Disorders of the Prostate

Benign Prostatic Hyperplasia

(Benign Prostatic Hypertrophy)

Nonmalignant enlargement of the prostate gland with age.

Benign prostatic hyperplasia (BPH) is clinically evident in 50% of men by age 50 and in 80% by age 80. Androgens, particularly dihydrotestosterone, appear to play a major role.

Hyperplasia of the prostate, with subsequent increase in the fibromuscular stroma, results in a narrowing of the urethral lumen as it traverses the prostate (static component). This narrowing creates bladder outlet obstruction. In addition, prostatic smooth muscle tone, mediated through -adrenergic receptors, creates further bladder outlet obstruction (dynamic component).

Symptoms, Signs, and Diagnosis

Symptoms of bladder outlet obstruction due to BPH include hesitancy, weakness of urinary stream, intermittency, and a feeling of incomplete bladder emptying. The bladder tends to become more irritable, manifested by urinary frequency, nocturia, and urgency. Urinary symptoms may be evaluated using the American Urological Association Symptom Score (see Table 117-1).

Initial evaluation should also include a history and digital rectal examination along with urinalysis and measurement of the serum creatinine level. Digital rectal examination may disclose enlargement of the gland, prostatic firmness, or a nodule, which increases the suspicion of prostate cancer.

A blood test to measure serum creatinine should be performed to assess kidney function. A urinalysis that reveals > 4 red blood cells per high-power field in uninfected urine requires intravenous urography and cystoscopy to rule out kidney or bladder cancer. An abdominal ultrasound may help differentiate obstructive from renal causes of an elevated creatinine level. Further diagnostic testing (eg, uroflowmetry, postvoid residuals, more complex urodynamic evaluation) may also be necessary.

Measurement of serum prostate-specific antigen (PSA) is not part of the diagnostic evaluation of BPH but may help exclude prostate cancer as a cause of urinary tract obstruction.

Treatment

BPH should be treated when symptoms are sufficiently bothersome or when evaluation discloses recurrent urinary tract infection or an increased creatinine level. Absolute indications for treatment, such as refractory urinary retention, are discussed below. Treatment usually starts with drug treatment. However, for patients with urinary retention, surgery may be appropriate initial treatment, because it maximally reduces outflow resistance.

Drug treatment: Drug treatment usually results in minimal objective improvement but significant symptomatic improvement. Selective and uroselective a-blockers reduce the dynamic component of obstruction. Selective -blockers block _1a and _1b subtypes equally. By blocking the _1a receptors of smooth muscle at the bladder neck, these drugs decrease outlet resistance. By blocking _1b receptors, these drugs may cause cardiovascular adverse effects, particularly hypotension. Dose titration over several weeks avoids hypotensive episodes. Uroselective -blockers have at least a 30-times greater affinity for _1a over _1b subtypes. They do not, therefore, require dose titration and have little effect on blood pressure.

Terazosin and doxazosin are selective -blockers; they are available in titration packs, which may make prescribing easier. The drugs are taken once a day at bedtime, thereby minimizing adverse effects of postural hypotension (in 6 to 8% of cases) and tiredness (in 6 to 10%). Other adverse effects include asthenia (in 6 to 10%) and dizziness (in 5 to 10%). Adverse effects tend to be minor and reversible through dose reduction. Tamsulosin is a uroselective -blocker. The dosage is 0.4 mg daily, one-half hour after the same meal each day. The incidence of cardiovascular adverse effects is low. In responsive patients, symptoms generally improve within a few days.

The 5-a-reductase inhibitor finasteride inhibits the conversion of testosterone to dihydrotestosterone. It shrinks overall gland size, thus reducing the static component of obstruction, and decreases obstructive events and the need for surgery in glands > 50 g. A 3-month trial is necessary to determine if finasteride is effective. The adverse effects of finasteride are minimal. About 5% of patients develop sexual dysfunction (ie, decreased libido, decreased ejaculatory volumes, erectile dysfunction). Finasteride also causes a 50% reduction in the serum PSA level; thus, a normal PSA level in men treated with finasteride is one half that of men not treated with this drug.

Minimally invasive therapy: New ablative technologies do not require that patients be hospitalized or given general or regional anesthesia. The effectiveness of these technologies is being evaluated. These technologies use different energies (eg, microwave, radiofrequency, ultrasound) to destroy prostatic tissue. A transurethral device (catheter) is placed after the patient is given local anesthesia or conscious sedation, and the surrounding prostatic tissue is heated to 60 to 100° C (140 to 212° F), causing tissue death. Cystoscopy performed months after an ablative procedure often does not show much obvious visual improvement; however, follow-up over several years has found sustained efficacy using subjective factors (eg, urinary frequency, nocturia).

An intraprostatic stent (a titanium alloy mesh tube) can be placed under local anesthesia inside the prostatic urethra, opening the urethra. Its placement has been suggested for elderly debilitated men poorly able to undergo anesthesia. Unfortunately, if an infection develops within the stent, surgical removal would be necessary. Surgical removal may be traumatic and challenging, requiring regional or general anesthesia.

Surgery: Surgical treatment remains the gold standard for symptomatic BPH. It provides the most reliable and immediate subjective and objective improvement. Surgery is recommended when BPH causes renal insufficiency, recurrent retention, recurrent urinary tract infection, bladder calculi, or gross hematuria. Hydronephrosis or a postvoid residual volume > 500 mL may also require surgical treatment. Open prostatectomy is usually reserved for patients with large prostate glands (> 100 g) or in whom other pathology (eg, a vesical calculus) exists. It requires an abdominal incision and longer convalescence than transurethral approaches. However, subsequent surgery is rarely needed. Transurethral resection of the prostate (TURP) is less invasive than open prostatectomy but requires regional or general anesthesia in an inpatient setting. Its complications include infection, bleeding, and a 20% risk of reoperation within 10 years. Retrograde ejaculation after surgery is usual, whereas impotence or incontinence is rare. Transurethral incision of the prostate (TUIP) is best for patients with glands < 30 g and obstruction at the bladder neck. The complications of TUIP are the same as those of TURP but are significantly less severe and less frequent.

Prostate Cancer

Prostate cancer affects about 2% of primary care patients > 50. Adenocarcinoma of the prostate is one of the most common cancers in American men. However, prostate cancer most often runs a protracted course, with other causes of death intervening; thus, most patients die with prostate cancer rather than of prostate cancer.

Prostate cancer is the second leading cause of cancer death in men after lung cancer. Estimates for the USA in 1998 were that 184,500 men would be diagnosed and 39,200 men would die of prostate cancer. Black men have a significantly higher risk of developing prostate cancer and have a higher mortality from the disease than do white men. The incidence increases with age; > 75% of cancers are diagnosed in men > 65.

Most patients are asymptomatic or have symptoms of obstructive uropathy. A few patients present with symptoms due to distant metastases, such as weight loss, bone pain, or neurologic symptoms.

Screening and Diagnosis

A majority of cases are discovered through screening with digital rectal examination (DRE) and serum prostate-specific antigen (PSA). The decision to screen for clinically localized prostate cancer, particularly in the elderly, is controversial. Screening is based on the hypothesis that early detection allows treatment of the cancer while it is still localized, thereby reducing mortality. However, the hypothesis that early treatment reduces mortality is unproven. Patients with well-differentiated cancer do just as well with or without treatment, and those with poorly differentiated cancers tend to do poorly with or without treatment.

Nonetheless, the American Cancer Society and the American Urological Association recommend annual screening with DRE and PSA for men >= 50 years with a life expectancy of >= 10 years. Thus, screening men > 75 years is probably not warranted.

DRE is an easy initial screening test for both prostate and rectal cancers. However, cancers diagnosed by DRE are usually already large, and more than half have already extended through the capsule, making cure less likely.

PSA is a serine kinase produced by benign and malignant prostatic epithelial cells. Serum PSA levels < 4 ng/mL are considered normal, levels of 4 to 10 ng/mL have a 25% positive predictive value for prostate cancer, and levels > 10 ng/mL have a 67% positive predictive value. Thus, even at high levels, the test is not specific. Other conditions (eg, benign prostatic hyperplasia, prostatitis, recent prostate biopsy) can also elevate PSA levels. Age-specific upper levels of normal of 4.5 ng/mL for men aged 60 and 6.5 ng/mL for men aged 70 have been suggested to try to reduce the number of biopsies having negative results.

The measurement of free vs. total PSA levels has been suggested to increase specificity further. In general, prostate cancers are associated with less free PSA. Thus, free PSA levels < 15 to 25% are an indication for biopsy. However, no standard percentage has been defined, and the range reflects the individual investigator's conclusions.

Despite low specificity, an abnormal DRE result or elevated PSA level is generally considered an indication for transrectal ultrasound (TRUS)-guided prostate biopsy. Thus, a positive DRE or PSA will statistically lead to a large number of TRUS findings that will prove to be negative.

Prostate cancer is staged using the TNM classification (see Table 117-2). It is most commonly graded using the Gleason system, which assesses the microscopic appearance of the prostate gland as a whole (ie, glandular architecture) more so than the individual cells. Grade 1 represents a glandular pattern close to normal, whereas grade 5 corresponds to sheets of cells with little gland formation. The Gleason score is reported as two numbers and their final sum. The first number represents the primary (most common) pattern of the glands, and the second number the secondary (second most common) pattern. A final sum of 2 to 4 is considered well-differentiated; 5 to 7, moderately differentiated; and 8 to 10, poorly differentiated.

Treatment

The treatment of prostate cancer is controversial, particularly in elderly patients.

Watchful waiting involves repeated measurements of serum PSA levels and monitoring of local symptoms. Watchful waiting is probably best for patients > 70 with moderately or well-differentiated, low-volume prostate cancer and a life expectancy of < 10 years. Although watchful waiting has no immediate effect on the quality of life, disease progression and tumor enlargement are possible. Intervention may be required if local symptoms worsen.

Radical prostatectomy involves complete removal of the gland and adnexal structures (eg, seminal vesicles), together with regional lymph nodes. Radical prostatectomy for elderly patients requires careful selection based on life expectancy and comorbid conditions. It is major surgery that requires general anesthesia. Arteriosclerotic cardiovascular disease, pulmonary disease, and renal insufficiency are significant risk factors for anesthesia. In addition, prostate cancer and pelvic surgery predispose elderly patients to thromboembolic events. Complications during or after radical prostatectomy include excessive blood loss, rectal laceration, incontinence, erectile dysfunction, and anastomotic stricture. A nerve-sparing radical prostatectomy may be attempted in a sexually potent man; however, the success rate of preserving potency decreases with age.

Radiation therapy uses conventional external beam, conformational external beam, or interstitial radiation. Conventional external beam radiation uses multiple or rotational fields. Conformational external beam radiation uses computer-guided CT to help precisely localize the treatment area. This technique allows the radiation dose to be increased to > 7000 cGy without an increase in morbidity. Acute adverse effects include radiation proctitis, cystitis, diarrhea, and fatigue. Late adverse effects include chronic proctitis, radiation cystitis, incontinence, erectile dysfunction, and urethral strictures.

Interstitial radiation therapy involves the insertion of radioactive seeds directly into the prostate under ultrasound or CT guidance. Various isotopes are used, including ¹²⁵I and palladium-103. Long-term data from ultrasound-placed seeds are awaited. Adverse effects include irritative voiding symptoms, urinary retention, rectal urgency, increased bowel movements, rectal bleeding or ulceration, and prostatorectal fistulas.

Hormonal therapy (eg, bilateral orchiectomy, gonadotropin-releasing hormone [GnRH] agonists, estrogen use) is the gold standard for treatment of locally advanced or metastatic prostate cancer. Hormonal therapy cannot cure prostate cancer but provides palliation (eg, decreased symptoms, improved quality of life) for most patients. Different hormonal therapies block different steps of androgen production, secretion, or function. Hormonal therapy suppresses 95% of serum testosterone.

Bilateral simple orchiectomy (ie, castration) is the simplest form of androgen deprivation. However, many patients have significant psychologic difficulty with castration and prefer medical management. GnRH agonists deplete pituitary luteinizing hormone and down-regulating GnRH receptors. They must be injected every 3 to 4 months. They are also expensive; Medicare pays only 80% of the cost. Nonsteroidal antiandrogens (eg, flutamide, bicalutamide, nilutamide) counteract the effect of dihydrotestosterone at the receptor within the prostate cancer cells. These drugs are expensive and must be taken daily. However, they do not cause erectile dysfunction. Ongoing studies are comparing antiandrogen monotherapy with standard hormonal therapy. All hormonal therapy can reduce secondary sex characteristics in men and induce hot flashes and gynecomastia.

Prostatitis

Inflammation of the prostate.

Prostatitis affects 1% of primary care patients > 50. Chronic prostatitis has a substantial effect on quality of life because of its relentless, uncomfortable symptoms.

Historically, prostatitis has been classified as acute or chronic bacterial prostatitis, chronic abacterial prostatitis, or prostatodynia. However, a new classification (see Table 117-3) is rapidly becoming standard.

Etiology and Pathogenesis

In cases of acute or chronic bacterial prostatitis, an identifiable uropathogen, usually a gram-negative organism, can be localized to the prostate. Escherichia coli is identified in about 80% of cases; Pseudomonas aeruginosa, Serratia, Klebsiella, and Proteus sp in 10 to 15%; and enterococci in 5 to 10%.

In cases of category III chronic prostatitis, in which there is no identifiable infection, several etiologic theories have been proposed. For example, in category IIIA chronic prostatitis, etiologic theories include fastidious organisms, an unknown noninfectious agent, chemical irritation from refluxed urine, an autoimmune response, and viruses. In category IIIB chronic noninflammatory abacterial prostatitis, the etiology is thought to be varied, possibly multifactorial. One theory is that bladder neck dysfunction, spasm of the pelvic floor, or both cause turbulent urinary flow in the prostatic urethra, resulting in intraprostatic reflux of urine causing chemical inflammation. The bladder neck dysfunction may result from a disturbance in muscle coordination at the bladder neck secondary to an abnormality in the pelvic sympathetic system, from fibrosis of the bladder neck, or from an acquired functional disorder (psychologic factors, particularly depression and somatization, may be exacerbatory). Some patients with category IIIB chronic prostatitis may also have other disorders (eg, interstitial cystitis, fibromyalgia, back problems).

Symptoms and Signs

The primary clinical feature of prostatitis is suprapubic, perineal, pelvic, scrotal, testicular, penile, or upper thigh pain. (In chronic prostatitis, by definition, the pain must be present for >= 3 months.) Urinary symptoms (eg, urgency, frequency, nocturia, dysuria) are primarily irritative. Sexual dysfunction (eg, painful ejaculation, postejaculatory pain, erectile dysfunction) may occur. Patients with acute bacterial prostatitis may present with a high fever, perineal and lower back pain, and severe urinary symptoms.

A comprehensive questionnaire may be used to assess symptom severity and to evaluate treatment efficacy.

Diagnosis

On palpation, the prostate may be tender, swollen, boggy, or firm but is usually unremarkable. A midstream urinalysis should be obtained to rule out infection or hematuria. Although uncommonly used, serial sampling using the Meares-Stamey four-glass test helps determine the site of infection in the urinary tract. A greater concentration of bacteria and white blood cells in samples obtained after prostatic massage is diagnostic for prostatitis. However, prostatic massage should not be performed if acute bacterial prostatitis is suspected, because it increases the risk of septicemia. If initial therapies fail, some patients may require urodynamic studies for evaluation of bladder neck dysfunction. Hydrodistention (in which the bladder is stretched with the patient under anesthesia and then examined for submucosal hemorrhage) can be both diagnostic and therapeutic for patients with IIIB chronic noninflammatory abacterial prostatitis who have interstitial cystitis. Evidence of petechial hemorrhages, submucosal bleeding, or Hunner's ulcers in the bladder epithelium after hydrodistention is diagnostic for interstitial cystitis.

Treatment

Patients with acute bacterial prostatitis should be admitted to the hospital and given intravenous antibiotics (eg, ampicillin, gentamicin). Patients with chronic bacterial prostatitis require 6 weeks of oral antibiotics (eg, doxycycline, co-trimoxazole, fluoroquinolones) to achieve prolonged therapeutic bactericidal levels in the prostatic ducts sufficient to overcome a protective barrier secreted by the bacteria.

In patients with negative results on culture, a reasonable approach is to give antibiotics for 2 weeks; treatment for a further 4 weeks should be given only if improvement occurs. If improvement does not occur, an -blocker should be given to treat bladder neck dysfunction; the dose is titrated to the dose recommended for benign prostatic hyperplasia. If effective, the -blocker should probably be continued for no less than 1 month, although there are no data on how long it should be continued.

Patients with chronic inflammatory or noninflammatory abacterial prostatitis who have interstitial cystitis may benefit from the antihistamine hydroxyzine. A 3-month course of hydroxyzine, an H₁ blocker, starting at 25 mg po at bedtime and increased to 75 mg po at bedtime, followed by reevaluation, improves symptoms in about 30% of patients. However, this drug may produce intolerable anticholinergic adverse effects in the elderly. Hydrodistention may also significantly decrease symptom severity in chronic noninflammatory abacterial prostatitis.

Bladder neck obstruction may require surgical incision of the bladder neck.