Urethritis

Urethritis is an inflammatory process of the urethra without concurrent bladder infection that is usually, but not always, caused by a sexually transmitted microorganism. Biologic agents associated with infectious urethritis in males include N. gonorrhoeae and C. trachomatis, U. urealyticum, and other, less common, mycobacteria; parasites (e.g., Trichomonas vaginalis); and viruses (herpes simplex virus [HSV]).^126,127 Infectious urethritis caused by N. gonorrhoeae often is called gonococcal urethritis (GU); infection caused by other microorganisms is called nongonococcal urethritis (NGU).¹²⁸ (Sexually transmitted urethritis is described in Chapter 24.) Nonsexual origins of urethritis include inflammation or infection as a result of urologic procedures, insertion of foreign bodies into the urethra, anatomic abnormalities, or trauma.

Noninfectious urethritis is rare and is associated with the ingestion of wood alcohol, ethyl alcohol, or turpentine. It is seen also with Reiter syndrome, which involves a number of mucocutaneous lesions.

Symptoms of urethritis include urethral tingling, itching, or burning sensation on urination (dysuria), frequency, and urgency. The individual may note a purulent or clear mucus-like discharge from the urethra. Nucleic acid detection amplification tests allow easy detection of N. gonorrhoeae and C. trachomatis in first-void urine.¹²⁸ Treatment consists of appropriate antibiotic therapy for infectious urethritis and avoidance of future chemical or mechanical irritation.

Urethral Stricture

A urethral stricture is a fibrotic narrowing of the urethra caused by scarring. The scars may be congenital but are more likely to result from trauma or untreated or severe urethral infections, most often from long-term use of indwelling urinary catheters. Large catheters and instruments cause internal trauma and ischemia, whereas external trauma, such as pelvic fracture, can partially or completely sever the urethra and cause severe and complex strictures.¹²⁹ In addition, a report has concluded that stricture may occur decades after initial hypospadias surgery.¹³⁰ Urethral carcinoma is a less common cause of urethral stricture. Prostatitis and infection secondary to urinary stasis are common complications. Severe and prolonged obstruction can result in hydronephrosis and renal failure. In addition, chronic, severe strictures may lead to urethral fistulas and periurethral abscesses.¹²⁹

The clinical manifestations of urethral stricture are caused by bladder outlet obstruction. The primary symptom is diminished force and caliber of the urinary stream; other symptoms include urinary frequency and hesitancy, mild dysuria, double urine stream or spraying, and postvoiding dribbling. Symptoms of acute urinary retention may occur in the presence of infection or urinary obstruction. Induration at the stricture site may be palpable. Tender, enlarged masses along the urethra usually indicate periurethral abscesses.

Urethral stricture is diagnosed on the basis of history, physical examination, urinary flow rates, voiding cystourethrogram, and urethroscopy; biopsy confirms carcinoma. Treatment is usually surgical and may involve urethral dilation, urethrotomy, or a variety of open surgical techniques. The choice of surgical intervention depends on the age of the individual and the severity of the problem. Strictures may recur up to 1 year after treatment. Follow-up is necessary during this time; urinary flow measurements and urethrogram help determine extent of residual obstruction.

Phimosis and Paraphimosis

Phimosis and paraphimosis are disorders in which the foreskin (prepuce) is “too tight” to be moved easily over the glans penis. Phimosis is a condition in which the foreskin cannot be retracted back over the glans, whereas paraphimosis is the opposite: the foreskin is retracted and cannot be moved forward (reduced) to cover the glans (Figure 23-22). Both conditions can cause penile pathologic conditions.

The inability to retract the foreskin is normal in infancy and is caused by congenital adhesions. During the first 3 years of life, these adhesions separate naturally with penile erections and are not an indication for circumcision. Although most cases occur in uncircumcised males, stenosis and resultant phimosis can occur in males with excessive skin remaining after circumcision.¹²⁹ Phimosis can occur at any age and is caused most commonly by poor hygiene and chronic infection. Chronic balanoposthitis (inflammation of the glans and prepuce) predisposes older diabetic men to phimosis. It rarely occurs with normal foreskin.

Edema, erythema, and tenderness of the prepuce and purulent discharge are usually the reasons for seeking treatment; inability to retract the foreskin is a less common complaint. Circumcision, if needed, is performed after infection has been eradicated. Complications of phimosis include inflammation of the glans (balanitis) or prepuce (posthitis) and paraphimosis. There is a higher incidence of penile carcinoma in uncircumcised males, but chronic infection, most likely with HPV, is usually the underlying factor in such cases.^131,132

Paraphimosis, in which the foreskin is retracted, can constrict the penis, causing edema of the glans. If edema is such that the foreskin cannot be reduced manually, surgery must be performed to prevent necrosis of the glans caused by constricted blood vessels. Severe paraphimosis is a surgical emergency and phimosis may require immediate release if there is urinary obstruction.

Peyronie Disease

Peyronie disease (bent nail syndrome) is a fibrotic condition of the tunica albuginea of the penis resulting in varying degrees of curvature and sexual dysfunction¹³³ (Figure 23-23). Peyronie disease develops slowly and is characterized by tough, fibrous thickening of the fascia in the erectile tissue of the corpora cavernosa. A dense fibrous plaque is usually palpable on the dorsum of the penile shaft. The problem usually affects middle-age men and is associated with painful erection, painful intercourse (for both partners), and poor erection distal to the involved area. In some cases, impotence or unsatisfactory penetration occurs. There is no pain when the penis is flaccid.

Although the exact cause is unknown, a local vasculitis-like inflammatory reaction occurs and decreased tissue oxygenation results in fibrosis and calcification. Peyronie disease is associated with Dupuytren contracture (a flexion deformity of the fingers or toes caused by shortening or fibrosis of the palmar or plantar fascia), diabetes, tendency to develop keloids, and in rare cases, use of beta-blocker medications.

There is no definitive treatment for Peyronie disease. Spontaneous remissions occur in as many as 50% of cases. Treatment with pharmacologic therapies include colchicine, aminobenzoate potassium (Potaba), L-carnitine, and liposomal superoxide dismutase.¹³³ Placation, as well as surgical resection of the fibrous plaque followed by grafting, has been successful.¹²⁹

Priapism

Priapism is an uncommon condition of prolonged penile erection. It is usually painful and is not associated with sexual arousal (Figure 23-24). Priapism is idiopathic in 60% of cases; the remaining 40% of cases are associated with spinal cord trauma, sickle cell disease, leukemia, pelvic tumors or infections, or penile trauma. Priapism also has been associated with cocaine use.¹³⁴ Intracavernous injection therapy for impotence seems to be the most common cause. Prolonged sexual stimulation often is associated with initial development of the idiopathic type.¹²⁹ The two corpora cavernosa within the erect penis are filled with blood and are tender to palpation; neither the corpus spongiosum nor the glans is engorged. The vascular congestion is thought to be associated with venous obstruction. If the erection remains over a period of days, edema and fibrosis develop, leading to erectile dysfunction (impotence).

Priapism is a urologic emergency. Treatment within hours is effective and prevents impotence. Conservative approaches include iced saline enemas, ketamine administration, and spinal anesthesia. Needle aspiration of blood from the corpus through the dorsal glans is often effective and is followed by catheterization and pressure dressings to maintain decompression. More aggressive surgical treatments include the creation of vascular shunts to maintain blood flow. Erectile dysfunction results in up to 50% of prolonged cases.

Balanitis

Balanitis is an inflammation of the glans penis (Figure 23-25) and usually occurs in conjunction with posthitis, an inflammation of the prepuce. It is associated with poor hygiene and phimosis. The accumulation under the foreskin of glandular secretions (smegma), sloughed epithelial cells, and Mycobacterium smegmatis can irritate the glans directly or lead to infection. Skin disorders (e.g., psoriasis, lichen planus, eczema) and candidiasis must be differentiated from inflammation resulting from poor hygienic practices. Balanitis is seen most commonly in men with poorly controlled diabetes mellitus and candidiasis. Antimicrobials are used to treat infection. Circumcision can prevent recurrences and can be considered after the inflammation has subsided.

Penile Cancer

In the United States, carcinoma of the penis is rare and affects about 1 in 100,000 men. Approximately 1290 cases and 290 deaths were estimated in the year 2009.¹ Although rare in North America and Europe, where it accounts for about 0.2% of cancers and 0.1% of cancer deaths in men, penile cancer may account for up to 10% of cancers in African and South American men.

In the United States it is twice as common in black men than in white men¹³¹ and in men older than age 50.¹³⁵ Major risk factors include infection with HPV (mainly serotypes 16, 18, 33, 35, and 45), smoking, and psoriasis treated with a combination involving the drug psoralen and ultraviolet (UV) light. Men circumcised at birth have less than half the chance of getting penile cancer than those who were not.¹³¹ Penile cancer is more common in men with phimosis and those with AIDS.¹³¹ About two thirds of men with penile cancer are diagnosed at more than 65 years of age.¹

Before the development of penile cancer, signs of premalignant cancer or epidermal cancer in situ are present.¹³⁶ These include thick white plaque (leukoplakia) that typically involves the meatus; red, inflamed areas of Paget disease; red, velvety, ulcerative lesions of erythroplasia of Queyrat that usually involve the glans; large, invasive, scaly growths of Buschke-Löwenstein tumor; red plaque with encrustations of Bowen disease; and in situ carcinoma that generally affects the penile shaft. Men with leukoplakia or erythroplasia of Queyrat may have concurrent invasive penile carcinoma.^131,137 Pain and bleeding are late signs of penile cancer. Condylomata (genital warts) caused by HPV may be involved in the development of precancerous lesions (see Chapter 24 for a discussion of HPV). At times the penis might be the site of metastatic spread of solid tumors from the bladder, prostate, rectum, or kidney. Early squamous cell carcinoma and premalignant epidermal lesions are easily treated but are often ignored. Delays in seeking treatment are attributed to denial, embarrassment, failure to detect lesions under a phimotic foreskin, fear, guilt, and ignorance.

Penile cancer is mostly squamous cell carcinoma, which usually begins as a small, fat, ulcerative or papillary lesion on the glans or foreskin that grows to involve the entire penile shaft (Figure 23-26). Extensive lesions are associated with metastases and a poor prognosis. These lesions are not as painful as the amount of tissue involvement would seem to indicate. The regional femoral and iliac nodes are common metastatic sites. Rarely the urethra and bladder are involved. Weight loss, fatigue, and malaise accompany chronic suppurative lesions. Untreated, progressive disease causes death within 2 years.

The specific diagnosis is made by biopsy after examination to document the location, size, and fixation of the lesion. After a positive biopsy, the extent of cancer spread is determined by imaging tests such as ultrasound, CT, or MRI. Fine-needle aspiration of lymph tissue confirms absence or presence of regional adenopathy.¹³¹ About 30% of penile cancers spread to lymph nodes before diagnosis.¹³⁵ Distant metastases occur in less than 10% of cases and may involve lung, liver, bone, or brain.¹³⁷ Staging of penile cancer uses a system created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (IUCC). The AJCC/IUCC staging system is also known as the tumor, node, metastasis (TNM) system.¹ Although this system initially seems cumbersome, it is a simple and easy method of communicating degree of cancer (Box 23-12).

For invasive penile carcinoma, complete excision leaving adequate tumor-free margins is the goal. A simple circumcision may be sufficient for localized lesions of the prepuce. If the primary site is glans and distal shaft, removal of the penis may be necessary. Although conventional radical surgery continues to be an effective approach, the emasculating nature of the treatment has serious psychologic and sexual consequences. Recent studies have challenged the conventional belief that a 2-cm margin was required for adequate cancer control.¹³⁸ Newer innovative surgical techniques can now preserve as much penile tissue and functional integrity as possible without compromising cancer control. Inguinal lymph nodes also are removed if metastasis to these structures is known or suspected. Palliative treatment with radiation or chemotherapy may be used when the disease is inoperable and bulky inguinal metastases have occurred. Options for individuals with carcinoma in situ include local excision, radiation, laser surgery, cryosurgery, chemosurgery, or chemotherapy with topical (5%) 5-FU. Differentiation, tumor stage, and age influence prognosis.¹³⁹ The 5-year survival rate for stage I disease is greater than 80%^1,135; average 5-year survival rate for all stages is 50%.^1,131

Disorders of the Scrotum

Men may seek treatment for painful or painless scrotal masses. Masses may be serious (cancer or torsion) or benign (hydrocele or cyst); they may require immediate surgical intervention or allow for careful observation. A flow diagram for diagnosing scrotal masses¹⁴⁰ is provided in Figure 23-27.

Varicocele, hydrocele, and spermatocele are common intrascrotal disorders.^141–143 A varicocele is an abnormal dilation of a vein within the spermatic cord and is classically described as a “bag of worms” (Figure 23-28). Most (95%) occur on the left side and may be painful or tender. Varicocele occurs in 10% of males and is seen most often after puberty. Sudden development of a varicocele in an older man is a late sign of renal tumor.¹⁴² Unilateral right-sided varicoceles are rare and result from compression or obstruction of the inferior vena cava by a tumor or thrombus. Color Doppler ultrasonography is used to confirm the diagnosis.¹⁴⁰

The cause of varicocele is incompetent or congenitally absent valves in the spermatic veins. The valves that normally prevent backflow are absent or do not close adequately, permitting blood to pool in the veins rather than flow into the venous system. Varicocele decreases blood flow through the testis. This interferes with spermatogenesis and is a cause of infertility.^141,142 If infertility is a problem, treatment consists of ligation of the spermatic vein or occlusion of the vein by percutaneous methods, such as balloon catheter and sclerosing fluids.^142,144 If varicocele is mild and fertility is not an issue, a scrotal support usually is sufficient to relieve symptoms of scrotal heaviness or “dragging.”

A hydrocele is a collection of fluid within the tunica vaginalis^140–142 (Figure 23-29). It is the most common cause of scrotal swelling. Hydroceles occur in 6% of male newborns and are congenital malformations (patent processus vaginalis) that often resolve spontaneously in the first year of life. Surgical ligation is recommended if hydrocele persists after age 1 year.¹⁴³ Hydroceles in adults may be caused by an imbalance between the secreting and absorptive capacities of scrotal tissues. Hydroceles range in size from slightly larger than the testes to the size of a grapefruit or larger and may be flaccid or tense. Compression of testicular blood supply may lead to atrophy.

The exact mechanism of idiopathic hydrocele is unknown. Secondary hydrocele may result from trauma or infection of the testis or epididymis or from a testicular tumor. Rapid accumulation of fluid occurs after local injury, radiotherapy, or infection (epididymitis or orchitis), or it may accompany testicular neoplasm. Chronic hydroceles are more common and occur in men older than 40 because of an imbalance between fluid secretion and reabsorption in the tunica vaginalis. A painless, extratesticular mass that easily transilluminates is found on physical examination. Ultrasonography of a large hydrocele, which may conceal a testicular tumor, is recommended. Treatment is usually not required unless a large, bulky hydrocele causes considerable physical discomfort or undesirable cosmetic appearance.¹⁴¹ Treatment for uncomplicated hydrocele is aspiration of the fluid and injection of a sclerosing agent into the scrotal sac.^140,145 The goal of treatment is to remove the hydrocele and prevent recurrence by sclerosing or excising the tunica vaginalis.

A spermatocele is a painless diverticulum of the epididymis located between the head of the epididymis and the testis. In other words, efferent ducts of the epididymis have potential for cystic dilation to form a spermatocele^140,142 (Figure 23-30). Spermatoceles are filled with milky fluid that contains sperm. Spermatocele is differentiated from a hydrocele in that aspiration of the hydrocele recovers a clear, yellow fluid, and unlike a hydrocele, a spermatocele does not cover the entire anterior surface of the testis. An epididymal cyst is similar to a spermatocele but does not communicate with the epididymis. Spermatoceles and epididymal cysts manifest as discrete, firm, freely mobile masses distinct from the testis that may be transilluminated. Epididymal cysts do not require treatment.¹⁴⁰ A spermatic cord tumor may feel like a tense spermatocele but does not contain fluid and will not transilluminate.¹⁴² Spermatoceles that cause pain or discomfort are excised. Usually, however, spermatoceles are asymptomatic or produce mild discomfort that is relieved by scrotal support. Neither hydroceles nor spermatoceles are associated with infertility.

Cryptorchidism and Ectopy

Cryptorchidism is a condition of testicular maldescent, whereas an ectopic testis has strayed from the normal pathway of descent. Ectopy may be caused by an abnormal connection at the distal end of the gubernaculum testis that leads the gonad to an abnormal position, usually at the superficial inguinal site. In cryptorchidism the descent of one or both testes is arrested, with unilateral arrest occurring more often than bilateral arrest.¹⁴² The testes may remain in the abdomen, or testicular descent may be arrested in the inguinal canal or the puboscrotal junction. About 3% to 6% of full-term infants and 20% to 30% of premature male infants have undescended testes at birth¹⁴³; half of such testes descend in the first month of life and a few more at puberty. The incidence of cryptorchidism in adults is 0.7% to 0.8%.¹⁴² Cryptorchidism is commonly associated with vasal or epididymal abnormalities. These congenital anomalies affect about one third to two thirds of newborns with cryptorchidism. Other structural anomalies include posterior urethral valves (less than 5%), upper tract abnormalities (less than 5%), and hypospadias. The presence of hypospadias as well as cryptorchidism raises the suspicion of mixed gonadal dysgenesis (intersex infant). It has been hypothesized that cryptorchidism may result from an absence or abnormality of the gubernaculum, a cordlike structure that extends from the lower pole of the testis to the scrotum; a congenital gonadal or dysgenetic defect that makes the testis insensitive to gonadotropins (a likely explanation for unilateral cryptorchidism); or lack of maternal gonadotropins (a likely explanation for bilateral cryptorchidism of prematurity).¹⁴² Mechanical possibilities include a short spermatic cord, fibrous bands or adhesions in the normal path of the testes, or a narrowed inguinal canal. Chromosomal studies do not support a genetic component. Physiologic cryptorchidism, also called retractile or migratory testis, is an involuntary retraction of the testes out of the scrotum that occurs with excitement, physical activity, or exposure to cold and is caused by the small mass of prepubertal testis and the strength of the cremaster muscle. This is a common phenomenon that is self-limiting (descent occurs at puberty).

Physical examination discloses the absence of one or both testes in the scrotum and an atrophic scrotum on the affected side. If the undescended testis is in a vulnerable position, for example, over the pubic bone, an individual may complain of severe pain secondary to trauma. The adult male with bilateral cryptorchidism may be infertile. Ultrasonography, CT, or MRI can be used to locate an intra-abdominal or nonpalpable testis.

Undescended testes are susceptible to neoplastic processes: the risk of testicular cancer is 35 to 50 times greater for men with cryptorchidism or a history of cryptorchidism than for the general male population. Because definite histologic change (decreased Leydig cells, loss of germ cells, and peritubular fibrosis) occurs in the cryptorchid testis by 1 year of age, surgical correction is recommended earlier.^142,146 Treatment often begins with administration of GnRH or hCG, hormones that may initiate descent, making surgery unnecessary. GnRH is given as a nasal spray in Europe and may enhance germ-cell counts even when the testis does not descend.¹⁴⁶ If hormonal therapy is not successful, the testis is located and moved surgically (orchiopexy) in young children or removed (orchiectomy) in adults and children older than 10 years.^142,146 The testis that is properly placed in the scrotum provides adequate hormonal function and gives the scrotum a normal appearance. A successful operation does not ensure fertility if the testis is congenitally defective. Approximately 20% of males with unilateral undescended testis remain infertile even though orchiopexy is performed by age 1 year; most individuals with treated or untreated bilateral testicular maldescent have poor fertility. In addition, placement of the cryptorchid testis into the scrotal sac does not decrease the potential for malignancy; it does facilitate examination and tumor detection.

Torsion of the Testis

Torsion of the testis is rotation of a testis, which twists blood vessels in the spermatic cord. It causes an acute scrotum, which is testicular pain and swelling (Figure 23-31). Differentiation between testicular torsion and two other common causes of an acute scrotum is based on physical examination and history^140,143 (Table 23-10). This event is most common among neonates and pubertal adolescents, but it can occur in males at any age.^140,143 Onset may be spontaneous or follow physical exertion or trauma. Torsion twists the arteries and veins in the spermatic cord, reducing or stopping circulation to the testis. Vascular engorgement and ischemia develop, causing scrotal swelling and pain. These manifestations are not relieved by scrotal elevation (Prehn sign), rest, or scrotal support. On physical examination, men have a tender, high-riding testis, a thickened spermatic cord, and an absent cremasteric reflex. Unlike epididymitis, the epididymis cannot be differentiated from the testis.¹⁴³ Diagnostic testing includes urinalysis (to rule out infection) and color Doppler ultrasonography.^125,142,143 Torsion of the testis is a surgical emergency. If the torsion cannot be reduced manually, surgery must be performed within 6 hours after the onset of symptoms to preserve normal testicular function. Surgery includes untwisting the spermatic cord and anchoring both testes in correct position within the scrotum to prevent recurrences. With successful manual detorsion, surgical fixation should be done within a few days.

Orchitis

Orchitis is an acute inflammation of the testes (Figure 23-32) and is uncommon except as a complication of systemic infection or as an extension of an associated epididymitis¹²⁷ (see p. 859). Infectious microorganisms may reach the testes through the blood or the lymphatics or, most commonly, by ascent through the urethra, vas deferens, and epididymis. Most cases of orchitis are actually cases of epididymo-orchitis. Occasionally, in middle-age men, a nonspecific, apparently noninfectious, inflammatory process (called granulomatis orchitis) can occur. It seems to be an autoimmune disease that triggers a granulomatous response to spermatozoa.

Mumps is the most common infectious cause of orchitis and usually affects postpubertal males. The onset is sudden, occurring 3 to 4 days after the onset of parotitis. Signs and symptoms include high fever, reaching 40° C (104° F), marked prostration, bilateral or unilateral erythema, edema and tenderness of the scrotum, and leukocytosis. An acute hydrocele may develop. Urinary signs and symptoms, which accompany epididymitis, are absent. Atrophy with irreversible damage to spermatogenesis may result in 30% of affected testes. Bilateral orchitis does not affect androgenic function but may cause permanent sterility.

Treatment is supportive and includes bed rest, scrotal support, elevation of the scrotum, hot or cold compresses, and analgesic agents for relief of pain. If an acute hydrocele develops, it is aspirated. Testicular abscess usually requires orchiectomy (removal of the testis). Appropriate antimicrobial drugs should be used for bacterial orchitis, and corticosteroids are indicated in proved cases of nonspecific granulomatous orchitis.

Cancer of the Testis

Testicular cancer is among the most curable of cancers; for nearly all common types, cure rates are more than 95%. Overall, testicular cancers are rare, accounting for only 1% of cancers and 0.24% of cancer deaths¹ in men, yet they are the most common form of cancer in young men between ages 15 and 35. Approximately 8400 cases and 380 deaths were estimated for 2009.¹ In the United States, the lifetime probability of developing testicular cancer is 0.2% for white men, an incidence that is four times higher than for blacks. Testicular tumors are slightly more common on the right side than on the left, a pattern that parallels the occurrence of cryptorchidism; about 1% to 2% of primary testicular cancers are bilateral (Figure 23-33), and 50% of these tumors arise from treated or untreated cryptorchid testes.

PATHOGENESIS Ninety percent of testicular cancers are germ-cell tumors arising from the male gametes. Germ-cell tumors constitute 90% of testicular cancers and can be broadly classified into two types: seminomas and nonseminomas. Seminomas are the most common, are the least aggressive, and make up about 30% to 35% of testicular cancers. Nonseminomas include embryonal carcinomas, teratomas, and choriocarcinomas, the most aggressive but rare (less than 1%) form of testicular cancer. Testicular cancers can include a mix of types.¹⁴⁷ In addition, testicular tumors can arise from specialized cells of the gonadal stroma. These tumors, which are named for their cellular origins, are Leydig cell, Sertoli cell, granulosa cell, and theca cell tumors and constitute less than 10% of all testicular cancers.¹⁴⁸

The cause of testicular neoplasms is unknown. A genetic predisposition is suggested by the fact that the incidence is higher among brothers, identical twins, and other close male relatives. Genetic predisposition is supported further by statistics showing that the disease is relatively rare among black Africans, black Americans, Asians, and native New Zealanders. Risk factors include history of cryptorchidism, abnormal testicular development, HIV and AIDS, Klinefelter syndrome, and history of testicular cancer.¹⁴⁷

CLINICAL MANIFESTATIONS Painless testicular enlargement commonly is the first sign of testicular cancer. Enlargement is usually gradual and may be accompanied by a sensation of testicular heaviness or dull ache in the lower abdomen.^147,148 Occasionally, acute pain occurs because of rapid growth, resulting in hemorrhage and necrosis. Ten percent of affected men have epididymitis, 10% have hydroceles,¹⁴⁸ and 5% have gynecomastia or hydrocele. Incidence of gynecomastia increases considerably (30% to 45%) in men with Sertoli or Leydig tumors. Approximately 10% of individuals already have symptoms related to metastases at the time of initial diagnosis, which correlates with the typical delay of 3 to 6 months from initial recognition to definitive treatment. Lumbar pain may be present and usually is caused by retroperitoneal node metastasis. Signs of metastasis to the lungs include cough, dyspnea, and bloody sputum (hemoptysis). Supraclavicular node involvement may cause difficulty swallowing (dysphagia) and neck swelling. Alterations in vision or mental status, papilledema, and seizures may be experienced with metastasis to the CNS. Approximately 10% of affected individuals are asymptomatic; the tumor may be detected by the man’s sexual partner or incidentally following trauma.

EVALUATION AND TREATMENT An incorrect diagnosis at the initial examination occurs in as many as 25% of men with testicular cancer. Epididymitis and epididymo-orchitis are the most common misdiagnoses; others include hydrocele and spermatocele. Evaluation begins with careful physical examination, including palpation of the scrotal contents with the individual in the erect and supine positions. The abdomen and lymph nodes are palpated to rule out metastases. Signs of testicular cancer include abnormal consistency, induration, nodularity, or irregularity of the testis. A firm, nontender testicular mass or diffuse enlargement is found in the majority of cases. Primary testicular cancer can be assessed rapidly and accurately by scrotal ultrasonography. Tumor markers are higher than normal in the presence of a tumor and may help detect a tumor that is too small to be palpated during physical examination or seen on imaging.¹⁴⁷ Tumor type is identified after inguinal biopsy or orchiectomy. Scrotal incisions may cause dissemination of the tumor and increase the risk of local recurrence and therefore are avoided. Chest x-ray, lymphangiogram, IVP, abdominal ultrasound, and CT are used in clinical staging of disease. Treatment is based on type of tumor, stage of disease, general health, and age. Besides surgery, treatment involves radiation and chemotherapy singly or in combination. A number of factors influence the prognosis (Table 23-11). They include histology of the tumor, stage of the disease, and selection of appropriate treatment. Serum markers, such as AFP, β-hCG, and lactate dehydrogenase, are useful for detecting metastases and assessing responses to therapy. Most individuals treated for cancer of the testis can expect a normal life span, although some have persistent paresthesias, Raynaud phenomenon, or infertility. Almost 90% of disease-related deaths occur in the first 2 years after cessation of therapy; disease-free survival of 3 years is considered a cure. Approximately 10% of men treated for testicular cancer will experience a relapse; if the relapse is discovered early and treated, 99% can be cured. Orchiectomy does not affect sexual function, but infertility can result from chemotherapy or surgical removal of affected abdominal lymph nodes if nerves necessary for ejaculation are severed. After orchiectomy, testicular silicone implants may be used to restore “normal” scrotal appearance.

Epididymitis

Epididymitis, or inflammation of the epididymis, generally occurs in sexually active young males (younger than 35 years) and is rare before puberty (Figure 23-34). In young men the usual cause is a sexually transmitted microorganism, such as N. gonorrhoeae or C. trachomatis. Men who practice unprotected anal intercourse may acquire sexually transmitted epididymitis because of E. coli, H. influenzae, tuberculosis (especially in regions where incidence of pulmonary tuberculosis is high), Cryptococcus, or Brucella.¹⁴⁹ In men older than 35 years, Enterobacter (intestinal bacteria) and Pseudomonas aeruginosa associated with urinary tract infections and prostatitis also may cause epididymitis. Besides an infectious etiology, epididymitis may result from a chemical inflammation caused by the reflux of sterile urine into the ejaculatory ducts.^149,150 It is associated with urethral strictures, congenital posterior valves, and excessive physical straining in which increased abdominal pressure is transmitted to the bladder. Chemical epididymitis is usually self-limiting and does not require evaluation or intervention unless it persists.

PATHOPHYSIOLOGY The pathogenic microorganism usually reaches the epididymis by ascending the vasa deferentia from an already infected urethra or bladder. The presence of bacteria initiates the inflammatory response, causing symptoms of bacterial epididymitis. Epididymitis caused by heavy lifting or straining results from reflux of urine from the bladder into the vas deferens and epididymis. Urine is extremely irritating to the epididymis and initiates an inflammatory response called chemical epididymitis.

CLINICAL MANIFESTATIONS Pain is the main symptom of epididymitis. Scrotal or inguinal pain is caused by inflammation of the epididymis and surrounding tissues. The pain is usually acute and severe. Flank pain may occur if, as the urethra passes over the spermatic cord, edematous swelling of the cord obstructs the urethra. The individual may have pyuria and bacteriuria and a history of urinary symptoms, including urethral discharge. The scrotum on the involved side is red and edematous as a result of inflammatory changes. The tail of the epididymis near the lower pole of the testis usually swells first; then swelling ascends to the head of the epididymis. The spermatic cord also may be swollen and tender.

Complications of epididymitis include abscess formation, infarction of the testis, recurrent infection, and infertility. Infarction probably is caused by thrombosis (obstruction by blood clots) of the prostatic vessels secondary to severe inflammation. Recurrent epididymitis may result from inadequate initial treatment or failure to identify or treat predisposing factors. Chronic epididymitis can cause scarring of the epididymal endothelium. Once scarring has occurred, treatment with antibiotics is ineffective because adequate antibiotic levels cannot be achieved within the epididymis.^149,150

EVALUATION AND TREATMENT A history of recent urinary tract infection or urethral discharge suggests the diagnosis of epididymitis. The relief of pain when the inflamed testis and epididymis are elevated (Prehn sign) is also diagnostic. Definitive diagnosis is based on culture or Gram stain of a urethral swab. Epididymal aspiration may be necessary to obtain a specimen, especially if the individual has been taking antibiotics and has sterile urine.

Treatment includes antibiotic therapy for the infection itself (see Chapter 24) and various measures to provide symptomatic relief. Bed rest and scrotal elevation are recommended until the scrotum is no longer tender. Scrotal elevation facilitates maximal lymphatic and venous drainage. Abscess formation is rare with antibiotic therapy. If an abscess occurs and persists, it is drained surgically and an orchiectomy may be indicated. Complete resolution of swelling and pain may take several weeks to months. The individual’s sexual partner should be treated with antibiotics if the causative microorganism is a sexually transmitted pathogen.

Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH), also called benign prostatic hypertrophy, is the enlargement of the prostate gland (Figure 23-35). (Because the major prostatic changes are caused by hyperplasia, not hypertrophy, benign prostatic hyperplasia is the preferred term.) This condition becomes problematic as prostatic tissue compresses the urethra, where it passes through the prostate. The prevalence among U.S. men 60 years and older is about 50% and among men 70 years or older 90%. ¹⁵¹ BPH is common and involves a complex pathophysiology with several endocrine and local factors and remodeled microenvironment. Its relationship to aging is well documented. At birth the prostate is pea sized, and growth of the gland is gradual until puberty. A period of rapid development continues until the third decade of life, when the prostate reaches adult size. Around 40 to 45 years of age, benign hyperplasia begins and continues slowly until death. Although dihydrotestosterone (DHT) is necessary for normal prostatic development, its role in BPH remains unclear. Among all androgen-metabolizing enzymes within the human prostate, 5α-reductase is the most powerful. This reductase corresponds to an age-dependent DHT level. Therefore, although 5α-reductase and DHT decrease with age in the epithelium, they remain relatively constant in the stroma of the prostate gland.

PATHOGENESIS Current causative theories of BPH focus on levels and ratios of endocrine factors such as androgens, estrogens, gonadotropins, and prolactin and changes in the balance between autocrine/paracrine growth-stimulatory and growth-inhibitory factors. These factors include insulin-like growth factors (IGFs), epidermal growth factor, nerve growth factor, fibroblast factors, IGF binding proteins, and transforming growth factor-beta (TGF-β).¹⁵²

Aging and circulating androgens are associated with BPH and enlargement. These factors are predisposed as disrupting the balance of growth factor signaling pathways and stromal/epithelial interactions creating a growth-promoting and tissue remodeling microenvironment.¹⁵³ All together these interactions lead to an increase in prostate volume. The remodeled stroma promotes local inflammation with altered cytokine, reactive oxygen/nitrogen species, and chemoattractants.¹⁵³ The resultant increased oxygen demands of proliferating cells causes a local hypoxia that induces angiogenesis and changes to fibroblasts. Functional and phenotypic changes (transdifferentiation) of fibroblasts to the myofibroblasts is a hallmark of the remodeled microenviroment.¹⁵³

BPH begins in the periurethral glands, which are the inner glands or layers of the prostate. The prostate enlarges as nodules form and grow (nodular hyperplasia) and glandular cells enlarge (hypertrophy). The development of BPH occurs over a prolonged period, and changes within the urinary tract are slow and insidious.

CLINICAL MANIFESTATIONS Clinical manifestations are a result of complex interactions involving prostatic urethral resistance to the mechanical and spastic effects of BPH, intravesical pressure during voiding, detrusor muscle strength, neurologic functioning, and general physical health.

During the early stages of urethral obstruction, the detrusor muscle hypertrophies to help the bladder force urine out against increasing resistance. Symptoms are considered obstructive (weak urinary stream, prolonged voiding, abdominal straining, hesitancy, intermittency, incomplete bladder emptying, postmicturitional dribble) or irritative (frequency and repeated urination, nocturia, urgency, incontinence, and bladder pain and dysuria)¹⁵⁴ and may wax and wane.¹⁵⁵ As obstruction progresses, often over a period of several years, the detrusor muscle decompensates and the bladder is unable to empty all of the urine. Increasing volumes of urine are retained until urine retention is chronic. The volume of urine retained may be great enough to produce uncontrolled “overflow incontinence” with any increase in intra-abdominal pressure. At this stage the force of the urinary stream is reduced significantly and much more time is required to initiate and complete voiding.

Progressive bladder distention causes sacculations or diverticular outpouchings of the bladder wall, and some neural degeneration of smooth muscle cells occurs. The ureters may be obstructed where they pass through the hypertrophied detrusor muscle. Hematuria, bladder or kidney infection, bladder calculi, acute urinary retention hydroureter, hydronephrosis, and renal insufficiency are common complications.¹⁵⁴ Some men initially have signs of uremia and renal failure. On digital rectal examination (DRE) the hyperplastic prostate is a soft or firm enlargement with smooth mucosal surface and no discernible distinction between lobes; asymmetry is common. The palpated prostate does not always reflect the degree of BPH because a substantial portion of the enlargement is intravesicular.¹⁵⁶ Thirty percent of men with mild to moderate symptoms improve with watchful waiting.

There is no way to reverse progressive BPH, but the hyperplasia is not always progressive. For these reasons, timing of intervention is variable and depends on severity of symptoms and the presence of complications. Annual DREs are used to screen men older than 40 years for BPH. If marked enlargement, moderate to severe symptoms, or complications are present, transrectal ultrasound (TRUS) is used to determine bladder and prostate volume and residual urine. Urinalysis, serum creatinine and blood urea nitrogen, uroflowmetry, postvoid residual (PVR) urine, pressure-flow study, cystometry, and cystourethroscopy are used to determine kidney and bladder function.¹⁵⁴ Physical examination with DRE and prostate-specific antigen (PSA) is conducted to determine hyperplasia.¹⁵⁷ PSA density (PSAD) is helpful in differentiating BPH from prostatic cancer. PSAD is calculated by dividing PSA serum levels by the volume of prostate tissue, which is determined by TRUS. When necessary, the hyperplastic tissue may be removed surgically to prevent the serious consequences of urethral obstruction. Glands less than 60 g are treated by transurethral resection, laser therapy, or microwave thermotherapy,¹⁵⁸ whereas larger glands are removed surgically (prostatectomy). A permanent indwelling catheter is inserted if the individual cannot tolerate surgery. BPH has been treated successfully with drugs. α₁-Adrenergic blockers (prazosin and tamsulosin) are used to relax the smooth muscle of the bladder and prostate. Antiandrogen agents, such as finasteride (Proscar), selectively block androgens at the prostate cellular level and cause the prostate gland to shrink.¹⁵⁹ These drugs offer an alternative to surgery for as many as 75% of men with mild prostate enlargement.¹⁵⁹ Neither α₁-adrenergic blockers nor finasteride seems to affect sexual desire or potency; finasteride may cause bone loss and lower levels of PSA. PSA is used as a screen for prostate cancer.

Prostatitis

Prostatitis is an inflammation of the prostate. Some degree of prostatic inflammation is present in 4% to 36% of the male population. This percentage increases to 50% in older men. Inflammation is usually limited to a few of the gland’s excretory ducts (Figure 23-36).

Prostatitis is characterized as (1) acute bacterial prostatitis, (2) chronic bacterial prostatitis, or (3) nonbacterial prostatitis. Prostatodynia (pain in the prostate) is sometimes considered a form of nonbacterial prostatitis. Men with prostatodynia have the same clinical manifestations as those with nonbacterial prostatitis, but physical and laboratory examinations do not show prostatic pathology. Prostatodynia may not be caused by a pathologic condition of the prostate but rather by spasms in the genitourinary tract or tension in the muscles of the pelvic floor.

A number of defense mechanisms normally protect the lower urogenital tract from infection. Mechanical defenses include urethral length, micturition (urination), and ejaculation. Structural malformations and instrumentation of the genitourinary tract may weaken these defense mechanisms. Chemical defenses include antimicrobial substances in the prostatic fluid. The most important of these is a zinc-containing polypeptide known as prostatic antibacterial factor. Coliform bacteria, particularly Enterobacter, E. coli, Enterococcus, Klebsiella, and Pseudomonas, are common pathogens of bacterial prostatitis. Ureaplasma and C. trachomatis also may be causative agents of infectious prostatitis.¹⁵⁰

Cancer of the Prostate

Prostate cancer is among the most common male cancers but the incidence varies greatly worldwide (Figure 23-37). It is the most common cancer in American males but the third most common cancer worldwide. In the United States it accounts for more than 14% of all cancer deaths; only lung cancer accounts for more deaths. Among countries with reliable cancer statistics, prostate cancer rates are highest in westernized countries, such as the United States and Western Europe and lowest in Asian countries. It also is rare in Africa, Central America, and South America. Screening with PSA can amplify the incidence of prostate cancer by allowing detection of prostate lesions that although meeting the pathologic criteria for malignancy, many believe to have low potential for growth and metastasis; however, this is controversial. Thus screening can amplify the incidence of prostate cancer by including the detection of these localized lesions. Therefore, the incidence rates in some countries, such as the United States, reflect clinical as well as latent (preclinical) disease compared with other countries that report only clinical disease. Comparing data in the pre-PSA era does reflect less extreme incidence rates, but the United States still has the highest rates. Data from the Surveillance, Epidemiology, and End Results (SEER) program show that incidence rates in the United States for white men increased 80% from 1983 to 1987 and 1988 to 1992 (possibly because of increased screening in asymptomatic men).¹⁶⁰

A small decline in the death rate has been noted during the past few years in the United States and other developing countries. The overall mortality rates are mostly in men older than 65; within younger groups, mortality has been stable across decades. Incidence increases with advancing age; more than 75% of all prostate cancer is diagnosed in men older than 65.¹ By age 85, about one in six American men will develop prostate cancer in their lifetime and about 3% will die from it. With aging, most of the androgen-metabolizing enzymes undergo significant alteration. The incidence is low in black African men worldwide; however, black African-American men have the highest rate of prostate cancer in the world and in the United States.

Galactorrhea

Galactorrhea (inappropriate lactation) is the persistent and sometimes excessive secretion of a milky fluid from the breasts of a woman who is not pregnant or nursing an infant. It can occur in men, may involve one or both breasts and is not associated with breast cancer.

Incidence is difficult to estimate because of differences among definitions of the condition, examination techniques, and populations of women who have been studied. Prevalence has been documented as 0.1% to 32% of all women.

PATHOPHYSIOLOGY Galactorrhea is a manifestation of pathophysiologic processes in the body, rather than a breast disorder. These processes are chiefly hormone imbalances caused by hypothalamic-pituitary disturbances, pituitary tumors, or neurologic damage. Exogenous causes include drugs, estrogen, and manipulation of the nipples. When caused by hyperprolactinemia it is manifested by the spontaneous appearance of a milky secretion from multiple duct openings, usually from both breasts. Galactorrhea caused by oral contraceptives (OCs) is more likely to occur with high-dose use; is characterized by clear, serous, or milky discharge from multiple ducts; and is noticeable during the drug-free interval between OC packets. In premenopausal women, unilateral or bilateral spontaneous multiple duct discharge that increases before menstruation often is caused by fibrocystic change. Unilateral, spontaneous, serous, or serosanguineous discharge from a single duct usually is caused by an intraductal papilloma; bloody discharge suggests cancer; bilateral, sticky, multicolored discharge from multiple ducts is often caused by duct ectasia; and purulent discharge indicates a subareolar abscess.¹⁹⁶

The most common cause of galactorrhea is nonpuerperal hyperprolactinemia, or excessive amounts of prolactin (the pituitary hormone that stimulates milk production) in the blood not related to pregnancy or childbirth. Nonpuerperal hyperprolactinemia can be caused by any factor that (1) stimulates or overstimulates the prolactin-secreting units of the pituitary gland; (2) interferes with production of prolactin-inhibiting factor (PIF), a neurotransmitter (probably dopamine) that inhibits prolactin secretion; or (3) interferes with pituitary receptors for PIF. A variety of exogenous agents (such as drugs) and disorders can trigger one of these three mechanisms, thereby causing hyperprolactinemia (Box 23-15).

Hypothyroidism causes increased secretion of hypothalamic TRH that stimulates prolactin release from the pituitary. Hypothyroidism also is associated with reduced metabolic clearance of prolactin, which prolongs its effects.

Many types of pituitary tumors cause hyperprolactinemia. Prolactinomas cause hyperprolactinemia by secreting prolactin, decreasing production of PIF, or putting pressure on the pituitary stalk such that delivery of PIF to the anterior pituitary is prevented. Growth hormone–secreting pituitary tumors may cause galactorrhea through the intrinsic lactogenic effect that growth hormone appears to have on mammary tissue. Prolactin-secreting lung and kidney tumors also cause hyperprolactinemia.

Chronic stress may cause hyperprolactinemia by inhibiting PIF release. Cervical spinal injuries, head trauma, encephalitis, meningitis, herpes zoster, or thoracotomy scars may stimulate the afferent portion of the suckling reflex arc, which is carried in the second to sixth thoracic nerves. The suckling reflex increases prolactin secretion.

Persistent and repeated sucking or squeezing of the nipples can induce galactorrhea, and has been documented in women who manipulate their breasts and nipples daily.¹⁹⁷ Monthly examination of the breasts for nipple discharge usually is not associated with the development of galactorrhea.

CLINICAL MANIFESTATIONS A small amount of breast milk expressed from the nipple of parous women usually is not a concern, and normal breast milk color can be other than white. Inappropriate lactation is manifested by the appearance of a milky breast secretion in nonpregnant, nonlactating women from one or both breasts. Most women with galactorrhea experience menstrual abnormality. If a pituitary process is involved, the woman usually experiences hirsutism and infertility; if a hypothalamic lesion is present, she may report such CNS symptoms as intractable headache, visual field disturbances, sleep disturbances, and abnormal temperature, thirst, or appetite.¹⁹⁸

EVALUATION AND TREATMENT Galactorrhea requires evaluation when it (1) occurs in nulliparous women or in parous women who have not been pregnant or have not breast-fed for 12 months or (2) is associated with amenorrhea, headache, visual field abnormalities, or other symptoms implying systemic illness. Evaluation includes a variety of diagnostic tests. When amenorrhea accompanies galactorrhea, the assessment is the same as for amenorrhea. Breast secretions are examined for fat globules and neoplastic cells to verify their source. Serum prolactin levels are measured. Because such variables as eating, sleeping, stress, and breast examinations increase prolactin levels, at least two positive results are needed for a diagnosis of hyperprolactinemia. Prolactin levels greater than 25 to 30 ng/ml (by radioimmunoassay) are elevated. Those in the range of 75 to 100 ng/ml are considered to be caused by a pituitary tumor until proved otherwise. Serum thyroxine and TSH levels are measured to rule out hypothyroidism, and LH and FSH levels are obtained if the individual is amenorrheic. CT, MRI, and carotid angiography may assist in the localization of adenomas.

Treatment is specific to the underlying cause and occurs after identification of the cause. Medical and surgical therapies may be involved. A pituitary microadenoma may be surgically removed, or treated medically with bromocriptine (Parlodel), which controls the tumor but does not cure it. A pituitary macroadenoma usually is treated medically because surgical and radiologic therapies seldom succeed.

Benign Breast Disease and Conditions

Benign breast disease (BBD) is a condition of noncancerous changes in the breast. Numerous benign alterations in ducts and lobules occur in the breast, including irregular lumps, cysts, sensitive nipples, and itching. The most common symptoms reported by women are pain, palpable mass, or nipple discharge; the majority of these prove to have a benign cause. However, histologic features, age at biopsy, and degree of family history have been found as major determinants of the risk of breast cancer after a diagnosis of BBD.¹⁹⁹ This risk varies according to the histologic category of BBD (moderate in women with proliferative lesions without atypia and substantial in women with atypical (atypia) hyperphasia [AH])²⁰⁰ (see p. 875). Among premenopausal women, the risk appears to be greater for those with atypical lobular hyperplasia (ALH) than with atypical ductal hyperplasia (ADH) (see p. 875). For postmenopausal women the risk of breast cancer was similar between those with ALH or ADH.²⁰⁰ Family history is reported as an independent risk factor for breast cancer. Women with atypia and a family history had a breast cancer risk four times the expected risk.¹⁹⁹ Risk was lower among those with atypia and no family history.

The College of American Pathologists has classified biopsy tissue according to breast cancer risk. These classifications are listed in Box 23-16. Benign epithelial lesions can be broadly classified according to their future risk of developing breast cancer as (1) nonproliferative breast lesions, (2) proliferative breast disease, and (3) atypical (atypia) hyperplasia.