Septal granulomatous panniculitis: Comparison of the pathology of erythema nodosum migrans (migratory panniculitis) and chronic erythema nodosum Cristianede Almeida Prestes, MD,* R. K. Winkelmann, MD, PhD, and W. P. Daniel Su, MD Rochester, Minnesota Fifty-eight cases ofseptalgranulomatous panniculitis werereviewed; 14caseswerediagnosed as erythema nodosum migrans (migratory panniculitis) and 36aschronicerythema nodosum on the basis of clinical and histopathologic features. Erythema nodosum migrans was characterized by markedly thickened and fibrotic septae, marked capillary proliferation (like granulation tissue), andmassive granulomatous reaction (with giant cells) along the borders of the widened septa. Hemorrhage was rare, and phlebitis was not seen. Chronicerythema nodosum showed mild septal change, little fibrosis, and lymphohistiocytic perivascular inflammation with only focal granulomatous formation. Phlebitis and hemorrhage were common. The condition termed erythema nodosum migrans has many of the sameclinical features as chronic erythema nodosum, and we think this term is preferable to migratory panniculitis. We believe that there are sufficient clinical and histopathologic features to justify considering erythema nodosum migrans as a unique clinicopathologic entity. (J AMACAD DERMATOL 1990;22:477-83.)
Typicalerythema nodosum is a well-established entity,' but there are variants that have a different evolution and clinical features and havebeen given different names by various authors. In 1954 Bafverstedt- described erythema nodosum migrans that occurred mostly in women. It presentswithpersistent nodular lesions that progress centrifugally; the lesions are minimally symptomatic and have an asymmetric or unilaterallocalization. The histologic features of erythemanodosum migrans were considered by Bafverstedt to be typical of erythema nodosum, but no descriptions were given. Vilanova and Pifiol Aguade3, 4 described subacute nodular migratory panniculitis, characterized by nodules on the legs that enlarged by confluence or Fromthe Department ofDermatology, Mayo Clinic and MayoFoundation. Accepted for publication May 5, 1989. Reprint requests: W. P. Daniel Su, MD, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. *Dr.de Almeida Prestes is Visiting Clinician. 16/1/13765
peripheral extension to form plaques up to 20 em in diameter. The nodules werelimitedin number,were mildly inflammatory, and did not ulcerate. Typically, in middle-aged women with sore throats, lesions developed on one leg. Although the disease frequently evolved in less than 1 year, it couldtake more than 3 years. The lesions cleared after treatment with potassium iodide. Histopathologically, migratorypanniculitis wasconsidered to bedifferent from erythema nodosum. Perry and Winkelmann' confirmed the occurrence ofthisdistinctclinical and pathologic syndrome. Fine and Meltzer'' in 1969 reported ninecases of the same condition, of which eight were in women. Fivepatientsinitiallyhad a solitary lesion onthe anterior aspectof the leg, and additional nodules subsequently developed in three ofthese. Three patients had multiple bilateral lesions whenfirstseen. There was a tendency for individual nodules to enlargeby peripheral extension, and in noinstancewerethe lesions as inflammatory as in acute erythema nodosum. Because of the close histologic resemblance to erythemanodosum, the authorspreferred to term this entity chronic erythema nodosum and believed
477
478
Journal of the American Academy of Derma toJogy
de Almeida Prestes et al.
Fig. 1. Erythema nodosum migrans, A, Markedly fibrotic and widened septa. B, Multiple giant cells in line along the borders of the widened septum. C, Granulation-type capillary proliferation. (A, B, and C, Hematoxylin-eosin stain; A, X 10; B, X 33; C, X 130.)
that it should be considered to be the same as subacute nodular migratory panniculitis, erythema nodosum migrans, nodular vasculitis, and probably erythema induratum. Because of the divergent opinions in the literature, we decided to evaluate our own experience with migratory panniculitis and erythema nodosum; we focused first on the histologic features of septal granuloma and subsequently correlated the clinical findings and course with the histopathology.
MATERIAL AND METHODS Our study reviewed cases of septal granulomatous panniculitis from the dermatopathology file at the Mayo Clinic for the period 1961 to 1987. We selected 58 cases in which there had been an excisional biopsythat included adequate subcutaneous tissue. Each case included slides stained with hematoxylin and eosin, and almost all cases had slides stained by the aldehyde-fuchsin elastic and periodic acid-Schiff methods. We assessed the quantity of fibrosisand thickness of the septum, the presence of capillary proliferation, phlebitis, panniculitis, vasculitis, granuloma formation, and lymphohistiocytic inflammation, and the quantity and pat-
tern of hemorrhage. The presence of other inflammatory cells was noted. The presenceof epidermal, appendageal, and dermal lesions was studied. From these slides, the cases were grouped as chronic erythema nodosum (mild changes) or erythema nodosummigrans (severechanges). We then grouped the cases as chronic "erythema nodosum or erythema nodosum migrans on the basis of clinical course and clinical picture without reference to the pathologicfeatures. Our clinicalcriteria were time for evolution, morphology,symptoms,number and sizeofthe lesions, localization (unilateral or bilateral), symmetry, and spreading character. Response to treatment was noted without reference to the other changes. Once the separate histologic and clinical groupings were made, we made a comparison between the respective groups to determine whether a concordance of diagnosis was possible.
RESULTS
Histopathologic findings The evaluation of the histologic specimens omitted 2 (3.4%) of the 58 cases because their pathologic changes were minimal and nonspecific. The remaining 56 cases had two distinct histopathologic patterns that separated them into groups of erythema
Volume 22 Number 3 March 1990
Septal granulomatous panniculitis 479
Fig. 2. Chronic erythema nodosum. A, Absence of fibrosis and thickness of septa. B, Focal septal granuloma formation. C, Extensive septal hemorrhage. (A, B, and C, Hematoxylineosin stain; A, X 8; B, X 33; C, X 85.)
nodosum migrans ( 18 cases) and chronic erythema nodosum (38 cases). Erythema nodosum migrans. Erythema nodosum migrans was characterized by fibrosis and markedly widened septa, with many granulomas composed of epithelioid cells and many giant cells. The multinucleated giant cells were found within the septa between fat lobules and numbered 10 or more per field. In most cases they were lined along the borders of the widened septa in a wall configuration, although occasionally the process was nodular and more confined to one or more areas (Fig. 1, A and B). A mild lymphocytic inflammation was observed. Scattered eosinophils were present in almost all cases. Neutrophils and plasma cells were rarely seen. The inflammatory reaction was confined to the septum. Inflammatory changes in the fat lobules were occasionally present and then were scarce and only at the periphery. Granulation tissue-like capillary proliferation (Fig. 1, C) was found in 15 cases (83%), as focal areas in four cases (27%), and with widespread foci at the septal borders of the fat lobules in 11 cases (73%). In all cases the capillary walls were composed
of a single or, sometimes, a double row of normal or swollen endothelial cells. Vasculitis and obstruction of the vascular lumen were not observed. Focal mild hemorrhage was present in only two cases (11 %), and phlebitis or periphlebitis was not found in any instance. Chronic erythema nodosum. Chronic erythema nodosum exhibited only discrete perivascular lymphocytic inflammation and a contiguous infiltrate in the deep dermis. The inflammatory pathologic changes were present in the septa. In 24 (63%) of the 38 cases, impressive lymphohistiocytic inflammation with occasional focal granuloma was also present about the vessels and individual fat cells at the periphery of fat lobules. Rarely, a diffuse mixture of lymphocytes and histiocytes was observed. Lymphocytic vasculitis was present in the small vessels in the septa and panniculus was found in 14 cases (37%). Our criteria of lymphocytic vasculitis are as defined before 7: (l) fibrinoid necrosis of blood vessel walls, (2) predominantly lymphocytic infiltrate involving and surrounding blood vessel walls, and (3) endothelial cell swelling or hyperplasia. Thrombosis and extravasation of leukocytes are common but not imperative as criteria. The septum was not fibrotic or
480
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Journal of the American Academy of Dermatology
Fig. 3. Erythema nodosum migrans: Unilateral single plaque formed by spreading of lesion.
widened (Fig. 2, A). Focal granuloma formation was observed in the septae in all cases (Fig. 2, B). Focal capillary proliferation was found in only five cases (13%). Phlebitis was found in 13 cases (34%). No thrombosed veins were present. Hemorrhage was present in 16 cases (42%). In 14, it was extensive and diffuse within the septum and almost always was associated with involvement of the periphery of the fat lobules (Fig. 2, C).
Fig. 4. Chronic erythema nodosum: Multiple bilateral symmetric nodules.
Clinical findings Clinically, 54 of the 56 cases could be grouped; two cases had confusing features that made the differentiation doubtful, thereby leaving 15cases (28%) of erythema nodosum migrans and 39 cases (72%) of chronic erythema nodosum. We considered erythema nodosum migrans cases to have chronic focal nodules that were not ulcerated and that spread into plaques, formed by extension or confluence of lesions, localized in the lower legs, usually unilaterally and with a limited number of lesions (Fig. 3). We considered as chronic erythema nodosum those cases with symmetric, nonulcerated lesions that were located on the legs (in some cases there also
were lesionselsewhereon the body) and that did not demonstrate a migratory tendency (Fig. 4). There was agreement between histologic and clinicaldiagnosesin 14o£18cases(78%) of erythema nodosum migrans and in 36 of 38 cases (95%) of chronic erythema nodosum. The comparisons were inconclusive in six cases. Erythema nodosum migrans. The 14 cases of erythema nodosum migrans included 12 women (86%) from 29 to 79 years old (mean age 50 years). The duration of the disease ranged from 21 days to 22 years (mean duration 4 years) overall; in 10 patients it ranged from 21 days to 3 years (mean 7.5
Volume 22 Number 3 March 1990
Septal granulomatous panniculitis 481
Table I. Associated conditions in patients with chronic erythema nodosum and erythema nodosum migrans Chronic erythema nodosum Conditions
No.
Sarcoidosis Streptococcal infection Other infection Birth control pills Other drugs Pregnancy Crohn's disease Thyroid disease Other Unknown Total
2
I
4
6 3 6
1
%
No.
6
0 5 0 0 0 0 0
11 17 8 17
2
3 6
2
6
0
10
36
months) and in four patients it ranged from 8 to 22 years. These four patients had an intermittent course of the disease with remission periods of 6 weeks to 6 months (in one case up to 3 years). Thirteen of the patients had unilateral lesions (93%) and only one had bilateral lesions (7%). The lesions were asymptomatic in five patients; in eight of the other nine, the degree of pain and tenderness was much less than usual in cases of erythema nodosum. Associated conditions were found in eight patients (57%): one euthyroid patient had granulomatous thyroiditis; two patients had hypothyroidism; and five patients had a streptococcal infection. Nine patients (64%) were treated with potassium iodide; in six (67%) the condition cleared or improved and three were lost to follow-up. Of the remaining 'patients, two were treated with a nonsteroidal anti-inflammatory drug; in one the lesions cleared and the other was lost to follow-up. Lesions of one patient treated with thyroxine cleared. Chronic erythema nodosum. Of these 36 patients 31 (86%) were women. The age of the patients ranged from 20 to 80 years (mean 45 years). The duration of the disease varied from 4 days to 13 years (mean 1.5 years); 26 patients (72%) had had their lesions for 4 days to 1 year (mean 3.5 months) and 10 patients (28%) had had lesions for 18 months to 13 years. Twenty-nine patients had lesions bilaterally (81 %) and seven had them unilaterally. Thirty-one patients had lesions only on their legs (86%); five also had lesions in other locations (14%). Associated conditions are described in Table I. Ten
Erythema nodoswn migrans
28
I
%
36
3
21
~
43
0
14
of 15 patients (67%) responded to nonsteroidal antiinflammatory agents; 7 of 10 patients responded to potassium iodide. DISCUSSION
We have found two general patterns of granulomatous histopathologic features and intensity of reaction of the subcutaneous tissue. In granulomatous and septal disease we could readily form two groups of cases: one with severe septal fibrosis, multiple granulomatous formations, and granulation tissuelike capillary proliferation; the other with mild septal change, mild and focal granulomas, and associated lymphocytic vascular inflammation, hemorrhage, and phlebitis (Table II). The histologic features of "classic" erythema nodosum are characterized by a polymorphous appearance of multiple elements including septae, blood vessels, and fat lobules.v? Septal inflammation around the veins with hemorrhage is a common finding.? The inflammation may extend into the lobular panniculitis, but the extension usually is in the periphery offat 10bules.9- 12 The histologic features of erythema nodosum? can be summarized as follows: lymphocytic inflammation, focal macrophages-lipophages, phlebitis, hemorrhage, and focal panniculitis. In 14 of 18 patients the pattern of severe septal fibrosis and granulomas correlated with chronic, unilateral, spreading, or migrating nodular disease. In 94% of cases with the mild granulomatous septal lesions there was no migratory character, and this histopathology generally was correlated with symmetric granulomatous erythema nodosum.'?
Journal of the American Academy of Dermatology
482 de Almeida Prestes et al.
Table II. Histopathologic features of erythema nodosum migrans and chronic erythema nodosum Erythema nodosum migram
Feature
Incidence(%)
Septal fibrosis Capillary proliferation Granulomatous reaction Hemorrhage Phlebitis
100 83 100
I
Intensity-
Incidence (%)
3-4
100
±
100 42 34
3-4 3-4
11
a
a
Chronic erythema nodosum
13
I
Intensity-
1 1 1 2
2
±, Slight. -On a scale of 0 to 4.
Table III. Clinical features of chronic erythema nodosum and erythema nodosum migrans
Mean age (yr) Female gender (%) Duration of disease (mean) All (yr) 72% (rna) Localization Legs (%) Legs andother (%) Symmetry Unilateral (%) Bilateral (%) Spreading (%) Significant associated symptoms (%) Associated conditions (%) Response to potassium iodide (No.)
Chronic erythema nodosum (n = 36)
Erythema nodosum rnigrans (n= 14)
45 86
50 86
1.5 3.5
4 7.5
86 14
100 0
14 86 0
93 7 100
72
83
7 57
7/10
6/9
The two groups had features in common (Table III), emphasizinga common etiopathology. Almost all patientsweremiddle-aged women. The erythema nodosum lesions healed more slowly than in usual patients, most requiring up to 3 to 4 months. This seemsreasonable on the basis of the granulomatous histologic findings. The erythema nodosum lesions alsocould be of short duration or asymmetricin occasionalcases. In oneinstanceof erythema nodosum migrans, other lesions werepresent on the other extremity. In seven patients with chronic erythema nodosum, the lesions were unilateral. In most patients the disease responded to treatment with potassium iodide (70% of each group).
Some of the etiologic factors of typical erythema nodosum were present. 13- 15 Only the chronic erythema nodosum group had an association with pregnancy, birth control pills, or sarcoidosis. Both groups had an association with streptococcal infection as emphasizedby Bafverstedt.e 13 by Vilanova and PifiolAguade,3,4 and,in a rare case,by Fine and Meltzer. 6 We believe that the mechanism of disease is the same in both groups and that both pathologic patterns represent more intense variations on the usual type oferythema nodosum response. Forstrom and Winkelmann'? pointed out that granulomas were less common and less florid in erythema nodosum than in erythema induratum and nodular vasculitis and were associated with all the other microscopic features of erythema nodosum, The cases of erythema nodosum migrans (migratory panniculitis) did not have these features and showed massing of histologic changes that were associated with chronic, recalcitrant lesions. The common presence of scattered eosinophils in erythema nodosummigrans may have significance in terms of the host response that produces this unique syndrome. Various types of erythema nodosum can be recognized. Erythema nodosum has long been considered to be an acute erythematous symmetric nodular disease. 14,16-18 We also recognize an acute celluliticform that is unilateral and very inflammatory, simulatingerysipelas.f 9, 13, 17 Additionaltypes to be considered include the following: (1) acute panniculitis in which there is occasional discharge from a sterile nodule'P; (2) acute phlebitis in which vein inflammation predominates/; (3) chronic erythema nodosum, which we now can see is characterized by mild granuloma formation; and (4) erythema nodosummigrans,whichis an evolution of
a
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Septal granulomatous panniculitis 483
granulomalesions to severe fibrosis and granulation tissue-type capillary proliferation.P We prefer the term erythema nodosum migrans rather than migratory panniculitis because we believe that this is related to erythema nodosum. In addition, involvement is onlyin the septa, not in the panniculus (thus it is not a true panniculitis). REFERENCES 1. Niemi KM, Forstrom L, Hannuksela M, et al. Nodules on the legs: a clinical, histological and immunohistological study of 82 patients representing different types of nodular panniculitis. Acta Derm Venereol (Stockh) 1977;57:14554. 2. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1954;34:181-93. 3. Vilanova X, Pifiol Aguade J. Hypodermit nodulaire subaigua migratrice. AnnDermatolSyph (Paris)1956;83:369404. 4. Vilanova X, Pifiol Aguade J. Subacute nodularmigratory panniculitis. Br J Dermatol 1959;71:45-50. 5. Perry HO, Winkelmann RK. Subacute nodularmigratory panniculitis. Arch DermatoI1964;89:17Q-9. 6. Fine RM, Meltzer RD . Chronic erythemanodosum. Arch DermatoI1969;100:33-8. 7. Massa MC, Su WPD. Lymphocytic vasculitis: is it a specific clinicopathologic entity? J Cutan Pathol 1984;11: 132-9. 8. LofgrenS, WahlgrenF.On thehisto-pathology oferythema nodosum. Acta Derm Venereal (Stockh) 1949;29:1-13.
9. Winkelmann RK, Forstrom L. New observations in the histopathology of erythema nodosum. J Invest Dermatol 1975;65:441-6. 10. ForstromL, Winkelmann RK. Granulomatous panniculitisinerythema nodosum. ArchDermatol1975;1 11 :335-40. 11. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott, 1983;246-7. 12. Mehregan AH . Pinkus' guide to dermatohistopathology. 4th ed. Norwalk, Conn: Appleton-Century-Crofts, 1986: 213. 13. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1968;48:381-4. 14. Hannuksela M. Erythemanodosum: withspecial reference tosarcoidosis; a clinical studyof 343 Finnish adultpatients. Ann Clin Res 1971;3(suppl 7):1-64. 15. Hannuksela M. Erythema nodosum migrans. Acta Derm Venereal (Stockh) 1973;53:313-7. 16. Bondi EE, Lazarus GS. Panniculitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in general medicine; vol 1. 3rd ed. New York: McGraw-Hill, 1987: 1141-4. 17. Hellerstrom S. Erythema nodosum. Acta Derm Venereal (Stockh) 1966;46:469-n. 18. Ryan TJ, WilkinsonDS. Cutaneous vasculitis: angiitis. In: RookA, Wilkinson DS, Ebling FJG, et al., eds, Textbook of dermatology; vol 2. 4th ed. Oxford: Blackwell, 1986: 1156-63. 19. ForstromL, Winkelmann RK. Acutepanniculitis: a clinical and histopathologic studyof 34 cases. Arch Dermatol 1977;113:909-17. 20. Thiers BH. Panniculitis. In:GreerKE, ed. Common problems in dermatology. Chicago: Year Book Medical Publishers, 1988:267-71.
CORRECTION In the articleby BernardW. Berger, MD, and Russell C. Johnson, PhD,entitled "Clinical and Microbiologic Findings inSixPatients withErythema Migrans ofLymeDisease" (J AM ACAD DERMATOL 1989;21:1188-91), page 1189, column 1, paragraph 4, the final sentence should read as follows: The second patient(No.4) required an additional 21-day courseofpenicillin 13months after hisinitial treatment for symptoms that may have represented recurrent Lymedisease or a newepisode of Lyme diseasewithout erythema migrans.
Typicalerythema nodosum is a well-established entity,' but there are variants that have a different evolution and clinical features and havebeen given different names by various authors. In 1954 Bafverstedt- described erythema nodosum migrans that occurred mostly in women. It presentswithpersistent nodular lesions that progress centrifugally; the lesions are minimally symptomatic and have an asymmetric or unilaterallocalization. The histologic features of erythemanodosum migrans were considered by Bafverstedt to be typical of erythema nodosum, but no descriptions were given. Vilanova and Pifiol Aguade3, 4 described subacute nodular migratory panniculitis, characterized by nodules on the legs that enlarged by confluence or Fromthe Department ofDermatology, Mayo Clinic and MayoFoundation. Accepted for publication May 5, 1989. Reprint requests: W. P. Daniel Su, MD, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. *Dr.de Almeida Prestes is Visiting Clinician. 16/1/13765
peripheral extension to form plaques up to 20 em in diameter. The nodules werelimitedin number,were mildly inflammatory, and did not ulcerate. Typically, in middle-aged women with sore throats, lesions developed on one leg. Although the disease frequently evolved in less than 1 year, it couldtake more than 3 years. The lesions cleared after treatment with potassium iodide. Histopathologically, migratorypanniculitis wasconsidered to bedifferent from erythema nodosum. Perry and Winkelmann' confirmed the occurrence ofthisdistinctclinical and pathologic syndrome. Fine and Meltzer'' in 1969 reported ninecases of the same condition, of which eight were in women. Fivepatientsinitiallyhad a solitary lesion onthe anterior aspectof the leg, and additional nodules subsequently developed in three ofthese. Three patients had multiple bilateral lesions whenfirstseen. There was a tendency for individual nodules to enlargeby peripheral extension, and in noinstancewerethe lesions as inflammatory as in acute erythema nodosum. Because of the close histologic resemblance to erythemanodosum, the authorspreferred to term this entity chronic erythema nodosum and believed
477
478
Journal of the American Academy of Derma toJogy
de Almeida Prestes et al.
Fig. 1. Erythema nodosum migrans, A, Markedly fibrotic and widened septa. B, Multiple giant cells in line along the borders of the widened septum. C, Granulation-type capillary proliferation. (A, B, and C, Hematoxylin-eosin stain; A, X 10; B, X 33; C, X 130.)
that it should be considered to be the same as subacute nodular migratory panniculitis, erythema nodosum migrans, nodular vasculitis, and probably erythema induratum. Because of the divergent opinions in the literature, we decided to evaluate our own experience with migratory panniculitis and erythema nodosum; we focused first on the histologic features of septal granuloma and subsequently correlated the clinical findings and course with the histopathology.
MATERIAL AND METHODS Our study reviewed cases of septal granulomatous panniculitis from the dermatopathology file at the Mayo Clinic for the period 1961 to 1987. We selected 58 cases in which there had been an excisional biopsythat included adequate subcutaneous tissue. Each case included slides stained with hematoxylin and eosin, and almost all cases had slides stained by the aldehyde-fuchsin elastic and periodic acid-Schiff methods. We assessed the quantity of fibrosisand thickness of the septum, the presence of capillary proliferation, phlebitis, panniculitis, vasculitis, granuloma formation, and lymphohistiocytic inflammation, and the quantity and pat-
tern of hemorrhage. The presence of other inflammatory cells was noted. The presenceof epidermal, appendageal, and dermal lesions was studied. From these slides, the cases were grouped as chronic erythema nodosum (mild changes) or erythema nodosummigrans (severechanges). We then grouped the cases as chronic "erythema nodosum or erythema nodosum migrans on the basis of clinical course and clinical picture without reference to the pathologicfeatures. Our clinicalcriteria were time for evolution, morphology,symptoms,number and sizeofthe lesions, localization (unilateral or bilateral), symmetry, and spreading character. Response to treatment was noted without reference to the other changes. Once the separate histologic and clinical groupings were made, we made a comparison between the respective groups to determine whether a concordance of diagnosis was possible.
RESULTS
Histopathologic findings The evaluation of the histologic specimens omitted 2 (3.4%) of the 58 cases because their pathologic changes were minimal and nonspecific. The remaining 56 cases had two distinct histopathologic patterns that separated them into groups of erythema
Volume 22 Number 3 March 1990
Septal granulomatous panniculitis 479
Fig. 2. Chronic erythema nodosum. A, Absence of fibrosis and thickness of septa. B, Focal septal granuloma formation. C, Extensive septal hemorrhage. (A, B, and C, Hematoxylineosin stain; A, X 8; B, X 33; C, X 85.)
nodosum migrans ( 18 cases) and chronic erythema nodosum (38 cases). Erythema nodosum migrans. Erythema nodosum migrans was characterized by fibrosis and markedly widened septa, with many granulomas composed of epithelioid cells and many giant cells. The multinucleated giant cells were found within the septa between fat lobules and numbered 10 or more per field. In most cases they were lined along the borders of the widened septa in a wall configuration, although occasionally the process was nodular and more confined to one or more areas (Fig. 1, A and B). A mild lymphocytic inflammation was observed. Scattered eosinophils were present in almost all cases. Neutrophils and plasma cells were rarely seen. The inflammatory reaction was confined to the septum. Inflammatory changes in the fat lobules were occasionally present and then were scarce and only at the periphery. Granulation tissue-like capillary proliferation (Fig. 1, C) was found in 15 cases (83%), as focal areas in four cases (27%), and with widespread foci at the septal borders of the fat lobules in 11 cases (73%). In all cases the capillary walls were composed
of a single or, sometimes, a double row of normal or swollen endothelial cells. Vasculitis and obstruction of the vascular lumen were not observed. Focal mild hemorrhage was present in only two cases (11 %), and phlebitis or periphlebitis was not found in any instance. Chronic erythema nodosum. Chronic erythema nodosum exhibited only discrete perivascular lymphocytic inflammation and a contiguous infiltrate in the deep dermis. The inflammatory pathologic changes were present in the septa. In 24 (63%) of the 38 cases, impressive lymphohistiocytic inflammation with occasional focal granuloma was also present about the vessels and individual fat cells at the periphery of fat lobules. Rarely, a diffuse mixture of lymphocytes and histiocytes was observed. Lymphocytic vasculitis was present in the small vessels in the septa and panniculus was found in 14 cases (37%). Our criteria of lymphocytic vasculitis are as defined before 7: (l) fibrinoid necrosis of blood vessel walls, (2) predominantly lymphocytic infiltrate involving and surrounding blood vessel walls, and (3) endothelial cell swelling or hyperplasia. Thrombosis and extravasation of leukocytes are common but not imperative as criteria. The septum was not fibrotic or
480
de Almeida Prestes et al.
Journal of the American Academy of Dermatology
Fig. 3. Erythema nodosum migrans: Unilateral single plaque formed by spreading of lesion.
widened (Fig. 2, A). Focal granuloma formation was observed in the septae in all cases (Fig. 2, B). Focal capillary proliferation was found in only five cases (13%). Phlebitis was found in 13 cases (34%). No thrombosed veins were present. Hemorrhage was present in 16 cases (42%). In 14, it was extensive and diffuse within the septum and almost always was associated with involvement of the periphery of the fat lobules (Fig. 2, C).
Fig. 4. Chronic erythema nodosum: Multiple bilateral symmetric nodules.
Clinical findings Clinically, 54 of the 56 cases could be grouped; two cases had confusing features that made the differentiation doubtful, thereby leaving 15cases (28%) of erythema nodosum migrans and 39 cases (72%) of chronic erythema nodosum. We considered erythema nodosum migrans cases to have chronic focal nodules that were not ulcerated and that spread into plaques, formed by extension or confluence of lesions, localized in the lower legs, usually unilaterally and with a limited number of lesions (Fig. 3). We considered as chronic erythema nodosum those cases with symmetric, nonulcerated lesions that were located on the legs (in some cases there also
were lesionselsewhereon the body) and that did not demonstrate a migratory tendency (Fig. 4). There was agreement between histologic and clinicaldiagnosesin 14o£18cases(78%) of erythema nodosum migrans and in 36 of 38 cases (95%) of chronic erythema nodosum. The comparisons were inconclusive in six cases. Erythema nodosum migrans. The 14 cases of erythema nodosum migrans included 12 women (86%) from 29 to 79 years old (mean age 50 years). The duration of the disease ranged from 21 days to 22 years (mean duration 4 years) overall; in 10 patients it ranged from 21 days to 3 years (mean 7.5
Volume 22 Number 3 March 1990
Septal granulomatous panniculitis 481
Table I. Associated conditions in patients with chronic erythema nodosum and erythema nodosum migrans Chronic erythema nodosum Conditions
No.
Sarcoidosis Streptococcal infection Other infection Birth control pills Other drugs Pregnancy Crohn's disease Thyroid disease Other Unknown Total
2
I
4
6 3 6
1
%
No.
6
0 5 0 0 0 0 0
11 17 8 17
2
3 6
2
6
0
10
36
months) and in four patients it ranged from 8 to 22 years. These four patients had an intermittent course of the disease with remission periods of 6 weeks to 6 months (in one case up to 3 years). Thirteen of the patients had unilateral lesions (93%) and only one had bilateral lesions (7%). The lesions were asymptomatic in five patients; in eight of the other nine, the degree of pain and tenderness was much less than usual in cases of erythema nodosum. Associated conditions were found in eight patients (57%): one euthyroid patient had granulomatous thyroiditis; two patients had hypothyroidism; and five patients had a streptococcal infection. Nine patients (64%) were treated with potassium iodide; in six (67%) the condition cleared or improved and three were lost to follow-up. Of the remaining 'patients, two were treated with a nonsteroidal anti-inflammatory drug; in one the lesions cleared and the other was lost to follow-up. Lesions of one patient treated with thyroxine cleared. Chronic erythema nodosum. Of these 36 patients 31 (86%) were women. The age of the patients ranged from 20 to 80 years (mean 45 years). The duration of the disease varied from 4 days to 13 years (mean 1.5 years); 26 patients (72%) had had their lesions for 4 days to 1 year (mean 3.5 months) and 10 patients (28%) had had lesions for 18 months to 13 years. Twenty-nine patients had lesions bilaterally (81 %) and seven had them unilaterally. Thirty-one patients had lesions only on their legs (86%); five also had lesions in other locations (14%). Associated conditions are described in Table I. Ten
Erythema nodoswn migrans
28
I
%
36
3
21
~
43
0
14
of 15 patients (67%) responded to nonsteroidal antiinflammatory agents; 7 of 10 patients responded to potassium iodide. DISCUSSION
We have found two general patterns of granulomatous histopathologic features and intensity of reaction of the subcutaneous tissue. In granulomatous and septal disease we could readily form two groups of cases: one with severe septal fibrosis, multiple granulomatous formations, and granulation tissuelike capillary proliferation; the other with mild septal change, mild and focal granulomas, and associated lymphocytic vascular inflammation, hemorrhage, and phlebitis (Table II). The histologic features of "classic" erythema nodosum are characterized by a polymorphous appearance of multiple elements including septae, blood vessels, and fat lobules.v? Septal inflammation around the veins with hemorrhage is a common finding.? The inflammation may extend into the lobular panniculitis, but the extension usually is in the periphery offat 10bules.9- 12 The histologic features of erythema nodosum? can be summarized as follows: lymphocytic inflammation, focal macrophages-lipophages, phlebitis, hemorrhage, and focal panniculitis. In 14 of 18 patients the pattern of severe septal fibrosis and granulomas correlated with chronic, unilateral, spreading, or migrating nodular disease. In 94% of cases with the mild granulomatous septal lesions there was no migratory character, and this histopathology generally was correlated with symmetric granulomatous erythema nodosum.'?
Journal of the American Academy of Dermatology
482 de Almeida Prestes et al.
Table II. Histopathologic features of erythema nodosum migrans and chronic erythema nodosum Erythema nodosum migram
Feature
Incidence(%)
Septal fibrosis Capillary proliferation Granulomatous reaction Hemorrhage Phlebitis
100 83 100
I
Intensity-
Incidence (%)
3-4
100
±
100 42 34
3-4 3-4
11
a
a
Chronic erythema nodosum
13
I
Intensity-
1 1 1 2
2
±, Slight. -On a scale of 0 to 4.
Table III. Clinical features of chronic erythema nodosum and erythema nodosum migrans
Mean age (yr) Female gender (%) Duration of disease (mean) All (yr) 72% (rna) Localization Legs (%) Legs andother (%) Symmetry Unilateral (%) Bilateral (%) Spreading (%) Significant associated symptoms (%) Associated conditions (%) Response to potassium iodide (No.)
Chronic erythema nodosum (n = 36)
Erythema nodosum rnigrans (n= 14)
45 86
50 86
1.5 3.5
4 7.5
86 14
100 0
14 86 0
93 7 100
72
83
7 57
7/10
6/9
The two groups had features in common (Table III), emphasizinga common etiopathology. Almost all patientsweremiddle-aged women. The erythema nodosum lesions healed more slowly than in usual patients, most requiring up to 3 to 4 months. This seemsreasonable on the basis of the granulomatous histologic findings. The erythema nodosum lesions alsocould be of short duration or asymmetricin occasionalcases. In oneinstanceof erythema nodosum migrans, other lesions werepresent on the other extremity. In seven patients with chronic erythema nodosum, the lesions were unilateral. In most patients the disease responded to treatment with potassium iodide (70% of each group).
Some of the etiologic factors of typical erythema nodosum were present. 13- 15 Only the chronic erythema nodosum group had an association with pregnancy, birth control pills, or sarcoidosis. Both groups had an association with streptococcal infection as emphasizedby Bafverstedt.e 13 by Vilanova and PifiolAguade,3,4 and,in a rare case,by Fine and Meltzer. 6 We believe that the mechanism of disease is the same in both groups and that both pathologic patterns represent more intense variations on the usual type oferythema nodosum response. Forstrom and Winkelmann'? pointed out that granulomas were less common and less florid in erythema nodosum than in erythema induratum and nodular vasculitis and were associated with all the other microscopic features of erythema nodosum, The cases of erythema nodosum migrans (migratory panniculitis) did not have these features and showed massing of histologic changes that were associated with chronic, recalcitrant lesions. The common presence of scattered eosinophils in erythema nodosummigrans may have significance in terms of the host response that produces this unique syndrome. Various types of erythema nodosum can be recognized. Erythema nodosum has long been considered to be an acute erythematous symmetric nodular disease. 14,16-18 We also recognize an acute celluliticform that is unilateral and very inflammatory, simulatingerysipelas.f 9, 13, 17 Additionaltypes to be considered include the following: (1) acute panniculitis in which there is occasional discharge from a sterile nodule'P; (2) acute phlebitis in which vein inflammation predominates/; (3) chronic erythema nodosum, which we now can see is characterized by mild granuloma formation; and (4) erythema nodosummigrans,whichis an evolution of
a
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Septal granulomatous panniculitis 483
granulomalesions to severe fibrosis and granulation tissue-type capillary proliferation.P We prefer the term erythema nodosum migrans rather than migratory panniculitis because we believe that this is related to erythema nodosum. In addition, involvement is onlyin the septa, not in the panniculus (thus it is not a true panniculitis). REFERENCES 1. Niemi KM, Forstrom L, Hannuksela M, et al. Nodules on the legs: a clinical, histological and immunohistological study of 82 patients representing different types of nodular panniculitis. Acta Derm Venereol (Stockh) 1977;57:14554. 2. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1954;34:181-93. 3. Vilanova X, Pifiol Aguade J. Hypodermit nodulaire subaigua migratrice. AnnDermatolSyph (Paris)1956;83:369404. 4. Vilanova X, Pifiol Aguade J. Subacute nodularmigratory panniculitis. Br J Dermatol 1959;71:45-50. 5. Perry HO, Winkelmann RK. Subacute nodularmigratory panniculitis. Arch DermatoI1964;89:17Q-9. 6. Fine RM, Meltzer RD . Chronic erythemanodosum. Arch DermatoI1969;100:33-8. 7. Massa MC, Su WPD. Lymphocytic vasculitis: is it a specific clinicopathologic entity? J Cutan Pathol 1984;11: 132-9. 8. LofgrenS, WahlgrenF.On thehisto-pathology oferythema nodosum. Acta Derm Venereal (Stockh) 1949;29:1-13.
9. Winkelmann RK, Forstrom L. New observations in the histopathology of erythema nodosum. J Invest Dermatol 1975;65:441-6. 10. ForstromL, Winkelmann RK. Granulomatous panniculitisinerythema nodosum. ArchDermatol1975;1 11 :335-40. 11. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott, 1983;246-7. 12. Mehregan AH . Pinkus' guide to dermatohistopathology. 4th ed. Norwalk, Conn: Appleton-Century-Crofts, 1986: 213. 13. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1968;48:381-4. 14. Hannuksela M. Erythemanodosum: withspecial reference tosarcoidosis; a clinical studyof 343 Finnish adultpatients. Ann Clin Res 1971;3(suppl 7):1-64. 15. Hannuksela M. Erythema nodosum migrans. Acta Derm Venereal (Stockh) 1973;53:313-7. 16. Bondi EE, Lazarus GS. Panniculitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in general medicine; vol 1. 3rd ed. New York: McGraw-Hill, 1987: 1141-4. 17. Hellerstrom S. Erythema nodosum. Acta Derm Venereal (Stockh) 1966;46:469-n. 18. Ryan TJ, WilkinsonDS. Cutaneous vasculitis: angiitis. In: RookA, Wilkinson DS, Ebling FJG, et al., eds, Textbook of dermatology; vol 2. 4th ed. Oxford: Blackwell, 1986: 1156-63. 19. ForstromL, Winkelmann RK. Acutepanniculitis: a clinical and histopathologic studyof 34 cases. Arch Dermatol 1977;113:909-17. 20. Thiers BH. Panniculitis. In:GreerKE, ed. Common problems in dermatology. Chicago: Year Book Medical Publishers, 1988:267-71.
CORRECTION In the articleby BernardW. Berger, MD, and Russell C. Johnson, PhD,entitled "Clinical and Microbiologic Findings inSixPatients withErythema Migrans ofLymeDisease" (J AM ACAD DERMATOL 1989;21:1188-91), page 1189, column 1, paragraph 4, the final sentence should read as follows: The second patient(No.4) required an additional 21-day courseofpenicillin 13months after hisinitial treatment for symptoms that may have represented recurrent Lymedisease or a newepisode of Lyme diseasewithout erythema migrans.
