Chapter 51. The Testis, Prostate, & Penis

Manifestations of Testicular Disease

Infertility

Either the male, the female, or both partners may be responsible for infertility, which is defined as the failure to conceive after 1 year of regular coitus without contraception. Male infertility, usually recognized by absence of spermatozoa (azoospermia) or decreased numbers of spermatozoa in semen (oligospermia), may result from one of three categories of disease:

Pretesticular Causes

These consist of endocrine disorders—most commonly hypopituitarism—in which failure of production of gonadotropins leads to testicular failure. These diseases are recognized by decreased pituitary gonadotropin levels in serum.

Posttesticular Causes

The most common mechanism is obstruction to the outflow of spermatozoa. Bilateral obstruction results in azoospermia. Obstructive infertility is responsible for up to 50% of cases of infertility and may be corrected surgically. The diagnosis is established by vasograms, in which dye is introduced into the duct system for radiographic visualization, and by testicular biopsy, which shows normal spermatogenesis.

Testicular Causes

Most of these conditions are untreatable and include any disorder associated with testicular atrophy (Table 51-1) plus either of the following specific abnormalities identifiable on testicular biopsies: (1) germ cell aplasia, in which there is a total absence of spermatocytes and the seminiferous tubules are lined entirely by Sertoli cells (also called “Sertoli cell only” syndrome); and (2) spermatocytic maturation arrest.

Testicular Masses or Enlargement

The presence of masses or enlargement of the testis represents the most common symptom of testicular disease. In general, acute inflammatory lesions are painful; chronic inflammatory lesions and neoplasms are usually painless. Scrotal swelling (Figure 51-1) should be carefully examined for evidence of an enlarged testis, and any patient with a testicular mass should be considered to have a neoplasm until proved otherwise.

Abnormal Production of Hormones

Hormones from functional testicular stromal tumors may produce precocious puberty in the child (androgens) or gynecomastia (estrogens).

Assessment of Testicular Dysfunction

Physical examination should be supplemented when necessary by ultrasonography and computerized tomography in the evaluation of testicular mass lesions. Testicular biopsy is useful in the diagnosis of mass lesions and in determining whether the cause of azoospermia is testicular or posttesticular. Serum levels of gonadotropins, androgens, and estrogens may be abnormal in testicular failure secondary to hypopituitarism and in functional testicular neoplasms.

A normal semen specimen has a volume of 3–4 mL and a sperm count of 30 × 106/mL, with 80% morphologically normal and motile spermatozoa.

Congenital Testicular Anomalies

Absence of one or both testes and fusion of testes are very rare anomalies. Klinefelter's syndrome (testicular dysgenesis) results in failure of normal testicular development at puberty (Chapter 15: Disorders of Development).

Abnormalities of Testicular Descent (Undescended Testis; Ectopic Testis; Cryptorchidism)

Normal descent of the testis through the inguinal canal into the scrotum occurs in the last trimester of pregnancy. The mechanism and factors that stimulate descent are uncertain.

Arrest of testicular descent is common, occurring in 3% of full-term male infants; in most of these cases, complete descent occurs in the first year of life. A testis that remains arrested at an extrascrotal location along the normal path of migration is called an undescended testis (Figure 51-2).

Rarely, the testis is located outside its normal descent route (ectopic testis; Figure 51-2).

An extrascrotal testis appears normal until about puberty, and placement in the scrotum before age 2 years is usually associated with normal development. After puberty, a misplaced testis becomes visibly atrophic (Figure 51-3), although subtle but irreversible histologic abnormalities probably begin much earlier. Failure of spermatogenesis is believed to be due to the higher temperature of an extrascrotal testis because the normally lower scrotal temperatures are necessary for normal spermatogenesis. Evidence is emerging, however, that some cases of maldescent occur because the testis is intrinsically abnormal.

Individuals with undescended testes have a greatly increased risk of developing malignant germ cell neoplasms if the maldescent is not corrected. A slightly increased risk of testicular cancer persists after the testis is replaced in the scrotum. In patients with one undescended testis, the normal testis also has a slightly increased risk of developing testicular cancer.

Testicular Atrophy

Atrophy of the seminiferous tubules is common, usually symptomless, and occurs secondary to many diseases (Table 51-1). The testes are smaller than normal. Microscopically, the seminiferous tubules show decreased diameter, increased thickness of the basement membrane, marked decrease in germ cells, and absent spermatogenesis. In complete atrophy, the tubules either contain only Sertoli cells or become completely occluded by fibrosis. The interstitium shows fibrosis. Leydig cells are usually present in normal numbers (Figure 51-3).

Inflammatory Lesions of the Testis & Epididymis

Acute Epididymo-Orchitis

Acute epididymo-orchitis is a common infection caused by bacteria that reach the epididymis from the urethra. Escherichia coli, gonococci, and chlamydiae are common culprits. Organisms reach the epididymis via the vas deferens secondary to reflux of infected urine from the prostatic urethra, or via the lymphatics of the spermatic cord. Acute pyogenic inflammation of the epididymis ensues, commonly extending into the testis.

Clinically, patients present with acute onset of fever, pain, and tenderness and redness of the scrotum extending along the spermatic cord. Resolution occurs rapidly with specific antibiotic therapy.

Complications include (1) fibrosis leading to obstruction of the epididymis, resulting in sterility only in those cases where both sides are affected; (2) vascular compromise, leading rarely to infarction of the testis; and (3) abscess formation in the scrotum.

Tuberculous Epididymoorchitis

Tuberculosis of the epididymis is common wherever there is a high incidence of tuberculosis. Eighty percent of patients have demonstrable (although often subclinical) lesions in the urinary tract. Tubercle bacilli gain access to the epididymis from the urethra.

Pathologically, there is a chronic granulomatous inflammation with caseous necrosis and fibrosis, leading to thickening of the epididymis. The inflammatory reaction frequently spreads to involve the testis (Figure 51-4).

Clinically, patients present with enlargement of the scrotum. Pain is usually not a major complaint. Caseous material may ulcerate and drain through the skin of the scrotum, usually the posterior aspect. The diagnosis is made by culture or by demonstration of acid-fast bacilli in caseous granulomas on tissue sections.

Mumps Orchitis

Orchitis occurs in 10–20% of cases of mumps in postpubertal males. It usually causes mild acute inflammation with testicular pain and mild swelling that resolves rapidly. In a small number of cases, severe inflammation results in testicular atrophy and sterility.

Syphilis

Syphilis affects the testis in the tertiary (late) stage and is characterized by formation of a rubbery firm mass of necrotizing chronic granulomatous inflammation known as a gumma. It is rare today because of better treatment of early syphilis. Syphilis is discussed in Chapter 54: Sexually Transmitted Infections.

Idiopathic Granulomatous Orchitis

This uncommon inflammatory lesion of the testis is of unknown cause; some patients have autoantibodies to testicular antigens, leading to the hypothesis that it is an autoimmune disease.

Grossly, the testis is enlarged and has a smooth capsule. On cut section, the normal structure of the testis is replaced by a firm, grayish-white multinodular lesion. Microscopically, there is destruction of seminiferous tubules and the presence of numerous lymphocytes, plasma cells, and multiple epithelioid granulomas with giant cells. Caseation does not occur.

Patients are usually middle-aged and present with moderately painful enlargement of the testis; clinically, this disorder is frequently mistaken for a neoplasm.

Sperm Granuloma

A sperm granuloma is a fairly common lesion that occurs in the testis and epididymis when there is leakage of spermatozoa into the interstitium. A common cause is a slipped vasectomy ligature.

Extravasation of spermatozoa leads to a granulomatous response with progressive fibrosis. The diagnosis is made by identification of spermatozoa within the inflammatory lesion.

Fournier's Scrotal Gangrene

This rare disease of adults is characterized by necrotizing cellulitis and fasciitis of the scrotum, caused usually by anaerobic bacteria. Acute inflammation with marked edema progresses rapidly to vascular thrombosis and gangrene of the scrotal skin, which then ulcerates and sloughs, leaving the testes exposed. The mortality rate is high unless treatment is started expeditiously.

Hydrocele

A hydrocele is a collection of fluid within the potential space between the two layers of the tunica vaginalis (Figure 51-1). The usual causes are trauma, infection, or tumor of the underlying testis. Congenital hydroceles also occur but are rare. Hydrocele fluid is usually clear and straw-colored; if it contains much blood, the term hematocele may be appropriate.

Testicular Torsion

Torsion of the testis is a common condition caused by twisting of the spermatic cord, leading to vascular obstruction. Abnormalities of the testis or its ligaments are predisposing factors. Torsion occurs commonly in incompletely descended testes.

Pathologically, there is edema, hemorrhage, and finally venous infarction of the testis. Clinically, the torsion causes sudden onset of severe pain with marked swelling of the scrotum (Figure 51-1). The testis is intensely tender. Orchiectomy is required in cases that have progressed to necrosis of testicular tissue.

Testicular Neoplasms

Testicular neoplasms are classified on a histogenetic basis. There are two main groups: germ cell neoplasms and stromal neoplasms (Table 51-2).

Germ Cell Neoplasms

Germ cell neoplasms account for over 95% of testicular tumors. They occur with an incidence of 2:100,000 males. In the age group from 15 to 34 years, they cause 10–12% of cancer deaths. They are more common in whites than blacks.

Etiology

The etiology of testicular germ cell neoplasms is unknown. Extrascrotal testes have an increased incidence of neoplasia (especially seminomas); 5% of testes in the abdominal cavity and 1% of testes in the inguinal canal develop cancer. The risk—approximately 30 times normal—is sufficient to warrant prophylactic orchiectomy if an undescended testis is discovered in an adult. When an undescended testis is detected early in life and surgically placed in the scrotum, the risk of germ cell neoplasia is only slightly increased.

Administration of diethylstilbestrol (DES) to the mother during pregnancy is associated with an increased incidence of testicular cancer in male offspring. There is no familial predisposition.

Classification

Germ cell tumors are presumed to arise in a primitive germ cell in the seminiferous tubules. They are classified according to their differentiation (Figure 51-5; Table 51-2). Germ cell neoplasms that show minimal differentiation and are composed of primitive germ cells are called embryonal carcinomas. Those that show recognizable differentiation are called seminomas (seminiferous differentiation), teratomas (somatic differentiation), choriocarcinomas (trophoblastic differentiation), or yolk sac carcinomas (yolk sac differentiation). Neoplasms composed of a single element account for 60%; the remainder are mixed tumors.

From a clinical standpoint, it is important to differentiate between seminoma and nonseminomatous germ cell neoplasms because the two groups are treated differently.

Pathology

Gross Appearance

(Figure 51-6.) All germ cell neoplasms appear as masses causing destruction of testicular substance. In small neoplasms, there may be residual testicular tissue, partially infiltrated by tumor. Seminomas and teratomas are often better circumscribed than are other types. Some gross differences exist between the different types of tumor (Table 51-2). Seminomas are firm and solid; teratomas commonly have a cystic component; embryonal carcinoma and yolk sac carcinoma are solid, fleshy, and friable; choriocarcinoma is associated with extensive hemorrhage.

Microscopic Appearance

Seminoma

Classic seminoma is characterized by nests of uniform large round cells that have distinct cell membranes, centrally placed nuclei, prominent nucleoli, and clear cytoplasm containing abundant glycogen; these cells resemble the primary spermatocytes in the seminiferous tubule. The nests of cells are separated by fibrous trabeculae infiltrated by numerous lymphocytes (Figure 51-7). Granulomatous inflammation with giant cells and necrosis is present in about 50% of cases and may dominate the histologic picture.

Two additional variants of seminoma are recognized: (1) Spermatocytic seminoma accounts for about 5% of cases, occurs in older individuals, and is characterized by maturation of the tumor cells, which resemble secondary spermatocytes. It does not metastasize. (2) Anaplastic seminoma is more pleomorphic and has a higher rate of mitotic figures (> 3 per high-power field). It tends to present at a more advanced stage of disease, but stage for stage it has a prognosis similar to that of classic seminoma.

Embryonal Carcinoma

Embryonal carcinoma is characterized by highly malignant primitive-appearing undifferentiated cells showing frequent mitoses and necrosis. The cells may be arranged in solid sheets or may show glandular and papillary patterns (Figure 51-8).

Teratoma

Teratoma is characterized by somatic differentiation. By definition, all three germ layers are represented. When only mature somatic structures such as skin and nerves (ectoderm), gut and respiratory epithelium (endoderm), and cartilage, bone, and muscle (mesoderm) are present, the term mature teratoma is used (Figure 51-9). When immature somatic structures such as neuroblastic tissue and undifferentiated mesenchymal cells are present, the neoplasm is called an immature teratoma. All teratomas in adults are biologically malignant; in contrast, in children under age 12 years, teratomas behave as benign neoplasms.

Yolk Sac Carcinoma

This tumor is characterized by differentiation toward yolk sac-like structures. Tumor cells assume a delicate reticular (lace-like) pattern or a papillary pattern in which structures that resemble glomeruli (glomeruloid or Schiller-Duval bodies) are present. Pink hyaline globules are often present in the cytoplasm of the cells of yolk sac carcinoma; these globules frequently stain positively for alpha-fetoprotein (AFP).

Choriocarcinoma

The presence of cytotrophoblastic and syncytiotrophoblastic giant cells, arranged in a manner resembling their relationship in chorionic villi, is characteristic. There is almost always extensive hemorrhage. The syncytiotrophoblastic cells secrete human chorionic gonadotropin (hCG) and stain positively for βhCG.

It must be emphasized that the presence of syncytiotrophoblastic giant cells alone does not permit a diagnosis of choriocarcinoma. Such cells are not uncommonly found scattered in all of the other germ cell neoplasms.

Tumor Markers

βhCG and AFP are extremely important tumor markers in germ cell neoplasms. High levels of βhCG are present in the serum in patients with choriocarcinoma. Mildly elevated serum βhCG levels occur in patients with other germ cell neoplasms containing a subpopulation of syncytiotrophoblastic giant cells. AFP levels in serum are markedly elevated in patients with yolk sac carcinoma and embryonal carcinoma. The absence of elevated βhCG and AFP in the serum indicates the absence of choriocarcinoma and yolk sac carcinoma. It should be noted that other nontesticular neoplasms are associated with elevation of βhCG (eg, rare cases of lung and gastric carcinoma) and AFP (eg, 90% of hepatocellular carcinomas) (see Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms).

These two tumor markers are also very useful in monitoring the treatment of patients with germ cell neoplasms. Elevation of βhCG or AFP in serum is a very sensitive indicator of the presence of that particular tumor type in the body. With removal of the tumor, either by surgery or by chemotherapy, the levels of these tumor markers drop; subsequent elevation indicates recurrence.

Biologic Behavior

All germ cell neoplasms of the testis should be considered malignant. The only exception is teratoma in children, which behaves as a benign neoplasm.

The metastatic potential is very high for these neoplasms. They spread by lymphatics to the retroperitoneal and para-aortic lymph nodes and via the bloodstream to the lungs and liver (Figure 51-10). Germ cell neoplasms are staged clinically by a combination of physical examination and computed tomography (CT) of the abdomen and chest (Table 51-3).

Clinical Presentation

Germ cell neoplasms usually present as a painless mass in the testis, often associated with a hydrocele.

Not uncommonly, the first manifestation of the neoplasm is at a metastatic site (retroperitoneum or lung). Germ cell tumors have a tendency to remain small at the primary site while metastases may become large (eg, in the retroperitoneum).

Treatment

Seminomas are extremely radiosensitive. All germ cell neoplasms are highly sensitive to modern combined chemotherapy. The use of orchiectomy and surgical removal of metastases from the lungs and retroperitoneum combined with aggressive chemotherapy has greatly improved the prognosis. While 90% of patients with testicular germ cell neoplasms died of their disease 20 years ago, the survival rate is now close to 90%, representing one of the most remarkable successes of cancer treatment. Failures of treatment are mainly those presenting in stages IIb and III (Table 51-3).

Gonadal Stromal Neoplasms

(Table 51-2)

Interstitial (Leydig) cell tumors constitute about 2% of testicular neoplasms and occur mainly in children and young adults. They often produce androgens, causing precocious puberty in children. More rarely, they secrete estrogens.

These neoplasms vary from 0.5 cm to over 10 cm in diameter and are usually well-circumscribed and yellowish-brown. Microscopically, there are sheets of large cells resembling interstitial cells. In 50% of cases, typical rod-shaped crystalloids of Reinke occur. Cytologic atypia may be present but is not necessarily an indicator of malignancy.

The biologic behavior of these tumors is usually benign, but about 10% are malignant. Prediction of malignant behavior is not possible by histologic examination.

Sertoli cell tumors are rare. They typically contain structures resembling seminiferous tubules with Sertoli cells. Sertoli cell tumors may secrete androgens or estrogens. Granulosa cell tumors are exceptionally rare in the testis. Production of estrogens may induce gynecomastia. Most are benign.

Malignant Lymphoma

Primary malignant lymphoma of the testis occurs most often in patients over 60 years of age and represents the most common neoplasm of the testis in this age group. It accounts for 2% of all testicular neoplasms. B-immunoblastic sarcoma is the most common histologic type.

Adenomatoid Tumor

Adenomatoid tumor is a benign neoplasm that usually arises in the epididymis, probably from mesothelial cells in the tunica vaginalis. Immunoperoxidase stains for keratin are positive. A similar tumor occurs also in the pelvic cavity in females, commonly on the external surface of the uterus and uterine tubes.

Adenomatoid tumors appear as small circumscribed firm nodules with a homogeneous grayish-white cut surface. Microscopically, they are composed of gland-like or slit-like spaces (hence adenomatoid) lined by flat to cuboidal mesothelial cells in a stroma composed of fibroblasts, smooth muscle cells, and collagen.

Structure & Function

The prostate gland weighs about 20 g and encircles the upper (prostatic) urethra (Figure 51-11). It is composed of two lateral lobes, a median lobe, and one anterior and one posterior lobe. The ejaculatory ducts pass through the gland to open into the prostatic urethra. Histologically, the prostate is a compound tubuloalveolar gland with a stroma composed of smooth muscle.

Prostatic secretion is the major volume component of seminal fluid. It is rich in acid phosphatase.

Anatomically, the prostate is closely related to the rectum, and rectal examination permits digital palpation of its posterior aspect. Needle biopsy is also possible through the rectal wall. Both fine-needle aspiration and core-needle biopsy can be performed, providing specimens for cytologic and histologic examination, respectively.

Manifestations of Prostatic Disease

Obstruction of Urinary Outflow

Enlargement of the prostate from any cause may cause acute retention of urine, with acute painful dilation of the bladder; or chronic retention of urine, characterized by incomplete emptying of the bladder, increased frequency, and a poor stream (decreased urinary flow). The bladder is dilated, and its wall undergoes hypertrophy. There is an increased incidence of infection of the stagnant bladder urine. Chronic renal failure may occur as a result of hydroureter and hydronephrosis.

Pain

Inflammatory lesions of the prostate cause perineal pain, aggravated by urination or by palpation of the prostate at rectal examination.

Hematuria

Hematuria may occur in benign prostatic hyperplasia, especially when there is infarction of a nodule. Hematuria is a late manifestation of prostatic cancer because that tumor most frequently arises in the peripheral zone of the gland.

Inflammation of the Prostate

Acute Prostatitis

Acute prostatitis is a common disease caused by gram-negative coliform bacteria, most commonly Escherichia coli. Gonococcal prostatitis is also common. Prostatitis is a frequent complication of lower urinary tract surgery.

Acute inflammation—sometimes with suppuration—can involve the gland focally or diffusely. Clinically, acute prostatitis is manifested as pain associated with urination or ejaculation. Marked tenderness is present over the enlarged prostate on rectal examination.

Chronic Prostatitis

Chronic prostatitis is common. While bacterial infection is frequently present, in many cases the cause is uncertain (abacterial prostatitis).

The gland is irregularly enlarged, firm, and infiltrated by numerous lymphocytes, plasma cells, macrophages, and neutrophils. Extravasation of secretions may provoke a foreign body type of granulomatous reaction (granulomatous prostatitis).

The symptoms of chronic prostatitis are vague. On examination, the gland feels irregular and firm, arousing a suspicion of cancer.

Benign Prostatic Hyperplasia (BPH)

When defined as an increase in the weight of the prostate, BPH is present in 50% of men between 40 and 60 years of age and 95% of men over 70. In most of these individuals, the condition is symptomless; however, clinically significant BPH is present in about 5–10% of men over 60 years of age. A small proportion of these individuals have symptoms severe enough to require surgery.

Etiology

The cause of prostatic hyperplasia is unknown. Changes in hormonal status are believed to be important; declining levels of androgens relative to estrogen levels are believed to stimulate glandular and stromal hyperplasia.

Pathology

Gross Findings

The periurethral part of the gland is most commonly involved (Figure 51-11). Overall, the gland is enlarged, often reaching massive size, and has a firm, rubbery consistency. Small nodules are present throughout the gland, usually 0.5–1 cm in diameter but sometimes much larger. Some of the larger nodules show cystic change. The urethra appears slit-like and compressed.

Microscopic Findings

The nodules are composed of a variable mixture of hyperplastic glandular elements and hyperplastic stromal muscle. The glands are larger than normal and lined by tall epithelium that is frequently thrown into papillary projections (Figure 51-12). Infarction of a nodule is common and may be associated with acute swelling that may precipitate acute pain and urinary retention. When infarction of a periurethral nodule occurs, the patient may develop hematuria.

Clinical Features

Obstruction to urinary outflow is responsible for the major symptoms. The patient commonly has difficulty initiating urination, and the decreased flow causes a poor urinary stream. Incomplete emptying of the bladder leads to chronic retention of urine and frequency. Bladder neck obstruction is caused by urethral compression and enlargement of the periurethal median lobe, which protrudes into the bladder and acts as a ball valve.

Complications include (1) chronic retention of urine, hypertrophy of bladder musculature, and the development of bladder diverticula; (2) acute retention of urine, often due to swelling of the prostate caused by infarction; (3) hematuria, also the result of infarction; (4) urinary infection because of urinary stasis; and (5) hydronephrosis and chronic renal failure.

Treatment of prostatic hyperplasia is surgical removal of the obstructing part of the gland, either by transurethral resection or open prostatectomy. The condition is not premalignant.

Neoplasms of the Prostate

Carcinoma of the Prostate

Carcinoma of the prostate is a common incidental finding at autopsy; it is present in 20–30% of men over 50 years and over 70% of men at 90 years. The vast majority of these cancers are not detected during life (occult cancers). Annually, 165,000 new cases are diagnosed and there are 35,000 deaths from prostate cancer in the United States. Ninety-nine percent of cases occur in men over 50 years of age. Prostatic cancer is most common in whites and uncommon in Asians. Prostate cancer has a familial tendency; a man with a father or brother with prostate cancer has double the risk compared with a man with a negative family history.

Etiology

The etiology of prostatic carcinoma is unknown. A study of the geographic distribution provides some insight. The low incidence in Japanese men increases to approach that of American whites when they emigrate to the United States, suggesting an important role for environmental factors.

Androgens are involved in the growth of prostatic carcinoma if not their causation. Most prostatic carcinomas arise in the subcapsular peripheral region of the posterior lobe of the prostate, a region of the gland that is most sensitive to changes in androgen levels. The fall in androgen levels in later life is associated with involutionary changes in the outer part of the gland, and it is in this region affected by these regressive changes that cancer arises.

The growth of prostatic carcinoma is androgen-dependent. Some degree of androgen dependency is shown by all prostatic carcinomas, permitting control of prostatic cancer by removing androgens. Bilateral orchiectomy or administration of estrogens causes regression of tumor, albeit temporarily.

Nodular hyperplasia of the prostate is not associated with an increased incidence of carcinoma.

Dysplastic changes in the prostatic epithelial cells (also called prostatic intraepithelial neoplasia [PIN]) precede the development of invasive cancer. The highest grade of this process (PIN 3) is almost invariably associated with carcinoma and is considered equivalent to carcinoma in situ. High-grade PIN is characterized by the following nuclear changes in a gland that has normal architecture: nuclear stratification, enlargement, and hyperchromasia with the presence of large nucleoli.

Pathology

Prostatic carcinoma appears grossly as a hard, irregular, ill-defined gray or grayish-yellow area on cut section. Over 75% of cancers occur in the outer part of the gland—mainly in the posterior part. The size of the neoplasm varies from microscopic to massive.

Histologically, prostatic carcinomas are adenocarcinomas arising in the glandular epithelium. The cancer may be well-differentiated, forming small or large glands (Figure 51-13A), or poorly differentiated, extensively invading the stroma. Several different histologic grading systems have been suggested because there is fairly good correlation between histologic grade and prognosis. The most widely used and the one that correlates best with survival is Gleason's system, which uses two numbers representing the two predominant patterns in the tumor. The best- and worst-differentiated patterns, according to this system, are 1,1 (pure grade 1 lesions) and 5,5 (pure grade 5 lesions), respectively; a grade 2,4 carcinoma would show a mixture of moderately and poorly differentiated areas.

Since most prostatic cancers occur in the outer part of the gland, urethral involvement occurs relatively late in the course of the disease. Urethral obstruction and hematuria occur with large tumors and rare central tumors.

Perineural invasion (Figure 51-13B) is a common feature of prostatic adenocarcinoma and is useful in making the histologic diagnosis of carcinoma in difficult cases. Its presence has no prognostic significance.

Spread

Local extension through the prostatic capsule into pelvic fat occurs early. Local structures such as the seminal vesicles, the base of the bladder, and the ureters are commonly involved. The rectum is rarely invaded, probably because of the presence of the rectovesical fascia.

Lymphatic spread to the regional lymph nodes (iliac, para-aortic, inguinal; Figure 51-14) is common. Hematogenous spread to the lumbosacral spine occurs early, via communications that exist between the prostatic and vertebral venous plexuses (Figure 51-15). Systemic hematogenous spread occurs late in the course of prostatic cancer and is more common in high-grade lesions.

Pathologic Staging

The clinicopathologic stage, which depends on the size of the tumor and the extent of spread (Table 51-4), has a much greater prognostic impact than any other factor, including histologic grading.

Clinical Features

Urinary symptoms such as altered flow, hematuria, and frequency occur late because of the usual peripheral posterior location of the tumor. The diagnosis can often be made by digital palpation of the gland at rectal examination. The cancerous area can be felt as a hard, irregular nodule. Back pain due to vertebral metastases is a common presenting feature. Skeletal metastases of prostatic cancer are associated with increased osteoblastic activity, leading to sclerotic lesions.

Prostatic cancer cells produce acid phosphatase. Serum prostatic acid phosphatase becomes elevated when the tumor infiltrates outside the capsule and is therefore not of great help in the diagnosis of early stage A or B carcinoma; it is a good confirmatory test in stage C and D carcinoma. An antigen derived from prostatic cancer cells—prostate-specific antigen (PSA)—may also be found in increased amounts in the blood; its detection is a useful diagnostic test.

Needle biopsy using a thin needle and ultrasound guidance provides tissue from suspicious areas for histologic diagnosis. In cases where doubt exists about whether an adenocarcinoma is of prostatic origin, as with a metastatic lesion, immunohistochemical staining for prostatic acid phosphatase or PSA reliably establishes prostatic origin (Figure 51-16).

Screening of asymptomatic men over age 50 years is now recommended, utilizing annual digital rectal examination and serum PSA assay. Marked elevation of serum PSA is virtually diagnostic of cancer. Mild and moderate serum PSA elevation occurs in benign hyperplasia and chronic prostatitis as well as cancer but is an indication for prostatic ultrasonography and directed fine-needle biopsy. Ten to 15 percent of patients with prostatic cancer have normal serum PSA levels, making this a very imperfect screening test.

Prognosis

The prognosis depends on the clinicopathologic stage and to a lesser extent on histologic grade. With early disease (stage B), 80% of patients survive 5 years and 60% survive 10 years following aggressive surgery with adjuvant radiotherapy and chemotherapy. Unfortunately, less than 20% of patients are diagnosed at this early stage. With advanced disease (stage D), the prognosis is poor, with only 20% surviving 5 years.

Other Prostatic Neoplasms

Neoplasms other than prostatic adenocarcinoma are rare. Embryonal rhabdomyosarcoma (a malignant tumor of immature muscle cells) is worthy of mention because it is the most common prostatic neoplasm in childhood. It is highly malignant.

Congenital Penile Anomalies

The most common congenital anomalies relate to the position of the urethral opening on the penis.

In hypospadias, the opening is situated on the ventral aspect of the penis at a variable distance from the tip. Minor degrees of hypospadias are common. In the most extreme form of hypospadias, the urethra opens at the root of the penis, resembling the clitoris and urethra in the female (ambiguous genitalia; Chapter 15: Disorders of Development).

Epispadias is the opening of the urethra on the dorsal aspect of the penis.

Phimosis is a frequent disorder that may be congenital or may be acquired by trauma or recurrent infection. It is characterized by an excessively small preputial orifice that prevents retraction over the glans and in extreme cases obstructs urinary outflow.

Penile Infections

Urethritis and the sexually transmitted diseases are discussed in Chapter 54: Sexually Transmitted Infections.

Penile Neoplasms

Condyloma Acuminatum

Condyloma acuminatum is a common benign neoplasm caused by human papilloma virus, which is transmitted sexually. Penile condylomas occur commonly on the coronal sulcus of the glans or the inner surface of the prepuce. They vary in size from 1 mm to several centimeters and appear grossly as wart-like or raspberry-like masses; they are frequently multiple.

Penile condylomas have histologic features of benign papillomas of squamous epithelium. Vacuolization of the cytoplasm (koilocytosis) is common and characteristic. The larger lesions—also called giant condylomas of Buschke and Lowenstein—are difficult to distinguish from well-differentiated verrucous type of squamous carcinoma.

Penile Carcinoma in Situ (Bowen's disease; Erythroplasia of Queyrat)

Penile carcinoma in situ appears clinically as a red plaque on the glans or prepuce. There is a high risk of subsequent invasive carcinoma.

Carcinoma of the Penis

Carcinoma of the penis is uncommon in the United States, representing less than 1% of cancers in males. The incidence is low in the circumcised male. Penile carcinoma is almost nonexistent in Jews, in whom circumcision is performed at birth, and is seen very infrequently in Moslems, in whom circumcision is performed in the early teens.

Penile carcinoma is common in Asian populations, accounting for as much as 10% of male cancers in some Asian countries. It occurs in the age group from 40 to 70 years.

Pathology & Clinical Features

The common sites for carcinoma of the penis are the glans and inner surface of the prepuce. The lesion is detected at an early stage, when the prepuce is retractable; detection may be delayed in patients with phimosis. The early lesion is commonly an area of epithelial thickening (leukoplakia) followed by formation of an elevated white papule. Ulceration follows, producing the characteristic indurated, painless ulcer with raised, everted edges (Figure 51-17). Less commonly, carcinoma appears as a papillomatous or warty growth.

Microscopically, penile carcinoma is a squamous carcinoma of variable differentiation. The degree of differentiation is not important from a prognostic standpoint. Penile carcinoma with a wart-like appearance and minimal invasion and cytologic abnormality is called verrucous carcinoma.

Behavior & Treatment

Penile carcinoma usually shows slow infiltrative growth locally, with invasion of the corpora cavernosa occurring early. At the time of presentation, about 25–30% of patients have regional (inguinal) lymph node involvement. Distant metastases occur only at a late stage.

With adequate surgical removal of the primary, which frequently entails partial or total penectomy and excision of regional inguinal lymph nodes, the overall 5-year survival rate approaches 50%. Radiation therapy is useful in controlling recurrent disease.

Scrotal disease is common secondary to underlying disorders of the testis or epididymis (eg, tuberculous epididymo-orchitis). In addition, the scrotum may be involved by skin diseases (Chapter 61: Diseases of the Skin), most commonly epidermal cysts, which frequently calcify. Necrotizing fasciitis of the scrotum (Fournier's gangrene) was described earlier in this chapter. The scrotum may rarely be the site of squamous carcinoma; historically, the scrotum was the first known site of a carcinogen-induced tumor (soot in chimney sweeps—Percivall Pott, 1714–1788). (See Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia.)