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## 2. Molecular Genetics |
While histopathological MB features are nearly indistinguishable from those observed in children, the distribution of molecular types is markedly different, with SHH-activated MB representing by far the most common molecular group in adults [35]. |
The recently released 2021 WHO Classification of Central Nervous System (CNS) Tumours [17] classifies MB primarily according to molecular features, recognizing histopathological patterns of clinical utility and thus promoting an integrated molecular and histopathological diagnostic approach. Four main genetically defin... |
[table] Table 1Medulloblastoma molecular types.Genetically DefinedWNT-ActivatedSHH-ActivatedNon-WNT/Non-SHH (Group 3 & 4)TP53-WildtypeTP53-Mutant Frequency in Adults (%) ** 14.560.72.622.2 Histologically Defined * ClassicDesmoplastic/ nodularLarge cell/anaplasticClassic,Large cell/anaplastic Immunophenotype Cytoplasmic... |
[table] Table 2Expected OS for molecular subtypes of adult medulloblastoma.Molecular Subtype5 Years Expected Overall SurvivalWNT100%SHH TP53 MUTATED<50%SHH TP53 WILD TYPE76%NON SHH-NON WNT47–50% |
[table] Table 3Expected OS for molecular subtypes of children medulloblastoma.Molecular SubtypeExpected SurvivalWNT>90%SHH - metastatic TP53 wild type50–75%- non metastatic TP53 wild type75–90%- metastatic TP53 mutated<50%GROUP 3 - metastatic<50%- non metastatic75–90%GROUP 4 - metastatic50–75%- non metastatic>90% |
Goschzik T et al. [37] reported a 5-year event free survival (EFS) of 60% and 5-year overall survival (OS) of 75.6%, in a cohort of 117 adult MBs. For SHH-TP53mut-MBs, EFS and OS were poor, whereas all other types had an outcome similar to published standard-risk patients with a 5-year EFS/OS between 60% and 80% each. ... |
### 2.1. Medulloblastoma Histologically Defined |
In absence of molecular information, MB can be diagnosed based on morphological features as MB histologically defined. |
Histopathological subtypes of MB include: classic, desmoplastic/nodular (D/N), MB with extensive nodularity (MBEN), and large cell/anaplastic (LC/A). |
Classic MB is a blue cell tumor without distinctive architectural features composed of cells with high NC ratio, a variable degree of nuclear anaplasia from slight to moderate and the frequent presence of Homer–Wright rosettes. Some cases show evidence of neuronal/neurocytic differentiation with the presence of nodules... |
Nodular/desmoplastic MB is characterized by the presence of varying degrees of neuronal differentiation, typically with a nodular appearance confirmed by the presence of a perinodular reticulin stain. The differentiating nodules characteristically show intense synaptophysin positivity and limited proliferation/Ki67 lab... |
Large cell/anaplastic MB is characterized by severe nuclear anaplasia and/or large cell appearance, i.e., cells with large roundish nuclei and prominent nucleoli. Synaptophysin stain is diffusely positive. |
Rare MB examples show evidence of melanotic or myogenic differentiation at times easily identifiable on H&E slides, sometimes exclusively by appropriate immunohistochemical markers. Mitotic activity is variable but generally high in the poorly differentiated components of the tumor. Prominent cell apoptosis and necrosi... |
Surrogate immunohistochemical markers are frequently used in clinical practice to predict molecular groups. In our experience, an immunohistochemical panel including YAP1, GAB1 and beta-catenin, simplified from the original panel described by Ellison et al., which also included filamin stain, can reliably identify in m... |
SHH-activated MB is typically GAB1 and YAP1 positive, with a characteristic pattern of expression in the primitive/poorly differentiated components and absent stain in differentiating nodules. Beta-catenin expression is cytoplasmic. WNT-activated tumors typically show nuclear expression of beta-catenin (at least focall... |
Additional markers have been proposed, including p75-NGFR and OTX2, to help with assignment to a specific MB entity and exclude other mimic histological tumors [17]. |
There are two major limitations of the immunohistochemical panel in “molecularly” classifying MB: (1) the inability to distinguish between groups 3 and 4, which is, however, not relevant in adults; (2) the occurrence of inconclusive immunohistochemical results, especially in rare histopathological subtypes (such as MB ... |
### 2.2. Medulloblastoma Molecularly Defined |
The histopathological patterns have characteristic and specific associations with molecular subgroups. For instance, all morphologically defined nodular/desmoplastic MB correspond to SHH-activated MB and most WNT-activated MB have classic morphology. There is, however, no 100% correspondence between histopathology and ... |
Molecular classification of MB, including WNT-activated, SHH-activated and TP53-wildtype, SHH-activated and TP53-mutant, non-WNT/non-SHH MB groups, can be achieved using a variety of molecular techniques, including methods based on mRNA such as NanoString and RNA-Seq [39,40,41,42,43], or based on DNA analysis such as c... |
MB molecularly defined in adults [11,24,46,47] shows a predominance of SHH-MB, typically TP53-wildtype [37], while SHH TP53-mutant MB cases seem to occur predominantly in children and adolescents. The frequency of WNT-MB is similar to that published for children (15% vs. 10%), and non-WNT/non-SHH-MB is relatively rare ... |
### 2.3. Medulloblastoma SHH-Activated and TP53-Wild Type |
SHH-activated TP53-wildtype MB represents the most frequent type [11], accounting for approximately 60% of MB in adults [37]. While SHH activation is, predominantly, associated with pathogenic mutations of Smoothened (SMO) in adults, Patched (PTCH1) mutations can be found in all age groups. |
Other frequent genetic alterations have been reported, including ELP11, DDX3X, and KMT2D mutations. PPM1D amplification has also been described as a driving molecular event in adult SHH-activated TP53-wildtype MB [49]. Copy number variations. involving 9q loss and 9p gain, are the most frequent abnormalities observed i... |
### 2.4. Medulloblastoma SHH-Activated TP53-Mutant |
TP53 mutation is rare (2.6%) in adult SHH-MB [37], but may occur de novo in recurrent tumors. TP53 gene sequencing is recommended in all SHH-MB by the World Health Organization [17]. |
Most instances of SHH-MB TP53-mutant in adults show somatic TERT promoter, DDX3X and U1 snRNA mutations [34]. |
Amplification of MYCN and GLI2 has been reported. In adults, MYCN amplification and TP53 mutation tend to occur together and are associated with a poor prognosis [17]. |
Loss of several chromosomes such as 17p, 3p, 10q, 14 q and gain of 3q has been reported in SHH-activated TP53-mutant MB. DNA methylation profile aligned with a SHH-activated MB, either TP53-wildtype or TP53 mutant, is considered the gold standard method for determining MB group status in children. Four molecular subgro... |
A consensus regarding these SHH subgroups and their defining features has not yet been reached through an international cooperative meta-analysis. Of the four proposed subgroups, the main subgroup occurring in adults is SHH-4, which is associated with near-universal U1 and TERT mutations and frequent somatic PTCH1 or S... |
TERT promoter mutations have been reported in most adult MBs, but only rarely in childhood MB [34,46,55]. |
SHH-3 is the other subgroup that may arise in adult patients and is associated with TP53 and ELP1 mutations [54]. The last two molecular SHH-subgroups occur mainly in young children: one (SHH-1) is enriched with somatic and germline suppressor of fused (SUFU) mutations and chromosome 2 gain, and the other (SHH-2) is ch... |
### 2.5. Medulloblastoma Non-WNT/Non-SHH-MB |
Non-WNT/non-SHH-MB represent 22.2% of adult MBs and are classified as group 3 and group 4 [37]. Group 3 is exceedingly rare in adults and the majority of adult Non-WNT/non-SHH-MB cases belong to subgroup 4 [11,21,24]. The most frequent genetic alterations in groups 3 and 4 involve KDM6A, OTX2, ZMYM3, KMT2D, TBR1 and PR... |
DNA methylation profiles of non-WNT/non-SHH-MB align with group 3 and group 4 MB, among which eight molecular subgroups have recently been identified and classified in a spectrum of group 3/group 4 MBs by DNA methylation profiling [23,37,50] (Table 1). Based on analysis of DNA methylation and transcriptomic data, these... |
In an international meta-analysis using DNA methylation and transcriptome data, Sharma et al. [57] found eight robust subgroups within MB group 3/4. Group 3 MBs consist only of subgroups 2, 3, and 4, whereas group 4 MBs include uppermost subgroups 6, 7, and 8. Subgroups 1 and 5 are intermediate subgroups, showing the m... |
### 2.6. Medulloblastoma WNT-Activated |
MB WNT-activated is the least common of the molecular groups in adults. In a recent study, 14.5% of adult MBs show WNT activation, mostly caused by activating somatic mutations in the CTNNB1 gene [37]. For a definite diagnosis of WNT-activated MBs sequencing is recommended to confirm the presence of a CTNNB1 mutation. ... |
Monosomy of 6 is found in >80% of WNT-activated MB, cytogenetically characterizing this group, especially in children [17]. The DNA methylation profile aligned with WNT-activated MB. Two molecular subgroups of WNT-activated MB have been proposed, WNT alfa and WNT beta [17]. WNT alfa MB is characterized by a monosomy of... |
## 3. Diagnostic Imaging |
MB patients typically present with symptoms of increased intracranial pressure based on an obstructive hydrocephalus and/or cerebellar symptoms (e.g., ataxia, gait disturbance) due to the tumor’s location in the posterior fossa. Thus, in the acute clinical setting, the first imaging technique is routinely an unenhanced... |
The basic brain MRI protocol for diagnostic image acquisition and response assessment in MBs comprises of a fluid attenuated inversion recovery (FLAIR) MR sequence (slice thickness ≤ 4 mm), a T2-weighted MR sequence (slice thickness ≤ 4 mm), a diffusion-weighted (DWI) MR sequence (slice thickness ≤ 4 mm) as well as iso... |
In MR imaging, MBs are characterized as intra-axial tumorous lesions with sharp margins and little edema. On T2-weighted images, lesions are hypo-to-hyperintense, and on T1-weighted images, lesions are typically hypointense in comparison to the normal grey matter depending on the histopathological and molecular subtype... |
In contrast to MB in children, which are located in the cerebellar midline arising from the vermis, MBs in adult patients are predominantly represented by the sonic hedgehog (SHH)-mutated tumor subtype (60–70%), which is primarily located in the cerebellar hemispheres [11]. This molecular subtype is characterized by a ... |
For further therapy monitoring, especially in clinical trials, the RAPNO committee developed specific response assessment criteria for MB and other seeding tumors [60]. |
Complete response (CR) is defined as the complete absence of all tumorous lesions in the brain and spine, independent if they are measurable or unmeasurable, or if they show contrast enhancement or not for at least 4 weeks. |
The definition of partial response (PR) is determined as a ≥50% decrease (compared with the baseline examination) in the sum of the product of perpendicular diameters of all (≤4) measurable lesions for at least 4 weeks and stable or reduced non-measurable disease. |
Disease progression (PD) is defined as a ≥25% increase in the sum of the products of perpendicular diameters of all (≤4) measurable lesions (compared to the smallest measurement at any time point), significant progression of non-measurable disease not assigned to prior therapy, or new tumoral lesions (all lesions suspe... |
Postoperative MR imaging to detect residual tumor formations is ideally obtained within 48 h after surgery. In case of substantial postsurgical changes that may mask the presence of tumor remnants, it is recommended to repeat MRI 2–3 weeks after surgery [60]. |
MBs have a tendency for leptomeningeal dissemination in the brain, but also seeding metastases along the spinal axis. Therefore, diagnostic MRI should also include the entire spine. Spinal MRI examinations should ideally comprise of a sagittal pre- and post-contrast T1-weighted sequence (slice thickness ≤ 3 mm), an axi... |
If patients present symptoms of extra-CNS involvement, systemic staging (such as contrast enhanced CT scan of the chest, the abdomen and the pelvis; whole body PET CT; bone scan, etc.) is required [59,63]. |
Given the high costs and the unavailability of molecular testing at various institutions around the world, there is a high need of imaging-based genetic tumor type correlation. Thus, currently various research groups are focusing on, amongst other topics, the MRI-based distinction of molecular MB subtypes using artific... |
## 4. Neurosurgical Aspects in Adult Medulloblastoma Surgery |
### 4.1. Preoperative Management |
After brain and spine magnetic resonance imaging is obtained, each patient should be discussed in a multidisciplinary brain tumor board. A chest and abdominal CT should also be considered to exclude a malignancy. The different treatment options should be discussed in detail with a special emphasis on age, co-morbiditie... |
However, whenever safely possible, a surgical resection should be attempted. Goal of the surgery is to provide tissue for histopathological and molecular examination, reduction of intracranial pressure by treating a potential hydrocephalus and reduction of the tumor mass effect. Administration of corticosteroids prior ... |
### 4.2. Surgical Considerations |
Medulloblastoma frequently presents emergently with signs and symptoms of increased intracranial pressure due to obstructive hydrocephalus. The presence of moderate to severe hydrocephalus has been demonstrated in 30–40% [66,67,68], thus not rarely requiring an emergent pre- or intraoperative CSF diversion. An emergent... |
The surgical plan should always be an attempt at GTR with a residual volume of less than 1·5 cm2. This is, however, not always safe or feasible. In such cases, maximal safe resection leaving a residual tumor behind rather than causing neurological deficits by aggressive resection is recommended [70]. In addition, in ca... |
In contrast to the pediatric population, up to 70% of adult medulloblastomas occur in cerebellar hemispheres with a predominance of the SHH subgroup [71]. In the pediatric population, 90% of medulloblastomas occur in the midline [72,73]. Therefore, the surgical approach is more often paramedian in the adults and a safe... |
Surgical complications occur up to 30% patients and include: hematoma, cerebrospinal fluid fistula, infection/meningitis, hydrocephalus, pseudomeningocele, and cranial nerve palsy [68]. Postoperative hydrocephalus, requiring permanent cerebrospinal fluid diversions, occurs in 14–37.5% of patients [68,71]. Cerebellar mu... |
Intraoperative CSF sampling can be obtained in order to assess CSF seeding. However, standard of care is CSF sampling via lumbar puncture, ideally prior to or 2 weeks after surgery [78]. Surgery should take place in high-volume centers (100 brain tumors per year). |
## 5. Role of Chemotherapy and Radiotherapy |
Within the mid of the 20th century the combination of tumor resection and adjuvant craniospinal irradiation (CSI) became available as the first curative treatment in children with MB [79]. With this concept overall 5- and 10-year survival rates of 56% and 43% were achievable [80]. Later, the addition of adjuvant chemot... |
More intensive approaches with hyperfractionated radiotherapy did not lead to a superior survival compared to conventional radiotherapy in average risk MB [85]. Together, these studies set the current standard for average risk MB in childhood involving 23.4 Gy CSI with single doses of 1.8 Gy, combined with CCNU, Cispla... |
### 5.1. Why It Is Difficult Translating Pediatric Experiences in the Adult Counterpart |
While treatment has evolved gradually in children mostly based on the results of large randomized clinical trials, this was not the case for adult patients [7]. Treatment of adults has therefore been more or less extrapolated from experiences in children. However, translation of pediatric experience to adult counterpar... |
#### 5.1.1. Molecular Differences between Tumors |
Adult and pediatric MBs are biologically and prognostically distinct [11,23]. SHH-MB (70%), Group 4 (20%) and WNT subtype are the dominant genetically defined subgroups. Adult SHH-MB differ from pediatric SHH tumors in a low frequency of p53 mutations and a higher frequency of TERT promoter mutations (SHH Delta) [51]. ... |
#### 5.1.2. Differences between Toxicity in Children and Adults |
Treatment toxicities differ significantly between children and adults. Chemotherapy-related hematologic toxicity and peripheral neurotoxicity appear more prominent in teenagers and young adults [88,89], while central neurotoxicity is more pronounced in pediatric patients, with increasing detrimental effects of radiothe... |
### 5.2. Results of German and Italian Trials for Adult MB |
Chemotherapy treatment recommendations for adults are based on sub-cohorts of pediatric trials and single arm prospective trials. The Packer regimen (vincristin during radiotherapy, followed by lomustine, cisplatin and vincristin) [82,83] was established in children [10,85,94] and has also been used in adults. In a sub... |
In an Italian phase II trial, 26 high-risk patients received two cycles of upfront chemotherapy followed by radiotherapy and chemotherapy. The 5-year PFS rate was 69%, and the 5-year OS rate was 73%. A follow-up analysis on low-risk patients from the same trial showed that cisplatin-based chemotherapy after radiotherap... |
Meta-analyses also suggest an increased efficacy of radio-chemotherapy in comparison to radiotherapy. In a large meta-analysis, adult patients receiving chemotherapy survived significantly longer (mOS: 108 months, 95% CI 68.6–148.4) than those treated with RT alone (mOS: 57 months, 95% CI 39.6–74.4) [14]. A retrospecti... |
### 5.3. New Techniques of Radiotherapy |
Craniospinal radiotherapy is a potentially toxic treatment. Within the last few decades, advanced 3D conformal treatment techniques like volumetric arc therapy (VMAT) and tomotherapy were introduced in order to reduce the dose to organs at risk outside the target volume and enhance speed and quality of treatment. Howev... |
### 5.4. Proton Treatment |
Tumor control does not differ between proton and photon treatment [101,102], but due to different physical properties of protons, normal tissue outside the target volume can be better spared from irradiation dose significantly [103,104,105,106,107]. |
This implies several advantages of proton radiotherapy. Most importantly, early (e.g., hematotoxicity [108,109]) and late toxicity (e.g., endocrine dysfunction, cardiotoxicity and ototoxicity) appear to be reduced with proton treatment [109,110,111,112,113]. As a further advantage, the risk of secondary cancers in orga... |
However, apart from estimations from plan comparisons, clinical evidence concerning this field is still sparse. In a retrospective series of 115 children with MB after photon CSI or proton CSI, the secondary tumor incidence rates were not different between the two groups [121]. Prospective data from controlled clinical... |
### 5.5. EORTC 1634-BTG Trial/Alliance AMBUSH Trial |
Two prospective randomized trials have recently been initiated. |
The Europe-based EORTC 1634-BTG/NOA-23 trial randomizes patients between standard dose (35.2 Gy, followed by a boost of 19.8 Gy to primary sites) vs. reduced-dosed cranio-spinal radiotherapy (23.4 Gy, followed by a boost of 30.6 Gy to primary sites) and SHH-subgroup patients between the SMO-inhibitor sonidegib in addit... |
The US-based AMBUSH trial assigns patients 18 years of age or older with MB to an average risk non-SHH subgroup, an average risk SHH-subgroup and a high-risk subgroup. All patients will receive protocol-directed comprehensive treatment with 23.4 Gy radiotherapy on the neuroaxis followed by a boost of 36 Gy to primary a... |
### 5.6. New Drugs |
Recent advances in the molecular characterization of MB have led to the development of targeted therapies, which have a better toxicity profile and a more selective spectrum of efficacy than the traditional cytotoxic therapies. |
Among the described molecular subgroups, the SHH-activated, TP53 wild-type subgroup is highly overrepresented in adult MB, with around 60 to 70% of cases [11], representing the population of choice for the development of targeted agents acting by the inhibition of the SHH-signaling pathway. SHH is a signaling cascade p... |
Vismodegib and sonidegib, two highly selective SHH inhibitors targeting the SMO receptor, have demonstrated a favorable toxicity profile and an encouraging efficacy in preclinical and clinical trials of patients affected by MB with activation of the SHH pathway [28,29,30,31,32,33,126,127,128,129]. |
A major issue for SHH-inhibitors in MB patients is the rise of early drug resistance, mostly associated with genetic alterations within or downstream the SMO, among SUFU and GLI, as well as among Phosphoinositide-3 kinase (PI3K) and MEK pathways [130,131,132]. Notably, for the future treatments of SHH-activated tumors,... |
## 6. Importance of Centralizing Adult Medulloblastoma Patients in Hub Centers |
Since adult MBs are rare and heterogeneous, it is difficult for clinicians to gain sufficient experience in the field. |
Rarity leads to major problems: difficulties in achieving correct diagnosis and treatment in adequate times; difficulties to identify specialists and centers of reference; difficulties in conducting clinical studies with an adequate sample; limited interest in research by pharmaceutical companies due to the reduced eco... |
Inequalities in European countries exist both in the access to diagnosis and treatment, as well as in the access to information. |
This is even more likely if low numbers of cases are treated/year, or if patients are handled without a multidisciplinary approach. It is, therefore, strongly recommended that the treatment of MB take place at designated centers of reference. |
The centralization of care in centers with expertise in the treatment of MB has been shown to improve the overall quality of care and survival of MB patients [133], providing more accurate diagnosis, more timely treatment through multidisciplinary teams, and the possibility of enrollment in clinical trials. |
It is recommended that patients with MB are followed by a multidisciplinary team composed of a neurosurgeon, pathologist, neuroradiologist, medical oncologist, radiotherapist, neurologist, psychologist, and a specialized palliative care team, to provide an approach capable of satisfying all the patient’s needs during t... |
The presence of a multi-disciplinary group of specialists is considered an indispensable criterion for the center inclusion into the ERN-European Reference Network. The ERN reference network for rare diseases and cancers was born in 2017 as a European organization for the improvement and enhancement of specialized care... |
In order to enter the ERNs, the centers have to meet some basic requirements, first of all ensuring the presence of a multidisciplinary team completely dedicated to the disease. |
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