4/24/2019 Erythema multiforme: histological features and mechanisms.

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24th April 2019

Erythema multiforme: histological features and

mechanisms.
Author: Dr Delwyn Dyall-Smith, Dermatologist, 2009.

Erythema multiforme: histological features and mechanisms. — codes and open

concepts

Histology of erythema multiforme

A skin biopsy of erythema multiforme (EM) may show in the epidermis/epithelium:

Apoptotic individual keratinocytes (cellular self-destruction, earliest histological change)

Hydropic degeneration of basal keratinocytes (swollen degenerating cells at the base of the epidermis)
Intercellular oedema (spongiosis)
Blisters within and under the epidermis/epithelium
Epithelial/epidermal necrosis without large sheets of epidermal necrosis, as seen in Stevens-Johnson syndrome / toxic epidermal
necrolysis (SJS/TEN).

Dermal changes may include:

Moderate/dense perivascular lymphocytic in ltrate in the papillary dermis and along the dermo-epidermal junction (DEJ)
Super cial dermal oedema
Eosinophilic in ltrates.

Direct immuno uorescence of erythema multiforme

Direct immuno uorescence is not speci c. It may show deposition of immune proteins C3 and brin along the DEJ and IgM, C3 and
brin around blood vessels.

Proposed mechanisms
Herpes simplex (HSV)-associated EM is a delayed type hypersensitivity (DTH) reaction that develops in response to infection in
predisposed individuals. The process has been well studied and involves several steps.

1. HSV infection of keratinocytes, which may or may not result in signs of clinical infection.
2. CD34+ cells (Langerhans precursor cells) transport HSV DNA fragments to distant keratinocytes.
3. HSV gene fragments are expressed in these distant keratinocytes. HSV DNA and HSV-encoded proteins can be detected in EM-
a ected epidermis. However, HSV virus cannot be cultured.
4. HSV-encoded proteins recruit HSV-speci c CD4+ T helper cells.
5. CD4+ T cells react to the HSV antigens by producing gamma-interferon.
6. Gamma-interferon initiates an in ammatory cascade resulting in the skin eruption of EM.

Drug-induced EM involves a di erent mechanism with elevated tumour necrosis factor alpha rather than gamma-interferon and
CD8+ cells and not CD4+ T helper cells.

Why is EM major now considered to be distinct from SJS/TEN?

EM major can usually be distinguished from SJS/TEN on a number of clinical criteria.

1. The type of skin lesion – the predominant skin lesion of EM is the typical and atypical target papules and plaques and not
macules which develop into sheets of skin detachment as seen in SJS/TEN. Skin detachment of more than 1% of the body surface
area is common in SJS/TEN but uncommon in EM.
2. Distribution of the skin lesions – in EM the lesions are predominantly acrally distributed, i.e., begin on hands and feet. In SJS/TEN
the eruption begins on the trunk.

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3. Mucosal involvement – although in EM Erythema multiforme:
major more histological
than two mucousfeatures and mechanisms.
membranes | DermNet
can be a ected, NZless common in EM and
this is
is milder (lesser severity and extent) compared to SJS/TEN.
4. Systemic symptoms such as fever and malaise, are absent or mild in EM but are prominent in SJS/TEN, especially in the
prodromal period. Fever, when present in EM, is mild (< 38.5 C) compared to high fevers with SJS/TEN. Patients with SJS/TEN are
systemically ill.
5. Outcome and prognosis – virtually all patients with EM recover with no sequelae. SJS/TEN has signi cant morbidity and mortality.
6. Recurrences – EM can frequently recur whereas recurrence is rare in SJS/TEN.Also, EM is predominantly a disease of young
adults (median age 24 years), especially males, whereas SJS/TEN typically a ects an older population (median age 45 years).

EM is predominantly a disease of young adults (median age 24 years), especially males, whereas SJS/TEN typically a ects an older
population (median age 45 years).

Other points of distinction.

1. Skin biopsy histology – in EM there is more dermal in ammation and individual keratinocyte necrosis compared to SJS/TEN
which shows minimal in ammation and sheets of epidermal necrosis.
2. Triggers – EM is triggered by an infection in the majority of cases compared to SJS/TEN which is predominantly caused by drugs.
3. Associations – EM is not associated with HIV, cancer and connective tissue disease, as reported with SJS/TEN. Tissue type marker
associations are di erent.
4. Mechanisms – EM involves CD4+ T cells and gamma-interferon whereas SJS/TEN involves Fas ligand, tumour necrosis factor
alpha and CD8+ cells.

In the majority of cases, EM can be diagnosed as a distinct entity from SJS/TEN although there remain some patients in whom the
distinction is not so clearcut.

 
Related information

On DermNet NZ

Erythema multiforme
Stevens-Johnson syndrome / toxic epidermal necrolysis
Dermatopathology index

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