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| REVIEW |
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| Year : 2020 | Volume
: 3
| Issue : 3 | Page : 90-96 |
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Is adult medulloblastoma merely the counterpart of pediatric medulloblastoma?
Gabriel Chun-Hei Wong, Kay Ka-Wai Li, Manix Fung-Man Poon, Ho-Keung Ng
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China
| Date of Submission | 18-Aug-2020 |
| Date of Decision | 22-Aug-2020 |
| Date of Acceptance | 25-Aug-2020 |
| Date of Web Publication | 17-Oct-2020 |
Correspondence Address:
Prof. Ho-Keung Ng
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_24_20
Medulloblastoma is one of the most common pediatric malignant brain tumors. Its understanding and treatment have advanced rapidly over the decade, with the identification of four distinct molecular groups. In contrast, adult medulloblastoma is a rare entity that accounts for <1% of adult central nervous system tumors, and is understudied in both its genetic landscape and clinical management. Adult medulloblastomas demonstrate many differences from pediatric medulloblastomas that are relevant to clinicians and biologists. Unlike its pediatric counterpart, adult medulloblastomas are typically located laterally in the cerebellum, are seldom metastatic, and commonly relapse beyond 5 years. The distribution and survival outcomes of molecular groups in adult medulloblastoma differ from those in pediatric medulloblastoma, with the sonic hedgehog-activated group being the predominant and most well-studied group in adults. Adult medulloblastomas also exhibit cytogenetic and mutational characteristics unique to this age group, such as the high frequency of telomerase reverse transcriptase promoter mutations and the paucity of MYC and MYCN amplifications. Clinical trials for adult medulloblastoma need to take into account the clinical and biological differences between adult and pediatric medulloblastomas, for example through the use of smoothened inhibitors in adult SHH medulloblastomas to lower the toxicities resulting from direct adoption of pediatric chemotherapeutic regimens. This review summarizes the clinical characteristics, molecular groups, genetic features, and treatment of adult medulloblastoma, with a focus on its differences from pediatric medulloblastoma. Keywords: Adult medulloblastoma, embryonal brain tumor, genetics, Group 3 medulloblastoma, Group 4 medulloblastoma, molecular, neuro-oncology, sonic hedgehog activated medulloblastoma, wingless-activated medulloblastoma
How to cite this article:
Wong GC, Li KK, Poon MF, Ng HK. Is adult medulloblastoma merely the counterpart of pediatric medulloblastoma?. Glioma 2020;3:90-6 |
How to cite this URL:
Wong GC, Li KK, Poon MF, Ng HK. Is adult medulloblastoma merely the counterpart of pediatric medulloblastoma?. Glioma [serial online] 2020 [cited 2023 Oct 2];3:90-6. Available from: http://www.jglioma.com/text.asp?2020/3/3/90/298396 |
| Introduction | |  |
Medulloblastoma is among the most common malignant brain tumors in children, but is rare in adults.[1] As a result, there is limited data on adult medulloblastoma, and its treatment is modeled after pediatric protocols.[2] However, studies show that adult medulloblastoma is biologically and clinically distinct from its pediatric counterpart.[3],[4] This review summarizes the clinical characteristics, molecular groups, genetic features, and treatment of adult medulloblastoma, with a focus on its differences from pediatric medulloblastoma.
| Database Search Strategy | | |
The authors searched the PubMed database for publications between January 2010 and June 2020 using the keyword combinations of “adult medulloblastoma” and “adult AND medulloblastoma.” English full-text articles that described the clinical or molecular characteristics or treatment of adult medulloblastoma were included. The reference lists of the included studies were additionally screened to identify relevant studies.
| Medulloblastoma | | |
Medulloblastoma is a malignant embryonal tumor of the cerebellum.[5] It commonly occurs in childhood, with an incidence of over 0.5 case/100,000 population at the age of 0–9 years.[6] The current mainstay of treatment consists of maximal safe resection followed by adjuvant chemotherapy and craniospinal irradiation, giving a 10-year survival rate of 66.1%.[6]
Medulloblastoma is a heterogeneous disease. Early studies identified histological variants with divergent outcomes, including desmoplastic/nodular (D/N), medulloblastoma with extensive nodularity (MBEN), and large cell or anaplastic (LC/A) medulloblastomas. Desmoplastic histology (D/N and MBEN) is associated with favorable disease outcome in infants, whereas LC/A tumors behave aggressively, compared to classic medulloblastoma.[7]
Molecular groups: medulloblastoma is not one disease but four
Since 2012, medulloblastoma has been classified into four major molecular groups: wingless-activated (WNT), sonic hedgehog-activated (SHH), Group 3, and Group 4.[8] The four groups have distinct developmental origins: WNT medulloblastomas develop from lower rhombic lip progenitors,[9] whereas SHH medulloblastomas arise from granule neuron precursor cells.[10] More recent RNA sequencing studies propose Nestin + cerebellar stem cells as the origin of Group 3 medulloblastomas, and unipolar brush cells and glutamatergic cerebellar nuclei as cellular origins of Group 4 medulloblastomas.[11],[12]
Genetically, 86% of WNT medulloblastomas are characterized by somatic hotspot activating mutations in exon 3 of CTNNB1, which lead to the stabilization of its protein product, β-catenin. Most CTNNB1-wildtype WNT tumors harbor germline loss-of-function mutations in the APC tumor suppressor gene that functions to degrade β-catenin. Other recurrent mutations in WNT include those of DDX3X (36%), SMARCA4 (19%), CSNK2B (14%), and TP53 (7%). Monosomy 6 is found in 83% of WNT patients.[13]
For the SHH subgroup, frequently altered SHH pathway genes include PTCH1 (43%), SUFU (10%), SMO (9%), GLI2 (9%), and MYCN (7%). PTCH1 and SUFU encode negative regulators of SHH signaling and are susceptible to loss-of-function mutations or deletions. SMO, GLI2, and MYCN are oncogenes. SMO is activated by mutations, whereas GLI2 and MYCN are commonly amplified. Non-SHH pathway genes that are mutated in SHH medulloblastomas include telomerase reverse transcriptase (TERT, 39%), DDX3X (21%), TP53 (13%), KMT2D (13%), CREBBP (10%), and TCF4 (8%). Cytogenetically, a subset of SHH tumors show 9q loss and 10q loss, which lead to loss of heterozygosity of the tumor suppressor genes PTCH1 and SUFU, respectively.[13]
MYC amplification is the hallmark feature of Group 3 medulloblastomas, present in 17% of samples. Additional driver events include amplifications or overexpression in GFI1 or GFI1B (15%), SMARCA4 mutations (9%), KBTBD4 hotspot insertions (6%), CTDNEP1 mutations (5%), KMT2D mutations (5%), MYCN amplifications (5%), and OTX2 amplifications (3%).[13] A defining cytogenetic feature for Groups 3 and 4 is isochromosome 17q, consisting of a lostparm and duplicated q arm on chromosome 17, present in around half of Group 3 medulloblastomas.[13]
The most frequent genetic events in Group 4 are the overexpression of PRDM6 (17%), GFI1B or GFI1 (12%) by enhancer hijacking. Other alterations are mutations in KDM6A (7%), ZMYM3 (6%), KMT2C (6%), or KBTBD4 (6%) and amplifications of OTX2 (6%) and MYCN (6%). Isochromosome 17q is present in over 75% of Group 4 tumors, alongside other cytogenetic aberrations.[13]
The four molecular groups differ not only in genetic features, but also in clinical characteristics.[14] Most importantly, they differ greatly in clinical outcome: WNT patients have a 5-year overall survival rate of over 95%, compared to just 50% in Group 3 patients. SHH and Group 4 have intermediate prognosis, with 5-year overall survival rates of about 75%. Molecular groups are now becoming an integral part of clinical risk stratification models, alongside clinical factors such as metastasis and anaplastic histology.[15],[16]
| Medulloblastoma in Adults | | |
Medulloblastoma is a predominantly childhood disease. In adults, it accounts for <1% of central nervous system tumors.[6] Although adult and pediatric medulloblastomas are treated similarly, studies have found substantial differences in their clinical characteristics, molecular group distribution, and genetic features.[3],[4]
Clinical characteristics of adult medulloblastoma
Adult medulloblastomas are clinically distinct from pediatric medulloblastomas in multiple aspects. In terms of tumor location, most pediatric medulloblastomas are found in the midline cerebellum, whereas adult medulloblastomas more commonly occur in lateral positions.[17],[18],[19],[20] Metastasis is infrequently seen in adult medulloblastomas.[14],[19] On imaging, adult medulloblastomas more frequently present with inhomogeneous contrast enhancement, and a more T1-hyperintense and T2-hypointense signal than pediatric medulloblastomas.[20] Histological differences have also been reported,[17],[21] and adult medulloblastomas less frequently display LC/A morphology when compared with pediatric medulloblastomas.[14]
Early studies described that adult medulloblastoma patients characteristically suffer from late relapses.[22],[23] According to surveillance data from the US Cancer Statistics-NPCR Registries 2001–2015,[6] the 5-year overall survival rates (95% confidence intervals) of medulloblastoma patients aged 15–39 years were 78.5% (76.3%–80.5%), compared to 72.3% (70.8%–73.8%) in children aged 0–14 years. However, the overall survival rates at 10 years were 67.9% (65.0%–70.5%) and 66.8% (65.0%–68.5%) in adults and children, respectively, indicating that disease outcome for adult patients declines more rapidly than pediatric patients beyond 5 years.
Molecular groups of adult medulloblastoma
Unlike pediatric medulloblastomas which are classified into four groups, two independent studies applying unsupervised hierarchical clustering on transcriptomic profiling data revealed only three major groups of adult medulloblastoma, which corresponded to the pediatric groups WNT, SHH, and Group 4.[19],[24] The identification of only three groups rather than four may be attributable to the low frequency of Group 3 adult cases, detected in only 6% of adult medulloblastomas.[14] An example of an adult Group 3 medulloblastoma with a hotspot KBTBD4 insertion is illustrated in [Figure 1]. | Figure 1: A case (male, 21 years old) of adult Group 3 medulloblastoma with nonmetastatic medulloblastoma in the fourth ventricle. The medulloblastoma showed (A) classic histology (×200) and had no MYC amplification but had a (B) hotspot KBTBD4 R297_M298insPRR insertion. The patient received gross total resection, adjuvant radiotherapy and chemotherapy, but experienced progression at 5.5 months and died at 10.5 months from diagnosis. Figures are original from the authors
Click here to view |
The group distribution differs between children and adults not only in Group 3. Group 4 represents the largest medulloblastoma group accounting for 34% of medulloblastomas overall, while SHH makes up 28% of all medulloblastomas.[14] In contrast, over half of the medulloblastomas in adults belong to the SHH group.[14],[19],[24],[25]
Literature has been inconsistent about the molecular group-specific survival of adult medulloblastoma patients [Table 1]. The 5-year overall survival rate of adult SHH patients was consistently estimated to be 75%–85% across studies.[14],[15],[19],[24] However, the reported 5-year overall survival rates for adult Group 4 patients ranged from 20% to 80%. Only the meta-analysis by Kool et al.[14] documented the 5-year overall survival rate of a small number of adult Group 3 patients, which was around 30%. For adult WNT patients, while some cohorts reported a 5-year overall survival rate of 100%, others reported a lower figure of 80%. In support for the latter finding, another study by Korshunov et al.[26] found that monosomy 6 or nuclear β-catenin accumulation, markers for WNT medulloblastoma, were not associated with favorable prognosis in adult medulloblastomas. Studies that compared the survival of adult molecular groups to pediatric ones suggested that adult WNT patients have worse outcome than pediatric WNT patients,[15],[27] whereas adult SHH patients have better outcome than pediatric SHH patients.[15],[28] An example of an adult WNT medulloblastoma with disease progression at 39 months and death at 42 months from diagnosis is illustrated in [Figure 2]. | Figure 2: A case (female, 29 years old) of adult wingless-activated medulloblastoma with nonmetastatic medulloblastoma in the cerebellar vermis. The medulloblastoma showed (A) classic histology (×400), and (B) hotspot CTNNB1 S33F mutation. The patient received gross total resection, adjuvant radiotherapy and chemotherapy, but experienced progression at 39 months and died at 42 months from diagnosis. Figures are original from the authors
Click here to view |
Genetic features of adult medulloblastoma
The first study that showed adult medulloblastoma is genetically distinct from pediatric medulloblastoma came in 2010 [Table 2]. Using array-based comparative genomic hybridization and fluorescent in situ hybridization, Korshunov et al.[26] showed that adult medulloblastomas rarely harbored MYC and MYCN amplifications, which are well-known poor prognosticators in pediatric medulloblastoma. Instead, adult medulloblastomas were enriched for CDK6 amplifications, which were associated with poor outcome along with 17q gain and 10q loss. The authors proposed a combined risk stratification algorithm for adult medulloblastomas, consisting of CDK6 amplification, 17q gain, and 10q loss.
With SHH being the most prevalent group in adults, Northcott et al.[29] compared the transcriptional, cytogenetic, and clinical profiles of adult, pediatric, and infant SHH medulloblastomas. Transcriptionally, the different age groups showed upregulation of different gene sets, with adult SHH medulloblastomas highly expressing HOX family genes involved in tissue development and synaptogenesis. Cytogenetically, 10q deletion and MYCN amplification were less frequent in adult SHH than in pediatric SHH patients. 10q deletion, 2 gain, 17p loss, 17q gain, and GLI2 amplification predicted worse survival in adult SHH than in pediatric SHH, indicating age-associated differences in tumor biology [Table 2].
A sequencing study by Kool et al.[30] in 2014 further demonstrated fundamental differences in the driver events of adult, pediatric, and infant SHH medulloblastomas. PTCH1 mutations were the only SHH pathway alteration seen in comparable frequency across age groups. SMO mutations were strongly enriched in adults, and SUFU mutations were almost exclusive to infants, whereas GLI2 and MYCN amplifications were frequently found concurrent to TP53 mutations in pediatric tumors. By treating patient-derived xenograft cell line and mouse models with sonidegib, they showed that SHH medulloblastomas with PTCH1 mutation responded well to SMO inhibition, while those with SUFU mutation or MYCN amplification were resistant, therefore predicting that the adult age group would be more responsive to this targeted therapy than infants and children. In addition, adult SHH medulloblastomas were also enriched in mutations in the TERT promoter, DDX3X, chromatin modification genes, and the PI3K/AKT pathway, compared to the other age groups [Table 2]. An example of an adult SHH medulloblastoma with hotspot SMO and TERT promoter mutations is illustrated in [Figure 3]. | Figure 3: A case (male, 38 years old) of adult sonic hedgehog-activated medulloblastoma with nonmetastatic medulloblastoma in the right cerebellar hemisphere. The medulloblastoma showed (A) desmoplastic/nodular histology (×100), (B) immunopositivity for YAP1 (×400), (C) hotspot SMO L412F mutation, and (D) hotspot TERT promoter C228T mutation. The patient received gross total resection, adjuvant radiotherapy and chemotherapy; experienced progression at 45 months; and was alive until lost to follow-up at 106 months from diagnosis. Figures are original from the authors
Click here to view |
The notion that different SHH medulloblastoma age groups represent biologically distinct disease subtypes was echoed by other studies. In 2017, Cavalli et al.[28] characterized a total of 12 medulloblastoma subtypes by combining methylation array and gene expression data. SHH medulloblastomas were divided into four subtypes: SHH-β and SHH-γ together constituted infant cases; SHH-α consisted of pediatric cases aged 3–16 years enriched for TP53 mutations, MYCN and GLI2 amplifications, and associated with a poor prognosis; and the majority of adult SHH cases were represented by SHH-δ which were strongly enriched for TERT promoter mutations and exhibited favorable clinical outcome, consistent with the molecular findings of Kool et al.[30]
Interestingly, the two WNT subtypes identified by Cavalli et al.[28] also showed different age distributions. Most adult WNT tumors belonged to WNT-β, a nonclassical WNT subtype, in which less than half of the cases harbored the hallmark aberration of monosomy 6.[28] This shows that genetic difference between adult and pediatric medulloblastoma is not limited to the SHH group. However, the genetic features of adult non-SHH medulloblastomas are still poorly understood.
Treatment of adult medulloblastoma
There is limited clinical evidence on the optimal management for adult medulloblastoma, and treatment protocols vary significantly across or even within centers.[31] Most protocols are based on pediatric experience, although adult patients often require chemotherapy dose reductions as they develop significant hematotoxicity and neurotoxicity.[32],[33],[34],[35]
The convention for adult medulloblastoma treatment consists of maximal safe resection followed by craniospinal irradiation with a boost to the posterior fossa or tumor bed, and chemotherapy used to be added only for high-risk patients, such as those with metastatic disease.[2],[36] The role of chemotherapy in standard risk adult medulloblastoma has only recently been established by a meta-analysis in 2016 and a large retrospective study in 2017,[37],[38] and has been incorporated into the European Association of Neuro-Oncology and EUropean Rare CANcer (EANO-EURACAN) clinical practice guideline in 2019.[35] Commonly used regimens are platinum-based chemotherapy with a combination of vincristine, etoposide, cyclophosphamide, or lomustine.[31],[32],[33],[34]
To minimize the side effects caused by traditional cytotoxic chemotherapy, targeted therapies for adult medulloblastoma are being investigated. A promising example is SMO inhibitors, which target the SHH pathway activated in over half of adult medulloblastomas. A Phase II trial of vismodegib in recurrent adult medulloblastoma demonstrated prolonged disease stabilization in 41% of SHH medulloblastoma cases, while non-SHH medulloblastomas and a small number of SHH cases with pathway alterations downstream to SMO were resistant to the SMO inhibitor.[39] Therapeutic responses were often transient,[39],[40],[41] as the tumors acquired resistance through hotspot D473H mutation in SMO,[42] downstream amplification of GLI2, or upregulation of the PI3K signaling pathway.[39],[43] These resistance mechanisms to SMO inhibitors can potentially be targeted with alternatively acting SMO antagonists,[44],[45] BET bromodomain inhibitors,[46] or PI3K inhibitors.[43]
Other drugs under investigation for adult medulloblastoma include pemetrexed and gemcitabine for Groups 3 and 4 (NCT01878617), as well as immunotherapy agents such as nivolumab (NCT03173950) and autologous dendritic cell vaccines (NCT01326104).
| Conclusion and Outlook | | |
Despite showing multiple differences from pediatric medulloblastoma, the clinical and biological understanding of adult medulloblastoma is limited. Biologically, multi-omic characterization of adult medulloblastoma is required to identify biomarkers and actionable targets in this age group. Clinically, more prospective trials are needed to define the optimal treatment for adult medulloblastoma. Given the rarity of this tumor type in adults, large multicenter collaborations will be essential. The scientific and clinical communities should expand upon the promising example of SMO inhibitors for adult SHH medulloblastomas, to work toward the development of molecularly informed risk stratification and treatment for adult medulloblastoma.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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