Pathology of the Male Reproductive System

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SECTION 1: PENIS

1. Malformations

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2. Inflammatory Lesions

• Candida albicans
• Anaerobic bacteria (including Gardnerella)
• Pyogenic bacteria

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3. Neoplasms of the Penis

Carcinoma in Situ (Penile Intraepithelial Neoplasia - PIN)

Invasive Squamous Cell Carcinoma of the Penis

• Rare in developed world; uncommon under age 40
• Risk factors: HPV infection (types 16 and 18), lack of circumcision, smoking, chronic inflammation
• Circumcised men are at virtually no risk - smegma is NOT carcinogenic; circumcision removes HPV/smegma nidus
• Location: Glans and inner surface of prepuce
• Gross: Papillary (exophytic, wart-like) or flat ulcerating lesion
• Microscopic: Moderately differentiated keratinizing squamous cell carcinoma
• Spread: Initially local; metastases to inguinal and iliac lymph nodes
• Prognosis: 5-year survival ~66% overall; >90% with localized lesions; drops with node involvement

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SECTION 2: SCROTUM, TESTIS, AND EPIDIDYMIS

1. Cryptorchidism and Testicular Atrophy

• Failure of one or both testes to descend into the scrotum
• Affects ~1% of boys by 1 year of age; most cases are unilateral
• Associated with increased risk of testicular atrophy and germ cell neoplasia (3-5x increased risk, even in the contralateral testis)
• Also associated with infertility
• Morphology: Fibrous thickening of the basement membrane of the seminiferous tubules; decreased number of spermatogenic cells; Leydig cells appear prominent
• Treatment: Orchidopexy (ideally by age 2) - reduces cancer risk though does not eliminate it

• Causes: Cryptorchidism, atherosclerosis, hypopituitarism, irradiation, orchitis, Klinefelter syndrome (47,XXY), estrogen therapy for prostate cancer
• Morphology: Tubular atrophy, fibrous replacement of stroma, Leydig cell prominence

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2. Inflammatory Lesions of the Testis and Epididymis

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3. Vascular Disturbances

• Twisting of the spermatic cord, cutting off venous drainage (first), then arterial supply
• Causes: Abnormal attachment ("bell-clapper deformity" - testis freely suspended), trauma, cremasteric reflex
• Results in: Hemorrhagic infarction of the testis
• Surgical emergency: Viability depends on duration - within 6 hours = ~100% salvage rate; after 24 hours = nearly 0%
• Both testes should be fixed (orchidopexy) due to bilateral predisposition

• Abnormal dilation of the pampiniform venous plexus
• Most common on left side (due to angle of left testicular vein draining into renal vein)
• Most common surgically correctable cause of male infertility
• Impairs spermatogenesis due to elevated scrotal temperature

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4. Testicular Neoplasms

Risk Factors for Testicular Germ Cell Tumors

• Cryptorchidism (most significant)
• Family history
• Klinefelter syndrome
• Carcinoma in situ (intratubular germ cell neoplasia - ITGCN)
• Prior contralateral testicular GCT
• White > Black (5:1 ratio)

Classification

1. Seminomas (~50%)
2. Nonseminomatous germ cell tumors (NSGCTs):
   • Embryonal carcinoma
   • Yolk sac tumor (Endodermal sinus tumor)
   • Choriocarcinoma
   • Teratoma (mature and immature)
   • Mixed germ cell tumors
3. Sex cord-stromal tumors: Leydig cell tumor, Sertoli cell tumor

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A. SEMINOMA (~50% of GCTs)

• Peak incidence: 30s-40s
• Arises from intratubular germ cell neoplasia (ITGCN)
• Gross: Large, homogeneous lobulated gray-white tumor; no hemorrhage or necrosis (key feature)
• Microscopic:
  • Sheets of large uniform cells with clear cytoplasm (glycogen-rich), distinct cell membranes, and large nuclei with prominent nucleoli
  • Delicate fibrous septae containing lymphocytic infiltrate
  • Granulomatous reaction in ~10-20%
  • No trophoblastic cells
• IHC: OCT3/4+, PLAP+, c-KIT (CD117)+, D2-40+; AFP-, hCG- (rarely hCG+ if syncytiotrophoblastic giant cells present)
• Tumor marker: hCG mildly elevated in ~10-20%; AFP always normal
• Spread: Lymphatic (retroperitoneal/para-aortic nodes initially); then hematogenous
• Radiosensitive and chemosensitive - best prognosis of all GCTs
• Prognosis: >95% cure rate at stage I and II

• Classic (typical) seminoma
• Spermatocytic seminoma (older men, 50s-60s; not associated with ITGCN; indolent; no metastasis)

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B. EMBRYONAL CARCINOMA

• Peak: 20s
• Gross: Smaller, heterogeneous with areas of necrosis and hemorrhage
• Microscopic:
  • Poorly differentiated primitive cells arranged in glands, tubules, papillary structures, or sheets
  • Large cells with indistinct cell borders, prominent nucleoli, overlapping nuclei
  • Frequent mitoses
• IHC: OCT3/4+, CD30+, PLAP+; AFP variable; hCG variable
• Tumor markers: AFP +/- ; hCG +/- (when syncytiotrophoblastic cells present)
• More aggressive than seminoma; frequently metastasizes

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C. YOLK SAC TUMOR (Endodermal Sinus Tumor)

• Most common testicular tumor in children under 3 years
• In adults, usually a component of mixed GCT
• Gross: Homogeneous, mucinous yellow-white
• Microscopic:
  • Reticular (lace-like) pattern - Schiller-Duval bodies (pathognomonic): glomeruloid structures with central capillary surrounded by tumor cells
  • Periodic Acid-Schiff (PAS)+ hyaline globules
• IHC: AFP+, SALL4+, Glypican-3+
• Tumor marker: AFP markedly elevated (diagnostic)

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D. CHORIOCARCINOMA

• Rarest pure form; most often a component of mixed GCT
• Mimics normal placental tissue
• Gross: Small primary tumor with extensive hemorrhage and necrosis; often hematogenous spread already at diagnosis
• Microscopic:
  • Two-cell population required:
    1. Cytotrophoblast - small polygonal cells with distinct borders
    2. Syncytiotrophoblast - large multinucleated giant cells with eosinophilic cytoplasm
  • Extensive hemorrhage and necrosis
• IHC: hCG+, HPL+
• Tumor marker: hCG markedly elevated - can cause gynecomastia in males
• Most aggressive testicular GCT; hematogenous spread (lungs, liver, brain) occurs EARLY, BEFORE lymphatic spread
• Worst prognosis

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E. TERATOMA

• Contains elements of more than one germ cell layer (ectoderm, mesoderm, endoderm) in various stages of differentiation
• Mature teratoma (adults): Contains well-differentiated tissues (cartilage, glands, respiratory epithelium, neural tissue, bone, fat); may behave malignantly in adults despite appearing "mature"
• Immature teratoma: Contains embryonic/fetal tissues; more aggressive
• Gross: Heterogeneous with cysts, cartilage, bone
• Microscopic (Fig 16.9): Disorganized collection of glands, cartilage, smooth muscle, and immature stroma
• Tumor markers: AFP +/- ; hCG +/- (depending on components)
• In children (prepubertal): Mature teratoma is benign
• In adults (postpubertal): All teratomas are considered malignant

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F. MIXED GERM CELL TUMORS

• Most common combination: Teratoma + Embryonal carcinoma = Teratocarcinoma
• Most GCTs in adults are mixed

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Tumor Markers Summary Table

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Clinical Staging of Testicular GCTs

• Spread: Seminomas and NSGCTs spread first to retroperitoneal (para-aortic) lymph nodes - EXCEPT choriocarcinoma, which spreads hematogenously first
• Treatment: Orchiectomy ± retroperitoneal lymph node dissection ± chemotherapy (BEP regimen: Bleomycin, Etoposide, cisPlatin) ± radiotherapy
• Prognosis: >90% cure rate overall with modern chemotherapy

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G. SEX CORD-STROMAL TUMORS

• Most common sex cord-stromal tumor
• Produces androgens (and sometimes estrogens)
• In children: Precocious puberty (isosexual pseudoprecocity)
• In adults: Gynecomastia (due to estrogen production), loss of libido, impotence
• Gross: Well-circumscribed, golden-brown/yellow tumor
• Microscopic: Large polygonal cells with abundant eosinophilic granular cytoplasm; Reinke crystalloids (rod-shaped eosinophilic intracytoplasmic crystals - pathognomonic)
• 90% benign; 10% malignant

• Rare; may cause gynecomastia
• Usually benign
• Microscopic: Cords or tubules of elongated cells with vacuolated cytoplasm

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SECTION 3: PROSTATE

Anatomy and Zones (Clinically Important)

• Peripheral zone (70-75% of gland): Site of most carcinomas (70-80%); accessible by digital rectal examination
• Transition (central) zone (25-30%): Site of most hyperplasia; causes obstructive urinary symptoms
• Central zone: Surrounds ejaculatory ducts

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1. Prostatitis

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2. Benign Prostatic Hyperplasia (BPH)

• Extremely common; histologic BPH in 20% of men by age 40, rising to >90% by age 80
• Symptomatic BPH in 50% of men by age 60

• Proliferation of both glandular epithelial cells and stromal cells (fibromuscular stroma)
• Testosterone converted to dihydrotestosterone (DHT) by 5-alpha reductase in prostate
• DHT binds androgen receptors, stimulates growth
• Estrogens may sensitize stroma to androgens

• Enlarged prostate (may reach 60-100g; normal ~20g)
• Well-defined nodules in the transition zone
• Cut section: Spongy appearance with cystic spaces containing milky secretions

• Nodular hyperplasia of glands and stroma
• Large acini lined by tall columnar cells over a basal cell layer (basal layer PRESERVED - unlike carcinoma)
• Concentric calcified deposits = corpora amylacea (prostatic calcifications; not diagnostic but common)
• Stromal nodules: Fibromuscular tissue without glandular proliferation

• Obstructive symptoms: Decreased urinary stream, hesitancy, incomplete emptying, dribbling
• Irritative symptoms: Urgency, frequency, nocturia (due to detrusor hypertrophy/instability)
• Complications: Urinary retention, hydroureter/hydronephrosis, UTI, bladder diverticula

• 5-alpha reductase inhibitors (finasteride, dutasteride) - block DHT production
• Alpha-1 blockers (tamsulosin, terazosin) - relax smooth muscle
• Surgery (TURP - transurethral resection of prostate)

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3. Carcinoma of the Prostate

• Most common cancer in men in Western countries
• Second most common cause of cancer death in men (after lung cancer)
• Rare under age 50; incidence increases sharply after 60
• Higher incidence in African Americans; lower in Asian populations
• Strong genetic component (BRCA2 mutations increase risk; BRCA1 to lesser extent)

• Driven by androgens (testosterone/DHT) acting via androgen receptor (AR)
• Molecular alterations: TMPRSS2-ERG gene fusion (most common, ~50% of prostate cancers); PTEN deletion; AR amplification in castration-resistant disease
• PIN (Prostatic Intraepithelial Neoplasia) = precursor lesion

• Low-grade PIN: Mild architectural and cytologic atypia; no clinical significance
• High-grade PIN (HGPIN): Architecturally complex glands with cytologic atypia; loss of basal cell layer focally; considered precursor to invasive carcinoma

• Often not visible grossly
• Firm, gray-white infiltrating lesion when visible
• "Rock-hard" consistency due to desmoplastic reaction

• Small-to-medium glands lined by a single layer of cuboidal cells (NO basal cell layer - this is critical!)
• Glands infiltrate between benign glands
• Perineural invasion (pathognomonic feature; characteristic of prostatic carcinoma)
• Nuclear enlargement, prominent nucleoli ("red nucleoli visible at low magnification")
• Absent basal cell layer (demonstrated by CK5/6 or p63 IHC negative)
• AMACR (alpha-methylacyl-CoA racemase/P504S) positive - key diagnostic marker

• Malignant glands: AMACR+, Basal cells (p63/CK5/6) ABSENT
• Benign glands: AMACR-, Basal cells (p63/CK5/6) PRESENT

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Gleason Grading System

• Based on glandular architecture (NOT cytology) - graded at low magnification
• Gleason Grade 1-5: Assigned to the two most common architectural patterns
• Gleason Score = Primary grade + Secondary grade (range 2-10)

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PSA (Prostate-Specific Antigen)

• Serine protease produced by prostatic epithelial cells (both benign and malignant)
• Organ-specific, not cancer-specific - also elevated in BPH, prostatitis, trauma
• Normal: <4 ng/mL; Grey zone: 4-10; Suspicious for carcinoma: >10
• PSA density (PSA/prostate volume) and PSA velocity (rate of rise) improve specificity
• Free:Total PSA ratio - lower ratio suggests carcinoma (PSA more bound to proteins in cancer)
• PSA failure after treatment = biochemical recurrence

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Routes of Spread

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Clinical Features and Staging

• T1: Not palpable/visible (clinically inapparent)
• T2: Palpable, confined to prostate
• T3: Extends beyond prostatic capsule (extracapsular extension, seminal vesicle involvement)
• T4: Fixed/invades adjacent structures

• Localized: Active surveillance (low-risk), radical prostatectomy, radiation therapy
• Advanced: Androgen deprivation therapy (ADT) - LHRH agonists (leuprolide) or antagonists (degarelix); bilateral orchiectomy
• Castration-resistant: Enzalutamide, abiraterone, docetaxel, sipuleucel-T (immunotherapy)
• Bone mets: Radium-223, zoledronic acid, denosumab

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SECTION 4: SEXUALLY TRANSMITTED INFECTIONS (Male Involvement)

1. Syphilis

• Organism: Treponema pallidum (spirochete)
• Primary: Hard chancre on glans/prepuce; painless ulcer with indurated base; heals spontaneously; regional lymphadenopathy
• Secondary: Condylomata lata (flat wart-like lesions on genitalia); systemic rash (palms and soles); mucous patches; lymphadenopathy
• Tertiary: Gummas (nodular granulomas with central necrosis); cardiovascular syphilis; neurosyphilis
• Morphology: Endarteritis obliterans + plasma cell-rich infiltrate (hallmark histology)
• Diagnosis: Dark-field microscopy; RPR/VDRL (screening) + TPHA/FTA-ABS (confirmatory)

2. Gonorrhea

• Organism: Neisseria gonorrhoeae (gram-negative diplococcus)
• Men: Acute urethritis (purulent discharge, dysuria); complications include epididymo-orchitis, prostatitis
• Morphology: Purulent exudate; gram-negative intracellular diplococci
• Complications: Stricture formation, infertility

3. Non-Gonococcal Urethritis (NGU)

• Most common cause: Chlamydia trachomatis (serovars D-K); also Ureaplasma urealyticum, Mycoplasma genitalium
• Milder symptoms than gonorrhea; mucopurulent discharge; frequently asymptomatic
• Complications: Epididymitis, Reiter syndrome (reactive arthritis: urethritis + arthritis + conjunctivitis + uveitis)

4. Lymphogranuloma Venereum (LGV)

• Organism: Chlamydia trachomatis serovars L1, L2, L3
• Small painless vesicle/papule → heals rapidly; then inguinal lymphadenopathy (bubo) - pathognomonic
• Stellate abscesses with epithelioid granulomas in nodes

5. Chancroid (Soft Chancre)

• Organism: Haemophilus ducreyi
• Painful genital ulcer with soft (non-indurated) edges; painful inguinal lymphadenopathy
• Distinguishes from syphilitic chancre (painless, hard)

6. Genital Herpes

• Organism: HSV-2 (mainly); HSV-1 increasing
• Painful vesicles/ulcers on glans, prepuce, shaft
• Recurrent; latent in sacral ganglia
• Microscopic: Intranuclear inclusions (Cowdry type A); multinucleated giant cells; cytopathic changes

7. Human Papillomavirus (HPV) Infection

• Low-risk types (6, 11): Condylomata acuminata (genital warts) - cauliflower-like exophytic lesions; koilocytic atypia (perinuclear halo + nuclear raisinoid changes)
• High-risk types (16, 18, 31, 33): Associated with penile SCC, anal cancer
• Microscopic: Koilocytes - hallmark of HPV infection

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SECTION 5: MALE INFERTILITY (Pathologic Basis)

• Azoospermia (no sperm)
• Oligospermia (<15 million/mL)
• Asthenospermia (poor motility)
• Teratospermia (abnormal morphology)

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KEY HIGH-YIELD SUMMARY TABLE

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