DESCRIPTION

Germ cell tumors (GCTs) are a heterogeneous group with a suspected common cell of origin, the primordial germ cell.

• Their location can be gonadal or extragonadal.
• The numerous histologic subtypes are broadly classified as mature or immature teratomas and malignant GCTs.
• See “Brain Tumor” chapter for primary CNS GCT.

EPIDEMIOLOGY

The incidence has a bimodal distribution with a smaller peak in early infancy and a larger peak in adolescence.

• In neonates, most extracranial GCTs are benign midline teratomas.
  • Despite being nonmalignant, they confer high morbidity secondary to hydrops fetalis and premature delivery.
• In children <15 years of age, GCTs occur at a rate of 2.4 cases per million children, and they account for 2–3% of all malignancies.
• In children 15 to 19 years, extracranial GCTs account for approximately 14% of cancer diagnoses; most GCTs in this age group are germinomas.
• Sacrococcygeal teratomas account for 50% of childhood teratomas.
  • They are most prevalent in infants (1:40,000 live births); with a female predominance (4:1)

RISK-FACTORS

• GCTs are thought to result from altered intrauterine events; potential risk factors include fetal chemical or hormone exposures or congenital abnormalities, primarily of sex chromosomes or sexual differentiation.
• In boys, increased risk of testicular or mediastinal GCT with cryptorchidism and Klinefelter syndrome respectively
• Approximately 50% of adolescent mediastinal GCTs are associated with Klinefelter syndrome.
• Disorders of sexual differentiation including Turner syndrome with any portion of Y chromosomal material, Frasier syndrome, Swyer syndrome, other androgen insensitivity syndromes, Denys-Drash syndrome are all associated with increased GCT in streak gonads.
• Streak gonads particularly associated with gonadoblastoma

GENERAL-PREVENTION

• Prophylactic gonadectomy is recommended for streak gonads in the specific syndromes mentioned above because of the increased risk of developing GCTs.
• Guidelines on the management of cryptorchidism recommend the following to decrease the future risk of testicular GCT:
  • Orchidopexy by 18 months of age
  • Consideration of orchiectomy of an undescended testis in all boys with a normal contralateral testis when orchidopexy is not feasible.
  • Consider orchiectomy or biopsy in a postpubertal boy with cryptorchidism.
  • Counsel all men with a history of cryptorchidism and/or their parents regarding the long-term risk of testicular cancer.

ETIOLOGY

• GCTs arise from primordial germ cells with molecular defects.
  • Germinomas (testicular seminomas and ovarian dysgerminomas) originate directly from undifferentiated primordial germ cells.
  • Embryonal carcinomas have early embryonic differentiation, so produce teratomas with all three germ layers (endoderm, ectoderm, mesoderm).
  • Yolk sac tumors and choriocarcinomas originate from primordial germ cells with extra-embryonic differentiation.
  • Mixed malignant GCTs contain various histologies.
• Primordial germs cells migrate through the midline from the yolk sac to the gonadal ridge; disruption of this migration likely explains the midline propensity of extragonadal GCTs.
• Certain oncogenic miRNAs (miR-371-373 and miR-302/367 clusters) are overexpressed in all malignant GCTs.
  • These are detectable in serum at time of diagnosis and should respond to treatment; this is more sensitive and specific than traditional biomarkers.
• Genetic profiles are different in children than adults, even for same histologic subtypes, suggesting gene expression may be driven, at least partially, by pubertal hormonal changes.
• Gain of short arm of chromosome 12, isochromosome 12p [or i(12)p] is present in >80% postpubertal GCTs.
• Malignant GCTs in children <4 years often contain cytogenetic abnormalities in chromosomes 1, 3, 6, 11 and others.
  • Deletion of 1q36 is present in 80–100% of infantile malignant GCTs in testicular as well as extragonadal sites.
  • Infantile yolk sack tumors include alterations including loss of 6q24-qter or 1p, gain of 20q and 1q, and c-myc or n-myc amplification.
• Single nucleotide polymorphisms (SNPs) in genes involved in KIT/ KITLG signaling, male germ cell development, increased telomerase activity, defective microtubules, and DNA damage repair pathways are implicated in GCT development.
• Epigenetics may also contribute to GCT development.
  • Yolk sac tumors have increased methylation.