Pediatric Testicular Tumors

Mark A. Williams, MD

Joe Welser, MD

February 12, 2014

Testicular Tumors

• 1% to 2% of all Pediatric Solid Tumors

• Annual Incidence of 1 in 100,000

• Majority occur in children < 2 years of age

• Teratoma now thought to be most common type

• Benign Tumors Account for 38% of cases

• Metastasis (Occurs in < 15% of tumors) – 28% to Lymph Nodes

– 40% Hematogenous

– 20% Both

Classification

Benign Malignant

Germ Cell Teratoma Epidermoid Cyst

Yolk Sac

Gonadal Stromal Leydig Cell Juvenile Granulosa Cell

Sertoli Cell

Para-Testicular Lipoma Leiomyoma

Rhabdomyosarcoma

Tumor Proportion By Type

Yolk Sac Teratoma

Epidermoid Cyst Leydig Cell

Sertoli Cell Granulosa Cell

Gonadoblastoma Other

Tumor Proportion By Age

Link to Cryptorchidism

• Incidence of testicular cancer in general population is approximately 5.4 per 100,000

• Wood and Elder (2009): Relative Risk of Malignant Transformation – 2.75 to 8 overall (< 0.5%) – 2 to 3 in boys undergoing prepubertal orchiopexy – Boys undergoing postpubertal orchiopexy are 2 to 6 times more

likely to develop testicular cancer – 74% of malignancies in persistent cryptorchid testes, are

seminoma – 63% of malignancies in post-orchiopexy patients, are non-

seminoma – No increased risk for tumors in the contralateral normally

descended testis

Link to Cryptorchidism (ctd)

• Cortes, et al (2004): Incidence of Pediatric Testicular Tumors in Patients with Cryptorchidism – 3.8% of children with abdominal undescended testes, abnormal

external genitalia, or abnormal karyotype – In patients without these characteristics, no cases of testicular

neoplasia – Found most often in bilateral cryptorchidism

• Petterson, et al (2007): Relative risk increases with age at orchiopexy

• Relative risk increases the more cephalad the undescended testis

• Other studies show presence of cancer in contralateral testis in 20% of cases

Chromosomal Abnormalities

• Benign Teratoma: No abnormality • Yolk-Sac Tumors: del(1p36) in 80% - 100% of cases • Intratubular Germ Cell Neoplasia: i(12p) • Post-Pubertal Germ-Cell Tumors

– Loss of chromosomes 11, 13, or 18 – Gain of chromosomes 7, 8, or X

• Patients with Disorders of Sex Development (DSD) have increased incidence – Hypovirilization and gonadal dysgenesis are at higher risk – Presence of Y chromosome in gonadal dysgenesis increases risk

to 10% by age of 20 – Intratubular germ cell neoplasia has been noted in 6% of

children with DSD

Diagnosis

• Most common Presentation: Painless testicular mass – 10% with history of hernia or hydrocele – 15% - 50% have hydrocele on physical exam

• May also present with acute abdominal pain • Must rule out epididymitis, hydrocele, hernia, and

torsion (neonate) • Testicular Ultrasound (with doppler): Cannot reliably

distinguish benign and malignant tumors – Anechoic cystic lesions suggest benign lesion – Sharp borders and low flow suggest benign – Useful to evaluate whether there is enough useful testicle

to salvage

Tumor Markers

• a-fetoprotein elevated in > 90% of yolk-sac tumors – All a-fetoprotein producing tumors have yolk-sac

elements

– T1/2 of 5 days

– Elevated for 6-9 months postpartum

– Also elevated in hepatoblastoma

• b-hCG not useful in prepubertal patients – Embryonal carcinoma and choriocarcinoma are rare

– Produced by some mixed teratomas

Yolk Sac Tumor

• AKA endodermal sinus tumor, embryonal adenocarcinoma, infantile adenocarcinoma of the testis, orchidoblastoma, or Telium tumor

• Most common malignant tumor in infants and young boys

• 3% of cases have a positive history of trauma

• Staging – a-fetoprotein

– CT of chest and abdomen

Yolk Sac Tumor - Pathology

Gross Pathology Microscopic Appearance

Yolk Sac Tumor – Pathology (ctd)

Schiller-Duvall Bodies Hyaline-like Globules

Children’s Oncology Group Staging System for Yolk Sac Tumors

I Limited to testis Completely resected by high inguinal orchiectomy Tumor markers negative Unknown tumor markers at diagnosis -> Need negative ipsilateral retroperitoneal lymph node biopsy if > 2cm on CT

II Microscopic residual disease Tumor markers remain elevated Tumor rupture or scrotal biopsy prior to complete orchiectomy

III Retroperitoneal lymph node involvement (> 4 cm on CT) RPLN < 4 cm, but > 2 cm need biopsy

IV Distant Metastasis

Yolk Sac Tumor - Treatment

• More than 90% present with Stage I disease

• Initial treatment: Radical inguinal orchiectomy (curative in most patients)

• Confirmed Stage I: Surveillance (36 months) – Physical Exam + AFP

– CXR + CT/MRI of retroperitoneum • Q1Month x 3, Q3Month x 1, Q6Month x 5

• Stage II and Above: Platinum-Based Chemotherapy (BEP) – Side effects: Ototoxicity, Nephrotoxicity

Yolk Sac Tumor – Treatment (ctd)

• Routine RPLND not indicated – Evidence of Residual or Recurrent disease – Normal or unknown AFP at diagnosis – Persistent retroperitoneal mass after chemotherapy – Persistent elevation of AFP with negative imaging after

chemotherapy

• Survival (6-year EFS) – Stage II: ~100% – Stage III: ~100% for age < 15 vs 83.3% – Stage IV: 94.4% for age < 15 vs 84% – Histology in patients < 15 was pure yolk-sac tumor (83%)

vs mixed germ-cell tumor in patients > 15

Teratoma

• Most common pediatric testis tumor

• Comprised of elements of more than one germ cell layer: endoderm, ectoderm, mesoderm

• Two types, both almost always benign

– Mature Teratoma

– Immature Teratoma: Immature tissue usually neuroepithelium

• Occasionally malignant

– Usually has yolk-sac tumor component

Teratoma – Gross Pathology

Mature Teratoma Immature Teratoma

Teratoma – Microscopic Appearance

Mature Teratoma Immature Teratoma

Teratoma (ctd)

• Diagnosis – Ultrasound of testis reveals a heterogeneous

lesion with internal echoes (calcification)

– AFP not elevated for the patient’s age

• Treatment – Testis-sparing procedures (enucleation)

– Should be done through inguinal incision

– Teratomas generally “shell out” easily due to pseudocapsule around the lesion

Epidermoid Cyst

• Monodermal Teratoma – Differentiated squamous-lined cysts

– Filled with keratinous debris

• AFP levels normal

• Suggested by characteristic appearance on ultrasound: Concentric rings of alternating hypo and hyperechoic layers (“onion-skin” appearance)

• Benign: May be managed by eneucleation

Epidermoid Cyst - Pathology

Gross Pathology Microscopic Appearance

Leydig Cell Tumor

• Most common stromal tumors of testis in children • Peak incidence at 4 to 5 years old • Arise from a common mesenchymal stem cell that can

differentiate into Leydig cells, Sertoli Cells, or granulosa cells

• Secrete testosterone: Cause 10% of precocious puberty in boys < 9 years old

• Classic triad – Testis mass – Precocious puberty – Elevated serum testosterone and urinary 17-ketosteroids

Leydig Cell Tumor (ctd)

• Differential Diagnosis

– Pituitary Lesions

– Leydig Cell Hyperplasia

– Large Cell Sertoli Cell Tumors

– Hyperplastic Testicular Nodules in Boys with CAH

• Treatment

– Resection (testis-sparing) is curative

– Hormonal effects not reversible

Leydig Cell Tumor - Pathology

Gross Pathology Microscopic Appearance

Leydig Cell Tumor – Pathology (ctd)

Reinke’s Crystals Germinal Epithelium Stimulated in Prepubertal Boy

Sertoli Cell Tumors

• Presents at earlier age than Leydig Cell Tumors • 10% Hormonally Active: Gynecomastia most

common effect • 1/3 Associated with Genetic Syndromes

– Peutz-Jehgers syndrome – Carney Complex

• Treatment – Observation in Infants (Metastasis Rare) – Metastasis Can Occur in Older Boys (10% overall rate)

• Orchiectomy (Eneucleation in pre-pubertal boys) • Must Exclude Retroperitoneal Spread

Sertoli Cell Tumor - Pathology

Gross Pathology Microscopic Appearance

Juvenile Granulosa Cell Tumor

• Most common testicular tumor of neonates

• Presents most often in the first 6 months of life (often detected at birth)

• May occur in children with ambiguous genitalia, intersex disorders, and sex-chromosome mosaicism

• Not associated with precocity

• Benign without recurrence

• Eneucleation (testis-sparing) is curative

Juvenile Granulosa Cell Tumor

Gross Pathology Microscopic Appearance

Gonadoblastoma

• Found in association with disorders of sex differentiation – Occur in abnormal gonads

• 22% streak, 18% dysgenetic, 60% indeterminate

• Originate in Surviving OCT-3/4 Positive Germ Cells in Areas of Undifferentiated Gonadal Tissue

• Combination of Germ-Cell Tumor and Gonadal Stromal Tumor

– Associated with the presence of Y chromosome • 80% occur in phenotypic females with 46 XY

– Mixed gonadal dysgenesis • 25% risk of tumor formation

• Incidence increases with age

Gonadoblastoma (ctd)

• Occur bilaterally in 10% – 33% of cases

• Benign in childhood

• As germ-cell elements outgrow stroma 10% - 60% will progress to dysgerminoma (seminoma) after puberty

• Treatment: Prepubertal gonadectomies in at-risk patients – All streak gonads should be removed

– All undescended testes should be removed

Gonadoblastoma - Pathology

Gross Pathology Microscopic Appearance

Intratubular Germ Cell Neoplasia

• Carcinoma In Situ

• Found in 80% of testes with malignant germ-cell tumors (8% contralateral) – Rarely in prepubertal germ-cell tumors

• Found in 2% - 8% of testes with cryptorchidism

• 90% of adults will develop a clinical germ-cell tumor within 7 years

• Treatment: Orchiectomy or Radiation

Testicular Microlithiasis

• Calcium testicular stones

• Found (usually incidentally) in 0.5% - 1% of all men, being discovered more frequently in children

• 80% Bilateral

• No confirmed relationship with testicular cancer – But, found in 50% of testes removed for tumors

• Treatment: Testicular Self-Examinations

Testicular Microlithiasis (ctd)

Appearance on Ultrasound ITGCN and Microlithiasis

Paratesticular Rhabdomyosarcoma

• 5% of “testicular” tumors • Most often arises in distal portion of spermatic cord

and may invade testis of surrounding tissues • 60% occur in the first 2 decades of life • Bimodal age distribution

– 3-4 months – 16 years

• Arises from mesenchymal tissue – 90% embryonal variant (better prognosis) – 30% - 50% have metastasis (usually lymph node) at

diagnosis

Paratesticular Rhabdomyosarcoma

Paratesticular Rhabdomyosarcoma - Pathology

Gross Pathology Microscopic Appearance

Paratesticular Rhabdomyosarcoma – Pathology (ctd)

Rhabdomyoblasts More Rhabdomyoblasts

Paratesticular Rhabdomyosarcoma – Grouping and Staging

Paratesticular Rhabdomyosarcoma - Prognosis

Paratesticular Rhabdomyosarcoma – Diagnosis and Management

• Usually presents as unilateral painless scrotal swelling or mass that is distinct from testis

• Ultrasound can be used to confirm solid nature of lesion • 60% to 80% are stage 1 at presentation • Initial Treatment: Radical Inguinal Orchiectomy • CT scan for staging

– Enlarged nodes have 65% - 94% chance of positive pathology – 14% false negative rate

• Chemotherapy alone (Vincristine and Actinomycin D) produced 5-year survival of 99.1% in low-risk patients (favorable histology, T1N0M0, Clinical Group I)

Paratesticular Rhabdomyosarcoma - RPLND

• Full RPLND morbid with up to 25% rate of serious complication

• Children > 10 years of age should have ipsilateral RPLND for staging before chemotherapy – Relapse-free survival lower than in younger boys

• Patients with positive lymph nodes require intensified chemotherapy as well as nodal irradiation – VAC = Vincristine, Actinomycin D, Cyclophosphamide

• Overall Survival > 90%