Sinonasal Papilloma

Slide 1 · SINONASAL PAPILLOMA

Morphology · Molecular pathogenesis · Diagnostic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning goals

Define sinonasal (Schneiderian) papilloma and identify its three variants.

Explain inverted, exophytic, and oncocytic epithelial growth patterns.

Integrate histology with EGFR, KRAS, and low-risk HPV associations.

Recognize recurrence risk, carcinoma red flags, and diagnostic mimics.

Slide 3 · Primary site: Schneiderian respiratory mucosa

Origin: Mucosa lining the nasal cavity and paranasal sinuses.

A true epithelial neoplasm rather than a nonspecific inflammatory polyp.

Anatomic location and architectural pattern are fundamental diagnostic clues.

Cilia

Stroma

Schematic — not a histologic specimen

Slide 4 · Respiratory epithelium provides the substrate

Normal sinonasal lining contains ciliated respiratory-type cells and mucocytes.

Papilloma epithelium may display respiratory, transitional, or squamous differentiation.

Background inflammation can coexist without defining the neoplasm.

Cilia

Stroma

Schematic — not a histologic specimen

Slide 5 · Sinonasal tumors form a diverse differential

Benign papilloma, inflammatory polyp, and respiratory epithelial hamartoma may appear polypoid.

Malignant epithelial lesions can also produce unilateral sinonasal masses.

Histologic architecture—not the word “polyp”—determines classification.

Slide 6 · Three recognized papilloma types

Inverted

Downward epithelial lobules

Oncocytic

Granular columnar lining

Exophytic

Outward fibrovascular fronds

Slide 7 · Current nomenclature

Sinonasal papilloma is often called Schneiderian papilloma.

WHO 5th edition (2022) retains inverted, oncocytic, and exophytic entities.

“Cylindrical-cell” and “fungiform” are historical descriptive synonyms for oncocytic and exophytic forms.

Slide 8 · Demographic pattern

Robbins: Most common in men aged 30–60 years.

Age and sex support clinical context but are not diagnostic criteria.

Interpret the epidemiologic statement at the group level; Subtype distributions differ.

Slide 9 · Benign does not imply clinically trivial

Non-invasive epithelial histology can coexist with significant local expansion.

An incompletely excised inverted papilloma may recur.

Inverted and oncocytic lesions require attention to associated dysplasia or carcinoma.

Slide 10 · Clinical presentation: Obstruction and bleeding

Unilateral nasal obstruction is a common presenting clue, particularly in inverted lesions.

Epistaxis, rhinorrhea, or recurrent sinus symptoms may occur.

Symptoms overlap with benign inflammatory disease: Tissue diagnosis is needed.

Slide 11 · A unilateral nasal mass warrants evaluation

Papilloma and carcinoma can mimic an inflammatory polyp on examination.

History, endoscopy, and imaging identify attachment and extent.

Biopsy should be interpreted with imaging and adequate sampling.

Slide 12 · Typical location of inverted papilloma

Frequently arises from the lateral nasal wall with extension to adjacent sinuses.

Site of attachment helps interpret focal hyperostosis on CT.

Septal origin is more characteristic of the exophytic subtype.

Slide 13 · The significance of local extension

Inverted papilloma can expand within nasal cavity and paranasal sinuses.

Possible extension to orbit or cranial vault.

Extent is an anatomic behavior; It is not itself histologic proof of carcinoma.

Slide 14 · Inverted papilloma: Defining architecture

Broad, bulbous lobules of neoplastic epithelium project downward.

Epithelial islands sit within stroma while retaining a basement membrane.

An endophytic growth configuration explains the term “inverted”.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Slide 15 · A native schematic of endophytic growth

Observe the direction from surface epithelium toward submucosal stroma.

Broad interconnected epithelial lobules create a pushing contour.

Distinguish this configuration from irregular destructive stromal invasion.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Slide 16 · Pushing growth is not synonymous with invasion

A benign inverted papilloma can contain extensive epithelial downgrowth.

Intact basement-membrane relationships and orderly maturation favor benignity.

Irregular infiltrative nests and desmoplasia require assessment for carcinoma.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Slide 17 · Low-power histology: What to locate first

Find the surface epithelium and identify its relation to subjacent stroma.

Look for broad tongues, ribbons, or nests of thickened epithelium.

Assess whether the deep border is circumscribed or destructive.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Slide 18 · Inverted papilloma: Epithelial differentiation

Nonkeratinizing squamous and transitional-type cells commonly predominate.

Respiratory-type columnar or ciliated elements may remain.

Different epithelial appearances can occur within one lesion.

Slide 19 · Mucocytes and intraepithelial microcysts

Goblet-type mucocytes may occur within the papillomatous epithelium.

Entrapped mucin may create intraepithelial microcystic spaces.

These findings support context, but are not unique to the inverted type.

Epithelial spaces (microcysts)

Schematic — not a histologic specimen

Slide 20 · Neutrophils can enter papilloma epithelium

Transepithelial neutrophils and microabscesses are recognized findings.

Inflammatory cells do not automatically signify epithelial invasion.

Interpret them together with the overall architecture and cytology.

Epithelial spaces (microcysts)

Schematic — not a histologic specimen

Slide 21 · Stroma and secondary inflammation

Stroma may be fibrous, edematous, or chronically inflamed.

Obstruction from the neoplasm can produce secondary polypoid inflammatory change.

The accompanying stroma should not obscure the epithelial tumor.

Slide 22 · Atypia: Architectural context is essential

Mild nuclear variation can be seen in otherwise benign epithelium.

Marked dysplasia, atypical mitoses, necrosis, or infiltrative growth are concerning.

A superficial fragment may not show the deepest tumor interface.

Slide 23 · Exophytic versus inverted architecture

Exophytic: Outward-growing finger-like projections with fibrovascular cores.

Inverted: Thick epithelium forms broad downward lobules into stroma.

Some papillomas have mixed surface and inward growth; Classify by the defining component.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Inverted = downward

Slide 24 · Morphology exercise: Downward islands

A biopsy shows bland squamous/transitional cells in downward stromal nests.

Basement-membrane relationships remain smooth and cohesive.

Interpretation: Inverted sinonasal papilloma, if representative.

Surface epithelium

Stroma

Schematic — not a histologic specimen

Slide 25 · EGFR in inverted papilloma

Robbins: Most inverted papillomas have EGFR gene mutations.

WHO 2022 review reports somatic EGFR alterations in approximately 90% of inverted cases in reviewed series.

This molecular association reinforces a neoplastic, subtype-specific pathogenesis.

Slide 26 · The HPV nuance in inverted papilloma

HPV DNA in a subset lacking EGFR mutations, often HPV 6 or 11.

WHO 2022 highlights low-risk HPV transcripts in some tumors but generally no active high-risk E6/E7 signal.

DNA detection alone is not synonymous with a transcriptionally active driver.

Slide 27 · Two alternative molecular patterns

Subtype-specific biology and progression

Pathway A: Somatic EGFR-altered inverted papilloma.

Pathway B: Less common low-risk HPV-associated inverted papilloma.

An individual tumor is not assumed to have both drivers; Most reports describe mutual exclusivity.

Illustrative conceptual grouping — not a quantitative model

Slide 28 · Molecular testing: Avoid overinterpretation

EGFR status can clarify biologic classification in a difficult case.

Neither EGFR mutation nor HPV DNA alone demonstrates invasive carcinoma.

Histology and sampling remain decisive for malignant transformation.

Slide 29 · Gross appearance of inverted papilloma

Often described as a pink-gray, lobulated, polypoid sinonasal mass.

Broad attachment and a folded surface may suggest the lesion endoscopically.

Gross examination should document size, attachment, and sampling of abnormal regions.

Slide 30 · Imaging: Complementary diagnostic value

CT maps bony anatomy and may show focal osteitis or hyperostosis.

MRI more clearly depicts soft-tissue extent and internal signal pattern.

Imaging supports localization; Histopathology makes the definitive diagnosis.

Slide 31 · Focal hyperostosis may identify attachment

On CT, focal bony thickening near a lesion may mark its origin.

This clue can guide the surgical assessment of the attachment site.

Hyperostosis must not be confused with unequivocal invasive bony destruction.

Slide 32 · MRI: Cerebriform architecture

WHO review notes a convoluted cerebriform pattern on T2 and post-contrast T1 MRI.

The pattern can support inverted papilloma when concordant with location.

It is suggestive rather than pathognomonic.

Simplified folded internal pattern

Schematic — not a histologic specimen

Slide 33 · Expansion, erosion, and malignant concern

Locally expansive benign papilloma may affect adjacent anatomy.

Destructive invasion, loss of expected tumor architecture, or a suspicious focal region warrants carcinoma exclusion.

Final categorization requires tissue correlation rather than imaging alone.

Slide 34 · Oncocytic papilloma: A distinct lineage

Oncocytic sinonasal papilloma is a separate WHO-recognized subtype.

It may have both outward and inward epithelial growth.

Its defining feature is the character of the lining epithelium.

Granular columnar lining

Intraepithelial microcysts

Schematic — not a histologic specimen

Slide 35 · Oncocytic epithelium: Cytologic identity

Tall columnar epithelial cells contain abundant granular eosinophilic cytoplasm.

Rounded nuclei tend to be relatively uniform in benign regions.

The granular cytoplasm distinguishes oncocytic from non-oncocytic papilloma.

Granular columnar lining

Intraepithelial microcysts

Schematic — not a histologic specimen

Slide 36 · Oncocytic microcystic change

Intraepithelial mucin-containing microcysts are common.

Mixed exophytic and endophytic architecture may be present.

Both the cell type and the architectural organization are needed for typing.

Epithelial spaces (microcysts)

Schematic — not a histologic specimen

Slide 37 · KRAS is the characteristic oncocytic driver

WHO 2022 describes recurrent hotspot KRAS mutations in oncocytic papilloma.

HPV infection is not regarded as an etiologic driver of this subtype.

This provides a biologic contrast with EGFR-altered inverted papilloma.

Slide 38 · Oncocytic versus inverted papilloma

Both can show endophytic components and intraepithelial microcysts.

Oncocytic: Diffuse granular eosinophilic columnar cells; Often KRAS-altered.

Inverted: Typically transitional/squamous thickening; Often EGFR-altered.

Slide 39 · Exophytic papilloma: Papillary surface growth

Also termed fungiform or septal papilloma.

Outward epithelial projections are supported by fibrovascular cores.

The lesion lacks the dominant deep broad epithelial ingrowth of inverted papilloma.

Papillary fronds

Fibrovascular cores

Schematic — not a histologic specimen

Slide 40 · Exophytic histology: Fibrovascular cores

Finger-like fronds are lined by stratified squamous or transitional-type epithelium.

Each frond encloses a connective tissue and vascular core.

Superficial HPV-related change may be visible, but need not be present.

Papillary fronds

Fibrovascular cores

Schematic — not a histologic specimen

Slide 41 · Low-risk HPV predominates in exophytic lesions

WHO 2022 identifies HPV types 6 and 11 in many exophytic papillomas.

This association differs from HPV-negative, KRAS-altered oncocytic tumors.

Low-risk HPV in papilloma does not imply the biology of an HPV-driven carcinoma.

Slide 42 · Exophytic tumors favor the anterior septum

Typical origin is the anterior/lower nasal septum.

This location provides a useful correlation with the outward-growing architecture.

Anatomic distribution supports, but does not replace, histologic classification.

Slide 43 · Three types: Morphological discrimination

Variant

Dominant histology

Frequent location / nuance

Inverted

Broad downward epithelial lobules

Lateral nasal wall / sinuses

Oncocytic

Granular eosinophilic columnar cells

Mixed growth; Microcysts

Exophytic

Fronds with fibrovascular cores

Often anterior nasal septum

Slide 44 · Three types: Molecular discrimination

Variant

Predominant association

Important caveat

Inverted

EGFR mutation

Occasional low-risk HPV subset

Oncocytic

KRAS hotspot mutation

HPV generally not etiologic

Exophytic

Low-risk HPV 6/11

Active high-risk HPV not typical

Slide 45 · P16 and HPV: A Diagnostic consideration:

Immunohistochemical p16 expression is not proof of transcriptionally active HPV in these lesions.

High-risk viral oncogenic activity is a different question from low-risk HPV DNA detection.

Use targeted tests only for a defined diagnostic problem.

Slide 46 · Classification is primarily histologic

Anatomic location, low-power growth pattern, and epithelial phenotype usually establish type.

Special stains or IHC have no universal diagnostic role in routine sinonasal papilloma.

Molecular tests may support selected difficult cases, not replace morphology.

Slide 47 · Inflammatory polyp: The major mimic

Inflammatory polyps typically have edematous stroma and a relatively thin epithelial covering.

Papilloma features prominent true epithelial proliferation with type-specific architecture.

The distinction matters because papillomas require attention to complete removal and follow-up.

Slide 48 · Respiratory epithelial adenomatoid hamartoma

REAH typically shows a glandular/adenomatoid proliferation of respiratory epithelium.

Thick hyalinized basement-membrane material around gland-like structures may help recognition.

Broad squamous/transitional epithelial islands favor inverted papilloma instead.

Slide 49 · Exophytic papilloma versus common squamous papilloma

True Schneiderian lesions arise within respiratory sinonasal mucosa.

A keratinizing vestibular squamous papilloma arises from skin-type lining.

Location and epithelial maturation help avoid conflating two sites.

Slide 50 · When oncocytic papilloma mimics a glandular tumor

Prominent columnar cells and cysts can create a gland-like impression.

The orderly papillomatous epithelium and absence of destructive infiltrative growth favor benign papilloma.

Unequivocal atypia or destructive growth demands exclusion of adenocarcinoma or another carcinoma.

Slide 51 · Carcinoma-associated warning signs

Conspicuous cytologic atypia or abnormal maturation.

Atypical mitoses, comedo-like necrosis, or destructive stromal nests.

An abrupt transition from benign papilloma to malignant epithelium.

Suspicious focal change should trigger adequate additional sampling.

Slide 52 · Dysplasia is not the same as invasion

Dysplasia refers to abnormal epithelial maturation and cytology within the epithelial compartment.

Invasive carcinoma requires destructive extension beyond normal epithelial boundaries.

A small or superficial specimen may establish atypia without resolving stromal invasion.

Slide 53 · Carcinoma can be synchronous or metachronous

Synchronous carcinoma is identified concurrently with papilloma.

Metachronous carcinoma is identified at a later clinical time point.

Record the timing and specimen context; The categories are not interchangeable.

Diagnostic or mechanistic sequence (schematic)

Slide 54 · Interpreting malignant transformation risk

Robbins gives malignant transformation in up to 5% of cases in its sinonasal papilloma discussion.

Published estimates vary by histologic subtype and study design; Avoid treating one number as universal.

Exophytic carcinoma is especially rare; Inverted and oncocytic types require greater vigilance.

Slide 55 · Additional progression-associated alterations

Subtype-specific biology and progression

WHO 2022 describes TP53 and/or CDKN2A alterations with carcinoma progression in inverted/oncocytic lesions.

These associations are not stand-alone clinical screening thresholds.

Structural histology remains the basis for identifying carcinoma.

Illustrative conceptual grouping — not a quantitative model

Slide 56 · Why inverted papilloma recurs

Residual epithelium at the site of attachment can seed local recurrence.

Anatomic complexity can make complete excision difficult.

Recurrence after insufficient removal does not, by itself, prove malignant transformation.

Diagnostic or mechanistic sequence (schematic)

Slide 57 · Why attachment-oriented excision matters

Surgical management aims to remove the lesion and address its attachment.

Imaging and endoscopy inform the surgical map.

Separate margin and specimen orientation information help clinicopathologic assessment.

Slide 58 · Follow-up is a pathology-informed decision

Recurrence surveillance is important after treatment, especially for inverted papilloma.

New symptoms or a concerning focal mass may require reassessment and sampling.

Intensity and duration of surveillance are clinical decisions informed by site, treatment, and findings.

Slide 59 · Structured pathology report essentials

Specify variant and specimen/site when available.

Describe epithelial atypia, dysplasia, or associated carcinoma explicitly.

Comment on margins only when their assessment is technically meaningful.

Correlate fragmented samples with operative localization.

Slide 60 · Diagnostic workflow for a sinonasal mass

Localize and image the mass, including possible attachment site.

Biopsy or excise with sufficient representation for histologic review.

Classify growth pattern and epithelium; Assess for dysplasia/invasion.

Convey extent and recurrence-relevant details to the treating team.

Diagnostic or mechanistic sequence (schematic)

Slide 61 · Case 1: Endophytic nasal mass

A middle-aged patient has a unilateral lateral-wall polypoid mass.

Biopsy shows thick bland epithelial lobules pushing downward into stroma.

Question: Which subtype and which common gene association?

Discussion answer (see speaker notes)

Slide 62 · Case 2: Papillary septal lesion

An anterior-septal lesion is composed of outward fronds with fibrovascular cores.

The epithelium resembles stratified transitional/squamous lining.

Question: Subtype and relevant viral association?

Discussion answer (see speaker notes)

Slide 63 · Case 3: Granular eosinophilic lining

A nasal lesion has mixed endophytic and exophytic growth and numerous epithelial microcysts.

The lining is composed of tall cells with granular eosinophilic cytoplasm.

Question: Subtype and characteristic molecular alteration?

Discussion answer (see speaker notes)

Slide 64 · Common diagnostic errors to avoid

Calling every sinonasal “polyp” an inflammatory lesion.

Mistaking benign endophytic lobules for destructive carcinoma.

Assuming oncocytic and exophytic papillomas share the EGFR driver.

Equating HPV DNA detection with transcriptionally active high-risk HPV.

Slide 65 · Integrated take-home distinctions

Variant

Dominant histology

Frequent location / nuance

Inverted

Broad downward epithelial lobules

Lateral nasal wall / sinuses

Oncocytic

Granular eosinophilic columnar cells

Mixed growth; Microcysts

Exophytic

Fronds with fibrovascular cores

Often anterior nasal septum

Slide 66 · Knowledge check

Which histologic boundary prevents benign endophytic growth being called invasion?

Which molecular alteration is most characteristic of oncocytic papilloma?

Why is p16 staining alone insufficient to infer active high-risk HPV?

How can CT hyperostosis help management of inverted papilloma?

Discussion answer (see speaker notes)

Slide 67 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Ch 16, p 673 (2026).

WHO Classification of Head and Neck Tumours. 5th ed. (2022); Thompson et al., Head Neck Pathol 2022.

“OSPs and ESPs and ISPs, Oh My!” Head Neck Pathol 2017; PMCID: PMC5550400.

“Sine Qua Non: Sinonasal Inverted Papilloma.” Head Neck Pathol 2021; PMCID: PMC8385096.