Evidence-Based Diagnostic Algorithm for Glioma: Analysis of the Results of Pathology Panel Review and Molecular Parameters of EORTC 26951 and 26882 Trials.
OBJECTIVE
With the rapid discovery of prognostic and predictive molecular parameters for glioma, the status of histopathology in the diagnostic process should be scrutinized. Our project aimed to construct a diagnostic algorithm for gliomas based on molecular and histologic parameters with independent prognostic values.


METHODS
The pathology slides of 636 patients with gliomas who had been included in EORTC 26951 and 26882 trials were reviewed using virtual microscopy by a panel of six neuropathologists who independently scored 18 histologic features and provided an overall diagnosis. The molecular data for IDH1, 1p/19q loss, EGFR amplification, loss of chromosome 10 and chromosome arm 10q, gain of chromosome 7, and hypermethylation of the promoter of MGMT were available for some of the cases. The slides were divided in discovery (n = 426) and validation sets (n = 210). The diagnostic algorithm resulting from analysis of the discovery set was validated in the latter.


RESULTS
In 66% of cases, consensus of overall diagnosis was present. A diagnostic algorithm consisting of two molecular markers and one consensus histologic feature was created by conditional inference tree analysis. The order of prognostic significance was: 1p/19q loss, EGFR amplification, and astrocytic morphology, which resulted in the identification of four diagnostic nodes. Validation of the nodes in the validation set confirmed the prognostic value (P < .001).


CONCLUSIONS
We succeeded in the creation of a timely diagnostic algorithm for anaplastic glioma based on multivariable analysis of consensus histopathology and molecular parameters.
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland. j.m.kros@erasmusmc.nl.
Johan M
JM
Kros
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Karin
K
Huizer
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Aurelio
A
Hernández-Laín
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Gianluca
G
Marucci
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Alex
A
Michotte
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Bianca
B
Pollo
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Elisabeth J
EJ
Rushing
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Teresa
T
Ribalta
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Pim
P
French
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
David
D
Jaminé
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Nawal
N
Bekka
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Denis
D
Lacombe
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Martin J
MJ
van den Bent
Johan M. Kros and Karin Huizer, Erasmus Medical Center; Pim French and Martin J. van den Bent, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Aurelio Hernández-Laín, Hospital Universitario 12 de Octubre Reseach Institute, Madrid; Teresa Ribalta, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gianluca Marucci, Bellaria Hospital, University of Bologna, Bologna; Bianca Pollo, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico "C. Besta," Milano, Italy; Alex Michotte, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; David Jaminé, Nawal Bekka, Denis Lacombe, and Thierry Gorlia, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; and Elisabeth J. Rushing, Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Thierry
T
Gorlia
D000328:Adult; D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001932:Brain Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D019317:Evidence-Based Medicine; D005260:Female; D005784:Gene Amplification; D005910:Glioma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008853:Microscopy; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014584:User-Computer Interface
D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D045643:DNA Repair Enzymes