ACM  >> Vol. 10 No. 3 (March 2020)

作者:  

高晓红,白茫茫:延安大学附属医院神经外科,陕西 延安;
王亚明:首都医科大学宣武医院神经外科,北京

关键词:
颅内生殖细胞肿瘤诊断治疗MiRNAIntracranial Germ Cell Tumors Diagnosis Therapy MiRNA

摘要:

颅内生殖细胞肿瘤是一种好发于儿童及青少年的罕见肿瘤,常位于颅内松果体区、蝶鞍区和基底节区。组织类型通常分为生殖细胞瘤和非生殖细胞性生殖细胞肿瘤。临床表现与病变位置和大小相关。诊断分为临床诊断和活检病理诊断。治疗主要是放化疗和手术结合。新型肿瘤标志物MiroRNA (MiRNA)将来可能用于颅内生殖细胞肿瘤的诊断与治疗后评估。组织病理及分子病理的明确可为颅内生殖细胞肿瘤的分型及患者靶向治疗提供依据。本文对颅内生殖细胞瘤的发展现况及诊疗进展作一综述。

Intracranial germ cell tumors (IGCTs) are uncommon tumours occurring in children and young adults with a tendency to appear in pineal, suprasellar and basal ganglia region. They are usually segregated into germinomas and nongerminomatous tumours (NGGCTs). The main clinical mani-festations of the tumors depend on their size and location. The diagnosis has been divided into clinical diagnosis and surgical biopsy pathology diagnosis. The tumor therapy regimen is mostly chemoradiotherapy and surgery. New tumor markers microRNA (MiRNA) may be potentially val-uable biomarkers in the diagnosis and evaluation of treatment of intracranial germ cell tumors in the future. Histopathology and molecular analyses are attempting to further specify the different IGCTs subtypes and are helping to direct the development of distinct therapeutic targets to improve treatment and prognosis. Here is to make a review of the current status and management in intracranial germ cell tumors

1. 引言

颅内生殖细胞肿瘤(Intracranial germ cell tumours, IGCTs)在世界各地区发病率差异性大,在欧美国家中约占儿童和年轻人(男:女4~5:1)原发性中枢神经系统肿瘤的3%~5% [1],而亚洲地区高达10%~15% [2] [3] [4]。但美国的一项研究发现日本与美国IGCTs的发病率基本一样,大约1/106 [5]。总体来说,男女发病率比例大约在3:1,松果体区GCTs几乎全是男性(11.5:1),而非松果体区男女比例大约1.9:1。IGCTs主要发生在人体中线部位 [6] [7],最常见的发病部位是松果体区和鞍上区,其他可能发病部位包括丘脑、基底节区、三脑室等。在两个及以上部位同时发现病灶,则被称为双灶或多灶生殖细胞瘤,大约占生殖细胞瘤的8%。WHO [8] 将IGCTs分为生殖细胞瘤和非生殖细胞瘤性生殖细胞肿瘤(non-germinomatous germ cell tumors, NGGCTs),NGGCTs包括畸胎瘤(成熟/未成熟)、胚胎性癌、绒毛膜癌、卵黄囊瘤和混合性生殖细胞肿瘤。在日本,生殖细胞肿瘤的亚型被分为预后良好、预后中等、预后不良三组 [6],预后良好组包括单纯生殖细胞瘤和成熟畸胎瘤;预后中等组,主要包括以生殖细胞瘤为主的混合型肿瘤,或畸胎瘤和未成熟畸胎瘤;而预后不良组,包括绒毛膜癌、卵黄囊瘤、胚胎性癌和由该组中任何亚型混合组成的肿瘤。IGCTs患者的预后跟病理亚型及治疗方案的选择相关。分子生物学及基因的明确将为IGCTs的靶向治疗提供研究依据。

2. 病因学

IGCTs病因不明,人们普遍认为其来源为胚胎发育早期迁移受阻的原始生殖细胞 [9],日本Fukushima [10] 等学者通过全基因组甲基化谱,也同样证实生殖细胞瘤起源于原始生殖细胞。但也有证据表明,IGCTs中的畸胎瘤可以由其它非原始生殖细胞产生,这表明其它生殖细胞肿瘤亚型也可能具有从非生殖细胞系发育而来的能力 [11]。然而,近年研究显示,颅内生殖细胞肿瘤可能来源于颅内神经干细胞 [12] [13]。这有可能推翻人们普遍接受的IGCTs来源于原始生殖细胞。总之,目前IGCTs病因仍不明了,仍需继续研究。

3. 临床症状

IGCTs的发病高峰期在20岁左右,临床症状主要与病变位置和大小相关。

最常见的部位是松果体区(50%~60%)和鞍区(30%~40%) [14]。发生在鞍区的GCTs,内分泌功能异常最为常见,大多数患者存在尿崩症的症状,如多尿、烦渴,同时也会伴随着其他内分泌失调表现,比如生长缓慢、皮质功能减退、性早熟和甲状腺功能低下。肿瘤进一步向上生长压迫视觉通路而引起视力视野损害,肿瘤向后上生长压迫第三脑室可引起脑积水和颅高压。松果体区GCTs往往很早出现颅高压症状,因肿瘤突入三脑室后部或阻塞中脑导水管,迅速引起阻塞性脑积水和颅高压,当肿瘤压迫四叠体上丘,可引起Parinaud综合征 [9]。值得注意的是,这个区域的肿瘤也可能出现内分泌功能异常,主要是性发育紊乱。丘脑基底节区的GCTs主要症状为锥体束症。

4. 诊断

诊断是基于临床表现,肿瘤标记物,脑脊液细胞学和影像学(见表1)。对于无分泌的肿瘤,活检对于准确的组织学分型至关重要,可排除其他恶性肿瘤。诊断时可能出现软脑膜(30%)和脑室(10%)播散 [14]。

Table 1. Major diagnostic tools for intracranial germ cell tumors

表1. 颅内生殖细胞肿瘤的主要诊断工具

MRI = Magnetic Resonance Imaging; MRS = Magnetic Resonance Spectroscopy。

4.1. 影像学

颅脑核磁共振扫描(Magnetic Resonance Imaging, MRI)是评估疾病严重程度的客观指标。在MRI中,生殖细胞瘤实质性部分表现为稍长T1、短T2信号;囊性部分呈长T1、长T2信号为主。一般来说,生殖细胞瘤明显强化(见图1)。T1图像出现高信号,如出血,高蛋白液体或脂肪和囊性成分,提示NGGCTs。畸胎瘤的不均匀性更强,大部分含有囊性成分,并在CT扫描上大多伴有钙化 [15]。通常基于影像学表现很难区分不同的组织学亚型。

(a) (b) (c) (d) (e) (f) (g) (h) a~d囊性部分呈长T1、T2信号为主,实性部分呈稍长T1、短T2信号;增强扫描实性病灶呈明显强化,囊性部分呈环样强化e~h放化疗后3个月,影像学上完全缓解

Figure 1. Germinoma magnetic resonance imaging of the brain

图1. 生殖细胞瘤 头颅核磁共振

4.2. 肿瘤标记物

IGCTs所表达的肿瘤标记物可帮助诊断及鉴别诊断。目前主要检查血清和脑脊液的甲胎蛋白(α-fetoprotein, AFP)和人绒毛膜促性腺激素(β-human chorionic gonadotropin, β-HCG)。然而,肿瘤标志物正常并不一定能排除IGCTs的存在 [16]。

肿瘤标志物AFP和β-HCG在诊断IGCTs中的敏感性和特异性有限 [17]。新型肿瘤标志物MiroRNA(MiRNA)将来可能用于IGCTs的诊断与治疗后评估。MiRNA一种大约含22个核苷酸的短链非编码RNA,它通过翻译抑制和/或降解mRNA(信使RNA)来调节基因表达 [18]。Palmer等 [19] 在48 例组织样本中发现,恶性生殖细胞肿瘤同对照组相比,miR-376、miR-371~373和miR-302簇等8个MiRNA过度表达,这种上调的表达不受患者年龄、组织亚型和肿瘤部位(卵巢、睾丸、性腺外)的影响,而在治疗后MiRNA水平下降。根据上述研究我们推断MiRNA将来可能应用于IGCTs的诊断与治疗后评估。

4.3. 病理学及分子生物学

在组织学上,生殖细胞瘤是由大小一致的圆形或多边形细胞构成,呈巢团状分布(见图2)。生殖细胞瘤内含有合体滋养层细胞可引起HCG升高。卵黄囊瘤一般表达AFP,绒毛膜癌和胚胎性癌表达HCG。畸胎瘤中可含有脂肪和钙化。成熟畸胎瘤属于良性病变,未成熟畸胎瘤属于恶变病变。混合性生殖细胞肿瘤指包含上述至少两种成分以上的混合成分。

Figure 2. Germinoma pathology (HE × 400)

图2. 生殖细胞瘤病理(HE × 400)

免疫组化染色,生殖细胞瘤高表达c-kit/CD117,OCT3/4,PLAP。胚胎癌高表达CD30,CK,AE1/3。绒毛膜癌高表达HCG,卵黄囊瘤高表达AFP [20] [21]。

研究表明IGCTs与KIT/RAS和AKT1/mTOR通路突变有关 [22]。等臂染色体12p是睾丸生殖细胞肿瘤(80%)经常发生的染色体异常 [23],而在IGCTs中只有25%的报道 [24]。有研究指出,在生殖细胞瘤中发现p14和c-kit基因异常 [25]。分子生物学及基因的明确将为IGCTs的靶向治疗提供研究依据。

5. 治疗

IGCTs依据各病理亚型不同治疗方案略有差异(见表2)。IGCTs单纯依靠化疗,不进行放射治疗,患者的治疗效果差,而且远期复发率会大大增加 [16] [26]。化疗方案基于顺铂或异环磷酰胺时,尿崩症的发生率增高 [27]。当患者接受放射治疗时,生存率显著提高 [28]。虽然放射治疗具有较高治愈率,但远期带来的神经认知功能障碍和神经内分泌的后遗症,严重影响患者的生长发育和生存质量 [16] [29]。

Table 2. Main treatments available for intracranial germ cell tumors

表2. 颅内生殖细胞肿瘤的治疗原则

生殖细胞瘤通过放射治疗加辅助化疗在一定程度上可以达到治愈 [29] [30]。研究显示,24例生殖细胞瘤患者接受低剂量放疗和化疗,包括卡铂、依托泊苷、异环磷酰胺在内的不同化疗药物,结果显示5年无进展生存率为96%,总体生存率为100% [16]。另一项研究表明,局部放疗联合化疗治疗无转移的生殖细胞瘤的生存率更高 [31]。环磷酰胺是另一种正在研究的用于治疗生殖细胞瘤的药物,被认为是一种可行且耐受良好的附加治疗方案 [32]。此外,治疗前和治疗后的神经心理和神经认知测试结果显示无显著差异 [16]。值得注意的是,大多数生殖细胞瘤会沿脑脊液播散。因此,生殖细胞瘤的治疗从高剂量的全脑全脊髓照射发展到现在进行包括以铂剂为基础的化疗,接着对肿瘤瘤床和整个脑室系统进行强化放射治疗 [3]。口服依托泊苷也可用于常规化疗和放疗后生殖细胞瘤的姑息性治疗 [33]。

只有20%~40%的NGGCTs仅通过放射治疗能得到有效控制,因此,在可能的情况下,除了手术切除外,还需要化疗和放射治疗 [30] [34] [35]。NGGCTs患者,接受放射治疗前行化疗能使生存率提高到60%~70% [36]。治疗NGGCTs最有效的化疗药物包括卡铂、顺铂、依托泊苷、异环磷酰胺、紫杉烷类等 [36]。Masutani等报道使用卡铂或顺铂联合依托泊苷作为治疗中等预后NGGCTs的方案,但是即使使用异环磷酰胺-顺铂-依托泊苷也不能改善NGGCTs的预后 [6]。除了成熟畸胎瘤外,单纯的手术切除治疗NGGCTs是不足的 [20] [34] [36]。在美国和日本,手术切除在IGCTs治疗中占有很大一部分比例,在日本表现更加突出 [5]。但是不同的是,在日本一般选择化疗和放疗结束后再行手术切除,而在欧美国家,手术切除时机选择在化疗和放疗之间 [20]。未成熟畸胎瘤对顺铂化疗方案的反应通常较差,但为了获得更好的疗效,仍需要化疗联合放疗,并在可行的情况下结合手术切除 [37]。

在美国,NGGCTs的治疗通常选择全脑全脊髓放疗和对肿瘤瘤床的强化放射治疗 [34];而日本的治疗方案更倾向于在肿瘤部位和病灶周围局部区域使用放射治疗中等预后的NGGCTs,全脑全脊髓放疗被用来治疗预后较差的NGGCTs [6] [38]。欧洲的治疗标准是选择局部放射治疗对于非转移性NGGCTs [39]。研究发现,全脑全脊髓放疗可提高预后较差的NGGCTs的总体生存率,但需注意的是全脑全脊髓放疗的照射剂量应大于36 Gy,原发肿瘤部位照射剂量应大于54 Gy [40]。一些研究发现,在放化疗后行手术切除残余肿瘤可提高患者的生存率,认为手术在治疗NGGCTs中起着重要作用,尤其是对放化疗不敏感的NGGCTs患者 [3] [41]。Kochi等 [41] 对11例NGGCTs患者进行化疗和全脑/全脑室放疗,并对肿瘤瘤床进行强化放疗,后再行手术切除残余肿瘤,总生存率达到91%。根据Delphi共识 [20],NGGCTs的治疗应包括化疗和放疗,其中全脑全脊髓放疗专门用于治疗转移性IGCTs和手术切除有肿瘤残留的患者。

内镜下第三脑室造瘘术在治疗脑积水和获得肿瘤活检方面比常规开颅手术或脑室外引流具有更高的安全性和诊断有效性,且并发症少,死亡率低 [11] [42]。根据Delphi共识,在非紧急情况下,内镜下第三脑室造瘘术在治疗梗阻性脑积水方面优于其他手术治疗方案 [20]。值得注意的是,内镜下第三脑室造瘘术存在一定的不足,手术可能造成穹窿损伤,获取肿瘤组织样本量少,尤其是对于肿瘤标记物阴性的NGGCTs患者 [11]。

伽玛刀放射治疗是另一种正在进行研究的干预方法,可能为IGCTs的治疗带来益处。一项回顾性研究发现,在治疗6个月后松果体区肿瘤体积平均缩小约50%,39%的患者在治疗后1年肿瘤完全消失,明确诊断的IGCTs,3年和5年生存率分别为62.4%和54.5%,3年和5年的局部肿瘤控制率分别为88%和77.3% [41]。Huang等 [37] 发现伽玛刀放射外科治疗的NGGCTs患者,5年的生存率明显增加。伽玛刀放射治疗是否可作为IGCTs患者的常规治疗,还有待进一步研究。

干细胞治疗是治疗IGCTs的另一个正在研究的领域。使用高剂量化疗联合自体干细胞移植的目的主要消除或减少对儿童IGCTs的照射剂量,以减少远期并发症的发生 [44]。Delphi共识 [20] 一致认为,对复发的恶性NGGCTs,应采用高剂量化疗,随后进行造血干细胞移植,并在可能的情况下进行手术和放疗。

6. 分子生物学和可能的治疗靶点

研究表明IGCTs与KIT/RAS和AKT1/mTOR通路突变有关 [11] [22] [36]。目前已经有8种靶向针对KIT酪氨酸激酶抑制剂已经得到批准,可能对IGCTs患者带来潜在的益处;此外,司美替尼在针对KRAS突变的非小细胞肺癌细胞的临床前试验中疗效明确 [45]。另一种酪氨酸激酶抑制剂达沙替尼已被建议用于IGCTs患者,可以对抗具有CBL突变的髓系白血病细胞系;然而,考虑到患者的多模态治疗方案,达沙替尼对IGCTs患者治疗获益的具体机制研究仍不清楚 [45] [46]。

7. 预后

一项针对373名松果体区GCTs患者的研究报告显示,5年生存率为80%,高于松果体区其他肿瘤类型,不良预后与性别、年龄、NGGCTs亚型及是否接受行放射治疗显著相关 [28]。与NGGCTs的生存率相比,生殖细胞瘤预后较好,甚至出现转移的患者的5年生存率和总体生存率大于90% [16] [36]。然而,一项对14名NGGCTs患者的研究发现,新式辅助化疗联合放射治疗后再行残余肿瘤全切除手术,5年总生存率达到93% [47]。Matsutani等 [38] 分析153例IGCTs患者,单纯生殖细胞瘤患者10年和20年生存率分别为93%和81%,成熟畸胎瘤和未成熟畸胎瘤患者10年生存率分别为93%和71%年,胚胎性癌,卵黄囊瘤,绒毛膜癌的3年生存率为27%。

8. 结论及未来方向

IGCTs是一组罕见的异质性恶性肿瘤,主要影响儿童和青少年。对生殖细胞瘤最有效的治疗方法是放射治疗加辅助化疗 [11]。另一方面,NGGCTs最好的治疗方法是化疗和放射治疗后,再行肿瘤全切除;对于成熟畸胎瘤单纯手术全切就可达到治愈。分子生物学的明确将进一步明确不同的IGCTs的亚型,有助于靶点治疗研究,以改善治疗和预后 [11]。

文章引用:
高晓红, 王亚明, 白茫茫. 颅内生殖细胞肿瘤研究进展[J]. 临床医学进展, 2020, 10(3): 270-278. https://doi.org/10.12677/ACM.2020.103043

参考文献

[1] Makino, K., Nakamura, H., Yano, S., et al. (2013) Incidence of Primary Central Nervous System Germ Cell Tumors in Childhood: A Regional Survey in Kumamoto Prefecture in Southern Japan. Pediatric Neurosurgery, 49, 155-158.
https://doi.org/10.1159/000358806
[2] Wong, T.T., Ho, D.M., Chang, K.P., et al. (2005) Primary Pediatric Brain Tumors: Statistics of Taipei VGH, Taiwan (1975-2004). Cancer, 104, 2156-2167.
https://doi.org/10.1002/cncr.21430
[3] Foo, A.S., Lim, C., Chong, D.Q., et al. (2014) Primary Intracranial Germ Cell Tumours: Experience of a Single South-East Asian Institution. Journal of Clinical Neuroscience, 21, 1761-1766.
https://doi.org/10.1016/j.jocn.2014.01.021
[4] Makino, K., Nakamura, H., Yano, S., et al. (2010) Popula-tion-Based Epidemiological Study of Primary Intracranial Tumors in Childhood. Child’s Nervous System, 26, 1029-1034.
https://doi.org/10.1007/s00381-010-1126-x
[5] Mccarthy, B.J., Shibui, S., Kayama, T., et al. (2012) Primary CNS Germ Cell Tumors in Japan and the United States: An Analysis of 4 Tumor Registries. Neuro-Oncology, 14, 1194-1200.
https://doi.org/10.1093/neuonc/nos155
[6] Matsutani, M. (2001) Combined Chemotherapy and Radiation Therapy for CNS Germ Cell Tumors: The Japanese Experience. Journal of Neuro-Oncology, 54, 311-316.
https://doi.org/10.1023/A:1012743707883
[7] Lee, S.H., Jung, K.W., Ha, J., et al. (2017) Nationwide Popula-tion-Based Incidence and Survival Rates of Malignant Central Nervous System Germ Cell Tumors in Korea, 2005-2012. Cancer Research and Treatment, 49, 494-501.
https://doi.org/10.4143/crt.2016.129
[8] Louis, D.N., Perry, A., Reifenberger, G., et al. (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathologica, 131, 803-820.
https://doi.org/10.1007/s00401-016-1545-1
[9] Packer, R.J., Cohen, B.H. and Cooney, K. (2000) Intracranial Germ Cell Tumors. Oncologist, 5, 312-320.
https://doi.org/10.1634/theoncologist.2000-0312
[10] Fukushima, S., Yamashita, S., Kobayashi, H., et al. (2017) Genome-Wide Methylation Profiles in Primary Intracranial Germ Cell Tumors Indicate a Primordial Germ Cell Origin for Germinomas. Acta Neuropathologica, 133, 445-462.
https://doi.org/10.1007/s00401-017-1673-2
[11] Huang X, Zhang R, Mao Y, et al. (2016) Recent Advances in Molecular Biology and Treatment Strategies for Intracranial Germ Cell Tumors. World Journal of Pediatrics, 12, 275-282.
https://doi.org/10.1007/s12519-016-0021-2
[12] Tan, C. and Scotting, P.J. (2013) Stem Cell Research Points the Way to the Cell of Origin for Intracranial Germ Cell Tumours. The Journal of Pathology, 229, 4-11.
https://doi.org/10.1002/path.4098
[13] Lee, S.H., Appleby, V., Jeyapalan, J.N., et al. (2011) Variable Methylation of the Imprinted Gene, SNRPN, Supports a Relationship between Intracranial Germ Cell Tumours and Neural Stem Cells. Journal of Neuro-Oncology, 101, 419-428.
https://doi.org/10.1007/s11060-010-0275-9
[14] Echevarria, M.E., Fangusaro, J. and Goldman, S. (2008) Pediatric Central Nervous System Germ Cell Tumors: A Review. Oncologist, 13, 690-699.
https://doi.org/10.1634/theoncologist.2008-0037
[15] Wu, C.C., Guo, W.Y., Chang, F.C., et al. (2017) MRI Features of Pediatric Intracranial Germ Cell Tumor Subtypes. Journal of Neuro-Oncology, 134, 221-230.
https://doi.org/10.1007/s11060-017-2513-x
[16] Cheng, S., Kilday, J.P., Laperriere, N., et al. (2016) Outcomes of Children with Central Nervous System Germinoma Treated with Multi-Agent Chemotherapy Followed by Reduced Radiation. Journal of Neuro-Oncology, 127, 173-180.
https://doi.org/10.1007/s11060-015-2029-1
[17] Takami H, Fukuoka K, Fukushima S, et al. (2019) Integrated Clinical, Histopathological, and Molecular Data Analysis of 190 Central Nervous System Germ Cell Tumors from the iGCT Consortium. Neuro-Oncology, 21, 1565-1577.
https://doi.org/10.1093/noajnl/vdz039.175
[18] Murray, M.J., Nicholson, J.C. and Coleman, N. (2015) Biology of Childhood Germ Cell Tumours, Focusing on the Significance of microRNAs. Andrology, 3, 129-139.
https://doi.org/10.1111/andr.277
[19] Palmer, R.D., Murray, M.J., Saini, H.K., et al. (2010) Malignant Germ Cell Tumors Display Common microRNA Profiles Resulting in Global Changes in Expression of Messenger RNA Targets. Cancer Research, 70, 2911-2923.
https://doi.org/10.1158/0008-5472.CAN-09-3301
[20] Murray, M.J., Bartels, U., Nishikawa, R., et al. (2015) Consensus on the Management of Intracranial Germ-Cell Tumours. The Lancet Oncology, 16, e470-e477.
https://doi.org/10.1016/S1470-2045(15)00244-2
[21] Gao, Y., Jiang, J. and Liu, Q. (2014) Clinicopathological and Immunohistochemical Features of Primary Central Nervous System Germ Cell Tumors: A 24-Years Experience. International Journal of Clinical and Experimental Pathology, 7, 6965-6972.
[22] Fukushima, S., Otsuka, A., Suzuki, T., et al. (2014) Mutually Exclusive Mutations of KIT and RAS Are Associated with KIT mRNA Expression and Chromosomal Instability in Primary Intracranial Pure Germinomas. Acta Neuropathologica, 127, 911-925.
https://doi.org/10.1007/s00401-014-1247-5
[23] Bosl, G.J., Ilson, D.H., Rodriguez, E., et al. (1994) Clinical Relevance of the i(12p) Marker Chromosome in Germ Cell Tumors. Journal of the National Cancer Institute, 86, 349-355.
https://doi.org/10.1093/jnci/86.5.349
[24] Sukov, W.R., Cheville, J.C., Giannini, C., et al. (2010) Isochromosome 12p and Polysomy 12 in Primary Central Nervous System Germ Cell Tumors: Frequency and Associ-ation with Clinicopathologic Features. Human Pathology, 41, 232-238.
https://doi.org/10.1016/j.humpath.2009.07.017
[25] Schneider, D.T., Zahn, S., Sievers, S., et al. (2006) Molecular Genetic Analysis of Central Nervous System Germ Cell Tumors with Comparative Genomic Hybridization. Modern Pathology, 19, 864-873.
https://doi.org/10.1038/modpathol.3800607
[26] Robertson, P.L., Jakacki, R., Hukin, J., et al. (2014) Multimo-dality Therapy for CNS Mixed Malignant Germ Cell Tumors (MMGCT): Results of a Phase II Multi-Institutional Study. Journal of Neuro-Oncology, 118, 93-100.
https://doi.org/10.1007/s11060-013-1306-0
[27] Afzal, S., Wherrett, D., Bartels, U., et al. (2010) Challenges in Management of Patients with Intracranial Germ Cell Tumor and Diabetes Insipidus Treated with Cisplatin and/or Ifosfamide Based Chemotherapy. Journal of Neuro-Oncology, 97, 393-399.
https://doi.org/10.1007/s11060-009-0033-z
[28] Al-Hussaini, M., Sultan, I., Abuirmileh, N., et al. (2009) Pineal Gland Tumors: Experience from the SEER Database. Journal of Neuro-Oncology, 94, 351-358.
https://doi.org/10.1007/s11060-009-9881-9
[29] Wong, K., Opimo, A.B., Olch, A.J., et al. (2016) Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature. Cureus, 8, e585.
https://doi.org/10.7759/cureus.585
[30] Claude, L., Faure-Conter, C., Frappaz, D., et al. (2015) Radiation Therapy in Pediatric Pineal Tumors. Neurochirurgie, 61, 212-215.
https://doi.org/10.1016/j.neuchi.2014.11.002
[31] Bouffet, E., Baranzelli, M.C., Patte, C., et al. (1999) Combined Treatment Modality for Intracranial Germinomas: Results of a Multicentre SFOP Experience. Societe Francaise d’Oncologie Pediatrique. British Journal of Cancer, 79, 1199-1204.
https://doi.org/10.1038/sj.bjc.6690192
[32] Malogolowkin, M.H., Krailo, M., Marina, N., et al. (2013) Pilot Study of Cisplatin, Etoposide, Bleomycin, and Escalating Dose Cyclophosphamide Therapy for Children with High Risk Germ Cell Tumors: A Report of the Children’s Oncology Group (COG). Pediatric Blood & Cancer, 60, 1602-1605.
https://doi.org/10.1002/pbc.24601
[33] Fukuoka, K., Yanagisawa, T., Suzuki, T., et al. (2015) Malignant Transformation of Germinoma 14 Years after Onset: Favorable Efficacy of Oral Etoposide. Pediatrics International, 57, 483-486.
https://doi.org/10.1111/ped.12559
[34] Frappaz, D., Conter, C.F., Szathmari, A., et al. (2015) The Management of Pineal Tumors as a Model for a Multidisciplinary Approach in Neuro-Oncology. Neurochirurgie, 61, 208-211.
https://doi.org/10.1016/j.neuchi.2014.03.003
[35] Jinguji, S., Yoshimura, J., Nishiyama, K., et al. (2015) Long-Term Outcomes in Patients with Pineal Nongerminomatous Malignant Germ Cell Tumors Treated by Radical Resection during Initial Treatment Combined with Adjuvant Therapy. Acta Neurochirurgica, 157, 2175-2183.
https://doi.org/10.1007/s00701-015-2614-2
[36] Dufour, C., Guerrini-Rousseau, L. and Grill, J. (2014) Central Nervous System Germ Cell Tumors: An Update. Current Opinion in Oncology, 26, 622-626.
https://doi.org/10.1097/CCO.0000000000000140
[37] Huang, X., Zhang, R. and Zhou, L.F. (2009) Diagnosis and Treatment of Intracranial Immature Teratoma. Pediatric Neurosurgery, 45, 354-360.
https://doi.org/10.1159/000257524
[38] Matsutani, M., Sano, K., Takakura, K., et al. (1997) Primary Intracranial Germ Cell Tumors: A Clinical Analysis of 153 Histologically Verified Cases. Journal of Neurosurgery, 86, 446-455.
https://doi.org/10.3171/jns.1997.86.3.0446
[39] Calaminus, G., Frappaz, D., Kortmann, R.D., et al. (2017) Out-come of Patients with Intracranial Non-Germinomatous Germ Cell Tumors-Lessons from the SIOP-CNS-GCT-96 Trial. Neuro-Oncology, 19, 1661-1672.
https://doi.org/10.1093/neuonc/nox122
[40] Kim, J.W., Kim, W.C., Cho, J.H., et al. (2012) A Multimodal Ap-proach Including Craniospinal Irradiation Improves the Treatment Outcome of High-Risk Intracranial Nongerminomatous Germ Cell Tumors. International Journal of Radiation Oncology, Biology, Physics, 84, 625-631.
https://doi.org/10.1016/j.ijrobp.2011.12.077
[41] Kochi, M., Itoyama, Y., Shiraishi, S., et al. (2003) Successful Treatment of Intracranial Nongerminomatous Malignant Germ Cell Tumors by Administering Neoadjuvant Chemo-therapy and Radiotherapy before Excision of Residual Tumors. Journal of Neurosurgery, 99, 106-114.
https://doi.org/10.3171/jns.2003.99.1.0106
[42] Herrada-Pineda, T., Revilla-Pacheco, F. and Manrique-Guzman, S. (2015) Endoscopic Approach for the Treatment of Pineal Region Tumors. Journal of Neurological Surgery Part A: Central European Neurosurgery, 76, 8-12.
https://doi.org/10.1055/s-0032-1330958
[43] Li, W., Zhang, B., Kang, W., et al. (2015) Gamma Knife Radiosur-gery (GKRS) for Pineal Region Tumors: A Study of 147 Cases. World Journal of Surgical Oncology, 13, 304.
https://doi.org/10.1186/s12957-015-0720-5
[44] Gardner, S.L. (2004) Application of Stem Cell Transplant for Brain Tumors. Pediatric Transplantation, 8, 28-32.
https://doi.org/10.1111/j.1398-2265.2004.00202.x
[45] Wang, L., Yamaguchi, S., Burstein, M.D., et al. (2014) Novel Somatic and Germline Mutations in Intracranial Germ Cell Tumours. Nature, 511, 241-245.
https://doi.org/10.1038/nature13296
[46] Osorio, D.S., Finlay, J.L., Dhall, G., et al. (2013) Feasibility of Dasatinib in Children and Adolescents with New or Recurrent Central Nervous System Germinoma. Pediatric Blood & Cancer, 60, E100-E102.
https://doi.org/10.1002/pbc.24567
[47] Nakamura, H., Makino, K., Kochi, M., Ushio, Y. and Kuratsu, J. (2011) Evaluation of Neoadjuvant Therapy in Patients with Nongerminomatous Malignant Germ Cell Tumors. Journal of Neurosurgery: Pediatrics, 7, 431-438.
https://doi.org/10.3171/2011.1.PEDS10433