Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.

Pediatric central nervous system germ cell tumors: a review.

Principles of treatment of the pineal region tumors.

The optimum management of localised intracranial germinoma remains controversial. Cure rates for this rare CNS tumour, which arises mainly in adolescents, exceed 90% at 10 years, and limitation of treatment-related late morbidity is therefore essential. Craniospinal radiotherapy plus boost is perceived to be the gold-standard treatment, but there have been suggestions that reduced-volume radiotherapy could be adequate for cure. We reviewed publications since 1988 to compare patterns of disease relapse and cure rates after craniospinal radiotherapy, reduced-volume irradiation alone (i.e., whole-brain or whole-ventricular irradiation followed by a boost), and focal or localised irradiation alone. The recurrence rate after whole-brain or whole-ventricular radiotherapy plus boost was 7.6% compared with 3.8% after craniospinal radiotherapy, with no predilection for isolated spinal relapses (2.9% vs 1.2%). We challenge the consensus that craniospinal radiotherapy is the best treatment for localised germinomas and conclude that reduced-volume radiotherapy plus boost should replace craniospinal radiotherapy when a radiotherapy-only approach is used.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(05)70245-X.pdf

Radiotherapy of localised intracranial germinoma: time to sever historical ties?

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

/pdf/novel-somatic-and-germline-mutations-in-intracranial-germ-5g9jfdcobp.pdf

Novel somatic and germline mutations in intracranial germ cell tumours

Purpose: To review cases of secondary intracranial meningiomas following high-dose cranial irradiation (≥ 10 Gy) identified in Slovenia between 1968 and 1998, to determine their histological profile and to review the literature on this topic. Methods and Materials: Personal files of patients treated for secondary intracranial meningioma during a 31-year period were reviewed. In cases which met the criteria for radiation-induced tumors, steroid hormone receptor and Ki-67 status were analyzed. For the literature review, computerized database systems and reference lists from respective publications were used. Results: Five patients (2 females, 3 males), 3–11 years old at the time of cranial irradiation, developed secondary meningioma after a latency period of 9.5–31.5 years. Three patients had multiple tumors and 2 developed recurrent disease. Of 9 histologically examined tumors, 5 were graded as benign and 4 as atypical meningiomas, with Ki-67 proliferative index 3.2 ± 3.6 and 10 ± 6, respectively. The ratio between positive and negative meningiomas regarding immunostaining for progesterone and estrogen receptors was eight-to-one and six-to-three, respectively. Cumulative actuarial risk of secondary meningioma in a cohort of 445 children 16 years or younger treated with high-dose cranial irradiation between 1968 and 1990 in Slovenia at 10, 20, and 25 years was 0.53%, 1.2%, and 8.18%, respectively. Out of 126 cases of radiation-induced meningiomas reported, 57% were females and 43% were males, with mean age at presentation 33 ± 17.3 years. The majority (68%) of patients was irradiated during childhood. The latency period was significantly shorter in those who aged 5 years or less at the time of cranial irradiation ( p = 0.04), and in those with atypical/anaplastic tumor ( p = 0.01). Correlation between radiation dose and latency period could not be found. Conclusion: Secondary meningiomas following high-dose cranial irradiation are characterized by younger age at presentation, by higher male-to-female ratio and by biologically more aggressive variants compared to primary spontaneous meningiomas. Latency period correlated with the age at the time of cranial irradiation and with tumor grade but not with irradiation dose. Ki-67 immunoreactivity correlated with histological grade. The progesterone and estrogen receptor immunoreactivity was high. The risk for development of secondary meningioma after high-dose cranial irradiation was increasing with the time of follow-up.

Secondary intracranial meningiomas after high-dose cranial irradiation: report of five cases and review of the literature.

Intracranial germ cell tumors are a heterogeneous group of lesions which occur in children and adults. Within the classification of intracranial germ cell tumors, there are a variety of different tumor types which carry different prognoses. The diagnosis of an intracranial germ cell tumor usually requires histological information, but a subgroup of tumors will secrete specific tumor markers, including α-fetoprotein and β-human chorionic gonadotropin, which may obviate the need for surgical intervention. The management of intracranial germ cell tumors in both children and adults remains unsettled. Germinomas have a good prognosis, as over 90% of patients can be effectively treated with radiation therapy. The dose and volume of radiation therapy needed for disease control is not well established, and controversy exists concerning the need for whole brain or craniospinal radiation therapy for localized tumors. Germinomas are also chemosensitive and recent reports suggest that the dose and volume of radiation therapy required for disease control can be lessened with the addition of adjuvant chemotherapy. The outcome for patients with nongerminomatous germ cell tumors is less favorable. Radiation therapy alone will result in disease control in 40%-60% of patients. The addition of chemotherapy to radiation therapy may improve the rate of survival. The Oncologist 2000;5:312-320

Kathleen Cooney

Papers

Intracranial Germ Cell Tumors