Child's Nervous System

, Volume 34, Issue 5, pp 809–815 | Cite as

Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation

Review Paper

Abstract

Purpose

Medulloblastoma (MDB) is a small cell poorly differentiated embryonal tumor of the cerebellum, which more frequently compromises children. Overall prognosis is favorable, but dependent of stage, histopathological pattern and molecular group. Approximately 30% of the affected patients will die from the disease. WHO 2016 Classification of Tumors of the Central Nervous System (CNS) has been classified MDB into four principal groups: WNT-activated MDB, SHH-activated MDB, group 3 MDB, and group 4 MDB. WNT-activated MDB is associated to monosomy 6, CTNNB1, DDX3X and TP53 mutations, beta-catenin nuclear immunoexpression, and a better prognosis than SHH-activated MDB.

Discussion

WNT-activated tumors account approximately for 10% of cases of MDBs, and are thought to arise from cells in the dorsal brain stem/lower rhombic lip progenitor cells. SHH-activated MDB more frequently arises in the lateral hemispheres of the cerebellum, and clinical outcome in this group is variable. TP53-mutant SHHactivated MDB usually shows the large cell/anaplastic pattern, and can be related to MYCN amplification, GLI2 amplification and 17p loss. TP53-wildtype SHH-activated MDB is more commonly of desmoplastic/nodular morphology, and can be related to PTCH1 deletion and 10q loss. Gene expression and methylation profiling is the gold standard for defining molecular groups of MDB. In immunohistochemistry assays, anti-GAB1 antibody expression is positive in tumors showing SHH pathway activation or PTCH mutation, while positive immunoexpression for YAP1 antibody can be only found in WNT-activated and SHH-activated MDB.

Keywords

Medulloblastoma WNT-activated SHH-activated Embryonal neuroepithelial tumor Central nervous system tumors Prognosis 

Introduction

Medulloblastoma (MDB) is defined as an embryonal neuroepithelial tumor (WHO grade IV) arising more commonly in the cerebellum or dorsal brain stem of children. MDB is composed of small round undifferentiated cells disposed in densely packed groupings and exhibits mild to moderate nuclear pleomorphism and a high mitotic index (Fig. 1) [1, 2, 3]. WHO 2016 Classification of Tumors of the Central Nervous System (CNS) has been classified MDB into four principal groups: WNT-activated MDB, sonic hedgehog (SHH)-activated MDB, group 3 MDB, and group 4 MDB. These groups were established from clustering analyses following transcriptome, methylome profiling, and microRNA [1, 2, 3, 4]. There is significant association between these molecular classification and clinical data and histopathological findings [3, 4, 5, 6, 7].
Fig. 1

Medulloblastoma: a small cell neuroectodermal tumor of the cerebellum, hematoxylin-eosin, 40×

WNT-activated MDB accounts approximately for 10% of cases of MDB and are thought to arise from cells in the dorsal brain stem/lower rhombic lip progenitor cells [1, 4, 6, 7]. At microscopy, the great majority of WNT-activated MDB has classic morphology, which denotes a low-risk tumor. Very rare cases of WNT-activated MDB show large cell/anaplastic pattern. Most common genetic alterations of WNT-activated MDB are mutations of CTNNB1, DDX3X, and TP53 genes [1, 2, 5, 7, 8]. SHH-activated MDB corresponds to a heterogeneous group that can be subdivided in TP53-mutant and TP53-wildtype, and account around 30% of cases of MDB. All nodular/desmoplastic MDB and MDB showing extensive nodularity are SHH-activated MDB. SHH-activated MDB looks to be derived from ATOH1-positive cerebellar granule neuron precursor. A proportion of SHH-activated MDB seems to arise from cerebellar granule neuron cell precursor of the external granule cell layer/cochlear nucleus [4, 6, 7, 9, 10, 11, 12, 13]. Non-WNT and non-SHH groups 3 and 4 MDB are considered provisional variants by WHO 2016, since these cases are not well divided in molecular analyses/clinical laboratory assays as WNT-activated/SHH-activated MDB [1, 3, 4, 6, 7, 14, 15, 16]. Proposed cell of origin of group 3 MDB is a CD133+ neural stem cell and is usually MDB with classic pattern (standard-risk tumor) or large cell/anaplastic morphology high-risk tumor). Group 3 MDB account for 20% of cases and are related to MYC amplification and isodicentric 17q [1, 3, 4, 6, 7, 14, 15, 16]. Group 4 MDB accounts for 40% of cases, is also related to MYC amplification and isodicentric 17q, and can compromise all age groups. Frequent genetic alterations of group 4 MDB are KDM6A and GFI1/GFI1B structural variants and 11p deletion [4, 7, 10, 16, 17, 18, 19]. Although not included in the WHO 2016 Classification of Tumors of the Central Nervous System, immunohistochemical assays for MYC, Beta-catenin, and TP53 antibodies also can be employed to determine a more integrated molecular/histopathological diagnosis, and anti-GAB1 antibody expression is positive in tumors showing SHH pathway activation or PTCH mutation [1, 4, 6, 7, 9, 19, 20, 21]. Table 1 demonstrates general findings of WNT-activated/SHH-ativated MDB.
Table 1

WNT-activated and SHHactivated medulloblastomas: general findings

The role of WNT and SHH pathways in the neoplastic transformation of cerebellum/dorsal stem cells and development of MDB

MDB is the most common CNS embryonal tumor of childhood and accounts for 25% of all intracranial neoplasms. Of all patients with MDB, around 78% are aged inferior to 19 years [4, 6, 7, 22]. Most cases of MDB arise into the cerebellar vermis or fourth ventricle as a gray circumscribed mass that determine increased intracranial pressure. On CT/MR, MDB is usually found as a solid, intensely contrast-enhancement tumoral mass [4, 10, 19, 23, 24]. MDB has potential to metastasize through the cerebrospinal fluid or spread outside the CNS. Morphological variants of MDB include classic pattern (Fig. 2), desmoplastic/nodular MDB, large cell/anaplastic MDB, and MDB with extensive nodularity [1, 4, 6, 7, 10, 19, 25]. Rare cases of MDB show areas with melanotic or myogenic differentiation [1, 4, 6, 7, 10, 19, 25]. Differential diagnosis includes high-grade small cell gliomas, embryonal tumor with multilayered rosettes, and atypical teratoid/rhabdoid tumors. Most MDB show positive immunoexpression for neuronal differentiation such as synaptophysin, NeuN, NCAM1, MAP2, neuron-specific enolase, and class III beta-tubulin [4, 6, 7, 10, 22, 26]. Positive expression for GFAP in immunohistochemistry evaluation is found in approximately 10% of cases of MDB, and positivity for NFP is rare. Rare cases of MDB show positive immunoexpression for desmin, myogenin, HMB-45, and melan-A [4, 6, 7, 10, 22, 26]. Almost all MDB show some cytoplasmic immunoreactivity for beta-catenin. WNT-activated MDB exhibits nuclear immunoreacivity for beta-catenin in most cells. Nuclear SMARCB1 and SMARCA4 expression is found in all MDB variants, and the loss of expression of one of these antibodies is a characteristic of atypical teratoid/rhabdoid tumor [4, 6, 7, 22, 26, 27]. Almost all MDB cases are sporadic, but the tumor is eventually associated to rare hereditary syndromes, compromising less than 5% of patients. Familial cancer syndromes featuring MDB include Nevoid basal-cell carcinoma syndrome (Gorlin syndrome), Turcot syndrome, subtype 1 Fanconi anemia, Rubenstein-Taybi syndrome, Coffin-Siris syndrome, and Li-Fraumeni syndrome [1, 4, 7, 8, 11, 15, 21, 27].
Fig. 2

Classic Medulloblastoma: A high grade densely cellular tumor exhibiting a solid pattern and prominent nuclear and cellular atypias, hematoxylin-eosin, 400×

Gene expression and methylation profiling is the gold standard for defining molecular groups of MDB. WNT-activated MDB (group 1 of WHO 2016 Classification of Tumors of the Central Nervous System) is typically found in children between 7 and 14 years and has an excellent prognosis with standard therapeutic approaches [1, 2, 4, 6, 7, 16, 19, 22, 28]. Nearly all WNT-activated MDB cases are classic tumors. Frequently mutated genes in WNT-activated MDB are CTNNB1 (90% of cases), TP53 (12.5% of cases), SMARCA4 (27% of cases), KMT2D (12.5% of cases), and DDX3X (50% of cases). Around 85% MDB that are characterized by WNT pathway activation show monosomy 6 and/or harbor a CTNNB1 mutation in exon 3, and these genetic alterations determine the positive immunoexpression for beta-catenin antibodies in tumor cell nuclei [1, 2, 7, 12, 16, 22, 29, 30]. TP53 mutations in WNT-activated MDB are not related to a worse prognosis, and the presence of APC germline mutations rare in this group of tumors [4, 5, 7, 8, 9, 10, 22, 31]. WNT pathway is fundamental for the normal development and organogenesis, including neural cells. This pathway regulates intracellular localization of the beta-catenin protein. Inactive WNT pathway determines the association between beta-catenin with a multimeric protein complex, which include AXIN1 protein, glycogen synthase kinase-3-beta, and APC gene [4, 8, 9, 11, 16, 17, 18, 28, 31, 32]. With this ligation, beta-catenin is phosphorylated and targeted for degradation via ubiquitin-dependent proteasomal pathways. Activation of WNT pathway determines glycogen synthase kinase-3-beta inhibition, destabilization of the APC/glycogen synthase kinase-3-beta/AXIN1 complex, and accumulation of beta-catenin in the nucleus. Translocation of beta-catenin to the nucleus leads to upregulation of cyclin D1 and MYC (promitotic genes) [7, 8, 9, 11, 16, 18, 26, 28, 31, 32]. CTNNB1 mutation compromises specifically the glycogen synthase kinase-3-beta phosphorylation domain of beta-catenin and promotes upregulation and nuclear accumulation of aberrant TCF/LEF target genes and tumorigenesis. CTNNB1 stimulates the producing of inhibitors such as Frizzled-related protein (sFRP) and WNT inhibitor factor 1 (WIF-1). Positive nuclear beta-catenin immunoexpression is strongly associated to CTNNB1 mutations in more than 80% of cases of MDB. The presence of APC mutations in sporadic cases of MDB does not determine upregulation of the WNT pathway [4, 7, 8, 9, 11, 16, 17, 18, 26, 28, 31, 32].

Clinical outcomes in SHH-activated MDB (group 2 of WHO 2016 Classification of Tumors of the Central Nervous System) are variable. SHH-activated MDB less frequently determines metastatic lesions than group 3 MDB [1, 5, 7, 22, 23, 28, 33]. Spread within the neuroaxis is a common feature of SHH-activated and TP53 mutant MDB. The analysis of PTHC mutations in sporadic MDBs identified the SHH signaling pathway in MDB tumorigenesis. Positive immunoexpression for YAP1 antibody can be only found in WNT-activated and SHH-activated MDB. Positive immunoexpression for GAB1 and YAP1 is widespread and strong in the great majority of cases of non-desmoplastic SHH-activated MDB. In nodular/desmoplastic MDB, strong expression for BAG1 and YAP1 is found within internodular regions [4, 6, 7, 22, 26, 28, 34]. SHH-activated MDB with cytological anaplasia is more prone to exhibit strong p53 expression, which is related to germline TP53 mutations. Desmoplastic/nodular MDB shows pathological activation of the SHH pathway, which is related to PTCH1, SMO, SHH, GLI2, MYCN, and SUFU gene mutations. Desmoplastic/nodular MDB correspond approximately for 20% of cases of this tumor and are not related to isochromosome 17q [1, 4, 6, 7, 10, 28, 31, 32, 35]. Activation of SHH pathway can be evaluated by GAB1 and TNFRSF16 in immunohistochemistry technique, in special in internodular areas [4, 8, 10, 11, 14, 26, 36]. MDB with extensive nodularity is usually SHH-activated tumor with an excellent prognosis, with overall survival rates of 95%. Large cell/anaplastic MDB is most frequent between SHH-activated and group 3 MDB, and are associated to GLI2 and MYCN amplification, TP53 mutations, a massive genomic rearrangement called chromothripsis, and a poor outcome with standard therapies. Five-year progression-free survival for large cell/anaplastic MDB is 30–40% [4, 5, 7, 9, 19, 31, 32, 37].

MDB, SHH-activated, and TP53 mutant are rare tumors with poor prognosis that compromise patients between 4 and 17 years and are defined as embryonal tumors of the cerebellum with evidence of SHH pathway activation and either germline or somatic TP53 mutation [1, 4, 7, 12, 28, 30, 33]. SHH pathway activation in TP53-mutant tumors is related to MYCN amplification, 17p loss, and GLI2, MYCN, or SHH gene amplification, and mutations in PTCH, SUFU, and SMO are uncommon. TP53-mutant SHH-activated MDB usually shows the large cell/anaplastic pattern. GLI2 amplification denotes a high-risk tumor [1, 4, 7, 12, 28, 33].

MDB, SHH-activated, and TP53-wildtype are related to germline or somatic mutations in the negative regulators PTCH or SUFU and somatic mutations in SMO, and generally compromise children aged four or less years [1, 7, 12, 22, 24, 25, 38]. Mutations DD3X or KMT2D genes, and amplification of MYCN or MYCL also can be found between these lesions. Some cases are associated to deletions in 9q and 14q chromosomes. TP53-wildtype SHH-activated MDB is more commonly of desmoplastic/nodular morphology, and is associated to PTCH deletion and 10q loss, which denote a low-risk tumor in infants [1, 4, 7, 12, 22, 24, 25, 37].

The SHH pathway plays a critical role in normal cerebellar development. SHH ligand is secreted by Purkinje neurons, which promote mitogenesis in external granular layer progenitor cells [4, 6, 10, 24, 28]. The response to SHH signal is controlled by PTCH and SMO, which are transmembrane proteins. PTCH suppresses SMO activity in the absence of SHH ligand. If there is SHH stimulation, this inhibition is released and promotes SMO-induced transcriptional response, which is regulated by GLI-1, GLI-2, and GLI-3, a family of transcription factors. SUFU (suppressor of fused) cooperate with Slimb (BTRCP, F-box protein) to inhibit GLI-1 mediated transcription [1, 24, 25, 37, 39, 40, 41, 42]. SHH-activated MDB (20% of cases) arise through multiple alternative components, such as PTCH mutations (around 10% of cases), SMO-activating mutations (around 5% of cases), and SUFU mutations (0–10% of cases) [1, 24, 25, 26, 37, 39, 40, 41]. Genetic alterations of the SHH pathway determines an inadequate constitutive activation of the signaling cascade, downstream mitotic effects regulated by overexpression of GLI proteins and PTCH gene (a GLI-dependent target gene), and downstream MYCN, cyclin D1, and BMI-1 function. Common genetic alterations in MDB also include MYC amplifications (5–15%), MYCN amplifications (5–15%), PIK3CA mutation (5%), CASP8 (35%), HIC-1 (35%), and RASSF1A (90%) [1, 24, 26, 37, 39, 40, 43].

TP53 is a fundamental regulator of the cell cycle and apoptosis. TP53 pathway includes p14 ARF , a cell cycle inhibitor that is expressed due to cellular stress and/or oncogene activation and is encoded by the INK4A/ARF locus. p14 ARF stabilizes p53 by sequestering MDM2, thus leading cells to apoptosis or cell cycle arrest [9, 12, 27, 36, 39]. Disruption of p53 pathway is related to p14 ARF hypermethylation, deletion or mutation, TP53 mutation, or amplification of MDM2 gene. PIK3CA is a member of the family of phosphatidylinositol 3′-cinase catalytic subunits, and its mutations has been identified in approximately 05% of MDBs. Epigenetic tumor suppressor gene inactivation in MDB is associated to RASSF1A (ras association domain protein 1), CASP8 (caspase 8), and HIC-1 genes [9, 12, 27, 36, 39, 44]. Table 2 exhibits the most frequent genetic alterations and clinical aspects of WNT-activated/SHH-ativated MDB.
Table 2

Medulloblastomas subtypes: most common molecular, histopathological, and clinical findings

MDB medulloblastoma

Final considerations and therapies targeting WNT and/or SHH pathways in cases of medullobastoma

Molecular indicators in MDB with favorable outcome include WNT-activated tumors, monosomy 6, CTNNB1 mutation, and beta-catenin nuclear immunoexpression. Molecular indicators indicative of poor outcome include MYC/MYCN amplifications, loss of chromosome 17p, and gain of chromosome 17q [4, 6, 7, 30, 45, 46]. Patients who developed MDB can be treated with a combination of surgery and/or radiotherapy/chemotherapy regimens. Surgery is considered a standard part of treatment for histologic confirmation of tumor type and as a means to improve outcome [1, 42, 43, 45, 46, 47, 48]. Standard-risk medulloblastoma can be defined as total or near-total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumor on early postoperative MRI, no CNS metastasis on MRI, no tumor cells on the cytospin of lumbar CSF, and no clinical evidence of extra-CNS metastasis. Low-risk MDB includes the WNT subgroup, which exhibits ß-catenin mutation (mandatory testing), or ß-catenin nuclear immuno-positivity by IHC (mandatory testing) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing). MDB can be grouped as a low-risk tumor if the patient has undergone total/near-total tumor resection. These cases can receive conventionally fractionated radiotherapy (once a day) with a dose of 54 Gy to the primary tumor and 18.0 Gy to the craniospinal axis. Chemotherapy is also a standard element in the treatment of MDB. Chemotherapy can be used to delay the need for radiation therapy in 20 to 40% of children younger than 3 to 4 years with non-disseminated MDB. Distinct chemotherapeutic regimens have been used, including the use of cisplatin, lomustine, vincristine, cyclophosphamide, etoposide, or even concomitant high-dose intravenous methotrexate and/or intrathecal methotrexate or mafosfamide, and/or intraventricular methotrexate [1, 42, 43, 45, 46, 47, 48, 49].

Prognosis in children is dependent on age, metastatic status at presentation, postoperative Karnofsky Performance Scale (KPS) score, molecular subtype, and completeness of surgical resection. Histopathologic subclassification of MDBs can modify therapeutic planning [4, 6, 7, 9, 19, 22, 30, 50, 51]. A higher prevalence of PTCH and SMO mutations in adult SHH-activated MDBs can predict responsiveness to inhibitors of the receptor SMO, and SHH-inhibiting drugs like vismodegib that act downstream SMO activity are currently in development. Investigation of target drugs able to suppress the WNT pathway can be also future adjuvant therapeutic modality [7, 13, 19, 41, 43, 45, 47, 52].

Notes

Compliance with ethical standards

Conflict of interest

The author declares that there is no conflict of interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.

Informed consent

Not applicable.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Department of Pathology, Santa Rita HospitalComplexo Hospitalar Santa CasaPorto AlegreBrazil
  3. 3.Hospital N. Sra. da ConceiçãoPorto AlegreBrazil
  4. 4.Universidade Luterana do BrasilCanoasBrazil
  5. 5.Instituto de CardiologiaFundação Universitária de CardiologiaPorto AlegreBrazil

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