Hirokazu Takami1,2, Kohei Fukuoka1,3, Shintaro Fukushima1, Taishi Nakamura1,4, Akitake Mukasa2,5, Nobuhito Saito2, Takaaki Yanagisawa3, Hideo Nakamura5,6, Kazuhiko Sugiyama7, Masayuki Kanamori8, Teiji Tominaga8, Taketoshi Maehara9, Mitsutoshi Nakada10, Yonehiro Kanemura11, Akio Asai12, Hideo Takeshima13, Yuichi Hirose14, Toshihiko Iuchi15, Motoo Nagane16, Koji Yoshimoto17, Akira Matsumura18, Kazuhiko Kurozumi19, Hiroyuki Nakase20, Keiichi Sakai21, Tsutomu Tokuyama22,23, Soichiro Shibui24,25, Yoichi Nakazato24, Yoshitaka Narita26, Ryo Nishikawa27, Masao Matsutani27, Koichi Ichimura1. 1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. 3. Division of Pediatric Neuro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan. 4. Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan. 5. Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 6. Department of Neurosurgery, Kurume University, Fukuoka, Japan. 7. Department of Neurosurgery, Hiroshima University Faculty of Medicine, Hiroshima, Japan. 8. Department of Neurosurgery, Tohoku University School of Medicine, Miyagi, Japan. 9. Department of Neurosurgery, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan. 10. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan. 11. Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan. 12. Department of Neurosurgery, Kansai Medical University Hospital, Osaka, Japan. 13. Department of Neurosurgery, University of Miyazaki Faculty of Medicine, Miyazaki, Japan. 14. Department of Neurosurgery, Fujita Health University Hospital, Aichi, Japan. 15. Department of Neurosurgery, Chiba Cancer Center, Chiba, Japan. 16. Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan. 17. Department of Neurosurgery, Kyusyu University Hospital, Fukuoka, Japan. 18. Department of Neurosurgery, University of Tsukuba Hospital, Ibaraki, Japan. 19. Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. 20. Department of Neurosurgery, Nara Medical University, Nara, Japan. 21. Shinshu Ueda Medical Center, Nagano, Japan. 22. Department of Neurosurgery, Hamamatsu University School of Medicine, Shizuoka, Japan. 23. Department of Neurosurgery, Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan. 24. Department of Neurosurgery and Neuro-oncology, National Cancer Center Hospital, Tokyo, Japan. 25. Department of Neurosurgery, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan. 26. Department of Pathology, Hidaka Hospital, Gunma, Japan. 27. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
Abstract
BACKGROUND: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. METHODS: Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. RESULTS: All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS: The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
BACKGROUND: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. METHODS: Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. RESULTS: All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS: The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
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