Neurosurgery notes/Tumours/Embryonal tumours/Other CNS embryonal tumors/Embryonal tumour with multilayered rosettes

Embryonal tumour with multilayered rosettes

View Details
Status
Done
logo
Parent item
Other CNS embryonal tumors

General

  • Do not use these terms
    • Embryonal tumour with abundant neuropil and true rosettes (ETANTR);
    • Embryonal tumour with abundant neuropil and ependymoblastic rosettes (ETANER);
    • Ependymoblastoma
    • Medulloepithelioma

Definition

  • Essential:
    • A CNS embryonal tumour with the morphological and immunohistochemical features of one of the three ETMR morphological patterns (AND)
      • Embryonal tumour with abundant neuropil and true rosettes
      • Ependymobiastoma
      • Medulloepithelioma
    • Genetic alteration defining one of the two ETMR molecular subtypes (AND-for unresolved lesions)
      • C19MC alteration
      • DICER 1 mutation
    • A DNA methylation profile aligned with ETMR

Numbers

  • Mainly kids <4yrs
  • Male: Female: 1 : 1

Localisation

  • Cerebral hemisphere (70%)
    • Frontal
    • Parietotemporal
  • Brain stem & cerebellum (30%)
  • Spinal (<1%)

Cell origin

  • Primitive cell population in the subventricular zone

CNS WHO grading

  • Grade 4

miRNA processing in ETMRs

  • Step 1: C19MC miRNAs are transcribed by RNA polymerase (RNA POL) into long non-coding RNA precursors (pri-miRNAs).
  • Step 2: The pri-miRNAs are processed in the nucleus by the microprocessor complex, which includes DGCR8 and DROSHA, generating pre-miRNAs.
  • Step 3: These pre-miRNAs are exported out of the nucleus by exportin-5 (XPO5) in complex with RAN.
  • Step 4: In the cytoplasm, DICER (along with TRBP) further cleaves the pre-miRNA into two mature miRNA strands: the 5p and 3p forms.
  • Step 5: One strand (either 5p or 3p, depending on the miRNA) is loaded into the Argonaute protein (AGO) to form the RNA-induced silencing complex (RISC); the other strand is usually degraded.
  • Step 6: The RISC complex uses the miRNA as a guide to bind target mRNA via the seed sequence.
  • Step 7: The outcome for the target mRNA can be repression of translation (red), degradation of mRNA (red), or formation of a scaffold (green), depending on the context. The coloring reflects whether translation decreases (red) or increases (green).
 
RNA C19MC POL R NA polyrnerase transcribes C 19MC miRNAs Long non-coding RNA containing pri-miRNAs DGCR8 DROSHA Drosha/DGCR8 process pri-rniRNAs into pre-miRNAs Nucleus XP05 Cytoplasm 4 RAN P05 exports pre-rniRNA out of the nucleus C19MC target genes Repression Of translation Degradation Of mRNA Formation Of a scaffold TTTTTT- DICER TRBP TTTTTTTT— 3p DICER IfTRBP cleave the pre-mRNA forming two mature miRNAs 5p dominant miRNAs 3p inant miRNAs DICER : TRBP DICER TRBP Wildtype DICERI 3p TTTTTT— ITTlTT•rr 3p AGO AGO DICE-RI RNASE-III mutations DICER TRBP 3p TTTTT•r DICER TRBP 3p AGO miRNAs are processed normally Abundance of 5p mature miRNAs is reduced U.U.UU.U.U.UU.UII.U @ RISC binds mRNA using seed sequence AGO One strand gets @ loaded In AGO and forms the RISC Degradation of one strand Loss of function Dicerl DICER TRBP DICER TRBP All miRNAs are depleted miRNA processing in ETMRs. a Overview of miRNA processing and maturation using the ClgMC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC. b Overview of different scenarios that mutations in DICERI have on the abundance of 3p and 5p forms of mature miRNAs
(a) Overview of miRNA processing and maturation using the C19MC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC.
  • Wildtype DICER1 (left):
    • Both 5p and 3p mature miRNAs are correctly processed. The dominant strand is loaded onto AGO and the non-dominant strand is degraded. miRNAs function normally.
  • DICER1 RNASE-III mutations (middle):
    • These mutations mainly affect the 5p processing. As a result, the amount of 5p mature miRNAs is reduced while 3p processing may be less affected.
    • Lead to Embryonal tumour with multi-layered rosettes, C19MC-altered
  • Loss-of-function DICER1 (right):
    • Both 5p and 3p mature miRNAs are severely depleted, and virtually no mature miRNAs are produced, resulting in wholesale loss of miRNA-mediated regulation.
    • Leads to Embryonal tumour with multi-layered rosettes, DICER1-altered
RNA C19MC POL R NA polyrnerase transcribes C 19MC miRNAs Long non-coding RNA containing pri-miRNAs DGCR8 DROSHA Drosha/DGCR8 process pri-rniRNAs into pre-miRNAs Nucleus XP05 Cytoplasm 4 RAN P05 exports pre-rniRNA out of the nucleus C19MC target genes Repression Of translation Degradation Of mRNA Formation Of a scaffold TTTTTT- DICER TRBP TTTTTTTT— 3p DICER IfTRBP cleave the pre-mRNA forming two mature miRNAs 5p dominant miRNAs 3p inant miRNAs DICER : TRBP DICER TRBP Wildtype DICERI 3p TTTTTT— ITTlTT•rr 3p AGO AGO DICE-RI RNASE-III mutations DICER TRBP 3p TTTTT•r DICER TRBP 3p AGO miRNAs are processed normally Abundance of 5p mature miRNAs is reduced U.U.UU.U.U.UU.UII.U @ RISC binds mRNA using seed sequence AGO One strand gets @ loaded In AGO and forms the RISC Degradation of one strand Loss of function Dicerl DICER TRBP DICER TRBP All miRNAs are depleted miRNA processing in ETMRs. a Overview of miRNA processing and maturation using the ClgMC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC. b Overview of different scenarios that mutations in DICERI have on the abundance of 3p and 5p forms of mature miRNAs
(b) Overview of different scenarios that mutations in DICER1 have on the abundance of 3p and 5p forms of mature miRNAs.
DICER1 Status
5p miRNA
3p miRNA
Overall Processing
Wildtype
Normal
Normal
Normal miRNA maturation
RNASE-III Mutations
Reduced
Normal
5p dominant miRNAs are reduced
Loss-of-function DICER1
Depleted
Depleted
All miRNAs depleted

Molecular subtype

  • Classified based on the miRNA pathway (mutually exclusive)
  • Embryonal tumour with multi-layered rosettes, C19MC-altered
    • 90% of all ETMRs
    • Structural alterations of a microRNA cluster on chromosome 19q13.42 (C19MC), including
      • Focal high-level amplification,
      • Fusion to TTYH1,
      • Other rare rearrangements (e.g. fusion to MYO9B or MIRLET7BHG),
    • All of which produce strong upregulation of this microRNA cluster as a driving event
  • Embryonal tumour with multi-layered rosettes, DICER1-altered
    • 5% of all ETMR
      • Almost all of these are in the setting of a DICER1 genetic tumour syndrome
        • 1st hit
          • Inherited through the germline
        • 2nd hit
          • Mutation in the (hotspot) RNase 11 lb domain that is important for microRNA processing

Histopathology

  • Microscopic
    • Multilayered rosettes
      • Pseudostratified neuroepithelium with a central, round, or slit-like lumen.
      • Nuclei of the rosette-forming cells tend to be pushed away from the lumen towards the outer cell border
    • Tumour contain both
      • Primitive embryonal regions
      • Differentiated regions with broad swaths of neoplastic neuropil
      Fig. 8.24 Embryonal tumour with abundant neurcOI and bue rosetes. 31*asIc pattem: areas of small embryonal cells with multilayered rosettes and neuropil-like areas With neopLastic neurocytc cells. Fig. 8.26 Multilayered rosette: a key diagnosbc feature of embryonal tumours with multilayered rosettes.
      Embryonal tumour with abundant neuropil and true rosettes. Biphasic histological pattern: areas of small embryonal cells with multilayered rosettes and neuropil-like areas with neoplastic neurocytic cells.
      Fig. 8.24 Embryonal tumour with abundant neurcOI and bue rosetes. 31*asIc pattem: areas of small embryonal cells with multilayered rosettes and neuropil-like areas With neopLastic neurocytc cells. Fig. 8.26 Multilayered rosette: a key diagnosbc feature of embryonal tumours with multilayered rosettes.
      Multilayered rosette: a key diagnostic feature of embryonal tumours with multilayered rosettes.
    • Base on molecular status there are now three subtypes along a spectrum of neoplastic progression. As they progress embryonal tumours with abundant neuropil and true rosettes lose their neuropil areas and become more ependymoblastoma and medulloepithelioma
      • Embryonal tumour with abundant neuropil and true rosettes (old name)
          • Consist of biphasic architecture
            • Dense clusters of small cell, with round or polygonal nuclei, scanty cytoplasm
            • Has large neuropil like areas
           
          Fig. 8.26 ETMR, with mophology of ernbyonal tumour w•lth abundant neuropil and bue rosett—. A Neoplastlc neurons bäween aggregates of •mall cells. B Rosettes in neuropil- like areas. C Single cells and clusters of LIN28.A-posittve tumour cells. Fig. 8.27 ETMR, with morphology of embryona' tumour with abundant neuropll and true rosettes. A Synaptophysin expression within neuropll areas. a Vimentin expression. C Intense LIN28A immunoreacttvity.
          ETMR, with morphology of embryonal tumour with abundant neuropil and true rosettes. (A) Neoplastic neurons between aggregates of small cells. (B) Rosettes in neuropil-like areas. (C) Single cells and clusters of LIN28A-positive tumour cells.
          Fig. 8.26 ETMR, with mophology of ernbyonal tumour w•lth abundant neuropil and bue rosett—. A Neoplastlc neurons bäween aggregates of •mall cells. B Rosettes in neuropil- like areas. C Single cells and clusters of LIN28.A-posittve tumour cells. Fig. 8.27 ETMR, with morphology of embryona' tumour with abundant neuropll and true rosettes. A Synaptophysin expression within neuropll areas. a Vimentin expression. C Intense LIN28A immunoreacttvity.
          ETMR, with morphology of embryonal tumour with abundant neuropil and true rosettes. (A) Synaptophysin expression within neuropil areas. (B) Vimentin expression. (C) Intense LIN28A immunoreactivity.
      • Ependymoblastoma
          • Sheets and clusters of poorly differentiated cells incorporating numerous multilayered rosettes,
          • No neuropil like matrix and ganglion cell elements
           
          ETMR, ependymoblastoma morphology. Nests of poorly differentiated tumour cells and numerous multilayered rosettes.
          ETMR, ependymoblastoma morphology. Nests of poorly differentiated tumour cells and numerous multilayered rosettes.
      • Medulloepithelioma (there is a different class of this based on not having C19MC alterations)
          • Papillary, tubular, and trabecular arrangements of neoplastic pseudostratified epithelium with an external (periodic acid—Schiff—positive and collagen IV-positive)
            • Limiting membrane: resembling the primitive neural tube.
            • Luminal surface tubules: cilia and blepharoblasts are absent.
          • Zones outside of papillary structure there are sheets of poorly differentiated cell
            • Contains the multi-layered pseudorosettes
          ETMR, medulloepithelioma morphology. Papillary-like and tubular structures resembling the primitive neural tube.
          ETMR, medulloepithelioma morphology. Papillary-like and tubular structures resembling the primitive neural tube.

Genetic profile

  • Chromosomal
    • Gains of chromosomes 2, 7q, and 11q
      • Focal high level amplicon at 19q13.42, spanning a 0.89 Mb region
        • Act as diagnostic marker for ETMR
          • Using FISH to diagnose
                • A blue and green specks on a dark background AI-generated content may be incorrect.
            • 96% of tumour samples are positive
        • One of the ways of complexing rearranging 19q13.42 is by fusing C19MC to the TTYH1 gene
          • Causing the promoter of TTYH1 to drive the expression of C19MC microRNAs
    • Loss of 6q

Clinical presentation

  • Obstruction HCP: H/A, N/V
  • Focal neurological signs
    • Ataxia
    • Weakness

Radiological

General

  • Large
  • Well demarcated
  • Solid mass
  • Often with significant mass effect
  • A minority of the reported cases have shown cystic components and microcalcifications.
  • Haemorrhage is present
  • Perifocal oedema absent

MRI

  • T1: decreased intensity
  • T2: increased intensity
  • T1 C+ (Gd): patchy or no contrast enhancement
  • DWI: restricted diffusion

MR spectroscopy

  • Shows choline peak and a high ratio of choline/aspartate suggesting hypercellularity of the tumour

Image

T1 different patient
T1 different patient
DWI
DWI
A close-up of a ct scan AI-generated content may be incorrect.
T1+C
A close-up of a brain scan AI-generated content may be incorrect.
ADC
A close-up of a brain scan AI-generated content may be incorrect.
T2
MRS
MRS
  • 2 year-old girl presented with left-sided weakness.
  • Methylation class of an embryonal tumour with multi-layered rosettes, C19MC-altered.
  • T2w (A), FLAIR (B), DWI (C), and T1w-CE (D) show a circumscribed mass in the pons that is hyperintense on FLAIR and T2w sequences.
  • The lesions demonstrate marked restricted diffusion without enhancement
 
notion image

Immunophenotype

  • Positive
    • At primitive neuroepithelial component of ETMR
      • Nestin
      • Vimentin
    • At multi-layered rosettes
      • Cytokeratins
      • EMA
      • CD99
    • Neuropil areas
      • Synaptophysin
      • NFPs
      • NeuN
    • In all regions
      • INI1
    • LIN28A protein
      • Suggested as immunohistochemical marker for ETMR
      • See pathobiology of tumour
      • Prominent in
        • Multi-layered rosettes
        • Poorly differentiated small cell areas
        • Papillary and tubular structures of the medulloepithelioma pattern
  • Negative
    • At multi-layered rosettes
      • Neuronal markers
      • Glial markers
  • Variable
  • Ki-67 proliferation index ranges from 20% to 80%

Prognosis

  • Spread
    • 75% are localized at presentation,
    • 25% tumour dissemination (stage M2-M4).
      • Rarely, ETMRs with extracranial invasive growth and extradural metastases have been reported
  • Poor prognostic factors
      • Survival times typically averaging 12 months after combination therapies
      • Patient survival does not differ significantly between the three histological types
      • There is a slight trend that C19MC − ETMR patients may do worse, but the difference with the C19MC + ETMRs is not significant
      Overall Survival 100% C19MC- 50% Cl 9MC+ 50 Time (months) 100
       
  • Good prognostic factors
    • Post treatment neuronal differentiation might have benefit to survival
    • Gross total resection
    • Radiotherapy
    • High dose chemo therapy
    • No mets
    • Not brainstem tumour