Olfactory Neuroblastoma

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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0006329 olfactory neuroblastoma

Primary MONDO disease identifier for this entry. The term denotes the right disease; its placement under extracranial neuroblastoma is disputed and is recorded in the entry notes.

NCIT

NCIT:C3789 Olfactory Neuroblastoma

NCIT disease concept for the same entity, under the same name.

NCIT

NCIT:C3789 Olfactory Neuroblastoma

NCIT disease concept for the same entity, under the same name.

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Pathophysiology

7

Recurrent Chromosomal Loss Without a Recurrent Driver Mutation

The genomic landscape is one of large-scale copy number change rather than point mutation. Panel sequencing of 560 tumour-associated genes in a 66-tumour cohort found no highly recurrent mutations, the only recurrently mutated genes being TP53 and DNMT3A, while copy number analysis of the core group showed a high frequency of combined loss of chromosomes 1 to 4, 8 to 10 and 12. A systematic review of the genomics reached the same conclusion, that recurrent mutations are uncommon.

Downstream

Malignant Transformation of Olfactory Epithelial Globose Basal Cells The chromosomal losses are the most consistent genomic abnormality in this tumour, but no source cited here shows that they cause the transformation. The link is recorded as UNKNOWN rather than left out, because the alternative would be a pathograph in which the tumour's main genomic finding appears nowhere.

Show evidence (3 references)

PMID:29730775 SUPPORT DIRECT PRIMARY RESULT Human clinical

"NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A."

The negative mutational result from a 66-tumour cohort, which is why this entry has no driver lesion to build on. Sequencing was of a 560-gene panel in a subset of the cohort, so it bounds recurrent mutation within those genes rather than genome-wide.

PMID:29730775 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12."

The positive genomic finding that stands in place of a driver mutation: highly recurrent combined whole-chromosome losses in the core methylation group. It is a description of the landscape, not a demonstration that these losses cause the tumour.

PMID:34401496 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies."

A systematic review of 36 studies reaching the same conclusion independently, and listing the genes reported as altered in at least one study. The review states its own limitation, that the rarity of the tumour has limited sample sizes.

Malignant Transformation of Olfactory Epithelial Globose Basal Cells

The tumour is linked by single-cell transcriptomics to globose basal cells, the stem and progenitor population of the olfactory epithelium. This is the cell-identity claim the rest of the mechanism rests on, and the study that made it states it was the first time the tumour had been linked to a specific cell type.

olfactory epithelial globose basal cell CL:0002171

olfactory epithelium UBERON:0001997

Downstream

Retained Globose Basal Cell Transcriptional Programme The transformed cell keeps the transcriptional identity of its parent population, which is what the tumour's markers and its differentiation behaviour read out.

Show evidence (2 references)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs)."

The study that identifies the cell of origin, by matching tumour transcriptomic programmes against a single-cell atlas of normal nasal mucosa. The atlas is integrated human and mouse, so the reference map is not purely human, and the inference is from transcriptional similarity rather than from lineage tracing.

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation."

The authors' own statement of what the work established and that it was the first such link, which is why this cell type is bound here and no earlier candidate is recorded.

Retained Globose Basal Cell Transcriptional Programme

The tumour expresses the globose basal cell transcription factor NEUROD1, whose expression distinguishes both low-grade and high-grade tumours from sinonasal undifferentiated carcinoma. The programme is not merely a marker: it is the retained developmental circuitry of the parent cell, and the two nodes below are its two consequences.

NEUROD1 hgnc:7762

DNA-binding transcription factor activity GO:0003700 ↑ INCREASED

Downstream

Proliferative EZH2-High Compartment The programme includes a stemness marker, and the cells expressing it are the proliferative compartment.

Divergent Neuronal and Sustentacular Differentiation The same programme preserves the regulatory circuit that decides between the two differentiation routes of the normal epithelium.

Show evidence (1 reference)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis."

Establishes that the globose basal cell transcription factor is expressed across the grade range, and that its expression separates this tumour from its most important mimic. The claim is about distinguishing the two, not about NEUROD1 driving the tumour.

Proliferative EZH2-High Compartment

Within the tumour there is a reproducible subpopulation of highly proliferative cells expressing EZH2, the globose basal cell stemness marker. The authors suggest on that basis that EZH2 inhibition may have a role in targeted treatment; that is a proposal from expression data, not a tested therapy, and no trial evidence is recorded in this entry.

positive regulation of cell population proliferation GO:0008284 ↑ INCREASED

Downstream

Sinonasal Mass Arising at the Cribriform Plate The proliferating compartment produces the mass that presents clinically.

Show evidence (1 reference)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB."

Identifies the proliferative compartment and its marker. The therapeutic suggestion in the second half of the sentence is the authors' inference from expression, and is recorded in this node's description as a proposal rather than as a treatment.

Divergent Neuronal and Sustentacular Differentiation

Single-cell transcriptomics of tumour parenchyma found a conserved globose basal cell regulatory circuit governing divergent neuronal versus sustentacular differentiation. This is the mechanistic counterpart of what pathologists grade: well-differentiated tumours show lobular architecture and neuronal morphology with Homer-Wright pseudorosettes and a fibrillary matrix, while poorly differentiated tumours lack neural morphology.

neuron differentiation GO:0030182 ⚠ ABNORMAL

Downstream

Sinonasal Mass Arising at the Cribriform Plate The degree of differentiation shapes the tumour that forms, and is what the Hyams system grades on the resulting tissue.

Show evidence (1 reference)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation."

The single-cell evidence that the tumour preserves the parent cell's differentiation circuitry. It establishes the circuit is present and active, not that its output determines Hyams grade, which is a connection this entry does not assert.

Sinonasal Mass Arising at the Cribriform Plate

The tumour forms in the olfactory cleft at the cribriform plate, at the roof of the nasal cavity, from where it obstructs the nasal airway, bleeds and destroys olfactory epithelium. Extension through the cribriform plate into the anterior cranial fossa is what makes local staging the dominant prognostic factor.

olfactory epithelium UBERON:0001997

Downstream

Local Invasion of the Skull Base and Orbit The tumour is locally aggressive and extends into neighbouring structures from its origin at the roof of the nasal cavity.

Nasal Obstruction A mass in the olfactory cleft obstructs the nasal airway.

Epistaxis The mass bleeds, typically after the obstruction is noticed.

Anosmia The tumour destroys and replaces olfactory epithelium, and smell loss can precede diagnosis by years.

Sinonasal Neoplasm The mass is what is seen on imaging and biopsied.

Show evidence (2 references)

PMID:24083125 SUPPORT DIRECT BACKGROUND Human clinical

"Esthesioneuroblastoma (ENB) is a rare malignant neuroendocrine tumor originating from the olfactory neuroepithelium in the cribriform plate."

States the site of origin. The sentence opens the paper's objective section and restates the established description rather than reporting this study's own finding, so it is graded BACKGROUND.

PMID:24083125 SUPPORT DIRECT PRIMARY RESULT Human clinical

"ENB has a variable outcome, which is primarily prognosticated by the extent of involvement at presentation (Kadish stage and lymph node metastasis) and higher Hyams pathologic grade."

The conclusion of a 109-patient single-institution series spanning 1962 to 2009, that local extent at presentation is the primary prognostic factor alongside grade. A retrospective series over nearly fifty years, so treatment was not uniform across it.

Local Invasion of the Skull Base and Orbit

The tumour is locally aggressive and may involve the skull base and the orbits, and it metastasises in 20 to 48 per cent of cases. Local extent is what the Kadish system stages and is the dominant prognostic factor, and orbital and intracranial extension produce the symptoms recorded below. Cervical lymph node spread is the other route and defines the modified Kadish stage D.

Downstream

Visual Impairment Orbital extension produces visual and ocular disturbance.

Headache Intracranial extension produces headache.

Cervical Lymph Node Metastasis The commonest metastatic site is the cervical nodes, which is the other route of spread beside direct local extension.

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."

States both halves of this node, local aggressiveness into skull base and orbit and a metastatic tendency, with a wide reported range for the latter. A review's synthesis of the literature rather than a measured series of its own.

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Histopathology

1

Hyams Grade and the Loss of Neuronal Morphology

The Hyams system grades histoarchitecture, mitoses, nuclear pleomorphism, neurofibrillary matrix, rosette formation and necrosis. Grades I and II show lobular architecture and neuronal morphology, including Homer-Wright pseudorosettes and a fibrillary matrix; grades III and IV generally lack neural morphology and show abundant mitoses, pronounced pleomorphism and necrosis. The grade predicts survival: in a 109-patient series median survival was 9.8 years for grades 1 to 2 against 6.9 years for grades 3 to 4, and grade remained significant on multivariate analysis.

Show evidence (2 references)

PMID:36841178 SUPPORT DIRECT BACKGROUND Human clinical

"Well-differentiated ONB (grades I and II) display lobular architecture and neuronal morphology (e.g., Homer-Wright pseudorosettes, fibrillary matrix) whereas poorly differentiated ONB (grades III and IV) generally lack neural morphology and display classic features of aggressive neoplasms such..."

Describes what the grades mean morphologically. The sentence is in the paper's introduction and restates the established grading system rather than reporting this study's own cases.

PMID:24083125 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Median survival was 9.8 years compared with 6.9 years with low (grade 1 to 2) versus high (grade 3 to 4) Hyams grade."

The survival difference by grade in a 109-patient retrospective series. The same analysis found grade significant on multivariate as well as univariate testing, alongside stage, nodal metastasis and age.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Blood 1

Epistaxis HP:0000421

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Nasal obstruction followed by epistaxis are typical early manifestations"

The same review sentence, cited here for the bleeding half of the presentation. No frequency is given.

Cardiovascular 1

Cervical Lymph Node Metastasis Cervical lymphadenopathy HP:0025289

Show evidence (2 references)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The typical sites of metastasis are cervical lymph nodes (10-33% of patients), bones, and lungs"

Names the cervical nodes as the commonest metastatic site with its reported range, alongside bone and lung. A review's synthesis, and the range is wide enough to show the underlying series disagree.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The incidence of cervical metastases at diagnosis is 5-8%, but the incidence of a later development increase to 20-25%."

Separates neck involvement at diagnosis from neck involvement developing later, which is the distinction that matters for surveillance. Still a review's synthesis rather than a cohort result.

Eye 1

Visual Impairment HP:0000505

Show evidence (1 reference)

PMID:37909011 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."

The orbital involvement this phenotype follows from. The sentence names the orbit as an invaded structure rather than naming visual impairment, so the symptom follows by one inferential step and the item is graded INDIRECT.

Head and Neck 3

Sinonasal Neoplasm Neoplasm of the nose HP:0012720

Show evidence (1 reference)

PMID:24083125 SUPPORT DIRECT BACKGROUND Human clinical

"Esthesioneuroblastoma (ENB) is a rare malignant neuroendocrine tumor originating from the olfactory neuroepithelium in the cribriform plate."

Locates the tumour in the nasal cavity at the cribriform plate, which is what the bound phenotype records. Graded BACKGROUND because the sentence restates the established description.

Nasal Obstruction Nasal congestion HP:0001742

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Nasal obstruction followed by epistaxis are typical early manifestations"

A review's statement of the typical presenting symptoms and their usual order. It is a synthesis citing earlier series rather than a result of its own, and gives no frequencies.

Anosmia HP:0000458

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Hyposmia and anosmia can precede the diagnosis of ONB by several years"

Records both the symptom and the long lead time before diagnosis. The review cites an earlier source for this and gives no quantification of how often or by how long.

Nervous System 1

Headache HP:0002315

Show evidence (1 reference)

PMID:37909011 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."

The skull base involvement this phenotype follows from. The sentence names the invaded structures rather than the symptom, so the item is graded INDIRECT.

💊

Medical Actions

3

Surgical Resection

Category: Therapeutic Action: surgical resection Ontology label: Surgical Procedure NCIT:C15329

Surgery is the primary local treatment. Open craniofacial resection was historically the standard operation; endoscopic endonasal approaches have largely replaced it over the last two decades, with lower complication rates and shorter hospital stay and, in the cited review's assessment, similar clinical outcome.

Mechanism Target:

Sinonasal Mass Arising at the Cribriform Plate — Resection removes the mass and, with it, the obstruction, bleeding and further local extension.

Show evidence (2 references)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Local treatment with surgery is frequently recommended for primary therapy."

The review's statement that surgery is the usual primary treatment. It is a synthesis of practice rather than a trial result.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"In the last years, endoscopic endonasal approaches have been largely introduced with lower complication rates, shorter hospital stay, and similar clinical outcome."

Records the shift in surgical approach and the claimed equivalence of outcome. The comparison is the review's summary of published series, not a randomised comparison, so the equivalence claim is weakly founded.

Postoperative Radiotherapy

Category: Therapeutic Action: radiation therapy Ontology label: Radiation Therapy NCIT:C15313

Radiotherapy is combined with surgery for more locally advanced resectable disease, and locally advanced disease generally needs a multidisciplinary approach with surgery, radiation and systemic therapy. The cited review also notes that Hyams grade may bear on decisions about induction chemotherapy and adjuvant radiotherapy.

Mechanism Target:

Sinonasal Mass Arising at the Cribriform Plate — Radiotherapy is directed at the primary site, as surgery is, and at the margin left after resection.

Show evidence (2 references)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"While a combination of surgery and postoperative RT is indicated for the management of more local advanced resectable cancers."

States the indication for adding postoperative radiotherapy. A review's synthesis of practice, with no comparative data quoted.

PMID:37909011 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical

"However, based on published data, Hyams grading may represent an important factor for decision making in therapeutic strategies such as induction chemotherapy and adjuvant radiotherapy (RT), and may also be considered in surveillance protocols."

Links the histological grade to treatment decisions. The review hedges it as what published data may support, so it is graded INDIRECT and the entry does not state grade-directed therapy as established practice.

Platinum-Based Chemotherapy

Category: Therapeutic Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Agent: cisplatin CHEBI:27899 etoposide CHEBI:4911

Chemotherapy is part of multimodal treatment for locally advanced disease: as induction before local treatment, concurrently with postoperative radiotherapy in patients at high risk of local recurrence, and in the palliative setting. Platinum plus etoposide is described as the most used regimen. Its place is unsettled. The cited review states that although multimodal therapy is agreed to be needed, the optimal use of chemotherapy is still unknown, and reports that the platinum and etoposide combination gave no survival benefit over other regimens. The underlying studies are retrospective.

Mechanism Target:

Proliferative EZH2-High Compartment — Cytotoxic chemotherapy is directed at the proliferating tumour cell population. The link records the target, not an established benefit.

Show evidence (3 references)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Platinum plus etoposide chemotherapy seems to be the most used regimen, even if not provide a survival benefit when compared with all other regimens."

Names the commonest regimen and, in the same sentence, reports that it did not outperform the alternatives. The review's own grammatical slip is quoted as printed. This is why the row records standard practice rather than established benefit.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Although there is agreement that multimodal therapy is needed, the optimal use of chemotherapy is still unknown."

The review's own statement that the role of chemotherapy is unsettled, which bounds every claim in this row.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"With the aim to increase local control some studies and referral centers advocate the use of concurrent chemoradiation (CT-RT) with cisplatin after surgery for patients at high risk of local recurrence (30)."

The postoperative chemoradiation setting, attributed by the review to some studies and referral centres rather than presented as a standard, which is how the description records it.

🔬

Diagnosis

2

Neuroendocrine Marker Panel with Absent Pan-Cytokeratin

The classical immunoprofile is neuroendocrine marker positivity in the absence of pan-cytokeratin. The cited review is explicit that the panel becomes less reliable in poorly differentiated, high-grade tumours, where the markers stop being mutually exclusive with those of sinonasal undifferentiated carcinoma. That failure at the high-grade end is the reason the newer markers below matter.

immunohistochemistry NCIT:C23020

Show evidence (1 reference)

PMID:36841178 SUPPORT DIRECT BACKGROUND Human clinical

"Classically, the diagnosis is made with immunohistochemical detection of neuroendocrine markers such as CD56/NCAM1, neuron-specific enolase (NSE/ENO4), synaptophysin (SYP), chromogranin A (CHGA), INSM1, and calretinin (CALB2) in the absence of pan-cytokeratin"

Lists the classical panel. The sentence is in the paper's introduction, summarising established practice with multiple citations rather than reporting the study's own results.

SSTR2 Immunohistochemistry

Somatostatin receptor 2 staining was present in 77 of 78 tumours and was much stronger than in histologic mimics, which makes it a useful diagnostic marker and suggests a role for somatostatin-analogue imaging and therapy. It carried no prognostic value in that study, and staining was slightly stronger in low-grade than high-grade tumours, so it should not be read as a grade or outcome marker.

immunohistochemistry NCIT:C23020

Show evidence (2 references)

PMID:33929681 SUPPORT DIRECT PRIMARY RESULT Human clinical

"SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB."

The comparison against 51 histologic mimics that supports the diagnostic use. H-score combines intensity and the proportion of cells stained, so the contrast is in staining strength rather than in a simple positive or negative call.

PMID:33929681 SUPPORT DIRECT PRIMARY RESULT Human clinical

"SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival."

The negative result that bounds the marker's use: it helps with diagnosis and not with prognosis. Recorded so the stain is not read as an outcome predictor.

🪜

Stages

4

Kadish A

Tumour restricted to the nasal cavity. Ten-year overall and disease-specific survival were reported as 83.4 per cent and 90 per cent.

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."

The definitions of the three original Kadish categories, quoted once and cited on each of the three stages it defines.

Kadish B

Tumour extending to the paranasal sinuses. Ten-year overall and disease-specific survival were reported as 49 per cent and 68.3 per cent.

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."

The same definition sentence, cited here for stage B.

Kadish C

Tumour extending beyond the paranasal cavities. Ten-year overall and disease-specific survival were reported as 38.6 per cent and 66.7 per cent.

Show evidence (1 reference)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."

The same definition sentence, cited here for stage C.

Kadish D

Cervical lymph node metastases. This stage is not in the original Kadish classification: Morita and colleagues added it. It carries by far the worst reported outcome, with ten-year overall and disease-specific survival of 13.3 per cent and 35.6 per cent.

Other staging systems exist and are not modelled here, including the American Joint Committee on Cancer tumour-nodal-metastasis system and the Dulguerov modification of it. Kadish with the Morita modification is recorded because the cited review describes it as the most commonly applied, and because it is the system this entry's prognostic statements rest on.

Show evidence (2 references)

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"The Kadish classification was later modified by Morita et al. (17) designating the class D that includes patients with cervical lymph node metastases (18)."

Records that stage D is Morita's addition and what it covers. The review attributes it to two earlier papers rather than reporting it as its own.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"A significant differences in clinical outcome has been showed between the four groups of the modified Kadish classification"

The statement that outcome differs significantly across the four modified-Kadish groups, which is what makes the staging prognostic. The review's own grammatical slip is quoted as printed, and the per-stage percentages in the stage descriptions come from the figures immediately following this sentence.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Olfactory Neuroblastoma:

Sinonasal Undifferentiated Carcinoma

Overlapping Features The most important mimic, and the one with a distinctly worse prognosis, so getting it wrong matters clinically. The classical neuroendocrine panel fails to separate them at the high-grade end, where the markers stop being mutually exclusive. NEUROD1 expression separates both low-grade and high-grade olfactory neuroblastoma from it.

Distinguishing Features

NEUROD1 expression, which distinguishes both low-grade and high-grade olfactory neuroblastoma from sinonasal undifferentiated carcinoma
Strong SSTR2 staining, much higher than in histologic mimics
The classical neuroendocrine panel, which separates them only at the lower grades

Show evidence (3 references)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis."

The marker that separates the two across the grade range, and the reason the distinction matters, stated in the same sentence.

PMID:36841178 SUPPORT DIRECT BACKGROUND Human clinical

"This combination can be useful for distinguishing it from many other sinonasal cancers, however these markers become far less reliable (i.e., fail to remain mutually exclusive) in the setting of poorly differentiated, high-grade tumors such as sinonasal undifferentiated carcinoma (SNUC)."

States where the classical panel fails, which is what makes this differential difficult rather than routine. An introduction sentence summarising established practice.

PMID:33929681 SUPPORT DIRECT PRIMARY RESULT Human clinical

"when restricting the group to SNUC and SNEC the same cutoff point yielded a sensitivity of 93.5% and specificity of 96.4%"

The performance of the SSTR2 stain against this differential specifically rather than against mimics in general: restricted to sinonasal undifferentiated carcinoma and sinonasal neuroendocrine carcinoma, the same cutoff gave 93.5 per cent sensitivity and 96.4 per cent specificity. A single-centre series, so not prospective figures.

IDH2-Mutant Sinonasal Carcinoma

Overlapping Features In the methylation reclassification cohort, 7 of 66 tumours carrying the institutional diagnosis of olfactory neuroblastoma formed a group with a CpG island methylator phenotype, strong cytokeratin expression, little or no chromogranin A, and an IDH2 hotspot mutation in every case; they clustered with sinonasal carcinoma with IDH2 mutation. These are generally read as misdiagnoses rather than as a subtype of this tumour, which is why no subtype is declared for them here.

Distinguishing Features

IDH2 hotspot mutation, present in all seven cases of that group
Strong cytokeratin expression with no or scarce chromogranin A
A CpG island methylator phenotype, clustering with IDH2-mutant sinonasal carcinoma rather than with core olfactory neuroblastoma

Show evidence (2 references)

PMID:29730775 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases."

Describes the group and its three separating features. Seven cases, all with the IDH2 mutation, which is what makes the separation clean in this cohort.

PMID:29730775 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis."

Gives the size of the core group against the whole cohort, which is what makes the point that a third of institutionally diagnosed cases fell elsewhere. The core group itself showed no overlap with other classes.

Neuroblastoma MONDO:0005072

Overlapping Features Shares the name and nothing else that matters. Neuroblastoma is a tumour of the sympathetic nervous system in young children, arising from neural crest-derived sympathoadrenal precursors, typically in the adrenal gland or paraspinal sympathetic chain. This tumour arises from olfactory epithelial globose basal cells in the nasal cavity, in adults. The two are confused in the literature and in ontologies rather than at the bedside, and this row exists to record the distinction explicitly.

Distinguishing Features

Origin from olfactory epithelial globose basal cells rather than from sympathoadrenal neural crest precursors
A sinonasal site at the cribriform plate rather than adrenal or paraspinal
Adults rather than young children, with a unimodal peak at about 50 to 60 years
No recurrent driver mutation, where neuroblastoma has recurrent MYCN amplification and ALK alterations

Show evidence (2 references)

PMID:36841178 SUPPORT DIRECT PRIMARY RESULT Human clinical

"These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation."

The cell-of-origin result, which is the substantive basis for separating this tumour from neuroblastoma: a different parent cell in a different epithelium. The sentence does not mention neuroblastoma, so the contrast itself is drawn by this entry from the two tumours' separate literatures.

PMID:37909011 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"ONB demonstrates an unimodal distribution with a more common presentation in adulthood around the age of 50-60 years"

The age distribution, one of the plainest separations from neuroblastoma, a tumour of young children. A review's synthesis citing an earlier source.

{ }

Source YAML

click to show

name: Olfactory Neuroblastoma
creation_date: '2026-10-30T16:00:00Z'
description: >-
  Olfactory neuroblastoma, also called esthesioneuroblastoma, is an uncommon
  malignant neuroectodermal tumour of the nasal cavity that arises from the
  olfactory epithelium at the cribriform plate. Despite its name it is not a
  form of neuroblastoma: it is a sinonasal tumour of adults with a different
  cell of origin, a different genomic landscape and a different clinical
  course, and this entry exists partly to keep the two apart.

  Single-cell transcriptomic work links the tumour to olfactory epithelial
  globose basal cells, the stem and progenitor population of the olfactory
  epithelium, and that was the first time the tumour was linked to a specific
  cell type. The tumour retains a globose basal cell programme: it expresses
  the globose basal cell transcription factor NEUROD1, which separates it from
  sinonasal undifferentiated carcinoma, it contains a reproducible
  highly proliferative subpopulation expressing the stemness marker EZH2, and
  it preserves a regulatory circuit that governs divergent neuronal versus
  sustentacular differentiation. That retained differentiation capacity is
  what the Hyams grading system reads off the slide.

  Its genomic landscape is unusual for a malignancy. Panel sequencing of 560
  tumour-associated genes found no highly recurrent mutations, with only TP53
  and DNMT3A recurrently mutated, while copy number analysis showed highly
  recurrent combined loss of whole chromosomes. There is therefore no driver
  lesion to anchor the entry on, and the mechanism recorded below is a
  cell-identity one rather than a mutational one.

  DNA methylation profiling has also shown that the institutional diagnosis is
  not a single thing: in a 66-tumour cohort only 42 (64 per cent) formed a
  core group, while others clustered with IDH2-mutant sinonasal carcinoma or
  with sinonasal carcinomas of other types. Those non-core cases are widely
  read as misdiagnosis rather than as subtypes of this tumour.
categories:
- Head and Neck Cancer
- Neuroendocrine Tumor
parents:
- sinonasal malignancy
synonyms:
- esthesioneuroblastoma
- ONB
- ENB
notes: >-
  This is not neuroblastoma, and the shared name is the whole reason the entry
  is here. Neuroblastoma (MONDO:0005072) is a tumour of the sympathetic
  nervous system arising from neural crest-derived sympathoadrenal precursors,
  predominantly in young children. Olfactory neuroblastoma arises from the
  olfactory epithelium, in adults, and has none of neuroblastoma's defining
  features: no MYCN amplification, no ALK dependency, no catecholamine
  secretion, and no shared genomic landscape. The Neuroblastoma entry's scope
  note points here.

  MONDO currently places this term under MONDO:0002749 extracranial
  neuroblastoma, alongside MONDO:0002433 malignant cranial nerve neoplasm,
  MONDO:0002722 olfactory nerve neoplasm and MONDO:0003142 intracranial
  primitive neuroectodermal tumor (hierarchical parents retrieved through the
  OLS4 API on 30 October 2026). Placing it under extracranial neuroblastoma is
  the classification this entry disagrees with, and a change request has been
  raised with MONDO. The mapping below is still skos:exactMatch, because the
  term denotes the right disease; it is the term's position in the hierarchy
  that is at issue, not its identity.

  No origin node is marked and no somatic lesion is recorded, because none is
  recurrent. The cell of origin is bound on the transformation node instead,
  which is the one thing the molecular work does establish.

  The entry does not cover olfactory carcinoma, a more aggressive sinonasal
  tumour with focal epithelial differentiation that has only recently been
  consolidated under that name and whose relationship to this tumour is
  described in the cited literature as unknown.
disease_term:
  preferred_term: olfactory neuroblastoma
  term:
    id: MONDO:0006329
    label: olfactory neuroblastoma
pathophysiology:
- name: Recurrent Chromosomal Loss Without a Recurrent Driver Mutation
  description: >-
    The genomic landscape is one of large-scale copy number change rather than
    point mutation. Panel sequencing of 560 tumour-associated genes in a
    66-tumour cohort found no highly recurrent mutations, the only recurrently
    mutated genes being TP53 and DNMT3A, while copy number analysis of the
    core group showed a high frequency of combined loss of chromosomes 1 to 4,
    8 to 10 and 12. A systematic review of the genomics reached the same
    conclusion, that recurrent mutations are uncommon.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:29730775
    reference_title: "DNA methylation-based reclassification of olfactory neuroblastoma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A."
    explanation: >-
      The negative mutational result from a 66-tumour cohort, which is why
      this entry has no driver lesion to build on. Sequencing was of a 560-gene
      panel in a subset of the cohort, so it bounds recurrent mutation within
      those genes rather than genome-wide.
  - reference: PMID:29730775
    reference_title: "DNA methylation-based reclassification of olfactory neuroblastoma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12."
    explanation: >-
      The positive genomic finding that stands in place of a driver mutation:
      highly recurrent combined whole-chromosome losses in the core methylation
      group. It is a description of the landscape, not a demonstration that
      these losses cause the tumour.
  - reference: PMID:34401496
    reference_title: "The genomics and epigenetics of olfactory neuroblastoma: A systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies."
    explanation: >-
      A systematic review of 36 studies reaching the same conclusion
      independently, and listing the genes reported as altered in at least one
      study. The review states its own limitation, that the rarity of the
      tumour has limited sample sizes.
  downstream:
  - target: Malignant Transformation of Olfactory Epithelial Globose Basal Cells
    causal_link_type: UNKNOWN
    description: >-
      The chromosomal losses are the most consistent genomic abnormality in
      this tumour, but no source cited here shows that they cause the
      transformation. The link is recorded as UNKNOWN rather than left out,
      because the alternative would be a pathograph in which the tumour's main
      genomic finding appears nowhere.
- name: Malignant Transformation of Olfactory Epithelial Globose Basal Cells
  description: >-
    The tumour is linked by single-cell transcriptomics to globose basal
    cells, the stem and progenitor population of the olfactory epithelium.
    This is the cell-identity claim the rest of the mechanism rests on, and
    the study that made it states it was the first time the tumour had been
    linked to a specific cell type.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: olfactory epithelial globose basal cell
    term:
      id: CL:0002171
      label: globose cell of olfactory epithelium
  locations:
  - preferred_term: olfactory epithelium
    term:
      id: UBERON:0001997
      label: olfactory epithelium
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs)."
    explanation: >-
      The study that identifies the cell of origin, by matching tumour
      transcriptomic programmes against a single-cell atlas of normal nasal
      mucosa. The atlas is integrated human and mouse, so the reference map is
      not purely human, and the inference is from transcriptional similarity
      rather than from lineage tracing.
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation."
    explanation: >-
      The authors' own statement of what the work established and that it was
      the first such link, which is why this cell type is bound here and no
      earlier candidate is recorded.
  downstream:
  - target: Retained Globose Basal Cell Transcriptional Programme
    causal_link_type: DIRECT
    description: >-
      The transformed cell keeps the transcriptional identity of its parent
      population, which is what the tumour's markers and its differentiation
      behaviour read out.
- name: Retained Globose Basal Cell Transcriptional Programme
  description: >-
    The tumour expresses the globose basal cell transcription factor NEUROD1,
    whose expression distinguishes both low-grade and high-grade tumours from
    sinonasal undifferentiated carcinoma. The programme is not merely a
    marker: it is the retained developmental circuitry of the parent cell, and
    the two nodes below are its two consequences.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NEUROD1
    term:
      id: hgnc:7762
      label: NEUROD1
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    modifier: INCREASED
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis."
    explanation: >-
      Establishes that the globose basal cell transcription factor is
      expressed across the grade range, and that its expression separates this
      tumour from its most important mimic. The claim is about distinguishing
      the two, not about NEUROD1 driving the tumour.
  downstream:
  - target: Proliferative EZH2-High Compartment
    causal_link_type: DIRECT
    description: >-
      The programme includes a stemness marker, and the cells expressing it
      are the proliferative compartment.
  - target: Divergent Neuronal and Sustentacular Differentiation
    causal_link_type: DIRECT
    description: >-
      The same programme preserves the regulatory circuit that decides between
      the two differentiation routes of the normal epithelium.
- name: Proliferative EZH2-High Compartment
  description: >-
    Within the tumour there is a reproducible subpopulation of highly
    proliferative cells expressing EZH2, the globose basal cell stemness
    marker. The authors suggest on that basis that EZH2 inhibition may have a
    role in targeted treatment; that is a proposal from expression data, not a
    tested therapy, and no trial evidence is recorded in this entry.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: positive regulation of cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB."
    explanation: >-
      Identifies the proliferative compartment and its marker. The therapeutic
      suggestion in the second half of the sentence is the authors' inference
      from expression, and is recorded in this node's description as a
      proposal rather than as a treatment.
  downstream:
  - target: Sinonasal Mass Arising at the Cribriform Plate
    causal_link_type: DIRECT
    description: >-
      The proliferating compartment produces the mass that presents clinically.
- name: Divergent Neuronal and Sustentacular Differentiation
  description: >-
    Single-cell transcriptomics of tumour parenchyma found a conserved globose
    basal cell regulatory circuit governing divergent neuronal versus
    sustentacular differentiation. This is the mechanistic counterpart of what
    pathologists grade: well-differentiated tumours show lobular architecture
    and neuronal morphology with Homer-Wright pseudorosettes and a fibrillary
    matrix, while poorly differentiated tumours lack neural morphology.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030182
      label: neuron differentiation
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation."
    explanation: >-
      The single-cell evidence that the tumour preserves the parent cell's
      differentiation circuitry. It establishes the circuit is present and
      active, not that its output determines Hyams grade, which is a
      connection this entry does not assert.
  downstream:
  - target: Sinonasal Mass Arising at the Cribriform Plate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The degree of differentiation shapes the tumour that forms, and is what
      the Hyams system grades on the resulting tissue.
- name: Sinonasal Mass Arising at the Cribriform Plate
  description: >-
    The tumour forms in the olfactory cleft at the cribriform plate, at the
    roof of the nasal cavity, from where it obstructs the nasal airway, bleeds
    and destroys olfactory epithelium. Extension through the cribriform plate
    into the anterior cranial fossa is what makes local staging the dominant
    prognostic factor.
  biological_scale: TISSUE
  locations:
  - preferred_term: olfactory epithelium
    term:
      id: UBERON:0001997
      label: olfactory epithelium
  evidence:
  - reference: PMID:24083125
    reference_title: "Long-term outcome of esthesioneuroblastoma: hyams grade predicts patient survival."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Esthesioneuroblastoma (ENB) is a rare malignant neuroendocrine tumor originating from the olfactory neuroepithelium in the cribriform plate."
    explanation: >-
      States the site of origin. The sentence opens the paper's objective
      section and restates the established description rather than reporting
      this study's own finding, so it is graded BACKGROUND.
  - reference: PMID:24083125
    reference_title: "Long-term outcome of esthesioneuroblastoma: hyams grade predicts patient survival."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "ENB has a variable outcome, which is primarily prognosticated by the extent of involvement at presentation (Kadish stage and lymph node metastasis) and higher Hyams pathologic grade."
    explanation: >-
      The conclusion of a 109-patient single-institution series spanning 1962
      to 2009, that local extent at presentation is the primary prognostic
      factor alongside grade. A retrospective series over nearly fifty years,
      so treatment was not uniform across it.
  downstream:
  - target: Local Invasion of the Skull Base and Orbit
    causal_link_type: DIRECT
    description: >-
      The tumour is locally aggressive and extends into neighbouring
      structures from its origin at the roof of the nasal cavity.
  - target: Nasal Obstruction
    causal_link_type: DIRECT
    description: A mass in the olfactory cleft obstructs the nasal airway.
  - target: Epistaxis
    causal_link_type: DIRECT
    description: The mass bleeds, typically after the obstruction is noticed.
  - target: Anosmia
    causal_link_type: DIRECT
    description: >-
      The tumour destroys and replaces olfactory epithelium, and smell loss
      can precede diagnosis by years.
  - target: Sinonasal Neoplasm
    causal_link_type: DIRECT
    description: The mass is what is seen on imaging and biopsied.
- name: Local Invasion of the Skull Base and Orbit
  description: >-
    The tumour is locally aggressive and may involve the skull base and the
    orbits, and it metastasises in 20 to 48 per cent of cases. Local extent
    is what the Kadish system stages and is the dominant prognostic factor,
    and orbital and intracranial extension produce the symptoms recorded
    below. Cervical lymph node spread is the other route and defines the
    modified Kadish stage D.
  biological_scale: TISSUE
  conforms_to: "invasion_and_metastasis#Local Invasion and Intravasation"
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."
    explanation: >-
      States both halves of this node, local aggressiveness into skull base
      and orbit and a metastatic tendency, with a wide reported range for the
      latter. A review's synthesis of the literature rather than a measured
      series of its own.
  downstream:
  - target: Visual Impairment
    causal_link_type: DIRECT
    description: Orbital extension produces visual and ocular disturbance.
  - target: Headache
    causal_link_type: DIRECT
    description: Intracranial extension produces headache.
  - target: Cervical Lymph Node Metastasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The commonest metastatic site is the cervical nodes, which is the other
      route of spread beside direct local extension.
phenotypes:
- category: Neoplastic
  name: Sinonasal Neoplasm
  description: >-
    A tumour of the nasal cavity, arising at its roof in the olfactory cleft
    and frequently extending through the cribriform plate into the anterior
    cranial fossa. Extent at presentation, staged by the Kadish system and its
    Morita modification, is the dominant prognostic factor.
  phenotype_term:
    preferred_term: Neoplasm of the nose
    term:
      id: HP:0012720
      label: Neoplasm of the nose
  evidence:
  - reference: PMID:24083125
    reference_title: "Long-term outcome of esthesioneuroblastoma: hyams grade predicts patient survival."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Esthesioneuroblastoma (ENB) is a rare malignant neuroendocrine tumor originating from the olfactory neuroepithelium in the cribriform plate."
    explanation: >-
      Locates the tumour in the nasal cavity at the cribriform plate, which is
      what the bound phenotype records. Graded BACKGROUND because the sentence
      restates the established description.
- category: Respiratory
  name: Nasal Obstruction
  description: >-
    Blockage of the nasal airway by the mass, described as the typical early
    manifestation, usually noticed before bleeding.
  phenotype_term:
    preferred_term: nasal obstruction
    term:
      id: HP:0001742
      label: Nasal congestion
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Nasal obstruction followed by epistaxis are typical early manifestations"
    explanation: >-
      A review's statement of the typical presenting symptoms and their usual
      order. It is a synthesis citing earlier series rather than a result of
      its own, and gives no frequencies.
- category: Respiratory
  name: Epistaxis
  description: >-
    Nose bleeding from the tumour, described with nasal obstruction as a
    typical early manifestation and usually following it.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Nasal obstruction followed by epistaxis are typical early manifestations"
    explanation: >-
      The same review sentence, cited here for the bleeding half of the
      presentation. No frequency is given.
- category: Neoplastic
  name: Cervical Lymph Node Metastasis
  description: >-
    The cervical lymph nodes are the commonest metastatic site, involved in
    10 to 33 per cent of patients. The incidence at diagnosis is 5 to 8 per
    cent and rises to 20 to 25 per cent later, so neck involvement is more
    often a development during follow-up than a presenting feature. It is
    also what the modified Kadish system calls stage D, the stage with by far
    the worst reported survival.
  phenotype_term:
    preferred_term: Cervical lymphadenopathy
    term:
      id: HP:0025289
      label: Cervical lymphadenopathy
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The typical sites of metastasis are cervical lymph nodes (10-33% of patients), bones, and lungs"
    explanation: >-
      Names the cervical nodes as the commonest metastatic site with its
      reported range, alongside bone and lung. A review's synthesis, and the
      range is wide enough to show the underlying series disagree.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of cervical metastases at diagnosis is 5-8%, but the incidence of a later development increase to 20-25%."
    explanation: >-
      Separates neck involvement at diagnosis from neck involvement developing
      later, which is the distinction that matters for surveillance. Still a
      review's synthesis rather than a cohort result.
- category: Ophthalmologic
  name: Visual Impairment
  description: >-
    Visual and ocular disturbance from orbital extension of the tumour. It is
    a consequence of local invasion rather than of the primary mass itself.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."
    explanation: >-
      The orbital involvement this phenotype follows from. The sentence names
      the orbit as an invaded structure rather than naming visual impairment,
      so the symptom follows by one inferential step and the item is graded
      INDIRECT.
- category: Neurological
  name: Headache
  description: >-
    Headache from intracranial extension through the cribriform plate. As
    with visual impairment, it is a consequence of local invasion rather than
    of the primary mass.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a locally aggressive neoplasm that may involve local structures such as the skull base and orbits, and has a tendency to metastasize in 20-48% of cases."
    explanation: >-
      The skull base involvement this phenotype follows from. The sentence
      names the invaded structures rather than the symptom, so the item is
      graded INDIRECT.
- category: Neurological
  name: Anosmia
  description: >-
    Loss of the sense of smell, which follows from the tumour arising in and
    destroying the olfactory epithelium. Reduced or absent smell can precede
    the diagnosis by several years, which is part of why these tumours present
    late.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyposmia and anosmia can precede the diagnosis of ONB by several years"
    explanation: >-
      Records both the symptom and the long lead time before diagnosis. The
      review cites an earlier source for this and gives no quantification of
      how often or by how long.
stages:
- name: Kadish A
  description: >-
    Tumour restricted to the nasal cavity. Ten-year overall and
    disease-specific survival were reported as 83.4 per cent and 90 per cent.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."
    explanation: >-
      The definitions of the three original Kadish categories, quoted once and
      cited on each of the three stages it defines.
- name: Kadish B
  description: >-
    Tumour extending to the paranasal sinuses. Ten-year overall and
    disease-specific survival were reported as 49 per cent and 68.3 per cent.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."
    explanation: The same definition sentence, cited here for stage B.
- name: Kadish C
  description: >-
    Tumour extending beyond the paranasal cavities. Ten-year overall and
    disease-specific survival were reported as 38.6 per cent and 66.7 per cent.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "This staging system classifies three categories: stage A, tumor restricted to the nasal cavity; stage B, tumor extending to the paranasal sinuses; stage C, tumor extending beyond the paranasal cavities."
    explanation: The same definition sentence, cited here for stage C.
- name: Kadish D
  description: >-
    Cervical lymph node metastases. This stage is not in the original Kadish
    classification: Morita and colleagues added it. It carries by far the
    worst reported outcome, with ten-year overall and disease-specific
    survival of 13.3 per cent and 35.6 per cent.
  notes: >-
    Other staging systems exist and are not modelled here, including the
    American Joint Committee on Cancer tumour-nodal-metastasis system and the
    Dulguerov modification of it. Kadish with the Morita modification is
    recorded because the cited review describes it as the most commonly
    applied, and because it is the system this entry's prognostic statements
    rest on.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The Kadish classification was later modified by Morita et al. (17) designating the class D that includes patients with cervical lymph node metastases (18)."
    explanation: >-
      Records that stage D is Morita's addition and what it covers. The review
      attributes it to two earlier papers rather than reporting it as its own.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A significant differences in clinical outcome has been showed between the four groups of the modified Kadish classification"
    explanation: >-
      The statement that outcome differs significantly across the four
      modified-Kadish groups, which is what makes the staging prognostic. The
      review's own grammatical slip is quoted as printed, and the per-stage
      percentages in the stage descriptions come from the figures immediately
      following this sentence.
histopathology:
- name: Hyams Grade and the Loss of Neuronal Morphology
  finding_term:
    preferred_term: lobular architecture with Homer-Wright pseudorosettes and fibrillary matrix in low-grade tumours, lost in high-grade tumours
  description: >-
    The Hyams system grades histoarchitecture, mitoses, nuclear pleomorphism,
    neurofibrillary matrix, rosette formation and necrosis. Grades I and II
    show lobular architecture and neuronal morphology, including Homer-Wright
    pseudorosettes and a fibrillary matrix; grades III and IV generally lack
    neural morphology and show abundant mitoses, pronounced pleomorphism and
    necrosis. The grade predicts survival: in a 109-patient series median
    survival was 9.8 years for grades 1 to 2 against 6.9 years for grades 3 to
    4, and grade remained significant on multivariate analysis.
  notes: >-
    No finding term is bound. A label search of NCIT through the OLS4 API on
    30 Oct 2026 for Small Round Cell, Round Cell Pattern and Myxoid returned
    disease concepts rather than morphology findings, and the composite the
    Hyams system grades is six features rather than one finding. Binding any
    single component, such as necrosis, would misrepresent the item.
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Well-differentiated ONB (grades I and II) display lobular architecture and neuronal morphology (e.g., Homer-Wright pseudorosettes, fibrillary matrix) whereas poorly differentiated ONB (grades III and IV) generally lack neural morphology and display classic features of aggressive neoplasms such as abundant mitoses, pronounced nuclear pleomorphism, and necrosis."
    explanation: >-
      Describes what the grades mean morphologically. The sentence is in the
      paper's introduction and restates the established grading system rather
      than reporting this study's own cases.
  - reference: PMID:24083125
    reference_title: "Long-term outcome of esthesioneuroblastoma: hyams grade predicts patient survival."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median survival was 9.8 years compared with 6.9 years with low (grade 1 to 2) versus high (grade 3 to 4) Hyams grade."
    explanation: >-
      The survival difference by grade in a 109-patient retrospective series.
      The same analysis found grade significant on multivariate as well as
      univariate testing, alongside stage, nodal metastasis and age.
diagnosis:
- name: Neuroendocrine Marker Panel with Absent Pan-Cytokeratin
  description: >-
    The classical immunoprofile is neuroendocrine marker positivity in the
    absence of pan-cytokeratin. The cited review is explicit that the panel
    becomes less reliable in poorly differentiated, high-grade tumours, where
    the markers stop being mutually exclusive with those of sinonasal
    undifferentiated carcinoma. That failure at the high-grade end is the
    reason the newer markers below matter.
  diagnosis_term:
    preferred_term: immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Classically, the diagnosis is made with immunohistochemical detection of neuroendocrine markers such as CD56/NCAM1, neuron-specific enolase (NSE/ENO4), synaptophysin (SYP), chromogranin A (CHGA), INSM1, and calretinin (CALB2) in the absence of pan-cytokeratin"
    explanation: >-
      Lists the classical panel. The sentence is in the paper's introduction,
      summarising established practice with multiple citations rather than
      reporting the study's own results.
- name: SSTR2 Immunohistochemistry
  description: >-
    Somatostatin receptor 2 staining was present in 77 of 78 tumours and was
    much stronger than in histologic mimics, which makes it a useful
    diagnostic marker and suggests a role for somatostatin-analogue imaging
    and therapy. It carried no prognostic value in that study, and staining
    was slightly stronger in low-grade than high-grade tumours, so it should
    not be read as a grade or outcome marker.
  diagnosis_term:
    preferred_term: immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  evidence:
  - reference: PMID:33929681
    reference_title: "SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB."
    explanation: >-
      The comparison against 51 histologic mimics that supports the
      diagnostic use. H-score combines intensity and the proportion of cells
      stained, so the contrast is in staining strength rather than in a simple
      positive or negative call.
  - reference: PMID:33929681
    reference_title: "SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival."
    explanation: >-
      The negative result that bounds the marker's use: it helps with
      diagnosis and not with prognosis. Recorded so the stain is not read as
      an outcome predictor.
differential_diagnoses:
- name: Sinonasal Undifferentiated Carcinoma
  description: >-
    The most important mimic, and the one with a distinctly worse prognosis,
    so getting it wrong matters clinically. The classical neuroendocrine panel
    fails to separate them at the high-grade end, where the markers stop being
    mutually exclusive. NEUROD1 expression separates both low-grade and
    high-grade olfactory neuroblastoma from it.
  distinguishing_features:
  - NEUROD1 expression, which distinguishes both low-grade and high-grade olfactory neuroblastoma from sinonasal undifferentiated carcinoma
  - Strong SSTR2 staining, much higher than in histologic mimics
  - The classical neuroendocrine panel, which separates them only at the lower grades
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis."
    explanation: >-
      The marker that separates the two across the grade range, and the reason
      the distinction matters, stated in the same sentence.
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "This combination can be useful for distinguishing it from many other sinonasal cancers, however these markers become far less reliable (i.e., fail to remain mutually exclusive) in the setting of poorly differentiated, high-grade tumors such as sinonasal undifferentiated carcinoma (SNUC)."
    explanation: >-
      States where the classical panel fails, which is what makes this
      differential difficult rather than routine. An introduction sentence
      summarising established practice.
  - reference: PMID:33929681
    reference_title: "SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "when restricting the group to SNUC and SNEC the same cutoff point yielded a sensitivity of 93.5% and specificity of 96.4%"
    explanation: >-
      The performance of the SSTR2 stain against this differential
      specifically rather than against mimics in general: restricted to
      sinonasal undifferentiated carcinoma and sinonasal neuroendocrine
      carcinoma, the same cutoff gave 93.5 per cent sensitivity and 96.4 per
      cent specificity. A single-centre series, so not prospective figures.
- name: IDH2-Mutant Sinonasal Carcinoma
  description: >-
    In the methylation reclassification cohort, 7 of 66 tumours carrying the
    institutional diagnosis of olfactory neuroblastoma formed a group with a
    CpG island methylator phenotype, strong cytokeratin expression, little or
    no chromogranin A, and an IDH2 hotspot mutation in every case; they
    clustered with sinonasal carcinoma with IDH2 mutation. These are generally
    read as misdiagnoses rather than as a subtype of this tumour, which is why
    no subtype is declared for them here.
  distinguishing_features:
  - IDH2 hotspot mutation, present in all seven cases of that group
  - Strong cytokeratin expression with no or scarce chromogranin A
  - A CpG island methylator phenotype, clustering with IDH2-mutant sinonasal carcinoma rather than with core olfactory neuroblastoma
  evidence:
  - reference: PMID:29730775
    reference_title: "DNA methylation-based reclassification of olfactory neuroblastoma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases."
    explanation: >-
      Describes the group and its three separating features. Seven cases, all
      with the IDH2 mutation, which is what makes the separation clean in this
      cohort.
  - reference: PMID:29730775
    reference_title: "DNA methylation-based reclassification of olfactory neuroblastoma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis."
    explanation: >-
      Gives the size of the core group against the whole cohort, which is what
      makes the point that a third of institutionally diagnosed cases fell
      elsewhere. The core group itself showed no overlap with other classes.
- name: Neuroblastoma
  disease_term:
    preferred_term: neuroblastoma
    term:
      id: MONDO:0005072
      label: neuroblastoma
  description: >-
    Shares the name and nothing else that matters. Neuroblastoma is a tumour
    of the sympathetic nervous system in young children, arising from neural
    crest-derived sympathoadrenal precursors, typically in the adrenal gland
    or paraspinal sympathetic chain. This tumour arises from olfactory
    epithelial globose basal cells in the nasal cavity, in adults. The two are
    confused in the literature and in ontologies rather than at the bedside,
    and this row exists to record the distinction explicitly.
  distinguishing_features:
  - Origin from olfactory epithelial globose basal cells rather than from sympathoadrenal neural crest precursors
  - A sinonasal site at the cribriform plate rather than adrenal or paraspinal
  - Adults rather than young children, with a unimodal peak at about 50 to 60 years
  - No recurrent driver mutation, where neuroblastoma has recurrent MYCN amplification and ALK alterations
  evidence:
  - reference: PMID:36841178
    reference_title: "Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation."
    explanation: >-
      The cell-of-origin result, which is the substantive basis for separating
      this tumour from neuroblastoma: a different parent cell in a different
      epithelium. The sentence does not mention neuroblastoma, so the contrast
      itself is drawn by this entry from the two tumours' separate literatures.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "ONB demonstrates an unimodal distribution with a more common presentation in adulthood around the age of 50-60 years"
    explanation: >-
      The age distribution, one of the plainest separations from
      neuroblastoma, a tumour of young children. A review's synthesis citing
      an earlier source.
treatments:
- name: Surgical Resection
  description: >-
    Surgery is the primary local treatment. Open craniofacial resection was
    historically the standard operation; endoscopic endonasal approaches have
    largely replaced it over the last two decades, with lower complication
    rates and shorter hospital stay and, in the cited review's assessment,
    similar clinical outcome.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: surgical resection
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Sinonasal Mass Arising at the Cribriform Plate
    description: >-
      Resection removes the mass and, with it, the obstruction, bleeding and
      further local extension.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Local treatment with surgery is frequently recommended for primary therapy."
    explanation: >-
      The review's statement that surgery is the usual primary treatment. It
      is a synthesis of practice rather than a trial result.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In the last years, endoscopic endonasal approaches have been largely introduced with lower complication rates, shorter hospital stay, and similar clinical outcome."
    explanation: >-
      Records the shift in surgical approach and the claimed equivalence of
      outcome. The comparison is the review's summary of published series, not
      a randomised comparison, so the equivalence claim is weakly founded.
- name: Postoperative Radiotherapy
  description: >-
    Radiotherapy is combined with surgery for more locally advanced resectable
    disease, and locally advanced disease generally needs a multidisciplinary
    approach with surgery, radiation and systemic therapy. The cited review
    also notes that Hyams grade may bear on decisions about induction
    chemotherapy and adjuvant radiotherapy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  target_mechanisms:
  - target: Sinonasal Mass Arising at the Cribriform Plate
    description: >-
      Radiotherapy is directed at the primary site, as surgery is, and at the
      margin left after resection.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "While a combination of surgery and postoperative RT is indicated for the management of more local advanced resectable cancers."
    explanation: >-
      States the indication for adding postoperative radiotherapy. A review's
      synthesis of practice, with no comparative data quoted.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "However, based on published data, Hyams grading may represent an important factor for decision making in therapeutic strategies such as induction chemotherapy and adjuvant radiotherapy (RT), and may also be considered in surveillance protocols."
    explanation: >-
      Links the histological grade to treatment decisions. The review hedges
      it as what published data may support, so it is graded INDIRECT and the
      entry does not state grade-directed therapy as established practice.
- name: Platinum-Based Chemotherapy
  description: >-
    Chemotherapy is part of multimodal treatment for locally advanced
    disease: as induction before local treatment, concurrently with
    postoperative radiotherapy in patients at high risk of local recurrence,
    and in the palliative setting. Platinum plus etoposide is described as
    the most used regimen. Its place is unsettled. The cited review states
    that although multimodal therapy is agreed to be needed, the optimal use
    of chemotherapy is still unknown, and reports that the platinum and
    etoposide combination gave no survival benefit over other regimens. The
    underlying studies are retrospective.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: cisplatin
      term:
        id: CHEBI:27899
        label: cisplatin
    - preferred_term: etoposide
      term:
        id: CHEBI:4911
        label: etoposide
  target_mechanisms:
  - target: Proliferative EZH2-High Compartment
    description: >-
      Cytotoxic chemotherapy is directed at the proliferating tumour cell
      population. The link records the target, not an established benefit.
  evidence:
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Platinum plus etoposide chemotherapy seems to be the most used regimen, even if not provide a survival benefit when compared with all other regimens."
    explanation: >-
      Names the commonest regimen and, in the same sentence, reports that it
      did not outperform the alternatives. The review's own grammatical slip
      is quoted as printed. This is why the row records standard practice
      rather than established benefit.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Although there is agreement that multimodal therapy is needed, the optimal use of chemotherapy is still unknown."
    explanation: >-
      The review's own statement that the role of chemotherapy is unsettled,
      which bounds every claim in this row.
  - reference: PMID:37909011
    reference_title: "Olfactory neuroblastoma: diagnosis, management, and current treatment options."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "With the aim to increase local control some studies and referral centers advocate the use of concurrent chemoradiation (CT-RT) with cisplatin after surgery for patients at high risk of local recurrence (30)."
    explanation: >-
      The postoperative chemoradiation setting, attributed by the review to
      some studies and referral centres rather than presented as a standard,
      which is how the description records it.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0006329
      label: olfactory neuroblastoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier for this entry. The term denotes the
      right disease; its placement under extracranial neuroblastoma is
      disputed and is recorded in the entry notes.
  ncit_mappings:
  - term:
      id: NCIT:C3789
      label: Olfactory Neuroblastoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCIT disease concept for the same entity, under the same name.

Olfactory Neuroblastoma

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