PATHOLOGY OF THE MALE GENITAL TRACT Xinmin Zhang, M.D.

2011 The purpose of this handout is to provide the student with a review of relevant diseases commonly seen in the male genital tract. I. Penis 1. Malformations a. Hypospadias = abnormal urethral opening(s) on the ventral surface of the penis. b. Epispadias = abnormal urethral opening(s) on the dorsal surface of the penis. Note: Both hypospadias and epispadias are often associated with other abnormalities of the genitourinary tract, including cryptorchidism. c. Phimosis = condition in which the orifice of the foreskin (prepuce) is too small to permit its normal retraction; this may result from anomalous development or represent a sequela of postinflammatory scarring. The significance of phimosis is that it allows for the accumulation of secretions and debris under the foreskin, and this predisposes toward infection and, possibly, cancer. 2. Infections Syphilis Gonorrhea Chancroid Fungi 3. Tumors Benign Tumors 1. Condyloma acuminatum: - Etiologic agent = Human Papilloma Virus (HPV), which is related to the common wart that causes verruca vulgaris. - Sexually transmitted process. - HPV comes in many different antigenic types (over 70); 6 and 11 have been clearly associated with condyloma acuminatum. - Gross = Single or multiple, red, velvety, papillary excrescences that vary in size from 1 several mm. in greatest dimension. (Look for them also in the anal region). - Micro = Branching, papillary connective tissue stroma covered by a hyperplastic (thickened) epidermis. The epidermal nuclei focally typically show enlargement and hyperchromasia with irregular outlines and perinuclear halos (=Koilocytes). Malignant Tumors 1. Carcinoma in-situ (= Bowens disease) Full thickness epidermal dysplasia but no evidence for invasive malignancy. Clinical (gross) appearance of the lesions may vary widely. 2. Invasive Squamous Cell Carcinoma - Represents 1% of all cancers in American males; usually seen in men 40-70 years of age. - Circumcision appears to offer protection from this type of cancer. - Gross = Varies from a papillary (exophytic) lesion to an ulceroinvasive lesion. Lymphogranuloma venereum (LGV) Herpes simplex Granuloma Inguinale Staphylococci

Micro = Rather typical squamous cell carcinoma; histologically sees nests and cords of malignant squamous cells infiltrating the dermis. Clinical courses = tend to be rather slow growing carcinomas that may metastasize to regional (inguinal and iliac) lymph nodes; distant metastasis is uncommon, unless the lesion is far advanced.

3. Giant Condyloma of Buschke-Lowenstein - Verrucous, low-grade squamous cell carcinoma. - Gross = Usually a single, very large, exophytic lesion that may cover and destroy much of the penis; is associated with HPV infection (especially types 6 and 11). It is locally invasive and may recur after excision. - Micro = Similar to condyloma acuminatum with additional feature of hyperplastic epithelium penetrating into subjacent dermis along a broad front. This lesion rarely, if ever, metastasizes. Therefore, in clinical behavior, it appears to occupy a position intermediate between a routine, strictly benign condyloma acuminatum, on the one hand, and squamous cell carcinoma on the other. II. Testis A. Cryptorchidism (= undescended testis) In fetal life, the testes arise within the coelomic cavity and then (through differential growth of the body as well as disproportionate growth of the caudal end of the urogenital ridge) they eventually come to lie in the low abdomen/pelvic brim = internal descent. Finally, they normally next proceed into the inguinal canal and ultimately, the scrotal sac = external descent. Therefore, testes may be abnormally positioned anywhere along this route! Most cases of cryptorchidism are idiopathic but some are due to genetic defects (i.e. Trisomy 13) or hormonal deficit (LH-RH). Most cases are unilateral but up to 25% are bilateral. 0.3 0.8% of adult male population suffers from cryptorchidism. Why is cryptorchidism important? 1. Histologic changes begin by 2 years of age and include loss of germ cell production and tubular fibrosis (scarring) that eventually produces a small, fibrotic testis. Sterility is therefore a major complication! 2. When the testis lies in the inguinal canal, it is more susceptible to traumatic injury than when it lies in scrotal sac. 3. Finally, cryptorchidism is associated with a 7 11x increased risk of developing testicular cancer. B. Atrophy Causes of testicular atrophy 1. Atherosclerosis 2. Cryptorchidism 3. End stage orchitis 4. Hypopituitarism 5. Generalized malnutrition 6. Obstruction to outflow of semen 7. Irradiation 8. Administration of estrogen-like compounds (i.e. DES for metastatic prostate cancer) 9. Exhaustion atrophy caused by persistently very high levels of FSH 10. Sex chromosomal abnormality (i.e. Klinefelters Syndrome = XXY)

C. Inflammatory Processes Testis is much less often affected by inflammatory processes than is the case for the epididymis. 1. Neisseria gonorrhoea (may cause supprative orchitis but more often causes severe acute inflammation in epididymis). 2. Mumps in the typical age group to be affected by mumps, there is usually no testicular involvement. However, when post-puberty males develop the infection 20-30% will suffer from mumps orchitis, which is unilateral about 70% of the time. Inflammatory cell process with lymphocytes, plasma cells, macrophages. Most patients with this do heal with no resultant infertility but sterility in the outcome in some patients. 3. Tuberculosis this infection almost always begins in the epididymis and may spread to the testis. Look for granulomatous inflammation and AFB organisms. 4. Syphilis unlike most other infections that involve both the testis and the epididymis, syphilis typically involves the testis first! Look for: gummas or a diffuse interstitial chronic inflammatory cell response with lymphocytes and plasma cells as well as an arteritis with prominent plasma cell cuffing. Organisms demonstrable with silver stain (i.e. WarthinStarry). 5. Granulomatous (Autoimmune) Orchitis this condition, presumed autoimmune in nature, is a rare disorder seen mostly in middle-aged men. Must rule out tuberculous orchitis before making this diagnosis. 6. Others in males older than 35 years, look for common urinary tract pathogens (especially E. coli and Pseudomonas). These usually do not involve testis bur are typically limited to epididymis. D. Testicular Neoplasms Testicular Neoplasmsmost important cause of firm, painless enlargement of the testis. Nearly all testicular neoplasms are malignant and 95% arise from germ cells. Most of the remaining neoplasms arise from Leydig and Sertoli cells (gonadal stromal tumors). 1. Germ Cell Tumors Epidemiology: Average incidence in the U.S. is approximately 2 per 100,000 males. Testicular neoplasms account for 10% of all cancers in males. Their peak incidence is in the 15 to 34 y.o. age group. Incidence rates are 6 to 10 x higher in whites than in blacks. Genetic influences are suggested in rare cases involving twins or fathers and sons. Cryptorchidism is a predisposing factor. The vast majority (95%) of testicular neoplasms are germ cell tumors and about 60% feature more than one histologic pattern. Classification of germ cell neoplasms: a. Seminoma: It is the most common pure, germ cell neoplasm. The typical seminoma consists of cells with large nuclei and clear cytoplasm. The fibrous stroma may contain syncytiotrophoblastic giant cells (which produce HCG) and lymphocytes. Two other types of seminoma exist: spermatocytic seminoma (good prognosis) and anaplastic seminoma (poor prognosis). Frequency: 85% typical; 10% anaplastic; 5% spermatocytic. Gross: Gray-white, lobulated tumor; hemorrhage and necrosis are usually not conspicuous. b. Embryonal carcinoma: Histologically, these neoplasms are composed of anaplastic, large cells with a high mitotic rate; this carcinoma may assume solid, tubular or papillary microscopic growth patterns. Appears grossly as a gray-white, poorly demarcated mass often with extensive areas of hemorrhage and necrosis.

Note: Some element of embryonal carcinomas is seen in 45% of all germ cell cancers. c. Teratoma: Tissues from all three germ cell lines (ectoderm, mesoderm and endoderm) may be present. The fully differentiated variant, mature teratoma is composed entirely of benign adult type tissues. The immature teratoma contains similar elements, which are incompletely differentiated but can be identified as embryonic tissues. In addition, there are teratomas with frank sarcoma or carcinoma (typically squamous cell carcinoma or adeno-carcinoma) developing in them. Typically, teratomas are multicystic and partly solid neoplasms, enlarging the testis in a nodular configuration. Hemorrhage and necrosis are not prominent. In the child, differentiated mature teratomas usually follow a benign course. In the postpubertal male all teratomas are regarded as malignant, capable of metastatic behavior whether the elements are mature or immature. d. Yolk sac tumor (= infantile embryonal carcinoma = endodermal sinus tumor): In its pure form, it is rare; however, it is the most common neoplasm affecting the testes of children under 3 years of age. Yolk sac tumors recapitulate the embryonic mammalian yolk sac and produce alphafetoprotein (AFP). Tumor cells vary from flattened to cuboidal to columnar cells and may be arranged in glandular, papillary or solid formations. Other features include Schiller-Duval bodies (resemble glomeruli) and hyaline globules which contain AFP. Grossly, these lesions are similar to embryonal carcinoma. e. Choriocarcinoma: Highly malignant, metastasizing via blood stream early and widely; produces HCG. Represent differentiation to extraembryonic structures (placenta) and are composed of cytotrophoblast and syncytiotrophoblast. Grossly, choriocarcinoma is an ill-defined mass or nodule which is hemorrhagic and necrotic appearing. Interestingly, these lesions are often quite small, giving no discernible testicular enlargement in many cases. f. Mixed germ cell tumor: Show mixture of 2 or more of the above histologic patterns and account for 60% of all testicular germ cell neoplasms! In general, the prognosis of a mixed germ cell tumor is determined by the most malignant element. The combination of embryonal carcinoma with teratoma is called teratocarcinoma. Clinical Parameters of Testicular Neoplasms: Most present as painless testicular enlargement; any testicular mass should be considered neoplastic until proven otherwise. By convention and for therapeutic reasons, we divide neoplasms of the testis into seminoma and nonseminomatous germ cell tumors (NSGCT). The latter lesions often present with distinctive clinical features and differ from seminomas with regard to therapy and prognosis. In general, testicular malignancies spread by the lymphatics; usually, this spread occurs first to the nodes. Hematogenous spread may also occur, however, and this is primarily to lungs, liver, brain and bones. Although most metastases are similar to the primary cancer, in some cases one sees a different histologic appearance in the metastasis as compared to the primary testicular lesion. Staging of testicular neoplasms: Stage I = confined to testis Stage II = distant spread confined to retroperitoneal nodes below the diaphragm. Stage III = metastases outside the retroperitoneal lymph nodes or above the diaphragm. Neoplastic (tumor) markers in the serum:

Alpha fetoprotein (AFP) produced by yolk sac tumors, embryonal carcinoma (also by hepatocellular carcinoma) Human chorionic gonadotropin (Beta-HCG) produced by choriocarcinomas, some embryonal carcinomas Placental alkaline phosphatase (PLAP) produced by seminomas NOTE: Elevations of AFP, Beta-HCG or both seen in nearly 90% of NSGCTs. The three major uses of these markers are: - in the initial evaluation of the testicular mass - in the staging of testicular germ cell neoplasms - in the monitoring response to therapy/recurrence assessment Take home points regarding seminoma vs. NSGCTs: - Seminomas tend to be confined to testis for a longer period of time than is the case for NSGCTs. (In fact, 70% of seminomas are stage I at the time of diagnosis whereas 60% of NSGCTs are stages II and III at the time of diagnosis). - Seminoma metastases typically involve lymph nodes-and hematogenous metastases from seminoma tend to occur late. For NSGCTs, metastases occur earlier and are more often hematogenous. - Seminomas are extremely radio-sensitive, whereas NSGCTs are relatively radioresistant. Summary: NSGCTs = more aggressive cancers with poorer prognosis than is the case for seminoma. The most aggressive of the NSGCTs = choriocarcinoma. Most patients with seminoma can be cured; among patients with NSGCTs, 80-85% can achieve complete remission with chemotherapy. Unfortunately, a substantial number of these eventually relapse and die of their NSGCTs 2. Other Testicular Neoplasms a. Leydig Cell Tumors: These arise from the interstitial cells of Leydig (which normally produce testosterone). Neoplastic cells may produce androgens, androgens and estrogen or even corticosteroid. Uncommon lesions (2% of all testicular neoplasms) seen mainly between ages of 20-60 years. Usually present with testicular mass but may first exhibit gynecomastia. Gross = Yellow-brown homogenous mass. Micro = large, round or polygonal cells with abundant eosinophilic cytoplasm and a central round nucleus; crystals of Reinke seen in cytoplasm in 25% of cases. 90% = benign. b. Steroli Cell Tumors (Androblastoma): Composed of Steroli cells or granulosa cells. Androgens or estrogens are produced but only infrequently in sufficient quantity to produce precocious masculinization or feminization. Occasionally, one sees gynecomastia. Gross = firm, small gray-white-yellow nodules. Micro = tall, columnar, polyhedral cells that grow in cords, reminiscent of spermatic tubules. 90% - benign c. Malignant Lymphoma: Accounts for 5% of all testicular neoplasms. Malignant lymphoma is the most common testicular cancer in men over age 60 years. In most instances, it is disseminated by the time of detection of testicular mass. Almost always is of the diffuse large cell type. Prognosis is poor.