Open Access, Peer-reviewed
pISSN 2288-2405
eISSN 2288-2413
    Brain Tumor Res Treat. 2023 Jan;11(1):28-38. English.
    Published online Jan 30, 2023.
    https://doi.org/10.14791/btrt.2022.0046
    Copyright © 2023 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology
    Review

    Medulloblastoma: Current Perspectives and Recent Advances

    Jung Yoon Choi
      • Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.
    • Correspondence: Jung Yoon Choi. Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul National University Cancer Research Institute, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-2072-0211, Fax: +82-2-743-3455, Email: choijy@snu.ac.kr
    Received December 20, 2022; Revised January 12, 2023; Accepted January 14, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Medulloblastoma is the most common embryonal tumor of the central nervous system in childhood. Combined multimodality approaches, including surgery, radiation, and chemotherapy, have improved the outcome of medulloblastoma. Advances in genomic research have shown that medulloblastoma is not a biologically or clinically discrete entity. Previously, the risk was divided according to histology, presence of metastasis, degree of resection, and age at diagnosis. Through the development of integrated genomics, new biology-based risk stratification methods have recently been proposed. It is also important to understand the genetic predisposition of patients with medulloblastoma. Therefore, treatment goal aimed to improve the survival rate with minimal additional adverse effects and reduced long-term sequelae. It is necessary to incorporate genetic findings into the standard of care, and clinical trials that reflect this need to be conducted.

    Keywords
    Medulloblastoma; Pediatrics; Molecular subgroup; Clinical trial; Antineoplastic protocols

    INTRODUCTION

    Medulloblastoma (MBL), one of the central nervous system (CNS) embryonal tumors arising from the cerebellum, is the most common pediatric malignant brain tumor. MBL is currently treated with maximal safe resection, chemotherapy, and craniospinal irradiation (CSI). With multimodal treatment and appropriate risk stratification, the long-term survival rate has improved in 70%–80% of all patients. Despite aggressive multimodal therapy, approximately 30% of patients eventually succumb to this disease, and survivors cope with the long-term side effects of treatment that have a significant impact on their quality of life. Recent molecular studies have demonstrated the clinical and biological heterogeneity of MBL. MBL is classified into at least four subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Previously, MBL has been stratified by age at diagnosis, metastatic status, tumor removal extent, and presence or absence of large cell/anaplastic (LC/A) histology. In this review, the epidemiology, diagnosis, clinical manifestation, classification, and current treatment strategies based on recently published studies are presented.

    EPIDEMIOLOGY

    CNS embryonal tumors are the most common group of malignant CNS tumors, which represents 20% of pediatric CNS tumors [1, 2, 3]. MBL comprises 15% of all pediatric CNS tumors, 40% of all posterior fossa (PF) tumors, and 90% of all embryonal tumors. MBL accounts for most embryonal tumors arising from the PF. The incidence in ages 0–19 years is 0.41 cases per 100,000 patient-years and decreases with age [4]. The peak incidence is between 5 and 7 years of age and occurs more frequently in males, with a male:female ratio of 1.7:1 [5].

    DIAGNOSIS AND CLINICAL MANIFESTATION

    The diagnosis of MBL is based on clinical symptoms and imaging findings, such as CT scan and MRI. MBL commonly presents with headaches (especially morning headaches), nausea/vomiting, lethargy, and ataxia, resulting from increased intracranial pressure and cerebellar dysfunction [6]. After surgery, a follow-up MRI is recommended to determine the size of the residual tumor. Histopathologic confirmation and classification are performed using integrated histopathology and molecular studies. Spine MRI is often done preoperatively to evaluate metastatic disease. If preoperative spine MRI was not performed, it is recommended to perform MRI more than 2 weeks after surgery to avoid false positives results [7]. To confirm cerebrospinal fluid (CSF) dissemination at diagnosis, CSF cytology tests are usually done 2–4 weeks after surgery [8]. The differential diagnosis of MBL is atypical teratoid/rhabdoid tumor, ependymoma, pilocytic astrocytoma, and choroid plexus papilloma.

    CLASSIFICATION

    According to the WHO 2021 CNS5 classification, MBL is molecularly classified into four groups: 1) WNT-activated, 2) SHH-activated and TP53-wildtype, 3) SHH-activated and TP53-mutant, and 4) non-WNT/non-SHH. In addition, MBL is histologically divided into four types: 1) classic, 2) desmoplastic/nodular (DN), 3) extensive nodularity (MBEN), and 4) LC/A [9]. It was updated to one category in the WHO 2021 CNS5 classification as “medulloblastoma, histologically defined” [10]. SHH MBL has been primarily associated with DN and MBEN histology [11]. LC/A MBL is commonly observed in SHH TP53-mutant and infant group 3 [12]. Classic MBL is observed in nearly all WNT and most groups 3 and 4 [13].

    As molecular subgroups have been incorporated into the WHO classification, more molecular tools are needed for precise classification. Modern diagnostic pathology for CNS tumors uses DNA/RNA analysis, methylome profiling, and microscopy and focuses on diagnostic and prognostic markers [14]. Molecular tools aid in classifying tumors, inform about the natural history of tumors, and advise about the probability of response to specific therapeutic regimens. Table 1 presents the key genes and proteins required for integrated diagnosis.

    Table 1
    Key diagnostic genes, molecules, and pathways [10]

    MOLECULAR SUBGROUPS

    MBL comprises four molecular disease subgroups, including WNT, SHH, group 3, and group 4, by consensus meeting [13]. Each group was defined based on genome-wide transcriptomic and methylomic signatures.

    WNT (wnt/wingless pathway) MBL

    The WNT subgroup accounted for approximately 10% of all MBL. WNT MBL usually develops in the midline cerebellum and may spread to the dorsal brainstem [15]. It usually presents with classic histology, and metastasis is rare at diagnosis, occurring in less than 5% of patients [12]. WNT MBL is characterized by mutations that cause constitutive activation of the WNT signaling pathway [16]. Approximately 85%–90% of patients with WNT MBL have a somatic activating mutation in exon 3 of CTNNB1. This stabilizes β-catenin and induces sustained activation of the WNT pathway [17]. Germline APC mutations are also associated with WNT MBL. Another hallmark of WNT MBL is monosomy 6, which usually coexists with a CTNNB1 mutation [18]. Other frequently mutated genes were DDX3X, SMARCA4, and CREBBP. Childhood WNT MBL (<16 years of age at diagnosis) shows a favorable prognosis, with a 5-year survival rate of more than 90%.

    SHH MBL

    The SHH subgroup is most common in infants and young adults, accounting for 25% of all MBL. SHH MBL commonly develops in the cerebellar hemispheres; however, some also occur in the midline [15]. It shows mutations or copy number alterations of genes related to the SHH signaling pathway [19]. Loss-of-function mutations or deletions in PTCH1 and SUFU and activating mutations in smoothened homolog (SMO), GLI1, and GLI2, as well as MYCN amplification, may be present. The hallmark cytogenetic events in SHH MBL include loss of chromosomes 9q and 10q, which induces loss of heterozygosity of PTCH1 and SUFU. TP53 mutations are associated with poor outcomes in patients with SHH MBL. TP53 loss-of-function mutations may co-occur with clustered chromosomal rearrangements, known as chromothripsis, with MYCN and/or GLI2 amplification [20].

    Robinson et al. [21] revealed that infant SHH could be classified into SHH-I and II, and SUFU aberrations and chromosome 2 gain were enriched in infant SHH-I. Another study suggested that the SHH group is divided into α, β, γ, and δ, and infant SHH-I and II correspond to SHH-β and SHH-γ, respectively [22]. The prognosis of SHH-γ (infant SHH-II) is better than that of SHH-β (infant SHH-I).

    Groups 3 and 4 MBL

    Groups 3 and 4 MBL are heterogeneous with some degree of molecular overlap and frequently arise in the midline, occupying the fourth ventricle [15].

    Group 3 MBL

    Group 3 comprised 25% of MBL, mainly in infants and young children. Outcomes are inferior to those of other subgroups, with a survival rate of 40%–60%. Metastatic disease at diagnosis appears in 40%–45% of patients. LC/A histology (40%) and high-level MYC amplification are features of group 3 MBL (17%) [23]. Common chromosomal structural alterations include gains in 1q, 7, and 17q and deletions in 10q, 11, 16q, and 17p. Aberrant activation of GFI1 and GFI1B by enhancer hijacking is observed in 15%–20% of group 3 MBL [24]. MYC amplification and isochromosome 17q are associated with poor prognostic biomarkers.

    Group 4 MBL

    Group 4 MBL is the most common subgroup, comprising 35% of cases, and occurs across the age spectrum. Group 4 MBL is commonly driven by enhancer hijacking-mediated PRDM6 overexpression (17%), associated with a focal tandem duplication of SNCAIP [19]. Gain of chromosomes 7 and 17q and deletion of chromosomes 8, 11, or 17p are common. Isochomosome 17q (80%) is the most common cytogenetic aberration but does not help predict survival. MYCN amplification and overexpression are common but are not associated with poor outcomes, such as SHH. As it is recently known that the prognosis is good for patients with chromosome 11 deletions, future Children’s Oncology Group (COG) studies are planning to lower the CSI dose for these patients [25, 26].

    Recently, a new classification was published for groups 3 and 4 MLB by analyzing 1,501 patients in groups 3 and 4 MBL cohorts. Groups 3 and 4 MBL are newly classified as types I–VIII by recent high-resolution subclassification approaches. Subtypes I, V, and VII were mixed with groups 3 and 4. Subtype III, classified as high-risk, is characterized by MYCC/MYCN amplification. Subtype VII is characterized by KBTBD4 mutation. Each type has different driver events and cytogenetics and differs in terms of survival [22, 27, 28].

    TREATMENT

    Current treatment for MBL consists of maximal safe resection, chemotherapy, and CSI. The surgical standard is maximal safe resection which was established based on several studies supporting the relationship between resection extent and survival rate [29, 30, 31]. Aggressive resection where high neurologic morbidity is expected, such as when the brainstem is involved, is not recommended. Previously MBL was treated with 36 Gy of post-operative CSI with a boost of 54–55.8 Gy to the PF after surgery because of the radiosensitivity of the tumor. Since the 1990s, several studies have reported that adjuvant chemotherapy has improved the outcomes of MBL [32, 33, 34, 35]. The factors that determine the prognosis of MBL are the extent of CNS disease at diagnosis, age at diagnosis, amount of residual disease after surgery, tumor histopathology, and biological and molecular tumor cell characteristics. This section describes the treatment strategies and outcomes according to the risk groups and strategies for optimizing risk stratification.

    Older children–average risk

    Average risk (AR) MBL was defined as non-metastatic MBL achieving gross total resection (GTR) not belonging to the LC/A histological subtype without MYC or MYCN amplification. Packer et al. [36, 37] showed excellent outcomes with a reduced dose of CSI (23.4 Gy) in young children (3–7 years) AR MBL due to long-term neurologic, cognitive, and endocrinologic sequelae of high-dose CSI. Therefore, the current treatment of AR MBL is CSI to 23.4 Gy with PF or involved field (IF) boost to 54 Gy followed by chemotherapy. Studies have also been conducted to determine which chemotherapeutic agents are effective. In the COG A9961 study, a randomized trial comparing chemotherapy based on cyclophosphamide, cisplatin and vincristine vs. lomustine (CCNU), cisplatin and vincristine was performed. There was no significant difference in survival between cyclophosphamide- and CCNU-based regimens [36].

    Subsequently, further efforts have been made to lower the radiation therapy (RT) dose and volume. In a phase III randomized trial, a comparison between a smaller boost (radiation to the tumor bed) and a standard volume boost (radiation to the entire PF) was conducted. In addition, young children (3–7 years) were randomly assigned to receive 23.4 Gy vs. 18 Gy CSI. The involved field radiation therapy (IFRT) was deemed non-inferior compared with that of posterior fossa radiation therapy (PFRT). Unfortunately, children receiving low-dose (LD) CSI showed inferior event-free survival (EFS) compared with those receiving standard-dose (SD) CSI (71.4% vs. 82.9%, p=0.028) [38]. There was no significant difference in outcomes between LD and SD CSI in the WNT, SHH, and group 3. However, group 4 patients receiving LD CSI showed worse EFS than those receiving SD CSI [38]. In the HIT-SIOP PNET 4 trial, hyperfractionated (HF) vs. conventional RT followed by maintenance chemotherapy was evaluated. Hyperfractionated radiation therapy (HFRT) did not improve survival in AR MBL [39]. The St Jude medulloblastoma (SJMB)-96 and -03 trials investigated risk-adapted radiotherapy with 23.4 Gy CSI for patients with AR MBL. Through risk-adapted radiotherapy followed by short, dose-intensive, alkylator-based chemotherapy, the 5-year EFS for patients with AR MBL was 82%–83% in SJMB-96 and -03 trials [40]. The clinical trials for AR MBL are summarized in Table 2.

    Table 2
    Clinical trials of average risk medulloblastoma

    Recently, the survival rate of AR MBL has been reported to be more than 80%. According to the molecular subgroup, the outcome was 5-year EFS 93%–98% for WNT, 75%–83% for SHH, 63%–67% for group 3, and 86%–87% for group 4 [38, 40]. The WNT subgroup had the best outcome, while group 3 had the worst outcome. The Current SIOP PNET 5 MBL trial has five different arms: WNT-activated MBL as low-risk, non-WNT MBL as standard risk, WNT-activated MBL with high-risk features, and SHH-activated MBL with biologically very high-risk features (SHH-activated, TP53 mutated). Efforts to lower the treatment intensity for the WNT subgroup are described below in ‘future risk stratification’ section.

    Older children - high risk

    In current practice, high risk (HR) MBL is currently defined as having one or more of the following clinical factors: metastatic disease (Chang stages M1–M4; M+), LC/A histology, MYC or MYCN amplification, or significant residual disease after surgery (>1.5 cm2; R+) [41]. Approximately 30% of patients have metastases, and they have a poor prognosis. In the Pediatric Oncology Group (POG) 9031 study, M4 disease showed a significantly lower 5-year EFS than that of M0–M3 disease (70% vs. 22%) [42]. There is some controversy as to whether the presence or absence of residual tumors predicts a poor prognosis. Recent studies have reported that the extent of residual tumors does not affect the prognosis [35, 43].

    A consensus on treatment for HR MBL has not yet been established. Currently, the standard dose of RT for HR MBL contains a dose of 36–39.6 Gy CSI and a boost of up to 54 Gy to the primary site. In the POG 9031 study, the 5-year EFS of the entire HR cohort improved to 68.1%. The relatively good outcome for M2–M3 disease (5-year EFS according to M stage: M0 74.0%, M1 64.9%, M2 69.2%, M3 61.6%, and M4 22.2%) could be attributed to the higher dose of CSI (40 Gy) [42]. However, the results of the SIOP/UKCCSG PNET-3 study, which applied pre-RT chemotherapy and RT to patients with M2–M3 MBL, were not satisfactory, suggesting that more intensive treatment is needed for HR MBL [44].

    In phase I/II study of M+ MBL (COG 99701), carboplatin RP2D, as a radiosensitizer, was determined to be 35 mg/m2/dose ×30, suggesting that this could be a good strategy for M+ MBL [43]. Carboplatin may enhance the production and persistence of single- and double-strand breaks in DNA. Subsequent COG ACNS0332 was a randomized phase III study evaluating carboplatin concurrently with RT in M0 with >1.5 cm2 residual, M+, or diffusely anaplastic MBL, regardless of M-stage or residual tumor. As the 5-year EFS was 66.4% with carboplatin and 59.2% without carboplatin (p=0.11), concurrent carboplatin did not significantly improve the EFS in all patients. However, the efficacy was proven in the group 3 subgroup (73.2% with carboplatin, 53.7% without carboplatin, p=0.047). Therefore, concurrent carboplatin treatment during radiotherapy is recommended for pediatric patients with HR group 3 MBL [25].

    High-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) have been applied in the SJMB-96, SJMB-03, HART, and PNET HR trials. The SJMB-96 study reported that a short, dose-intense, alkylator-based chemotherapeutic regimen was helpful in improving the outcome of HR MBL [45]. Gandola et al. [46] reported a 5-year progression-free survival (PFS) rate of 72 % with intensive postoperative chemotherapy, HFRT, and HDC/ASCT. In PNET HR+5, the 5-year PFS was 76% by applying two courses of pre-RT chemotherapy, two courses of high-dose thiotepa and ASCT, and maintenance temozolomide in HR MBL [47]. In Korea, a strategy of implementing reduced-dose craniospinal radiotherapy (CSRT) and applying tandem HDC/ASCT has been attempted [48, 49]. Sung et al. [49] reported that reducing the CSRT dose (23.4 or 30.6 Gy) and applying tandem HDC/ASCT (carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimen) did not reduce survival (5-year EFS 70%) in HR MBL. Clinical trials for HR MBL are summarized in Table 3.

    Table 3
    Clinical trial results of high-risk medulloblastoma

    As shown in a previous study, the survival rate of HR MBL was improved by up to 70%. Histologically, DN MBL has the best prognosis, LC/A MBL has the worst prognosis, and the classic type has an intermediate prognosis (5-year EFS, 89% for DN, 61% for classic, and 40% for LC/A MBL in the HIT 2000 study). According to the molecular subgroup, 5-year EFS or PFS was 92%–100% for WNT, 25%–60% for SHH, 40%–60% for group 3, and 65%–68% for group 4 among clinical trials for HR MBL [25, 40, 50].

    The current SIOP-Europe HR MBL trial recruits patients with any HR factor (M+, LC/A pathology, MYC amplification, MYCN amplification, or TP53 somatic mutation [both in SHH tumors only]) from February 2021. They compared conventional radiotherapy vs. HF/accelerated radiotherapy vs. HDC with thiotepa, followed by conventional radiotherapy. They also compared two different maintenance chemotherapies, vincristine, CCNU, and cisplatin alternative with vincristine, and cyclophosphamide vs. temozolomide [51].

    Infant MBL

    Limitations in the use of RT due to the high vulnerability of the developing brain and the high dissemination rate at diagnosis have resulted in a low survival rate in infant MBL. Several alternative treatments for avoiding RT have been attempted, including intraventricular or high-dose methotrexate (HD MTX), HDC/ASCT, and primary focal site RT [52].

    The COG P9934 trial tested focal RT for PF with 18 or 23.4 Gy [53]. The COG 99703 study demonstrated a 5-year PFS of 69.6% and 5-year OS of 76.1% with induction chemotherapy (cisplatin, cyclophosphamide, vincristine, and etoposide) and three cycles of HDC (carboplatin and thiotepa) and ASCT [54]. The HeadStart III trial also used 3–5 cycles of adjuvant chemotherapy (cyclophosphamide, vincristine, etoposide, and HD MTX) and one cycle of HDC (thiotepa, etoposide, and carboplatin) and ASCT [55]. Carboplatin, thiotepa, etoposide, and busulfan are commonly used in HDC regimens. In the HIT 2000 study, systemic chemotherapy, intraventricular MTX, and risk-adapted local RT were applied to avoid CSI instead of HDC/ASCT in patients with non-metastatic MBL younger than 4 years of age [56]. The prognostic factors were M2 or higher, molecular subgroups, and histology. The COG ACNS0334 trial evaluated the role of HD MTX in young children aged under 3 years at diagnosis. After surgery, three cycles of induction chemotherapy were administered, including cisplatin, cyclophosphamide, vincristine, etoposide, and ±HD MTX in a randomized manner, followed by three cycles of consolidation (carboplatin, thiotepa) and ASCT. In preliminary data, the arm with HD MTX showed better 2-year EFS than that of the arm without HD MTX, but the difference was not statistically significant. The contribution of HD MTX was prominent in group 3 (5-year overall survival of 80% with HD MTX vs. 40% without HD MTX) [52]. Clinical trials on infant MBL are summarized in Table 4.

    Table 4
    Clinical trial results of infant medulloblastoma

    In the infant group, the SHH group showed a higher survival rate than that of group 3. DN/MBEN showed more than 90% of 5-year PFS, but non-DN/MBEN showed a lower 5-year PFS of less than 60% [54]. DN/MBEN MBL showed higher rate of GTR than classic MBL. In multivariate analysis, incomplete resection (GTR vs. non-GTR) and metastases were independent prognostic factors in young children [57]. This implicates that maximal safe resection is the reasonable strategy for the treatment of MBL. The ongoing HeadStart 4 trial investigates treatment reduction from two cycles to a single cycle of HDC/ASCT in children younger than 6 years with SHH MBL, TP53 wild-type, regardless of metastasis or extent of resection (NCT02875314) [52].

    New approaches to incorporate subgroups into management

    Currently, it is accepted that the WNT subgroup aged under 16 years is regarded as a low-risk group because of its favorable prognosis. In the WNT subgroup, the difference in the EFS according to the traditional HR and AR categories is not significant. Therefore, efforts are being made to lower the intensity of treatment because the treatment results of the WNT group aged under 16 years are good. Prospective clinical trials currently being conducted for the WNT group include SIOP-PNET5 (NCT02066220), ANCS1422 (NCT02724579), and SJMB-12 (NCT01878617) [58, 59]. In these studies, attempts to reduce the CSI dose are commonly applied (Table 5).

    Table 5
    Ongoing clinical trials in WNT medulloblastoma

    Although infant SHH MBL with DN histology usually shows favorable outcomes, SHH MBL with TP53-mutant and MYCN amplification shows disappointing survival. Therefore, novel treatment strategies are needed. In systematic review of phase I and II clinical trials, SMO inhibitors showed 37% and 0% of objective response rate in recurrent SHH and non-SHH MBL, respectively [60]. Based on these evidence, vismodegib, an SMO inhibitor, has been evaluated in newly diagnosed SHH MBL (>12 years) (NCT01878617).

    Immunotherapy has been limited in MBL due to the lack of immunogenic antigens, tumor microenvironment, and blood-brain barrier. However, many efforts have been made to overcome limitations [26]. Early-phase clinical trials of chimeric antigen receptor T-cell therapy targeting NKG2DL, GD2, HER2, EGFR, G7-H3, natural kille (NK) cells, and dendritic cell therapy are also ongoing [61, 62].

    FUTURE RISK STRATIFICATION

    MBL was initially classified into four molecularly distinct subgroups and was further refined into 12 subtypes [19]. Prospective studies in which risk stratification was classified according to age, extent of resection, and metastasis also applied sub-analysis according to molecular subgroup and suggested future risk stratification. For example, the COG ACNS 0332 study analyzed metastatic WNT MBL as a favorable risk and group 3 with MYC or MYCN amplification as a very high-risk. In addition, MBL with chromosome 11 loss or chromosome 17 gain had superior survival in group 4 with 91.7% of 5-year EFS. They suggested therapy reduction in the WNT subgroup with metastatic disease and the group 4 subgroup with chromosome 11 loss and/or chromosome 17 gain [25]. In the SJMB-03 trial, WNT, low-risk SHH, low-risk groups 3 and 4, which are low groups with 5-year PFS expected to exceed 90%, and HR SHH, HR combined groups 3 and 4, which are very high-risk groups with 5-year PFS expected to be <60% were classified [40]. Accordingly, the combined groups 3 and 4 may be classified as low risk as M0 and subtype VII; intermediate risk as M0 and subtypes I, II, IV, V, VI, and VIII; and HR as M disease or subtype III or MYC amplification. However, this classification is not definitive and should be more accurately verified in future prospective clinical trials.

    GERMLINE PREDISPOSITION

    MBL has been associated with rare germline predisposition syndromes, including Gorlin syndrome (SUFU and PTCH1) [63], Li-Fraumeni syndrome, APC-associated polyposis syndromes [64], and Fanconi anemia [65]. Waszak et al. [66] reported that 6% of patients with MBL had germline mutations; APC, BRACA2, PALB2, PTCH1, SUFU, and TP53 were highly associated with MBL. WNT MBL is known to be related to germline APC mutations; germline APC and somatic CTNNB1 mutations are mutually exclusive. Therefore, if there is no somatic CTNNB1 exon mutation in WNT MBL, APC testing is recommended. All SHH tumors should be screened for somatic and germline TP53 mutations after appropriate genetic counseling. SUFU and PTCH1 mutations are also highly associated with SHH MBL. PALB2 and BRCA2 could be found in SHH and groups 3 and 4 MBL.

    LATE EFFECTS

    Patients with MBL have a high incidence of treatment-related secondary neoplasms and physical, neurocognitive, endocrine, and auditory late sequelae [67, 68]. Growth hormone deficiency and primary hypothyroidism are the most common endocrinologic complications [68]. Children receiving CSI have a greater risk of neurocognitive effects such as working memory, processing speed, and fine-motor functioning [69]. To reduce neurotoxicity, reduced-dose CSI, a smaller boost to the tumor bed, HFRT, and proton therapy have been attempted. COG developed a standard neuropsychological and behavioral battery to measure intelligence, processing speed, attention, memory, language preference, behavioral/social/emotional function, executive function, adaptive function, and quality of life [70]. Therefore, it is necessary to detect the late effects early and provide appropriate interventions.

    CONCLUSION

    Noteworthy progress has enabled us to better understand the clinical, biological, and molecular characteristics, resulting in biology-based risk stratification and tailoring treatment intensity to disease risk. Ongoing research focuses on careful treatment reduction in low-risk patients and novel therapies in high-risk patients. Ultimately, it should be in the direction of improving the quality of life while increasing the survival rate of patients with MBL.

    Notes

    Ethics Statement:Not applicable

    Conflicts of Interest:The author has no potential conflicts of interest to disclose.

    Funding Statement:None

    Availability of Data and Material

    Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

    References

      1. Park HJ, Moon EK, Yoon JY, Oh CM, Jung KW, Park BK, et al. Incidence and survival of childhood cancer in Korea. Cancer Res Treat 2016;48:869–882.
      1. Withrow DR, Berrington de Gonzalez A, Lam CJK, Warren KE, Shiels MS. Trends in pediatric central nervous system tumor incidence in the United States, 1998-2013. Cancer Epidemiol Biomarkers Prev 2019;28:522–530.
      1. Tulla M, Berthold F, Graf N, Rutkowski S, von Schweinitz D, Spix C, et al. Incidence, trends, and survival of children with embryonal tumors. Pediatrics 2015;136:e623–e632.
      1. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro Oncol 2021;23 12 Suppl 2:iii1–i105.
      1. Sun T, Plutynski A, Ward S, Rubin JB. An integrative view on sex differences in brain tumors. Cell Mol Life Sci 2015;72:3323–3342.
      1. Ramaswamy V, Remke M, Shih D, Wang X, Northcott PA, Faria CC, et al. Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent. Pediatr Blood Cancer 2014;61:1190–1194.
      1. Meyers SP, Wildenhain SL, Chang JK, Bourekas EC, Beattie PF, Korones DN, et al. Postoperative evaluation for disseminated medulloblastoma involving the spine: contrast-enhanced MR findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes. AJNR Am J Neuroradiol 2000;21:1757–1765.
      1. Fouladi M, Gajjar A, Boyett JM, Walter AW, Thompson SJ, Merchant TE, et al. Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 1999;17:3234–3237.
      1. Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, et al. “Large cell/anaplastic” medulloblastomas: a pediatric oncology group study. J Neuropathol Exp Neurol 2000;59:857–865.
      1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 2021;23:1231–1251.
      1. Korshunov A, Sahm F, Stichel D, Schrimpf D, Ryzhova M, Zheludkova O, et al. Molecular characterization of medulloblastomas with extensive nodularity (MBEN). Acta Neuropathol 2018;136:303–313.
      1. Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, group 3, and group 4 medulloblastomas. Acta Neuropathol 2012;123:473–484.
      1. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012;123:465–472.
      1. Pratt D, Sahm F, Aldape K. DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology. Neuro Oncol 2021;23 23 Suppl 5:S16–S29.
      1. Perreault S, Ramaswamy V, Achrol AS, Chao K, Liu TT, Shih D, et al. MRI surrogates for molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol 2014;35:1263–1269.
      1. Duchartre Y, Kim YM, Kahn M. The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 2016;99:141–149.
      1. Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, et al. Medulloblastoma. Nat Rev Dis Primers 2019;5:11
      1. Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, et al. Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 2006;5:2666–2670.
      1. Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017;547:311–317.
      1. Rausch T, Jones DT, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012;148:59–71.
      1. Robinson GW, Rudneva VA, Buchhalter I, Billups CA, Waszak SM, Smith KS, et al. Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 2018;19:768–784.
      1. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 2017;31:737–754.e6.
      1. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012;488:49–56.
      1. Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014;511:428–434.
      1. Leary SES, Packer RJ, Li Y, Billups CA, Smith KS, Jaju A, et al. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: a randomized clinical trial from the Children’s Oncology Group. JAMA Oncol 2021;7:1313–1321.
      1. Lazow MA, Palmer JD, Fouladi M, Salloum R. Medulloblastoma in the modern era: review of contemporary trials, molecular advances, and updates in management. Neurotherapeutics 2022;19:1733–1751.
      1. Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M, et al. Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of group 3 and group 4 subtypes. Acta Neuropathol 2019;138:309–326.
      1. Kumar R, Liu APY, Northcott PA. Medulloblastoma genomics in the modern molecular era. Brain Pathol 2020;30:679–690.
      1. Albright AL, Wisoff JH, Zeltzer PM, Boyett JM, Rorke LB, Stanley P. Effects of medulloblastoma resections on outcome in children: a report from the Children’s Cancer Group. Neurosurgery 1996;38:265–271.
      1. Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, et al. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 2016;17:484–495.
      1. Wong TT, Liu YL, Ho DM, Chang KP, Liang ML, Chen HH, et al. Factors affecting survival of medulloblastoma in children: the changing concept of management. Childs Nerv Syst 2015;31:1687–1698.
      1. Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, et al. The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 1990;72:572–582.
      1. Krischer JP, Ragab AH, Kun L, Kim TH, Laurent JP, Boyett JM, et al. Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group study. J Neurosurg 1991;74:905–909.
      1. Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 1994;81:690–698.
      1. Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, et al. Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 study. J Clin Oncol 2003;21:1581–1591.
      1. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202–4208.
      1. Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 1999;17:2127–2136.
      1. Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, et al. Children’s Oncology Group phase III trial of reduced-dose and reduced-volume radiotherapy with chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2021;39:2685–2697.
      1. Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 2012;30:3187–3193.
      1. Gajjar A, Robinson GW, Smith KS, Lin T, Merchant TE, Chintagumpala M, et al. Outcomes by clinical and molecular features in children with medulloblastoma treated with risk-adapted therapy: results of an international phase III trial (SJMB03). J Clin Oncol 2021;39:822–835.
      1. Polkinghorn WR, Tarbell NJ. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 2007;4:295–304.
      1. Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, et al. High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol 2013;31:2936–2941.
      1. Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a children’s oncology group phase I/II study. J Clin Oncol 2012;30:2648–2653.
      1. Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, et al. Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 2005;41:727–734.
      1. Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 2006;7:813–820.
      1. Gandola L, Massimino M, Cefalo G, Solero C, Spreafico F, Pecori E, et al. Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 2009;27:566–571.
      1. Dufour C, Foulon S, Geoffray A, Masliah-Planchon J, Figarella-Branger D, Bernier-Chastagner V, et al. Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5. Neuro Oncol 2021;23:1163–1172.
      1. Choi JY, Kang HJ, Hong KT, Hong CR, Lee YJ, Park JD, et al. Tandem high-dose chemotherapy with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin regimens for pediatric high-risk brain tumors. Int J Clin Oncol 2019;24:1515–1525.
      1. Sung KW, Lim DH, Son MH, Lee SH, Yoo KH, Koo HH, et al. Reduced-dose craniospinal radiotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk medulloblastoma. Neuro Oncol 2013;15:352–359.
      1. von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Müller K, et al. Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters. J Clin Oncol 2016;34:4151–4160.
      1. Bailey S, André N, Gandola L, Massimino M, Rutkowski S, Clifford SC. Clinical trials in high-risk medulloblastoma: evolution of the SIOP-Europe HR-MB trial. Cancers (Basel) 2022;14:374
      1. Lafay-Cousin L, Dufour C. High-dose chemotherapy in children with newly diagnosed medulloblastoma. Cancers (Basel) 2022;14:837
      1. Ashley DM, Merchant TE, Strother D, Zhou T, Duffner P, Burger PC, et al. Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children’s Oncology Group study P9934. J Clin Oncol 2012;30:3181–3186.
      1. Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, et al. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatr Blood Cancer 2016;63:1527–1534.
      1. Dhall G, O’Neil SH, Ji L, Haley K, Whitaker AM, Nelson MD, et al. Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on “head start” III: a multi-institutional, prospective clinical trial. Neuro Oncol 2020;22:1862–1872.
      1. Mynarek M, von Hoff K, Pietsch T, Ottensmeier H, Warmuth-Metz M, Bison B, et al. Nonmetastatic medulloblastoma of early childhood: results from the prospective clinical trial HIT-2000 and an extended validation cohort. J Clin Oncol 2020;38:2028–2040.
      1. Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, et al. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 2010;28:4961–4968.
      1. Mynarek M, Milde T, Padovani L, Janssens GO, Kwiecien R, Mosseri V, et al. SIOP PNET5 MB trial: history and concept of a molecularly stratified clinical trial of risk-adapted therapies for standard-risk medulloblastoma. Cancers (Basel) 2021;13:6077
      1. Gottardo NG, Hansford JR, McGlade JP, Alvaro F, Ashley DM, Bailey S, et al. Medulloblastoma down under 2013: a report from the third annual meeting of the international medulloblastoma working group. Acta Neuropathol 2014;127:189–201.
      1. Li Y, Song Q, Day BW. Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis. Acta Neuropathol Commun 2019;7:123
      1. Schakelaar MY, Monnikhof M, Crnko S, Pijnappel E, Meeldijk J, Ten Broeke T, et al. Cellular immunotherapy for medulloblastoma. Neuro Oncol. 2022 Oct 11;
        [Epub]. Available at: https://doi.org/10.1093/neuonc/noac236.
      1. Kabir TF, Kunos CA, Villano JL, Chauhan A. Immunotherapy for medulloblastoma: current perspectives. Immunotargets Ther 2020;9:57–77.
      1. Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 2014;32:4155–4161.
      1. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, et al. The molecular basis of Turcot’s syndrome. N Engl J Med 1995;332:839–847.
      1. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 2007;39:162–164.
      1. Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 2018;19:785–798.
      1. Salloum R, Chen Y, Yasui Y, Packer R, Leisenring W, Wells E, et al. Late morbidity and mortality among medulloblastoma survivors diagnosed across three decades: a report from the childhood cancer survivor study. J Clin Oncol 2019;37:731–740.
      1. Laughton SJ, Merchant TE, Sklar CA, Kun LE, Fouladi M, Broniscer A, et al. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 2008;26:1112–1118.
      1. Levitch CF, Holland AA, Bledsoe J, Kim SY, Barnett M, Ramjan S, et al. Comparison of neuropsychological functioning in pediatric posterior fossa tumor survivors: medulloblastoma, low-grade astrocytoma, and healthy controls. Pediatr Blood Cancer 2022;69:e29491
      1. Embry L, Annett RD, Kunin-Batson A, Patel SK, Sands S, Reaman G, et al. Implementation of multi-site neurocognitive assessments within a pediatric cooperative group: can it be done? Pediatr Blood Cancer 2012;59:536–539.
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    MeSH Terms
    Antineoplastic Protocols
    Central Nervous System
    Diagnosis
    Drug Therapy
    Genetic Predisposition to Disease
    Genomics
    Humans
    Medulloblastoma*
    Neoplasm Metastasis
    Pediatrics
    Standard of Care
    Survival Rate
    Metrics
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