Raphaël Calmon1,2,3, Volodia Dangouloff-Ros4,5,6, Pascale Varlet7,8, Christophe Deroulers9, Cathy Philippe10, Marie-Anne Debily11, David Castel11, Kevin Beccaria12,13, Thomas Blauwblomme12,13, David Grevent1,2,3, Raphael Levy1,2,3, Charles-Joris Roux1,2,3, Yvonne Purcell14, Ana Saitovitch2,3, Monica Zilbovicius2,3, Christelle Dufour11,15, Stéphanie Puget12,13, Jacques Grill11,15, Nathalie Boddaert1,2,3. 1. Pediatric Radiology Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 149 rue de Sèvres, F-75015, Paris, France. 2. Université de Paris, INSERM ERL UA10, F-75015, Paris, France. 3. Université de Paris, UMR 1163, Institut Imagine, F-75015, Paris, France. 4. Pediatric Radiology Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 149 rue de Sèvres, F-75015, Paris, France. volodia.dangouloff-ros@aphp.fr. 5. Université de Paris, INSERM ERL UA10, F-75015, Paris, France. volodia.dangouloff-ros@aphp.fr. 6. Université de Paris, UMR 1163, Institut Imagine, F-75015, Paris, France. volodia.dangouloff-ros@aphp.fr. 7. Neuropathology Department, Sainte-Anne Hospital, F-75014, Paris, France. 8. Université de Paris, INSERM U894, IMA BRAIN, F-75014, Paris, France. 9. Université Paris-Saclay, CNRS/IN2P3, IJCLab, F-91405, Orsay, France. 10. Université Paris-Saclay, Neurospin, Institut Joliot, CEA, Gif-sur-Yvette, France. 11. Université Paris-Saclay, UMR8203, CNRS, F-94805, Villejuif, France. 12. Pediatric Neurosurgery Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, F-75015, Paris, France. 13. Université de Paris, F-75015, Paris, France. 14. Radiology Department, Fondation Rothschild, F-75019, Paris, France. 15. Department of Pediatric and Adolescent Oncology, Institut Gustave Roussy, F-94805, Villejuif, France.
Abstract
OBJECTIVES: The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. METHODS: Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. RESULTS: H3.1K27M mutated tumors showed higher ADC values (median 3151 μm2/s vs 1741 μm2/s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density (p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity-related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. CONCLUSIONS: H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity-related gene expression. KEY POINTS: • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor's enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor's enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).
OBJECTIVES: The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. METHODS: Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. RESULTS: H3.1K27M mutated tumors showed higher ADC values (median 3151 μm2/s vs 1741 μm2/s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density (p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity-related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. CONCLUSIONS: H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity-related gene expression. KEY POINTS: • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor's enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor's enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).
Entities:
Keywords:
Child; Diffuse intrinsic pontine glioma; Diffusion magnetic resonance imaging; Genetic association studies; Perfusion-weighted magnetic resonance imaging
Authors: David Castel; Thomas Kergrohen; Arnault Tauziède-Espariat; Alan Mackay; Samia Ghermaoui; Emmanuèle Lechapt; Stefan M Pfister; Christof M Kramm; Nathalie Boddaert; Thomas Blauwblomme; Stéphanie Puget; Kévin Beccaria; Chris Jones; David T W Jones; Pascale Varlet; Jacques Grill; Marie-Anne Debily Journal: Acta Neuropathol Date: 2020-03-19 Impact factor: 17.088
Authors: David N Louis; Arie Perry; Guido Reifenberger; Andreas von Deimling; Dominique Figarella-Branger; Webster K Cavenee; Hiroko Ohgaki; Otmar D Wiestler; Paul Kleihues; David W Ellison Journal: Acta Neuropathol Date: 2016-05-09 Impact factor: 17.088
Authors: Stephanie Puget; Kevin Beccaria; Thomas Blauwblomme; Thomas Roujeau; Syril James; Jacques Grill; Michel Zerah; Pascale Varlet; Christian Sainte-Rose Journal: Childs Nerv Syst Date: 2015-09-09 Impact factor: 1.475
Authors: David Castel; Cathy Philippe; Raphaël Calmon; Ludivine Le Dret; Nathalène Truffaux; Nathalie Boddaert; Mélanie Pagès; Kathryn R Taylor; Patrick Saulnier; Ludovic Lacroix; Alan Mackay; Chris Jones; Christian Sainte-Rose; Thomas Blauwblomme; Felipe Andreiuolo; Stephanie Puget; Jacques Grill; Pascale Varlet; Marie-Anne Debily Journal: Acta Neuropathol Date: 2015-09-23 Impact factor: 17.088
Authors: Lindsey M Hoffman; Sophie E M Veldhuijzen van Zanten; Niclas Colditz; Joshua Baugh; Brooklyn Chaney; Marion Hoffmann; Adam Lane; Christine Fuller; Lili Miles; Cynthia Hawkins; Ute Bartels; Eric Bouffet; Stewart Goldman; Sarah Leary; Nicholas K Foreman; Roger Packer; Katherine E Warren; Alberto Broniscer; Mark W Kieran; Jane Minturn; Melanie Comito; Emmett Broxson; Chie-Schin Shih; Soumen Khatua; Murali Chintagumpala; Anne Sophie Carret; Nancy Yanez Escorza; Timothy Hassall; David S Ziegler; Nicholas Gottardo; Hetal Dholaria; Renee Doughman; Martin Benesch; Rachid Drissi; Javad Nazarian; Nada Jabado; Nathalie Boddaert; Pascale Varlet; Géraldine Giraud; David Castel; Stephanie Puget; Chris Jones; Esther Hulleman; Piergiorgio Modena; Marzia Giagnacovo; Manila Antonelli; Torsten Pietsch; Gerrit H Gielen; David T W Jones; Dominik Sturm; Stefan M Pfister; Nicolas U Gerber; Michael A Grotzer; Elke Pfaff; André O von Bueren; Darren Hargrave; Guirish A Solanki; Filip Jadrijevic Cvrlje; Gertjan J L Kaspers; William P Vandertop; Jacques Grill; Simon Bailey; Veronica Biassoni; Maura Massimino; Raphaël Calmon; Esther Sanchez; Brigitte Bison; Monika Warmuth-Metz; James Leach; Blaise Jones; Dannis G van Vuurden; Christof M Kramm; Maryam Fouladi Journal: J Clin Oncol Date: 2018-05-10 Impact factor: 44.544
Authors: Gang Wu; Alexander K Diaz; Barbara S Paugh; Sherri L Rankin; Bensheng Ju; Yongjin Li; Xiaoyan Zhu; Chunxu Qu; Xiang Chen; Junyuan Zhang; John Easton; Michael Edmonson; Xiaotu Ma; Charles Lu; Panduka Nagahawatte; Erin Hedlund; Michael Rusch; Stanley Pounds; Tong Lin; Arzu Onar-Thomas; Robert Huether; Richard Kriwacki; Matthew Parker; Pankaj Gupta; Jared Becksfort; Lei Wei; Heather L Mulder; Kristy Boggs; Bhavin Vadodaria; Donald Yergeau; Jake C Russell; Kerri Ochoa; Robert S Fulton; Lucinda L Fulton; Chris Jones; Frederick A Boop; Alberto Broniscer; Cynthia Wetmore; Amar Gajjar; Li Ding; Elaine R Mardis; Richard K Wilson; Michael R Taylor; James R Downing; David W Ellison; Jinghui Zhang; Suzanne J Baker Journal: Nat Genet Date: 2014-04-06 Impact factor: 38.330
Authors: Peter Raab; Rouzbeh Banan; Arash Akbarian; Majid Esmaeilzadeh; Madjid Samii; Amir Samii; Helmut Bertalanffy; Ulrich Lehmann; Joachim K Krauss; Heinrich Lanfermann; Christian Hartmann; Roland Brüning Journal: Cancers (Basel) Date: 2022-03-09 Impact factor: 6.639