Germ Cell Tumors

Definition

Typically, pineal and suprasellar tumors of children or adolescents, with similar morphology to their gonadal and extragonadal counterparts.

Clinical Features

Uncommon
≈90% present first two decades of life
- rates peak at 10–12 years
In Western series:
- ≤0.5% of primary intracranial neoplasms
- 3% of primary intracranial neoplasms in children
Incidence increased ≈ fivefold in Japan and Taiwan1,2
Male:female ratio 2:1 when all sites considered
- gender distribution varies with localization
  - most pineal examples affect boys
  - suprasellar lesions more common in girls.
Generally sporadic
May:
- complicate Klinefelter's syndrome 3
- be increased incidence in Down syndrome2,4
If suprasellar:
- visual field defects
- diabetes insipidus
- hypothalamopituitary failure
If pineal region:
- compress tectal plate and aqueduct
- symptoms and signs of obstructive hydrocephalus
- often vertical gaze paresis (Parinaud's syndrome)
May be precocious puberty (isosexual pseudoprecocity) in boys due to:
- β-human chorionic gonadotropin (β-HCG) secretion by neoplastic syncytiotrophoblast:5,6
  - may stimulate testosterone production
- release of immature testes from tonic inhibitory controls secondary to pineal and hypothalamic injury
Exceptionally precocious puberty in girls:
- may be additional elaboration of cytochrome p450 aromatase, which catalyzes estrogen formation from C19 steroids 7

Germinoma

Most common

Teratoma

Majority of congenital CNS germ cell tumors8

Pathogenesis

Morphologic homologs of germinal tumors arising in gonads (and other extragonadal sites)
May derive from primordial germ cells that aberrantly migrate to developing central neuraxis from fetal yolk sac:2
- long presumed
- controversial

Gross Pathology

Predilection for midline:
- like other extragonadal germ cell tumors
- 80–90% along axis from suprasellar cistern and infundibulum to pineal gland
  - most common neoplasms in latter location
- exceptionally:
  - synchronous suprasellar and pineal region presentation
  - confined to:
    - cerebral hemispheres
    - basal ganglia or thalami (may be bilateral)
    - ventricles
    - spinal cord
    - sella turcica
Macroscopic features those of the more common gonadal counterparts2,9,10

Teratoma

Rarely:
- contain fetus-like bodies 11
May undergo spontaneous maturation:12
- re-resection specimens composed entirely of fully differentiated somatic tissue elements:
  - usually derive from initially immature teratomatous neoplasms or mixed germ cell tumors subjected to adjuvant therapy:
    - apparent maturation may simply reflect selective ablation of incompletely differentiated cellular components
- growing teratoma syndrome:
  - progressive seemingly paradoxical enlargement of these ostensibly mature neoplasms13

Histopathology

Histologic criteria governing identification and subclassification as for more common gonadal counterparts2,9,10

Germinoma

Histologically identical to seminoma
Minority harbor syncytiotrophoblastic giant cell elements:
- associated with elevated β-HCG in serum and CSF
May elicit florid lymphoplasmacytic and granulomatous reaction that masquerades as:
- other inflammatory process 14
Ultrastructurally:
- may be more likely than seminoma to show epithelial differentiation2,15

Special Stains and Immunohistochemistry

Immunohistochemical criteria governing identification and subclassification as for more common gonadal counterparts 2,9,10
Screening for α-FP:
- critical to detect minor components of yolk sac tumor
- may label teratomatous glands of enteric type

Germinoma

Like seminoma:
- cytoplasmic immunolabeling (often membranous) for placental alkaline phosphatase (PLAP)
- does not label for:
  - α-fetoprotein (α-FP)
  - β-HCG
May:
- be more likely than seminoma to express cytokeratins
- show limited cytoplasmic CAM 5.2 labeling:
  - often paranuclear
  - only focally apparent
Typically AE1/3 negative
Cell membrane immunolabeling for CD 117 (c-kit):
- more constant and intense than in PLAP preparations
Minority harbor syncytiotrophoblastic giant cell elements that are:
- β-HCG-immunoreactive

Diagnosis

Only germinomas and teratomas are likely to be pure form 1,2
Embryonal carcinoma, yolk sac tumor and choriocarcinoma may all arise within CNS:
- only rarely unalloyed form
- far more frequent within mixed germ cell tumors, which often contain elements of germinoma and teratoma
Report of a mixed germ cell neoplasm should specify:
- participating tumor types
- relative representation

Germinoma

Screening for PLAP:
- mandatory for inflamed biopsy material deriving from suprasellar–pineal axis 16
- complicated by:
  - potential for sampling error
  - failure of 5–10% to express antigen
- use cell membrane immunolabeling for CD 117 (c-kit) in difficult circumstances

Teratoma

Includes:
- mature teratoma:
  - entirely adult-type tissues
- immature teratoma:
  - incompletely differentiated components exhibiting fetal appearances
- teratoma with malignant transformation:
  - spawning secondary cancer of conventional somatic type, such as:
    - sarcoma of undifferentiated or rhabdomyosarcomatous aspect1,9,10,17
    - leiomyosarcoma 18
    - adenocarcinomas of enteric type19
    - squamous carcinoma1
    - erythroleukemia20
    - mature pineal teratoma partially overgrown by malignant hemangioendothelioma
    - carcinoid within a teratomatous tumor of the spinal axis (controversial)21–23

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Germ Cell Tumors

Genetics

At least a subset manifest genetic abnormalities characteristic of testicular (and mediastinal) primaries,2,24
such as:
- X chromosome gains
- isochromosome 12p

Prognosis

Histologic subtype is most important prognostic factor 1,25
Best outcomes for:
- pure germinomas in localized form:
  - generally radiocurable as well as chemosensitive
- mature teratomas that can be completely resected
Rarely extraneural spread, which includes:
- spontaneous systemic metastasis (mainly lung, bone)
- seeding of peritoneal cavity via ventriculoperitoneal shunts for obstructive hydrocephalus
May be intermediate risk of recurrence and progression for:
- mixed tumors composed mainly of germinoma and teratomatous elements 1

Germinoma

Spontaneous regression recorded:26
- may be mediated by tumor-infiltrating lymphocytes characteristic of this neoplasm
Presence of syncytiotrophoblastic giant cells sometimes associated with:
- increased local failure
- modest decrement in survival following irradiation1
May:
- destructively infiltrate local structures
- disseminate via CSF

Yolk Sac Tumors, Embryonal Carcinomas, Choriocarcinomas, and Mixtures Thereof

Frequently resist surgery and adjuvant treatment
High mortality rate
Destructively infiltrate local structures
May disseminate via CSF

References

1 Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, et al. Primary intracranial germ cell tumors. A clinical analysis of 153 histologically verified cases. J Neurosurg. 1997;86:446–455.

2 Rosenblum MK, Matsutani M, Van Meir EG. CNS germ cell tumours. Kleihues P, Cavenee WK editor. World Health Organization classification of tumours. Pathology and genetics-tumours of the nervous system. Lyon: IARC Press; 2000.

3 Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer. 1995;71:416–420.

4 Hashimoto T, Sasagawa I, Ishigooka M, Kubota Y, Nakada T, Fujita T, et al. Down's syndrome associated with intracranial germinoma and testicular embryonal carcinoma. Urol Int. 1995;55:120–122.

5 Aguzzi A, Hedinger CE, Kleihues P, Yasargil MG. Intracranial mixed germ cell tumor with syncytiotrophoblastic giant cells and precocious puberty. Acta Neuropathol (Berl). 1988;75:427–431.

6 Hisa S, Morinaga S, Kobayashi Y, Ojima M, Chikaoka H, Sasano N. Intramedullary spinal cord germinoma producing HCG and precocious puberty in a boy. Cancer. 1985;55:2845–2849.

7 O'Marcaigh AS, Ledger GA, Roche PC, Parisi JE, Zimmerman D. Aromatase expression in human germinomas with possible biological effects. J Clin Endocrinol Metab. 1995;80:3763–3766.

8 Ferreira J, Eviatar L, Schneider S, Grossman R. Prenatal diagnosis of intracranial teratoma. Prolonged survival after resection of a malignant teratoma diagnosed prenatally by ultrasound. A case report and literature review. Pediatr Neurosurg. 1993;19:84–88.

9 Bjornsson J, Scheithauer BW, Okazaki H, Leech RW. Intracranial germ cell tumors. Pathobiological and immunohistochemical aspects of 70 cases. J Neuropathol Exp Neurol. 1985;44:32–46.

10 Rueda-Pedraza ME, Heifetz SA, Sesterhenn IA, Clark GB. Primary intracranial germ cell tumors in the first two decades of life. A clinical, light-microscopic, and immunohistochemical analysis of 54 cases. Perspect Pediatr Pathol. 1987;10:160–207.

11 Naudin ten Cate L, Vermeij-Keers C, Smit DA, Cohen-Overbeek TE, Gerssen-Schoorl KB, Dijkhuizen T. Intracranial teratoma with multiple fetuses: pre- and post-natal appearance. Hum Pathol. 1995;26:804–807.

12 Shaffrey ME, Lanzino G, Lopes MB, Hessler RB, Kassell NF, VandenBerg SR. Maturation of intracranial immature teratomas. Report of two cases. J Neurosurg. 1996;85:672–676.

13 O'Callaghan AM, Katapodis O, Ellison DW, Theaker JM, Mead GM. The growing teratoma syndrome in a nongerminomatous germ cell tumor of the pineal gland. A case report and review. Cancer. 1997;80:942–947.

14 Kraichoke S, Cosgrove M, Chandrasoma PT. Granulomatous inflammation in pineal germinoma. A cause of diagnostic failure at stereotaxic brain biopsy. Am J Surg Pathol. 1988;12:655–660.

15 Min KW, Scheithauer BW. Pineal germinomas and testicular seminoma. A comparative ultrastructural study with special references to early carcinomatous transformation. Ultrastruct Pathol. 1990;14:483–496.

16 Nikas DC, De Girolami U, Zamani AA, Pinkus GS, Bello L, Kirsch M, et al. Idiopathic pinealitis. Case report. J Neurosurg. 1999;91:330–334.

17 Preissig SH, Smith MT, Huntington HW. Rhabdomyosarcoma arising in a pineal teratoma. Cancer. 1979;44:281–284.

18 Skullerud K, Stenwig AE, Brandtzaeg P, Nesland JM, Kerty E, Langmoen I, et al. Intracranial primary leiomyosarcoma arising in a teratoma of the pineal area. Clin Neuropathol. 1995;14:245–248.

19 Freilich RJ, Thompson SJ, Walker RW, Rosenblum MK. Adenocarcinomatous transformation of intracranial germ cell tumors. Am J Surg Pathol. 1995;19:537–544.

20 Heimdal K, Evensen SA, Fossa SD, Hirschberg H, Langholm R, Brogger A, et al. Karyotyping of a hematologic neoplasia developing shortly after treatment for cerebral extragonadal germ cell tumor. Cancer Genet Cytogenet. 1991;57:41–46.

21 Ironside JW, Jefferson AA, Royds JA, Taylor CB, Timperley WR. Carcinoid tumour arising in a recurrent intradural spinal teratoma. Neuropathol Appl Neurobiol. 1984;10:479–489.

22 al-Sarraj ST, Parmar D, Dean AF, Phookun G, Bridges LR. Clinicopathological study of seven cases of spinal cord teratoma. A possible germ cell origin. Histopathology. 1998;32:51–56.

23 Koen JL, McLendon RE, George TM. Intradural spinal teratoma. Evidence for a dysembryogenic origin. Report of four cases. J Neurosurg. 1998;89:844–851.

24 Okada Y, Nishikawa R, Matsutani M, Louis DN. Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors. J Neuropathol Exp Neurol. 2002;61:531–538.

25 Schild SE, Scheithauer BW, Haddock MG, Wong WW, Lyons MK, Marks LB, et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer. 1996;78:2564–2571.

26 Ide M, Jimbo M, Yamamoto M, Hagiwara S, Aiba M, Kubo O. Spontaneous regression of primary intracranial germinoma. A case report. Cancer. 1997;79:558–563.

Last updated: 18 Feb 2006