Erythema Multiforme

Slide 1 · Erythema Multiforme

Clinical morphology · cytotoxic interface injury · diagnostic distinction

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

By the end of the lecture, learners should be able to:

Recognize characteristic targetoid lesions and their distributions.

Relate CD8⁺ T-cell-mediated keratinocyte damage to interface dermatitis.

Interpret the main epidermal and dermal histologic changes.

Distinguish erythema multiforme from SJS/TEN and other mimics.

Slide 3 · Erythema multiforme: The core entity

An acute immune-mediated mucocutaneous reaction pattern

Often associated with infection; Herpes simplex virus is a prominent trigger.

Shows a polymorphic eruption with characteristic target lesions.

Typical episodes are self-limited, but recurrence and mucosal disease matter.

Slide 4 · “Multiforme” describes lesion diversity

Elementary lesion

Clinical appearance

Implication

Macule

Flat discoloration

Early or evolving lesion

Papule / plaque

Elevated solid lesion

Common precursor to a target

Vesicle / bulla

Fluid-containing lesion

More intense epidermal injury

Erosion

Superficial surface loss

After blister rupture / sloughing

Slide 5 · A practical EM phenotype spectrum

Predominantly cutaneous

Mucosal-predominant / more severe

Typical targets

EM may involve oral mucosa

Painful erosions

Risk of impaired oral intake

Slide 6 · EM and SJS/TEN: Distinguish the taxonomies

Historical Robbins passage

Contemporary classification

Describes SJS and TEN alongside severe EM

Highlights severe mucosal and epidermal loss

EM is generally distinct from SJS/TEN

Distribution, target type, detachment and illness distinguish them

Slide 7 · Three questions anchor initial assessment

What is the dominant lesion?

Where is the eruption distributed?

How extensive is mucosal / skin loss?

Pattern recognition must be paired with assessment for severe cutaneous adverse reactions.

Slide 8 · Trigger categories in the Robbins account

Category

Examples reported

Infection

Herpes simplex; Mycoplasma; Fungal / bacterial infections

Medication

Sulfonamides, penicillin, hydantoins, others

Malignancy

Carcinomas and lymphomas (reported association)

Systemic inflammatory disease

Lupus, dermatomyositis, polyarteritis nodosa

Slide 9 · Herpes simplex is a leading precipitant

Clinical history should interrogate recurrent HSV infection.

EM may follow clinically evident oral or genital herpes.

HSV-associated EM can recur with subsequent episodes of infection.

Absence of reported cold sores does not eliminate an HSV association.

Slide 10 · Other infectious associations require context

Key Diagnostic Features

Interpretation

Mycoplasma

Histoplasmosis and coccidioidomycosis

Typhoid and leprosy

The list is historical and broad

Association ≠ established trigger in an individual

Use clinical evidence for microbiologic attribution

Slide 11 · Mycoplasma-related mucositis: Current terminology

Respiratory infectious syndrome

Prominent mucositis ± limited rash

Consider RIME as a separate phenotype

RIME = reactive infectious mucocutaneous eruption.

Slide 12 · Drug attribution is a differential diagnosis problem

A medication history is necessary, but the pattern matters.

Multiple drug associations with erythema multiforme.

Drug-triggered SJS/TEN and fixed drug eruption can mimic targetoid EM.

Record agent, start/stop dates, systemic features, and prior exposures.

Slide 13 · Associated neoplastic and connective-tissue disease

Additional clinical associations.

Carcinomas and lymphomas appear association list.

Lupus erythematosus, dermatomyositis and polyarteritis nodosa are also listed.

An isolated typical eruption does not justify assuming occult cancer or systemic autoimmunity.

Slide 14 · Reconstruct the clinical chronology

Recent HSV or other infection

Onset of fixed acral papules

Evolution into targets / occasional blisters

Resolution or recurrence

Schematic typical sequence; Individual patients vary.

Slide 15 · CD8⁺ cytotoxic T cells drive epidermal injury

A cell-mediated cytotoxic mechanism.

Skin-homing CD8⁺ cytotoxic T lymphocytes interact with epidermal cells.

Keratinocyte degeneration and death result at the epidermal–dermal interface.

The same general pattern may arise in other cytotoxic interface reactions.

Slide 16 · Why the basal epidermis is vulnerable

Cytotoxic lymphocytes reach skin

Lymphocytes align at dermoepidermal junction

Injured basal / suprabasal keratinocytes

Conceptual schematic. Molecular effector molecules not specified excerpt.

Slide 17 · The cytotoxic-interface injury sequence

Immunologic trigger

Skin-directed cellular response

Interface keratinocyte injury

Epidermal necrosis ± blister

The causal arrows are conceptual; Antigenic recognition is incompletely defined.

Slide 18 · The recognized epidermal antigens remain uncertain

Do not over-specify molecular targets.

The epidermal antigens targeted in EM remain unknown.

Known association with HSV does not identify a single universal EM antigen.

Clinical trigger, immune mechanism and microscopic pattern are distinct levels of evidence.

Slide 19 · Interface dermatitis is a reaction pattern

Epidermis

Papillary dermis

Schematic interface reaction: Lymphocytes at the junction and injured keratinocytes

Slide 20 · Why the characteristic target forms

Concentric color is a clinical clue

Color zones coexist in a single lesion

The central dusky region may blister

Not every lesion becomes a perfect target

Schematic lesion

Slide 21 · Individual lesions can have different forms

Observed structure

Microscopic correlate

Erythematous papule

Inflammatory cells / dermal edema

Central dusky area

Keratinocyte damage / epidermal necrosis

Vesicle or bulla

Epidermal injury with cleavage

Shallow erosion

Loss of damaged superficial epithelium

Slide 22 · Classic targets have concentric zones

Concentric architecture

Outer inflammatory erythematous ring

Paler, edematous intermediate zone

Dusky or blistered center reflects injury

Schematic target lesion — not a clinical photograph

Slide 23 · An atypical target is not a unique diagnosis

Typical EM targets

Alternative targetoid lesions

Often raised and sharply outlined

Usually three color zones

Common on acral / extensor sites

May have only two indistinct zones

Flat dusky macules raise SJS/TEN concern

History and distribution remain decisive

Slide 24 · Targets appear different across skin tones

Lighter skin

Darker skin

Erythematous outer rims often obvious

Central dusky or blistered zone

Areas may appear violaceous or hyperpigmented

Gray-silver central zones

Look for surface relief, edema and central injury

Slide 25 · Acral and extensor distribution is characteristic

Hands and feet

Forearms / lower limbs

Elbows, knees and sometimes trunk

Typical distribution pattern, not an absolute rule.

Slide 26 · Symmetry strengthens the EM pattern

Distribution adds specificity to morphology.

Limited EM often affects the extremities symmetrically.

A full examination may reveal more diagnostic targets than the index lesion.

Atypical patterns require an expanded differential.

Slide 27 · Evolution is dynamic, but lesions remain fixed

The timeline can distinguish EM from transient eruptions.

Macules or papules can evolve into characteristic targets.

Lesions may remain in the same location for several days.

Individual wheals disappearing within hours instead suggest urticaria.

Slide 28 · Constitutional symptoms are variable

Interpret systemic symptoms together with the skin phenotype.

Malaise or fever may reflect the preceding infection.

Disproportionate systemic illness suggests reconsideration of the diagnosis.

Rapid diffuse epidermal loss is a major warning sign for SJS/TEN.

Slide 29 · Mucosal involvement modifies disease severity

Possible mucosal sites

Functional impact

Oral cavity and lips

Urogenital mucosa

Eyes, less often

Erosions may be painful

Oral intake may become difficult

Ocular findings require immediate attention

Slide 30 · Oral EM: Erosion follows blister rupture

Mucosal epithelial injury

Fragile blister

Painful erosion / pseudomembrane

Reduced food and fluid intake

Conceptual progression, not a literal time course for every lesion.

Slide 31 · Ocular symptoms are clinically consequential

Eye involvement changes triage.

Conjunctival injury may coexist with oral or cutaneous disease.

Potential sequelae include keratitis and conjunctival scarring.

Suspected ocular involvement warrants ophthalmology assessment.

Slide 32 · EM minor versus EM major

Feature

EM minor

EM major

Cutaneous targets

Characteristic

Characteristic, sometimes widespread

Mucosal involvement

None or limited

Prominent / significant

Systemic threat

Usually limited

May impair oral intake; Assess eyes

Classification caution

Not SJS

Not synonymous with SJS

Slide 33 · Bridge the visible lesion to the microscope

Target-like papule

Dermal edema + interface cytotoxicity

Keratinocyte death / altered pigmentation

Blister or erosion if severe

Relationship is mechanistic interpretation rather than a specimen-specific observation.

Slide 34 · Histologic pattern: The core triad

Compartment

Recognizable finding

Superficial dermis

Perivascular lymphocytic infiltrate and edema

Dermoepidermal junction

Lymphocytic interface activity

Epidermis

Scattered apoptotic / necrotic keratinocytes

Slide 35 · Superficial perivascular lymphocytes

Read the dermal infiltrate in anatomic context.

A superficial perivascular lymphocytic infiltrate is.

The infiltrate is part of the interface reaction pattern.

Lymphocytes around vessels alone are not diagnostic of EM.

Slide 36 · Papillary dermal edema accompanies inflammation

Interstitial fluid provides a morphologic correlate for raised lesions.

Dermal edema in early targetoid lesions.

Edema contributes to a swollen or pale zone of the clinical target.

Edema is nonspecific and must be interpreted with keratinocyte injury.

Slide 37 · Lymphocytes concentrate at the junction

Epidermis

Papillary dermis

Schematic: Basal-junction lymphocytic accumulation

Slide 38 · Scattered apoptotic keratinocytes are central

Epidermis

Papillary dermis

Schematic: Red compact circles mark keratinocyte injury

Slide 39 · The intraepidermal response may intensify

Temporal progression in lymphocyte location.

Initially, lymphocytes cluster at the dermoepidermal junction.

Later, lymphocytes migrate upward into the epidermis.

Progression may accompany more extensive epithelial cell damage.

Slide 40 · Confluent necrosis produces blistering and erosion

Scattered keratinocyte death

Discrete / confluent necrosis

Epidermal separation

Shallow erosion after sloughing

More diffuse denudation requires consideration of severe alternative diagnoses.

Slide 41 · Morphologic evolution across an EM lesion

Relative stage

Pathologic emphasis

Possible appearance

Early

Interface lymphocytes; Basal injury

Erythematous / edematous papule

Established

Apoptotic keratinocytes; Edema

Dusky central target

More injured

Necrosis and blister formation

Vesicle / bulla / erosion

Slide 42 · When a skin biopsy is useful

Histology is ancillary to the clinical pattern.

Consider biopsy if lesions are atypical or severe.

Use it to investigate mimics, particularly blistering disease.

Request clinical distribution, lesion timing and medication history for interpretation.

Slide 43 · Interface change is not pathognomonic

Findings supporting EM

Important caveats

Scattered apoptotic keratinocytes

Vacuolar interface change

Superficial inflammation and edema

Fixed drug eruption can show interface injury

Lupus and other interface disorders overlap

Clinical phenotype often decides the differential

Slide 44 · EM is usually a clinicopathologic diagnosis

Observe morphology and distribution

Ask about infection and medicines

Assess mucosal / systemic severity

Biopsy when uncertainty persists

No single blood test or histologic feature confirms all cases.

Slide 45 · Differential: EM versus urticaria

Feature

EM

Urticaria

Lesion persistence

Fixed for days

Wheals often resolve within hours

Typical surface

Target with dusky / injured center

Edematous wheal

Mucosal erosions

Possible

Not typical of uncomplicated urticaria

Histologic emphasis

Interface damage

Dermal edema ± sparse infiltrate

Slide 46 · Differential: Fixed drug eruption

Erythema multiforme

Fixed drug eruption

Symmetric acral targets common

Often linked to preceding infection

Lesions arise in multiple sites

Recurs in the same location after exposure

Can have dusky or bullous center

Medication re-exposure history is decisive

Slide 47 · Differential: EM versus SJS/TEN

Axis

Erythema multiforme

SJS/TEN

Typical lesion

Raised, well-demarcated targets

Flat atypical targets / purpuric macules

Predominant site

Acral / extensor

Often truncal onset

Skin detachment

Limited / uncommon

Can be extensive

Systemic illness

Often limited

Potentially severe / life-threatening

Slide 48 · RIME is a key mucosal-predominant mimic

Reactive infectious mucocutaneous eruption (RIME)

Often follows a respiratory infectious episode.

Mucositis may dominate, sometimes with relatively sparse skin lesions.

Modern classifications distinguish RIME from classic EM and SJS/TEN.

Slide 49 · Severe skin or mucosal disease changes urgency

Immediate specialist or emergency assessment is appropriate for:

Rapidly progressive widespread blistering or detachment.

Marked systemic illness with severe oral or genital erosions.

Painful red eyes, photophobia, or visual symptoms.

Slide 50 · Management follows trigger, symptoms and severity

Identify / address trigger

Relieve cutaneous and oral symptoms

Evaluate mucosal function

Escalate severe or ocular cases

Teaching overview only; Not a dosing protocol.

Slide 51 · Recurrent HSV-associated EM: Evidence and strategy

Recurrence is a clinically distinct management problem.

Review overt or possible recurrent HSV and medication exposures.

Suppressive oral antiviral treatment may reduce recurrent attacks.

The intervention evidence remains limited; One small randomized trial supports continuous acyclovir.

Slide 52 · Prognosis: Most episodes resolve

Expected outcome varies with phenotype.

Uncomplicated EM is commonly self-limited.

Transient postinflammatory pigment changes may persist.

Recurrent attacks and significant mucosal or ocular disease require follow-up.

Slide 53 · Clinical application: Symmetric acral targets

A young adult develops well-circumscribed, concentric lesions on both hands several days after an episode of herpes labialis. There is no skin detachment or marked systemic illness.

What is the leading diagnosis, and which trigger is most plausible?

Slide 54 · Clinical application: Fixed dark plaque

A patient develops a sharply demarcated dusky plaque at precisely the same site after repeatedly taking the same medication. A previous attack left residual pigmentation.

Which targetoid mimic should be prioritized?

Slide 55 · Clinical application: Severe mucocutaneous illness

A recently medicated patient becomes systemically unwell with widespread dusky macules, painful mucosal erosions and sheets of skin detachment.

What is the urgent diagnostic alternative to uncomplicated EM?

Slide 56 · Case answer: HSV-associated EM

Most likely: Erythema multiforme following herpes labialis.

Concentric target lesions and symmetric acral distribution favor EM.

The recent herpes simplex episode is a plausible precipitant.

Absence of marked illness or detachment argues against SJS/TEN in this vignette.

Slide 57 · Case answer: Fixed drug eruption

Most likely: Fixed drug eruption rather than recurrent EM.

Repeat occurrence at precisely the same site is the decisive clue.

Drug-associated dusky plaques may simulate EM targets.

Prior residual pigment supports the longitudinal clinical pattern.

Slide 58 · Case answer: Suspect SJS/TEN

Urgently evaluate for Stevens–Johnson syndrome / toxic epidermal necrolysis.

Widespread dusky macules and epidermal detachment are critical clues.

Severe mucosal injury and systemic illness support this alternative.

Emergency specialist assessment takes priority over routine EM follow-up.

Slide 59 · Integrated diagnostic synthesis

Targets + acral symmetry

Keratinocyte-centered interface injury

Correlate trigger / mucosal severity

Exclude SJS/TEN and mimics

Integrate morphology, histology, severity and modern disease taxonomy.

Slide 60 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 25, pp. 1048–1049.

DermNet. Erythema multiforme. 2022.

Kechichian E, et al. Erythema multiforme. 2024. PMCID: PMC11585783.

DermNet. Stevens–Johnson syndrome / toxic epidermal necrolysis.

de Risi-Pugliese T, et al. JEADV. 2019;33:842–849.