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Draft:CIMPACT-NOW

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cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy)

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cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was created under the sponsorship of the International Society of Neuropathology (ISN)[1] in late 2016—following publication of the 2016 Updated 4th Edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System “blue book”[2]—to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications[3][4]. While it is understood that the major impact on international brain tumor classification comes about through the WHO classification update process (cIMPACT-NOW is “Not Official WHO”), it has been hoped that this additional process will “see impact” in selected tumor types and in periods between the WHO classification updates. Thus, cIMPACT-NOW updates are not intended to supplant the existing WHO classification, but to provide possible guidelines for practicing diagnosticians and future WHO classification updates.

Work on the 2016 Updated 4th Edition World Health Organization (WHO) Classification of Tumours of the Central Nervous System[2][5] brought up the question of how tumor classifications could keep up with the rapid pace of molecular discoveries in neuro-oncology. Discussions by a number of tumor neuropathologists, led by David Louis[6] and Andreas von Deimling[7], resulted in the idea of a consortium that worked in the time periods between WHO classifications. Each update is the product of a cIMPACT-NOW working committee, with vetting of the guidelines by all members of both the cIMPACT-NOW Steering Committee and Clinical Advisory Panel, as well as by members of the ISN Executive.

The 2021 5th Edition World Health Organization (WHO) Classification of Tumours of the Central Nervous System[8][9] largely adopted the recommendations of the first seven cIMPACT-NOW updates. For example, Mortensen et al. stated that "In 2018 the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) released their third update, wherein they recommended IDH-wildtype diffuse astrocytic tumors with either TERT promoter mutation, EGFR gene amplification or a combination of gain of entire chromosome 7 and loss of entire chromosome 10 (+7/−10) should be considered WHO grade 4 due to much more aggressive behavior, despite lacking the typical histological features... In cIMPACT-NOW update 6, with sufficient clinical data confirming that survival for DAG-G is similar to glioblastomas IDH-wildtype, the following diagnostic criteria were suggested for glioblastoma: microvascular proliferation, or necrosis, or one (or more); TERT promoter mutation, EGFR amplification or + 7/− 10. These suggestions were incorporated into the fifth edition of WHO-CNS (WHO-CNS5)."[10] The availability of these recommendations was especially helpful for updating the 5th edition since the Covid-19 pandemic necessitated on-line meetings of the expert editorial panel, which made detailed discussions more difficult.

Gonzalez Castro summarized that the first seven cIMPACT-NOW updates "translate to recent advances in our understanding of the molecular underpinnings of CNS tumors. Salient recommendations include those that provide guidance for how even in the absence of histopathological characteristics of the highest malignancy grade, molecular markers can be used to reach a diagnosis of glioblastoma, IDH–wild-type or astrocytoma, IDH-mutant, grade IV. The cIMPACT-NOW guidelines have important implications for clinical practice and for the design and interpretation of clinical trials. Additionally, cIMPACT-NOW has proposed several changes regarding diagnostic principles and nomenclature, as well as made suggestions on which tumor types have now emerged as mature enough to deserve a separate status in a next WHO [5th edition] classification."[11] A concern was added that "the fact that these updates have been published in neuropathology journals may have limited the propagation of this information to the wider clinical neuro-oncology community."[11]

Following the success of the WHO CNS 5th edition capitalizing on cIMPACT-NOW updates, cIMPACT-NOW began a second phase, transferring overall leadership from David Louis[6] to Pieter Wesseling[12] and reconstituting its committees in order to formulate new topics and new working groups. To date, this second phase has resulted in four new updates (cIMPACT-NOW updates 8, 9, 10, and 11) and two working committees still in progress. The 11 published updates are summarized below.  The interested reader is referred to the full publications for detailed information. All cIMPACT-NOW updates have been published as public access.

cIMPACT-NOW Update 1

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cIMPACT-NOW Update 1 came from deliberations of Working Committee 3 and was published in 2018[13]. It clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the term NEC (Not Elsewhere Classified), allowing the ready distinction of diagnoses that result from lack of necessary diagnostic (e.g., molecular) information from diagnoses that have had necessary diagnostic testing that shows non-canonical results.

  1. For an NOS designation, diagnostic information (histological or molecular) necessary to assign a more specific WHO diagnosis is not available.
  2. For an NEC designation, necessary diagnostic testing has been successfully performed, but the results do not readily allow for a WHO 2016 diagnosis, e.g., because of mismatch between clinical, (immuno)histological and/or genetic features, or because it concerns a new/emerging entity that is not yet part of the WHO classification.

cIMPACT-NOW Update 2

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cIMPACT-NOW Update 2 also came from deliberations of Working Committee 3 and was published in 2018[14]. It issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M-mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant.

  1. The term Diffuse Midline Glioma, H3 K27M­­–mutant should be reserved for tumors that are diffuse (i.e., infiltrating), midline, gliomas and H3 K27M-mutant, and should not be applied to other tumors (e.g., ependymomas) that can be H3 K27M–mutant.
  2. In the setting of a diffuse astrocytic-appearing WHO grade II or III glioma that has IDH mutation as well as loss of ATRX nuclear expression and/or strong, diffuse p53 immunopositivity, a diagnosis of Diffuse Astrocytoma, IDH-mutant or Anaplastic Astrocytoma, IDH-mutant can be rendered in the absence of 1p/19q testing.

cIMPACT-NOW Update 3

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cIMPACT-NOW Update 3 came from Working Committee 1 and was published in 2018[15]. It determined molecular criteria that could be used in the setting of an IDH-wildtype WHO grade II or grade III diffuse astrocytic glioma to infer that the tumor would follow a course more similar to a WHO grade IV glioblastoma.

  1. For diffuse astrocytic gliomas of histologic grade II and III, the finding of any or all of the following molecular criteria corresponds to WHO grade IV behavior and tumors can be referred to as Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV:
  2. EGFR amplification

and/or

  1. Whole chromosome 7 gain and whole chromosome 10 loss (+7/-10)

and/or

  1. TERT promoter mutation

These criteria have been investigated in series such as those of Molica et al., who concluded that "Our data set on 313 cases confirmed the favorable prognostic value of IDH1/2 mutations, and validated the cIMPACT-NOW 3 signature as high-risk marker, thus confirming prognostically relevant subgroups."[16] Studies have also evaluated the addition of radiological information to the pathology-based criteria of cIMPACT-NOW.[17] The recommendations of cIMPACT-NOW Update 3 and Update 5 were endorsed by European Association of Neuro-Oncology (EANO) guidelines[18] and subsequently incorporated into the 5th edition of the CNS WHO Classification.[9]

cIMPACT-NOW Update 4

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cIMPACT-NOW Update 4 came from Working Committee 2 and was published in 2019[19]. It reviewed the status of WHO grade II IDH-wt / H3-wt diffuse gliomas, focusing on those with a BRAFV600E mutation, FGFR1 alteration, or a MYB or MYBL1 rearrangement, which tend to present in childhood, and recommended the use of an integrated diagnosis to combine their histologic and genetic features, as suggested in the following:

  1. Diffuse glioma, MYB-altered
  2. Diffuse glioma, MYBL1-altered
  3. Diffuse glioma, FGFR1 TKD-duplicated
  4. Diffuse glioma, FGFR1-mutant
  5. Diffuse glioma, BRAFV600E-mutant (but without CDKN2A/B deletion)
  6. Diffuse glioma, other MAPK pathway alteration

cIMPACT-NOW Update 5

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cIMPACT-NOW Update 5 came from Working Committee 1 and was published in 2020[20]. It reviewed data to propose an approach to grading of IDH-mutant diffuse astrocytomas and suggested clear separation of IDH-wildtype from IDH-mutant astrocytic tumors as well as the use of Arabic rather than Roman numerals for grading. A highly significant feature of this update was the recommendation that molecular information should be used for diagnoses: both the establishment of IDH mutation status and the determination of whether CDKN2A homozygous deletion is present. The recommendations of cIMPACT-NOW Update 3 and Update 5 were endorsed by European Association of Neuro-Oncology (EANO) guidelines[18] and subsequently incorporated into the 5th edition of the CNS WHO Classification.[9] In addition, given the importance of tumor grading for diffuse astrocytomas, the criteria are being revisited in 2025 as part of another cIMPACT-NOW working committee.

cIMPACT-NOW Update 6

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cIMPACT-NOW Update 6 came from an expanded version of Working Committee 3 and was published in 2020[21]. This update was different from the prior five updates in that it was the produce of an in-person meeting in Utrecht and included WHO representatives, the latter being included because it was anticipated that WHO CNS meetings would begin in early 2020. The meeting was fortunate because the Covid-19 pandemic prevented in-person WHO meetings in the spring of 2020. cIMPACT-NOW Update 6 review possible new entities that might be considered for inclusion in the next WHO classification. The group recommended a substantial number of newly recognized types and subtypes for inclusion in future CNS tumor classifications and also endorsed a number of principles relating to classification categories, approaches to classification, nomenclature, and grading. One of the major recommendations related to a molecular definition of glioblastoma, i.e., if a tumor was IDH- and H3-wildtype and had either TERT promoter mutation, EGFR amplification or +7/−10 copy number changes-- a definition that was incorporated into the 2021 5th edition CNS WHO classification[8] and used by subsequent papers as criteria for further study.[22] The proposal of new tumor types also prompted further studies by other groups, such as Chen et al., of some of these entities, leading to further definitional refinements.[23]

cIMPACT-NOW Update 7

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cIMPACT-NOW Update 7 came from Working Committee 2 and was published in 2020[24]. The group reviewed data on ependymal tumors and made recommendations about the molecular classification of these lesions, including the distinction of PFA and PFB posterior fossa ependymomas and the incorporation of specific molecular markers (e.g., C11orf95 [at the time], YAP1 and MYCN. Importantly, the recommended classification and significance of molecular alterations were dependent on anatomic site, prompting incorporation of anatomic site into the classification proposal. This combined anatomical-molecular approach formed the basis of the 2021 5th edition CNS WHO classification[8] and the reclassification by cIMPACT-NOW Update 7 was cited by a large ependymoma consortium as reinforcing the importance of reclassification of ependymal tumors as new molecular data emerges.[25]

cIMPACT-NOW Update 8

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cIMPACT-NOW Update 8 was the first update following the 2021 5th edition CNS WHO classification. It came from Working Committee 1 and was published on line in 2024[26]. The group addressed the influence of recently identified molecular markers on the grading of meningiomas, proposing to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants. Guidance was also provided for more standardized morphological evaluation and interpretation, e.g., pertaining to brain invasion. Using recommendations of the cIMPACT-NOW Update 8, an independent study from Landry et al. confirmed the value of assessing copy number changes (in particular, 1p and 22q loss as well as 1q gain) in grading meningiomas, including that "additional investigation into the role of 1p loss without 22q loss is needed, given the rarity of this event, aligning our conclusions with the recent cIMPACT-NOW statement."[27]

cIMPACT-NOW Update 9

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cIMPACT-NOW Update 9 came from Working Committee 1 and was published on line in 2024[28]. The group addressed the rapidly burgeoning area of DNA methylation profiling for CNS tumor diagnosis. Use of DNA methylation signatures had been endorsed in the 2021 CNS WHO classification in specific situations, but the use of the technology had broadened considerably since then. Recommendations emphasized the attributes and limitations of the modality and that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. The group also stressed the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array.

cIMPACT-NOW Update 10

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cIMPACT-NOW Update 10 came from Working Committee 1 and was published on line in 2025[29]. The group addressed the thorny problem of how to define a tumor type in light of the wide array of data types now available (e.g., clinical, histopathological, genetic, genomic and other -omics, DNA methylation). The eventual recommendations proposed that different combinations of such features could fulfill criteria to define a type and potentially a subtype, and suggested the types of publications necessary to support definition of a new tumor type or subtype.

cIMPACT-NOW Update 11

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A working group has submitted a manuscript addressing clarifications to the 5th Edition CNS WHO classification[8], with the manuscript now in press.

  1. ^ "International Society of Neuropathology, News". 2019-03-20.
  2. ^ a b World Health Organization Histological Classification of Tumours of the Central Nervous System, updated 4th edition (Updated 4th ed.). Lyon, France: International Agency for Research on Cancer. 2016.
  3. ^ Louis, D. N.; Aldape, K.; Brat, D. J.; Capper, D.; Ellison, D. W.; Hawkins, C.; Paulus, W.; Perry, A.; Reifenberger, G.; Figarella-Branger, D.; Wesseling, P.; Batchelor, T. T.; Gregory Cairncross, J.; Pfister, S. M.; Rutkowski, S.; Weller, M.; Wick, W.; von Deimling, A. (2017). "cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy): a new initiative in advancing nervous system tumor classification". Brain Pathology. 27 (6): 851–852. doi:10.1111/bpa.12457. PMC 8028991. PMID 27997995.
  4. ^ Louis, D. N.; Aldape, K.; Brat, D. J.; Capper, D.; Ellison, D. W.; Hawkins, C.; Paulus, W.; Perry, A.; Reifenberger, G.; Figarella-Branger, D.; Wesseling, P.; Batchelor, T. T.; Cairncross, J. G.; Pfister, S. M.; Rutkowski, S.; Weller, M.; Wick, W.; von Deimling, A. (2017). "Announcing cIMPACT-NOW: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy". Acta Neuropathologica. 133 (1): 1–3. doi:10.1007/s00401-016-1646-x. PMID 27909809.
  5. ^ Louis, D. N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W. K.; Ohgaki, H.; Wiestler, O. D.; Kleihues, P.; Ellison, D. W. (2016). "The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary". Acta Neuropathological. 131 (6): 803–820. doi:10.1007/s00401-016-1545-1. PMID 27157931.
  6. ^ a b "David Louis". Retrieved 2025-07-25.
  7. ^ "Andreas von Deimling". {{cite web}}: |archive-date= requires |archive-url= (help)
  8. ^ a b c d World Health Organization Histological Classification of Tumours of the Central Nervous System. Lyon, France: International Agency for Research on Cancer. 2021.
  9. ^ a b c Louis, D. N.; Perry, A.; Wesseling, P.; Brat, D. J.; Cree, I. A.; Figarella-Branger, D.; Hawkins, C.; Ng, H. K.; Pfister, S. M.; Reifenberger, G.; Soffietti, R.; von Deimling, A.; Ellison, D. W. (2021). "The 2021 WHO Classification of Tumors of the Central Nervous System: a summary". Neuro-Oncology. 23 (8): 1231–1251. doi:10.1093/neuonc/noab106. PMC 8328013. PMID 34185076.
  10. ^ Mortensen, D. "Impact of new molecular criteria on diagnosis and survival of adult glioma patients". IBRO Neuroscience Reports. PMID 36204252.
  11. ^ a b Gonzalez Castro, LN. "The cIMPACT-NOW updates and their significance to current neuro-oncology practice". Neuro-Oncology Practice. PMID 33664964.
  12. ^ "Pieter Wesseling". Retrieved 2025-07-25.
  13. ^ Louis, D. N.; Wesseling, P.; Paulus, W.; Giannini, C.; Batchelor, T. T.; Cairncross, J. G.; Capper, D.; Figarella-Branger, D.; Lopes, M. B.; Wick, W.; Van Den Bent, M. (2018). "cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC)". Acta Neuropathologica. 135 (3): 481–484. doi:10.1007/s00401-018-1808-0. PMID 29372318.
  14. ^ Louis, D. N.; Giannini, C.; Capper, D.; Paulus, W.; Figarella-Branger, D.; Lopes, M. B.; Batchelor, T. T.; Cairncross, J. G.; Van Den Bent, M.; Wick, W.; Wesseling, P. (2018). "cIMPACT-NOW update 2: diagnostic clarifications for Diffuse Midline Glioma, H3 K27M–mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant". Acta Neuropathologica. 135 (4): 639–642. doi:10.1007/s00401-018-1826-y. PMID 29497819.
  15. ^ Brat, D. J.; Aldape, K.; Colman, H.; Holland, E. C.; Louis, D. N.; Jenkins, R. B.; Kleinschmidt-Demasters, B. K.; Perry, A.; Reifenberger, G.; Stupp, R.; von Deimling, A.; Weller, M. (2018). "cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV"". Acta Neuropathologica. 136 (5): 805–810. doi:10.1007/s00401-018-1913-0. PMC 6204285. PMID 30259105.
  16. ^ Molica, C. "Optimizing the risk stratification of astrocytic tumors by applying the cIMPACT-NOW Update 3 signature: real-word single center experience". Science Reports. PMID 37973912.
  17. ^ Roux, A (2021). "Prognostic relevance of adding MRI data to WHO 2016 and cIMPACT-NOW updates for diffuse astrocytic tumors in adults". Brain Pathology. PMID 33336392.
  18. ^ a b Weller, M. "EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood". Nature Reviews Clinical Oncology. PMID 33293629.
  19. ^ Ellison, D. W.; Hawkins, C.; Jones DTW; Onar-Thomas, A.; Pfister, S. M.; Reifenberger, G.; Louis, D. N. (2019). "cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation". Acta Neuropathologica. 137 (4): 683–687. doi:10.1007/s00401-019-01987-0. PMID 30848347.
  20. ^ Brat, D. J.; Aldape, K.; Colman, H.; Figrarella-Branger, D.; Fuller, G. N.; Giannini, C.; Holland, E. C.; Jenkins, R. B.; Kleinschmidt-Demasters, B.; Komori, T.; Kros, J. M.; Louis, D. N.; McLean, C.; Perry, A.; Reifenberger, G.; Sarkar, C.; Stupp, R.; Van Den Bent, M. J.; von Deimling, A.; Weller, M. (2020). "cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas". Acta Neuropathologica. 139 (3): 603–608. doi:10.1007/s00401-020-02127-9. PMC 8443062. PMID 31996992.
  21. ^ Louis, D. N.; et al. (2020). "cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading". Brain Pathology. 30 (4): 844–856. doi:10.1111/bpa.12832. PMC 8018152. PMID 32307792.
  22. ^ Teske, N. "Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?". J Neuro-Oncology. PMID 34902093.
  23. ^ Chen, W (2020). "Central nervous system neuroepithelial tumors with MN1-alteration: an individual patient data meta-analysis of 73 cases". Brain Tumor Pathology. PMID 32601775.
  24. ^ Ellison, D. W.; Aldape, K. D.; Capper, D.; Fouladi, M.; Gilbert, M. R.; Gilbertson, R. J.; Hawkins, C.; Merchant, T. E.; Pajtler, K.; Venneti, S.; Louis, D. N. (2020). "cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors". Brain Pathology. 30 (5): 863–866. doi:10.1111/bpa.12866. PMC 8018155. PMID 32502305.
  25. ^ Tauziede-Espariat, A. "Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions". Acta Neuropathologica Communications. PMID 34389065.
  26. ^ Sahm, F.; Aldape, K. D.; Brastianos, P. K.; Brat, D. J.; Dahiya, S.; von Deimling, A.; Giannini, C.; Gilbert, M. R.; Louis, D. N.; Raleigh, D. R.; Reifenberger, G.; Santagata, S.; Sarkar, C.; Zadeh, G.; Wesseling, P.; Perry, A. (2025). "cIMPACT-NOW update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas". Neuro-Oncology. 27 (2): 319–330. doi:10.1093/neuonc/noae170. PMC 11812049. PMID 39212325.
  27. ^ Landry, AP (2025). "Chromosome 1p Loss and 1q Gain for Grading of Meningioma". JAMA Oncology. PMID 40178835.
  28. ^ Aldape, K.; Capper, D.; von Deimling, A.; Giannini, C.; Gilbert, M. R.; Hawkins, C.; Hench, J.; Jacques, T. S.; Jones, D.; Louis, D. N.; Mueller, S.; Orr, B. A.; Nasrallah, M.; Pfister, S. M.; Sahm, F.; Snuderl, M.; Solomon, D.; Varlet, P.; Wesseling, P. (2025). "cIMPACT-NOW update 9: Recommendations on utilization of genome-wide DNA methylation profiling for central nervous system tumor diagnostics". Neuro-Oncology Advances. 7 (1): vdae228. doi:10.1093/noajnl/vdae228. PMC 11788596. PMID 39902391.
  29. ^ Hawkins, C.; Aldape, K.; Capper, D.; von Deimling, A.; Giannini, C.; Gilbert, M. R.; Jacques, T. S.; Jones, D.; Komori, T.; Louis, D. N.; Mueller, S.; Nasrallah, M.; Orr, B. A.; Perry, A.; Pfister, S. M.; Sahm, F.; Sarkar, C.; Snuderl, M.; Solomon, D.; Varlet, P.; Wesseling, P.; Reifenberger, G. (2025). "cIMPACT-NOW update 10: Recommendations for defining new types for central nervous system tumor classification". Brain Pathology: e70018. doi:10.1111/bpa.70018. PMID 40420507.
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