Nongerminomatous Malignant Germ Cell Tumors Research Articles

GCT-45. YOLK SAC TUMOR IN THE CEREBELLAR VERMIS - A CASE REPORT

Yolk sac tumor (YST) is a non-germinomatous malignant germ cell tumor in a young child. It usually arises along a midline axis, mostly pineal region or suprasellar compartment, and it is exceedingly rare to locate in a cerebellar vermis. In the present report, we describe a case of a pure YST located in the cerebellar vermis and review the previous literature. A three-year-old boy visited a local clinic for gait disturbance and frequent vomiting. Gadolinium-enhanced magnetic resonance imaging (MRI) showed a homogeneously-enhanced mass with a cystic component in his cerebellar vermis, and it resulted in hydrocephalus. By its location and his age, our pre-operative diagnosis was a medulloblastoma, and we performed a total resection of the tumor with ventricular drainage. Unexpectedly, the histological investigation revealed it to be a YST. We confirmed that the serum levels of α-fetoprotein (AFP) had elevated at 3176.4 ng/ml in his preserved sample, obtained before the surgery, and it was consistent with the pathological diagnosis. He is receiving chemotherapy consisting of ifosfamide, cisplatin, and etoposide, followed by radiation therapy. In this case, pre-operative MRI revealed that the tumor did not grow into the IVth ventricle in spite of midline location, which was not typical for medulloblastoma. Of note, serum AFP levels had increased, and they might contribute to a precise pre-operative diagnosis and be able to propose an alternative treatment plan, such as neoadjuvant chemotherapy to reduce surgical risk. As a conclusion, a YST should be considered even if it locates in a cerebellar vermis.

NQPC-02 Long-term survival in patients with primary intracranial germ cell tumors treated with surgery, platinum-based chemotherapy, and radiotherapy: a single-institution study

Purpose: In the present study, we performed a retrospective review of patients receiving carboplatin based chemotherapy followed by radiotherapy for newly diagnosed primary intracranial germ cell tumors. In order to identify an optimal germ cell tumor treatment strategy, we evaluated treatment outcomes and toxicity and compliance.Methodology: This study included 110 consecutive patients with newly diagnosed primary intracranial germ cell tumors. The drug doses and administration schedule of carboplatin-etoposide (CARB-VP) were as follows: carboplatin (300 mg/m2 daily for 1 days), and etoposide (100 mg/m2 on days 1 to 3). Ifosfamide-carboplatin-etoposide (ICE) treatment comprised ifosfamide (1500 mg/m2 daily for 3 days), carboplatin (300 mg/m2 daily for 1 days), and etoposide (100 mg/m2 daily for 3 days). Patients with germinomatous germ cell tumors (pure germinoma or germinoma with STGC) basically receive three cycles of CARB-VP and a total dose of 30Gy whole ventricular radiotherapy. We delivered combination therapy consisting of combined ICE chemotherapy and craniospinal irradiation followed by the complete resection of the residual tumor for nongerminomatous malignant germ cell tumors.Results: The median follow-up time was 11.0 years (range, 0.5–37.8 years). The 5-year total survival rates of germinomatous and nongerminomatous germ cell tumors were 97.2% and 66.7%, respectively. The 10-year and 20-year total survival rates of germinomatous germ cell tumors were 95.7% and 90.0%, respectively. Adverse events related to carboplatin based chemotherapy are not detected. Furthermore, no treatment-related deaths were observed.Conclusions: Our treatment with surgery, carboplatin based chemotherapy followed by radiotherapy is effective in treating primary intracranial germ cell tumors, especially in germinomatous group.

Primary intracranial germ cell tumors in children 36-year experience of a single center.

Intracranial germ cell tumors (ICGCTs) comprise approximately 0.4%-3% of all brain tumors. In this study, we aim to evaluate clinical characteristics, treatment and outcomes of patients with ICGCT. All patients with ICGCT diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated, retrospectively. We identified 52 patients (male/female: 2.46) diagnosed with ICGT. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others (P = 0.028). The primary site was pineal region in 20 patients, nonpineal region in 32 which included six bifocal involvements. Pineal location was more common in boys than girls (P = 0.02). Histopathological diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumors in 14 and immature teratoma in 4. The mean age for germinoma was higher than that of nongerminomatous tumors (P = 0.032). Patients treated with surgery and radiotherapy and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12-228 months. Relapsed/progressive disease was observed in 11 patients. Nongerminomatous tumors more frequently showed relapse/progression than germinoma (P = 0.06). Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates for germinoma were better than malignant nongerminomatous tumors. Although the ratio of ICGCTs to central nervous system tumors in our series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than developed western and eastern developed countries.

Detection of Relapse by Tumor Markers Versus Imaging in Children and Adolescents With Nongerminomatous Malignant Germ Cell Tumors: A Report From the Children's Oncology Group.

To investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance. We retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers. A total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse. Tumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.

Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment

The notable survival chances of intracranial germ cell tumors (icGCTs) lead to a rising concern over long-term neurocognitive outcome. Yet, prior evidence related to this issue fails to provide a comprehensive examination of the effects of tumor location and radiotherapy. We attempt to explore their impacts on the neuropsychological functions and life quality in children with icGCT after multimodality treatments. A retrospective review of 56 patients diagnosed with icGCTs at age <20 and treated at the Taipei Veterans General Hospital was provided. Intelligence, memory, visual organization, attention, and executive function were assessed by neurocognitive tests; adaptation to life, emotional and behavioral changes, interpersonal relationships, and impact on the family were evaluated by parent-report instruments. Effects of tumor locations (germinomas and nongerminomatous malignant germ cell tumors in the pineal, suprasellar, and basal ganglia) and irradiation on these measurements were examined. Patients with tumors in the basal ganglia region had lower full-scale IQs than those with tumors in the pineal or suprasellar regions. Subscores of intelligence scale and short-term retention of verbal and visual stimuli showed evident group differences, as did the quality of life and adaptive skills, particularly in psychosocial domains. Patients treated with whole-ventricular irradiation had better outcomes. Extensive irradiation field and high irradiation dosage influenced intellectual functions, concept crystallization, executive function, and memory. Tumor location and irradiation field/dosage appear to be the crucial factors related to certain neuropsychological, emotional, and behavioral dysfunctions that in turn alter the quality of life in children with icGCTs who survive after treatment.

The treatment and prognosis of intracranial nongerminomatous malignant germ cell tumors in pineal region

Objective To investigate the clinical feature,treatment and prognosis of intracranial nongerminomatous malignant germ cell tumors (NGMGCTs) in pineal region.Methods Records of 34 such kind patients treated in our hospital between Jan 2000 and Jan 2010 were reviewed retrospectively.Clinical manifestations,diagnosis,treatment and outcome were analyzed in each patient.All tumors were microsurgically removed by occipital transtentorial approach (Poppen) and treated with radiotherapy combined chemotherapy.Results The tumor was totally removed in 32 cases,sub - totally in 2.In these 34 cases,all were verified by pathology,viz.11 immature teratomas,2 teratoma with malignant transformation,6 choriocarcinoma,2 embryonal carcinomas and 1 yolk sac tumors,12 mix germ cell tumors.Thirty - one patients were followed up.The overall 1 - year survival rate was 97％,3 - year survival rate 62％ and 5 -year survival rate 44％.Immature teratomas 1 - year survival rate was 100％,3 - year survival rate 67％.Teratoma with malignant transformation 1 - year survival rate was 100％,1 - year survival rate was 33％.Choriocarcinoma,embryonal carcinomas and yolk sac tumors 1 - year survival rate was 88％,3 - year survival rate 55％,5 - year survival rate 33％.Mix germ cell tumors 1 - year survival rate was 100％,3 -year survival rate 67％,5 - year survival rate 67％.Conclusion The majority of pineal region NGMGCTs can be diagnosed by clinical manifestations,imaging data and tumor markers pre - operatively Surgery remains the first choice for NGMGCT based on tumor histology.Combined regimen of surgical resection,radiotherapy and chemotherapy is mostly effective. Key words: Pineal region; Germ cell tumors; Prognosis; Treatment

Therapy-associated secondary tumors in patients with non-germinomatous malignant germ cell tumors

We report three patients with non-germinomatous malignant germ cell tumor (NGMGCT) who developed therapy-associated secondary tumors. They were diagnosed as having NGMGCT by elevated serum levels of α-fetoprotein (AFP), human chorionic gonadotropin (HCG), or β-HCG. Preoperatively, all patients received a combination of etoposide and platinum-based chemotherapy and radiotherapy; neo-adjuvant therapy (NAT) was followed by complete excision of the residual tumor. Postoperatively, all underwent maintenance chemotherapy and all remained free of NGMGCT without recurrence. However, they developed therapy-associated secondary tumors, i.e. glioblastoma, meningioma, or cavernous angioma after 10.1, 9.8, and 8.2 years, respectively. The patient with glioblastoma died one year after its detection. The other two patients are currently alive; the meningioma was completely removed and the cavernous angioma is being monitored without additional treatment. To the best of our knowledge, therapy-associated secondary tumors in patients treated for NGMGCT are rare.

Evaluation of neoadjuvant therapy in patients with nongerminomatous malignant germ cell tumors

The authors evaluated the effectiveness of a neoadjuvant therapy (NAT) consisting of combined chemo and radiotherapy followed by complete resection of the residual tumor in patients with nongerminomatous malignant germ cell tumors (NGMGCTs). The authors treated 14 consecutive patients in whom NGMGCTs were diagnosed based on elevated levels of the tumor markers α-fetoprotein, human chorionic gonadotropin, and the β-subunit of human chorionic gonadotropin (β-HCG). Chemotherapy and radiotherapy were performed, and after the serum tumor markers level was in the normal or near-normal range, the residual tumors were completely resected. Residual tumors were confirmed in 11 of the 14 patients after NAT, and total removal was successful in 10 of the 11 patients. In the other patient the residual tumor could not be completely excised because it was attached to a deep vein. The follow-up duration ranged from 1.2 to 22.2 years. The 5-year event-free and total survival rates were 86% and 93%, respectively. Although 3 patients died, 2 of tumor recurrence and 1 of a radiation-induced secondary tumor (glioblastoma), the other 11 are alive and without evidence of tumor recurrence. The authors consider their NAT protocol for NGMGCT to be highly effective in relation to survival for the patients with NGMGCT, but there are several quality of life issues that need to be resolved.

Clinical features and microsurgical management of rare tumors in the sellar region

To investigate the clinical characteristics and microsurgical managements of rare tumors in the sellar region. Six rare cases of tumors in the sellar region treated by microsurgery from Jan 2000 to Jan 2010 were reviewed retrospectively. Subsequent treatments were according to the status of preoperative alpha fetal protein (AFP) and human chorionic gonadotropin (HCG) measurement as well as confirmed by histopathological examination in all six patients. Total resection of the tumor was achieved in 2 cases and subtotal resection in 4 cases. Postoperative histopathology confirmed that the lesions were tumors in 5 cases and fungal pseudotumor in 1 case. Moreover, variety of histological types were observed in the present series, including leiomyosarcoma, malignant yolk sac tumor, mixed germ cell tumor, embryonal carcinoma, pilocytic astrocytoma and fungal pseudotumor, respectively. The serum levels of AFP and HCG were elevated to some extent in the patients with malignant yolk sac tumor, mixed germ cell tumor or embryonal carcinoma. Follow-up was conducted in all patients for 1 month to 3 years. The patients with malignant yolk sac tumor and embryonal carcinoma as well as leiomyosarcoma died in 5, 6, 10 months after operation, respectively. Subarachnoid hemorrhage occurred in the case of fungal pseudotumor at 2 months after surgery. The other two patients were surviving well. Rare non-germinomatous malignant germ cell tumors are predominantly susceptible to the sellar region. Furthermore, High misdiagnosis rate and poor prognosis are characteristic in the present study. Dynamic AFP and HCG detection may play an important role in the diagnosis of those non-germinomatous malignant germ cell tumors located in the sellar region. The importance of awareness of the presence of such rare lesions in the sellar region is emphasized.

What’s growing on? The growing teratoma syndrome

The growing teratoma syndrome (GTS) consists of a mature teratoma paradoxically enlarging during or after chemotherapy for malignant nongerminomatous germ cell tumors. We report two cases of GTS occurring in association with NSGCT of the pineal gland. Although an unusual event, clinicians and radiologists should be aware of its natural history. When normalized tumor markers after chemotherapy are associated with imaging features of a growing mass, the hypothesis of GTS must be taken in consideration. When early diagnosed, GTS can be managed surgically with good results.

Histologically confirmed intracranial germ cell tumors; an analysis of 62 patients in a single institute

This study was undertaken to document the clinicopathologic characteristics of histologically verified, primary intracranial germ cell tumors (GCTs), determine treatment outcomes, and to identify prognostic factors. The records of 62 patients (45 males and 17 females) with a primary intracranial GCT were retrospectively analyzed. Mean patient age was 18 years, and median follow-up was 41 months. The most common histological subtypes were germinoma (48.4%), followed by mixed GCT (27.4%), and teratoma (19.4%). In 23 patients (37.1%), disease onset occurred between 16 and 20 years. Germinomas and malignant non-germinomatous germ cell tumors were most prevalent in the pineal gland, suprasellar region, and basal ganglia, whereas teratomas dominated at other sites. Synchronous bifocal GCTs were found in six patients. Five-year overall survival (OS) rates according to a therapeutic classification proposed by Sawamura were 82.93%, 83.08%, and 64.71% in the good, intermediate, and poor prognosis groups, respectively (P = 0.2839). Five-year OSs in patients with normal tumor marker (alphaFP or betaHCG) and patients with elevated marker were 85.26% and 66.96%, respectively (P = 0.0568). Five of six patients with alpha-fetoprotein (alpha-FP) of >1,000 ng/ml succumbed to disease, whereas all five patients with a beta-human chorionic gonadotropin of >1,000 mIU/ml survived. Mixed GCTs are more common in Korea than in the West. Sawamura's classification of intracranial GCT may be a fine tool for stratifying patients' survival. Patients with elevated tumor marker levels may appear to have poorer OS independent of histology. In particular, high titers of alpha-FP seem to impact prognosis.

Modified grading system for clinical outcome of intracranial non-germinomatous malignant germ cell tumors

This study investigated the clinical outcome of intracranial non-germinomatous malignant germ cell tumors (NGMGCTs). All histologically proven cases of NGMGCTs treated in Shanghai Huashan Hospital, Fudan University were reviewed. A total of 39 cases were analyzed. There were 15 mixed germ cell tumors, 15 immature teratomas, 7 embryonal carcinomas and 2 yolk sac tumors. Patients were treated surgically first, followed by radiotherapy and/or chemotherapy. Some patients also received gamma knife surgery. The common 5-year survival rate was 36.8%. According to Matsutani's grading system, the 5-year actuarial survival rate for patients in the intermediate and poor prognosis groups were 45.8 and 14.3%, respectively. Individual analysis of each type of tumor showed that the median survival time of embryonal carcinoma was 27 months, which is very close to that of the intermediate group (28 months). We therefore classified embryonal carcinoma into the intermediate group where the 5-year actuarial survival rate for patients in the new intermediate prognosis group was 42.6%. Further analysis of immature teratoma cases found that the 5-year survival rate of patients with immature teratoma who received gamma knife surgery is 100%. This rate exhibited a significant difference (P=0.0049) compared to that of patients who did not undergo gamma knife surgery. In conclusion, we consider surgery as the first choice of treatment although for different histologis, the type of the tumor should be treated separately.

Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations

BackgroundIntracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.ResultsWe identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.ConclusionsOur results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

Grading system for diagnosis and treatment of intracranial nongerminomatous malignant germ cell tumors

To discuss the clinical feature, treatment and prognosis of intracranial nongerminomatous malignant germ cell tumors (NGMGCT). The records of 39 patients receiving treatment at our hospital between 1995 and 2007 were reviewed retrospectively. According to the classification of Matsutani, they were grouped into intermediate prognosis and poor prognosis groups based on tumor histology. Clinical manifestations, diagnosis, treatment and outcome were analyzed in each group. In these 39 cases, there were 15 mix germ cell tumors, 15 immature teratomas, 7 embryonal carcinomas and 2 yolk sac tumors. All patients were treated surgically. The tumor was totally removed in 29 cases, sub-totally in 5 and partially in 3. Biopsy was performed in the other 2 cases. Thirty-four patients (87.2%) were followed up. The overall 5-year survival rate was 36.8%. The 5-year actuarial survival rate for patients in the intermediate prognosis and poor prognosis groups were 42.6% and 0 respectively. Chemoradiotherapy had a significant correlation with the prognosis of intermediate prognosis group (P = 0.039). The 5-year survival rate of immature teratoma patients receiving post-operative gamma knife surgery was 100%. It had significant difference (P = 0.0049) as compared to the 5-year survival rate of patients receiving no gamma knife surgery. NGMGCT can be divided into the intermediate and poor groups based on the prognosis (P = 0.0003). Embryonal carcinoma can be classified to the intermediate prognosis group because of its similar prognosis with immature teratoma and mixed tumors composed mainly of germinoma or teratoma. Surgery remains the first choice for NGMGCT since treatment should be based on tumor histology. For patients in the intermediate prognosis group, a combined regimen of surgical resection, radiotherapy, chemotherapy and gamma knife surgery is mostly effective.

Intracranial teratomas in children: the role and timing of surgical removal

In this study, the authors report their experience with the surgical treatment of intracranial teratomas with an emphasis on the indications for delayed resection after oncological treatment. The authors retrospectively reviewed the cases of 14 children with intracranial teratomas. The mean age at diagnosis was 10.5 years (range 2 days-18 years), and 11 patients were male. The final histological analysis revealed pure mature teratoma in 5 cases, mixed teratoma with germinoma in 3 cases, and nongerminomatous malignant germ cell tumor in 6 cases. Thirteen patients underwent tumor resection, and these patients were divided into 2 subgroups according to the timing of surgery. In Group A, 10 patients underwent resection as the primary treatment because no tumor markers were detected in 4 patients, a teratomatous component was revealed on biopsy sampling in 3 patients, and a large tumor volume in 3 patients. In Group B, 3 patients underwent removal of residual pure mature teratoma after oncological treatment. Seven of the 8 patients (87.5%) with pure mature teratomas or with mixed teratoma and germinoma are currently alive (mean follow-up of 9 years); the eighth patient died of postoperative meningitis. Two of the 6 patients (33%) with mixed nongerminomatous malignant germ cell tumors died of tumor progression regardless of the timing of surgery. The results of this study support the belief that microsurgical removal is the only effective treatment for intracranial teratomas. Surgery may be performed as the primary therapy when there is evidence of a noninvasive teratoma, and as a secondary therapy if there is only a partial response to neoadjuvant therapy or if progression is observed in mixed malignant germ cell tumors.

Carbon 11–labeled methionine positron emission tomography for detection of residual viable tumor cells after adjuvant therapy in nongerminomatous malignant germ cell tumors in 2 cases including an autopsy case

Background The treatment of intracranial NGMGCTs is generally based on chemotherapy and radiotherapy. To avoid the potential of tumor recurrence, we normally have the residual mass lesion removed after adjuvant therapy. However, since 1988 we have treated 15 patients with NGMGCT and pathologically evaluated 12 such patients after adjuvant therapy by a new method we have developed and found viable tumor cells in 4 (33%) of 12 patients. Based on our experience, therefore, we feel we have been able to develop a reliable diagnostic tool for confirming the presence or absence of viable tumor cells in residual mass after adjuvant therapy for patients with NGMGCT. Case Description We describe here 2 patients with NGMGCTs who underwent MET-PET. Patient 1 was an 11-year-old boy with immature teratoma. On gadolinium (Gd)-enhanced magnetic resonance imaging (MRI), a high-intensity area was found in his right cerebellar hemisphere and a high uptake in MET-PET was confirmed in the same region. We judged it as the recurrence of the tumor. Finally, he died and was autopsied. Patient 2 was a 16-year-old girl with an NGMGCT who received combined chemo- and radiotherapy that led to a reduction in the volume of the tumor. Her serum β-HCG and HCG levels also returned to the reference range. However, the mass did not disappear and another MRI scan disclosed a residual Gd-enhanced lesion. To assess whether there were residual viable tumor cells, MET-PET was performed, and it demonstrated no hyper-uptake region in the residual mass. We, therefore, did not surgically remove the mass and kept the patient under observation. There has not been any tumor recurrence in this patient for more than 2 years. Conclusion In these 2 cases, the increased MET uptake was more specific of tumor tissue and more accurate than MR Gd enhancement. MET-PET may be a useful diagnostic tool for predicting viable tumor cells after adjuvant therapy in patients with NGMGCT, thus allowing further surgical intervention.

Evaluation of Residual Tissues after Adjuvant Therapy in Germ Cell Tumors

Objective: Germ cell tumors are the tumors sensitive for adjuvant therapy such as radiotherapy and chemotherapy. We evaluated the pathological findings of these heterogeneous tumors to determine the persistence of residual viable tumor cells after adjuvant therapy. Patients and Methods: Between 1988 and 2005, we treated 31 patients with germinoma or germinoma with syncytiotrophoblastic giant cells (STGC) and 15 patients with non-germinomatous malignant germ cell tumors (NGMGCTs). All 46 patients received a combination of chemo- and radiotherapy. A second-look operation was performed in 3 of 31 patients with germinomas or germinomas with STGC and 12 of 15 patients with NGMGCTs. The follow-up period was 2–139 months (median 95) in patients with germinomas or germinomas with STGC (group 1) and 10–202 months (median 65) in NGMGCT patients (group 2). Results: Post-treatment, 3 group 1 and 12 group 2 patients manifested residual tumors. The pathological diagnosis in group 1 patients was mature teratoma, pineal cyst, and fibrous tissue with calcification; in group 2 it was yolk sac tumor (n = 1), immature teratoma (n = 3), mature teratoma (n = 4), and necrosis or fibrous tissue (n = 4). While no group 1 patients manifested tumor cells, MIB-1-positive viable tumor cells were present in resected tissues from one-third of the group 2 patients (3 immature teratomas and 1 yolk sac tumor). Conclusion: The absence of viable tumor cells in residual tissue indicates that the combination of cisplatin-based chemo- and radiotherapy was effective in our germinoma patients. On the other hand, in patients with NGMGCTs, these cells persisted despite this combination therapy.

Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization

The limited information available to date regarding the genetic alterations in germ cell tumors of the central nervous system has raised concerns about their biologic relationship to other germ cell tumor entities. We investigated fresh-frozen or archival tumor samples from 19 patients with central nervous system germ cell tumors (CNS-GCTs), including seven germinomas, eight malignant nongerminomatous germ cell tumors and four teratomas, using chromosomal comparative genomic hybridization to determine recurrent chromosomal imbalances. All 15 malignant CNS-GCTs and two of four teratomas showed multiple chromosomal imbalances. Chromosomal gains (median: 4 gains/tumor, range: 0–9 gains/tumor) were observed more frequently than losses (median: 1.6 losses/tumor, range: 0–6 losses/tumor). Gain of 12p, which is considered characteristic for germ cell tumors of the adult testis, was detected in 11 of 19 tumors and 10 of 15 malignant CNS-GCTs. In one tumor, gain of 12p was confined to an amplicon at 12p12, corresponding to the commonly amplified region on 12p. Other common gains were found on chromosome arms 1q and 8q (n=9, each). Among the chromosomal losses, parts of chromosome 11 (n=5), 18 (n=4), and 13 (n=3) were deleted most frequently. Notably, we observed no difference in the genetic profiles of germinomatous and nongerminomatous CNS-GCTs; however, the average number of imbalances was higher in the latter group. A meta-analysis comparing 116 malignant gonadal and extragonadal germ cell tumors revealed that the genomic alterations in CNS-GCTs are virtually indistinguishable from those found in their gonadal or other extragonadal counterparts of the corresponding age group. These data strongly argue in favor of common pathogenetic mechanisms in gonadal and extragonadal germ cell tumors.

Impact of Surgery, Chemotherapy and Irradiation on Long Term Outcome of Intracranial Malignant Non-Germinomatous Germ Cell Tumors: Results of the German Cooperative Trial MAKEI 89

Malignant non-germinomatous intracranial germ cell tumors (MNGGCTs) are a heterogenous group of neoplastic lesions. Their treatment concept follows a multimodal concept that may include tumor resection for local tumor control, craniospinal irradiation to cover leptomenigeal tumor spread and chemotherapy to eliminate systemic tumor dissemination. A Platinum-based chemotherapy proven to be highly effective in testicular and non-testicular malignant germ cell tumors in adults as well as in children has also been chosen for intracranial sites. While therapeutic concepts have been thoroughly evaluated for children and adolescents with extracranial nongonadal GCTs, no such detailed long term follow-up data are available for intracranial MNGGCTs. This paper reports on the long-term outcome of 41 patients with intracranial malignant non-germinomatous GCTs enrolled into the German prospective protocol MAKEI 89. The analysis focuses on the impact of surgery, radio- and chemotherapy. Between January 1989 and January 1994, 41 patients with malignant intracranial non-germinomatous GCTs were registered. Patients were compared in respect to protocol (n = 27) and non-protocol treatment (n = 14). Estimated were with chi (2) and Fisher exact test the impact of surgery, chemotherapy and irradiation on outcome. The estimated (Kaplan-Meier) 5-year event free survival (EFS) of patients treated according to protocol recommendations was 0.59 +/- 0.06 (n = 27), compared to an EFS of 0.37 +/- 0.33 for patients with different treatments (n = 14) (p = 0.70, log-rank). The 5-year relapse-free survival rate (RFS) was 0.74 +/- 0.06 in protocol patients and 0.38 +/- 0.33 in non-protocol patients (median observation time of 112 months after diagnosis for surviving patients) (p = 0.14, log-rank). Surgery, complete or incomplete had no significant impact on survival (p = 0.12). Radiotherapy, in terms of craniospinal irradiation had a significant influence on survival (p = 0.035) as well as a cumulative cisplatin dose >/= 400 mg/m (2) (p = 0.002). Cisplatin chemotherapy and craniospinal irradiation with tumor boost are of significant influence on long term survival in patients with MNGGCTs. The exclusion of major surgery at diagnosis using modern advances in neurosurgery or related tumor resection after neoadjuvant chemotherapy will allow a further reduction of treatment related mortality and long lasting morbidity. The analysis reveals that, given effective treatment, intracranial malignant non-germinomatous GCTs should not longer carry a poor prognosis.

Occipital transtentorial approach to pineal region tumors

The surgical techniques and results of the occipital transtentorial approach to pineal region tumors using the lateral-semiprone position are described. The lateral-semiprone position and infrasplenial approach can compensate for the disadvantages of the occipital transtentorial approach and provides wide exposure of pineal region tumors. The infrasplenial approach is helpful in separating the internal cerebral veins from the tumor, especially when the tumor is tightly adherent to the veins. Pineal region tumors must be removed through a limited space between important deep veins. Therefore, piecemeal resection is mandatory to avoid injury to the veins. We have operated on 82 pineal region tumors through the occipital transtentorial approach. The extent of tumor removal primarily depended on the nature of the tumor but little on its location. There were no surgical deaths in our series, but homonymous hemianopsia occurred in 5 patients and ocular movement was disturbed in 5 patients. Ataxia of both extremities and the trunk and slight motor weakness of the right extremity occurred in one patient. Extensive removal was considered an important factor in prolonging survival in patients with teratomas, nongerminomatous malignant germ cell tumors, and pineocytomas.