| Abstract|| |
The latest fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5) has been built on the prior WHO 2016 classification as well as recommendations put forward by seven updates of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT). Various new tumor types and subtypes have been recognized which are of clinical significance. Tumor groups have been restructured and the nomenclature of some tumor types has also been revised. The use of terms 'entity' and 'variant' have been replaced by 'type' and 'subtype'. Significant changes have been introduced in the grading of tumors viz. use of Arabic numerals, grading within individual tumor types and combined histological and molecular grading. The terms 'Not otherwise specified' and 'Not elsewhere classified' can now be used for all tumor types. WHO CNS5 also for the first time endorses the use of DNA methylation profiling for the diagnosis of some tumor types/subtypes. Finally, the importance of combining histology with molecular parameters is emphasized for the “layered reporting” and “integrated diagnosis”, which will provide valuable diagnostic, prognostic, and predictive information, as well as for some entities, suggest targeted therapies.
Keywords: 5th edition, CNS, updates, WHO
|How to cite this article:|
Mahajan S, Suri V, Sahu S, Sharma MC, Sarkar C. World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5): What's new?. Indian J Pathol Microbiol 2022;65, Suppl S1:5-13
|How to cite this URL:|
Mahajan S, Suri V, Sahu S, Sharma MC, Sarkar C. World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5): What's new?. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 24];65, Suppl S1:5-13. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/5/345057
| Introduction|| |
The World Health Organization (WHO) classification of tumors of the central nervous system (CNS) was first published in 1979 and has been revised four times since then (1993, 2000, 2007, and 2016).,,,, Up to 2007 (4th edition), the WHO classification and grading of brain tumors have been based primarily on their histopathological findings, supplemented with immunohistochemistry (IHC) for tumor markers and proliferation index. Further depending upon the extent of anaplastic features, histological grades were assigned to each tumor from WHO grade I to IV, with WHO grade I implying an indolent tumor usually associated with a favorable outcome, and WHO grade IV connoting an aggressive tumor with poor prognosis., Thus, for the past many decades, histological classification served as the 'gold standard' for the diagnosis and clinical management of brain tumors. However, this system was associated with low inter-observer concordance and also did not provide discernment of the underlying biology of these tumors. Hence, it could not be relied upon as a sole factor for the tailored treatment of individual patients.
Over the last few decades, high-throughput genome-wide molecular profiling has revealed characteristic genetic and epigenetic alterations associated with different types of brain tumors. This has led to refinement and transformation in the approach to the diagnosis of brain tumors and has greatly increased our understanding of their biology. The 2016 updated 4th edition of WHO classification of CNS tumors included for the first time molecular parameters along with histological characteristics and thus provided an integrated approach to the diagnosis of CNS tumors. Conventional histology-based diagnostics was replaced with an integrated layered diagnostic system incorporating molecular alterations that enabled more precise tumor categorization, prognostication, and treatment selection.,,
However, the rapid pace of advancement into the molecular insights of CNS tumors with the discovery of novel distinct entities, promising biomarkers, and newer drug targets instigated the need to expedite the revision of the WHO 2016 classification. Hence, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (c-IMPACT) was constituted as a forum to evaluate and propose changes to future tumor classifications. c-IMPACT has published seven updates which have contributed significantly to the preparation of the fifth edition of WHO classification of CNS tumors published in 2021.,,,,,, The WHO CNS5 has been built on the prior WHO 2016 classification by emphasizing more on molecular alterations along with their clinicopathological utility both in terms of classification and grading. This will be manifested in a “layered report format” wherein histomorphological features, grade and molecular data will be combined in the form of an integrated diagnosis.
The present review provides a summary of the important changes introduced in the 5th edition of the WHO classification of CNS tumors.
| CNS Tumor Taxonomy|| |
Hybrid approach to the organization of tumor groups
WHO CNS5 follows a hybrid/mixed approach for the grouping of tumors.
- Some groups are grouped according to the genetic changes that are essential for making a complete diagnosis, for example, IDH and H3 status, MAPK alteration, etc.
- At the other extreme, for some tumor groups like meningiomas, molecular approaches are rarely or almost never used for diagnosis
- For yet other tumors, for example, glioneuronal and neuronal tumors, grouping is by histological and histogenetic similarities though molecular alterations are different
- For some tumor groups, molecular features are used to identify new types and subtypes, e.g., medulloblastoma
Use of terms type/subtype instead of entity/variant
Prior CNS tumors classifications used the terms “entity” and “variant”. In WHO CNS5 classification the term 'type' is used instead of 'entity' and 'sub-type' instead of 'variant'. This has been done in order to standardize the terminology with other organ systems.
'Type' is used to describe a “neoplasm in which multiple parameters (eg, clinical, anatomic, histopathologic, and/or molecular) differ from other types (eg, myxoid glioneuronal tumor)”. 'Subtype' describes a “variant of a type in which a single or couple of parameters (eg, clinical, anatomic, histopathologic, and/or molecular) suggest that it differs from other subtypes and thus makes it desirable to recognize the variant separately (eg, Two subtypes of diffuse leptomeningeal glioneuronal tumor)”. Furthermore, only 'types' are listed in the main classification while “subtypes” are described under individual sections/chapters. For example, meningioma is a single type listed in the classification while all the histological subtypes and grades are described individually within the meningioma chapter. Similarly, medulloblastomas, histologically defined, have been enlisted as a single type in the classification and the subtypes are dealt with individually in the text.
Restructuring of tumor groups
Tumor groups have been restructured as shown in [Table 1].
A salient feature of WHO CNS5 is that adult type and pediatric type diffuse gliomas have been classified separately for the first time based on their clinical and molecular characteristics, although they share overlapping histomorphological features. Pediatric type diffuse gliomas have been further divided into high and low grade types. This distinction is an important step towards separating these two prognostically and biologically different set of tumors for better clinical management. Further, molecular analysis will play a very important role in the diagnosis and grading of both adult type and pediatric type diffuse gliomas in WHO CNS5.
Another salient feature is a new classification system for ependymomas in WHO CNS5 by combining anatomic site, histopathology, and molecular features.
| Revisions in Nomenclature of Genes and Proteins|| |
The WHO CNS5 classification of tumors uses
- Hugo Gene Nomenclature Committee system for gene symbols and gene names.
- Human Genome Variation Society recommendations for sequence variants. and
- Reporting guidelines for chromosomal alterations of the International System for Human Cytogenetic Nomenclature 2020.
- Gene symbols are written in italics, but not proteins and gene groups (eg. family of IDH genes are not italicized).
- For histone sequence alterations, WHO CNS5 classification uses the legacy protein numbering system in parenthesis after the protein level variant description (“prefix c” for sequence alteration and “prefix p” for protein sequence), for example, H3–3A: c. 83 A > T p. Lys 28 Met (K27M).
| Changes in Grading Of CNS Tumors|| |
Numerous changes in grading have been introduced in WHO CNS5.
Use of the term 'CNS WHO grade'
The term 'CNS WHO grade' will now be used while assigning grades to tumors. This change highlights differences in grading criteria of CNS tumors as compared with grading criteria of non-CNS neoplasms, for example, Glioblastoma (GB), IDH wild type, CNS WHO grade 4.
Use of Arabic numerals for grading
In order to bring uniformity on grading with other non-CNS neoplasms, WHO CNS 5 classification has changed use of grading numerals from Roman (I, II, III, IV) to Arabic (1, 2, 3, 4). Arabic numerals are also preferred because of the danger of typographical errors within tumor grading systems in Roman numerals (eg, II mistaken for III or III mistaken for IV) which could have serious clinical consequences.
Grading within individual tumor types
The previous classification assigned one tumor grade to each entity, for example, anaplastic astrocytoma was always grade III and could never be assigned grade I, II, or IV. In WHO CNS 5 classification, grading within individual tumor types has now been introduced in many categories of tumors in order to conform with WHO grading in non-CNS tumor types, for example, Astrocytoma, IDH mutant can either be WHO CNS grade 2, 3, or 4. This has replaced terms such as diffuse astrocytoma, anaplastic astrocytoma, IDH mutant GB.
Combined histological and molecular grading
CNS tumor grading has been traditionally based on histological features but now it is known that certain molecular markers can also provide important prognostic information. Hence in WHO CNS5 such molecular biomarkers have been added to histological findings for grading of some tumors. Infact, in some tumors, molecular markers now prevail over histopathology for their diagnosis and grading, for example, (i) CDKN2A/B homozygous deletion in the grading of IDH mutant astrocytomas. The presence of this molecular alteration makes the tumor grade 4 even if the tumor appears low grade on histology. (ii) A panel of TERT promoter (TERTp) mutation, EGFR amplification, and + 7/10- copy number changes allow a diagnosis of GB, IDH wild-type, CNS WHO grade 4 even without classical histologic features.,
Clinicopathological grading and grades not assigned to some tumors
WHO CNS5 has retained the range of grades assigned to various CNS tumors to predict survival as in prior editions, which has been historically based on the natural history of biological behavior of tumors when almost no treatments were available. However, with the advancement of new and effective therapeutic modalities, WHO CNS5 has also argued against the need to grade each and every tumor as predicting natural history and survival is difficult nowadays since almost all patients receive some form of therapy to improve the outcomes. For example, WNT-activated medulloblastoma is designated CNS WHO grade 4 as it is an aggressive tumor if left untreated, however, it shows a favorable prognosis if treated using a modern therapeutic regime. Hence grades have not been assigned to some tumors wherein data on outcomes is still debatable or where grades will cause confusion in clinical care e.g., astroblastoma, MN1 altered.
Expression of mitosis
Mitosis will be expressed as 'per mm2' along with per 10 high power fields.
| Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC)|| |
”Not otherwise specified” (NOS) indicates that the molecular information necessary to assign a specific WHO diagnosis is not available because test(s) is/are not available or not performed or not successful. This provides an alert to the oncologist that a complete molecular workup has not been undertaken or technology has been a failure.
The term “Not elsewhere classified” (NEC) indicates that the necessary diagnostic testing has been successfully performed but the results do not allow for a standard WHO diagnosis because there is a discrepancy between the clinical, histological, immunohistochemical, and genetic features. A descriptive diagnostic report can be given in such cases.
These terms can be used for any tumor type (not reserved for specific tumor types) e.g., Tumor with typical embryonal tumor with multilayered rosettes (ETMR) histomorphology and IHC but
- C19MC alteration or DICER1 mutation testing not performed:
Report as ETMR, NOS
- Tested but did not have C19MC alteration or DICER1 mutation; Report as ETMR, NEC
| Revisions in Tumor Nomenclature|| |
In the WHO CNS5 classification, names of tumors have been simplified as much as possible and only location, age or genetic markers/molecular alterations with clinical utility have been used in the name. For example, extraventricular neurocytoma versus central neurocytoma, astroblastoma MN1 altered, diffuse midline glioma, H3K27M altered. Modifier terms like 'anaplastic' (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma') now do not appear in the classification. Overall, the nomenclature of 13 tumors has been revised in order to specify their exclusive molecular alteration or to bring uniformity in tumor names with those in other WHO tumor books. The tumors with revised nomenclature are enlisted in the classification table [Table 2] and marked with*
|Table 2: Classification of tumors of the Central Nervous System (WHO CNS 5),,,|
Click here to view
| Newly Recognized Types of Tumors|| |
Many newly recognized types have been introduced by WHO CNS5 (total 22), some of which display distinct histopathological and/or genetic characteristics. The newly recognized tumors are enlisted under their respective tumor group in [Table 2] and marked with **. Some of these entities are still provisional (Three) and are marked in the table in italics. These tumors have been found to be distinct clinicopathologically and have distinct molecular alterations and/or methylation class, however, the published literature is still limited to a few case reports and series to ascertain the true nature of these entities.
| New Additions in the Text Section of Individual Tumor Types|| |
Essential and desirable diagnostic criteria
Essential and desirable diagnostic criteria for each tumor type have been provided in a tabular form. The essential diagnostic criteria are considered as the definitive or the must-have features. The desirable diagnostic criteria are the ones, which will support a diagnosis but are not needed per se.
Diagnostic molecular pathology
A paragraph on diagnostic molecular pathology has been added for each tumor type.
DNA methylation profiling
DNA methylation profiling has emerged as an important molecular method for CNS tumor classification. Many CNS tumor types can be diagnosed based on their methylation profiling especially some tumors with atypical morphological features as well as some rare tumor types and subtypes, for example, High grade astrocytoma with piloid features. Further, copy number profiles can also be obtained from the methylation classifier.,,,
WHO CNS5 endorses a methylome classifier for many CNS tumor types and subtypes. However, owing to problems related to methodology as well as the global availability of the test, it does not recommend methylome profiling as a primary or routine diagnostic test. For now, the WHO CNS5 classification includes the information about methylation profiling in the definitions and essential/desirable diagnostic criteria only for tumors in which the method can provide more useful guidance for diagnosis.
| Integrated Diagnosis|| |
The use of layered and integrated diagnostic reports is one of the vital features of the WHO CNS5 classification (as introduced in the 2016 classification) as it is crucial to compile the full range of diagnostic data available. The report should have integrated diagnosis at the top followed by layers that display histological typing, grading and molecular information [Table 3].
| Conclusions|| |
The adoption of the WHO CNS5 will help in the accurate diagnosis and prognostication of CNS tumors as well as improvement of their management. The importance of molecular testing has been elevated in WHO CNS5 and this will have a clinical impact in many cases, for example, diagnosis of astrocytoma, IDH mutant grade 4 and GB, IDH wild type based on molecular parameters even in the absence of high-grade features on histology.
The improved definition and recognition of new tumor entities are expected to lead to the design of more specific therapies which will facilitate improved patient management. The changes in this classification will also have important implications for the design, implementation, and interpretation of clinical trials. Many genetic alterations identified are targetable and the WHO CNS5 will ensure enrolling of more homogeneous populations of patients in clinical trials, thus facilitating proper evaluation of targeted therapies.
However, it must be emphasized that any classification is imperfect and primed for changes and modifications with advancing knowledge. WHO CNS5 classification thus represents the most recent knowledge in the field but is likely to be an intermediate stage for more precise future classifications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zulch KJ. Histological Typing of Tumors of the Central Nervous System. Vol 21. Geneva: World Health Organization; 1979.
Kleihues P, Burger PC, Scheithauer BW. Histological Typing of Tumors of the Central Nervous System. Berlin: Springer Verlag; 1993.
Kleihues P, Cavenee WK. World Health Organization Classification of Tumors of the Nervous System. Lyon: WHO/IARC; 2000.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. World Health Organization Histological Classification of Tumors of the Central Nervous System. 4th
ed. Lyon: International Agency for Research on Cancer; 2007.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumors of the Central Nervous System. Revised 4th
ed. Lyon: International Agency for Research on Cancer; 2016.
Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M. Advances in the molecular genetics of gliomas-Implications for classification and therapy. Nat Rev Clin Oncol 2017;14:434-52.
Pietrak B, Zhao H, Qi H, Quinn C, Gao E, Boyer JG, et al
. A tale of two subunits: How the neomorphic R132H IDH1 mutation enhances production of αHG. Biochemistry 2011;50:4804-12.
Louis DN, Perry A, Reifenberger G, Deimling AV, Branger DF, Cavenee WK, et al
. The 2016 World health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016;131:803-20.
Louis DN, Wesseling P, Brandner S, Brat DJ, Ellison DW, Giangaspero F, et al
. Data sets for the reporting of tumors of the central nervous system: Recommendations from the international collaboration on cancer reporting. Arch Pathol Lab Med 2020;144:196-206.
Louis DN, Wesseling P, Paulus W, Giannini C, Batchelor TT, Cairncross JG, et al
. cIMPACT-NOW update 1: Not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol 2018;135:481-4.
Louis DN, Giannini C, Capper D, Paulus W, Branger DF, Lopes MB, et al
. cIMPACT-NOW update 2: Diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 2018;135:639-42.
Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al
. cIMPACT-NOW update 3: Recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol 2018;136:805-10.
Ellison DW, Hawkins C, Jones DTW, Thomas AO, Pfister SM, Reifenberger G, et al
. cIMPACT-NOW update 4: Diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol 2019;137:683-7.
Brat DJ, Aldape K, Colman H, Branger DF, Fuller GN, Giannini C, et al
. cIMPACT-NOW update 5: Recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 2020;139:603-8.
Louis DN, Wesseling P, Aldape K, Brat DJ, Capper D, Cree IA, et al
. cIMPACT-NOW update 6: New entity and diagnostic principle recommendations of the cIMPACT Utrecht meeting on future CNS tumor classification and grading. Brain Pathol 2020;30:844-56.
Ellison DW, Aldape KD, Capper D, Fouladi M, Gilbert MR, Gilbertson RJ, et al
. cIMPACT-NOW update 7: Advancing the molecular classification of ependymal tumors. Brain Pathol 2020;30:863-6.
WHO Classification of Tumors Editorial Board. World Health Organization Classification of Tumors of the Central Nervous System. 5th
ed. Lyon: International Agency for Research on Cancer; 2021.
Bruford EA, Braschi B, Denny P, Jones TEM, Seal RL, Tweedie S. Guidelines for human gene nomenclature. Nat Genet 2020;52:754-8.
den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, Jordan JM, et al
. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat 2016;37:564-9.
McGowan-Jordan J, Hastings RJ, Moore S, editors. An International System for Human Cytogenomic Nomenclature. Basel: S. Karger; 2020.
von Deimling A, Ono T, Shirahata M, Louis DN. Grading of diffuse astrocytic gliomas: A review of studies before and after the advent of IDH testing. Semin Neurol 2018;38:19-23.
Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, et al
. International society of neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014;24:429-35.
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al
. DNA methylation-based classification of central nervous system tumors. Nature 2018;555:469-74.
Capper D, Stichel D, Sahm F, Jones DT, Schrimpf D, Sill M, et al
. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: The Heidelberg experience. Acta Neuropathol 2018;136:181-210.
Jaunmuktane Z, Capper D, Jones DT, Schrimpf D, Sill M, Dutt M, et al
. Methylation array profiling of adult brain tumors: Diagnostic outcomes in a large, single centre. Acta Neuropathol Commun 2019;7:24.
Priesterbach-Ackley LP, Boldt HB, Petersen JK, Bervoets N, Scheie D, Ulhoi P, et al
. Brain tumor diagnostics using a DNA methylation-based classifier as a diagnostic support tool. Neuropathol Appl Neurobiol 2020;46:478-92.
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]