Medulloblastoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[3]

Overview

Medulloblastoma arises from the cerebellar stem cells, which are normally involved in the anatomical development of the cerebellum and posterior cranial fossa structures. Medulloblastoma is an invasive and rapidly growing brain tumor which may metastasize to different organs of the body. Genes involved in the pathogenesis of medulloblastoma include CTNNB1 gene, PTCH1 gene, MLL2 gene, SMARCA4 gene, DDX3X gene, CTDNEP1 gene, KDM6A gene, and TBR1 gene. Medullobastomas are associated with a number of syndromes that include Gorlin syndrome and Turcot syndrome.^[1] On gross pathology, a pink, solid, and well circumscribed mass is a characteristic finding of medulloblastoma. On microscopic histopathological analysis, round tumor cells, elevated mitotic rate, increased nucleus:cytoplasmic ratio, and Homer-Wright rosettes are characteristic findings of medulloblastoma.^[2]

Pathogenesis

Medulloblastoma arises from the cerebellar stem cells, which are normally involved in the anatomical development of the cerebellum and posterior cranial fossa structures.^[1]^[3]
Medulloblastoma is usually located at the infratentorial region, where it forms a mass between the brain stem and the cerebellum in the vicinity of the fourth ventricle.
Medulloblastoma is an invasive and rapidly growing brain tumor.
Unlike most brain tumors, medulloblastoma may spread through the cerebrospinal fluid and metastasize to different organs of the body.

Genetics

Development of medulloblastoma is the result of multiple genetic mutations.^[1]^[4]^[5]^[6]
Genes involved in the pathogenesis of medulloblastoma include:

CTNNB1 gene on chromosome 3
PTCH1 gene located on chromosome 9
MLL2 gene located on chromosome 12
SMARCA4 gene located on chromosome 19
DDX3X gene located on X chromosome
CTDNEP1 gene located on chromosome 17
KDM6A gene located on X chromosome
TBR1 gene located on chromosome 2

Medulloblastoma may be classified into at least four major subtypes based on a molecular classification system which includes:^[7]^[8]^[9]

WNT subgroup:

Present among 10% of medulloblastoma patients
Cytogenetic markers include classic monosomy 6
Molecular markers include beta-catenin

SHH subgroup:

Present among 25% of medulloblastoma patients
Cytogenetic markers include chromosome 9q deletion
Molecular markers include SFRP1 or GAB1

Group 3:

Present among 30% of medulloblastoma patients
Cytogenetic markers include isochromosome 17q
Molecular markers include MYC activation

Group 4:

Present among 35% of medulloblastoma patients
Cytogenetic markers include isochromosome 17q
Molecular markers are still under investigation

Characteristics of Molecular Subtypes of Medulloblastoma

Comparison of the various subgroups of medulloblastoma including their affiliations with previously published papers on medulloblastoma molecular subgrouping.^[10]

Associated Conditions

Medulloblastoma is associated with a number of syndromes that include:^[1]^[11]

Gross Pathology

On gross pathology, a pink, solid, and well circumscribed mass is a characteristic finding of medulloblastoma.^[1]
The following image demonstrates the gross pathology observed in medulloblastoma:

Medulloblastoma observed as a pink and well circumscribed mass^[11]

Microscopic Pathology

On microscopic histopathological analysis, round tumor cells, elevated mitotic rate, increased nucleus:cytoplasm ratio, and Homer-Wright rosettes are characteristic findings of medulloblastoma.^[2]^[13]
Medulloblastoma may be classified into two subtypes based on WHO histological classification system which include classic medulloblastoma and variant medulloblastoma.
Variant medulloblastoma may be further classified into desmoplastic medulloblastoma, large cell medulloblastoma, anaplastic medulloblastoma, and medulloblastoma with extensive nodularity.^[2]^[11]
The table below differentiates between the five main groups of medulloblastoma according to the WHO histological classification system:^[14]


Grade	Histologic features

Classic medulloblastoma	Dense sheet like growth of cells Hyperchromatic round-to-oval nucleus Increased mitotic activity Conspicuous apoptosis Homer-Wright rosettes Necrosis is less common
Desmoplastic medulloblastoma variant	Brain tissue invasion 4 or more mitosis/10 HPF Necrosis Increased cell count High nucleus:cytoplasm ratio Increased nucleoli size Presence of sheeting
Medulloblastoma with extensive nodularity variant	Cellular uniformity Fine fibrillary matrix Occasional presence of mature ganglion cells
Large cell / anaplastic medulloblastoma variant	Demonstrate high mitotic activity Pleomorphism Large round nucleus with variable eosinophilic cytoplasm Hemorrhage Necrosis is common

Shown below is a series of microscopic images observed in medulloblastoma:

Medulloblastoma ^[2]
Medulloblastoma^[2]
Medulloblastoma demonstrating Homer-Wright rosettes^[2]
Medulloblastoma demonstrating cerebellar infiltrative growth^[2]
Medulloblastoma demonstrating demsomplastic nodular growth^[2]
Anaplastic large cell medulloblastoma^[2]
Medulloblastoma^[2]
Desmoplastic medulloblastoma on reticulin stain demonstrating pale islands structure^[2]
Desmoplastic medulloblastoma on MIB-1 immunostaining^[2]
Medulloblastoma demonstrating areas of geographic necrosis^[2]
Medulloblastoma demonstrating epitheloid ribboning and nuclear moulding of tumor cells^[2]
Medulloblastoma demonstrating partial MAP2 immunoreactivity^[2]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 Medulloblastoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Medulloblastoma Accessed on September, 28 2015
↑ ^2.00 ^2.01 ^2.02 ^2.03 ^2.04 ^2.05 ^2.06 ^2.07 ^2.08 ^2.09 ^2.10 ^2.11 ^2.12 ^2.13 ^2.14 Medulloblastoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Medulloblastoma Accessed on September, 28 2015
↑ Evans G, Burnell L, Campbell R, Gattamaneni HR, Birch J (1993). "Congenital anomalies and genetic syndromes in 173 cases of medulloblastoma". Med. Pediatr. Oncol. 21 (6): 433–4. PMID 8515724.
↑ Kozmik Z, Sure U, Rüedi D, Busslinger M, Aguzzi A (June 1995). "Deregulated expression of PAX5 in medulloblastoma". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5709–13. doi:10.1073/pnas.92.12.5709. PMC 41766. PMID 7777574.
↑ Yokota N, Aruga J, Takai S, Yamada K, Hamazaki M, Iwase T, Sugimura H, Mikoshiba K (January 1996). "Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma". Cancer Res. 56 (2): 377–83. PMID 8542595.
↑ Katsetos CD, Liu HM, Zacks SI (October 1988). "Immunohistochemical and ultrastructural observations on Homer Wright (neuroblastic) rosettes and the "pale islands" of human cerebellar medulloblastomas". Hum. Pathol. 19 (10): 1219–27. PMID 3139544.
↑ Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T; et al. (2012). "Subgroup-specific structural variation across 1,000 medulloblastoma genomes". Nature. 488 (7409): 49–56. doi:10.1038/nature11327. PMC 3683624. PMID 22832581.
↑ Leary SE, Olson JM (2012) The molecular classification of medulloblastoma: driving the next generation clinical trials. Curr Opin Pediatr 24 (1):33-9. DOI:10.1097/MOP.0b013e32834ec106 PMID: 22189395
↑ Sure U, Berghorn WJ, Bertalanffy H, Wakabayashi T, Yoshida J, Sugita K, Seeger W (1995). "Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute". Acta Neurochir (Wien). 132 (1–3): 59–65. PMID 7754860.
↑ Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC; et al. (2012). "Molecular subgroups of medulloblastoma: the current consensus". Acta Neuropathol. 123 (4): 465–72. doi:10.1007/s00401-011-0922-z. PMC 3306779. PMID 22134537.
↑ ^11.0 ^11.1 ^11.2 Medulloblastoma. Radiopaedia(2015) http://radiopaedia.org/articles/medulloblastoma Accessed on September, 28 2015
↑ Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (November 1991). "The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma". Br. J. Cancer. 64 (5): 959–61. PMC 1977448. PMID 1931625.
↑ McLendon RE, Friedman HS, Fuchs HE, Kun LE, Bigner SH (February 1999). "Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study". Histopathology. 34 (2): 154–62. PMID 10064395.
↑ Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A; et al. (2007). "The 2007 WHO classification of tumours of the central nervous system". Acta Neuropathol. 114 (2): 97–109. doi:10.1007/s00401-007-0243-4. PMC 1929165. PMID 17618441.

Template:WikiDoc Sources

[wiki-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Medulloblastoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Medulloblastoma Accessed on September, 28 2015

[patho-2] 2.00 ^2.01 ^2.02 ^2.03 ^2.04 ^2.05 ^2.06 ^2.07 ^2.08 ^2.09 ^2.10 ^2.11 ^2.12 ^2.13 ^2.14 Medulloblastoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Medulloblastoma Accessed on September, 28 2015

[pmid8515724-3] Evans G, Burnell L, Campbell R, Gattamaneni HR, Birch J (1993). "Congenital anomalies and genetic syndromes in 173 cases of medulloblastoma". Med. Pediatr. Oncol. 21 (6): 433–4. PMID 8515724.

[pmid7777574-4] Kozmik Z, Sure U, Rüedi D, Busslinger M, Aguzzi A (June 1995). "Deregulated expression of PAX5 in medulloblastoma". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5709–13. doi:10.1073/pnas.92.12.5709. PMC 41766. PMID 7777574.

[pmid8542595-5] Yokota N, Aruga J, Takai S, Yamada K, Hamazaki M, Iwase T, Sugimura H, Mikoshiba K (January 1996). "Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma". Cancer Res. 56 (2): 377–83. PMID 8542595.

[pmid3139544-6] Katsetos CD, Liu HM, Zacks SI (October 1988). "Immunohistochemical and ultrastructural observations on Homer Wright (neuroblastic) rosettes and the "pale islands" of human cerebellar medulloblastomas". Hum. Pathol. 19 (10): 1219–27. PMID 3139544.

[pmid22832581-7] Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T; et al. (2012). "Subgroup-specific structural variation across 1,000 medulloblastoma genomes". Nature. 488 (7409): 49–56. doi:10.1038/nature11327. PMC 3683624. PMID 22832581.

[pmid22189395-8] Leary SE, Olson JM (2012) The molecular classification of medulloblastoma: driving the next generation clinical trials. Curr Opin Pediatr 24 (1):33-9. DOI:10.1097/MOP.0b013e32834ec106 PMID: 22189395

[pmid7754860-9] Sure U, Berghorn WJ, Bertalanffy H, Wakabayashi T, Yoshida J, Sugita K, Seeger W (1995). "Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute". Acta Neurochir (Wien). 132 (1–3): 59–65. PMID 7754860.

[pmid22134537-10] Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC; et al. (2012). "Molecular subgroups of medulloblastoma: the current consensus". Acta Neuropathol. 123 (4): 465–72. doi:10.1007/s00401-011-0922-z. PMC 3306779. PMID 22134537.

[radio-11] 11.0 ^11.1 ^11.2 Medulloblastoma. Radiopaedia(2015) http://radiopaedia.org/articles/medulloblastoma Accessed on September, 28 2015

[pmid1931625-12] Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (November 1991). "The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma". Br. J. Cancer. 64 (5): 959–61. PMC 1977448. PMID 1931625.

[pmid10064395-13] McLendon RE, Friedman HS, Fuchs HE, Kun LE, Bigner SH (February 1999). "Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study". Histopathology. 34 (2): 154–62. PMID 10064395.

[pmid17618441-14] Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A; et al. (2007). "The 2007 WHO classification of tumours of the central nervous system". Acta Neuropathol. 114 (2): 97–109. doi:10.1007/s00401-007-0243-4. PMC 1929165. PMID 17618441.

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