The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary

Acta Neuropathol (2016) 131:803–820 DOI 10.1007/s00401-016-1545-1 REVIEW The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary David N. Louis1 · Arie Perry2 · Guido Reifenberger3,4 · Andreas von Deimling4,5 · Dominique Figarella‑Branger6 · Webster K. Cavenee7 · Hiroko Ohgaki8 · Otmar D. Wiestler9 · Paul Kleihues10 · David W. Ellison11 Received: 22 January 2016 / Revised: 8 February 2016 / Accepted: 9 February 2016 / Published online: 9 May 2016 © Springer-Verlag Berlin Heidelberg 2016 Abstract The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M–mutant; RELA fusion–positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma—a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors. * David N. Louis 6 Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France 7 Ludwig Institute for Cancer Research, University of California San Diego, San Diego, CA, USA 8 Department of Pathology, University of California San Francisco, San Francisco, CA, USA International Agency for Research on Cancer (IARC), Lyon, France 9 Department of Neuropathology, Heinrich Heine University, Duesseldorf, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany 10 Medical Faculty, University of Zurich, Zurich, Switzerland 11 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA 1 2 3 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, WRN225, 55 Fruit Street, Boston, MA 02114, USA 4 German Cancer Consortium (DKTK), Partner Site Essen/ Duesseldorf, Germany 5 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany Introduction For the past century, the classification of brain tumors has been based largely on concepts of histogenesis that tumors can be classified according to their microscopic similarities with different putative cells of origin and their presumed levels of differentiation. The characterization of such histological similarities has been primarily dependent on light microscopic features in hematoxylin and eosin-stained sections, immunohistochemical expression of lineageassociated proteins and ultrastructural characterization. 13 804 For example, the 2007 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (2007 CNS WHO) grouped all tumors with an astrocytic phenotype separately from those with an oligodendroglial phenotype, no matter if the various astrocytic tumors were clinically similar or disparate [26]. Studies over the past two decades have clarified the genetic basis of tumorigenesis in the common and some rarer brain tumor entities, raising the possibility that such an understanding may contribute to classification of these tumors [25]. Some of these canonical genetic alterations were known as of the 2007 CNS WHO, but at that time it was not felt that such changes could yet be used to define specific entities; rather, they provided prognostic or predictive data within diagnostic categories established by conventional histology. In 2014, a meeting held in Haarlem, the Netherlands, under the auspices of the International Society of Neuropathology, established guidelines for how to incorporate molecular findings into brain tumor diagnoses, setting the stage for a major revision of the 2007 CNS WHO classification [28]. The current update (2016 CNS WHO) thus breaks with the century-old principle of diagnosis based entirely on microscopy by incorporating molecular parameters into the classification of CNS tumor entities [27]. To do so required an international collaboration of 117 contributors from 20 countries and deliberations on the most controversial issues at a three-day consensus conference by a Working Group of 35 neuropathologists, neurooncological clinical advisors and scientists from 10 countries. The present review summarizes the major changes between the 2007 and 2016 CNS WHO classifications. Classification The 2016 CNS WHO is summarized in Table 1 and officially represents an update of the 2007 4th Edition rather than a formal 5th Edition. At this point, a decision to undertake the 5th Edition series of WHO Blue Books has not been made, but given the considerable progress in the fields, both the Hematopoietic/Lymphoid and CNS tumor volumes were granted permission for 4th Edition updates. The 2016 update contains numerous differences from the 2007 CNS WHO [26]. The major approaches and changes are summarized in Table 2 and described in more detail in the following sections. A synopsis of tumor grades for selected entities is given in Table 3. General principles and challenges The use of “integrated” [28] phenotypic and genotypic parameters for CNS tumor classification adds a level of objectivity that has been missing from some aspects of the 13 Acta Neuropathol (2016) 131:803–820 diagnostic process in the past. It is hoped that this additional objectivity will yield more biologically homogeneous and narrowly defined diagnostic entities than in prior classifications, which in turn should lead to greater diagnostic accuracy as well as improved patient management and more accurate determinations of prognosis and treatment response. It will, however, also create potentially larger groups of tumors that do not fit into these more narrowly defined entities (e.g., the not otherwise specified/NOS designations, see below)—groups that themselves will be more amenable to subsequent study and improved classification. A compelling example of this refinement relates to the diagnosis of oligoastroc (...truncated)