9. Pathology of the male genital tract PATHOLOGY OF THE MALE GENITAL SYSTEM DISORDERS OF THE PENIS AND THE MALE URETHRA Congenital abnormalities of the urethra Abnormal location of the urethral orifice • Hypospadias: the meatus is situated on the ventral surface of the penis or in the perineum • Epispadias: the meatus opens on the dorsal aspect of the penis Posterior urethral valve • In the prostatic portion of the urethra • Connective tissue covered by transitional epithelium bulges into the lumen Consequence Outflow obstruction bilateral hydronephrosis, recurrent urinary tract infections (UTIs) Urethritis Pathogenesis • Gram-neg. bacteria in individuals with abnormal urinary tract (E. coli, Enterobacter, Proteus, etc.) • Polyresistant nosocomial strains after catheterization, cystoscopy (e.g., Pseudomonas) • Sexually transmitted: Neisseria gonorrhoeae; Chlamydia trachomatis, and Ureaplasma urealyticum Gonorrhoea • 2-7 days after exposure: acute purulent urethritis • Complications: purulent prostatitis, seminal vesiculitis, epididymitis • Late consequences: Urethral stricture UTO Fibrosis of the prostate Fibrosis of the epididymis; if bilateral: obstructive azoospermia Urethritis induced by Chlamydia or Ureaplasma • Mild mucopurulent urethral discharge • Complications: acute cystitis; frequently turns into chronic chronic seminal vesiculitis, prostatitis, epididymitis Venereal ulceration of the glans penis • Genital herpes: HSV2, HSV1 (increasing incidence due to practice of oral sex); painful vesicles ulcer + inguinal lymphadenitis • Firm chancre: Treponema pallidum; painless firm ulcer + painless inguinal lymphadenitis; heals with a subtle scar; 2 months later: secondary syphilis: gen. lymph node enlargement, mucocutaneous lesions • Soft chancre (chancroid): Hemophilus ducreyi; common in Africa and Southeast Asia; painful soft ulcer + painful inguinal lymphadenitis with central abscesses Phimosis • Abnormally small orifice in the foreskin; does not permit the retraction of the foreskin over the glans penis • Acquired (inflammatory scarring) or congential • Consequences Accumulation of secretion and cell debris under the prepuce: balanitis - inflamm. of the glans, posthitis - inflamm. of the prepuce balanoposthitis Lower urinary tract obstruction In adults: disturbed sexual life Tumors of the penis Strong association with HPV-infection Condyloma acuminatum (venereal wart) • Single or multiple reddish, cauliflowerlike lesions, involving the coronal sulcus, the inner prepuce • LM: acanthosis, papillomatosis, vacuolation of epithelial cells (koilocytes) • Benign; however, tends to recur after excision Squamous cc in situ • In men usually older than 35 years • Bowen disease: involves the shaft of the penis and the scrotum; erythroplasia of Queyrat: appears on the glans and prepuce • Gross: gray-white or red shiny plaques • Over the span of years, both can transform into invasive squamous cell cc Invasive carcinoma of the penis • Infrequent; peak: around age 65 • Risk factors: HPV 16 and 18; 30 or more sexual partners, chronic irritation, no circumscision, smoking • Gross: ulcerative or a fungating lesion on the glans or foreskin • LM: well or moderately diff. squamous cell cc • Slow course; lymphatic metastases in the inguinal nodes • 5-y-survival rate: 70% PATHOLOGY OF THE PROSTATE • Inflammation • Hyperplasia • Carcinoma 1 9. Pathology of the male genital tract PROSTATITIS • Acute • Chronic • Granulomatous Acute prostatitis Pathogenesis • Colonization: from direct extension from the urethra (urethritis) or the bladder (cystitis) • Agents: E. coli, enterococci, gonococci purulent inflammation Morphology • LM: accumulation of ng-s within and around acini • Large abscesses can develop in gonococcal prostatitis, in diabetics Clinical features • Tender and swollen prostate • Difficulty in micturition with perineal or rectal pain (dysuria) • Fever Outcome • Heals completely or with scarring (insuff. antibiotic th) • Can turn into chronic prostatitis Chronic prostatitis Pathogenesis • Bacterial: Gram-neg. microorganisms • Non-bacterial: Ureaplasma or Chlamydia - the most common type of prostatic inflammation Morphology • LM: dilated glands filled with ng-s and foamy ma-s, stroma: ly-s, ma-s Clinical features • Difficulty in micturition + low back pain • Disturbed ejaculation • Harbours foci of infection, causing arthritis, myositis, neuritis, iritis Outcome • Acinar atrophy, stromal fibrosis Granulomatous prostatitis Pathogenesis • Secretions escape into the stroma and elicite inflammation Morphology • Destructed acini, surrounded by epitheloid cells, giant cells, ly-s, plasma cells + dense fibrosis Clinical features • Disturbed micturition • ”Stony hard” prostate by palpation because of marked fibrosis clinically simulates prostatic cc • Dg.: biopsy of the prostate NODULAR HYPERPLASIA • Very common, the incidence increases with age: up to 70% of men by age 60 years • The nodules arise from the inner portions of the prostate (central zone [close to the bladder]), periurethral zone) • Compression of the prostatic urethra obstruction of the urinary flow Pathogenesis • A relative increase in the level of estrogens that occurs with aging may facilitate the growth promoting effect of dihydrotestosterone (castrated boys do not develop NH when they age) • DHT increases the production of fibroblast growth factor-7 by stromal cells • FGF-7 inhibits apoptosis of glandular epithelial cells and stimulates stromal cell proliferation nodular overgrowth of the glands and the fibromuscular tissue Morphology • Gross: nodular enlargement (60-100 g; normal: 20 g), the nodules have no capsule • LM: hyperplasia of glands and stromal fibroblasts and smooth muscle cells • Glands are lined by an inner secretory columnar layer and an outer layer of basal cells (positive with high molecular weight cytokeratins) Mechanic consequences of urethra obstruction • Bladder: detrusor muscle hypertrophy (first concentric, then dilative residual urine), diverticula • Bilateral ureterectasis, pyelectasis, and hydronephrosis Infectious consequences of urethra obstruction • Infection of residual urine in the bladder: acute cystitis ascending pyelonephritis • Recurrent infectious episodes + urinary tract obstruction: chronic pyelonephritis Clinical features • Difficulty in micturition: delay in starting to pass urine; poor, intermittent stream, dribbling at the end of micturition • If there is cystitis: frequency, lower abdominal pain, dysuria, hematuria • If there is bilateral hydronephrosis: azotemia, chronic renal insufficiency + renal hypertension • Emergency situation: acute complete obstruction painful distension of the urinary bladder risk of bladder rupture, acute postrenal uremia Therapy • Pharmacologic: inhibition of DHT and/or relaxation of smooth muscles by blocking alpha adrenergic receptors • Surgical: transurethral resection 2 9. Pathology of the male genital tract PROSTATE CARCINOMA (PCC) • The most common non-skin malignancy in males in the developed countries • Peak: between the ages 65 and 75 years Pathogenesis Androgens, diet, hereditary factors, and acquired somatic mutations have roles • The tumor cells express androgen-receptors (ARs); growth of the tumor is inhibited by androgen deprivation and administration of estrogens • Race: rare in Asians who live in Asia; common in Caucasians (particularly in Scandinavia) and Afro-Americans • ARs with shorter glutamine repeats (common in Afro-Americans) are more sensitive to androgens, whereas ARs with more numerous repeats (common in Asians) are less sensitive • Diet: increased fat and/or meat consumption • Family history (germline mutations): 2x risk in a man with a father or brother who developed PCC • Acquired mutations: creation of TPRSS2-ETS fusion gene, activation of the oncogenic pathway PI3K/AKT signaling pathway, and inactivation of the tumor suppressor gene PTEN Morphology Gross • PCCs arise multifocally in the peripheral posterior zone of the prostate, facilitating palpation during rectal digital examination • Appear as multifocal firm, grayish-yellowish masses LM • Precursor lesion: prostatic intraepithelial neoplasia (PIN): cytologic atypia in glands, but the outer basal layer of cells is retained • The invasive cancers are adenocarcinomas: the atypical glands are lined by a single layer of epithelium • Gleason score system of grading: combination of very well (score 1); well (score 2); moderately (score 3); poorly (score 4); very poorly (score 5) differentiated patterns. Example: adenocarcinoma of prostate, Gleason score: 2+4= 6 Spread • Continuously: involvement of the entire prostate the seminal vesicles the bladder neck • Lymphatic metastases in nodes below the bifurcation of the common iliac arteries • Hematogeneous metastases: to the spine, pelvis, and ribs; to the lungs Clinical presentation Prostate specific antigen • Normal acini produce a protein, termed prostate specific antigen (PSA), which liquifies the semen • Tumor cells also elaborate PSA • Elevation in serum PSA level is of value in the diagnosis of prostate carcinoma (normal up to 4 ng/L, suspicious above 10 ng/L, almost sure >20 ng/L) Non-metastatic, clinically localized prostate cancer • Difficulty of micturition, urinary retention; urinary tract infection • Raised PSA on screening Metastatic disease • Back pain from vertebral metastases + pathologic bone fracture • Anaemia + uraemia because of urinary tract obstruction • High levels of serum PSA Dg.: ultrasound-guided transrectal biopsy Prognosis • Non-metastatic prostate cancer: radical prostatectomy or radiotherapy + anti-testosterone blockade: favourable outcome • Metastatic disease: worse outcome; anti-testosterone th + radioth - response can be achieved in a few individuals NON-TUMOROUS DISORDERS OF THE SPERMATIC CORD AND THE TESTIS Twisting of the spermatic cord • Torsion and subsequent hemorrhagic necrosis of the testis because of venous obstruction • Most common in 10-to-25 year-olds • Acute dramatic testicular pain; requires immediate surgery to save the testicle Varicocele • Varicosity of the pampiniform venous plexus within the spermatic cord • Frequent in young men; more common on the left side (the left internal spermatic vein empties into the renal vein, the right internal spermatic vein drains directly the inferior vena cava) • Consequence: the intrascrotal temperature raises a reduction in the rate of spermiogenesis oligospermia in the semen danger of infertility Hydrocele Serous fluid accumulates in the tunica vaginalis Causes • Right sided HF • Blockade of lymphatic drainage of scrotum • Epididymo-orchitis Cryptorchidism A failure of descent of testis; affects 1% of 1-y-old boys • Undescended testis may be abdominal, in the inguinal canal or at the external inguinal ring • Mainly unilateral; affects the right testis more frequently; association with other urological abnormalities and/or inguinal hernias • Consequences 3 9. Pathology of the male genital tract - The malpositioned testis undergoes atrophy; the contralateral, descended testis can also display histological signs of atrophy Bilateral and some unilateral cases infertility Risk of testicular cancer Testicular inflammation (orchitis) Acute orchitis Pathogenesis • Result of urethritis, cystitis, or seminal vesiculitis spread along the vas deferens and epididymis • Under age 35: Neisseria gonorrhoeae, Ureaplasma, Chlamydia • Older patients: Gram-neg. bacteria Morphology • Acute purulent epididymo-orchitis • Large destructive abscesses may develop • Healing: by scar formation Clinical features • Painful, enlarged, firm testis • Fever • Orchiectomy may be necessary Chronic orchitis Pathogenesis • If acute orchitis is not treated or inadequately treated • Mumps-virus induced orchitis after puberty Morphology • One or both testes may be involved in a focal or diffuse fashion • LM: interstitial ly-c infiltrates and fibrosis, tubular hyalinization Outcome • Testicular atrophy; bilateral involvement infertility Granulomatous orchitis Uncommon, in middle-aged males Pathogenesis: autoimmune mechanism is suspected Morphology • Gross: the testis is enlarged, the tunica albuginea is thickened • LM: intratubular inflammation composed of epitheloid cells, multinucleated giant cells, ly-s, pl-s Clinical features • Painless to moderately tender testicular mass of sudden onset • Simulates tumor or tbc fibrosis Male infertility • Infertile couple: no success during a 12-month period of wished gestation • Male partner disease is present in 25-40% of the couples • Evaluation reveals azoospermic or oligospermic (< 20 M sperms/ml) ejaculate [normospermic more than 40 M sperms/ml] Testicular biopsy from azoospermic men 4 conditions • Normal spermatogenesis Bilateral posttesticular obstruction, commonly due to previous gonorrhea • Germ cell aplasia (Sertoli cell only sy) Congenital or acquired; FSH • Maturation arrest The spermatogenic process abruptly fails to progress one of the early stages of maturation Causes: varicocele, mumps orchitis, exposure to lead or petroleum, etc. • Tubular hyalinization and peritubular fibrosis Causes: trauma, alcoholism, diabetes, irradiation Testicular biopsy from oligospermic men 4 conditions • Spermatogenic hypoplasia Spermatogenic cells are present in reduced numbers. Causes: idiopathic, malnutrition, antecedent febrile illness, varicocele, insecticides, chemotherapy. May respond to clomiphen citrate • Incomplete maturation arrest Causes: varicocele, mumps orchitis, exposure to lead or petroleum, etc. • Focal peritubular fibrosis and tubular hyalinization Causes: trauma, alcoholism, diabetes, irradiation • Sloughing of immature germ cells Sertoli cells and spermatogonia appear normal, the spermatocytes have sloughed into the lumen. Causes: varicocele, mumps orchitis, etc. Treatment option: in vitro fertilization • Mature spermatids (if any) in the biopsy specimen can be selectively isolated and injected into oocytes; 4 9. Pathology of the male genital tract • • preembryos are transferred to the cavity of uterine corpus where they implant 2010: Nobel prize for IVF: Robert Edward, Cambridge, UK; the gynecologist Patrick Steptoe, inventor of embryotransfer, died earlier TESTICULAR TUMORS • 95% of testicular tumors arise from the germinal (seminiferus) epithelium, termed germ cell tumors • Malignant (exception: dermoid cyst in childhood) • Occur with increased frequencies in association with undescended testis General features • Present with Insidious painless enlargement of the testis • Lymphatic metastases: in nodes along the aorta and mediastinum • Hematogeneous metastases: lungs, followed by liver, brain, and bones • Treatment: radical orchiectomy + postoperative therapy (radiation, chemotherapy) Histogenesis • Precursor: intratubular germ cell tumor (ITGCT) • Occurs in utero, but remains dormant untill puberty, malignant transformation in adulthood • ITGCT cells give rise to seminoma or transform into a totipotential neoplastic cell ( e.g., embryonal carcinoma) capable of further differentiation Seminomas • Most frequent germ cell tumors, mainly at about age 40 • Gross: well-demarcated homogeneous, lobulated bulky mass (sometimes ten times the size of the normal testis; the tunica albuginea is saved • LM: the seminoma cells have clear, glycogen containing cytoplasm; the nucleus has a prominent nucleolus; lymphocytes in the stroma • Remain confined to the testis for long intervals; produce lymphatic metastases; hematogeneous metastases occur late • Radiosensitive; the overall prognosis is good Non-seminomatous germ cell tumors • Highly malignant tumors, peak: about 30 y of age • Gross: infiltrative tumors with necrosis + hemorrhage • LM Composed of a single histologic type: embryonal cc, choriocc (serum marker: hCG), yolk sac cc (serum marker: alfa-fetoprotein), teratoma Mixed: contain more than one element, most common: embryonal cc + teratoma + yolk sac cc • At dg.: lymph node and lung metastases • Prognosis: chemotherapy achieves remission in the majority of cases • Pure choriocc: particularly agressive, extensive hematogeneous metastases can be present even with small primary lesion – the prognosis is dismal 5
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