20 - Arthritis Musculoskeletal Disorders

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 23 - Urology

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23

Urology

Marshall L. Stoller MD

Christopher J. Kane MD, FACS

Peter R. Carroll MD, FACS

Urologic Evaluation

History

Pain

Pain in the genitourinary tract is usually associated with distention of a hollow viscus (ureteral obstruction, urinary retention) or the capsule of an organ (acute prostatitis, acute pyelonephritis). Pain may be local or referred. Pain associated with malignancy is usually a late manifestation and indicative of advanced disease.

A. Renal Pain

Pain of renal origin is usually located in the ipsilateral costovertebral angle. It may radiate to the umbilicus and may be referred to the ipsilateral testicle in men or the labium in women. In infection, the pain is typically constant, whereas in obstruction it may come and go. Nausea and vomiting may result from reflex stimulation of the celiac ganglion. Patients with intraperitoneal pathology will typically lie motionless to avoid pain, while patients with renal disease will move about to try to find a more comfortable position.

B. Ureteral Pain

Ureteral pain is usually acute and a result of obstruction. Distention of the ureter along with hyperperistalsis and spasm of the smooth muscle of the ureter may result in two different pain patterns. Distention may cause a constant dull ache, while the spasms result in colic. The site of obstruction is often predicted by the site of pain. Upper ureteral obstruction may result in pain referred to the scrotum in males or to the labium in females. Midureteral obstruction may cause pain in the lower quadrant and thus may be confused with appendicitis in right-sided ureteral obstruction or diverticulitis in left-sided ureteral obstruction. Lower ureteral obstruction may cause inflammation of the ureteral orifice and thus be associated with symptoms of vesical irritability.

C. Vesical Pain

Acute urinary retention results in severe suprapubic discomfort. Chronic urinary retention is usually painless despite tremendous vesical distention. Suprapubic pain not related to the act of micturition is rarely vesical in origin. Acute cystitis pain is usually referred to the distal urethra and is associated with micturition.

D. Prostatic Pain

Prostatic pain is associated with inflammation and is located in the perineum. Pain radiates to the lumbosacral spine, inguinal canals, or lower extremities. Because of its location near the bladder neck, inflammatory processes of the prostate result in irritative voiding complaints.

E. Penile Pain

Pain in the flaccid penis is secondary to inflammatory processes caused by sexually transmitted diseases or paraphimosis, a condition of the uncircumcised male in which the retracted foreskin is trapped behind the glans penis, resulting in vascular congestion and painful swelling of the glans. Pain in the erect penis may be due to Peyronie's disease (fibrous plaque of the tunica albuginea, resulting in painful curvature of the erect penis) or to priapism (prolonged painful erection).

F. Testicular Pain

Acute conditions such as trauma, torsion of the testis or one of its appendices, or epididymo-orchitis cause acute pain within the scrotum with radiation to the ipsilateral groin. Chronic pain may persist for months following successful treatment of acute epididymitis. Chronic pain produced by a varicocele or hydrocele results in “heaviness” without radiation. Disorders of the kidney, retroperitoneal structures, or inguinal canal may result in pain referred to the testis.

Hematuria

Gross hematuria in adults is considered a sign of malignancy until proved otherwise.

The character of the hematuria may provide a clue to the site of origin. Initial hematuria, the presence of blood at the beginning of the urinary stream that clears during the stream, implies an anterior (penile) urethral source. Terminal hematuria, the presence of blood at the end of the urinary stream, implies a bladder neck or prostatic urethral source. Total hematuria, the presence of blood throughout the urinary stream, implies a bladder or upper tract source.

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Associated symptoms provide clues to the cause. Hematuria associated with renal colic suggests ureteral stone, but the passage of blood clots from a bleeding tumor mimics this scenario. Irritative voiding symptoms in a young woman may suggest acute bacterial infection and associated hemorrhagic cystitis, yet the same picture in an older woman or in any male raises concerns about neoplasm. In any situation, if cultures are negative or hematuria persists after therapy, further evaluation is warranted. In the absence of other symptoms, gross hematuria may be more indicative of tumor, but staghorn calculi, glomerulonephropathies, and polycystic kidney disease are in the differential.

Irritative Voiding Symptoms

Urgency is the sudden desire to void. It is observed in inflammatory conditions such as cystitis or in hyperreflexic neuropathic conditions such as neurogenic bladders resulting from upper motor neuron lesions. Dysuria (painful urination) is usually associated with inflammation. The pain is typically referred to the tip of the penis in men or to the urethra in women. Frequency is the increased number of voids during the daytime, and nocturia is nocturnal frequency. Adults normally void five or six times a day and once at most during the nighttime hours. Increased numbers of voidings may result from increased urinary output or decreased functional bladder capacity. Diabetes mellitus, diabetes insipidus, excess fluid ingestion, and diuretics (including caffeine and alcohol) are a few of the causes of increased urinary output. Decreased functional bladder capacities may result from bladder outlet obstruction (increased residual urine volume results in a lower functional capacity), neurogenic bladder disorders (spasticity and reduced compliance), extrinsic bladder compression (uterine fibroids, radiation-induced fibrosis, pelvic neoplasms), or psychological factors (anxiety).

Obstructive Voiding Symptoms

Hesitancy is a delay in the initiation of micturition. It results from the increased time required for the bladder to attain the high pressure necessary to exceed that of the urethra in the obstructed setting. Decreased force of stream results from the high resistance the bladder faces and is often associated with a decrease in caliber of the stream. Intermittency and postvoid dribbling are interruption of the urinary stream and the uncontrolled release of the terminal few drops of urine, respectively. Obstructive symptoms are most commonly due to benign prostatic hyperplasia, urethral stricture, or neurogenic bladder disorders. Prostatic or urethral carcinoma and foreign body are other causes.

Incontinence

Urinary incontinence is the involuntary loss of urine. The history permits subclassification into one of four categories of incontinence. Such a distinction is necessary, as the evaluation and treatment vary with each of the categories. With total incontinence, patients lose urine at all times and in all positions. Stress incontinence is the loss of urine associated with activities that result in an increase in intra-abdominal pressure (coughing, sneezing, lifting, exercising). Uncontrolled loss of urine preceded by a strong urge to void is known as urge incontinence. Chronic urinary retention may result in overflow incontinence.

Systemic Manifestations

Fever, when associated with other symptoms of a urinary tract infection (see below), helps localize the site of infection. In women, high fevers occur in acute pyelonephritis. Fevers are not typical of uncomplicated cystitis. In men, a febrile urinary tract infection implies acute pyelonephritis, acute prostatitis, or acute epididymitis. Fever may also be associated with malignancy of the kidney, bladder, or testis.

Weight loss and malaise may also be associated with tumor or disease states associated with chronic renal failure.

Other Symptoms

Hematospermia, the presence of blood in the ejaculate, results from inflammation of the prostate or seminal vesicles. Blood in the initial portion of the ejaculate implicates the prostate, whereas terminal hematospermia implies a seminal vesicle origin. Workup should include urinalysis, digital rectal examination (DRE) with prostate massage, and microscopic evaluation of the expressed prostatic secretions. More invasive procedures such as cystoscopy or transrectal ultrasound with prostate biopsy are reserved for patients with hematuria or abnormal rectal examinations, respectively. Persistent hematospermia warrants similar testing. The risk of malignancy with isolated hematospermia, normal urinalysis, and normal DRE is low.

Pneumaturia, the presence of gas in the urine, is usually secondary to a fistula between the bladder and the gastrointestinal tract. Diverticulitis is the most common cause, followed by colonic carcinoma, Crohn's disease, and radiation enteritis. The patient reports bubbles or particulate matter in the urine. On occasion, pneumaturia may be due to infection by gas-producing organisms.

Urethral discharge is the most common symptom of sexually transmitted diseases. Dysuria and urethral itching are seen in association with the discharge. A bloody urethral discharge, especially in an elderly patient, suggests urethral carcinoma.

Cloudy urine may be secondary to a urinary tract infection, yet in the absence of infection it can be a result of an alkaline urinary pH. Such conditions result in phosphate crystal precipitation. Chyluria, the presence of lymph in the urine, results from a fistula between the urinary tract and the lymphatic system. Filariasis,

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tuberculosis, and retroperitoneal tumors are some of the possible causes of this rare symptom.

Physical Examination

General Examination

The pallor of anemia and cachexia may be seen in malignancy. Gynecomastia may occur with testicular carcinomas or as a complication of hormonal therapy in prostatic cancer. Hypertension can be a result of renovascular disease or adrenal cancer.

Detailed Examination

A. Kidney

Because of the liver, the right kidney is lower than the left. The lower pole of the right kidney may be palpable in thin patients, yet the left kidney is usually not palpable unless abnormally enlarged. To palpate the kidney, one hand is placed posteriorly over the costovertebral angle to push the kidney anteriorly, while the second hand is placed anteriorly under the costal margin. With inspiration, the kidney may be palpated between the two hands.

Auscultation of the upper abdominal quadrants in hypertensive patients may reveal a systolic bruit associated with renal artery stenosis or an arteriovenous malformation; however, aortic bruits or transmitted heart murmurs may give similar findings.

Patients with flank pain should be tested for hyperesthesia of the overlying skin by pin testing, as this may be secondary to nerve root irritation and radiculitis rather than being of renal origin.

B. Bladder

The normal adult bladder is not palpable unless filled with at least 150 mL of urine. Percussion is better than palpation in diagnosing the distended bladder. Dullness is appreciated over the full bladder and changes to tympany if the air-filled bowel is anterior to the bladder.

Bimanual examination under anesthesia is helpful in the evaluation of patients with suspected bladder neoplasms. In the male, the bladder is palpated between the abdominal wall and the rectum while in the female it is palpated between the abdominal wall and the vagina. This is the best means of assessing vesical mobility and thus resectability.

C. Penis

The foreskin must be retracted in the uncircumcised male to permit inspection of the urethral meatus and glans. The position of the urethral meatus and the presence of urethral discharge, inflammation, penile tumor, and skin lesions must be noted. In phimosis, the foreskin cannot be retracted over the glans. In paraphimosis, the foreskin has been left retracted behind the glans, resulting in painful engorgement and edema of the glans. If not attended to, this may result in glandular ischemia. Congenital anomalies of position of the urethral meatus are called hypospadias when the meatus is located on the ventral aspect of the penis, scrotum, or perineum and epispadias when it is located on the dorsal aspect of the penis. A thick yellow urethral discharge is seen in gonococcal urethritis, whereas a thin clear or white discharge is noted in nongonococcal urethritis. Palpation of the dorsal penile shaft for plaques of Peyronie's disease and of the ventral surface for urethral tumors should be performed.

D. Scrotum and Its Contents

The most common referral to the urologist concerning the scrotum is for evaluation of a mass. It is important to determine whether the lesion resides within the testicle or is related to the epididymis or cord structures. The testes are palpated between the fingertips of both hands. Normal testes measure 4.5 × 2.5 cm and are rubbery in consistency. The epididymis rests posterolateral to the testis and varies in its degree of testicular attachment. Masses arising from within the testes are usually malignant; those from the epididymis and spermatic cord structures are usually benign. Transillumination will frequently distinguish solid and cystic lesions.

The history and physical examination can determine the diagnosis in the majority of cases. Tumors of the testis are usually painless, firm, solid lesions within the substance of the testis. These lesions do not transilluminate.

Acute epididymitis is an acute infectious process and is associated with painful enlargement of the epididymis. Fever and irritative voiding symptoms are common. In advanced states, the infection can spread to the testis, making the distinction between the epididymis and the testicle difficult on physical examination. The entire scrotal contents may be painful on palpation, yet relief may be offered to the supine patient by elevation of the scrotum above the pubic symphysis (Prehn's sign).

A hydrocele is a collection of fluid between the two layers of the tunica vaginalis. The diagnosis is readily made by transillumination. Evaluation of the testis is necessary, as approximately 10% of testicular tumors may have an associated hydrocele.

A varicocele is engorgement of the internal spermatic veins above the testis. These almost always occur on the left side as the left spermatic vein empties into the left renal vein while the right empties into the inferior vena cava below the level of the renal vein. Varicoceles should diminish in size or disappear with the patient in the supine position. The sudden onset of a right varicocele should raise the question of a retroperitoneal malignancy resulting in obstruction of the right spermatic vein.

Torsion of the testis typically occurs in the 10- to 20-year age group and presents with acute onset of pain and swelling within the testis. Examination reveals a painful testis that may have a “high lie” in relation to the other testis. The acute onset, lack of voiding symptoms, and the different age distribution may help distinguish it from epididymitis.

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Torsion of the appendices of the testis or epididymis may be indistinguishable from torsion of the testis and affects a similar age group as torsion of the testis. On occasion a small palpable lump on the superior pole of the testis or epididymis is discernible that may appear blue when the skin is pulled tautly over it (“blue dot sign”).

E. Rectal Examination in the Male

Inspection for anal pathology (fissures, warts, carcinoma, hemorrhoids) should be performed first. Upon insertion of the finger, anal tone can be estimated and a bulbocavernosus reflex can be elicited. As the anal and urinary sphincter derive from a common innervation, clues to neurogenic disorders may be obtained. The entire prostate is then examined, with attention being directed toward size and consistency. The normal prostate is approximately 4 × 4 cm and weighs 25 g. Normal consistency is that of the contracted thenar eminence with the thumb opposed to the little finger. Rubbery enlargement of the prostate is noted in benign prostatic hyperplasia. Induration may be perceived with carcinoma but also with chronic inflammation. The remainder of the rectum is then examined to exclude primary rectal disease.

F. Pelvic Examination in the Female

Examination of the introitus should include inspection for atrophic changes, ulcers, discharge, and warts. The urethral meatus can be inspected for caruncles (more commonly seen in postmenopausal patients, and as a reddened area at the inferior margin of the meatus) and palpated for tumors or diverticula. Bimanual examination of the bladder, uterus, and adnexa should be performed with two fingers in the vagina and one hand on the abdomen, and attention is directed toward abnormal masses.

Urinalysis

Collection of Specimens

In the male, a clean-catch urine specimen is obtained in separate aliquots. Such a scheme may permit localization of disease. The first 5–10 mL is collected and represents the urethral specimen; a midstream specimen reflects conditions in the bladder and upper urinary tracts. If necessary, the prostate is then massaged and the expressed secretions collected. If no fluid is obtained, the next 2–3 mL of urine is collected, which reflects prostatic pathology. (See also Hematuria.)

Dipstick Urinalysis

A. pH

There is no role for dipstick urinalysis screening for urinary tract disorders in asymptomatic adults except for pregnant women. Urinary pH (range 5.0–8.0) may be helpful in the diagnosis and treatment of some urologic conditions. Alkaline urine in a patient with a urinary tract infection suggests the presence of a urea-splitting organism, most commonly Proteus mirabilis, though some strains of Klebsiella, Pseudomonas, Providencia, and Staphylococcus may also produce urease. Acidic urine in a patient with urolithiasis suggests uric acid or cystine stones. Failure to acidify the urine below a pH of 5.5 despite a metabolic acidosis suggests a distal renal tubular acidosis.

B. Protein

Dipsticks using bromphenol blue can detect protein in concentrations exceeding 10 mg/dL. It measures albumin and is not sensitive for the light chain of immunoglobulins (Bence Jones proteins). False-positive results are seen in urine containing numerous leukocytes or epithelial cells. (See Proteinuria in Chapter 22.)

C. Urobilinogen and Bilirubin

Urobilinogen is formed from the catabolism of conjugated bilirubin in the gut by bacteria, and the majority is cleared by the liver. Normally, only 1–4 mg of urobilinogen is excreted in the urine per day. Hemolytic processes or hepatocellular disease can lead to increased urinary levels, while complete biliary obstruction or broad-spectrum antibiotics that alter the gut bacterial flora may result in absent urinary urobilinogen. Unconjugated bilirubin is not filtered by the glomerulus, while only 1% of conjugated bilirubin is filtered. Normally no bilirubin is detected by urinary dipstick, since only concentrations greater than 0.4 mg/dL are detectable. Conditions manifesting elevated conjugated bilirubin in the serum will result in higher urinary levels. Ascorbic acid may cause false-negative results, while phenazopyridine may cause false-positive results.

D. Glucose and Ketones

Only small amounts of glucose are normally excreted in the urine, and these levels are below the sensitivity of the dipstick. Any positive finding requires evaluation for diabetes. The test is specific for glucose and does not cross-react with any other sugars. Ascorbic acid or elevated ketones may result in false-negative results.

Ketones are not normally found in the urine, but fasting, postexercise states, and pregnancy may result in elevated urinary ketones. Diabetics often demonstrate elevated urinary ketone levels prior to an elevation in serum levels. False-positive results occur in dehydration or in the presence of levodopa metabolites, mesna (sodium mercaptoethanesulfonate), and other sulfhydryl-containing compounds.

E. Nitrites

Normally, the urine does not contain nitrites. Many gram-negative bacteria can reduce nitrate to nitrite, which is thus an indicator of bacteriuria. However, the low sensitivity of the test requires clarification. Adequate numbers of bacteria must be present (105 organisms/mL),

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nitrates must be available in the urine, and the bacteria must be in contact with the urine for a sufficient time (usually 4 hours). Therefore, the first morning voided sample is preferable. False-negative results may be due to non-nitrate-reducing organisms, frequent urination, dilute or acidic urine (pH < 6.0), and the presence of urobilinogen. False-positive results are usually secondary to contaminated specimens, so that bacteria are indeed present in the sample yet not present in the urinary tract.

F. Leukocyte Esterase

Leukocyte esterase is an enzyme produced by white cells. The dipstick detects leukocytes in the urine, which is thus suggestive but not diagnostic for bacteria. False-positive tests result from specimen contamination. False-negative tests result from high specific gravity, glycosuria, the presence of urobilinogen, and medications, including rifampin, phenazopyridine, and ascorbic acid.

G. Blood

The urinary dipstick for blood measures intact erythrocytes, free hemoglobin, and myoglobin. False-positive results in women may occur as a result of contamination at collection with menstrual blood. Concentrated urine may also cause a false-positive result, as patients normally excrete 1000 erythrocytes per milliliter of urine. Vigorous exercise and vitamins or foods associated with high oxidant levels may also give a false-positive result. High ascorbic acid levels may give a false-negative result.

Microscopic Urinalysis

A. Leukocytes

The presence of more than five leukocytes per high-power field is considered significant pyuria. Leukocytes in the urine are indicative of injury to the urinary tract, which may or may not be due to infection. Other causes of pyuria include calculous disease, strictures, neoplasm, genitourinary tuberculosis, glomerulonephropathy, or interstitial cystitis. Leukocyte counts will vary by the state of hydration, method of collection, and degree of injury to the urinary tract.

B. Erythrocytes

The presence of more than five erythrocytes per high-power field on a single occasion or more than three erythrocytes per high-power field on multiple examinations is considered significant and warrants further investigation. (See Evaluation of Hematuria, below.) The appearance of the red cells sometimes provides a clue to their origin within the urinary tract. Dysmorphic (irregularly shaped) cells have an uneven distribution of hemoglobin and cytoplasm, and usually indicate glomerular disease. Red cells that are round, with evenly distributed hemoglobin, suggest disease along the epithelial lining of the urinary tract. All patients with hematuria (even with concurrent anticoagulants) require further diagnostic workup (see below); morphology, though of interest, is not of sufficient accuracy to allow firm diagnostic conclusions.

C. Epithelial Cells

The presence of squamous epithelial cells in the urinary sediment is indicative of contamination and thus requires a repeat collection. Transitional epithelial cells are occasionally noted in normal urinary sediment, but if present in large numbers or clumps they cause concern about possible neoplasm. Cytologic examination may be necessary to confirm the finding.

D. Bacteria and Yeasts

The identification of organisms in an uncontaminated specimen implies infection, which must be confirmed by culture. The presence of several organisms per high-power field usually correlates with a culture count of 105 organisms per milliliter. Gram staining may further aid in characterizing the organism. Candida albicans is the most common yeast seen in the urine, and characteristic budding and clumps are typically observed. For yeast, colony count per milliliter does not necessarily correlate with the severity of infection.

E. Casts

Casts are formed in the distal tubules and collecting ducts as a result of Tamm-Horsfall mucoprotein precipitation (the most common excreted protein in urine). They congregate near the edges of the coverslip and are detected best in a fresh specimen viewed under low power. If the urine is devoid of cells, hyaline casts are formed. Casts with entrapped red cells are indicative of glomerulonephritis or vasculitis. Leukocyte casts are suggestive of pyelonephritis. Epithelial casts in small numbers are normal, but in large numbers they suggest intrinsic renal disease. Granular casts result from degeneration of other cellular casts and also suggest intrinsic renal disease.

F. Crystals

Uric acid, oxalate, and cystine crystals are more often precipitated in acid urine, while phosphate crystals are more commonly seen in alkaline urine. The presence of uric acid, phosphate, and oxalate crystals can be seen in normal patients as well as in stone-formers. Cystine crystals, with a characteristic hexagonal benzene ring shape, are seen only in patients with cystinuria and are thus pathologic.

Evaluation of Hematuria

If gross hematuria occurs, a description of the timing (initial, terminal, total) may provide a clue to the localization of disease. Associated symptoms (ie, renal colic, irritative voiding symptoms, constitutional symptoms) should be investigated. Drug ingestion and associated

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medical problems may also provide diagnostic clues. Anticoagulants, analgesic abuse (papillary necrosis), cyclophosphamide (chemical cystitis), antibiotics (interstitial nephritis), diabetes mellitus, sickle cell trait or disease (papillary necrosis), a history of stone disease, or malignancy should all be investigated. The presence of hematuria in patients receiving anticoagulation therapy warrants a complete evaluation consisting of upper tract imaging, cystoscopy, and urine cytology.

Physical examination should emphasize signs of systemic disease (fever, rash, lymphadenopathy, abdominal or pelvic masses) as well as signs of medical renal disease (hypertension, volume overload). Urologic evaluation may demonstrate an enlarged prostate, flank mass, or urethral disease.

Initial laboratory investigations include a urinalysis and urine culture. Proteinuria and casts suggest renal origin. Irritative voiding symptoms, bacteriuria, and a positive urine culture in the female suggest urinary tract infection, but follow-up urinalysis is important after treatment to ensure resolution of the hematuria.

Further evaluation includes urinary cytology, upper tract imaging, and cystoscopy. Cytology especially assists in the diagnosis of bladder neoplasm, and three voided samples are recommended to maximize sensitivity. Upper tract imaging (usually abdominal and pelvic CT scanning with and without contrast) may identify neoplasms of the kidney or ureter as well as identifying benign conditions such as urolithiasis, obstructive uropathy, papillary necrosis, medullary sponge kidney, or polycystic kidney disease. CT urography and MRI have replaced intravenous pyelography (IVP) when imaging the upper tracts for sources of hematuria. The role of ultrasonographic evaluation of the urinary tract for hematuria is unclear. Although it may provide adequate information for the kidney, its sensitivity in detecting ureteral disease is lower. In addition, its higher degree of operator dependence may further confound the issue. Cystoscopy can be used to assess for bladder or urethral neoplasm, benign prostatic enlargement, and radiation or chemical cystitis. For gross hematuria, cystoscopy is ideally performed while the patient is actively bleeding to allow better localization (ie, lateralize to one side of the upper tracts, bladder, or urethra).

In patients with gross or microscopic hematuria, an upper tract source (kidneys and ureters) can be identified in 10% of cases. For upper tract sources, stone disease accounts for 40%, medical renal disease (medullary sponge kidney, glomerulonephritis, papillary necrosis) for 20%, renal cell carcinoma for 10%, and transitional cell carcinoma of the ureter or renal pelvis for 5%. In the absence of infection, gross hematuria from a lower tract source is most commonly from transitional cell carcinoma of the bladder. Microscopic hematuria in the male is most commonly from benign prostatic hyperplasia. In patients with negative evaluations, repeat evaluations are warranted to avoid a missed malignancy; however, the ideal frequency of such evaluations is not defined. Urinary cytology can be repeated in 3–6 months, and cystoscopy and upper tract imaging after a year.

Avidor Y et al: Clinical significance of gross hematuria and its evaluation in patients receiving anticoagulant and aspirin treatment. Urology 2000;55:22.

Chow KM et al: Asymptomatic isolated microscopic haematuria: long-term follow-up. QJM 2004;97:739.

Grossfeld G et al: Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy—part I: definition, detection, prevalence, and etiology. Urology 2001;57:599.

Ripley TL et al: Early evaluation of hematuria in a patient receiving anticoagulant therapy and detection of malignancy. Pharmacotherapy 2004;24:1638.

Rosenstein D et al: Urologic emergencies. Med Clin North Am 2004;88:495.

Yun EJ et al: Evaluation of the patient with hematuria. Med Clin North Am 2004;88:329.

Genitourinary Tract Infections

Urinary tract infections are among the most common entities encountered in medical practice. In acute infections, a single pathogen is usually found, whereas two or more pathogens are often seen in chronic infections. Coliform bacteria are responsible for most non-nosocomial, uncomplicated urinary tract infections, with Escherichia coli being the most common. Such infections typically are sensitive to a wide variety of orally administered antibiotics and respond quickly. Nosocomial infections often are due to more resistant pathogens and may require parenteral antibiotics. Renal infections are of particular concern because if they are inadequately treated, loss of renal function may result. Previously, a colony count > 105/mL was considered the criterion for urinary tract infection. However, it is now recognized that up to 50% of women with symptomatic infections have lower counts. In addition, the presence of pyuria correlates poorly with the diagnosis of urinary tract infection, and thus urinalysis alone is not adequate for diagnosis. With respect to treatment, soft-tissue infections (pyelonephritis, prostatitis) require intensive therapy for 1–2 weeks, while mucosal infections (cystitis) may require 1–3 days of therapy.

Classification & Pathogenesis

First infections—ie, first documented infections—in young women tend to be uncomplicated. Unresolved bacteriuria occurs

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when the urinary tract is never sterilized during therapy. This may result from bacterial resistance to therapy, noncompliance, mixed infections with organisms having different susceptibilities, renal insufficiency, or the rapid emergence of resistance from an initially sensitive organism. Persistent bacteriuria occurs when the urinary tract is initially sterilized during therapy but a persistent source of infection in contact with the urinary tract remains. This may result from infected stones, chronic pyelonephritis or prostatitis, vesicoenteric or vesicovaginal fistulas, obstructive uropathy, foreign bodies, or urethral diverticula. Reinfections occur when new infections with new pathogens occur following successful treatment.

Ascending infection from the urethra is the most common route. Women are particularly at risk for urinary tract infections because the female urethra is short and the vagina becomes colonized with bacteria. Sexual intercourse is a major precipitating factor in young women, and the use of diaphragms and spermicidal creams (alters normal vaginal bacterial flora) further increases the risk for cystitis. Pyelonephritis most commonly results from ascent of infection up the ureter. Hematogenous spread to the urinary tract is uncommon, the exceptions being tuberculosis and cortical renal abscesses. Lymphogenous spread is rare. Direct extension from other organs may occur, especially from intraperitoneal abscesses in inflammatory bowel disease or pelvic inflammatory disease.

Susceptibility Factors

A. Bacterial Virulence Factors

Over 90% of first infections are caused by E coli. Although there are over 150 strains of E coli, most infections are caused by only five serogroups (O1, O4, O6, O18, and O75). It appears that strains implicated in infection have a higher degree of bacterial adherence, which is mediated by the bacterial fimbriae or pili. A relationship between the type of fimbriae and the type of infection exists. P-fimbriated strains of E coli are associated with pyelonephritis in normal urinary tracts, whereas strains without P fimbriae are associated with pyelonephritis only when vesicoureteral reflux is present.

B. Host Susceptibility Factors

1. Bladder and upper tract factors

Intrinsic defense mechanisms in the bladder include efficient emptying of the bladder with voiding, which decreases colony counts; a protective glycosaminoglycan layer, which interferes with bacterial adherence; and the antimicrobial properties of urine (high osmolality and extremes of pH). The presence of vesicoureteral reflux, diminished renal blood flow, or intrinsic renal disease may increase the likelihood of upper tract involvement.

2. Female-specific factors

The anatomically short female urethra facilitates the ascent of organisms from the introitus into the bladder. Women with recurrent urinary tract infections have more adhesive receptors on their genitourinary mucosa and therefore have more binding sites for pathogens. Women whose mucosal secretions lack fucosyltransferase activity (“nonsecretors”) are more prone to urinary tract infections. The lack of this enzyme results in lack of expression of the A, B, and H blood group antigens that normally may mask some of the bacterial adhesin receptors, making these receptors more available for pathogen binding.

3. Male-specific factors

A higher incidence of urinary tract infections in the uncircumcised male in comparison to the circumcised male has been observed. The mucosal surface of the foreskin has a propensity for colonization with P-fimbriated bacteria in a fashion analogous to that of the female introitus. The prostate in normal males secretes zinc, which is a potent antibacterial agent and thus prevents ascending infection. Lower zinc levels are seen in prostatic secretions of men with bacterial prostatitis.

Prevention of Reinfections

Prophylactic antibiotic therapy is given to prevent recurrence after treatment of urinary tract infection. Women who have more than three episodes of cystitis per year are considered candidates for prophylaxis. Prior to institution of therapy, a thorough urologic evaluation is warranted to exclude any anatomic abnormality (stones, reflux, fistula, etc). Only selected antimicrobial agents are effective in prophylaxis. To be successful, the agent must eliminate pathogenic bacteria from the fecal or introital reservoirs and not cause bacterial resistance. Single dosing at bedtime or at the time of intercourse is the recommended schedule. The three most commonly used agents for prophylaxis are trimethoprim-sulfamethoxazole (40 mg/200 mg), nitrofurantoin (100 mg), and cephalexin (250 mg).

Deville WL et al: The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy. BMC Urol 2004;4:4.

Hooton TM et al: Acute uncomplicated cystitis in an era of increasing antibiotic resistance: a proposed approach to empirical therapy. Clin Infect Dis 2004;39:75.

Johnson JR: Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis 2004;39:873.

Liu H et al: Appropriate antibiotic treatment of genitourinary infections in hospitalized patients. Am J Med 2005;118(Suppl 7A):14S.

Miller LG et al: Treatment of uncomplicated urinary tract infections in an era of increasing antimicrobial resistance. Mayo Clin Proc 2004;79:1048.

Tambyah PA: Catheter-associated urinary tract infections: diagnosis and prophylaxis. Int J Antimicrob Agents 2004;24(Suppl 1):44.

Acute Cystitis

Essentials of Diagnosis

  • Irritative voiding symptoms.

  • Patient usually afebrile.

  • Positive urine culture; blood cultures may also be positive.

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General Considerations

Acute cystitis is an infection of the bladder most commonly due to the coliform bacteria (especially E coli) and occasionally gram-positive bacteria (enterococci). The route of infection is typically ascending from the urethra. Viral cystitis due to adenovirus is sometimes seen in children but is rare in adults.

Clinical Findings

A. Symptoms and Signs

Irritative voiding symptoms (frequency, urgency, dysuria) and suprapubic discomfort are common. Women may experience gross hematuria, and symptoms in women may often appear following sexual intercourse. Physical examination may elicit suprapubic tenderness, but examination is often unremarkable. Systemic toxicity is absent.

B. Laboratory Findings

Urinalysis shows pyuria and bacteriuria and varying degrees of hematuria. The degree of pyuria and bacteriuria does not necessarily correlate with the severity of symptoms. Urine culture is positive for the offending organism, but colony counts exceeding 105/mL are not essential for the diagnosis.

C. Imaging

Follow-up imaging is warranted only if pyelonephritis, recurrent infections, or anatomic abnormalities are suspected.

Differential Diagnosis

In women, infectious processes such as vulvovaginitis and pelvic inflammatory disease can usually be distinguished by pelvic examination and urinalysis. In men, urethritis and prostatitis may be distinguished by physical examination (urethral discharge or prostatic tenderness). Cystitis in men is rare and implies a pathologic process such as infected stones, prostatitis, or chronic urinary retention requiring further investigation.

Noninfectious causes of cystitis-like symptoms include pelvic irradiation, chemotherapy (cyclophosphamide), bladder carcinoma, interstitial cystitis, voiding dysfunction disorders, and psychosomatic disorders.

Treatment

Uncomplicated cystitis in women can be treated with short-term antimicrobial therapy, which consists of single-dose therapy or 1–3 days of therapy. Trimethoprim-sulfamethoxazole can be ineffective in significant numbers of patients because of the emergence of resistant organisms. Fluoroquinolones and nitrofurantoin are now the drugs of choice for uncomplicated cystitis (Table 23-1). Because uncomplicated cystitis is rare in men, elucidation of the underlying problem with appropriate investigations is warranted. Hot sitz baths or urinary analgesics (phenazopyridine, 200 mg orally three times daily) may provide symptomatic relief.

Prognosis

Infections typically respond rapidly to therapy, and failure to respond suggests resistance to the selected drug or anatomic abnormalities requiring further investigation.

Fihn SD: Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003;349:259.

Gupta K: Addressing antibiotic resistance. Dis Mon 2003;49:99.

Nicolle LE: Urinary tract infection: traditional pharmacologic therapies. Am J Med 2002;113(Suppl 1A):35S.

Acute Pyelonephritis

Essentials of Diagnosis

  • Fever.

  • Flank pain.

  • Irritative voiding symptoms.

  • Positive urine culture.

General Considerations

Acute pyelonephritis is an infectious inflammatory disease involving the kidney parenchyma and renal pelvis. Gram-negative bacteria are the most common causative agents including E coli, Proteus, Klebsiella, Enterobacter, and Pseudomonas. Gram-positive bacteria are less commonly seen but include Enterococcus faecalis and Staphylococcus aureus. The infection usually ascends from the lower urinary tract—with the exception of S aureus, which usually is spread by a hematogenous route.

Clinical Findings

A. Symptoms and Signs

Symptoms include fever, flank pain, shaking chills, and irritative voiding symptoms (urgency, frequency, dysuria). Associated nausea and vomiting, and diarrhea are common. Signs include fever and tachycardia. Costovertebral angle tenderness is usually pronounced.

B. Laboratory Findings

Complete blood count shows leukocytosis and a left shift. Urinalysis shows pyuria, bacteriuria, and varying degrees of hematuria. White cell casts may be seen. Urine culture demonstrates heavy growth of the offending agent, and blood culture may also be positive.

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Table 23-1. Empirical therapy for urinary tract infections.

Diagnosis Antibiotic Route Duration Cost per Duration Noted1
Acute pyelonephritis Ampicillin, 1 g every 6 hours, and gentamicin, 1 mg/kg every 8 hours Intravenously 21 days $780.00 not including intravenous supplies
Ciprofloxacin, 750 mg every 12 hours Orally 21 days $229.00
Ofloxacin, 200–300 mg every 12 hours Orally 21 days $270.00
Trimethoprim-sulfamethoxazole, 160/800 mg every 12 hours2 Orally 21 days $46.00
Chronic pyelonephritis Same as for acute pyelonephritis, but duration of therapy is 3–6 months      
Acute cystitis Cephalexin, 250–500 mg every 6 hours Orally 1–3 days $16.00/3 days (500 mg)
Ciprofloxacin, 250–500 mg every 12 hours Orally 1–3 days $31.00/3 days (500 mg)
Nitrofurantoin (macrocrystals), 100 mg every 12 hours Orally 7 days $26.00
Norfloxacin, 400 mg every 12 hours Orally 1–3 days $24.00/3 days
Ofloxacin, 200 mg every 12 hours Orally 1–3 days $32.00/3 days
Trimethoprim-sulfamethoxazole, 160/800 mg, two tablets2 Orally Single dose $2.00
Acute bacterial prostatitis Same as for acute pyelonephritis   21 days  
Chronic bacterial prostatitis Ciprofloxacin, 250–500 mg every 12 hours Orally 1–3 months $311.00/1 month
(500 mg)
Ofloxacin, 200–400 mg every 12 hours Orally 1–3 months $407.00/1 month
(400 mg)
Trimethoprim-sulfamethoxazole, 160/800 mg every 12 hours2 Orally 1–3 months $69.00/1 month
Acute epididymitis        
Sexually transmitted Ceftriaxone, 250 mg as single dose, plus: Intramuscularly 10 days $17.00/250 mg
Doxycycline, 100 mg every 12 hours Orally $27.00
Non-sexually transmitted Same as for chronic bacterial prostatitis Orally 3 weeks  
5Average wholesale price, (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
2Increasing resistance noted (up to 20%).

C. Imaging

In complicated pyelonephritis, renal ultrasound may show hydronephrosis from a stone or other source of obstruction.

Differential Diagnosis

Acute intra-abdominal disease such as appendicitis, cholecystitis, pancreatitis, or diverticulitis must be distinguished from pyelonephritis. A normal urinalysis is usually seen in gastrointestinal disorders; however, on occasion, inflammation from adjacent bowel (appendicitis or diverticulitis) may result in hematuria or pyuria. Abnormal liver function tests or elevated amylase levels may assist in the differentiation. Lower lobe pneumonia is distinguishable by the abnormal chest radiograph.

In males, the main differential diagnosis for acute pyelonephritis includes acute epididymitis, acute prostatitis, and acute cystitis. Physical examination and the location of the pain should permit this distinction.

Complications

Sepsis with shock can occur with acute pyelonephritis. In diabetics, emphysematous pyelonephritis resulting from gas-producing organisms may be life-threatening if not adequately treated. Healthy adults usually recover

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complete renal function, yet if coexistent renal disease is present, scarring or chronic pyelonephritis may result. Inadequate therapy could result in abscess formation.

Treatment

Severe infections or complicating factors require hospital admission. Urine and blood cultures are obtained to identify the causative agent and to determine antimicrobial sensitivity. Intravenous ampicillin and an aminoglycoside are initiated prior to obtaining sensitivity results (Table 23-1). In the outpatient setting, quinolones or nitrofurantoin may be initiated (Table 23-1). Antibiotics are adjusted according to sensitivities. Fevers may persist for up to 72 hours; failure to respond warrants radiographic imaging (ultrasound) to exclude complicating factors that may require intervention. Catheter drainage may be necessary in the face of urinary retention and nephrostomy drainage if there is ureteral obstruction. In inpatients, intravenous antibiotics are maintained for 24 hours after the fever resolves, and oral antibiotics are then given to complete a 7-day course of therapy. Follow-up urine cultures are mandatory several weeks following the completion of treatment.

Prognosis

With prompt diagnosis and appropriate treatment, acute pyelonephritis carries a good prognosis. Complicating factors, underlying renal disease, and increasing patient age may lead to a less favorable outcome.

Miller O 2nd et al: Urinary tract infection and pyelonephritis. Emerg Med Clin North Am 2001;19:655.

Acute Bacterial Prostatitis

Essentials of Diagnosis

  • Fever.

  • Irritative voiding symptoms.

  • Perineal or suprapubic pain; exquisite tenderness common on rectal examination.

  • Positive urine culture.

General Considerations

Acute bacterial prostatitis is usually caused by gram-negative rods, especially E coli and Pseudomonas species and less commonly by gram-positive organisms (eg, enterococci). The most likely routes of infection include ascent up the urethra and reflux of infected urine into the prostatic ducts. Lymphatic and hematogenous routes are probably rare.

Clinical Findings

A. Symptoms and Signs

Perineal, sacral, or suprapubic pain, fever, and irritative voiding complaints are common. Varying degrees of obstructive symptoms may occur as the acutely inflamed prostate swells, which may lead to urinary retention. High fevers and a warm and often exquisitely tender prostate are detected on examination. Care should be taken in performing a gentle rectal examination, as vigorous manipulations may result in septicemia. Prostatic massage is contraindicated.

B. Laboratory Findings

Complete blood count shows leukocytosis and a left shift. Urinalysis shows pyuria, bacteriuria, and varying degrees of hematuria. Urine cultures will demonstrate the offending pathogen.

Differential Diagnosis

Acute pyelonephritis or acute epididymitis should be distinguishable by the location of pain as well as by physical examination. Acute diverticulitis is occasionally confused with acute prostatitis; however, the history and urinalysis should permit clear distinction. Urinary retention from benign or malignant prostatic enlargement is distinguishable by initial or follow-up rectal examination.

Treatment

Hospitalization may be required, and parenteral antibiotics (ampicillin and aminoglycoside) should be initiated until organism sensitivities are available (Table 23-1). After the patient is afebrile for 24–48 hours, oral antibiotics (eg, quinolones) are used to complete 4–6 weeks of therapy. If urinary retention develops, urethral catheterization or instrumentation is contraindicated, and a percutaneous suprapubic tube is required. Follow-up urine culture and examination of prostatic secretions should be performed after the completion of therapy to ensure eradication.

Prognosis

With effective treatment, chronic bacterial prostatitis is rare.

Hua VN et al: Acute and chronic prostatitis. Med Clin North Am 2004;88:483.

Chronic Bacterial Prostatitis

Essentials of Diagnosis

  • Irritative voiding symptoms.

  • Perineal or suprapubic discomfort, often dull and poorly localized.

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  • Positive expressed prostatic secretions and culture.

General Considerations

Although chronic bacterial prostatitis may evolve from acute bacterial prostatitis, many men have no history of acute infection. Gram-negative rods are the most common etiologic agents, but only one gram-positive organism (Enterococcus) is associated with chronic infection. Routes of infection are the same as discussed for acute infection.

Clinical Findings

A. Symptoms and Signs

Clinical manifestations are variable. Some patients are asymptomatic, but most have varying degrees of irritative voiding symptoms. Low back and perineal pain are not uncommon. Many patients report a history of urinary tract infections. Physical examination is often unremarkable, though the prostate may feel normal, boggy, or indurated.

B. Laboratory Findings

Urinalysis is normal unless a secondary cystitis is present. Expressed prostatic secretions demonstrate increased numbers of leukocytes (> 10 per high-power field), especially lipid-laden macrophages. Leukocyte and bacterial counts from expressed prostatic secretions do not correlate with severity of symptoms. However, this finding is consistent with inflammation and is not diagnostic of bacterial prostatitis. Culture of the secretions or the postprostatic massage urine specimen is necessary to make the diagnosis.

C. Imaging

Imaging tests are not necessary, though pelvic radiographs or transrectal ultrasound may demonstrate prostatic calculi.

Differential Diagnosis

Chronic urethritis may mimic chronic prostatitis, though cultures of the fractionated urine may localize the source of infection. Cystitis may be secondary to prostatitis, but fractionated urine samples should localize the infection. Anal disease may share some of the symptoms of prostatitis, but physical examination should permit a distinction between the two.

Treatment

Few antimicrobial agents attain therapeutic intraprostatic levels in the absence of acute inflammation. Trimethoprim does diffuse into the prostate, and trimethoprim-sulfamethoxazole is associated with the best cure rates (Table 23-1). Other effective agents include carbenicillin, erythromycin, cephalexin, and the quinolones. The optimal duration of therapy remains controversial, ranging from 6 to 12 weeks. Symptomatic relief may be provided by anti-inflammatory agents (indomethacin, ibuprofen) and hot sitz baths.

Prognosis

Chronic bacterial prostatitis is difficult to cure, but its symptoms and tendency to cause recurrent urinary tract infections can be controlled by suppressive antibiotic therapy.

Nonbacterial Prostatitis

Essentials of Diagnosis

  • Irritative voiding symptoms.

  • Perineal or suprapubic discomfort, similar to that of chronic bacterial prostatitis.

  • Positive expressed prostatic secretions, but culture is negative.

General Considerations

Nonbacterial prostatitis is the most common of the prostatitis syndromes, and its cause is unknown. Speculation implicates chlamydiae, mycoplasmas, ureaplasmas, and viruses, but no substantial proof exists. In some cases, nonbacterial prostatitis may represent a noninfectious inflammatory disorder. Some investigators have postulated an autoimmune origin. Because the cause of nonbacterial prostatitis remains unknown, the diagnosis is usually one of exclusion.

Clinical Findings

A. Symptoms and Signs

The clinical presentation is identical to that of chronic bacterial prostatitis; however, no history of urinary tract infections is present. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) has been validated to quantify symptoms of chronic nonbacterial prostatitis or chronic pelvic pain syndrome (CPPS).

B. Laboratory Findings

Increased numbers of leukocytes are seen on expressed prostatic secretions, but all cultures are negative.

Differential Diagnosis

The major distinction is from chronic bacterial prostatitis. The absence of a history of urinary tract infection and of positive cultures makes the distinction (Table 23-2). In older men with irritative voiding symptoms and negative cultures, the possibility of bladder cancer must be excluded. Urinary cytologic examination and cystoscopy are warranted.

Table 23-2. Clinical characteristics of prostatitis and prostatodynia syndromes.

Findings Acute Bacterial Prostatitis Chronic Bacterial Prostatitis Nonbacterial Prostatitis Prostatodynia
Fever +
Urinalysis +
Expressed prostatic secretions Contraindicated + +
Bacterial culture + +

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Treatment

Because of the uncertainty regarding the etiology of nonbacterial prostatitis, a trial of antimicrobial therapy directed against Ureaplasma, Mycoplasma, or Chlamydia is warranted. Erythromycin (250 mg orally four times daily) can be initiated for 14 days yet should be continued (for 3–6 weeks) only if a favorable clinical response ensues. Some symptomatic relief may be obtained with anti-inflammatory agents or sitz baths. Dietary restrictions are not necessary unless the patient relates a history of symptom exacerbation by certain substances such as alcohol, caffeine, and perhaps certain foods.

Prognosis

Annoying, recurrent symptoms are common, but serious sequelae have not been identified.

Krieger JN et al: Does the chronic prostatitis/pelvic pain syndrome differ from nonbacterial prostatitis and prostatodynia? J Urol 2000;164:1554.

Litwin MS: A review of the development and validation of the National Institutes of Health Chronic Prostatitis Symptom Index. Urology 2002;60(6 Suppl):14.

Nickel JC et al: Prevalence, diagnosis, characterization, and treatment of prostatitis, interstitial cystitis, and epididymitis in outpatient urological practice: the Canadian PIE Study. Urology 2005;66:935.

Prostatodynia

Prostatodynia is a noninflammatory disorder that affects young and middle-aged men and has variable causes, including voiding dysfunction and pelvic floor musculature dysfunction. The term “prostatodynia” is a misnomer, as the prostate is actually normal.

Clinical Findings

A. Symptoms and Signs

Symptoms are the same as those seen with chronic prostatitis, yet there is no history of urinary tract infection. Additional symptoms may include hesitancy and interruption of flow. Patients may relate a lifelong history of voiding difficulty. Physical examination is unremarkable, but increased anal sphincter tone and periprostatic tenderness may be observed.

B. Laboratory Findings

Urinalysis is normal. Expressed prostatic secretions show normal numbers of leukocytes. Urodynamic testing may show signs of dysfunctional voiding (detrusor contraction without urethral relaxation, high urethral pressures, spasms of the urinary sphincter) and is indicated in patients failing empiric trials of α-blockers or anticholinergics.

Differential Diagnosis

Normal urinalysis will distinguish it from acute infectious processes. Examination of expressed prostatic secretions will distinguish this entity from prostatitis syndromes (Table 23-2).

Treatment

Bladder neck and urethral spasms can be treated by α-blocking agents (terazosin, 1–10 mg orally once a day, or doxazosin, 1–8 mg orally once a day). Pelvic floor muscle dysfunction may respond to diazepam and biofeedback techniques. Sitz baths may contribute to symptomatic relief.

Prognosis

Prognosis is variable depending upon the specific cause.

Krieger JN: The problem with prostatitis. What do we know? What do we need to know? J Urol 2004;172:432.

Schaeffer A et al: Chronic prostatitis. Clin Evid 2003;(10): 994.

Zvara P et al: Minimally invasive therapies for prostatitis. Curr Urol Rep 2004;5:320.

Acute Epididymitis

Essentials of Diagnosis

  • Fever.

  • Irritative voiding symptoms.

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  • Painful enlargement of epididymis.

General Considerations

Most cases of acute epididymitis are infectious and can be divided into one of two categories that have different age distributions and etiologic agents. Sexually transmitted forms typically occur in men under age 40 years, are associated with urethritis, and result from Chlamydia trachomatis or Neisseria gonorrhoeae. Non-sexually transmitted forms typically occur in older men, are associated with urinary tract infections and prostatitis, and are caused by gram-negative rods. The route of infection is probably via the urethra to the ejaculatory duct and then down the vas deferens to the epididymis. Amiodarone has been associated with self-limited epididymitis.

Clinical Findings

A. Symptoms and Signs

Symptoms may follow acute physical strain (heavy lifting), trauma, or sexual activity. Associated symptoms of urethritis (pain at the tip of the penis and urethral discharge) or cystitis (irritative voiding symptoms) may occur. Pain develops in the scrotum and may radiate along the spermatic cord or to the flank. Fever and scrotal swelling are usually apparent. Early in the course, the epididymis may be distinguishable from the testis; however, later the two may appear as one enlarged, tender mass. The prostate may be tender on rectal examination.

B. Laboratory Findings

Complete blood count shows leukocytosis and a left shift. In the sexually transmitted variety, Gram staining of a smear of urethral discharge may be diagnostic of gram-negative intracellular diplococci (N gonorrhoeae). White cells without visible organisms on urethral smear represent nongonococcal urethritis, and C trachomatis is the most likely pathogen. In the non-sexually transmitted variety, urinalysis shows pyuria, bacteriuria, and varying degrees of hematuria. Urine cultures will demonstrate the offending pathogen.

C. Imaging

Scrotal ultrasound may aid in the diagnosis if examination is difficult because of the presence of a large hydrocele or because questions exist regarding the diagnosis.

Differential Diagnosis

Tumors generally cause painless enlargement of the testis. Urinalysis is negative, and examination reveals a normal epididymis. Scrotal ultrasound is helpful to define the pathology. Testicular torsion usually occurs in prepubertal males but is occasionally seen in young adults. Acute onset of symptoms and a negative urinalysis favor testicular torsion or torsion of one of the testicular or epididymal appendages. Prehn's sign (elevation of the scrotum above the pubic symphysis improves pain from epididymitis) may be helpful but is not reliable.

Treatment

Bed rest with scrotal elevation is important in the acute phase. Treatment is directed toward the identified pathogen (Table 23-1). The sexually transmitted variety is treated with 10–21 days of antibiotics, and the sexual partner must be treated as well. Non-sexually transmitted forms are treated for 21–28 days with appropriate antibiotics, at which time evaluation of the urinary tract is warranted to identify underlying disease.

Prognosis

Prompt treatment usually results in a favorable outcome. Delayed or inadequate treatment may result in epididymo-orchitis, decreased fertility, or abscess formation.

Chan PT et al: Inflammatory conditions of the male excurrent ductal system. Part I. J Androl 2002;23:453.

Hagley M: Epididymo-orchitis and epididymitis: a review of causes and management of unusual forms. Int J STD AIDS 2003;14:372.

Urinary Stone Disease

Urinary stone disease is exceeded in frequency as a urinary tract disorder only by infections and prostatic disease and is estimated to afflict 240,000–720,000 Americans per year. Men are more frequently affected by urolithiasis than women, with a ratio of 3:1. Initial presentation predominates in the third and fourth decades. The ratio of men to women approaches parity in the sixth and seventh decades.

Urinary calculi are polycrystalline aggregates composed of varying amounts of crystalloid and a small amount of organic matrix. Stone formation requires saturated urine that is dependent upon pH, ionic strength, solute concentration, and complexation. There are five major types of urinary stones: calcium oxalate, calcium phosphate, struvite, uric acid, and cystine. The most common types are composed of calcium, and for that reason most urinary stones (85%) are radiopaque. Uric acid stones can be radiolucent yet frequently are composed of a combination of uric acid and calcium oxalate and thus are radiopaque. Cystine stones frequently have a smooth-edged ground-glass appearance.

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Geographic factors contribute to the development of stones. Areas of high humidity and elevated temperatures appear to be contributing factors, and the incidence of symptomatic ureteral stones is greatest during hot summer months.

Diet and fluid intake may be important factors in the development of urinary stones. Those afflicted with recurrent urinary stone disease are encouraged to maintain a diet restricted in sodium and protein intake. Sodium should be restricted to 100 mEq/d. Increased sodium intake will increase sodium and calcium excretion, increase monosodium urate saturation (that can act as a nidus for stone growth), increase the relative saturation of calcium phosphate, and decrease urinary citrate excretion. All of these factors encourage stone growth. Protein intake should be limited to 1 g/kg/d. An increased protein load can also increase calcium, oxalate, and uric acid excretion and decrease urinary citrate excretion.

Carbohydrates and fats have not been proved to have any impact on urinary stone disease. Bran can significantly decrease urinary calcium by increasing bowel transit time and mechanically binding to calcium. Excess intake of oxalate and purines can increase the incidence of stones in predisposed individuals. Although a reduction in dietary calcium results in reduced urinary calcium, the concurrent increase in urinary oxalate may promote stone formation. Only type II absorptive hypercalciuric patients (see below) benefit from a low-calcium diet. Persons in sedentary occupations have a higher incidence of stones than manual laborers.

Genetic factors may contribute to urinary stone formation. Cystinuria is an autosomal recessive disorder. Homozygous individuals have markedly increased excretion of cystine and frequently have numerous recurrent episodes of urinary stones despite attempts to optimize medical treatment. Distal renal tubular acidosis may be transmitted as a hereditary trait, and urolithiasis occurs in up to 75% of patients affected with this disorder.

Clinical Findings

A. Symptoms and Signs

Obstructing urinary stones usually present with colic. Pain usually occurs suddenly and may awaken patients from sleep. It is localized to the flank, is usually severe, and may be associated with nausea and vomiting. Patients are constantly moving—in sharp contrast to those with an acute abdomen. The pain may occur episodically and may radiate anteriorly over the abdomen. As the stone progresses down the ureter, the pain may be referred into the ipsilateral testis or labium. If the stone becomes lodged at the ureterovesicular junction, patients will complain of marked urinary urgency and frequency. Stone size does not correlate with the severity of the symptoms.

B. Metabolic Evaluation

Stone analysis should be performed on recovered stones. Controversy exists in deciding which patients need a thorough metabolic evaluation for stone disease. Uncomplicated first-time stone-formers should probably undergo blood screening for abnormalities of serum calcium, phosphate, electrolytes, and uric acid as a baseline.

More extensive evaluation is required in recurrent stone-formers or patients with a family history of stone disease. A 24-hour urine collection on a random diet should ascertain volume, urinary pH, and calcium, uric acid, oxalate, phosphate, sodium, and citrate excretion. A second collection on a restricted calcium (400 mg/d) and sodium (100 mEq/d) diet is undertaken to subcategorize patients, if necessary. Serum parathyroid hormone (PTH) and calcium load tests can be performed at a third visit. A calcium load test is performed as follows: After a patient has been on a restricted calcium diet for at least 1 week, the patient is told to fast from 9 PM. The patient discards the early morning voided specimen (7 AM). While still fasting, the patient voids at 9 AM, which is the fasting sample. The patient then ingests 1 g of calcium gluconate, and all urine is collected from 9 AM to 1 PM, the calcium load sample. Table 23-3 demonstrates the diagnostic criteria for the hypercalciuric states. (See discussion below.)

Table 23-3. Diagnostic criteria of different types of hypercalciuria.

  Absorptive Type I Absorptive Type II Absorptive Type III Resorptive Renal
Serum          
   Calcium N N N N
   Phosphorus N N N
   PTH N N N
Vitamin D N N
Urinary calcium          
   Fasting N N
   Restricted N
   After calcium load
PTH = parathyroid hormone; ↑= elevated; ↓ = low; N = normal.

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C. Laboratory Findings

Urinalysis usually reveals microscopic or gross hematuria (~90%). However, the absence of microhematuria does not exclude urinary stones. Infection must be excluded, because the combination of infection and urinary tract obstruction requires prompt intervention as described below. Urinary pH is a valuable clue to the cause of the possible stone. Normal urine pH is 5.85. There is a normal postprandial urinary alkaline tide. Numerous dipstick measurements are valuable in the complete workup of a stone patient. Persistent urinary pH below 5.5 is suggestive of uric acid or cystine stones, both relatively radiolucent as seen on plain films of the abdomen. In contrast, a persistent pH above 7.2 is suggestive of a struvite infection stone, radiopaque on plain films.

D. Imaging

A plain film of the abdomen and renal ultrasound examination will diagnose most stones. Spiral CT has emerged as a first-line tool in evaluating flank pain. All stones whether radiopaque or radiolucent on plain abdominal radiographs will be visible on noncontrast CT except the rare calculi due to the protease inhibitor indinivir. Stones suspected of being located at the ureterovesicular junction can be imaged with abdominal ultrasonography with the aid of the acoustic window of a full bladder. Alternatively, transvaginal or transrectal ultrasonography will help identify calculi near the ureterovesicular junction.

Medical Treatment & Prevention

To reduce the recurrence rate of urinary stones, one must attempt to achieve a stone-free status. Small stone fragments may serve as a nidus for future stone development. Selected patients must be thoroughly evaluated to reduce stone recurrence rates. Uric acid stone-formers may have recurrences within months if appropriate therapy is not initiated. If no medical treatment is provided after surgical stone removal, stones will generally recur in 50% of patients within 5 years. Of greatest importance in reducing stone recurrence is an increased fluid intake. Absolute volumes are not established, but doubling previous fluid intake is recommended. Patients are encouraged to ingest fluids during meals, 2 hours after each meal (when the body is most dehydrated), and prior to going to sleep in the evening—enough to awaken the patient to void—and to ingest additional fluids during the night. Increasing fluids only during daylight hours may not dilute a supersaturated urine overnight and thus initiate a new stone.

A. Calcium Nephrolithiasis

1. Hypercalciuric

Hypercalciuric calcium nephrolithiasis (> 200 mg/24 h; > 4 mg/kg/24 h) can be caused by absorptive, resorptive, and renal disorders.

Absorptive hypercalciuria is secondary to increased absorption of calcium at the level of the small bowel, predominantly in the jejunum, and can be further subdivided into types I, II, and III. Type I absorptive hypercalciuria is independent of calcium intake. There is increased urinary calcium on a regular or even a calcium-restricted diet. Treatment is centered upon decreasing bowel absorption of calcium. Cellulose phosphate, a chelating agent, is an effective form of therapy. An average dose is 10–15 g in three divided doses. It binds to the calcium and impedes small bowel absorption due to its increased bulk. Cellulose phosphate does not change the intestinal transport mechanism. It should be given with meals so it will be available to bind to the calcium. Taking this chelating agent prior to bedtime is ineffective. Postmenopausal women should be treated with caution. It is interesting, however, that there is no enhanced decline in bone density after long-term use. Inappropriate use without an initial metabolic evaluation (see above) may result in a negative calcium balance and a secondary parathyroid stimulation. Long-term use without follow-up metabolic surveillance may result in hypomagnesuria and secondary hyperoxaluria and recurrent calculi. Routine follow-up every 6–8 months will help encourage medical compliance and permit adjustments in medical therapy based upon repeat metabolic studies.

Thiazide therapy is an alternative to cellulose phosphate in the treatment of type I absorptive hypercalciuria. Thiazides decrease renal calcium excretion but have no impact on intestinal absorption. This therapy results in increased bone density of approximately 1% per year. Thiazides have limited long-term utility (< 5 years) since they may lose their hypocalciuric effect with continued therapy.

Type II absorptive hypercalciuria is diet dependent. Decreasing calcium intake by 50% (approximately 400 mg/d) will decrease the hypercalciuria to normal values (150–200 mg/24 h). There is no specific medical therapy.

Type III absorptive hypercalciuria is secondary to a renal phosphate leak. This results in increased vitamin D synthesis and secondarily increased small bowel absorption of calcium. This can be readily reversed by orthophosphates (250 mg three to four times per day). Orthophosphates do not change intestinal absorption but rather inhibit vitamin D synthesis.

Resorptive hypercalciuria is secondary to hyperparathyroidism. Hypercalcemia, hypophosphatemia, hypercalciuria, and an elevated PTH value are found. Appropriate surgical resection of the parathyroid adenoma cures the disease and the urinary stones. Medical management is invariably a failure.

Renal hypercalciuria occurs when the renal tubules are unable to efficiently reabsorb filtered calcium, and hypercalciuria results. Spilling calcium in the urine results in secondary hyperparathyroidism. Serum calcium typically is normal. Thiazides are effective long-term therapy in patients with this disorder.

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2. Hyperuricosuric

Hyperuricosuric calcium nephrolithiasis is secondary to dietary excesses or uric acid metabolic defects. Both disorders can be treated with purine dietary restrictions or allopurinol therapy (or both). In contrast to uric acid nephrolithiasis, patients with hyperuricosuric calcium stones typically maintain a urinary pH greater than 5.5. Monosodium urates absorb and adsorb inhibitors and promote heterogeneous nucleation. Hyperuricosuric calcium nephrolithiasis is probably secondary to epitaxy, or heterogeneous nucleation. In such situations, similar crystal structures (ie, uric acid and calcium oxalate) can grow together with the aid of a protein matrix infrastructure.

3. Hyperoxaluric

Hyperoxaluric calcium nephrolithiasis is usually due to primary intestinal disorders. Patients usually present with a history of chronic diarrhea frequently associated with inflammatory bowel disease or steatorrhea. Increased bowel fat combines with intraluminal calcium to form a soap-like product. Calcium is therefore unavailable to bind to oxalate, which is then freely and rapidly absorbed. A small increase in oxalate absorption will significantly increase stone formation. If the diarrhea or steatorrhea cannot be effectively curtailed, oral calcium supplements should be given with meals. More than 2 g/d of ascorbic acid will increase urinary oxalate levels. Emphasis on encouraging increased fluid intake is required for these patients as for all stone-formers.

4. Hypocitraturic

Hypocitraturic calcium nephrolithiasis may be secondary to chronic diarrhea, type I (distal) renal tubular acidosis, chronic hydrochlorothiazide treatment, and, in rare cases, is idiopathic. Any condition that results in metabolic acidosis (including prolonged fasting, hypomagnesemia, and hypokalemia) will decrease urinary citrate excretion, since it will be consumed by the citric acid cycle within the mitochondria of proximal tubular cells. Hypocitraturia is frequently associated with other forms of calcium stone formation. Citrate appears to bind to calcium in solution, thereby decreasing available calcium for stone formation. Potassium citrate supplements are usually effective. Urinary citrate is decreased in acidosis and is increased during alkalosis. The potassium will supplement the frequently associated hypokalemic states, and citrate will help to correct the acidosis. A typical dose is 20 mEq three times a day (available in solution and in 10-mEq waxed tablets), or 30 mEq of crystal formulations twice a day.

B. Uric Acid Calculi

The average urinary pH is 5.85. Uric acid stone-formers typically have urinary pH values less than 5.5. The pK of uric acid is 5.75, at which point half of the uric acid is ionized as a urate salt and is soluble, while the other half is insoluble. Increasing the pH above 6.5 dramatically increases solubility and can effectively dissolve large calculi. Potassium citrate is the most frequently used medication to increase urinary pH. It can be given in liquid preparation, as crystals that need to be taken with fluids, or as tablets (10 mEq), two by mouth three or four times daily. Compliant urinary alkalinization may dissolve uric acid calculi at a rate of 1 cm (as measured on plain abdominal radiograph) of stone per month. Patients with uric acid calculi should be given Nitrazine pH paper with which to monitor the effectiveness of their urinary alkalinization. Other contributing factors include hyperuricemia, myeloproliferative disorders, malignancy with increased uric acid production, abrupt and dramatic weight loss, and uricosuric medications. If hyperuricemia is present, allopurinol (300 mg/d) may be given. Although pure uric acid stones are relatively radiolucent, most have some calcium components and can be visualized on plain abdominal radiographs. Renal ultrasonography is a helpful adjunct for appropriate diagnosis and long-term management.

C. Struvite Calculi

Struvite stones are synonymous with magnesium-ammonium-phosphate stones. They are commonly seen in women with recurrent urinary tract infections recalcitrant to appropriate antibiotics. They rarely form as ureteral stones without prior upper tract endourologic intervention. Frequently, a struvite stone is discovered as a large staghorn calculus forming a cast of the renal collecting system. Struvite stones are radiodense. Urinary pH is high, usually above 7.2. These stones are formed secondary to urease-producing organisms, including Proteus, Pseudomonas, Providencia, and, less commonly, Klebsiella, Staphylococcus, and Mycoplasma. An E coli urinary tract infection is not consistent with an infectious reservoir originating from a struvite calculus. These frequently large stones are relatively soft and amenable to percutaneous nephrolithotomy. Appropriate perioperative antibiotics are required. They can recur rapidly, and efforts should be taken to render the patient stone-free. Postoperative irrigation through nephrostomy tubes can eliminate small fragments. Acetohydroxamic acid is an effective urease inhibitor, but it is poorly tolerated by most patients because of its gastrointestinal toxicity.

D. Cystine Calculi

Cystine stones are a result of abnormal excretion of cystine, ornithine, lysine, and arginine. Cystine is the only amino acid that becomes insoluble in urine. These stones are particularly difficult to manage medically. Prevention is centered around increased fluid intake, alkalinization of the urine above pH 7.5 (monitored with Nitrazine pH paper), and a variety of medications including penicillamine and tiopronin (α-mercaptoproprionylglycine). There are no known inhibitors of cystine calculi.

Surgical Treatment

Forced intravenous fluids will not push stones down the ureter. Effective peristalsis directing a bolus of

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urine down the ureter requires opposing ureteral walls to approach each other and touch, which large dilated systems cannot do. In fact, diuresis is counterproductive and will exacerbate the pain. Associated fever may represent infection, a medical emergency requiring prompt drainage by a ureteral catheter or a percutaneous nephrostomy tube. Antibiotics alone are inadequate unless obstruction is drained.

A. Ureteral Stones

Impediment to urine flow by ureteral stones usually occurs at three sites: (1) at the ureteropelvic junction, (2) at the crossing of the ureter over the iliac vessels, and finally (3) as the ureter enters the bladder at the ureterovesicular junction. Prediction of spontaneous stone passage is difficult. Stones less than 6 mm in diameter as seen on a plain abdominal radiograph will usually pass spontaneously. Conservative observation with appropriate pain medications is appropriate for the first 6 weeks. There is new evidence that oral corticosteroids, α-blockers, and calcium channel blockers may enhance stone passage of observed ureteral stones. α-Blockers are safe and well tolerated. Typical agents and dosages are tamsulosin, 0.4 mg orally once daily; terazosin, 5 mg orally once daily; or doxazosin, 4 mg orally once daily. If spontaneous stone passage has failed, either because of lack of progression of the stone or intolerance of the pain, therapeutic intervention is required. Distal ureteral stones are best managed either with ureteroscopic stone extraction or in situ extracorporeal shock wave lithotripsy (SWL). Ureteroscopic stone extraction involves placement of a small endoscope through the urethra and into the ureter. Under direct vision, basket extraction or fragmentation followed by extraction is performed. Complications during endoscopic retrieval increase as the duration of conservative observation increases beyond 6 weeks. Indications for earlier intervention include severe pain unresponsive to medications, fever, persistent nausea and vomiting requiring intravenous hydration, social requirements requiring return to work, or anticipated travel. Most upper tract stones that enter the bladder can exit the urethra with minimal discomfort.

In situ SWL, an alternative, utilizes an external energy source that is focused upon the stone. This focused energy is additive, resulting in minimal tissue insult except at the focus where the stone is positioned with the aid of fluoroscopy or ultrasonography. This can be performed under anesthesia as an outpatient procedure and usually results in stone fragmentation. Most stone fragments will pass uneventfully within 2 weeks, but those that have not passed within 3 months are unlikely to pass without intervention. Women of childbearing age are best not treated with SWL for a stone in the lower ureter, as the impact upon the ovary is unknown.

Proximal and midureteral stones—those above the inferior margin of the sacroiliac joint—can be treated with SWL or ureteroscopy. SWL is delivered directly to the stone (in situ) without the need to push the stone back into the renal pelvis. To help ensure adequate drainage after SWL, a double J ureteral stent is frequently placed. Double J stents do not ensure passage of stone fragments after SWL. Occasionally, stone fragments will obstruct the ureter after SWL. Conservative management will usually result in spontaneous resolution with eventual passage of the stone fragments. If this is unsuccessful, adequate proximal drainage through a percutaneous nephrostomy tube will facilitate passage. In rare instances, ureteroscopic extraction will be required.

B. Renal Stones

Patients with renal calculi presenting without pain, urinary tract infections, or obstruction need not be treated. They should be followed with serial abdominal radiographs or renal ultrasonographic examinations. If calculi are growing or become symptomatic, intervention should be undertaken. Renal stones less than 2 cm in diameter are best treated with SWL. Stones located in the inferior calix frequently result in suboptimal stone-free rates as measured at 3 months by x-ray. Such stones and others of larger diameter are best treated via percutaneous nephrolithotomy. Perioperative antibiotic coverage should be given on the basis of preoperative urine cultures.

Dellabella M et al: Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. J Urol 2005;174:167.

Heneghan JP et al: Helical CT for nephrolithiasis and ureterolithiasis: comparison of conventional and reduced radiation-dose techniques. Radiology 2003;229:575.

Maalouf NM et al: Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 2004; 13:181.

Pak CY: Medical management of urinary stone disease. Nephron Clin Pract 2004;98:c49.

Pak CY et al: Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am J Med 2003;115: 26.

Parmar MS: Kidney stones. BMJ 2004;328:1420.

Stoller ML et al: The primary stone event: a new hypothesis involving a vascular etiology. J Urol 2004;171:1920.

Tiselius HG: Epidemiology and medical management of stone disease. BJU Int 2003;91:758.

Urinary Incontinence

Urinary incontinence is most common in older patients. Its prevalence varies from 5% to 15% in the community to perhaps more than 50% in long-term care facilities. The normal urinary bladder can store relatively large volumes of urine at low pressures. Continence is dependent upon a compliant reservoir and sphincteric efficiency that has two components: the

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involuntary smooth muscle of the bladder neck and the voluntary skeletal muscle of the external sphincter. (See also discussion in Chapter 4.)

Classification

Urinary incontinence occurs when urine leaks involuntarily and can be classified into one of four categories.

A. Total Incontinence

With total incontinence, patients lose urine at all times and in all positions. This results when sphincteric efficiency is lost (previous surgery, nerve damage, cancerous infiltration) or when an abnormal connection between the urinary tract and the skin exists that bypasses the urinary sphincter (vesicovaginal or ureterovaginal fistulas).

B. Stress Incontinence

Stress incontinence is the loss of urine associated with activities that result in an increase in intra-abdominal pressure (coughing, sneezing, lifting, exercising). Patients do not leak in the supine position. Laxity of the pelvic floor musculature—most commonly seen in the multiparous woman or in patients who have undergone pelvic surgery—results in urethral sphincteric insufficiency.

C. Urge Incontinence

The uncontrolled loss of urine that is preceded by a strong, unexpected urge to void is known as urge incontinence. It is unrelated to position or activity and is indicative of detrusor hyperreflexia or sphincter dysfunction. Inflammatory conditions or neurogenic disorders of the bladder are commonly associated with urge incontinence.

D. Overflow Incontinence

Chronic urinary retention may result in overflow incontinence. Incontinence results from the chronically distended bladder receiving an additional increment of urine, so that intravesical pressure just exceeds the outlet resistance, allowing a small amount of urine to dribble out.

Clinical Findings

A. Symptoms and Signs

The history is the most important step in the evaluation of urinary incontinence. It may be supplemented with a voiding diary prepared by the patient. Physical examination is important to exclude fistula for cases of total incontinence, neurologic abnormalities in cases of urge incontinence (spasticity, flaccidity, rectal sphincter tone), or the distended bladder in cases of overflow incontinence. Rectal examination will reveal the general function of the pelvic floor. Normal anal tone suggests an intact external sphincter. A tender levator ani suggests an overfacilitated pelvic floor. A lax sphincter suggests a lower motor neuron lesion. The bulbocavernosus reflex further confirms the integrity of the lower motor neurons. This reflex is confirmed by feeling an anal contraction in response to pressure on the glans penis or the clitoris.

B. Laboratory Findings

Urinalysis and urine culture are important to exclude urinary tract infection in cases of urge incontinence. Abnormal renal function may be detected in cases of overflow incontinence. Patients in whom overflow incontinence is suspected can have postvoid residual urine volume assessed by urethral catheterization or ultrasonography.

C. Special Tests

Urinary continence depends upon both bladder and sphincteric mechanisms; dysfunction of either component may result in incontinence. Urodynamic evaluation can assess both bladder and sphincteric function. Such testing is indicated in patients with moderate to severe incontinence, those suspected of having neurologic disease, and those with urge incontinence when infection and neoplasm have been excluded.

Bladder capacity, accommodation, sensation, voluntary control, contractility, and response to pharmacologic intervention can be assessed by cystometry. Cystometry is performed by filling the bladder with water and simultaneously recording intravesical pressure.

During filling, the normal bladder has the ability to maintain a low pressure. As volume increases, compliance increases. Normal sensation is first appreciated with volumes less than 150 mL. There is a strong sensation prior to micturition. Normal capacity in an adult bladder is 350–500 mL. Micturition is consciously initiated starting with pelvic floor relaxation followed by a sustained bladder contraction. Normal bladder function will empty the bladder completely. Uninhibited contractions during the normal filling phase are abnormal and are usually associated with a strong urge to void. Causes of decreased urinary capacity include incontinence, infections, interstitial cystitis, radiation damage, upper motor neuron lesions, and postoperative changes. Increased bladder capacity is seen with chronic urinary tract obstruction, lower motor neuron lesions, and sensory neuropathies.

Responses to routine medications during cystometry will help confirm a diagnosis and facilitate appropriate therapy. Lack of an appropriate detrusor contraction may be secondary to poor bladder muscle function or inadequate filling.

Sphincteric function assessment is necessary in the evaluation of urinary incontinence. More formal evaluation of the urinary sphincter may be performed using urethral profilometry, electromyography, or combined video studies.

Treatment

A. Total Incontinence

True incontinence is due to anatomic abnormalities, either congenital or acquired. Congenital defects, including bladder exstrophy, ectopic ureteral orifices, and urethral diverticula, and acquired lesions such as vesicovaginal fistulas require surgical correction. Sphincter injuries following prostatectomy may be managed by periurethral bulking

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agents, a urethral sling, or placement of an artificial urinary sphincter.

B. Stress Incontinence

In patients with stress urinary incontinence, the bladder neck will descend below the midportion of the pubic symphysis when viewed on a lateral stress cystogram. Urodynamic investigations usually reveal a shortened functional urethral length, decreased urethral closure pressure, minimal augmentation of closure pressure with stress activities, decreased urethral pressure and length when assuming an upright position, and decreased closure pressure with bladder filling.

If hypoestrogenism of the vagina or urethra is discovered, topical estrogen creams applied locally are indicated. Surgical treatment is centered upon placing the bladder neck into an appropriate anatomic location, allowing increased intra-abdominal pressure to be transmitted to both the bladder and the bladder neck. These procedures also lengthen the urethra. Transvaginal sling suspension or suprapubic (culpocystourethropexy) approaches can pull the bladder neck into proper position. Less invasive procedures include periurethral injectables to increase outlet resistance and insertion of tension-free vaginal tape. Surgery is usually corrective in the short- to intermediate-term. Long-term outcomes are variable and depend on patient factors and the procedure.

C. Urge Incontinence

The etiology of urge urinary incontinence includes urethral or detrusor instability or a combination of these mechanisms. Treatment is medical rather than surgical. Effective agents include anticholinergic medications (oxybutinin, 5–15 mg/d, or tolterodine, 2–4 mg/d) or tricyclic antidepressants (imipramine, 25–75 mg orally at bedtime). Sacral nerve stimulation can be effective in treating refractory urinary urge incontinence.

D. Overflow Incontinence

Placement of a urethral catheter is both diagnostic and therapeutic in the acute setting. Further treatment must address the underlying disease. Men with benign prostatic hyperplasia can be treated with medical therapy, prostatectomy, or newer less invasive procedures (see below). Patients with urethral strictures can be treated with a direct internal urethrotomy or open urethroplasty. Neurogenic causes (external sphincteric spasticity) may be managed with intermittent catheterization regimens with or without pharmacotherapy.

Assessment and treatment of urinary incontinence. Scientific Committee of the First International Consultation on Incontinence. Lancet 2000;355:2153.

Khullar V et al: Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology 2004;64:269.

Moore K: Duloxetine: a new approach for treating stress urinary incontinence. Int J Gynaecol Obstet 2004;86(Suppl 1):S53.

Nygaard IE et al: Stress urinary incontinence. Obstet Gynecol 2004;104:607.

Parmet S et al: JAMA patient page. Stress incontinence. JAMA 2003;290:426.

Schuessler B et al: Pharmacologic treatment of stress urinary incontinence: expectations for outcome. Urology 2003;62(4 Suppl 1):31.

Teleman PM et al: WHILA study group: overactive bladder: prevalence, risk factors and relation to stress incontinence in middle-aged women. BJOG 2004;111:600.

Watson NM: Use of the Agency for Health Care Policy and Research Urinary Incontinence Guideline in nursing homes. J Am Geriatr Soc 2003;51:1779.

Interstitial Cystitis

Essentials of Diagnosis

  • Pain with a full bladder or urinary urgency.

  • Submucosal petechiae on cystoscopic examination.

  • Diagnosis of exclusion.

General Considerations

Interstitial cystitis is characterized by pain with bladder filling that is relieved by emptying and is often associated with urgency and frequency. This is a diagnosis of exclusion, and patients must have a negative urine culture and cytology and no other obvious cause such as radiation cystitis, chemical cystitis (cyclophosphamide), vaginitis, urethral diverticulum, or genital herpes. Up to 40% of patients referred to urologists for interstitial cystitis may actually be found to have a different diagnosis after careful evaluation.

Population-based studies have demonstrated a prevalence of between 18 and 40 per 100,000 people. Both sexes are involved, but most patients are women, with a mean age of 40 years at onset. Patients with interstitial cystitis are more likely to report bladder problems in childhood, and there appears to be a higher prevalence in Jewish women. Up to 50% of patients may experience spontaneous remission of symptoms, with a mean duration of 8 months without treatment.

The etiology of interstitial cystitis is unknown, and it is most likely not a single disease but rather several diseases with similar symptoms. Associated diseases include severe allergies, irritable bowel syndrome, or inflammatory bowel disease. Theories regarding the cause of interstitial cystitis include increased epithelial permeability, neurogenic causes (sensory nervous system abnormalities), and autoimmunity.

Clinical Findings

A. Symptoms and Signs

Pain with bladder filling that is relieved with urination or urgency, frequency, and nocturia are the most common

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symptoms. Exposures such as pelvic radiation or prior cyclophosphamide should be inquired about. Examination should exclude genital herpes, vaginitis, or a urethral diverticulum.

B. Laboratory Findings

Urinalysis and urine culture are obtained to exclude infectious causes. Urinary cytology is obtained to exclude bladder malignancy. Urodynamic testing assesses bladder sensation and compliance and excludes detrusor instability.

C. Cystoscopy

The bladder is distended with fluid (hydrodistention) to detect glomerulations (submucosal hemorrhage), which may or may not be present. Biopsy should be performed to exclude other causes such as carcinoma, eosinophilic cystitis, and tuberculous cystitis. The presence of submucosal mast cells is not needed to make the diagnosis of interstitial cystitis.

Differential Diagnosis

Exposures to radiation or cyclophosphamide are obtained by the history. Bacterial cystitis, genital herpes, or vaginitis can be excluded by urinalysis, culture, and physical examination. A urethral diverticulum may be suspected if palpation of the urethra demonstrates an indurated mass that results in the expression of pus from the urethral meatus. Urethral carcinoma presents as a firm mass on palpation.

Treatment

There is no cure for interstitial cystitis, but most patients achieve symptomatic relief from one of several approaches, including hydrodistention, which is usually done as part of the diagnostic evaluation. Approximately 20–30% of patients will notice symptomatic improvement following this maneuver. Also of importance is the measurement of bladder capacity during hydrodistention, since patients with very small bladder capacities (< 200 mL) are unlikely to respond to medical therapy.

Amitriptyline is often used as first-line medical therapy in patients with interstitial cystitis. Both central and peripheral mechanisms may contribute to its activity. Nifedipine and other calcium channel blockers have also demonstrated some activity in patients with interstitial cystitis. Pentosan polysulfate sodium (Elmiron) is an oral synthetic sulfated polysaccharide that helps restore integrity to the epithelium of the bladder in a subset of patients and has been evaluated in a placebo-controlled trial. Other options include intravesical instillation of dimethyl sulfoxide (DMSO), heparin, or bacillus Calmette-Guérin (BCG), the latter achieving up to 60% response rates. A group of investigators and the Interstitial Cystitis Clinical Trials Group performed a randomized controlled trial that showed no statistically significant improvement with intravesical BCG over placebo.

Other treatment modalities include transcutaneous electric nerve stimulation (TENS) and acupuncture. Surgical therapy for interstitial cystitis should be considered only as a last resort and may require cystourethrectomy with urinary diversion.

Chancellor MB et al: Treatment of interstitial cystitis. Urology 2004;63(3 Suppl 1):85.

Comiter CV: Sacral neuromodulation for the symptomatic treatment of refractory interstitial cystitis: a prospective study. J Urol 2003;169:1369.

Irwin P et al: Reinvestigation of patients with a diagnosis of interstitial cystitis: common things are sometimes common. J Urol 2005;174:584.

Mayer R et al; Interstitial Cystitis Clinical Trials Group: A randomized controlled trial of intravesical bacillus Calmette-Guerin for treatment refractory interstitial cystitis. J Urol 2005;173:1186.

Propert KJ et al: A prospective study of interstitial cystitis: results of longitudinal followup of the interstitial cystitis data base cohort. The Interstitial Cystitis Data Base Study Group. J Urol 2000;163:1434.

Selo-Ojeme DO et al: Interstitial cystitis. J Obstet Gynaecol 2004;24:216.

van Ophoven A et al: A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol 2004;172:533.

Male Erectile Dysfunction & Sexual Dysfunction

Erectile dysfunction is defined as the consistent inability to maintain an erect penis with sufficient rigidity to allow sexual intercourse. This condition is thought to affect 10 million American men, and its incidence is age related. Approximately 25% of all men older than age 65 years suffer from this disorder. Most cases of male erectile disorders have an organic rather than a psychogenic cause. Normal male erection is a neurovascular phenomenon relying on an intact autonomic and somatic nerve supply to the penis, smooth and striated musculature of the corpora cavernosa and pelvic floor, and arterial inflow supplied by the paired pudendal arteries. Erection is precipitated and maintained by an increase in arterial flow, active relaxation of the smooth muscle elements of the sinusoids within the corporal bodies of the penis, and an increase in venous resistance. Contraction of the bulbocavernosus and ischiocavernosus muscles results in further rigidity of the penis. The neurotransmitters that initiate and contribute to male erection include nitric oxide, vasoactive intestinal peptide, acetylcholine, and prostaglandins.

Male sexual dysfunction may be manifested in a variety of ways, and the history is critical to the proper

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classification and subsequent treatment. Androgens have a strong influence on the sexual desire of men. A loss of libido may indicate androgen deficiency on the basis of either hypothalamic, pituitary, or testicular disease. Serum testosterone and gonadotropin levels may help localize the site of disease. Loss of erections may result from arterial, venous, neurogenic, or psychogenic causes. Concurrent medical problems may damage one or more of the mechanisms. In addition, many medications, especially antihypertensives, are associated with erectile dysfunction. Centrally acting sympatholytics (methyldopa, clonidine, reserpine) can result in loss of erection, while vasodilators, α-blockers, and diuretics rarely alter erections. β-Blockers and spironolactone may result in loss of libido. It is important to determine whether the patient ever has any normal erections in the early morning or during sleep. If normal erections do occur, an organic cause is unlikely. The gradual loss of erections over a period of time is more suggestive of an organic cause. The loss of emission (lack of antegrade seminal fluid during ejaculation) may result from several underlying disorders. Retrograde ejaculation may occur as a result of mechanical disruption of the bladder neck, especially following transurethral resection of the prostate or sympathetic denervation as a result of medications (α-blockers), diabetes mellitus, or radical pelvic or retroperitoneal surgery. Androgen deficiency may also result in lack of emission by decreasing the amount of prostatic and seminal vesicle secretions. If libido and erection are intact, the loss of orgasm is usually of psychological origin. Premature ejaculation is usually an anxiety-related disorder and rarely has an organic cause. The history may elucidate the presence of a new partner, unreasonable expectations about performance, or emotional disorders. Pharmacologic therapy with clomipramine 25 mg prior to intercourse has been effective in delaying ejaculation.

Clinical Findings

A. Symptoms and Signs

Erectile dysfunction should be clearly distinguished from problems of ejaculation, libido, and orgasm. The degree of the dysfunction (whether chronic, occasional, or situational) as well as its timing should be noted. The history should include inquiries about hyperlipidemia, hypertension, depression, neurologic disease, diabetes mellitus, renal failure, and adrenal and thyroid disorders. Trauma to the pelvis or pelvic or peripheral vascular surgery also identifies patients at increased risk of impotence. A complete recording of drug use should be made, since about 25% of all cases of sexual dysfunction may be drug related. The excessive use of alcohol and recreational drugs should be recorded as well, since each is associated with an increased risk of sexual dysfunction. Depression is a risk factor for erectile dysfunction.

During the physical examination, secondary sexual characteristics should be assessed. Neurologic and peripheral vascular examination should be performed. Motor and sensory examination should be performed as well as palpation and quantification of lower extremity vascular pulsations. The genitalia should be examined, noting the presence of penile scarring or plaque formation (Peyronie's disease) and any abnormalities in size or consistency of either testicle. Examination of the prostate is essential.

B. Laboratory Findings

Laboratory evaluation is limited and should consist of a complete blood count, urinalysis, lipid profile, determination of serum testosterone, glucose, and prolactin. Patients with abnormalities of testosterone or prolactin require further evaluation with measurement of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and endocrinologic consultation is advised.

C. Special Tests

Further testing is based on the patient's goals. Patients who will accept only noninvasive forms of therapy may be offered medical therapy or a vacuum constriction device, as described below. Most patients undergo further evaluation with direct injection of vasoactive substances into the penis. Such substances (prostaglandin E1, papaverine, or a combination of drugs) will induce erections in men with intact vascular systems. Patients who respond with a rigid erection require no further vascular evaluation. However, organic and psychogenic impotence can be differentiated by use of nocturnal penile tumescence testing, where the frequency as well as the rigidity of erections are recorded by a simple device attached to the penis before sleep. Patients with psychogenic impotence will have nocturnal erections of adequate frequency and rigidity.

Additional vascular testing is indicated in patients who fail to achieve an erection with injection of vasoactive substances on serial attempts using increasing doses or combination of drugs and who would consider vascular reconstructive surgery. Diagnostic tests, such as duplex ultrasound, penile cavernosography, and pudendal arteriography, can separate arterial from venous erectile dysfunction and help predict which patients may benefit from vascular surgery.

Treatment

The vast majority of men suffering from erectile dysfunction can be treated successfully with one of the approaches outlined below. Men who do not suffer from organic dysfunction will probably benefit from behaviorally oriented sex therapy.

A. Hormonal Replacement

Testosterone injections (200 mg intramuscularly every 3 weeks) or topical patches (2.5–6 mg/d) are offered to men with documented androgen deficiency who have undergone endocrinologic evaluation as described and

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in whom prostatic cancer has been excluded by prostate-specific antigen (PSA) screening and DRE.

B. Vacuum Constriction Device

The vacuum constriction device is a cylindric device that draws the penis into an erect state by inducing a vacuum within the cylinder. Once adequate tumescence has been achieved, a rubber constriction device or band is placed around the proximal penis to prevent loss of erection, and the cylinder is removed. Such devices are suitable for patients with venous disorders of the penis and those who fail to achieve an adequate erection with injection of vasoactive substances. Complications are rare.

C. Vasoactive Therapy

Direct injection of vasoactive prostaglandins into the penis is an acceptable form of treatment for most men with impotence. These injections are performed using a tuberculin syringe. The base and lateral aspect of the penis is used as the injection site to avoid injury to the superficial blood supply located anteriorly. Complications are rare and include dizziness, local pain, fibrosis, and infection. A prolonged erection requiring aspiration of blood and injection of epinephrine and phenylephrine to achieve detumescence occurs very rarely. A mechanism of delivering vasoactive prostaglandins (alprostadil) via a urethral suppository has been developed, and results are good. Pellet sizes are 125, 250, 500, and 1000 mcg.

Sexual stimulation with subsequent nitric oxide neural release will initiate penile erections. Decreasing the breakdown of cyclic guanosine monophosphate (cGMP) has revolutionized the treatment of erectile dysfunction. Sildenafil (Viagra) inhibits phosphodiesterase 5 (PDE-5)—itself an inhibitor of erection—and allows cGMP to function unopposed. Ordinarily, nitric oxide-mediated release from parasympathetic nerves and endothelium generates this compound, and prolongation of its half-life results in sustained inflow of blood into the erect penis. Fifty milligrams taken 1 hour prior to anticipated sexual activity is recommended, with peak action at 2 hours. There is no effect on libido, nor is priapism a problem, but the additive effect on nitrates may lead to exaggerated cardiac preload reduction and hypotension. Thus, the drug is contraindicated in patients taking nitroglycerin. All patients being evaluated for acute chest pain should be asked if they are taking sildenafil before administering nitroglycerin. Fixed atherosclerotic disease in the aortoiliac system is associated with diminished efficacy. Newer PDE-5 inhibitors, including vardenafil (Levitra) and tadalafil (Cialis), have a longer half-life and are similarly effective. Some patients who do not respond to one PDE-5 inhibitor may respond to one of the other agents. Apomorphine SL is a dopamine D1 and D2 agonist and is now approved for use in Europe.

D. Penile Prostheses

Prosthetic devices may be implanted directly into the paired corporal bodies. Such prostheses may be rigid, malleable, hinged, or inflatable. Each is manufactured in a variety of sizes and diameters. Inflatable models may result in a more cosmetic appearance but may be associated with a greater likelihood of mechanical failure.

E. Vascular Reconstruction

Patients with disorders of the arterial system are candidates for various forms of arterial reconstruction, including endarterectomy and balloon dilation for proximal arterial occlusion and arterial bypass procedures utilizing arterial (epigastric) or venous (deep dorsal vein) segments for distal occlusion. Patients with venous disorders may be managed with ligation of certain veins (deep dorsal or emissary veins) or the crura of the corpora cavernosa. Experience with vascular reconstructive procedures is still limited, and many patients so treated still fail to achieve a rigid erection.

Carson CC et al; Patient Response with Vardenafil in Sildenafil Non-Responders (PROVEN) Study Group: Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU Int 2004;94: 1301.

Gonzalgo ML et al: Clinical efficacy of sildenafil citrate and predictors of long-term response. J Urol 2003;170:503.

Lue TF: Erectile dysfunction. N Engl J Med 2000;342:1802.

Montague DK et al: Contemporary aspects of penile prosthesis implantation. Urol Int 2003;70:141.

Morales A: Erectile dysfunction: an overview. Clin Geriatr Med 2003;19:529.

Mulhall JP: Deciphering erectile dysfunction drug trials. J Urol 2003;170(2 Pt 1):353.

Nehra A et al: Vardenafil improved patient satisfaction with erectile hardness, orgasmic function and sexual experience in men with erectile dysfunction following nerve sparing radical prostatectomy. J Urol 2005;173:2067.

Seftel AD: Erectile dysfunction in the elderly: epidemiology, etiology and approaches to treatment. J Urol 2003;169:1999.

Seidman SN: The aging male: androgens, erectile dysfunction, and depression. J Clin Psychiatry 2003;64(Suppl 10):31.

Waldinger MD: On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment. Eur Urol 2004;46(4):510.

Male Infertility

Primary infertility affects 15–20% of married couples. Approximately one-third of cases result from male factors, one-third from female factors, and one-third from combined factors. It is thus critical to have simultaneous evaluation of both partners. Clinical evaluation is warranted following 6 months of unprotected intercourse. Endocrinologic profiles and detailed semen analyses are the cornerstones of laboratory investigations after the history and physical examination (see Figure 23-1). Oligospermia is the presence of less than 20 million sperm/mL in the ejaculate; azoospermia is the absence of sperm. As spermatogenesis takes approximately 74 days, it is thus important to review events from the past 3 months.

Figure 23-1. Male infertility: evaluation of male factor infertility. FSH = follicle-stimulating hormone; LH = luteinizing hormone; PRL = prolactin; T = testosterone. (From

Nicoll D et al [editors]: Pocket Guide to Diagnostic Tests. McGraw-Hill, 2004

. Adapted, with permission, from

Swerdloff RS, Boyers SM: evaluation of the male partner of an infertile couple: an algorithmic approach. JAMA 1982;247:2418

. Copyright © 1982 by The American Medical Association.)

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Clinical Findings

A. Symptoms and Signs

The history should include prior testicular insults (torsion, cryptorchidism, trauma), infections (mumps orchitis, epididymitis), environmental factors (excessive heat, radiation, chemotherapy), medications (anabolic steroids, cimetidine, and spironolactone may affect spermatogenesis; phenytoin may lower FSH; sulfasalazine and nitrofurantoin affect sperm motility), and drugs (alcohol, marijuana). Sexual habits, frequency and timing of intercourse, use of lubricants, and each partner's previous fertility experiences are important. Loss of libido and headaches or visual disturbances may indicate a pituitary tumor. The past medical or surgical history may reveal thyroid or liver disease (abnormalities of spermatogenesis), diabetic neuropathy (retrograde ejaculation), radical pelvic or retroperitoneal surgery (absent seminal emission secondary to

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sympathetic nerve injury), or hernia repair (damage to the vas deferens or testicular blood supply).

Physical examination should pay particular attention to features of hypogonadism: underdeveloped secondary sexual characteristics, diminished male pattern hair distribution (axillary, body, facial, pubic), eunuchoid skeletal proportions (arm span 2 inches > height; upper to lower body ratio < 1.0), and gynecomastia. The scrotal contents should be carefully evaluated. Testicular size should be noted (normal size approximately 4.5 × 2.5 cm, volume 18 mL). Varicoceles should be looked for in the standing position and on occasion may be appreciated only with the Valsalva maneuver. The vas deferens, epididymis, and prostate should be palpated.

B. Laboratory Findings

Semen analysis should be performed after 72 hours of abstinence. The specimen should be analyzed within 1 hour after collection. Abnormal sperm concentrations are less than 20 million/mL. Normal semen volumes range between 1.5 and 5 mL (volumes < 1.5 mL may result in inadequate buffering of the vaginal acidity and may be due to retrograde ejaculation or androgen insufficiency). Normal sperm motility and morphology demonstrate 50–60% motile cells and more than 60% normal morphology. Abnormal motility may result from antisperm antibodies or infection. Abnormal morphology may result from a varicocele, infection, or exposure history.

Endocrinologic evaluation is warranted if sperm counts are low or if there is a clinical basis (from the history and physical examination) for suspecting an endocrinologic origin. Testing should include serum FSH, LH, and testosterone. Elevated FSH and LH and low testosterone (hypergonadotropic hypogonadism) are associated with primary testicular failure, which is usually irreversible. Low FSH and LH associated with low testosterone occur in secondary testicular failure (hypogonadotropic hypogonadism) and may be of hypothalamic or pituitary origin. Such defects may be correctable. In such cases, serum prolactin should be checked to exclude pituitary prolactinoma.

C. Imaging

Scrotal ultrasound may detect a subclinical varicocele. Vasography may be required in patients with suspected ductal obstruction.

D. Special Tests

Azoospermic patients should have postmasturbation urine samples centrifuged and analyzed for sperm to exclude retrograde ejaculation. Azoospermic patients and patients with ejaculate volumes less than 1 mL should have fructose levels determined on the ejaculate. Fructose is produced in the seminal vesicles and if absent in the ejaculate implies obstruction of the ejaculatory ducts.

Treatment

A. General Measures

Education with respect to the proper timing for intercourse in relation to the female's ovulatory cycle as well as the avoidance of spermicidal lubricants should be discussed. In cases of toxic exposure or medication-related factors, the offending agent should be removed. Patients with active genitourinary tract infections should be treated with appropriate antibiotics.

B. Endocrine Therapy

Hypogonadotropic hypogonadism may be treated with chorionic gonadotropin once primary pituitary disease has been excluded or treated. Dosage is usually 2000 international units intramuscularly three times a week. If sperm counts fail to rise after 12 months, FSH therapy should be initiated. Menotropins (Pergonal) is available as a premixed vial of 75 international units of FSH and 75 international units of LH. The usual dosage ranges from one-half to one vial intramuscularly three times per week.

C. Retrograde Ejaculation Therapy

Oligospermic patients with retrograde ejaculation may benefit from α-adrenergic agonists (pseudoephedrine, 60 mg orally three times a day) or imipramine (25 mg orally three times a day). Medical failures may require the collection of postmasturbation urine for intrauterine insemination or electroejaculation in the case of absent emission.

D. Varicocele

Surgical approaches to varicoceles may be accomplished via a scrotal, inguinal, or laparoscopic approach. More recently, percutaneous venographic approaches have been developed, obviating the need for an anesthetic.

E. Ductal Obstruction

The level of obstruction must be delineated via a vasogram prior to operative treatment. Mechanical obstruction of the ejaculatory duct may be corrected by transurethral resection and unroofing of the ducts in the prostatic urethra. Obstruction of the vas deferens is best managed by a microsurgical approach, and a vasovasostomy or vasoepididymostomy may be required.

F. Assisted Reproductive Techniques

Advances in reproductive technology may provide alternatives to patients who have failed other means of treating reduced sperm counts and motility. Such measures include intrauterine insemination, in vitro fertilization, and gamete intrafallopian transfer.

Brugh VM 3rd et al: Male factor infertility: evaluation and management. Med Clin North Am 2004;88:367.

Hirsh A: Male subfertility. BMJ 2003;327:669.

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Makar RS et al: The evaluation of infertility. Am J Clin Pathol 2002;117(Suppl):S95.

Benign Prostatic Hyperplasia

Essentials of Diagnosis

  • Obstructive or irritative voiding symptoms.

  • May have enlarged prostate on rectal examination.

  • Absence of urinary tract infection, neurologic disorder, stricture disease, prostatic or bladder malignancy.

General Considerations

Benign prostatic hyperplasia is the most common benign tumor in men, and its incidence is age related. The prevalence of histologic benign prostatic hyperplasia in autopsy studies rises from approximately 20% in men aged 41–50 years, to 50% in men aged 51–60, and to over 90% in men over 80 years of age. Although clinical evidence of disease occurs less commonly, symptoms of prostatic obstruction are also age related. At age 55 years, approximately 25% of men report obstructive voiding symptoms. At age 75 years, 50% of men report a decrease in the force and caliber of the urinary stream.

Risk factors for the development of benign prostatic hyperplasia are poorly understood. Some studies have suggested a genetic predisposition and some have noted racial differences. Approximately 50% of men under age 60 years who undergo surgery for benign prostatic hyperplasia may have a heritable form of the disease. This form is most likely an autosomal dominant trait, and first-degree male relatives of such patients carry an increased relative risk of approximately fourfold.

Etiology

The etiology is not completely understood, but the disorder seems to be multifactorial and under endocrine control. The prostate is composed of both stromal and epithelial elements, and each, either alone or in combination, can give rise to hyperplastic nodules and the symptoms associated with benign prostatic hyperplasia. Each element may be targeted in medical management schemes.

Laboratory and clinical studies have identified two factors necessary for the development of benign prostatic hyperplasia: dihydrotestosterone (DHT) and aging. Animal studies have demonstrated that the aging prostate becomes more sensitive to androgens. Prostatic growth in aging dogs appears to be related more to a decrease in cell death than to an increase in cell proliferation. Laboratory studies have suggested several theories in this area: (1) stromal-epithelial interactions (stroma cell may regulate growth of epithelial cell or other stromal cells via a paracrine or autocrine mechanism by secreting growth factors such as basic fibroblast growth factor or transforming growth factor-β), and (2) aging may result in stem cells undergoing a block in the maturation process, preventing them from entering into programmed cell death (apoptosis). The impact of aging in animal studies appears to be mediated via estrogen synergism. In canines, estrogens induce the androgen receptor; alter steroid metabolism, resulting in higher levels of intraprostatic DHT; inhibit cell death when given in the presence of androgens; and stimulate stroma collagen production.

Studies have demonstrated that benign prostatic hyperplasia is under endocrine control. Castration results in the regression of established disease and improvement in urinary symptoms. Administration of a luteinizing hormone-releasing hormone (LHRH) analog in men reversibly shrinks established benign prostatic hyperplasia, resulting in objective improvement in flow rate and subjective improvement in symptoms. Further investigations have demonstrated a positive correlation between levels of free testosterone and estrogen and the volume of the gland. The latter may suggest that the association between aging and benign prostatic hyperplasia might reflect increasing estrogen levels of aging, resulting in induction of the androgen receptor and thus sensitizing the prostate to free testosterone. However, no studies to date have been able to demonstrate elevated estrogen receptor levels in humans with the disease.

Pathology

Benign prostatic hyperplasia is truly a hyperplastic process, resulting from an increase in cell numbers. Microscopic evaluation reveals a nodular growth pattern consisting of varying amounts of stroma or epithelium. Stroma is composed of varying amounts of collagen and smooth muscle. The differential representation of various histologic components of benign prostatic hyperplasia in part explains the potential responsiveness to medical therapy. Thus, α-blocker therapy may result in excellent responses in patients with benign prostatic hyperplasia when there is a significant component of smooth muscle, while hyperplasia composed predominantly of epithelium might respond better to 5α-reductase inhibitors. Patients with significant components of collagen in the stroma may not respond to either form of medical therapy. Responsiveness to specific therapy cannot reliably be predicted (see below).

As benign prostatic hyperplasia nodules in the transition zone enlarge, they compress the outer zones of

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the prostate, resulting in the formation of a “surgical capsule.” This boundary separates the transition zone from the peripheral zone of the gland and serves as a cleavage plane for open enucleation of the prostate during simple prostatectomy (surgery that removes the zone of the prostate around the urethra leaving the peripheral portion of the prostate and prostate capsule).

Pathophysiology

The symptoms of benign prostatic hyperplasia can be related either to the obstructive component of the prostate or to the secondary response of the bladder to the outlet resistance. The obstructive component can be subdivided into mechanical obstruction and dynamic obstruction.

As prostatic enlargement occurs, mechanical obstruction may result from intrusion into the urethral lumen or bladder neck, resulting in a higher bladder outlet resistance. Prostatic size on DRE correlates poorly with symptoms.

The dynamic component of prostatic obstruction explains the variable nature of the symptoms. The prostatic stroma is composed of smooth muscle and collagen and is rich in adrenergic nerve supply. The level of autonomic stimulation thus sets a “tone” to the prostatic urethra. α-Blocker therapy decreases this tone, resulting in a decrease in outlet resistance.

The irritative voiding complaints (see below) of benign prostatic hyperplasia result from the secondary response of the bladder to the increased outlet resistance. Bladder outlet obstruction results in detrusor muscle hypertrophy and hyperplasia as well as collagen deposition. The latter is most likely responsible for a decrease in bladder compliance, but detrusor instability also occurs. On gross inspection, thickened detrusor muscle bundles are seen as trabeculations on cystoscopic examination. If left unchecked, mucosal herniation between detrusor muscle bundles ensues, resulting in diverticulum formation (“false” diverticula composed of mucosa and serosa only).

Clinical Findings

A. Symptoms

The symptoms of benign prostatic hyperplasia can be divided into obstructive and irritative complaints. Obstructive symptoms include hesitancy, decreased force and caliber of the stream, sensation of incomplete bladder emptying, double voiding (urinating a second time within 2 hours), straining to urinate, and postvoid dribbling. Irritative symptoms include urgency, frequency, and nocturia.

The American Urological Association (AUA) has developed a self-administered questionnaire that is reliable in identifying patients who need therapy and in monitoring the response to therapy. The AUA symptom index (Table 23-4) is perhaps the single most important tool used in the evaluation of patients with this disorder and should be calculated for all patients before starting therapy. The answers to seven questions quantitate the severity of obstructive or irritative complaints on a scale of 0–5. Thus, the score can range from 0 to 35, in increasing severity of symptoms.

Table 23-4. American Urological Association symptom index for benign prostatic hyperplasia.1

Questions to Be Answered Not at All Less Than One Time in Five Less Than Half the Time About Half the Time More Than Half the Time Almost Always
1. Over the past month, how often have you had a sensation of not emptying your bladder completely after you finish urinating? 0 1 2 3 4 5
2. Over the past month, how often have you had to urinate again less than 2 hours after you finished urinating? 0 1 2 3 4 5
3. Over the past month, how often have you found you stopped and started again several times when you urinated? 0 1 2 3 4 5
4. Over the past month, how often have you found it difficult to postpone urination? 0 1 2 3 4 5
5. Over the past month, how often have you had a weak urinary stream? 0 1 2 3 4 5
6. Over the past month, how often have you had to push or strain to begin urination? 0 1 2 3 4 5
7. Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning? 0
(None)
1
(1 time)
2
(2 times)
3
(3 times)
4
(4 times)
5
(5 times)
1Sum of seven circled numbers equals the symptom score. See text for explanation.
Reproduced, with permission, from Barry MJ et al: The American Urological Association symptoms index for benign prostatic hyperplasia. J Urol 1992;148:1549.

A detailed history focusing on the urinary tract should be obtained to exclude other possible causes of symptoms such as prostate cancer or disorders unrelated to the prostate such as urinary tract infection, neurogenic bladder, or urethral stricture.

B. Signs

A physical examination, DRE, and a focused neurologic examination should be performed on all patients. The size and consistency of the prostate should be noted, but prostate size does not correlate with the severity of symptoms or the degree of obstruction. Benign prostatic hyperplasia usually results in a smooth, firm, elastic enlargement of the prostate. Induration, if detected, must alert the physician to the possibility of cancer, and further evaluation is needed (ie, PSA, transrectal ultrasound, and biopsy). Examination of the lower abdomen should be performed to assess for a distended bladder.

C. Laboratory Findings

Urinalysis should be performed to exclude infection or hematuria, and serum creatinine should be measured to assess renal function. Renal insufficiency from benign prostatic hyperplasia is fairly rare, occurring in only about 2% of patients with lower urinary tract symptoms on initial presentation. If renal insufficiency is detected, upper urinary tract imaging is warranted. Patients with renal insufficiency are at an increased risk for complications following operative treatment for benign prostatic hyperplasia. A serum PSA is considered optional, yet most physicians will include it in the initial evaluation. PSA certainly increases the ability to detect prostate cancer over DRE alone; however, because there is much overlap between levels seen in benign prostatic hyperplasia and prostate cancer, its use remains controversial (see below in the section on screening for prostate cancer).

D. Imaging

Upper tract imaging (IVP, CT, or renal ultrasound) is recommended only in the presence of concomitant urinary tract disease or complications from benign prostatic hyperplasia (ie, hematuria, urinary tract infection, renal insufficiency, history of stone disease).

E. Cystoscopy

Cystoscopy is not recommended to determine the need for treatment but may assist in determining the surgical approach in patients opting for invasive therapy.

F. Additional Tests

Cystometrograms and urodynamic profiles should be reserved for patients with suspected neurologic disease or those who have failed prostate surgery. Flow rates,

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postvoid residual urine determination, and pressure-flow studies are considered optional.

Differential Diagnosis

Other obstructive conditions of the lower urinary tract such as urethral stricture, bladder neck contracture, bladder stone, or carcinoma of the prostate must be considered when evaluating men with presumptive benign prostatic hyperplasia. A history of prior urethral instrumentation, urethritis, or trauma should be elucidated to exclude urethral stricture or bladder neck contracture. Hematuria and pain are commonly associated with bladder stones. Carcinoma of the prostate may be detected by abnormalities on the DRE or an elevated PSA (see below). A urinary tract infection can mimic the irritative symptoms of benign prostatic hyperplasia and can be readily identified by urinalysis and culture; however, a urinary tract infection can also be a complication of benign prostatic hyperplasia. Carcinoma of the bladder, especially carcinoma in situ, may also present with irritative voiding complaints; however, urinalysis usually shows evidence of hematuria. Patients with a neurogenic bladder may also have many of the same symptoms and signs as those with benign prostatic hyperplasia; however, a history of neurologic disease, stroke, diabetes mellitus, or back injury may be obtained, and diminished perineal or lower extremity sensation or alterations in rectal sphincter tone or the bulbocavernosus reflex might be observed on examination. Simultaneous alterations in bowel function (constipation) might also suggest the possibility of a neurologic disorder.

Treatment

Clinical practice guidelines exist for the evaluation and treatment of patients with benign prostatic hyperplasia (Figure 23-2). Following evaluation as outlined above, patients should be offered various forms of therapy for benign prostatic hyperplasia. Patients are advised to consult with their primary care physicians and make an educated decision on the basis of the relative efficacy and side effects of the treatment options (Table 23-5).

Figure 23-2. Benign prostatic hyperplasia decision diagram. DRE = digital rectal examination; PSA = prostate-specific antigen; BPH = benign prostatic hyperplasia; TUIP = transurethral incision of the prostate; TURP = transurethral resection of the prostate.

Patients with mild symptoms (AUA scores 0–7) should be managed by watchful waiting only. Absolute surgical indications are refractory urinary retention (failing at least one attempt at catheter removal), large bladder diverticula, or any of the following sequelae of benign prostatic hyperplasia: recurrent urinary tract infection, recurrent gross hematuria, bladder stones, or renal insufficiency.

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A. Watchful Waiting

The risk of progression or complications is uncertain. However, in men with symptomatic disease, it is clear that progression is not inevitable and that some men undergo spontaneous improvement or resolution of their symptoms.

Retrospective studies on the natural history of benign prostatic hyperplasia are inherently subject to bias, relating in part to patient selection and also to the type and extent of follow-up. Very few prospective studies addressing the natural history have been reported. One small series demonstrated that approximately 10% of symptomatic men may progress to urinary retention while 50% of patients demonstrate marked improvement or resolution of symptoms. Recently, a large randomized study was reported comparing finasteride with placebo in men with moderate to severely symptomatic disease and enlarged prostates on DRE. Patients in the placebo arm demonstrated a 7% risk of developing urinary retention over 4 years.

Men with moderate or severe symptoms can also be managed in this fashion if they so choose. The optimal interval for follow-up is not defined, nor are the specific end points for intervention.

B. Medical Therapy

1. α-Blockers

The human prostate and bladder base contains α1-adrenoceptors, and the prostate will show a contractile response to such agonists. The contractile properties of the prostate and bladder neck seem to be mediated primarily by α1a-receptors. α-Blockade has been shown to result in both objective and subjective degrees of improvement in the symptoms and signs of benign prostatic hyperplasia in some patients. α-Blockers can be classified according to their receptor selectivity as well as their half-life (Table 23-6).

The efficacies of phenoxybenzamine and prazosin are comparable with respect to symptomatic relief; however, the higher side-effect profile of phenoxybenzamine, resulting from its lack of α-receptor specificity, precludes its use in patients with benign prostatic hyperplasia. Prazosin is effective; however, it requires dose titration and twice daily dosing. Typical side effects

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include orthostatic hypotension, dizziness, tiredness, retrograde ejaculation, rhinitis, and headache.

Table 23-5. Balance sheet for benign prostatic hyperplasia treatment outcomes.1

Outcome TUIP Open Surgery TURP Watchful Waiting α-Blockers Finasteride2
Chance for improvement1 78–83% 94–99.8% 75–96% 31–55% 59–86% 54–78%
Degree of symptom improvement (% reduction in symptom score) 73% 79% 85% Unknown 51% 31%
Morbidity and complications1 2.2–33.3% 7–42.7% 5.2–30.7% 1–5% 2.9–43.3% 13.6–8.8%
Death within 30–90 days1 0.2–1.5% 1–4.6% 0.5–3.3% 0.8% 0.8% 0.8%
Total incontinence1 0.1–1.1% 0.3–0.7% 0.7–1.4% 2% 2% 2%
Need for operative treatment for surgical complications1 1.3–2.7% 0.6–14.1% 0.7–10.1% 0 0 0
Impotence1 3.9–24.5% 4.7–39.2% 3.3–34.8% 3% 3% 2.5–5.3%
Retrograde ejaculation 6–55% 36–95% 25–99% 0 4–11% 0
Loss of work in days 7–21 21–28 7–21 1 3.5 1.5
Hospital stay in days 1–3 5–10 3–5 0 0 0
190% confidence interval.
2Most of the data reviewed for finasteride are derived from three trials that have required an enlarged prostate for entry. The chance of improvement in men with symptoms yet minimally enlarged prostates may be much less, as noted from the VA Cooperative Trial.
TUIP = transurethral incision of the prostate; TURP = transurethral resection of the prostate.

Long-acting α-blockers allow for once-a-day dosing, but dose titration is still necessary. Terazosin is started at a dosage of 1 mg orally daily for 3 days, increased to 2 mg orally daily for 11 days, then 5 mg orally daily. Additional dose escalation to 10 mg orally daily can be performed if necessary. Doxazosin is started at a dosage of 1 mg orally daily for 7 days, increased to 2 mg orally daily for 7 days, then 4 mg orally daily. Additional dose escalation to 8 mg orally daily can be performed if necessary. Side effects are similar to those described above for prazosin. Terazosin improves symptoms and in numerous studies is superior to placebo or finasteride. Alfuzosin is a long-acting α-blocker; its dose is 10 mg orally once daily and does not require titration.

The most recent advance in α-blocker therapy has been the identification of subtypes of α1-receptors. The α1a-receptors are localized to the prostate and bladder neck, and selective blockade results in fewer systemic side effects (orthostatic hypotension, dizziness, tiredness, rhinitis, and headache), thus obviating the need for dose titration. The dose of tamsulosin is 0.4 mg orally daily taken 30 minutes after a meal. Several randomized, double-blind, placebo-controlled trials have been performed comparing terazosin, doxazosin, tamsulosin, and alfuzosin with placebo. All agents have demonstrated safety and efficacy.

2. 5α-Reductase inhibitors

Finasteride is a 5α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone. This drug impacts upon the epithelial component of the prostate, resulting in reduction in size of the gland and improvement in symptoms. Six months of therapy is required for maximum effects on prostate size (20% reduction) and symptomatic improvement.

Several randomized, double-blind, placebo-controlled trials have been performed comparing finasteride with placebo. Efficacy, safety, and durability are well established. However, symptomatic improvement is seen only in men with enlarged prostates (> 40 mL). Side effects include decreased libido, decrease in volume of ejaculate, and impotence. Serum PSA is reduced by approximately 50% in patients receiving finasteride therapy. Therefore, in order to compare with pre-finasteride levels, the serum PSA of a patient taking finasteride should be doubled.

Table 23-6. α-Blockade for benign prostatic hyperplasia.

Agent Action Dose
Phenoxybenzamine α1- and α2-Blockade 5–10 mg twice daily
Prazosin α1-Blockade 1–5 mg twice daily
Terazosin α1-Blockade 1–10 mg daily
Doxazosin α1-Blockade 1–8 mg daily
Alfuzosin α1-Blockade 10 mg daily
Tamsulosin α1a-Blockade 0.4 or 0.8 mg daily

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A recent report suggests that finasteride therapy may decrease the incidence of urinary retention and the need for operative treatment in men with enlarged prostates and moderate to severe symptoms. The larger the prostate over 40 mL, the greater the apparent relative-risk reduction. However, optimal identification of appropriate patients for prophylactic therapy remains to be determined. Dutasteride is a well-tolerated 5α-reductase inhibitor that appears to be similar to finasteride in its effectiveness; its dose is 0.5 mg orally daily.

3. Combination therapy

The four-arm Veterans Administration Cooperative Trial compared placebo, finasteride alone, terazosin alone, and combination of finasteride and terazosin. Over 1200 patients participated, and significant decreases in symptom scores and increases in urinary flow rates were seen only in the arms containing terazosin. However, enlarged prostates were not an entry criterion; in fact, prostate size in this study was much smaller than in previous controlled trials using finasteride (32 versus 52 mL). Other randomized, placebo-controlled trials comparing finasteride with placebo in men with lower urinary tract symptoms and large prostates showed finasteride to be beneficial for reducing symptoms, increasing urinary flow rate, and reducing the risk of complications due to benign prostatic hyperplasia as well as reducing the number of men who required surgery for benign prostatic hyperplasia. The Medical Therapy of Prostatic Symptoms (MTOPs) trial is a large, randomized, placebo-controlled trial comparing finasteride, doxazosin, the combination of the two, and placebo in 3047 men observed for a mean of 4.5 years. Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy. Combination therapy had the risks of additional side effects and the cost of two medications.

4. Phytotherapy

Phytotherapy is the use of plants or plant extracts for medicinal purposes. Its use in benign prostatic hyperplasia has been popular in Europe for years, and its use in the United States is growing as a result of patient-driven enthusiasm. Several plant extracts have been popularized, including the saw palmetto berry, the bark of Pygeum africanum, the roots of Echinacea purpurea and Hypoxis rooperi, pollen extract, and the leaves of the trembling poplar. The mechanisms of action of these agents are unknown. A recent, prospective, randomized, double-blind, placebo-controlled trial revealed no improvement in symptoms, urinary flow rate, or quality of life for men with benign prostatic hyperplasia with saw palmetto treatment compared with placebo.

C. Conventional Surgical Therapy

1. Transurethral resection of the prostate (TURP)

Ninety-five percent of simple prostatectomies can be performed endoscopically. Most of these procedures are performed under a spinal anesthetic and require a 1- to 2-day hospital stay. Symptom scores and flow rate improvement are superior following TURP relative to any minimally invasive therapy; however, the length of the hospital stay is greater. Much controversy revolves around possible higher rates of morbidity and mortality associated with TURP in comparison with open surgery, but the higher rates observed in one study probably related to more significant comorbidities in the TURP patients compared with the patients who received open surgical treatment. Several other studies could not confirm the difference in mortality when controlling for age and comorbidities. The risks of TURP include retrograde ejaculation (75%), impotence (5–10%), and urinary incontinence (< 1%). Complications include bleeding, urethral stricture or bladder neck contracture, perforation of the prostate capsule with extravasation, and, if severe, transurethral resection syndrome, a hypervolemic, hyponatremic state resulting from absorption of the hypotonic irrigating solution. Clinical manifestations of the syndrome include nausea, vomiting, confusion, hypertension, bradycardia, and visual disturbances. The risk of transurethral resection syndrome increases with resection times over 90 minutes. Treatment includes diuresis and, in severe cases, hypertonic saline administration.

2. Transurethral incision of the prostate (TUIP)

Men with moderate to severe symptoms and small prostates often have posterior commissure hyperplasia or an “elevated bladder neck.” These patients will often benefit from incision of the prostate. The procedure is more rapid and less morbid than TURP. Outcomes in well-selected patients are comparable, though a lower rate of retrograde ejaculation has been reported (25%). The technique involves two incisions using the Collins knife at the 5 and 7 o'clock positions. The incisions are started just distal to the ureteral orifices and extended outward to the verumontanum.

3. Open simple prostatectomy

When the prostate is too large to remove endoscopically, open enucleation is necessary. What size is “too large” depends upon the surgeon's experience with TURP. Glands over 100 g are usually considered for open enucleation. In addition to size, other relative indications for open prostatectomy include concomitant bladder diverticulum or bladder stone and whether dorsal lithotomy positioning is or is not possible.

Open prostatectomies can be performed with either a suprapubic or retropubic approach. Simple suprapubic prostatectomy is performed transvesically and is the operation of choice if there is concomitant bladder pathology. After the bladder is opened, a semicircular incision is made in the bladder mucosa distal to the trigone. The dissection plane is initiated sharply, and blunt dissection with the finger is then performed to deliver the adenoma. The apical dissection should be performed sharply to avoid injury to the distal sphincteric mechanism. After the adenoma is removed, hemostasis is attained with suture ligatures

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and both a urethral and a suprapubic catheter are inserted prior to closure.

In simple retropubic prostatectomy, the bladder is not entered but rather a transverse incision is made in the surgical capsule of the prostate and the adenoma is enucleated as described above. Only a urethral catheter is needed at the end of the case.

D. Minimally Invasive Therapy

1. Laser therapy

Many techniques of laser surgery for the prostate have been described. Two main energy sources of lasers have been utilized—neodymium:yttrium-aluminum-garnet (Nd:YAG) and holmium-YAG.

Several different coagulation necrosis techniques have been described. Transurethral laser-induced prostatectomy (TULIP) is performed under transrectal ultrasound guidance. The instrument is placed in the urethra and transrectal ultrasound is used to direct the device as it is slowly pulled from the bladder neck to the apex. The depth of treatment is monitored with ultrasound.

Most urologists prefer to use visually directed laser techniques. Visual coagulative necrosis is performed under cystoscopic control, and the laser fiber is pulled through the prostate at several designated areas depending upon the size and configuration of the gland. Four-quadrant and sextant approaches have been described for lateral lobes, with additional treatments directed at enlarged median lobes. Coagulative techniques do not create an immediate visual defect in the prostatic urethra—tissue is sloughed over the course of several weeks up to 3 months following the procedure.

Visual contact ablative techniques take longer in the operating room because the fiber is placed in direct contact with the prostate tissue, which is vaporized. A new laser technique that is gaining popularity is photovaporization of the prostate (PVP) using a high-power KTP laser. An immediate defect is obtained in the prostatic urethra, similar to that seen during TURP.

Interstitial laser therapy places fibers directly into the prostate, usually under cystoscopic control. At each puncture, the laser is fired, resulting in submucosal coagulative necrosis. Irritative voiding symptoms may be less in these patients as the urethral mucosa is spared and prostate tissue is resorbed by the body rather than sloughed.

Advantages to laser surgery include minimal blood loss, rare occurrence of transurethral resection syndrome, the ability to treat patients while on anticoagulation therapy, and outpatient surgery. Disadvantages are the lack of tissue for pathologic examination, the longer postoperative catheterization time, the more frequent irritative voiding complaints, and the expense of laser fibers and generators.

Large multicenter, randomized studies with long-term follow-up are needed in comparing laser prostate surgery with TURP and other forms of minimally invasive surgery.

2. Transurethral needle ablation of the prostate (TUNA)

This procedure uses a specially designed urethral catheter that is passed into the urethra. Interstitial radiofrequency needles are then deployed from the tip of the catheter, piercing the mucosa of the prostatic urethra. Radiofrequencies are then used to heat the tissue, resulting in coagulative necrosis. Bladder neck and median lobe enlargement are not well treated by TUNA. Subjective and objective improvement in voiding occurs. In randomized trials comparing TUNA to TURP, similar improvement was seen when comparing life scores, peak urinary flow rates, and postvoid residual urine.

3. Transurethral electrovaporization of the prostate

This technique uses the standard resectoscope but replaces a conventional loop with a variation of a grooved rollerball. High current densities result in heat vaporization of tissue, creating a cavity in the prostatic urethra. Because the device requires slower sweeping speeds over the prostatic urethra and the depth of vaporization is approximately one-third of a standard loop, this procedure usually takes longer than a standard TURP. Long-term comparative data are needed.

4. Hyperthermia

Microwave hyperthermia is most commonly delivered with a transurethral catheter. Some devices cool the urethral mucosa to decrease the risk of injury. However, if temperatures do not go above 45°C, cooling is unnecessary. Symptom score and flow rate improvement are obtained, but (as with laser surgery) large randomized studies with long-term follow-up are needed to assess durability and cost-effectiveness.

5. High-intensity focused ultrasound (HIFU)

HIFU is another means of performing thermal tissue ablation. A specially designed dual-function ultrasound probe is placed in the rectum. This probe allows transrectal imaging of the prostate and also delivers short bursts of high-intensity focused ultrasound energy, which heats the prostate tissue and causes coagulative necrosis. Bladder neck and median lobe enlargement are not well treated by HIFU. Ongoing clinical trials demonstrate some improvement in symptom score and flow rate, but the durability of the response is not known.

6. Intraurethral stents

Intraurethral stents are placed endoscopically in the prostatic fossa to keep the prostatic urethra patent. They are usually covered by urothelium within 4–6 months following insertion. These devices are typically used for patients with limited life expectancies who are not deemed good surgical or anesthetic candidates; however, with the advent of other minimally invasive techniques requiring minimal anesthesia (conscious sedation, or prostatic blocks), their application has become more limited.

7. Transurethral balloon dilation of the prostate

Balloon dilation of the prostate is performed with specially designed catheters that permit dilation of the prostatic fossa alone or dilation of the prostatic fossa and bladder neck. The technique is most effective in small prostates (< 40 mL), and although it may result in improvement in symptom score and flow rates, the effects are transient. This technique is rarely used today.

Andriole GL et al: Safety and tolerability of the dual 5-alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol 2003;44:82.

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Bent S et al: Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354:557.

Bhargava S et al: A rational approach to benign prostatic hyperplasia evaluation: recent advances. Curr Opin Urol 2004; 14:1.

Djavan B et al: Benign prostatic hyperplasia progression and its impact on treatment. Curr Opin Urol 2004;14:45.

Dutkiewicz S: Long-term treatment with doxazosin in men with benign prostatic hyperplasia: 10-year follow-up. Int Urol Nephrol 2004;36:169.

Kaplan SA: Use of alpha-adrenergic inhibitors in treatment of benign prostatic hyperplasia and implications on sexual function. Urology 2004;63:428.

Kortmann BB et al: Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials. Urology 2003;62:1.

McConnell JD et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387.

O'Leary MP: Lower urinary tract symptoms/benign prostatic hyperplasia: maintaining symptom control and reducing complications. Urology 2003;62(3 Suppl 1):15.

Schulman CC: Lower urinary tract symptoms/benign prostatic hyperplasia: minimizing morbidity caused by treatment. Urology 2003;62(3 Suppl 1):24.

Thorpe A et al: Benign prostatic hyperplasia. Lancet 2003;361:1359.

Wilt TJ et al: Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003;(1):CD002081.

Malignant Genitourinary Tract Disorders

Prostate Cancer

Essentials of Diagnosis

  • Prostatic induration on DRE or elevation of PSA.

  • Most often asymptomatic.

  • Rarely: systemic symptoms (weight loss, bone pain).

General Considerations

Prostatic cancer is the most common cancer detected in American men and the second leading cause of cancer-related death. In the United States in 2005, over 232,000 new cases of prostate cancer were diagnosed, and about 30,300 deaths resulted. However, the clinical incidence of the disease does not match the prevalence noted at autopsy, where more than 40% of men over 50 years of age are found to have prostatic carcinoma. Most such occult cancers are small and contained within the prostate gland. Few are associated with regional or distant disease. The incidence of prostatic cancer increases with age. Whereas 30% of men aged 60–69 years will have the disease, autopsy incidence increases to 67% in men aged 80–89 years. Although the prevalence of prostatic cancer in autopsy specimens around the world varies little, the clinical incidence is considerably different (high in North America and European countries, intermediate in South America, and low in the Far East), suggesting that environmental or dietary differences among populations may be important for prostatic cancer growth. A 50-year-old American man has a lifetime risk of 40% for latent cancer, 9.5% for developing clinically apparent cancer, and a 2.9% risk of death due to prostatic cancer. Blacks, men with a family history of prostatic cancer, and those with a history of high dietary fat intake are at increased risk of developing it.

Clinical Findings

A. Symptoms and Signs

Prostate cancer may be manifested as focal nodules or areas of induration within the prostate at the time of DRE. However, a large number of prostate cancers are associated with palpably normal prostates and are detected on the basis of elevations in serum PSA.

Rarely, patients present with signs of urinary retention (palpable bladder) or neurologic symptoms as a result of epidural metastases and cord compression. Obstructive voiding symptoms are most often due to benign prostatic hyperplasia, which occurs in the same age group. However, large or locally extensive prostatic cancers can cause obstructive voiding symptoms. Lymph node metastases can lead to lower extremity lymphedema. As the axial skeleton is the most common site of metastases, patients may present with back pain or pathologic fractures.

B. Laboratory Findings

1. Serum tumor markers

PSA is a glycoprotein produced only in the cytoplasm of benign and malignant prostate cells. The serum level correlates with the volume of both benign and malignant prostatic tissue. Measurement of PSA may be useful in detecting and staging prostatic cancer, monitoring response to treatment, and detecting recurrence before it becomes obvious clinically. As a first-line screening test, PSA will be elevated in approximately 10–15% of men self-referred for screening. Approximately 18–30% of men with intermediate degrees of elevation (4.1–10 ng/mL; normal < 4 ng/mL) will be found to have prostatic cancer. Between 50% and 70% of those with elevations greater than 10 ng/mL will have prostatic cancer. (See age-specific PSA reference ranges under Screening for Prostatic Cancer, below.) Patients with intermediate levels of PSA will usually have localized and therefore

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potentially curable cancers. However, it should be remembered that approximately 20% of patients who undergo radical prostatectomy for localized prostatic cancer will have normal levels of PSA.

In untreated patients with prostatic cancer, the level of PSA correlates with the volume and stage of the disease. Whereas most organ-confined cancers are associated with PSA levels less than 10 ng/mL, more advanced disease (seminal vesicle invasion, lymph node involvement, or occult distant metastases) is more common in patients with PSA levels in excess of 40 ng/mL. Approximately 98% of patients with metastatic prostatic cancer will have elevated PSA. However, there are occasional cancers that are localized despite substantial elevations in PSA. Therefore, treatment decisions in patients with untreated cancers cannot be made on the basis of PSA testing alone. A rising level of PSA after treatment is usually consistent with progressive disease whether it is locally recurrent or metastatic.

2. Miscellaneous laboratory testing

Patients in urinary retention or those with ureteral obstruction due to locally or regionally advanced prostatic cancers may present with elevations in serum urea nitrogen or creatinine. Patients with bony metastases may have elevations in alkaline phosphatase or hypercalcemia. Laboratory and clinical evidence of disseminated intravascular coagulation can occur in patients with advanced prostatic cancers.

3. Prostatic biopsy

Transrectal ultrasound-guided biopsy is a better method for detection of prostatic cancer than finger-guided biopsy. The use of a spring-loaded, 18-gauge biopsy needle has allowed transrectal biopsy to be performed with little patient discomfort and low attendant morbidity. Local anesthesia is commonly used and increases the tolerability of the procedure. The specimen preserves glandular architecture and allows for accurate grading as described below. Transrectal ultrasound-guided biopsy specimens are taken from the apex, mid portion, and base of the prostate in men who have an abnormal DRE or an elevated serum PSA. Extended-pattern biopsies, including a total of at least ten biopsies, are associated with improved cancer detection and risk stratification of patients with newly diagnosed disease. Patients with abnormalities of the seminal vesicles can have guided biopsies of these structures performed to allow for detection of local tumor invasion.

C. Imaging

Modern transrectal ultrasound instrumentation provides high-definition images of the prostate. Transrectal ultrasonography has been used largely for the staging of prostatic carcinomas. In addition, transrectal ultrasound-guided—rather than digitally guided—biopsy of the prostate is a more accurate way to investigate suspicious lesions. Most prostatic cancers are hypoechoic.

MRI of the prostate allows for evaluation of the prostatic lesion as well as regional lymph nodes. The positive predictive value for detection of both capsular penetration and seminal vesicle invasion is similar for both transrectal ultrasound and MRI. CT scanning plays little role in evaluation because of its inability to accurately identify or stage prostatic cancers.

Radionuclide bone scan is superior to conventional plain skeletal x-rays in detecting bony metastases. Most prostatic cancer metastases are multiple and are most commonly localized to the axial skeleton. Because of the high frequency of abnormal scans in patients in this age group resulting from degenerative joint disease, plain films are often useful in evaluating patients with indeterminate radionuclide findings. Intravenous urography and cystoscopy are not routinely used to evaluate patients with prostatic cancer.

Imaging can be tailored to the likelihood of advanced disease in newly diagnosed patients. Asymptomatic patients with well to moderately well differentiated cancers—thought to be localized to the prostate on DRE and transurethral ultrasound and associated with normal or only modest elevations of PSA (ie, < 10 ng/mL)—need no further evaluation.

Those with more advanced local lesions, symptoms of metastases (ie, bone pain), high-grade prostate cancer, and elevations in PSA greater than 20 ng/mL should undergo radionuclide bone scan. Cross-sectional imaging of the prostate is usually indicated only in those patients in the latter group who have negative bone scans in an attempt to detect lymph node metastases. Patients found to have enlarged pelvic lymph nodes are candidates for fine-needle aspiration. Despite application of modern and sophisticated imaging, understaging of prostatic cancer occurs in at least 20% of patients.

Screening for Prostatic Cancer

The reported incidence of prostate cancer rose significantly in the United States when early detection techniques (PSA testing and transrectal ultrasound) became widely available. The goal of a screening effort should be to detect and effectively treat only those prostatic carcinomas most likely to cause morbidity or mortality if left untreated. Detection of latent, nonprogressive cancers would expose patients to unnecessary treatment and its attendant complications and costs. Whether screening for prostatic cancer will result in a decrease in yearly mortality rates due to the disease is the subject of much current debate.

The screening tests currently available include DRE, PSA testing, and transrectal ultrasound. Depending on the patient population being evaluated, detection rates using DRE alone will vary from 1.5% to 7%. Unfortunately, most cancers detected in this way are advanced (stages T3 or greater). Transrectal ultrasound should not be used as a first-line screening tool because of its expense, its low specificity (and therefore high biopsy rate), and the fact that it increases the detection rate very little when compared with the combined use of DRE and PSA testing.

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PSA testing will increase the detection rate of prostatic cancers compared with DRE. Approximately 2–2.5% of men older than 50 years of age will be found to have prostatic cancer using PSA testing compared with a rate of approximately 1.5% using DRE alone. PSA is not specific for cancer, and there is considerable overlap of values between men with benign prostatic hyperplasia and those with prostatic cancers. The sensitivity, specificity, and positive predictive value of PSA and DRE are listed in Table 23-7. PSA-detected cancers are more likely to be localized compared with those detected with DRE alone.

To improve the performance of PSA as a screening test, several investigators have developed alternative methods for its use. The serial measurement of PSA (PSA velocity) may increase specificity for cancer detection with little loss in sensitivity. A rate of change in PSA greater than 0.75 ng/mL per year is associated with an increased likelihood of cancer detection. In a patient with a normal DRE, an elevated PSA, and a normal transrectal ultrasound, the indications for prostate biopsy may be refined by calculating PSA density (serum PSA/volume of the prostate as measured by ultrasound). Patients with high PSA density are more likely to have disease in spite of a normal DRE and normal transrectal ultrasound. Some have found measurement of PSA transition zone density (the zone of the prostate that undergoes enlargement during development of benign prostatic hyperplasia) to be more predictive of the presence or absence of cancer than PSA density calculated using the entire prostate volume. As PSA concentration is directly related to patient age, establishment of age-specific reference ranges would increase specificity (fewer older men with benign prostatic hyperplasia would undergo evaluation) and increase sensitivity (more younger men with cancer would undergo evaluation). Age-specific reference ranges have been established: men 40–49, < 2.5 ng/mL; men 50–59, < 3.5 ng/mL; men 60–69, < 4.5 ng/mL; and men 70–79, < 6.5 ng/mL (based on a previously normal serum PSA of < 4 ng/mL). Black men have lower age-specific reference ranges (age 40–49, < 2 ng/mL; age 50–59, < 4 ng/mL; age 60–69, < 4.5 ng/mL; age 70–79, < 5.5 ng/mL). The most recent attempt at refining PSA has been the measurement of free serum and protein-bound levels (cancer patients have a lower percentage of free serum PSA). Numerous centers are analyzing this assay to define an optimal cutoff level. Generally, men with free fractions exceeding 25% are unlikely to have prostate cancer, whereas those with free fractions less than 10% have an approximately 50% chance of having prostate cancer. Early reports using cutoffs of 18–20% of free PSA resulted in 5–10% lost sensitivity for 15–40% gains in specificity. The frequency of PSA testing remains a matter of some debate. In men with a normal DRE and a PSA > 2.5 ng/mL, PSA testing should be performed yearly because approximately 50% of these patients convert to having a PSA > 4 ng/mL. It can be performed biennially in those with a normal DRE and serum PSA < 2.5 ng/mL. Conversion in this group is much less likely.

Table 23-7. Screening for prostatic cancer: Test performance.

Test Sensitivity Specificity Positive Predictive Value
Abnormal PSA (> 4 ng/mL) 0.67 0.97 0.43
Abnormal DRE 0.50 0.94 0.24
Abnormal PSA or DRE 0.84 0.92 0.28
Abnormal PSA and DRE 0.34 0.995 0.49
DRE = digital rectal examination; PSA = prostate-specific antigen.
Modified from Kramer BS et al: Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914.

Pathology & Staging

The majority of prostatic cancers are adenocarcinomas. Most arise in the periphery of the prostate (peripheral zone), though a small percentage arise in the central (5–10%) and transition zones (20%) of the gland. Most pathologists employ the Gleason grading system whereby a “primary” grade is applied to the architectural pattern of cancerous glands occupying the largest area of the specimen and a “secondary” pattern is assigned to the next largest area of cancerous growth. Grading is based on architectural (rather than histologic) criteria, and five possible “grades” are possible. Adding the score of the primary and secondary patterns gives a Gleason score. Grade correlates well with tumor volume, stage, and prognosis. The TNM classification of the American Joint Cancer Committee for prostatic cancer is shown in Table 23-8.

The likelihood of success of surveillance or treatment can be predicted using risk assessment tools that combine stage, grade, PSA level, and number and extent of positive prostate biopsies among other information. Several tools are available on the Internet for private use (eg, http://www.mskcc.org/mskcc/html/5794.cfm). One of the most widely used risk prediction tools is the Kattan nomogram; it uses serum PSA to predict the likelihood that a patient will be disease-free at 5 years after radical prostatectomy or radiation therapy, depending on the tumor stage, grade, and PSA level.

The patterns of prostatic cancer progression have been well defined. The likelihood of both local invasion and metastases is greater in larger or less well-differentiated cancers. Small and well-differentiated cancers (grades 1 and 2) are usually confined within the prostate, whereas large-volume (> 4 mL) or poorly differentiated (grades 4 and 5) cancers are more commonly

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locally extensive or metastatic to regional lymph nodes or bone. Penetration of the prostatic capsule by cancer is common and often occurs along perineural spaces. Seminal vesicle invasion is associated with a high likelihood of regional or distant disease. Lymphatic metastases are most often identified in the obturator lymph node chain. The axial skeleton, as mentioned previously, is the most common site of distant metastases.

Table 23-8. TNM staging system for prostate cancer.

T: Primary tumor
   Tx Cannot be assessed
   T0 No evidence of primary tumor
   T1a Carcinoma in 5% or less of tissue resected; normal DRE
   T1b Carcinoma in more than 5% of tissue resected; normal DRE
   T1c Detected from elevated PSA alone; normal DRE
   T2a Tumor in ≤1/2 of one lobe
   T2b Tumor in >1/2 of one lobe
   T2c Tumor in both lobes
   T3a Extracapsular extension
   T3b Seminal vesicle involvement
   T4 Adjacent organ involvement
N: Regional lymph nodes
   Nx Cannot be assessed
   N0 No regional lymph node metastasis
   N1 Metastasis in one or more regional lymph nodes
M: Distant metastasis
   Mx Cannot be assessed
   M0 No distant metastasis
   M1a Metastasis to nonregional lymph node(s)
   M1b Metastasis to bone(s)
   M1c Metastasis to other site(s) with or without bone disease
DRE = digital rectal examination; PSA = prostate-specific antigen.

Treatment

A. Localized Disease

What constitutes the optimal form of treatment for patients with clinically localized cancers remains controversial. Treatment decisions are at present made on the basis of tumor grade and stage and the age and health of the patient. Although selected patients may be candidates for surveillance based on age or health and the presence of small-volume or well-differentiated cancers, most patients with an anticipated survival in excess of 10 years should be considered for treatment. Both radiation therapy and radical prostatectomy allow for acceptable levels of local control. The first large, prospective, randomized trial of watchful waiting compared with radical prostatectomy was reported recently. Six hundred ninety-five men were randomized and monitored for a median of 8.2 years. Radical prostatectomy reduced disease-specific mortality, overall mortality, and risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years was small, but the reductions in the risks of metastasis and local tumor progression were substantial. This trial accrued patients in Sweden between 1989 and 1999, so the patients enrolled likely had a greater burden of disease than is average for patients who are newly diagnosed in areas where PSA screening is common. Patients need to be advised of all treatment options (including surveillance) along with the particular benefits, risks, and limitations.

B. Radical Prostatectomy

In radical prostatectomy, the seminal vesicles, prostate, and ampullae of the vas deferens are removed. Refinements in technique have allowed maintenance of urinary continence in most patients and erectile function in selected patients. Radical prostatectomy can be performed via open retropubic surgery, transperineally, or laparoscopically, with or without the assistance of surgical robotics. Local recurrence is uncommon after radical prostatectomy, and its incidence is related to pathologic stage. Organ-confined cancers rarely recur. However, cancers found to be locally extensive (capsular penetration, seminal vesicle invasion) are associated with higher local (10–25%) and distant (20–50%) relapse rates.

Ideal candidates for the procedure include healthy patients with stages T1 and T2 prostatic cancers. Patients with advanced local tumors (T3 and T4) and those with lymph node metastases are rarely candidates for this procedure, although surgery is sometimes used in combination with hormonal therapy and postoperative radiation therapy for select high-risk patients.

Patients with advanced pathologic stage or positive surgical margins are at an increased risk for local and distant tumor relapse. Such patients are often considered candidates for adjuvant therapy (radiation for positive margins or androgen deprivation for lymph node metastases). Although adjuvant radiation seems to be associated with fewer local recurrences (0–5% with radiation versus 15–30% without), it has little or no impact on distant failure rates (30–35% with radiation versus 30–45% without).

C. Radiation Therapy

Radiation can be delivered by a variety of techniques including use of external beam radiotherapy and transperineal implantation of radioisotopes. Morbidity is limited, and the survival of patients with localized cancers (T1, T2, and selected T3) approaches 65% at 10 years. As with surgery, the likelihood of local failure correlates with technique and tumor stage. The likelihood of a positive prostatic biopsy more than 18 months after radiation varies between 20% and 60% in selected series. Patients with local recurrence are at

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an increased risk of cancer progression and cancer death compared with those who have negative biopsies. Ambiguous target definitions, inadequate radiation doses, and understaging of patients may be responsible for the failure noted in some series. Newer techniques of radiation (implantation, conformal therapy using three-dimensional reconstruction of CT-based tumor volumes, heavy particle, charged particle, and heavy charged particle) may improve local control rates. Three-dimensional conformal radiation delivers a higher dose because of improved targeting and appears to be associated with improved efficacy and a lower likelihood of adverse side effects compared with previous radiation techniques. As a result of improvements in imaging—most notably transrectal ultrasound—there has been a resurgence of interest in brachytherapy, the implantation of permanent or temporary radioactive sources (palladium, iodine, or iridium) into the prostate. Brachytherapy can be combined with external beam radiation in patients with higher-grade or higher-volume disease or as monotherapy in those with low-grade or low-volume malignancies.

D. Surveillance

A positive impact of localized prostatic cancer treatment with regard to survival has not been conclusively demonstrated. Surveillance alone may be an appropriate form of management for selected patients with prostatic cancer. However, many patients in such series are older and have very small and well-differentiated cancers. Because of profound stage migration due to the widespread use of serum PSA screening, patients with prostate cancer in heavily screened societies have cancers that are lower stage and grade and with lower serum PSA at diagnosis. Depending on the age and health of the patient, many of these very low-volume, low-grade cancers may never progress to clinical significance. So, careful surveillance of low-risk patients with serial PSA levels, rectal examination, and periodic repeat prostate biopsies to assess grade and extent of tumor is reasonable. The goal of surveillance is to recognize and treat patients with early evidence of progression effectively and to avoid treatment in patients who may never experience progression. End points for intervention in patients on surveillance regimens have not been clearly defined and surveillance regimens remain investigational.

E. Cryosurgery

Cryosurgery is a technique whereby liquid nitrogen is circulated through small hollow-core needles inserted into the prostate under ultrasound guidance. The freezing process results in tissue destruction. There has been a resurgence of interest in less invasive forms of therapy for localized prostate cancer as well as several recent technical innovations, including improved percutaneous techniques, expertise in transrectal ultrasound, improved cryotechnology, and better understanding of cryobiology. The positive biopsy rate after cryoablation ranges between 7% and 23%.

F. Locally and Regionally Advanced Disease

Prostatic cancers associated with minimal degrees of capsular penetration are candidates for standard irradiation or surgery. Those with locally extensive cancers, including those with seminal vesicle and bladder neck invasion, are at increased risk for both local and distant relapse despite conventional therapy. Currently, a variety of investigational regimens are being tested in an effort to improve local and distant relapse rates in such patients. Combination therapy (androgen deprivation combined with surgery or irradiation), newer forms of irradiation, and hormonal therapy alone are being tested in such patients, as are neoadjuvant and adjuvant chemotherapy. Neoadjuvant and adjuvant androgen deprivation therapy combined with external beam radiation therapy have demonstrated improved survival over external beam radiation therapy alone.

G. Metastatic Disease

Since death due to prostatic carcinoma is almost invariably a result of failure to control metastatic disease, research has emphasized efforts to improve control of distant disease. It is well known that most prostatic carcinomas are hormone dependent, and approximately 70–80% of men with metastatic prostatic carcinoma will respond to various forms of androgen deprivation. Testosterone, the major circulating androgen, is produced by Leydig cells in the testes (95%), with a smaller amount being produced by peripheral conversion of other steroids. Although 98% of serum testosterone is protein bound, free testosterone enters prostate cells and is converted to DHT, the major intracellular androgen. DHT binds a cytoplasmic receptor protein, and the complex moves to the cell nucleus, where it modulates transcription. Androgen deprivation may be induced at several levels along the pituitary-gonadal axis using a variety of methods or agents (Table 23-9). Use of LHRH agonists (leuprolide, goserelin)—drugs delivered in monthly or 3-monthly depot—has allowed induction of androgen deprivation without orchiectomy or administration of diethylstilbestrol. Presently, administration of LHRH agonists and orchiectomy are the most common forms of primary androgen blockade used. Because of its rapid onset of action, ketoconazole should be considered in patients with advanced prostatic cancer who present with spinal cord compression, bilateral ureteral obstruction, or disseminated intravascular coagulation. Although testosterone is the major circulating androgen, the adrenal gland secretes the androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Some investigators believe that suppressing both testicular and adrenal androgens will allow for a better initial and longer response than methods that inhibit production of only testicular androgens. Complete androgen blockade can be achieved by combining an antiandrogen with use of an LHRH agonist or orchiectomy. Nonsteroidal antiandrogen agents appear to act by competitively binding the receptor for DHT, the intracellular androgen responsible

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for prostatic cell growth and development. A meta-analysis of trials comparing the use of either an LHRH agonist or orchiectomy alone with the use of either in combination with an antiandrogen agent shows marginal (if any) benefit to the use of combination therapy. However, patients at risk of disease-related symptoms (bone pain, obstructive voiding symptoms) due to the initial elevation of serum testosterone that accompanies the use of an LHRH agonist should receive antiandrogens initially. Bisphosphonates are increasingly being used with metastatic bone disease.

Table 23-9. Androgen ablation for prostatic cancer.

Level Agent Dose Sequelae
Pituitary, hypothalamus Estrogens 1–3 mg daily Gynecomastia, hot flushes, thromboembolic disease, erectile dysfunction
LHRH agonists Monthly or 3-monthly depot injection Erectile dysfunction, hot flushes, gynecomastia, rarely anemia
Adrenal Ketoconazole 400 mg three times daily Adrenal insufficiency, nausea, rash, ataxia
Aminoglutethimide 250 mg four times daily Adrenal insufficiency, nausea, rash, ataxia
Corticosteroids Prednisone: 20–40 mg daily Gastrointestinal bleeding, fluid retention
Testis Orchiectomy   Gynecomastia, hot flushes, erectile dysfunction
Prostate cell Antiandrogens Flutamide: 250 mg three times dailyBicalutamide: 50 mg daily No erectile dysfunction when used alone; nausea, diarrhea
LHRH = luteinizing hormone-releasing hormone.

Docetaxel has recently been shown to improve survival in men with hormone-refractory prostate cancer. Docetaxel is the first cytotoxic chemotherapy agent to improve survival in patients with prostate cancer. Current research is underway combining docetaxel with hormonal therapy, radiation therapy, and surgery to find effective combinations for high-risk patients. Immune therapies are also under intense investigation and have shown promise for patients with advanced prostate cancer.

Bill-Axelson A et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352:1977.

Carroll PR et al: Third international conference on innovations and challenges in prostate cancer: prevention, detection and treatment. J Urol 2003;170:S3.

Guise TA et al: Role of bisphosphonates in prostate cancer bone metastases. Semin Oncol 2003;30:717.

Han M et al: Prostate-specific antigen and screening for prostate cancer. Med Clin North Am 2004;88:245.

Hernandez J et al: Diagnosis and treatment of prostate cancer. Med Clin North Am 2004;88:267.

Hernandez J et al: Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. Cancer 2004;101:894.

Higgins B et al: The Prostate Cancer Prevention Trial: current status. J Urol 2004;171(2 Pt 2):S15.

Hittelman AB et al: Update of staging and risk assessment for prostate cancer patients. Curr Opin Urol 2004;14:163.

Kattan MW et al: Algorithms for prostate-specific antigen recurrence after treatment of localized prostate cancer. Clin Prostate Cancer 2003;1:221.

Klotz LH et al: Active surveillance with selective delayed intervention for favorable risk prostate cancer: clinical experience and a 'number needed to treat' analysis. Can J Urol 2006; 13 (Suppl 1):48.

Meng MV et al: Treatment of patients with high risk localized prostate cancer: results from cancer of the prostate strategic urological research endeavor (CaPSURE). J Urol 2005;173: 1557.

Nelson JB et al: Prostate cancer: radical prostatectomy. Urol Clin North Am 2003;30:703.

Parnes HL et al: Prostate cancer chemoprevention agent development: the National Cancer Institute, Division of Cancer Prevention portfolio. J Urol 2004;171:S68.

Petrylak DP et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513.

Shinohara K: Prostate cancer: cryotherapy. Urol Clin North Am 2003;30:725.

Wilson SS et al: Screening for prostate cancer: current recommendations. Urol Clin North Am 2004;31:219.

Bladder Cancer

Essentials of Diagnosis

  • Irritative voiding symptoms.

  • Gross or microscopic hematuria.

  • Positive urinary cytology in most patients.

  • Filling defect within bladder noted on imaging.

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General Considerations

Bladder cancer is the second most common urologic cancer; it occurs more commonly in men than women (2.7:1), and the mean age of patients at diagnosis is 65 years. Cigarette smoking and exposure to industrial dyes or solvents are risk factors for the disease and account for approximately 60% and 15% of new cases, respectively.

Clinical Findings

A. Symptoms and Signs

Hematuria—gross or microscopic, chronic or intermittent—is the presenting symptom in 85–90% of patients with bladder cancer. Irritative voiding symptoms (urinary frequency and urgency) will occur in a small percentage of patients as a result of the location or size of the cancer. Most patients with bladder cancer will fail to have signs of the disease because of its superficial nature. Masses detected on bimanual examination may be present in patients with large-volume or deeply infiltrating cancers. Hepatomegaly or supraclavicular lymphadenopathy may be present in patients with metastatic disease, and lymphedema of the lower extremities may be present as a result of locally advanced cancers or metastases to pelvic lymph nodes.

B. Laboratory Findings

Urinalysis will reveal hematuria in the majority of cases. On occasion, it may be accompanied by pyuria. Azotemia may be present in a small number of cases associated with ureteral obstruction. Anemia may occasionally be due to chronic blood loss or to bone marrow metastases. Exfoliated cells from normal and abnormal urothelium can be readily detected in voided urine specimens. Cytology may be useful in detecting the disease at the time of initial presentation or to detect recurrence. Cytology is very sensitive in detecting cancers of higher grade and stage (80–90%) but less so in detecting superficial or well-differentiated lesions (50%). Sensitivity of detection using exfoliated cells may be enhanced by flow cytometry.

C. Imaging

Bladder cancers may be detected using intravenous urography, ultrasound, CT, or MRI where filling defects within the bladder are noted. However, the presence of cancer is confirmed by cystoscopy and biopsy, so imaging is useful primarily for evaluating the upper urinary tract and in staging the more advanced lesions.

D. Cystourethroscopy and Biopsy

The diagnosis and staging of bladder cancers are made by cystoscopy and transurethral resection. If cystoscopy—performed usually under local anesthesia—confirms the presence of bladder cancer, the patient is scheduled for transurethral resection under general or regional anesthesia. A careful bimanual examination is performed initially and at the end of the procedure, noting the size, position, and degree of fixation of a mass, if present. Any suspicious lesions are resected using electrocautery. Resection is carried down to the muscular elements of the bladder wall so as to allow complete staging. Random bladder and, on occasion, prostatic urethral biopsies are performed to detect occult disease elsewhere in the bladder and, therefore, identify patients at high risk of recurrence and progression.

Pathology & Selection of Treatment

Ninety-eight percent of primary bladder cancers are epithelial malignancies, with the majority being transitional cell carcinomas (90%). These latter cancers most often appear as papillary growths, but higher-grade lesions are often sessile and ulcerated. Grading is based on histologic appearance: size, pleomorphism, mitotic rate, and hyperchromatism. The frequency of recurrence and progression are strongly correlated with grade. Whereas progression may be noted in few grade I cancers (19–37%), it is common with poorly differentiated lesions (33–67%). Carcinoma in situ is recognizable as a flat, nonpapillary, anaplastic epithelium and may occur focally or diffusely, but it is most often found in association with papillary bladder cancers. Its presence identifies a patient at increased risk of recurrence and progression.

Adenocarcinomas and squamous cell cancers account for approximately 2% and 7%, respectively, of all bladder cancers detected in the United States. The latter is often associated with schistosomiasis, vesical calculi, or chronic catheter use.

Bladder cancer staging is based on the extent of bladder wall penetration and the presence of either regional or distant metastases. The TNM classification of the American Joint Cancer Committee for bladder cancer is shown in Table 23-10.

The natural history of bladder cancer is based on two separate but related processes: tumor recurrence and progression to higher-stage disease. Both are related to tumor grade and stage. At initial presentation, approximately 50–80% of bladder cancers will be superficial: Ta, Tis, or T1. Lymph node metastases and progression are uncommon in such patients when they are properly treated, and survival is excellent at 81%. Patients with superficial cancers (Ta, T1) are treated with complete transurethral resection and the selective use of intravesical chemotherapy. The latter is used to prevent or delay recurrence. Patients who present with large, high-grade, recurrent Ta lesions or T1 cancers and those with carcinoma in situ are good candidates for intravesical chemotherapy. Patients with more invasive (T2, T3) but still localized cancers are at risk of both nodal metastases and progression, and they require more aggressive surgery, irradiation, or the combination of chemotherapy and selective surgery or irradiation due to the much higher risk of progression compared to patients with lower-stage lesions. Patients with evidence of lymph node or distant metastases should undergo systemic chemotherapy initially.

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Table 23-10. TNM staging system for bladder cancer.

T: Primary tumor
   Tx Cannot be assessed
   T0 No evidence of primary tumor
   Tis Carcinoma in situ (CIS)
   Ta Noninvasive papillary carcinoma
   T1 Invasion into lamina propria
   T2a Invasion into superficial layer of muscularis propria
   T2b Invasion into deep layer of muscularis propria
   T3a Microscopic invasion into perivesical tissue
   T3b Macroscopic invasion into perivesical tissue
   T4a Invasion into adjacent organs
   T4b Invasion into pelvic sidewall
N: Regional lymph nodes
   Nx Cannot be assessed
   N0 No regional lymph node metastasis
   N1 Metastasis in a single lymph node 2 cm or less
   N2 Metastasis in a single lymph node > 2 cm and < 5 cm or multiple nodes none > 5 cm
   N3 Metastasis in lymph node > 5 cm
M: Distant metastasis
   Mx Cannot be assessed
   M0 No distant metastasis
   M1 Distant metastasis present

Treatment

A. Intravesical Chemotherapy

Immunotherapeutic or chemotherapeutic agents can be delivered directly into the bladder by a urethral catheter. They can be used to eradicate existing disease or to reduce the likelihood of recurrence in those who have undergone complete transurethral resection. Such therapy is more effective in the latter situation. Most agents are administered weekly for 6–12 weeks. The use of maintenance therapy after the initial induction regimen may be beneficial. Efficacy may be increased by prolonging contact time to 2 hours. Common agents include thiotepa, mitomycin, doxorubicin, and BCG, the latter being the most effective agent when compared with the others. BCG and mitomycin have similar efficacy in retarding disease progression and patient survival. Side effects of intravesical chemotherapy include irritative voiding symptoms and hemorrhagic cystitis. Systemic effects are rare. Patients who develop symptoms from BCG may require antituberculous therapy.

B. Surgical Treatment

Although transurethral resection is the initial form of treatment for all bladder cancers as it is diagnostic, allows for proper staging, and will control superficial cancers, muscle infiltrating cancers will require more aggressive treatment. Partial cystectomy may be indicated in patients with solitary lesions and those with cancers in a bladder diverticulum. Radical cystectomy entails removal of the bladder, prostate, seminal vesicles, and surrounding fat and peritoneal attachments in men and in women also the uterus, cervix, urethra, anterior vaginal vault, and usually the ovaries. Bilateral pelvic lymph node dissection is performed simultaneously.

Urinary diversion can be performed using a conduit of small or large bowel. However, continent forms of diversion have been developed that avoid the necessity of an external appliance and significantly improve quality of life for patients who are candidates.

C. Radiotherapy

External beam radiotherapy delivered in fractions over a 6- to 8-week period is generally well tolerated, but approximately 10–15% of patients will develop bladder, bowel, or rectal complications. Unfortunately, local recurrence is common after radiotherapy (30–70%). Increasingly, radiotherapy is being combined with systemic chemotherapy in an effort to improve local and distant relapse rates.

D. Chemotherapy

Fifteen percent of patients with newly diagnosed bladder cancer will present with metastatic disease, and 40% of those thought to have localized disease at the time of cystectomy or definitive radiotherapy will develop metastases usually within 2 years after the start of treatment. Cisplatin-based combination chemotherapy will result in partial or complete responses in 15–35% and 15–45% of patients, respectively.

Combination chemotherapy has been integrated into trials of surgery and radiotherapy. It has been used to decrease recurrence rates with either modality and in an attempt to preserve the bladder in those treated with radiation. Chemotherapy should be considered before surgery in those with bulky lesions or those suspected of having regional disease. Chemoradiation may be best suited for those with T2 or limited T3 disease without hydronephrosis. Alternatively, chemotherapy has been employed postoperatively in patients who have undergone cystectomy and have been found to be at high risk of recurrence. In current practice, adjuvant chemotherapy when indicated—ie, when the primary tumor invades perivesical fat or adjacent organs or when lymph nodes are found to have metastatic disease—is being offered mainly to patients being treated with radical cystectomy.

Carroll PR: Urothelial carcinoma: cancers of the bladder, ureter and renal pelvis. In: Smith's General Urology, 16th ed. Tanagho EA, McAninch JW (editors). McGraw-Hill, 2003.

Droller MJ: Primary care update on kidney and bladder cancer: a urologic perspective. Med Clin North Am 2004;88:309.

Kim HL et al: The current status of bladder preservation in the treatment of muscle invasive bladder cancer. J Urol 2000; 164(3 Part 1):627.

Krejci KG et al: Immunotherapy for urological malignancies. J Urol 2004;171(2 Pt 1):870.

Shelley MD et al: Intravesical bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2003;(3):CD003231.

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Cancers of the Ureter & Renal Pelvis

Cancers of the renal pelvis and ureter are rare and occur more commonly in smokers, in those with Balkan nephropathy, in those exposed to Thorotrast (a contrast agent with radioactive thorium in use until the 1960s), or in those with a long history of analgesic abuse. The majority are transitional cell carcinomas. Gross or microscopic hematuria occurs in most patients, and flank pain secondary to bleeding and obstruction occurs less commonly. Like primary bladder cancers, urinary cytology is often positive. The most common signs identified at the time of IVP or CT include an intraluminal filling defect, unilateral nonvisualization of the collecting system, and hydronephrosis. Ureteral and renal pelvic tumors must be differentiated from calculi, blood clots, papillary necrosis, or inflammatory or infectious lesions. On occasion, such lesions are accessible to direct biopsy, fulguration, or resection using a ureteroscope. Treatment is based on the site, size, depth of penetration, and number of tumors present. Most such cancers are excised with laparoscopic or open nephroureterectomy (renal pelvic and upper ureteral lesions) or segmental excision of the ureter (distal ureteral lesions). Endoscopic resection may be indicated in patients with limited renal function and in the management of focal, low-grade, upper tract cancers.

Primary Tumors of the Kidney

1. Renal Cell Carcinoma

Essentials of Diagnosis

  • Gross or microscopic hematuria.

  • Flank pain or mass in some patients.

  • Systemic symptoms such as fever, weight loss may be prominent.

  • Solid renal mass on imaging.

General Considerations

Renal cell carcinoma accounts for 2.6% of all adult cancers. In the United States in 2005, approximately 36,160 cases of renal cell carcinoma were diagnosed and 12,660 deaths resulted. Renal cell carcinoma has a peak incidence in the sixth decade of life and a male-to-female ratio of 2:1.

The cause is unknown. Cigarette smoking is the only significant environmental risk factor that has been identified. Familial settings for renal cell carcinoma have been identified (von Hippel-Lindau syndrome) as well as an association with dialysis-related acquired cystic disease, but sporadic tumors are far more common.

Table 23-11. TNM staging system for kidney cancer.

T: Primary tumor
   Tx Cannot be assessed
   T0 No evidence of primary tumor
   T1 Tumor 7 cm or less limited to kidney
   T1a Tumor 4 cm or less limited to kidney
   T1b Tumor more than 4 cm but not more than 7 cm limited to kidney
   T2 Tumor > 7 cm limited to kidney
   T3a Tumor invades adrenal gland or perinephric tissue
   T3b Tumor extends into renal vein or vena cava
   T3c Tumor extends into renal vein or vena cava above diaphragm
   T4 Tumor invades outside of Gerota's fascia
N: Regional lymph nodes
   Nx Cannot be assessed
   N0 No regional lymph node metastasis
   N1 Metastasis in a single lymph node
   N2 Metastasis in multiple nodes
M: Distant metastasis
   Mx Cannot be assessed
   M0 No distant metastasis
   M1 Distant metastasis present

Renal cell carcinoma originates from the proximal tubule cells. Various cell types (clear, granular, spindle) and histologic patterns (acinar, papillary, solid) are observed. However, cell type and histologic pattern do not affect treatment. The TNM classification of the American Joint Cancer Committee for kidney cancer is shown in Table 23-11.

Clinical Findings

A. Symptoms and Signs

Historically, 60% of patients presented with gross or microscopic hematuria. Flank pain or an abdominal mass was detected in approximately 30% of cases. The triad of flank pain, hematuria, and mass was found in only 10–15% of patients and is often a sign of advanced disease. Symptoms of metastatic disease (cough, bone pain) occur in 20–30% of patients at presentation. Because of the more widespread use of ultrasound and CT scanning for diverse indications, renal tumors are being detected incidentally in patients with no urologic symptoms.

B. Laboratory Findings

Hematuria is present in 60% of patients. Paraneoplastic syndromes are not uncommon in renal cell carcinoma. Erythrocytosis from increased erythropoietin production occurs in 5%, though anemia is far more common; hypercalcemia may be present in up to 10% of patients. Stauffer's syndrome is a reversible syndrome of hepatic dysfunction in the absence of metastatic disease.

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C. Imaging

Renal masses are often first detected by intravenous urography or CT scans. Further evaluation requires ultrasound to determine whether it is solid or cystic. CT scanning is the most valuable imaging test for renal cell carcinoma. It confirms the character of the mass and further stages the lesion with respect to regional lymph nodes, renal vein, or hepatic involvement. It also provides valuable information regarding the contralateral kidney (function, bilaterality of neoplasm). Chest radiographs exclude pulmonary metastases, and bone scans should be performed for large tumors and in patients with bone pain or elevated alkaline phosphatase levels. MRI and duplex Doppler ultrasonography are excellent methods of assessing for the presence and extent of tumor thrombus within the renal vein or vena cava in selected patients.

Differential Diagnosis

Solid lesions of the kidney are renal cell carcinoma until proved otherwise. Other solid masses include angiomyolipomas (fat density usually visible by CT), transitional cell cancers of the renal pelvis (more centrally located, involvement of the collecting system, positive urinary cytology reports), adrenal tumors (superoanterior to the kidney) and oncocytomas (indistinguishable from renal cell carcinoma preoperatively), and renal abscesses.

Treatment & Prognosis

Radical nephrectomy is the primary treatment for localized renal cell carcinoma. Patients with a single kidney, bilateral lesions, or significant medical renal disease should be considered for laparoscopic or open partial nephrectomy. Patients with a normal contralateral kidney and good renal function but a small cancer may be good candidates for partial nephrectomy as well. The use of radiofrequency or cryosurgical ablation is being studied. Tumors confined to the renal capsule (T1-T2) demonstrate 5-year disease-free survivals of 90–100%. Tumors extending beyond the renal capsule (T3 or T4) and node-positive tumors have 50–60% and 0–15% 5-year disease-free survivals, respectively.

No effective chemotherapy is available for metastatic renal cell carcinoma. Vinblastine is the single most effective agent, with short-term partial response rates of 15%. Bevacizumab can prolong time to progression in those with metastatic disease. Biologic response modifiers have received much attention, including interferon-α and interleukin-2. Partial response rates of 15–20% and 15–35%, respectively, have been reported. Responders tend to have lower tumor burdens, metastatic disease confined to the lung, and a high performance status. Patients with metastatic kidney cancer and good performance status who have resectable primary tumors should undergo cytoreductive nephrectomy if possible. Two randomized trials have shown a benefit to surgery followed by the use of systemic therapy—specifically, biologic response modifiers—compared with the use of systemic therapy alone.

Several new drugs, specifically, vascular endothelial growth factor (VEGF) and Raf-kinase inhibitors, have recently demonstrated effectiveness in patients with advanced kidney cancer. The drugs are oral agents, well tolerated, and active especially against clear cell carcinoma with ~40% response rates. The sequencing and combination of these agents, with and without cytokine therapy, is an active area of investigation.

One subgroup of metastatic patients has demonstrated long-term survival, namely, those with solitary resectable metastases. In this setting, radical nephrectomy with resection of the metastasis has resulted in 5-year disease-free survival rates of 15–30%. Bisphosphonates can be effective for metastatic bone disease.

Dhote R et al: Risk factors for adult renal cell carcinoma. Urol Clin North Am 2004;31:237.

Flanigan RC et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655.

Mickisch GH et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966.

Motzer RJ et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16.

Motzer RJ et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454.

Rini BI: New approaches in advanced renal cell carcinoma. Urol Oncol 2005;23:65.

Saika T et al: Long-term outcome of laparoscopic radical nephrectomy for pathologic T1 renal cell carcinoma. Urology 2003; 62:1018.

2. Other Primary Tumors of the Kidney

Oncocytomas account for 3–5% of renal tumors and are indistinguishable from renal cell carcinoma by all imaging modalities. The biologic potential of these lesions is not well defined. These tumors are seen in other organs, including the adrenals, the salivary glands, and the thyroid and parathyroid glands.

Angiomyolipomas are rare benign tumors composed of fat, smooth muscle, and blood vessels. They are most commonly seen in patients with tuberous sclerosis (often multiple and bilateral) or in young to middle-aged women. CT scanning may identify the fat component, which is diagnostic for angiomyolipoma. Asymptomatic lesions less than 5 cm in diameter usually do not require intervention.

Secondary Tumors of the Kidney

The kidney is not an infrequent site for metastatic disease. Of the solid tumors, the lung is the most common (20%), followed by breast (10%), stomach (10%), and

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the contralateral kidney (10%). Lymphoma, both Hodgkin's and non-Hodgkin's, may also involve the kidney, though it tends to be a diffusely infiltrative process resulting in renal enlargement rather than a discrete mass.

Primary Tumors of the Testis

Essentials of Diagnosis

  • Commonest neoplasm in men aged 20–35 years.

  • Typical presentation as a patient-identified painless nodule.

  • Orchiectomy necessary for diagnosis.

General Considerations

Malignant tumors of the testis are rare, with approximately two to three new cases per 100,000 males being reported in the United States each year. Ninety to 95 percent of all primary testicular tumors are germ cell tumors (seminoma and nonseminoma), while the remainder are nongerminal neoplasms (Leydig cell, Sertoli cell, gonadoblastoma). The lifetime probability of developing testicular cancer is 0.2% for an American white male. For the purposes of this review, we will consider only germ cell tumors. Survival in testicular cancer has improved dramatically in recent years as a result of the development and application of effective combination chemotherapy.

Testicular cancer is slightly more common on the right than on the left, which parallels the increased incidence of cryptorchism on the right side. One to 2 percent of primary testicular tumors are bilateral, and up to 50% of these men have a history of unilateral or bilateral cryptorchism. Primary bilateral testicular tumors may occur synchronously or asynchronously but tend to be of the same histology. Seminoma is the most common histologic finding in bilateral primary testicular tumors, while malignant lymphoma is the most common bilateral testicular tumor.

Although the cause of testicular cancer is unknown, both congenital and acquired factors have been associated with tumor development. Approximately 5% of testicular tumors develop in a patient with a history of cryptorchism, with seminoma being the most common. However, 5–10% of these tumors occur in the contralateral, normally descended testis. The relative risk of development of malignancy is highest for the intra-abdominal testis (1:20) and lower for the inguinal testis (1:80). Placement of the cryptorchid testis into the scrotum (orchiopexy) does not alter the malignant potential of the cryptorchid testis; however, it does facilitate examination and tumor detection.

In animal models, exogenous estrogen administration during pregnancy has been associated with an increased relative risk for testicular tumors ranging from 2.8 to 5.3. Other acquired factors such as trauma and infection-related testicular atrophy have been associated with testicular tumors; however, a causal relationship has not been established.

Histopathology & Clinical Staging

From a treatment standpoint, testicular carcinoma can be divided into two major categories: (1) nonseminomas, which include embryonal cell carcinomas (20%), teratomas (5%), choriocarcinomas (< 1%), and mixed cell types (40%), and (2) seminomas (35%). In a commonly used staging system for nonseminoma germ cell tumors, a stage A lesion is confined to the testis; stage B demonstrates regional lymph node involvement in the retroperitoneum; and stage C indicates distant metastasis. For seminoma, the M.D. Anderson system is commonly used. In this system, a stage I lesion is confined to the testis, a stage II lesion has spread to the retroperitoneal lymph nodes, and a stage III lesion has supradiaphragmatic nodal or visceral involvement. The TNM classification of the American Joint Cancer Committee for testis cancer is shown in Table 23-12.

Clinical Findings

A. Symptoms and Signs

The most common symptom of testicular cancer is painless enlargement of the testis. Sensations of heaviness are not unusual. Patients are usually the first to recognize an abnormality, yet the typical delay in seeking medical attention ranges from 3 to 6 months. Acute testicular pain resulting from intratesticular hemorrhage occurs in approximately 10% of cases. Ten percent of patients are asymptomatic at presentation, and 10% manifest symptoms relating to metastatic disease such as back pain (retroperitoneal metastases), cough (pulmonary metastases), or lower extremity edema (vena cava obstruction).

Table 23-12. TNM staging system for testicular cancer.

T: Primary tumor
   Tx Cannot be assessed
   T0 No evidence of primary tumor
   Tis Intratubular cancer (carcinoma in situ)
   T1 Limited to testis without vascular invasion
   T2 Invades beyond tunica albuginea or into epididymis, or limited to testis with vascular invasion
   T3 Invades spermatic cord
   T4 Invades scrotum
N: Regional lymph nodes
   Nx Cannot be assessed
   N0 No regional lymph node metastasis
   N1 Metastasis in a single lymph node 2 cm or less
   N2 Metastasis in a single lymph node > 2 cm and < 5 cm or multiple nodes none > 5 cm
   N3 Metastasis in lymph node > 5 cm
M: Distant metastasis
   Mx Cannot be assessed
   M0 No distant metastasis
   M1a Metastasis to nonregional lymph node(s) or lung(s)
   M1b Distant metastasis to sites other than nonregional lymph node(s) or lung(s)

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A testicular mass or diffuse enlargement of the testis is found in the majority of cases on physical examination. Secondary hydroceles may be present in 5–10% of cases. In advanced disease, supraclavicular adenopathy may be detected, and abdominal examination may palpate a retroperitoneal mass. Gynecomastia is seen in 5% of germ cell tumors.

B. Laboratory Findings

Several biochemical markers are important in the diagnosis and treatment of testicular carcinoma, including human chorionic gonadotropin (hCG), α-fetoprotein, and lactate dehydrogenase (LDH). α-Fetoprotein is never elevated in seminomas, and while hCG is occasionally elevated in seminomas, levels tend to be lower than those seen in nonseminomas. LDH may be elevated in either type of tumor. Liver function tests may be elevated in the presence of hepatic metastases, and anemia may be present in advanced disease. In patients with advanced disease who will receive chemotherapy, renal function is assessed with a 24-hour urine creatinine clearance.

C. Imaging

Scrotal ultrasound can readily determine whether the mass is intratesticular or extratesticular in origin. Once the diagnosis of testicular cancer has been established by inguinal orchiectomy, clinical staging of the disease is accomplished by chest, abdominal, and pelvic CT scanning.

Differential Diagnosis

An incorrect diagnosis is made at the initial examination in up to 25% of patients with testicular tumors. The differential diagnosis of scrotal masses has been discussed previously in this chapter. Scrotal ultrasonography should be performed if any uncertainty exists with respect to the diagnosis. Although most intratesticular masses are malignant, one benign lesion, an epidermoid cyst, may rarely be seen. Epidermoid cysts are usually very small benign nodules located just underneath the tunica albuginea; on occasion, however, they can be large.

Treatment

Inguinal exploration with early vascular control of the spermatic cord structures is the initial intervention to exclude neoplasm. If cancer cannot be excluded by examination of the testis, radical orchiectomy is warranted. Scrotal approaches and open testicular biopsies should be avoided. Further therapy is dependent upon the histology of the tumor as well as the clinical stage.

The 5-year disease-free survival rates for stage I and IIa (retroperitoneal disease < 10 cm in diameter) seminomas treated by radical orchiectomy and retroperitoneal irradiation are 98% and 92–94%, respectively. High-stage seminomas of stage IIb (> 10 cm retroperitoneal involvement) and stage III receive primary chemotherapy (etoposide and cisplatin or cisplatin, etoposide, and bleomycin). Ninety-five percent of patients with stage III disease will attain a complete response following orchiectomy and chemotherapy. Surgical resection of residual retroperitoneal masses is warranted only if the mass is larger than 3 cm in diameter, under which circumstances 40% will harbor residual carcinoma.

Up to 75% of stage A nonseminomas are cured by orchiectomy alone. Currently, such patients may be treated by modified retroperitoneal lymph node dissections designed to preserve the sympathetic innervation for ejaculation. Selected patients who meet specific criteria may be offered surveillance. These criteria are as follows: (1) tumor is confined within the tunica albuginea; (2) tumor does not demonstrate vascular invasion; (3) tumor markers normalize after orchiectomy; (4) radiographic imaging shows no evidence of disease (chest x-ray and CT); and (5) the patient is reliable. Patients most likely to experience relapse on a surveillance regimen include those with predominantly embryonal cancer and those with vascular or lymphatic invasion identified in the orchiectomy specimen. Surveillance should be considered an active process both by the physician and by the patient. Patients are followed monthly for the first 2 years and bimonthly in the third year. Tumor markers are obtained at each visit, and chest x-ray and CT scans are obtained every 3–4 months. Follow-up continues beyond the initial 3 years; however, the majority of relapses will occur within the first 8–10 months. With rare exceptions, patients who relapse can be cured by chemotherapy or surgery. The 5-year disease-free survival rate for patients with stage A disease ranges from 96% to 100%. For low-volume stage B disease, 90% 5-year disease-free survival is attainable.

Patients with bulky retroperitoneal disease (> 3 cm nodes) or metastatic nonseminomas are treated with primary cisplatin-based combination chemotherapy following orchiectomy (etoposide and cisplatin or cisplatin, etoposide, and bleomycin). If tumor markers normalize and a residual mass greater than 3 cm is apparent on imaging studies, resection of that mass is mandatory because 20% of the time it will harbor residual cancer and 40% of the time it will be teratoma. Even if patients have a complete response to chemotherapy, retroperitoneal lymphadenectomy is advocated by some as 10% of patients may harbor residual carcinoma and 10% may have teratoma in the retroperitoneum. If tumor markers fail to normalize following primary chemotherapy, salvage chemotherapy is required (cisplatin, etoposide, bleomycin, ifosfamide).

Prognosis

Patients with bulky retroperitoneal or disseminated disease treated with primary chemotherapy followed

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by surgery have a 5-year disease-free survival rate of 55–80%.

Heidenreich A et al: Organ-sparing surgery for malignant germ cell tumor of the testis. J Urol 2001;166:2161.

Huyghe E et al: Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170:5.

Jewett MA et al: Management of recurrence and follow-up strategies for patients with nonseminoma testis cancer. Urol Clin North Am 2003;30:819.

Patel MI et al: Management of recurrence and follow-up strategies for patients with seminoma and selected high-risk groups. Urol Clin North Am 2003;30:803.

Secondary Tumors of the Testis

Secondary tumors of the testis are rare. Lymphoma is the most common testis tumor in a patient over the age of 50 years and is the most common secondary neoplasm of the testis, accounting for 5% of all testicular tumors. It may be seen in three clinical settings: (1) as a late manifestation of widespread lymphoma, (2) as the initial presentation of clinically occult disease, and (3) as primary extranodal disease. Radical orchiectomy is indicated to make the diagnosis. Prognosis is related to the stage of disease.

Metastasis to the testis is rare. The most common primary site is the prostate, followed by the lung, gastrointestinal tract, melanoma, and kidney.

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