Signalment:  

6 month old, male, Ptc +/- Background strain: C56BL/6;129SJThe mouse was hunched, lethargic and had a rough hair coat.

Gross Description:  

A soft tissue mass was present in the cranial vault. The mass was attached to the cerebellum and compressed the adjacent brain parenchyma.

Morphologic Diagnosis:  

Brain: Medulloblastoma

Condition:  

Medulloblastoma

Contributor Comment:  

A densely cellular mass is present in the cranium. The mass arises from the cerebellum and compresses the entire brain. The cells are arranged in densely packed sheets with occasionally rosette formation. Neoplastic cells have elongated carrot shaped nuclei with dense chromatin and moderate pale eosinophilic cytoplasm with indistinct cell borders. Anisokaryosis and anisocytosis are minimal. Mitotic figures are rare. 

Patched (Ptc) controls growth and pattern formation in early neural development and adult cerebellum. Ptc gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein. Shh binds to Ptc, activates smoothened which leads to over expression of Gli-1 and some Wnt and TGF-+�-� gene families. Without Hh signaling, Ptc represses transcription of these target genes and itself. ^2,3,4 Absence of Ptc causes derepression of target genes. Hedgehog (Hh) protein induces a high level of Ptc transcription through inhibition of Ptc function. While many aspects of signaling remain obscure it is clear that balance between Hh protein and Ptc is critical for normal development. Ptc expression is reduced by up to 50% in Ptc heterozygous mice. This causes ectopic expression of Shh target genes and uncontrolled cell proliferation. In Ptc heterozyogous mice, medulloblastomas have been reported as early as 5 weeks in 8.3% of mice.³ Tumor incidence increases with age in Ptc heterozygous mice with an incidence of about 30% at six months of age. Ptc mutation has been associated with basal cell carcinoma, fibroma, medulloblastoma and rhabdomyosarcoma in man.⁴

Medulloblastomas arise from primitive neuroectodermal cells. Some cells may express neurofilament protein or synaptophysisn. However, the majority of the cells will be undifferentiated. During fetal development, cerebellar granular cells develop in the external granular layer then migrate past Purkinje cells to form the granule cell layer. Remnants of the fetal external granular layer in the form of proliferative rests are thought to be the source of medulloblastoma cells.⁵ Medulloblastomas occur with some frequency in young cattle and dogs and sporadically in pigs and cats.⁷

JPC Diagnosis:  

Cerebellum: Medulloblastoma

Conference Comment:  

The contributor gives an excellent explanation of the functions of Ptc in cell growth regulation. Activation of the hedgehog pathway is shown to influence the growth of several neoplasms including medulloblastomas. Hedgehog effectors Gli1 and BclII are increased in areas of decreased apoptosis within medulloblastomas.¹

Medulloblastomas are a subset of the primitive neuroectodermal tumors (PNETs). Medulloblastomas are derived from a germinal neuroepithelial cell and presumably arise from the matrix cells of the external granular layer.⁶ Typical light microscopic findings can include palisading of neoplastic cells and rosette formation, polygonal to elongate (carrot shaped) nuclei, and frequent mitoses. Immunohistochemical reactivity for various neural markers can vary according to the degree of differentiation.

In this case, there is extension into the inner ear in some sections.

References:

1. Bar EE, Chaudhry A, Farah MH, Eberhart CG: Hedgehog signaling promotes medulloblastoma survival via BclII. Am J Pathol 170:347-355, 2007
2. Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Ruiz i Altaba A: The sonic hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128:5201-5212, 2001
3. Goodrich LV, Milenkovi_ L, Higgins KM, Scott MP: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109-1113, 1997
4. Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, M+�-+ller U, Samson, E, Quintanilla-Martinez L, Zimmer A: Patched target Igf2 is Indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275:28341-28344, 2000
5. Kim JYH, Nelson AL, Algon SA, Graves O, Sturla LM, Goumnerova LC, Rowitch DH, Segal RA, Pomeroy SL: Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Developmental Biology 263:50-66, 2003
6. Koestner A, Higgins RJ: Tumors of the nervous system. In: Tumors in Domestic Animals, ed. Meuten DJ, 4th ed., p. 715. Blackwell Publishing, Ames, IA, 2002
7. Summers BA, Cummings JF, de Lahunta A: Tumors of the central nervous system. In: Veterinary Neuropathology, 1st ed., pp. 378-379. Mosby-Year Book Inc, St. Louis, MO, 1995
8. Wetmore C, Eberhart DE, Curran T: Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513-516, 2001

A virtual slide is not available for this case.

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