Erythema
Nodosum
Luis Requena1 and Celia Requena2
Dermatology Online Journal 8 (1): 4
Luis Requena1 and Celia Requena2
Dermatology Online Journal 8 (1): 4
1. Department of
Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; and
2. Department of Dermatology, Hospital General Universitario, Universidad de
Valencia, Valencia, Spain.
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Abstract
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Erythema nodosum is the
most frequent clinico-pathological variant of the panniculitides. The disorder
is a cutaneous reaction consisting of inflammatory, tender, nodular lesions,
usually located on the anterior aspects of the lower extremities. The process
may be associated with a wide variety of diseases, being infections,
sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications,
autoimmune disorders, pregnancy, and malignancies the most common associated
conditions. The typical eruption consists of a sudden onset of symmetrical,
tender, erythematous, warm nodules and raised plaques usually located on the
shins, ankles and knees. Often the lesions are bilaterally distributed. At
first, the nodules show a bright red color, but within a few days they become
livid red or purplish, and finally they exhibit a yellow or greenish appearance
taking on the look of a deep bruise. Ulceration is never seen and the nodules
heal without atrophy or scarring. Some clinical variants of erythema nodosum
have been described under different names, including erythema nodosum migrans,
subacute nodular migratory panniculitis, and chronic erythema nodosum, but
probably they are just clinical variants which may all be included within the
spectrum of erythema nodosum. Histopathologically, erythema nodosum is the
stereotypical example of a mostly septal panniculitis with no vasculitis. The
septa of subcutaneous fat are always thickened and variously infiltrated by
inflammatory cells that extend to the periseptal areas of the fat lobules. The
composition of the inflammatory infiltrate in the septa varies with age of the
lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for
the septal thickening, whereas fibrosis, periseptal granulation tissue,
lymphocytes, and multinucleated giant cells are the main findings in late stage
lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is
the presence of the so-called Miescher's radial granulomas, which consist of
small, well-defined nodular aggregations of small histiocytes arranged radially
around a central cleft of variable shape. Treatment of erythema nodosum should
be directed to the underlying associated condition, if identified. Usually,
nodules of erythema nodosum regress spontaneously within a few weeks, and bed
rest is often sufficient treatment. Aspirin, nonsteroidal anti-inflammatory drugs,
such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be
helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are
rarely indicated in erythema nodosum and before these drugs are administered an
underlying infection should be ruled out.
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Introduction
Erythema nodosum is the most frequent
clinico-pathological variant of the septal panniculitides. The disorder
usually exhibits an acute onset and is clinically characterized by the
eruption of erythematous tender nodules and plaques located predominantly
over the extensor aspects of the lower extremities. The lesions show
spontaneous regression, without ulceration, scarring, or atrophy, and
recurrent episodes are uncommon. Erythema nodosum is a cutaneous reactive
process that may be triggered by a wide variety of possible stimuli.
Infectious diseases, sarcoidosis, rheumatologic diseases, inflammatory bowel
diseases, medication reactions, autoinmune disorders, pregnancy, and
malignancies the most common associated conditions.
Erythema nodosum was originally described in
1798 by the English dermatologist, Willan, in his classic monograph on
erythemas, and this author emphasized the higher frequency of the process in
women.[1]The disorder was
further delineated by Wilson in 1842, who considered erythema nodosum to be a
part of erythema multiforme because he had observed urticaria, figurate
erythema, purpura, and the nodose lesions to overlap.[2] Later, Hebra, in 1860, expanded the clinical
characteristics of the process and described the color changes in the
evolution of the lesions, proposing the term dermatitis contusiformis to name
the disorder.[3]
Clinical features
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Figure 1
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Fig. 1.- Typical eruption of erythema nodosum
shows erythematous nodules and plaques on the anterior aspects of the legs.
This patient had also ulcerative colitis.
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This process can occur at any age, but most
cases appear between the second and fourth decades of the life, with the peak
of incidence being between 20 and 30 years of age, due to the high incidence
of sarcoidosis at this age.[4] Several studies
have demonstrated that erythema nodosum occurs three to six times more
frequently in women than in men, however, the sex incidence before puberty is
approximately equal.[5, 6] In general, erythema nodosum is seen in younger
patients than erythema induratum of Bazin. Racial and geographic differences
of incidence vary throughout the world, also depending on the prevalence of
diseases that are etiologic factors. Prevalence of erythema nodosum in a
semirural area of England over a 2-year period gave a figure of 2.4 per 1000
population per year.[7] Prevalence varies
also according to the type of the patients attended to in a clinic: the
average hospital incidence was about 0.5 percnet of new cases seen in
Departments of Dermatology in England[8] and about 0.38 percent of all patients seen in a
Department of Internal Medicine in Spain.[9] In a recent study, the average annual incidence
rate of biopsy proven erythema nodosum in a hospital of the northwestern Spain
for the population 14 years and older was 52 cases per million of persons,
although certainly this rate underestimated the authentic incidence of the
disease because only included cases confirmed by biopsy.[10] Most cases of erythema nodosum occur within the
first half of the year, probably due to the more frequent incidence of
streptococcal infections in this period of the year, and there is no
difference in distribution between urban and rural areas.[8, 10] Familial cases are usually due to an infectious
etiology.
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Figure 7
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Fig. 7.- Late stage lesion of erythema nodosum
shows the appearance of a deep bruise ("erythema contusiformis").
This patient had also lung sarcoidosis.
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The typical eruption is quite characteristic
and consists of a sudden onset of symmetrical, tender, erythematous, warm
nodules and raised plaques usually located on the shins, ankles and knees.
The nodules, which range from 1 to 5 cm or more in diameter, are usually
bilaterally distributed (Figures 1-3). Nodules may become confluent resulting
in erythematous plaques (Figure 4). In rare instances, more extensive lesions
may appear, involving the thighs, extensor aspects of the arms, neck, and
even the face. At first, the nodules show a bright red color and are raised
slightly above the skin. Within a few days, they become flat, with a livid
red or purplish color (Figures 5-7). Finally, they exhibit a yellow or
greenish appearance often taking on the look of a deep bruise ("erythema
contusiformis"). This contusiform color evolution is quite
characteristic of erythema nodosum and allows a specific diagnosis in late
stage lesions. Ulceration is never seen in erythema nodosum and the nodules
heal without atrophy or scarring. Usually acute bouts of erythema nodosum are
associated with a fever of 38-39 C°, fatigue, malaise, arthralgia, headache,
abdominal pain, vomiting, cough, or diarrhea. Episcleral lesions and
phlyctenular conjunctivitis may also accompany the cutaneous lesions. Less
frequent clinical manifestations associated with erythema nodosum are
lymphadenopathy, hepatomegaly, splenomegaly and pleuritis.[11] The eruption generally lasts 3-6 weeks, but
persistence beyond this time is not unusual. Recurrences are exceptional.
Erythema nodosum in children has a much
shorter duration than in adults, arthralgias are seen in a minority of the
patients and fever is an accompaying manifestation in fewer than half of the
cases.[12, 13, 14]
Clinical variants
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Figure 8
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Fig. 8.- Subacute nodular migratory
panniculitis of Vilanova and Piñol. The lesion consisted of a unilateral
erythematous plaque that extended peripherally and healed at the center. The
progressing border is brightly erythematous, whereas the resolving center has
a yellowish hue.
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Some clinical variants
of erythema nodosum have been described under different names. These variants
include erythema nodosum migrans,[15, 16, 17, 18] subacute nodular
migratory panniculitis of Vilanova and PiÒol,[19, 20] and chronic
erythema nodosum.[21] Erythema nodosum
migrans was reported by Bafverstedt in 1954 as an entity clinically different
from classic erythema nodosum, but with identical histopathologic findings.[15] The lesions were unilateral and only one or few
lesions were present. They consisted of erythematous plaques that extended
peripherally and healed at the center and were preferentially located on the
lateral rather the anterior side of the leg. The progressing border is brightly
erythematous, whereas the resolving center has a yellowish hue (Figure 8). The
lesions are painless or less tender than those of classic erythema nodosum. In
1973 Hannuksela reported on 438 patients with subcutaneous nodules on the lower
extremities, of these 56 had features that were interpreted as erythema nodosum
migrans.[16] Similar cases
appeared in the literature shortly after.[17, 18] The term subacute
nodular migratory panniculitis was coined by Vilanova and Piñol in 1956 for a
variant of septal panniculitis which they considered to be clinical and
histopathologically different from erythema nodosum.[19] This opinion was supported by Perry and
Winkelmann in 1964.[20] Fine and Meltzer
favored the name chronic erythema nodosum as the best denomination for lesions
previously described as erythema nodosum migrans or subacute nodular migratory
panniculitis.[21] However, more
recently, some authors still believe that erythema nodosum migrans and chronic
erythema nodosum are two different clinico-pathological entities.[18] These authors studied 58 examples of
granulomatous septal panniculitis, and 36 cases were considered to be chronic
erythema nodosum, whereas 14 cases were interpreted as erythema nodosum
migrans. The basis of their classification was mostly clinical, they analyzed
features such as: duration, morphology, number, location, symmetry, pattern of
extension, and associated systemic manifestations. Histopathologically, lesions
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erythema nodosum migrans showed marked
thickening of the septa of subcutaneous fat, with an abundant number of
granulomas containing frequent multinucleated giant cells, granulation tissue
and conspicuous proliferations of capillaries at the separation between septa
and fat lobules. In lesions of erythema nodosum migrans there was no evidence
of phlebitis. In contrast, lesions interpreted as chronic erythema nodosum
showed a lesser degree of thickening of the septa and less inflammatory
infiltrate, but phlebitis and extravasated erythrocytes were prominent and
characteristic findings.[18] In our opinion,
these histopathologic differences do not separate erythema nodosum migrans
from chronic erythema nodosum, and they are probably expressions of the
different stage of evolution of lesions rather than two different entities.
At the present moment, most authors believe that erythema nodosum migrans,
subacute nodular migratory panniculitis, and chronic erythema nodosum are
clinical variants which may all be included within the spectrum of erythema
nodosum.[22]
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Figure 9
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Fig. 9.- A rare variant of erythema nodosum in
children and young adults is characterized by lesions only involving the
palms or soles and often the process is unilateral. This boy shows a solitary
erythematous nodule on the sole and the histopathologic study demonstrated
features of erythema nodosum.
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A rare variant of erythema nodosum in children
and young adults is characterized by lesions only involving the palms or
soles (Figure 9), and often the process is unilateral.[23, 24, 25, 26] These children developed painful erythematous
nodules usually after physical activity. Histopathologic features of these
lesions of unilateral palmar or plantar erythema nodosum are similar to those
of classical erythema nodosum.
Etiology
Erythema nodosum may be associated with a wide
variety of disease processes and its observation must always be followed by a
search for underlying etiology. A review of the literature reveals that the
list of etiologic factors which can lead to erythema nodosum is long and
varied, including infections, drugs, malignant diseases, and a wide group of
miscellaneous conditions (Table 1).[8, 27-121]
Although there are considerable geographic variations related to endemic
infections, in our country streptococcal infections are the most frequent
etiologic factor for erythema nodosum in children, whereas other infectious
processes, drugs, sarcoidosis, autoimmune disorders and inflammatory diseases
of the bowel are the most commonly associated disorders in adults.
The relationship between a previous episode of
upper respiratory infection by group A β-hemolytic streptococcus and erythema
nodosum is well-known, especially in children and young adults. Usually, the
cutaneous lesions appear two or three weeks after the throat infection and
they are accompanied by an elevation of the antistreptolysin-O (ASO) titre.
An intradernal positive test to streptococcal antigens is often seen in patients
with erythema nodosum secondary to streptococcal infections, although when
the cutaneous nodules develop the cultures of routine throat swabs usually do
not detect microorganisms.[10, 46]
Tuberculosis is now an uncommon etiologic
factor for erythema nodosum in our country and other areas of southern
Europe.[10, 11, 122] These cases are seen only in children and the
cutaneous lesions usually indicate a primary pulmonary infection, being
concomitant with the conversion of the tuberculin test.[48]
Drugs are frequently implicated as the cause
of erythema nodosum. Sulphonamides, bromides, and oral contraceptive pills
have been long recognized as the most common medications responsible for
acute bouts of erythema nodosum, but the list of possibilities is very large
(Table 1). In recent years, the amount of hormones in contraceptive pills has
been lowered markedly, and thus erythema nodosum secondary to this medication
is now rare. In those cases in which the patient develops erythema nodosum
after having taken an antibiotic for an infectious disease, it is difficult
to discern whether the cutaneous reaction is due to the antiobiotic or the
infectious agent.
Sarcoidosis constitutes one of the most common
etiologic factors in adult patients with secondary erythema nodosum in our
country.[10] In some
countries, specially in northern Europe, erythema nodosum and bilateral hilar
adenopathy are frequently seen as early manifestations of sarcoidosis (Lofgren's
syndrome).[123] However,
erythema nodosum and bilateral hilar adenopathy are not exclusively seen with
sarcoidosis and they have also been associated with lymphoma, tuberculosis,
streptococcal infections, coccidioidomycosis, and histoplasmosis.[124] Furthermore, a recent prospective study in
France demonstrated that a significant percentage of patients presented with
Lofgren's syndrome as the first manifestation of acute infection due to
Chlamydia pneumoniae.[125]
In adults, erythema nodosum associated with
enteropathies often correlates with a flare-up of the disease, although the
cutaneous eruption may preceed the clinical appearance of the inflammatory
bowel disease. Ulcerative colitis is more frequently associated with erythema
nodosum than Crohn's disease.[103,120]
Many patients with Behçet disease develop
lesions that clinically resemble those of erythema nodosum.[99] Histopathologic studies, however, have
demonstrated that a significant proportion of these patients with Behçet
syndrome and erythema nodosum-like lesions showed a mostly lobular
panniculitis with the frequent finding of leukocytoclastic or lymphocytic
vasculitis.[126, 127] In other words, some patients with Behçet
disease show a panniculitis different from that of erythema nodosum.
The simultaneous occurrence of Sweet syndrome
and erythema nodosum have been considered a rare association.[117, 128, 129, 130, 131, 132, 133] In 1992, Cohen et al. reviewed the world
literature and found 8 biopsy-proven cases, none of which was associated with
an underlying malignant neoplasm.[123] In 1993, Wilkinson et al. described two
additional cases, one occurred in association with sarcoidosis and the other
one appeared after an upper respiratory tract infection.[129] In 1995 Ben-Noun also reported a case that
occurred after a streptococcal pharyngitis.[130] In 1995 Suzuki et al. described a patient with
acute myelogenous leukemia in whom Sweet syndrome also developed.[131] There was rapid improvement of the cutaneous
lesions after treatment with prednisolone, but one year later, erythema
nodosum reappeared. In 1999, Watz et al. reported two patients with
simultaneous occurrence of Sweet syndrome and erythema nodosum, one patient
with acute myelogenous leukemia and the other patient with Crohn's disease.[132] However, recently Ginarte and Toribio
commented that the association between Sweet syndrome and erythema nodosum is
not as rare as the review of the published case reports seems to indicate,
since this carries an important bias.[133] These authors reviewed several series of
patients with Sweet syndrome and found that 15-30 percent of patients with
Sweet syndrome showed biopsy-proved erythema nodosum.[134, 135, 136, 137, 138] Based on these data, Ginarte and Toribio
concluded that the simultaneous occurrence of these two reactive processes is
a frequent feature that may be due to a common underlying mechanism of
pathogenesis (streptococcal upper respiratory tract infection or inflammatory
bowel disease) and they respond to the same treatment (corticosteroids,
potassium iodide), also supporting a close relationship between them.[133]
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Pathogenesis
Erythema nodosum is
considered to be a hypersensitivity response to a wide variety of inciting
factors. The variability of possible antigenic stimuli that can induce erythema
nodosum indicates that this disorder is a cutaneous reactive process and that
the skin has limited responses to different provoking agents. Erythema nodosum
probably results from the formation of immune complexes and their deposition in
and around venules of the connective tissue septa of the subcutaneous fat.
Circulating immunocomplexes and complement activation have been recorded in
patients with erythema nodosum.[141, 142, 143] Histopathologic features in fully developed
lesions also suggest a delayed hypersensitivity mechanism and direct
immunofluorescence studies have shown deposits of immunoglobulins in the blood
vessel walls of the septa of subcutaneous fat.[144, 145] However, other authors failed to demonstrate
circulating immunocomplexes in patients with erythema nodosum, and a type IV
delayed hypersensitivity reaction may also play an important role in the
pathogenesis of the disorder.[146]
Early lesions of
erythema nodosum are histopathologically characterized by a neutrophilic
inflammatory infiltrate involving the septa of the subcutaneous tissue. Recent
investigations have demonstrated that patients suffering from erythema nodosum
had a fourfold higher percentage of reactive oxygen intermediates (ROI)
produced by activated neutrophils in their peripheral blood compared with
healthy volunteers. Furthermore, the percentage of ROI-producing cells in
patients with erythema nodosum correlated with the clinical severity. These
data support that ROI might play a role in the pathogenesis of erythema
nodosum. ROI might exert their effects by oxidative tissue damage and by
promoting tissue inflammation.[147]
Patients with erythema
nodosum associated with sarcoidosis produce an uncommon tumor necrosis
factor,TNF-α II. These patients showed a nucleotide exchange, (G-A) at position
-308 in the human TNF-α gene promoter, whereas patients with erythema nodosum
without underlying sarcoidosis displayed a similar allele frequency compared
with controls. These results support the notion that erythema nodosum in
association with sarcoidosis might be pathogenetically linked to altered TNF-α
production due to a genetic promoter polymorphism.[148] In contrast, other authors have found that the
proinflammatory cytokine pattern showed increased interleukin-6 serum
concentrations both in infectious and non infectious disease-related erythema
nodosum, whereas a minor involvement of TNF was found in these patients.[118]
The reason the
anterior aspects of the legs are so susceptible for the development of lesions
of erythema nodosum is unknown. Some authors have proposed that there is no
other site on the skin surface where the combination of a relatively sparse
arterial supply is associated with a venous system subject to gravitational
effects and cooling and a lymphatic system which is hardly rich enough to meet
the requirements of any increase in fluid load and which has no mechanical
stimulus. The skin of the shins has no underlying muscle pump and receives
little in the way of massage. All these local anatomic factors would favor the
location of the lesions of erythema nodosum on the shins.[8]
Laboratory
abnormalities
Since the list of
possible etiologic factors in erythema nodosum is extensive, a rational,
cost-effective diagnostic approach in patients with erythema nodosum is
desirable. A complete clinical history should be elicited in all patients, with
reference of previous diseases, medications, foreign travel, pets and hobbies,
as well as familial cases.
Initial evaluation
should include complete blood count, determination of the sedimentation rate,
antistreptolysin-O (ASO) titer, urinalysis, throat culture, intradermal
tuberculin test and chest roentgenogram. The white blood count is normal or
only slightly raised, but the erythrocyte sedimentation rate is often very
high, returning to normal when the eruption fades. In children, the elevation
of the erythrocyte sedimentation rate correlates significantly with the number
of cutaneous lesions.[14] The
rheumatoid factor is usually negative but there is a temporary rise in the
α2-globulin. A high antistreptolysin titre is seen in those cases of erythema
nodosum associated with a streptococcal throat infection. Usually, a
significant change, at least 30%, in (ASO) titer in two consecutive
determinations performed in a 2-4 week interval indicates recent streptococcal
infection.[10] When the etiology
is doubtful, a sample of blood should be serologically investigated for those
bacterial, virological, fungal or protozooal infections more prevalent in that
area.
In those cases suspected
of being tuberculous, an intradermal tuberculin test should be performed, but
the results must be interpreted in the context of the tuberculous prevalence in
the studied area. In Spain, a significant percentage of healthy adults show
positive results for the tuberculin test. In sarcoidosis, there is a decrease
in the degree of reactivity of previously positive patients. The Kvein test is
now less used because of fears of AIDS transmission.
A chest X-ray should
be performed in all patients with erythema nodosum to rule out pulmonary
diseases as the cause of the cutaneous reactive process. Radiologically
demonstrable bilateral hilar lymphadenopathy with febrile illness and erythema
nodosum with no evidence of tuberculosis characterize Lofgren's syndrome, which
in most cases represents an acute variant of pulmonary sarcoidosis with a
benign course. This syndrome is more frequent in females, especially during
pregnancy and the puerperium.[123]
Histopathology
Histopathologically,
erythema nodosum is the stereotypical example of a mostly septal panniculitis
with no vasculitis. The septa of subcutaneous fat are always thickened and
variously infiltrated by inflammatory cells that extend to the periseptal areas
of the fat lobules. Usually, a superficial and deep perivascular inflammatory
infiltrate predominantly composed of lymphocytes is also seen in the overlying
dermis. This dermal inflammation along with vasodilatation probably accounts
for the erythematous appearance of early lesions, whereas the changes in the
subcutis are responsible for the nodularity of the lesions on palpation.
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Figure 10A
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Figure 10B
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Figure 10C
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Figure 10D
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Fig. 10.-
Histopathologic features of an early lesion of erythema nodosum. A: Scanning
power shows thickened septa with inflammatory infiltrate. B: Sometimes, in
early lesions the inflammatory cell infiltrate may be more apparent in the
fat lobules than in the septa, because inflammatory cells extend into the
periphery of the fat lobules between individual fat cells in a lace-like
fashion, and the process appears as a predominantly lobular panniculitis. C:
However, in contrast with authentic lobular panniculitis, necrosis of the
adipocytes is not prominent despite the intense neutrophilic infiltrate. D:
Higher magnification demonstrates the abundant number of neutrophils. Note
the incipient formation of a Miescher's radial granuloma in the upper part of
the picture. (A-D, Hematoxylin-eosin stain; original magnifications: A, x20,
B, x40, C, x200, D, x400).
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Figure 11A
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Figure 11B
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Figure 11C
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Figure 11D
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Fig. 11.-
Histopathologic features of a fully developed lesion of erythema nodosum. A:
Scanning power shows sparse inflammatory infiltrate involving mostly the
septa. B: Numerous Miescher's radial granulomas involving the septa. C:
Higher magnification shows the characteristic features of Miescher's radial
granuloma: Small histiocytes around central clefts of variable shape. D:
Still higher magnification demonstrates the palisaded arrangement of the
histiocytes around the clefts. (A-D, Hematoxylin-eosin stain; original
magnifications: A, x20, B, x40, C, x200, D, x400).
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The composition of the
inflammatory infiltrate in the septa varies with the age of the lesion. In
early lesions, edema, hemorrhage, and neutrophils (Figure 10) are responsible
for the septal thickening, whereas fibrosis, periseptal granulation tissue,
lymphocytes, and multinucleated giant cells are the main findings in late stage
lesions of erythema nodosum.[139] In rare instances eosinophils are the
predominant inflammatory cells in early lesions of erythema nodosum.[149] Sometimes,
in these early lesions the inflammatory cell infiltrate may be more apparent in
the fat lobules than in the septa, because inflammatory cells extend into the
periphery of the fat lobules between individual fat cells in a lace-like
fashion, and the process appears as a predominantly lobular panniculitis.
However, in contrast with authentic lobular panniculitis, necrosis of the
adipocytes is not prominent. A histopathologic hallmark of erythema nodosum is
the presence of the so-called Miescher's radial granulomas, that consist of
small, well-defined nodular aggregations of small histiocytes around a central
stellate or banana shaped cleft (Figure 11).[150, 151, 152] The nature of the central cleft is unknown and
although some authors have considered them as lymphatic spaces, our
immunohistochemical and ultrastructural studies of cases of Miescher's radial
granulomas have failed to demonstrate endothelial or other cellular lining of
these clefts.[8] In early lesions,
Miescher's radial granulomas appear scattered in the septa and surrounded by
neutrophils. In older nodules of erythema nodosum, histiocytes coalesce to form
multinucleated giant cells, many of which still retain in their cytoplasm a
stellate central cleft reminiscent of those centers of Miescher's radial
granuloma (Figures 12-14). Sometimes Miescher's radial granulomas are
conspicuous in the septa, but occasionally serial sections may be necessary to
identify them. In our view, these Miescher's radial granulomas are present in
all stages of the evolution of erythema nodosum lesions and they should be
searched for in order to make a specific diagnosis.[152] However, in our experience, Miescher's radial
granulomas are specific for erythema nodosum, other authors believe that
similar granulomas may be present in lesions of Sweet syndrome, erythema
induratum of Bazin, Behçet disease, and necrobiosis lipoidica.[22] Another histopathologic characteristic of
erythema nodosum is the absence of vasculitis, although in rare instances a
necrotizing small vessel vasculitis with fibrinoid necrosis of the vessel walls
has been described in the septa.[153] Histopathologic study of a series of 79 cases of
erythema nodosum, demonstrated that authentic leukocytoclastic vasculitis is
usually absent, and only 18 of 79 specimens disclosed slight nonspecific
changes in some isolated veins and venules, whereas many other vessels were
intact in the middle of the inflammatory nodule.[152] In contrast with these findings, ultrastructural
studies in erythema nodosum have described damage to endothelial cells of the
small vessels of the septa of subcutaneous fat with some extension of
inflammatory cells into the vessel walls.[154, 155]
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Figure 12A
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Figure 12B
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Figure 12C
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Figure 12D
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Fig. 12.-
Histopathologic features of a late stage lesion of erythema nodosum. A:
Scanning power shows thickened septa. B: Higher magnification shows
inflammatory infiltrate involving mostly the septa. C: Still higher
magnification demonstrates the abundant number of multinucleated giant cells
in the septa. D: Many of the multinucleated giant cells keep in their
cytoplasm a stellate central cleft reminiscent of those centers of Miescher's
radial granuloma. (A-D, Hematoxylin-eosin stain; original magnifications: A,
x20, B, x40, C, x200, D, x400).
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Figure 13A
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Figure 13B
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Figure 13C
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Figure 13D
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Fig. 13.-
Histopathologic features of a late stage lesion of erythema nodosum. This
patient had also Crohn's disease A: Scanning power shows thickened septa with
inflammatory infiltrate. B: Higher magnification shows thickened septa with
inflammatory infiltrate and small size fat lobules. C: Still higher
magnification shows that the thickened septa contain abundant blood vessels
and inflammatory infiltrate. D: Still higher magnification demonstrates the
abundant number of multinucleated giant cells in the septa. E: Still higher
magnification shows the multinucleated giant cells surrounding clefts. (A-E,
Hematoxylin-eosin stain; original magnifications: A, x20, B, x40, C, x200, D,
x400, E, x600).
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Figure 13E
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Figure 14A
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Figure 14B
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Figure 14C
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Figure 14D
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Figure 14E
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Fig. 14.-
Histopathologic features of a late stage lesion of erythema nodosum. This
patient had also Crohn's disease A: Scanning power shows thickened septa with
inflammatory infiltrate. B: Higher magnification shows thickened septa with
inflammatory infiltrate that extends to the periphery of the fat lobule. C:
Still higher magnification shows the granulomatous nature of the inflammatory
infiltrate of the septa. D: Still higher magnification demonstrates the
abundant number of multinucleated giant cells in the granulomatous infiltrate
of the septa. E: Close-up view of the multinucleated giant cells (A-E,
Hematoxylin-eosin stain; original magnifications: A, x20, B, x40, C, x200, D,
x400, E, x600).
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In late stage lesions
of erythema nodosum, the inflammatory infiltrate in the septa is sparse, and
there are markedly widened septa with granulation tissue at the interface
between connective tissue septa and fat lobules. (Figure 15) As erythema
nodosum evolves, the septa become fibrotic and replaced by granulomas, and the
fat lobules become progressively replaced and effaced by widening septa, which
can even completely obliterate the lobules. In these late lesions it may be
difficult to establish whether the lesion is a mostly septal or mostly lobular
panniculitis, because the entire subcutaneous tissue is effaced by a fibrotic
and granulomatous process. With time, despite the striking fibrosis, the
lesions resolve without atrophy or scarring of the involved septa.
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Figure 15A
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Figure 15B
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Figure 15C
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Figure 15D
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Fig. 15.-
Histopathologic features of a resolving lesion of erythema nodosum. A:
Scanning power shows thickened septa with inflammatory infiltrate at the
interface between connective tissue septa and the fat lobules. B: Higher
magnification shows thickened septa with inflammatory infiltrate that extends
to the periphery of the fat lobule. C: Still higher magnification shows that
the inflammatory infiltrate consists of granulation tissue. D: Still higher
magnification demonstrates the abundant number of capillary blood vessels and
the inflammatory infiltrate at the interface between the septa and the fat
lobules. (A-D, Hematoxylin-eosin stain; original magnifications: A, x20, B,
x40, C, x200, D, x400).
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Differential
Diagnosis
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Figure 16
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Fig. 16.- Erythema induratum of Bazin involving the
posterior aspect of the leg of an adult woman with erythrocyanotic
circulation and ulcerated lesions.
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Erythema induratum of
Bazin is the main differential diagnosis for erythema nodosum. The clinical
picture or erythema nodosum differs from erythema induratum of Bazin in showing
lesions usually located on the shins that regress in a few weeks with no tendency
for necrosis and scarring. In contrast, typical lesions of erythema induratum
of Bazin appear on the posterior aspects of the legs of adult women with
erythrocyanotic circulation, are more persistent, often ulcerate (Figure 16),
and regress leaving an atrophic scar. In atypical cases, the differential
diagnosis between these two entities may be solved by histopathological
examination, because erythema nodosum is a mostly septal panniculitis, whereas
erythema induratum of Bazin is a predominantly lobular panniculitis (Figure
17).[157] For this
differential diagnosis, biopsy specimens taken by scalpel excision are
preferable to punch biopsies, and when available, early lesions from as
proximal a site as possible should be selected. Table 2 summarizes the main
clinical and histopathological differences between erythema nodosum and
erythema induratum of Bazin.
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Figure 17A
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Figure 17B
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Figure 17C
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Figure 17D
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Fig. 17.-
Histopathologic features of erythema induratum of Bazin. A: Scanning power
shows a mostly lobular panniculitis. B: Higher magnification shows thickened
septa, but the inflammatory infiltrate involves mostly the fat lobules. C:
Still higher magnification shows the inflammatory infiltrate in the fat
lobules and the involvement of a blood vessel in the thickened septa. D:
Still higher magnification demonstrates that the inflammatory infiltrate
involves the vessel wall and obliterates the lumen. (A-D, Hematoxylin-eosin
stain; original magnifications: A, x20, B, x40, C, x200, D, x400).
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Cutaneous lesions of
superficial thrombophlebitis may show a clinical appearance similar to that of
erythema nodosum. However, the lesions are usually located on the sides of the
lower legs and consist of hard, irregular and fibrotic cords or plaques rather
than erythematous nodules (Figure 18). A biopsy of these lesions demonstrates
that the affected vein appears with luminal thrombosis and with inflammatory
infiltrate within its wall (Figure 19). In contrast to erythema nodosum, and
despite the intense damage of the involved vein with dense inflammatory
infiltrate, lesions of superficial thrombophlebitis show little or no
inflammatory infiltrate in the connective tissue of the septa and the adjacent
fat lobule, and the process is more vasculitic than panniculitic.[158]
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Figure 18
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Fig. 18.- Superficial thromboflebitis.
Erythematous nodules in liner arrangement with a cordlike thickening of the
subcutis along the involved vein.
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Figure 19A
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Figure 19B
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Figure 19C
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Figure 19D
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Fig. 19.-
Histopathologic features of superficial thrombophlebitis. A: Scanning power
shows thrombosis of a large blood vessel within thickened septa. B: Higher
magnification shows the inflammatory infiltrate centered in a large blood
vessel of the thickened septa. C: Still higher magnification shows that the
involved vessel had several muscular fascicles in its wall. D: Still higher
magnification demonstrates the inflammatory infiltrate involving the muscular
layers of this vein and the obliteration of its lumen. (A-D, Hematoxylin-eosin
stain; original magnifications: A, x20, B, x40, C, x200, D, x400).
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Cutaneous
polyarteritis nodosa can also present as bilateral tender erythematous nodules
on the lower legs. However, the involved area usually shows livedo reticularis;
the nodules are preferentially located on the calves and often ulcerate (Figure
20). Histopathologically, lesions of cutaneous polyarteritis nodosa show
vasculitis involving medium sized arteries and arterioles at the septa of the
subcutaneous tissue. The involved vessels appear with a thickened wall, and
characteristically, the tunica intima of the involved artery exhibits an
eosinophilic ring of fibrinoid necrosis, giving a targetlike appearance to the
vessels (Figure 21).[158] As in superficial
thrombophlebitis, cutaneous polyarteritis nodosa is a vasculitic process with
little or no inflammatory involvement of the adjacent septa and lobules of the
subcutaneous tissue.
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Figure 21A
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Figure 21B
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Figure 21C
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Figure 21D
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Fig. 21.-
Histopathologic features of cutaneous polyarteritis nodosa. A: Scanning power
shows sparse inflammatory infiltrate in the subcutis. B: Higher magnification
shows the inflammatory infiltrate centered in a blood vessel. C: Still higher
magnification shows an eosinophilic ring of fibrinoid necrosis at the tunica
intima of the involved blood vessel. D: Still higher magnification of the
eosinophilic ring of fibrinoid necrosis giving a targetlike appearance to the
vessel. (A-D, Hematoxylin-eosin stain; original magnifications: A, x20, B,
x40, C, x200, D, x400).
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Figure 22
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Fig. 22.- Subcutaneous sarcoidosis.
Erythematous nodule on the forearm. This patient had also lung sarcoidosis.
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Because fully
developed lesions of erythema nodosum are histopathologically characterized by
a granulomatous component, subcutaneous sarcoidosis (Figure 22) should also
considered. However, in subcutaneous sarcoidosis granulomatous involvement
predominates in the fat lobules rather than in the septa (Figure 23), and the
septa do no exhibit the fibrosis and the thickening usually seen in fully developed
lesions of erythema nodosum.[157]
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Figure 23A
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Figure 23B
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Figure 23C
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Figure 23D
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Fig. 23.-
Histopathologic features of subcutaneous sarcoidosis. A: Low-power view shows
the involvement of the fat lobules. Note sparing of the dermis. B: Higher
magnification demonstrates the granulomatous nature of the inflammatory
infiltrate. C: Still higher magnification shows that each collection of
inflammatory cells consisted of small noncaseating granuloma. D: Still higher
magnification demonstrates the presence of multinucleated giant cell in the
noncaseating granuloma. (A-D, Hematoxylin-eosin stain; original
magnifications: A, x40, B, x80, C, x200, D, x400).
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Erythema nodosum
leprosum is an inadequate term to describe an immune-complex vasculitic process
involving the dermis of patients with lepromatous leprosy. The term is
misleading because it may easily be confused with authentic erythema nodosum.
In most cases the process develops when therapy results in massive death of
lepra bacilli and the lesions present not only as nodules, but also as
necrotic, pustular or hemorrhagic lesions.[159] The face, which is rarely involved in authentic
erythema nodosum, is a frequent location for lesions of erythema nodosum
leprosum .[159] In doubtful cases
a biopsy should easily distinguish between the two. Erythema nodosum leprosum
is a process involving the dermis, and when it extends to the subcutaneous fat,
the small blood vessels of the fat lobule are severely damaged and appear with
fibrinoid necrosis of their wall and luminal thrombi. Special stains
demonstrate numerous dead and degenerated acid-fast bacilli.[160] In contrast, biopsies of erythema nodosum show a
mostly septal panniculitis without vasculitis.
Plantar erythema
nodosum should be differentiated from the so-called traumatic plantar
urticaria, which consists of tender erythematous nodules which develop on the
soles of children after physical activity.[161] Some authors believe that plantar erythema
nodosum and traumatic plantar urticaria in children are the same entity rather
than two different processes, although the lesions reported as traumatic
plantar urticaria regressed in a few hours or days. Furthermore, histopathologic
study demonstrated a perivascular inflammatory infiltrate of neutrophils and
lymphocytes in the papillary and reticular dermis.[161] However, the biopsies of those cases reported as
traumatic plantar urticaria contained no subcutaneous fat at all, and therefore
a diagnosis of plantar erythema nodosum could be not definitely ruled out.[161, 162] Palmoplantar erythema nodosum in children should
be also differentiated from idiopathic palmoplantar neutrophilic eccrine hidradenitis,
which is also clinically characterized by painful erythematous nodules
involving the palms and soles of children that appear after physical activity.[163, 164, 165, 166, 167, 168, 169, 170] However, the histopathologic differential
diagnosis between idiopathic palmoplantar neutrophilic hidradenitis and
erythema nodosum is straightforward, because in the former the neutrophilic
infiltrate is surrounding and within the eccrine coils of the deeper dermis,
whereas in early erythema nodosum, neutrophils of the inflammatory infiltrate
are interstitially arranged between collagen bundles of the septa of the
subcutaneous tissue.
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Figure 24
|
Figure 25A
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Figure 25B
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Figure 25C
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Figure 25D
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Figure 25E
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Fig. 24.-
Subcutaneous lymphoma mimicking erythema nodosum. Erythematous tender nodules
on the lower extremities.
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Fig. 25.-
Histopathologic features of subcutaneous "panniculitic" lymphoma. A:
Scanning power shows the involvement of both septa and fat lobules. B: Higher
magnification shows the infiltrate involving the fat lobules and the
thickened septa. C: Still higher magnification demonstrates that the cell
infiltrate extends from the septa into the periphery of the fat lobules
between individual fat cells in a lace-like fashion. D: Still higher
magnification demonstrates atypical lymphocytes with pleomorphic and
hyperchromatic nuclei. E: Still higher magnification shows better that these are
not inflammatory but neoplastic lymphocytes (A-E, Hematoxylin-eosin stain;
original magnifications: A, x20, B, x40, C, x200, D, x300, E, x400).
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Cutaneous B-cell
lymphoma may present with erythematous tender nodules on the lower extremities
mimicking erythema nodosum clinically (Figure 24).[171, 172] However histopathologic study reveals atypical
lymphocytes, with hyperchromatic nuclei and mitotic figures involving both the
septa and the fat lobule (Figure 25) or within the lumina of the blood vessels
of the subcutaneous fat in cases of intravascular B-cell subcutaneous
lymphoma.[171, 172]
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Figure 26
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Fig. 26.- In elderly patients, especially those with
severe venous insufficiency and gravitational edema of the lower extremities,
the acute episode of erythema nodosum may be followed by a persistent
erythematous swelling of the ankles.
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Prognosis
Most cases of erythema
nodosum regress spontaneously in 3-4 weeks. More severe cases require about 6
weeks to resolve. Relapses are exceptional, but they are more common in
patients with idiopathic erythema nodosum and erythema nodosum associated with
nonstreptococcal or streptococcal upper respiratory tract infections. [10] In elderly patients, especially those with severe
venous insufficiency and gravitational edema of the lower extremities, the
acute episode of erythema nodosum may be followed by a persistent erythematous
swelling of the ankles (Figure 26).
Complications of erythema
nodosum are uncommon. One patient developed retrobulbar optic nerve neuritis
during the acute episode of erythema nodosum, and another patient with chronic
hepatitis C had erythema nodosum with concomitant erythema multiforme and
lichen planus that coincided with the reactivation of viral replication.[173, 174]
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Treatment
Treatment of erythema nodosum should be
directed to the underlying associated condition, if identified. Usually,
nodules of erythema nodosum regress spontaneously within a few weeks, and bed
rest is often sufficient treatment. Aspirin and nonsteroidal
anti-inflammatory drugs such as oxyphenbutazone, in a dosage of 400 mg per day,
indomethacin, in a dosage of 100 to 150 mg per day, or naproxen, in a dosage
of 500 mg per day, may be helpful to enhance analgesia and resolution.[175, 176, 177] If the lesions persist longer, potassium
iodide in a dosage of 400 to 900 mg daily or a saturated solution of
potassium iodide, 2 to 10 drops in water or orange juice three times per day,
has been reported to be useful.[178, 179, 180] The mechanism of action of potassium iodide in
erythema nodosum is unknown, but a theoretical mechanism involves its
stimulation of heparin release from mast cells. Heparin acts to suppress
delayed hypersensitivity reactions. The reported response in some patients
with erythema nodosum lesions to heparinoid ointment under occlusion supports
this proposed mechanism of action.[181] On the other hand, potassium iodide also
inhibits neutrophil chemotaxis.[182] Potassium iodide is contraindicated during
pregnancy, because it can produce a goiter in the fetus. Severe
hypothyroidism secondary to exogenous intake of iodide has been also described
in patients with erythema nodosum treated with potassium iodide.[183]
Systemic corticosteroids are rarely indicated
in erythema nodosum and before these drugs are administered an underlying
infection should be ruled out. When administered, prednisone in a dosage of
40 mg per day has been followed by resolution of the nodules in few days.
Intralesional injection of triancinolone acetonide, in a dosage of 5 mg/ml,
into the center of the nodules may cause them to resolve.
|
1. Willan
R. On Cutaneous Diseases, vol 1. London: J. Johnson, St. Paul's Church-Yard,
1798.
2. Wilson E. Practical and Theoretical Treatise on the Diagnoses, Pathology, and Treatment of Diseases of the Skin. London: Churchill, 1842.
3. Hebra F. Diseases of the Skin, vol. 1. London: New Sydenham Society, 1860.
4. James DG. Dermatological aspects of sarcoidosis. Quart J Med 1959;28:109-24.
2. Wilson E. Practical and Theoretical Treatise on the Diagnoses, Pathology, and Treatment of Diseases of the Skin. London: Churchill, 1842.
3. Hebra F. Diseases of the Skin, vol. 1. London: New Sydenham Society, 1860.
4. James DG. Dermatological aspects of sarcoidosis. Quart J Med 1959;28:109-24.
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