GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMOR IN KOREA?

Abstract PURPOSE To evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT). MATERIALS AND METHODS Fifty-seven patients with intracranial germ cell tumor treated with PBT between 2009 and 2016 were retrospectively analyzed. RESULTS Median follow-up duration was 63.7 months (range, 5.6–204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients (35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients except 2 patients received chemotherapy before PBT. Twenty-one patients (36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Two patients with pure germinoma in basal ganglia showed disease relapse at 3.0 and 6.9 years after PBT at the primary site and pituitary gland, respectively. There was one patient with NGGCT who died of chemotherapy-related mortality at 4.7 years after PBT while her disease was complete remission. The 7-year progression-free survival and overall survival were 70.8% and 100% for focal germinoma, 100% and 100% for disseminated germinoma, 100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively. CONCLUSIONS PBT of pure germinoma resulted in comparable clinical outcomes to that with photon radiotherapy. Our result for NGGCT is also excellent compared to other reports. Failure patterns of germ cell tumors originating in basal ganglia needs to be assessed in large pooled data.

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MPC-08 CLINICOPATHOLOGICAL ANALYSIS OF 12P GAIN IN INTRACRANIAL GERM CELL TUMORS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.105 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii23-ii23

Author(s):

Kaishi Satomi ◽

Hirokazu Takami ◽

Shintaro Fukushima ◽

Yoichi Nakazato ◽

Shota Tanaka ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumor ◽

Copy Number ◽

Mature Teratoma ◽

Methylation Status ◽

Germ Cell Tumors ◽

Copy Number Variations ◽

Cell Tumor ◽

Testicular Germ Cell ◽

Intracranial Germ Cell Tumor

Abstract BACKGROUND Gain of short arm of chromosome 12 (12p) is commonly observed in testicular germ cell tumors (tGCTs). 12p gain is also frequently seen in intracranial GCTs (iGCTs). However, little is known about the clinical significance of 12p gain in iGCTs. MATERIALS AND METHODS We have collected over 200 fresh frozen tissue samples of iGCTs through the Intracranial Germ Cell Tumor Genome Analysis Consortium in Japan. Firstly, we analyzed DNA methylation status in 83 iGCTs, 3 seminomas and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA). Idat files were processed using R (Version 3.5.3) and minfi package (1.30.0) to generate copy number variations. Compared with average genome-wide copy number level, 12p gain was determined. Then, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival (OS). Those tumors that consist of only either germinoma and/or mature teratoma components were classified as Favorable Histology (FH) and all the others that contains malignant histological components were classified as Unfavorable Histology (UFH). RESULT 12p gain was observed in 100% (3/3) of seminoma, 13.6% (3/22) of germinoma, 16.7% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor, 100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma. In total, 44.6% (37/83) of iGCT showed 12p gain. Regarding histological classification, the 12p gain rate in UFH (72%, 18/25) was significantly higher than that in FH (12.1%, 4/33, P<0.01). Both PFS and OS were significantly worse in iGCTs with 12p gain (PFS: P=0.027, OS: P=0.0012). DISCUSSION 12p gain can be a molecular marker to predict prognosis and histological malignancy in iGCTs.

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Site of metastases does not influence the clinical outcome of children with metastatic Germ Cell Tumors (GCT). A report from the Childrens Oncology Group (COG)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9002 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9002-9002

Author(s):

M. H. Malogolowkin ◽

W. B. London ◽

B. Cushing ◽

R. Giller ◽

M. Davis ◽

...

Keyword(s):

Clinical Outcome ◽

Germ Cell ◽

Germ Cell Tumor ◽

Germ Cell Tumors ◽

Stage Iv ◽

Yolk Sac ◽

Cell Tumor ◽

High Dose ◽

Metastatic Site ◽

Yolk Sac Tumors

9002 Background: To describe the clinical outcome of children with metastatic GCT (stage IV) at diagnosis according to the primary metastatic site(s). Methods: From March 1990 to February 1996, 299 children and adolescents with stage III/IV gonadal and stage I-IV extragonadal GCT were eligible for a Pediatric Intergroup high-risk (HR) GCT trial. Patients were randomized to receive 4–6 courses of cisplatin (P) standard dose [ 20 mg/m2/day (d) × 5] or high-dose (HDP) [40 mg/m2/d × 5] with etoposide (E) 100 mg/m2/d × 5 and bleomycin (B) 15 mg/m2 on d1. We retrospectively investigated the outcome of patients with stage IV and compared their outcome according to metastatic site(s). Results: There were 133 patients with stage IV disease. The median age was 2.6 years (y) [range, 3 d-19.3 y], 70 were female. Primary sites included: 43 testicular, 14 ovarian, 76 extragonadal (45 sacroccocygeal, 28 mediastinal, 3 other). Histologies included: 66 pure yolk sac tumors, 21 immature teratomas and yolk sac tumors, 26 mixed germ cell tumors, 7 pure germinoma/seminoma/dysgerminomas, 1 immature teratoma with a non-classic germ cell tumor, 2 mixed germ cell tumor admixed with a nonclassic germ cell tumor, 5 pure choriocarcinomas, and 5 patients with unknown histology. There were no statistically significant differences in the 5-year EFS or OS rates by site of metastases. Of the 19 patients with either bone or brain involvement, 17 patients had bone and 3 had brain metastases. Conclusion: The outcome for patients with metastatic GCT is excellent with contemporary cisplatin-based regimes and is independent of the site of metastatic disease. [Table: see text] No significant financial relationships to disclose.

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Proton Beam Therapy for Loco-Regional Control of a Recurrent Mixed Malignant Germ Cell Tumor of the Skull in a 22-Month-Old Girl

Klinische Pädiatrie ◽

10.1055/s-0030-1252018 ◽

2010 ◽

Vol 222 (03) ◽

pp. 175-179 ◽

Cited By ~ 1

Author(s):

G. Calaminus ◽

U. Göbel ◽

J. Schrum ◽

O. Wittkugel ◽

M. Westphal ◽

...

Keyword(s):

Germ Cell ◽

Proton Beam ◽

Germ Cell Tumor ◽

Proton Beam Therapy ◽

Cell Tumor ◽

Regional Control ◽

Malignant Germ Cell Tumor

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GCT-34. ELUCIDATION OF THE MECHANISMS OF TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMOR BY WHOLE GENOME SEQUENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa222.253 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii334-iii335

Author(s):

Yuki Yamagishi ◽

Hirokazu Takami ◽

Daichi Narushima ◽

Yuko Matsushita ◽

Eiji Sugihara ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumor ◽

Genome Sequence ◽

Germ Cell Tumors ◽

Genetic Alterations ◽

Cell Tumor ◽

Whole Genome Sequence ◽

Whole Genome ◽

Intracranial Germ Cell Tumor ◽

Structural Abnormalities

Abstract Intracranial germ cell tumors (iGCT) are heterogenous group of primary brain tumors that consist of various subtype, and driver genetic alterations in iGCTs remain largely unknown. We have previously reported in a study of whole exome sequence that iGCTs frequently harbored mutations in the KIT gene and its downstream MAPK/PI3K pathway, regardless of tumor subtype. However, no mutations were detected in about one-quarter of germinomas and half of non-germinomatous germ cell tumors. A genome-wide methylation profiling revealed that only germinomas exhibited extreme DNA hypomethylation among iGCTs. Moreover, in mixed iGCT tumors which contained more than one tumor subtypes, each component exhibited distinct methylation status depending on the subtype, while they shared the same mutations. These data suggested that not only mutations in the coding region as previously reported, but also genetic alterations in regulatory regions including promoters and enhancers as well as non-coding RNA genes may be involved in the tumorigenesis of iGCTs. In order to comprehensively search for driver gene alterations, we performed whole genome sequence in 18 paired tumor blood samples from iGCT tumors (16germinomas and two yolk sac tumors (YST)) registered in the Intracranial Germ Cell Tumor Genome Analysis Consortium. In a preliminary analysis of four cases, YSTs harbored a significantly higher number of structural abnormalities, compared with germinomas. Of note, 62 structural abnormalities were clustered within the small genomic region of 95Mb at 1q21-44 in one YST case, suggesting a possibility of chromothripsis. A full analysis of somatic alterations is underway and will be reported.

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Possible common origin of α-fetoprotein- and human chorionic gonadotropin—secreting cells in intracranial germ cell tumor

Journal of Neurosurgery ◽

10.3171/jns.1998.88.3.0576 ◽

1998 ◽

Vol 88 (3) ◽

pp. 576-580 ◽

Cited By ~ 1

Author(s):

Haruhiko Kishima ◽

Keiji Shimizu ◽

Yasuyoshi Miyao ◽

Eiichiro Mabuchi ◽

Toru Hayakawa

Keyword(s):

Germ Cell ◽

Germ Cell Tumor ◽

Chorionic Gonadotropin ◽

Germ Cells ◽

Human Chorionic Gonadotropin ◽

Cultured Cells ◽

Germ Cell Tumors ◽

Cell Tumor ◽

Intracranial Germ Cell Tumor ◽

Surgical Specimen

✓ A primary intracranial germ cell tumor in a 16-year-old boy secreted both a-fetoprotein (AFP) and human chorionic gonadotropin (HCG). The tumor, located in the right thalamus, contained germinomatous, trophoblastic, and endodermal sinus components. To identify AFP- and HCG-secreting cells, germ cells from the surgical specimen were cultured in vitro. These cultured cells secreted AFP and HCG for 10 weeks, and immunohistochemical studies showed that some of the cells secreted both AFP and HCG. These findings suggest that multipotential germ cells migrate to the encephalic region and may become germ cell tumors containing various types of tissue.

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Successful Combination Chemotherapy (Cisplatinum, Vinblastine, and Bleomycin) against Peritoneal Dissemination of Intracranial Germ Cell Tumor

Neurosurgery ◽

10.1227/00006123-198606000-00024 ◽

1986 ◽

Vol 18 (6) ◽

pp. 802-804 ◽

Cited By ~ 11

Author(s):

Eiji Kumura ◽

Norio Arita ◽

Toru Hayakawa ◽

Yukitaka Ushio ◽

Hiroyuki Nakata ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumor ◽

Combination Chemotherapy ◽

Peritoneal Dissemination ◽

Germ Cell Tumors ◽

Cell Tumor ◽

Intracranial Germ Cell Tumor ◽

Computed Tomographic ◽

The Third ◽

Intracranial Germ Cell Tumors

Abstract We found combination chemotherapy with cisplatinum, vinblastine, and bleomycin (PVB therapy) effective in the treatment of a patient with a pineal germ cell tumor with peritoneal dissemination. The metastatic complication may have been attributable to the ventriculoperitoneal shunt tube. After the first course of PVB therapy, the disseminated tumors were decreased in size; no residual tumors were detected after the third course by laparoscopic examination, computed tomographic scanning, or echogram. Our results suggest that combined PVB therapy is effective in the treatment of extraneural metastasis from intracranial germ cell tumors. (18:802-804, 1986)

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GCT-43. GAIN OF SHORT ARM OF CHROMOSOME 12 IS A MOLECULAR MARKER TO PREDICT PROGNOSIS AND REPRESENTS AN EARLY EVENT IN TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.261 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii336-iii336

Author(s):

Kaishi Satomi ◽

Hirokazu Takami ◽

Shintaro Fukushima ◽

Yoichi Nakazato ◽

Shota Tanaka ◽

...

Keyword(s):

Molecular Marker ◽

Germ Cell ◽

Germ Cell Tumor ◽

Mature Teratoma ◽

Germ Cell Tumors ◽

Cell Tumor ◽

Chromosome 12 ◽

Early Event ◽

Testicular Germ Cell ◽

Intracranial Germ Cell Tumor

Abstract Gain of short arm of chromosome 12 (12p) is commonly observed in testicular germ cell tumors (tGCTs) and also seen in intracranial GCTs (iGCTs). However, little is known about the clinical significance of 12p gain in iGCTs. We have collected over 200 fresh frozen tissue samples of iGCTs through the Intracranial Germ Cell Tumor Genome Analysis Consortium in Japan. Firstly, we analyzed DNA methylation profile in 83 iGCTs, 3 tGCTs (seminomas) and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA, USA) in order to determine 12p gain status. Then, fluorescence in situ hybridization (FISH) study was carried out on 3 mixed iGCT cases using 12p/CEP12 probe (Abbott Molecular, Abbott park, IL, USA). Lastly, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival (OS). Gain of 12p was observed in 100% (3/3) of seminoma, 14% (3/22) of germinoma, 17% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor, 100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma. In total, 45% (37/83) of iGCT showed 12p gain. Different histological components in each mixed GCT shared the same 12p copy number status within each mixed GCT case. Both PFS and OS were significantly worse in iGCTs with 12p gain (PFS: P=0.027, OS: P=0.0012). Gain of 12p can be a molecular marker to predict prognosis and represents an early event in tumorigenesis prior to histological differentiation in iGCTs.

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GCT-06. DIAGNOSIS OF A RARE CASE OF RECURRENT GERM CELL TUMOR BY CSF PLACENTAL ALKALINE PHOSPHATASE PRESENTING WITH DIFFUSE INTRAAXIAL ABNORMALITY IN THE LOWER BRAINSTEM

Neuro-Oncology ◽

10.1093/neuonc/noaa222.228 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii329-iii329

Author(s):

Hiroki Yamada ◽

Tomohiro Abiko ◽

Hirokazu Fujiwara ◽

Kazunari Yoshida ◽

Hikaru Sasaki

Keyword(s):

Alkaline Phosphatase ◽

Germ Cell ◽

Germ Cell Tumor ◽

Rare Case ◽

Cervical Spinal Cord ◽

Germ Cell Tumors ◽

Cell Tumor ◽

Placental Alkaline Phosphatase ◽

Steroid Pulse ◽

Platinum Based Chemotherapy

Abstract INTRODUCTION Germ cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy. CONCLUSION We report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.

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GCT-15. INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM

Neuro-Oncology ◽

10.1093/neuonc/noaa222.235 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii330-iii331

Author(s):

Hirokazu Takami ◽

Koichi Ichimura ◽

Kohei Fukuoka ◽

Akitake Mukasa ◽

Nobuhito Saito ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Basal Ganglia ◽

Pineal Gland ◽

Germ Cell ◽

Prognostic Significance ◽

Germ Cell Tumors ◽

Molecular Data ◽

Molecular Heterogeneity ◽

Intracranial Germ Cell Tumor

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 Consortium were reviewed. A total of 190 cases were classified as primary 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 PFS than those at atypical sites (p=0.03). A molecular-clinical association study revealed frequent MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and 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 These in-depth findings of this study regarding the clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

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