CNS & pituitary tumors
Embryonal tumors
Medulloblastoma
SHH activated
Author: John DeWitt, M.D., Ph.D.
Resident / Fellow Advisory Board: Meaghan Morris, M.D., Ph.D.
Editorial Board Member: Maria Martinez-Lage, M.D.
Last author update: 16 February 2021
Last staff update: 9 August 2023
Copyright: 2019-2023, PathologyOutlines.com, Inc.
PubMed Search: SHH activated CNS tumor review[PT]
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: DeWitt J. SHH activated. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumortumorSHHactivated.html. Accessed September 25th, 2023.
Definition / general
- An embryonal tumor of the cerebellum with molecular evidence of SHH pathway activation (2016 WHO definition)
Essential features
- WHO grade 4 tumors
- Medulloblastomas which fall into the desmoplastic / nodular or medulloblastoma with extensive nodularity histologic categories almost invariably demonstrate SHH activation
- Typically occur in children under 4 years of age, adolescents or young adults
- Those with concurrent TP53 mutation have much worse clinical outcomes and often display large cell / anaplastic histology
- SHH activation can be determined by molecular studies demonstrating mutations in this pathway, genome expression analysis, methylation classification or by immunohistochemistry demonstrating GAB1 expression
ICD coding
- ICD-10: C71.6 - malignant neoplasm of the cerebellum
Epidemiology
- TP53 wildtype tumors largely show a bimodal age distribution with cases most common in infants and young adults
- TP53 mutant cases tend to arise in children aged 4 - 17
- M:F = 1.5:1
- References: J Pediatr Hematol Oncol 2009;31:970, J Clin Neurosci 2012;19:1541, Nat Rev Cancer 2012;12:818, Cancer Cell 2014;25:393
Sites
- Cerebellum; can involve both the hemispheres or vermis with site of origin possibly age dependent, with 1 study showing hemispheric tumors are more common in older children and young adults and those centered in the vermis more often occurring in infants (Acta Neuropathol 2014;127:931)
Pathophysiology
- Cerebellar granule cell neuron precursors are thought to give rise to SHH activated medulloblastoma (Cancer Cell 2008;14:123, Cancer Cell 2008;14:135)
Etiology
- High proportion of TP53 mutant cases contain germline TP53 mutations (Li-Fraumeni syndrome) suggestive of a causal role (J Clin Oncol 2013;31:2927)
Clinical features
- SHH activated and TP53 mutant cases associated with Li-Fraumeni syndrome (Cell 2012;148:59, J Clin Oncol 2013;31:2927)
- SHH activated medulloblastoma is also associated with nevoid basal cell carcinoma syndrome (Gorlin syndrome) (J Clin Oncol 2014;32:4155)
Diagnosis
- Patients often present with signs and symptoms of increased cranial pressure (headaches, nausea, vomiting) secondary to obstruction of cerebrospinal fluid (CSF) flow from a large mass impinging on the fourth ventricle
- Signs of cerebellar ataxia are common
- Cases presenting with CSF dissemination may show more specific neurologic signs
- Imaging of the head (CT, MRI) will show a large mass in the lateral hemisphere or involving midline structures
- Diagnosis determined by biopsy or resection, with ancillary studies necessary for medulloblastoma molecular subtyping (immunohistochemistry or methylation profiling or sequencing)
- References: Nature 2010;468:1095, Pediatr Blood Cancer 2013;60:1408
Radiology description
- On CT or MRI: solid, intensely contrast enhancing masses, which are often located in the lateral cerebellar hemisphere but also can be found arising in the midline
- Grape-like pattern may be seen in cases shown to have histology with extensive nodularity (J Neurosurg 1999;91:971, AJNR Am J Neuroradiol 2002;23:1564)
- Edema may be a common imaging feature (Neuroradiology 2011;53:387)
Radiology images
Contributed by John DeWitt, M.D., Ph.D.
CT scan with contrast
Coronal T1 postcontrast
Sagittal T1 postcontrast
Axial T1 postcontrast
Prognostic factors
- TP53 mutated tumors typically have a much worse outcome
- 5 year survival of 81% in TP53 wildtype tumors versus 41% in those harboring TP53 mutation (J Clin Oncol 2013;31:2927)
- Presentation with CSF spread is poor prognostic factor
- Histologic subtype can be important in predicting prognosis with those with desmoplastic histology (desmoplastic / nodular and medulloblastoma with extensive nodularity) having a relatively good prognosis versus those with large cell / anaplastic morphology performing poorly
- Tumors with alterations in SMO or PTCH1 are sensitive to SMO inhibitors, while those with downstream alterations (SUFU, GLI2, MYCN) are refractory (Cancer Cell 2014;25:393, J Clin Oncol 2015;33:2646)
Case reports
- 15 month old girl with Fanconi anemia and a novel mutation in SHH activated medulloblastoma (Biomark Res 2015;3:13)
- 18 month old boy with a novel germline GNAS mutation in SHH activated medulloblastoma (Pediatr Blood Cancer 2020;67:e28103)
- 19 year old woman with headache and vomiting (Surg Neurol Int 2018;9:34)
Treatment
- SMO inhibitors can be used in SHH activated medulloblastomas that are susceptible (those harboring SMO or PTCH1 mutations) (Cancer Cell 2014;25:393, J Clin Oncol 2015;33:2646)
- Standard treatment includes surgery, radiation, and chemotherapy
- Whole cranial - spinal radiation required in cases with CSF dissemination or drop metastasis
Gross description
- In general, medulloblastomas present grossly as pink to gray, soft and friable masses arising in cerebellar hemisphere or vermis (with expansion and filling of the fourth ventricle)
- SHH activated medulloblastomas can be more firm and nodular due to increased desmoplastic stroma in many SHH activated tumors
- Areas of gross necrosis may be seen but tend to be less than non-SHH activated tumors
- In disseminated disease, nodules may be grossly evident throughout areas of CSF flow along the neuroaxis
Frozen section description
- On frozen section, a dominant population of undifferentiated cells with a high N/C ratio and frequent mitotic figures is often seen
- In cases with desmoplastic / nodular or extensive nodularity histology, these features may be seen at frozen section as well
Frozen section images
Contributed by John DeWitt, M.D., Ph.D.
Pleomorphic undifferentiated cells
Microscopic (histologic) description
- Medulloblastomas in general have 4 distinct histologic patterns: classical, desmoplastic / nodular, medulloblastoma with extensive nodularity and large cell / anaplastic
- SHH activated medulloblastomas can present with any of these histologic phenotypes; however, desmoplastic / nodular and extensive nodularity histologic patterns invariably fall into this molecular subtype
- Classic medulloblastoma:
- Small blue round cell tumor
- Syncytial arrangement of densely packed undifferentiated cells (embryonal cells)
- Mitosis with apoptotic bodies
- Homer Wright rosettes
- Desmoplastic / nodular medulloblastoma:
- Densely packed, undifferentiated cells with hyperchromatic and pleomorphic nuclei, which produce dense intercellular reticulin fiber network with nodular reticulin free zones
- Medulloblastoma with extensive nodularity:
- Expanded lobular architecture as reticulin free nodular zones are enlarged and rich in neuropil-like tissue
- Large cell / anaplastic medulloblastoma:
- Anaplasia with marked nuclear pleomorphism, high mitotic count and apoptotic counts
- Nuclear molding and cell wrapping
Microscopic (histologic) images
Contributed by John DeWitt, M.D., Ph.D.
Sheets of undifferentiated cells
Vague nodular formation
Vague nodular formation with reticulin
Neuron specific enolase (NSE)
Ki67
Synaptophysin
Beta catenin
INI1
Contributed by Meaghan Morris, M.D., Ph.D.
Anaplasia in medulloblastoma
Virtual slides
Images hosted on other servers
Medulloblastoma,
desmoplastic / nodular
histologic subtype
Positive stains
- Synaptophysin: positive at least focally in the majority of medulloblastomas
- NeuN: positivity may be seen in nodules of neurocytic differentiation, particularly in cases with nodular / desmoplastic or extensive nodularity histology
- p53: strong pathologic p53 positivity may be seen in some cases and is often associated with anaplasia; often correlated with underlying somatic or germline (Li-Fraumeni) TP53 mutation (J Clin Oncol 2010;28:1345, Cell 2012;148:59)
- Ki67: many positive cells will be seen due to the highly proliferative nature of the tumor; in desmoplastic / nodular histology, Ki67 is higher in the internodular areas and lower in the pale islands
- GAB1: positive in SHH activated medulloblastoma
- YAP1: positive in SHH and WNT activated medulloblastoma
- SMARCB1 / INI1 and SMARCA4 / BRG1: expression is maintained; loss of expression of either of these markers would be consistent with a diagnosis of atypical teratoid / rhabdoid tumor and not medulloblastoma
- Beta catenin: should show cytoplasmic expression; nuclear expression would be consistent with medulloblastoma, WNT activated
Molecular / cytogenetics description
- By definition, molecular studies will show activating mutations in the SHH signaling pathway, with a recent study identifying mutations in known pathway genes in 87% of cases (Cancer Cell 2014;25:393)
- Associated with high level amplifications in other genes, including MYCL, GLI2, PPM1D, YAP1 and MDM4 (Nature 2012;488:49)
- Homozygous deletions of PTCH1 and PTEN appear to occur overwhelmingly in the SHH activated subtype of medulloblastoma compared to other groups (Nature 2012;488:49)
- Point mutations in TP53 are associated with chromothripsis and a very poor outcome (Cell 2012;148:59, J Clin Oncol 2013;31:2927)
Sample pathology report
- Brain, cerebellum, resection:
- Medulloblastoma, classical type, SHH activated and TP53 wildtype, WHO grade 4 (see comment)
- Comment:
- Integrated diagnosis: medulloblastoma, classical type, SHH activated and TP53 wildtype
- Histological diagnosis: medulloblastoma, classical type
- WHO (histological) grade: 4 of 4
- Molecular information:
- P53: scattered positive cells (immunohistochemistry consistent with wildtype)
- INI1: retained (immunohistochemistry consistent with wildtype)
- Beta catenin: diffuse cytoplasmic staining (immunohistochemistry consistent with nonactivated)
- YAP1: positive (immunohistochemistry)
- GAB1: positive (immunohistochemistry)
- Histological features in the tumor include high cell density, hyperchromasia and mitoses. Prominent anaplastic features, such as pleomorphism, prominent nucleoli or cell wrapping, are not appreciated. Desmoplastic or nodular areas are not present. Overall, the histologic and molecular characteristics are consistent with the classical histologic subtype and the SHH activated molecular group.
Differential diagnosis
- Other molecular subtypes of medulloblastoma:
- WNT activated:
- Will show strong nuclear positivity with beta catenin staining
- Group 3 / 4:
- Will not subtype into WNT activated or SHH activated by immunohistochemistry
- Further expression profiling or methylation profiling can identify these specific subtypes
- WNT activated:
- Atypical teratoid / rhabdoid tumor:
- Will show loss of INI1 staining by immunohistochemistry
- Other embryonal tumors:
- CNS neuroblastoma:
- Embryonal tumor with multilayered rosettes
- C19MC altered:
- These tumors will typically be found in the supratentorial region and will lack histologic and molecular features of medulloblastoma
- CNS neuroblastoma:
Additional references
Board review style question #1
A histologic section of a tumor resected from the posterior fossa of a young man is shown. What is the most likely diagnosis?
- Metastatic lung adenocarcinoma
- Medulloblastoma, desmoplastic / nodular, SHH activated
- Choroid plexus papilloma
- Pilocytic astrocytoma
- Hemangioblastoma
Board review style answer #1
B. Medulloblastoma, desmoplastic / nodular, SHH activated
This is the best answer as the image shows sheets of undifferentiated cells consistent with medulloblastoma. Metastatic lung adenocarcinoma would commonly show gland formation and is unlikely in a young man. Choroid plexus papilloma would show well differentiated cells with a prominent papillary growth pattern. Pilocytic astrocytoma would show prominent glial cells with long thin processes. Hemangioblastoma would show a prominent vascular pattern with interspersed tumor cells and hemorrhage.
Comment Here
Reference: SHH activated
This is the best answer as the image shows sheets of undifferentiated cells consistent with medulloblastoma. Metastatic lung adenocarcinoma would commonly show gland formation and is unlikely in a young man. Choroid plexus papilloma would show well differentiated cells with a prominent papillary growth pattern. Pilocytic astrocytoma would show prominent glial cells with long thin processes. Hemangioblastoma would show a prominent vascular pattern with interspersed tumor cells and hemorrhage.
Comment Here
Reference: SHH activated
Board review style question #2
What additional genetic alteration portends a particularly poor prognosis in medulloblastoma, SHH activated?
- TP53 mutation
- EGFR amplification
- IDH mutation
- TERT promoter mutation
- 1p19q codeletion
Board review style answer #2
A. TP53 mutation
This is the best answer as the presence of TP53 mutation in medulloblastoma, SHH activated is associated with a poor prognosis. EGFR amplification is often present in glioblastoma, IDH wildtype. IDH mutation is associated with improved prognosis in infiltrating gliomas. TERT promoter mutation is seen in oligodendroglioma, IDH mutant, 1p19q codeleted and often present in glioblastoma, IDH wildtype. 1p19q codeletion is seen in oligodendroglioma, IDH mutant, 1p19q codeleted.
Comment Here
Reference: SHH activated
This is the best answer as the presence of TP53 mutation in medulloblastoma, SHH activated is associated with a poor prognosis. EGFR amplification is often present in glioblastoma, IDH wildtype. IDH mutation is associated with improved prognosis in infiltrating gliomas. TERT promoter mutation is seen in oligodendroglioma, IDH mutant, 1p19q codeleted and often present in glioblastoma, IDH wildtype. 1p19q codeletion is seen in oligodendroglioma, IDH mutant, 1p19q codeleted.
Comment Here
Reference: SHH activated
