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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 190-205

Diagnosis and management of central nervous system embryonal tumors in the molecular era: A contemporary review


1 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, Maharashtra, India

Date of Web Publication02-Nov-2021

Correspondence Address:
Dr. Vani Santosh
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru- 560029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_427_21

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  Abstract 


Central nervous system (CNS) embryonal tumors exhibit significant biological heterogeneity and pose challenges in diagnosis and clinical management. Among these, medulloblastoma is the most common and extensively studied tumor. Advances in understanding the molecular alterations of these tumors, using genomic and epigenomic platforms, have led to refinement in their diagnosis, classification, and guiding clinical management. This review discusses the current understanding of the molecular underpinnings of CNS embryonal tumors and details their clinical presentation, histopathological, and molecular features. Based on the recent discoveries, the current state of management of medulloblastoma and other embryonal tumors, including the recent biomarker-based clinical trials, is reviewed.

Keywords: Atypical teratoid rhabdoid tumor, central nervous system embryonal tumors, clinical presentation, embryonal tumor with multilayered rosettes, management, medulloblastoma, molecular genetics


How to cite this article:
Santosh V, Rao S, Dasgupta A, Gupta T. Diagnosis and management of central nervous system embryonal tumors in the molecular era: A contemporary review. Int J Neurooncol 2021;4, Suppl S1:190-205

How to cite this URL:
Santosh V, Rao S, Dasgupta A, Gupta T. Diagnosis and management of central nervous system embryonal tumors in the molecular era: A contemporary review. Int J Neurooncol [serial online] 2021 [cited 2021 Dec 5];4, Suppl S1:190-205. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/3/190/329822




  Introduction Top


Embryonal tumors encompass a wide variety of central nervous system (CNS) tumors, which are believed to have originated from fetal embryonic cells in the brain.[1] Our understanding of embryonal tumors has evolved enormously since the initial recognition of these tumors. However, what has remained constant is the fact that embryonal tumors pose a challenge in diagnosis as well as management and are generally associated with a poor prognosis, excepting for an favorable biology observed in localized medulloblastoma, which has an excellent long-term survival. The nomenclature of embryonal tumor based on the cell of origin was proposed initially by Bailey and Cushing, who laid down the foundation for the classification of tumors of the CNS.[1] However, it was not until the second edition of the World Health Organisation (WHO) classification of CNS tumors that the embryonal tumors were recognized as a tumor category separate from the aggressive glial tumors and pineal region tumors such as the pineoblastoma.[2] Further expansion of the embryonal tumors ensued in the subsequent editions of the WHO classification of the CNS tumors, which were mainly centered on the histopathological features. In the WHO 2000 edition, the newer entity, atypical teratoid rhabdoid tumor (AT/RT) and the histologic subtype of medulloblastoma, large cell/anaplastic (LC/A) medulloblastoma, were added.[3] In the WHO 2007 edition, naming of supratentorial primitive neuro-ectodermal tumor (PNET) was modified to CNS PNET, which included tumor entities such as ganglioneuroblastoma, neuroblastoma, medulloepithelioma, and ependymoblastoma.[4] The entity “embryonal tumor with abundant neuropil and true rosettes (ETANTR)” was described in this fascicle although not included in the classification. Subsequently, with the efforts by several research groups, understanding of the biology of embryonal tumors has exponentially grown, with the recognition of significant molecular heterogeneity within these embryonal tumors, resulting in the integration of molecular data in their classification in the WHO 2016 update classification of CNS tumors.[5] Beyond the WHO 2016 classification also, knowledge of molecular genetics has further expanded leading to the recognition of newer tumor entities and several molecular subtypes within each tumor entity, some of which will be incorporated in the WHO 2021 classification of CNS tumors.

This review discusses the recent concepts in the understanding of embryonal tumor entities with respect to clinical and imaging characteristics, neurosurgical aspects, histopathology, molecular genetics, and their management.


  Clinical Presentation of the Embryonal Tumors Top


Medulloblastoma is the most common malignant embryonal tumor of the CNS, typically seen in childhood and much less commonly in adolescents and young adults.[6] Patients with medulloblastoma generally present acutely or subacutely with features of raised intracranial pressure such as headache, nausea, vomiting, blurring of vision, and cranial nerve deficits or signs and symptoms of cerebellar/brainstem involvement in the form of ataxia, dysarthria, dysmetria, and gaze palsy.[7],[8],[9] Similarly, other embryonal CNS tumors can have variable and myriad presentations depending on the anatomic location of tumor (in the supratentorial or infratentorial compartment) and associated obstructive hydrocephalus. Since a significant proportion of infants and toddlers are also affected with embryonal CNS tumors, diagnosis can sometimes be challenging with generalized symptoms such as increasing irritability, lethargy, poor feeding, vomiting, developmental delay, and failure to thrive. Careful inspection and history should be sought toward the presence of spinal symptoms such as backache, weakness of the limbs, and bladder/bowel incontinence, given the high propensity of cerebrospinal fluid (CSF) dissemination seen in over 30% of all embryonal CNS tumors at initial diagnosis.


  Imaging and Diagnostic Workup Top


Although computed tomography imaging of the brain is more frequently undertaken as first-line imaging due to wider availability and faster acquisition, magnetic resonance imaging (MRI) remains the preferred and recommended imaging modality for children with suspected CNS tumors due to exquisite anatomic resolution, multiparametric nature, and ability to image the entire neuraxis (brain and spine) in one session. Recommended MRI sequences include pre- and postcontrast T1-weighted images, T2-weighted images, and fluid-attenuation inversion recovery images, supplemented with perfusion-weighted imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy, as these advanced sequences can provide useful information in predicting tumor histology or ruling out nonneoplastic etiologies.[10],[11],[12] Medulloblastoma is seen typically to arise from the vermis in the midline posterior fossa filling the fourth ventricle causing obstructive hydrocephalus;[9],[13],[14] less commonly, it is located laterally in the cerebellar hemisphere, particularly in adolescents and young adults with or without extension to the foramen.[15],[16] On T1-weighted MRI, medulloblastoma appears hypointense to isointense compared to the surrounding white matter and exhibits variable contrast enhancement. Signal characteristics are quite variable on T2-weighted images, with densely cellular component of the tumor being hypointense and less cellular areas being iso- to hyperintense. Intratumoral or peritumoral cysts, if any, appear hyperintense, while calcification generally exhibits low signal on T2-weighted images. Due to its densely packed and highly cellular nature, medulloblastoma shows restricted diffusion with corresponding low apparent diffusion co-efficient values.[13],[14] Some of the semantic imaging features that are selectively enriched and suggestive of specific molecular subgroups include intratumoral hemorrhage in wingless (WNT) subgroup medulloblastoma; lateralized hemispheric location, intratumoral cysts, and significant peri-lesional edema in sonic hedgehog (SHH) subgroup medulloblastoma; patchy heterogenous enhancement with inferior location in Group 3 subgroup; and faint/subtle enhancement or largely nonenhancing tumor with inferior extension in Group 4 subgroup.[15] AT/RTs are more prevalent in infants (mostly <3 years) and younger children (<5 years) with over 50% of tumors having infratentorial location, with a multitude of features including lateralized location, heterogeneous contrast enhancement, peripheral cysts, presence of intratumoral hemorrhage, and perilesional edema.[12],[17] The MRI characteristics can vary according to the molecular subgroups as well as infratentorial location, peripheral tumor cysts, substantial contrast enhancement, absence of edema in AT/RT-TYR, variable contrast enhancement, hemorrhage in AT/RT-SHH, and supratentorial location with strong contrast enhancement in AT/RT-MYC.[18] Embryonal tumor with multilayered rosettes (ETMR) commonly involves infants and young children (typically <3 years) with a slightly higher predilection for supratentorial location.[19] The usual features include large tumors, heterogeneous or weak enhancement, intratumoral macrovessels, calcifications, and frequently no perilesional edema.[19] Apart from the standard brain tumor protocol, sagittal fat-suppressed postcontrast MRI of the spine is strongly recommended in suspected embryonal tumors as a screening tool to rule out any neuraxial dissemination. Representative MRI sequences of children with specific embryonal CNS tumors (medulloblastoma, AT/RT, and ETMR) are presented in [Figure 1].
Figure 1: Representative preoperative magnetic resonance imaging findings in embryonal central nervous system tumors comprising one case each of medulloblastoma (a), atypical teratoid rhabdoid tumor (b), and embryonal tumor with multilayered rosettes (c). Each row contains postcontrast axial T1W image, axial T2W image, coronal T2W image, and GRE image (from left to right) for each individual patient. MRI findings in a 10-year-old boy with Group 4 medulloblastoma (a) with heterogeneous contrast uptake and intervening nonenhancing areas, T2W isointense signal with dilation of superior recess of the fourth ventricle superiorly (appreciated on coronal view) and lack of blooming (intratumoral calcification or hemorrhage) on GRE. AT/RT in a 2-year-old infant (b) with predominantly nonenhancing tumor and intervening focal enhancing areas with supra- and infratentorial extensions (seen on coronal T2W image). The presence of multiple peripheral cystic areas can be seen on the T2W axial image and sites of punctate hemorrhage on GRE. MRI characteristics (c) in a 3-year-old girl diagnosed as ETMR. The tumor can be seen as having predominantly enhancing regions and large cystic regions located medially and superiorly without significant peri-lesional edema. GRE sequence shows the presence of macrovessels within the tumor, quite characteristic of ETMR. GRE: Gradient-echo, ETMR: Embryonal tumor with multilayered rosettes, AT/RT: Atypical teratoid rhabdoid tumor

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Preoperative CSF sampling via lumbar puncture is not routinely recommended due to the high risk of tonsillar herniation in the presence of raised intracranial pressure consequent to the presence of a large mass in the posterior fossa. Other routine investigations (complete blood count, biochemistry, viral markers, and chest X-ray) are done preoperatively in accordance with standard institutional protocols toward fitness for general anesthesia required for neurosurgical decompression.


  Neurosurgery Top


Maximal safe resection of the tumor via microneurosurgical approach is the recommended first-line treatment in the multimodality management of medulloblastoma and other embryonal CNS tumors. Neurosurgical excision provides immediate amelioration of symptoms from mass effect, relieves obstructive hydrocephalus, re-establishes CSF pathways, provides tissue for histopathological and molecular diagnostics, and achieves adequate cytoreduction, facilitating further adjuvant therapy. Technological advancements in neurosurgical techniques have significantly reduced intraoperative and postoperative complications, with < 1% mortality in contemporary practice. In the pre-MRI era, Chang's classification of operative staging was proposed in the year 1969, which included the size and extent of the primary tumor and the burden of metastatic disease.[20] Due to better appreciation of the tumor on MRI and absence of significant prognostic impact of the tumor stage on outcomes as demonstrated in subsequent studies, Chang's staging system is no longer routinely used in modern neurosurgical practice. The principles of neurosurgery remain maximal safe resection, avoiding extensive and aggressive attempts at debulking, particularly in proximity to eloquent areas, such as infiltration into the brainstem for infratentorial tumors and the insular region/thalamus for supratentorial embryonal tumors. For medulloblastoma, the extent of resection has been incorporated into risk stratification for deciding the intensity of adjuvant therapy. Recent work has demonstrated that the prognostic impact of gross/total resection/near-total resection gets largely attenuated when accounting for molecular subgrouping. The survival benefit of residual tumor ≤1.5 cm2 is limited to patients with Group 4 medulloblastoma,[21] suggesting that aggressive resections with significant potential for precipitating morbidity may be avoided for other subgroups as more robust data becomes available. Following surgery, an MRI of the brain needs to be undertaken to assess the extent of resection and burden of residual disease, along with an MRI of the spine, if not done in the preoperative setting. Such imaging should be conducted within the initial 48–72 h of surgery or at least 2–3 weeks later to avoid confounding results from postoperative blood products, leptomeningeal enhancement, or subdural collection.[22] In the absence of leptomeningeal disease or equivocal findings, CSF examination (malignant cell cytology and biochemistry) should be done in all patients with embryonal CNS tumors, preferably after 2–3 weeks from surgery, to avoid false-positive results. The use of ventriculoperitoneal shunt is not routinely recommended since definitive surgery with removal of the primary tumor is effective in reversing obstructive symptoms and there is potential risk of other neurological complications or disseminating tumors in the extraneuraxial compartment.[23],[24]


  Histopathology and Molecular Genetics of Central Nervous System Embryonal Tumors Top


Medulloblastoma

Medulloblastoma is presumed to arise from the progenitor cells which are present in the cerebellum during brain development.[5] The clinical and histopathological characteristics of the tumor was first described by Bailey and Cushing, who hypothesized that the tumor took origin from “medulloblasts''which represent the multipotent stem cells of the neural tube.[1] The understanding of these tumors has evolved over a period and now refined in the molecular era.

Medulloblastomas are uniformly considered as WHO grade IV tumors, even though there exist differences in the clinical behavior between their histologic subtypes and molecular subgroups. Until the WHO 2007 classification of CNS tumors, histological classification alone was given significance.[4],[5] During the past two decades, several researchers used high-throughput technologies including gene expression profiling, transcriptome, and DNA methylation profiling studies to stratify medulloblastoma into molecular subgroups which had prognostic significance.[25],[26],[27] However, bioinformatic analysis of the results derived from these platforms showed that there were inconsistencies in the number of molecular subgroups that were identified by the different researchers and to complicate the issue, each research group assigned their own nomenclatures to the molecular subgroups that were identified.[28] Therefore, in the year 2010, a consensus was arrived at by the research groups, identifying four distinct molecular subgroups of medulloblastoma: WNT, SHH, Group 3, and Group 4, which were distinct in their demographic, clinical, and molecular features.[2] Subsequently, based on the recommendation of the “International Medulloblastoma Working Group,” histopathological and molecular classification was introduced in the WHO 2016 classification of CNS tumors.[5] Unlike the gliomas, where molecular classification is integrated into the histopathological classification, the two have remained distinct and separate in medulloblastoma due to the recognition that both histology and genetics have clinical and prognostic significance. Moreover, histopathological subtyping of medulloblastoma has clinical utility particularly when molecular testing is not feasible or is limited.

Histologic subtypes

Classic medulloblastoma

This is the most common histologic subtype, often located in the cerebellar midline involving the fourth ventricle cavity, sometimes closely apposed to the brain stem. The tumor is characterized by densely packed sheets of primitive appearing embryonal cells exhibiting high nucleo: cytoplasmic (N: C) ratio, hyperchromatic nuclei, and a high proliferation. Apoptosis and necrosis may also be present. Homer-Wright rosettes, composed of central neuropil surrounded by embryonal cells, are seen in some classic medulloblastomas. Although these tumors do not show nodular desmoplasia within the tumor, a streaming desmoplastic response can occur where there is leptomeningeal infiltration by the tumor cells. In addition, focal neurocytic areas without nodular desmoplasia can also be seen. Some tumors show myogenic and melanotic differentiation.

Desmoplastic/nodular medulloblastoma

Desmoplastic/nodular (D/N) medulloblastoma is usually located in the cerebellar hemisphere, with few in the vermis. Most cerebellar hemispheric tumors are seen in adults. This subtype is defined by pale nodules of neurocytic cells which are reticulin-poor interspersed by highly cellular, reticulin-rich internodular zones composed of poorly differentiated proliferating cells.

Medulloblastoma with extensive nodularity

Medulloblastoma with extensive nodularity (MBEN) is located most often in the cerebellar midline and largely affect infants. ''Bunch of grapes''-like appearance is the typical imaging appearance of this subtype. On histology, this subtype closely resembles the D/N medulloblastoma except that the nodular pale neurocytic zones are substantially expanded and the internodular region is sparse.

Large cell/anaplastic (LC/A) medulloblastoma

This is considered the most aggressive histologic subtype of medulloblastoma. LC/A can have anaplastic and/or large cell morphology. Anaplastic morphology is characterized by cells exhibiting significant nuclear atypia, presence of nuclear molding, cell–cell wrapping, and frequent apoptosis including formation of apoptotic lakes. Large cell morphology also has similar nuclear features; however, the cells are larger, with prominent nucleolus and moderate-to-abundant cytoplasm.

The histological subtypes of medulloblastoma are depicted in [Figure 2].
Figure 2: Histoloical subtypes of medulloblastoma. Classic medulloblastoma with characteristic Homer Wright rosettes (a, H and E, ×100). Desmoplastic nodular medulloblastoma composed of nodules, which are highlighted by reticulin silver stain (b, H and E, ×40 and inset, reticulin).Medulloblastoma with extensive nodularity are characterized by minimal internodular zone (c, H and E, ×10 and inset, reticulin). Large cell anaplastic medulloblastoma exhibiting cell–cell wrapping (arrows, d, H and E, ×100) and apoptotic lakes (inset, d). Less common subtypes are medulloblastoma with melanotic differentiation (e, H and E, ×100 and inset, HMB-45) and medulloblastoma with myogenic differentiation (f, H and E, ×100 and inset, desmin)

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Molecular subgroups

The biological heterogeneity of medulloblastoma is reflected in their molecular subgroups. The four recognized molecular subgroups are WNT-activated, SHH-activated, and non-WNT/non-SHH (Group 3 and Group 4).

WNT -activated medulloblastoma

The WNT subgroup occurs mainly in children and adolescents, and occasionally in adults.[29] These tumors are commonly located in the cerebellopontine angle. A midline location with involvement of brain stem can also be seen.[30] They constitute approximately 10% of medulloblastoma and are commonly of classic, followed by LC/A, histologic subtype. The large majority of WNT medulloblastomas harbor mutations in the CTNNB1 gene that encodes for β-catenin, which can be detected by immunohistochemistry. This mutation co-occurs with monosomy 6. Other genetic alterations include mutations in the genes such as DDX3X, SMARCA4, PIK3CA, CSNK2B, TP53, and EPHA7.[25],[31],[32] Apart from monosomy 6, these tumors have a balanced genome. The proposed cell of origin is the progenitor cell in the lower rhombic lip of the developing brain stem.[33] WNT medulloblastomas have an excellent overall prognosis in children with the current management strategies, but it is not the case in adults.[34] Furthermore, monosomy 6 may be absent in a subset of adult WNT tumors.[35]

SHH-activated medulloblastoma

The SHH subgroup has a bimodal distribution and affects infants and adults.[29] These tumors are localized to the cerebellar hemispheres and account for about 30% of medulloblastomas.[30] All the histologic subtypes can be associated with this subgroup; however, D/N and MBEN are the commonly encountered subtypes. The tumor cells express GAB1 which aids in their diagnosis. Some of the altered genes in the SHH pathway include PTCH1, SUFU, SMO, GLI1, and 2. MYCN amplification, TP53 mutations, and altered TP53 and PI3K pathways are noted in this subgroup. In addition, TERT promoter mutations are seen mostly in adult patients.[29] TP53 mutations are commonly found in the DNA-binding regions encoded by exons 4 through 8.[36] Deletion of PTCH gene and 10q loss is usually associated with germline mutations in SUFU. Apart from clinical parameters such as age and metastatic stage, TP53 mutations and MYCN amplification have been associated with worse outcomes. The cell of origin of the SHH medulloblastoma is believed to be the granule cell progenitor cells, which are programmed to form the external granule cell layer in the developing cerebellum.[33]

Non-WNT/non-SHH medulloblastoma

As the specific drivers for Group 3 and Group 4 medulloblastoma are not known, they are grouped together as non-WNT/non-SHH subgroup. They are mostly located in the inferior portion of the midline in the cerebellum.[30] However, these groups have distinct methylation profiles and prognoses. Group 3 tumors are associated with the worst prognosis and are frequently metastatic, while Group 4 patients have an intermediate prognosis. Group 3 medulloblastomas account for about 25% of medulloblastomas, occur in infancy and childhood, and very rarely in adults. Although both the subgroups are mostly associated with classic histologic subtype, LC/A histology can be seen in both the subgroups, although most often seen in Group 3 tumors. MYC amplification is the hallmark molecular alteration noted in Group 3 tumors. Other alterations include mutations or amplifications of genes such as SMARCA4, CTDNEP1, KMT2D, MYCN, and OTX2.[29],[35] Group 4 affects all age groups and accounts for about 35% of medulloblastomas. These tumors are characterized by MYCN amplification apart from other genetic alterations.[29]

The molecular subgroups of medulloblastoma are depicted in [Figure 3].
Figure 3: The molecular subgroups of medulloblastoma. (a-e) WNT activated medulloblastoma with nuclear positivity for β-catenin (b) and YAP1 (c), immunonegative for GAB1 (d). OTX2 is diffusely positive (e). (f-j) SHH activated medulloblastoma exhibiting immunonegativity for β-catenin (g), immunopositivity for YAP1 (h) and GAB1 (i). OTX2 is negative (j). (k-o) Non-WNT non-SHH medulloblastoma with immunonegativity for β-catenin (l), YAP1 (m), and GAB1 (n). OTX2 is diffusely positive (o). (a-o × 100). WNT: Wingless, SHH: Sonic hedgehog

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Association with familial tumor syndromes

Although a large proportion of medulloblastoma are sporadic in origin, there are some familial tumor syndromes that predispose to their development. For example, germline TP53 point mutations, seen in Li–Fraumeni syndrome, can predispose to SHH medulloblastoma.[37] Turcot syndrome, in individuals with germline APC mutations and a predisposition to colon cancer, can predispose to WNT medulloblastoma. Association with germ line mutations is less known in Group 3 and Group 4 tumors. However, it has been shown that occasional cases of these groups are associated with a germline mutation of CREBBP (Rubinstein–Taybi syndrome), as well as the DNA repair genes PALB2 and BRCA2.[38]

Testing platforms

Identification of the molecular subgroups of medulloblastoma may be achieved by various methodologies including methylation profiling and gene expression analysis using nanostring technology. However, these are not feasible methods for day-to-day practice. Hence, the most practical approach is to use immunohistochemistry-based molecular stratification, which can identify WNT, SHH, and non-WNT/non-SHH groups. Monosomy 6 (WNT subgroup) and cMYC amplification status (Group 3) can be assessed by fluorescence in situ hybridization (FISH) technique. The commonly used immunohistochemical markers are β-catenin, GAB1, YAP1, and p53. β-catenin immunopositivity is seen in WNT group, GAB1 in SHH group, and YAP1 immunoreactivity is noted in both these groups, while all three are negative in Group 3/Group 4 medulloblastoma.[39] P53 has a role in the SHH group of medulloblastoma. Few pathologists also use other markers such as OTX2 and filamin A. Filamin A is positive in the WNT and SHH group and OTX2 immunoreactivity is seen in all the non-SHH medulloblastomas.[40],[41] The Indian Society of Neuro-oncology consensus guidelines suggests the panel of standard immunohistochemical markers for routine use. Other markers tested on platforms such as FISH, DNA sequencing, qPCR or NanoString, can be kept optional, based on the technical and economic situation.[9]

Molecular subtypes within subgroups of medulloblastoma

Beyond the consensus classification of medulloblastoma into four molecular groups, multidimensional omics data have helped identify additional molecular subdivisions, now referred to as molecular subtypes. Accurate assignment of patients into the relevant molecular subtypes has become essential for prognosis and refined treatment strategies. Recently, three independent research groups analyzed DNA methylation data as well as gene expression data and identified the structure within subgroups.[26],[27],[42] Cavalli et al., combined DNA methylation and gene expression analysis using the similarity network fusion approach to identify subtypes within the four groups of medulloblastoma. This study identified 12 subtypes, 2 in WNT (WNTα, β), 4 in SHH (SHHα, β, γ, δ), 3 in Group 3 (α, β, γ), and 3 in Group 4 (α, β, γ). WNTα tumors occur in children and show monosomy 6; whereas, WNTβ tumors arise in older children and young adults and do not harbor monosomy 6. SHHα tumors occur in childhood and are enriched for Tp53 mutations, and therefore, are associated with a worse outcome. SHHβ and SHHγ occur in infants. SHH γ usually has the MBEN histology and a balanced genome. SHHδ occur mostly in adults and harbor TERT promoter mutation.[42]

Similarly, Schwalbe et al., also used DNA methylation profiling analysis and identified seven molecular subgroups of medulloblastoma, which included WNT, SHH infants, SHH adults, Group 3 high-risk, Group 3 low-risk, Group 4 high-risk, and Group 4 low-risk subtypes.[27] Furthermore, in a combined analysis of Group 3 and Group 4 tumors, Hovestadt et al., identified eight molecular subtypes, designated I to VIII, which was further confirmed in a combined analysis of 1501 cases belonging to Group 3 and 4.[26] While subtypes II, III, and IV conform to Group 3, subtypes VI, VII, and VIII conform to Group 4. However, an overlap of subgroups 3 and 4 is seen in these subtypes. Subtypes I and V comprise a mix of Group 3 and Group 4 tumors. Therefore, these subtypes are characterized by the molecular and clinical attributes coming from both Group 3 and Group 4 tumors, indicating that these two molecular subgroups of medulloblastoma represent a continuum.

These studies have provided key insights into the diverse molecular mechanisms of medulloblastoma and emphasize that further stratification into clinically significant molecular subgroups and subtypes would improve disease risk stratification and could improve diagnostic and treatment decisions. However, the stratification requires high-throughput technologies and at this point of time, practical implementation of these methods is challenging. Identification of immunohistochemical markers/surrogates would make it more attainable across all the centers in the country/worldwide.

Atypical Teratoid/Rhabdoid Tumor

Atypical Teratoid/Rhabdoid Tumor (AT/RT) is predominantly a tumor of infants and young children, with adults being affected uncommonly. Unlike medulloblastoma, AT/RTs can occur throughout the neuraxis, i.e. supratentorial, infratentorial, and spinal regions.[43] In adults, these tumors are usually localized to the cerebral hemispheric and sellar regions.[44] Histologically, the tumor is heterogeneous and characterized by undifferentiated cells, rhabdoid cells, and proportion of cases displaying epithelial and mesenchymal differentiation. The presence of rhabdoid cells, although variable in proportion, is the characteristic feature of this tumor. By immunohistochemistry, the tumor cells express glial fibrillary acidic protein (GFAP), vimentin, epithelial membrane antigen (EMA), and smooth muscle antigen (SMA), in a patchy pattern. The morphological heterogeneity is, however, in striking contrast to a unifying genetic event, which is seen in >95% of the cases, characterized by mutation in chromosome 22, resulting in inactivation of SWItch/sucrose nonfermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B1 (SMARCB1) gene.[45] Approximately 5% of AT/RTs harbor BRG1 (SMARCA4) mutations. SMARCB1 and SMARCA4 mutations can be immunohistochemically identified by loss of nuclear expression of INI1 or BRG1 respectively in the tumor cells. The histological and immunohistochemical features of AT/RT are depicted in [Figure 4]a and [Figure 4]b. As per the WHO 2016 classification of CNS tumors, AT/RT is defined by loss of either INI1 protein (SMARCB1 gene), or rarely, BRG1 protein (SMARCA4 gene), in the absence of which the tumors are designated as embryonal tumor with rhabdoid features.[46] AT/RTs can occur either sporadically or in the setting of rhabdoid tumor predisposition syndrome. Renal and extrarenal (soft tissue) rhabdoid tumors are morphologically and genetically akin to AT/RT.[45]
Figure 4: Histological and immunohistochemical features of AT/RT and ETMR. (a and b) show undifferentiated and rhabdoid cells in AT/RT (a, H and E, ×200) displaying loss of INI1 immunoreactivity (b, ×100) (c-e) ETMR composed of tumor cells dispersed over a neuropil stroma (c, H and E, ×40) and displaying multilayered rosettes (d, H and E, ×400). Neuropil is synaptophysin immunopositive (e, ×100) and LIN28A is positive in the cells forming rosettes (f, ×40). AT/RT: Atypical teratoid/rhabdoid tumor, ETMR: Embryonal tumor with multilayered rosettes

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Molecular subgroups

Although genetically similar, AT/RTs are now divided into three epigenetic subgroups, which explain their clinical and molecular heterogeneity. Torchia et al., classified AT/RT into Group 1, Group 2A, and Group 2B, by using methylation array profiling and gene expression array profiling approaches. Group 1 tumors showed overexpression of ASCL1.[47] Johann et al., using similar platforms, identified AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC groups, which are the consensus groups recognized currently.[48] AT/RT-TYR tumors account for about 34% of cases and are commonly located in the infratentorial region, while the other two groups are frequently seen in supratentorial locations. AT/RT-TYR tumors affect mostly infants, AT/RT-MYC tumors are seen in young children (median age 27 months) with AT/RT-SHH being intermediate in age at presentation (median age 20 months). AT/RT-TYR group show overexpression of melanosomal genes such as TYR, TYRP, MITF, and transcription factors including OTX2. AT/RT-SHH group accounts for about 44% of cases.[49] These tumors overexpress SHH pathway genes, GLI2, BOC, PTCHD2, and MYCN.[48] They also harbor heterozygous point mutations of SMARCB1. AT/RT-MYC group account for about 22% of cases and are characterized by broad deletions of SMARCB1 and expression of MYC oncogene and HOX cluster of developmental genes.[48] Immune cell infiltrates are reported in AT/RT subgroups and immunotherapy could have a potential therapeutic benefit in these patients. Recent data suggest that AT/RT-SHH tumors arise from neural progenitor cells, whereas the AT/RT-TYR and AT/RT-MYC groups arise from other progenitors outside the neurectoderm. The identification of these molecular groups in AT/RT is believed to pave the way to novel therapeutic targets which may lead to improvement in survival in a subset of patients with AT/RT.

Embryonal Tumor With Multilayered Rosettes

Embryonal tumor with multi-layered rosettes (ETMRs) are overly aggressive embryonal tumors, typically characterized by C19 MC alterations. This entity includes three histological phenotypes ETANTR, ependymoblastoma, and medulloepithelioma. ETANTR was first described in the year 2000 by Eberhart et al.[50] The tumors are characterized by the typical “ependymoblastic” rosettes and neuropil-like areas containing differentiated neurocytes with or without ganglion cells. Similarities in genetic alteration, histopathological, and clinical features including dismal prognosis were also noted in ependymoblastoma, and the term ETMR-C19 MC altered was initially used to describe these two entities.[31],[32] The tumors were characterized by multilayered rosettes on histology and typically harbored an amplification of a large miRNA cluster on chromosome 19q13.42 (C19MC). Subsequently, Nobusawa et al., noted this genetic alteration in medulloepithelioma, which was then included under the ETMR entity.[51] Currently, these three phenotypes are considered as a morphological spectrum of ETMR with diverse differentiation.

ETMRs occur in young children, usually <4 years, and are most often located in the cerebral hemispheres, although they can occur at other sites in the neuraxis, including brain stem and spinal cord. Morphologically, the ETANTR phenotype is characterized by a biphasic pattern with dense clusters of primitive neuroepithelial cells exhibiting high nuclear:cytoplasmic (N:C) ratio, brisk mitosis, and forming distinct multilayered true rosettes at places. These cells are dispersed over a neuropil-like stroma that contains differentiated neurocytes, sometimes with ganglion cells. Ependymoblastoma phenotype is composed of dense aggregates of similar primitive neuroepithelial cells, forming multilayered rosettes at foci, but without the neuropil-like stroma. The medulloepithelioma phenotype of ETMR is characterized by the primitive neuroepithelial cells arranged in papillary, tubular, and/or trabecular structures that resembles a primitive neural tube. These structures have an external limiting membrane which is positively stained with periodic acid–Schiff and is collagen IV positive. These tumors also have clusters of multilayered rosettes and can occasionally show mesenchymal or melanotic differentiation.

By immunohistochemistry, the primitive neuroepithelial cells in ETMR, including those forming multilayered rosettes, show immunopositivity for nestin and vimentin and can be focally positive for cytokeratin, EMA, and CD99. They show retained expression of INI1. The neuropil-like stroma, neurocytes, and ganglion cells are positive for synaptophysin, neurofilament, and NeuN. GFAP highlights the stellate, reactive astrocytes. LIN28A is a surrogate marker for C19MC altered tumors. Strong cytoplasmic staining is seen in ETMRs, mainly localized to undifferentiated cells, including multilayered rosettes and the papillary or tubular structures of medulloepithelioma. However, LIN28A staining is not specific to ETMR since it can be positive in a few AT/RT,[53] gliomas, germ cell tumors, and few non-CNS tumors. The histological and immunohistochemical features of ETMR are depicted in [Figure 4]c, [Figure 4]d, [Figure 4]e, [Figure 4]f. The large majority (>90%) of ETMRs show the characteristic C19MC alterations at 19q13.42, which is considered a pathognomonic diagnostic marker of these tumors (ETMR, C19MC altered). C19 MC amplification can be identified by the FISH technique. A small subset (<5%) harbor mutations in the DICER1 gene. ETMR-DICER1 mutant can be a part of the DICER1 genetic tumor syndrome with germline mutations of DICER1.[54] A few other tumors harbor genetic alterations other than C19MC or DICER1 alterations. Such tumors are designated as ETMR-not otherwise specified) (NOS) or not elsewhere classified (NEC).

Central Nervous System Neuroblastoma

This is an embryonal tumor characterized morphologically by small undifferentiated embryonal cells exhibiting high N: C ratio and brisk mitosis. The cells can show variable neurocytic differentiation. Nuclear palisading over a neuropil-rich stroma and calcification can be seen. These tumors show activation of the transcription factor Forkhead Box R2 (FOXR2) by structural rearrangements, most often gene fusion with other partners.[55] They are cerebral hemispheric masses, occurring in young children. Occasionally, the tumor has been reported in the lateral ventricles. By immunohistochemistry, the tumor is diffusely positive for synaptophysin and OLIG2, negative for GFAP and vimentin, and shows overexpression of FOXR2 and NKX 2-1.[56] A subset of tumors harbor other genetic alterations such as MYCN amplification. These tumors are designated as CNS neuroblastoma, NEC. Ganglioneuroblastomas have foci of ganglion cells and areas of calcification. Their association with FOXR2 activation is unclear.

Central Nervous System Tumor With BCOR Internal Tandem Duplication

This is a high-grade neuroepithelial tumor which was first described by Sturm et al., who demonstrated an in-frame internal tandem duplication (ITD) of the BCOR gene by DNA and RNA sequencing studies.[55] The tumor usually affects adolescent and young adult patients and is known to involve supratentorial as well as infratentorial regions of the brain. Histopathologically, they are characterized by relatively monomorphic population of round to oval cells with resemblance to an ependymoma. Perivascular pseudorosette-like arrangement is seen.[57] Although palisading necrosis can be seen, microvascular proliferation is notably absent.

This tumor is molecularly characterized by Internal Tandem Duplication (ITD) at the 3' end of BCOR gene resulting in overexpression of BCOR protein which can be detected by immunohistochemistry. However, recently, it has come to light that not all BCOR immunopositive tumors harbor BCOR-ITD, they may have other alterations such as fusions similar to extra-CNS BCOR-altered tumors, which include clear cell sarcoma of the kidney, primitive myxoid mesenchymal tumor of infancy and others.[58],[59],[60] Other than BCOR, these tumors express diffuse vimentin positivity with variable immunoreactivity to GFAP, OLIG2, S100, and EMA. Tumors with BCOR-ITD tend to have a poor prognosis. Treatment with multidrug regimen and craniospinal irradiation (CSI) has been shown to result in a better response in these tumors.[61]


  Risk Stratification in Medulloblastoma and Other Embryonal Central Nervous System Tumors Top


After neurosurgical excision, risk stratification is used to determine the intensity of adjuvant treatment regimens. Conventionally, only clinicoradiological criteria were used for risk stratification in medulloblastoma. Children 3 years or older with residual tumor ≤1.5 cm2 and absence of metastatic disease were classified as having average-risk disease; while, presence of any one feature – age <3 years, residual tumor >1.5 cm2, or leptomeningeal metastases – was considered as having high-risk disease.[62] With better biological insights, refinement of risk stratification has been proposed in the molecular era based on expected 5-year overall survival into the following groups: low risk (survival >90%), standard risk (survival >75%–90%), high risk (survival >50%–75%), and very high risk (survival <50%).[63] In general, the presence of LC/A histology, TP53 mutation in SHH subgroup, MYC amplification in Group 3, and chromosome 11 loss in Group 4 tumors should also be treated as high-risk disease.[9],[28] Both AT/RT and ETMR have poor long-term outcomes and should be considered as high-risk disease and treated aggressively with age-appropriate multimodality adjuvant therapy.


  Adjuvant Therapy in Medulloblastoma and Other Embryonal Central Nervous System Tumors Top


Radiation therapy (RT) forms a crucial component in the adjuvant treatment in patients with medulloblastoma. CSI involves delivering RT to the entire neuraxis due to the higher risk of CSF dissemination, drastically improved the outcomes of medulloblastoma, as historically described by Paterson and Farr in the year 1953.[64] Technological advances from kilovoltage to megavoltage beams and from two-dimensional to three-dimensional (3D) imaging have ushered the conformal era in contemporary RT practice. Techniques such as 3D-conformal RT and intensity-modulated RT along with volumetric image guidance have significantly improved treatment planning, verification, and delivery.[9] With the advent of proton beam therapy, it has been possible to further reduce the spill of radiation to the normal tissues, showing better preservation of neurocognitive function than traditional photon-based therapy.[65] It is crucial to start RT within 4–6 weeks from surgery since a longer gap can lead to inferior outcomes.[66] The presence of cerebellar mutism syndrome following surgery, as reported in approximately 25% of patients,[67] should not be considered as a criterion to delay or deny adjuvant therapy.

Typical risk-stratified doses and volumes of irradiation used in medulloblastoma are summarized in [Table 1]. In children with average risk disease, it is recommended to treat with reduced-dose CSI (23.4 Gy in 13–14 fractions) plus boost irradiation (30.6 Gy in 17 fractions) of the tumor-bed with adequate margins for total primary site dose of 54 Gy in 30–31 fractions over 6 weeks along with weekly vincristine during the course of RT.[68] Subsequently, after sufficient myelo-recovery (generally 4 weeks after RT), 6–8 cycles of adjuvant systemic chemotherapy with regimens containing cisplatin, lomustine, vincristine or cisplatin, cyclophosphamide, and vincristine are recommended[9] to compensate for reduction in dose of CSI and achieve optimal outcomes. The same regimen can also be considered for adolescents and young adults with average-risk medulloblastoma; however, it is well known that older patients have poor tolerance and reduced compliance to chemotherapy compared to children.[69] Hence, in postpubertal children (>15 years) and adults (>18 years) with average-risk disease, standard-dose CSI (35–36 Gy in 20–21 fractions) plus tumor-bed boost (18–19.8 Gy in 10–11 fractions) for the total primary site and dose of 54–55 Gy in 30–32 fractions over 6–6.5 weeks can be a suitable alternative regimen avoiding upfront chemotherapy. The role of adjuvant chemotherapy in improving survival for average-risk medulloblastoma in adolescents and young adults remains controversial.[70] In patients (both children and adults) with high-risk medulloblastoma,[71] it is recommended to treat with full-dose CSI (35–36 Gy in 20–21 fractions) plus boost irradiation (18–19.8 Gy/10–11 fractions) of the entire posterior fossa/tumor bed with margins for total primary site dose of 54–55 Gy in 30–32 fractions over 6–6.5 weeks. Focal nodular metastatic neuraxial deposits should also be boosted (5.4–9 Gy in 3–5 fractions). Alternatively, in patients with a high burden of leptomeningeal metastases, extended-dose of CSI (39.6–40 Gy in 22–24 fractions) can be offered followed by boost to posterior fossa/tumor-bed boost (14.4 Gy in 8 fractions) and dominant metastatic sites (5.4–9 Gy in 3–5 fractions as per tolerance), limiting the total primary site dose to 54–55 Gy in 30–32 fractions over 6–6.5 weeks. The use of daily carboplatin concurrently with RT followed by standard adjuvant systemic chemotherapy has shown encouraging survival outcomes in high-risk/metastatic medulloblastoma and supratentorial embryonal tumors (which were earlier referred to as PNET)[72],[73] and can be adopted judiciously in clinical practice with good supportive care. All patients with AT/RT and ETMR over the age of 3 years should be treated aggressively with full-dose/extended-dose CSI plus boost irradiation followed by adjuvant systemic chemotherapy, akin to high-risk medulloblastoma. With the incorporation of molecular subgrouping of medulloblastoma in the 2016 update of the WHO classification of CNS tumors,[5] several prospective trials [Table 2] are now using upfront molecular testing to assign therapy in medulloblastoma to optimize treatment intensity and strike the right balance between cure and quality of survival.
Table 1: Risk-stratified radiotherapy dose-volume guidelines for medulloblastoma/embryonal central nervous system tumors

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Table 2: Clinical trials using upfront molecular testing for assigning adjuvant therapy in medulloblastoma

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In infants and young children (<3 years) with medulloblastoma, preirradiation chemotherapy is often considered to delay the detrimental effects of RT on the brain in an early developmental stage. Such patients are typically treated with nonintensive chemotherapy regimens for 6–12 cycles or till the age of 3 years (whichever is earlier) after which RT is offered to achieve long-term disease control and survival. Chemotherapy regimens for infantile embryonal CNS tumors generally include agents such as etoposide, cyclophosphamide/ifosfamide, cisplatin/carboplatin, vincristine, or high-dose systemic methotrexate, with or without intrathecal methotrexate.[74],[75] Several groups have reported acceptable outcomes using high-dose myeloablative chemotherapy with autologous hematopoietic stem-cell rescue and avoidance or reduction in RT doses and volumes.[76] Recommended diagnostic workup as well as age-appropriate risk-stratified management algorithm for medulloblastoma is depicted in [Figure 5].
Figure 5: Age-appropriate and risk-stratified management algorithm for medulloblastoma. MRI: Magnetic resonance imaging, CSF: Cerebrospinal fluid, CSI: Craniospinal irradiation, LCA: Large-cell/anaplastic, Chr: Chromosome, HDCT: High-dose chemotherapy, AHSCR: Autologous hematopoietic stem-cell rescue

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  Treatment of Other Embryonal Tumors Top


In general, AT/RT and ETMR are associated with poor survival outcomes. Historically, the median survival has ranged between 1–2 years for AT/RT and 1 year for ETMR, with infants and young children (<3 years) having dismal outcomes.[44],[77],[78],[79],[80] Given their recent inclusion as specific entities within embryonal CNS tumors, further complicated by the rarity of such tumors, there is a scarcity of published data and lack of international consensus on appropriate management of these tumors with widely varying treatment protocols across different institutions. Since most patients are diagnosed during the first 3 years, the use of RT remains challenging. However, given the relatively poor prognosis with a relative lack of long-term survivors (precluding concerns of late treatment toxicities), focal conformal RT is often considered at a younger age (>6 months for infratentorial tumors and >12 months for supratentorial tumors) in such tumors.[81] The ACNS 0333 trial, including 65 patients with AT/RT, used two cycles of induction chemotherapy (methotrexate, vincristine, etoposide, cyclophosphamide, cisplatin), followed by three cycles of high-dose myeloablative chemotherapy (carboplatin, thiotepa) with autologous stem-cell rescue and focal conformal RT (50.4 Gy in <3 years and 54 Gy for others) as part of aggressive multimodality therapy. Outcomes were reported to be much better than previously reported retrospective series, with 4-year event-free survival and overall survival of 37% and 43%, respectively.[81] In a small case series of five children with ETMR, modified IRS-III chemotherapy regimen (vincristine, cisplatin, doxorubicin, cyclophosphamide, etoposide, actinomycin D, intrathecal methotrexate, and cytarabine) led to disease control over 18 months in 4 patients.[82] The use of proton therapy has been reported in a case series of 7 patients of ETMR with a median survival of 16 months, compared to the historical control of 10 months from 204 patients obtained through literature review.[83] Furthermore, the authors found that over 90% of infants/children with ETMR surviving beyond 3 years had been treated with RT at initial diagnosis, suggesting a crucial role of RT in its management. Further multicentric prospective trials are warranted in future to explore the optimal treatment modalities for these rare entities balancing survival and toxicity.


  Posttreatment Surveillance Top


Following the completion of planned treatment, it is essential to follow all patients periodically for early detection of relapse (recurrence/progression), if any, as well as timely identification and appropriate management of treatment-related morbidity. Detailed clinical examination should be performed at follow-up visits supplemented with periodic surveillance MRI of the brain and spine. Salvage therapy is often decided on an individual case basis depending upon age of the patient, disease-free interval, pattern of relapse, and performance status, which are strong determinants of outcomes. Patients with localized relapse, as often encountered in the adult SHH subgroup and some children with Group 4 medulloblastoma, are often amenable to aggressive therapy with re-excision, focal re-irradiation, and salvage chemotherapy with encouraging survival outcomes.[84] Patients with multifocal disease or widespread leptomeningeal dissemination usually have a guarded/poor prognosis and are often candidates for best supportive care alone with appropriate referral to palliative care services as available.

Medulloblastoma has a negative impact on health-related quality of life across the globe.[85] Survivors often suffer from significant treatment-related toxicities from each of the individual modalities including surgery, RT, and chemotherapy. Late treatment-related toxicities encountered in long-term survivors include neurocognitive decline, endocrine dysfunction, hearing impairment, skeletal retardation and bony deformity, cardiopulmonary insufficiency, cerebrovascular accident, and second malignant neoplasms.[86] It is crucial to perform a detailed systemic examination with timely referral to appropriate healthcare specialists for management of such late effects.[87]

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