Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium

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.

“Not all that glitters is gold”: insights from the Far East and how to solve a conundrum

“…Takami and colleagues 1 report on the clinical, histopathological, and molecular features of central nervous system (CNS) germ cell tumors (GCTs). They conducted a retrospective series of 190 cases classified as primary GCTs, based on a central review from the I ntracranial Germ Cell Tumor (iGCT) Genome Analysis Consortium.…”

“…6 To date, however, studies using imatinib or dasatinb as novel therapeutic agents in progressive or relapsed GCT patients with inhibition of the Kit/Ras/Raf/mitogen-activated protein kinase (MAPK) and/or the Akt1/phosphatidylinositol-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway have yielded disappointing results. 7,8 Using array-comparative genomic hybridization and either whole-exome or targeted sequencing, Takami and colleagues 1 undertook molecular analyses on 123 and 74 of the 190 cases (74 were analyzed for both), respectively. These relatively limited molecular analyses confirmed numerous chromosomal aberrations, some which were found to be independent markers of worse prognosis (2q, 8q gain, 5q, 9p/q, 13q, 15q loss).…”

Histopathology of Parasellar Neoplasms

“…Mixed types with the presence of different tumour components are not uncommon [ 4 ]. Germ cell tumours can be divided into two risk groups: germinomas and non-germinomas, with significantly better prognosis after radio- and chemotherapy for the former group [ 91 ]. The most frequent subtype, germinoma is characterised by sheets of rounded CD117, D2-40, OCT4 and NANOG-positive cells surrounded by lymphocytes, dominantly of T-cell phenotype (Fig.…”

“…Recent molecular investigations of germ cell tumours revealed mutations in the MAPK pathway frequently associated with male gender [ 91 ]. Recurrent mutations in the mTOR pathway in intracranial germ cell tumours have emerged as potential therapeutic targets [ 92 ].…”

Diagnostic Capability of Cerebrospinal Fluid-Placental Alkaline Phosphatase Value in Intracranial Germ Cell Tumor

“…Most types of IGCT, particularly germinoma, are radiosensitive and chemosensitive [2, 5-13]. Due to the risk of invasiveness and dissemination, surgery is performed to diagnose most patients [14].…”