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Manifestations of Testicular Disease
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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:
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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.
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Posttesticular Causes
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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.
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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.
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Testicular Masses or Enlargement
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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.
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Abnormal Production of Hormones
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Hormones from functional testicular stromal tumors may produce precocious puberty in the child (androgens) or gynecomastia (estrogens).
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Assessment of Testicular Dysfunction
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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.
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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.
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Congenital Testicular Anomalies
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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).
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Abnormalities of Testicular Descent (Undescended Testis; Ectopic Testis; Cryptorchidism)
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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.
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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).
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Rarely, the testis is located outside its normal descent route (ectopic testis; Figure 51-2).
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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.
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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.
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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).
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Inflammatory Lesions of the Testis & Epididymis
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Acute Epididymo-Orchitis
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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.
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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.
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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.
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Tuberculous Epididymoorchitis
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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.
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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).
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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.
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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.
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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.
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Idiopathic Granulomatous Orchitis
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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.
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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.
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Patients are usually middle-aged and present with moderately painful enlargement of the testis; clinically, this disorder is frequently mistaken for a neoplasm.
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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.
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Extravasation of spermatozoa leads to a granulomatous response with progressive fibrosis. The diagnosis is made by identification of spermatozoa within the inflammatory lesion.
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Fournier's Scrotal Gangrene
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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.
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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.
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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.
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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.
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Testicular neoplasms are classified on a histogenetic basis. There are two main groups: germ cell neoplasms and stromal neoplasms (Table 51-2).
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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.
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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.
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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.
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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.
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From a clinical standpoint, it is important to differentiate between seminoma and nonseminomatous germ cell neoplasms because the two groups are treated differently.
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(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.
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Microscopic Appearance
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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.
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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.
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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).
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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.
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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).
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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.
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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.
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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).
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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.
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All germ cell neoplasms of the testis should be considered malignant. The only exception is teratoma in children, which behaves as a benign neoplasm.
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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).
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Clinical Presentation
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Germ cell neoplasms usually present as a painless mass in the testis, often associated with a hydrocele.
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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).
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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).
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Gonadal Stromal Neoplasms
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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.
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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.
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The biologic behavior of these tumors is usually benign, but about 10% are malignant. Prediction of malignant behavior is not possible by histologic examination.
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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.
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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.
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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.
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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.