Testis and epididymis

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

Reference: AJSP 2003;27:469

Embryology of testis

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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

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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

Drawings: image1, image2, image3, image4, image5, image6 image7, image8, image9, image10

Gross images: image1

Micro images: #1; #2; contributed by Dr. Asmaa Gaber Abdou, Menofiya University, Egypt - #1

Efferent ducts: image1, image2

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

Micro image: image1

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

Micro images: image1, image2, image3, image4

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

Micro images: image1, image2, image3, image4, image5, image6

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

Micro images: image1, image2

Paradidymis (organ of Giraldes): remnant of mesonephric tubules

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

Cryptorchidism

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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

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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

Gross images: atrophy (comparison to normal testis)

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

Micro images: image1, image2, image3

Gonadotropin deficiency

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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

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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

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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:

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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:

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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:

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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):

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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

Infertility

Infertility-general

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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

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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

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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

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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

Micro images: #1; contributed by Dr. Asmaa Gaber Abdou, Menofiya University, Egypt - #1; #2

Germ cell aplasia

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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

Micro images: #1; #2

contributed by Dr. Asmaa Gaber Abdou, Menofiya University, Egypt - Sertoli cell only and Leydig cell hyperplasia #1; #2

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

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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

Micro images: image1, image2, image3

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

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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

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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

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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

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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

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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

Micro images: #1; #2

Congenital adrenal hyperplasia

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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

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Bilateral dysgenetic testis, mullerian structures, cryptorchidism, inadequate virilization

May be XO/XY mosaics

Infertile, no spermatogenesis

Gonadal dysgenesis-general

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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

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(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

Micro images (Mod Path subscribers): image1, image2

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

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

Male pseudohermaphroditism

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XY, testes present, phenotype ambiguous or female

Persistent mullerian duct syndrome

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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

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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

Micro images: image1, image2, image3, image4

References: Archives 2000;124:694

True hermaphroditism

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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

Micro images: image1, image2, image3

Micro images (Mod Path subscribers): image1

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
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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

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

Gonorrhea

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

Testis involved only if untreated

Histoplasma capsulatum

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May resemble sperm granuloma

Leprosy

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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

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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

Micro images: image1

Pyogenic epididymo-orchitis

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Usually due to E. coli

Resembles granulomatous orchitis

Complications: venous thrombosis, septic testicular infarct

Syphilis

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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

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

Non-neoplastic testicular lesions

Adrenal cortical rests

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

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

Anorchia

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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

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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

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Accumulation of lymph in tunica vaginalis, usually due to elephantiasis

Cystic dysplasia

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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

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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

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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

Micro images: image1, image2

Granulomatous orchitis

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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

Micro images: image1, image2, image3

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

DD: infection, lymphoma

Hematocele

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

Hydrocele

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

Diagnose by transillumination

Note: take sufficient sections to rule out a malignant mesothelioma

Gross images: image1

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

Juvenile xanthogranuloma

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Rare

Macroorchidism

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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

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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)

Micro images: image1, image2

EM: bacteria within phagolysosomes of histiocytes

DD: Leydig cell tumor, granulomatous orchitis

Meconium periorchitis

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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

Micro images: image1, image2, image3

References: Hum Path 1986;17:807

Necrotizing vasculitis

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May be associated with polyarteritis nodosa or an isolated finding

Nodular and diffuse fibrous proliferation

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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

Gross/micro images: image1

Micro images: image1, image2

Positive stains: smooth muscle actin (myofibroblasts)

DD: spindle cell mesothelioma

References: Hum Path 1990;21:866

Polyorchism

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

Radiation effects

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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

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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

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Rare; also called Rosai-Dorfman disease

Spermatocele

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Small cystic accumulation of semen, often in efferent ducts

Micro images: image1, image2

Splenogonadal fusion syndrome

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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

Gross/micro images: image1, image2

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

Micro images: image1, image2

DD: sarcoma, teratoma, lymphoproliferative tumor

References: Archives 2003;127:e277

Varicocele

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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

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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

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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

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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-germ cell tumors

Germ cell tumors - general

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90%+ of all testicular tumors; 60% are mixed histologic types

Peak age 15-34 years; most common tumor in men 25-29 years

Arise from seminiferous epithelium; have totipotent properties

1-2% are bilateral; 15% are bilateral if two undescended testes

Bilateral tumors are usually classical seminoma; in elderly, usually spermatocytic seminoma or lymphoma

p53 mutations are common

In prepubertal boys, germ cells with abundant clear cytoplasm adjacent to germ cell tumors do NOT represent ITGCN (negative for PLAP and c-kit), although may be p53+, PCNA+, Hum Path 1997;28:404

Case report of ITGCN (PLAP+) in fetus with Down’s syndrome, Mod Path 1992;5:547

Prognostic factors: invasion through tunica vaginalis, Leydig cell hyperplasia, vascular invasion

Predisposing factors: cryptorchidism (10% of tumors, higher position in abdomen increases risk); genetics (Whites have 5x risk compared to Blacks; siblings of affected patients have 10x risk); testicular dysgenesis (testicular feminization > Klinefelter’s); Li-Fraumeni syndrome; prior testicular germ cell tumor; prior intratubular germ cell neoplasia

May be associated with multiple cutaneous atypical nevi

Usually presents as slowly enlarging painless testicular mass

Tumor regression may occur, identified by fibrosis, hemosiderin laden macrophages, chronic inflammatory cells and calcification

Classification: most important distinction is seminoma vs. non seminomatous germ cell tumor (NSGCT)

Treatment: initially orchiectomy with high ligation of spermatic cord

Seminoma – also radiation of retroperitoneum, chemotherapy if advanced disease

Spermatocytic seminoma – surgery adequate

Teratomas in children – surgery adequate

Non seminomatous germ cell tumors stages 1 & 2: treatment variable; some prefer lymph node dissection with further therapy dependent on presence/absence of tumor, some prefer watchful waiting unless aggressive features (vascular invasion, predominance of embryonal carcinoma)

Most patients who die of tumor die within 2 years of diagnosis

Late recurrences (after complete response for 2 years): 90% were initially stage 1, 60% had teratoma (pure or mixed) in the recurrence, 47% had yolk sac (including unusual patterns, pure or mixed), also embryonal carcinoma, nongerm cell malignant tumor; % alive with no evidence of disease after mean 5 year follow up was related to histology of recurrence: teratoma only 79% vs. 36% for pure germ cell tumor or pure nongerm cell malignant tumor vs. 17% if patient had both yolk sac and other nonteratomatous germ cell tumor vs. 0% with nonteratomatous germ cell tumor and nongerm cell malignant tumor, AJSP 2000;24:257

Positive stains: PLAP, AJSP 1987;11:21

Negative stains: RNA binding motif, Hum Path 2000;31:1116

Isochromosome 12p

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Isochromosome 12p or extra 12p seen in almost all cases; highly specific for germ cell tumors

Also seen in ovarian germ cell neoplasms; occasionally in acute leukemia, embryonal rhabdomyosarcoma, neuroepithelioma

Chromosome has identical arms, probably from misdivision of centromere

Extra copies of 12p associated with tumor progression and treatment failure, particularly in non-seminomatous germ cell tumors

Associated with increased levels of PTH related peptide, also on 12p

Intratubular germ cell neoplasia

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Aka IGCNU, ITGCN

In situ stage of germ cell neoplasia; don’t call carcinoma in situ since not an epithelial lesion

Seen in 90-100% of testes adjacent to germ cell tumor; less often in childhood yolk sac tumors and childhood teratoma

Also associated with gonadal dysgenesis, androgen insensitivity syndrome, infertility (0.4-1.0%), cryptorchidism (2-8% of patients), contralateral testis in patients with prior testicular tumor (5%)

Commonly extends to rete testis in germ cell tumors, resembling invasive seminoma, Hum Path 1994;25:235

50% progress to germ cell tumor in 5 years (all types except spermatocytic seminoma)

In prepubertal boys, germ cells with abundant clear cytoplasm adjacent to germ cell tumors do NOT represent ITGCN (are negative for PLAP and c-kit), although may be p53+, PCNA+, Hum Path 1997;28:404, AJSP 1994;18:947

Note: PLAP also positive in infantile germ cells until age one

Treatment: watchful waiting (clinical and ultrasound examination) and serum measurement of hCG, AFP, human placental lactogen (HPL); some recommend orchiectomy and biopsy of contralateral testis, others recommend radiation therapy

Classification: unclassified (at base of tubules, resembles seminoma, PLAP+, PAS+ without diastase), extratubular extension (microinvasion), intratubular seminoma (pagetoid spread, packs tubules, totally replaces normal Sertoli and germ cells), intratubular embryonal carcinoma (necrotic foci common, Archives 2002;126:487), other

Micro: pagetoid pattern of large cells (fried eggs, 3x normal) with clear cytoplasm, hyperchromatic nuclei, prominent nucleoli, frequent mitoses, resemble seminoma cells; present along thickened / hyalinized tubular basement membrane; displaces Sertoli cells toward the lumen; spermatogenesis usually absent; may have calcifications (microliths)

Micro images: image1, image2, image3, PLAP

Micro images (intratubular embryonal carcinoma): image1

Positive stains: PLAP (membrane accentuated, in 97% of cases), PAS without diastase (contains glycogen)

Negative stains: RNA binding motif, Hum Path 2000;31:1116

References: Mod Path 1988;1:475, Archives 1985;109:555, Hum Path 1990;21:941, Hum Path 1988;19:663

Post-chemotherapy resections

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Presence of tumor after chemotherapy may determine need for additional chemotherapy

Therapy related changes are foamy macrophages, fibroblastic proliferation, necrotic tumor cells

Persistent teratoma often shows therapy related atypia in tumor and stroma, but this has no prognostic significance

Seminoma

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Also called classic seminoma

30-50% of testicular germ cell tumors

Mean age 40 years vs. 25 years for nonseminomatous germ cell tumors (NSGCT); rare in infants

In ovary, called dysgerminoma

Also present in mediastinum, pineal gland, retroperitoneum

40% have increased serum PLAP (placental alkaline phosphatase)

70% of patients have stage 1 disease

May metastasize to lymph nodes or bone; late hematogenous spread may occur

Presence of elevated serum hCG does not change classification and has no clinical significance; however elevated AFP indicates a non-seminomatous germ cell component (or liver disease), even if not seen histologically

Case report with coexisting sarcoidosis, Hum Path 1984;15:394

Treatment: radiation therapy (very radiosensitive), cisplatin based chemotherapy for bulky retroperitoneal disease or supradiaphragmatic involvement

Prognosis: 95% cure rate for stages 1 or 2

Gross: bulky, homogenous gray-white with lobulated and bulging cut surface, usually well demarcated; 50% involve entire testis; invasion of tunica albuginea in <10%; usually no hemorrhage, no cystic change, no extensive necrosis

Gross images: image1, image2, image3, image4

Micro: sheets of relatively uniform tumor cells are divided into poorly demarcated lobules by delicate fibrous septa with T lymphocytes and plasma cells; cells are large, round-polyhedral with distinct cell membranes, abundant clear/watery cytoplasm (glycogen), large central nuclei, 1-2 prominent often elongated and irregular nucleoli; usually minimal mitotic figures; tubular preservation may occur at periphery of tumor; 10% have significant NSGCT component; granulomatous inflammation with Langhans type multinucleated giant cells present in 20%; infarction and edema (seen occasionally) simulates microcystic yolk sac tumor; rarely is marked fibrosis, osseous metaplasia (Archives 1993;117:321) or pagetoid spread to rete testis

"Anaplastic" terminology is outdated

Note: if tumor entirely necrotic, trichrome stain and PLAP may be helpful, Archives 2002;126:205

Micro images: image1, image2, image3, image4, image5, image6, image7, image8, image9, necrosis1, necrosis2

Positive stains: PLAP (almost all); ferritin, PAS with and without diastase, vimentin, angiotensin-1-converting enzyme (Hum Path 2000;31:1466)

Negative stains: cytokeratin (may be weak/focal; syncytiotrophoblastic giant cells are positive), AFP, hCG (syncytiotrophoblastic giant cells are positive), CD30, EMA

EM: glycogen, annulate lamellae (parallel arrays of cisternae with small annuli or circular fenestrae at regular intervals along their length), disbursed nucleolonema (network of strands)

EM images: seminoma

Variants:

Seminoma with early carcinomatous transformation: similar to embryonal carcinoma

Seminoma with trophoblastic giant cells: 10-20% of seminomas; giant cells often related to blood vessels; no cytotrophoblasts present; hCG serum level < 1000 u/L; uncertain if more aggressive behavior

DD: granulomas, pleomorphic seminoma cells

Tubular seminoma: <10 cases reported; tumor cells form tubular structures of various sizes and shapes, areas of classic seminoma present, otherwise similar to classic seminoma; may resemble yolk sac tumor, embryonal carcinoma, Sertoli cell tumor (use immunohistochemistry to differentiate), AJCP 1994;102:397

Spermatocytic seminoma

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Mean age 55; only occurs in descended testes (not in mediastinum)

1-2% of germ cell tumors

Benign (rare documented cases with metastases), but associated with sarcomas demonstrating skeletal muscle differentiation, widespread distant metastases and poor prognosis, AJCP 1990;94:89, AJSP 1988;12:75

Note: the most common testicular tumor in men age 60+ is diffuse large B cell lymphoma

Gross: pale gray, mucoid, edematous; soft, friable cut surface; 10% bilateral

Micro: nodules of cells with edema filled spaces causing pseudoalveolar appearance; three types of cells - medium cells (15-18 microns) with round nuclei, filamentous chromatin and eosinophilic cytoplasm (resemble spermatocytes but diploid); small cells (6-8 microns) with narrow rim of eosinophilic cytoplasm resembling lymphocytes; giant cells (50-100 microns) with one or more nuclei

May have numerous mitoses

Anaplastic variant described with predominantly medium cells containing prominent nucleoli

Usually no stroma, no lymphocytes, no glycogen, no granulomas

Not associated with intratubular germ cell neoplasia or NSGCT

Note: may have intratubular growth, just like classic seminoma

Resembles seminomas in old dogs

Micro images: image1

Cytology images: image1, image2

Positive stains: CAM5.2 (40%)

Negative stains: PLAP, hCG, AFP, CEA, EMA, HPL, NSE, angiotensin 1 converting enzyme (ACE), keratin (may have focal staining)

EM: cytoplasmic bridges between tumor cells resembles those between spermatocytes; thickening of plasma membrane, microtubules between cells; minimal or no glycogen

Nonseminomatous germ cell tumors (NSGCT) - general

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More aggressive than seminomas

60% present with stage 2 or 3 disease

Metastasize earlier than seminoma, using hematogenous route

Metastases may not resemble primary tumor

Radioresistant

80% have elevated AFP or hCG at diagnosis

One study claims increased metastases in Stage A patients if MIB-1 in 52%+ of cells, Mod Path 1995;8:492

Prognosis: 95% cure rate if no lymph node or metastatic involvement; 40-95% with metastases

Poor prognosis if extensive pulmonary disease

Treatment: surgery plus chemotherapy; 80-85% have complete response to chemotherapy, most are cured

Gross: variegated appearance since usually a mixture of different components

Gross images: image1, image2, image3, image4, image5

Micro images: image1, image2

Carcinoid

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Also called pure neuroendocrine carcinoma

Presumed to be a monodermal teratoma, although 20% have other teratomatous elements

Rare, mean age 46

10% have clinical carcinoid syndrome

May develop metastastic disease - associated with carcinoid syndrome, tumor size 7 cm or more

Gross: solid, yellow-tan, well circumscribed; cysts reflect other teratomatous elements

Micro: islands of cells forming small acini, cords forming rosettes or sheets; cells have granular eosinophilic cytoplasm, round nuclei with granular chromatin; usually no intratubular germ cell neoplasia, no/minimal mitotic activity, usually minimal atypia or necrosis

Micro images: image1, image2

Positive stains: chromogranin, synaptophysin, cytokeratin, serotonin

EM: neurosecretory granules

DD: metastatic carcinoid (usually bilateral, multifocal, vascular invasion, case report of metastasis to scrotum at AJCP 1991;96:664)

Reference: AJCP 2003;120:182, Archives 1981;105:515

Choriocarcinoma

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0.3% to 1% of germ cell tumors are pure choriocarcinoma, but mixed tumors are more common

May present initially with metastases (liver, lung, mediastinum, retroperitoneum) with normal testis or small tumor, but with increased serum hCG

Identical tumors arise in placenta, ovary, mediastinum or abdomen (from sequestered cell rests)

Usually fatal if pure

Hematogenous spread early to lungs, liver and brain

Case report of monophasic tumor with only rare syncytiotrophoblasts, AJSP 1997;21:282

Gross: small, may be replaced by fibrous scar with hemosiderin because it outgrows blood supply; resembles disintegrating clot

Micro: hemorrhage and necrosis common; cytotrophoblast (polygonal/round cells with distinct cell borders, clear cytoplasm and single bland nucleus) and syncytiotrophoblast (large multinuclear cell with eosinophilic and vacuolated cytoplasm) are closely intermingled in biphasic plexiform pattern as in chorionic villi; only significant if major component of tumor; no effect on prognosis if part of mixed tumor; intratubular germ cell neoplasia in adjacent testis is common

Micro images: image1, image2, image3, image4, image5, hCG

Positive stains: hCG, HPL and EMA (syncytiotrophoblast, not cytotrophoblast), cytokeratin, cytokeratin 7 (may not stain other germ cell tumors), PLAP (50%), CEA (25%, AJCP 1986;86:538)

DD: hemorrhagic testicular necrosis (trauma, torsion, clotting abnormalities), syncytiotrophoblasts present in other germ cell tumors

Diffuse embryoma

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Immature mixed germ cell tumor with diffuse, orderly arrangement of embryonal and yolk sac elements; may have scattered trophoblastic components

Case report (2 cases): 37 and 38 years old, confined to testis, no evidence of disease 11 years / 9 months after surgery, AJCP 1994;102:402

References: AJSP 1983;7:633

Embryonal carcinoma

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Usually age 20-30's

Pure tumors represent 2% of germ cell tumors, but 85% of NSGCT have embryonal carcinoma component

65% have metastases at diagnosis, often with associated symptoms (back pain, dyspnea, neurologic symptoms)

Treatment is controversial as 97% of stage I are disease free after orchiectomy; some recommend watchful waiting; others retroperitoneal lymph node dissection and chemotherapy if nodal metastases are present

For advanced disease, give cisplatin-based chemotherapy and remove residual masses

Gross: Usually doesn't replace entire testes; variegated or pale-gray, poorly demarcated with hemorrhage and necrosis; usually invades tunica albuginea

Gross images: embryonal carcinoma and teratoma

Micro: solid, pseudoglandular, alveolar, tubular or papillary patterns; primitive epithelial type cells with minimal features of differentiation; high grade features of large, epithelioid, anaplastic cells with prominent nucleoli, indistinct cell borders with nuclear overlapping, pleomorphism, frequent mitoses, also giant cells with granular, pink, amphophilic cytoplasm; often mixed with other non-seminomatous germ cell tumors; no distinct fibrous septa

Intratubular embryonal carcinoma often present adjacent to invasive lesion, often with calcifications

Stromal component suggests presence of teratoma

Vascular invasion may be artifactual (loosely cohesive cells that don’t conform to shape of vessel); true vascular invasion (groups of cells that conform to shape of vessel or are adherent by thrombus) is a poor prognostic factor and should be reported

Micro images: image1, image2, image3, image4

Positive stains: hCG or AFP in mixed tumors, cytokeratin, CD30, PLAP

Negative stains: EMA, mucin

EM: poorly differentiated adenocarcinoma with prominent Golgi complex, irregular nucleus with large complex nucleolus and cytoplasmic inclusions, long tight junctions

DD at extratesticular site: poorly differentiated carcinoma (EMA+, PLAP-, mucin+)

Mixed germ cell tumors

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60% of testicular tumors

Recommended to diagnose as “mixed germ cell tumor” and list components with percentage involvement

Don’t overlook yolk sac tumor foci

Don’t overlook non-germ cell component (case report of meningiomas in a mixed germ cell tumor, AJCP 1999;23:1131)

Placental site trophoblastic tumor

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Rare, resembles uterine tumor of same name

Case report in 16 month infant, treated with orchiectomy, well after 8 years follow up, AJSP 1997;21:282

Micro: proliferation of intermediate trophoblasts, identical to uterine tumor

Positive stains: hPL

PNET

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Primitive NEuroectodermal Tumor

Composed entirely of immature neural tissue such as neuroblastoma

Considered a monodermal teratoma

Often fatal if metastases present (extratesticular), longer survival if neuroblastoma-like metastases

May arise in germ cell tumors and be testicular, extratesticular or both, AJSP 1997;21:896

Gross: gray-white, necrotic

Micro: small cells with minimal cytoplasm in sheets, tubules, rosettes, pseudorosettes, medullary tubules and focally forming glia; overt overgrowth over immature teratoma by these cells

Positive stains: synaptophysin, NSE, chromogranin, HBA-71, GFAP

EM: neurosecretory granules

References: Archives 1983;107:643

Polyembryoma

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Immature mixed germ cell tumor with multiple embryoid bodies (central core of embryonal carcinoma cells, amnion-like cavity and yolk sac tumor component)

Resembles embryonic yolk sac

Behaves like other mixed germ cell tumors

Teratocarcinoma

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Tumors with mixture of teratoma and embryonal carcinoma

Sarcomatous elements may be present

Currently called “mixed NSGCT”

Teratoma

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5% of germ cell tumors

Tumors contain cellular components derived from 2 or 3 germ layers

Children: usually age 3 or less; second most common testicular tumor after yolk sac; not associated with intratubular germ cell neoplasia; no need for lymph node dissection after orchiectomy since almost never metastasize; usually are pure; associated with Down’s syndrome, Klinefelter’s syndrome, xeroderma pigmentosa, spina bifida, hemihypertrophy

Adults: presumption of malignant behavior regardless of differentiation of tumor; rare, 2-3% are pure; recur as teratoma (14%) or embryonal carcinoma (18%)

Gross: large (5-10 cm), multinodular, heterogenous (solid, cartilaginous, cystic)

Gross images: image1, teratoma and embryonal carcinoma

Micro:

Mature teratomas - differentiated cells or organoid structures including cartilage, nerve, various differentiated epithelium

Immature teratomas – usually in adults, have foci resembling embryonic or fetal structures, usually without cytologic atypia; includes primitive neuroectoderm, poorly formed cartilage, neuroblasts, loose mesenchyme, primitive glandular structures; some pathologists use high or low grade terminology based on cellularity and mitotic activity

Teratoma with malignant transformation – focal malignancy of somatic type, such as squamous cell carcinoma, adenocarcinoma, sarcoma (adults)

Dermoid cysts – rare, may represent direct transformation from a nonmalignant germ cell; appear to be benign even in adults; resemble ovarian dermoid cysts (cystic structure filled with keratin and hair); may resemble pilomatrixoma with “shadow” squamous epithelium, calcification and ossification; also have smooth muscle bundles, sweat glands (eccrine/apocrine), glands lined by ciliated epithelium; no atypia, no mitoses, no intratubular germ cell neoplasia, AJSP 2001;25:788

Micro images: image1, image2, image3, image4, image5, image6, immature #1, #2, #3

DD: epidermoid cysts (no adnexal structures, no intratubular germ cell neoplasia)

Yolk sac tumor

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Also called endodermal sinus tumor of Teilum (endoderm is embryonic layer closest to yolk sac)

Considered a unilaterally developed teratoma mimicking embryonal yolk sac tissue

Most common testicular tumor age 3 or less; often pure; good prognosis at this age (80%+ are stage I)

Adults: usually part of a mixed tumor, has prognosis of embryonal carcinoma

95%+ of patients with tumors containing yolk sac elements have elevated serum AFP, although some children have physiologic elevations of AFP without yolk sac tumors

Tumors usually aneuploid

After treatment, may give rise to spindle cell sarcoma with myxoid or collagenous stroma

May arise from seminoma in some cases, AJCP 1992;97:468

AFP: major serum protein of early fetus, produced by fetal gut, hepatocytes, yolk sac

Gross: nonencapsulated, homogenous, yellow-white, mucinous, soft, multicystic; adult cases often have hemorrhage and necrosis

Micro: lace like (reticular), papillary or cord-like pattern of cuboidal/elongated cells; also other patterns (see below); cells have bland nuclei; 50% of tumors have Schiller-Duval bodies (also called endodermal sinuses, with central capillary and visceral and parietal layer of cells resembling primitive glomeruli)

Tumor cells have eosinophilic hyaline globules (within and outside cytoplasm) that are positive for alpha-1-antitrypsin and PAS+ with diastase; uncommon in seminoma and embryonal carcinoma

Intratubular germ cell neoplasia not present in young patients (Archives 1988;112:641), often present after puberty

Yolk sac is the most commonly overlooked component of NSGCT

Eleven microscopic patterns:

Endodermal sinus (perivascular, festoon): predominance of Schiller-Duval bodies, plus fibrous cores of tissue draped (festooned) by tumor cells or spaces, micro: image1, image2, image3

Glandular-alveolar: primitive glands with apical brush border, resembling GI epithelium; glands may develop from cystic alveolar-like spaces; resemble teratomas but AFP+ and no circumferential smooth muscle

Hepatoid: clusters of polygonal cells with eosinophilic cytoplasm, round nuclei, prominent nucleoli, arranged in trabecular, nested or sheet-like patterns; intensely positive for AFP, micro: image1

Macrocystic: from merging of macrocysts

Myxomatous: cells in thin cords or trabeculae in mucoid stroma; occasionally form skeletal muscle and cartilage (some call yolk sac tumor with rhabdomyoblastic differentiation)

Papillary: fibrous papillary cores or papillary epithelium projecting into cystic spaces; cells have high nuclear/cytoplasmic ratios, hobnail configuration

Parietal: predominance of basement membrane between tumor cells (parietal layer of embryonic yolk sac produces a thick basement membrane); present in 90%+ yolk sac tumors; focal wispy to band like deposits of eosinophilic matrix; usually with other patterns

Polyvesicular vitelline: irregular vesicles lined by flat, cuboidal or columnar cells; vacuoles often present

Reticular: most common; microcystic or honeycomb or lace-like pattern; cells may resemble lipoblasts or signet ring cells; microcysts may merge to form macrocysts, micro: image1, image2, image3

Sarcomatoid: proliferation of spindle cells associated with myxomatous pattern; cytokeratin positive

Solid: sheet like cells that resemble seminoma but without fibrous stroma and lymphocytes; microcystic areas and other typical yolk sac patterns usually present; cytokeratin positive (seminomas are negative); may have blastema-like cells (small, primitive), micro: image1, image2

Micro images: contributed by Dr. Asmaa Gaber Abdou, Menofiya University, Egypt - metastatic to abdomen #1; #2; #3; #4

Positive stains: AFP (image1, diffuse through cytoplasm and hyaline globules, although pediatric tumors are often AFP negative), cytokeratin, variable CD30

EM: epithelial cells with tight junctional complexes, apical microvilli, extracellular deposits of basal lamina, glycogen

Note: AFP also found in embryonal carcinomas, teratocarcinomas, tumors without microscopic yolk sac elements and hepatocellular carcinoma

DD: microcystic Leydig cell tumors (AJSP 1999;23:546, no recurrence or metastasis, diffusely positive for vimentin, negative for AFP and PLAP)

References: Hum Path 1978;9:553

Sex cord stromal tumors

Sex cord stromal tumors - general

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Neoplasms containing epithelial elements of sex cord origin (Sertoli and granulosa cells) admixed with elements of mesenchymal origin (Leydig and theca-lutein cells) in varying combinations and degrees of differentiation

4% of testicular tumors; almost all are immunoreactive for alpha inhibin except fibromas, myxomas and sclerosing stromal tumors

References: Hum Path 1998;29:840

Classification:

Fibromas

Granulosa cell tumor (adult, juvenile)

Leydig (interstitial) cell tumor

Mixed or Unclassified Gonadal-Stromal Tumors

Sertoli cell tumors

Tumors of Adrenogenital Syndrome Type

Fibromas

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Rare, benign behavior

Ages 21-74 years, painless testicular masses

Two types – resembling ovarian fibroma and resembling solitary fibrous tumor of pleura

Ovarian fibroma-like: probably derived from testicular stromal cells

Solitary fibrous tumor-like: may occur in relation to tunica albuginea or paratestis, case report at Archives 1992;116:277

Case report with focal sex cord component (inhibin+, CD99+), Archives 1999;123:391, micro image

Gross: circumscribed, whorled white nodules, arise from tunica albuginea, may extend into testis or paratestis, 1-4 cm

Micro: moderately cellular, bland spindle cells without atypia, stroma is myxoid, vascular or collagenous; ovarian-type have storiform pattern and hyaline fibrous plaques; solitary fibrous type have random spindle cells

Positive stains: vimentin, CD34 in solitary fibrous-like tumors

Negative stains: S100, keratin, desmin, actin

DD: nodular and profuse fibrous proliferation (less cellular, more inflammatory cells)

References: AJSP 1997;21:296

Granulosa Cell Tumor

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Resembles analogous ovarian tumor

Anti-mullerian hormone immunostaining is specific for Sertoli and granulosa cells and gonadoblastomas (vs. Leydig cells, other tumor types), although may be positive in only a few cells, Hum Path 2000;31:1202

Adult form

Rare, age 20-53 years

Usually non functional; may be associated with gynecomastia

Usually benign; metastases in 10-20% (associated with size >7 cm, hemorrhage, necrosis, angiolymphatic invasion)

Gross: yellow, homogenous, well circumscribed

Gross/micro images: image1

Micro: microfollicular pattern with Call-Exner bodies (pseudorosettes, pseudotubules); also diffuse, trabecular, insular, macrofollicular, gyriform, solid, cystic or gyriform patterns; uniform round cells with scant cytoplasm, angular grooved nuclei; focal atypia, rare mitoses

Micro images: image1, image2, image3, image4

Positive stains: CK 8/18, vimentin, SMA (smooth muscle actin), inhibin, CD99, S100

Negative stains: CD45/LCA, EMA, keratin, mucicarmine

DD: carcinoid tumor

References: Archives 2000;124:1525, Hum Path 1993;24:1120, Mod Path 1997;10:693

Juvenile form

Most common neonatal testicular tumor; 6% of childhood testicular tumors

Average age of onset is less than 1 month; may be congenital

Associated with trisomy 12

Associated with sex chromosome mosaicism if abnormal external genitalia, AJSP 1994;18:316, AJSP 1986;10:577, AJSP 1985;9:737

No association with endocrine manifestations

No metastases, no local recurrences (after orchiectomy)

Gross: mostly cystic, partially solid

Micro: variable sized follicles and amphophilic cystic fluid; spindled smooth muscle and theca cells, polygonal granulosa cells that may appear luteinized; cells have eosinophilic cytoplasm, hyperchromatic nuclei, no grooves; tumor may infiltrate, be densely cellular, have numerous mitoses; cystic fluid is mucicarmine positive

Positive stains: vimentin, low molecular weight cytokeratin, actin, desmin, CD99

EM: granulosa cells with continuous basal lamina, cytoplasmic filaments with evenly distributed dense bodies resembling smooth muscle, AJSP 1996;20:72

References: AJSP 1985;9:87, Archives 1988;112:1129

Leydig (interstitial) cell tumors - Testis chapter

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1-3% of testicular tumors, 3% are bilateral

Any age, mostly 20-60 years old

Often secrete androgens, estrogens or corticosteroids; patients may present with gynecomastia or other feminizing symptoms (Hum Path 1977;8:621), or with precocious puberty without spermatocytic maturation

10% in adults have malignant behavior with metastases to lymph nodes, lung, liver; usually are large (> 5 cm) with necrosis, vascular invasion, nuclear atypia, numerous mitoses, atypical mitotic figures, infiltrative margins, aneuploid, higher MIB-1 activity (AJSP 1998;22:1361)

Case reports: Case of Week #122, 43 year old man with 2 primary malignant Leydig cell tumors (Hum Path 1997;28:1318), metastases to perirenal fat 17 years later (Archives 1999;123:1104)

Treatment: orchiectomy, lymph node dissection if malignant, possibly testis-sparing surgery for young men (Int J Clin Pract 2003;57:912)

Gross: solid, well circumscribed nodules 5 cm or less, distinct golden-brown homogenous cut surface; 10% have extratesticular extension

Micro: sheets, nests, ribbons or cords of large, round/polygonal cells with defined cell borders, eosinophilic cytoplasm and round central nuclei; also vacuoles, lipofuscin or Reinke crystals (35%); may have endocrine atypia; occasionally adipose differentiation, which should not be confused with extratesticular extension (AJSP 2002;26:1424); no/rare mitotic activity

Unusual features are spindle cells, pseudoglandular structures, microcystic change, small cells with scanty cytoplasm, myxoid degeneration, calcification and ossification

Leydig (interstitial) cell tumors - Testis chapter (continued)

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Micro image: various images; image #1; #2; #3; Reinke crystals #1; #2; inhibin; cytokeratin; metastases to perirenal fat - #1; #2; #3

case of week - #1; #2; #3; #4; inhibin

contributed by Dr. Mowafak Hamodat, Eastern Health of Newfoundland and Labrador, St. John’s, Canada - #1; #2; #3; pan-keratin #1; #2; calretinin #1; #2; inhibin, synaptophysin, vimentin

Cytology images: #1; #2; #3
Positive stains: steroid hormones, vimentin, inhibin, calretinin, MelanA, keratin (variable)

Negative stains: anti-mullerian hormone, S100 (usually)

EM: abundant smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae, Reinke’s crystals (long tapered crystals)

DD: nodular Leydig cell hyperplasia (associated with cryptorchidism, usually 1 cm or less, multifocal, does not destroy surrounding tubules), large cell calcifying Sertoli cell tumor (usually multifocal, bilateral, more stroma, calcifications, intratubular growth, no Reinke’s crystals, slightly different immunostaining pattern, Pathol Int 2005;55:366), testicular tumors of adrenogenital syndrome (bilateral, multifocal, clinical symptoms, laboratory findings, shrink after corticosteroid therapy)

References: AJSP 1985;9:177, Archives 2007;131:311, eMedicine

Mixed germ cell-sex cord stromal tumors

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Gonadoblastoma

Almost always associated with pure or mixed gonadal dysgenesis or male pseudohermaphroditism (intersex syndrome)

80% are phenotypic females

20% are phenotypic males, present with gynecomastia, hypospadias, cryptorchidism; usually 46 XY or 45X/46XY

1/3 bilateral

Considered by some an in situ form of malignant germ cell tumor, which may progress to seminoma or embryonal carcinoma

Treatment: bilateral gonadectomy, curative if no invasive component

Gross: tan-yellow with diffuse gritty calcifications

Micro: hyaline bodies surrounded by seminoma-like cells, sex cord cells and calcifications; 2/3 have aggregates of Leydig-like cells

Positive stains: anti-mullerian hormone

EM: some cells show Charcot-Bottcher filaments of Sertoli cells

References: Hum Path 1986;17:531

Not gonadoblastoma

Rare, adults ages 30-69 years

Not associated with gonadal dysgenesis or male pseudohermaphroditism (intersex syndrome)

No metastases

Treatment: orchiectomy

Gross: gray-white, solid/cystic

Micro: seminoma-like cells, sex-cord like cells resemble Sertoli or granulosa cells; no degenerative changes of gonadoblastoma (i.e. no calcifications)

DD: sex cord stromal tumors with entrapped germ cells (AJSP 2000;24:535, germ cells usually at periphery and in clusters, resemble spermatogonia with round nuclei, uniform dusty chromatin, indistinct nucleoli, negative stains for PLAP, inhibin, glutathione-S-transferase

Mixed or unclassified sex-cord stromal tumors

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Mixed sex cord stromal elements or undifferentiated features

15% associated with gynecomastia

50% in children

Benign behavior in children; malignant behavior in 20% of older patients

May resemble granulosa cell tumors

Poor prognostic factors: large size, invasive growth pattern, angiolymphatic invasion, nuclear atypia, mitotically active, necrosis

Micro: usually relatively short spindle cells with prominent nuclear grooves and intermixed epithelioid cells, located adjacent to rete testes; may resemble smooth muscle; reticulin surrounds aggregates of cells but not individual cells

Micro images: image1

Positive stains: S100, smooth muscle actin

EM: desmosomes, numerous thin filaments, focal dense-bodies

DD: sex cord stromal tumors with entrapped germ cells (germ cells usually at periphery and in clusters, resemble spermatogonia with round nuclei, uniform dusty chromatin, indistinct nucleoli, negative stains for PLAP, inhibin, glutathione-S-transferase)

References: AJSP 2000;24:535, Mod Path 1997;10:693

Sertoli cell tumors-general

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Sertoli cell only or mixture with granulosa cell tumors

Anti-mullerian hormone immunostaining specific for Sertoli and granulosa cells and gonadoblastomas (vs. Leydig cells, other tumor types), although may be positive in only a few cells, Hum Path 2000;31:1202

Case reports of feminizing tumors (gynecomastia, rapid growth, advanced bone age) in 2 boys with Peutz-Jeghers syndrome, AJSP 1995;19:50

Case report with extensive heterologous sarcomatous component, Archives 1998;122:907

Sertoli cell hyperplasia

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Seen in 50% with cryptorchid testes, 20% of autopsy testes

Micro: small sclerotic tubules with interstitial fibrosis; tubules with only Sertoli cells are called “Picks” adenoma, but are not neoplastic

Micro images: image1, image2

Sertoli cell proliferations of infantile testis

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Strongly associated with Peutz-Jeghers syndrome (67%), gynecomastia (80%)

Often bilateral

1 of 6 cases associated with large cell calcifying Sertoli cell tumor

May represent proliferative lesions with neoplastic potential or the intraepithelial stage of some Sertoli cell tumors, AJSP 2001;25:1237

Micro: tubules with large and proliferative Sertoli cells replacing germ cells, but limited by basement membrane; basement membranes often thickened and invaginated; no mitoses or atypia

Positive stains: inhibin

Sertoli cell adenoma

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Associated with testicular feminization/androgen insensitivity syndrome

Resembles sex cord stromal tumors with annular tubules seen in Peutz-Jeghers syndrome

Benign

Micro: elongated seminiferous tubules lined by Sertoli like cells

Sertoli cell tumor, NOS

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Also called androblastoma

1/3 present with gynecomastia without virilism (in contrast to childhood Leydig cell tumors which present with gynecomastia AND virilism)

10% malignant (to local lymph nodes); prognostic factors for malignancy include nuclear pleomorphism, large size (> 5 cm), mitoses, necrosis, nuclear atypia, angiolymphatic invasion

Treatment: orchiectomy (radiation and chemotherapy have little effect)

Gross: firm small nodules, well circumscribed, homogenous gray-white to yellow, focally cystic or hemorrhagic

Micro: trabeculae or cords resembling immature seminiferous tubules lined by Sertoli-like cells; solid pattern resembles seminoma; may have prominent lymphoid aggregates; may have acellular or vascular fibrous stroma; tumor cells with moderate pale to lightly eosinophilic cytoplasm, often large cytoplasmic vacuoles, usually minimal nuclear atypia, minimal mitotic activity

Positive stains: vimentin, cytokeratin AE1/AE3, alpha-1-antitrypsin, neuron specific enolase, inhibin (variable), EMA, S100 (weak if present)

Negative stains: PLAP

EM: cells interconnected by desmosomes; abundant smooth ER, lipid droplets, Charcot-Bottcher filaments

DD: seminoma with tubular pattern (intratubular germ cell neoplasia present, PLAP+, inhibin-, larger and more pleomorphic nuclei, more mitotic activity, AJSP 2002;26:541), spermatocytic seminoma, androgen insensitivity syndrome (hamartomatous nodules of small tubules lined by Sertoli cells, Archives 1999;123:225, micro images #1, #2, #3 (EM), #4, #5 )

References: AJSP 1998;22:709

Sclerosing Sertoli cell tumor

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Very rare, adults (mean age 30-35 years, range 18-80 years)

Painless testicular mass, no hormonal manifestations

Indolent (no metastases)

Not associated with Peutz-Jeghers syndrome

Gross: small (< 2 cm), well circumscribed, hard, yellow-white-tan

Micro: tubules, cords, nests of Sertoli like cells in hypocellular, markedly fibrous stroma; tumor cells have pale cytoplasm with occasional lipid vacuoles; may have mitoses, atypia

Positive stains: keratin, vimentin, SMA

Negative stains: PLAP

DD: adenomatoid tumor, metastatic carcinoma

Reference: AJSP 1991;15:829

Large cell calcifying Sertoli cell tumor

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Patients usually under age 20

Part of Carney syndrome with testicular Leydig cell tumors, pituitary tumors, pigmented nodular hyperplasia of adrenal cortex, myxomas of skin, soft tissue, heart and breast; spotty skin pigmentation (Peutz-Jeghers syndrome)

Gynecomastia is common clinical presentation

Usually benign

Calcification may be related to strong S100 staining (S100 binds calcium), Hum Path 2002;33:285

Features associated with malignancy: age >35, size > 4 cm, no association with a syndrome, unilateral, unifocal, extratesticular spread, 4+ mitoses/10 HPF, significant atypia, necrosis, angiolymphatic invasion (1 feature is suspicious for malignancy, 2 features suggests malignant behavior is likely)

Gross: 25% bilateral and multifocal; well circumscribed, white-tan cut surface, <2 cm

Gross images: image1, image2, image3

Micro: sheets, nests, cords and solid tubules of cells with abundant eosinophilic cytoplasm separated by fibrous tissue with marked calcification; usually marked neutrophilic infiltration

Micro images: image1, image2, image3, image4, image5, image6, S100

Positive stains: S100 (strong and diffuse), vimentin

Negative stains: keratin (usually), EMA, AFP, hCG, SMA

EM: Charcot-Bottcher crystals

References: AJCP 1991;96:717, AJSP 1997;21:1271

Sertoli-Leydig cell tumor

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Rare, 6 cases identified

2 of 6 had gynecomastia, one clinically malignant

Gross: yellow, solid, lobulated

Micro: definite Sertoli cell pattern, neoplastic Leydig cells, sex cord patterns of ovarian Sertoli-Leydig cell tumor

Positive stains: CD99 (Mod Path 1998;11:769)

Tumors of adrenogenital syndrome type

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May be hyperplasia of ectopic adrenal cells, not a neoplasm

Palpable bilateral masses in testes of young adults

2/3 have salt-wasting adrenogenital syndrome

Gross: hilar, bilateral, well circumscribed brown-green masses, separated into lobules by dense fibrous bands

Gross/micro images: image1

Micro: sheets, nests and cords of cells with abundant eosinophilic cytoplasm, often with lipochrome pigment; no Reinke’s crystals

Case report: similar tumors in 36 year old woman with congenital adrenal hyperplasia due to 21-OHase deficiency, who received corticosteroids since birth, developed virilizing symptoms and had bilateral ovarian tumors, AJSP 2001;25:1443

References: Archives 2000;124:785

Other tumors not specific to testis

Adenoid cystic carcinoma

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Radiosensitive

Perineural invasion common

Anaplastic large cell lymphoma

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Case report in 56 year old Saudi, Mod Path 1996;9:812

Micro: anaplastic large cells resembling Reed-Sternberg cells with horseshoe, wreath-like or multiple nuclei, multiple nucleoli; may have diffuse neutrophilic infiltration

Positive stains: CD30/Ki-1, UCHL-1

Angiosarcoma

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Case report of 23 year old man with mature teratoma and retroperitoneal metastasis with mature teratoma and angiosarcoma, Archives 2003;127:360

Micro images: image1

Brenner tumor

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Case report of malignant Brenner tumor of testis and epididymis in 62 year old man, Archives 1991;115:524

Micro: nests of transitional epithelium with focal mucinous differentiation, surrounded by dense fibrous tissue

Chondrosarcoma

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Case report of 2.5 cm testicular tumor in 24 year old man with metastases to retroperitoneal lymph nodes and i(12p), AJSP 1993;17:738

Granulocytic sarcoma

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Tumorous masses of myeloid leukemic infiltrates

Rare; case reports of men ages 48 and 71 years, Mod Path 1997;10:320

Gross: cream-colored to yellow-tan, rubbery-to-firm testicular tumors with extensive paratesticular spread

Micro: primitive cells with scant cytoplasm; or cells with eosinophilic, occasionally granular cytoplasm; prominent myelocytes with round, eccentric nuclei and moderately abundant cytoplasm resembling plasma cells

Positive stains: chloroacetate esterase, myeloperoxidase, lysozyme,CD45/LCA, CD43

Negative stains: CD20, CD3

DD: lymphoma, plasmacytoma

Hemangioma

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Case report of epithelioid (histiocytic) hemangioma in 29 year old man, AJSP 1990;14:584

Micro: small tubules, some with red blood cells, lined by mesothelial-like cells with uniform, vesicular nuclei

Positive stains: vimentin, factor 8

Negative stains: cytokeratin, EMA

DD: adenomatoid tumor

Interdigitating dendritic cell tumor

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Extremely rare tumor that usually arises in lymph nodes, AJSP 1999;23:1141

Gross: light tan, solid, may replace entire testis

Micro: whorls and fascicles of spindle cells mixed with small lymphocytes

Positive stains: S100 (strong), vimentin (strong), CD68 (focal), CD4 (focal)

Negative stains: CD1a, CD3, CD20, CD21, CD23, CD34, CD35, CD45, actin, desmin, HMB45, cytokeratin, PLAP

EM: complex interdigitating cytoplasmic dendritic processes, abundant rough endoplasmic reticulum, abundant mitochondria

DD: mesenchymal sarcoma, spindle cell carcinoma, follicular dendritic cell tumor, nodular and diffuse fibrous proliferation

Leukemia

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Leukemic involvement of testis common with ALL (8% clinically, 20% microscopically), also AML

Bilateral involvement common

Testis may be first site of relapse

Treatment: radiation therapy, although bone marrow relapse is common

Micro: monomorphic interstitial infiltrate

DD: large cell lymphoma (need clinical history), orchitis (heterogeneous cell population), seminoma (has intratubular germ cell neoplasia, PLAP+)

Lymphoma

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5% of testicular malignancies

50% of testicular neoplasms in men age 60+, 20% are bilateral (may still be clonal)

Occur at any age (range 16 to 91 years, mean 56 years), 50% with bilateral tumors have lymphoma

Usually disseminated at presentation

Almost always diffuse large B cell subtype, rarely anaplastic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma

Better prognosis if tumor is a primary (5 year survival 60% vs. 17% for disseminated disease/other stages) and unilateral

May progress in Waldeyer’s ring

Case report: follicular lymphoma, large cell type in 6 year old boy, but tumor negative for bcl-2 and t(14;18), Archives 2001;125:551

Treatment: orchiectomy and radiation

Gross: white-tan-pink, fleshy, resembles seminoma, often extratesticular involvement

Micro: splaying apart but relative sparing of tubules by lymphoma cells; vascular invasion in 60%, significant sclerosis in 30%; noncohesive cells with large irregular nuclei, prominent nucleoli, pleomorphism; no intratubular germ cell neoplasia

Micro images: follicular lymphoma

Positive stains: CD20, LCA/CD45

Negative stains: PLAP

DD: spermatocytic seminoma, classic seminoma, chronic orchitis (patchy heterogenous infiltrate)

References: AJSP 1994;18:376, Hum Path 1993;24:675

Mesothelioma

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Benign or malignant

Benign papillary mesothelioma

Case Report: 69 year old man with scrotal swelling, Archives 2000;124:143

Gross: 1.5 cm polypoid pedunculated nodule near head of epididymis

Micro: papillae lined by cuboidal cells with complex branching pattern but no atypia; lymphoplasmacytic infiltrate in stroma

Micro images: image1, image2, image3, image4, image5

Positive stains: vimentin, CAM 5.2, p53 (although benign)

Malignant mesothelioma of testis

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Originates from tunica vaginalis (image), which derives from evagination of peritoneum into scrotum

Epidemiology: rare, mean age 55 years, but varies from children to elderly (AJSP 1995;19:815)

Clinical: usually associated with asbestos exposure (Orphanet J Rare Dis 2008 Dec 19;3:34)

Initial symptom often a hydrocele

Often fatal, even in patients with negative resection margins; mean disease specific survival of 29 months (Urology 2005;66:397)

Case reports: 59 year old man (Case of Week #148), no history of asbestos exposure (Cases J 2008 Nov 14;1:310)

Treatment: radial orchiectomy, some recommend retroperitoneal lymph node dissection

Gross: multifocal, friable, papillary tumor within hydrocele sac, often extends into adjacent structures

Gross images: Case of Week - #1; #2

Micro: usually purely epithelioid (not spindled), papillary or tubulopapillary pattern with single layer of atypical mesothelium overlying fibrovascular core; stromal invasion present; variable psammoma bodies

Micro images: Case of Week - low power; high power; calretinin #1; #2; WT1

Positive stains: calretinin, EMA, thrombomodulin, CK7, CK5/6 (variable) (Am J Surg Pathol 2006;30:1)

Negative stains: CK20, CEA

Differential diagnosis:

• adenocarcinoma - more common in the epididymis than in tunica vaginalis, back to back glands or a poorly differentiated pattern, often necrosis and mitotic figures, CK20+, BerEp4+, CEA+, calretinin-, thrombomodulin-, no long thin microvilli on EM

• well differentiated papillary mesothelioma - very rare, papillary but not tubular, papillae are lined by cuboidal cells with a complex branching pattern but no atypia and no invasion; stroma has lymphoplasmacytic infiltrate

• mesothelial hyperplasia - no mass, no complex arborizing papillae, not invasive

Metastases to testes

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Rarely is the first clinical sign of disease

Mean age 57 years, older than germ cell tumors

Lung, prostate, skin (Merkel cell tumors, AJCP 1990;94:384, melanoma) are usual primary sites

Metastases from prostate are usually incidental

20% are bilateral

Gross: multinodular involvement

Gross images: prostate #1, #2

Micro: interstitial pattern, often angiolymphatic invasion, no intratubular germ cell neoplasia

Micro images: prostate #1, #2, #3, prostate (PSA)

Positive stains: mucin (teratomatous elements and yolk sac tumors may also be positive), EMA

Negative stains: PLAP (usually)

DD: Leydig or other sex cord stromal tumor, embryonal carcinoma (particularly if testis is first clinical site of disease)

Mucinous cystadenocarcinoma

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Case report of 59 year old man with bilateral tumor, Archives 1992;116:1360

Gross: well demarcated, multiple cavities, may involve epididymis

Micro: mucus cells and epithelial cells with basal hyperchromatic nuclei

Myeloid tumor

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Case report of extramedullary myeloid tumor (CMML) in 66 year old man with myelodysplasia, Archives 1996;120:389

Micro: large, polygonal cells with pale blue-pink cytoplasm

Positive stains: CD45, CD43, myeloperoxidase, lysozyme, chloroacetate esterase

Ossified intratesticular mucinous tumor

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Case report, Archives 1999;123:244

69 year old man with incidental 7.5 cm solid/cystic tumor completely replacing testis, no extension to tunica albuginea or epididymis; no evidence of disease 3 years after orchiectomy

Micro: bland mucinous epithelium, rare atypia; also mature bone, fibrous stroma with cholesterol clefts, multinucleated giant cells, lymphocytes, foamy macrophages

Osteosarcoma

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Case reports, Archives 1981;105:38, Hum Path 1990;21:932

Pilomatricoma

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Resembles skin lesions of same name

Case report, Archives 1995;119:96

Considered a monodermal teratomatous tumor of follicular differentiation

Plasmacytoma

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Myeloma present in almost all cases either before or after the testicular plasmacytoma

Often men age 40+

Gross: soft, fleshy, tan-gray-white, focally hemorrhagic

Micro: central effacement of tubules by atypical plasma cells (bi- or multinucleated); anaplastic cells may obliterate parenchyma or invade between seminiferous or epididymal tubules; tubules often spared at periphery; no globular differentiation

Micro images: image1, image2, image3, image4

Positive stains: light chain restriction (i.e. staining by kappa OR lambda but not both), CD45 (LCA)

Negative stains: CD3, CD20, CD30, PLAP

References: AJSP 1997;21:590

Miscellaneous

Staging

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Pathologic staging (pT), requires histologic examination

Primary tumor (T)

pTX: primary tumor cannot be assessed

pT0: no evidence of primary tumor (i.e. scar but no tumor in testis)

pTis: intratubular germ cell neoplasia (“carcinoma in situ”, although not an epithelial lesion)

pT1: tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

pT2: tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

pT3: tumor invades the spermatic cord with or without vascular/lymphatic invasion

pT4: tumor invades the scrotum with or without vascular/lymphatic invasion

Regional lymph nodes (N)

pNX: regional lymph nodes cannot be assessed

pN0: no regional lymph node metastasis

pN1: metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive lymph nodes, none more than 2 cm in greatest dimension

pN2: metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or 6 or more lymph nodes positive, none more than 5 cm in greatest dimension; or evidence of extranodal extension of tumor

pN3: metastasis with a lymph node mass more than 5 cm in greatest dimension

Distant metastasis (M)

MX: distant metastasis cannot be assessed

M0: no distant metastasis

M1: distant metastasis

M1a: nonregional nodal or pulmonary metastasis

M1b: distant metastasis other than nonregional lymph nodes and lungs

S classification (serum tumor markers)

SX: marker studies not available or not performed

S0: marker studies within normal limits

S1: LDH < 1.5 x normal AND hCG < 5000 mIu/ml AND AFP < 1000 ng/ml

S2: LDH 1.5-10 x normal OR hCG 5,000-50,000 mIu/ml OR AFP 1000-10,000 ng/ml

S3: LDH > 10 x normal OR hCG > 50,000 mIu/ml OR AFP >10,000 ng/ml

Reference for LDH: AJCP 1982;78:178

Stage

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0: pTis N0 M0 S0

I: pT1-T4 N0 M0 SX

IA: pT1 N0 M0 S0

IB: pT2-pT4 N0 M0 S0

IS: any pT N0 M0 S1-S3

II: any pT N1-N3 M0 SX

IIA: any pT N1 M0 S0-S1

IIB: any pT N2 M0 S0-S1

IIC: any pT N3 M0 S0-S1

III: any pT any N, M1, SX

IIIA: any T any N M1a, S0-S1

IIIB: any T N1-N3 M0 S2 OR any T any N M1a S2

IIIC: any T N1-N3 M0 S3 OR any T any N M1a S3 OR any T any N M1b any S

Features to report

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Tumor size

Histological subtypes present

% of various types (should state if embryonal component > 50%)

Penetration of tunica albuginea, other structures

Involvement of spermatic cord

Angiolymphatic invasion

Intratubular germ cell neoplasia

Margin of spermatic cord

Mitotic figures

Necrosis

Presence of Leydig cell hyperplasia, hemosiderin-laden macrophages, intratubular calcification, testicular atrophy, testicular development abnormalities

For lymph nodes, diameter of largest node, presence of extranodal extension, number of involved nodes

Grossing orchiectomy specimens

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Spermatic cord margin (sample before cut into tumor since contamination is a common problem, Mod Path 1996;9:762)

Tumor (1 section per cm, representing all grossly different features)

Tumor and tunica

Tumor and hilum (site of extratesticular extension in >90% , AJCP 1999;111:534)

Tumor and normal testis

Normal testis

Epididymis

Paratesticular tumors

Desmoplastic small round cell tumor

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Occur in young men (mean 28 years, range 17-37 years)

Present with scrotal mass

Aggressive, with nodal and pulmonary metastases, AJSP 1997;21:219

Gross: 3-4 cm gray-white firm mass, often near epididymis

Micro: nests and cords of small blue cells with scanty cytoplasm in desmoplastic stroma, sometimes with tubules and pseudorosettes; mitotically active; similar to abdominal tumor of same name

Positive stains: keratin, vimentin, desmin, NSE

Negative stains: S100

Leiomyosarcoma

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Mean age 62 (range 34-86 years)

After 4 year follow up, 30% recurred, 30% had metastases (lymph nodes, lungs, liver), 30% died (all grade 3 tumor patients, AJSP 2001;25:1143)

Rare myxoid variant, AJSP 2000;24:927

Gross: usually involves tunica, spermatic cord; rarely scrotal dartos muscle or subcutaneous tissue; mean 5 cm

Gross images: image1

Micro: intersecting bundles of smooth muscle cells with atypia and mitotic figures; may have focal cytoplasmic vacuoles indenting blunt-ended nuclei; may have epithelioid, inflammatory areas

Micro images: image1, image2

Positive stains: muscle specific actin, smooth muscle actin, desmin; CD34 (33%); occasionally focal cytokeratin and S100

Liposarcoma

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Rare; mean 63 years, range 41 to 87 years

Usually involves spermatic cord; also testicular tunica; rarely epididymis

Usually well differentiated or dedifferentiated liposarcomas

Well differentiated tend to recur, often late; dedifferentiated usually don’t recur; metastases are uncommon

May have areas of low grade leiomyosarcomatous differentiation, which doesn’t affect prognosis, AJSP 2002;26:742

Report of well differentiated inflammatory liposarcoma at many sites including paratesticular, AJSP 1997;21:518

Report of dedifferentiated liposarcomas, AJSP 1994;18:1213

Treatment: radical orchiectomy

Gross: mean 12 cm (range 3 to 30 cm)

Micro: atypical cells with large, hyperchromatic nuclei, within fibrous septa or fat; marked variation in adipocytes size; usually lipoblasts

Micro images: image1, image2, image3

DD: extension from primary retroperitoneal sarcoma, well differentiated resemble benign fatty tumors (no atypical cells), inflammatory liposarcoma resembles lymphoma (monoclonal, usually B not T cell) and inflammatory fibrous pseudotumor (spindle cells usually bland), sclerosing liposarcomas resemble fibromatosis (more cellular, no atypia, denser collagen, CD34 negative)

References: AJSP 2003;27:40

Lymphoma

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Rare to involve paratesticular regions without testicular involvement

Case report (2 cases) of 35 and 61 year old men with diffuse large cell lymphoma, Archives 2001;125:428

Micro images: image1

Ovarian surface epithelial-like tumors

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Ages 11-68 (mean 47)

Due to mullerian metaplasia of mesothelium or embryonic mesothelial inclusions

Often serous borderline tumors (see below), Brenner tumor; other types also

Treatment: radical orchiectomy

Gross: exophytic papillary lesions involving testicular parenchyma, tunica vaginalis, paratesticular tissue

Micro: serous borderline tumors have arborizing pattern of epithelium overlying fibrovascular cores with detached epithelial fragments; invasive tumors have destructive stromal invasion

Positive stains (papillary serous tumors): B72.3, PLAP, Leu-M1 (CD15), CA125, variable CEA

DD: mesothelioma (narrower papillae, less budding, less stratification, less psammoma bodies)

Reference: AJCP 1986;86:146

Paratesticular multicystic mass of Wolffian origin

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Case report of unilateral multicystic mass in connective tissue adjacent to the vas deferens in 46-year-old man., AJCP 1994;101:543

May represent cystic hyperplasia of vestigial Wolffian duct remnants

Gross: distinct from epididymis and vas deferens; multicystic

Micro: simple, ciliated, and cuboidal to columnar epithelium; no sperm present; cysts surrounded by smooth muscle connective tissue collars

Rhabdomyoma

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Case report in tunica vaginalis of 19 year old, Mod Path 1997;10:608

Micro: proliferation of elongated or round cells with distinct cross striations surrounded by connective tissue

Rhabdomyosarcoma

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Common non-germ cell tumor of scrotal contents in children/teens

Classified into embryonal, alveolar and pleomorphic types; embryonal classified as spindle cell (see below) or botryoid

Usually invades testis at presentation

Often (40%) metastases to retroperitoneal lymph nodes

May represent overgrowth of sarcomatous component of a teratoma, particularly in young patients

Pleomorphic variant is aggressive, Mod Path 2001;14:595

Treatment: surgery, chemotherapy, radiation therapy may cure many patients

Micro: usually embryonal subtype (small blue cells with myxoid stroma); spindle cell subtype has fasciculated or storiform growth pattern of elongated spindle cells with collagen between tumor cells

Micro images: image1, image2, image3, image4, image5

Spindle cell variant of embryonal rhabdomyosarcoma - Testis chapter

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First described in 1992 (AJSP 1992;16:229)

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Differential diagnosis:

● fibrosarcoma - herringbone pattern, may have similar morphology but no rhabdomyoblasts, negative for skeletal muscle markers

● infantile fibromatosis - deep location, fascicles of spindle cells, no cross striations, no undifferentiated cells

● leiomyosarcoma - usually high grade, cigar shaped nuclei, no rhabdomyoblasts, often positive for caldesmon, negative for myoglobin

● neuromuscular hamartoma of soft tissue - usually age < 2 years, affects brachial plexus or sciatic nerve, multinodular growth with connective tissue separating nodules, no rhabdomyoblasts, muscular component is positive for desmin and muscle specific actin, neural component is positive for S100

● rhabdomyoma - benign tumor of skeletal muscle differentiation, no rhabdomyoblasts, no pleomorphism, no necrosis

Serous borderline paratesticular tumor

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Borderline tumors also called low malignant potential

Rare; presents as testicular mass, mean age 56 years (range 14-77 years)

Arises from tunica albuginea or intratesticular

Treatment: orchiectomy

Gross: 1-6 cm, cystic

Micro: resembles ovarian counterpart, broad intracystic papillae lined by stratified epithelial cells with mild atypia; may have psammoma bodies

Micro images: image1, image2, image3, image4

Note: paratesticular serous carcinomas can have a borderline component

Positive stains: CK 7, estrogen receptor, progesterone receptor, CD15, MOC-31

Negative stains: CK20, CEA, HER2, calretinin

DD: well differentiated mesothelioma (papillae lined by cuboidal mesothelial cells without stratification, calretinin positive, negative for ER, PgR, CD15, MOC-31)

Reference: AJSP 2001;25:373

Serous papillary carcinoma

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Mean age 31 years, range 16 to 42 years

Gross: solid, white-tan, poorly circumscribed, often gritty masses involving soft tissue between testis and epididymis, paratesticular soft tissue or visceral tunica vaginalis

Micro: invasive, well-formed papillae lined by serous cuboidal or columnar cells with eosinophilic cytoplasm and marked atypia, abundant psammoma bodies; areas of borderline serous tumor often present

Positive stains: AE1/AE3, S100, EMA, Ber-EP4, LeuM1 (CD15), B72.3, variable CEA, PLAP

EM: gland formation with delicate luminal microvilli and cilia

References: AJSP 1995;19:1359, Hum Path 1992;23:75

Smooth muscle hyperplasia of testicular adnexa

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Benign cause of intrascrotal mass

Due to nonneoplastic excess of native smooth muscle in paratestis or spermatic cord between or around vessels or efferent ducts

Mean age 63 years (range 46 to 81 years)

Gross: mean 2.5 cm, range 6 mm to 7 cm

Micro: fascicles of smooth muscle in periductal, perivascular, interstitial, or mixed pattern; no cohesive, interlacing growth pattern of leiomyoma

Gross/micro images: image1

References: AJSP 1999;23:903, Archives 2003;127:E111

Epididymis

Normal

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Connects efferent ductules to vas deferens

Has head, body and tail

Composed of columnar cells (tall, ciliated with PAS+ nuclear inclusions), clear cells, basal contractile cells (actin positive)

May have “monster” cells similar to seminal vesicle (no significance), AJSP 1981;5:483

Tubules have thick muscular coat

Drawings: image1, image2

Micro images: image1, image2, image3, image4, image5, image6, image7

Positive stains: CD10

References: AJSP 2003;27:469

Nonpathologic morphologic variations:

Intranuclear eosinophilic inclusions: 72%, usually older patients

Lipofuscin pigment: 33%, usually in efferent ducts and associated with obstructive changes

Cribriform hyperplasia: 42%, usually NOT in normal testis

Paneth cell-like metaplasia: 8%, with hyalin-like globules that are positive for PAS with and without diastase digestion, associated with obstructive changes

Nuclear atypia: 14%, similar to that in seminal vesicles, associated with older age

Note: rarely present within hernia sacs, AJSP 1999;23:880

References: AJSP 1998;22:990

Epididymitis

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Primary cause of epididymal obstruction

Usually related to cystitis, prostatitis, urethritis that spreads through vas deferens or lymphatics

May cause testicular ischemia and necrosis, later scarring and infertility with preservation of Leydig cells and preserved sexual activity

Acute disease: epididymis enlarged, covered with fibrin, may contain pus and rupture

Brucellosis: affects testis and epididymis in 20% of cases; has granulomatous appearance

Gonorrhea: affects epididymis before testis

Tuberculosis: may cause confluent caseation that spreads into testis and simulates malignancy; may cause scrotal fistula; should culture to rule out M. kansasii and M. avium-intracellulare