Medulloblastoma, sonic hedgehog (SHH) activated tumors are malignant tumors of the central nervous system. They are the second most common medulloblastoma group, divided according to TP53 mutation status into TP53-wildtype and TP53-mutant that are distinct entities differing in their molecular, epidemiological and histological characteristics.
Overall, they are found most commonly in adults and infants, but infrequently also in children. Although they can arise from the vermis of the cerebellum (especially in infants) they are most frequently located laterally within the cerebellar hemispheres.
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Epidemiology
SHH-activated TP53-wildtype medulloblastomas are twice as common as those with TP53-mutations and account for approximately 20% of all medulloblastoma. They have a M:F ratio of 1:1. They are most frequently encountered in adults (>16 years) and infants (<4 years) 1-2,4,5.
SHH-activated TP53-mutant medulloblastomas are account for only 10% of all medulloblastoma, occur primarily in children and have a predilection of males (M:F 3:1) 5.
Pathology
These tumors are characterized by upregulation of the SHH pathway, which can occur through various mechanisms, including SHH signaling, genome maintenance (TP53), chromatin modulation and transcriptional regulation 11.
Approximately 40% of individuals with SHH-activated medulloblastoma will harbor a mutation in a cancer-predisposing gene 6. This includes ELP1 gene which predisposes individuals to SHH-activated TP53 wildtype tumors and can be assessed using immunohistochemistry 6.
SHH-activated tumors are divided into two groups based on TP53 status and four subgroups on the basis of DNA-methylation or transcriptome profiling 5.
The SHH-3 subgroup is only seen in tumors with TP53 mutations, whereas all four subgroups can be encountered in tumors without TP53 mutations 5.
In parallel with molecular subgroups, SHH-activated tumors can demonstrate various histologies, with desmoplastic/nodular/medulloblastoma with extensive nodularity (MBEN) primarily seen in TP53-wildtype tumors, whereas classic, large cell/anaplastic encountered in TP53 mutant tumors 2,5.
Importantly, almost all desmoplastic/nodular/medulloblastoma with extensive nodularity (MBEN) tumors are SHH subtype 2.
Radiographic features
The radiographic features of SHH subgroup tumors are variable, to a degree depending on histological subtype.
When they are of classic or large cell/anaplastic histology and located in the midline, they are essentially indistinguishable from non-WHT/non-SHH group 3 and group 4 tumors 3.
The desmoplastic/nodular/medulloblastoma with extensive nodularity (MBEN) tumors, on the other hand, tend to occur in the lateral parts of the cerebellar hemispheres 3.
MRI
MRS: prominent choline and lipid concentrations, low creatine levels and the absence of the taurine peak10
For more details on radiographic features, please refer to the general article on medulloblastoma.
Treatment and prognosis
Surgery is the first line of therapy (as is the case in all subgroups) with the aim being histological proof, molecular subtyping and maximal tumor resection, with adjuvant therapy depending on an overall risk profile (see general article on medulloblastoma) 2.
The incidence of CNS metastatic disease in the SHH subgroup at diagnosis is relatively common in infants (17%) and children (22%) but is uncommon in adults 1.
SHH tumors have an intermediate prognosis compared to other subtypes of medulloblastoma; that is, better than group 3 tumors, but significantly worse than WNT subtypes. Prognosis is also strongly influenced by age 1,4:
77% 10-year overall survival in infants
51% 10-year overall survival in children
35% 10-year overall survival in adults
Prognosis is also influenced by histological subtype, with extensive desmoplastic and nodular subtype - dominating SHH medulloblastomas in infants - probably accounting for the improved survival 4.
Tumors with ELP1 mutations appear to have a generally more favorable prognosis 6.
History and etymology
The hedgehog gene was named in the fruit fly as mutations of this gene leading to loss of function result in the fly embryo being covered in denticles, resembling the spikes of a hedgehog. In mammals there are three hedgehog genes: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) 7.
The name Sonic was given by Bob Riddle, a post-doctoral fellow in Cliff Tabin's lab after seeing the character in his daughters comic book promoting or inspired by Sega's Sonic the Hedgehog video game released in 1991 8,9.
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