to this operation by Walsh can lead to preservation of the neurovascular bundles that lie posterolateral to the prostate. This modification has led to the preservation of erectile function in about 60–70% of cases. Laparoscopic approaches to radical prostatectomy generate similar oncological results to the open approach with a more rapid recovery.
Radical prostatectomy specimen for a T2a prostate cancer. Preoperative prostate-specific antigen was 6 ng/mL; postoperative levels remained undetectable at 8 years. The patient is fully continent.
Robotic radical prostatectomy
The da Vinci surgical system is a master and slave device. It has three-dimensional high-definition vision, 5–10 times magnification, seven degrees of movement and tremor-free movements of the instruments. It is a very useful tool to work deep in the pelvis, hence it became very popular for radical prostatectomy. However, oncological results are similar to open radical prostatectomy with minimal morbidity and early recovery.
Radical radiotherapy for early prostate cancer
EBRT can be administered in fields that conform to the contours of the prostate, thereby limiting exposure of adjacent tissues. Survival rates following the treatment of T1 and low-volume T2 disease are not greatly different from those following radical prostatectomy, although histological evidence of persistent tumour is found within the prostate in about 30% of treated patients even beyond 24 months. Patients with locally advanced disease (T3) may be treated by radiotherapy. The treatment requires the patient to attend hospital on a daily basis for between 4 and 6 weeks. Some local complications are inevitable, namely irritation of the bladder with urinary frequency, urgency and sometimes urge incontinence and similar problems affecting the rectum with diarrhoea and, occasionally, late radiation proctitis and cystitis. Development of erectile dysfunction occurs less frequently than following radical prostatectomy, but is present in up to 30% of cases. Newer radiotherapy techniques (image-guided radiation therapy [IGRT]/intensity-modulated radiation therapy [IMRT]) have reduced the morbidity of bowel and bladder dysfunction. EBRT is rendered more effective with a period of neoadjuvant and adjuvant androgen ablation, with its inherent effects on libido.
Under TRUS guidance, radioactive seeds are permanently implanted into the prostate. A computer program converts accurate ultrasound measurements of the prostate gland to construct a plan of the gland. Under anaesthesia, the patient is placed in the lithotomy position and, according to the template plan, seeds are placed through transperineal needles. The radioisotopes commonly used are iodine-125 and palladium-103. These isotopes deliver an intense, confined radiation dose locally in the prostate, which falls off rapidly to spare the surrounding structures. This method is called low-doserate (LDR) brachytherapy and it is suitable for low-volume, favourable, intermediate-risk prostate cancer. High-dose-rate (HDR) brachytherapy is another technique; it can be used to treat high-risk and locally advanced tumours. A major factor is the reduced peroperative complications and generally low morbidity. Long-term cancer survival results from institutions specialising in the procedure are encouraging.
It is only feasible up to a moderate size of the gland and in patients with no prior urinary tract symptoms.
Proton beam therapy
The radiation treatment is delivered at the end of the particles’ path with the suggestion that surrounding structures can be spared. Studies comparing standard EBRT treatment with proton beam therapy are still ongoing, but early indications point to no superiority of proton beam treatment.
This freezes the cells and induces cancer cell death at –40°C. Although it is a minimally invasive method, there is higher risk of incontinence (up 20%) and rectourethral fistula formation (6%). Most studies are non-comparative, and this treatment is only offered as part of clinical trials.
High-intensity focused ultrasound
In contrast to cryotherapy, high-intensity focused ultrasound (HIFU) aims at heating the prostate to 65°C using ultrasound waves delivered through a transducer placed in the rectum. It is a minimally invasive technique; however, it cannot reach the anterior part of the prostate, and side effects include rectourethral fistula in up to 5% of patients. There is a lack of comparative studies and it should only be offered in clinical trials.
There is still debate about the timing of androgen ablation treatment in patients with locally advanced or metastatic disease without symptoms. The options are androgen deprivation at diagnosis or careful review, reserving active treatment for the later development of symptoms. Patients with poorly differentiated disease are at risk of a catastrophic event such as spinal cord compression; in these patients, early androgen ablation can prolong the time to complications. Also, patients with local or general symptoms should be offered androgen deprivation.
Surgical castration: orchidectomy
Bilateral subcapsular or total orchidectomy is the cheapest and most efficient method to achieve immediate castration in patients with advanced and metastatic prostate cancer. It eliminates all testosterone production from the testes. It is a very valuable option if androgen deprivation therapy is not desired or available, especially in patients who have no regular access to healthcare support, in patients who travel constantly and in patients who may struggle with compliance, or simply if patients want to avoid repeated injections and choose this method. In 1941, prostate cancer was shown to be responsive to such treatment by Charles Huggins, the only urologist to win a Nobel Prize.
Medical castration/androgen deprivation therapy
Medical forms of androgen ablation have been available since the discovery of stilboestrol. The other commonly available treatments to reduce testosterone levels to the castrated range are LHRH agonists. These agents initially stimulate hypothalamic LHRH receptors but, because of their constant presence (rather than the normal diurnal rhythm), they then downregulate the receptors, resulting in cessation of pituitary LH production and, hence, a decrease in testosterone production. In the first 10 days or so, serum testosterone levels may increase, and it is wise to give flutamide, bicalutamide or cyproterone acetate for this period. LHRH agonists may be given by monthly, 3-monthly or 6-monthly depot injection. The counterintuitive testosterone surge associated with LHRH agonist therapy has led to the development of the gonadotropin-releasing hormone (GnRH) antagonists, whose mechanism of action is a direct effect on testosterone suppression. Thus, GnRH antagonists cause competitive receptor binding that blocks the action of GnRH on the pituitary, so there is no initial surge in gonadotropin or testosterone. Release of LH and follicle-stimulating hormone (FSH) is blocked and thus testicular testosterone production is rapidly suppressed. Suppression of FSH is believed to be associated with a lower incidence of cardiovascular morbidity and mortality.
Other treatments that block the androgen receptor have become available recently. Cyproterone acetate also has some progestogenic effect, while flutamide and bicalutamide are pure antiandrogens. In general, oral antiandrogen monotherapy has not been shown to be as good as LHRH agonists/antagonists or orchidectomy. Androgen ablation can be administered in an intermittent fashion governed by serum PSA levels. In high-volume disease, a combination of androgen deprivation therapy and taxane chemotherapy is advocated from the beginning for a better outcome.
Recently, agents such as enzalutamide (a second-generation androgen receptor blocker), abiraterone (a drug that blocks the production of testosterone from its precursors) and taxane chemotherapy have all been shown to promote survival in metastatic prostate cancer. Many clinical trials are under way to ascertain which drugs should be used in which patients and the therapeutic landscape is changing rapidly.
Radiotherapy for symptomatic metastases is an excellent form of palliative treatment, often producing dramatic pain relief in men with hormone-relapsed prostate cancer that can last up to 6 months. When multiple sites are involved, intravenous radiopharmaceuticals such as strontium-89 can be employed. Strontium is a bone-seeking isotope that delivers effective radiotherapy to metastatic areas. It appears to be as effective as hemibody irradiation in the treatment of men with metastatic hormone-relapsed disease; however, the duration of response has been disappointing.
Radium-223 dichloride is a radioactive isotope that specifically targets bone lesions. It has been approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases, without known visceral metastases.
Previously, chemotherapy treatment was reserved for patients who fail hormone treatment. The results from the STAMPEDE trial have shown significant improvement in survival if docetaxel chemotherapy is used upfront at diagnosis of metastatic prostate cancer alongside hormone treatment. This is the current standard treatment in patients fit enough to receive chemotherapy.
Tuberculosis of the Prostate and Seminal Vesicles
Tuberculosis of the prostate and seminal vesicles is rare and associated with renal tuberculosis. In 30% of cases, there is a history of pulmonary tuberculosis within 5 years of the onset of genital tuberculosis.
Tuberculosis of one or both seminal vesicles may be found when examining a patient with chronic tuberculous epididymitis, no symptoms being referable to the internal genitalia. On rectal examination, the affected vesicle is found to be nodular.
When the prostate is involved, rectal examination reveals nodules in one or both lateral lobes. Patients with tuberculous prostatitis usually present with the following:
- urethral discharge;
- painful, sometimes blood-stained, ejaculation;
- mild ache in the perineum;
- abscess formation.
Special forms of investigation
Radiography sometimes displays areas of calcification in the prostate and/or the seminal vesicles. Intravenous urography or CT urography may show tubercular involvement of kidney, ureter or bladder. Urine examination may show sterile pyuria, and bacteriological examination of the seminal fluid may yield positive cultures for tubercle bacilli.
The general treatment is that for tuberculosis. If a prostatic abscess forms, it should be drained transurethrally.
Acute seminal vesiculitis
Acute seminal vesiculitis occurs in association with prostatitis. Prior to the antibiotic treatment of gonorrhoea, gonococcal vesiculitis was common.
Chronic seminal vesiculitis
Chronic seminal vesiculitis usually presents with haematospermia and pain on intercourse. TRUS demonstrates the features of distension and thickening and the presence of turbid fluid. The treatment is the same as for chronic prostatitis.
Tuberculous seminal vesiculitis
The clinical features and treatment have been discussed above.
Diverticulum of the seminal vesicle
Diverticulum of the seminal vesicle occurs occasionally. In such cases, the kidney on that side is absent and the diverticulum represents an abortive ureteric bud. This is also known as Zinner syndrome. Usually symptoms appear in the second or third decade in the form of LUTS, scrotal pain or painful ejaculation.
Cyst of the seminal vesicle
A cyst of the seminal vesicle is uncommon and rarely requires treatment. It may be removed by dissection through an incision similar to that for perineal prostatectomy if it is large or giving rise to symptoms. Laparoscopic or robotic procedures are also commonly employed.