Olfactory Neuroblastoma

Slide 1 · Olfactory Neuroblastoma

Morphology, diagnostic reasoning and clinicopathologic correlation

Head and neck pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Localize the typical anatomic origin and connect site to presenting symptoms.

Recognize characteristic lobular small-round-cell morphology and neurofibrillary stroma.

Construct a defensible immunohistochemical and differential-diagnostic approach.

Distinguish tumor grade from anatomic extent and interpret outcome variability.

Site / symptoms

Morphologic pattern

IHC and mimics

Grade / stage / outcome

Slide 3 · A sinonasal neuroectodermal neoplasm

Olfactory neuroblastoma is a malignant neoplasm associated with specialized olfactory mucosa.

Robbins locates its origin particularly near the superior nasal cavity and cribriform plate.

Neural and neuroendocrine differentiation informs its microscopic and immunophenotypic profile.

Cranial compartment

Cribriform region / skull base

Olfactory mucosal region

Superior nasal cavity

Inferior nasal cavity

Slide 4 · Terminology: Two names, one entity

Olfactory neuroblastoma and esthesioneuroblastoma are alternative names for the same lesion.

The term describes its olfactory-region association and primitive neural phenotype.

Do not assume a tumor is olfactory neuroblastoma from the name “neuroblastoma” alone.

Olfactory neuroblastoma

=

Esthesioneuroblastoma

Slide 5 · Olfactory mucosa is the site of origin

The source identifies neuroectodermal olfactory cells within the nasal mucosa.

Its superior location explains why the cribriform plate must be considered.

Anatomic localization is an input to diagnosis; Histology and IHC must still agree.

Cranial compartment

Cribriform region / skull base

Olfactory mucosal region

Superior nasal cavity

Inferior nasal cavity

Slide 6 · Why the cribriform plate matters

It forms the superior boundary of the nasal cavity near the olfactory region.

Tumor proximity creates a potential route for skull-base and intracranial extension.

Assessment of local extent therefore requires more than inspection of the nasal lumen.

Cranial vault

Cribriform plate / skull base

Superior nasal cavity

Adjacent sinonasal spaces

Assess superior extension

Slide 7 · Anatomic diagnosis starts with location

A superior nasal cavity lesion is anatomically compatible with olfactory neuroblastoma.

Site is a clue, not a substitute for determining differentiation and lineage.

The diagnostic record should preserve the mass location and its relationship to the skull base.

LOCATION

MORPHOLOGY

LINEAGE / IMMUNOPHENOTYPE

Slide 8 · Age distribution is broad

Cases can occur at any age.

A peak during the fifth and sixth decades.

Patient age alone cannot establish or exclude the diagnosis.

Can occur at any age

Age spectrum

Peak: 5th–6th decades

Qualitative distribution — no incidence histogram

Slide 9 · Epidemiology: An interpretive caution

A typical age range is useful for clinical suspicion, not a deterministic cutoff.

An unusual patient age should broaden the differential rather than end the workup.

The relevant diagnostic evidence remains location, morphology and differentiation.

LOCATION

MORPHOLOGY

LINEAGE / IMMUNOPHENOTYPE

Slide 10 · Two common presenting symptoms

Nasal obstruction is a typical presentation.

Epistaxis is another typical presentation.

Neither symptom is specific to this tumor; Each requires contextual evaluation.

Nasal cavity mass

Obstruction of airflow

Epistaxis

Symptoms are suggestive, not diagnostic

Slide 11 · Obstruction reflects local tumor mass

A space-occupying lesion in the nasal cavity narrows the airway.

The obstruction can resemble symptoms caused by non-neoplastic sinonasal lesions.

Anatomic examination and tissue sampling are needed to resolve the cause.

Nasal cavity mass

Obstruction of airflow

Epistaxis

Symptoms are suggestive, not diagnostic

Slide 12 · Epistaxis reflects a vascular environment

Fibrovascular stroma within the tumor.

A nasal mass with bleeding may therefore be consistent with this phenotype.

Epistaxis is not uniquely diagnostic: Other vascular and epithelial lesions can bleed.

Tumor lobules

Fibrovascular septa

Schematic cellular architecture — not a micrograph

Slide 13 · Opening clinical problem

An adult has persistent unilateral nasal obstruction and episodic epistaxis. Imaging demonstrates an upper nasal cavity mass.

Which features would support olfactory neuroblastoma, and what competing tumors must be excluded?

Slide 14 · Initial diagnostic question: What lineage?

Establish whether the sampled lesion is neuroectodermal, epithelial, hematolymphoid or mesenchymal.

Avoid final classification based on symptoms and a small round blue cell morphology alone.

Use anatomy, architecture and a targeted immunohistochemical panel together.

Primitive sinonasal malignancy

Neuroectodermal

Epithelial

Hematolymphoid

Mesenchymal

Work from morphology to lineage-specific evidence

Slide 15 · The small-round-blue-cell family

Olfactory neuroblastoma in the small round blue cell category.

Morphologic mimics listed include lymphoma, small cell carcinoma, Ewing sarcoma and rhabdomyosarcoma.

Shared cytologic resemblance creates a diagnostic problem, not a unified lineage.

High nuclear-to-cytoplasmic ratio

Stylized small round cells — not histologic evidence

Slide 16 · Architecture is more informative than color

A low-power survey looks for well-circumscribed nests and lobules.

These groups are separated by fibrovascular stroma.

Pattern recognition at low magnification precedes cytologic refinement.

Tumor lobules

Fibrovascular septa

Schematic cellular architecture — not a micrograph

Slide 17 · Typical nests and lobules

The neoplastic cells form discrete cohesive appearing aggregates.

Stromal septa delineate boundaries between lobules.

Atypical or high-grade examples may lose portions of this organized pattern.

Tumor lobules

Fibrovascular septa

Schematic cellular architecture — not a micrograph

Slide 18 · Fibrovascular stroma defines the spaces

Connective tissue separates tumor nests rather than forming a diffuse cellular sheet.

Vascular channels may be evident within intervening stroma.

Assess both neoplastic cell islands and their intervening background.

Tumor lobules

Fibrovascular septa

Schematic cellular architecture — not a micrograph

Slide 19 · Nuclear appearance in typical tumors

Tumor cells are relatively monotonous and small at conventional H&E review.

The blue-cell appearance principally reflects densely staining nuclei.

Low-grade examples often have relatively uniform, stippled nuclear chromatin.

High nuclear-to-cytoplasmic ratio

Stylized small round cells — not histologic evidence

Slide 20 · Neurofibrillary stroma is diagnostically valuable

The fibrillary background represents tangled neuronal cell processes.

It differs conceptually from ordinary connective-tissue septa.

Its presence adds evidence of neural differentiation beyond cell shape alone.

Fibrillary neuronal processes

Neurofibrillary matrix schematic — not H&E

Slide 21 · Reading the fibrillary matrix

Search for delicate fibrillary material between or around tumor cells.

Distinguish this background from pale fibrovascular septa and processing artifacts.

High-grade lesions may have less recognizable neuropil, increasing diagnostic difficulty.

Fibrillary neuronal processes

Neurofibrillary matrix schematic — not H&E

Slide 22 · Source figure: A verbal reconstruction

Robbins Figure 16.13 describes small monotonous round cells.

An eosinophilic fibrillary stroma surrounds the cells.

The cells appear to swirl around a blood-filled vascular channel.

Vascular channel

Perivascular cell arrangement

Original schema of textual figure description — not H&E

Slide 23 · Rosettes: An additional histologic clue

Some tumors form neuroblastic rosette-like arrangements.

A pseudorosette can organize tumor cells around a fibrillary central zone.

Rosettes support a neuroblastic pattern but are not exclusive to this entity.

Tumor cells

Central fibrillary zone

Rosette/pseudorosette concept — not a micrograph

Slide 24 · Recognizing atypical morphology

The classic lobular/neurofibrillary phenotype is easiest to recognize in lower-grade areas.

Atypia, necrosis and increased mitoses complicate high-grade interpretation.

A small biopsy may not represent the highest-grade component of a heterogeneous tumor.

Lower-grade appearance

Higher-grade appearance

More lobular/neuropil

More atypia/necrosis

Qualitative contrast only — not grading specimens

Slide 25 · Ultrastructure supports secretory differentiation

Membrane-bound secretory granules on electron microscopy.

Such granules are consistent with neuroendocrine differentiation.

Modern diagnosis generally integrates morphology and IHC; Ultrastructure is corroborative.

Membrane-bound secretory granules

Cell ultrastructure schematic — not electron microscopy

Slide 26 · Four markers emphasized

Synaptophysin and chromogranin demonstrate neuroendocrine-associated proteins.

INSM1 and CD56 provide additional evidence of neuroendocrine differentiation.

Positive staining is interpreted alongside architecture, site and exclusion of mimics.

Synaptophysin

Chromogranin

INSM1

CD56

Markers describe differentiation, not unique tumor identity

Slide 27 · Synaptophysin: Vesicle-associated marker

Synaptophysin is a commonly positive neuroendocrine marker in olfactory neuroblastoma.

Its staining provides evidence of differentiation, not a tumor-specific fingerprint.

Other neuroendocrine neoplasms can express synaptophysin.

Synaptophysin

Neuroendocrine differentiation

Interpret within a lineage-specific panel

Slide 28 · Chromogranin: Secretory granule association

Chromogranin is included among positive markers.

Expression complements synaptophysin in assessing neuroendocrine phenotype.

Staining must be evaluated in a panel rather than treated as independently diagnostic.

Chromogranin

Neuroendocrine differentiation

Interpret within a lineage-specific panel

Slide 29 · INSM1: Nuclear neuroendocrine marker

INSM1 is explicitly named marker set.

A nuclear staining pattern offers information complementary to cytoplasmic markers.

Neuroendocrine lineage confirmation does not alone distinguish ONB from carcinoma.

INSM1

Neuroendocrine differentiation

Interpret within a lineage-specific panel

Slide 30 · CD56: Useful but not a stand-alone test

CD56 is part of the textbook-supported immunophenotype.

Because CD56 is not tumor specific, interpretation requires other markers and morphology.

A single positive CD56 result cannot establish olfactory neuroblastoma.

CD56

Neuroendocrine differentiation

Interpret within a lineage-specific panel

Slide 31 · Neuroendocrine positivity is a phenotype

A positive panel supports neuroendocrine differentiation.

Phenotypic overlap with small cell neuroendocrine carcinoma remains possible.

Therefore, resolve epithelial lineage, architecture and anatomic context as well.

LOCATION

MORPHOLOGY

LINEAGE / IMMUNOPHENOTYPE

Slide 32 · Peripheral S100 sustentacular pattern

S100-positive sustentacular cells can outline tumor nests, especially in lower-grade lesions.

The peripheral pattern is different from diffuse staining of the tumor-cell population.

This is useful supplementary diagnostic evidence, not among the primary four diagnostic markers.

S100-positive peripheral sustentacular rim

S100 staining-pattern schematic — not IHC specimen

Slide 33 · Cytokeratin: A nuanced discriminator

Olfactory neuroblastoma is usually non-epithelial in immunophenotype.

Focal keratin expression may occur, so isolated focal positivity does not automatically exclude it.

Strong diffuse epithelial staining should prompt scrutiny for a carcinoma mimic.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 34 · Exclusion markers prevent anchoring

CD45 supports a hematolymphoid differential when positive in tumor cells.

Myogenin and desmin can direct attention toward skeletal muscle differentiation.

CD99/NKX2.2, interpreted with morphology and molecular studies, can aid Ewing workup.

Primitive sinonasal malignancy

Neuroectodermal

Epithelial

Hematolymphoid

Mesenchymal

Work from morphology to lineage-specific evidence

Slide 35 · A staged IHC workup

First integrate tumor location, architecture and routine morphology.

Then evaluate neuroendocrine, epithelial, lymphoid and muscle-lineage markers.

Reserve molecular confirmation for cases where the phenotype suggests a specific genetically defined mimic.

Site + architecture

Neuroendocrine IHC

Exclude mimics by lineage

Resolve difficult cases

Slide 36 · Differential: Lymphoma

Lymphoma is one of the textbook-listed small-round-cell mimics.

Consider lymphoid lineage when cells lack characteristic lobular/neuropil architecture.

CD45 and appropriate subtype markers are more informative than nuclear size alone.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 37 · Differential: Small cell carcinoma

Both tumors can express neuroendocrine markers, so positivity alone is insufficient.

An epithelial keratin phenotype and different growth architecture favor carcinoma.

Correlate immunophenotype with location and morphology.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 38 · Differential: Ewing sarcoma

Ewing sarcoma belongs to the textbook-listed small-round-blue-cell differential.

CD99/NKX2.2 can raise suspicion but require contextual interpretation.

Appropriate molecular investigation can establish a characteristic Ewing-family rearrangement.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 39 · Differential: Rhabdomyosarcoma

Rhabdomyosarcoma is another textbook-listed morphologic mimic.

Skeletal muscle-lineage markers redirect the differential away from a neural tumor.

Lineage evidence is decisive when primitive cytology overlaps.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 40 · Adjacent sinonasal entity: NUT carcinoma

NUT carcinoma follows ONB as a separate entity Chapter 16.

Its poorly differentiated appearance can complicate sinonasal differential diagnosis.

NUT nuclear immunohistochemistry and fusion testing are entity-directed ancillary studies.

Shared small-cell appearance

Resolve by phenotype + architecture

One stain ≠ one diagnosis

Slide 41 · Compact differential-diagnostic matrix

Entity

Useful discriminators

Olfactory neuroblastoma

Lobules; Neuropil; NE markers; Peripheral S100 cells

Small cell carcinoma

Neuroendocrine markers with epithelial keratin phenotype

Lymphoma

CD45 and lineage-specific hematolymphoid markers

Rhabdomyosarcoma

Desmin / nuclear myogenin support muscle lineage

Ewing sarcoma

CD99 / NKX2.2; Confirm with suitable molecular studies

Slide 42 · Avoid interpreting one stain in isolation

A neuroendocrine-positive, keratin-positive lesion has more than one plausible classification.

A strong sustentacular pattern is helpful only in compatible morphologic context.

Integrate multiple concordant findings and investigate discordance.

LOCATION

MORPHOLOGY

LINEAGE / IMMUNOPHENOTYPE

Slide 43 · Low-grade morphology: Recognizable organization

Well-delineated lobules and conspicuous neuropil favor a lower-grade appearance.

Uniform nuclei and limited atypia contribute to histologic assessment.

Grade assignment requires systematic review, not one isolated feature.

Lower-grade appearance

Higher-grade appearance

More lobular/neuropil

More atypia/necrosis

Qualitative contrast only — not grading specimens

Slide 44 · High-grade morphology: Diagnostic difficulty

Marked atypia, necrosis and mitotic activity can obscure typical features.

Growth may appear more diffuse as lobularity and neuropil become less conspicuous.

High-grade examples warrant a particularly broad sinonasal malignancy differential.

Lower-grade appearance

Higher-grade appearance

More lobular/neuropil

More atypia/necrosis

Qualitative contrast only — not grading specimens

Slide 45 · Hyams grading: A composite assessment

The Hyams system evaluates several histologic characteristics together.

Features include architecture, neurofibrillary matrix, cytologic atypia, mitoses and necrosis.

Four original grades are often considered as lower grade (I–II) versus higher grade (III–IV).

Architecture

Neuropil / rosettes

Atypia / mitoses

Necrosis

Slide 46 · Grade and stage answer different questions

Grade: What aggressive features are visible under the microscope?

Stage: How far has the tumor extended anatomically?

Both dimensions matter when interpreting treatment strategy and prognosis.

HISTOLOGIC GRADE

Cytology · Mitotic activity · Necrosis · Architecture

ANATOMIC EXTENT

Local spread · Skull-base involvement · Other sites

Slide 47 · Anatomical spread is clinically central

The lesion starts near the superior nasal cavity and cribriform region.

The skull base, adjacent sinuses and intracranial compartment are relevant to mapping extent.

Extent assessment cannot be inferred reliably from a small biopsy alone.

Cranial vault

Cribriform plate / skull base

Superior nasal cavity

Adjacent sinonasal spaces

Assess superior extension

Slide 48 · Clinical stage systems are not histologic grades

Modified Kadish and Dulguerov schemes are used to describe clinical extent.

Both incorporate local spread; Detailed categorization depends on the specified system.

Use a named and dated staging scheme in reports rather than an ambiguous “stage”.

Nasal cavity

Primary region

Adjacent sinonasal spaces

Local extension

Skull base / further spread

Advanced involvement

Conceptual progression only; Not a formal stage table

Slide 49 · Imaging complements pathologic diagnosis

Pathology establishes lineage and histologic grade in sampled tissue.

Cross-sectional imaging delineates lesion extent and skull-base relationships.

Multidisciplinary correlation is required before definitive local treatment planning.

PATHOLOGY

Lineage / grade

IMAGING

Extent / skull base

MULTIDISCIPLINARY

Treatment synthesis

Slide 50 · Report elements that answer clinical questions

Specify the histopathologic diagnosis and recognizable morphological grade features.

Document the pattern and breadth of immunohistochemical findings.

Correlate with site, imaging and surgical margin status where material permits.

Anatomic site

Architecture + differentiation

Histologic grade

Extent / margin correlation

Slide 51 · Genetics are heterogeneous

Chromosomal gains and losses vary between cases.

This heterogeneity argues against a single uniform genomic alteration.

Molecular findings should not replace the morphologic and phenotypic diagnostic framework.

Genomic heterogeneity

Chromosomal gain

Chromosomal loss

Variable combinations

Conceptual categories — no invented karyotype or cohort data

Slide 52 · A molecular result needs a question

Molecular tests may help resolve genetically defined differential diagnoses.

Do not order a broad panel without a morphology-driven diagnostic hypothesis.

No unique, universally required molecular signature for ONB is stated.

Site + architecture

Neuroendocrine IHC

Exclude mimics by lineage

Resolve difficult cases

Slide 53 · Treatment is typically multimodal

Combinations of surgery, radiotherapy and chemotherapy.

Stage and grade influence treatment selection and expected outcome.

There is no single uniform modality appropriate for all disease extents.

Surgery

Radiotherapy

Chemotherapy

Combined according to clinical context

Slide 54 · Surgical therapy: Local control

Resection targets local tumor removal when anatomically feasible.

The proximity to the skull base makes complete extent assessment important.

Surgical planning requires clinical and imaging information beyond microscopic diagnosis.

Cranial vault

Cribriform plate / skull base

Superior nasal cavity

Adjacent sinonasal spaces

Assess superior extension

Slide 55 · Radiotherapy: A complementary modality

Radiotherapy is included’s treatment combinations.

Use may depend on resection status, disease extent and multidisciplinary decisions.

Treatment decisions should not be inferred from a limited histologic section.

Surgery

Radiotherapy

Chemotherapy

Combined according to clinical context

Slide 56 · Chemotherapy: Context-dependent use

Chemotherapy is one possible component of multimodal treatment.

Its role varies with stage, grade and clinical treatment strategy.

A pathology lecture cannot substitute for current tumor-board planning.

Surgery

Radiotherapy

Chemotherapy

Combined according to clinical context

Slide 57 · Outcome spans a broad range

Five-year survival rates ranging from 40% to 90%.

The source explicitly qualifies this range by tumor stage, grade and combined therapy.

It is not a patient-specific probability or a uniform contemporary benchmark.

Five-year survival

40%–90%

Across differing stage, grade and treatment contexts

Source-reported range; Not a patient-level estimate

Slide 58 · Why a single survival number misleads

A localized lower-grade lesion and an advanced higher-grade lesion are not equivalent.

Study era, treatment strategy and case mix influence reported estimates.

When presenting a prognosis, identify cohort, endpoint and risk context.

HISTOLOGIC GRADE

Cytology · Mitotic activity · Necrosis · Architecture

ANATOMIC EXTENT

Local spread · Skull-base involvement · Other sites

Slide 59 · Follow-up needs a long-term perspective

Disease control and surveillance are distinct from initial pathologic classification.

Local recurrence or distant spread may change clinical management.

Interval and modality of surveillance require local specialist protocols.

Cranial vault

Cribriform plate / skull base

Superior nasal cavity

Adjacent sinonasal spaces

Assess superior extension

Slide 60 · Case 1: Classic low-power morphology

A superior nasal cavity tumor shows sharply defined lobules of uniform small blue cells, separated by fibrovascular septa. Delicate neuropil is conspicuous.

Which additional evidence most directly supports olfactory neuroblastoma?

Slide 61 · Case 1: Diagnostic synthesis

Synaptophysin, chromogranin and INSM1 positivity support neuroendocrine differentiation.

A peripheral S100 sustentacular pattern would strengthen this interpretation.

The final diagnosis still requires exclusion of epithelial and other small-round-cell mimics.

Synaptophysin

Chromogranin

INSM1

CD56

Markers describe differentiation, not unique tumor identity

Slide 62 · Case 2: The high-grade pitfall

A sinonasal biopsy contains a diffuse small-cell malignancy with brisk mitoses, necrosis and strong synaptophysin staining. No classic lobules are evident.

Why is “olfactory neuroblastoma” not yet a secure final diagnosis?

Slide 63 · Case 2: Resolving uncertainty

High-grade ONB can lose recognizable lobularity and neuropil.

Small cell neuroendocrine carcinoma may share neuroendocrine positivity.

Assess keratins, other lineage markers and the full clinical/imaging context before classification.

Primitive sinonasal malignancy

Neuroectodermal

Epithelial

Hematolymphoid

Mesenchymal

Work from morphology to lineage-specific evidence

Slide 64 · Case 3: Prognosis and communication

Two confirmed ONBs have different anatomic extents and histologic grades. A team asks for one universal five-year survival percentage.

How should the pathologist communicate the evidence without false precision?

Slide 65 · Case 3: Evidence-based response

Describe histologic grade and documented anatomic extent separately.

Explain that an overall 40–90% five-year survival range across varied cases.

Avoid assigning a personalized prognosis without stage, grade and relevant cohort data.

Five-year survival

40%–90%

Across differing stage, grade and treatment contexts

Source-reported range; Not a patient-level estimate

Slide 66 · Integrated diagnostic synthesis

Site: Superior nasal cavity / olfactory mucosal region.

Morphology: Circumscribed nests, fibrovascular septa and neurofibrillary background.

Phenotype: Multiple neuroendocrine markers; Targeted exclusion of mimics.

Clinicopathology: Histologic grade, extent and treatment context together matter.

Superior nasal site

Lobular + fibrillary H&E

Neuroendocrine IHC panel

Exclude competing lineages

Slide 67 · Selected reading and source provenance

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Ch. 16, p. 674.

WHO 5th edition sinonasal/skull-base update. Head Neck Pathol. 2022. PMCID: PMC9018924.

Small-round-cell sinonasal tumor IHC review. Head Neck Pathol. 2024. PMCID: PMC10844182.

Olfactory Neuroblastoma review. Head Neck Pathol. 2009. PMCID: PMC2811627.

Hyams grading refinement. Head Neck Pathol. 2025. PMCID: PMC12307849.

Treatment evaluation review. 2024. PMID: 38762332.