Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy.

Background: Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients. Methods: We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. Results: Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm. Conclusions: Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.

Lacrimal Sac Smooth Muscle Tumor of Uncertain Malignant Potential.

A 13-year-old male presented with recurrent left nasolacrimal duct obstruction following endoscopic dacryocystorhinostomy 4 years prior at an outside institution. The past medical history was significant for stage IV neuroblastoma, diagnosed at age 2, requiring surgical resection, induction chemotherapy, autologous bone marrow transplantation and radiation, currently in remission. Preoperative CT scan demonstrated a 2 cm ovoid mass centered in the left lacrimal fossa, consistent with dacryocystocele; however, a solid tumor could not be ruled out. Subsequent surgical exploration of the lacrimal sac revealed a friable, solid mass filling the lacrimal sac, and extending into the duct. The mass was grossly resected with preservation of the lacrimal drainage system and placement of indwelling silicone stents. Histopathology confirmed the diagnosis of smooth muscle tumor of uncertain malignant potential. The patient remained free of epiphora and showed no clinical or radiographic evidence of recurrence at 6 months of follow up.

Orbital schwannomatosis in the absence of neurofibromatosis.

PURPOSE: The aim of this study was to describe 3 cases of primary orbital schwannomatosis without associated systemic neurofibromatosis. METHODS: This is a retrospective interventional study of 3 patients who presented with multiple, distinct masses in the orbit (n = 3) as well as in the hemiface (n = 1). The clinical presentation, imaging features, surgical procedures, and outcomes were defined. RESULTS: Two women and a man presented with of exophthalmos and diplopia. Pain was the most prominent complaint in 2 patients. None of the patients had associated systemic neurofibromatosis by history or examination. Radiologic evaluation with computed tomography or magnetic resonance imaging of orbit revealed multiple well-demarcated intraconal and extraconal masses. Masses were excised, and histopathology confirmed all masses to be schwannomas. Postoperative follow-up was uneventful with alleviation of primary complaints in all patients. CONCLUSIONS: Multiple orbital schwannomas (primary orbital schwannomatosis) may be observed in patients without systemic association of neurofibromatosis. Management includes surgical excision of the tumors to achieve relief from their mass effects.