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Germ Cell Tumors

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Molecular Pathology of Nervous System Tumors

Part of the book series: Molecular Pathology Library ((MPLB,volume 8))

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Abstract

Central nervous system (CNS) germ cell tumors (GCTs) are separated into germinomas and nongerminomatous germ cell tumors (NGGCTs). The latter group includes teratoma (mature and immature), teratoma with malignant transformation, yolk sac tumor, embryonal carcinoma, choriocarcinoma, and mixed GCTs. CNS GCTs can be classified based on their histologic appearance and immunohistochemical profiles with histologic subtype being the best predictor of outcome. Germinomas respond exceptionally well to chemotherapy and irradiation and have been shown to have survival rates in excess of 90 %. In contrast, NGGCTs are more resistant to therapy and require more intensive chemotherapy, as well as higher doses of irradiation. There is little information on the histogenesis and molecular genetics of CNS GCTs. Fluorescent in situ hybridization (FISH) studies have shown a gain of X chromosome in a majority of GCTs. Other studies have shown that 12p abnormalities (gains and isochromosome 12p) are common, especially in germinomas. Gene expression analysis studies show overexpression of self-renewing pluripotency genes and genes responsible for tumor growth and differentiation in various tumors with no significant differences in gene expression between CNS GCTs of similar histology arising at different sites and different ages within the pediatric age group. Differences in microRNA expression have been demonstrated between histologic subtypes of CNS GCTs, and their potential use as a biomarker in the serum and cerebrospinal fluid is being explored. KIT mutations are the most commonly found abnormality on whole genome sequencing, predominantly in germinomas, followed by genes involved in the MAPK signaling pathway, suggesting a role for KIT inhibitors in the management of these tumors.

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Abbreviations

AFP:

Alpha-fetoprotein

βhCG:

β human chorionic gonadotropin

CBTRUS:

Central Brain Tumor Registry of the United States

CCKBR:

Cholecystokinin B receptor

CGH:

Comparative genomic hybridization

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

FISH:

Fluorescent in situ hybridization

GCTs:

Germ cell tumors

hPL:

Human placental lactogen

JMJD:

Jumonji domain-containing

miRNA:

microRNA

NGGCTs:

Nongerminomatous germ cell tumors

PLAP:

Placental alkaline phosphatase

qRT-PCR:

Quantitative reverse transcriptase polymerase chain reaction

SNRPN:

Small nuclear ribonucleoprotein polypeptide N

WES:

Whole exome sequencing

WHO:

World Health Organization

YST:

Yolk sac tumors

References

  1. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 2012;14 Suppl 5:v1–49.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Kamoshima Y, Sawamura Y. Update on current standard treatments in central nervous system germ cell tumors. Curr Opin Neurol. 2010;23(6):571–5.

    Article  PubMed  Google Scholar 

  3. 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(3):446–55.

    Article  CAS  PubMed  Google Scholar 

  4. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. 1985;63(2):155–67.

    Article  CAS  PubMed  Google Scholar 

  5. Rosenblum MK, Nakazato Y, Matsutani M. CNS germ cell tumors. In: Louis DN, Oghaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC Press; 2007. p. 197–204.

    Google Scholar 

  6. Motzer RJ, Amsterdam A, Prieto V, Sheinfeld J, Murty VV, Mazumdar M, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol. 1998;159(1):133–8.

    Article  CAS  PubMed  Google Scholar 

  7. Raisanen JM, Davis RL. Congenital brain tumors. Pathology (Phila). 1993;2(1):103–16.

    CAS  Google Scholar 

  8. Isaacs Jr H. I. Perinatal brain tumors: a review of 250 cases. Pediatr Neurol. 2002;27(4):249–61.

    Article  PubMed  Google Scholar 

  9. Buetow PC, Smirniotopoulos JG, Done S. Congenital brain tumors: a review of 45 cases. AJR Am J Roentgenol. 1990;155(3):587–93.

    Article  CAS  PubMed  Google Scholar 

  10. Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol. 2005;29(3):368–71.

    Article  PubMed  Google Scholar 

  11. Hattab EM, Tu P, Wilson JD, Cheng L. C-kit and HER2/neu expression in primary intracranial germinoma (abstract). J Neuropathol Exp Neurol. 2004;63(5):547.

    Google Scholar 

  12. Iczkowski KA, Butler SL, Shanks JH, Hossain D, Schall A, Meiers I, et al. Trials of new germ cell immunohistochemical stains in 93 extragonadal and metastatic germ cell tumors. Hum Pathol. 2008;39(2):275–81.

    Article  CAS  PubMed  Google Scholar 

  13. Takeshima H, Kaji M, Uchida H, Hirano H, Kuratsu J. Expression and distribution of c-kit receptor and its ligand in human CNS germ cell tumors: a useful histological marker for the diagnosis of germinoma. Brain Tumor Pathol. 2004;21(1):13–6.

    Article  CAS  PubMed  Google Scholar 

  14. Mei K, Liu A, Allan RW, Wang P, Lane Z, Abel TW, et al. Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases. Mod Pathol. 2009;22(12):1628–36.

    Article  CAS  PubMed  Google Scholar 

  15. Zynger DL, McCallum JC, Luan C, Chou PM, Yang XJ. Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: immunohistochemical investigation with analysis of histological growth patterns. Histopathology. 2010;56(6):750–7.

    Article  PubMed  Google Scholar 

  16. Ho DM, Liu HC. Primary intracranial germ cell tumor. Pathologic study of 51 patients. Cancer. 1992;70(6):1577–84.

    Article  CAS  PubMed  Google Scholar 

  17. Inoue HK, Naganuma H, Ono N. Pathobiology of intracranial germ-cell tumors: immunochemical, immunohistochemical, and electron microscopic investigations. J Neurooncol. 1987;5(2):105–15.

    Article  CAS  PubMed  Google Scholar 

  18. Iwato M, Tachibana O, Tohma Y, et al. Molecular analysis for p53 and mdm2 in intracranial germ cell tumors. Acta Neuropathol. 2000;99:21–5.

    Article  CAS  PubMed  Google Scholar 

  19. Iwato M, Tachibana O, Tohma Y, et al. Alterations of the INK4a/ARF locus in human intracranial germ cell tumors. Cancer Res. 2000;60:2113–5.

    CAS  PubMed  Google Scholar 

  20. Lee SH, Appleby V, Jeyapalan JN, Palmer RD, Nicholson JC, Sottile V, et al. Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells. J Neurooncol. 2011;101(3):419–28.

    Article  CAS  PubMed  Google Scholar 

  21. 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(6):531–8.

    CAS  PubMed  Google Scholar 

  22. Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD, et al. Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol. 2006;19(6):864–73.

    CAS  PubMed  Google Scholar 

  23. Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W. Comparative genomic hybridization in pineal germ cell tumors. J Neuropathol Exp Neurol. 2000;59(9):815–21.

    CAS  PubMed  Google Scholar 

  24. Hattab EM, Zhang SB, Wilson JD, Tu PH, Cheng L. Chromosome 12p abnormalities in germinoma of the central nervous system: A FISH analysis of 23 cases (abstract). Brain Pathol. 2006;16 Suppl 1:S155.

    Google Scholar 

  25. Palmer RD, Barbosa-Morais NL, Gooding EL, Muralidhar B, Thornton CM, Pett MR, et al. Pediatric malignant germ cell tumors show characteristic transcriptome profiles. Cancer Res. 2008;68(11):4239–47.

    Article  CAS  PubMed  Google Scholar 

  26. Palmer RD, Murray MJ, Saini HK, van Dongen S, Abreu-Goodger C, Muralidhar B, et al. Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Res. 2010;70(7):2911–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Murray MJ, Halsall DJ, Hook CE, Williams DM, Nicholson JC, Coleman N. Identification of microRNAs From the miR-371~373 and miR-302 clusters as potential serum biomarkers of malignant germ cell tumors. Am J Clin Pathol. 2011;135(1):119–25.

    Article  CAS  PubMed  Google Scholar 

  28. Terashima KS J, Luan J, Yu A, Suzuki T, Nishikawa R, Matsutani M, et al., eds. microRNA 371-373 and 302A in cerebrospinal fluid are potential tumor-derived biomarkers for intracranial germ cell tumors. 3rd International CNS Germ Cell Tumor Symposium; Cambridge; 2013.

    Google Scholar 

  29. Shibamoto Y, Abe M, Yamashita J, Takahashi M, Hiraoka M, Ono K, et al. Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys. 1988;15(2):285–90.

    Article  CAS  PubMed  Google Scholar 

  30. Aoyama H, Shirato H, Kakuto Y, Inakoshi H, Nishio M, Yoshida H, et al. Pathologically-proven intracranial germinoma treated with radiation therapy. Radiother Oncol. 1998;47(2):201–5.

    Article  CAS  PubMed  Google Scholar 

  31. Khatua S, Dhall G, O’Neil S, Jubran R, Villablanca JG, Marachelian A, et al. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer. 2010;55(1):42–6.

    PubMed  Google Scholar 

  32. Matsutani M. Long-term followup of germinomas treated by ventricular irradiation with 24 Gy and concurrently administered carboplatin and etoposide chemotherapy [abstract GCT 02]. Neuro Oncol. 2010;12(6):ii28.

    Google Scholar 

  33. Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre ML, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol. 2013;15(6):788–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H. Germ cell tumours of the central nervous system: treatment consideration based on 111 cases and their long-term clinical outcomes. Eur J Cancer. 1998;34(1):104–10.

    Article  CAS  PubMed  Google Scholar 

  35. Sano K. So-called intracranial germ cell tumours: are they really of germ cell origin? Br J Neurosurg. 1995;9(3):391–401.

    Article  CAS  PubMed  Google Scholar 

  36. Ogawa K, Shikama N, Toita T, Nakamura K, Uno T, Onishi H, et al. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys. 2004;58(3):705–13.

    Article  PubMed  Google Scholar 

  37. Dearnaley DP, A’Hern RP, Whittaker S, Bloom HJ. Pineal and CNS germ cell tumors: Royal Marsden Hospital experience 1962–1987. Int J Radiat Oncol Biol Phys. 1990;18(4):773–81.

    Article  CAS  PubMed  Google Scholar 

  38. Hoffman HJ, Otsubo H, Hendrick EB, Humphreys RP, Drake JM, Becker LE, et al. Intracranial germ-cell tumors in children. J Neurosurg. 1991;74(4):545–51.

    Article  CAS  PubMed  Google Scholar 

  39. Goldman S, Bouffet E, Fisher G, Wharam MD, Shaw D, Chuba PJ, et al. A phase II trial of neoadjuvant chemotherapy +/- second-look surgery prior to radiotherapy for non-germinomatous germ cell tumors (NGGCT): Children’s Oncology Group Study ACNS0122 [abstract GCT 06]. Neuro Oncol. 2010;12(6):ii29.

    Google Scholar 

  40. Aoyama H, Shirato H, Yoshida H, Hareyama M, Nishio M, Yanagisawa T, et al. Retrospective multi-institutional study of radiotherapy for intracranial non-germinomatous germ cell tumors. Radiother Oncol. 1998;49(1):55–9.

    Article  CAS  PubMed  Google Scholar 

  41. Phi JH, Kim SK, Park SH, Hong SH, Wang KC, Cho BK. Immature teratomas of the central nervous system: is adjuvant therapy mandatory? J Neurosurg. 2005;103(6 Suppl):524–30.

    PubMed  Google Scholar 

  42. Ichimura K, Fukushima S, Totoki Y, et al., eds. Exome sequencing of intracranial germ cell tumours. 3rd International CNS Germ Cell Tumor Symposium; Cambridge; 2013.

    Google Scholar 

  43. Wang L, Terashima K, Yamaguchi S, et al., eds. Exome sequencing of CNS germ cell tumors reveals frequent mutations in KIT and KRAS pathways and JMJD genes. 3rd International CNS Germ Cell Tumor Symposium; Cambridge; 2013.

    Google Scholar 

  44. Tian X, Fang J. Current perspectives on histone demethylases. Acta Biochim Biophys Sin (Shanghai). 2007;39(2):81–8.

    Article  CAS  Google Scholar 

  45. Fukushima S, Otsuka A, Suzuki T, et al., eds. Mutually exclusive mutations of c-kit and RAS are associated with chromosomal instability in primary intracranial germinomas. 3rd International CNS Germ Cell Tumor Symposium; Cambridge; 2013.

    Google Scholar 

  46. Osorio DS, Finlay JL, Dhall G, Goldman S, Eisenstat D, Brown RJ. Feasibility of dasatinib in children and adolescents with new or recurrent central nervous system germinoma. Pediatr Blood Cancer. 2013;60(9):E100–2.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

    Girish Dhall M.D.

  2. IU Health Pathology Laboratory, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Ashley A. Ibrahim M.D.

  3. IU Health Pathology Laboratory, Indiana University School of Medicine, 350 West 11th Street, 4th Floor, Indianapolis, IN, 46202, USA

    Eyas M. Hattab M.D.

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  1. Girish Dhall M.D.
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  3. Eyas M. Hattab M.D.
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Correspondence to Girish Dhall M.D. .

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Editors and Affiliations

  1. Associate Professor of Pediatrics and Otolaryngology, NYU Langone Medical Center, New York, New York, USA

    Matthias A. Karajannis

  2. Professor of Pathology and Neurosurgery, NYU Langone Medical Center, New York, New York, USA

    David Zagzag

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Dhall, G., Ibrahim, A.A., Hattab, E.M. (2015). Germ Cell Tumors. In: Karajannis, M., Zagzag, D. (eds) Molecular Pathology of Nervous System Tumors. Molecular Pathology Library, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1830-0_11

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  • DOI: https://doi.org/10.1007/978-1-4939-1830-0_11

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