Abstract
Radiation therapy is sometimes performed to control intracranial acute lymphoblastic leukemia (ALL), but may lead to radiation-induced malignant glioma. The clinical, radiological, histological, and molecular findings are described of three cases of radiation-induced glioblastoma after the treatment for ALL. They received radiation therapy at age 6–8 years. The latency from radiation therapy to the onset of radiation-induced glioblastoma was 5–10 years. Magnetic resonance imaging demonstrated diffuse lesions with multiple small enhanced lesions in all cases. Histological examination showed that the tumors consisted of mainly small round astrocytic atypical cells in one case, and astrocytic atypical cells with elongated cytoplasm and nuclear pleomorphism with small cell component in two cases. Microvascular proliferation was present in all cases. Immunohistochemical analysis for B-Raf V600E, and mutational analysis for the isocitrate dehydrogenase (IDH) 1, IDH2, and H3F3A gene revealed the wild-type alleles in all three cases. The integrated diagnoses were IDH wild-type glioblastoma, and local irradiation and concomitant temozolomide were performed. After the initial treatment, significant shrinkage of the diffuse lesion and enhanced lesion was found in all cases. Radiation-induced glioblastoma occurring after the treatment for ALL had unique clinical, radiological, histological, and molecular characteristics in our three cases.
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Introduction
Acute lymphoblastic leukemia (ALL) is the most common neoplasm in childhood, but more than half of patients who achieved complete remission with chemotherapy suffered recurrence in the central nervous system (CNS) [1]. Prophylactic therapy with craniospinal irradiation and CNS-directed chemotherapy was introduced in the early 1970s, which significantly improved the prognosis for pediatric ALL [2]. However, cranial irradiation in childhood is associated with severe side effects including developmental and endocrinal disorders, radiation-induced necrosis, vascular complications, and secondary neoplasm [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. Risk-stratified effective and intensive chemotherapy, and both intrathecal and systemic CNS-directed treatment have improved 5-year event-free survival rates for childhood ALL to > 85% [34,35,36]. Craniospinal irradiation is now limited to patients with CNS involvement at initial onset (8.7%) or relapse (2.5%) [35]. Consequently, improvements in intensive chemotherapy have eliminated the necessity for craniospinal irradiation therapy in most cases, but radiation therapy remains indispensable in the treatment of ALL.
Radiation-induced neoplasm is a relatively rare complication of radiation therapy. The cumulative incidence of intracranial tumor is 3.0% at 30 years, and cranial irradiation carries the risk for the formation of radiation-induced intracranial tumor [15]. Furthermore, radiation-induced malignant glioma may occur after the treatment for ALL [4, 5, 9,10,11,12,13,14,15,16,17,18, 20, 22,23,24,25,26,27,28,29,30,31,32,33]. Some clinical aspects including the frequency, primary neoplasms, and latency of ALL-related glioblastoma and other central nervous system (CNS) tumors have been reported [5, 6, 31]. The cumulative incidence of all intra-cranial tumors at 20 years is 1.39%, and histology of secondary tumors was high grade glioma in 10, low grade glioma in 1, and meningioma in 11 [5]. Risk factors for developing secondary CNS tumors was the presence of CNS leukemia, cranial irradiation in dose dependent manner, and less than 6 years [5]. Four of 1612 cases (0.25%) with acute lymphoblastic leukemia developed radiation-induced glioblastoma with median follow-up period of 15.9 years [5]. The five most frequent primary lesions of radiation-induced malignant glioma were ALL (31.8%), medulloblastoma (13%), pituitary adenoma (10.8%), craniopharyngioma (8%), and tinea capitis (4%) [4]. However, the radiological, histological, molecular characteristics, and treatment outcomes after radiation therapy and temozolomide (TMZ) remain unclear due to the rarity of ALL-related glioblastoma.
We present the clinical, radiological, histological, and molecular findings of three cases of radiation-induced glioblastoma after radiation therapy for ALL.
Materials and methods
All histological materials were immediately fixed in 10% buffered formalin (Wako, Osaka, Japan) at room temperature for several days, and cut into 2-µm thick paraffin sections. Immunohistochemical examination was performed using automated immunostaining systems with Ventana Benchmark ULTRA (Roche, Basel, Switzerland) for glial fibrillary acidic protein (GFAP), vimentin, TP53, p16, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and B-Raf (BRAF) V600E, and Autostainer Link 48 for Ki-67. The primary antibodies were rabbit monoclonal antibody for GFAP (EP672Y, Roche), vimentin (V9, Roche), and mouse monoclonal antibody for TP53 (DO-7, Roche), p16 (E6H4, Roche), ATRX (CL0537, Abcam, Cambridge, UK), BRAF (VE1, Roche), and Ki-67 (MIB-1, Aligent, Santa Clara, USA). Immunoreactivity of TP53 and Ki-67 was semi-quantified as labeling indexes by counting stained tumor cells among 1000 cells in the regions with the most immunoreactivity. The cut-off value of the labeling index was 10% for TP53 staining [37]. Immunostaining for O6-methylguanine methyltransferase (MGMT) was performed with anti-MGMT antibody (MT3.1, Merck, Darmstadt, Germany). Antigen retrieval was accomplished for MGMT by heating in an autoclave for 5 min at 121 °C in citric acid buffer (2 mmol/L citric acid and 9 mmol/L trisodium citrate dehydrate, pH 6.0) [37].
The detection of mutation on IDH1 and IDH2 gene were performed with high resolution melting analysis with cobas z 480 system (Riche Molecular Diagnostics, Pleasanton, USA). The forward and reverse primer sequences for the IDH1 gene were 5′-CGGTCTTCAGAGAAGCCATT-3′ and 5′-CACATTATTGCCAACATGAC-3′. The forward and reverse primer sequences for the IDH2 gene were 5′-GGGGTTCAAATTCTGGTTGA-3′ and 5′-CTAGGCGAGGAGCTCCAGT-3′. The PCR conditions for amplification of IDH1 and IDH2 were as follows. 95 °C for 10 min, 50 cycles of PCR consisting of denaturation at 95 °C for 10 s, annealing at 65 − 53 °C for 10 s with touchdown method and extension at 72 °C 10 s. The detections of mutation on IDH1 and IDH2 gene were performed by 95 °C for 1 min, 40 °C for 1 min, and gradual heating from 65 to 95 °C. Genetic analysis of the H3F3 gene used DNA purified from tissue sections using a nucleic acid extraction kit (RecoverAll Total Nucleic Acid Isolation, Ambion K.K., Tokyo, Japan) following the manufacturer’s instructions. Mutations of H3F3A gene was investigated using an automated gene analyzer based on the probe quench method, i-densy (Arkray, Kyoto, Japan), following the manufacturer’s instructions.
Case reports
Case 1
A 2-year-old boy without familial history of neoplasm was diagnosed with ALL. He was treated with chemotherapy and achieved complete remission. He suffered recurrence of ALL in the meninges of the left cerebral hemisphere at age 8 years [18]. He received intrathecal administration of methotrexate and cytarabine, and craniospinal irradiation 18 Gy, and achieved complete remission. He presented with progressive right upper limb ataxia and severe headache at age 13 years. Magnetic resonance (MR) imaging showed diffuse lesion in the right cerebellar hemisphere and the right side of the pons, and multiple enhanced lesions in the cerebellar hemisphere and vermis (Fig. 1a). He underwent resection of the cerebellar lesion (Fig. 1b). Histologically, tumor consisted of atypical cells with elongated cytoplasm and nuclear pleomorphism in the fibrillary background (Fig. 1d). Monomorphic small cell component was also found in addition to the pleomorphic tumor cells (Fig. 1e). There was microvascular proliferation, but not necrosis (Fig. 1e). Immunohistochemical examination detected weak and focal staining for GFAP and vimentin, positive staining for ATRX and TP53, and negative staining for p16 and BRAF V600E (Table 1). MGMT was diffusely expressed (Fig. 1f). The Ki-67 labeling index was 56.7% (Fig. 1g). The tumor did not have any mutation on the IDH1/2 gene or mutation of K27M, G34R, and G34V on the H3F3A genes (Table 1). The integrated diagnosis was IDH wild-type glioblastoma. He received craniospinal irradiation 30 Gy with concomitant TMZ, after which the diffuse lesion on the right side of the pons disappeared (Fig. 1c). However, he had recurrent enhanced lesion on the pons 7 months after the initial treatment [18], and he died of progressive disease 14 months after initial treatment.
Case 2
A 6-year-old girl without familial history of neoplasm was diagnosed with ALL based on positive cytology in the cerebrospinal fluid. She achieved complete remission after chemotherapy and craniospinal irradiation 12 Gy according to the Japan Association Childhood Leukemia Study Group ALL-02 Protocol [38]. She presented with generalized convulsions at age 16 years. MR imaging showed diffuse lesion in the right insula, temporal, and frontal lobe (Fig. 2a), and multiple small enhanced lesions in the right temporal and parietal lobes (Fig. 2a). She underwent resection of the enhanced lesion (Fig. 2b). Histologically, the lesion consisted of mainly small neoplastic cells of high nuclear/cytoplasmic ratio with high cellularity, showing as small cell glioblastoma-like feature (Fig. 2d). There was microvascular proliferation, but not necrosis (Fig. 2e). Immunohistochemical examination demonstrated strong staining for GFAP and vimentin, positive staining for p16 and ATRX, and negative staining for TP53, or BRAF V600E (Table 1). MGMT was focally and weakly expressed (Fig. 2f). The Ki-67 labeling index was 60.0% (Fig. 2g). Genetic analysis did not detect any mutation on the IDH1/2 gene or mutation of K27M, G34R, and G34V on the H3F3A genes (Table 1). The integrated diagnosis was IDH wild-type glioblastoma. She received irradiation 50 Gy to the local site with concomitant TMZ, and the diffuse lesion on the right cerebrum disappeared after 1 cycle of TMZ. She received 24 cycles of TMZ, and has remained well without recurrence for 28 months after initial treatment (Fig. 2c).
Case 3
A 7-year-old girl without familial history of neoplasm was diagnosed with ALL associated with Philadelphia chromosome. She achieved complete remission after chemotherapy, followed by bone marrow transplantation. Whole body irradiation 12 Gy, including craniospinal irradiation 12 Gy, was performed as part of the bone marrow transplantation. She presented with simple partial seizure and paresis of the face at age 16 years. MR imaging showed diffuse lesion in the right frontal and parietal lobes, and multiple enhanced lesions in the right precentral and middle frontal gyri (Fig. 3a). She underwent stereotactic biopsy of the enhanced lesion. Histologically, atypical glial cells with eosinophilic cytoplasm proliferated with high cellularity. Moderate nuclear pleomorphism and small cell component were also noted. There was microvascular proliferation, but not necrosis (Fig. 3c). Immunohistochemical examination demonstrated strong staining for GFAP and vimentin, positive staining for p16, TP53, and ATRX, and negative staining for and BRAF V600E (Table 1). MGMT was focally and weakly expressed (Fig. 3d). The Ki-67 labeling index was 45.8% (Fig. 3e). Genetic analysis did not detect any mutation on the IDH1/2 gene or mutation of K27M, G34R, and G34V on the H3F3A genes (Table 1). The integrated diagnosis was IDH wild-type glioblastoma. She received irradiation 50 Gy to the local site with concomitant TMZ. The diffuse lesion and gadolinium-enhanced lesion were significantly decreased at 1 month after the completion of initial treatment (Fig. 3b).
Discussion
This study describes the clinical course, radiological and histological findings, and molecular analysis of three cases of radiation-induced glioblastoma occurring after complete remission of ALL. In our series, the age at radiation was 8, 6, and 7-years-old. The radiation dosage was 18, 12, and 12 Gy. The latency for developing glioblastoma was 5, 9, and 10 years after irradiation. In the previous report, 34 cases with radiation-induced glioblastoma after remission of ALL have reported [4, 9,10,11, 13, 14, 17, 20, 22,23,24,25,26,27,28,29,30,31]. The clinical, histological, and radiological characteristics of the cases in previously report and present study were shown in Table 2. The age at radiation was 2–26 years-old (median age 5 years-old). The radiation dosage was 12–48 Gy (median dosage 19.5 Gy), and 5 (13.5%) and 11 (29.7%) of them received low dosage irradiation 12 and 18 Gy, respectively (Table 2). In this way, the clinical features of this entity were young age at radiation and low dosage radiation therapy. There are some explanations for these characteristics as follows. The low dosage irradiation 12–24 Gy were performed for the purpose of prophylaxis and treatment for CNS lesion [36], and the risk for developing radiation induced glioma were highest in younger than 5-years-old. Because the risk for radiation induced glioblastoma have linear relationship to radiation dosage over a wide range of 0–50 Gy [33], even craniospinal irradiation12 Gy could induce radiation-induced glioblastoma. Furthermore, the latency for developing glioblastoma were 3–17 years (median 9 years) (Table 2), and was shorter than radiation-induced meningioma after the treatment for ALL [31]. Radiation-induced malignant glioma after the treatment for ALL was reported to develop with significantly shorter latency than medulloblastoma and pituitary adenoma [4]. Chemotherapy, including etoposide and cyclophosphamide, may influence the development of secondary neoplasm after intensive treatment for relapsed acute lymphoblastic leukemia in childhood [19]. Such chemotherapy combined with radiation therapy may promote earlier development of glioblastoma in patients with ALL.
MR imaging demonstrated diffuse lesions on T2-weighted images with small gadolinium-enhanced lesions in all of our patients. The radiological findings have been variously described [9, 11, 14, 17, 20, 23, 25, 30] (Table 2). The report of the MR imaging findings is limited to six case report [9, 17, 20, 23, 25], and it was similar to our cases in two of six previous cases [9, 17]. Otherwise, the radiological characteristics were cyst formation in 3 of 13 cases [9, 14, 23] and multiple enhanced lesions in 7 of 13 cases [9, 14, 17] (Table 2). These changes may indicate that small multiple enhanced lesions, as observed in this series, show further progression.
Although undifferentiated histological features may be nonspecific features of glioblastoma, 10 of 12 cases with radiation induced glioblastoma after the treatment of ALL had of small cell components [9, 20] (Table 2) Microvascular proliferation were found in all of our three cases and another 13 cases (Table 2). In contrast, necrosis was present only in 5 of 11 cases (Table 2). Other histological features were gliosarcoma [12] and giant cell glioblastoma [13]. Immunohistochemical analysis found no specific pattern of expression of various proteins in our cases, and there were few reports of immunohistochemical finding. In previous report and present cases, radiation-induced glioblastoma after ALL treatment had positive expression of TP53 in five of nine cases [20]. Recently, Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer, and mutation on the p53 gene were frequently found in CNS tumor and leukemia [39]. Considering that there were five cases (13%) with short latency less than 5 years (Table 2), some cases with glioblastoma after the treatment of ALL might have cancer-predisposing germline mutation on p53. In this study, the tumors had high Ki67 labeling index. In previous reports, it ranged from 10 to 43% [20, 23]. No correlations were reported between tumor control and Ki-67 labeling index [20]. Further analysis may identify useful prognostic or predictive markers for this entity.
The molecular findings of radiation-induced glioblastoma after ALL treatment are unclear. This is the first report to describe the molecular findings of glioblastoma after the treatment of ALL. Somatic mutations in BRAF, IDH, and H3F3A gene are important in the gliomatogenesis of pediatric and adolescent glioblastoma [40]. None of our three cases had the mutation observed in sporadic cases. Similarly, no aberrations in IDH1 and IDH2, human telomerase reverse transcriptase promotor, H3F3A or BRAF gene were found in four cases of radiation-induced glioma which developed after radiation therapy for medulloblastoma, craniopharyngioma, primitive neuroectodermal tumor, and pituitary adenoma [21]. These findings indicate that radiation-induced glioblastoma after the treatment for ALL or other primary lesions includes aberrant pathways different to those in sporadic cases. Recently, homozygous germline mutations in the MSH6 gene were reported to lead to gliomatosis cerebri and T-cell acute lymphoblastic lymphoma in an 11-year-old female and glioblastoma in her 10-year brother [41]. Therefore, clinicians should consider the possibilities of cancer predisposing syndrome to treat malignant brain tumor after the treatment for ALL.
Our three cases were treated with irradiation to the local brain and concomitant monotherapy with TMZ. The effect of combination therapy of radiation and TMZ on radiation-induced glioblastoma after the treatment for ALL is unclear. Diffuse lesion in all patients and gadolinium-enhanced lesion in Case 3 responded immediately after concomitant radiation and TMZ. Similarly, two patients survived without recurrence for 9 and 11 months after total resection, concomitant radiation and TMZ, and maintenance of TMZ [9]. To elucidate the effect of radiation therapy and TMZ to this entity, further accumulation of information is necessary in the future.
Conclusion
Radiation-induced glioblastoma after the treatment for ALL has unique clinical, radiological, histological, and molecular characteristics.
References
Simone JV (2006) History of the treatment of childhood ALL: a paradigm for cancer cure. Best Pract Res Clin Haematol 19:353–359
Pui CH, Thiel E (2009) Central nervous system disease in hematologic malignancies: historical perspective and practical applications. Semin Oncol 36:S2–S16
Pui CH, Cheng C, Leung W et al (2003) Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349:640–649
Elsamadicy AA, Babu R, Kirkpatrick JP, Adamson DC (2015) Radiation-induced malignant gliomas: a current review. World Neurosurg 83:530–542
Walter AW, Hancock ML, Pui CH et al (1998) Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 16:3761–3767
Pennybacker J, Russell DS (1948) Necrosis of the brain due to radiation therapy; clinical and pathological observations. J Neurol Neurosurg Psychiatry 11:183–198
Gamis AS, Nesbit ME (1991) Neuropsychologic (cognitive) disabilities in long-term survivors of childhood cancer. Pediatrician 18:11–19
Shalet SM (1986) Irradiation-induced growth failure. Clin Endocrinol Metab 15:591–606
Wang Z, Terakawa Y, Goto H et al (2016) Glioblastoma in long-term survivors of acute lymphoblastic leukemia: report of two cases. Pediatr Int 58:520–523
Shapiro S, Mealey J Jr, Sartorius C (1989) Radiation-induced intracranial malignant gliomas. J Neurosurg 71:77–82
Menon R, Muzumdar D, Shah A, Goel A (2007) Glioblastoma multiforme following cranial irradiation and chemotherapy for acute lymphocytic leukaemia. Report of 3 cases. Pediatr Neurosurg 43:369–374
Kaschten B, Flandroy P, Reznik M, Hainaut H, Stevenaert A (1995) Radiation-induced gliosarcoma. Case report and review of the literature. J Neurosurg 83:154–162
Chung CK, Stryker JA, Cruse R, Vanucci R, Towfighi J (1980) Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphoblastic leukaemia. Cancer 47:2563–2566
Fontana M, Stanton C, Pompili A et al (1987) Late multifocal gliomas in adolescents previously treated for acute lymphoblastic leukemia. Cancer 60:1510–1518
Hijiya N, Hudson MM, Lensing S et al (2007) Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297:1207–1215
Ganapule AP, Varghese SS, Chacko G, Aparna I, Viswabandya A (2016) Glioblastoma multiforme in a post allogeneic stem cell transplant patient. A case report and literature review of post transplant neurological tumors. Indian J Hematol Blood Transfus 32(Suppl 1):192–195
Shah KC, Rajshekhar V (2004) Glioblastoma multiforme in a child with acute lymphoblastic leukemia: case report and review of literature. Neurol India 52:375–377
Saito R, Sonoda Y, Kumabe T, Nagamatsu K, Watanabe M, Tominaga T (2011) Regression of recurrent glioblastoma infiltrating the brainstem after convection-enhanced delivery of nimustine hydrochloride. J Neurosurg Pediatr 7:522–526
Borgmann A, Zinn C, Hartmann R et al; ALL-REZ BFM Study Group (2008) Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44:257–268
Romeike BF, Kim YJ, Steudel WI, Graf N (2007) Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies. Childs Nerv Syst 23:185–193
Nakao T, Sasagawa Y, Nobusawa S et al (2017) Radiation-induced gliomas: a report of four cases and analysis of molecular biomarkers. Brain Tumor Pathol 34:149–154
Donson AM, Erwin NS, Kleinschmidt-DeMasters BK, Madden JR, Addo-Yobo SO, ForemanNK (2007) Unique molecular characteristics of radiation-induced glioblastoma. J Neuropathol Exp Neurol 66:740–749
Joh D, Park BJ, Lim YJ (2011) Radiation-induced glioblastoma multiforme in a remitted acute lymphocytic leukemia patient. J Korean Neurosurg Soc 50:235–239
Muzumdar DP, Desai K, Goel A (1999) Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphoblastic leukaemia: a case report. Neurol India 47:142–144
Prasad G, Haas-Kogan DA (2009) Radiation-induced gliomas. Expert Rev Neurother 9:1511–1517
Salvati M, Frati A, Russo N,et al (2003) Radiation-induced gliomas: report of 10 cases and review of the literature. Surg Neurol 60:60–67
Salvati M, D’Elia A, Melone GA et al (2008) Radio-induced gliomas: 20-year experience and critical review of the pathology. J Neurooncol 89:169–177
Sanders J, Sale GE, Ramberg R, Clift R, Buckner CD, Thomas ED (1982) Glioblastoma multiforme in a patient with acute lymphoblastic leukemia who received a marrow transplant. Transplant Proc 14:770–774
Stragliotto G, Packer RJ, Rausen AR et al (1998) Outcome of post-radiation secondary glioblastoma in children. Med Pediatr Oncol 30:194–195
Symss NP, Pande A, Chakravanthy MV, Ramamurthi R (2006) Glioblastoma multiforme occurring in a child with acute lymphoblastic leukemia. J Pediatr Neurosci 1:63–65
Walter AW, Hancock ML, Pui CH et al (1998) Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Childrenʼs Research Hospital. J Clin Oncol 16:3761–3767
Rimm IJ, Li FC, Tarbell NJ, Winston KR, Sallan SE (1987) Brain tumors after cranial irradiation for childhood acute lymphoblastic leukemia. A 13-year experience from the Dana-Farber Cancer Institute and the Children’s Hospital. Cancer 59:1506–1508
Inskip PD, Sigurdson AJ, Veiga L et al (2016) Radiation-related new primary solid cancers in the childhood cancer survivor study: comparative radiation dose response and modification of treatment effects. Int J Radiat Oncol Biol Phys 94:800–807
Pui CH, Pei D, Campana D et al (2014) A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia 28:2336–2343
Stary J, Zimmermann M, Campbell M et al (2002) Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 32:174–184
Richards S, Pui CH, Gayon P (2013) Childhood Acute Lymphoblastic Leukemia Collaborative Group (CALLCG). Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 60:185–195
Kanamori M, Kumabe T, Sonoda Y, Nishino Y, Watanabe M, Tominaga T (2009) Predictive factors for overall and progression-free survival, and dissemination in oligodendroglial tumors. J Neurooncol 93:219–228
Hasegawa D, Imamura T, Yagi K et al (2016) Risk-adjusted therapy of acute lymphoblastic leukemia can optimize the indication of stem cell transplantation and cranial irradiation: results of Japan Association Childhood Leukemia Study Group (JACLS) protocol ALL-02. Blood 128:3973 (58th ASH annual meeting December 3–6, San Diego)
Zhang J, Walsh MF, Wu G et al (2015) Germline mutations in predisposition genes in pediatric cancer. NEngl J Med 373:2336–2346
Louis DN, Ohgaki H, Wiestler OD et al (2016) WHO classification of tumours of the central nervous system. IARC Publications, Lyon
Ilencikova D, Sejnova D, Jindrova J, Babal P (2011) High-grade brain tumors in siblings with biallelic MSH6 mutations. Pediatr Blood Cancer 57:1067–1070
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Kajitani, T., Kanamori, M., Saito, R. et al. Three case reports of radiation-induced glioblastoma after complete remission of acute lymphoblastic leukemia. Brain Tumor Pathol 35, 114–122 (2018). https://doi.org/10.1007/s10014-018-0316-1
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DOI: https://doi.org/10.1007/s10014-018-0316-1