Durable Major Response With Pazopanib in Recurrent, Heavily Pretreated Metastatic Esthesioneuroblastoma Harboring a Fumarate Hydratase Mutation


Marianne Spengler , MD1; Megan Wheelden , MD1; Heath B. Mackley, MD2; and Joseph J. Drabick, MD1

Esthesioneuroblastoma (also known as olfactory neuroblastoma) is a rare cancer of neural crest origin that arises in the olfactory epithelium of the upper nasal cavity. It accounts for only 3%-5% of sinonasal tumors.1 Patients commonly present with epistaxis, nasal obstruction, and olfactory and ophthalmic disturbances.2,3 Definitive diagnosis requires both radiography and histopathology. Computed tomography and magnetic resonance imaging (MRI) are used to detail bony involvement and tumor extension to adjacent structures for staging.2 Histologically, esthesioneuroblastoma appears as characteristic nests of small blue cells separated by fibrovascular septa. Immunohistochemistry aids in distinguishing esthesioneuroblastoma from other small, round, blue cell neoplasms occurring in the sinonasal tract, such as lymphoma, Ewing’s tumor, and rhabdomyosarcoma.1

Owing to its rarity and resultant lack of prospective randomized studies to guide therapy, there is currently no defined standard first-line treatment for esthesioneuroblastoma. The generally accepted standard of care is extrapolated from treatment of other head and neck cancers and usually consists of surgery followed by radiation and sometimes chemotherapy,2,4 although neoadjuvant concurrent chemoradiation for locally advanced esthesioneuroblastoma has also been described.5

The clinical course of treated esthesioneuroblastoma is variable, with published 5-year survival rates ranging from 45% to 90%.2,6,7 Recurrences occur within the first 2-3 years in up to 50% of cases, but recurrences are common as far as 5-10 years after initial diagnosis.1,4 Cervical nodal metastasis and distant metastasis occur in 25% and 10% of cases, respectively.1,8 For recurrent or progressive disease after initial therapy, systemic chemotherapy has been disappointing.3,9 The introduction of biologically targeted agents, including small molecules and monoclonal antibodies, has provided additional treatment options for many cancers, including esthesioneuroblastoma. Several case reports have shown success with these agents,10 and we add to the growing evidence base by presenting a case of recurrent metastatic esthesioneuroblastoma in which a prolonged partial response was achieved with pazopanib for over 4 years and ongoing as of this report.

Pazopanib is an oral multi-tyrosine kinase inhibitor (TKI) that targets angiogenesis by inhibiting vascular endothelial growth factor receptors (vascular endothelial growth factor receptor [VEGFR]-1, -2, and -3), platelet-derived growth factor receptors (platelet-derived growth factor receptor-α and -β), stem cell factor receptor (c-KIT), and fibroblast growth factor receptor-1 and -3.11 It is approved by the US Food and Drug Administration for treatment of renal cell carcinoma and certain types of soft tissue sarcoma

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