Neurosurgery notes/Tumours/Germ cell tumours

Germ cell tumours

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Germinoma
Embryonal carcinoma
GCT management
Non germinomas

Definition

  • In the CNS, the morphological, Immunophenotypic, and (in some respects) genetic homologues of gonadal and other extraneuraxial germ cell neoplasms.

Numbers

  • CNS germ cell tumours principally affect children and adolescents
  • CNS is the 2nd most common location for extragonadal germ cell tumours
  • Eastern Asia>EU/USA.
    • Eastern Asia (Japan; Taiwan, China; and the Republic of Korea)
      • 2-3% of all primary intracranial neoplasms
      • 8-15% of paediatric
    • EU/USA
      • 0.3-0.6% of primary intracranial tumours
      • 3-4% of paeds
  • Age
    • 90% of cases occur < 20 years
      • Fetal and neonatal: mature / immature teratomas
      • < 3 years old: yolk sac tumours, NGGCTs (non-germinomatous germ cell tumors)
      • Pubertal: seminomas, dysgerminomas
    • Peaks occurring just after birth and in early adolescence
      • Peak incidence occurs in patients aged 10-14 years
  • Gender
    • Location differences
      • Boys: Majority in pineal region
      • Girls: Majority in suprasellar region
    • Males
      • 89% of teratomas
      • 78% of germinomas
      • 75% of other germ cell tumour
  • Germinomas
    • Male
    • Pineal
    • Asian
  • Non germinomas
    • No sex, race or location association except for infants

Germ cell tumour histological subtypes

Germinoma (41.1%, some say 70-80% ): (Very early in development)

  • Resemble premodial cells
  • Pure germinomas containing syncytiotrophoblastic giant cells are recognized as a distinct variant (5.2%)

Non germinoma (later during development)

  • Have characteristics associated with the embryonic stage of development (e.g. the pluripotent nature of teratomas)

CNS WHO grading

  • All germ cells excluding mature teratoma are regarded as malignant

Localisation

  • 80% of CNS germ cell tumours arise along a midline axis extending from
    • The pineal gland (their most common site) to
    • The suprasellar compartment (their next most common site)
      • Neurohypophyseal / infundibular stalk
      • Intraventricular
      • Diffuse periventricular
      • Thalamostriate
      • Cerebral hemispheric
      • Cerebellar
      • Bulbar
      • Intramedullary
      • Intrasellar variants can be encountered
      • Congenital holocranial examples (usually teratomas).
  • Germinomas
    • Suprasellar compartment
    • Basal ganglionic / thalamic regions
  • Non-germinomatous
    • Pineal region
    • Suprasellar compartment, either simultaneously or sequentially.
    • Bilateral basal ganglionic and thalamic lesions are also well recognized.
Other sites of germ cell tumours
  • Gonadal - germinoma = seminoma = dysgerminoma
  • Retroperitoneal
  • Mediastinal
  • Pelvic - sacrococcygeal
  • Intra-oral
  • Intracranial - pineal, suprasellar, bifocal (pathognomonic), third ventricular, posterior fossa

Cell of origin (3 theories)

  • Germ cells are
    • Pluripotent (can differentiate into any cell)
    • Originate from the yolk sac of embryo at 3rd to 4th wk of gestation
    • Originally these cells are destined for the ovaries or testes
    • Aberrantly migrate to other regions
      • Trap in the midline location
  • Teratomas can arise from other nonprogenitor germ cells, suggesting that other germs cells might be able to do the same
  • Endogenous neural stem cells in the brain are the likely origin of primary CNS Germ cell tumour
    • Over expression of Oct4 gene can stimulate the development of normal progenitor cells from neural stem cells

Aetiology

  • Increase gonadotropin levels: because
    • CNS germ cell tumours’ predilection to occur in peripubertal patients,
    • Their localization in diencephalic centres regulating gonadal activity, and
    • Their increased incidence in Klinefelter syndrome
      • The association with Klinefelter syndrome could also reflect X chromosome over dosage, a common genetic feature of these neoplasms.

Clinical presentation

  • Clinical presentation and their duration can vary with histological type and location.
  • Duration variation
    • Germinomas: more protracted symptomatic interval
  • Location variation
    • Pineal lesions
      • Hydrocephalus
        • Compression and obstruct the cerebral aqueduct
      • Parinaud syndrome (paralysis of upwards gaze and convergence)
        • Compressing and invading the tectal plate
    • Neurohypophyseal / suprasellar lesion
      • Visual field defects: Compressing the optic chiasm
      • Pituitary failure (delayed growth and sexual maturation) and diabetes insipidus
        • Compression of hypothalamohypophyseal axis
  • Secretory symptoms
    • Boys
      • Neoplastic syncytiotrophoblasts secrete hCG → can sti. testosterone production → can cause precocious puberty (isosexual pseudoprecocity) in boys.
    • Girls
      • Neoplastic syncytiotrophoblasts secrete hCG → can sti. testosterone production + expression of cytochrome P450 aromatase → Aromatase catalyses the conversion of C19 steroids to oestrogen → may explain the rare instances of precocious puberty in girls with hCG-producing tumours (but most of the time Girls DO NOT have precocious puberty)
      • hCG may also have some intrinsic FSH-like activity

Molecular pathogenesis

  • Two main pathways affected (either one of the two pathways is mutated in 60% of tumours)
    • Upregulated KIT/RAS signalling through (combination of all three mutations >50% of cases)
      • KIT mutation (26%)
        • At exon 17 and 11
        • There are targeted therapies vs KIT mutation
      • Ras mutation (either KRAS or NRAS) (19%)
        • Encodes downstream targets of the c-Kit receptor
        • No targeted therapies yet
      • Caspase B-lineage lymphoma (CBL) mutation
        • Encodes a RING finger ubiquitin E3 ligase
        • 11q loss
        • Negative regulator of KIT expression
    • Upregulated AKT/mTOR signalling through (19%)
      • AKT1 amplification

Genetics

Chromosomal

  • Gains of
    • 12p
    • 8q
    • 1q
    • 2p
    • 7q
    • 10q
    • X (hence association with Klinefelter)
  • Losses of
    • 11q
    • 13
    • 5q
    • 10q
    • 18q
 

Increase susceptibility with

  • Klinefelter syndrome (47XXY)
    • Due to increase X chromosome
  • Down syndrome
    • Has Inc. Risk of testicular germ cell cancer
  • NF1

Differential diagnosis

  • Teratoma vs Dermoid
    • Presence of an enhancing nodule in teratoma may help distinguish it from a dermoid
  • Pineal tumours