Medulloblastoma

Medulloblastoma is a malignant small round cell tumour that is found in the cerebellum.

Morphologically identical supratentorial tumours are called primitive neuroectodermal tumour (PNET).

General

Mostly paediatric population (mean age: 9 years).
May be seen as a component of nevoid basal cell carcinoma syndrome (NBCCS) AKA Gorlin syndrome, Li-Fraumeni syndrome, Turcot syndrome, Rubinstain-Taybi syndrome and Nijmegen breakage syndrome.
- Show molecularly spatially homogeneous transcriptomes, allowing for accurate subgrouping of tumors from a single biopsy.^[1]
Commonly spread via cerebrospinal fluid (CSF).^[2]
- May be detected in CSF cytopathology specimens.
All subgroups correspond to WHO grade IV.

Gross

Location: cerebellum - key feature or dorsal brainstem (lower rhombic lip).
- Morphologically identical supratentorial tumours are called primitive neuroectodermal tumour (PNET).
- Supratentorial and spinal metastases from initial tumor possible.

Microscopic

Features:^[3]

Small round cell tumour.
Homer-Wright rosettes:
- Rosette with a meshwork of fibers (neuropil) at the centre.^[4]

IHC

MAP2 usu. +ve
Synaptophysin +ve (weak to strong)
NSE +ve/-ve
NF +ve/-ve
Chromogranin +ve/-ve
GFAP +ve/-ve (mostly along blood vessels)
Vimentin +ve
Nestin +ve
INI1 retained (no loss)

DDx:

Small round cell tumours.
- AT/RT (INI1 loss)
- CNS-PNET
- ETMR (LIN28)-positive
- Ewing Sarcoma family members
- Small cell glioblastoma

Images

Medulloblastoma. (WC/KGH)
Medulloblastoma. (WC/KGH)
Homer-Wright rosettes in a medulloblastoma. (WC/jensflorian)
Cerebellar infiltrative growth. (WC/jensflorian)
Demsomplastic nodular medullloblastoma. (WC/jensflorian)
Anaplastic large cell medulloblastoma. (WC/jensflorian)
Medulloblastoma cells smear. (AFIP)
Medulloblastoma in the cerebellum. (AFIP)
Reticulin stain highlighting "pale islands" in a desmoplastic medulloblastoma (WC/jensflorian)
MIB-1 immunostaining in desmoplastic medulloblastoma (WC/jensflorian)

Case:

Classic Medulloblastoma of the SHH type. (WC/jensflorian)
Epitheloid ribboning and nuclear moulding of tumor cells. (WC/jensflorian)
Areas of geographic necrosis. (WC/jensflorian)
Partial MAP2 immunoreactivity. (WC/jensflorian)

www:

Subtypes

Histologically defined

Classic medulloblastoma (~85% of all medulloblastomas).
Variants of medulloblastoma (~15% of all medulloblastomas together):
1. Anaplastic / Large cell variant.
2. Desmoplastic/nodular medulloblastoma (DNMB).
3. Medulloblastoma with extensive nodularity (MBEN).

Anaplastic variant

Features:

Larger cells.
Severe anaplasia.
Polygonal cells.

Desmoplastic/nodular variant

Features:

Nodular, reticulin-free zones (pale islands).
- Mitotic activity is reduced.
Densely packed internodal, reticulin-positive tumor areas.
Absence of neuroblastic rosettes.
Neuronal markers (NeuN, Synaptophysin) can be +ve.

Genetically defined

WNT (brainstem-related, usu. CTNNB1 mutations, less common: CSNK2B, AXIN2, APC, approx. 10%).^[5]
- Caution: Some WNT-activated MB may show additional subclonal SHH-mutations.^[6]
SHH (PTCH1 & SUFU in infant, PTCH1, SMO, Gli2, MYCN in non-infant, approx 30%).^[7]
- infantile and adult cases are biologically different, esp p53 mutant tumors are associated with poor outcome.^[8]
Group 3 (approx. 20%).
Group 4 (approx. 40%).
- Group 3+4 are often designated together as Non-Wnt/Non-SHH tumours.

Prognosis

Prognosis based on histology:^[9]^[10]^[11] DNMB & MBEN > classic > anaplastic & large cell variant.
Prognosis based on genetics:^[12] WNT > SHH (without Tp53 mut) > Group 4 > Group 3 > SHH (with Tp53 mut).

References

↑ Morrissy, AS.; Cavalli, FMG.; Remke, M.; Ramaswamy, V.; Shih, DJH.; Holgado, BL.; Farooq, H.; Donovan, LK. et al. (May 2017). "Spatial heterogeneity in medulloblastoma.". Nat Genet 49 (5): 780-788. doi:10.1038/ng.3838. PMID 28394352.
↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 424 Q34. ISBN 978-1416025887.
↑ URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q93-Ans.htm. Accessed on: 26 October 2010.
↑ Wippold FJ, Perry A (March 2006). "Neuropathology for the neuroradiologist: rosettes and pseudorosettes". AJNR Am J Neuroradiol 27 (3): 488–92. PMID 16551982.
↑ Wefers, AK.; Warmuth-Metz, M.; Pöschl, J.; von Bueren, AO.; Monoranu, CM.; Seelos, K.; Peraud, A.; Tonn, JC. et al. (2014). "Subgroup-specific localization of human medulloblastoma based on pre-operative MRI.". Acta Neuropathol 127 (6): 931-3. doi:10.1007/s00401-014-1271-5. PMID 24699697.
↑ Iorgulescu, JB.; Van Ziffle, J.; Stevers, M.; Grenert, JP.; Bastian, BC.; Chavez, L.; Stichel, D.; Buchhalter, I. et al. (Apr 2018). "Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation.". Acta Neuropathol 135 (4): 635-638. doi:10.1007/s00401-018-1819-x. PMID 29435664.
↑ Neumann, JE.; Swartling, FJ.; Schüller, U. (Jul 2017). "Medulloblastoma: experimental models and reality.". Acta Neuropathol. doi:10.1007/s00401-017-1753-3. PMID 28725965.
↑ Kool, M.; Jones, DT.; Jäger, N.; Northcott, PA.; Pugh, TJ.; Hovestadt, V.; Piro, RM.; Esparza, LA. et al. (Mar 2014). "Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.". Cancer Cell 25 (3): 393-405. doi:10.1016/j.ccr.2014.02.004. PMID 24651015.
↑ Gulino A, Arcella A, Giangaspero F (November 2008). "Pathological and molecular heterogeneity of medulloblastoma". Curr Opin Oncol 20 (6): 668–75. doi:10.1097/CCO.0b013e32831369f4. PMID 18841049.
↑ Rutkowski S, von Hoff K, Emser A, et al. (November 2010). "Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis". J Clin Oncol 28 (33): 4961–4968. doi:10.1200/JCO.2010.30.2299. PMID 20940197.
↑ Rutkowski, S.; Bode, U.; Deinlein, F.; Ottensmeier, H.; Warmuth-Metz, M.; Soerensen, N.; Graf, N.; Emser, A. et al. (Mar 2005). "Treatment of early childhood medulloblastoma by postoperative chemotherapy alone.". N Engl J Med 352 (10): 978-86. doi:10.1056/NEJMoa042176. PMID 15758008.
↑ Ramaswamy, V.; Remke, M.; Bouffet, E.; Bailey, S.; Clifford, SC.; Doz, F.; Kool, M.; Dufour, C. et al. (Jun 2016). "Risk stratification of childhood medulloblastoma in the molecular era: the current consensus.". Acta Neuropathol 131 (6): 821-31. doi:10.1007/s00401-016-1569-6. PMID 27040285.

[1] Morrissy, AS.; Cavalli, FMG.; Remke, M.; Ramaswamy, V.; Shih, DJH.; Holgado, BL.; Farooq, H.; Donovan, LK. et al. (May 2017). "Spatial heterogeneity in medulloblastoma.". Nat Genet 49 (5): 780-788. doi:10.1038/ng.3838. PMID 28394352.

[2] Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 424 Q34. ISBN 978-1416025887.

[3] URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q93-Ans.htm. Accessed on: 26 October 2010.

[4] Wippold FJ, Perry A (March 2006). "Neuropathology for the neuroradiologist: rosettes and pseudorosettes". AJNR Am J Neuroradiol 27 (3): 488–92. PMID 16551982.

[5] Wefers, AK.; Warmuth-Metz, M.; Pöschl, J.; von Bueren, AO.; Monoranu, CM.; Seelos, K.; Peraud, A.; Tonn, JC. et al. (2014). "Subgroup-specific localization of human medulloblastoma based on pre-operative MRI.". Acta Neuropathol 127 (6): 931-3. doi:10.1007/s00401-014-1271-5. PMID 24699697.

[6] Iorgulescu, JB.; Van Ziffle, J.; Stevers, M.; Grenert, JP.; Bastian, BC.; Chavez, L.; Stichel, D.; Buchhalter, I. et al. (Apr 2018). "Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation.". Acta Neuropathol 135 (4): 635-638. doi:10.1007/s00401-018-1819-x. PMID 29435664.

[7] Neumann, JE.; Swartling, FJ.; Schüller, U. (Jul 2017). "Medulloblastoma: experimental models and reality.". Acta Neuropathol. doi:10.1007/s00401-017-1753-3. PMID 28725965.

[8] Kool, M.; Jones, DT.; Jäger, N.; Northcott, PA.; Pugh, TJ.; Hovestadt, V.; Piro, RM.; Esparza, LA. et al. (Mar 2014). "Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.". Cancer Cell 25 (3): 393-405. doi:10.1016/j.ccr.2014.02.004. PMID 24651015.

[pmid18841049-9] Gulino A, Arcella A, Giangaspero F (November 2008). "Pathological and molecular heterogeneity of medulloblastoma". Curr Opin Oncol 20 (6): 668–75. doi:10.1097/CCO.0b013e32831369f4. PMID 18841049.

[pmid20940197-10] Rutkowski S, von Hoff K, Emser A, et al. (November 2010). "Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis". J Clin Oncol 28 (33): 4961–4968. doi:10.1200/JCO.2010.30.2299. PMID 20940197.

[11] Rutkowski, S.; Bode, U.; Deinlein, F.; Ottensmeier, H.; Warmuth-Metz, M.; Soerensen, N.; Graf, N.; Emser, A. et al. (Mar 2005). "Treatment of early childhood medulloblastoma by postoperative chemotherapy alone.". N Engl J Med 352 (10): 978-86. doi:10.1056/NEJMoa042176. PMID 15758008.

[12] Ramaswamy, V.; Remke, M.; Bouffet, E.; Bailey, S.; Clifford, SC.; Doz, F.; Kool, M.; Dufour, C. et al. (Jun 2016). "Risk stratification of childhood medulloblastoma in the molecular era: the current consensus.". Acta Neuropathol 131 (6): 821-31. doi:10.1007/s00401-016-1569-6. PMID 27040285.

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