Prostate Disorders: Benign and Malignant

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[edit] Prostate Disorders: Benign and Malignant

Ronald A. Morton

Herbert Lepor

[edit] BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is a benign proliferative process of the stromal and epithelial elements of the prostate.Macroscopic enlargement of the prostate often results from the proliferative process.The macroscopic prostatic enlargement may be associated with bothersome urinary symptoms, bladder outlet obstruction, or both problems.Until recently, the treatment options for BPH were limited to watchful waiting or prostatectomy.Now, however, medical and minimally invasive surgical strategies are presently available.Four drugs have FDA approval for the treatment of BPH.Three are α-blocking agents (terazosin [Hytrin], doxazosin [Cardura], and tamsulosin [Flomax]), and one is a blocker of 5α-reductase (finasteride [Proscar]).In addition, a number of minimally invasive strategies have been designed to heat the prostate.These include transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA).The diagnosis and treatment of BPH are complex and cannot be reduced to a simple flow chart.This chapter provides the primary care physician with a practical overview of the management of this condition.

[edit] Epidemiology and Natural History

The prevalence of microscopic BPH has been determined from reported autopsy data.One study reported that microscopic BPH was rarely identified in male patients younger than 40 years of age.The prevalence of microscopic BPH was observed to be age dependent: 50% and 90% of men developed histologic BPH by age 60 and 80 years, respectively.The prevalence of macroscopic BPH has been determined from the database of the Baltimore Longitudinal Study of Aging (BLSA).Approximately 50% of men were observed to have prostatic enlargement by age 70 based on a digital rectal examination (DRE).The BLSA also revealed that the prevalence of clinical BPH is age dependent.Approximately 70% of men also developed symptoms of prostatism by age 70 years.Although microscopic, macroscopic, and clinical BPH are age-dependent events, no compelling evidence indicates that these phenomena are causally related.

The natural history of BPH is poorly understood.Several cohort studies have followed groups of patients with clinical BPH retrospectively and prospectively.The available natural history data strongly indicate that clinical BPH is not always a progressive process; in fact, in some series only 30% to 40% of cases progressed symptomatically over a 5-year period.Based on the natural history data, patients should not be encouraged to pursue intervention solely to prevent the ravages of untreated BPH.It is difficult to determine from the existing literature whether race is a determinant for the development of BPH, since a universally accepted definition of clinical BPH does not exist.Although sporadic case-controlled studies have implicated dietary factors, smoking, body habitus, sexual history, and socioeconomic status in the pathogenesis of BPH, these associations are tenuous.

[edit] Pathogenesis

The development of BPH depends on aging and the presence of testes.The testes represent the primary source of circulating androgens.The embryologic development of the prostate and the development of BPH depend on dihydrotestosterone (DHT).The enzyme catalyzing the conversion of testosterone to DHT is 5α-reductase.Male individuals affected with a genetic deficiency of the enzyme 5α-reductase have a rudimentary prostate.BPH also rarely develops in male patients castrated before puberty.It is generally believed that androgens play a permissive role in the pathogenesis of BPH.The specific biochemical events initiating the hyperplastic process, however, remain unknown.Although many growth factors have been identified in the prostate, their precise role in the pathogenesis of BPH is unknown.

[edit] Pathophysiology

The clinical manifestations associated with BPH include obstructive and irritative urinary symptoms, incomplete bladder emptying, detrusor instability, urinary tract infection (UTI), bladder calculi, urinary retention, renal insufficiency, and hematuria (Box 152-1).The most prevalent clinical manifestation of BPH is urinary symptoms.The obstructive urinary symptoms are hesitancy and straining to initiate urination, diminished caliber of and interrupted urinary stream, and postmicturition dribbling.The irritative symptoms are diuria, nocturia, urinary urgency, incontinence, and dysuria.These symptoms collectively are referred to as prostatism. Several symptom indices have been developed to quantify the severity of prostatism.The International Prostate Symptom Score (I-PSS) has been validated and has gained the greatest level of clinical application.The I-PSS is self-administered and provides an excellent instrument for assessing baseline severity, response to therapy, and disease progression (Fig.152-1).The numeric score of symptoms provides an objective assessment of the degree of prostatism.

Figure 152-1 International Prostate Symptom Score (I-PSS).

The pathophysiology of urinary symptoms is unclear.Because prostatic enlargement and urinary symptoms are age-dependent events, it has been assumed that these phenomena are causally related.The presumed mechanism for the development of symptoms was the bladder outletobstruction resulting from the enlarged prostate.Recent studies have challenged these assumptions.The examination of several large BPH clinical databases has demonstrated unequivocally that no direct relationship exists between prostate size and symptom severity or prostate size and degree of bladder outlet obstruction.

Incomplete bladder emptying is often attributed to bladder outlet obstruction secondary to BPH.The presumed consequences of incomplete bladder emptying include bladder calculi and UTI.Although the postvoid residual (PVR) can be measured precisely by catheterization or ultrasonography, the residual volume in a single patient is highly variable.Another limitation of PVR is that no consensus exists regarding the amount that represents a clinically or pathologically significant level.For example, no data suggest that the threshold PVR is associated with the development of irreversible bladder damage, urosepsis, or urinary retention.

Although no direct relationship exists between prostate size and bladder outlet obstruction, BPH has been implicated as a cause of obstruction.Several mechanisms unrelated to prostate size may cause obstruction.A prominent median lobe, a noncompliant prostatic capsule, and predominantly stromal hyperplasia have been implicated as prostate-dependent factors causing bladder outlet obstruction.Bladder outlet obstruction can be measured noninvasively by uroflowmetry or invasively by multichannel urodynamics.Uroflowmetry simply measures the maximum urinary flow rate.A reduced rate indicates bladder outlet obstruction.The primary limitation of uroflowmetry is that an acontractile bladder may also result in a decreased urine flow rate.Multichannel urodynamics allows for the simultaneous determination of both the bladder pressure at the time of voiding and the urine flow rate.A decreased urine flow rate at elevated detrusor pressures is pathognomonic for outlet obstruction.Although multichannel urodynamics quantifies bladder outlet obstruction, the precise clinical and pathologic significance of these measurements is equivocal.For example, it is unknown what level of obstruction is associated with the development of irreversible bladder dysfunction or the predisposition to develop life-threatening complications of BPH.Furthermore the irritative voiding symptoms associated with prostatism may also be unrelated to the degree of obstruction.

[edit] Evaluation of the Patient with BPH

[edit] History.

A detailed urologic history and focused general medical history are essential in the evaluation of male patients with BPH (Box 152-2).The severity of symptoms should be quantified using a validated instrument such as the I-PSS.Validated questionnaires such as this offer a means of quantifying symptoms, following up on therapy, and determining when therapy is indicated.The history should also determine the level of “bother” and the impact of the urinary symptoms on quality of life.It is not unusual for patients with identical symptom scores to have very different perceptions of the degree of bother resulting from the symptoms.

Other urologic and nonurologic conditions may masquerade as prostatism.Adult-onset diabetes mellitus (AODM) may result in diuria and nocturia because of the obligatory loss of urine associated with glucosuria.AODM may also cause neuropathic bladder dysfunction.Primary neurologic disorders such as Parkinson's disease and secondary neurologic conditions such as cerebrovascular accidents (CVAs) often cause detrusor instability, resulting in urinary frequency, urgency, and urge incontinence.Prostate cancer and transitional cell carcinoma of the bladder may also cause irritative urinary symptoms.Older women suffer irritative voiding symptoms similar to those of older men, in whom these symptoms are ascribed to prostatism.More recent data appear to imply that aging and ischemia of the detrusor muscle may be responsible for some of these voiding problems.

The role of the bladder is to store urine under low pressure and empty urine in socially acceptable circumstances.Medications may affect bladder emptying and storage and therefore may interfere with bladder function and cause symptoms of prostatism.Bladder contraction is a parasympathetic event mediated by muscarinic cholinergic receptors, whereas bladder outlet resistance is a sympathetic function mediated predominantly by the α₁-adrenoceptor.Therefore muscarinic cholinergic antagonists such as propantheline (Probanthine) or α-adrenergic agonists such as phenylephrine may impede bladder emptying and exacerbate or independently cause BPH-like symptoms.

[edit] Physical Examination.

The physical examination should include careful palpation of the prostate (Box 152-3).The DRE should focus on identifying stony hard nodules, induration, tenderness, or asymmetric enlargement.Although the size is often estimated, this observation has limited clinical significance.The rectal tone should be assessed to identify an underlying neurologic condition.The suprapubic region may be percussed for a large PVR.

[edit] Laboratory Assessment.

A urinalysis is a simple and often informative screening test for genitourinary diseases (Box 152-4).It is recommended that all men with BPH undergo this simple test.The presence of glucosuria may be the initial presentation for AODM.The presence of microscopic hematuria requires additional imaging anddiagnostic studies to exclude genitourinary malignancies or benign conditions such as nephrolithiasis.The presence of pyuria or bacteriuria indicates the need for a urine culture.Additional testing is required to determine the etiology of the UTI.A serum creatinine test is often recommended to identify significant renal disease resulting from bladder outlet obstruction.This recommendation is not based on data defining the specificity and sensitivity of a serum creatinine test to identify BPH-dependent renal dysfunction.If the serum creatinine level is elevated, the PVR should be determined.

The role of serum prostate-specific antigen (PSA) determination for screening prostate cancer has become less controversial.The controversy involves not whether screening increases detection but whether increased detection achieves increased survival.Although the data to resolve this controversy are not available, individuals with BPH should routinely undergo a baseline PSA determination.Where appropriate, men with elevated PSA levels should be evaluated for prostate cancer.

Uroflowmetry, multichannel urodynamics, and PVR have already been discussed.Although these studies may provide valuable information related to the level of obstruction or the indications for intervention, the data derived from these studies are often too nonspecific to establish definitive treatment recommendations (Box 152-5).Therefore these studies may be considered options.Uroflowmetry offers a simple noninvasive baseline that can easily be followed to determine the results of therapy.Cystoscopy and imaging of the upper urinary tract by intravenous pyelography (IVP), ultrasound, and computed tomography (CT) scans should not be routinely obtained as part of the evaluation of BPH.If the history, physical examination, or laboratory studies suggest specific abnormalities, these tests may be indicated.

[edit] Indications for Intervention

The indications for therapeutic intervention in BPH may be stratified as absolute vs.relative (Box 152-6).Absolute indications imply that the patient's overall well-being is compromised if treatment is not rendered.Urinary retention, refractory hematuria, and UTIs secondary to BPH are widely accepted absolute indications for intervention.Only a small subset of patients with BPH have these absolute indications for intervention.

The relative indications for intervention include bothersome urinary symptoms, incomplete bladder emptying, and bladder outlet obstruction.Severe symptoms in the absence of absolute indications for intervention do not jeopardize the patient's health status.It is imperative to determine both the level of bother and the risk that the patient is willing to assume to alleviate the urinary symptoms.Physicians cannot impart their own perception of risk/benefit for patients.Although incomplete bladder emptying and urodynamic evidence of bladder outlet obstruction may exacerbate urinary symptoms and lead to UTI and irreversible bladder dysfunction, no data precisely define the clinical, physiologic, and pathologic implications of these findings.Therefore the treatment recommendations by different physicians vary and reflect individual bias.

[edit] Treatment

[edit] Prostatectomy.

There are several surgical and minimally invasive approaches for the treatment of BPH (Box 152-7).The prostatic tissue may be removed by open enucleation orby transurethral resection of the prostate (TURP).The surgical approach is based on the size of the prostate and the surgeon's preference.Approximately 90% of prostatectomies are performed via the transurethral route.Open prostatectomy requires a lower abdominal incision and hospitalization ranging from 5 to 7 days.TURP requires no surgical incision, and the hospital stay is approximately 2 to 3 days.Table 152-1 presents the risks associated with TURP.Although the complications after prostatectomy are rarely life-threatening, the inherent risks may discourage patients with relative indications from pursuing surgical intervention.Approximately 80% to 90% of patients achieve marked to moderate symptom improvement after TURP and are very satisfied with the treatment outcome.The mean improvement in the urine flow rate is approximately 100%.

Table 152-1 Morbidity Associated With Transurethral Prostatectomy (TURP)

Laser energy has recently been advocated as another method for removing the obstructing prostatic tissue.The primary advantage of laser ablation over prostatectomy is that irrigation fluid is not resorbed and therefore the risks of hyponatremia and fluid overload are alleviated.Bleeding is negligible, and transfusions are rarely, if ever, required.

Retrograde ejaculation is also a rare outcome.The patients are often discharged on the day of surgery.The preliminary data suggest that the prostatic defect after laser ablation is far less than that achieved with TURP and that many patients experience irritative symptoms for several months.The improvements in symptom score, bladder emptying, and urine flow rate approximate, but are not equivalent to, those with TURP.The reduced cost from shorter hospitalization is balanced by the cost of the laser fiber and the new technology.The long-term effectiveness of laser ablation has yet to be defined.It is likely that patients will choose a less invasive and safer procedure such as laser ablation even if the level of improvement is slightly less than with TURP.

Transurethral incision of the prostate (TUIP) is an alternative surgical procedure that is less invasive than TURP.The bladder neck and prostatic adenoma are deeply incised without resecting prostatic tissue.Randomized studies have demonstrated that the effectiveness of TURP and TUIP are comparable.The intraoperative time, blood loss, and complications are less with TUIP.TUIP is not recommended if the prostate is larger than 30 gm.Approximately half the patients undergoing TURP are candidates for TUIP.

[edit] Minimally Invasive Intervention.

Balloon dilation of the prostate (BDP) has been advocated for the treatment of BPH.Although the initial uncontrolled reports were encouraging, a randomized, double-blind study reported that BDP and cystoscopy achieve equivalent therapeutic benefit.This study suggested that the observed effectiveness of BDP is likely a placebo response.

Permanent indwelling prostatic stents are endoscopically positioned in the prostatic urethra and eventually become covered by transitional epithelium.Occasional stone formation on the uncovered stent and severe irritative voiding symptoms are the primary limitations of the procedure.

Heating the prostate with microwave energy (transurethral microwave therapy [TUMT]) is another method used to destroy prostatic tissue.The microwave energy is delivered to the prostate by a transurethral catheter.The urethra is cooled to improve patient tolerance.Longitudinal studies have shown excellent symptomatic relief with modest change in the peak urinary flow rate.Sham controlled studies have shown statistically significant differences between TUMT and sham groups in terms of both urinary flow rates and symptom scores on questionnaires.The cost of the microwave energy machine is presently about $120,000.Prostatic heating strategies are usually used after oral medical therapy has failed.

[edit] Medical Therapy

[edit] α-Blockade.

The rationale for α-blockers in BPH is based on several morphologic, physiologic, and pharmacologic observations.Double immunoenzymatic staining and color-assisted image analysis have revealed that smooth muscle accounts for 40% of the tissue volume of the prostate.In vitro isometric tension studies have demonstrated that the contractile properties of prostate smooth muscle are mediated primarily by α₁-adrenoceptors.Radioligand receptor binding studies have shown that the human prostate contains a relative abundance of α-adrenoceptors.Based on the physiologic and pharmacologic observations just mentioned, α₁-adrenergic blockers should decrease the resistance along the prostatic urethra by relaxing the smooth muscle component of the prostate.

Several different α-blockers have been investigated for the treatment of BPH.These α-blockers can be subgrouped according to the α-adrenoceptor subtype selectivity and the duration of serum elimination half-lives (Box 152-8).Phenoxybenzamine antagonizes α₁- and α₂-adrenoceptors,whereas prazosin, alfuzosin, indoramin, terazosin, doxazosin, and tamsulosin are selective α₁-antagonists.The advantage of the selective α₁-antagonists is that the incidence and severity of adverse events are far less than with the nonselective α-blockers.Terazosin (Hytrin), doxazosin (Cardura), and tamsulosin (Flomax) are FDA approved for the treatment of BPH in the United States.The advantages of the long-acting, once-a-day α-blockers are improved compliance and tolerance.The most common adverse events associated with selective α₁-blockers include dizziness, lightheadedness, and asthenia.The administration of a once-a-day formulation at bedtime appears to reduce the incidence and severity of these adverse events.

Lepor et al reported the results of a phase III multicenter, double-blind, parallel-group, randomized, placebo-controlled study of once-a-day administration of terazosin to patients with symptomatic BPH.A total of 285 patients received either placebo or 2, 5, or 10 mg of terazosin once daily.The level of improvements in the symptom scores were dose dependent (Table 152-2).The percentages of patients exhibiting a greater than 30% improvement in the total symptom scores for the placebo and 2-, 5-, and 10-mg treatment groups were 40%, 51%, 57%, and 60%, respectively.The changes in peak urine flow rate were also dose dependent.The percentages of patients experiencing a greater than 30% increase in the peak flow rate in the placebo and 2-, 5-, and 10-mg treatment groups were 26%, 40%, 35%, and 52%, respectively.A significantly greater proportion of patients in the 10-mg treatment group exhibited a more than 30% improvement in symptom scores compared with the placebo group.An interim analysis of an open-label study evaluating the long-term safety and effectiveness of terazosin for BPH indicates that improvements in symptom scores and urine flow rates are maintained throughout a 2-year follow-up.

Table 152-2 Effectiveness of Terazosin (TRZ) for Benign Prostatic Hyperplasia

✢Values correspond to the means of the changes from baseline in each man and therefore cannot be derived from the baseline and 12-week results.

†Comparison between mean %Δ placebo vs.TRZ.

‡Boyarsky symptom score.

Overall, the adverse events in the four treatment groups were minor and reversible.Although a higher incidence of asthenia, influenza syndrome, and dizziness were observed in the terazosin treatment groups, the differences from placebo were not statistically significant.Only one patient in the 10-mg treatment group developed syncope at the 5-mg dose.

One of the presumed limitations of α-blockers for the treatment of BPH was the consequences of lowering blood pressure in relatively elderly normotensive patients.The observed effect of terazosin on baseline systolic blood pressure in normotensive and hypertensive patients was 3 mm Hg and 14 mm Hg, respectively.These data demonstrate that terazosin lowers blood pressure in patients with BPH when it is a desired physiologic outcome.

Three multicenter, randomized placebo-controlled studies have evaluated the safety and effectiveness of doxazosin for the treatment of BPH.A long-term open-label doxazosin study demonstrated that the level of its effectiveness is similar to that of terazosin.

Tamsulosin, an α₁-blocker, has the benefit of no need for dose escalation and an improved safety profile in that it causes much less orthostatic hypotension.It does, however, cause more retrograde ejaculation.Men treated with tamsulosin appear to have the same results in terms of symptom score and peak flow rate changes as those treated with the other α-blocking agents.

There is a definite physiologic and pharmacologic rationale for a blockade in BPH.Multicenter, randomized placebo-controlled studies have consistently and unequivocally demonstrated the ability of α-blockers to relieve symptoms of BPH and increase urine flow rates.The clinical response is rapid and durable.The presumed advantages of the long-acting selective α₁-blockers include better compliance and tolerance.Selective α₁-blockers lower bloodpressure in these patients when it is a desired clinical outcome.Since approximately 50% of men with BPH are also hypertensive, the ability to treat BPH and hypertension simultaneously and effectively with a single drug is a distinct advantage of selective α₁-blockers.

[edit] Androgen Suppression.

The reduction of prostate volume after castration in male patients with BPH was observed 100 years ago.Castration never gained widespread acceptance for the treatment of BPH because of the psychologic impact of removal of the testes and the subsequent development of impotence, loss of libido, and hot flashes resulting from the imbalance of androgens and estrogens.Medical castration can be achieved by drugs that block the action or synthesis of either testosterone or DHT.The morbidity associated with the drugs lowering serum testosterone levels often counterbalances the therapeutic benefit, especially in BPH therapy.Since the maintenance of prostate volume depends on tissue levels of DHT, a drug that selectively blocks the production or action of DHT would achieve involution of the prostate without the problematic adverse events associated with castrate levels of serum testosterone.Finasteride, a 5α-reductase inhibitor, lowers serum and prostatic levels of DHT without lowering serum testosterone levels.Finasteride is the only hormonal therapy that is FDA approved for BPH.

A multicenter, randomized, placebo-controlled, double-blind study recently evaluated the safety and effectiveness of finasteride in men with BPH.A total of 895 patients were randomized to receive daily placebo or 1 or 5 mg of finasteride for 12 months.Table 152-3 summarizes the improvements in symptom scores, flow rate, and prostate volume.The effect of finasteride on these outcome measures was statistically significant.

Table 152-3 Effectiveness of Finasteride for Benign Prostatic Hyperplasia

✢Values correspond to the means of the changes from baseline in each man and therefore cannot be derived from the baseline and 52-week results.

†Comparison between mean %Δ placebo vs.finasteride.

‡Modified Boyarsky score.

Adverse events were rare in the placebo and treatment groups.The differences between decreased libido (4.7% vs.1.3%) and ejaculatory dysfunction (4.4% vs.1.7%) in the 5-mg and placebo groups were statistically significant.The percentages of patients who developed an adverse event resulting in premature withdrawal in the placebo and 5-mg treatment groups were only 6% and 5%, respectively.The short-term safety profile of finasteride is exceedingly favorable.The durability of the therapeutic response is maintained at 36 months in a subset of patients.

A definite rationale exists for androgen suppression in the treatment of BPH.Finasteride represents the only drug that has been studied in a multicenter trial with sufficient numbers of patients and adequate follow-up.Androgen suppression causes prostate involution primarily by affecting prostatic epithelium.It is not surprising that only a relatively modest reduction in prostate volume occurs, since only 10% of the prostate volume is accounted for by the epithelium.Although the differences between placebo and 5 mg of finasteride are modest, the differences are statistically significant.The adverse events associated with finasteride are minimal and reversible.Finasteride is likely to benefit a relatively small subset of patients with clinical BPH.More recent studies have shown that finasteride works best in patients with larger prostates.It probably should not be used in patients with small prostates (PSA values<3).Longitudinal studies have shown that men with larger prostates who are treated with finasteride have a statistically lower potential to develop urinary retention.

[edit] Summary

Enlargement of the prostate secondary to BPH is essentially an inescapable phenomenon for the aging male population.The pathophysiology of clinical BPH is poorly understood.Evaluation of men with clinical BPH is targeted to identify other conditions that may masquerade as BPH.Prostatectomy, thermotherapy, and medical therapy represent the treatment strategies presently accepted for the treatment of clinical BPH.

Individuals with absolute indications should be offered prostatectomy, although recent data demonstrate a reasonable success rate in treating patients in urinary retention with thermotherapy.Most patients who do not have life-threatening consequences of BPH and who are bothered by their symptoms should be offered medical therapy.When medical therapy fails or is not well tolerated, the patient usually goes on to receive more invasive therapy.The treatment decision should be based on the patient's perception of bother from the symptoms and the risks the patient is willing to incur to achieve the desired therapeutic response.

[edit] PROSTATE CANCER

Prostate cancer is now the most frequently diagnosed cancer in American men, accounting for 32% of all diagnosed malecancers.Prostate cancer is second only to lung cancer as a cause of male cancer deaths.In 1997, there were approximately 180,000 new cases of prostate cancer diagnosed and 36,000 deaths from prostate cancer.In addition to this critical number of clinically manifested prostate cancers, autopsy studies forecast that 11 million men in the United States over age 45 harbor histologic (clinically silent) prostate cancer.African-American men represent a particularly high-risk group.The incidence of prostate cancer in African-American men is 50% higher than in Caucasian Americans.Moreover, the 5-year survival rate from 1983 to 1989 for Caucasian Americans was 79%, whereas for African-Americans it was 64%.Patients with hereditary prostate cancer characterized by early age at onset and autosomal dominant inheritance represent a second high-risk group.

The etiology of this exceedingly common cancer is unknown.Unlike other solid tumors such as colon and breast cancer, no candidate genes or genetic loci have been identified to explain the hereditary form of the disease.

[edit] Clinical Presentation

The presentation of prostate cancer depends on the stage at the time of diagnosis.In its early stages, prostate cancer is asymptomatic.Early cases are often diagnosed by DRE during routine physical examination or during examination for another illness (Box 152-9).PSA has had a profound impact on the clinical presentation of prostate cancer.In 1988, PSA became widely available as a serum marker for prostate cancer.It is a serine protease produced only by prostatic epithelium.Although produced by both normal and malignant cells, the contribution to serum levels differs greatly for these two cell populations.The contribution to serum PSA by BPH tissue is 0.3 ng/ml/cm³of tissue.Elevations in PSA levels correlate with increasing clinical stage and pathologic grade and stage of prostate cancer.However, a wide variation in prostatic epithelial/stromal ratios among patients limits the predictive value of a single PSA measurement in a given individual.The normal reference range for serum PSA is also age dependent.Nevertheless, PSA can assist in differentiating between benign and malignant conditions of the prostate.

The normal reference range for PSA is up to 4 ng/ml.Values between 4 and 10 ng/ml fall into the indeterminate range.Values greater than 10 ng/ml are highly suggestive but not diagnostic for prostate cancer.Three observations have provided guidelines for interpreting PSA data in the ambiguous middle range.Ultrasound has been used to measure prostate volume and then calculate the amount of PSA per unit volume of tissue.This value has been termed PSA density (PSAD). A PSAD value of 0.15 or greater in association with a PSA value between 4 and 10 suggests that a needle biopsy of the prostate is indicated regardless of DRE findings.Such biopsies should be performed with transrectal ultrasound guidance (TRUS).Researchers with the BLSA measured the change in serial PSA levels on historic samples from men with known outcomes.This has been termed PSA velocity (PSAV) or rate of PSA change. The researchers were able to establish that a PSAV of 0.75 ng/ml/yr correlated with the development and diagnosis of clinically significant prostate cancers.This value has been confirmed by two larger studies.Consequently, men with a PSA level of 4 to 10 ng/ml and serial PSA measurements demonstrating a PSAV of 0.75 ng/ml/yr should undergo a full evaluation for prostate cancer.Age-associated reference ranges for PSA also have been described.The following normal values have been recommended for PSA: up to 2.5 ng/ml for men age 40 to 49, up to 3.5 ng/ml for men age 50 to 59, up to 4.5 ng/ml for men age 60 to 69, and up to 6.5 ng/ml for men age 70 and older.More recently, it has been shown that measurement of the unbound or free PSA (PSA II) may be helpful in interpreting PSA levels of 4 to 10 ng/ml.If the free PSA is greater than 25%, the condition is usually benign disease.Conversely, when the free PSA is less than 10% the patient usually has an underlying malignancy.Unfortunately, most patients do not have a free PSA in either extreme, thereby making the test not helpful in many patients.It does become one of the variables along with PSAD, age-related PSA, and PSAV that is used to determine the need for repeated biopsies.More recently a study looking at the use of the bound PSA has been published that shows only a modest increase in sensitivity.

Each of these PSA derivatives has certain disadvantages.PSAD is hampered by the inability of current radiologic techniques to measure prostate volume precisely and by the wide variance in prostatic epithelial/stromal ratios.The age-specific reference ranges were determined in a single community consisting only of Caucasians.Attempts to generalize these data to other populations have yielded inconsistent results.The optimal interval between PSA measurements necessary to calculate PSAV has yet to be determined.In general, most urologists perform TRUS-guided prostate biopsies (usually 6 to 12 biopsies are taken from prescribed areas of the prostate) in patients with abnormal rectal examination or PSA values higher than 4 ng/ml (in the 50-to 75-year-old age group).The PSA derivatives already described can be used to obviate a prostate biopsy but are usually used to determine the need for subsequent biopsies when follow-up PSA determinations are obtained.For example, a patient may have a PSA value of 5 ng/ml and undergo a negative biopsy.He may return 1 year later with a PSA determination of 5.6 ng/ml.Should he have another biopsy? Should he be worried? Here one can take into account his prostate volume, PSAV, and even his free PSA to answer these questions.

There have been recent technologic improvements in radiologic techniques for imaging prostate cancer.These include TRUS, pelvic magnetic resonance imaging (MRI), and improved radionuclide bone scan.Despite these advances before routine PSA screening, only approximately 40% of men thought to have clinically localized prostate cancer did not have organ-confined disease at the time of radical prostatectomy.This number has improved in more recent studies.In fact the majority of radical prostatectomies arenow performed on men with stage T1c disease (normal rectal examination and elevated PSA level).The realization that PSA can help detect prostate cancer at an earlier stage than was previously thought possible has led to the use of PSA as a screening test for prostate cancer.In five large studies of screening PSA, the sensitivity ranged from 46% to 89.5% and the specificity from 59% to 91.2%.These studies encompass both office-and community-based populations.Because of the low sensitivity of PSA in these studies, the value of PSA screening has come into question.It has also been the impetus for the development of the PSA variants.PSA screening will not be universally accepted until the death rate from this disease decreases.Because of the slow progression of prostate cancer, this is not likely to occur until 2004 or 2005.

Despite growing efforts to identify men with early stage prostate cancer, patients continue to come to medical attention with advanced-stage disease (although the authors have seen a stage migration in that a lower percentage of patients come to medical attention with advanced disease).At presentation, these men may have hematuria, lower urinary tract obstruction, or pain from bone metastasis.The axial skeleton, particularly the pelvis and lumbar spine, is most susceptible to metastatic spread of prostate cancer.Other sites of metastasis include the seminal vesicles by local extension and lymphatic spread to the obturator and external iliac nodes.

[edit] Diagnosing and Staging

Patients identified at risk for having prostate cancer by DRE, PSA, or TRUS should undergo transrectal biopsy of the prostate.This can be performed as an outpatient procedure, with oral antibiotic prophylaxis initiated the night before the procedure (fluoroquinolone).Biopsies in the setting of an elevated PSA level without obvious findings on DRE should be performed with TRUS guidance.Prostate cancer sometimes appears as a hypoechoic lesion on ultrasound.The presence of a hypoechoic lesion on ultrasound is not pathognomonic for prostate cancer, and its absence does not rule out the disease.Biopsies should therefore be taken from each sextant of the prostate to ensure maximal diagnostic accuracy.Once the presence of prostate cancer is confirmed with a biopsy specimen, the tumor is assigned a grade.The most common grading system in use today is the Gleason grading system.This system is based on the glandular architecture of the two most frequently seen patterns in the tumor.Each pattern is given a Gleason grade from 1 to 5, with a grade of 1 being the most differentiated.The sum of the two grades is the Gleason score.Therefore the Gleason score can range from 2 to 10.

Clinical staging is used to determine the initial mode of therapy.Radiologic modalities (e.g., pelvic CT scan) for evaluating pelvic lymph nodes are of little benefit in the staging of prostate cancer unless the pelvic lymph nodes are enlarged, which usually will not occur until the PSA level is 20 ng/ml or higher.Enlarged nodes on CT scan may be biopsied by skinny needle to aid in clinical staging.The clinical staging of prostate cancer can be accomplished with DRE, radionuclide bone scan, PSA analysis, and findings on transurethral prostatectomy when appropriate.As with pelvic CT scan, the bone scan is usually not “positive” until the PSA value is significantly elevated.At present the TNM staging of prostate cancer has been adopted worldwide (Table 152-4).Organ-confined tumors are designated either T1 or T2; the ability to palpate the tumor on DRE is the feature that separates these groups.T1 tumors are nonpalpable tumors diagnosed via TURP (T1a, T1b) or biopsy performed for an elevated PSA level only (T1c).T1 tumors detected during TURP are subdivided into two groups based on the percentage of resected tissue that is cancerous: T1a is 5% or less, and T1b is greater than 5%.This distinction has prognostic significance: 16% of men with untreated T1a disease develop metastatic disease at 10 years, whereas 35% of men with T1b disease have metastatic disease at 5 years and 20% die of prostate cancer in 5 to 10 years.Palpable T2 tumors are further stratified with respect to the size of the nodule.T2a disease is tumor involving half a lobe or less, T2bdisease is tumor in more than half a lobe but not both lobes, and T2c disease is tumor involving both lobes.T3 disease encompasses local spread outside the prostate.T3a are tumors with unilateral extracapsular extension, and T3b tumors have bilateral extracapsular extension.T3c represents seminal vesicle involvement.T4 stage tumors have greater degrees of local extension with involvement of contiguous organs (see Table 152-4).

Table 152-4 Staging of Prostate Cancer: TNM Classification

[edit] Treatment

The treatment of prostate cancer is dictated by the clinical stage at presentation, the patient's age, and the patient's general health.The optimal treatment is highly controversial (Box 152-10).Treatment options include watchful waiting, hormonal therapy, radical prostatectomy, radiation therapy, TURP, and chemotherapy.The objectives of treatment depend on the stage and realistic expectations.The goals of therapy include cure, increased survival, relief of urinary retention and bothersome urinary symptoms, and palliation of systemic metastasis (Box 152-11).

Radical prostatectomy and radiation therapy are offered with the intent to cure T1 and T2 disease.The limitations of treatment result in part from the limitations of clinical staging, since approximately half of the patients with clinically localized disease do not have pathologically organ-confined disease.The morbidity of treatment also is a factor.Moreover, 60% to 75% of patients treated with radiation therapy have positive results from prostate needle biopsies 18 months after treatment.A more recent addition to external beam radiation therapy has been brachytherapy using radioactive seeds.A recent study reported that 79% of men who had PSA levels less than 10 ng/ml and a Gleason grade 6 or less enjoyed a 79% biochemically disease-free survival (no rise in PSA) 8 years after radioactive seed implantation.These numbers are similar to those for radical prostatectomy outcomes; however, they essentially come from one center and represent a relatively short follow-up period, especially with respect to the existing radical prostatectomy data.The major morbidities related to the surgical treatment of localized prostate cancer are erectile dysfunction and urinary incontinence.Postoperative erectile dysfunction occurs in essentially 100% of patients undergoing a standard radical prostatectomy, in which both cavernosal nerves are cut.After a nerve-sparing radical prostatectomy, the rate is 10% to 60%.It should be mentioned that for Viagra to successfully work for postoperative erectile dysfunction, at least one cavernosal nerve must be spared.The incontinence rate for radiation therapy is approximately 2%, whereas for radical prostatectomy, it ranges from 2% to 10%.The incontinence rate after radical prostatectomy is likely to be reduced in academic centers where greater numbers of prostatectomies are performed.After brachytherapy, the rate of erectile dysfunction is 25%, and the incontinence rate is less than 2%.

With the widespread availability of PSA testing, prostate cancer is now diagnosed earlier and with greater frequency.Autopsy studies consistently show that 15% to 30% of men over age 50 harbor histologically identifiable prostate cancer cells.This percentage increases to 50% to 60% of men older than 90 years of age.These types of studies document the presence of a large population of asymptomatic men with prostate cancer who never have any adverse effects from the disease.These data had prompted some to advocate that cancers diagnosed via PSA level alone (T1c) may be clinically insignificant and not require treatment; however, a recent study reviewed the pathologic findings of 157 consecutive patients with clinical stage T1c disease and found that 84% of tumors were significant and that definitive treatment was justified in most patients.At present, studies imply that watchful waiting is adequate for men with stage T2 cancers or less.Although of interest, these studies have been imperfect in that some men received hormonal therapy; the mean age of patients in these studies was generally 70 or older (patients who would not be treated aggressively under standard guidelines); and the studies were biased toward patients with low-grade disease.Watchful waiting is used in older patients (usually older than 70 years) with Gleason 6 or less tumors.Watchful waiting does not mean “benign neglect.” It implies that periodic PSA determinations are obtained, and if the PSA is rising, appropriate therapy is started.At present, the biologic potential of a given tumor cannot be reliably predicted.Furthermore, no consistent data have been presented suggesting that young healthy patients do not benefit from aggressive treatment of prostate cancer.In general, patients younger than 70 years of age are preferentially offered surgery, whereas those over 70 years are offered radiation therapy.Obviously, many other issues such as other health problems and patient preference must be taken into consideration before determining a treatment for clinically localized prostate cancer.

Stage T3 tumors extend through the prostatic capsule, and 50% to 80% of these patients have lymph node metastases.Because there is no proven adjuvant therapy for prostate cancer, these patients do not benefit from radical prostatectomy.To achieve local control of their disease, external beam radiation therapy may be offered.

At this time, patients with known distant metastases cannot be cured, and treatment efforts for this group are largely palliative.Hormonal therapy aimed at decreasingserum testosterone levels via castration or luteinizing hormone–releasing hormone (LHRH) agonist therapy should be begun with the development of symptoms of metastatic disease.An antiandrogen must be given for approximately 3 to 4 weeks in conjunction with LHRH agonist therapy to avoid the testosterone flare response.The benefit of long-term combination therapy (LHRH agonist and antiandrogen) remains moot.In patients with asymptomatic metastatic prostate cancer, it is not known whether there is a survival benefit from early vs.delayed hormonal manipulation.

To date, efforts to develop chemotherapeutic regimens for prostate cancer have been disappointing.Since all tumors may eventually acquire a hormonally insensitive phenotype, hormonal therapy inevitably fails.Many single agents, combinations of chemotherapy agents, and various vaccines are being tested in clinical trials for relapsing or hormonally refractory disease.

[edit] ADDITIONAL READINGS

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