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TPM3-NTRK1 fusion in a pleomorphic xanthoastrocytoma presenting with haemorrhage in a child
  1. Katherine Clark Pehlivan1,
  2. Denise M Malicki2,
  3. Michael L Levy3 and
  4. John Ross Crawford4
  1. 1Neurosciences, University of California San Diego, San Diego, California, USA
  2. 2Pathology, Rady Children's Hospital University of California San Diego, San Diego, California, USA
  3. 3Neurosurgery, University of California San Diego, San Diego, California, USA
  4. 4Neurosciences and Pediatrics, University of California San Diego, San Diego, California, USA
  1. Correspondence to Dr John Ross Crawford; jrcrawford{at}ucsd.edu

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Description

A previously healthy 6-year-old boy presented with acute onset of headache, vomiting and right sided weakness. CT imaging was performed which revealed an intracerebral left-sided 7 cm haemorrhagic mass associated with midline shift (figure 1). The patient subsequently developed signs of herniation syndrome and an emergent evacuation of the hematoma and a gross total tumour resection was performed. The tumour consisted of a moderately cellular proliferation of spindle cells with pleomorphic nuclei, which stained positive for glial fibrillary acidic protein (GFAP) and low Ki67, consistent with a diagnosis of pleomorphic xanthoastrocytoma (PXA), WHO Grade II (figure 2). A DNA-based next generation sequencing panel consisting of 397 cancer-related genes (table 1) performed on paraffin-embedded formalin fixed tumour demonstrated a TPM3-NTRK1 fusion between TPM3 exon 7 and NTRK1 exon 10 and loss of CDKN2A and CDKN2B.

Figure 1

Axial and coronal non-contrast CT images reveal a haemorrhagic parenchymal mass in the posterior frontoparietal region associated with vasogenic oedema and midline shift.

Figure 2

H&E stained section of tumour at 200× magnification demonstrates cellular proliferation of spindle cells with pleomorphic nuclei consistent with a diagnosis of pleomorphic xanthoastrocytoma.

Table 1

Next generation cancer gene panel

PXA represents less than 1% of paediatric brain tumours. Upfront treatment generally involves surgical resection followed by observation. However PXAs may recur in about 40% of patients within 10 years.1 Molecularly, almost two-thirds of cases harbour a BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E mutation and malignant variants have been reported.2 To our knowledge, our case is the first reported TPM3-NTRK1 fusion in a PXA. NTRK fusions are quite rare in paediatric low grade glioma (LGG), typically identified in <1% of LGGs. Out of 461 samples of LGG sequenced through the cancer genome atlas, NTRK fusions were identified in only 2 and both of these involved NTRK2 fusions.3 Interestingly this combination of TPM3-NTRK1 fusion and loss of CDKN2A and CDKN2B has been reported in one prior paediatric case, which was classified as an LGG, not otherwise specified.4

NTRK fusions represent a pharmacologically targetable genomic alteration. NTRK inhibitors are currently in clinical trials for patients with primary central nervous system tumours with promising results.5 Early results from a trial of larotrectinib has shown an overall response rate of 36% in 14 evaluable patients and tumour control rate of 71% of patients with stable disease or response.5 In the case of our patient who remains in remission, the use of an NTRK inhibitor would be considered a potential alternative to chemotherapy or radiation at time of recurrence. In summary, our case highlights a rare variant of PXA presenting with acute haemorrhage defined by a novel TPM3-NTRK1 fusion that may be amenable to targeted therapy.

Learning points

  • Pleomorphic xanthoastrocytoma (PXA) may present with acute intracranial haemorrhage.

  • NTRK fusions can occur in PXAs in paediatric patients.

  • Although BRAF V600E mutations are the most common molecular aberration in PXAs, molecular genetic testing on these tumours may identify other pharmacologically targetable mutations.

References

Footnotes

  • Contributors KCP, DMM, MLL and JRC were responsible for the design and writing of the manuscript and approval of its content.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Parental/guardian consent obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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