OLGA M BAUSA, M.D, DPSP

1. MALE GENITAL TRACT OLGA M BAUSA, M.D, DPSP

2. Penis - congenital anomalies, inflammations & tumors • CONGENITAL ANOMALIES • Hypospadias and Epispadias - Abnormal openings either on the ventral surface of the penis (hypospadias) or on the dorsal surface (epispadias). - Malformation of the urethral groove and canal • Associated with failure of normal descent of the testes • and malformations of the urinary tract

3. Clinical significance: opening may often be constricted • resulting in urinary tract obstruction and increased risk • of ascending UTIs; : opening is near the base of the penis, normal ejaculation and insemination are blocked causing sterility in men • Phimosis • Conditiion in which the orifice of the prepuce is too • small too permit its normal retraction • Result from anomalous development; frequent repeated • attacks of infection that cause scarring of the preputial • ring

4. Clinical significance: favors development of secondary • infections and carcinoma • paraphimosis: marked constriction and swelling will • block the prepuce; due to forced retraction over the • glans penis • INFLAMMATIONS - Usually involve the glans and prepuce • Specific infections : syphilis, gonorrhea, chancroid, • granuloma inguinale, lymphopathia venerea, genital • herpes

5. - Non specific infection: balanoposthitis - balanoposthitis is infection of the glans and prepuce; caused by C. albicans, anaerobic bacteria, Gardnerella, and pyogenic bacteria • Due to poor local hygiene in uncircumcised males, • with accumulation of smegma which acts as local • irritant • TUMORS • Benign Tumors Condyloma Acuminatum– caused by human papilloma- virus (HPV) type 6 and 11

6. Related to the common wart ( verruca vulgaris); occur • in the genital areas in either sex • morphology: on the penis, occur most often about the • coronal sulcus & inner surface of the prepuce : consist of single or multiple sessile or pedunculated, red papillary excrescences from 1 mm to several mm in diameter

7. micro: branching, villous, papillary connective tissue • stroma covered by epithelium

8. :epithelium shows vacuolization ( koilocyto- sis which is characteristic of HPV infection) : tend to recur but do not develop into inva- sive carcinoma

9. Malignant Tumors Carcinoma in Situ – or high grade squamous intraepi- thelial carcinoma - malignant cells are confined to the epithelium, with no evidence of local invasion or dis- tant mets - precancerous condition a. Bowen disease – both men & women, over 35 years; in men, it involves the skin of the shaft of the penis and scrotum

10. - grossly: solitary, thickened, gray white, opaque plaque with shallow ulceration & crusting - in the glans & prepuce, appears as single or multiple shiny red, velvety, plaques referred to as Erythroplasia of Queyrat - histo: epidermis shows proliferation with nu- merous mitoses, some atypical; cells are markedly dys- plastic with large hyperchromatic nuclei & lack of order- ly maturation - occurrence of visceral cancer in 1/3 of patients may develop into infiltrating squamous cell CA in approx 10% of patients

11. b. Bowenoid papulosis – occurs in sexually active adults - gross: multiple, reddish brown papular lesions - never develops into invasive carcinoma & spontaneously regresses in many cases Invasive Carcinoma – Squamous Cell Carcinoma - uncommon malignancy, < 1% of cancers in males; associated with circumcision; HPV type 16 & 18; affects males, 40 to 70 years

12. - Gross: begins on the glans or inner surface of prepuce near the coronal sulcus : two patterns – papillary & flat : papillary – simulate condyloma acuminata; cauliflower-like fungating mass : flat – appear as areas of epithelial thickening with graying & fissuring of mucosal surface; ulcerated papule usually develops

13. - histo: both papillary & flat lesions are squamous cell CA with varying degrees of differentiation - Verrucous carcinoma: uncommon, well-differen- tiated variant of squamous cell carcinoma with low ma- lignant potential; locally invasive but rarely metastasize - other subtypes: basaloid, warty and papillary - clinical course: slow growing, locally invasve; not painful unless there is ulceration & infection; fre- quently bleeds; inguinal & iliac LN mets in early stage; widespread dissemination uncommon

14. - prognosis: 66% 5- year survival rate without involvement of inguinal LN : 27% 5-year survival with LN mets • Testis and Epididymis • CONGENITAL ANOMALIES Cryptorchidism – undescended testes ; 1% of 1 year- old boys - complete or incomplete failure of the intra-abdominal testes to descend into the scrotal sac

15. Two phases of testicular descent: • Transabdominal phase – testis lie within the lower • abdomen or brim of the pelvis; controlled by mulle- • rian inhibiting substance - 5% to 10 % of cases • Inguinoscrotal phase – testes descend through the • inguinal canal into the scrotal sac; androgen depen- • dent; mediated by androgen-induced release of cal- • citonin gene-related peptide from the genitofemoral • nerve

16. - morphology : unilateral in most cases; bilateral in 25% of patients - histo: arrest in development of germ cells with marked hyalinization & thickening of basement membrane of spermatic tubules - concomitant increase in interstitial stroma and promi- nent Leydig cells • Cryptorchid testis is small, firm due to the fibrotic • changes

17. Contralateral (descended testis) has also been noted to • be deficient in germ cells in patients with unilateral • cryptorchidism • Bilateral cryptorchidism will lead to sterility; infertility • also noted in cases of uncorrected unilateral cryptor- • chidism • Undescended testis is at greater risk of developing car- • cinoma than is the descended testis

18. REGRESSIVE CHANGES • Atrophy – causes: • Progressive atherosclerotic narrowing of blood • supply in old age b. End stage of an inflammatory orchitis c. cryptorchidism d. hypopituitarism e. Generalized malnutrition or cachexia f. irradiation g. Prolonged administration of female sex hormones

19. in treatment of patients with carcinoma of prostate h. Exhaustion atrophy Findings Associated with Decreased Fertility a. hypospermatogenesis b. maturation arrest c. vas deferens obstruction • INFLAMMATIONS - More common in the epididymis than in the testis • gonorrhea & tuberculosis arise in the epididymis; • syphilis affects the testis first

20. Non-Specific Epididymitis and Orchitis - commonly related to infections in the urinary tract • In childhood, epididymitis is associated with conge- • nital genitourinary abnormality & infection with Gm- • negative rods - Chlamydia trachomatis & Neisseria gonorrhoeae: sexually active males < 35 years - E. coli & Pseudomonas: males >35 years • morphology: congestion, edema & infiltration by • neutrophils, macrophages & lymphocytes : limited to the interstitial connective tissue and extends to the tubules and may progress

21. to frank abscess or suppurative necrosis of the entire epididymis • Extend to the testis; fibrous scarring of both epididy- • mis & testis will lead to sterility; interstitial cells of • Leydig not completely destroyed • Granulomatous (Autoimmune) Orchitis - rare cause of unilateral testicular enlargement in middle aged men • sudden onset of moderately tender testicular mass • associated with fever

22. - histo: granulomas confined within spermatic tubules • Specific Inflammations Gonorrhea • Infection is from posterior urethra → prostate → • seminal vesicles → epididymis • Can spread to the testis & produce suppurative • orchitis Mumps • Systemic viral disease; commonly affects school- • age children; testicular involvement is uncommon

23. Orchitis may develop in 20% to 30% of postpubertal • males; develops about 1 week after onset of swelling • of the parotid glands Tuberculosis - Begins in the epididymis & may spread to the testis - Usually represents a secondary spread from other involvements of the genital tract ( tuberculous prosta- titis, seminal vesiculitis) - Appears as caseating granulomatous inflammation Syphilis - Both are affected in acquired and congenital syphilis

24. Production of gummas or a diffuse interstitial infla- • mmation (edema, lymphocytic and plasma cell infil- • tration) with characteristic hallmark of all syphilitic • infecions ( obliterative endarteritis with perivascular • cuffing of lymphocytes & plasma cells) • VASCULAR DISTURBANCES • Torsion • Twisting of the spermatic cord; cut off venous drai- • nage and arterial supply to the testis • Two types: neonatal torsion occurs in utero or after • birth; lacks associated anatomic defect

25. : adult torsion is seen in adolescence; sudden onset of testicular pain; results from bilateral anatomic defect ( bell clapper abnormality) - morphology: range from intense congestion to wide- spread extravasation of blood into the interstitial ti- ssue of the testis & epididymis • Late stages, testis is markedly enlarged & converted • into a sac of soft, necrotic, hemorrhagic tissue

26. Spermatic Cord and Paratesticular Tumors - Lipomas are common in the proximal spermatic cord - Adenomatoid tumor, most common benign paratesti- cular tumor : usually small nodules near the upper pole of the epididymis; well-circumscribed, minimally invasive into the surrounding tissue • Most common malignant paratesticular tumors are • rhabdomyosarcoma (children) and liposarcoma • (adults)

27. TESTICULAR TUMORS • Two major categories: germ cell tumors • : nongerminal tumors Pathologic Classification of Common Testicular Tumors Germ Cell Tumors Seminoma Spermatocytic Seminoma Embryonal Carcinoma Yolk Sac (Endodermal Sinus) Tumor Choriocarcinoma Teratoma

28. Sex cord-Stromal Tumors Leydig Cell Tumor Sertoli Cell Tumor

29. Germ Cell Tumors Seminoma - Most common type of germinal tumor (50%) - Uniform population of cells - Almost never occur in infants; peak in the thirties - In the ovaries, it is called dysgerminoma - morphology: • classic or typical seminoma – bulky masses; 10x the • the normal size

30. gross: homogeneous, gray-white, lobulated cut • surface, devoid of hemorrhage or necrosis : tunica albuginea is not penetrated but exten- sion to the epididymis, spermatic cord, or scrotal sac may occur • micro: sheets of uniform cells divided into poorly • demarcated lobules by delicate septa of fibrous tissue : classic seminoma cell is large, round to poly- hedral with distinct cell membrane; clear or watery- appearing cytoplasm & large central nucleus with one or two prominent nucleoli : cytoplasm contains glycogen

31. : cells do not contain alpha- fetoprotein (AFP) or human chorionic gonadotropin (HCG) : stain positively for placental alkaline phosphatase : 15% of seminomas contain syncytio- trophoblasts; serum HCG levels are elevated ; septa is infiltrated with T lymphocytes : “anaplastic seminoma” shows greater cellular & nuclear irregularity with more frequent tumor giant cells & many mitoses

32. Spermatocytic Seminoma - do not arise from an intratubular germ cell neoplasia - uncommon tumor (1% to 2% of all testicular germ cell neoplasms) - affects males over 65 years; slow- growing tumor; rarely metastasize; excellent prognosis • gross: larger than classic seminoma; pale gray, soft, • cut surface sometimes with mucoid cysts • micro: three cell populations, all intermixed • medium-sized cells (15-18 µm) – most nume- • rous; round nucleus & eosinophilic cytoplasm

33. Smaller cells (6-8 µm) – narrow rim of eosino- • philic cytoplasm resembling secondary sper- • matocytes c. Scattered giant cells (50-100 µm) – either uninucleate or multinucleate Embryonal Carcinoma - 20 to 30 year age group - more aggressive than seminomas • gross: smaller than seminoma; does not involve • the entire testis

34. : cut sections, mass is variegated, poorly de- marcated with foci of hemorrhage & necrosis : extension to the epididymis or cord is rare • micro: alveolar or tubular patterns, sometimes with • papillary convolutions : undifferentiated lesions present as sheets of cells; epithelial, large & anaplastic with hyperchro- matic nuclei & prominent nucleoli : mitotic figures & tumor giant cells

35. Syncytial cells containing HCG & cells containing • AFP are detected by immunoperoxidase techniques Yolk Sac Tumor • Infantile embryonal carcinoma or endodermal sinus • tumor - most common testicular tumor in infants & children up to 3 years; very good prognosis • adults, pure form is rare; frequently, yolk sac occur in • combination with embryonal carcinoma

36. gross: nonencapsulated with homogeneous, yellow • white, mucinous appearance • micro: lace-like (reticular) network of cuboidal or • elongated cells; papillary structures or solid cord • of cells : structures resembling endodermal sinuses (Schiller-Duval bodies) seen in 50% of cases : tumor cells contain AFP and alpha1-antitrypsin

37. Choriocarcinoma • Highly malignant testicular tumor composed of both • syncytiotrophoblastic and cytotrophoblastic cells • Also arise in the placental tissue, ovary or seques- • tered rests of totipotential cells (mediastinum or • abdomen) • gross: no testicular enlargement; small palpable • nodule (< 5 cm in diameter); hemorrhage & • necrosis common • micro: contain two types of cells

38. : syncytiotrophoblastic cell is large with many irregular or lobular hyperchromatic nuclei & abundant eosinophilic vacuolated cytoplasm; contain HCG : cytotrophoblastic cell – polygonal, distinct cell border & clear cytoplasm; cords & masses with single, uniform nucleus Teratoma • Group of complex tumors with various cellular or • organoid components derived from more than • one germ layer

39. - Any age, infancy to puberty - Pure teratoma common in infants & children - morphology: large tumors (5 to 10 cm in diameter) : heterogeneous, with solid, sometimes cartilaginous & cystic areas : hemorrhage & necrosis denotes admix ture with embryonal CA, chorioCA or both : helter-skelter collection of undifferentiated cells or organoid structures (neural tissue muscle bundles, islands of cartilage, squamous epithelium, thyroid gland, bronchial or bronchiolar epith, intestinal wall or brain substance all embedded

40. - non-germ cell tumors arising in a teratoma ; tera toma with malignant transformation; derivatives of one or more germ cell layers (focus of SQ cell CA, mucin-secreting adenoCA or sarcoma) - Good prognosis in children • In postpubertal male, all teratomas are malignant & • capable of metastatic behavior, regardless whether • the elements are mature or immature

41. Mixed Tumors • 60% of cases; common mixtures include teratoma, • embryonal CA & yolk sac tumor; seminoma with • embryonal CA;& embryonal CA with teratoma (tera- • tocarcinoma) • Two broad categories of testicular tumors: • Seminoma • - Nonseminomatous germ cell tumor (NSGCT) • Clinical Manifestations of Testicular Tumors - Painless enlargement of the testis

42. - Characteristic mode of spread: • lymphatic spread – common to all forms of testicular tumors; first to be involved are the retroperitoneal para-aortic nodes - mediastinal and supraclavicular nodes • hematogenous spread – lungs; liver, brain & bones • Histology of metastases maybe different from that of • the testicular lesion: teratoma may show foci of cho- • riocarcinoma in the lymph nodes

43. Clinical Differences Between Seminoma & NSGCT - seminoma: remain localized to the testis for a long time; approx 70 % present in clinical stage I • NSGCT: approx 60% present with advanced stage • (stages II & III) - seminoma: metastases involved lymph nodes • NSGCT: mets occur earlier & use the hematogenous • route more frequently

44. : pure choriocarcinoma most aggressive of the NSGCT; spreads predominantly & rapidly by the bloodstream; involves the lungs & liver - seminoma: extremely radiosensitive - NSGCT: relatively radioresistant Three Clinical Stages of Testicular Tumors • Stage I: Tumor confined to the testis, epididymis or spermatic cord • Stage II: Distant spread confined to retroperitoneal nodes below the diaphragm

45. Stage III: Metastases outside the retroperitoneal nodes or above the diaphragm • Germ cell tumors of the testis secrete polypeptide hor- • mones & certain enzymes detected in blood by sensi- • tive assays • Biologic markers: α-fetoprotein (AFP); human chorio- • nic gonadotrophin ( HCG); placental alkaline phospha- • tase, placental lactogen & lactate dehydrogenase (LDH) • Molecular markers in diagnosis of GCT: transcription • factor encoded by OCT3/4 gene, X chromosome; de- • tected by immunoperoxidase & PCR techniques

46. LDH: also produced in skeletal & cardiac muscles; • elevation not specific for GCT; degree of eleva- • tion correlates with the mass of tumor cells • AFP: major serum protein of the early fetus; synthe- • sized by the fetal gut, liver cells, & yolk sac; one • year after birth, serum levels of AFP fall to • < 16 ng/ml • HCG: glycoprotein consisting of two dissimilar poly- • peptide units, α and β; synthesized & secreted • by placental syncytiotrophoblast

47. ↑ serum AFP is produced by yolk sac tumors; ↑ HCG is • produced by choriocarcinoma Value of Serum Markers in Testicular Tumors is Fourfold: • In the evaluation of testicular masses • In the staging of testicular germ cell tumors; persistent elevation of HCG or AFP after orchiectomy indicates stage II disease even if LN appear normal by CT scan • In assessing tumor burden; levels of LDH are related to tumor mass • In monitoring the response to therapy

48. Prognosis: • seminoma: best prognosis; > 95% of patients with • stage I & II disease can be cured • NSGCT: approx 90% of patients can achieve complete • remission with aggressive chemotherapy : pure choriocarcinoma has the poorest prog- nosis Tumors of Sex Cord-Gonadal Stroma • Leydig (Interstitial) Cell Tumors - Derived from the stroma; may elaborate androgens

49. or combinations of androgens & estrogens, and corti- costeroids - Affects any age, more common in 20-60 years of age • Most common presenting feature is testicular swelling; • in some patients, gynecomastia maybe the 1st symptom • In children, hormonal effects (sexual precocity) are the • dominating features - morphology: circumscribed nodules < 5 cm in diameter : cut section shows distinct golden, golden brown surface : micro- Leydig cells are large, round or polygonal with abundant granular eosino-

50. philic cytoplasm with a round central nuc- leus; cytoplasm contains lipid granules, vacuoles or lipofuscin pigment : characteristic rod-shaped crystalloids of Reinke occur in 25% of the tumors : 10% of the tumor in adults are invasive; most are benign • Sertoli Cell Tumors (Androblastoma) • Composed entirely of Sertoli cells or may have a • component of granulosa cells