1023 Chapter 21 - The Lower Urinary Tract and Male Genital System Jonathan I. Epstein MD • Chapter 21 - The Lower Urinary Tract and Male Genital System – The Lower Urinary Tract • NORMAL – Ureters » CONGENITAL ANOMALIES » INFLAMMATIONS • Morphology. » TUMORS AND TUMOR-LIKE LESIONS » OBSTRUCTIVE LESIONS • Sclerosing Retroperitoneal Fibrosis. – Urinary Bladder » CONGENITAL ANOMALIES • Diverticula. • Exstrophy. • Miscellaneous Anomalies. » INFLAMMATIONS • Acute and Chronic Cystitis • Morphology. • Special Forms of Cystitis • Interstitial Cystitis (Hunner Ulcer). • Malacoplakia. • Polypoid Cystitis. » METAPLASTIC LESIONS • Cystitis Glandularis and Cystitis Cystica. • Squamous Metaplasia. • Nephrogenic Metaplasia (Nephrogenic Adenoma). » NEOPLASMS • Urothelial (Transitional Cell) Tumors • Morphology. • Other Types of Carcinoma • Epidemiology and Pathogenesis. • Clinical Course. • Mesenchymal Tumors • Benign. • Sarcomas. • Secondary Tumors » OBSTRUCTION • Morphology. – Urethra » INFLAMMATIONS » TUMORS AND TUMOR-LIKE LESIONS – The Male Genital Tract – Penis » CONGENITAL ANOMALIES • Hypospadias and Epispadias • Phimosis » INFLAMMATIONS » TUMORS • Benign Tumors • Condyloma Acuminatum • Morphology. • Malignant Tumors • Carcinoma in Situ • Invasive Carcinoma • Morphology. • Clinical Course. – Testis and Epididymis » CONGENITAL ANOMALIES • Cryptorchidism • Morphology. » REGRESSIVE CHANGES • Atrophy • Findings Associated with Decreased Fertility » INFLAMMATIONS • Non-Specific Epididymitis and Orchitis • Morphology. • Granulomatous (Autoimmune) Orchitis • Specific Inflammations • Gonorrhea • Mumps • Tuberculosis • Syphilis » VASCULAR DISTURBANCES • Torsion • Morphology. • Spermatic Cord and Paratesticular Tumors » TESTICULAR TUMORS • Germ Cell Tumors • Classification and Histogenesis. • Pathogenesis • Seminoma • Morphology. • Spermatocytic Seminoma • Morphology. • Embryonal Carcinoma • Morphology. • Yolk Sac Tumor • Morphology. • Choriocarcinoma • Morphology. • Teratoma • Morphology. • Mixed Tumors • Clinical Features of Testicular Tumors. • Tumors of Sex Cord-Gonadal Stroma • Leydig (Interstitial) Cell Tumors • Morphology. • Sertoli Cell Tumors (Androblastoma) • Morphology. • Gonadoblastoma • Testicular Lymphoma » MISCELLANEOUS LESIONS OF THE TUNICA VAGINALIS – Prostate » INFLAMMATIONS • Morphology. » BENIGN ENLARGEMENT • Nodular Hyperplasia (Benign Prostatic Hyperplasia) • Incidence. • Etiology and Pathogenesis. • Morphology. • Clinical Course. » TUMORS • Adenocarcinoma • Incidence. • Etiology. • Morphology. • Grading and Staging. • Clinical Course. • Miscellaneous Tumors and Tumor-Like Conditions 1024 The Lower Urinary Tract NORMAL Despite differing embryonic origins, the various components of the lower urinary tract come to have many morphologic similarities. The renal pelves, ureters, bladder, and urethra (except for its terminal portion) are lined by a special form of transitional epithelium (urothelium) that is two to three cells thick in the pelvis, three to five cells thick in the ureters, and three to seven cells thick in the bladder. The surface layer consists of large, flattened "umbrella cells" that cover several underlying cells. The umbrella cells have a trilaminar asymmetric unit membrane and possess apical plaques composed of specific proteins called uroplakins. Toward the basal layer, the cells become smaller or more cylindrical (particularly in contracted bladders), but they are capable of some flattening when the underlying wall is stretched. This epithelium rests on a well- developed basement membrane, beneath which there is a lamina propria. The lamina propria in the urinary bladder contains wisps of smooth muscle that form a discontinuous muscularis mucosae. It is important to differentiate the muscularis mucosae from the deeper well-defined larger muscle bundles of the detrusor muscle (muscularis propria), since bladder cancers are staged on the basis of invasion of the latter. The bladder musculature is capable of great thickening if there is obstruction to the flow of urine. Several variants of the normal epithelial patterns may be encountered. Nests of urothelium or inbudding of the surface epithelium may be found occasionally in the mucosa lamina propria; these are referred to as Brunn nests. The ureters lie throughout their course in a retroperitoneal position. Retroperitoneal tumors or fibrosis may trap the ureters in neoplastic or dense, fibrous tissue, sometimes obstructing them. As ureters enter the pelvis, they pass anterior to either the common iliac or the external iliac artery. In the female pelvis, they lie close to the uterine arteries and are therefore vulnerable to injury in operations on the female genital tract. There are three points of slight narrowing: at the ureteropelvic junction, where they enter the bladder, and where they cross the iliac vessels, all providing loci where renal calculi may become impacted when they pass from the kidney to the bladder. As the ureters enter the bladder, they pursue an oblique course, terminating in a slitlike orifice. The obliquity of this intramural segment of the ureteral orifice permits the enclosing bladder musculature to act like a sphincteric valve, blocking the upward reflux of urine even in the presence of marked distention of the urinary bladder. As discussed in Chapter 20 , a defect in the intravesical portion of the ureter leads to vesicoureteral reflux. The orifices of the ureters demarcate an area at the base of the bladder known as the trigone. In women, the trigone is frequently covered by glycogenated squamous epithelium, a normal finding, not metaplasia resulting from injury. The close relationship of the female genital tract to the bladder makes possible the spread of disease from one tract to the other. In middle-aged and elderly women, relaxation of pelvic support leads to prolapse (descent) of the uterus, pulling with it the floor of the bladder. In this fashion, the bladder protrudes into the vagina, creating a pouch (cystocele) that fails to empty readily with micturition. In men, the seminal vesicles and prostate have similar close relationships, being situated just posterior and inferior to the neck of the bladder. Thus, enlargement of the prostate, so common in middle to later life, constitutes an important cause of urinary tract obstruction. In the subsequent sections, we discuss the major pathologic lesions in the ureters, urinary bladder, and urethra separately.  Ureters CONGENITAL ANOMALIES Congenital anomalies of the ureters occur in about 2% or 3% of all autopsies. Although most have little clinical significance, certain anomalies may contribute to obstruction to the flow of urine and thus cause clinical disease. Anomalies of the ureterovesical junction, potentiating reflux, are discussed with pyelonephritis in Chapter 20 . Double ureters (derived from a double or split ureteral bud) are almost invariably associated either with totally distinct double renal pelves or with the anomalous development of a large kidney having a partially bifid pelvis terminating in separate ureters. Double ureters may pursue separate courses to the bladder but commonly are joined within the bladder wall and drain through a single ureteral orifice. The majority of double ureters are unilateral and of no clinical significance. Ureteropelvic junction obstruction, a congenital disorder, results in hydronephrosis. It usually presents in infants or children, much more commonly in boys, usually in the left ureter. However, it is bilateral in 20% of cases and may be associated with other congenital anomalies. It is the most common cause of hydronephrosis in infants and children. In adults, ureteropelvic junction obstruction is more common in women and is most often unilateral. There is agenesis of the kidney on the opposite side in a significant number of cases, probably resulting from obstructive lesions in utero. Diverticula, saccular outpouchings of the ureteral wall, are uncommon lesions that are usually asymptomatic and found incidentally on imaging studies. They appear as congenital or acquired defects and are of importance as pockets of stasis and secondary infections. Dilation (hydroureter), elongation, and tortuosity of the ureters may occur as congenital anomalies or as acquired defects. Congenital hydroureter is thought to reflect some neurogenic defect in the innervation of the ureteral musculature. Massive enlargement of the ureter is known as megaloureter and is probably due to a functional defect of ureteral muscle. Hydronephrosis and decreased renal 1025 function results if the lesion goes untreated. These anomalies are sometimes associated with some congenital defect of the kidney. INFLAMMATIONS Ureteritis may develop as one component of urinary tract infections. The morphologic changes are entirely nonspecific. Only infrequently does such ureteritis make a significant contribution to the clinical problem. Persistence of infection or repeated acute exacerbations may give rise to chronic inflammatory changes within the ureters. Morphology. In certain cases of long-standing chronic ureteritis, specialized reaction patterns are sometimes observed. The accumulation or aggregation of lymphocytes in the subepithelial region may cause slight elevations of the mucosa and produce a fine granular mucosal surface (ureteritis follicularis). At other times, the mucosa may become sprinkled with fine cysts varying in diameter from 1 to 5 mm (ureteritis cystica). These changes are also found in the bladder (described in greater detail later, in the section on the urinary bladder). The cysts may aggregate to form small, grapelike clusters ( Fig. 21-1 ). Histologic sections through such cysts demonstrate a lining of modified transitional epithelium with some flattening of the superficial layer of cells. TUMORS AND TUMOR-LIKE LESIONS Primary neoplasia of the ureter is rare. Small benign tumors of the ureter are generally of mesenchymal origin. The two most common are fibroepithelial polyps and leiomyomas. The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass projecting into the lumen. The lesion occurs more commonly in the ureters (left more often than right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose, vascularized connective tissue mass lying beneath the mucosa. Primary malignant tumors of the ureter follow patterns similar to those arising in the renal pelvis, calyces, and bladder, and the majority are transitional cell carcinomas ( Fig. 21-2 ). They Figure 21-1 Opened ureters showing ureteritis cystica. Note the smooth cysts projecting from the mucosa. Figure 21-2 Papillary transitional cell carcinoma extensively involving the ureter. (Courtesy of Dr. Cristina Magi-Galluzzi, The Johns Hopkins Hospital, Baltimore, MD.) cause obstruction of the ureteral lumen and are found most frequently during the sixth and seventh decades of life. They are sometimes multiple and occasionally occur concurrently with similar neoplasms in the bladder or renal pelvis. OBSTRUCTIVE LESIONS A great variety of pathologic lesions may obstruct the ureters and give rise to hydroureter, hydronephrosis, and sometimes pyelonephritis ( Chapter 20 ). Obviously, it is not the ureteral dilation that is of significance in these cases, but the consequent involvement of the kidneys. The more important causes, divided into those of intrinsic and those of extrinsic origin, are cited in Table 21-1 . Unilateral obstruction TABLE 21-1 -- Major Causes of Ureteral Obstruction Intrinsic Calculi Of renal origin, rarely more than 5 mm in diameter Larger renal stones cannot enter ureters Impact at loci of ureteral narrowing—ureteropelvic junction, where ureters cross iliac vessels, and where they enter bladder— and cause excruciating "renal colic" Strictures Congenital or acquired (inflammations) Tumors Transitional cell carcinomas arising in ureters Rarely, benign tumors or fibroepithelial polyps Blood clots Massive hematuria from renal calculi, tumors, or papillary necrosis Neurogenic Interruption of the neural pathways to the bladder Extrinsic Pregnancy Physiologic relaxation of smooth muscle or pressure on ureters at pelvic brim from enlarging fundus Periureteral Salpingitis, diverticulitis, peritonitis, sclerosing retroperitoneal inflammation fibrosis Endometriosis With pelvic lesions, followed by scarring Tumors Cancers of the rectum, bladder, prostate, ovaries, uterus, cervix, lymphomas, sarcomas 1026 typically results from proximal causes, whereas bilateral obstruction arises from distal causes, such as nodular hyperplasia of the prostate. Only sclerosing retroperitoneal fibrosis is discussed further. Sclerosing Retroperitoneal Fibrosis. This refers to an uncommon cause of ureteral narrowing or obstruction characterized by a fibrous proliferative inflammatory process encasing the retroperitoneal structures and causing hydronephrosis. The disorder occurs in middle to late age. In some cases, specific causes can be identified, such as drugs (ergot derivatives, β-adrenergic blockers), adjacent inflammatory conditions (vasculitis, diverticulitis, Crohn disease), or malignant disease (lymphomas, urinary tract carcinomas). However, 70% of cases have no obvious cause and are considered primary or idiopathic (Ormond disease). Several cases have been reported with similar fibrotic changes in other sites (referred to as mediastinal fibrosis, sclerosing cholangitis, and Riedel fibrosing thyroiditis), suggesting that the disorder is systemic in distribution but preferentially involves the retroperitoneum. Thus, an autoimmune reaction, sometimes triggered by drugs, has been proposed. On microscopic examination, the inflammatory fibrosis is marked by a prominent inflammatory infiltrate of lymphocytes, often with germinal centers, plasma cells, and eosinophils. Sometimes, foci of fat necrosis and granulomatous inflammation are seen in and about the fibrosis. Urinary Bladder Diseases of the bladder, particularly inflammation (cystitis), constitute an important source of clinical signs and symptoms. Usually, however, these disorders are more disabling than lethal. Cystitis is particularly common in young women of reproductive age and in older age groups of both sexes. Tumors of the bladder are an important source of both morbidity and mortality. CONGENITAL ANOMALIES Diverticula. A bladder or vesical diverticulum consists of a pouchlike eversion or evagination of the bladder wall. Diverticula may arise as congenital defects but more commonly are acquired lesions from persistent urethral obstruction. Congenital diverticula may be due to a focal failure of development of the normal musculature or to some urinary tract obstruction during fetal development. Acquired diverticula are most often seen with prostatic enlargement (hyperplasia or neoplasia), producing obstruction to urine outflow and marked muscle thickening of the bladder wall. The increased intravesical pressure causes outpouching of the bladder wall and the formation of diverticula. They are frequently multiple and have narrow necks located between the interweaving hypertrophied muscle bundles. In both the congenital and acquired forms, the diverticulum usually consists of a round to ovoid, saclike pouch that varies from less than 1 cm to 5 to 10 cm in diameter. Although most diverticula are small and asymptomatic, they may be clinically significant, as they constitute sites of urinary stasis and predispose to infection and the formation of bladder calculi. They may also predispose to vesicoureteral reflux as a result of impingement on the ureter. Rarely, carcinomas may arise in bladder diverticuli. When invasive cancers arise in diverticula, they tend to be more advanced in stage as a result of diverticula's thin or absent muscle wall. Exstrophy. Exstrophy of the bladder implies the presence of a developmental failure in the anterior wall of the abdomen and in the bladder, so that the bladder either communicates directly through a large defect with the surface of the body or lies as an opened sac ( Fig. 21-3 ). These lesions are amenable to surgical correction, and long-term survival is possible. The exposed bladder mucosa may undergo colonic glandular metaplasia and is subject to the development of infections that often spread to upper levels of the urinary system. In the course of persistent chronic infections, the mucosa often becomes converted into an ulcerated surface of granulation tissue, and the preserved marginal epithelium becomes transformed into a stratified squamous type. There is an increased tendency toward the development of carcinoma later in life, mostly adenocarcinoma of the colon. Patients also have an increased risk of adenocarcinoma arising from the bladder remnant. Miscellaneous Anomalies. Vesicoureteral reflux is the most common and serious anomaly. As a major contributor to renal infection and scarring, it was discussed earlier in Chapter 20 in the consideration of pyelonephritis. Abnormal connections between the bladder and the vagina, rectum, or uterus may create congenital fistulas. Rarely, the urachus may remain patent in part or in whole (persistent urachus). When it is totally patent, a fistulous urinary tract is created that connects the bladder with the umbilicus. At times, the umbilical end or the bladder end remains patent, while the central region is obliterated. A sequestered umbilical epithelial rest or bladder diverticulum is formed that may provide a site for the development of infection. At other times, only the central region of the urachus persists, giving rise to urachal cysts, lined by either transitional or metaplastic epithelium. Carcinomas, mostly glandular tumors resembling colonic adenocarcinomas, may arise in such cysts. These account for only a minority of all bladder cancers (0.1% to 0.3%) but 20% to 40% of bladder adenocarcinomas. Figure 21-3 Exstrophy of the bladder in a newborn boy. The tied umbilical cord is seen above the hyperemic mucosa of the everted bladder. Below is an incompletely formed penis with marked epispadias. (Courtesy of Dr. John Gearhart, The Johns Hopkins Hospital, Baltimore, MD.) 1027 INFLAMMATIONS Acute and Chronic Cystitis The pathogenesis of cystitis and the common bacterial etiologic agents are discussed in Chapter 20 in the consideration of urinary tract infections. As was emphasized earlier, bacterial pyelonephritis is frequently preceded by infection of the urinary bladder, with retrograde spread of microorganisms into the kidneys and their collecting systems. The common etiologic agents of cystitis are the coliforms: Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter. Women are more likely to develop cystitis as a result of their shorter urethras. Tuberculous cystitis is almost always a sequel to renal tuberculosis. Candida albicans (Monilia) and, much less often, cryptococcal agents cause cystitis, particularly in immunosuppressed patients or those receiving long-term antibiotics. Schistosomiasis (Schistosoma haematobium) is rare in the United States but is common in certain Middle Eastern countries, notably Egypt. Viruses (e.g., adenovirus), Chlamydia, and Mycoplasma may also be causes of cystitis. Predisposing factors include bladder calculi, urinary obstruction, diabetes mellitus, instrumentation, and immune deficiency. Patients receiving cytotoxic antitumor drugs, such as cyclophosphamide, sometimes develop hemorrhagic cystitis. Finally, radiation of the bladder region gives rise to radiation cystitis. Morphology. Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the bladder. In gross appearance, there is hyperemia of the mucosa, sometimes associated with exudate. When there is a hemorrhagic component, the cystitis is designated hemorrhagic cystitis. This form of cystitis sometimes follows radiation injury or antitumor chemotherapy and is often accompanied by epithelial atypia. Adenovirus infection also causes a hemorrhagic cystitis. The accumulation of large amounts of suppurative exudate may merit the designation of suppurative cystitis. When there is ulceration of large areas of the mucosa, or sometimes the entire bladder mucosa, this is known as ulcerative cystitis. Persistence of the infection leads to chronic cystitis, which differs from the acute form only in the character of the inflammatory infiltrate. There is more extreme heaping up of the epithelium with the formation of a red, friable, granular, sometimes ulcerated surface. Chronicity of the infection gives rise to fibrous thickening in the muscularis propria and consequent thickening and inelasticity of the bladder wall. Histologic variants include follicular cystitis, characterized by the aggregation of lymphocytes into lymphoid follicles within the bladder mucosa and underlying wall, and eosinophilic cystitis, manifested by infiltration with submucosal eosinophils together with fibrosis and occasionally giant cells. Most cases of eosinophilic cystitis represent nonspecific subacute inflammation, although, rarely, these lesions are manifestations of a systemic allergic disorder. The ubiquitous presence of mild chronic inflammation in the bladder unaccompanied by clinical symptoms should not be glorified with the diagnosis of chronic cystitis. All forms of clinical cystitis are characterized by a triad of symptoms: (1) frequency, which in acute cases may necessitate urination every 15 to 20 minutes; (2) lower abdominal pain localized over the bladder region or in the suprapubic region; and (3) dysuria—pain or burning on urination. Associated with these localized changes, there may be systemic signs of inflammation such as elevation of temperature, chills, and general malaise. In the usual case, the bladder infection does not give rise to such a constitutional reaction. The local symptoms of cystitis may be disturbing, but these infections are also important as antecedents to pyelonephritis. Cystitis is sometimes a secondary complication of some underlying disorder such as prostatic enlargement, cystocele of the bladder, calculi, or tumors. These primary diseases must be corrected before the cystitis can be relieved. Special Forms of Cystitis Several special variants of cystitis are distinctive by either their morphologic appearance or their causation. Interstitial Cystitis (Hunner Ulcer). This is a persistent, painful form of chronic cystitis occurring most frequently in women and associated with inflammation and fibrosis of all layers of the bladder wall. It is characterized clinically by intermittent, often severe, suprapubic pain, urinary frequency, urgency, hematuria, and dysuria without evidence of bacterial infection, and cystoscopic findings of fissures and punctate hemorrhages (glomerulations) in the bladder mucosa after luminal distention. Some but not all patients exhibit morphologic features of chronic mucosal ulcers (Hunner ulcers), which is termed the late (classic, ulcerative) phase. Inflammatory cells and granulation tissue may involve the mucosa, lamina propria, and muscularis, and mast cells may be particularly prominent. In the early (nonclassic, nonulcerative) form of interstitial cystitis, recent submucosal hemorrhages are noted. Although mast cells are characteristic of this disease, there is no uniformity in the literature as to their specificity and diagnostic utility. The major role of biopsy is not to specifically diagnose the disease as much as it is to rule out flat carcinoma in situ, which may clinically mimic interstitial cystitis. The condition is of unknown etiology but is thought by some to be of autoimmune origin, particularly because it is sometimes associated with lupus erythematosus and other autoimmune disorders. Malacoplakia. This designation refers to a peculiar pattern of vesical inflammatory reaction characterized macroscopically by soft, yellow, slightly raised mucosal plaques 3 to 4 cm in diameter ( Fig. 21-4 ) and histologically by infiltration with large, foamy macrophages with occasional multinucleate giant cells and interspersed lymphocytes.  The macrophages have an abundant granular cytoplasm. The granularity is periodic acid- Schiff positive and due to phagosomes stuffed with particulate and membranous debris of bacterial origin. In addition, laminated mineralized concretions resulting from deposition of calcium in enlarged lysosomes, known as Michaelis-Gutmann bodies, are typically present, both within the macrophages and between cells ( Fig. 21-5 ). Similar lesions have been described in the colon, lungs, bones, kidneys, prostate, and epididymis. Malacoplakia is clearly related to chronic bacterial infection, mostly by E. coli or occasionally Proteus species. It occurs with increased frequency in immunosuppressed transplant recipients. The unusual-appearing macrophages and giant phagosomes point to defects in phagocytic or degradative 1028 Figure 21-4 Cystitis with malacoplakia of bladder showing inflammatory exudate and broad, flat plaques. function of macrophages such that phagosomes become overloaded with undigested bacterial products. Polypoid Cystitis. Polypoid cystitis is an inflammatory condition resulting from irritation to the bladder mucosa. Although indwelling catheters are the most commonly cited culprits, any injurious agent may give rise to this lesion. The urothelium is thrown into broad, bulbous, polypoid projections as a result of marked submucosal edema. Polypoid cystitis may be confused with papillary urothelial carcinoma both clinically and histologically. METAPLASTIC LESIONS Cystitis Glandularis and Cystitis Cystica. These terms refer to common lesions of the urinary bladder in which nests Figure 21-5 Malacoplakia, PAS stain. Note the large macrophages with granular PAS-positive cytoplasm and several dense, round Michaelis-Gutmann bodies surrounded by artifactual cleared holes in the upper middle field. of transitional epithelium (Brunn nests) grow downward into the lamina propria and undergo transformation of their central epithelial cells into cuboidal or columnar epithelium lining (cystitis glandularis) or cystic spaces lined by urothelium (cystitis cystica). As the two processes often coexist, the condition is typically referred to as cystitis cystica et glandularis. In a variant of cystitis glandularis, goblet cells are present, and the epithelium resembles intestinal mucosa (intestinal or colonic metaplasia). Both variants are common microscopic incidental findings in relatively normal bladders. In contrast to earlier reports, lesions exhibiting extensive intestinal metaplasia have recently been shown not to be associated with an increased risk for the development of adenocarcinoma. In cystitis cystica, the cysts are usually 0.1 to 1 cm in diameter, filled with clear fluid, and lined by cuboidal or urothelial cells. As was noted, similar cysts occur in the pelvis and ureter (ureteritis and pyelitis cystica). Squamous Metaplasia. As a response to injury, the urothelium often converts to squamous epithelium, which is a more durable lining. This contrasts with the normal finding of glycogenated squamous epithelium commonly found in women at the trigone. Nephrogenic Metaplasia (Nephrogenic Adenoma). Nephrogenic metaplasia also represents a reaction of the urothelium to injury.  The overlying urothelium may be focally replaced by cuboidal epithelium, which can assume a papillary growth pattern. In addition, a tubular proliferation in the underlying lamina propria and superficial detrusor muscle may produce lesions that histologically mimic a carcinoma. Although typically less than a centimeter in diameter, they may be sizable, and thus, they may also clinically resemble cancer. NEOPLASMS Neoplasms of the bladder pose biologic and clinical challenges. Despite significant inroads into their origins and improved methods of diagnosis and treatment, they continue to exact a high toll in morbidity and mortality. The incidence of bladder epithelial tumors in the United States has been steadily increasing during the past years and is now more than 57,000 new cases annually. Despite improvements in detection and management of these neoplasms, the death toll remains at about 12,000 annually because the increased prevalence offsets such gains as have been made. About 95% of bladder tumors are of epithelial origin, the remainder being mesenchymal tumors ( Table 21-2 ). Most epithelial tumors are composed of urothelial (transitional) type cells and are thus interchangeably called urothelial or transitional tumors, but squamous and glandular carcinomas also occur. Here, we discuss the urothelial cell tumors in some detail and only touch on the others. Urothelial (Transitional Cell) Tumors These represent about 90% of all bladder tumors and run the gamut from small, benign lesions that might never recur to aggressive cancers associated with a high risk of death. Many of these tumors are multifocal at presentation. Although most commonly seen in the bladder, any of the lesions 1029 TABLE 21-2 -- Tumors of the Urinary Bladder Urothelial (transitional cell) tumors Inverted papilloma Papilloma (exophytic) Urothelial tumors of low malignant potential Papillary urothelial carcinoma Carcinoma in situ Squamous cell carcinoma Mixed carcinoma Adenocarcinoma Small cell carcinoma Sarcomas described below may be seen at any site where there is urothelium, from the renal pelvis to the distal urethra. There are two distinct precursor lesions to invasive urothelial carcinoma. The more common are noninvasive papillary tumors, which appear to arise from papillary urothelial hyperplasia. These lesions demonstrate a range of atypia, and several grading systems exist to reflect their biologic behavior. The other precursor lesion is flat urothelial carcinoma, which is simply referred to as carcinoma in situ (CIS). This lesion is by definition high grade and hence not assigned a grade. In about half the patients with invasive bladder cancer, at the time of presentation the tumor has already invaded the bladder wall, and there is no associated precursor lesion. In these cases, it is presumed that the precursor lesion has been destroyed by the high-grade invasive component, which typically appears as a large mass that is often ulcerated. Although invasion into the lamina propria worsens the prognosis, the major decrease in survival is associated with tumor invading the muscularis propria (detrusor muscle). Once muscularis propria invasion occurs, there is a 50% 5-year mortality rate. Table 21-3 lists two of many systems of grading these tumors.    The World Health Organization (WHO) 1973 classification grades tumors into a rare totally benign papilloma and three grades of transitional cell carcinoma (grades I, II, and III). A more recent classification, based on a consensus TABLE 21-3 -- Grading of Urothelial (Transitional Cell) Tumors WHO/ISUP Grades * Urothelial papilloma Urothelial neoplasm of low malignant potential Papillary urothelial carcinoma, low grade Papillary urothelial carcinoma, high grade WHO Grades † Urothelial papilloma Urothelial neoplasm of low malignant potential Papillary urothelial carcinoma, Grade 1 Papillary urothelial carcinoma, Grade 2 Papillary urothelial carcinoma, Grade 3 WHO, World Health Organization; ISUP, International Society of Urological Pathology. *Adopted as the WHO System in 2004. †The 1973 WHO grades. Figure 21-6 Four morphologic patterns of bladder tumors. reached at a conference by the International Society of Urological Pathology (ISUP) in 1998, recognizes a rare benign papilloma, a group of papillary urothelial neoplasms of low malignant potential, and two grades of carcinoma (low and high grade). This system was adopted by the WHO in 2004. Morphology. The gross patterns of urothelial cell tumors vary from purely papillary to nodular or flat. The tumors may also be invasive or noninvasive ( Fig. 21-6 ). Papillary lesions appear as red, elevated excrescences varying in size from less than 1 cm in diameter to large masses up to 5 cm in diameter ( Fig. 21-7 ). Multicentric origins may produce separate tumors. As was noted, the histologic changes encompass a spectrum from benign papilloma to highly aggressive anaplastic cancers. Overall, the majority of papillary tumors are low grade. Most arise from the lateral or posterior walls at the bladder base. Figure 21-7 Cross-section of bladder with upper section showing a large papillary tumor. The lower section demonstrates multifocal smaller papillary neoplasms. (Courtesy of Dr. Fred Gilkey, Sinai Hospital, Baltimore, MD.) 1030 Figure 21-8 Papilloma consisting of small papillary fronds lined by normal-appearing urothelium. Papillomas represent 1% or fewer of bladder tumors, most commonly seen in younger patients. The tumors usually arise singly as small (0.5 to 2.0 cm), delicate, structures, superficially attached to the mucosa by a stalk. The individual finger-like papillae have a central core of loose fibrovascular tissue covered by transitional epithelial cells that are histologically identical to normal urothelium ( Fig. 21-8 ). True recurrences rarely if ever occur. In contrast to the above described exophytic papilloma, inverted papillomas are benign lesions consisting of interanastomosing cords of cytologically bland urothelium extending down into the lamina propria.  Papillary urothelial neoplasms of low malignant potential (PUNLMP) share many histologic features with papilloma, the only differences being either thicker urothelium or diffuse nuclear enlargement in PUNLMP. Mitotic figures are rare. At cystoscopy, PUNLMP tend to be larger than papillomas and may be indistinguishable from low- and high-grade papillary cancers. PUNLMP may recur with the same morphology, are not associated with invasion, and only rarely recur as higher-grade tumors associated with invasion and progression. Low-grade papillary urothelial carcinomas are characterized by an orderly appearance both architecturally and cytologically. The cells are evenly spaced (i.e., maintain polarity) and cohesive. There is minimal but definite evidence of nuclear atypia consisting of scattered hyperchromatic nuclei, infrequent mitotic figures predominantly towards the base, and mild variation in nuclear size and shape ( Fig. 21-9 ). Low-grade cancers can recur and, although infrequent, can invade. Only rarely do these tumors pose a threat to the patient's life. High-grade papillary urothelial cancers contain cells that may be dyscohesive and have large hyperchromatic nuclei. Some of the tumor cells show frank anaplasia ( Fig. 21-10 ). Mitotic figures, including atypical ones, are frequent. Architecturally, there is disarray with loss of polarity. These tumors have a much higher incidence of invasion into the muscular layer, a higher risk of progression than low-grade lesions, and significant metastatic potential. In most analyses, less than 10% of low-grade cancers invade, but as many as 80% of high-grade Figure 21-9 Low-grade papillary urothelial carcinoma with an overall orderly appearance, a thicker lining than papilloma, and scattered hyperchromatic nuclei and mitotic figures (arrows). papillary urothelial cell carcinomas are invasive.  Aggressive tumors may not only extend into the bladder wall but, with progression, invade the adjacent prostate, seminal vesicles, ureters, and retroperitoneum. Some produce fistulous communications to the vagina or rectum. About 40% of these deeply invasive tumors metastasize to regional lymph nodes. Hematogenous dissemination, principally to the liver, lungs, and bone marrow, generally occurs late, and only with highly anaplastic tumors. Carcinoma in situ (CIS) is defined by the presence of any cytologically malignant cells within a flat urothelium.     CIS may range from full-thickness cytologic atypia to scattered malignant cells in an otherwise normal urothelium, the latter termed pagetoid spread ( Fig. 21-11 ). A common feature shared with high-grade papillary urothelial carcinoma is the lack of cohesiveness, which leads to the shedding of malignant cells into the urine. This may give rise to denuded urothelium with only a few CIS cells clinging to the basement membrane. Grossly, CIS usually appears as an area of mucosal reddening, granularity, or thickening without an intraluminal mass. It is commonly Figure 21-10 High-grade papillary urothelial carcinoma with marked cytologic atypia. 1031 Figure 21-11 A, Normal urothelium with uniform nuclei and well-developed umbrella cell layer. B, Flat carcinoma in situ with numerous cells having enlarged and pleomorphic nuclei. multifocal and may involve most of the bladder surface and extend into the ureters and urethra. Although carcinoma in situ is most often found in bladders harboring other patterns of transitional cell carcinoma, about 1% to 5% of cases occur in the absence of such tumors. If untreated, 50% to 75% of CIS cases progress to muscle-invasive cancer. Invasive urothelial cancer, which is detected early, may be superficial in the lamina propria and can be associated with either papillary urothelial cancer, usually high grade, or with CIS. The extent of the invasion is of prognostic significance. Understaging on biopsy is a significant problem; on resection, there may be cancer invading the muscularis propria ( Fig. 21-12 ). The extent of spread at the time of initial diagnosis is the most important factor in determining the outlook for a patient. Thus, staging, in addition to grade, is critical in the assessment of bladder neoplasms. The staging system most commonly used is given in Table 21-4 . Unusual variants of urothelial cancer include the nested variant with deceptively bland cytology lymphoepithelioma-like carcinoma and small cell carcinoma.   Other Types of Carcinoma Squamous cell carcinomas represent about 3% to 7% of bladder cancers in the United States, but in countries endemic for urinary schistosomiasis, they occur much more frequently.  Pure squamous cell carcinomas are nearly always associated with chronic bladder irritation and infection. Mixed urothelial cell TABLE 21-4 -- Pathologic T (Primary Tumor) Staging of Bladder Carcinoma AJCC/UICC Depth of Invasion Noninvasive, papillary Ta Carcinoma in situ (noninvasive, flat) Tis Lamina propria invasion T1 Muscularis propria invasion T2 Microscopic extravesicle invasion T3a Grossly apparent extravesicle invasion T3b Invades adjacent structures T4 AJCC/UICC, American Joint Commission on Cancer/Union Internationale Contre le Cancer. carcinomas with areas of squamous carcinoma are more frequent than pure squamous cell carcinomas. Most are invasive, fungating tumors or infiltrative and ulcerative. True papillary patterns are almost never seen. The level of cytologic differentiation varies widely, from the highly differentiated lesions producing abundant keratohyaline pearls to anaplastic giant Figure 21-12 Opened bladder showing a high-grade invasive urothelial cell carcinoma at an advanced stage. The aggressive multinodular neoplasm has fungated into the bladder lumen and spread over a wide area. The yellow areas represent areas of ulceration and necrosis. 1032 cell tumors showing little evidence of squamous differentiation. They often cover large areas of the bladder and are deeply invasive by the time of discovery. Adenocarcinomas of the bladder are rare and they are histologically identical to adenocarcinomas seen in the gastrointestinal tract.  Some arise from urachal remnants or in association with extensive intestinal metaplasia (discussed earlier). Urachal tumors occur in the dome or anterior wall, arise within the wall rather than from the mucosa, and extend out of the bladder towards the umbilicus. Rare variants of adenocarcinoma are the highly malignant signet-ring cell carcinoma, and mixed adenocarcinoma and urothelial cell carcinomas. Epidemiology and Pathogenesis. The epidemiology of carcinoma of the bladder resembles that of bronchogenic carcinoma, being more common in men than in women, in industrialized than in developing nations, and in urban than in rural dwellers. The male to female ratio for transitional cell tumors is approximately 3:1. About 80% of patients are between the ages of 50 and 80 years. Bladder cancer, with rare exception, is not familial. A number of factors have been implicated in the causation of transitional cell carcinoma. Some of the more important contributors include the following: • Cigarette smoking is clearly the most important influence, increasing the risk threefold to sevenfold, depending on the pack-years and smoking habits. Fifty per cent to 80% of all bladder cancers among men are associated with the use of cigarettes. Cigars, pipes, and smokeless tobacco invoke a much smaller risk. • Industrial exposure to arylamines, particularly 2-naphthylamine as well as related compounds, as was pointed out in the earlier discussion of chemical carcinogenesis ( Chapter 7 ). The cancers appear 15 to 40 years after the first exposure. • Schistosoma haematobium infections in areas where these are endemic (Egypt, Sudan) are an established risk. The ova are deposited in the bladder wall and incite a brisk chronic inflammatory response that induces progressive mucosal squamous metaplasia and dysplasia and, in some instances, neoplasia. Seventy per cent of the cancers are squamous, the remainder being urothelial cell carcinoma. • Long-term use of analgesics, implicated also in analgesic nephropathy ( Chapter 20 ). • Heavy long-term exposure to cyclophosphamide, an immunosuppressive agent, induces, as noted, hemorrhagic cystitis and increases the risk of bladder cancer. • Prior exposure of the bladder to radiation, often performed for other pelvic malignancies, increases the risk of urothelial carcinoma. In this setting, bladder cancer occurs many years after the radiation. How these influences induce cancer is unclear, but a number of genetic alterations have been observed in urothelial cell carcinoma.      The cytogenetic and molecular alterations are heterogeneous. Particularly common (occurring in 30% to 60% of tumors studied) are chromosome 9 monosomy or deletions of 9p and 9q as well as deletions of 17p, 13q, 11p, and 14q. The chromosome 9 deletions are the only genetic changes that are present frequently in superficial papillary tumors and occasionally in noninvasive flat tumors. The 9p deletions (9p21) involve the tumor-suppressor gene p16INK4a, which encodes an inhibitor of a cyclin-dependent kinase ( Chapter 7 ). The 9q deletion includes numerous other potential tumor-suppressor loci, but their identity is not yet known. On the other hand, many invasive urothelial cell carcinomas show deletions of 17p, including the region of the p53 gene, as well as mutations in the p53 gene, suggesting that these contribute to the progression of urothelial cell carcinoma. Mutations in p53 are also found in flat in situ cancer lesions. The 13q deletion involves the retinoblastoma gene and is also present in invasive tumors. Deletions of 14q are seen exclusively in flat lesions or invasive tumors but not in papillary tumors, and a putative tumor-suppressor gene is being pursued. Increased expression of RAS and epidermal growth factor receptors is also seen in some bladder cancers. On the basis of these findings, a model for bladder carcinogenesis has been proposed. In this two-pathway model, the first pathway is initiated by deletions of tumor-suppressor genes on 9p and 9q, leading to superficial papillary tumors, a few of which may then acquire p53 mutations and progress to invasion; a second pathway, possibly initiated by p53 mutations, leads to CIS and, with loss of chromosome 9, progresses to invasion. Clinical Course. Bladder tumors classically produce painless hematuria. This is their dominant and sometimes only clinical manifestation. Frequency, urgency, and dysuria occasionally accompany the hematuria. When the ureteral orifice is involved, pyelonephritis or hydronephrosis may follow. About 60% of neoplasms, when first discovered, are single, and 70% are localized to the bladder. Patients with urothelial tumors, whatever the grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade. The risk of recurrence and progression is related to several factors, including tumor size, stage, grade, multifocality, prior recurrence rate, and associated dysplasia and/or carcinoma in situ in the surrounding mucosa.      Although the term "recurrence" is used, most of the subsequent tumors arise at different sites from the original lesion. Recurrent tumors reflect new tumors in some cases, and in other instances, they share the same clonal abnormalities as the initial tumor and represent a true recurrence of the initial lesion as a result of shedding and implantation of the original tumor cells. The most important factors for progression-free survival are grade, presence of lamina propria invasion, and associated carcinoma in situ. Papillomas, papillary urothelial neoplasms of low malignant potential, and low-grade papillary urothelial cancer yield a 98% 10-year survival rate regardless of the number of recurrences; only a few patients (<10%) experience progression of their disease to higher-grade lesions. In contrast, only about 40% of individuals with a high-grade cancer survive 10 years; the tumor is progressive in 65%. Approximately 70% of patients with squamous cell carcinomas are dead within the year. The clinical challenge with these neoplasms is early detection and adequate follow-up. Although cystoscopy and biopsy are the mainstays of diagnosis, carcinoma in situ that produces no or only subtle gross mucosal changes and early small papillary lesions may be difficult to detect. Of value in these circumstances are cytologic examinations and tests that detect the presence 1033 of various urine markers such as human complement factor H-related protein, telomerase, fibrin-fibrinogen degradation products, mucins, CEA, hyaluronic acid, hyaluronidase, nuclear matrix proteins, and DNA content.    The major deficiency with cytologic examination is the underrecognition of low-grade papillary neoplasms. The predominant limitation of many of the tests measuring urine markers is their relatively low specificity, because positive test results may occur in conditions associated with injured urothelium. The treatment for bladder cancer depends on the grade, the stage, and whether the lesion is flat or papillary. For small, localized papillary tumors that are not high grade, the initial diagnostic transurethral resection is all that is done. Patients are closely followed with periodic cystoscopies and urine cytology for the rest of their life for tumor recurrence. Research is ongoing as to whether less invasive urine marker studies can be substituted for some of the follow-up tests so as to lengthen the intervals between the more invasive cystoscopic procedures. When a patient presents with multifocal bladder tumors, instillation of topical chemotherapy into the bladder, in the immediate postoperative period, can reduce the likelihood of tumor recurrence. After the biopsy site has healed, patients who are at high risk of recurrence and/or progression (CIS; papillary tumors that are high-grade, multifocal, have a history of rapid recurrence, or are associated with lamina propria invasion) receive topical immunotherapy consisting of intravesical installation of an attenuated strain of Mycobacterium tuberculosis called Bacillus Calmette-Guérin (BCG). The therapy presumably works by eliciting a local cell- mediated immune reaction that destroys tumor cells. Radical cystectomy is typically performed for (1) tumor invading the muscularis propria, (2) CIS or high-grade papillary cancer refractory to BCG, and (3) CIS extending into the prostatic urethra and extending down the prostatic ducts beyond the reach of BCG. Advanced bladder cancer is treated by chemotherapy. Mesenchymal Tumors Benign. A great variety of benign mesenchymal tumors may arise in the bladder. Collectively, they are rare. The most common is leiomyoma. They all tend to grow as isolated, intramural, encapsulated, oval to spherical masses, varying in diameter up to several centimeters. On occasion, they assume submucosal pedunculated positions. They have the histologic features of their counterparts elsewhere. Sarcomas. True sarcomas are distinctly uncommon in the bladder. Inflammatory pseudotumors, postoperative spindle cell nodules, and various carcinomas may assume sarcomatoid growth patterns and be mistaken histologically for sarcomas.  As a group, sarcomas tend to produce large masses (varying up to 10 to 15 cm in diameter) that protrude into the vesical lumen. Their soft, fleshy, gray-white gross appearance suggests their sarcomatous nature. The most common sarcoma in infancy or childhood is embryonal rhabdomyosarcoma. In some cases, they present as a polypoid, grapelike mass (sarcoma botryoides). The most common sarcoma in the bladder in adults is leiomyosarcoma. Secondary Tumors Secondary malignant involvement of the bladder is most often by direct extension from primary lesions in nearby organs, cervix, uterus, prostate, and rectum. On casual inspection of the bladder, secondary tumors may appear as primary carcinomas of this organ. Hemorrhage, ureteral obstruction, and vesicovaginal fistulas are the common sequelae. Distinction between primary adenocarcinoma of the bladder (urethral or otherwise) from local extension of colorectal cancer can be difficult. Lymphomas may also involve the bladder as a component of systemic disease but also, rarely, as primary bladder lymphoma. OBSTRUCTION Obstruction to the bladder neck is of major clinical importance, not only for the changes that are induced in the bladder, but also because of its eventual effect on the kidney. A great variety of intrinsic and extrinsic diseases of the bladder can narrow the urethral orifice and cause partial or complete vesical obstruction. In males, the most important lesion is enlargement of the prostate gland due either to nodular hyperplasia or to carcinoma ( Fig. 21-13 ). Outlet obstruction is somewhat less common in females and is most often caused by cystocele of the bladder. The other, less frequent, causes are: (1) congenital narrowings or strictures of the urethra; (2) inflammatory strictures of the urethra; (3) inflammatory fibrosis and contraction of the bladder after varying types of cystitis; (4) bladder tumors, either benign or malignant, when strategically located; (5) secondary invasion of the bladder neck by growths arising in perivesical structures, such as the cervix, vagina, prostate, and rectum; (6) mechanical obstructions caused by foreign bodies and calculi; and (7) injury to the innervation of the bladder, causing neurogenic bladder. Morphology. In the early stages, there is only some thickening of the bladder wall, presumably due to hypertrophy of the smooth muscle. The mucosal surface at this time may be entirely normal. With progressive hypertrophy of the muscle coat, the individual muscle bundles greatly enlarge and produce trabeculation of the bladder wall. In the course of time, crypts form and may then become converted into true acquired diverticula. In some cases of acute obstruction or in terminal disease, when the patient's normal reflex mechanisms are depressed, the bladder may become extremely Figure 21-13 Hypertrophy and trabeculation of bladder wall secondary to polypoid hyperplasia of the prostate. 1034 Figure 21-14 Carcinoma of urethra with typical fungating growth. dilated. The enlarged bladder may reach the brim of the pelvis or even the level of the umbilicus. In these cases, the bladder wall is markedly thinned, and the trabeculation becomes totally unapparent. Urethra INFLAMMATIONS Urethritis is classically divided into gonococcal and non-gonococcal urethritis. Gonococcal urethritis is one of the earliest manifestations of this venereal infection. Nongonococcal urethritis is common and can be caused by a variety of bacteria, among which E. coli and other enteric organisms predominate. Urethritis is often accompanied by cystitis in women and by prostatitis in men. In many instances, bacteria cannot be isolated. Various strains of Chlamydia (e.g., C. trachomatis) are the cause of 25% to 60% of nongonococcal urethritis in men and about 20% in women. Mycoplasma (Ureaplasma urealyticum) also accounts for the symptoms of urethritis in many cases. Urethritis is also one component of Reiter syndrome, which comprises the clinical triad of arthritis, conjunctivitis, and urethritis. The morphologic changes are entirely typical of inflammation in other sites within the urinary tract. The urethral involvement is not itself a serious clinical problem but may cause considerable local pain, itching, and frequency and may represent a forerunner of more serious disease at higher levels of the urogenital tract. TUMORS AND TUMOR-LIKE LESIONS Urethral caruncle is an inflammatory lesion presenting as a small, red, painful mass about the external urethral meatus in the female patient. Caruncles may be found at any age but are more common in later life. The lesion consists of a hemispheric, friable, 1- to 2-cm nodule that occurs singly, either just outside or just within the external urethral meatus. It may be covered by an intact mucosa but is extremely friable, and the slightest trauma may cause ulceration of the surface and bleeding. On histologic examination, it is composed of a highly vascularized, young, fibroblastic connective tissue, usually heavily infiltrated with leukocytes. The overlying epithelium, where present, is either transitional or squamous cell in type. Surgical excision affords prompt relief and cure. Benign epithelial tumors of the urethra include squamous and transitional cell papillomas, inverted papillomas, and condylomas. Primary carcinoma of the urethra is an uncommon lesion ( Fig. 21-14 ). It tends to occur in advanced age in women. Tumors arising within the proximal urethra tend to show urothelial differentiation and are analogous to those occurring within the bladder. Those lesions found within the distal urethra are more typically squamous carcinomas. Glandular carcinomas less frequently occur in the urethra as primary tumors, and are also more frequent in women. Some lesions are similar to those described in the bladder, arising through metaplasia or less commonly from periurethral glands. The other, rarer, variant of urethral adenocarcinoma is clear cell adenocarcinoma. Cancers arising within the prostatic urethra are dealt with in the section on the prostate. The Male Genital Tract Penis The penis can be affected by congenital anomalies, inflammations, and tumors, the most important of which are inflammations and tumors. The venereal infections (e.g., syphilis and gonorrhea) usually begin with penile lesions. Carcinoma of the penis, although not one of the more common neoplasms in North America, accounts for about 1% of cancers in men. 1035 CONGENITAL ANOMALIES The penis is the site of many varied forms of congenital anomalies, only some of which have clinical significance. These range from congenital absence and hypoplasia to hyperplasia, duplication, and other aberrations in size and form. Most of these deviations are extremely uncommon and are readily apparent on inspection. Certain other anomalies are more frequent and therefore have greater clinical significance. Hypospadias and Epispadias Malformation of the urethral groove and urethral canal may create abnormal openings either on the ventral surface of the penis (hypospadias) or on the dorsal surface (epispadias).  Although more frequent with epispadias, either of these two anomalies may be associated with failure of normal descent of the testes and with malformations of the urinary tract. Hypospadias, the more common of the two, occurs in approximately 1 in 300 live male births. Even when isolated, these urethral defects may have clinical significance because often the abnormal opening is constricted, resulting in urinary tract obstruction and an increased risk of ascending urinary tract infections. When the orifices are situated near the base of the penis, normal ejaculation and insemination are hampered or totally blocked. These lesions therefore are possible causes of sterility in men. Phimosis When the orifice of the prepuce is too small to permit its normal retraction, the condition is designated phimosis. Such an abnormally small orifice may result from anomalous development but is more frequently the result of repeated attacks of infection that cause scarring of the preputial ring. Phimosis is important because it interferes with cleanliness and permits the accumulation of secretions and detritus under the prepuce, favoring the development of secondary infections and possibly carcinoma. When a phimotic prepuce is forcibly retracted over the glans penis, marked constriction and subsequent swelling may block the replacement of the prepuce, creating what is known as paraphimosis. Not only is this condition extremely painful, but also it may be a potential cause of urethral constriction and serious acute urinary retention. INFLAMMATIONS Inflammations of the penis almost invariably involve the glans and prepuce and include a wide variety of specific and nonspecific infections. The specific infections—syphilis, gonorrhea, chancroid, granuloma inguinale, lymphopathia venerea, genital herpes—are sexually transmitted and are discussed in Chapter 8 and Chapter 22 . Only the nonspecific infections causing so-called balanoposthitis need description here. Balanoposthitis refers to infection of the glans and prepuce caused by a wide variety of organisms. Among the more common agents are Candida albicans, anaerobic bacteria, Gardnerella, and pyogenic bacteria. Most cases occur as a consequence of poor local hygiene in uncircumcised males, with accumulation of desquamated epithelial cells, sweat, and debris, termed smegma, acting as local irritant. Persistence of such infections leads to inflammatory scarring and, as was mentioned earlier, is a common cause of phimosis. TUMORS Tumors of the penis are, on the whole, uncommon. The most frequent neoplasms are carcinomas and a benign epithelial tumor: condyloma acuminatum. In addition to the clearly defined benign and malignant categories, however, there are several forms of carcinoma in situ, exemplified by Bowen disease. Benign Tumors Condyloma Acuminatum Condyloma acuminatum is a benign tumor caused by human papillomavirus (HPV). It is related to the common wart (verruca vulgaris) and may occur on any moist mucocutaneous surface of the external genitals in either sex. There is ample evidence that HPV and associated diseases are sexually transmitted. Of the various antigenically and genetically distinct types of HPV that have been identified, type 6 and, less frequently, type 11 have been clearly associated with condylomata acuminata. The antigens and genomes of these HPV types can be demonstrated in most lesions by immunoperoxidase and DNA hybridization techniques, respectively. Morphology. Condylomata acuminata may occur on the external genitalia or perineal areas. On the penis, these lesions occur most often about the coronal sulcus and inner surface of the prepuce. They consist of single or multiple sessile or pedunculated, red papillary excrescences that vary from 1 mm to several millimeters in diameter ( Fig. 21-15 ). Histologically, a branching, villous, papillary connective tissue stroma is covered by epithelium that may have considerable superficial hyperkeratosis and thickening of the underlying epidermis (acanthosis) ( Fig. 21-16 ). Figure 21-15 Condyloma acuminatum of the penis. 1036 Figure 21-16 Condyloma acuminatum of the penis. Low magnification reveals the papillary (villous) architecture. The normal orderly maturation of the epithelial cells is preserved. Clear vacuolization of the prickle cells (koilocytosis), characteristic of HPV infection, is noted in these lesions ( Fig. 21-17 ). The basement membrane is intact, and there is no evidence of invasion of the underlying stroma. Condylomata acuminata tend to recur but do not evolve into invasive cancers. Malignant Tumors Carcinoma in Situ As discussed in Chapter 7 and Chapter 22 , carcinoma in situ (high-grade squamous intraepithelial neoplasia) is a histologic term used to describe epithelial lesions in which the cytologic changes of malignancy are confined to the epithelium, with no evidence of local invasion or distant metastases. It is considered a precancerous condition because of its potential to evolve into invasive cancer. In the external male genitalia, two distinct lesions that display histologic features of carcinoma in situ have been described: Bowen disease and bowenoid papulosis. All Figure 21-17 Condyloma acuminatum of the penis. The epithelium shows vacuolization (koilocytosis), characteristic of human papillomavirus (HPV) infection. these lesions have a strong association with infection by HPV. Data compiled from a large number of studies reveal that HPV DNA, most commonly type 16, is found in approximately 80% of cases. Bowen disease occurs in the genital region of both men and women, usually in those over the age of 35 years. In men, it is prone to involve the skin of the shaft of the penis and the scrotum. Grossly, it appears as a solitary, thickened, gray-white, opaque plaque with shallow ulceration and crusting. It can also manifest on the glans and prepuce as single or multiple shiny red, sometimes velvety, plaques where it is clinically referred to as Erythroplasia of Queyrat. Histologically, the epidermis shows proliferation with numerous mitoses, some atypical. The cells are markedly dysplastic with large hyperchromatic nuclei and lack of orderly maturation ( Fig. 21-18 ). Nevertheless, the dermal-epidermal border is sharply delineated by an intact basement membrane. Over the span of years, Bowen disease may transform into infiltrating squamous cell carcinoma in approximately 10% of patients. Another feature that is said to be associated with Bowen disease is the occurrence of visceral cancer in approximately one third of the patients. However, in the absence of long-term studies, this issue remains unresolved. Bowenoid papulosis occurs in sexually active adults. Clinically, it differs from Bowen disease by the younger age of patients and the presence of multiple (rather than solitary) pigmented (reddish brown) papular lesions. In some cases, the lesions may be verrucoid and readily mistaken for condyloma acuminatum. Histologically, bowenoid papulosis is indistinguishable from Bowen disease and is also related to HPV 16. In contrast to Bowen disease, bowenoid papulosis virtually never develops into an invasive carcinoma, and in many cases, it spontaneously regresses. Invasive Carcinoma Squamous cell carcinoma of the penis is an uncommon malignancy in the United States, accounting for less than 1% of cancers in males. By contrast, the incidence of squamous cell carcinoma of the penis ranges from 10% to 20% of male Figure 21-18 Bowen disease (carcinoma in situ) of the penis. The epithelium above the intact basement membrane (not seen in this picture) shows hyperchromatic, dysplastic dyskeratotic epithelial cells with scattered mitoses above the basal layer. 1037 malignancies in some parts of Asia, Africa, and South America. A striking correlation exists between the practice of circumcision and the occurrence of penile cancer. Circumcision confers protection; hence, this cancer is extremely rare among Jews and Moslems and is correspondingly more common in populations in which circumcision is not routinely practiced. It is postulated that circumcision is associated with better genital hygiene, which, in turn, reduces exposure to carcinogens that may be concentrated in smegma and decreases the likelihood of infection with potentially oncogenic human papillomavirus (HPV). This notion is supported by the observation that HPV DNA can be detected in the cancer cells in approximately 50% of patients.  HPV type 16 is the most frequent culprit, but as with other genitourinary malignancies, HPV 18 is also implicated. Carcinoma in situ (Bowen disease), the presumed precursor lesion of invasive squamous cell carcinoma of the penis, has a much stronger association with HPV, being detected in 80% of lesions. This disparity suggests that infection with HPV is not sufficient for transformation and that it probably acts in concert with other carcinogenic influences. These may include carcinogens in cigarette smoke, which elevates the risk of developing cancer of the penis. Carcinomas are usually found in patients between the ages of 40 and 70. Morphology. Squamous cell carcinoma of the penis usually begins on the glans or inner surface of the prepuce near the coronal sulcus. Two macroscopic patterns are seen: papillary and flat. The papillary lesions simulate condylomata acuminata and may produce a cauliflower- like fungating mass. Flat lesions appear as areas of epithelial thickening accompanied by graying and fissuring of the mucosal surface. With progression, an ulcerated papule develops ( Fig. 21-19 ). Histologically, both the papillary and the flat lesions are squamous cell carcinomas with varying degrees of differentiation. Verrucous carcinoma is an uncommon, well-differentiated variant of squamous cell carcinoma that has low malignant potential. These tumors are locally invasive, but they rarely metastasize. As the name indicates, these tumors have a verrucous (papillary) appearance, similar to condylomata acuminata, but they are larger than the usual condylomata. In contrast to condylomata Figure 21-19 Carcinoma of the penis. The glans penis is deformed by a firm, ulcerated, infiltrative mass. acuminata, however, verrucous carcinomas can invade the underlying tissues. Other, less common, subtypes of penile squamous carcinoma include basaloid, warty, and papillary variants.  Clinical Course. Invasive squamous cell carcinoma of the penis is a slowly growing, locally invasive lesion that often has been present for a year or more before it is brought to medical attention. The lesions are not painful until they undergo secondary ulceration and infection. Frequently, they bleed. Metastases to inguinal and iliac lymph nodes characterize the early stage, but widespread dissemination is extremely uncommon until the lesion is far advanced. Clinical assessment of regional lymph node involvement is notoriously inaccurate; 50% of men with penile squamous cell carcinoma and clinically enlarged inguinal nodes have only reactive lymphoid hyperplasia when examined histologically. The prognosis is related to the stage of the tumor. In persons with limited lesions without involvement of the inguinal lymph nodes, there is a 66% 5-year survival rate, whereas metastasis to the lymph nodes carries a grim 27% 5-year survival. Testis and Epididymis The major pathologic involvements of the testis and epididymis are quite distinct. In the case of the epididymis, the most important and frequent involvements are inflammatory diseases, whereas in the testis, the major lesions are tumors. Their close anatomic relationship, however, permits the extension of any of these processes from one organ to the other. CONGENITAL ANOMALIES With the exception of incomplete descent of the testes (cryptorchidism), congenital anomalies are extremely rare and include absence of one or both testes, fusion of the testes (so-called synorchism), and the formation of clinically insignificant cysts within the testis. Cryptorchidism Cryptorchidism is synonymous with undescended testes and is found in approximately 1% of 1-year-old boys. This anomaly represents a complete or incomplete failure of the intra-abdominal testes to descend into the scrotal sac. It usually occurs as an isolated anomaly but may be accompanied by other malformations of the genitourinary tract, such as hypospadias. Testicular descent occurs in two morphologically and hormonally distinct phases. During the first, transabdominal, phase, the testis comes to lie within the lower abdomen or brim of the pelvis. This phase is believed to be controlled by a hormone called müllerian-inhibiting substance. In the second, or inguinoscrotal, phase, the testes descend through the inguinal canal into the scrotal sac. This phase is androgen dependent and is possibly mediated by androgen-induced release of calcitonin gene-related peptide from the genitofemoral nerve. Although testes may be arrested anywhere along their pathway of descent, defects in transabdominal 1038 descent are uncommon, accounting for approximately 5% to 10% of cases. In most patients, the undescended testis is palpable in the inguinal canal. The precise cause of cryptorchidism is still poorly understood. Despite the fact that testicular descent is controlled by hormonal factors, cryptorchidism is only rarely associated with hormonal disorders. It may be one of several congenital defects in chromosomal disorders, such as trisomy 13. The condition is completely asymptomatic, and it is found by the patient or the examining physician only when the scrotal sac is discovered not to contain the testis. Morphology. Cryptorchidism is unilateral in most cases, but it may be bilateral in 25% of patients. Histologic changes in the malpositioned testis begin as early as 2 years of age. They are characterized by an arrest in the development of germ cells associated with marked hyalinization and thickening of the basement membrane of the spermatic tubules ( Fig. 21-20 ). Eventually, the tubules appear as dense cords of hyaline connective tissue outlined by prominent basement membranes. There is concomitant increase in interstitial stroma. Because Leydig cells are spared, they appear to be prominent. As might be expected with progressive tubular atrophy, the cryptorchid testis is small in size and firm in consistency, owing to fibrotic changes. Histologic deterioration, leading to a paucity of germ cells, has also been noted in the contralateral (descended) testis in patients with unilateral cryptorchidism, supporting a hormonal basis for the development of this condition. Cryptorchidism is of more than academic interest for many reasons. When the testis lies in the inguinal canal, it is particularly exposed to trauma and crushing against the ligaments and bones. A concomitant inguinal hernia accompanies such malposition of the testis in about 10% to 20% of cases. From the morphologic changes, it is apparent that bilateral cryptorchidism may result in sterility. Infertility, however, is also noted in a significant number of cases with uncorrected unilateral cryptorchidism because, as was mentioned earlier, the contralateral descended testis may also be deficient in germ Figure 21-20 A, Normal testis shows tubules with active spermatogenesis. B, Testicular atrophy. The tubules show Sertoli cells but no spermatogenesis. There is thickening of basement membranes and an apparent increase in interstitial Leydig cells. cells. In addition, the undescended testis is at a greater risk of developing testicular cancer than is the descended testis. During the first year of life, the majority of inguinal cryptorchid testes will descend spontaneously into the scrotum. Persistently undescended testes require surgical correction, preferably before histologic deterioration sets in at around 2 years of age. Orchiopexy (placement in the scrotal sac) does not guarantee fertility; deficient spermatogenesis has been reported in 10% to 60% of patients in whom surgical repositioning was performed.  To what extent the risk of cancer is reduced after orchiopexy is also unclear. According to some studies, orchiopexy of unilateral cryptorchidism before 10 years of age protects against cancer development. This is not universally accepted, however. Malignant change may occur in the contralateral, normally descended testis. These observations suggest that cryptorchidism is associated with an intrinsic defect in testicular development and cellular differentiation that is unrelated to anatomic position. REGRESSIVE CHANGES Atrophy Atrophy is a regressive change that affects the scrotal testis, and it may have a number of causes, including (1) progressive atherosclerotic narrowing of the blood supply in old age; (2) the end stage of an inflammatory orchitis, whatever the etiologic agent; (3) cryptorchidism; (4) hypopituitarism; (5) generalized malnutrition or cachexia; (6) irradiation; (7) prolonged administration of female sex hormones, as in treatment of patients with carcinoma of the prostate; and (8) exhaustion atrophy, which may follow the persistent stimulation produced by high levels of follicle-stimulating pituitary hormone. The gross and microscopic alterations follow the pattern already described for cryptorchidism. When the process is bilateral, as it frequently is, sterility results. Atrophy or sometimes improper development of the testes occasionally occurs as a primary failure of genetic origin. The resulting condition, called Klinefelter syndrome, represents a sex chromosomal disorder (discussed in detail in Chapter 5 , along with other cytogenetic diseases). 1039 Findings Associated with Decreased Fertility Atrophy represents the end-stage of many forms of testicular injury. Prior to this terminal nonspecific histologic appearance, several other patterns are recognized that are associated with decreased fertility. These include hypospermatogenesis, maturation arrest, and findings associated with vas deferens obstruction. In some instances, a specific cause for the testicular injury can be found, and if it can be removed prior to the development of atrophy, testicular function can be restored. INFLAMMATIONS Inflammations are distinctly more common in the epididymis than in the testis. It is classically taught that, of the three major specific inflammatory states, gonorrhea and tuberculosis almost invariably arise in the epididymis, whereas syphilis affects the testis first. Non-Specific Epididymitis and Orchitis Epididymitis and possible subsequent orchitis are commonly related to infections in the urinary tract (cystitis, urethritis, genitoprostatitis), which presumably reach the epididymis and the testis through either the vas deferens or the lymphatics of the spermatic cord. The cause of epididymitis varies with the age of the patient. Although uncommon in children, epididymitis in childhood is usually associated with a congenital genitourinary abnormality and infection with Gram-negative rods. In sexually active men younger than age 35 years, the sexually transmitted pathogens Chlamydia trachomatis and Neisseria gonorrhoeae are the most frequent culprits. In men older than age 35, the common urinary tract pathogens, such as Escherichia coli and Pseudomonas, are responsible for most infections. Morphology. The bacterial invasion sets up a nonspecific acute inflammation characterized by congestion, edema, and infiltration by neutrophils, macrophages, and lymphocytes. Although the infection, in the early stage, is more or less limited to the interstitial connective tissue, it rapidly extends to involve the tubules and may progress to frank abscess formation or complete suppurative necrosis of the entire epididymis ( Fig. 21-21 ). Usually, having involved the epididymis, the infection extends into the testis to evoke a similar inflammatory reaction. Such inflammatory involvement of the epididymis and testis is often followed by fibrous scarring, which, in many cases, leads to sterility. Usually, the interstitial cells of Leydig are not totally destroyed, so sexual activity is not disturbed. Granulomatous (Autoimmune) Orchitis Among middle-aged men, a rare cause of unilateral testicular enlargement is nontuberculous, granulomatous orchitis. It usually presents as a moderately tender testicular mass of sudden onset sometimes associated with fever. It may appear insidiously, however, as a painless testicular mass mimicking a testicular tumor, hence its importance. Histologically, the Figure 21-21 Acute epididymitis caused by gonococcal infection. The epididymis is replaced by an abscess. A normal testis is seen on the right. orchitis is distinguished by granulomas that are seen restricted within spermatic tubules. The lesions closely resemble tubercles but differ in that the granulomatous reaction is present diffusely throughout the testis and is confined to the seminiferous tubules. Although an autoimmune basis is suspected, the cause of these lesions remains unknown. Specific Inflammations Gonorrhea Extension of infection from the posterior urethra to the prostate to the seminal vesicles and then to the epididymis is the usual course of a neglected gonococcal infection. Inflammatory changes similar to those described in the nonspecific infections occur, with the development of frank abscesses in the epididymis, resulting in extensive destruction of this organ. In the more neglected cases, the infection can then spread to the testis and produce a suppurative orchitis. Mumps Mumps is a systemic viral disease that most commonly affects school-age children. Testicular involvement is extremely uncommon in this age group. In postpubertal males, however, orchitis may develop and has been reported in 20% to 30% of male patients. Most often, the acute interstitial orchitis develops about 1 week after onset of swelling of the parotid glands. Rarely, cases of orchitis precede the parotitis or may be unaccompanied by parotid gland involvement. Tuberculosis Tuberculosis almost invariably begins in the epididymis and may spread to the testis. In many of these cases, there is associated tuberculous prostatitis and seminal vesiculitis, and it is believed that epididymitis usually represents a secondary spread from these other involvements of the genital tract. The infection invokes the classic morphologic reactions of caseating granulomatous inflammation that are characteristic of tuberculosis elsewhere. 1040 Syphilis The testis and epididymis are affected in both acquired and congenital syphilis, but almost invariably, the testis is involved first by the infection. In many cases, the orchitis is not accompanied by epididymitis. The morphologic pattern of the reaction takes two forms: the production of gummas or a diffuse interstitial inflammation characterized by edema and lymphocytic and plasma cell infiltration with the characteristic hallmark of all syphilitic infections (i.e., obliterative endarteritis with perivascular cuffing of lymphocytes and plasma cells). VASCULAR DISTURBANCES Torsion Twisting of the spermatic cord may cut off the venous drainage and the arterial supply to the testis. Usually, however, the thick-walled arteries remain patent, so intense vascular engorgement and venous infarction follow. There are two types of testicular torsion. Neonatal torsion occurs either in utero or shortly after birth. It lacks any associated anatomic defect to account for its occurrence. Adult torsion is typically seen in adolescence, presenting as sudden onset of testicular pain. In contrast to neonatal torsion, adult torsion results from a bilateral anatomic defect in which the testis has increased mobility, giving rise to what is termed the bell-clapper abnormality. It often occurs without any inciting injury; sudden pain heralding the torsion may even occur during sleep. Torsion is one of the few urologic emergencies. If the testis is explored surgically and manually untwisted within approximately 6 hours after the onset of torsion, there is a good chance that the testis will remain viable. To prevent the catastrophic occurrence of subsequent torsion in the contralateral testis, the testis that is unaffected by torsion is surgically fixed to the scrotum (orchiopexy). Morphology. Depending on the duration of the process, the morphologic changes range from intense congestion to widespread extravasation of blood into the interstitial tissue of the testis and epididymis. Eventually, hemorrhagic infarction of the entire testis occurs ( Fig. 21-22 ). In the late stages, the testis is markedly enlarged and is converted virtually into a sac of soft, necrotic, hemorrhagic tissue. Figure 21-22 Torsion of the testis. Spermatic Cord and Paratesticular Tumors Lipomas are common lesions involving the proximal spermatic cord. They are often identified at the time of inguinal hernia repair. Although diagnosed as "lipomas," many of these lesions probably represent retroperitoneal adipose tissue that has been pulled into the inguinal canal along with the hernia sac, rather than a true neoplasm. The most common benign paratesticular tumor is adenomatoid tumor. Although these lesions are mesothelial in nature, they are not referred to as mesotheliomas, in order to distinguish them from other mesothelial lesions that may occur at this site. Adenomatoid tumors are usually small nodules that typically occur near the upper pole of the epididymis. Although they are grossly well circumscribed, microscopically they may be minimally invasive into the surrounding tissue, including the adjacent testis. The importance of this lesion is that it is one of the few benign tumors seen near the testis. If the urologist can identify the nature of this lesion with the aid of intraoperative frozen sections, local excision of the adenomatoid tumor can spare the patient orchiectomy. The most common malignant paratesticular tumors located at the distal end of the spermatic cord are rhabdomyosarcomas in children and liposarcomas in adults. TESTICULAR TUMORS Testicular neoplasms span an amazing gamut of anatomic types.    They are divided into two major categories: germ cell tumors and nongerminal tumors derived from stroma or sex cord. Approximately 95% arise from germ cells. Most of these germinal tumors are highly aggressive cancers that are capable of rapid, wide dissemination, although with current therapy, most can be cured. Nongerminal tumors, in contrast, are generally benign, but some elaborate steroids, leading to interesting endocrinologic syndromes. Germ Cell Tumors Approximately 8000 cases of testicular tumors are diagnosed per year in the United States, resulting in about 400 deaths per year. For unexplained reasons, there is a worldwide increase in the incidence of these tumors. In the 15- to 34-year age group, when these neoplasms have a peak incidence, they constitute the most common tumor of men and cause approximately 10% of all cancer deaths. In the United States, these tumors are much more common in whites than in blacks (ratio 5:1). Classification and Histogenesis. As one might guess, germ cells are multipotential, and once they become cancerous, they are not inhibited in their lines of differentiation. Table 21-5 lists the most common germ cell tumors and the classification system that is most widely used in the United States. Testicular germ cell tumors may be divided into two categories on the basis of whether they are composed of a single histologic pattern or more than one. Tumors with a single histologic pattern constitute about 40% of all testicular neoplasms and are listed in Table 21-5 . In approximately 60% of the tumors, there is a mixture of two or more of the histologic patterns. 1041 TABLE 21-5 -- Pathologic Classification of Common Testicular Tumors Germ Cell Tumors Seminoma Spermatocytic seminoma Embryonal carcinoma Yolk sac (endodermal sinus) tumor Choriocarcinoma Teratoma Sex Cord-Stromal Tumors Leydig cell tumor Sertoli cell tumor Most tumors in this group originate from intratubular germ cell neoplasia (ITGCN).  ITGCN is seen adjacent to all germ cell tumors in adults except for spermatocytic seminoma and epidermoid and dermoid cysts. With rare exceptions, it is also not seen in pediatric tumors (teratomas, yolk sac tumors). ITCGN is encountered with a high frequency in the following conditions, listed in order of increasing risk: cryptorchidism, prior germ cell tumors, strong family history of germ cell tumor, androgen insensitivity syndrome, and gonadal dysgenesis syndrome. Untreated ITGCN progresses to invasive germ cell tumor in approximately 50% of cases over 5 years of follow-up. Thus its significance is similar to carcinoma in situ in other organs. If ITGCN is identified, it is treated by low-dose radiotherapy, which destroys the germ cells yet maintains the androgen production of the Leydig cells. Neoplastic germ cells may differentiate along gonadal lines to give rise to seminoma or transform into a totipotential cell population that gives rise to nonseminomatous tumors. Such totipotential cells may remain largely undifferentiated to form embryonal carcinoma or may differentiate along extraembryonic lines to form yolk sac tumors or choriocarcinomas. Teratoma results from differentiation of the embryonic carcinoma cells along the lines of all three germ cell layers. Some studies suggest that seminomas are not end-stage neoplasms. Similar to embryonal carcinomas, seminomas may also act as precursors from which other forms of testicular germ cell tumors originate. This view is supported by the fact that cells that form intratubular germ cell neoplasias (the presumed precursors of all types of germ cell tumors) share morphologic and molecular characteristics with tumor cells in seminomas. Despite the fascination of pathologists with the heterogeneity of testicular tumors, from a clinical standpoint the most important distinction in germ cell tumors is between seminomas and nonseminomatous tumors. As will be discussed later, this clinical distinction has important bearings on treatment and prognosis. Pathogenesis As with all neoplasms, little is known about the ultimate cause of germ cell tumors. Several predisposing influences, however, are important: (1) cryptorchidism, (2) testicular dysgenesis, and (3) genetic factors, all of which may contribute to a common denominator: germ cell maldevelopment. Reference has already been made to the increased incidence of neoplasms in undescended testes. In most large series of testicular tumors, approximately 10% are associated with cryptorchidism. The higher the location of the undescended testicle (intra-abdominal versus inguinal), the greater is the risk of developing cancer. Patients with disorders of testicular development (testicular dysgenesis), including testicular feminization and Klinefelter syndrome, harbor an increased risk of developing germ cell tumors. The risk is highest in patients with testicular feminization. In cryptorchid and dysgenetic testes, foci of intratubular germ cell neoplasms can be detected at a high frequency before the development of invasive tumors. Genetic predisposition also seems to be important, although no well-defined pattern of inheritance has been identified. In support, striking racial differences in the incidence of testicular tumors can be cited. Blacks in Africa have an extremely low incidence of these neoplasms, which is unaffected by migration to the United States. Familial clustering has been reported, and according to one study, sibs of affected individuals have a tenfold higher risk of developing testicular cancer than does the general population. As with all tumors, genomic changes are undoubtedly important in the pathogenesis of testicular cancers. An isochromosome of the short arm of chromosome 12, i(12p), is found in virtually all germ cell tumors, regardless of their histologic type. In the approximately 10% of cases in which i(12p) is not detected, extra genetic material derived from 12p is found on other chromosomes. Obviously, dosage of genes located on 12p is critical for the pathogenesis of germ cell tumors, and several candidate genes have been identified, including a novel gene, called DAD-R, that prevents apoptosis.  It is of interest that i(12p) is also noted in ovarian germ cell neoplasms, suggesting that the events leading to this alteration may be critical to the molecular pathogenesis of all germ cell neoplasms. With this background of pathogenesis, we can discuss the morphologic patterns of germ cell tumors, followed by the clinical features that are common to most germinal tumors. Seminoma Seminomas are the most common type of germinal tumor (50%) and the type most likely to produce a uniform population of cells. They almost never occur in infants; they peak in the thirties. An identical tumor arises in the ovary, where it is called dysgerminoma ( Chapter 22 ). Morphology. If not otherwise specified, the term "seminoma" refers to "classic" or "typical" seminoma. Spermatocytic seminoma, despite its nosologic similarity, is actually a distinct tumor; it has been segregated into a separate category and will be discussed later. Seminomas produce bulky masses, sometimes 10 times the size of the normal testis. The typical seminoma has a homogeneous, gray-white, lobulated cut surface, usually devoid of hemorrhage or necrosis ( Fig. 21-23 ). In more than half of cases, the entire testis is replaced. Generally, the tunica albuginea is not penetrated, but occasionally, extension to the epididymis, spermatic cord, or scrotal sac occurs. Microscopically, the typical seminoma presents sheets of uniform cells divided into poorly demarcated lobules by delicate septa of fibrous tissue ( Fig. 21-24A ). The classic seminoma cell is large and round to polyhedral and has a distinct cell membrane; a clear or watery-appearing cytoplasm; and a large, 1042 Figure 21-23 Seminoma of the testis appears as a fairly well circumscribed, pale, fleshy, homogeneous mass. central nucleus with one or two prominent nucleoli ( Fig. 21-24B ). Mitoses vary in frequency. The cytoplasm contains varying amounts of glycogen. Classic seminoma cells do not contain α-fetoprotein (AFP) or human chorionic gonadotropin (HCG). The tumor cells stain positively for placental alkaline phosphatase, and scattered cells may be keratin positive. Approximately 15% of seminomas contain syncytiotrophoblasts. In Figure 21-24 Seminoma. A, Low magnification shows clear seminoma cells divided into poorly demarcated lobules by delicate septa. B, Microscopic examination reveals large cells with distinct cell borders, pale nuclei, prominent nucleoli, and a sparse lymphocytic infiltrate. this subset of patients, serum HCG levels are also elevated, although not to the extent seen in patients with choriocarcinoma. The amount of stroma in typical seminomas varies greatly. Sometimes it is scant; at other times, it is abundant. Usually, well-defined fibrous strands are present, creating lobules of neoplastic cells. The septa are usually infiltrated with T lymphocytes, and in some tumors, they also bear prominent granulomas. The term "anaplastic seminoma" is used by some to indicate greater cellular and nuclear irregularity with more frequent tumor giant cells and many mitoses. However, because "anaplastic seminoma" is not associated with a worse prognosis when matched for stage with classic seminoma, and is not treated differently, most authorities do not recognize "anaplastic seminoma" as a distinct entity. Spermatocytic Seminoma Although related by name to seminoma, spermatocytic seminoma is a distinctive tumor both clinically and histologically. It is one of the two variants of germ cell tumors that do not arise from an intratubular germ cell neoplasia, the other being teratomas of children. Spermatocytic seminoma is an uncommon tumor, representing 1% to 2% of all testicular germ cell neoplasms. The age of involvement is much later than for most testicular tumors: Affected individuals are generally over the age of 65 years. In contrast to classic seminoma, it is a slow-growing tumor that rarely if ever produces metastases; hence, the prognosis is excellent. Morphology. Grossly, spermatocytic seminoma tends to be larger than classic seminoma and presents with a pale gray, soft, cut surface sometimes with mucoid cysts. Spermatocytic seminomas have three cell populations, all intermixed: (1) medium-sized cells (15 to 18 µm), which are the most numerous, containing a round nucleus and eosinophilic cytoplasm; (2) smaller cells (6 to 8 µm), with a narrow rim of eosinophilic cytoplasm resembling secondary spermatocytes; and (3) scattered giant cells (50 to 100 µm), either uninucleate or multinucleate. In some intermediate-sized cells, chromatin is similar to that seen in 1043 the meiotic phase of non-neoplastic spermatocytes (spireme chromatin), thus justifying the term spermatocytic seminoma. Embryonal Carcinoma Embryonal carcinomas occur mostly in the 20- to 30-year age group. These tumors are more aggressive than seminomas. Morphology. Grossly, the tumor is smaller than seminoma and usually does not replace the entire testis. On cut surfaces, the mass is often variegated, poorly demarcated at the margins, and punctuated by foci of hemorrhage or necrosis ( Fig. 21-25 ). Extension through the tunica albuginea into the epididymis or cord is not infrequent. Histologically, the cells grow in alveolar or tubular patterns, sometimes with papillary convolutions ( Fig. 21-26 ). Embryonal carcinomas lack the well-formed glands with basally situated nuclei and apical cytoplasm seen in teratomas. More undifferentiated lesions may present sheets of cells. The neoplastic cells have an epithelial appearance and are large and anaplastic, with hyperchromatic nuclei having prominent nucleoli. In contrast to seminoma, the cell borders are usually indistinct, and there is considerable variation in cell and nuclear size and shape. Mitotic figures and tumor giant cells are frequent. Within this background, syncytial cells containing HCG, cells containing AFP, or both may be detected by immunoperoxidase techniques. Most Figure 21-25 Embryonal carcinoma. In contrast to the seminoma illustrated in Figure 21-23 , the embryonal carcinoma is a hemorrhagic mass. Figure 21-26 Embryonal carcinoma shows sheets of undifferentiated cells as well as primitive glandular differentiation. The nuclei are large and hyperchromatic. authorities allow for focal AFP positivity within an embryonal carcinoma without classifying the tumor as a mixed tumor. However, some purists designate any AFP positivity in an embryonal carcinoma, even if unaccompanied by yolk sac differentiation on the H&E stained section, as focal yolk sac tumor in a mixed tumor. Yolk Sac Tumor Also known as infantile embryonal carcinoma or endodermal sinus tumor, the yolk sac tumor is of interest because it is the most common testicular tumor in infants and children up to 3 years of age, and in this age group, it has a very good prognosis. In adults, the pure form of this tumor is rare; instead, yolk sac elements frequently occur in combination with embryonal carcinoma. Morphology. Grossly, the tumor is nonencapsulated, and on cross-section, it presents a homogeneous, yellow-white, mucinous appearance. Characteristic on microscopic examination is a lacelike (reticular) network of medium-sized cuboidal or elongated cells. In addition, papillary structures or solid cords of cells may be found. In approximately 50% of tumors, structures resembling endodermal sinuses (Schiller-Duval bodies) may be seen; these consist of a mesodermal core with a central capillary and a visceral and parietal layer of cells resembling primitive glomeruli. Present within and outside the cytoplasm are eosinophilic, hyalin-like globules in which AFP and α1 -antitrypsin can be demonstrated by immunocytochemical staining. The presence of AFP in the tumor cells is highly characteristic, and it underscores their differentiation into yolk sac cells. Choriocarcinoma Choriocarcinoma is a highly malignant form of testicular tumor that is composed of both cytotrophoblastic and syncytiotrophoblastic cells. Identical tumors may arise in the placental tissue, ovary, or sequestered rests of totipotential cells 1044 (e.g., in the mediastinum or abdomen). In its "pure" form, choriocarcinoma is rare, constituting fewer than 1% of all germ cell tumors. As will be emphasized later, foci of choriocarcinoma are much more common in mixed patterns. Morphology. Despite their aggressive behavior, pure choriocarcinomas are usually small lesions. Often, they cause no testicular enlargement and are detected only as a small palpable nodule. Because they are rapidly growing, they may outgrow their blood supply, and sometimes the primary testicular focus is replaced by a small fibrous scar, leaving only widespread metastases. Typically, these tumors are small, rarely larger than 5 cm in diameter. Hemorrhage and necrosis are extremely common. Histologically, the tumors contain two cell types ( Fig. 21-27 ). The syncytiotrophoblastic cell is large and has many irregular or lobular hyperchromatic nuclei and an abundant eosinophilic vacuolated cytoplasm. As might be expected, HCG can be readily demonstrated in the cytoplasm of syncytiotrophoblastic cells. The cytotrophoblastic cells are more regular and tend to be polygonal with distinct cell borders and clear cytoplasm; they grow in cords or masses and have a single, fairly uniform nucleus. More anatomic details are available in the discussion of these neoplasms in the female genital tract ( Chapter 22 ). Teratoma The designation teratoma refers to a group of complex tumors having various cellular or organoid components reminiscent of normal derivatives from more than one germ layer. They may occur at any age from infancy to adult life. Pure forms of teratoma are fairly common in infants and children, second only in frequency to yolk sac tumors. In adults, pure teratomas are rare, constituting 2% to 3% of germ cell tumors. As with embryonal carcinomas, their frequency in combination with other histologic types is about 45%. Figure 21-27 Choriocarcinoma shows clear cytotrophoblastic cells with central nuclei and syncytiotrophoblastic cells with multiple dark nuclei embedded in eosinophilic cytoplasm. Hemorrhage and necrosis are prominent. Morphology. Grossly, teratomas are usually large, ranging from 5 to 10 cm in diameter. Because they are composed of various tissues, the gross appearance is heterogeneous, with solid, sometimes cartilaginous and cystic areas ( Fig. 21-28 ). Hemorrhage and necrosis usually indicate admixture with embryonal carcinoma, choriocarcinoma, or both. Teratomas are composed of a heterogeneous, helter-skelter collection of differentiated cells or organoid structures, such as neural tissue, muscle bundles, islands of cartilage, clusters of squamous epithelium, structures reminiscent of thyroid gland, bronchial or bronchiolar epithelium, and bits of intestinal wall or brain substance, all embedded in a fibrous or myxoid stroma ( Fig. 21-29 ). Elements may be mature (resembling various tissues within the adult) or immature (sharing histologic features with fetal or embryonal tissue). Dermoid cysts and epidermoid cysts, common in the ovary ( Chapter 22 ), are rare in the testis. These cysts should not be considered teratomas, since they have a uniformly benign behavior regardless of the patient's age. Rarely, non-germ cell tumors may arise in a teratoma. These tumors are referred to as "teratoma with malignant transformation," and they reveal malignancy in derivatives of one or more germ cell layers. Thus, there may be a focus of squamous cell carcinoma, mucin-secreting adenocarcinoma, or sarcoma. The importance of recognizing a non-germ cell malignancy arising in a teratoma is that when the non-germ cell component spreads outside of the testis it does not respond to chemotherapy, and the only hope for cure resides in the local resection of the tumor. These non-germ cell malignancies have some of the same chromosome abnormalities (isochromosome 12p) as the germ cell tumors from which they arose. In children, differentiated mature teratomas may be expected to behave as benign tumors, and almost all these patients have a good prognosis. In the postpubertal male, all teratomas are regarded as malignant and capable of metastatic behavior, regardless of whether the elements are mature or immature. Consequently, it is not critical to note histologic differentiation in a postpubertal male with a testicular teratoma. Figure 21-28 Teratoma of the testis. The variegated cut surface with cysts reflects the multiplicity of tissue found histologically. 1045 Figure 21-29 Teratoma of the testis consisting of a disorganized collection of glands, cartilage, smooth muscle, and immature stroma. Mixed Tumors About 60% of testicular tumors are composed of more than one of the "pure" patterns. Common mixtures include teratoma, embryonal carcinoma, and yolk sac tumor; seminoma with embryonal carcinoma; and embryonal carcinoma with teratoma (teratocarcinoma). In most instances, the prognosis is worsened by the inclusion of more aggressive elements. Clinical Features of Testicular Tumors. From a clinical standpoint, tumors of the testis are segregated into two broad categories: seminoma and nonseminomatous germ cell tumors (NSGCT). NSGCT is an umbrella designation that includes tumors of one histologic type, such as embryonal cell carcinoma, as well as those with more than one histologic pattern. As is evident from the later discussion, seminomas and NSGCT not only present with somewhat distinctive clinical features, but they also differ with respect to therapy and prognosis. First we offer some general comments on the clinical manifestations of testicular tumors as a group. Although painless enlargement of the testis is a characteristic feature of germ cell neoplasms, any testicular mass should be considered neoplastic unless proved otherwise. Biopsy of a testicular neoplasm is associated with a risk of tumor spillage, which would necessitate excision of the scrotal skin in addition to orchiectomy. Consequently, the standard management of a solid testicular mass is radical orchiectomy based on the presumption of malignancy. Testicular tumors have a characteristic mode of spread, the knowledge of which is helpful in treatment. Lymphatic spread is common to all forms of testicular tumors, and in general, retroperitoneal para-aortic nodes are the first to be involved. Subsequent spread may occur to mediastinal and supraclavicular nodes. Hematogenous spread is primarily to the lungs, but liver, brain, and bones may also be involved. Although most testicular tumors metastasize "true," the histology of metastases may sometimes be different from that of the testicular lesion. Thus, an embryonal carcinoma may present a teratomatous picture in the secondary deposits. Conversely, a teratoma may show foci of choriocarcinoma in the lymph nodes. As was discussed earlier, because all these tumors are derived from totipotential germ cells, the apparent "forward" and "backward" differentiation that is seen in different locations is not entirely surprising. Another explanation for the differing morphologic patterns at metastatic sites is that the primary tumor is mixed, and that minor components in the primary lesion, that were unresponsive to chemotherapy survived, resulting in the dominant metastatic pattern. With this background, we now highlight the clinical differences between seminoma and NSGCT. Seminomas tend to remain localized to the testis for a long time; hence, approximately 70% present in clinical stage I (discussed later). In contrast, approximately 60% of patients with NSGCT present with advanced clinical disease (stages II and III). Metastases from seminomas typically involve lymph nodes. Hematogenous spread occurs later in the course of dissemination. NSGCT not only metastasize earlier but also use the hematogenous route more frequently. The rare pure choriocarcinoma is the most aggressive of the NSGCT. It might not cause any testicular enlargement but instead spreads predominantly and rapidly by the bloodstream. Therefore, lungs and liver are involved early in virtually every case. From a therapeutic viewpoint, seminomas are extremely radiosensitive, whereas NSGCT are relatively radioresistant. To summarize, as compared with seminomas, NSGCT are biologically more aggressive and in general have a poorer prognosis. In the United States, three clinical stages of testicular tumors are defined: • Stage I: Tumor confined to the testis, epididymis, or spermatic cord • Stage II: Distant spread confined to retroperitoneal nodes below the diaphragm • Stage III: Metastases outside the retroperitoneal nodes or above the diaphragm Stages II and III are further subdivided ("early" or "advanced") on the basis of tumor burden in the secondary deposits. Germ cell tumors of the testis often secrete polypeptide hormones and certain enzymes that can be detected in blood by sensitive assays. Such biologic markers include α- fetoprotein (AFP), human chorionic gonadotrophin (HCG), placental alkaline phosphatase, placental lactogen, and lactate dehydrogenase (LDH). HCG, AFP, and LDH are widely used clinically and have proved to be valuable in the diagnosis and management of testicular cancer. Recent studies suggest that certain molecular markers may be of value in diagnosis of germ cell tumors. For example, the transcription factor encoded by OCT3/4 gene is expressed in primordial germ cells, as well as in seminomas and embryonal carcinomas, and testicular germ cell tumors reveal inactivation of the X- chromosome. These can be detected by immunoperoxidase and PCR techniques, respectively. LDH is produced in many tissues, including skeletal and cardiac muscles; hence, elevations of this enzyme are not specific for testicular tumors. The degree of LDH elevation correlates with the mass of tumor cells, however, and the levels of this enzyme provide a tool to assess tumor burden. AFP is the major serum protein of the early fetus and is synthesized by the fetal gut, liver cells, and yolk sac. One year after birth, the serum levels of AFP fall to less than 16 ng/mL, which is undetectable except by the most sensitive assays. HCG is a glycoprotein consisting of two dissimilar polypeptide units called α and β. It is normally synthesized and secreted by the 1046 placental syncytiotrophoblast. The β subunit of HCG has unique sequences that are not shared with other human glycoprotein hormones; therefore, the detection of HCG in the serum is based on a radioimmunoassay using antibodies to its β chain. As might be expected from the histogenesis and morphology, elevated levels of these markers are most often associated with nonseminomatous tumors. Marked elevation of serum AFP or HCG levels is produced by yolk sac tumor and choriocarcinoma elements, respectively. Both these markers are elevated in more than 80% of patients with NSGCT at the time of diagnosis. In the context of testicular tumors, the value of serum markers is fourfold: • In the evaluation of testicular masses • In the staging of testicular germ cell tumors. For example, after orchiectomy, persistent elevation of HCG or AFP indicates stage II disease even if the lymph nodes appear of normal size by computed tomography scanning. • In assessing tumor burden. The levels of LDH in particular are related to tumor mass and provide an independent prognostic marker in patients with these tumors. • In monitoring the response to therapy. After eradication of tumors, there is a rapid fall in serum level of AFP and HCG. With serial measurements, it is often possible to predict recurrence before the patients become symptomatic or develop any other clinical signs of relapse. As was stated earlier, approximately 15% of seminomas have syncytiotrophoblastic giant cells and an associated relatively minimal elevation of HCG levels. The prognosis of these tumors, however, is no different than those without HCG elevation. The therapy and prognosis of testicular tumors depend largely on clinical stage and on the histologic type. Seminoma, which is extremely radiosensitive and tends to remain localized for long periods, has the best prognosis. More than 95% of patients with stage I and II disease can be cured. Among nonseminomatous tumors, the histologic subtype does not influence the prognosis significantly; hence, these tumors are treated as a group. Although they do not share the excellent prognosis of seminoma, approximately 90% of patients with nonseminomatous tumors can achieve complete remission with aggressive chemotherapy, and most can be cured. Pure choriocarcinoma has a dismal prognosis. However, when it is a minor component of a mixed germ cell tumor, the prognosis is not so adversely affected. With all testicular tumors, distant metastases, if present, usually occur within the first 2 years after treatment. Tumors of Sex Cord-Gonadal Stroma As is indicated in Table 21-5 , sex cord-gonadal stroma tumors are subclassified on the basis of their presumed histogenesis and differentiation. The two most important members of this group—Leydig cell tumors (derived from the stroma) and Sertoli cell tumors (derived from the sex cord)—are described here. Details of these tumors and others not described can be found in a review. Leydig (Interstitial) Cell Tumors Tumors of Leydig cells are particularly interesting because they may elaborate androgens or combinations of androgens and estrogens, and some have also elaborated corticosteroids.  They arise at any age, although most of the reported cases have been noted between 20 and 60 years of age. As with other testicular tumors, the most common presenting feature is testicular swelling, but in some patients, gynecomastia may be the first symptom. In children, hormonal effects, manifested primarily as sexual precocity, are the dominating features. Morphology. These neoplasms form circumscribed nodules, usually less than 5 cm in diameter. They have a distinctive golden brown, homogeneous cut surface. Histologically, tumorous Leydig cells usually are remarkably similar to their normal forebears in that they are large and round or polygonal, and they have an abundant granular eosinophilic cytoplasm with a round central nucleus. Cell boundaries are often indistinct. The cytoplasm frequently contains lipid granules, vacuoles, or lipofuscin pigment, but most characteristically, rod- shaped crystalloids of Reinke occur in about 25% of the tumors. Approximately 10% of the tumors in adults are invasive and produce metastases; most are benign. Sertoli Cell Tumors (Androblastoma) These tumors may be composed entirely of Sertoli cells or may have a component of granulosa cells. Some induce endocrinologic changes. Either estrogens or androgens may be elaborated but only infrequently in sufficient quantity to cause precocious masculinization or feminization. Occasionally, as with Leydig cell tumors, gynecomastia appears. Morphology. These neoplasms appear as firm, small nodules with a homogeneous gray-white to yellow cut surface. Histologically, the tumor cells are arranged in distinctive trabeculae with a tendency to form cordlike structures resembling immature seminiferous tubules. Most Sertoli cell tumors are benign, but occasional tumors (approximately 10%) are more anaplastic and pursue a malignant course. Gonadoblastoma Gonadoblastomas are rare neoplasms containing a mixture of germ cells and gonadal stromal elements, almost always arising in dysgenetic gonads. In some cases, the germ cell component becomes malignant, giving rise to an invasive seminoma. Testicular Lymphoma Although not primarily a tumor of the testis, testicular lymphoma is included here because affected patients present with only a testicular mass. Lymphomas account for 5% of testicular neoplasms and constitute the most common form of testicular neoplasm in men over the age of 60. In most cases, disseminated disease is already present at the time of detection of the testicular mass; only rarely does it remain confined to the testis. The histologic type in almost all cases is the diffuse large cell lymphoma (see non- Hodgkin lymphomas, Chapter 14 ). The prognosis is extremely poor. 1047 MISCELLANEOUS LESIONS OF THE TUNICA VAGINALIS Brief mention should be made of the tunica vaginalis. As a serosa-lined sac immediately proximal to the testis and epididymis, it may become involved by any lesion arising in these two structures. Clear serous fluid may accumulate from neighboring infections or tumors, often spontaneously and without apparent cause (hydrocele). Considerable enlargement of the scrotal sac is produced, which can be readily mistaken for testicular enlargement. By transillumination, however, it is usually possible to define the clear, translucent character of the contained substance, and many times the opaque testis can be outlined within this fluid-filled space. Hydrocele sacs frequently contain benign mesothelial proliferations. Rarely, malignant mesotheliomas also can be seen arising from the tunica vaginalis. Hematocele indicates the presence of blood in the tunica vaginalis. It is an uncommon condition that is usually encountered only when there has been either direct trauma to the testis or torsion of the testis with hemorrhagic suffusion into the surrounding tunica vaginalis or in hemorrhagic diseases associated with widespread bleeding diatheses. Chylocele refers to the accumulation of lymph in the tunica and is almost always found in patients with elephantiasis who have widespread, severe lymphatic obstruction. For clarity's sake, mention should be made of the spermatocele and varicocele, which refer to a small cystic accumulation of semen in dilated efferent ducts or ducts of the rete testis (spermatocele) or to a dilated vein in the spermatic cord (varicocele), respectively. Varicoceles may be asymptomatic but have also been implicated in some men as a contributing factor to infertility, whereby they may be repaired surgically. Prostate In the normal adult, the prostate weighs approximately 20 grams. The prostate is a retroperitoneal organ encircling the neck of the bladder and urethra and is devoid of a distinct capsule. In the adult, prostatic parenchyma can be divided into four biologically and anatomically distinct zones or regions: the peripheral, central, and transitional zones and the region of the anterior fibromuscular stroma ( Fig. 21-30 ). The types of proliferative lesions are different in each region. For example, most hyperplasias arise in the transitional zone, whereas most carcinomas originate in the peripheral zone. Histologically, the prostate is a compound tubuloalveolar organ, which, in one plane of section, presents small to fairly large glandular spaces lined by epithelium. Characteristically, the glands are lined by two layers of cells: a basal layer of low cuboidal epithelium covered by a layer of columnar secretory cells ( Fig. 21-31 ). In many areas, there are small papillary inbuddings of the epithelium. These glands all have a distinct basement membrane and are separated by an abundant fibromuscular stroma. Testicular androgens are clearly of prime importance in controlling prostatic growth because castration leads to atrophy of the prostate. Only three pathologic processes affect the prostate gland with sufficient frequency to merit discussion: inflammation, benign nodular enlargement, and tumors. Of these three, the benign nodular enlargements are by far the most common and Figure 21-30 Adult prostate. The normal prostate contains several distinct regions, including a central zone (CZ), a peripheral zone (PZ), a transitional zone (TZ), and a periurethral zone. Most carcinomas arise from the peripheral glands of the organ and may be palpable during digital examination of the rectum. Nodular hyperplasia, in contrast, arises from more centrally situated glands and is more likely to produce urinary obstruction early on than is carcinoma. occur so often in advanced age that they can almost be construed as a "normal" aging process. Prostatic carcinoma is also an extremely common lesion in men and therefore merits careful consideration. The inflammatory processes are, for the most part, of less clinical significance and can be treated briefly. INFLAMMATIONS Prostatitis may be divided into several categories: acute and chronic bacterial prostatitis and chronic abacterial prostatitis and granulomatous prostatitis.  Figure 21-31 Benign prostate gland with basal cell and secretory cell layer. 1048 Acute bacterial prostatitis typically results from bacteria that cause urinary tract infections. Thus, most cases are caused by various strains of E. coli, other Gram-negative rods, enterococci, and staphylococci. The organisms become implanted in the prostate, usually by intraprostatic reflux of urine from the posterior urethra or from the urinary bladder, but occasionally, they seed the prostate by the lymphohematogenous routes from distant foci of infection. Prostatitis sometimes follows some surgical manipulation on the urethra or prostate gland itself, such as catheterization, cystoscopy, urethral dilation, or resection procedures on the prostate. Clinically, acute bacterial prostatitis is associated with fever, chills, and dysuria. On rectal examination, the prostate is exquisitely tender and boggy. The diagnosis can be established by urine culture and clinical features. Chronic bacterial prostatitis is difficult to diagnose and treat. It may present with low back pain, dysuria, and perineal and suprapubic discomfort. Alternatively, it may be virtually asymptomatic. A common clinical setting is recurrent urinary tract infections (cystitis, urethritis) caused by the same organism. Because most antibiotics penetrate the prostate poorly, bacteria find safe haven in the parenchyma and constantly seed the urinary tract. Diagnosis of chronic bacterial prostatitis depends on documentation within the expressed prostatic secretions of leukocytosis and positive bacterial cultures of the prostatic secretions. In most cases, there is no antecedent acute attack, and the disease appears insidiously and without obvious provocation. The implicated organisms are the same as those cited as causes of acute prostatitis. Chronic abacterial prostatitis is the most common form of prostatitis seen today. Clinically, it is indistinguishable from chronic bacterial prostatitis. There is no history, however, of recurrent urinary tract infection. Expressed prostatic secretions contain more than 10 leukocytes per high-power field, but bacterial cultures are uniformly negative. Granulomatous prostatitis may be specific, where an etiologic infectious agent may be identified. In the United States, the most common cause is related to instillation within the bladder of Bacillus Calmette-Guérin (BCG) for treatment of superficial bladder cancer. BCG is an attenuated tuberculous strain that gives rise to a histologic picture in the prostate indistinguishable from that seen with systemic tuberculosis. However, in this setting, the finding of granulomas in the prostate is of no clinical significance, requiring no treatment. Fungal granulomatous prostatitis is typically seen only in immunocompromised hosts. Nonspecific granulomatous prostatitis is relatively common and represents a reaction to secretions from ruptured prostatic ducts and acini. Although some of these men have a recent history of urinary tract infection, bacteria are not seen within the tissue in these cases. Morphology. Acute prostatitis may appear as minute, disseminated abscesses; as large, coalescent focal areas of necrosis; or as a diffuse edema, congestion, and boggy suppuration of the entire gland. When these reactions are fairly diffuse, they cause an overall soft, spongy enlargement of the gland. In men with symptoms of acute or chronic prostatitis, surgical specimens are uncommonly examined under the microscope, as the disease is treated medically. In fact, biopsy of the prostate in a patient with acute prostatitis is contraindicated, as it may lead to sepsis. It is common in prostate specimens removed surgically (for other reasons) to find histologic evidence of acute or chronic inflammation in the absence of clinical symptoms of prostatitis. In these instances, the etiologic infectious agents have yet to be identified. In the absence of clinical features of prostatitis, these prostate specimens are diagnosed in descriptive terms as showing "acute inflammation" or "chronic inflammation." The histologic diagnosis of "chronic prostatitis," both bacterial and abacterial, should be restricted to those cases of inflammatory reaction in the prostate characterized by the aggregation of numerous lymphocytes, plasma cells, and macrophages as well as neutrophils within the prostatic substance only if accompanied by clinical signs and symptoms of chronic prostatitis. BENIGN ENLARGEMENT Nodular Hyperplasia (Benign Prostatic Hyperplasia) Nodular hyperplasia, still referred to by the term benign prostatic hyperplasia (BPH), is an extremely common disorder in men over age 50.  It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress and narrow the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra. Incidence. Histologic evidence of nodular hyperplasia can be seen in approximately 20% of men 40 years of age, a figure that increases to 70% by age 60 and to 90% by age 70. There is no direct correlation, however, between histologic changes and clinical symptoms. Only 50% of those who have microscopic evidence of nodular hyperplasia have clinically detectable enlargement of the prostate, and of these individuals, only 50% develop clinical symptoms. Nodular hyperplasia of the prostate is a problem of enormous magnitude, approximately 30% of white American males over 50 years of age have moderate to severe symptoms. Etiology and Pathogenesis. Much has been learned about the origins of prostatic hyperplasia. There is little doubt that this form of prostatic enlargement is related to the action of androgens. For example, prepubertal castration prevents the development of nodular hyperplasia. Dihydrotestosterone (DHT), a metabolite of testosterone, is the ultimate mediator of prostatic growth ( Fig. 21-32 ). It is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, these cells are the main site for the synthesis of DHT. Once synthesized, DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. Although testosterone can also bind to the androgen receptors and cause growth stimulation, 1049 Figure 21-32 Simplified scheme of the pathogenesis of prostatic hyperplasia. The central role of the stromal cells in generating dihydrotestosterone should be noted. DHT is 10 times more potent because it dissociates from the androgen receptor more slowly. While DHT appears to be the major trophic factor mediating prostatic hyperplasia, estrogens also appear to play a role, perhaps by rendering cells more susceptible to the action of DHT. Stromal-epithelial interactions mediated by peptide growth factors are also integral to the process. In addition to the mechanical effects Figure 21-33 Nodular prostatic hyperplasia. A, Well-defined nodules of BPH compress the urethra into a slitlike lumen. B, A microscopic view of a whole mount of the prostate shows nodules of hyperplastic glands on both sides of the urethra. of the enlarged prostate, clinical symptoms of lower urinary tract obstruction are also due to smooth muscle-mediated contraction of the prostate. The tension of prostate smooth muscle is mediated by the α1 -adrenoreceptor localized to the prostatic stroma. This is the basis of the common use of α-adrenergic receptor antagonists for the relief of urinary obstruction in patients with BPH. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase is given to men with this condition. Therapy with 5α-reductase inhibitor markedly reduces the DHT content of the prostate, and in a proportion of cases, there is a decrease in prostatic volume and urinary obstruction. The fact that not all patients benefit from androgen-depriving therapy suggests that prostatic hyperplasia may be etiologically heterogeneous, and in some cases, factors other than androgens may be more important. Morphology. In the usual case of prostatic enlargement, the prostate weights between 60 and 100 gm. Careful studies have demonstrated that nodular hyperplasia of the prostate originates almost exclusively in the inner aspect of the prostate gland, in the transition zone (see Fig. 21-33A ). The first nodules are composed almost entirely of stromal cells; later, predominantly epithelial nodules arise. From their origin in this strategic location, the nodular enlargements may encroach on the lateral walls of the urethra to compress it to a slitlike orifice. In some cases, nodular enlargement may project up into the floor of the urethra as a hemispheric mass directly beneath the mucosa of the urethra, which is termed "median lobe hypertrophy" by clinicians. 1050 On cross-section of the affected prostate, the nodules usually are fairly readily identified. They vary in color and consistency. In nodules with primarily glandular proliferation, the tissue is yellow-pink with a soft consistency, and a milky white prostatic fluid oozes out of these areas. In those primarily due to fibromuscular involvement, each nodule is pale gray, tough, does not exude fluid, and is less clearly demarcated from the surrounding prostatic capsule. Although the nodules do not have true capsules, the compressed surrounding prostatic tissue creates a plane of cleavage about them, which the surgeon uses in the enucleation of prostatic masses as a treatment for very large growths of BPH. Microscopically, the hallmark of BPH is nodularity due to glandular proliferation or dilation and to fibrous or muscular proliferation of the stroma ( Fig. 21-33B ). The proportion of these elements varies from nodule to nodule, ranging from purely stromal fibromuscular nodules to fibroepithelial nodules with a glandular predominance. Glandular proliferation takes the form of aggregations of small to large to cystically dilated glands, lined by two layers, an inner columnar and an outer cuboidal or flattened epithelium, based on an intact basement membrane. Although the epithelium is characteristically thrown up into numerous papillary buds and infoldings, this finding is not specific for BPH. The diagnosis of BPH cannot usually be made on needle biopsy, as the histology of glandular or mixed glandular-stromal nodules of BPH cannot be appreciated on this limited sampling. Also, needle biopsies do not typically sample the transition zone where BPH occurs, and with the exception of stromal nodules, the histology of the prostate glands on needle biopsy does not correlate with gland size or lower urinary tract obstructive symptoms. Two other histologic changes associated with BPH are (1) foci of squamous metaplasia and (2) small areas of infarction. The former tend to occur in the margins of the foci of infarction as nests of metaplastic reactive squamous cells that can be confused with adenocarcinoma of the prostate or urothelial carcinoma involving the prostate. Clinical Course. Symptoms of nodular hyperplasia, when present, relate to two secondary effects: (1) compression of the urethra with difficulty in urination and (2) retention of urine in the bladder with subsequent distention and hypertrophy of the bladder, infection of the urine, and development of cystitis and renal infections. Patients experience frequency, nocturia, difficulty in starting and stopping the stream of urine, overflow dribbling, and dysuria (painful micturition). In many cases, sudden, acute urinary retention appears for unknown reasons and persists until the patient receives emergency catheterization. In addition to these difficulties in urination, prostatic enlargement results in the inability to empty the bladder completely. Presumably, this inability is due to the raised level of the urethral floor so that, at the conclusion of micturition, a considerable amount of residual urine is left. This residual urine provides a static fluid that is vulnerable to infection. On this basis, catheterization or surgical manipulation provides a real danger of the introduction of organisms and the development of pyelonephritis. Many secondary changes occur in the bladder, such as hypertrophy, trabeculation, and diverticulum formation. Hydronephrosis or acute retention, with secondary urinary tract infection and even azotemia or uremia, may develop. Nodular hyperplasia is not considered to be a premalignant lesion. Mild cases of BPH may be treated without medical or surgical therapy, such as by decreasing fluid intake, especially prior to bedtime; moderating the intake of alcohol and caffeine-containing products; and following timed voiding schedules. The most commonly used and effective medical therapy for symptoms relating to benign hyperplasia are α-blockers, which decrease prostate smooth muscle tone via inhibition of α1 -adrenergic receptors.   Another common pharmacologic therapy aims to decrease symptoms by physically shrinking the prostate with an agent that inhibits DHT. Various plant extracts are also in wide use as a treatment (phytotherapy) for this condition, although their efficacies have not been well documented. For moderate to severe cases that are recalcitrant to medical therapy, a wide range of more invasive procedures exists. Transurethral resection of the prostate (TURP) is effective in reducing symptoms, improving flow rates, and decreasing postvoid residual urine. It is indicated as a first line of therapy in certain circumstances, such as recurrent urinary retention. Owing to its morbidity and cost, alternative procedures have been developed. These include high- intensity focused ultrasound, laser therapy, hyperthermia, transurethral electrovaporization, intraurethral stents, and transurethral needle ablation using radiofrequency. TUMORS Adenocarcinoma Adenocarcinoma of the prostate is the most common form of cancer in men and the second leading cause of cancer death. In 2003, approximately 220,900 new cases were detected, of which approximately 29,000 are likely to be lethal. In addition to these lethal neoplasms, there is an even more frequent anatomic form of prostatic cancer in which a microscopic focus of cancer is discovered as an incidental finding, either at postmortem examination or in a surgical specimen that was removed for other reasons (e.g., nodular hyperplasia). Incidence. Cancer of the prostate is typically a disease of men over age 50. However, in men who are at increased risk (see the discussion of etiology), recommendations are for screening for prostate cancer to begin at age 40. Even for men without increased risk factors, consideration has been given to screening, initially at age 40 and again at age 45, to detect uncommon cases of prostate cancer before they become incurable. The age-adjusted incidence of prostate cancer in the United States is 69 per 100,000. The incidence of latent prostatic cancer is even higher. It increases from 20% in men in their fifties to approximately 70% in men between the ages of 70 and 80 years. There are some remarkable and puzzling national and racial differences in the incidence of this disease. Prostatic cancer is uncommon in Asians. The age-adjusted incidence per 100,000 among Japanese is in the range of 3 to 4 and that for the Chinese in Hong Kong is only 1, compared with a rate of 50 to 60 among whites in the United States. The disease is even more prevalent among blacks in the 1051 United States, who have the highest rate among 24 countries having reasonably accurate mortality data. Despite the greater than tenfold differences in the incidence of clinically evident cancers, the age-adjusted incidence of the so-called latent or histologic form of prostate cancer is virtually identical in Japanese and U.S. white populations. Assuming that prostate cancer, similar to other cancers, arises from accumulation of multiple genetic events, these observations indicate that whereas the initial molecular events that give rise to latent cancers occur at the same rate in Japanese and American men, the probability of acquiring additional mutations, presumably environmentally induced, is lower in Japanese men. This notion is supported by the fact that in Japanese immigrants to the United States, the incidence of the disease seems to have risen, but not nearly to the level of that of native-born Americans. Also, as the diet in Asia becomes more Westernized, the incidence of clinical prostate cancer in this region of the world appears to be increasing. Etiology. Little is known about the causes of prostatic cancer. Several risk factors, such as age, race, family history, hormone levels, and environmental influences, are suspected of playing roles.    The association of this form of cancer with advancing age and the enigmatic differences among races have already been mentioned. The tendency for the incidence of this disease to rise among those having a low-incidence rate when they migrate to a high-incidence locale is consistent with a role for environmental influences. There are many candidate environmental factors, but none has been proven to be causative. For example, increased consumption of fats has been implicated. Other dietary products, for which there is evidence that they may prevent, inhibit, or delay progression of prostate cancer, include lycopenes (found in tomatoes), vitamin A, vitamin E, selenium, and soy products. As with nodular hyperplasia of the prostate, androgens are believed to play a role in the pathogenesis of prostate cancer. Support for this general thesis lies in the inhibition of these tumors that can be achieved with orchiectomy. Neoplastic epithelial cells, similar to their normal counterparts, possess androgen receptors. No significant or consistent alterations in the levels or metabolism of testosterone, however, have been disclosed in any studies. It seems more likely, therefore, that the role of hormones in this malignancy is essentially permissive because androgens are required for the maintenance of the prostatic epithelium. Androgen receptor (AR) gene mutations have been reported in only a minority of prostate cancers. However, AR gene amplification may also influence androgen-sensitivity of prostatic epithelium. The AR gene is polymorphic, with individuals having variable lengths of CAG repeats. Studies have shown that prostate cells with short CAG repeats have an increased sensitivity to androgens. The shortest CAG repeats on average are found in African Americans, Caucasians have an intermediate length, and Asians have the longest. Correspondingly, African Americans have the highest incidence and mortality of prostate cancer, and Asians have much lower risk. Much interest has focused on the genetics and molecular pathogenesis of prostate cancer.      In approximately 10% of white American men, the development of prostate cancer has been linked to germ line inheritance of prostate cancer susceptibility genes. In one third of these familial cases, a susceptibility gene has been mapped to chromosome 1q24-25. Subsequently, numerous other chromosomal loci have been linked to prostate cancer. Men with one first-degree relative with prostate cancer have a twofold higher risk, and those with two first-degree relatives have a fivefold greater risk of developing prostate cancer compared with men with no family history. Men with a strong family history of prostate cancer also tend to develop the disease at an earlier age. In addition, putative cancer-suppressor genes that are lost early in prostate carcinogenesis have been localized to chromosomes 8p, 10q, 13q, and 16q. In most instances, the identity of the relevant genes at these loci is unknown. p53 mutations in primary prostate cancer are relatively low and are more frequently seen in metastatic disease, suggesting that p53 mutations are late events in prostate carcinogenesis. Other tumor-suppressor genes that are thought to play a role in prostate cancer include PTEN and KAI1. Prostate cancers also show a relatively frequent loss of E-cadherin and CD44. Although there are conflicting studies concerning HER-2/neu overexpression in prostate cancer, the prevailing view is that levels are relatively low; therefore, it is unlikely that prostate cancer will benefit from therapy with currently available antibodies to HER- 2/neu. Using cDNA microarray technology, a number of studies have identified cohorts of genes that are specifically overexpressed in prostate cancer, including hepsin, a transmembrane serine protease, and α-methylacyl COA racemase, an enzyme involved in the breakdown of branched fatty acids. Using similar genomic approaches, the transcription factor EZH2 has been shown to be consistently overexpressed in locally aggressive and metastatic prostate cancer. One of the most common genetic alterations in prostate cancer is hypermethylation of glutathione S-transferase (GSTP1) gene promoter. More than 90% of prostate cancers show hypermethylation of the gene, which turns off its expression. The GSTP1 gene is located on chromosome 11q13, and it is an important part of the pathway that prevents damage from a wide range of carcinogens. Morphology. The terms "prostate cancer" and "prostate adenocarcinoma," when used without qualifications, refer to the common or acinar variant of prostate cancer. Our discussion here is focused on this variant. Other forms are briefly discussed later. In approximately 70% of cases, carcinoma of the prostate arises in the peripheral zone of the gland, classically in a posterior location, often rendering it palpable on rectal examination ( Fig. 21-34 ). Characteristically, on cross-section of the prostate, the neoplastic tissue is gritty and firm, but when embedded within the prostatic substance, it may be extremely difficult to visualize and be more readily apparent on palpation. Spread of prostate cancer occurs by direct local invasion and through the bloodstream and lymph. Local extension most commonly involves the seminal vesicles and the base of the urinary bladder, which may result in ureteral obstruction. Hematogenous spread occurs chiefly to the bones, particularly the axial skeleton, but some lesions spread widely to viscera. Massive visceral dissemination is an exception rather than the rule. The bony metastases are typically osteoblastic and, in men, point strongly to prostatic cancer ( Fig. 21-35 ). The bones that are commonly involved, in descending order of frequency, are lumbar spine, proximal 1052 Figure 21-34 Adenocarcinoma of the prostate. Carcinomatous tissue is seen on the posterior aspect (lower left). Note the solid whiter tissue of cancer in contrast to the spongy appearance of the benign peripheral zone on the contralateral side. femur, pelvis, thoracic spine, and ribs. Lymphatic spread occurs initially to the obturator nodes followed by perivesical, hypogastric, iliac, presacral, and paraaortic nodes. Lymph node spread occurs frequently and often precedes spread to the bones. Histologically, most lesions are adenocarcinomas that produce well-defined, readily demonstrable gland patterns.   The neoplastic glands are typically smaller than benign glands and are lined by a single uniform layer of cuboidal or low columnar epithelium. In contrast to benign glands, prostate cancer glands are more crowded, characteristically lacking branching and papillary infolding. The outer basal layer of cells typical of normal and hyperplastic glands is absent. The cytoplasm of the tumor cells ranges from pale to clear, as is seen in benign glands, to a distinctive amphophilic appearance. Nuclei are large and often contain one or more large nucleoli. There is some variation in nuclear size and shape, but in general, pleomorphism is not marked. Mitotic figures are extremely uncommon. Figure 21-36 A, Photomicrograph of a small focus of adenocarcinoma of the prostate demonstrating small glands crowded in between larger benign glands. B, Higher magnification shows several small malignant glands with enlarged nuclei, prominent nucleoli, and dark cytoplasm, compared to the larger benign gland (top). Figure 21-35 Metastatic osteoblastic prostatic carcinoma within vertebral bodies. The histologic diagnosis of prostate cancer on biopsy specimens is one of the more difficult challenges for pathologists. In part, the difficulty stems from the scant amount of tissue available for histologic examination removed by the needle biopsy; in addition, biopsy often samples only a few malignant glands among many benign glands ( Fig. 21- 36 ). The histologic clues to malignancy may be subtle, thus 1053 increasing the likelihood of underdiagnosis. There are a few histologic findings that are specific for prostate cancer, such as perineural invasion; in general the diagnosis is made on the basis of a constellation of architectural, cytological, and ancillary findings ( Fig. 21-37 ). As was discussed earlier in the chapter, one feature that distinguishes benign and malignant prostate glands is that benign glands contain basal cells that are absent in cancer. Pathologists have exploited this finding by using various immunohistologic markers to label basal cells. Using cDNA microarrays, markers have also been found that are relatively specific for prostate cancer. These markers, while improving the accuracy of the diagnosis of prostate cancer, have their limitations and must be used in conjunction with routine H&E-stained sections. In approximately 80% of cases, prostatic tissue removed for carcinoma also harbors presumptive precursor lesions, referred to as high-grade prostatic intraepithelial neoplasia (PIN).     These lesions consist of benign glands with intra-acinar proliferations of cells that demonstrate nuclear anaplasia. High-grade PIN consists of more widely separated, larger branching glands with papillary infolding, in contrast to invasive cancer, which is typically characterized by small, crowded glands with straight luminal borders. Cytologically, the two processes may be identical. PIN glands are surrounded by a patchy layer of basal cells and an intact basement membrane. There are several lines of evidence that link high-grade PIN to invasive cancer. First, both high- grade PIN and cancer typically predominate in the peripheral zone and are relatively uncommon in other zones. If one compares prostates without cancer to those with cancer, prostates containing cancer have a higher frequency and a greater extent of high-grade PIN. High-grade PIN is also often seen in proximity to cancer, with the cancer in some cases appearing to bud off of the high-grade PIN. Studies have revealed that many of the molecular changes that are seen in invasive cancers are also present in PIN. Such data strongly support the notion that PIN is an intermediate lesion between normal glands and invasive cancer. Figure 21-37 Carcinoma of the prostate showing perineural invasion by malignant glands. Compare to a benign gland (left). Given the above findings, one might wonder why the term "carcinoma in situ" of the prostate is not used for lesions categorized as "high-grade PIN." What is lacking in our knowledge of high-grade PIN is its natural history. How often does untreated high-grade PIN progress to invasive cancer, and if it does progress, how long does it take to do so? What is known is that men with high-grade PIN found on biopsy are at increased risk of having prostate cancer, so repeat biopsy is often performed to look for cancer that might have been missed initially. Grading and Staging. Several grading systems have been described, of which the Gleason system is the best known.    According to the Gleason system, prostate cancers are stratified into five grades on the basis of glandular patterns and degree of differentiation as seen under low magnification. Grade 1 represents the most well-differentiated tumors, in which the neoplastic glands are uniform and round in appearance and are packed into well- circumscribed nodules ( Fig. 21-38 ). By contrast, grade 5 tumors show no glandular differentiation, and the tumor cells infiltrate the stroma in the form of cords, sheets, and nests. The other grades fall in between. Most tumors contain more than one pattern, in which case one assigns a primary grade to the dominant pattern and a secondary grade to the subdominant pattern. The two numeric grades are then added to obtain a combined Gleason grade or score. Thus, for example, a tumor with a dominant grade 3 and a secondary grade 4 would achieve a Gleason score of 7. Tumors with only one pattern are treated as if their primary and secondary grades are the same; hence, the number is doubled. Thus, under this schema the most well-differentiated tumors have a Gleason score of 2 (1 + 1) and the least-differentiated tumors merit a score of 10 (5 + 5). Gleason scores are often combined into groups with similar biologic behavior: 2 to 4 representing well-differentiated cancer, 5 to 6 representing intermediate-grade cancer, 7 representing moderate to poorly differentiated cancer, and 8 to 10 representing high-grade cancer. Gleason scores of 2 to 4 are typically found in small tumors within the transition zone. In surgical specimens, such low-grade cancer is typically an incidental finding on transurethral resection performed for symptoms of BPH. The majority of potentially treatable cancers that are detected on needle biopsy have Gleason scores of 5 to 7. Tumors with Gleason scores 8 to 10 tend to be advanced cancers that are unlikely to be curable. While there is some evidence that certain prostate cancers may become less differentiated over time, in general the Gleason score remains stable over a period of several years. Grading is of particular importance in prostatic cancer because it is the best marker, along with the stage, for predicting prognosis. Staging of prostatic cancer is also important in the selection of the appropriate form of therapy. The most common staging system is the TNM system. Stage T1 refers to cancer found incidentally either on trans-urethral resection done for BPH symptoms (T1a and T1b depending on the extent and grade) or on needle biopsy, typically performed for elevated serum PSA levels (stage T1c).  Stage T2 is organ-confined cancer. Stage T3a and T3b tumors show extraprostatic extension, with and without seminal vesicle invasion, respectively. Stage T4 reflects direct invasion of contiguous organs. Any spread of 1054 Figure 21-38 A, Low-grade (Gleason score 1 + 1 = 2) prostate cancer consisting of back to back, uniformly sized malignant glands. Glands contain eosinophilic intraluminal prostatic crystalloids, a feature that is more commonly seen in cancer than in benign glands and more frequently seen in lower grade than in higher grade prostate cancer. B, Needle biopsy of the prostate with variably sized, more widely dispersed glands of moderately differentiated (Gleason score 3 + 3 = 6) adenocarcinoma. C, Poorly differentiated Gleason score (5 + 5 = 10) adenocarcinoma composed of sheets of malignant cells. tumor to the lymph nodes, regardless of extent, is eventually associated with a fatal outcome, such that the staging system merely records the presence or absence of this finding (N0/N1). Clinical Course. As was discussed earlier, the incidence of cancers found incidentally increases with age, approaching 70% or more in men past the age of 80 years. These microscopic cancers are asymptomatic and are discovered incidentally at autopsy or in tissue removed for nodular hyperplasia of the prostate. The long-term significance of these lesions is still not entirely clear. It is generally accepted that most patients with stage T1a cancer do not show evidence of progressive disease when followed for 10 or more years. Five per cent to 25% of patients, however, do develop local or distant spread. This is more likely in younger patients (less than 60 years), who have a longer life expectancy. For patients in this age group, most authorities recommend careful follow-up studies so that if progression occurs, the cancer can be detected early, at a stage amenable to surgical cure. Stage T1b lesions are more ominous. Approximately 30% to 50% can be expected to progress over a period of 5 years, with a mortality of 20% if left untreated. Patients with clinically localized disease do not have urinary symptoms, and the lesion is discovered by the finding of a suspicious nodule on rectal examination or elevated serum prostate-specific antigen level (discussed later). Most prostatic cancers arise peripherally, away from the urethra; therefore, urinary symptoms occur late. Patients with clinically advanced prostatic cancer may present with urinary symptoms, such as difficulty in starting or stopping the stream, dysuria, frequency, or hematuria. Some patients come to attention because of back pain caused by vertebral metastases. The finding of osteoblastic metastases in bone is virtually diagnostic of this form of cancer in men. The outlook for these patients is universally fatal. Careful digital rectal examination may detect some early prostatic carcinomas because of their posterior location, although the test suffers from both low sensitivity and low specificity. While there are characteristic findings of prostate cancer on transrectal ultrasonography (TRUS) and other imaging modalities, the poor sensitivity and specificity of these tests also limit their diagnostic utility. The major role of TRUS in the diagnosis of prostate cancer is in guiding the placement of the needle biopsies to thoroughly sample the gland. A transperineal or transrectal biopsy is required to confirm the diagnosis. Several procedures are used to determine the extent of disease. The involvement of lymph nodes is poorly detected by computed tomography scans or magnetic resonance imaging. Because microscopic metastases may be missed by either of these two procedures, many centers use pelvic lymphadenectomy as a staging procedure. Some centers forgo pelvic lymphadenectomy prior to surgery in men who are predicted to have a low risk of metastatic disease based on serum PSA levels, clinical stage, and biopsy findings. If pelvic lymph nodes are involved, curative surgery (radical prostatectomy) will often be abandoned. Osseous metastases may be detected by skeletal surveys or the much more sensitive radionuclide bone scanning. Prostate-specific antigen (PSA) has been used in the diagnosis and management of prostate cancer.      PSA is a product of prostatic epithelium and is normally secreted in the semen. It is a serine protease whose function is to cleave 1055 and liquefy the seminal coagulum formed after ejaculation. In normal men, only minute amounts of PSA circulate in the serum. Elevated blood levels of PSA occur in association with localized as well as advanced cancer. In most laboratories, a serum level of 4 ng/mL as reported on laboratory reports is a cut-off point between normal and abnormal. However, as will be discussed below, this simplified approach to serum PSA tests is dangerous and has led to the delay in diagnosis of many prostate cancers. PSA is organ specific but not cancer specific. Although serum levels of PSA are elevated to a lesser extent in benign nodular hyperplasia, as compared to cancer, there is considerable overlap. Other factors such as benign prostatic hyperplasia, prostatitis, infarct, instrumentation of the prostate, and ejaculation also increase serum PSA levels. Furthermore, 20% to 40% of patients with organ-confined prostate cancer have a PSA value of 4.0 ng/mL or less. Whereas most readers of this text will not directly practice pathology, almost all will be confronted with evaluation of a serum PSA test, either as a treating primary care physician, in addressing the results of a family member's or friend's test or, for the male readers, reviewing their own test results. The widespread use of this test, along with its complexity and the corresponding increased risk of it being interpreted incorrectly, warrants greater coverage of this topic. This test differs from most other laboratory tests that a physician can order in that it is a cancer detection test. Consequently, physicians should adopt foolproof mechanisms to ensure that tests come back from the lab, abnormal values are recorded, and patients are contacted for follow-up of elevated levels. Numerous medical malpractice cases result from the mishandling of serum PSA test results and the subsequent delay in diagnosis. Several refinements in the estimation and interpretation of PSA values have been proposed. These include the ratio between the serum PSA value and volume of prostate gland (PSA density), the rate of change in PSA value with time (PSA velocity), the use of age-specific reference ranges, and the ratio of free and bound PSA in the serum. Men with enlarged hyperplastic prostate glands will have higher total serum PSA levels than will men with small glands. The measurement of serum PSA density factors out the contribution of benign prostatic tissue to serum PSA levels. Serum PSA density reflects the PSA produced per gram of prostate tissue. It is calculated by dividing the total serum PSA level by the estimated gland volume (usually determined by transrectal ultrasound measurements), with an upper normal value of approximately 0.15. As men age, their prostates tend to enlarge with benign prostatic hyperplasia. One would then anticipate that, overall, older men would have higher serum PSA levels than younger men. Derived from measurements of serum PSA levels in a large group of men of varying ages without prostate cancer, the recommended age-specific upper reference ranges for serum PSA are 2.5 ng/mL for men 40 to 49 years of age, 3.5 ng/mL for men 50 to 59 years, 4.5 ng/mL for men 60 to 69 years, and 6.5 ng/mL for men 70 to 79 years. Consequently, a serum PSA value of 3.5 might appear as "normal" on a lab test, yet would be a worrisome finding in a man in his forties, warranting additional evaluation. Another way of interpreting serum PSA tests is to assess PSA velocity, also referred to as the rate of change of PSA. Men with prostate cancer demonstrate an increased rate of rise in PSA compared to men who do not have prostate cancer. The rate of change in PSA that best distinguishes between men with and without prostate cancer is 0.75 ng/mL per year. For this test to be valid, it requires that there be at least three PSA measurements over a period of 1.5 to 2 years. That is because there is substantial short-term variability (up to 20%) between repeat PSA measurements. A significant rise in serum PSA levels, despite the latest serum PSA test being below the normal cutoff (<4 ng/mL), is abnormal and should prompt a work-up. Studies have revealed that immunoreactive PSA (the form that is detected by the widely used antibody test) exists in two forms: a major fraction bound to α1 -antichymotrypsin and a minor free fraction. The percentage of free PSA (free PSA ÷ total PSA × 100) is lower in men with prostate cancer than in men with benign prostatic diseases. Furthermore, it appears that per cent free PSA is most valuable in discriminating between benign and malignant disease when the total PSA level is in the "gray zone" of 4 to 10 ng/mL. When per cent free PSA is higher than 25%, it indicates a lower risk of cancer, whereas per cent free PSA values of less than 10% are worrisome for cancer. Until the value of these refinements in the estimation and interpretations of PSA levels is better established, serum PSA by itself cannot be used for detection of early cancer. When combined with rectal examination and transrectal ultrasonography, however, measurement of PSA levels is useful in detection of early-stage cancers. Because many small cancers localized to the prostate may never progress to clinically significant invasive cancers, there is considerable uncertainty about the management of small lesions that are detected because of an elevated PSA level. This has resulted in some controversy regarding the role of widespread screening for prostate cancer. Much effort is therefore being focused on devising criteria by which the localized lesions that are most likely to progress can be distinguished from those that may remain innocuous. Although serum PSA levels are less than perfect for detection of early prostate cancer, there is little doubt that serial measurements of PSA are of great value in assessing the response to therapy. For example, a rising PSA level after radical prostatectomy or radiotherapy for localized disease is indicative of recurrent or disseminated disease. Immunohistochemical localization of PSA on tissue sections can also help the pathologist in determining whether a metastatic tumor originated in the prostate. Cancer of the prostate is treated by surgery, radiotherapy, and hormonal manipulations. More than 90% of patients who are treated by any of these methods can expect to live for 15 years. Currently, the most common treatment for clinically localized prostate cancer is radical prostatectomy. Major improvements in surgical technique, reducing the risk of intra-operative blood loss and postoperative impotence and incontinence, have popularized this procedure. The prognosis following radical prostatectomy is based on the pathologic stage, margin status, and Gleason grade. Alternative treatments for localized prostate cancer are external beam radiotherapy or interstitial radiotherapy, the latter consisting of placing radioactive seeds throughout the prostate (brachytherapy). External beam radiotherapy is also used to treat prostate cancer that is too locally advanced to be cured by surgery. The Gleason grade along with clinical stage and serum PSA values are important factors to predict the outcome following radiotherapy. Because some prostate cancers have a relatively indolent course, it can take as much 1056 as 10 years to see benefit from surgery or radiotherapy. Thus, watchful waiting is an appropriate treatment for many older men or those with significant comorbidity. Even some younger men with prostate cancer may elect watchful waiting if they present with low serum PSA values and limited cancer on biopsy that is not high grade. In these men, the risk of missing more extensive, higher-grade cancer on initial biopsy or progression of cancer that is truly limited at presentation, even with close follow-up and repeat biopsies, must be balanced against the potential morbidity of definitive therapy. Endocrine therapy is the mainstay for treatment of advanced, metastatic carcinoma. Because prostatic cancer cells depend on androgens for their sustenance, the aim of endocrine manipulations is to deprive the tumor cells of testosterone. This can be achieved by orchiectomy or by administration of synthetic agonists of luteinizing hormone-releasing hormone. Long-term administration of luteinizing hormone-releasing hormone agonists (after an initial transient increase in luteinizing hormone secretion) suppresses luteinizing hormone release, achieving in effect a pharmacologic orchiectomy. Although antiandrogen therapy does induce remissions, tumor progression leads to emergence of testosterone-insensitive clones; hence, despite all forms of treatment, patients with disseminated cancers have a poor prognosis. Both antiandrogen therapy and radiation induce morphologic changes in the prostate that alter both the non-neoplastic and cancerous tissue.  Miscellaneous Tumors and Tumor-Like Conditions Although acinar adenocarcinoma of the prostate is the most common tumor within the prostate, brief mention of other, less frequent variants and types is warranted. Prostate adenocarcinomas may also arise from prostatic ducts. Ductal adenocarcinomas arising in peripheral ducts may present in a fashion similar to that of ordinary prostate cancer, whereas those arising in the larger periurethral ducts present with signs and symptoms similar to urothelial cancer (hematuria and urinary obstructive symptoms). Ductal adenocarcinomas are associated with a relatively poor prognosis, although early detection and treatment may be curative with surgery or radiation. Prostate cancer may show squamous differentiation, either following hormone therapy or de novo, resulting in either adenosquamous or pure squamous cancer. Prostate cancers that reveal abundant mucinous secretions are termed colloid carcinoma of the prostate. The most aggressive variant of prostate cancer is small cell cancer. In some cases, the small cell cancer represents dedifferentiation of recurrent acinar adenocarcinoma; in other cases, men present with de novo small cell carcinoma of the prostate. Almost all such cases are rapidly fatal. The most common tumor to secondarily involve the prostate is urothelial cancer.   Two distinct patterns of involvement exist. Large, invasive urothelial cancers can directly invade from the bladder into the prostate. 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