Neurosurgery notes/Tumours/Embryonal tumours/Other CNS embryonal tumors/Atypical teratoid/rhabdoid tumour (AT/RT)

Atypical teratoid/rhabdoid tumour (AT/RT)

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Other CNS embryonal tumors

General

  • Teratoid: teratoma tumour cells comes from many layers of the trilaminar layer
  • Rhabdoid: large cells

Definition

  • Essential:
    • A CNS embryonal tumour with a polyimmunophenotype AND
      • Loss of nuclear SMARCB1 or SMARCA4 expression in tumour cells OR (for unresolved lesions)
        • A DNA methylation profile aligned with atypical teratoid/rhabdoid tumour
  • Desirable:
    • Rhabdoid cells
    • SMARCB1 or SMARCA4 alteration

Epidemiology

  • Account for > 10% of all CNS tumours in infants
  • < 3 years: 1-2% of all paediatric brain tumours
  • Rarely in children aged > 6 years
  • Very rare in adult patients
  • Male to female = 1.6-2.0 : 1

CNS WHO grading

  • Grade 4

Cell of origin

  • Most likely a pluriopotent fetal cells because:
    • Neural, epithelial, and mesenchymal markers can all be expressed, and
    • Tumour is more commonly in young children and occasionally infants than adults

Localisation

  • Ratio of supratentorial to infratentorial tumours was 4:3
    • Supratentorial tumours
      • Fq in cerebral hemispheres
      • Less fq in the ventricular system, suprasellar region, or pineal gland.
    • Infratentorial tumours (50%)
      • Cerebellar hemispheres
      • Cerebellopontine angle
      • Brain stem
        • Relatively prevalent in the first 2 years of life
    • Very rare: Spinal cord

Molecular subtype

  • All three have SMARCB1 inactivation

ATRT-TYR (tyrosine kinase)

  • Overexpression tyrosine kinase protein
    • Function
      • Physiologically catalyzes the synthesis of melanin in melanocytes
      • An important protagonist in neural tube development
  • Prototypic type of biallelic SMARCB1 inactivation in the ATRT-TYR group is
    • Whole or partial loss of one copy of chromosome 22 AND
    • An inactivating (eg, point) mutation in SMARCB1 on the other allele

ATRT-SHH (Sonic hedgehog)

  • Overexpression of both
    • Sonic hedgehog (SHH) and
    • Notch pathway members, such as
      • GLI2, PTCH1, and BOC (all SHH pathway) OR
      • ASCL1, HES1, DTX1 (all regulators of the Notch pathway)
  • Why SMARCB1 loss does not activate the SHH pathway to the same extent in the other subgroups remains unknown but may be related to different cellular origins for these subgroups. Thus
  • Enrichment of genes involved in “axon guidance pathways” and “neuronal system” pathways

ATRT-MYC

  • Elevated expression of the MYC oncogene
    • As opposed to the MYCN oncogene, which is enriched in the ATRT-SHH group.
    • However, different from other MYC or MYCN driven paediatric brain tumours like MB-Group 3, MB-SHH, and HGG-MYCN, MYC or MYCN amplifications have not been observed respectively in ATRT-MYC and ATRT-SHH tumours.
    • MYC and MYCN are similar both in (A) structure (homologous sequences in red), and (B) biological functions. However, MYC and MYCN differ in (C) the spatiotemporal expression levels. In particular, MYCN is preferentially expressed in neural tissue, whereas MYC is more ubiquitously expressed
  • Overexpression of several HOXC cluster genes, driven by super enhancers (ie, very long stretched enhancers with abundant H3K27-acetylation signal)
Molecular subgroup Torchia et. al., 2015 Torchia et. al., 2016 Han et. al., 2016 Johann et. al., 2016 Age and Gender Distribution Tumor Location ChQ2 CNA SMARCBI Alterations Major oncogenic pathways and transcriptional features ATRT-TYR Group2 Group2A hiC1 ATRT-TYR Age Gro.. Infant, 0-1 Year 12 Months 57% 43% 25% 75% Point Mutations / Focal Deleti BMP Signaling Melanogenesis (TYR, TYRP, MITF) Mesenchymal Genes (OTX2, PDGFRB, BMP4) ATRT-SHH Groupl Groupl hiC2 ATRT-SHH Age Todd% 2-5 Years Median age: 20 Months ATRT-MYC Group2 Group2B hiC3 ATRT-MYC Age ("00th.) Older patients, Years Median . 27 Months 55% 65% Di plOid 45% 35% 52% 50% 48% 38% spina Mutations / Focal Neurogenesis SHH Signalling (GL12, BOC, PTCHD2) NOTCH Signalling (ASCLI, CBL, HESI) MYCN Diploid Broad Deletio ns MYC HOX Cluster Genes
Copy number aberrations (CNAs)

Genetic profile

  • Can occur
    • Sporadically or
    • As part of a rhabdoid tumour predisposition syndrome
      • Familial cases of rhabdoid tumours, i.e. in
        • Rhabdoid tumour predisposition syndrome 1 (involving the SMARCB1 gene)
        • Rhabdoid tumour predisposition syndrome 2 (involving the SMARCA4 gene)

Histopathology

Macroscopic

  • Gross appearance similar to that of medulloblastoma and other CNS embryonal tumours.
  • Soft, pinkish-red, and often appear to be demarcated from adjacent parenchyma.
    • Can be hard and white if has large amounts of mesenchymal tissue
  • Fq has necrotic foci and haemorrhage.
  • Tumours in CP angle
    • Wrap themselves around cranial nerves and vessels
    • Invade brain stem and cerebellum to various extents
      •  
notion image

Microscopic

  • Difficult to recognise solely on the basis of histopathological criteria → need molecular diagnosis
  • Classically
    • A population of cells with classic rhabdoid features
      • Rhabdoid cells may be arranged nests or sheets and often have a jumbled appearance
      • Rhabdoid
          • Many large cells
          • Eccentrically located nuclei
            • Vesicular chromatin (large amounts vesicles in the chromatin-cystic chromatin because increase protein synthesis)
          notion image
        • Abundant cytoplasm with an obvious eosinophilic globular cytoplasmic inclusion
        • Prominent eosinophilic nucleoli
        • Well-defined cell borders
        notion image
         
    • Most tumours contain variable components with primitive features
      • Neuroectodermal features
        • Most commonly encountered (2/3)
      • Mesenchymal features
        • Less common and
        • Presents as areas with spindle cell features and a basophilic or mucopolysaccharide-rich background.
      • Epithelial features
        • Least common
        • Can take the form of papillary structures, adenomatous areas, or poorly differentiated ribbons and cords.
        • Poorly differentiated neuroepithelial cells that can differentiation along neuronal, astrocytic, myogenic, or melanocytic lines.
  • Rare variant
    • Myxoid matrix occurs uncommonly
    • In cases where this is the predominant histopathological pattern, distinction from choroid plexus carcinoma can be challenging.

Immunophenotype

  • Rhabdoid cells
    • Positive: EMA, SMA, and vimentin, GFAP, NFP, synaptophysin, and cytokeratins
  • Germ cell markers and markers of skeletal muscle differentiation are not typically expressed.
  • Loss of SMARCB1 protein (INI1)
    • A sensitive and specific test for the diagnosis of AT/RT.
    • In normal tissue and most neoplasms,
      • SMARCB1 is a constitutively expressed nuclear protein
    • In AT/ RT, there is loss of nuclear expression of SMARCB1
      • Paediatric CNS embryonal tumours without rhabdoid features, but with loss of SMARCB1 expression in tumour cells, qualify as AT/RTs as well
    • Other tumours with loss/inactivation of SMARCB1
      • Cribiform neuroepithelial tumours:
        • Definition:
          • SMARCBI-deficient non-rhabdoid tumours forming cribriform strands, trabeculae, and well-defined surfaces
        • Rare
        • An epithelioid variant of AT/RT but is characterized by a relatively favourable prognosis
      • Choroid plexus carcinomas with inactivation of SMARCB1,
        • Some believe that this tumor whould be diagnosed as AT/RT, and that classic choroid plexus carcinomas do not lose SMARCB1 expression
  • Rarely, tumours with clinical and morphological features of AT/RT and retained SMARCB1 expression are encountered.
  • Children Ki-67 proliferation index of > 50%. No data for adults

Clinical features

  • Variable, depending on the age
  • Infants (< 3 yrs)
    • Non-specific signs of lethargy, vomiting, and/or failure to thrive.
    • Specific signs of head tilt and cranial nerve palsy (6th & 7th)
  • > 3 yrs
    • Headache and hemiplegia

Radiology

General

  • Atypical teratoid/rhabdoid tumour are usually large and very heterogeneous masses.
  • They may be difficult to distinguish from a PNET by imaging.

EURHAB protocol

  • MRI Brain and spine (T1 + C + T2)
    • If spine not done pre op: complete < 48 hours of the first surgical procedure.

CT

  • Often isodense to grey matter
  • May demonstrate heterogeneous enhancement
  • Calcification is common
  • May show associated obstructive hydrocephalus
CT
CT
 
CT+C
CT+C

MRI

  • Can show necrosis, multiple foci of cyst formation and sometimes haemorrhage:
  • T1:
    • iso- to slightly hyperintense to grey matter (haemorrhagic areas can be more hyperintense)
  • T2:
    • Generally hyperintense (haemorrhagic areas can be hypointense)
    • Peripheral cysts
  • T1 C+ (Gd):
    • Heterogeneous enhancement
  • SWI
    • Haemorrhage
  • MR spectroscopy
    • Cho: elevated
    • NAA: decreased
  • DWI
    • Almost all restrict diffusion
Images
T1
T1
Gradient echo
Gradient echo
T1+C
T1+C
DWI
DWI
 
T2
T2
 
  • An 11-month-old boy with hydrocephalus. SMARCB1 mutation.
  • Methylation profiling showed AT/RT, subclass SHH.
  • T2w (A), DWI (B), and T1w-CE (C, D) show a large, lobulated intraventricular lesion expanding the 3rd ventricle with extension into the right lateral ventricle and associated hydrocephalus.
  • The lesion demonstrates restricted diffusion, but only minimal enhancement. Intraspinal metastases are present.
notion image
  • A 16-month-old boy presented with difficulty walking and vomiting. Molecular: SMARCB1 mutation, methylation subclass SHH.
  • T2w (A), T1w-CE (B), ADC (C), and SWI (D) show a heterogenous lesion expanding the 4th ventricle which contains multiple cysts.
  • The lesion is characterised by minimal focal enhancement, restricted diffusion, and microhaemorrhages
notion image

Differential diagnosis

Features
Medulloblastoma
AT/RT
Age
Much more common than AT/RT in children above the age of 5 years
Most common embryonal tumour in children under 2 years
  • They may be difficult to distinguish from a PNET by imaging.

Prognosis

  • Seeding via the cerebrospinal fluid pathways
    • 1/4 of all patients at presentation
    • Need imaging of whole CNS axis
  • Poor
  • Canadian Brain Tumour Consortium
    • Children given
      • High-dose chemotherapy, +/- radiation, vs
        • 2-year overall survival rate of 60% ± 12.6%
      • Standard dose therapy
        • 2-year overall survival rate of 21.7% ± 8.5%
  • From genomic and transcriptional analysis of AT/RT, suggest that AT/RT may be form from two different molecular classes, with distinct outcomes.
    • AT/RT that are supratentorial and with markers that show they are from the forebrain regions
      • More favourable response to therapy,
      • Better longterm survival
        • Even for the favourable subgroup this remains an aggressive disease,
          • 5-year progression-free and overall survival rates of 60%
          • Recurrence occurring in about 1/3.
    • AT/RT that are infratentorial and with mesenchymal lineage markers
      • Worse long-term survival

Treatment based on EURHAB protocol

Surgery

  • For HCP
    • Ventricular access device
    • Shunts
  • For tumour
    • Maximal safety resection
    • LP for CSF evaluation > 14 days post operation
    • Post-operative MRI < 48 hours after surgery
      • To assess residual disease.

Chemo

  • Initial therapy:
    • IT Methotrexate
    • Doxyrubacin, Iphosphamide/phosphamide, Carboplatin, Etoposide, Vincristine, Actinomycin
  • High dose chemotherapy
    • Alternative to radiotherapy
    • Indication
      • For pt with morbidity (principally in terms of neuro-developmental outcome) of radiation therapy is deemed too severe.
        • Eg: Infants with a large supra-tentorial tumour, for whom extensive irradiation of cerebral cortex would be required.
    • Carboplatin and ThioTEPA

Radiotherapy

  • 54Gy in 30 fractions over 42 days
  • Radiotherapy is advised for most patients.
  • > 18 months of age (as pt outcome very poor)
    • Rt given earliest opportunity for primary tumour
      • Dose: 54.0 Gy as 5 fractions of 1.8 Gy per week
    • If there is metastatic disease, delayed RT until after the intensive phase of chemotherapy.
      • Dose: Craniospinal dose of 24 Gy
  • < 18 months
    • RT is generally not recommended
      • Give High dose chemo instead
    • RT can be delayed until the patient has reached 18 month of age.