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Why “neuroblastoma”? • Embryonal tumors are highly malignant, poorly differentiated neoplasms, occurring especially in young children and adolescents • They are a very heterogeneous group, with tumor cells that may display differentiation along multiple lineages • Tumors with only neuronal differentiation are termed CNS neuroblastomas or, if ganglion cells are also present, CNS ganglioneuroblastomas • These latter are exceedingly rare!!! Neuroblastoma • 7-8% of all pediatric tumors Other embryonal tumors including - 3rd most common malignancy (after leukemia & CNS tumors) neuroblastoma, ATRT… • 90% of patients < age 5 years Andrea Rossi, MD • Origin: sympathetic nervous Neuroradiology Unit system G. Gaslini Children’s Hospital - Genoa, Italy [email protected]
NBL metastases
Extra-axial Intra-axial >> hemorrhagic
Why “…”? WHO classification of CNS tumors 2007 Aims of this lecture:
To not deal with peripheral neuroblastoma
To provide information regarding the recent advances in the understanding of CNS embryonal tumors, with the exception of medulloblastoma
To highlight some relevant neuroimaging features and pitfalls in these tumors
Louis et al. IARC, Lyon 2007
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WHO classification of CNS tumors 2007 Primitive neuroectodermal tumors (PNET) • WHO grade IV • Supratentorial embryonal tumor composed of undifferentiated or poorly differentiated neuroepithelial cells • Age range: 4 weeks to 10 years • Biological behavior: markedly aggressive, poor response to therapy, but unpredictable based on histology & imaging
Louis et al. IARC, Lyon 2007
WHO classification of CNS tumors 2007 WHO classification of CNS tumors 2016
*
Louis et al. IARC, Lyon 2007 *new entities; provisional entities Louis et al. 2016 Acta Neuropathol
Neuroblastoma Medulloblastoma PNET Pineoblastoma
Ependymoma Medulloblastoma PNET Central neurocytoma Glioblastoma Pilocytic astrocytoma
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Embryonal Tumors and Rosettes Embryonal Tumor with Multilayered Rosettes (ETMR) perceived as a poorly defined diagnosis, several proposals made to retire it Embryonal tumor with abundant neuropil Ependymoblastoma: concentric rings of primitive tumor cells around a and true rosettes central lumen, the cells facing the lumen sometimes forming an internal Ependymoblastoma (ETANTR) Medulloepithelioma limiting membrane, and with the cells in the outer rim merging with the (EBL) (MEPL) surrounding undifferentiated neuroectodermal cells
C19MC present in 95% C19MC present in 75%
• primarily occur in children < 2 yrs age
Medulloepithelioma: distinctive, pseudostratified epithelium, arranged • poor outcome despite aggressive in papillary and tubular patterns that resemble the structure of the primitive treatment neural tube with a limiting membrane on the outside of these structures • defined histologically by rosettes, which resemble primitive neural tubes First report in 2000, never made it into the WHO classification • amplifications at 19q13.42 ETANTR (embryonal tumor with abundant neuropil and involving the C19MC cluster true rosettes): combining features of ependymoblastoma and central neuroblastoma, such that clusters of primitive appearing cells alternate with Korshunov A et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and a nuclear regions of neuropil, more mature appearing neuronal elements, medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol. 2014 Aug;128(2):279-89. and true ependymoblastic rosettes containing well-formed central lumina
ETMR
Picard D et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: Archer TC, Pomeroy SL. A developmental program drives aggressive embryonal brain tumors. Nat Genet. 2014 Jan;46(1):2-3. an integrative genomic analysis. Lancet Oncol. 2012 Aug;13(8):838-48.
LIN28A binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis
• A biologic diagnosis with LIN28A immuno-histochemistry and the search for amplification of the locus 19q13.42 should be systematically done to ensure diagnosis • Prognosis remains dismal, but complete surgical removal seems to be an important part of the treatment • Radiotherapy may be another crucial point of the treatment but has to be balanced with neurocognitive toxicity that can be caused in young children ETMR ATRT Anaplastic ependymoma • Chemotherapy and maintenance chemotherapy may be useful, but their respective roles remain to be determined Korshunov A et al. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathol. 2012 Dec;124(6):875-81.
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All embryonal tumors (not just medulloblastoma) may involve the posterior cranial fossa
© Edmonson CA, 2016
Location: • Cerebral hemispheres 76 % ETMR ATRT MB • Cerebellum 11 % • Brain stem 9 % • Pre-sacral space 2 % • Optic nerve 2 %
ETMR • 3-year-old boy Neuroradiological features • History of headaches • Large size • Cerebral hemispheric location • Admitted for first seizure • Structural heterogeneity Disclaimer: imaging at Ancona (Pol. Salesi), patient (hemorrhage, calcification, necrosis, cysts) • Lack of perifocal edema referred to Gaslini Inst. for surgical management • Restricted diffusion • Mild/Lack of contrast enhancement +C
CNS embryonal tumor, NOS, F 2y
+C
Color-coded ADC
Exophytic behavior
ETANTR CNS embryonal tumor, NOS M 2y
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• Deletion at 22q11.2 Atypical teratoid rhabdoid tumor (ATRT) • Loss of expression of the INI1 • Malignant embryonal CNS tumor (WHO grade IV) (SMARCB1) gene • Less than 2% of all CNS tumors in the pediatric • SWI/SNF chromatin-remodeling population but 10% of those seen in children under complex 12 months of age • Composed of rhabdoid cells, with or without fields resembling embryonal tumors, epithelial tissue, and neoplastic mesenchyme • Ubiquitous, >> kidney (MRT-K)
cytogenetics
Sredni ST, Tomita T. Rhabdoid tumor predisposition syndrome. Pediatr Dev Pathol. 2015 ; 18:49-58.
• Deletion at 22q11.2 • Loss of expression of the INI-1 INI1/SNF5 (SMARCB1) immunostaining (SMARCB1) gene • SWI/SNF chromatin-remodeling complex
• Second gene: BRG-1 (SMARCA4) on chr. 19 Fruhwald MC et al. Pediatr Blood Cancer 2006; 47:273–278 • Mutations can involve the positive negative somatic or germ lines
• No mut: CNS embryonal tumor ATRT with rhabdoid features Sredni ST, Tomita T. Rhabdoid tumor predisposition syndrome. Pediatr Dev Pathol. 2015 ; 18:49-58.
Malignant rhabdoid tumor of the kidney
Rhabdoid tumor predisposition syndrome (RTPS)
2004 Histology: PNET, no rhabdoid cells Germline inactivation of 1 allele of a gene. Some familial cases. Immunostaining: INI1 - RTPS1: mutation in the INI-1 (SMARCB1) gene RTPS2: mutation in the BRG-1 (SMARCA4) gene ATRT
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Rhabdoid tumor predisposition syndrome (RTPS)
Germ-line INI1 mutations appear to be more common in patients with multicentric tumors, in those presenting < 1 year, and in
familial cases Sredni ST, Tomita T. Rhabdoid tumor predisposition syndrome. Pediatr Dev Pathol. 2015 ; 18:49-58.
ATRT: location ATRT are typically structurally heterogeneous • Posterior fossa 52% • Supratentorial 39% Tumor aggressiveness • Pineal 5% No respect of anatomic • Spinal 2% boundaries (i.e., meninges) • Multifocal 2%
Admixture of:
• Solid components • Cystic-necrotic regions • Hemorrhage • Calcifications • Vasogenic edema
ATRT can be primitively intra-axial, extra-axial, or both
Marginal cysts
Prenatal ASL assessment Fetal MRI
ATRT, F 6m
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ATRT, F 6m ATRT, M 2m
ASL ATRT: special features
Rapid disease progression and recurrences age 4 days despite chemo- and radiotherapy
age 5 months 22/3/2002 9/5/2002
Disseminated ATRT, M 8y
Lack of enhancement in embryonal tumors Metastases of non enhancing tumors may also not enhance!
FLAIR T1 +C FLAIR T1 +C
medulloblastoma ATRT ETMR 02/05/2008 15/10/2008 Restricted diffusion due to high cellularity DWI ADC DWI ADC
Medulloblastoma - off therapy for 1 year
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Conclusions:
1. The neuro-oncological world is changing fast! 2. Neuroradiologists need to keep updated and must not be left behind if they want to stay relevant 3. In the new WHO classification, several tumors span various histologies (and imaging features!) but comprise single molecular diseases 4. These new categories warrant specific therapeutic strategies 5. Embryonal tumors have been markedly restructured in the new classification 6. “PNETs” no longer exist THANK YOU!
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