WHO-Klassifikation und molekulare Diagnostik von Tumoren des zentralen Nervensystems

Zusammenfassung

Diese Übersichtsarbeit gliedert sich in zwei für die klinische Praxis relevante Teilbereiche: Zum einen wird die aktuelle WHO-Klassifikation der Tumoren des zentralen Nervensystems (ZNS) vorgestellt. Fokussiert wird auf die Gliome, die häufigsten primären intrazerebralen Tumoren, sowie die wesentlichen Charakteristika neuer Tumorentitäten und -varianten. Die WHO-Klassifikation beruht auf histologischen und immunhistochemischen Kriterien. Mit den Fortschritten der Molekularbiologie sind eine Vielzahl von genetischen Aberrationen in ZNS-Tumoren identifiziert worden, die zum Teil für eine erweiterte molekularpathologische Diagnostik in Frage kommen. Hierzu zählen die Analyse der Promotormethylierung des MGMT-Gens in Glioblastomen, der Nachweis von Allelverlusten auf den Chromosomenarmen 1p und 19q in oligodendroglialen Tumoren, die Bestimmung von Mutationen des IDH1-Gens in diffusen Gliomen sowie der Nachweis von BRAF-Translokationen/-Duplikationen in pilozytischen Astrozytomen. Auf den Nutzen dieser molekularen Marker wird im zweiten Teil eingegangen.

Summary

This review focuses on two main aspects we consider as relevant for clinical practice: First, we introduce the new WHO classification of tumors of the central nervous system in its revised 2007 edition. We particularly delineate histopathological features of gliomas, which are the most frequent primary intracerebral tumors, and describe the characteristics of the newly introduced tumor entities and variants, all of which are still mainly defined by histological criteria. With recent advances in molecular biology, a plethora of genetic aberrations has been identified in the different types of CNS tumors. To date, few of these factors qualify for an application in the molecular diagnostics of brain tumors, including the testing for promoter methylation of the MGMT gene in glioblastomas, detection of chromosomal deletions on 1p and 19q in oligodendroglial tumors, mutation analysis of the IDH1 gene in diffuse gliomas and analysis for duplication/translocation of BRAF in pilocytic astrocytoma. The second part will focus on delineating the adjunct value of the diagnostic assessment of these novel molecular markers.

Schlüsselwörter

Gliom - Klassifikation - molekulare Diagnostik - MGMT - 1p/19q - IDH1

Keywords

Glioma - classification - molecular diagnostics - MGMT - 1p/19q - IDH1

• Literatur

• 1 Balss J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008; 116: 597-602.
• 2 Bar EE. et al. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008; 67: 878-887.
• 3 Brat DJ. et al. Newly codified glial neoplasms of the 2007 WHO Classification of Tumours of the Central Nervous System: angiocentric glioma, pilomyxoid astrocytoma and pituicytoma. Brain Pathol 2007; 17: 319-324.
• 4 Brat DJ. et al. Pituicytoma: a distinctive low-grade glioma of the neurohypophysis. Am J Surg Pathol 2000; 24: 362-368.
• 5 Cairncross G. et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 2006; 24: 2707-2714.
• 6 Cairncross JG. et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90: 1473-1479.
• 7 Dahiya S. et al. Spindle cell oncocytoma of the adenohypophysis: report of two cases. Acta Neuropathol 2005; 110: 97-99.
• 8 Deshmukh H. et al. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene 2008; 27: 4745-4751.
• 9 Griffin CA. et al. Identification of der(1;19) (q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 2006; 65: 988-994.
• 10 Hegi ME. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997-1003.
• 11 Jeibmann A. et al. Prognostic implications of atypical histologic features in choroid plexus papilloma. J Neuropathol Exp Neurol 2006; 65: 1069-1073.
• 12 Jones DT. et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68: 8673-8677.
• 13 Jouvet A. et al. Papillary tumor of the pineal region. Am J Surg Pathol 2003; 27: 505-512.
• 14 Kleihues P, Burger PC, Scheithauer BW. (Hrsg). Histological typing of tumours of the central nervous system. World Health Organization international histological classification of tumours. Heidelberg: Springer; 1993
• 15 Kleihues P, Cavenee WK. (Hrsg). World Health Organization Classification of Tumours. Pathology and genetics of tumours of the nervous system. Lyon: IARC Press; 2000
• 16 Kleihues P, Ohgaki H. Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1999; 01: 44-51.
• 17 Kloub O. et al. Spindle cell oncocytoma of the adenohypophysis: report of two recurrent cases. Am J Surg Pathol 2005; 29: 247-253.
• 18 Komori T. et al. Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 1998; 22: 1171-1183.
• 19 Komori T, Scheithauer BW, Hirose T. A rosetteforming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor?. Am J Surg Pathol 2002; 26: 582-591.
• 20 Lellouch-Tubiana A. et al. Angiocentric neuroepithelial tumor (ANET): a new epilepsy-related clinicopathological entity with distinctive MRI. Brain Pathol 2005; 15: 281-286.
• 21 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. (Hrsg). WHO Classification of tumours of the central nervous system. Lyon: IARC; 2007
• 22 Louis DN. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114: 97-109.
• 23 Miller CR. et al. Significance of necrosis in grading of oligodendroglial neoplasms: a clinicopathologic and genetic study of newly diagnosed high-grade gliomas. J Clin Oncol 2006; 24: 5419-5426.
• 24 Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol (Berl) 2005; 109: 93-108.
• 25 Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005; 64: 479-489.
• 26 Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170: 1445-1453.
• 27 Parsons DW. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807-1812.
• 28 Pfister S. et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in lowgrade astrocytomas. J Clin Invest 2008; 118: 1739-1749.
• 29 Preusser M. et al. Angiocentric glioma: report of clinicopathologic and genetic findings in 8 cases. Am J Surg Pathol 2007; 31: 1709-1718.
• 30 Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 2003; 62: 111-126.
• 31 Riemenschneider MJ, Reifenberger G. Astrocytic tumors. Recent Results Cancer Res 2009; 171: 3-24.
• 32 Riemenschneider MJ, Reifenberger G. Molecular neuropathology of gliomas. Int J Mol Sci 2009; 10: 184-212.
• 33 Roncaroli F, Scheithauer BW. Papillary tumor of the pineal region and spindle cell oncocytoma of the pituitary: new tumor entities in the 2007 WHO Classification. Brain Pathol 2007; 17: 314-318.
• 34 Roncaroli F. et al. Spindle cell oncocytoma’ of the adenohypophysis: a tumor of folliculostellate cells?. Am J Surg Pathol 2002; 26: 1048-1055.
• 35 Rosenblum MK. The 2007 WHO Classification of Nervous System Tumors: newly recognized members of the mixed glioneuronal group. Brain Pathol 2007; 17: 308-313.
• 36 Schiffer D. et al. Histologic prognostic factors in ependymoma. Childs Nerv Syst 1991; 07: 177-182.
• 37 Stupp R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 434-435.
• 38 Stupp R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-996.
• 39 Tihan T. et al. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol 1999; 58: 1061-1068.
• 40 Ulm AJ. et al. Pituicytoma: report of two cases and clues regarding histogenesis. Neurosurgery 2004; 54: 753-757.
• 41 Vajtai I, Sahli R, Kappeler A. Spindle cell oncocytoma of the adenohypophysis: report of a case with a 16-year follow-up. Pathol Res Pract 2006; 202: 745-750.
• 42 van den Bent MJ. et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 2006; 24: 2715-2722.
• 43 Wang M. et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 2005; 64: 875-881.
• 44 Watanabe T. et al. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009; 174: 1149-1153.
• 45 Yan H. et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765-773.
• 46 Zülch KJ. (Hrsg). Histological typing of tumours of the central nervous system. Geneva: World Health Organization; 1979