cIMPACT-NOW (important updates available)

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 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”—to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. 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.  More information on cIMPACT-NOW can be found in the following publications:

Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, Paulus W, Perry A, Reifenberger G, Figarella-Branger D, Wesseling P, Batchelor TT, Cairncross JG, Pfister SM, Rutkowski, Weller M, Wick W, von Deimling A.  cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy): a new initiative in advancing nervous system tumor classification. Brain Pathol 27:851-852, 2017. PMID:27997995

Louis DN, Aldape K, Brat DJ, Capper D, Ellison DW, Hawkins C, Paulus W, Perry A, Reifenberger G, Figarella-Branger D, Wesseling P, Batchelor TT, Cairncross JG, Pfister SM, Rutkowski, Weller M, Wick W, von Deimling A.  Announcing cIMPACT-NOW: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. Acta Neuropathol 133:1-3, 2017. PMID:27909809

Since its inception, cIMPACT-NOW has at regular intervals facilitated input and consensus review of novel diagnostically relevant data and determined how such information can be practically incorporated into CNS tumor classifications.  This has resulted in a series of updates, which are summarized below.  Each update is the product of one of the three cIMPACT-NOW Working Committees, with vetting of the guidelines by all members of both the Steering Committee and Clinical Advisory Panel (see below).  The interested reader is referred to the full publications for detailed information.

cIMPACT Update 1

cIMPACT Update 1 came from deliberations of Working Committee 3 and was published in 2018. 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.

The full reference for cIMPACT Update 1 can be found at:

Louis DN, Wesseling P, Paulus W, Giannini C, Batchelor TT, Cairncross JG, Capper D, Figarella-Branger D, Lopes MB, Wick W, van den Bent M. cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC). Acta Neuropathol 135(3):481-484, 2018.  PMID:29372318

cIMPACT Update 2

cIMPACT Update 2 also came from deliberations of Working Committee 3 and was published in 2018. 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.

The full reference for cIMPACT Update 2 can be found at:

Louis DN, Giannini C, Capper D, Paulus W, Figarella-Branger D, Lopes MB, Batchelor TT, Cairncross JG, van den Bent M, Wick W, Wesseling P. cIMPACT-NOW update 2: diagnostic clarifications for Diffuse Midline Glioma, H3 K27M–mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant. Acta Neuropathol 135:639-642, 2018. PMID: 29497819

cIMPACT Update 3

cIMPACT Update 3 came from Working Committee 1 and was published in 2018. 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

The full reference for cIMPACT Update 3 can be found at:

Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, Kleinschmidt-DeMasters BK, Perry A, Reifenberger G, Stupp R, von Deimling A, Weller M. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 136:805-810, 2018.  PMID: 30259105

cIMPACT Update 4

cIMPACT Update 4 came from Working Committee 2 and was published in 2019. 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

The full reference for cIMPACT Update 4 can be found at:

Ellison DW, Hawkins C, Jones DTW, Onar-Thomas A, Pfister SM, Reifenberger G, Louis DN.  cIMPACT-NOW update 4: diffuse gliomas characterized byMYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol. https://doi.org/10.1007/s00401-019-01987-0.  PMID: 30848347

cIMPACT-NOW Rosters

STEERING COMMITTEE

David Louis (chair)

Ken Aldape

Dan Brat

David Capper

David Ellison

Dominique Figarella-Branger

Cynthia Hawkins

Takashi Komori (round 2)

Catriona McLean (round 2)

Werner Paulus

Arie Perry

Guido Reifenberger

Andreas von Deimling

Pieter Wesseling

CLINICAL ADVISORY PANEL

Tracy Batchelor

J. Gregory Cairncross

Maryam Fouladi (round 2)

Stefan Pfister

Stefan Rutkowski (round 1)

Michael Weller

Wolfgang Wick

WORKING COMMITTEE 1:

Dan Brat (chair)

Ken Aldape

Howard Colman

Eric Holland

David Louis

Robert Jenkins

Bette Kleinschmidt-DeMasters

Takashi Komori (round 2)

Catriona McLean (round 2)

Arie Perry

Guido Reifenberger

Roger Stupp

Andreas von Deimling

Michael Weller

WORKING COMMITTEE 2 (round 1):

David Ellison (chair)

Cynthia Hawkins

David Jones

David Louis

Arzu Onar

Stefan Pfister

Guido Reifenberger 

Stefan Rutkowski

WORKING COMMITTEE 2 (round 2):

David Ellison (chair)

Ken Aldape

David Capper

Maryam Fouladi

Mark Gilbert

Richard Gilbertson

Cynthia Hawkins

David Louis

Tom Merchant

Kristian Pajtler

Sriram Venneti

WORKING COMMITTEE 3 (round 1):

David Louis (chair)

Tracy Batchelor

J.Gregory Cairncross 

David Capper 

Dominique Figarella-Branger 

Caterina Giannini

M.Bea Lopes

Werner Paulus 

Martin van den Bent

Pieter Wesseling 

Wolfgang Wick

WORKING COMMITTEE 3 (round 2; Utrecht meeting)

David Louis (chair, organizer)

David Ellison (organizer)

Pieter Wesseling (organizer)

Ken Aldape

Dan Brat

David Capper

Charles Eberhart

Dominique Figarella-Branger

Maryam Fouladi

Greg Fuller

Caterina Giannini

Christine Haberler

Cynthia Hawkins

Takashi Komori

Max Kros

HK Ng

Brent Orr

Sung-Hye Park

Werner Paulus

Arie Perry

Torsten Pietsch

Guido Reifenberger

Marc Rosenblum

Felix Sahm

Chitra Sarkar

David Solomon

Uri Tabori

Martin van den Bent

Andreas von Deimling

Michael Weller