Olfactory Neuroblastoma: How Molecular Research Is Reshaping a Rare Nasal Cancer

Table of Contents

• Key Points
• Background: Why This Research Matters
• What Is Olfactory Neuroblastoma?
• Current Standard Treatment
• How Doctors Currently Assess Prognosis
• A New Way to Classify ONB: Three Molecular Functional States
• The Proliferative Functional State
• The Neuroendocrine-Differentiated Functional State
• The Mesenchymal and Stromal-Associated Functional State
• The Molecular Landscape of ONB
• Genomic Alterations in ONB
• Epigenetic Dysregulation
• Neuroendocrine-Associated Transcription Factors
• The Tumor Microenvironment
• Emerging Targeted Treatment Strategies
• Clinical Implications: What This Means for Patients
• Limitations: What the Research Could Not Prove
• Recommendations and Future Directions
• Frequently Asked Questions
• Source Information

Key Points

• Olfactory neuroblastoma is a rare cancer of the upper nasal cavity, accounting for about 2–6% of nasal and sinus cancers, with new cases peaking between ages 40 and 60.
• Standard treatment is multimodal, mainly surgery plus radiotherapy, with chemotherapy reserved for advanced, recurrent, or metastatic disease; recurrence rates remain substantial.
• Current staging and grading systems do not fully explain why patients with similar grades can have very different disease trajectories and treatment responses.
• A recent review proposes three conceptual molecular functional states—proliferative, neuroendocrine-differentiated, and mesenchymal/stromal-associated—but these are not validated subtypes.
• Targeted strategies such as PRRT, anti-angiogenic, epigenetic, immunotherapy, and DNA-damage-response approaches are being explored, but none is standardized and evidence remains limited.

Background: Why This Research Matters

Olfactory neuroblastoma (ONB) is a rare cancer that starts in the upper part of the nasal cavity. It accounts for approximately 2–6% of all cancers that begin in the nasal cavity and sinuses. The disease can occur at any age, but new cases peak in people between 40 and 60 years old. Men and women are affected equally.

ONB behaves very differently from one patient to the next. Some tumors grow slowly and stay in one place. Others are highly aggressive and invade nearby tissue, come back after treatment, or spread to distant parts of the body. Because the disease is so rare, doctors still do not fully understand its biology or the best way to treat it.

This review article brings together recent molecular research on ONB. The authors explain how new genomic and transcriptomic studies are changing the way scientists think about this cancer. The review also discusses emerging targeted treatment strategies and the challenges that remain.

What Is Olfactory Neuroblastoma?

Olfactory neuroblastoma, also called esthesioneuroblastoma, is a malignant tumor that arises from the olfactory epithelium (the smell-sensing tissue) in the sinonasal tract. The sinonasal tract includes the nasal cavity and the sinuses. The tumor is a neuroectodermal neoplasm, which means it develops from cells related to the nervous system.

ONB shows a broad spectrum of clinical behavior. At one end of the spectrum, the tumor is indolent (slow-growing) and stays localized. At the other end, the tumor is highly aggressive, with local invasion, recurrence, and distant metastasis (spread to other organs).

Because ONB is rare, its biological characteristics and optimal treatment remain incompletely understood. This lack of knowledge is a major challenge for doctors who treat patients with this disease.

Current Standard Treatment

The current standard treatment for ONB is multimodal therapy, which means using more than one treatment approach. The main combination is surgery plus radiotherapy. Chemotherapy is mainly reserved for advanced, recurrent, or metastatic disease.

Surgical techniques have improved over time. Craniofacial resection and endoscopic skull-base surgery have improved local disease control. Radiation techniques have also advanced. Intensity-modulated radiotherapy and stereotactic techniques have enhanced treatment precision.

Despite these advances, recurrence rates remain substantial. This is especially true for advanced-stage tumors. The long-term management of recurrent or treatment-refractory ONB (tumors that do not respond to treatment) continues to be a major clinical challenge.

How Doctors Currently Assess Prognosis

Doctors currently assess the prognosis of ONB mainly through clinical staging systems. The two main systems are the modified Kadish classification and the Dulguerov classification. In addition, the Hyams histological grading system is used to evaluate the tumor's microscopic features.

The Kadish system stratifies tumors based on anatomical extension (how far the tumor has spread within the nasal cavity and sinuses). The Hyams grading system evaluates histopathological differentiation and mitotic activity (how fast cells are dividing). The Hyams grading system also evaluates necrosis (dead tissue within the tumor). The Hyams grading system also evaluates neurofibrillary matrix formation (a structural feature seen under the microscope).

Recent multicenter studies and meta-analyses have confirmed that these systems have prognostic significance for survival and recurrence outcomes. However, these classification systems do not fully explain the marked heterogeneity (diversity) observed in treatment response and clinical outcome.

Patients with similar pathological grades may have substantially different disease trajectories. This observation points to underlying molecular and biological diversity that current staging systems cannot capture.

A New Way to Classify ONB: Three Molecular Functional States

Recent genomic and transcriptomic studies have identified distinct transcriptional programs in ONB. These programs are associated with proliferative activity, neuroendocrine differentiation, and stromal or mesenchymal signaling. This suggests that biologically diverse functional states exist within ONB.

The authors of this review integrate these observations into a proposed conceptual framework. The framework includes three molecular functional states:

• Proliferative — tumors with high cell-cycle activity
• Neuroendocrine-Differentiated — tumors enriched in neuroendocrine programs
• Mesenchymal/Stromal-Associated — tumors linked to stromal remodeling and aggressive behavior

The authors emphasize that this framework is intended to help interpret current molecular evidence. It is not a validated molecular classification system. The stromal- and angiogenesis-associated transcriptional signatures identified in current studies may reflect stromal or microenvironment-associated signals. They do not conclusively demonstrate a tumor-cell-intrinsic mesenchymal differentiation program.

Therefore, the proposed Mesenchymal/Stromal-Associated state should be interpreted as a conceptual stromal-associated functional state. Its biological basis requires further validation.

The table below shows how the proposed functional states relate to previously published molecular classification frameworks of ONB.

• Proliferative state: Corresponds to the basal-like subgroup described in one framework and the basal subtype within the Neural–Basal–Mesenchymal (NBM) classification in another. It represents a conceptual functional state integrating proliferative transcriptional programs reported across recent studies.
• Neuroendocrine-Differentiated state: Corresponds to the neural-like subgroup and the neural subtype within the NBM classification. It represents a conceptual functional state integrating neuroendocrine differentiation programs reported across recent studies.
• Mesenchymal/Stromal-Associated state: Not identified in one framework and not specifically described in another. It is a conceptual functional state proposed in this review based primarily on the mesenchymal subtype described by Yang et al. (2024).

The proposed molecular functional states represent a conceptual integration of transcriptional programs described in previous molecular classification studies. They do not represent formally established molecular subtypes.

The Proliferative Functional State

Transcriptomic studies have identified ONB subgroups that show proliferative transcriptional programs and progenitor-like characteristics. In this review, these observations are conceptually integrated into a proliferative functional state. This is not a formally established molecular subtype.

These tumors demonstrate elevated expression of genes associated with mitotic progression (cell division), DNA replication, and cellular proliferation. Research on small-cell lung cancer (SCLC) suggests that proliferative transcriptional states may correlate with more aggressive clinicopathologic features.

In some studies, tumors with increased proliferative signatures have been associated with higher Hyams grade, increased mitotic activity, necrosis, and reduced neurofibrillary matrix formation. These features suggest a more aggressive tumor biology.

The Neuroendocrine-Differentiated Functional State

Neuroendocrine differentiation is a defining feature of ONB and remains central to its pathologic diagnosis. However, recent transcriptomic studies suggest that the degree of neuroendocrine-associated signaling may vary across tumors.

Neuroendocrine-enriched ONB states demonstrate increased expression of markers and transcriptional regulators associated with neuroendocrine lineage differentiation. These include synaptophysin, chromogranin A, INSM1, SSTR2, ASCL1, and NEUROD1. These tumors may share certain biological features with other neuroendocrine neoplasms.

Somatostatin receptor 2 (SSTR2) is frequently expressed in neuroendocrine-enriched ONB. SSTR2 represents one of the characteristic markers of this transcriptional state. Beyond its diagnostic value, SSTR2 also provides the biological rationale for receptor-targeted imaging and peptide receptor radionuclide therapy (PRRT). These approaches are discussed in the targeted therapy section below.

The Mesenchymal and Stromal-Associated Functional State

Transcriptomic analyses have identified subsets of ONB that demonstrate increased expression of genes associated with stromal organization, extracellular matrix (ECM) remodeling, and angiogenesis-related pathways. Angiogenesis is the formation of new blood vessels. These findings suggest that certain tumors may exhibit microenvironmental and stromal features distinct from more neuroendocrine-differentiated states.

The biological significance of mesenchymal or stromal-associated transcriptional programs in ONB remains incompletely understood. However, stromal enrichment and angiogenesis-related signaling have been associated with aggressive behavior in several solid malignancies. These features may contribute to intertumoral heterogeneity (differences between tumors) in ONB.

Angiogenesis-related pathways have attracted particular interest in this context. Some studies have reported increased microvessel density and angiogenesis-associated marker expression in ONB, especially in advanced disease. Nevertheless, clinical evidence supporting anti-angiogenic therapy in ONB remains limited.

The composition of the tumor microenvironment (TME) may also influence immune-cell infiltration and therapeutic response. Stromal remodeling and immune exclusion have been described in other malignancies. However, comparable mechanisms in ONB have not yet been well characterized.

These transcriptional states do not exist in isolation. They are likely driven by specific genomic alterations and maintained by a supportive TME. To fully understand the biological basis of these states, researchers must look beyond the transcriptome to identify the upstream drivers.

Current evidence remains insufficient to establish these transcriptional states as validated molecular subtypes. They should be regarded as emerging transcriptional programs reflecting distinct functional states. Future studies integrating transcriptomic, genomic, and clinical data will be required to determine their biological and clinical relevance.

The Molecular Landscape of ONB

Building on the biological framework described above, the review now explores the upstream genomic and epigenomic mechanisms that orchestrate these distinct molecular states. Genomic refers to changes in DNA sequence. Epigenomic refers to changes that affect gene activity without altering the DNA sequence itself.

Genomic Alterations in ONB

Compared with more common solid tumors, the genomic landscape of ONB remains poorly characterized. This is largely because of its rarity and the limited availability of large sequencing cohorts. Nevertheless, recent molecular studies have identified several recurrent alterations that may play a role in ONB pathogenesis.

IDH2 mutations — particularly involving the R172 hotspot — have been reported in a subset of sinonasal tumors historically diagnosed as ONB. These mutations represent one of the most notable molecular alterations associated with this diagnostic spectrum. Mutant IDH2 promotes accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). This metabolite has been linked to epigenetic dysregulation, altered DNA methylation, and impaired cellular differentiation.

The identification of IDH2 alterations has generated interest in the potential application of mutant-IDH inhibitors. However, such therapeutic implications remain exploratory in sinonasal tumors. They should be interpreted cautiously until validated in molecularly confirmed ONB cohorts.

The interpretation of IDH2 R172 mutations in ONB requires caution. Recent molecular studies have suggested that some IDH2-mutant sinonasal tumors may represent a distinct molecular entity rather than conventional ONB. This includes cases historically diagnosed as sinonasal undifferentiated carcinoma (SNUC) or poorly differentiated sinonasal carcinoma. Therefore, some previously reported IDH2-mutant ONB cases may warrant reassessment based on integrated morphological, immunophenotypic, and molecular features. Whether IDH2 R172 mutations represent a bona fide ONB driver remains unresolved.

Accordingly, IDH2 R172 mutations should not currently be regarded as a defining genomic alteration in conventional ONB. Molecular findings from IDH2-mutant sinonasal tumors should be interpreted with caution until validated in diagnostically confirmed ONB cohorts.

Other reported genomic abnormalities include:

• TP53 mutations
• Alterations affecting the PI3K/AKT/mTOR signaling pathway
• DMD deletions (dystrophin gene deletions)
• NOTCH pathway dysregulation

However, no single dominant oncogenic driver has been consistently identified across published cohorts. This suggests substantial molecular heterogeneity among ONB tumors.

Copy-number alterations appear to be more frequent in biologically aggressive tumors. Several studies using comparative genomic hybridization have identified recurrent chromosomal gains and losses in ONB. This suggests underlying chromosomal instability. Some reports have suggested associations between chromosomal instability and adverse clinical behavior. However, these findings remain limited by small sample size and cohort heterogeneity.

In contrast to sinonasal undifferentiated carcinoma and several other head and neck malignancies, ONB generally exhibits a relatively low tumor mutational burden (TMB). TMB is a measure of how many mutations are present in a tumor's DNA.

Taken together, the available data support the concept that ONB comprises a biologically heterogeneous group of tumors rather than a single molecular entity.

The table below summarizes the molecular alterations and biological features reported in ONB.

• Genomic alterations: IDH2 mutations, chromosomal instability, copy-number alterations, TP53 mutations, alterations in the PI3K/AKT/mTOR pathway, DMD deletions, NOTCH pathway dysregulation. Biological relevance: molecular heterogeneity and altered tumor biology.
• Epigenetic dysregulation: DNA methylation changes; EZH2-associated transcriptional regulation. Biological relevance: altered transcriptional regulation and tumor progression.
• Neuroendocrine differentiation: Neuroendocrine markers INSM1, CHGA, SYP, CD56; transcription factors ASCL1, NEUROD1, OTX2. Biological relevance: supports neuroendocrine lineage characteristics of ONB.
• Proliferative signaling: Cell-cycle-related transcriptional programs and increased proliferative activity. Biological relevance: associated with aggressive clinicopathologic behavior.
• Tumor microenvironment: Variable immune infiltration and stromal composition. Biological relevance: potential influence on immune activity and therapeutic responsiveness.
• Angiogenesis-associated signaling: Increased microvessel density, VEGF expression, and angiogenesis-related signaling. Biological relevance: potential role in tumor progression and aggressive disease behavior.
• Stromal remodeling: ECM organization and stromal-associated transcriptional programs. Biological relevance: tumor heterogeneity and invasive phenotype.
• Molecular heterogeneity: Proliferative, neuroendocrine-differentiated, and stromal-associated transcriptional states. Biological relevance: provides insight into subtype-associated biology and intertumoral heterogeneity.

Epigenetic Dysregulation

Epigenetic dysregulation has been increasingly implicated in the molecular biology of ONB. Alterations involving DNA methylation, chromatin remodeling, and transcriptional regulation have been reported in recent molecular profiling studies. These alterations may contribute to neuroendocrine differentiation and tumor heterogeneity.

Methylation profiling analyses suggest that ONB has epigenetic features distinct from those of other sinonasal malignancies. These findings support the possibility that epigenetic alterations contribute to tumor classification and biological behavior. In addition, tumors harboring IDH2 mutations may demonstrate altered methylation patterns associated with impaired cellular differentiation and transcriptional dysregulation.

Epigenetic regulators such as enhancer of zeste homolog 2 (EZH2) have also been implicated in several neuroendocrine malignancies. EZH2-associated chromatin remodeling has been linked to tumor progression and lineage plasticity in other neuroendocrine tumor types, such as treatment-induced neuroendocrine prostate cancer. However, there is still a lack of distinct evidence supporting a comparable role in ONB.

Emerging evidence from other malignancies further suggests that epigenetic alterations may influence immune signaling and antigen presentation. Although these mechanisms have not been well characterized in ONB, they have generated interest in the potential integration of epigenetic therapies with immunotherapeutic approaches in recurrent or advanced disease.

Neuroendocrine-Associated Transcription Factors

ONB characteristically expresses multiple neuroendocrine lineage markers and transcriptional regulators. Conventional neuroendocrine markers — including synaptophysin, chromogranin A, CD56, and INSM1 — are frequently expressed. These markers remain important in routine pathologic diagnosis.

Recent transcriptomic studies have further identified differential expression of developmental transcription factors associated with neural and neuroendocrine differentiation. These include OTX2, ASCL1, and NEUROD1.

Among these, OTX2 has attracted particular interest because of its established role in neuroectodermal development and neuronal lineage specification. Increased OTX2 expression has been reported in ONB and may contribute to maintenance of neuroendocrine differentiation programs.

ASCL1 and NEUROD1 are well-recognized regulators of neuroendocrine lineage states in SCLC and other neuroendocrine malignancies. Their expression in ONB further supports the neuroendocrine phenotype of the tumor. However, their precise biological and therapeutic significance in ONB remains unclear.

INSM1 has recently emerged as a sensitive marker of neuroendocrine differentiation in ONB and other neuroendocrine neoplasms. In addition to its diagnostic utility, INSM1 expression may reflect underlying lineage-specific transcriptional programs involved in neuroendocrine differentiation.

Collectively, neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1) and lineage-associated transcription factors (OTX2, ASCL1, NEUROD1) define a coordinated neuroendocrine regulatory network in ONB. This network reflects both diagnostic and biological dimensions of neuroendocrine differentiation.

Beyond their diagnostic utility, these molecular alterations — ranging from transcriptional dysregulation to specific genomic mutations — carry significant biological implications. For instance, the epigenetic reprogramming driven by IDH2 mutations and the genomic instability associated with TP53 pathway abnormalities may directly influence tumor progression and therapeutic response. Consequently, these features represent promising targets for precision medicine approaches.

The Tumor Microenvironment

The tumor microenvironment (TME) is increasingly recognized as an important component of ONB biology. The TME includes the cells, blood vessels, and other structures that surround and support a tumor.

Recent studies have identified heterogeneous patterns of immune-cell infiltration, stromal immune localization, and immune checkpoint expression across ONB specimens. Immune checkpoints are proteins that regulate immune responses and can be exploited by tumors to evade the immune system.

Emerging evidence also suggests that immunosuppressive microenvironmental features may contribute to disease progression and therapeutic resistance. Accordingly, immunotherapeutic approaches and TME-directed strategies are being explored in recurrent or advanced ONB.

Emerging Targeted Treatment Strategies

Patients with recurrent or metastatic ONB often have limited systemic treatment options. There is no standardized targeted therapeutic strategy for these patients. Despite advances in molecular research, evidence supporting targeted therapies in ONB remains limited because of the rarity of the disease and the lack of large prospective studies.

Current knowledge is derived largely from retrospective analyses, small case series, and extrapolation from other neuroendocrine malignancies. Nevertheless, continued progress in molecular profiling and translational research has improved the understanding of the biological heterogeneity of ONB. This progress may facilitate the development of biomarker-guided therapeutic strategies.

Several potential targeted treatment strategies have generated interest based on molecular findings. These include:

• Peptide receptor radionuclide therapy (PRRT): This approach targets somatostatin receptor 2 (SSTR2), which is frequently expressed in neuroendocrine-enriched ONB. PRRT delivers radiation directly to tumor cells that express SSTR2.
• Anti-angiogenic therapy: This approach targets the formation of new blood vessels that supply the tumor. Angiogenesis-related pathways have attracted interest because some studies have reported increased microvessel density and angiogenesis-associated marker expression in ONB, especially in advanced disease.
• Epigenetic-targeted therapy: This approach targets the epigenetic changes that affect gene activity without altering the DNA sequence. Epigenetic dysregulation has been increasingly implicated in ONB biology.
• Immunotherapy: This approach harnesses the immune system to fight the tumor. Immunosuppressive microenvironmental features may contribute to disease progression and therapeutic resistance, making immunotherapy an area of active investigation.
• DNA-damage-response-targeted approaches: These approaches target the mechanisms that tumor cells use to repair DNA damage. Genomic instability and chromosomal instability have been reported in ONB.

The authors note that although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging.

Clinical Implications: What This Means for Patients

The findings summarized in this review have several important implications for patients with ONB.

First, ONB is not a single uniform disease. It is a group of tumors with different biological characteristics. This means that two patients with the same pathological grade may have very different disease trajectories and responses to treatment.

Second, current staging and grading systems — while still clinically valuable — do not fully explain the differences in treatment response and clinical outcome among patients. Molecular profiling may eventually provide additional information that helps doctors predict how a patient's tumor will behave.

Third, several potential targeted treatment strategies are being explored for recurrent or advanced ONB. These include PRRT, anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. However, none of these strategies is currently standardized, and evidence supporting their use remains limited.

Fourth, the identification of specific molecular alterations — such as IDH2 mutations, TP53 mutations, and alterations in the PI3K/AKT/mTOR pathway — may eventually guide treatment decisions. However, the clinical implications of these findings are still being clarified.

Fifth, the tumor microenvironment may influence how well a patient responds to treatment. Immune-cell infiltration, angiogenesis, and immune checkpoint expression vary across ONB specimens. These features may affect therapeutic response and are being investigated as potential targets for treatment.

Limitations: What the Research Could Not Prove

The authors acknowledge several important limitations of the current evidence.

The rarity of ONB is the most significant limitation. Because the disease is rare, there are few large studies. Most current knowledge comes from retrospective analyses and small case series rather than large prospective studies.

No single dominant oncogenic driver has been consistently identified across published cohorts. This suggests substantial molecular heterogeneity among ONB tumors and complicates the development of targeted therapies.

The proposed molecular functional states — Proliferative, Neuroendocrine-Differentiated, and Mesenchymal/Stromal-Associated — are conceptual frameworks. They are not validated molecular classification systems. Current evidence remains insufficient to establish them as validated molecular subtypes.

The interpretation of IDH2 R172 mutations in ONB requires caution. Some IDH2-mutant sinonasal tumors may represent a distinct molecular entity rather than conventional ONB. Whether IDH2 R172 mutations represent a bona fide ONB driver remains unresolved.

The biological significance of mesenchymal or stromal-associated transcriptional programs in ONB remains incompletely understood. The stromal- and angiogenesis-associated transcriptional signatures identified in current studies may reflect stromal or microenvironment-associated signals rather than a tumor-cell-intrinsic mesenchymal differentiation program.

Clinical evidence supporting anti-angiogenic therapy in ONB remains limited. Comparable mechanisms of stromal remodeling and immune exclusion in ONB have not yet been well characterized.

There is still a lack of distinct evidence supporting a comparable role for EZH2 in ONB. The mechanisms by which epigenetic alterations influence immune signaling and antigen presentation have not been well characterized in ONB.

No formal systematic review methodology was applied because this article is a narrative review. Given the rarity of ONB, pivotal studies on extrapulmonary neuroendocrine carcinomas and small-cell lung cancer (SCLC) were also included to elucidate potential shared molecular mechanisms and therapeutic implications.

Recommendations and Future Directions

The authors outline several priorities for future research and clinical practice.

1. Larger clinical studies are needed. Because ONB is rare, multicenter collaborations will be essential to gather enough patients for meaningful research.
2. Better biomarkers are needed. Identifying reliable biomarkers will help doctors predict which patients are likely to respond to which treatments.
3. Integration of transcriptomic, genomic, and clinical data is needed. Future studies should combine these types of data to determine the biological and clinical relevance of the proposed molecular functional states.
4. Validation of molecular subtypes is needed. The proposed functional states should be validated in diagnostically confirmed ONB cohorts before they can be used in clinical practice.
5. Biomarker-driven therapy should be explored. As molecular profiling improves, it may become possible to match patients with targeted treatments based on the specific molecular features of their tumors.
6. Precision oncology approaches should be developed. The ultimate goal is to provide individualized patient management based on the molecular characteristics of each patient's tumor.

The authors conclude that although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging. Continued progress in molecular profiling and translational research has improved the understanding of the biological heterogeneity of ONB. This progress may facilitate the development of biomarker-guided therapeutic strategies for precision oncology.

Frequently Asked Questions

What is olfactory neuroblastoma?

Olfactory neuroblastoma, also called esthesioneuroblastoma, is a rare malignant tumor that starts in the smell-sensing tissue of the upper nasal cavity. It accounts for about 2–6% of cancers beginning in the nasal cavity and sinuses. It can occur at any age, but new cases peak between ages 40 and 60, and men and women are affected equally.

How is olfactory neuroblastoma usually treated?

The current standard treatment is multimodal therapy, mainly surgery plus radiotherapy. Chemotherapy is generally reserved for advanced, recurrent, or metastatic disease. Surgical techniques such as craniofacial resection and endoscopic skull-base surgery, and radiation techniques such as intensity-modulated radiotherapy, have improved local control. Even so, recurrence rates remain substantial, especially for advanced-stage tumors.

Why do two patients with the same tumor grade have different outcomes?

Olfactory neuroblastoma is not one uniform disease. It is a group of tumors with different biological programs, including proliferative, neuroendocrine-differentiated, and mesenchymal/stromal-associated states. Current staging and grading systems, such as Kadish, Dulguerov, and Hyams, are clinically valuable but do not fully explain the differences in treatment response and clinical outcome between patients.

What are the three proposed molecular functional states of olfactory neuroblastoma?

A recent review proposes three conceptual molecular functional states: proliferative, with high cell-cycle activity; neuroendocrine-differentiated, enriched in neuroendocrine programs; and mesenchymal/stromal-associated, linked to stromal remodeling and aggressive behavior. The authors stress these are frameworks to interpret current molecular evidence, not a validated classification system, and they require further validation in confirmed olfactory neuroblastoma cohorts.

What targeted treatments are being explored for recurrent or advanced olfactory neuroblastoma?

Several targeted strategies are being explored, including peptide receptor radionuclide therapy targeting SSTR2, anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. None is currently standardized, and evidence supporting their use remains limited because the disease is rare and large prospective studies are lacking. Most knowledge comes from retrospective analyses, small case series, and extrapolation from other neuroendocrine malignancies.

What does an IDH2 mutation mean in olfactory neuroblastoma?

IDH2 mutations, particularly the R172 hotspot, have been reported in a subset of sinonasal tumors historically diagnosed as olfactory neuroblastoma. However, some IDH2-mutant sinonasal tumors may represent a distinct molecular entity rather than conventional olfactory neuroblastoma. Whether IDH2 R172 mutations are a true driver remains unresolved, so they should not currently be regarded as a defining genomic alteration in conventional olfactory neuroblastoma.

What are the main limitations of the current research on olfactory neuroblastoma?

The rarity of olfactory neuroblastoma is the most significant limitation. Most knowledge comes from retrospective analyses and small case series rather than large prospective studies. No single dominant oncogenic driver has been consistently identified. The proposed molecular functional states are conceptual frameworks, not validated subtypes. The biological significance of stromal-associated programs remains incompletely understood, and clinical evidence for anti-angiogenic therapy is limited.

My olfactory neuroblastoma was diagnosed as a specific grade — should I get a second opinion on the pathology and molecular features before treatment?

Patients with similar pathological grades can have substantially different disease trajectories, because olfactory neuroblastoma is a group of tumors with different biological characteristics rather than one uniform disease. Current staging and grading systems do not fully explain differences in treatment response and outcome. A second opinion can review the pathology, Hyams grade, and molecular features such as IDH2 status, which may require cautious interpretation and reassessment. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Pathological Pathways of Olfactory Neuroblastoma: From Molecular Mechanisms to Targeted Therapy: A Narrative Review.

Authors: Zhou W, Liu X, Hu J, Chen Y, Liu F, Zhong B.

Affiliation: Department of Otolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu 610041, China

Publication details: Cancers 2026, 18, 2510. Published 5 August 2026. DOI: 10.3390/cancers18152510

Article type: Narrative review

Note: This patient-friendly article is based on peer-reviewed research. The original article is a narrative review, which means the authors did not apply formal systematic review methodology. The findings and conclusions summarized here reflect the authors' interpretation of the available evidence at the time of publication.