New Observations in the Histopathology of Erythema Nodosum

NEW OBSERVATIONS IN THE HISTOPATHOLOGY OF ERYTHEMA NODOSUM

R. K. WINKELMANN , M .D., PHD., AND LARS FORSTROM, M.D. Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Erythema nodosum presents variable clinical and histologic patterns of response in the vessels, septa, and fat lobules of t he subcutaneous tissue. Acute or chronic phlebitis with hemorrhage may be commonly observed; acute panniculitis is observed in foci, but at times it may be the principal histologic feature; lymphocytic infiltration of fat lobules is often found, and lymphoid nodules are not infrequent; rarely, chronic granulomatous lesions involve septa or fat lobules; and proliferative lipocyte response may be observed. Because these variable histologic patterns may be coexistent, excision biopsy and multiple sections are necessary to recognize them. The variable histologic features correlate with t he different clinical forms: acute nodular, chronic nodular, migrating plaque lesion, cellulitis, and the rare suppurative form . This variety of panniculus response in erythema nodosum can be explained on the basis of host-tissue response to a delayed hypersensitivity reaction to an antigenic stimulus.

Erythema nodosum may be defined clinically as effort required to biopsy by t he excision technique. an immunobiologically reactive inflammatory syn However, in our experience, less than half of the drome involving the small vessels of the subcuta punch biopsies in erythema nodosum show signifi neous tissue and dermis which produces crops of cant pathologic change and, of these, only 10 to red nodules of short duration. Recent study has 20 % can be interpreted reliably. Such a significant emphasized that, in addition to its classic relation failure rate should discourage clinicians from using ship to tuberculosis and streptococcal disease, the procedure and should explain why dermatopa erythema nodosum is significantly related to sar thologists have been so dissatisfied with small coidosis and Yersinia [1, 2 ]. Many viral, bacterial, samples of a variegated pathologic picture. The and fungal diseases are associated with this reac clinical course of the patient has been a more tion, often under circumstances that have raised reliable guide to diagnosis than have pathologic the question of whether the infectious agent or the findings obtained under limiting circumstances. drug therapy was responsible for the reaction [3 ,4 ]. An additional fundamental problem in using The diagnosis of erythema nodosum is based pathologic findings in defining the range of mainly on the sudden appearance of the lesions, changes in the erythema nodosum reaction has their clinical appearance as locali zed or diffuse been the choice of study material. Most studies areas of redness, and the rapid resolution of the have rejected cases in which the histology did not inflammation with therapy of bed rest and wet fit clearly defined limits accepted by the author. dressings. The histopathologic features have been Since this is a natural desire-to have a " pure" considered diagnostic but not specific [4- 9]. case group for study-in studying a polymorphous In our recent studies of panniculitis, some prob pathologic process, cases at the edge of easy lems in the diagnosis of erythema nodosum have recognition are excluded. While studying 51 cases become apparent-we found erythema nodosum of acute panniculitis, we discovered that half were associated with acute and chronic panniculitis. We typical clinical examples of erythema nodosum wish to demonstrate t he polymorphous and focal (confirmed by fo ll ow-up; unpublished data). histologic nature of erythema nodosum, involving While reviewing granulomatous panniculitis, we as it does vessels, septa, and panniculus and to also discovered 5 clear-cut cases of recurrent ery indicate the many avoidable problems that arise. thema nodosum [10]. Examination of fat necrosis The first problem is one of sampling the dermis and superficial thrombophlebitis . also demon and subcutaneous tissue. Excision biopsy must be strated a few cases in which the crops were of short the accepted standard for the histopathologic duration-red nodules that could be described best study of subcutaneous inf1ammation. In erythema in terms of erythema nodosum. Our purpose in this nodosum, the punch biopsy technique has been report is to show the broad range of changes in used frequently because of its ease and general vessels, septa, and panniculus that may be ob availability, in contrast to the time-consuming served in erythema nodosum. The polymorphous nature of erythema nodosum pathology (Tab. I) indicates the variety of vessel Reprint requests to: Dr. R. K. Winkelma nn, Depart ment of Dermatology, Mayo Clinic a nd Mayo Founda disease and its consequences, the perivascular tion, Rochester, Minnesota 55901. septal inflammation and reaction, and fina ll y the 441 442 WINKELMANN AND FORSTROM Vol. 65, No.5 panniculitis that can occur. The pathologic process served. The reaction may be acute and may must be considered primarily as vascular inflam demonstrate acute thrombophlebitis with com mation, and most changes are related to this. plete destruction of the vessel wall and a red blood However, the coexistence of hemorrhage, acute cell-polymorphonuclear cell coagulum in the panniculitis or fat necrosis (or both), and granu lumen (Fig. IA) . The vessel wall is permeated by lomas is (or should be) part of the expected polymorphonuclear leukocytes and red blood cells. microscopic findings of this reaction. Any individ However, t he vascular inflammation usually is ual feature may be predominant in a given area of characterized by a lymphocytic cellular infiltra a biopsy specimen, so that multiple sections are tion. All the veins in the dermis may be surrounded necessary to recognize the variations and localiza and permeated by lymphocytes. The larger subcu tions of the pathologic process. The acute reactions taneous veins may show a similar focal change. involve polymorphonuclear leukocytes, and the Frequently, the vein may demonstrate extensive chronic reactions demonstrate lymphocytes and endothelial proliferation and separation of the varied numbers of histiocytes. Such histopatho muscular laminae of the vein wall s by a mixed logic changes represent the variable reactions by inflammatory infiltrate composed of lymphocytes, which the pattern of erythema nodosum is dis histiocytes, and occasional polymorphonuclear played at both clinical and microscopic levels. leukocytes. The inflammation may progress to a granuloma, with luminal and mural histiofibro VESSEL INFLAMMATION blastic response and often including giant cells The veins are the major vessels involved in (Fig. IB). This is the natural evolution of thrombo erythema nodosum. Lofgren and Wahlgren [8] phlebitis, and it is repeated in erythema nodosum. observed that 40 % of patients with erythema Final fibrosis of the vessel wall and lumen may be nodosum had thrombophlebitis, and our experi observed. We emphasize that these histopathologic ence agrees with this. If a large biopsy specimen is differences in vessels represent a range that may be taken and enough sections are cut, a large vein found sequentially in one biopsy specimen or may with acute inflammation will be frequently ob- be observed individually. It is this range of vascu lar reaction that must be considered in relation to TABLE 1. Histopathology of erythema nodosum other hi stopathologic observations. The acute vascular lesion gives rise to septal Phlebitis hemorrhage and hemorrhage in t he subcutaneous Lymphocytic fat lobules. While such hemorrhage has long been Polymorphonuclear leukocytic recognized clinically as a major feature of ery Hemorrhagic thema nodosum (that is, the synonym, erythema Septal in!1 ammation contusiformis), pathologic description has not em Acute phasized this. It is not unusual to find a given Chronic, granulomatous histologic section of erythema nodosum demon Panniculi tis strating diffuse hemorrhage with mild, perivascu Acute lar inflammation. We believe that, microscopi Chronic, granulomatous cally, hemorrhage may be a major feature of erythema nodosum and may be associated with

FIG. 1. Acute thrombophlebitis in erythema nodosu m. A: Note peripheral inl1ammation of fat lobule related to ~e s.se l s (H & E, x 12). B: Marked end othelial ce ll swelling and proliferation, with mild lymphocytic in!1 ammatory II1flltrate of vell1 wall muscle layers (H & E, x 12). Nov. 1975 HISTOPATHOLOGY IN EHYTHEMA NODO 'UM 443 PANNI ULITI The inflammation of t he fat lobules in erythema nodosum is usuall y seen at the periphery. The central area is frequently spared the pathologic change, and this has been considered to be signifi cant fo r the diagnosis of erythema nodosum. All of the changes of inf1ammation-acute polymorpho nuclear leukocyte or lymphocyte int1ammation (or both) and granulomatou , necrobiotic, degenera t ive, and vascular proliferative changes-are ob served in the periphery of the fat lobule. Associated findings of hemorrhage and, more rarely, plasma cell infil tration and fat cell proliferation are also observed . Significant primary fat necrosis is not found.

AC UTE PANN ICULITI FIG. 2. Lymphohistiocytic infiltrate at edge of fat lobule, showing giant cell s a nd mild lymphocytic vascu The fat lobule may be replaced completely by lar inflammation (H & E, x 140). acute panniculitis. This replacement may consist of masses of polymorphonuclear leukocytes a nd other pathologic findings or may be the unique, but mononuclear cells (Fig. 3A). Associated with this nonspecific, observations of a given biopsy sample. acute cellular infiltration is necrosis of the cellular infiltrate itself and secondary necrosis of the fat SEPTAL INFLAMMATION lobule. The inf1ammatory cells may replace most The major blood vessels in t he fat travel in t he of the fat lobule, and the remaining fat cells may septa of t he fat lobules, and because t he inf1amma enlarge, becoming microcystic (Fig. 3B). Fat cell tion is related to the ve sels primarily, it is proliferation may not be observed. Proliferative fat observed in the septal connective tissue around the cell reaction does occur, however, in the panniculi vessels. Acute septal inf1ammation with necrosis tis of erythema nodosum. The immature fat cells may appear at first to be a primary focal infection may proliferate in a sea of acute and chronic (or similar to one), producing necrosis of connec inf1ammation of the fat lobule (Fig. 3C). ti ve tissue in ·a mass of polymorphonuclear leuko A more typical form of panniculit is in erythema cytes. In all instances, multiple sections reveal the nodosum is the lymphocytic infiltration. This ap primary vessel involvement. Only one septal area parently represents an extension of the perivascu is usually involved, emphasizing the focal vascular lar and septal lymphocytic vasculitis, principally change. Hemorrhage may occur after the develop involving veins. The lymphocytes may encircle ment of the acute septal inflammation and may be each fat cell in a complete necklace, and polymor seen adjacent to it. In many patients, the perivas phonuclear leukocytes or nuclear dust may be cular septal inflammation is lymphocytic and associated with the infiltration . This form of in septal invasion by chronic, round cells is observed. t1ammation is frequently less destructive and more The lymphohistiocytic reaction may be observed in focal, though most of a fat lobule may be involved. an acute lesion when the lesion biopsied is only 24 Secondary fat necrosis associated with the lympho hours old. As the lesions develop, hi stiocytic and cytic inflammation may occur, with giant cells and giant cell changes occur (Fig. 2). The radially microcyst formation. The blood vessels of t he fat organized histiocytes may form a micronodule (the lobule itself usually show minimal change until the Miescher granuloma), which may be observed in entire lobule is replaced by inf1ammation. the septa or in the periphery of a fat lobule. The connective tissue of the septa may demonstrate a CHRON IC GRANULOMATOUS PANNICULITIS fibrinoid change, and associated with this change The lymphocytic inflammation usually blends is a septal, granulomatous int1ammation composed into a patchy, lymphohistiocytic, gqll1ulomatous of histiocytes, lymphocytes, and giant cell masses. reaction. The macrophage-histiocyte reaction is no Caseation is not observed, but the inf1ammatory longer manifested as the occasional microscopic changes produce necrobiosis of the adjacent con- Miescher nodule but becomes large granulomatous / nective tissue. As t he inf1ammation encroaches on masses and nodules (Fig. 4). These granulomatous the fat lobul es, the fat lobule vessels proliferate, or tuberculoid nodules of epithelioid cells are forming granulation tissue with acute infi ltration surrounded by lymphocytes, although occasionall y of polymorphonuclear leukocytes and perivascular t he nodules a re relatively' free of lymphocytes, as fibrosis. This septal inflammation can heal, with in sarcoid tubercles. Caseation is not observed, and only fibrosis and thickening of the septum or with no bacilli are observed in special stains or cultures . massive scar formation and obli teration of fat Fluoroscopy and polarization do not reveal unusual lobules. substances. No asteroid or Schaum ann's bodies are 444 WINKELMANN AND FORSTHOM Vol. 65, N o.5

FIG. 4. Histiocytic- granulomatous panniculitis in ery t hema nodosum (H & E , x 110) .

TABLE II . Clinical syndromes of erythema nodosum

Nodular erythema Acute Chronic Migratory Erysipeloid erythema Thrombophlebitis Acute panniculitis

[11] and of Hannuksela [2 ], but because of the many histiopathol oglc features showing involve ment of t he vessels, septa, and fat lobules in acute, subacute, and chronic inl1ammation with hemor rhage and fibrosis, the microscopic findings often are not compatibl e with the clinical diagnos is. For instance, a clinician may take a biopsy spec imen in erythema nodosum and receive a histopathologic diagnosis of acute panniculitis, thrombophlebitis, granulomatous or nodular vasculitis, or migratory panniculitis. Each of these diagnoses has a distinct and separate implication for the clinical expression and prognosis of disease, and yet each has a histopathologic pi cture similar to that in ery thema nodosum. In erythema nodosum, there is FIG. 3. A: Infiltration of fat lobule with acute infl am some correlation between the clinical manifesta matory cell s and mild secondary fat nec rosis (H & E , tions (Tab. II) and the histologic patterns (Tab. I). x 53). B: Replacement of fat lobule by polymorphonu clear cell s and lymphocytes with mi crocyst form ation (H The interpretation of the subcutaneous histopa & E , x 28). C: Early proliferative fat ce ll response to thology may be simplified by examination of the inflammation of fat lobul e (H & E, x llO). rare cases in which the veins or fat lobules may be principall y involved. The blood vessels involved in superficial thrombophlebitis are much larger than observed, though giant cells are frequent. In 2 of 5 the muscular veins, which become inf1amed in patients studied, t he t uberculoid masses replaced atypical erythema nodosum. The acute panniculi most of the fat lobules; these were the 2 patients tis in erythema nodosum is focal and related to the with septal hyalinization, fibrosis, and thickening. vessels or is associated with hemorrhage. Vascular changes were minimal in all 5 patients. Some patients with erythema nodosum develop individual lesions t hat may last for several months, DISCUSSION to which the term "chronic erythema nodosum" Erythema nodosum is an easily defined clinical can be applied and contrasted with the common or disease, as illustrated by t he studies of Hellerstrom acute recurrent erythema nodosum. Fine and Nov.1975 HISTOPATHOLOGY IN ERYTH EMA NODOSUM 445 Meltzer [1 2 ] proposed that chronic red nodul es vascul ar inf1ammation may also produce the acute wit h focal granulomatous histologic features be polymorphonuclear leukocytic and thrombotic in called " chronic erythema nodosum." Biifverstedt f1amm ation of medium or large vessels, septa, and [1 3,14] and Vi lanova and Pinol Aguade [1 5 ] dis fat. This seems reasonable but remains unproved. cussed migratory panniculitis as a separate ent ity Two types of erythema nodosum may exist, based because of the clinical and histologic findings. The on the pathologic findings. One type is an acute, clinical presentation of the chronic spread of nodu vascula r, and septal leukocytic inf1ammation and lar inflammation is a unique clinical response that panniculitis, and the other type, which has t he clinicians must recognize, but we [10] agree with sa me clinical picture, is a delayed hypersensit ivi ty Fine and Meltzer [1 2 ] and with Hannuksela [2] lymphocytic acute inf1ammatory involvement of that the granulomatous septal int1ammation in t he same port ions of the skin. The immunologic vading the fat lobules also may be found in and clinical data, plus the histologic findings of erythema nodosum. Hannuksela's [16 ] study of 56 mingling, suggest that these are not two separate cases of erythema nodosum migrans gives specific microscopic definitions of two pathogenetic proc support to the unity of the acute, chronic, and esses but rather are variations in the intensity of migratory forms of erythema nodosum because the the host-tissue inflammatory response to t he de histopathologic changes were compatible with layed hypersensitivity reaction of the vessels. those of erythema nodosum (accumulations of Acute panniculitis is considered to be equivalent lymphocytes, histiocytes, and occasional giant to the first stage of Weber-Christian disease. We cells in the septum of fat lobules and between fat found t hat most patients with t his histopathologic cells). Perry and Winkelmann [1 7 ], using t he diagnos is have erythema nodosum, and t his should microscopic criteria of septal granuloma forma help us understand many instances in which either t ion, found that 4 of 14 patients with t hese term is used. The clinician can ignore the patho histologic changes had cl inicall y typical erythema logic report that suggests severe disease in his nodosum. One of t he 14 patients had clinicall y and patient who has short-li ved, red nodul es of the histologically migratory panniculit is, but the le lower legs. Similarl y, the dermatopathologists will s io ns were of such short duration t hat erythema find it easier to understand acute panniculitis if nodosum was considered the likely diagnosis. Han most of the cases co nsidered are erythema nodo nuksela [2] observed that both migratory and sum and jf t he hi stopathologic fi ndings can be typical erythema nodosum had the same spectrum labeled as such. Some of our other cases of acute of causative agents. Contrace ptive hormone medi panniculitis, which earlier might have been labeled cation frequently was related to nodules of longer Weber- Christian disease, have been related to t he duration, as were sarcoidosis and unknown ca uses syndrome of acute panniculi t is with or without fat whether the clinical pattern was t he chronic, necrosis or pancreatic disease and have been asso migratory, or typical form of erythema nodosum. ciated with amylase or lipase (or both) in the Therefore, septal granulomas do occur in erythema lesions, as well as in t he blood or urine. T he nodosum and, together with t he rare cases of demonstra tion of t he second stage of Weber- Chris granulomatous panniculi tis, define a unique histo tian disease, t hat of lipocyte proliferation (proli fe r pathologic and clinical evolution of the erythema ative atrophy), in erythema nodosum further em nodosum problem. T his chronic evolution is proba phasizes the lack of specifi city in the histologic bly related more to host response t han to antigen features of this ent ity. The fina l stage of fibrosis in source. Weber- Christian di sease has no specificity 'at all . The cause of erythema nodosum is still debated. The granulomatous panniculitis observed in ery For instanpe, some authors consid er erythema t hema nodosum is also consistent with t he conce pt nodosum a vasculi tis or an infla mmation of the of delayed hypersensit ivity cellular inflammation. arteries. Studies wit h immunofluorescence have The reaction is lymphohistiocytic in part, and failed to reveal t he findings associated with the granuloma formation is a natural end poin t of immune complex pathogenes is of necrotizing or cellular immune responses. The differentia l diag " a llergic" vasculi t is. The evidence for considering nosis of t his hi stologic- cl inical pattern further erythema nodosum as a delayed hypersensit ivity indicates that the delayed immune-response mech cellular response of the vessels, principa lly to anism must be seriously consid ered. T he syn microbiologic or other ant ige ns, a ppears to be dromes of erythema induratum, nodular vasculi tis s ignificant. The histopathologic findings support (nontuberculous erythema induratum) , t uber t his position, as does t he occasional re lationship of culoid leprosy, and sarcoid indicate that granulo erythema nodosum to erythema multiforme. The matous erythema nodosum might be considered a major dermal and subcutaneous inflammation is tuberculoid histologic response of t he subcutane lymphocytic. 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