Embryonal   central   nervous tumors  are  aggressive, specifically medulloblastomas  are  very  aggressive  and  most  common  malignant  brain  tumor of childhood , remain a  major cause  of  morbidity  and  mortality.It  count  approximately  20%  of  all primary CNS tumors.[1] According  to  WHO 2016 classification  they are designated  as grade¬-IV  owing  to their  behaviour  of  aggressiveness  and  high  potential  of proliferativeness  and  poor  outcome.  Long  established, variants of  medulloblastomas  are  mostly  stratified  based  on  histological  and  radiological  criterias  with  reference  to  age of  onset, metastatic  spread  and  residual  tumor after  surgery. However aggressive multinodal  teatment  protocol  carries  high morbidity; thus differentiation   between  favourable  and  poor  outcome  will  be  highly  desirable.  With extensive effort   recent WHO 2016 Integrated diagnosis that includes both genotyping and histological typing , enables  us  to  classify  medulloblastoma into molecular  subgroup  like  wingless(WNT), sonic hedge hog(SHH) and  two  additional   subgroups,  group 3  and  group 4. In the near future, this subclassification will be used to select targeted therapies and improve understanding of the behaviour of this disease. However, other than the WNT group, which is consistently associated with excellent survival,SHH tumors, group 3 tumors, and group 4 tumors show heterogeneous outcomes.

AIMS & OBJECTIVES

1. To study the histological features of adult and paediatric medulloblastoma and classify them into the histological subtypes as defined by WHO -2016.                                                                                                      
2. To study the expression profile of   the immunohistochemical marker GAB-1 and β-Catenin in paediatric and adult medulloblastoma

All the procedures carried out in the retrospective study were approved by the Institutional Review Board of S.C.B MCH Cuttack. There were a total of 38 cases of medulloblastomas retrieved from the database of the Department of General Pathology, S.C.B MCH Cuttack from November 2018 to October 2020 Biopsy samples of 38 cases of  clinically  and  radiologically  suspective cases of  medulloblastomas  were  subjective  to  histopathological  examination. 36 had sufficient tissues in paraffin block for additional immonohistochemical study were subjective to  immunohistochemical  study  of GAB-1 and β-catenin..

Immunostaining for β-catenin was considered positive if there was uniform intense nuclear and/or cytoplasmic staining in more than 10% of tumour cells. Cytoplasmic staining in the absence of nuclear staining was considered negative. GAB-1 was considered positive if uniform intense cytoplasmic or cytoplasmic membrane labeling was seen in more than 10% of the tumour cells.

Statistical Analysis: Statistical analysis was done with the Chi square tests using SPSS software. A p value of less than 0.05 was considered significant. The patient demographic details and the morphological features of each tumor subtype were analyzed. A pie chart for correlation between morphological subtypes and immunohistochemical markers was performed. The specificity and sensitivity GAB-1 among the desmoplastic and non-desmoplastic histological subtypes were calculated.

There was a total of 38 cases of medulloblastoma from November 2018 to October 2020. Of these 36 cases were included in the study based on the defined inclusion and exclusion criteria that are outlined in the materials and method section. The study population included 8 adults (22%) and 28 children (78%) (p<0.001, stastistically significant) (Figure 1).

Figure 1: Age distribution among children and adults of medulloblastoma

The M:F ratio was approximately 2:1 with 70% (25 cases) males and 30% (11 cases) females(p<0.008,statistically significant)

Figure 2 : Gender distribution in medulloblastomas

 In children there was clear male preponderance with nearly two third of the cases being males 17/25

Figure 3: Gender distribution among children

Figure 4: Gender distribution among adults.

In adults there was near equal gender distribution. Male 6 cases anf female 5 cases.

Histological subtypes:

We found all five histological subtypes of medulloblastoma in the study population. The predominant subtype corresponded to the Classic variant at 58.3% (21cases).Desmoplastic medulloblastomas formed the next major group with 22.2% (8 cases),followed by the Large Cell variant at 11.1% (4 cases). There were 5.8%(2 cases) and2.6%(1 case)of the Anaplastic and Medulloblastoma  with extensive nodularity (MBEN) subtypes respectively. (Figure 5)

Figure 5: Distribution of cases by histological subtype in the study population.

Table no-1

In adults although Classic variant was the predominant subtype, the Desmoplastic variant came a close second constituting 50% and 33% of cases respectively (Figure 6).On the other hand in children, the Classic variant constituted nearly two thirds of the cases (62%) as opposed to only 20 % being Desmoplastic. (Figure 7).

Figure 6: Distribution of cases by histological subtype in adults

Figure 7: Distribution of cases by histological subtype in children.

Histological Features:

The Classic subtype was characterized by closely packed round to oval cells with hyperchromatic(carrot shaped) nuclei surrounded by scant cytoplasm and high mitotic activity.(Figures 17(a-b)

The Desmoplastic variant was characterized nodular pattern and reticulin free zones (pale islands) which were surrounded by densely packed cells with dense intercellular reticulin(Figure 18). Those cases with only dense collagenous and reticulin fibres without any nodular pattern were not classified as Desmoplastic or nodular variant(Figure18).

The MBEN variant was characterized by expanded lobular architecture with enlarged reticulin free zones rich in neuropil like tissue.The tumour cells had uniform nuclei and clear cytoplasm resembling neurocytes.(Figure 19)

The Large Cell variant was characterized by monomorphous population of cells with large, round, vesicular nuclei, prominent nucleoli and variable amount of cytoplasm with abundant mitotic and apoptotic figures.(Figure 20)

The Anaplastic variant was characterized by the presence of increased nuclear pleomorphism, nuclear moulding, cell-cell wrapping and high mitotic activity. Apoptosis was prominent in this variant. Presence of the above mentioned features in focal areas was not considered sufficient to diagnose an anaplastic variant.(Figure 21).

Site:

It was found that 8(22.2%) cases of medulloblastoma arose in the cerebellar hemisphere and 28(77.8%) in the midline(p<0.001,statistically significant) (Figure 8)

Figure 8: Distribution of medulloblastoma by site

β-catenin immunoexpression:

β-catenin showed cytoplasmic positivity in 8 cases(Figure 25(b)) and both nuclear and cytoplasmic positivity in 10 cases.(Figure 25(a)) Nuclear positivity in the absence of cytoplasmic staining was seen in 2 cases and in 16 cases there was no immunostaining. (Figure 25(c)). Thus 55.8% (20) cases were immunopositive and 44.2% (16) cases were immunonegative for β-catenin.

Figure 9: β-catenin immunoexpression

Table no-2

Demographic profile and β-catenin immunoexpression:

β-catenin immunoexpression was seen in 78% children versus 22% of adults, this difference was statistically significant. (p <0.001) (Figure 10)

Figure 10: β-catenin immunoexpression among children and adults.

β-catenin immunoexpression and histological subtypes:

Figure 11: Prevalence of β-catenin positivity in the histological subtypes.

Among the five histological patterns β-catenin immunoexpression was seen in the majority of cases with Classic histology( 88%) followed by Large 8% and Anaplastic variants 4%.{p<0.001,statistically significant(classic vs others)}

Table no-3

GAB-1 immunohistochemistry:

GAB-1 immunoexpression was seen in 27.7% (10) of SHH cases(p<0.002,statistically significant) (Figure 12)

Figure 12: Distribution of Molecular Subtype SHH/NON SHH TYPE

GAB-1 immunoexpression was seen in 33 % children versus 67% of adults, this difference was not statistically significant(p=0.08). (Figure 13)

Figure 13: GAB-1 immunoexpression among children and adults.

GAB-1 immunoexpression and histological subtype

Nearly three fourth of the cases were of the Desmoplastic variant (6cases),  3cases of classic variants and 1 case of large cell variant show  GAB-1immunopositivity

Figure 14: Prevalence of GAB-1 immunoexpression in the histological subtypes

Table no-4

Photographs of CT Scan & MRI Scan, Pictomicrograph of H&E stain, pictomicrograph of  immunostain and photograph of immunomarkers are given below:

Figure 15: CT Scan of medulloblastoma in right cerebellar hemisphere both noncontrast(A) and contrast(B)

Figure 16: Coronal T1 weighted MRI(contrast) revealing an enhanced posterior midline cerebellar mass

Figure 17(a):  Classic medulloblastoma with medium sized hyperchromatic nuclei and scanty cytoplasm(H&E,x100)

Figure 17(b):   classic medulloblastoma showing Homer Wright rosette  (H&E, x100)

Figure 18 : Desmoplastic/Nodular medulloblastoma highlighting pale nodule (H&E,x100)

Figure 19: Medulloblastoma with extensive nodularity(MBEN) (H&E,x40)

Figure 20: Large cell medulloblastoma with vesicular nuclei and prominent nucleoli(H&E,x100)

Figure 21: Anaplastic medulloblastoma showing nuclear pleomorphism and brisk mitotic activity(H&E,x100)

Figure 22: Medulloblastoma with extensive nodularity(H&E,x40)  : Gab-1 showing cytoplasmic positivity in Invasive ductal carcinoma,Breast as positive control(H&E,x100)

Figure 23: Medulloblastoma with extensive nodularity(H&E,x40) : β-Catenin showing cytoplasmic positivity in colon adeno carcinoma as positive control(H&E,x100)

Figure 24(a): Gab-1 cytoplasmic membrane immunopositivity(x100)

Figure 24(b): Gab-1 immunonegativity in classic medulloblastoma(x100)

Figure 25(a): β-Catenin both nuclear and cytoplasmic membrane immunopositivity(x100)

Figure 25(b): β-Catenin cytoplasmic membrane immunopositivity(x40)

There was a total of 38 cases of medulloblastoma from November 2018 to October 2020. Of these 36 cases were included in the study based on the defined inclusion and exclusion criteria that are outlined in the materials and method section. The study population included 8 adults (22%) and 28 children (78%) (p<0.001, stastistically significant) (Figure 1).

Figure 1: Age distribution among children and adults of medulloblastoma

The M:F ratio was approximately 2:1 with 70% (25 cases) males and 30% (11 cases) females(p<0.008,statistically significant)

Figure 2 : Gender distribution in medulloblastomas

 In children there was clear male preponderance with nearly two third of the cases being males 17/25

Figure 3: Gender distribution among children

Figure 4: Gender distribution among adults.

In adults there was near equal gender distribution. Male 6 cases anf female 5 cases.

Histological subtypes:

We found all five histological subtypes of medulloblastoma in the study population. The predominant subtype corresponded to the Classic variant at 58.3% (21cases).Desmoplastic medulloblastomas formed the next major group with 22.2% (8 cases),followed by the Large Cell variant at 11.1% (4 cases). There were 5.8%(2 cases) and2.6%(1 case)of the Anaplastic and Medulloblastoma  with extensive nodularity (MBEN) subtypes respectively. (Figure 5)

Figure 5: Distribution of cases by histological subtype in the study population.

Table no-1

In adults although Classic variant was the predominant subtype, the Desmoplastic variant came a close second constituting 50% and 33% of cases respectively (Figure 6).On the other hand in children, the Classic variant constituted nearly two thirds of the cases (62%) as opposed to only 20 % being Desmoplastic. (Figure 7).

Figure 6: Distribution of cases by histological subtype in adults

Figure 7: Distribution of cases by histological subtype in children.

Histological Features:

The Classic subtype was characterized by closely packed round to oval cells with hyperchromatic(carrot shaped) nuclei surrounded by scant cytoplasm and high mitotic activity.(Figures 17(a-b)

The Desmoplastic variant was characterized nodular pattern and reticulin free zones (pale islands) which were surrounded by densely packed cells with dense intercellular reticulin(Figure 18). Those cases with only dense collagenous and reticulin fibres without any nodular pattern were not classified as Desmoplastic or nodular variant(Figure18).

The MBEN variant was characterized by expanded lobular architecture with enlarged reticulin free zones rich in neuropil like tissue.The tumour cells had uniform nuclei and clear cytoplasm resembling neurocytes.(Figure 19)

The Large Cell variant was characterized by monomorphous population of cells with large, round, vesicular nuclei, prominent nucleoli and variable amount of cytoplasm with abundant mitotic and apoptotic figures.(Figure 20)

The Anaplastic variant was characterized by the presence of increased nuclear pleomorphism, nuclear moulding, cell-cell wrapping and high mitotic activity. Apoptosis was prominent in this variant. Presence of the above mentioned features in focal areas was not considered sufficient to diagnose an anaplastic variant.(Figure 21).

Site:

It was found that 8(22.2%) cases of medulloblastoma arose in the cerebellar hemisphere and 28(77.8%) in the midline(p<0.001,statistically significant) (Figure 8)

Figure 8: Distribution of medulloblastoma by site

β-catenin immunoexpression:

β-catenin showed cytoplasmic positivity in 8 cases(Figure 25(b)) and both nuclear and cytoplasmic positivity in 10 cases.(Figure 25(a)) Nuclear positivity in the absence of cytoplasmic staining was seen in 2 cases and in 16 cases there was no immunostaining. (Figure 25(c)). Thus 55.8% (20) cases were immunopositive and 44.2% (16) cases were immunonegative for β-catenin.

Figure 9: β-catenin immunoexpression

Table no-2

Demographic profile and β-catenin immunoexpression:

β-catenin immunoexpression was seen in 78% children versus 22% of adults, this difference was statistically significant. (p <0.001) (Figure 10)

Figure 10: β-catenin immunoexpression among children and adults.

β-catenin immunoexpression and histological subtypes:

Figure 11: Prevalence of β-catenin positivity in the histological subtypes.

Among the five histological patterns β-catenin immunoexpression was seen in the majority of cases with Classic histology( 88%) followed by Large 8% and Anaplastic variants 4%.{p<0.001,statistically significant(classic vs others)}

Table no-3

GAB-1 immunohistochemistry:

GAB-1 immunoexpression was seen in 27.7% (10) of SHH cases(p<0.002,statistically significant) (Figure 12)

Figure 12: Distribution of Molecular Subtype SHH/NON SHH TYPE

GAB-1 immunoexpression was seen in 33 % children versus 67% of adults, this difference was not statistically significant(p=0.08). (Figure 13)

Figure 13: GAB-1 immunoexpression among children and adults.

GAB-1 immunoexpression and histological subtype

Nearly three fourth of the cases were of the Desmoplastic variant (6cases),  3cases of classic variants and 1 case of large cell variant show  GAB-1immunopositivity

Figure 14: Prevalence of GAB-1 immunoexpression in the histological subtypes

Table no-4

Photographs of CT Scan & MRI Scan, Pictomicrograph of H&E stain, pictomicrograph of  immunostain and photograph of immunomarkers are given below:

Figure 15: CT Scan of medulloblastoma in right cerebellar hemisphere both noncontrast(A) and contrast(B)

Figure 16: Coronal T1 weighted MRI(contrast) revealing an enhanced posterior midline cerebellar mass

Figure 17(a):  Classic medulloblastoma with medium sized hyperchromatic nuclei and scanty cytoplasm(H&E,x100)

Figure 17(b):   classic medulloblastoma showing Homer Wright rosette  (H&E, x100)

Figure 18 : Desmoplastic/Nodular medulloblastoma highlighting pale nodule (H&E,x100)

Figure 19: Medulloblastoma with extensive nodularity(MBEN) (H&E,x40)

Figure 20: Large cell medulloblastoma with vesicular nuclei and prominent nucleoli(H&E,x100)

Figure 21: Anaplastic medulloblastoma showing nuclear pleomorphism and brisk mitotic activity(H&E,x100)

Figure 22: Medulloblastoma with extensive nodularity(H&E,x40)  : Gab-1 showing cytoplasmic positivity in Invasive ductal carcinoma,Breast as positive control(H&E,x100)

Figure 23: Medulloblastoma with extensive nodularity(H&E,x40) : β-Catenin showing cytoplasmic positivity in colon adeno carcinoma as positive control(H&E,x100)

Figure 24(a): Gab-1 cytoplasmic membrane immunopositivity(x100)

Figure 24(b): Gab-1 immunonegativity in classic medulloblastoma(x100)

Figure 25(a): β-Catenin both nuclear and cytoplasmic membrane immunopositivity(x100)

Figure 25(b): β-Catenin cytoplasmic membrane immunopositivity(x40)

Figure 25(c): β-Catenin immunonegativity in classic medulloblastoma(x40)

Figure 26: Gab-1 Immunomarker (Merck Millipore)

Figure 27: β-Catenin Immunomarker (Ready to use by   Dako)

Figure 25(c): β-Catenin immunonegativity in classic medulloblastoma(x40)

Figure 26: Gab-1 Immunomarker (Merck Millipore)

Figure 27: β-Catenin Immunomarker (Ready to use by   Dako)

Medulloblastomas are high grade embryonal tumours of the central nervous system accounting for nearly 20% of childhood brain tumors and less than 1% of adult CNS tumors.[1] Although high grade, current management strategies have resulted in better long-term survival. The 2007 WHO classification defines five histological subtypes of medulloblastoma, namely the Classic, Desmoplastic/nodular, Medulloblastoma with extensive nodularity, Anaplastic and Large Cell variants.[2-3] The developing cerebellum undergoes differentiation aided by signaling pathways such as SHH, Notch and WNTpathways.[4] A key mechanism involved, in tumorigenesis is believed to be dysregulation of some of these signaling pathways.[5] The wingless (WNT) and sonic hedgehog (SHH) signaling pathways are prime amongst those incriminated and several studies have identified the involvement of these two pathways in different subsets of medulloblastomas reliably and consistently.

The study was carried out with the aim of prognostic implication and targeted therapy of medulloblastomas by categorize them as per WHO 2016 classification using immune histochemical markers of GAB-1 and β-catenin in adult and paediatrics medulloblastomas.

Medulloblastomas are 10 times more common in children when compared to adults.[6] In the study more than three fourths of the medulloblastomas were seen in children. The majority of the paediatric medulloblastomas in this study were seen between the ages of 5 and 16 years. The reported incidence of adult medulloblastoma is upto 30%. In the study 22% of medulloblastomas were seen in adults.[7] In the study, a male preponderance was noted with twice as many males as females in the overall cohort. Amongst children, nearly two third of medulloblastomas were seen in males which is in keeping with the published literature.[8] In contrast there was an almost equal gender distribution in adults.

Medulloblastomas occur at two sites, the cerebellar hemispheres and in the midline from the cerebellar vermis projecting into the fourth ventricle and impinging on brain stem.

Most medulloblastomas arise in the midline.  In the study over three fourths of the cases were seen in the midline (77.8%)

Histological subtypes:

All the five histological subtypes as defined by the WHO2016 were noted in this study.Among the five histological subtypes the Classic variant was found to be the predominant subtype constituting about 58.3%(21 cases) followed by the Desmoplastic variant 22.2% (8 cases) and the Large Cell variant at 11.1% (04 cases), Anaplastic 5.8%(02 cases),MBEN 2.6%(01 case). The prevalence of the different subtypes is similar to that reported by others.[9]

In adults, nearly a third of the cases were of the Desmoplastic variant in contrast to children, where the Desmoplastic variant constituted only 1/5th of the cases.  There were 33% Desmoplastic medulloblastoma among adult in the study.

Homer Wright rosettes are described as a feature of medulloblastoma. Although not universally seen, at least 40% of medulloblastomas are reported to contain Homer Wright rosettes, particularly in the Classic variant.  In the study Homer Wright rosettes were seen in 33.7% (07 cases).

Wingless Pathway Tumors

The WNT/ β-catenin signaling pathway plays a role in regulating embryogenesis of the brain. WNT/ β-catenin signaling pathway activation when unregulated leads to upregulation of transcription and imbalance in cell proliferation resulting in tumor formation.[10]

Nuclear expression of β-catenin with activation of WNT signaling pathways are seen in 10% of the sporadic medulloblastomas. [11] In the study, 55.8% of cases showed immunopositivity β-catenin . This is much higher than that reported by several who found positivity for β-catenin in 5-15% of medulloblastomas. [11-12]

In the study, among the five histological patterns, β-catenin immunoexpression was seen in a majority of the cases with Classic histology 88% (17 out of 21 cases).

None of the Desmoplastic variant or medulloblastoma with extensive nodularity were β-catenin positive. Subsets of both Classic and Large Cell variants have been found to have activation of the WNT signaling pathway.[11] In the study 2 of 4 Large Cell variants and 1 of 2 and Anaplastic variants showed nuclear positivity for β-catenin.

Sonic Hedgehog Pathway Tumors:

In the study, GAB-1 immunoexpression was seen in 27.7% (10) of cases. The Shh sub group of tumors are seen in about 30% of medulloblastomas overall. [11] The Shh subgroup has a bimodal distribution, seen more commonly in children younger than 3 years and in patients older than 16 years. They have an equal gender distribution. [11] In the study, 33% of GAB-1 positive cases were seen in children, however there was no increase in any particular age group of children. There was a slight male preponderance.

Nearly three fourths of the cases with GAB-1 expression were of the desmoplastic variant. This data is keeping with previous studies. Amongst the desmoplastic medulloblastomas, (6/10) cases showed GAB-1 immunopositivity compared to the study by Ellison et al  in which 54% of desmoplastic tumours were of the Shh subgroup. [13]

Non-WNT/Shh Tumors

Group 3 and Group 4 tumors are considered in the non-WNT/SHh subgroup.  Genetic driver mutations in these are yet to be established. There were 6 cases belonging to the non WNT/Shh subgroup in the study, comprising 16.6% of cases. Kaur et al reported a prevalence of 44.6% of this sub group. [14]

Group 3 medulloblastomas are common in children, have the least favorable outcomes and have an increased incidence of leptomeningeal dissemination. They account for 25% of all medulloblastomas. [15] This group is characterized by large cell/anaplastic histology, chromosome 7 gain, chromosome 8 loss and NPR-3 expression.

Molecular sub grouping has allowed for categorization of medulloblastomas in ways that have prognostic and therapeutic significance. The study represents the first step in characterization of the cohort of cases seen in institution of the study. Apart from expanding the panel of markers to completely characterize this cohort, future studies will require incorporation of more detailed genomic platforms to segregate these tumors in appropriate subtypes. Studies aimed at correlating treatment protocols and outcome with these histological and molecular subtypes are warranted to optimize treatment protocols and for prognostication. While we utilized antibodies to GAB-1 and β-catenin to identify the two major subtypes of medulloblastomas, namely Shh and WNT, a larger panel of antibodies is required to better characterize this heterogeneous group of tumors.

Validation of the study:

• Medulloblastoma more prevalent in children78%(28/36) than adult 22%(8/36),Smoll et al[16].
• Medulloblastoma were more common in male i.e 2/3rd of the female in children as compared to adult where gender distribution is near equal, Leary SES et al.[17]
• Prevalence of Desmoplastic variant of medulloblastoma more common in adult compared to children, Min et al.[18]
• GAB-1 positive SHH subgroup medulloblastomas were found in 27.7% as compared to 30% in literature,Zhukova et al.[19]
• GAB-1 were more prevalent in Desmoplastic variant of medulloblastoma as reported in the literature.

β-Catenin subgroup medulloblastomas were found in 55.8%,and are more prevalent in classic variant.

Medulloblastomas are primarily tumors of childhood and highly   aggressive.The recent 2016 integreted diagnosis classified medulloblastoma into molecular type i.e WNT/SHH/Group3/Group4 type. The recent advance in management protocol has improved the duration of survival and quality of life. WNT subgroup consistently associated with better prognosis but SHH subgroup shows heterogenous outcome and management of SHH type is challenging.GAB-1 antibody is useful molecular marker for the diagnosis of SHH subgroup medulloblastoma.β-Catenin antibody is useful molecular marker for the diagnosis of WNT subgroup medulloblastoma. We demonstrated here how combination of genomic and genetic analysis of brain tumors can predict differential response to therapies and provide insight into ways that favourable signalling pathways may be mimicked by pharmacological intervention.

1. Bien-Willner GA, López-Terrada D, Bhattacharjee MB, Patel KU, Stankiewicz P, Lupski JR, et al. Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement. Neuro-Oncol. 2012 Jul;14(7):831–40.
2. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl). 2007 Aug;114(2):97–109
3. David w Ellison,james Dalton,mehmet kocak,department of pathology ms#250,st jude children'sresearch hospital,262,TN 38105,USA,PMC3519926. ACTA
4. Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC-H, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011 Jan 28;331(6016):435–9.
5. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010 Dec 23;468(7327):1095–9.
6. Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci Off J Neurosurg Soc Australas. 2012 Nov;19(11):1541–4.
7. Millard NE, Braganca KCD. Medulloblastoma. J Child Neurol. 2015 Sep 2;0883073815600866.
8. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012 Aug 2;488(7409):43–8
9. Massimino M, Antonelli M, Gandola L, Miceli R, Pollo B, Biassoni V, et al. Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer. 2013 Feb;60(2):210–6.
10. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010 Dec 23;468(7327):1095–9.
11. Millard NE, Braganca KCD. Medulloblastoma. J Child Neurol. 2015 Sep 2;0883073815600866.
12. Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer. 2002 Jan 15;94(2):552–60.
13. Ellison D. Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol. 2002 Aug;28(4):257–84
14. Kaur K, Kakkar A, Kumar A, Mallick S, Julka PK, Gupta D, et al. Integrating Molecular Subclassification of Medulloblastomas into Routine Clinical Practice: ASimplified Approach. Brain Pathol Zurich Switz. 2015 Jul 29;
15. Gupta T, Shirsat N, Jalali R. Molecular Subgrouping of Medulloblastoma: ImpactUpon Research and Clinical Practice. Curr Pediatr Rev. 2015;11(2):106–19.
16. Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci Off J Neurosurg Soc Australas. 2012 Nov;19(11):1541–4.
17. Leary SES, Olson JM. The molecular classification of medulloblastoma: driving the next generation clinical trials. Curr Opin Pediatr. 2012 Feb;24(1):33–9.90
18. Min HS, Lee JY, Kim S-K, Park S-H. Genetic grouping of medulloblastomas by representative markers in pathologic diagnosis. Transl Oncol. 2013 Jun;6(3):265–72.
19. Nataliya Zhukova, Vijay Ramaswamy,Marc Remke, Dianna C Martin,university of Toronto,Dept of Pediatrics,Division of Hematology/Oncology,The Hospital for sick children,24 dec 2014 Acta Neuropathologica Communications(2014)2:174