Introduction/Clinical/Pathogensis
Erythema nodosum (EN) is clinically typified by symmetric crops of tender red or violaceus nodules lasting
3-6 weeks and resolving with a bruise-like appearance without ulceration or scarring, characteristically
involving the anterior shins of women in the 3rd - 6th decades of life. Lesions may be accompanied by
fever, arthralgia, and malaise. Clinically, cases of EN may be subdivided into an acute form and a chronic
form, the latter also known as EN migrans or subacute nodular migratory panniculitis. With respect to the
former, in addition to the shins, lesions may be seen on the calves, thighs, forearms, hands and face.
Erythema nodosum may be associated with sarcoidosis, Sweet's syndrome, inflammatory bowel disease,
underlying malignancy (solid organ cancers, leukemia and lymphoma), drug ingestion (especially sulfonamides,
birth control pills, and antibiotics) and infection (particularly with microbes having superantigen
properties). The pathophysiologic basis of erythema nodosum is thus likely a hypersensitivity reaction.
One recent study looked at epidemiologic and demographic features associated with erythema nodosum. In this
study there was a female predominance whereby the female: male ratio was 5 : 1 and the mean age was 31
years. Twenty eight % of patients had confirmed streptococcal infections, 11% sarcoidosis, 1.5%
enteropathies, 1.5% Chlamydia infections, 0.8% Mycoplasma infections, 0.8% Yersinia infections, 0.8%
hepatitis B, and 0.8% tuberculosis (one case). The causative factor could not be determined in 55% of
patients. Based on this study exhaustive investigations for erythema nodosum is likely not cost effective.
Acute erythema nodosum associated with granulomatous hilar adenopathy and arthralgias defines the entity of
Lofgren's syndrome or so called acute transient sarcoidosis. Recently an abnormal response to an infectious
trigger has been proposed, suggesting that this entity should be considered distinct from chronic
sarcoidosis. Light microscopically cases of erythema nodosum associated with Lofgren's syndrome show
features typical of the superantigen id reaction within the overlying dermis including a variable vacuolar
interface dermatititis with a concomitant diffuse interstitial granulomatous dermatitis. A seasonal
clustering of Lofgren's syndrome has been described in New Zealand with a clustering in the spring months
and predilection to involve women.
Erythema nodosum in pregnant patients with coccidiomycosis may be associated with a better outcome,
typically pregnant patients with this form of fungal infection may develop disseminated disease associated
with considerable morbidity.
Histopathology
The histopathologic manifestations of EN depend upon the age of lesion biopsied, as well as, the underlying
etiopathogenic association.
In its incipient phase, EN manifests edema of the septum with a perivascular mixed inflammatory infiltrate
which includes mononuclear cells and neutrophils; some cases show perivascular fibrin deposits. In cases
associated with infection by microbial pathogens with superantigen properties (i.e.Yersinia, mycoplasma,
streptococcus,etc.) there may be an interstitial granuloma annulare-like inflammatory infiltrate in the
overlying dermis accompanied by a lymphocytic interface dermatitis. In the setting of antecedent
streptoccocal infection or inflammatory bowel disease, neutrophilic microabscesses may also be seen in the
deep dermis and septal collagen. Lesions associated with Hodgkin's disease frequently show striking tissue
eosinophilia. More mature lesions of erythema nodosum manifest broadening of the septae by an infiltrate
which also includes multinucleated histiocytes; some of these may show cleft-like spaces, so-called
Miescher's granuloma. The Miescher's granuloma is held to represent tropism of multinucleated histiocytes
to lymphatic spaces, although this has never been decisively proven. Over time, the infiltrate also extends
out into the paraseptal lobular region, associated with fat necrosis and accumulations of paraseptal foamy
histiocytes. In its end stage, striking widening of the septae is associated with fibrosis and encirclement
of atrophic fat lobules. Vascular changes are variable and comprise endothelial swelling of septal vessels
including both capillaries and veins, lymphocyte cuffing and, in some cases, a true leukocytoclastic or
mononuclear cell vasculitis with mural fibrin deposition.
Reference
Barnhill RL. Panniculitis and fasciitis. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook
of Dermatopathology. New York : McGraw-Hill Co, 1998:233-256.
