Necrotizing Lesions of the Nose and Upper Airways

Slide 1 · Necrotizing lesions of the nose and upper airways

Invasive fungal infection · Granulomatosis with polyangiitis · Extranodal NK/T-cell lymphoma

Mechanisms · Morphology · Clinicopathologic differential

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the three major etiologic categories of destructive nasal lesions.

Explain how fungal invasion, vasculitis, and neoplastic angioinvasion cause tissue necrosis.

Distinguish the characteristic morphology and relevant associated findings.

Apply a tissue- and context-based differential to selected clinical patterns.

Slide 3 · A destructive nasal lesion is a pattern, not a diagnosis

Ulceration and necrosis may arise through fundamentally different processes.

Infection

Invasive hyphae damage vessels and adjacent tissue.

Inflammation

Necrotizing granulomatous vasculitis disrupts vascular integrity.

Neoplasia

Angioinvasive lymphoid tumor produces ischemic necrosis.

Slide 4 · Three major causes named

Acute invasive fungi

Mucormycosis and invasive aspergillosis

Particularly with diabetes or immunosuppression

GPA

Necrotizing granulomas and vasculitis

May involve upper airway, lungs, and kidneys

Extranodal NK/T lymphoma

EBV-associated malignant lymphoid proliferation

Destructive nasal/nasopharyngeal mass

Slide 5 · The local anatomical field

Nasal cavity

Ulceration and destructive mucosal lesions

Paranasal sinuses

Entry and extension of invasive disease

Nasopharynx / upper airway

Malignant and inflammatory injury

Orbit / cranial vault

Potential sites of serious spread

Slide 6 · Why the vessels matter

Vessel invasion or inflammation

Fungi, vasculitis, or tumor

Wall injury

Impaired integrity or occlusion

Ischemia / infarction

Reduced perfusion of tissue

Ulcer and necrosis

Destructive surface lesion

Different etiologies converge on loss of tissue viability.

Slide 7 · The competing mechanisms of necrosis

Fungi

Hyphae enter tissues and arterial walls

Thrombosis, infarction, extension

GPA

Granulomatous inflammation plus necrotizing vasculitis

Ulceration and local destruction

NK/T lymphoma

Neoplastic cells surround and invade vessels

Ischemic necrosis within mass

Slide 8 · Context: Ordinary rhinitis is different

Common rhinitis

Edematous, red mucosa

Catarrhal discharge; Usually transient

Destructive pathology

Ulceration with deep necrosis

Requires explanation beyond routine rhinitis

Superinfection can coexist with a primary destructive process.

Slide 9 · Sinusitis can become a pathway for extension

Rhinitis / sinusitis

Mucosal edema and impaired drainage

Persistent infection

In selected cases, severe disease

Adjacent tissues

Orbit or surrounding bone

Intracranial compartment

Potential cranial complications

Spread beyond the sinuses is uncommon but consequential.

Slide 10 · Shared necrosis, distinct clinical contexts

Pattern

Clues in provided Robbins sections

Predisposing immune/metabolic defect

Prioritize invasive fungal infection

Sinus disease with lung and renal findings

Consider granulomatosis with polyangiitis

Destructive mass with EBV-associated tumor

Consider extranodal NK/T-cell lymphoma

Slide 11 · Do not diagnose by necrosis alone

Necrotic debris can conceal the process responsible for injury.

The key tissue features differ: Fungal hyphae, granulomatous vasculitis, or neoplastic lymphoid cells.

Clinical associations and lesions at distant sites provide vital context.

A concurrent bacterial infection may complicate, rather than explain, an underlying neoplasm.

Slide 12 · Interpretation begins with three questions

Necrotizing ulceration / mass

Are fungal elements invading tissue?

Invasive fungal infection

Is there granulomatous vasculitis?

GPA in suitable clinical context

Is there angioinvasive atypical lymphoid proliferation?

Extranodal NK/T lymphoma

Slide 13 · Invasive fungal infection: Fundamental lesion

Acute invasive fungal infection is a key cause of necrotizing nasal lesions.

Mucormycosis is specifically emphasized for diabetic and immunosuppressed patients.

Invasion of vascular structures distinguishes dangerous tissue-destructive disease.

Invasive aspergillosis can also produce comparable rhinocerebral lesions.

Slide 14 · Causative fungi in mucormycosis

Environmental members of Mucormycotina.

Mucor species

Opportunistic infection after spore exposure

Rhizopus species

An important cause of invasive disease

Rhizomucor / Cunninghamella

Additional implicated genera

Slide 15 · Who is vulnerable to mucormycosis?

Host defense and metabolic factors shape invasion risk.

Defective leukocyte defense

Neutropenia or corticosteroid exposure

Metabolic environment

Diabetes mellitus; Especially ketoacidosis

Increased available iron

Iron overload; Deferoxamine treatment

Slide 16 · Airborne spores establish the route of entry

Environmental spores

Widespread in dust and air

Inhalation

Common route into host

Sinonasal deposition

One site of initial invasion

Deep tissue extension

In a susceptible host

Percutaneous and gastrointestinal routes occur but are less relevant to nasal disease.

Slide 17 · Macrophages provide the early barrier

Germinating spores

Initial fungal challenge

Macrophage uptake

Phagocytosis

Nonoxidative killing

Early control of sporangiospores

Failure of defense

Greater chance of established infection

Protection depends on functional innate immune cells.

Slide 18 · Neutrophils confront established hyphae

Effective defense

Neutrophils directly damage hyphal walls

Growth constrained after germination

Compromised defense

Fewer or dysfunctional neutrophils

Invasion becomes more likely

The fungal challenge changes from spores to invasive hyphae.

Slide 19 · The innate inflammatory response

Hyphal components

Recognized by TLR2

Innate signaling

Proinflammatory activation

Cytokines

IL-6 and TNF

Effector response

Recruitment and activity of host defense

Inflammation alone does not compensate for severe phagocyte dysfunction.

Slide 20 · Free iron favors fungal growth

Ketoacidosis / altered iron binding

Higher iron availability

Mucormycotina growth

Free iron is a growth promoter

Invasive disease

Increased risk in susceptible hosts

Deferoxamine may also function as a siderophore for these fungi.

Slide 21 · Angioinvasion is the destructive turning point

Schematic – not a histologic image

Vessel lumen

Invasive hyphae

Hyphae invade arterial walls.

Thrombi compromise distal perfusion.

Necrosis develops in surrounding tissue.

Slide 22 · Mucormycosis: Defining tissue morphology

Broad hyphae of variable width are characteristically pauciseptate or nonseptate.

Frequent approximately right-angle branching is described.

Fungal elements may be demonstrable on H&E and special fungal stains.

Arterial wall invasion and adjacent necrosis provide the destructive context.

Slide 23 · Mucorales versus Aspergillus: Hyphal pattern

Mucormycotina

Aspergillus

Broad, irregular

Narrower, more uniform

Pauciseptate / nonseptate

Septate hyphae

Often near-right-angle branching

Typically acute-angle branching

Schematic morphology, not a photomicrograph

Slide 24 · Aspergillus can also invade vessels

Vascular invasion in invasive aspergillosis.

Hemorrhagic infarction may accompany necrotizing inflammation.

Rhinocerebral aspergillosis in immunosuppressed patients can resemble mucormycosis.

Morphology and clinical setting together guide interpretation of fungal lesions.

Slide 25 · The major rhinocerebral route

Paranasal sinuses

Frequent initial disease location

Periorbital tissues

Contiguous spread

Cranial vault

Further penetration

Brain / arteries

Meningoencephalitis or infarction

Slide 26 · Arterial invasion explains cerebral infarcts

Fungal arterial invasion

Vascular injury

Thrombosis

Occlusion of arterial lumen

Reduced blood flow

Cerebral ischemia

Infarction

Neurologic damage

Rhinocerebral infection can also be complicated by meningoencephalitis.

Slide 27 · The sinus lesion can be only the beginning

At the primary site

Mucosal and deep tissue necrosis

Local angioinvasion

With extension

Orbital or cranial involvement

Meningoencephalitis / cerebral infarction

The relevant biological behavior is invasion, not mere fungal presence.

Slide 28 · A conceptual sequence of invasive fungal damage

Host susceptibility

Diabetes or phagocyte impairment

Inhaled fungal spores

Entry into nasal sinuses

Hyphal germination

Failure of containment

Vascular penetration

Necrosis and contiguous spread

Each arrow represents a mechanistically plausible transition.

Slide 29 · Case A: Rapid destructive sinonasal disease

A patient with diabetes and ketoacidosis develops extensive necrotizing sinonasal disease with possible orbital extension.

Predisposing metabolic condition

Anatomical spread from sinuses

Tissue destruction rather than ordinary rhinitis

Which etiologic category should move to the top of the differential?

Slide 30 · Case A: Explanation

Acute invasive fungal infection — particularly mucormycosis

Diabetes with ketoacidosis is a major setting for rhinocerebral disease.

Angioinvasive fungi can progress from the nasal sinuses toward the orbit and brain.

Histologic identification of invasive hyphae differentiates infection from GPA and lymphoma.

Slide 31 · Fungal injury: Reasoning checkpoints

Predisposition

Neutropenia, corticosteroids, diabetes, abnormal iron availability

Organism pattern

Broad pauciseptate hyphae versus narrower septate acute-branching hyphae

Destructive mechanism

Vascular invasion, thrombosis, tissue infarction

Potential extension

Orbit, cranial vault and brain

Slide 32 · GPA is an ANCA-associated necrotizing vasculitis

Granulomatosis with polyangiitis is the current name; Wegener granulomatosis is historical.

Necrotizing granulomatous inflammation affects respiratory tissue.

Vasculitis involves small and medium-sized vessels.

Necrotizing glomerulonephritis is a major systemic component.

Slide 33 · The classic GPA triad

Respiratory tract

Necrotizing granulomas

Blood vessels

Necrotizing or granulomatous vasculitis

Kidneys

Focal necrotizing / crescentic GN

Three linked manifestations of one systemic inflammatory disease

Slide 34 · GPA: Upper and lower respiratory involvement

Upper respiratory tract

Ear, nose, sinuses and throat

Ulceration and granulomatous sinusitis

Lower respiratory tract

Lung nodules and infiltrates

Necrosis, cavitation or hemorrhage

Limited disease may remain confined to the respiratory tract.

Slide 35 · Upper-airway GPA causes destructive ulceration

Nasal, palatal and pharyngeal ulcerative lesions can occur.

Granulomatous sinusitis reflects inflammatory tissue injury.

Small- or medium-vessel involvement contributes to necrosis.

The same process can occur alongside lung or renal disease.

Slide 36 · Vascular pathology in GPA

Schematic – not a histologic image

Vessel lumen

Inflammatory cell ring

Small- to medium-sized vessels are injured by necrotizing inflammation.

Granulomatous inflammation may accompany vasculitis.

The respiratory tract is a prominent site of disease.

Slide 37 · Granulomatous destruction is more than vasculitis

Complementary manifestations of immune injury — not a fixed chronological sequence.

Immune response

A T-cell–mediated reaction to inhaled agents.

Granulomatous injury

Necrotizing granulomas can affect mucosa and lung.

Vascular injury

Small- and medium-vessel inflammation contributes to destruction.

Slide 38 · GPA: Proposed immunopathogenesis

An abnormal immune response to usually innocuous inhaled agents.

T-cell–mediated hypersensitivity is considered likely.

PR3-ANCA is strongly associated with the disease.

Both immune effector activity and vascular injury contribute to disease expression.

Slide 39 · PR3-ANCA identifies the main antibody target

Proteinase 3

Neutrophil granule constituent

PR3-directed ANCA

Circulating autoantibody

Leukocyte activation

ROS and proteolytic enzymes

Endothelial injury

Necrotizing vasculitis

A general ANCA-associated vasculitis mechanism; Not a complete model for every GPA lesion.

Slide 40 · Why ANCA-associated lesions are pauci-immune

Autoantibody target

Neutrophil constituents

No requirement for deposited circulating immune complexes

Vascular injury

Activated leukocytes release toxic mediators

Little detectable antibody/complement in vessel lesions

Pauci-immune describes the immunopathologic pattern, not absence of immune activity.

Slide 41 · PR3-ANCA: Association is not morphology

PR3-ANCA in up to 95% of GPA cases.

PR3-ANCA can assist assessment of response and early relapse.

The characteristic clinicopathologic pattern remains important.

The upper-airway differential still includes fungal infection and malignant lymphoma.

Slide 42 · Lung involvement contributes diagnostic context

Several lung manifestations.

Nodular disease

Granulomata may coalesce into radiologically evident lesions.

Cavitation

Necrotizing pulmonary nodules may cavitate.

Alveolar hemorrhage

Prominent in some cases of pulmonary vasculitis.

Slide 43 · Renal GPA: Focal to crescentic injury

Focal capillary necrosis

Early glomerular injury

Segmental glomerular damage

May include loop thrombosis

Parietal proliferation

Formation of crescents

Impaired filtration

Clinically important systemic organ injury

A spectrum from focal necrosis to diffuse crescentic lesions.

Slide 44 · What changes when GPA becomes systemic?

Site

Documented expression

Nose / palate / pharynx

Ulceration and granulomatous sinusitis

Lungs

Nodules, cavitation, infiltrates, hemorrhage

Kidneys

Necrotizing glomerulonephritis; crescents

Other organs

Eyes, skin, heart and additional sites may be affected

Slide 45 · GPA compared with two related vasculitides

Vasculitis

Discriminating textbook pattern

GPA

Necrotizing granulomas; upper airways; often PR3-ANCA

Microscopic polyangiitis

Necrotizing small-vessel injury; granulomas absent

Eosinophilic granulomatosis with polyangiitis

Asthma, eosinophils and necrotizing granulomatous vasculitis

Slide 46 · Case B: Sinonasal lesions with other organ clues

Persistent necrotizing sinonasal lesions occur with pulmonary nodules and glomerular injury.

Respiratory tract lesions above and below the larynx

Renal necrotizing pathology

Systemic rather than isolated local process

Which of the three Robbins causes best accounts for the complete pattern?

Slide 47 · Case B: Explanation

Granulomatosis with polyangiitis

The classical triad links respiratory granulomas, necrotizing vasculitis and glomerulonephritis.

PR3-ANCA is an informative associated marker.

Fungal invasion and an EBV-associated destructive lymphoma require different tissue evidence.

Slide 48 · GPA: Treatment principle and disease course

The disease was often fatal before effective immunosuppression.

Corticosteroids and other immunosuppressive agents changed prognosis markedly.

The resulting course as chronic, relapsing and remitting.

Clinical response and serologic follow-up require interpretation together.

Slide 49 · GPA: Diagnostic synthesis

Local injury

Necrotizing granulomas and small-/medium-vessel vasculitis

Upper airway

Granulomatous sinusitis; Nasal, palatal or pharyngeal ulceration

Systemic clues

Pulmonary nodules/cavities, glomerulonephritis

Immune context

Strong association with PR3-ANCA; Pauci-immune vasculitis

Slide 50 · Extranodal NK/T-cell lymphoma: Destructive neoplasm

A malignant NK-/T-lineage proliferation can present as a destructive nasopharyngeal mass.

The tumor infiltrate surrounds and enters small vessels.

Vascular destruction leads to extensive ischemic necrosis.

The malignancy is strongly associated with Epstein–Barr virus.

Slide 51 · Nasal lymphoma: Epidemiologic context

These are associations reported by Robbins, not diagnostic criteria.

Demographic tendency

More often men in their fifth or sixth decade.

Population distribution

More common in Asian and Latin American populations.

Geographic pattern

Rare in the United States/Europe; More common in Asia.

Slide 52 · Why does the lymphoma ulcerate?

Angiocentric infiltrate

Tumor cells surround small vessels

Angioinvasion

Tumor enters vascular walls

Local ischemia

Perfusion becomes compromised

Necrosis / ulceration

Destructive nasopharyngeal lesion

Vascular invasion is a direct link between tumor biology and the clinical lesion.

Slide 53 · Tumor-associated vascular injury

Schematic – not a histologic image

Vessel lumen

Angioinvasive tumor cells

Neoplastic lymphoid cells cluster around vessels.

Cells invade vessel walls and produce ischemia.

The resulting necrosis may obscure the tumor.

Slide 54 · The lymphoma phenotype has NK-cell features

Most described tumors have an NK-cell phenotype.

Lack of T-cell receptor gene rearrangement supports NK rather than conventional T-cell origin.

Cytoplasmic large azurophilic granules resemble those of normal NK cells.

No single phenotype element should substitute for identifying the neoplastic process.

Slide 55 · EBV is central to this neoplasm

EBV-positive progenitor

Viral association

Clonal expansion

Identical EBV episomes in tumor

Malignant population

EBV-associated NK/T neoplasm

Angioinvasive mass

Destructive local behavior

The mechanism of EBV entry into these cells is uncertain.

Slide 56 · The EBV evidence is clonality, not coincidence

Association

Strong link of neoplasm to EBV

Malignant cells harbor the virus

Clonality

Identical viral episomes within a patient

Supports origin from one infected precursor

Uncertainty about how EBV enters cells lacking the usual B-cell receptor CD21.

Slide 57 · Molecular abnormalities are heterogeneous

Recurrent changes without a unique defining chromosomal aberration.

JAK/STAT pathway

Recurrent pathway gene alterations

Epigenetic regulators

Altered chromatin-related control

TP53

Reported recurrent mutations

Slide 58 · What makes the clinical course severe?

Aggressive local invasion and infectious complications both matter.

Local spread

Destruction of surrounding tissues

Cranial penetration

Extension toward the cranial vault

Secondary infection

Bacterial infection and potential septic dissemination

Slide 59 · Bacterial infection may conceal the primary lesion

Visible complication

Ulceration and secondary infection

Inflammation can dominate sampled necrotic tissue

Underlying disease

EBV-associated lymphoid malignancy

Angiodestruction explains primary tissue injury

Do not equate a superimposed infection with the full cause of a destructive mass.

Slide 60 · Local control does not eliminate recurrence risk

Localized cases may respond to radiotherapy.

Relapse and recurrence remain important problems.

Advanced disease has a generally poor prognosis.

The chapter describes resistance to conventional chemotherapy in many cases.

Slide 61 · Aggressive disease may require other modalities

The hematopathology chapter discusses allogeneic transplantation in advanced disease.

Immune checkpoint inhibitors may produce responses in this virus-associated neoplasm.

These approaches carry important risks and are not universal recommendations.

For a pathology lecture, the central requirement is correct tissue classification.

Slide 62 · Case C: Destructive nasopharyngeal mass

An adult presents with a destructive nasopharyngeal mass, ulceration and a superimposed bacterial infection. Biopsy suggests angioinvasive lymphoid malignancy.

A true mass-forming lymphoid proliferation

Vascular invasion causing ischemic necrosis

The relevant tumor category is strongly EBV-associated

Identify the major diagnostic category and explain the necrosis.

Slide 63 · Case C: Explanation

Extranodal NK/T-cell lymphoma, nasal type

Tumor cells center on and invade small vessels.

Vessel injury leads to ischemia and extensive local necrosis.

EBV association is strong; Bacterial infection may be superimposed.

Slide 64 · Lymphoma: Essential discriminating features

Local lesion

Destructive nasal or nasopharyngeal mass

Microscopic behavior

Perivascular and angioinvasive tumor cells

Pathogenesis

Ischemic necrosis from vascular injury

Biologic association

EBV-positive malignant population

Slide 65 · The three patterns: One-page differential

Feature

Invasive fungal disease

GPA

NK/T lymphoma

Predisposition

Diabetes / immune deficit

Autoimmune context

EBV-associated tumor

Tissue mechanism

Hyphal vascular invasion

Necrotizing vasculitis

Tumor angioinvasion

Tissue clue

Fungal hyphae

Granulomas + vessels

Atypical lymphoid cells

Other sites

Orbit / brain extension

Lungs / kidneys

Local / cranial spread

Slide 66 · Three vascular routes to the same tissue endpoint

Fungal angioinvasion

Organism breaches artery

Thrombus and infarction

Immune-mediated vasculitis

Inflammation targets vessel wall

Necrosis with granulomas

Neoplastic angioinvasion

Tumor clusters invade vessels

Ischemic tumor-associated necrosis

Slide 67 · Comparison: What confirms the lesion category?

Cause

Distinctive positive evidence

Mucormycosis / invasive fungi

Tissue-invasive hyphae with compatible fungal morphology

GPA

Respiratory granulomatous vasculitis; renal/pulmonary context and PR3-ANCA support

NK/T lymphoma

Angioinvasive neoplastic lymphoid infiltrate with EBV association

Slide 68 · A tissue-section interpretation framework

Destructive sinonasal lesion

Invasive fungal profiles

Seek vessel-invading hyphae

Granulomatous vascular injury

Integrate airway, lung and kidney

Atypical lymphoid angioinvasion

Integrate NK phenotype and EBV

Slide 69 · Diagnostic pitfall: A necrotic sample

Necrosis is a shared consequence and is not etiology-specific.

Fungal elements, vasculitic structures, or viable tumor cells are the distinguishing findings.

A destructive mass with surface infection can still be lymphoma.

A systemic respiratory–renal pattern should not be reduced to local sinusitis.

Slide 70 · Diagnostic pitfall: Anatomic overlap

Both fungi and lymphoma

May show extensive local necrosis

May extend toward the cranial compartment

GPA and infection

Both may involve sinuses and lung

Mechanisms differ: Immune injury vs invasive organism

Site alone cannot resolve the etiologic differential.

Slide 71 · Integrated application: Choose the defining clue

Observed constellation

Highest-yield interpretation

Ketoacidosis + arterial fungal invasion

Rhinocerebral mucormycosis

Necrotizing granulomas + crescentic GN

GPA

EBV-associated angioinvasive lymphoid mass

Extranodal NK/T lymphoma

Slide 72 · Rapid recall: Explain the necrosis

Fungal infection

Hyphae → vessel wall

GPA

Immune vasculitis + granulomas

NK/T lymphoma

Tumor cells → vessel wall

Shared endpoint: Tissue destruction; Distinct etiologies require distinct evidence.

Slide 73 · Three exam-level take-home principles

Interpretation rests on cause and mechanism, not ulcer appearance alone.

Identify the invasive agent

Hyphae in tissue support infection.

Search for the systemic signature

Respiratory granulomas plus vasculitis and renal injury suggest GPA.

Recognize EBV-linked malignancy

Angioinvasive lymphoid cells indicate NK/T lymphoma.

Slide 74 · Primary reference and expansion sources

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Ch. 16, “Necrotizing Lesions of the Nose and Upper Airways,” p. 673.

Same textbook, Ch. 8, “Mucormycosis” and “Aspergillosis,” pp. 352–353.

Same textbook, Ch. 11, “ANCA-Associated Vasculitis” and “Granulomatosis With Polyangiitis,” pp. 469–470.

Same textbook, Ch. 13, “Extranodal NK-/T-Cell Lymphoma,” pp. 552–553.