Case Report, J Neurosci Clin Res Vol: 5 Issue: 2
Pediatric Embryonal Tumors in True Rosettes (Etmrs) Presenting as a Low Grade Gliomaâ An Unusual Case ReportSibhi Ganapathy1* and Nikunj Godhani2
1 Department of Neurosurgery, Manipal Hospital Whitefield, Bangalore, India
2 Department of Neurosurgery, Sakra Institute of Neurosciences, Bangalore, India
*Corresponding Author : Ganapathy S
Department of Neurosurgery, Manipal Hospital Whitefield, Bangalore, India
Tel: + 09686617831
Received date: July 10, 2020; Accepted date: July 20, 2020; Published date: July 31, 2020
Citation: Ganapathy S, Godhani N (2020) Pediatric Embryonal Tumors in True Rosettes (Etmrs) Presenting as a Low Grade Glioma– An Unusual Case Report. J Neurosci Clin Res 5:2. DOI: 10.37532/jnscr.2020.5(2).119
Pediatric Embryonal Tumors in Multilayered Rosettes (ETMR) are rare aggressive tumors with poor survival statistics, defined by the 2016 WHO classification of brain tumors. The tumors have a characteristic radiological appearance on MR imaging of the brain, which is easily decipherable. This combined with a clinical picture of raised intracranial pressure symptoms, seizures and rapidly progressive new onset neurological deficits make the diagnosis fairly obvious. The final confirmation of the diagnosis is done by immunehistochemical analysis of the C19Myc gene alteration. Rarely certain radiological presentations are uncharacteristic and resemble other more benign pathologies with overlapping clinical presentations. This can be misleading, as ETMRs require aggressive surgery followed by adjuvant chemotherapy and radiation to ensure best possible survival. We present such a case report of what appeared to be a low-grade glioma in the frontal lobe. This tumor presented with 1 episode of generalized tonic clonic seizures not unusual as a presenting complaint in low grade gliomas per se. Surgical debulking under Ultrasonic guidance was done and the specimen sent to histopathological analysis. The histopathological analysis showed a surprise ETMR diagnosis which was sent for confirmation to 2 other centers. This case report highlights the need to keep ETMRs as a rare differential diagnosis for even low-grade gliomas of the brain, thereby allowing accurate prognostication only after histopathological and immunohistochemical assessment. We present a brief literature review on unusual presentations of ETMRs reported in literature to further illustrate the chimeric nature of this rare disease.
Keywords: ETMR; PNET; Low grade glioma
Embryonal tumor with multi-layered rosettes C19MC-altered (ETMR) is a WHO grade IV aggressive embryonal tumor, which is newly defined in the 2016 WHO Classification of Tumors of the Central Nervous System (CNS) . ETMR mainly affects children aged < 4 years old and demonstrates a rapid growth and an aggressive clinical course (the mean survival is 12 months after combination therapies) . Most paediatric CNS embryonal neoplasms were previously diagnosed as embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL) and medulloepithelioma (ME), and any CNS embryonal tumor with C19MC amplification or fusion were included in this entity . This definition distinguished ETMR from the previously defined CNS primitive neuroectodermal tumors (PNETs), in which ME and EBL are also included irrespective of the C19MC locus amplification status.
Amplification of the C19MC locus at 19q13.42 was observed in 37/40 (93%) of the tumors morphologically diagnosed as EBL or ETANTR . Nobusawa et al.  found 19q13.42 amplification in ETANTR, EBL, and ME, but not in AT/ RT. Korshunov et al.  showed that LIN28A, an RNA-binding protein that inhibits the processing of pre-let-7 miRNAs, is a highly specific immunohistochemical diagnostic marker of ETMR .
ETMRs are aggressive tumors. They therefore exhibit some characteristic features that are identifiable on MRI and CT scan of the brain . Hence a clear diagnosis is usually made on radiology itself before subjecting he operative specimen to histopathological and immunohistochemical analysis. We present a rare case of what radiologically appeared to be a low-grade glioma, but histologically was seen to be an aggressive ETMR. We present a radiological review of ETMR presentations and discuss its impact on treatment and prognosis.
A 2-year-old child presented to our clinic with an episode of nonfebrile, generalized Tonic Clonic Seizures. The seizure profile was as follows. Aura was absent. The ictus consisted of tonic-clonic movements of Bilateral upper and lower limbs, coupled with tongue bite and incontinence. The ictus lasted for 1-2 min. In the Post-ictal state, the child was confused & drowsy for 15 min before regaining normal consciousness. The child was immediately evaluated for the cause of this new onset seizure. The MRI of the child showed a left frontal lesion with minimal enhancement of contrast. The lesion was well demarcated with a uniform consistency. No cystic or hyperintense regions were seen. The surrounding brain appeared normal with no oedema. There was no mass effect on the surrounding brain seen. (Figure 1) The possible differential diagnoses considered were ganglioglioma, or Pleomorphic Xanthoastrocytoma. (PXA) Based on this, she was advised surgery. She was taken up for a left frontal craniotomy, and navigation and ultrasound guided excision of the lesion under general anesthesia.
Total excision of the affected lesion was confirmed by on-table neuro-ultrasound of the tumor bed. (Figure 2) Ultrasonic localization was essential as tumor tissue was indistinguishable from the normal brain parenchyma. No oedema, or increased vascularity was seen in comparison to the normal tissue. Post Excision the child was observed for 3 days in hospital, and then eventually discharged on antiepileptics to review after a week in order to obtain the histopathological diagnosis and thereby plan adjuvant therapy if required. No decongestants were added as there was absolutely no oedema and postoperative CT scans of the brain showed no such features.
The Histopathological analysis showed a biphasic cellular tumor composed of monomorphic cells arranged in sheets and papillary pattern interspersed with foci of small embryonal cells with hyperchromatic nuclei, scant cytoplasm, brisk mitotic activity, apoptotic bodies and necrosis. The cells were seen on a background of fibrillary stroma, with ganglionic cells also were seen. The cells show focal perivascular resetting, occasional focus of palisading cells with papillary like configuration occasionally. The presence of multilayered rosettes is unequivocal. (Figure 3) Immunohistochemical stains done show INI-1 retained expression, Neu-N positive confirming the presence of embryonic component, Synaptophysin positive for the fibrillary stroma alone, GFAP-negative indicating no proliferative glial component and a MIB-1 index of80% indicating WHO grade 4 tumor. LIN28A was done as a surrogate marker for C19Myc detection. It was strongly positive indicating C19Myc amplification. (Figure 4)
The child was reviewed, and her relatives were counselled about the negative turn of events. They were advised to go for adjuvant therapy but were lost to follow up.
CNS embryonal tumors include several groups of paediatric brain tumors with typical multi-layered rosettes. These are supratentorial primitive neuroectodermal tumors (PNET), medulloblastoma (infratentorial location), medulloepithelioma, neuroblastoma, ependymoblastoma, and atypical teratoid/rhabdoid tumors (AT/RT) . The 2016 WHO Classification proposed a new integrated diagnostic criterion for C19MC- altered ETMR . If ETMR diagnosis is suggest- ed histologically, then 19q13.42 amplification should be assessed using FISH. If ETMR is diagnosed on the basis of histology alone, the tumors may be diagnosed as ETMR, NOS (not otherwise specified) .
Most C19MC-altered ETMRs have been reported as case reports (Table 1) [4-8]. ETMRs may develop in both the supratentorial and infratentorial compartments. The most common site is the cerebral hemisphere, with a frequent involvement of the frontal and parietotemporal.
|2y||Personality changes and ataxia+ICP headache||Cerebellar Vermis||Subtotal||NeuN, Syn, INI1 positive MIB1 47%||Yes||>17months|
|2y9m||M||Increased Head circumference||Left Parieto-Occipital lobe||Near total||INI1, Syn, NF positive||Yes||10months|
|2y5m||M||Progressive visual loss||Bilateraal Parietal lobes||Subtotal||INI1, NeuN, NF, p53, Syn, Vim positive MIB1 70%||No||NA|
|4y||M||Left hemiplegia with ICP headache||Right Mid pons||Subtotal||INI1, Syn, LIN28A positive||No||NA|
|2y||M||Dysarthria, dysphagia and ataxia||Basilar Pns||Subtotal||INI1, Syn positive||Yes||7months|
|2y9m||M||Vomiting, Gait disturbances||Intramedullary mass||Subtotal||INI1, LIN28A, NeuN, NF, Syn positive MIB1 70%||Yes||6months|
|8m||F||Left eye ptosis with ICP headache||Left Cerebellar hemisphere||Subtotal||INI1, p53, NF, Syn, Vim, positive MIB1 80%||No||1week|
|2y||F||Seizures, left hemipariesis with ICP headache||Right Parieto-Occipital Lobe||Total||Syn, Vim positive||Yes||>6months|
Table 1: showing case reports in of paediatric ETMRs in the last 5 years.
Regions, as seen in our patient . In addition to the supratentorial compartment, they can also originate in the cerebellum, brainstem, and spinal cord [7,8]. For the radiological features, the head computed tomographic (CT) image shows a hyper attenuating mass in the cerebral hemi-sphere. MRI is generally suggestive of an aggressive lesion well demarcated and enhancing with contrast along with significant surrounding oedema and mass effect. The lesion maybe variegated with cystic components as well. In our case, MRI showed well-defined margins, minimal vasogenic oedema, and subtle enhancement lesions . There are no specific radiological features distinguishing ETMR andother brain tumors . But the aggressive nature of the disease is well documented and can be discerned by indirect features such as surrounding brain oedema, contrast enhancement and rapid rate of growth. This was also not present here in our case.
In summary, C19MC-altered ETMR is a new entity that has a poor outcome in children. The incidence of ETMR remains unclear, because only single cases reports have become available so far. However, epidemiological data may be obtained in the future, as a new ICD-O code (9478/3) has been assigned to this new entity (2016 WHO Classification). The most common clinical manifestations are symptoms and signs of increased intracranial pressure and focal neurological signs. The radiological features are similar to other brain tumors. The integrated diagnosis should be based on histology (CNS embryonal tumor with multi-layered rosettes), immunoreactivity (synaptophysin, and the specific biomarker LIN28A), and genetics (amplification of C19MC locus at 19q13.42 by FISH wherever possible) to reliably diagnose this novel aggressive brain tumor.
- Louis DN, Ohgaki H, Wiestler OD, Deimling AV, Branger DF et al. (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica 131: 803-820.
- Korshunov A, Remke M, Gessi M, Ryzhova M, Hielscher T et al. (2010) Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 120: 253-260.
- Nobusawa S, Yokoo H, Hirato J, Kakita A, Takahashi H et al. (2012) Analysis of chromosome 19q13.42 amplification in embryonal brain tumors with ependymoblastic multilayered rosettes. Brain Pathol 22: 689-697.
- Korshunov A, Ryzhova M, Jones DT, Northcott PA, Sluis PV et al. (2012) LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathol 124: 875-881.
- Spence T, Sin-Chan P, Picard D, Barszczyk M, Hoss K et al. (2014)CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol 128: 291-303.
- Scheithauer BW (2009) Development of the WHO classification of tumors of the central nervous system: a historical perspective. Brain Pathol 19: 551-564.
- Wang J, Liu Z, Fang J, Du J, Cui Y et al. (2016) Atypical teratoid/rhabdoid tumors with multi- layered rosettes in the pineal region. Brain Tumor Pathol 33: 261-266.
- Pfister S, Remke M, Castoldi M, Bai AHC, Muckenthaler MU et al. (2009) Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a paediatric embryonal tumor with abundant neuropil and true rosettes. Acta Neuropathol 117: 457-464.