ABSTRACT
EMBRYOLOGY/ANATOMY/PHYSIOLOGY
●● Gonadal development starts with formation of urogenital ridge
●● Urogenital ridge composed of mesonephros and gonadal ridge
●● Normal male differentiation depends on expression of SRY gene on Y chromosome
derived somatic cells in testicular stroma ●● SRY expression activated by WT1 ●● In gonadal blastema, celomic epithelial cells
express SOX9 and anti-müllerian hormone (AMH)
●● By the sixth to eighth weeks of embryonic life, celomic epithelial cells start to organize into tubular structures forming primordial sex cords
●● Fibrous tunica albuginea is formed at eighth week of gestation
●● Morphology of seminiferous tubules unchanged from birth to puberty
●● Testicular development complete by eighth week of embryonic life (abdominal organ at this time)
●● AMH appears at 12th-16th weeks; helps in regression of müllerian duct and upper vagina
●● Testosterone peaks at 12th-16th week; helps in differentiation of wolffian ducts, epididymis, vas deferens, and seminal vesicles
●● Rete-testis develops from mesonephric remnants in proximity of seminiferous cords
●● At 8th-15th weeks, transabdominal phase of testicular descent occurs (dependent on androgen expression)
●● Gubernaculum (caudal ligament of testis) helps in migrating the testis down to inguinal region
●● At 28th-35th weeks, inguino-scrotal phase of testicular development, mediated by gubernaculum and dependent on androgen expression
AT PUBERTY
●● Sertoli cells stimulated by luteinizing hormone and follicle-stimulating hormone, acquire adult phenotype
●● Tight junctions (blood-testis-barrier) formed between Sertoli cells
●● Sertoli cells secrete fluid, seminiferous tubules, acquire lumina
●● AMH (anti-müllerian hormone) production stops
●● Germ cells enter meiosis and enter tubular luminal compartment
CONGENITAL ANOMALIES
Cryptorchidism/undescended testis
●● Unilateral/bilateral testes fail to migrate to base of scrotum
●● Incidence increased in premature males at birth
lar contour ●● Thick basement membranes, lack of
spermatogenesis ●● Sertoli cell only pattern in testis
Prepubertal macroorchidism
●● Idiopathic, McCune-Albright syndrome, fragile X syndrome
●● Variable hormonal deficiencies and developmental anomalies (based on stage at which testicular damage occurred)
●● Etiology: Genetic, intrauterine infection, testicular infarction
Other anomalies
●● Agonadism, anorchidism, testicular agenesis, rudimentary testes, hypoplastic testes
ACQUIRED DISORDERS
Testicular torsion
●● Medical emergency, most common cause of testicular infarct
●● Delayed repair (if done after 8 hours): Testicular viability lost, permanent ischemic injury
infar ction of testis, necrosis of seminiferous tubular cell layer
Epididymoorchitis
tory ducts cause epididymitis ●● Predisposing factors: Trauma, hematologi-
cal spread, urinary tract infection, urologic abnormalities
●● Etiologic agents: Escherichia coli, chemical epididymitis, mumps virus, coxsackie B virus
●● Granulomatous-orchiepididymitis (tuberculosis in endemic regions)
Testicular microliths
Sertoli cells, followed by mineralization ●● Bad prognosis
TESTICULAR NEOPLASMS
●● Most common are the germ cell tumors followed by sex-cord stromal tumors
●● Juvenile granulosa cell tumor: Most common in newborns
●● Rhabdomyosarcoma: Most common paratesticular tumor
Germ cell tumors
Yolk cell tumor
levels ●● Not hormonally active ●● Metastases at time of presentation common
(hematogenous or lymphatic) ●● Various histologic subtypes: Microcystic,
reticular, endodermal sinus pattern, polyvesicular vitelline, hepatoid
●● Meshwork of vacuolated cells with eosinophilic hyaline globules, Schiller-Duval bodies
derm, and ectoderm)
tal tissue derived from three germ layers ●● Immature elements: Embryonal type of
neuroectodermal or other tissue
Fetus in fetu
●● Extensive maturation/organization of a teratoma
Epidermoid cyst
nous material ●● Lined by keratinized squamous epithelium ●● Confined to testicular parenchyma ●● Enucleation has excellent prognosis
Intratubular germ cell neoplasia
●● Neoplastic proliferation of germ cells within the seminiferous tubules
olated cytoplasm, coarse chromatin, and prominent nucleoli
●● Not reliably detected in at-risk prepubertal patients
Embryonal carcinoma
●● Common component in mixed GCT, but rare in pure form
●● Sheets of large undifferentiated pleomorphic cells with prominent nucleoli and atypical mitoses, necrosis
●● May show primitive gland or papillary formations
Seminoma
●● Sheets/aggregates of uniform cells with clear cytoplasm, well-defined cell borders, large regular nuclei, prominent nucleoli
●● Neoplastic cells resemble primitive germ cells
Choriocarcinoma
●● Rare as pure form but may be a component of mixed GCT
Mixed germ cell tumor
●● Combination of two or more germ cell tumors
cell neoplasia
Sex-cord stromal tumors
●● Composed of specialized supportive components of male and female gonad
Leydig cell tumor
●● Precocious puberty, increased levels of testosterone
●● More common with Klinefelter syndrome, cryptorchidism
●● Sheets of large polygonal cells, abundant granular eosinophilic cytoplasm
Melan-A ●● May be seen in adrenogenital syndrome or
Nelson syndrome
Sertoli cell tumor
●● Genetic or syndromic associations (androgen insensitivity syndrome, Peutz-Jeghers syndrome)
●● Precocious puberty, increased estradiol levels, gynecomastia
without pleomorphism ●● Positive for vimentin and CK
Large cell calcifying Sertoli cell tumor
dant myxohyaline stroma ●● Large areas of calcification
Juvenile granulosa cell tumor
structural abnormalities of Y chromosome ●● Solid and cystic pattern ●● Cysts lined by proliferated granulosa cells
internally and theca cells externally ●● Interfollicular areas: Nodules and sheets of
tumor cells, mitotically active ●● Positive for vimentin, CK, S100, Inhibin
Gonadoblastoma
●● Associated with mixed gonadal dysgenesis with ambiguous genitalia and presence of Y chromosome
●● Nests of large/pale germ cells, admixed with sex-cord cells (with small dark and angular nuclei)
●● Hyalinized nodules of basement membrane-like material surrounded by tumor cells
Sex-cord stromal tumor with annular tubules
CONGENITAL ANOMALIES
●● Complete absence of vas deferens (most common), epididymis, seminal vesicle
hernia sac); tubular structures, narrower than vas deferens, no smooth muscle in wall
●● Cystic fibrosis: Aplasia/hypoplasia of vas deferens/epididymis
●● Congenital absence of bilateral vas deferens: Defects in CFTR gene
●● Heterotopic tissue in paratesticular region (splenogonadal fusion tissue, immature renal, testicular, adrenal tissue)
VARICOCELE
●● Dilatation of veins in pampiniform plexus of spermatic cord (adolescent boys)
HYDROCELE
●● Fluid accumulation in processus vaginalis/ tunica vaginalis
MECONIUM PERIORCHITIS
●● Large solitary/multinodular paratesticular mass along spermatic cord
●● In utero perforation of gastrointestinal tract → meconium leak in peritoneal cavity → tunica albuginea via processus vaginalis
●● Fibrous tissue, macrophages, foreign body giant cells with brown bile pigment, cholesterol clefts, dystrophic calcification
PARATESTICULAR TISSUE TUMORS
Malignant mesothelioma
●● Resemble pleural and peritoneal counterparts
●● Range from well-differentiated (tubulepapillary architecture) to completely undifferentiated forms (solid diffuse growth pattern)
●● Mesothelial cells positive for CK5/6, calretinin
Desmoplastic small round cell tumors
●● Small round cells with epithelial growth pattern
resulting in gene fusion EWS-WT1
Rhabdomyosarcoma
●● Most common paratesticular sarcoma in children
Melanotic neuroectodermal tumor
●● Tumor of facial/skull bones, but may be found in epididymis
Adenomatoid tumor
●● Tubules and cords of low cuboidal/flat mesothelial cells in fibrotic stroma
Miscellaneous tumorous lesions
●● Nodular mesothelial hyperplasia, hemangioma, juvenile xanthogranulomatosis
HYPOSPADIAS
●● Abnormal opening of urethral meatus on ventral surface of penis
●● Associated with chordee (abnormal ventral curvature of penis)
EPISPADIAS
●● Abnormal opening of urethral meatus on dorsal surface of penis
CUTANEOUS VIRAL INFECTIONS
●● Papillomavirus causes bowenoid papulosis, condyloma acuminata (HPV-16)
BALANITIS XEROTICA OBLITERANS
●● Thick white plaque on prepuce, glans, and meatus
●● Keratotic and atrophic epidermis, slight liquefactive degeneration of basal cell layer
●● Thick subepithelial hyalinized acellular material
●● Dense lymphoplasmacytic infiltrate below hyalinized zone
PENILE NEOPLASMS
CONGENITAL ANOMALIES
●● Hypoplasia of prostate and dilation of prostatic urethra in prune-belly syndrome
ACQUIRED ANOMALIES
Rhabdomyosarcoma
●● Any congenital condition presenting with atypical development of chromosomal, gonadal and/or anatomical (genital) sex
●● DSDs get initiated in utero and final phenotypic changes occur at puberty
●● Prevalence of germ cell tumors increased with DSD (especially patients containing Y chromosome in their genome)
DYSGENETIC GONAD
ian stroma intermixed with abnormally developed sex-cord-like structures containing primitive germ cells
CLASSIFICATION OF DSD
Normal sex chromosomes
Female pseudohermaphroditism
Male pseudohermaphroditism
DHT) ●● Androgen insensitivity syndrome (testicu-
lar feminization syndrome) ●● Persistent müllerian duct syndrome
Abnormal sex chromosomes
When sexual ambiguity frequently exists
When sexual ambiguity infrequently exists
Three types of sex
SRY
SRY
Phenotypic sex
●● Development of ductal system/external genitalia regulated by müllerian inhibiting substance (MIS/AMH)
●● Anti-müllerian hormone (AMH) secreted by Sertoli cells
●● Phenotypic sex determined by steroid hormones of the testis (testosterone/DHT) and ovary (estrogen/progesterone) also
DEFECTS OF WILMS TUMOR (WT1) SUPPRESSOR GENE
●● WT-KTS isoform required for cell survival and proliferation in bipotential gonad (both males and females)
●● Mutation of this gene associated with genital and kidney defects, increased risk for Wilms tumor and mental retardation
●● Three syndromes: WAGR, Denys-Drash, and Frasier
