Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors

Author:

Hayashi Takahiro12ORCID,Tateishi Kensuke123ORCID,Matsuyama Shinichiro12ORCID,Iwashita Hiromichi4ORCID,Miyake Yohei12ORCID,Oshima Akito12ORCID,Honma Hirokuni12ORCID,Sasame Jo12ORCID,Takabayashi Katsuhiro12ORCID,Sugino Kyoka123ORCID,Hirata Emi12ORCID,Udaka Naoko5ORCID,Matsushita Yuko6ORCID,Kato Ikuma7ORCID,Hayashi Hiroaki28ORCID,Nakamura Taishi129ORCID,Ikegaya Naoki1ORCID,Takayama Yutaro12ORCID,Sonoda Masaki12ORCID,Oka Chihiro12ORCID,Sato Mitsuru1ORCID,Isoda Masataka12ORCID,Kato Miyui23ORCID,Uchiyama Kaho23ORCID,Tanaka Tamon12ORCID,Muramatsu Toshiki12ORCID,Miyake Shigeta1ORCID,Suzuki Ryosuke110ORCID,Takadera Mutsumi1112ORCID,Tatezuki Junya11ORCID,Ayabe Junichi12ORCID,Suenaga Jun1ORCID,Matsunaga Shigeo13ORCID,Miyahara Kosuke14ORCID,Manaka Hiroshi15ORCID,Murata Hidetoshi1ORCID,Yokoyama Takaakira16ORCID,Tanaka Yoshihide12ORCID,Shuto Takashi13ORCID,Ichimura Koichi6ORCID,Kato Shingo17ORCID,Yamanaka Shoji5ORCID,Cahill Daniel P.18ORCID,Fujii Satoshi57ORCID,Shankar Ganesh M.18ORCID,Yamamoto Tetsuya1ORCID

Affiliation:

1. 1Department of Neurosurgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

2. 2Neurosurgical-Oncology Laboratory, Yokohama City University, Yokohama, Japan.

3. 3Laboratory of Biopharmaceutical and Regenerative Science, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan.

4. 4Department of Pathology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

5. 5Department of Diagnostic Pathology, Yokohama City University Hospital, Yokohama, Japan.

6. 6Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan.

7. 7Department of Molecular Pathology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

8. 8Department of Pediatrics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

9. 9Department of Neurosurgery, Yokohama City University Medical Center, Yokohama, Japan.

10. 10Department of Neurosurgery, Odawara Municipal Hospital, Odawara, Japan.

11. 11Department of Neurosurgery, Yokohama City Minato Red Cross Hospital, Yokohama, Japan.

12. 12Department of Neurosurgery, Yokosuka Kyosai Hospital, Yokosuka, Japan.

13. 13Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan.

14. 14Department of Neurosurgery, National Hospital Organization Yokohama Medical Center, Yokohama, Japan.

15. 15Department of Neurosurgery, Yokohama Minami Kyosai Hospital, Yokohama, Japan.

16. 16Department of Neurosurgery, Hiratsuka Kyosai Hospital, Hiratsuka, Japan.

17. 17Department of Clinical Cancer Genomics, Yokohama City University, Yokohama, Japan.

18. 18Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

Abstract Purpose: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. Experimental Design: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. Results: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. Conclusions: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Funder

Japan Society for the Promotion of Science

Strategic Research Promotion of Yokohama City University Research

Yokohama Foundation for Advanced Medical Science

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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