Imaging Characteristics, Pathological Features, and Prognoses of the Molecular Subgroups of Medulloblastoma Eede# Eede-203 University of South Florida Department of Radiology Tampa General HospitalJohns Hopkins All Children’s Hospital Johns Hopkins All Children’s Hospital Lowell D. Dawson, MD Ryan Murtagh, MD, MBA Ignacio Gonzalez-Gomez, MD Jennifer Neville Kucera, MD MS

Disclosure Slide  We have no financial relationships to disclose related to the content of this presentation.

Purpose  With the recent discovery of tumor genomics of medulloblastoma it is important to understand the differing radiographic presentations as well as prognostic data as influenced by these molecular sub- groups.

Approach  Detailed in the exhibit are the following:  Clinical presentation  Epidemiology  Age criteria as reported by Kool and associates are as follows:  Infants (aged 16 years)  Imaging features of medulloblastoma demonstrating contrasting geographic locations  Prognoses as influenced by the different molecular sub-groups are reported as 5 and 10 year overall survival after resection with follow up chemotherapy and/or radiation  Example pathological slides

Findings  Medulloblastoma is a common malignant brain tumor found predominantly in the pediatric population but can also be seen in the adult population  With the help of tumor genomics we now know medulloblastoma can be grouped into 4 sub groups:  Wingeless type (WNT)  Sonic Hedgehog (SHH)  Group 3  Group 4

Findings: Clinical Presentation Growth of these tumors are very rapid. Most patients present with symptoms of increased intracranial pressure secondary to obstructive hydrocephalus including the following:  Nausea  Vomiting  Seizures  Headache  Visual disturbances  Drowsiness  Decreased consciousness

Findings: Imaging Features  Geographic findings are strongly influenced by molecular sub-group  For all sub-groups there are general radiologic features found on CT and MR  CT Findings  Usually there is a hyperdense mass arising from the cerebellar vermis or roof of the 4 th ventricle  Restricted diffusion is usually present  In older patients necrosis/cyst formation may be present, calcifications may also be present  Enhancement is usually present  MR Findings  T1W1: Hypointense to grey matter  FLAIR: Iso-hyperintense to grey matter, edema  DWI/ADC: Restricted diffusion with correlating low signal on ADC  Majority of tumors enhance heterogeneously

Case 1 43 y/o female presents to the ED reporting dizziness without additional symptoms. She denies headaches, nausea, vomiting, tinnitus, or hearing changes. MR T1WI SAG demonstrates hypo-intense signal within the right cerebellopontine angle

Case 1 MR DWI demonstrates restricted diffusion within the right cerebellopontine angle MR ADC demonstrates correlating low signal within the right cerebellopontine angle

Case 1 MR T1WI C+ demonstrates a thick peripherally enhancing mass within the right cerebellopontine angle MR FLAIR sequence demonstrates a hyperintense mass within the right cerebellopontine angle with surrounding edema

Case 1: Wingless Sub-Group (WNT)  Epidemiology:  Smallest molecular sub-group representing approximately 11% of medulloblastoma cases  Mostly occurs in children and adults  M:F 1:1  Geographic radiological features:  WNT group mainly found in the region of the cerebellar peduncle/cerebellopontine angle  Prognosis:  5 and 10 year overall survival is 95% in children, and 100% in adults  Best prognosis

Case 2 61 y/o presents with dizziness and headache. Denies visual or auditory changes. MR T1WI demonstrates an iso-low signal mass within the cerebellar vermis Courtesy of Drs. Eric Steckler and Eric Carolan Mayo Clinic Rochester, MN

Case 2 MR DWI demonstrates mild restricted diffusion within the cerebellar vermis MR ADC correlates with mild low signal within the cerebellar vermis Courtesy of Drs. Eric Steckler and Eric Carolan Mayo Clinic Rochester, MN

Case 2 MR T2 demonstrates a cerebellar vermis mass with foci of hyper-intense signaling and surrounding edema MR T1W1 C+ demonstrates heterogeneous enhancement within the cerebellar vermis Courtesy of Drs. Eric Steckler and Eric Carolan Mayo Clinic Rochester, MN

Case 2: Sonic Hedgehog Sub-Group (SHH)  Epidemiology:  2 nd largest molecular sub-group representing approximately 28% of medulloblastoma cases  Demonstrated in infants and adults  M:F 1:1  Geographic radiological features: Cerebellar hemisphere or midline with extensive nodularity  Prognosis: 5 and 10 year overall survival:  Infants 77%  Children 68 and 51%, respectively  Adults 75 and 34%, respectively  Good prognosis in infants, Intermediate in children and adults

Case 3 3 y/o with macrocephaly and developmental delay presents for routine follow-up imaging. MR T1WI Sag demonstrates a midline, mixed solid and cystic mass, arising from the 4 th ventricle

Case 3 FLAIR imaging demonstrates a midline mass arising from the 4 th ventricle with heterogeneous intensity containing solid and cystic components DWI demonstrates restricted diffusion within the ventricular mass MR T1WI C+ demonstrates prominent enhancement within the midline cerebellar region most likely arising from the 4 th ventricle

Case 3: Group 3 Sub-Group  Epidemiology  3 rd largest molecular sub-group representing approximately 27% of medulloblastoma cases  M>F  Infants and Children  Geographic radiological features: Midline poorly defined tumor with prominent enhancement  Prognosis: 5 and 10 year survival  Infants 45 and 39%, respectively  Children 58 and 50%, respectively  Worse prognosis out of all sub-types

Case 4 7 y/o with vomiting for 3 weeks and headache for the past 3 days. MR T1WI Sag demonstrates a large intraventricular tumor within the posterior fossa which is slightly hypo- intense to grey matter

Case 4 MR DWI demonstrates mild restricted diffusion MR ADC demonstrates mixed signal intensity

Case 4 MR T1WI C+ demonstrates mottled enhancement FLAIR demonstrates a mass within the posterior fossa that is slightly hyperintense to grey matter with central area of necrosis

Case 4: Group 4 Sub-Group  Epidemiology  Group 4 represents the largest molecular sub-group with approximately 34% of medulloblastoma cases  M>F  Predominant in children, rare in infants and adults  MRI features: Midline well defined tumor with little to no enhancement  Prognosis: 5 and 10 year overall survival similar to Group 3  Intermediate prognosis

Histology  The molecular sub-groups have replaced the older classification criteria which was previously based on histological and morphological findings. The four main traditional sub-types which are expressed in the molecular sub-groups are as follows:  Classic  Desmoplastic  Large Cell  Anaplastic

Classic Histology Diffuse hypercellular, fairly uniform tumor with focal discrete areas of neuropil formation seen as irregular pink anucleated areas Expressed in all molecular sub-groups

Desmoplastic Histology Primitive tumor with nodular areas of neurocytic differentiation (stars) The internodular areas contain primitive cells and vascular structures Expressed in SHH molecular sub-group

Large Cell Histology Hypercellular tumor composed of primitive cells with a diffuse pattern of growth, forming sheets of neoplastic cells with scattered confluent and individual cell necrosis (arrows) Expressed in SHH, Group 3, and Group 4, rarely in WNT molecular sub-group

Anaplastic Histology Primitive and highly cellular tumor with a diffuse pattern of growth Irregularly shaped with variable size ranging from small to large Adjacent cells exhibit nuclear “molding” (arrowhead) and focally cell “wrapping” by adjacent tumor cells (notched arrow) Expressed in the SHH, Group 3 and Group 4, rarely WNT molecular sub-types

Question 1 Which one of the molecular sub-groups of medulloblastoma is predominantly found in the cerebellar hemispheres and carries the worst prognosis? A. SHH B. WNT C. Group 3 D. Group 4

Question 2 Which molecular sub-group of medulloblastoma displays restricted diffusion on MR DWI? A. SHH B. WNT C. Group 3 D. Group 4 E. All of the above

Question 3 Which molecular sub-group has a bi-modal distribution in infants and adults? A. SHH B. WNT C. Group 3 D. Group 4

Question 4 What molecular sub-group is the most prevalent within the population? A. SHH B. WNT C. Group 3 D. Group 4

Question 5 Which molecular sub-group carries the best prognosis? A. SHH B. WNT C. Group 3 D. Group 4

Conclusion  The characteristic imaging features with correlating classic histopathologic appearance of medulloblastoma has been well documented in the literature.  However, with the help of tumor genomics we now understand that medulloblastoma is comprised of 4 distinct molecular sub-groups: WNT, SHH, Group 3 and Group 4.  For those involved in imaging of medulloblastoma it is important to understand these molecular sub-groups as they determine the clinical presentation, radiologic findings, and prognostic information.

References  1. Koeller KK, Rushing EF. Medulloblastoma: A Comprehensive Review with Radiologic-Pathologic Correlation. Radiographics 2003; 23:  2. Taylor MD, Northcott PA, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathologica 2012: Apr; 123 (4):  3. Li, KK, Lau KM, Ng HK. Erratum: Signaling pathway and molecular subgroups of medulloblstoma. International Journal of Clinical and Experimental Pathology 2015 Sep 1; 8(9):  4. Zhen-Yu Zhang, et al. Medulloblastoma in China: Clinicopathologic Analyses of SHH, WNT, and Non-SHH/WNT Molecular Subgroups Reveal Different Therapeutic Responses to Adjuvant Chemotherapy. PLoS One. 2014; 9(6): e  5. Kool M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathologica 2012 Apr;123(4):