颅内成熟畸胎瘤全切除术后远期再发2例及文献复习

目的探讨颅内成熟畸胎瘤全切除后远期再发颅内肿瘤的性质及其发病机制。方法报告2例颅内成熟畸胎瘤病人．分别于全切除术后21个月、8年再次发生颅内肿瘤,均行2次手术治疗。结果影像学资料显示再发肿瘤部位与首发肿瘤有差异,术后病理分别为生殖细胞瘤、恶性畸胎瘤。结论颅内成熟畸胎瘤全切除术后远期再发不同部位的颅内肿瘤应首先考虑为新生的异时性肿瘤,多为恶性生殖细胞肿瘤,尤以生殖细胞瘤为著。     

Podoplanin expression in primary central nervous system germ cell tumors: a useful histological marker for the diagnosis of germinoma

Podoplanin, a mucin-like transmembrane sialoglycoprotein, promotes platelet aggregation and may be involved in cancer cell migration, invasion, metastasis, and malignant progression. Podoplanin/aggrus is highly expressed in testicular seminoma, suggesting that it may be a sensitive marker for testicular seminomas. Here we investigated the expression of podoplanin in central nervous system (CNS) germ cell tumors (GCTs) by immunohistochemical staining of tumor samples from 62 patients. In 40 of 41 (98%) germinomas (including germinomatous components in mixed GCTs), podoplanin was diffusely expressed on the surface of germinoma cells; lymphocytes, interstitial cells, and syncytiotrophoblastic giant cells were negative for podoplanin. Except for immature teratomas (12/17; 71%), podoplanin expression was absent in non-germinomatous GCTs, including seven teratomas, seven embryonal carcinomas, seven yolk sac tumors, and seven choriocarcinomas. In immature teratomas, focal podoplanin staining was observed in fewer than 10% of immature squamous and columnar epithelial cells. Thus, podoplanin expression may be a sensitive immunohistochemical marker for germinoma in CNS GCTs. As such, it may be useful for diagnosis, for monitoring the efficacy of treatment, and as a potential target for antibody-based therapy.Kazuhiko Mishima and Yukinari Kato contributed equally to this work.     

Histochemistry with Helix pomatia agglutinin in human germ cell tumors: detection of nongerminomatous components and correlation between HPA reactivity and radiosensitivity in germinomas

Binding sites of Helix pomatia agglutinin (HPA) were examined in 32 patients with intracranial human germ cell tumors. HPA reactivity was found in vascular endothelial cells and erythrocytes of patients with blood type A or AB. HPA-positive neoplastic cells were seen in one yolk sac carcinoma in a patient with blood group. A, and in embryonal carcinomas and teratomas irrespective of blood group type. Although in 10 out of 18 germinomas neoplastic cells were totally negative for HPA, another 8 germinomas showed HPA-positive neoplastic cells which were distributed sporadically or in an area and independent of blood group types. HPA-negative germinoma patients showed a very good response to radiotherapy, whereas 4 out of 8 HPA-positive tumors showed poor radiosensitivity, with a residual lesion seen on computed tomography even after the total radiation dose of 40–50 Gy. These findings suggest that HPA-positive neoplastic cells in germinomas indicate components of differentiation of non-germinomatous germ cells. HPA-positive germinomas might be less radiosensitive than HPA-negative germinomas.     

Intracranial germ cell tumors: a retrospective study of 44 children

This 16-year retrospective study review sought to determine the factors influencing prognosis and treatment results of all patients with primary intracranial germ cell tumors treated at our hospital who were younger than 17 years of age at the time of diagnosis. A total of 44 patients were treated during the study period, including 32 males and 12 females with a male:female ratio of 2.67:1. The median age at diagnosis was 12 years and 5 months of age (range = 2-16 years). The 44 intracranial germ cell tumors consisted of 27 pure germinomas (61.4%) and 17 nongerminomatous germ cell tumors, including 10 mixed germ cell tumors (22.7%), three yolk sac tumors (7.8%), two immature teratomas (4.5%), and two choriocarcinomas (4.5%). Univariate analysis of prognostic factors using Kaplan-Meier survival estimates revealed that only histologic tumor type was correlated with outcome (P < 0.005). The projected 5-year overall survival and event-free survival rate of patients with germinomas vs those with intracranial germ cell tumors were 92.6%, 92.6% vs 47.3%, and 42.1%, respectively. Our analysis suggests that radiation involving the spinal axis has limited usefulness in patients with intracranial germ cell tumor, although better results have been obtained for germinomas using radiotherapy in this study.     

Treatment of germ cell tumors in the pineal region

The authors retrospectively analyzed 107 patients with primary intracranial germ cell tumor (GCT), who were treated at the Department of Neurosurgery, Yonsei Medical Center between January 1986 and January 1996. The incidence of GCT was 2.8% in pediatric patients with intracranial tumor. Of the 107 tumors, 60 were located in the pineal region, 30 in the suprasellar region, 16 in basal ganglia or the thalamic region, and 1 in the posterior fossa. The 60 pineal GCT consisted of 39 germinomas (29 pure germinomas, 6 germinomas with STGC, 4 germinomas mixed with teratoma), 5 mature teratomas, and 16 nongerminomatous GCT. Thirty patients underwent surgery: their operations took the form of total resection in 14 cases, subtotal resection in 10, and biopsy in 6. Thirty patients (27 with germinomas, 3 with endodermal sinus tumors) were managed without surgery on the basis of radiological findings and tumor markers. The 5-year survival was 91% for 39 patients with germinomas, 80% for 5 with mature teratomas, and 49% for 16 with nongerminomatous GCT. Univariate analysis of prognostic factors with the Kaplan-Meier survival curve showed that histological tumor type, radiological findings, results of tumor marker studies, and response to trial radiation or chemotherapy were highly correlated with outcome. Chemotherapy was beneficial as the method of trial treatment in pineal GCT and treatment in recurrent tumors. The administration of trial chemotherapy or radiotherapy without tissue biopsy is well justified as a treatment modality in pineal GCT suspected on the basis of radiological findings and tumor marker studies. Aggressive multimodality approaches with surgery, radiotherapy, and chemotherapy are necessary to improve the outcome in these tumors. We propose new protocol for treatment of germ cell tumors in the pineal region, which is based on a minimally invasive approach.     

Immature teratoma of the tectum mesencephali with histopathological detection of rudimentary eye anlage in a 3‐year‐old boy: Report of a rare case

Intracranial teratoma is a rare neoplasm derived from omnipotent germinal cells that can contain mesoderm, endoderm and/or ectoderm layer tissue. Histologically teratomas are characterized by abnormal structures like teeth or bone that can be further subdivided into mature and immature according to the presence of incompletely differentiated tissue. Characteristic intracranial teratomas are space‐occupying lesions in the pineal region and often present with hydrocephalic symptoms due to aqueduct stenosis. A 3‐year‐old boy presented with a peracute hemiparesis, fatigue and speech deficit. MRI diagnostics showed a cystic, partially solid, inhomogeneous contrast‐enhancing formation at the top of the tectum mesencephali with consecutive aqueduct compression. The patient underwent a sub‐occipital craniotomy via a supracerebellar approach and complete resection was achieved. The histopathological examination mainly showed mature tissue of ectodermal, mesodermal and endodermal origin. However, small areas of undifferentiated neuroectodermal tissue within an optic vesicle formation were detected, leading to the diagnosis of an immature teratoma. In due course, the patient was discharged in good health without neurological deficits. To our knowledge, optic vesicle‐containing intracranial germ cell tumors are extremely rare. Here we report a unique case with immature neuroectodermal tissue within an optic vesicle formation in an otherwise mature teratoma.     

Comparative genomic hybridization in pineal germ cell tumors

Fifteen primary pineal germ cell tumors (8 germinomas, 4 mixed teratomas-germinomas, 2 immature teratomas, and 1 yolk sac tumor) and 2 recurrences of the yolk sac tumor were studied by comparative genomic hybridization (CGH). An average of 1.8 chromosomal changes per germinoma (0.5 gains vs 1.3 losses), 5.5 per mixed teratoma-germinoma (3.0 gains vs 2.5 losses), 3.5 per immature teratoma (2.0 gains vs 1.5 losses), and 2.0 in the yolk sac tumor (2 gains vs 0 losses) were found; the first recurrence showed 7 (4 gains vs 3 losses), the second 13 imbalances (8 gains vs 5 losses). The most frequent imbalances were gains on 12p (40%), 8q (27%), and 1q (20%) as well as losses on 13q (47%), 18q (33%), 9q and 11q (20% each). Among germinomas, the most common chromosomal changes were -13q and -18q (38% each), in mixed teratomas-germinomas +8q (100%), +12p (75%), -13q (75%) and -9q (50%). Seven high-level gains were identified: 5 in mixed teratomas-germinomas (+8q: 3 cases, + 12p: 2 cases), 1 each in a germinoma (+2p) and an immature teratoma (+12p). Minimal common regions of over- and underrepresentation were found on +8q11.22-21.1, +12p11.1-12.1, -9q32-qter, -11q23.2-qter, -13q32-qter and -18q22-qter. Our findings suggest, that imbalances in cerebral germ cell tumors affect the same chromosomes as among their extracerebral counterparts, albeit in a considerably lower frequency among cerebral germinomas where +12p does not seem to play a major role.     

Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors

Twenty-five primary intracranial germ cell tumors (11 germinomas, 5 teratomas, 5 mixed teratomas-germinomas. 1 mixed choriocarcinoma-teratoma, 1 yolk sac tumor, 1 mixed yolk sac tumor-teratoma, and 1embryonal carcinoma; from 24 males and 1 female) were studied by fluorescence in situ hybridization with probes to the X and Y chromosomes, chromosome 12p, the CDKN2A/p16 gene, and chromosome 13q-loci previously noted to be altered in either intracranial or systemic germ cell tumors. An increased number of X chromosomes, typically 1 extra copy, was observed in 23 of 25 cases (92%), with methylation-sensitive PCR demonstrating that the additional X chromosomes were hypomethylated in 13 of 16 (81%) studied tumors. Five cases (20%) had increased copy numbers of 12p (including tumors with isochromosome 12p), and 3 (12%) had 13q loss. No tumors had CDKN2A/p16 deletion or mutation, and 16 of 25 (64%) were positive for p16 expression by immunohistochemistry. Genetic alterations such as isochromosome 12p, 13q loss and CDKN2A/p16 are therefore not common in intracranial germ cell tumors. However, gains of hypomethylated, active X chromosomes occur in nearly all intracranial germ cell tumors, regardless of histological subtype. Along with the observed male predominance of intracranial germ cell tumors and the predisposition in Klinefelter syndrome patients for these lesions, the data argue strongly that sex chromosome aberrations, rather than isochromosome 12p, are integral to intracranial germ cell tumorigenesis     

Radioimmunoassay of alpha-fetoprotein in children with primary intracranial tumors.

Serum alpha-fetoprotein (AFP) was measured in 10 cases of primary brain tumors in children (4 cases of medulloblastoma, 4 cases of germ cell tumor and 2 cases of astrocytoma). As a result, elevation in AFP was observed only in a case of embryonal carcinoma that showed partial mixture of germinoma. The absence of AFP elevation in 3 other cases of pure germinoma (atypical teratoma; pinealoma) agrees with reports which describe that, in the germ cell tumor of the gonads, a rise in AFP is not observed in pure seminoma but is found in embryonal carcinoma and endodermal sinus tumor (yolk sac tumor). The fluctuations in AFP in serum and cerebrospinal fluid are considered to be of significance in the diagnosis and treatment of primary intracranial malignant germ cell tumors.     

Dolichos biflorus agglutinin binding to intracranial germ-cell tumors: detection of embryonal components in germinomas

Summary Dolichos biflorus agglutinin (DBA) binding was examined in 32 cases of intracranial human germcell tumors. In embryonal carcinomas, intense DBA binding sites were found on the free surface and cytoplasm of embryonal cells. In teratomas, glandular structures often had positive DBA binding sites. Yolk sac carcinomas and choriocarcinomas showed negative DBA affinity. Of 19 cases of germinomas, 10 showed no DBA-positive cells, while sporadically and/or collectively distributed-DBA positive cells were found in the other 9 cases. Common brain tumors such as gliomas, neurinomas and meningiomas were negative for DBA staining. Considering the cellular carbohydrate structure, these findings suggest that DBA-positive cells in germinoma might be evidence of differentiation into embryonal or some somatic components. In addition, because of the absence of DBA binding sites in the common brain tumors, the identification of such binding sites in brain tumors might act as a marker for embryonal or somatic components, especially among germ-cell tumors.     

Adenocarcinoma arising from intracranial recurrent mature teratoma and featuring mutated KRAS and wild‐type BRAF genes

Malignant transformation or recurrence of intracranial mature teratoma is an extremely rare occurrence, compared to the usual ovarian counterpart. Previously, yolk sac tumor elements have been considered to be selective progenitors of enteric‐type adenocarcinoma arising from intracranial germ cell tumors. However, the present case demonstrates the occurrence of enteric‐type adenocarcinoma in recurrent intracranial mature cystic teratoma 12 years after gross total removal, a case of which has not previously been documented in the literature. The 11.5‐cm long, dura mater‐based tumor on the right fronto‐temporal lobe displaced the brain; however, the patient had no neurologic symptoms or discomfort other than pus‐like discharge on the scalp. Microscopic examinations revealed a small focus of adenocarcinoma and dysplastic colonic mucosa in the mature cystic teratoma. No immature elements were seen. The cystic wall was almost denuded and showed an exuberant xanthogranulomatous reaction with foreign‐body type giant cells engulfing keratin materials and cholesterol clefts, suggesting that chronic inflammation due to repeated cyst wall rupture and the previous resection may contribute to malignant transformation. The adenocarcinoma showed strong immunohistochemical expression of CK20 and p53, but CK7 in patches. The molecular profile of the adenocarcinoma showed a mutation in KRAS and wild‐type BRAF, which might be associated with malignant transformation of intracranial mature teratomas. In conclusion, the intracranial mature teratomas should require long‐term follow‐up, and clinicians, radiologists and pathologists should be aware of the potential for malignant progression of recurrent intracranial mature cystic teratoma despite gross total resection and no neurologic symptoms.     

松果体区非生殖细胞瘤性恶性生殖细胞肿瘤的治疗

目的 探讨松果体区非生殖细胞瘤性恶性生殖细胞肿瘤(NGMGCTs)的临床特点、治疗和预后.方法 回顾性分析了2000年1月至2010年1月经病理证实的34例高度恶性NGMGCTs 患者的临床特点、血清肿瘤标记物检测、治疗方法及预后.所有患者均行枕部经小脑幕(Poopen)入路显微手术切除肿瘤,并行辅助放化疗.结果 全切除32例,近全切除2例,术后病理示未成熟畸胎瘤11例,畸胎瘤恶性变2例,胚胎癌2例,卵黄囊瘤l例,绒毛膜上皮癌6例,混合性生殖细胞肿瘤12例.共随访31例患者,随访时间6个月至10年,1年生存率为97％,3年生存率为62％,5年生存率为44％.结论 多数松果体区NGMGCTs根据临床表现、影像学资料和肿瘤标记物可在术前定性,以手术为主术后辅以化疗和放疗的综合治疗可以获得良好疗效.     

松果体区生殖细胞肿瘤放射外科治疗的合理性探讨

目的 探讨立体定向放射外科作为一线方案治疗松果体区生殖细胞肿瘤的合理性.方法 回顾性分析14例经伽玛刀或X-刀治疗的松果体区生殖细胞肿瘤患者的临床资料,重点研究肿瘤放射外科治疗后变化及复发、转移情况.结果 14例患者于放射外科治疗后11 d至106个月再次入院.肿瘤放射外科治疗后缓慢增大1例,无明显变化2例,缩小后再增大1例,基本消失后原位复发2例,消失后周边复发4例,原位复发并种植转移2例,原位消失但出现种植转移2例.病理为:生殖细胞瘤5例、混合型生殖细胞肿瘤4例、成熟畸胎瘤3例、非成熟畸胎瘤和卵黄囊瘤各1例.结论 放射外科不能作为松果体区生殖细胞肿瘤的单一治疗方法.假使已采用放射外科治疗,则应依据肿瘤标记物结果和治疗后肿瘤的变化情况,及时手术或综合治疗.

Abstract：

Objective To discuss the rationality of the stereotaxic radiosurgery as the first therapy strategy on pineal region germ cell tumors.Methods To retrospectively analyze the clinical materials of 14cases which received the treatment of gamma knife or X- knife.The condition of tumor changing,recurring and metastasize post- radiosurgery were emphasized.Methods All the patients of 14 cases were admitted again from 11 days to 106 months after which had received radiosurgery.The tumor increasing slowing with 1cases,no marked change with 2 cases,repeated increasing after diminution with 1 case,situ recur after essential disappear with 2 cases,ambitus recur after disappear with 4 cases,situ recur and implantation metastasis 2 cases,situ disappear but implantation metastasis with 2 cases.The pathology results were 5germinomas,4 mixed germ cell tumors,3 mature teratomas,1 unmature teratoma and 1 yolo sac tumor.Conclusion Radiosurgery cant be regarded as the exclusive treatment for pineal region germ cell tumors.If the patients received the radiosurgery,they should be operated or combined therapy in time according the results of tumor marker and the condition of tumor changing.     

Treatment of intracranial germ cell tumours and other tumours of the pineal region

The management of patients with central nervous system germ-cell tumours is evolving, and a definitive standard has not been achieved. A large amount of data indicate that radiotherapy alone results in long-term relapse free survival rates of about 90% in patients with germinoma. Various prospective trials evaluated the results of combinations of chemotherapy and reduced dose and/or volume radiotherapy. The survival rates of combined treatment approaches were similar to the rates achieved with craniospinal radiotherapy alone. Nevertheless, the relapse rates were probably higher due to the significant number of relapses that arouse outside the volume treated with radiotherapy. Additional studies are necessary to determine the appropriate radiotherapy volumes and the role of combined treatments. Chemotherapy alone results in high relapse rates and can not be recommended. Mature teratomas are benign germ cell tumours that can be controlled with complete surgical resection in over 90% of cases. Non-germinoma germ cell tumours are a heterogeneous group of tumours that includes very aggressive tumours such as mixed and pure choriocarcinomas, yolk sac tumours, and embryonal carcinomas; and tumours with intermediate aggressiveness such as mixed tumours with germinoma and teratoma, immature teratomas and teratomas with malignant transformation. Both radiotherapy alone and chemotherapy alone result in quite low rates of tumour control and current treatment approaches include chemotherapy and radiotherapy, with surgical removal of the tumour in some patients. Pineocytomas are benign tumours that are controlled in most cases by complete surgical resection or partial surgical resection and local field irradiation. Current treatment approaches for pineoblastomas include surgery, chemotherapy, and craniospinal irradiation with a local boost. Chemotherapy alone was used to delay irradiation in infants with very little success.     

Primary intracranial germ cell tumours

Summary A histological study has been made of a retrospective series of 17 primary intracranial germ cell tumours found in a collection of 3550 intracranial neoplasms (incidence of 0.48%). All, except for two differentiated teratomas (one extracerebral in a neonate and another in the lateral ventricle), were situated in the midline in persons aged 5 to 37 years (13 males, 4 females). 12 tumours were located in or originated from the (para)pineal region, two of them also invaded the hypothalamus, while three germinomas occupied the retrochiasmal (supra/intrasellar) region without pineal involvement. There were 11 rather pure tumours (7 germinomas, 4 teratomas of various differentiation) and six mixed neoplasms (2 germinomas with teratoid areas, 3 embryonal carcinomas containing elements of endodermal sinus tumour, choriocarcinoma and germinoma, and one teratocarcinoma with endodermal sinuses). Only one case showed prominent features of endodermal sinus tumour, but characteristic elements of this type were present in four other mixed tumours. All germinomas and germinomatous parts of mixed neoplasms showed an inflammatory reaction of varying intensity, in 6 cases associated with multinucleated giant cells, which may be related to the prognosis of these tumours (one patient with hypothalamic germinoma is alive 6 years after radiotherapy). The close structural similarities between the various types of intracranial and gonadal dysgerminomas and their frequent combination within the same tumour support the concept of a common histogenesis of germ cell tumours regardless of their site of origin. Difficulties of classification may arise from the rather frequent occurrence of mixed germ cell neoplasms.Dedicated to E. Frauchiger, on the occasion of his 70th anniversary.     

Multiple intracranial mixed germ cell tumors

A case of sequential occurrence of multiple intracranial mixed germ cell tumors is presented. An 8-year-old boy with a cystic calcified tumor in the basal ganglia and an increased serum α-fetoprotein concentration was initially treated with radiotherapy. Six years later, a tumor composed of embryonal carcinoma and immature teratoma arose from the right temporo-parietal lobe. This tumor was treated successfully with surgery and radiochemotherapy. The possibility of multicentricity or intra-axial metastasis distant from the original site during the long-term course should be considered in treatment for intracranial germ cell tumors. Received: 6 November 1995 Revised: 17 July 1996     

Immature teratoma of the pineal gland with isochromosome 12p

An immature teratoma arising in the pineal gland in a 27-year-old male was shown to present an isochromosome 12p as evidenced by cytogenetic and fluorescence in situ hybridization analysis. As i(12p) is characteristic of gonadal germ cell tumors, this case indicates that similar genetic pathways may operate in gonadal and intracranial teratomas. Received: 20 May 1997 / Revised, accepted: 23 June 1997     

松果体区肿瘤的MRI表现与其病理学对照研究

目的探讨不同病理性质的松果体区肿瘤MRI表现,评价其临床诊断价值。方法回顾性分析1999年1月至2009年1月经开颅手术治疗的131例松果体区肿瘤患者的MRI及病理学资料,并进行对比分析。结果这131例松果体区肿瘤中,纯生殖细胞瘤21例,畸胎瘤18例,混合性生殖细胞肿瘤12例,绒毛膜癌6例,胚胎性癌2例,内胚窦瘤1例,神经上皮肿瘤27例,松果体实质肿瘤17例,脑膜瘤14例和其它肿瘤13例。本组生殖细胞肿瘤60例,MRI增强后均有不同程度的强化,含有小囊状改变39例;其中生殖细胞瘤21例,5例MRI有较典型蝶形征;畸胎瘤18例,13例MRI有较典型的峰窝状改变;绒毛膜癌6例,5例MRI示出血。脑膜瘤14例,MRI示边界清楚,增强扫描均明显均匀强化,局部硬膜增厚6例;松果体实质肿瘤17例、神经上皮肿瘤27例及其他肿瘤13例,MRI表现各式各样。结论松果体区肿瘤的MRI表现与病理类型有关,部分MRI征象对一些肿瘤的诊断有较大特异性,但敏感度不高,依据MRI仍不能完全鉴别出松果体区肿瘤的病理性质。     

37例颅内成熟及未成熟畸胎瘤治疗临床分析

目的 探讨颅内成熟及未成熟畸胎瘤的有效治疗措施。方法 成熟畸胎瘤19例，未成熟畸胎瘤18例，37例患者均行开颅手术，其中成熟畸胎瘤全切除9例，近全切除2例，大部切除7例，活检1例。未成熟畸胎瘤全切除6例，近全切除6例，大部切除6例。全部诊断得到病理检查证实。首次治疗的患者出院时常规嘱放疗，其中成熟畸胎瘤4例未放疗。结果 成熟畸胎瘤随访14例，1例手术死亡，5例放疗后肿瘤复发，复发时间分别是4个月1例，半年2例，8月及2年各1例。这5例患者在二次手术后病理检查结果转变为未成熟畸胎瘤，并分别在第二次术后2个月～8个月之内死亡，5例死亡患者平均生存15个月。存活的8例患者中2例患者分别在第一次术后2年及4年肿瘤复发，并再次接受手术治疗。4例未行放疗。至随访时最长已生存4年6个月，最短1年1个月，平均已生存22个月。未成熟畸胎瘤随访16例，均行放疗，死亡15例。其中7例明确肿瘤复发，二次住院治疗。15例死亡患者平均生存17个月。结论 (1)为提高成熟及未成熟畸胎瘤的治疗效果，应尽量做到手术全切除肿瘤。(2)提示病理科医师术中所见，建议多切片病理检查。(3)病理检查明确诊断为成熟畸胎瘤时，患者仍应定期复查CT或MRI，严密观察病情变化。(4)如病理检查结果明确为未成熟畸胎瘤，则应进行全方位治疗，即手术、放疗、化疗。