Year Ii Organ Systems - Reproduction Self-Study

YEAR II ORGAN SYSTEMS - REPRODUCTION SELF-STUDY

PATHOLOGY OF THE TESTES AND PENIS

I. REQUIRED READING Kumar, Abbas, Fausto & Mitchell, Robbins Basic Pathology, 9th ed., Elsevier- Saunders, 2013; Ch. 17, The Male Genital System and Lower Urinary Tract; pp. 657-663.

II. LEARNING OBJECTIVES

Upon completion of the lecture, laboratory and required reading the student will be able to:

1. Describe the general morphological patterns and pathogenesis of testicular hypoplasia and atrophy with particular reference to the following:

Cryptorchidism Klinefelter syndrome (XXY) Hypopituitarism Mumps and other causes of orchitis Alcoholic cirrhosis Androgen insensitivity syndrome Exposure to antiandrogens and other chemotherapeutics

2. Describe the major gross and microscopic features of the following tumors:

Germ cell tumors of testis: Non-germ cell tumors of testis: seminoma Leydig embryonal carcinoma Sertoli yolk sac (endodermal sinus) tumor teratoma, mature and immature choriocarcinoma Carcinoma of penis

3. Correlate the pathologic features with the major symptoms produced by these tumors.

III. NON-NEOPLASTIC DISEASES OF THE TESTES

The gonads are homologous organs in the male and the female, and the diseases of the testis and ovary therefore are closely parallel. In the light of these homologies, a rational classification of diseases of the gonads can be made.

Each gonad has a dual function: (1) production of gametes; and (2) the secretion of sex hormones. In clinical practice, however, male hypogonadism is a term generally used to mean deficient production of androgen by the testis (interstitial cells of Leydig), whereas the term infertility is applied when referring to deficient production of spermatozoa by the germinal epithelium.

Pathology

1. Epididymitis and Orchitis

Although inflammation of the epididymis is more common than that of the testis, epididymitis can spread to involve the testis. The morphological patterns are similar to inflammation elsewhere in the body: congestion; edema; and infiltration by neutrophils, macrophages, and lymphocytes. Typically, the initial inflammation is limited to the interstitium; however, this can extend to involve the tubules. In some cases, abscess formation may occur leading to significant loss of tissue; this may lead to tubular atrophy (see below). Often, the significant numbers of Leydig cells are spared, maintaining testosterone production. 31

2. Hypoplasia

Hypoplasia is the condition of defective or incomplete development. The hypoplastic testis fails to develop at the usual time (puberty in the male should be completed by age 20) but instead remains small and retains infantile characteristics. Testis biopsy shows small tubules without lumens, containing undifferentiated germinal epithelium, immature Sertoli cells and an occasional spermatogonium. Some of the conditions that result in hypoplastic testis are given below.

a. Cryptorchidism If the testes fail to descend, but instead remain within the abdominal cavity, the condition is known as cryptorchidism. The abdominal environment is unfavorable (presumably due to increased temperature), and the cryptorchid testis does not develop normally. Its overall dimensions are small and the tubules are less than normal diameter. Maturation of the germinal epithelium fails to occur, and Sertoli cells and spermatogonia make up the tubular lining. Leydig cells on the other hand are prominent or frankly hyperplastic. Opinions differ concerning the optimal management of cryptorchid testis, but if descent is delayed beyond puberty, there is little chance of normal gametogenesis. The risk of malignancy in an abdominal testis is increased, and the usual neoplasm is a germinal tumor.

b. Male pseudohermaphroditism and androgen insensitivity syndrome (AIS) A true hermaphrodite has gonadal tissue of both sexes. In contrast, a pseudohermaphrodite either has testes or ovaries but not both, and the external genitalia are not congruent with the gonads. Instead, the external genitalia resemble those of the opposite sex. The condition is designated male pseudohermaphroditism if the gonads are male. Thus a male pseudohermaphrodite has testes but has female external genitalia and body habitus. Although the karyotype is 46,XY the patient resembles a normal woman, with unremarkable breasts, female external genitalia and sparse body hair. The gonads, which often are contained within inguinal hernias, resemble testes grossly. Microscopically, undeveloped tubules are seen in a fibrous stroma containing scattered clumps of interstitial cells. Incidence of gonadal tumors is said to be increased.

Male pseudohermaphroditism derives from a defective virilization of the male embryo, usually resulting from impaired androgen synthesis or action (or both). The most common form of male pseudohermaphroditism is the familial disorder known as complete androgen insensitivity syndrome (AIS).

c. Klinefelter syndrome or aneuploidy X (47,XXY). Klinefelter syndrome is the result of genetic abnormality, and the usual karyotype is 47,XXY. The affected adult is a phenotypic male with small testes and eunuchoid proportions; gynecomastia and mental dullness may be present. At puberty, the testes fail to develop; instead, a distinctive form of testicular tubular sclerosis occurs, characterized by hyalinization of tubules and failure of development of germinal epithelium. Large clumps of interstitial cells appear. Urinary gonadotrophin is elevated. Chromosomal variants of the syndrome include mosaicism (47,XXY/46,XY) and other karyotypes (48,XXXY and 49,XXXXY). In most cases of Klinefelter syndrome, sterility is absolute, with azoospermia.

d. Destruction of pituitary If pituitary destruction occurs in childhood, gonadotrophic hormone will fail to be secreted, puberty will not occur and the testes will remain immature. Dwarfism may also be present as a result of deficiency of growth hormone.

e. Selective failure of gonadotrophin secretion In this condition, puberty fails to occur at the expected time and secondary sexual development is absent. With failure of testosterone production by the testis, epiphyses fail to close, skeletal growth continues and body habitus becomes eunuchoid (length from pubis-to-crown is less than pubis-to-heel; span exceeds height). Body hair is scant and voice remains high pitched.

3. Absent Germ Cells (Sertoli Cell-Only Syndrome) 32 Germ cells are absent in the testes, and the tubules are lined only by Sertoli cells. The testes are slightly smaller than normal, but in all other respects, physical findings are normal, and the patient is not eunuchoid. However, semen analysis reveals azoospermia, and the patient is sterile. Biopsy is required for diagnosis. In most cases the etiology is unknown (idiopathic), although in some cases it has been linked with genetic lesions on the Y chromosome. Sertoli only syndrome may also be seen in the context of other diseases, such as cryptorchidism, Klinefelter syndrome, radiation therapy; and history of severe trauma.

4. Atrophy Under this designation will be discussed some of the conditions manifested by bilateral shrinkage of the fully developed testes, or by diminution of their component tissues. Etiologies are diverse, and in some cases, unknown. The degree of atrophy need not be great to cause profound functional effects, since a relatively small loss of cells from the germinal epithelium may result in infertility. Semen analysis and testicular biopsy are sensitive indicators of the status of the germinal epithelium and interstitial tissue.

a. Destruction of pituitary Hypophyseal damage occurring postpuberally, after the testes are fully developed, results in testicular changes which may range from hypospermatogenesis to advanced atrophy, depending upon the extent of injury to the pituitary.

b. Hypospermatogenesis (proportional hypoplasia) In hypospermatogenesis, all cell types of the germinal epithelium are present in the usual proportion, but the number of cells of each type is reduced. Leydig cells are intact. This condition is an important cause of infertility. Endocrinologic status is otherwise apparently normal.

c. Inflammatory orchitis, especially associated with mumps Mumps may be complicated by orchitis, and though usually unilateral, both testes may be involved. The incidence of orchitis is low in children but rises with adolescence. The acute stage, with leukocytic infiltration of tubules, vascular engorgement, hemorrhage and edema, rarely is seen by the pathologist. Not all tubules are involved to the same extent. With healing, the tubules may undergo atrophy and sclerosis, but fortunately, a significant degree of atrophy occurs in only about half the cases. Other causes of inflammatory orchitis may lead to testicular atrophy.

d. Irradiation The germinal epithelium is a radiosensitive tissue, and severe radiation injury may cause permanent loss of the germ cells, tubular sclerosis and interstitial fibrosis. With less intense irradiation exposure, destruction is not complete and regeneration of the germinal epithelium may occur.

e. Chemotherapeutic agents Substances that inhibit cell division or prevent differentiation or both can damage the germinal epithelium by interfering with mitosis or preventing differentiation of the post-mitotic cells into spermatozoa (i.e., cause maturation arrest). Among these compounds are many of the drugs used to treat cancer and leukemia, including alkylating agents, folic acid antagonists, antibiotics, alkaloids, colchicine and urethane.

f. Cirrhosis and alcohol use In cirrhosis and in other types of chronic active liver disease, the germinal epithelium frequently atrophies and the testicular tubules shrink, with thickening of the tunica propria. One proposed explanation for this is that the diseased liver is unable to conjugate the estrogens normally formed endogenously in the male by the testis and adrenal. Therefore, excretion is impaired, the level of circulating estrogens rises and the germinal epithelium is damaged. However, alcohol is known to interfere with the function of the Leydig cells, Sertoli cells, and the production of pituitary gonadotropins, leading to reduced levels of testosterone and impairment of spermatogenesis.

33 g. Estrogen and antiandrogens Whether the source of the hormone is exogenous (as a therapeutic) or endogenous (e.g., an estrogen-secreting tumor of adrenal), an excess of estrogen has profound effects upon the testis causing decreased spermatogenesis, lipid accumulation in Sertoli cells, atrophy of the germinal epithelium, and loss of Leydig cells. Eventually the tunica propria thickens and the tubules shrink. Antiandrogens (such as given to treat carcinoma of the prostate) produce similar histological changes

IV. TUMORS OF THE TESTIS

A. Germinal Tumors

Germ cell tumors arise from malignant cells. They resemble caricatures of primordial germ cells and their progeny, the embryo and placenta.

1. Incidence: Germinal tumors constitute 95% of testicular tumors. Typically occur age 17-40; also seen in infants (age 0-3), and rarely in older men. Incidence has doubled in the past 20 years.

2. Symptoms: Usually presents as a painless lump in testis. Occasionally painful, and may be mistaken for epididymitis. May present with symptoms of metastases (back pain, hemoptysis).

3. Spread: Primarily via lymphatics, first to lymph nodes in upper retroperitoneum (around aorta and vena cava near renal vessels). May develop huge masses there. Then to lung via cisterna chylae and supraclavicular node. Other sites (liver, bones, brain) are rare. 5% risk of second tumor in opposite testis.

4. Tumor markers: Alpha fetal protein (AFP) and beta HCG are useful markers when elevated (primarily in nonseminoma). LDH may also be elevated with advanced disease.

5. Staging: Done with CT scan of chest, abdomen and pelvis and markers after orchiectomy.

Stage A (or I): Tumor confined to testis Stage B (or II): Metastases to retroperitoneal nodes B1 - Microscopic disease, < 6 nodes involved, and all < 2 cm diameter B2 - Macroscopic disease, > 6 nodes or node >2m but < 5 cm. B3 - Palpable disease or mass > 5cm on CT. Stage C (or III): Metastases outside of retroperitoneum

6. Pathology:

GERM CELL TUMORS

DIFFERENTIATION TUMOR

SEMINIFEROUS  SEMINOMA PRIMITIVE EPITHELIAL  EMBRYONAL CA GERM CELL  (CIS)  SOMATIC  TERATOMAS YOLK SAC  YOLK SAC CA TROPHOBLASTIC  CHORIOCA

Germ cell tumors are believed to arise from malignant cells within the testicular tubules, where they form intratubular germ cell neoplasia (ITGCN), also known as carcinoma in situ (CIS). It is becoming widely accepted that ITGCN (CIS) is the precursor of all germ cell neoplasms, both the seminomas and the non-seminomas.

34 Germ cell tumors may occur in pure form (I.e., pure seminoma, pure embryonal carcinoma, pure teratoma) or as a mixture of types. It is important to know that clinicians separate the seminomas from the non-seminomatous tumors because the prognosis and treatment of the seminomas is entirely different.

a. Seminoma: Most common germ cell neoplasm (about 30%). Occasionally beta-HCG is slightly elevated, but not AFP. Gross: Bulging, grey-white, lobulated, homogenous; focal necrosis may be present. Micro: Monotonous cells resembling primitive germ cells (uniform, distinct borders, clear cytoplasm). Cells form sheets and nests supported by thin fibrous trabeculae. Focal infiltration by lymphocytes and occasional non-caseating granulomas are characteristic.

b. Embryonal carcinoma: Makes up about 20% of germinal tumors. Highly malignant, usually advanced at presentation. Elaborates AFP. Gross: Variegated cut surface: grey-white with foci of hemorrhage and necrosis. Early invasion of tunica albuginea, epididymis, cord and blood vessels and lymphatics. Micro: Sheets of primitive epithelial cells mixed with frequent mitoses and necrosis. May form glandular, tubular, or reticular patterns.

c. Teratoma (mature and immature): Never considered benign in the adult testis. Degree of malignancy is variable depending on maturation. Mature teratoma is common in infants. Gross: Typically multicystic, with cysts containing gelatinous fluid or cheesy material. May have islands of cartilage or bone. Micro: Disordered array of mature and/or immature somatic tissues imitating any of the three germ layers.

d. Yolk sac (endodermal sinus) tumor: Rare in adults, common among infant testis tumors. Elaborates AFP. Gross: Solid, fleshy, soft, friable. Micro: differentiation toward yolk sac structures; reticular pattern with glomeruloid or Schiller Duval bodies, and AFP-positive hyaline globules.

e. Choriocarcinoma: Highly malignant, rare, worst prognosis of all nonseminoma cell types. Gross: Hemorrhagic mass with viable grey-white tumor only at periphery. Primary may regress after metastasizing, leaving only a pigmented scar in testis. Micro: Biphasic growth composed of a soft mixture of neoplastic cytotrophoblastic and syncytiotrophoblastic cells. Stains for beta-HCG.

7. Prognosis: Overall prognosis is excellent with combined therapy (surgery and chemotherapy, or radiotherapy for pure seminoma only). Over 90% of all patients are cured. Cure rate depends primarily on stage pf disease and cell type.

B. Gonadal Stromal Tumors (Non-germinal Tumors)

The non-germinal tumors are derived from the non-germinal elements of the testis: the interstitial cells of Leydig, Sertoli cells, and specialized gonandal stroma.

1. Interstitial cell tumor (Leydig cell tumor): rare, usually benign, may produce androgen. In boys, may lead to premature musculoskeletal development and precocious enlargement of phallus. Gross: small, well-circumscribed, yellowish-brown. Micro: Cells resembling Leydig cells, crystalloids of Reinke may be present.

2. Sertoli cell tumor: rare, usually benign. Produces estrogen, and may cause gynecomastia. Common in the dog, producing an arresting syndrome of feminization; animal is sexually attractive to other males, has enlarged mammary glands, and atrophy of the opposite testis. Gross: solid, circumscribed, firm, pale yellow. Micro: Composed of tubules lined or filled with epithelium, in a pattern resembling developing testes.

V. CARCINOMA OF THE PENIS

1. Incidence: Occurs primarily in tropical climates: almost exclusively in uncircumcised men. Most common > age 60, but occurs as young as 30. Associated with human papilloma virus.

2. Symptoms: Non-healing sore on foreskin or glans. May be mistaken for sexually transmitted disease.

3. Pathology: Almost invariably squamous cell carcinoma. Gross: Carcinoma-in situ presents as erythroplasia of Queyat (red area on glans) or Bowen disease (crusted plaque on shaft). Progresses to invasive cancer with ulceration or formation of papillomatous warty lesion. Micro: Squamous cell carcinoma, in situ or invasive.

4. Staging: Stage I - confined to glans/foreskin Stage II - invades corpura or urethra Stage III - regional (inguinal) nodes involved Stage IV - distant metastases

5. Prognosis: directly depends on presenting stage. Excellent cure rate for stage I-III tumors treated surgically. <50% cure rate for stage III, <20% for stage IV.

VI. MALE FACTOR INFERTILITY

Infertility is defined as the lack of pregnancy after one year of regular unprotected intercourse. By this definition, 10-15% of couples in the U.S. are infertile. Defects in the male reproductive system account for about 50% of these cases. Infertility due to disorder of the male partner is referred to as male factor infertility. A comprehensive discussion of the subject is beyond the scope of this lecture, but a few highlights will be reviewed.

The preceding discussion of the pathology of the testis included the major disorders of the testis, and most of these are associated with infertility. Other important conditions which may affect fertility include intrinsic abnormalities of the spermatozoa, impaired sperm transport, and varicocele.

Semen analysis (mandatory) will reveal abnormalities of spermatozoa, including diminished numbers, reduced count, abnormal motility and morphology, and total absence of sperm in the ejaculate (azoospermia). In azoospermia, obstruction of transport of sperm must be differentiated from lack of spermatozoa due to abnormality of seminiferous tubules.

Varicocele is defined as varicose veins in the spermatic cord. It is more frequent in men with an infertile marriage or a low sperm count. Also, varicocele may be accompanied by an arrest of testicular growth. However, it must be remembered that many men have varicocele but no problem with fertility. It is not clear how varicocele impairs testicular function. Scrotal hyperthermia and hypoxia have been postulated as causes. Does ligation benefit fertility in men with varicocele? The issue has been debated, and the procedure continues to be recommended by some experts.