John W Rutland1, Corey M Gill2, Joshua Loewenstern2, Hanane Arib3, Margaret Pain2, Melissa Umphlett4, Yayoi Kinoshita4, Russell B McBride4,5, Joshua Bederson2, Michael Donovan4, Robert Sebra3,6, Raj K Shrivastava2, Mary Fowkes4. 1. Department of Neurosurgery, Icahn School of Medicine At Mount Sinai, 1468 Madison Avenue; Floor 8, New York, NY, 10129, USA. jack.rutland@icahn.mssm.edu. 2. Department of Neurosurgery, Icahn School of Medicine At Mount Sinai, 1468 Madison Avenue; Floor 8, New York, NY, 10129, USA. 3. Department of Genetics and Genomic Sciences, Icahn School of Medicine At Mount Sinai, New York, NY, USA. 4. Department of Pathology, Icahn School of Medicine At Mount Sinai, New York, NY, USA. 5. The Institute for Translational Epidemiology, Icahn School of Medicine At Mount Sinai, New York, NY, USA. 6. Sema4, A Mount Sinai Venture, Stamford, CT, USA.
Abstract
BACKGROUND: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown. METHODS: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study. RESULTS: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046. CONCLUSIONS: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.
BACKGROUND: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown. METHODS: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study. RESULTS: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046. CONCLUSIONS: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.
Authors: Leland Rogers; Igor Barani; Marc Chamberlain; Thomas J Kaley; Michael McDermott; Jeffrey Raizer; David Schiff; Damien C Weber; Patrick Y Wen; Michael A Vogelbaum Journal: J Neurosurg Date: 2015-01 Impact factor: 5.115
Authors: Corey M Gill; Joshua Loewenstern; John W Rutland; Hanane Arib; Nancy Francoeur; Ying-Chih Wang; Nataly Fishman; Margaret Pain; Melissa Umphlett; Yayoi Kinoshita; Russell B McBride; Joshua Bederson; Michael Donovan; Melissa Smith; Robert Sebra; Raj K Shrivastava; Mary Fowkes Journal: Neuro Oncol Date: 2020-07-07 Impact factor: 12.300
Authors: Corey M Gill; Joshua Loewenstern; John W Rutland; Hanane Arib; Margaret Pain; Melissa Umphlett; Yayoi Kinoshita; Russell B McBride; Joshua Bederson; Michael Donovan; Robert Sebra; Mary Fowkes; Raj K Shrivastava Journal: Neurosurgery Date: 2020-02-01 Impact factor: 4.654
Authors: Wenya Linda Bi; Lakshmi Nayak; David M Meredith; Joseph Driver; Ziming Du; Samantha Hoffman; Yvonne Li; Eudocia Quant Lee; Rameen Beroukhim; Mikael Rinne; Ricardo McFaline-Figueroa; Ugonma Chukwueke; Christine McCluskey; Sarah Gaffey; Andrew D Cherniack; Jennifer Stefanik; Lisa Doherty; Christina Taubert; Meghan Cifrino; Deborah LaFrankie; Thomas Graillon; Patrick Y Wen; Keith L Ligon; Ossama Al-Mefty; Raymond Y Huang; Alona Muzikansky; E Antonio Chiocca; Sandro Santagata; Ian F Dunn; David A Reardon Journal: Neuro Oncol Date: 2022-01-05 Impact factor: 12.300