Adult (post-puberty): each testis weights 15-19g, measures 5 x 3 cm; takes 70 days for cells to mature from spermatogonium to primary spermatocyte to secondary spermatocyte to spermatid to spermatozoa; maturation is orderly along length of tubule, but often not present in biopsy cross section

Embryology of testis

Presence of Y chromosome (possibly sex determining region Y) determines formation of testis

Germ cells migrate to genital ridge, tubules formed by day 45; wolffian ducts (form epididymis, vas deferens, seminal vesicles) develop by day 25, mullerian ducts (form uterus and upper vagina) by day 43

If no Y, gonad becomes an ovary; if Y present becomes a testis

If Y present, Sertoli cells develop from genital ridge and secrete anti-mullerian hormone / Mullerian inhibiting factor (AMH) by day 62, causing ipsilateral regression of mullerian duct by day 75-80; lack of Sertoli cells means no AMH, no regression and presence of uterus and upper vagina

If Y present, Leydig cells arise by day 64 and produce testosterone, which causes development of Wolffian duct structures (epididymis, vas deferens, seminal vesicles) if functional androgen receptors are also present

If no testosterone is produced, Wolffian duct structures degenerate

Exogenous androgens or their production by maternal tumor or congenital adrenal hyperplasia cause development of Wolffian duct system regardless of presence of Y chromosome

Development of external genitalia requires testosterone plus androgen receptors plus 5 alpha reductase, which converts testosterone to dihydrotestosterone (DHT), which causes development of external genitalia between days 120-140, including elongation of phallus

If ovaries or no gonads present, internal ducts are female

If DHT not present, external genitalia is female

Anatomy and histology

Paired organ suspended in scrotum by spermatic cord

Each testis is attached to an epididymis, which connects rete testis to vas deferens

Testis is composed of convoluted seminiferous tubules in a stroma with Leydig cells

Three layers: outer serosa (tunica vaginalis, extension of peritoneal cavity) with mesothelial cells; tunica albuginea (tough fibrous septa that extends into testis and separates it into 250 lobules of 1-4 seminiferous tubules), inner tunica vasculosa

Seminiferous tubules converge into rete testis at hilum, anastomose into efferent tubules that penetrate tunica albuginea to form head of epididymis

Epididymis (see below):

Interstitium: contains Leydig cells and stromal elements (collagen and myoid cells that surround seminiferous tubules)

Leydig cells: single (20 microns) or in clusters between seminiferous tubules, produce testosterone in response to luteinizing hormone (LH); often associated with nerve fibers and blood vessels; have abundant pink cytoplasm with lipid, lipochrome pigment, Reinke crystalloids (hexagonal prisms by EM), round nuclei with distinct nucleoli; fewer Leydig cells in elderly

Mediastinum: posterior testicular capsule with vasculature, nerves, mediastinum of rete testis (where tubules converge)

Rete testis: at testicular hilum; complex tubular architecture may resemble teratoma; connects testicular tubules to 12-15 ciliated efferent ducts, which merge into a single duct, the epididymis at its head; rete lined by flattened to columnar epithelium with numerous microvilli; efferent duct lumina are narrower than epididymis, lined by ciliated columnar cells with microvilli

Seminiferous tubules: 150-250 microns in diameter; lined by multilayered epithelium with most mature cells towards lumina; have basal lamina, outer myoid cells (positive for desmin, muscle specific actin, vimentin) and collagen; contain Sertoli cells, spermatogonia (types A and B), primary spermatocytes, secondary spermatocytes, spermatids and spermatozoa; all except spermatozoa are held together by a narrow cytoplasmic bridge

Immature tubules are positive for alpha inhibin

Sertoli cells: columnar, on basement membrane, surround germ cell elements with cytoplasmic extensions, form blood-testis barrier; 7% of tubular cells; may contain Charcot-Bottcher crystalloids (bundles of microfilaments); have irregular, highly folded nuclei with prominent nucleoli; produce anti-mullerian hormone, which causes regression of mullerian duct structures in utero; after birth, secrete androgen-binding protein and are responsive to FSH; also produce inhibin

Vas deferens: see below

Vestigial remnants:

Appendix epididymis: remnant of mesonephric duct

Appendix testis (hydatid of Morgani)

Remnant of mullerian duct; attached to tunica albuginea at upper testicular pole; present in 90% of males

May undergo hemorrhagic infarction from twisting on its pedicle

Gross: round/oval, 1-10 mm, pedunculated

Micro: columnar epithelium with vascular fibrous core with smooth muscle cells; may have glandular-like structures due to surface invaginations

Paradidymis (organ of Giraldes): remnant of mesonephric tubules

Vas aberrans (organ of Haller): remnant of mesonephric tubules

Cryptorchidism

Permanent retention of testis outside scrotum

Due to complete or incomplete failure of intra-abdominal testes to descend into scrotal sac, occasionally associated with other GU malformations such as hypospadias

Occurs in 10% of newborn boys, 1% of 1 year old boys; associated with trisomy 13

Testicular descent occurs in 2 phases: (1) abdomen to pelvic brim, controlled by anti-mullerian hormone; (2) pelvic rim to scrotum, androgen dependent, may be mediated by androgen induced release of calcitonin gene-related peptide from genitofemoral nerve

Cryptorchid testis usually (80%) found in inguinal canal; usually is no apparent hormonal disorder

Bilateral in 25% of cases

Cryptorchid testis are prone to trauma, torsion, inguinal hernia (10-20% of cases), sterility

Associated with 5-50x increased risk of testicular carcinoma, usually seminoma (higher risk if abdominal vs. inguinal location); may have cancer in normal descended testes too; biopsies suggested of both testes to detect intratubular germ cell neoplasia (50% with positive biopsy develop germ cell tumor at 5 years vs. minimal with negative biopsy)

Orchiopexy (placement in scrotal sac) should be done before age 2-3 to reduce risk of malignancy; deficient spermatogenesis persists in 10-60%; better fertility if orchiopexy done at younger age

Gross: small, firm, brown testis

Micro: marked hyalinization and thickening of tubular basement membrane, prominent Leydig cells, often hyperplastic Sertoli cells with atrophy of other cells (arrest in germ cell development); variable intratubular germ cell neoplasia; other testis often has paucity of germ cells; may have nodules of hyperplastic Sertoli cells or clusters of persistent immature tubules (“Pick’s adenomas”)

References: Hum Path 1980;11:666

Atrophy

Causes: atherosclerosis (Archives 1985;109:663), mumps or other inflammatory orchitis (particularly if post-pubertal), cryptorchidism, hypopituitarism, cachexia, semen outflow obstruction, radiation, chemotherapy (cyclophosphamide), female sex hormones, hepatic cirrhosis (causes elevated serum estrogen), exhaustion after persistent FSH stimulation, Klinefelter’s syndrome, the nematocide dibromochloropropane, AIDS (AJCP 1990;93:196), testicular regression syndrome

Testicular regression syndrome: patient has only rudimentary epididymis and spermatic cord with vas deferens; testicular tissue is replaced by fibrovascular nodule (mean 1.1 cm), also calcification, hemosiderin; due to cryptorchidism, possibly testicular infarct, Archives 2000;124:694

Post-vasectomy: thickening of tubular wall, reduced spermatids, reduced Sertoli cells, variable interstitial fibrosis

Micro: small tubules, thick basement membranes, few/no germ cells; interstitial fibrosis, often increased Leydig cells

Gonadotropin deficiency

For normal function, require intact axis of GnRH to FSH/LH

Prepubertal:

Delayed puberty: failure of adolescent development by age 16

Deficiency if gonadotropins were never secreted normally

Most patients with associated syndromes have major congenital anomalies

Kallmann’s syndrome: young adults/teenagers with prepubertal testes, anosmia/hyposmia (loss/reduction in sense of smell), cleft lip/palate, color blindness, short fourth metacarpals

LH mutation preventing binding to receptor: high LH, normal FSH, low testosterone, no Leydig cells, maturation arrest

Treatment: exogenous FSH and LH produce normal appearing and functioning testes

Micro: resembles prepubertal child; small testes without lumina, prepubertal Sertoli cells, scattered spermatogonia; no recognizable Leydig cells

Postpubertal:

Selective LH deficiency: normal FSH, active spermatogenesis with normal tubules, low LH and testosterone, low semen volume, reduced/absent Leydig cells

Selective FSH deficiency: normal LH, normal testosterone, variable sperm counts, low FSH, infertile with hypospermatogenesis, spermatogenesis with germ cell aplasia and incomplete maturation arrest

Other causes: pituitary or hypothalamic trauma, surgery, tumors, radiation, androgens / estrogens

Histology progresses from incomplete to complete maturation arrest, germ cell hypoplasia, germ cell aplasia, sclerotic tubules; tubules have thick/fibrotic walls, may have loss of Leydig cells

High dose estrogens for sex-change patients cause immature Sertoli cells, germ cell hypoplasia and Leydig cell atrophy

Low dose estrogens for prostate adenocarcinoma cause maturation arrest and partial Leydig cell atrophy

Treatment: FSH and LH produce normal appearing and functioning testes

Testotoxicosis

Form of male sexual precocity with active Leydig cell differentiation and premature onset of spermatogenesis without pituitary gonadotropin stimulation

Due to apparent inherited intratesticular defect

Micro: Leydig cells appear fully differentiated; no Reinke crystals; germ cells at all stages of spermatogenesis present but with disordered maturation; structural abnormalities in spermatids

References: Archives 1985;109:990

Testicular biopsy

Most biopsies have 3-5 lobules plus septa of tunica albuginea

Usually see many spermatozoa, “perfect” tubules mixed with occasional tubules with scattered “disorganized “ spermatogenesis

In young men, ratio of germ cells to Sertoli cells is usually 13:1

Indicated for azoospermia (no sperm present) without endocrine abnormalities, since biopsies may show focal spermatogenesis

Multinucleated giant stromal cells are associated with testicular atrophy due to estrogens

Hyalinized tubules with elastic fibers indicate hyalinization developed post-puberty

Zenker’s and Bouin’s fixative is preferred, as formalin introduces significant artifact

Biopsy results for azoospermia:

Germ cell aplasia/Sertoli cell only syndrome (29%): tubular basement membrane thickening, no germ cells, usually normal number of Leydig cells

Spermatocytic arrest (26%): usually early (no spermatids, no spermatozoa), normal Leydig cells; may be late (no spermatozoa only)

Generalized fibrosis (18%)

Normal (27%): usually associated with bilateral obstruction as seen in Young’s syndrome (also chronic sinopulmonary infections) or testicular blockage (50% of tubules lack lumina; disorderly maturation of germ cells); surgery (epididymovasotomy, vasovasotomy) is often successful

Azoospermia due to known obstruction: usually reduction in spermatids only due to increased hydrostatic pressure (47%), severity related to cause/span of obstruction; also normal testes (28%), reduction of primary spermatocytes and spermatids (9%), reduction in all germ cell types (13%), hyalinization (2%), AJSP 1999;23:1546

Biopsy results for no sperm count due to endocrine abnormalities:

Hypogonadotrophic eunuchoidism (60%): low FSH and LH levels; small infantile tubules with few/no Leydig cells, scattered spermatogonia and Sertoli cells

Klinefelter’s syndrome (30%): XXY karyotype, tubular fibrosis, prominent basement membrane thickening and Leydig cell hyperplasia; associated with increased incidence of breast carcinoma, possibly Leydig cell tumors, mediastinal germ cell tumors

Testicular aplasia: high urinary LH and FSH

Biopsy results for oligospermia:

Incomplete spermatocytic arrest: some tubules normal, some with arrest

Regional or incomplete fibrosis

Spermatogenic hypoplasia: tubules with reduced number of germ cells that are also disordered

Tubular hyalinization: includes Kleinfelter’s syndrome (small diameter tubules with thickened basement membrane and increased Leydig cells)

Normal: associated with duct obstruction

Sloughing and disorganization: lumina contain desquamated immature cells, disorganized spermatogenesis (associated with hypoplasia, duct obstruction and mechanical damage to specimen)

Other causes of oligospermia: varicocele, cystic fibrosis causing obstruction in epididymis and vas deferens

Fine needle aspiration (FNA):

Used to differentiate normal testis, hypospermatogenesis, early and late maturation arrest, Sertoli cell only patterns

Minimally invasive, may replace testis biopsy

2-11 aspiration sites, 10-30 needle excursions/site; adequate if 100 clusters of 20 or more testis cells

May be more representative than biopsy since more sampling

Interpretation should focus on relative abundance of germ cells (primary spermatocytes, spermatids, mature sperm with tail) and Sertoli (support) cells

Frequency of clinical diagnoses: idiopathic non-obstructive (50%), varicocele (18%), genetic (8%), cryptorchidism (8%), cancer (8%), obstruction (7%), Kartageners syndrome (1%)

Hypospermatogenesis: presence but paucity of all germ cell types

Sertoli cell only: no primary spermatocytes, no spermatids, no spermatozoa

Early maturation arrest: primary spermatocytes but no spermatids, no spermatozoa

Late maturation arrest: all cells but spermatozoa

Note: FNA cannot assess basement membrane, which is important for neoplasm and CIS diagnoses

References: AJSP 2001;25:71-79

Infertility

Infertility-general

Causes: pretesticular, testicular, post-testicular

Pretesticular: extragonadal endocrine disorders (hypothalamic, pituitary, adrenal); includes elevated prolactin levels

Testicular: (see below), little treatment currently available

Posttesticular: duct obstruction (congenital, inflammatory, postsurgical); surgical treatment often successful since spermatogenesis is normal

Note: impaired sperm motility due to epididymal or immunologic factors is considered posttesticular

Evaluation: history and physical examination, semen analysis, WBC count in semen, detection of anti-sperm antibodies, sperm function tests (cervical mucus interaction, ova penetration, hemizonal assay)

Testicular biopsy is helpful for azoospermia without endocrine abnormalities

RNA binding motif: nuclear immunostain identifies spermatogenesis in biopsies that appear to be Sertoli cell only, Hum Path 2001;32:36

References: AJSP 2001;25:71, Archives 1995;119:722, Archives 1984;108:35

Normal spermatogenesis

Not every tubule has complete spermatogenesis

Number of late spermatids correlates best with sperm counts

Some patients have normal sperm counts but low motility or duct obstruction; EM may show round-headed sperm or immotile-cilia syndrome

Hypospermatogenesis

Reduced spermatogenesis (reduction in number of germ cells, thin epithelial layer) without a focal point of arrest

Mild if changes in occasional tubules; severe if significant reductions in all tubules

Often is thickening of tunica propria, interstitial fibrosis, tubular sclerosis, germ cell disorganization and sloughing into lumina

Not specific as to etiology; differential diagnosis includes toxins, excess heat, varicocele, hypothyroidism

References: Archives 1982;106:231

Maturation arrest

Complete maturation arrest: germ cell maturity ceases at a specific point; sperm counts usually zero

Incomplete maturation arrest: similar to complete but a few late spermatids are present in a few seminiferous tubules; patients are usually oligospermic

Same etiologies as hypospermatogenesis; also postpubertal gonadotropin deficiency, alkylating agents, radiation therapy

Non-zero sperm counts indicate late spermatids are present somewhere in testis, although perhaps not in area biopsied

Micro: numerous spermatogonia, few spermatocytes, no mature spermatozoa; Sertoli cells prominent since reduced germ cells; tubules often contain degenerated cells with irregular dense nuclei

Germ cell aplasia

Aka Sertoli cell only syndrome

Charcot-Bottcher crystals sometimes seen as thin eosinophilic lines in various directions

Causes: del Castillo’s syndrome (normal serum testosterone, normal secondary sex characteristics, high normal FSH, soft small testes, azoospermia), gonadotropin deficiency, cryptorchidism, orchitis, prostate cancer hormonal therapy

Micro: tubules are reduced in diameter and lined only by post-pubertal Sertoli cells; Sertoli cells are perpendicular to basement membrane; may resemble palm trees waving in a breeze; cells have nuclear indentations and prominent nucleoli

DD: intratubular germ cell neoplasia, post-chemotherapy (alkylating agents), post-radiation therapy

Germ cell aplasia and focal spermatogenesis

Two populations of tubules; one population with small tubules exhibiting germ cell aplasia, other population has reduced spermatogenesis

Usually very low sperm count

Klinefelter’s syndrome

47XXY, reduced body and pubic hair, gynecomastia in 40-80%, high FSH, variable LH

Increased risk of breast cancer

Gross: small, firm testes

Micro: reduced number of intratubular germ cells, some tubules are Sertoli cell only; also tubular sclerosis, Leydig cell nodules (appear hyperplastic due to tubular atrophy), focal spermatogenesis

EM: no annulate lamellae in Sertoli cells; microcrystal formation but no Reinke crystal’s in Leydig cells, Archives 1982;106:228

46XX with de la Chapelle’s syndrome

Small stature (smaller than Klinefelter’s), sparse pubic and facial hair, occasional gynecomastia, possibly reduced size of testes, prostate, penis; high FSH and LH, low testosterone; may be due to XXY with loss or translocation of Y during development

Tubular sclerosis / interstitial fibrosis only

Seen in association with hypospermatogenesis, cryptorchidism, karyotypic abnormalities

Rare to have biopsies with only this finding

Due to FSH/LH deficiency, remote chronic orchitis, remote ischemia, idiopathic

Excurrent duct obstruction

Excurrent means distal to rete testis

Congenital or acquired

Occurs in 10% of biopsies for infertility

Associated with azoospermia, normal-sized testes and active (but not necessarily normal) spermatogenesis

Congenital: agenesis or atresia of epididymis or vas deferens, atrophy from secretions in cystic fibrosis

Acquired: infection, sterilization, inadvertent surgical ligation of vas deferens

Partial excurrent duct obstruction is likely if sperm count is appreciably lower than that expected from biopsy

Micro: active spermatogenesis, germ cell disorganization and sloughing; variable interstitial fibrosis and sperm granulomas; no tubular basement membrane thickening

Reference: AJSP 1999;23:1546

Intersex syndromes

Intersex syndromes - general

Discordance between genetic sex, gonadal sex, genital tract sex or phenotypic sex

Photograph and label specimen and orient with surgeon

6% incidence of intratubular germ cell neoplasia (IGCN) unclassified, AJSP 1993;17:1124

Androgen insensitivity syndrome

Called testicular feminization if complete

Most frequent cause of male pseudohermaphroditism; either XY or XXY

Lack of androgen receptor due to mutations in gene on X chromosome, causes tall phenotypic female with well-formed breasts, absent/scanty pubic and axillary hair, shallow vagina and lack of upper vagina because anti-mullerian hormone (AMH) causes mullerian duct regression

Patients also have bilateral cryptorchidism with intraabdominal, inguinal or labial testes; usually no wolffian or mullerian derivatives

Recommend gonadectomy by puberty since associated with germ cell tumors (30% by age 50)

Case report of associated seminoma, Mod Path 1993;6:89

Gross: tan-brown testes with multiple white nodules of Sertoli cells and wolffian/mullerian duct cysts at lateral pole of testis

Micro: small seminiferous tubules without lumina composed of Sertoli cells only, usually immature, with sparse spermatogonia, marked Leydig cell hyperplasia (often without Reinke’s crystals), ovarian type stroma; nodules are probably hamartomas of Sertoli cells

Congenital adrenal hyperplasia

Due to various enzymatic defects that cause different patterns of synthesis of glucocortical, mineralocorticoid and sex-hormone synthesis

Genetic males have cryptorchidism, viable wolffian duct structures, female or ambiguous genitalia, no mullerian duct structures

Testes resemble cryptorchid testes

May have bilateral Leydig cell hyperplasia with 21-OHase, 11-OHase and 17beta-hydroxysteroid dehydrogenase deficiencies; treat with corticosteroids or surgical excision

Dysgenetic male pseudohermaphroditism

Bilateral dysgenetic testis, mullerian structures, cryptorchidism, inadequate virilization

May be XO/XY mosaics

Infertile, no spermatogenesis

Gonadal dysgenesis-general

Ambiguous genitalia, persistent mullerian duct structures and wolffian duct derivatives, karyotypes with Y, potential for neoplastic transformation of gonads

Note: some don’t separate types of gonadal dysgenesis

DD: true hermaphroditism (no risk of germ cell tumors, differentiated ovary and testicular tissue)

Gonadal dysgenesis-mixed

(a) Testis plus contralateral streak gonad OR (b) testis and contralateral gonadal agenesis OR (c) hypoplastic gonads with tubules in one gonad OR (d) streak gonad with contralateral tumor

Mullerian structures present since no/minimal AMH produced

Usually bilateral fallopian tubes

Usually incomplete masculinization of external genitalia, poor development of ipsilateral wolffian duct structures

External genitalia are male, female or ambiguous (ambiguous in most patients, 2/3 raised as female)

Phenotypic females may develop signs of virilization at puberty

Karyotypes: 45 X0/46 XY, 46 XY most common

Associated with low immunoglobulin levels, aberrant bony development of inner ear structures, cardiovascular and renal anomalies

Treatment: early bilateral gonadectomy advocated if Y chromosome material is present to prevent gonadoblastoma (1/3) or other germ cell tumors; also to prevent virilization if patient is raised as female

Micro: tubules with mild hypospermatogenesis to total sclerosis; streak gonad has ovarian stroma without primordial ovarian follicles; streak ovary has primitive sex-cordlike structures within ovarian-type stroma, variable germ cell components, resembles either gonadoblastoma, granulosa cell or Sertoli cell tumors

DD: true hermaphroditism (histology is important in distinguishing, clinical features are not)

References: Mod Path 2002;15:1013, Archives 1990;114:679, Hum Path 1982;13:700

Gonadal dysgenesis-pure

Bilateral streak gonads, internal mullerian structures, 46 XY, female phenotype, no sign of Turner’s syndrome

Male pseudohermaphroditism

XY, testes present, phenotype ambiguous or female

Persistent mullerian duct syndrome

Rare, mullerian duct structures persist due to lack of AMH effect due to either mutation in AMH gene on #19p or abnormality of receptor gene on #12

X linked or autosomal recessive

Phenotypic male, normal external genitalia, unilateral or bilateral cryptorchidism, may have empty hemiscrotum, normal wolffian duct derivatives; however also have mullerian duct derivatives (uterus and usually 2 fallopian tubes) within an inguinal hernia

Two forms: (a) unilateral cryptorchidism and contralateral hernia, (b) bilateral cryptorchidism, uterus in pelvis, both testes embedded in broad ligament

15% risk of germ cell tumors, including intratubular germ cell neoplasia

Case report of clear cell adenocarcinoma in uterus, AJSP 2002;26:1231

DD: mixed gonadal dysgenesis (higher risk of germ cell tumors leads to bilateral gonadectomies)

Testicular regression syndrome

Paucigonadal or agonadal individuals with male, female or ambiguous phenotype

Either (a) no gonadal or testicular formation OR (b) regression of testicular tissue with residual fibrovascular nodule (mean 1.1 cm), calcification and hemosiderin

Rudimentary epididymis and spermatic cord are present

External genitalia depends on chronology of gonadal injury

Causes: cryptorchidism, possibly testicular infarct, infection, trauma, torsion or prenatal hormone induced atrophy due to overproduction of androgens

Micro: regressed testis indicated by fibrosis, hemosiderin, calcification or Leydig cells near epididymis or proximal vas deferens; presence of only fat and connective tissue does not rule out an intraabdominal testis

References: Archives 2000;124:694

True hermaphroditism

Unequivocal ovarian and testicular tissue in the same patient as either bilateral or unilateral ovatestes or as a testis opposite an ovary, regardless of karyotype

Ovary is usually normal; testis usually lacks spermatogonia

No streak gonads present; usually no associated gonadoblastomas

Usually no other developmental malformations, and patients may have normal sexual and reproductive functions

Treatment: after assign gender, remove inappropriate gonad and biopsy remaining tissue

Micro: ovarian compartment has numerous primordial follicles with primary oocytes and a few primary or antral follicles

DD: mixed gonadal dysgenesis (histology is important in distinguishing these diagnoses, clinical features are not)

References: Mod Path 2002;15:1013

Infectious testicular lesions

AIDS
Markedly reduced spermatogenesis, arrested maturation, germ cell aplasia, tubular hyalinization, interstitial inflammation and fibrosis, reduction in Leydig cells, Sertoli cell only pattern

May be associated with other infections (CMV, toxoplasmosis, mycobacteria, Histoplasma, Candida)

Does not appear to be immune mediated, Hum Path 1989;20:572

References: Mod Path 1989;2:233, Hum Path 1989;20:210

Brucellosis

Affects testis and epididymis in 20% of cases; has granulomatous appearance

Gonorrhea

Usually spreads from posterior urethra to prostate, seminal vesicles and epididymis

Testis involved only if untreated

Histoplasma capsulatum

May resemble sperm granuloma

Leprosy

Doesn’t occur in U.S.

3 phases of testicular involvement: (1) vascular phase in which blood vessel walls and interstitium are stuffed with lepra cells; (2) interstitial phase with endarteritis, Leydig cell clusters, interstitial fibrosis, histiocytes containing acid-fast bacteria and reduced spermatogenesis; (3) obliterative phase with dense fibrosis, no detectable tubules, reduced vessels, rare acid-fast bacteria; associated with gynecomastia

Mumps

Testicular infections rare in infected children but occur in 20-30% of postpubertal men 1 week after parotiditis

1/3 of postpubertal infected men develop testicular atrophy, 2-10% become infertile

Pyogenic epididymo-orchitis

Usually due to E. coli

Resembles granulomatous orchitis

Complications: venous thrombosis, septic testicular infarct

Syphilis

Testis usually involved first

Gross: discrete gummas contribute to enlarged, irregular testis

Micro: gummas (diffuse interstitial inflammation with edema, lymphocytes and plasma cells) with obliterative endarteritis and perivascular cuffing; spirochetes usually noted in gummatous but not fibromatous stages

Tuberculosis

Usually begins in epididymis and spreads to testis; prostate and seminal vesicles are usually also infected

Non-neoplastic testicular lesions

Adrenal cortical rests

Occur in 4-15% of testis, paratesticular tissue, spermatic cord or epididymis

Small, round, yellow; adrenal cortical tissue only; no adrenal medullary tissue

Anorchia

No testis found; if phenotypically normal male and vas deferens is present, indicates a testicular regression syndrome caused by infection, trauma, torsion or prenatal hormone induced atrophy due to overproduction of androgens

Position of regressed testis is indicated by presence of fibrosis, hemosiderin, calcification or Leydig cells near epididymis or proximal vas deferens; presence of fat and connective tissue only does not rule out an intraabdominal testis

Chemotherapy effect

Dose related changes to seminiferous tubules occur due to alkylating agents, may cause germ cell aplasia

After cyclophosphamide, patients become azoospermic until 15-49 months after therapy ceases; spermatogenesis may not return in some with germ cell aplasia

Tubules are also damaged by methotrexate for psoriasis, ara-C for ALL, DBCP exposure in petrochemical workers

Chylocele

Accumulation of lymph in tunica vaginalis, usually due to elephantiasis

Cystic dysplasia

Rare congenital disorder with numerous irregular cystic spaces in mediastinum testis

May be due to defect in connection between rete testis/seminiferous tubules and efferent tubules

Micro: cysts lined by flattened to cuboidal epithelium separated by incomplete connective tissue septa; resembles rete testis

Positive stains: keratin, vimentin, EMA

References: Archives 1984;108:579, Hum Path 1993;24:1142

Cysts

Epidermoid cysts (below), cysts of tunica albuginea, rete testis, efferent ducts or testicular parenchyma have been described

These cysts are benign; have ciliated/non-ciliated epithelium, usually cuboidal to columnar epithelium

Tunica albuginea cysts are probably of mesothelial origin

References: Archives 1989;113:902

Epidermoid cyst

Benign, <1% of testicular tumors

May represent monodermal teratoma, but if no adnexal structures or other tissue types are found after thorough sampling, then there are no metastases (thus, sample thoroughly to look for adnexal structures)

Some may be neoplastic based on similar allelic loss as malignant germ cell tumors, Archives 2003;127:858

Patients usually ages 10-39

Gross: intraparenchymal lesion, usually adjacent to tunica albuginea, mean 2 cm, contains white grumous keratin debris

Micro: cyst with keratinized squamous epithelial lining contains a granular cell layer, cyst filled with laminated keratin; cyst rupture may cause granulomatous reaction; no intratubular germ cell neoplasia, no adnexal structures, no other tissue types

Granulomatous orchitis

Rare; sudden onset of tender testicular mass, variable fever, usually men 40-59 years

May be a response to acid-fast products of disintegrated sperm, post-infectious, or due to trauma or sarcoidosis

Resembles pyogenic epididymo-orchitis (above)

Benign, although also associated with seminoma

Recommend cultures to rule out infectious process (TB, syphilis, sarcoidosis, leprosy, brucellosis)

Gross: solid, unilateral, nodular enlargement of testis; resembles lymphoma

Micro: lymphocytes and plasma cells infiltrate interstitium and surround seminiferous tubules; giant cells and histiocytes that resemble but are not actual granulomas

References: Hum Path 1990;21:1080 (lymphocytic orchitis)

DD: infection, lymphoma

Hematocele

Blood in tunica vaginalis; related to testicular trauma, torsion or hemorrhagic diseases

Hydrocele

Accumulation of clear serous fluid between visceral and parietal layers of tunica vaginalis; associated with trauma and epididymitis

Diagnose by transillumination

Micro: loose connective tissue with mesothelial lining; if long-standing, may have chronic inflammatory infiltrate, fibrosis, squamous metaplasia

Juvenile xanthogranuloma

Rare

Macroorchidism

Increased testicular size due primarily to increased tubular length, Hum Path 1992;23:1011

Associated with fragile X syndrome; also sexual precocity, pituitary adenomas that secrete FSH

Malakoplakia

Affects testis alone or testis and epididymis

Culture often grows coliforms

Gross: associated with abscesses and thrombosed blood vessels; testis is enlarged, tan-yellow-brown

Micro: tubular atrophy, sheets of histiocytes with Michaelis-Gutmann bodies (intracellular and extracellular round structures containing iron and calcium)

EM: bacteria within phagolysosomes of histiocytes

DD: Leydig cell tumor, granulomatous orchitis

Meconium periorchitis

Due to meconium peritonitis in fetal life

Patients may have cystic fibrosis

Meconium leaks from perforated viscus into peritoneum, through a patent processus vaginalis into scrotum

Patients present with testicular mass during infancy

Gross: yellow-green mass adherent to testis with multifocal dystrophic calcification

Micro: pigment laden macrophages, myxoid stroma, squames, lanugo hair, calcification and mesothelial hyperplasia

References: Hum Path 1986;17:807

Necrotizing vasculitis

May be associated with polyarteritis nodosa or an isolated finding

Nodular and diffuse fibrous proliferation

Aka fibrous pseudotumor, inflammatory pseudotumor

Reactive fibrous “tumors”, usually between testicular tunica layers; also involves epididymis and spermatic cord

Ages 7-95 years, peaks in 20’s

Often a history of trauma or infection

Treatment: excision

Gross: multinodular thickening of peritesticular tissue or discrete mass of firm white tissue up to 15 cm; may be an associated hydrocele or hematocele

Micro: dense fibrous tissue, fibroblasts, inflammatory cells, dystrophic calcification; with time, is reduced cellularity and increased fibrosis

Positive stains: smooth muscle actin (myofibroblasts)

DD: spindle cell mesothelioma

References: Hum Path 1990;21:866

Polyorchism

Multiple testes within a scrotal sac; either one common or separate epididymis

Radiation effects

Germ cells have variable sensitivity to radiation; type B spermatogonia are most sensitive, spermatids are least sensitive

Therapeutic radiation may cause only temporary infertility with recovery in 30-80 weeks, delayed if combined with chemotherapy

Radiation for intratubular germ cell neoplasia causes germ cell aplasia

Radiation exposure at Hiroshima and Nagasaki, Japan in 1945 caused increased tubular sclerosis, vascular hyalinization

Silicon implants

Elicit chronic inflammatory responses (B, T cells, macrophages) in adjacent capsule, similar to breast implants, Mod Path 1999;12:706

Sinus histiocytosis with massive lymphadenopathy

Rare; also called Rosai-Dorfman disease

Spermatocele

Small cystic accumulation of semen, often in efferent ducts

Splenogonadal fusion syndrome

Also called ectopic scrotal spleen, testicular-splenic fusion

Rare congenital condition of gonad fusing with ectopic splenic tissue; patients usually present before age 20, 50%+ are less than age 10

In males, involves left testis only; occurs in females also

Fusion may be continuous (attaching to spleen) or discontinuous (intrascrotal splenic nodules attached to testis, spermatic cord, epididymis, appendix of testis or appendix of epididymis); continuous form is associated with limb-bud anomalies such as peromelia (severe congenital anomalies of extremities identical to thalidomide embryopathy) and micrognatia (small jaw); discontinuous type is rarely associated with cardiac defects

Case report of associated embryonal and yolk sac tumor, Archives 2002;126:1222

Gross: splenic tissue well demarcated from gonad

Micro: normal splenic parenchyma with variable fibrosis, thrombi, calcification, fatty degeneration, hemosiderin

DD: sarcoma, teratoma, lymphoproliferative tumor

References: Archives 2003;127:e277

Varicocele

Abnormal dilation and tortuosity of veins in pampiniform plexus of spermatic cord, probably due to insufficiency of venous valves

Often associated with infertility; after treatment, 40-55% are fertile

90% on left; 10% bilateral

Isolated right sided varicocele is associated with situ inversus, venous thrombosis or venous compression from space occupying lesion

Treatment: ligation or occlusion of left spermatic vein

Micro: variable thickening of venous wall with fibrosis, decreased spermatogenesis in tubules with germ cell degeneration and increased Leydig cells

Adolescent varicocele: pathologic changes found at or soon after puberty, consisting of tubular sclerosis, premature germ cell sloughing, small vessel sclerosis and variable hypospermatogenesis, AJCP 1988;89:321

Vasculitis

Biopsy most diagnostic in patients with testicular symptoms (pain, enlargement or shrinking)

Wedge biopsy should contain capsule, tunica vasculosa and testicular parenchyma

Testicular neoplasms

Testicular neoplasms - general

Less than 1% of all malignancies in males; highly curable even if advanced

95% are germ cell tumors (aggressive but curative), 5% are sex cord-stromal tumors (usually benign but associated with hormonal syndromes); also mixed, tumors not specific to testis, metastases

Lymphatic spread common to periaortic, iliac, mediastinal and supraclavicular nodes, not to inguinal nodes unless previous scrotal or inguinal surgery or invasion of scrotal wall

Usually spreads to ipsilateral nodes first

Hematogenous spread to liver, lungs, brain, bones

Metastases may differ from primary lesion histologically

LDH levels correlate with tumor cell mass

Serum tumor markers are used for staging (S category), assessing tumor burden (LDH), response to therapy (AFP, hCG); obtain immediately after orchiectomy and if elevated, recheck to determine if elevation persists (indicates residual disease)

Classification

WHO classification

Intratubular germ cell neoplasia

Seminoma (classic, tubular)

Spermatocytic seminoma

Nonseminomatous germ cell tumors

Embryonal carcinoma

Yolk sac tumor / endodermal sinus tumor

Teratoma: mature, immature, with malignant transformation

Choriocarcinoma

Mixed

Polyembryoma

Diffuse embryoma

Practical classification

Seminoma or nonseminomatous germ cell tumor (NSGCT)

Biologically, seminoma and NSGCT are closely linked but treatment is different

Rarely, patient has mixed seminoma and NSGCT

Testis and epididymis

Table of Contents

Rete testis: normal

Non-neoplastic: adenomatous hyperplasia, calcifying nodules, cystic dilation (transformation), cystic dysplasia, dysgenesis