Introduction: Low-grade neuroepithelial tumors are a heterogeneous group of central nervous system tumors that are generally indolent in nature but in rare instances can progress to include leptomeningeal dissemination. Case Presentation: We present a case of a patient with a low-grade neuroepithelial tumor of indeterminate type with symptomatic leptomeningeal dissemination despite 3 chemotherapy regimens and radiotherapy. Somatic targetable mutation testing showed an FGFR1_TACC1 fusion. Therapy with pazopanib/topotecan was initiated, and disease stabilization was achieved. He received pazopanib/topotecan for a total of 2 years and is now >2 years from completion of treatment and continues to do well with no evidence of disease. Discussion: This case highlights the utility of targetable mutation testing in therapeutic decision-making and the novel use of systemic pazopanib/topotecan therapy for refractory low-grade neuroepithelial tumor within the context of this clinical situation and specific mutation profile.

Established Facts

  • Pazopanib has moderate selectivity against FGFR1-3.

  • Topotecan has shown utility in brain tumors due to its ability to penetrate the blood-brain barrier and inhibiting effects on cell growth in human glioma cells.

Novel Insights

  • Pazopanib/topotecan therapy was found to be effective in a case of refractory low-grade neuroepithelial tumor with an FGFR_TACC1 fusion.

Pediatric low-grade neuroepithelial tumors are a heterogeneous group of central nervous system tumors. Individuals may present with generalized symptoms such as nausea, vomiting, and lethargy as well as localized symptoms depending on the location of the tumor [1]. Low-grade neuroepithelial tumors are generally indolent tumors. One retrospective cohort study showed a 94.6% five-year overall survival (OS) and a 69.4% five-year progression-free survival (PFS) [2]. Another study demonstrated that gross total resection was highly predictive of PFS [3]. The 5-year PFS for patients with gross total resection was 94% compared to 59% and 53% for patients with residual tumor <1.5 cm3 and ≥1.5 cm3, respectively [3]. Treatment of pediatric low-grade neuroepithelial tumors varies depending on the extent of surgical resection. Following gross total resection, close clinical and/or radiographic follow-up is preferred [1]. For patients with subtotal resection or unresectable tumor, adjuvant treatment is controversial, and a “wait and see approach” is often taken with chemotherapy administered at first signs of progression [1].

A previously healthy 12-year-old boy was brought to the emergency department by an ambulance due to abrupt onset of vomiting and confusion which quickly progressed to obtundation. Head CT showed a bifrontal mass with calcifications and ventriculomegaly requiring placement of bilateral occipital external ventricular catheters. Magnetic resonance imaging (MRI) of the brain showed a heterogeneous multilobulated mass extending between the frontal lobes, encasing the anterior cerebral arteries (Fig. 1a, b). MRI of the spine was negative. Partial resection of the tumor was performed along with removal of the left external ventricular catheter due to fenestration of the septum during surgery resulting in communication between the 2 lateral ventricles. His right external ventricular catheter was slowly weaned and removed 6 days following surgery. Pathology showed a low-grade neuroepithelial tumor of indeterminate type (Fig. 2a–d). Initial follow-up MRI at 3 months following surgery showed stable disease (Fig. 1c, d). MRI at 10 months following surgery showed progression; vincristine and carboplatin were initiated. Follow-up MRI showed ongoing progression, and thus chemotherapy was changed to thioguanine/procarbazine/lomustine/vincristine (TPCV) and eventually vinorelbine; however, sequential MRIs continued to show radiographic progression. During vinorelbine treatment, he presented with abrupt onset of somnolence and was found to have tumor-related obstructive hydrocephalus (Fig. 1e) requiring emergent ventriculoperitoneal shunt placement 2 years following his original diagnosis. Radiation therapy was initiated due to symptomatic local tumor progression. Proton beam therapy was chosen to minimize dose to the cerebral arteries and optic pathways. He received 5,400 cGy to areas of residual tumor. Pre-radiation imaging showed localized disease; however, after radiation therapy was completed, MRI showed concern for new development of diffuse leptomeningeal disease involving the brain and the cervical spine (Fig. 1f). Cerebrospinal fluid cytology was negative for malignant cells but was not assessed for protein. He was initially observed; however, MRI demonstrated ongoing progression of diffuse leptomeningeal disease (Fig. 1g). Somatic targetable mutation testing showed an FGFR1_TACC1 fusion and a BRCA2 mutation. The latter was confirmed to be of germline origin with no evidence for a second somatic mutation. He had seizures controlled on levetiracetam.

Fig. 1.

Radiology: Magnetic resonance images. a Initial presentation, coronal T2 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). b Initial presentation, sagittal T1 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). c Postoperative T2 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). d Postoperative sagittal T1 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). e Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) demonstrates development of obstructive hydrocephalus and transependymal edema (white arrow heads) during vinorelbine treatment. f Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with new pachymeningeal enhancement (white arrow). g Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with progressive pachymeningeal and leptomeningeal enhancement (white arrows). h Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with progressive pachymeningeal and leptomeningeal enhancement (white arrows). i Axial postcontrast FLAIR sequence (1.5 T MRI). Less prominent appearance of the primary lesion (black arrows) as well as less conspicuous meningeal enhancement (white arrows) 2 months after starting pazopanib and topotecan therapy. j Axial postcontrast FLAIR sequence (1.5 T MRI). Continued improvement with less prominent appearance of the primary lesion (black arrows) as well as continued resolving meningeal enhancement (white arrows) 7 months after starting pazopanib and topotecan therapy. k Axial postcontrast FLAIR sequence (3.0 T MRI). Continued improvement with less prominent appearance of the primary lesion (black arrows) as well as continued resolving meningeal enhancement 19 months after starting pazopanib and topotecan therapy. l Axial postcontrast FLAIR sequence (3.0 T MRI). Stable appearance of the primary lesion (black arrows) with no new meningeal enhancement following completion of pazopanib and topotecan therapy.

Fig. 1.

Radiology: Magnetic resonance images. a Initial presentation, coronal T2 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). b Initial presentation, sagittal T1 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). c Postoperative T2 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). d Postoperative sagittal T1 sequence. Mass (black arrows) indicates relationship to the optic pathway (white arrows). e Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) demonstrates development of obstructive hydrocephalus and transependymal edema (white arrow heads) during vinorelbine treatment. f Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with new pachymeningeal enhancement (white arrow). g Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with progressive pachymeningeal and leptomeningeal enhancement (white arrows). h Axial postcontrast FLAIR sequence (1.5 T MRI). Enhancing mass (black arrows) with progressive pachymeningeal and leptomeningeal enhancement (white arrows). i Axial postcontrast FLAIR sequence (1.5 T MRI). Less prominent appearance of the primary lesion (black arrows) as well as less conspicuous meningeal enhancement (white arrows) 2 months after starting pazopanib and topotecan therapy. j Axial postcontrast FLAIR sequence (1.5 T MRI). Continued improvement with less prominent appearance of the primary lesion (black arrows) as well as continued resolving meningeal enhancement (white arrows) 7 months after starting pazopanib and topotecan therapy. k Axial postcontrast FLAIR sequence (3.0 T MRI). Continued improvement with less prominent appearance of the primary lesion (black arrows) as well as continued resolving meningeal enhancement 19 months after starting pazopanib and topotecan therapy. l Axial postcontrast FLAIR sequence (3.0 T MRI). Stable appearance of the primary lesion (black arrows) with no new meningeal enhancement following completion of pazopanib and topotecan therapy.

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Fig. 2.

Pathology: hematoxylin and eosin stains. a Cytologic preparation showing neoplastic population with oval nuclei, fine chromatin, and delicate cytoplasmic processes. Original magnification, ×400. b Histology showing moderately cellular clear cell neoplasm. Original magnification, ×200. c Histology showing scatter dense areas. Original magnification, ×200. d Histology showing scattered irregular microcystic spaces.

Fig. 2.

Pathology: hematoxylin and eosin stains. a Cytologic preparation showing neoplastic population with oval nuclei, fine chromatin, and delicate cytoplasmic processes. Original magnification, ×400. b Histology showing moderately cellular clear cell neoplasm. Original magnification, ×200. c Histology showing scatter dense areas. Original magnification, ×200. d Histology showing scattered irregular microcystic spaces.

Close modal

Based on the FGFR1_TACC1 fusion, pazopanib/topotecan therapy was initiated at 15 years of age. He received 800 mg oral pazopanib once daily, and 8 mg oral topotecan once weekly, based on dosing from a phase I trial [4]. MRIs throughout treatment with pazopanib/topotecan showed overall improvement in primary tumor size and leptomeningeal enhancement (Fig. 1i–k) compared to pretreatment imaging (Fig. 1h). Although the decrease in primary tumor size may be related to prior radiation therapy, the improving areas of leptomeningeal disease were not within the radiation field. He received pazopanib/topotecan for a total of 2 years and is now >2 years from completion of treatment and 6 years from initial diagnosis and remains alive and well. The most recent MRI study continues to show stable disease (Fig. 1l). He has hypothyroidism and adrenal insufficiency which are expected based on tumor location. An echocardiogram shortly after starting pazopanib/topotecan showed low-normal cardiac ejection fraction which was asymptomatic and of unclear etiology with no previous studies for comparison. No other significant side effects were noted during pazopanib/topotecan therapy.

Leptomeningeal dissemination (LMD) is a rare complication of low-grade neuroepithelial tumors. A retrospective study of 427 pediatric patients with low-grade neuroepithelial tumors found 177 patients with progression, and of those patients only 7% (13/177) had LMD with a 5- and 10-year OS of 68% compared to 83% for those who progressed only at the primary site [5]. Leptomeningeal dissemination was defined by neuroimaging, clinical neurologic signs, cerebrospinal fluid cytology, or biopsy confirmation [5]. No standard of care is defined for LMD, and treatment of the 13 patients varied from supportive care to surgical resection, radiation, systemic chemotherapy, or a combination [5]. Additionally, a study of 599 patients with low-grade gliomas found 38 patients (6.3%) with metastatic disease, 84% (32/38) with LMD [6]. The OS of the 38 patients with metastatic disease at 5, 10, and 15 years was 80.7%, 63.0%, and 50.9%, respectively [6]. The HIT-LGG-1996 study reported 61 patients with low-grade gliomas with disseminated disease out of 1,181 total patients (5.2%) [7]. The authors did not report OS for all 61 patients with disseminated disease, but the 5-year OS for patients with disseminated disease at diagnosis (n = 23) was 73% [7]. Reported incidence and outcomes are inconsistent for patients with disseminated low-grade neuroepithelial tumors [5‒7].

Current chemotherapy options for patients with low-grade neuroepithelial tumors include carboplatin and vincristine which have been shown to be effective in tumor reduction or stabilization with a 3-year PFS of 68% [8]. Additionally, a randomized trial that compared carboplatin and vincristine with TPCV demonstrated higher event-free survival for patients treated with TPCV although the difference was not statistically significant [9]. Vinorelbine has also showed promise in progressive unresectable low-grade glioma with the advantage of low toxicity [10]. Despite treatment with carboplatin and vincristine, TPCV, and vinorelbine chemotherapy regimens and radiotherapy, our patient demonstrated symptomatic progression. In this case, proton beam radiation therapy was preferred over traditional radiotherapy due to its ability to spare critical surrounding structures and the potential for decreased long-term toxicity.

An FGFR1_TACC1 fusion was found on testing of our patient’s tumor. The frequency of FGFR-TACC fusions in pediatric low-grade gliomas is 6–7% [11]. The incidence of FGFR1_TACC1 is considerably lower than FGFR3_TACC3 rearrangements, but based on available information, the biological and oncogenic effects are similar [12]. Additionally, a clinical analysis of >1,000 pediatric low-grade gliomas found 14 tumors with FGFR1_TACC1 fusion alterations; none of them resulted in death at a median follow-up of 11.3 years [13]. The FGFR1_TACC1 fusion was assigned within the low-risk category with a 10-year OS of 98% compared to 92% and 41% for the intermediate- and high-risk categories, respectively [13]. The FGFR family encompasses 4 transmembrane tyrosine kinase receptors (FGFR1-4) and is a fundamental receptor in the tyrosine kinase signaling pathway [14]. The TACC protein family contains 3 members (TACC1-3) and mediates localization to the centrosome and mitotic spindle [11]. The FGFR-TACC fusions generate an oncogene that combines growth-promoting effects with aneuploidy [11].

After continued disease progression and targetable mutation testing in the adolescent described in this case report, pazopanib/topotecan therapy was initiated. Pazopanib is a tyrosine kinase inhibitor that is selective for multiple receptors that promote angiogenesis [15]. Pazopanib has moderate selectivity against FGFR1-3 [15]. The efficacy of pazopanib against FGFR amplification has been demonstrated in a patient with metastatic breast cancer with FGFR1 amplification, metastatic endometrial carcinoma with FGFR2 amplification, and urothelial carcinoma with a FGFR3-activating mutation [16‒18]. Topotecan is a topoisomerase I inhibitor that has shown utility in brain tumors due to its ability to penetrate the blood-brain barrier and inhibiting effects on cell growth in human glioma cells [19, 20].

The use of pazopanib and topotecan together has shown significant antitumor activity in mouse models of aggressive extracranial pediatric solid tumors [21]. Additionally, a phase I trial showed a 1.7-fold increase in topotecan exposure when co-administered with pazopanib as well as demonstrating preliminary efficacy in individuals with advanced platinum-resistant ovarian cancer, all of whom were previously treated with carboplatin [4]. Topotecan alone has shown utility in pediatric patients with newly diagnosed medulloblastoma and supratentorial primitive neuroectodermal tumor [22]. Additionally, topotecan showed potential efficacy in a phase I trial of pediatric patients with refractory solid tumors including complete response in neuroblastoma and stable disease in neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma [23]. Oral topotecan has also been shown to be somewhat effective in pediatric patients with recurrent or progressive high-grade glioma [24].

The adolescent presented in this case report was found to be heterozygous for a BRCA2 mutation without a second somatic mutation. BRCA mutations are generally associated with adult cancers, and tumorigenesis in germline BRCA1/2 generally obeys the 2-hit hypothesis, thus the relationship of his tumor to his underlying germline alteration remains unclear [25].

In conclusion, we present a case of low-grade neuroepithelial tumor of indeterminate type which progressed to include LMD with successful disease control using pazopanib/topotecan therapy. This case highlights the utility of targetable mutation testing in therapeutic decision-making and the novel use of systemic pazopanib/topotecan therapy to control refractory low-grade neuroepithelial tumor within the context of this specific mutation profile.

We wish to thank the individual and family in this report for their support of this publication. We also wish to thank Dr. Michael McCue, Peter Clarine, and Therese Stussy for their clinical care and expertise.

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Ethical approval was not required for this study in accordance with national guidelines. Written informed consent was obtained from the individual participant for publication of this case report and any accompanying images.

The authors declare no conflicts of interest.

No funds, grants, or other support was received.

A.T.N. wrote the manuscript. A.B. and M.S. contributed to patient care and edited the manuscript. S.P. and W.M. provided the figures, captions, and edited the manuscript. U.T. provided expert consultation and edited the manuscript. K.A.P.S. wrote the manuscript and contributed to patient care.

All data generated or analyzed during this study are included in this article. Further inquiries may be directed to the corresponding author.

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