Updated Insights into the Molecular Pathophysiology of Olfactory Neuroblastoma Using Multi-Omics Analysis

Abstract

Background/Objectives: Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare neuroectodermal malignancy of the nasal cavity characterized by aggressive local invasion and variable metastatic potential, with diverse clinical behavior, often presenting at advanced stages. ONB poses challenges for targeted therapeutic strategies, despite advances in surgical and multimodal treatment strategies, because of the rarity of this disease and the limited understanding of its molecular pathophysiology. Methods: A comprehensive review of genomic, multi-omic, and molecular studies was performed to integrate known targeted sites in ONB with the current understanding of its pathophysiology. Results: Recent genetic and molecular studies have identified significant epigenetic and signaling pathway alterations that are critical in pathogenesis and treatment resistance and may serve as potential therapeutic targets. Additionally, novel discovered immunohistochemical and transcriptomic markers, such as IDH2, NEUROD1, and OTX2, offer improved diagnostic specificity and prognostication. Multi-genomic platforms (i.e., multi-omics), involving the combined integration of transcriptomics, epigenetics, and proteomics findings, have led to several recent insights, including the subclassification of neural and basal genomic subtypes, the identification of key driver mutations, and new insights into disease development. This review synthesizes current knowledge on the molecular landscape of ONB, including its tumor origin, immune microenvironment, genetic alterations, and key molecular pathways involved in its pathogenesis. Conclusions: Future research may benefit from integrating these findings into precision medicine approaches, enabling earlier diagnosis and more accurate prognosis.

Keywords: esthesioneuroblastoma; genetic alterations; molecular markers; molecular pathways; olfactory neuroblastoma; therapy.

Figure 1

Tumor microenvironment of olfactory neuroblastoma. Some important factors involved in the regulation of the tumor microenvironment of olfactory neuroblastoma are shown based on the available supportive evidence. Targeted therapy with immunomodulators has been supported as a potential treatment path. Important genomic subclasses demonstrate distinct genomic distinctions. Basal ONB shows greater infiltration of tumor-infiltrating lymphocytes compared with neural ONB. DC: dendritic cell; MDSC: myeloid-derived suppressor cell; NK: natural killer; TAM: tumor-associated macrophage.

Figure 2

Signaling pathogenesis of olfactory neuroblastoma. Some important signaling factors involved in tumor pathogenesis are shown in olfactory neuroblastoma. Therapeutic targets with vismodegib, 177Lu-Dotatate, tyrosine kinase inhibitors (e.g., sunitinib, pazopanib, imatinib), and everolimus have been investigated. EGFR: epidermal growth factor receptor; FGFR: fibroblast growth factor receptor; HIF-1A: hypoxia-inducible factor 1 alpha; MAPK: mitogen-activated protein kinase; NF1: neurofibromin 1; PI3K: phosphoinositide 3-kinase; PTCH: patched receptor; Shh: sonic hedgehog; SMO: smoothened receptor; SSTR2: somatostatin receptor 2; TRKA: neurotrophic tyrosine receptor kinase.