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New Observations in the Histopathology of Erythema Nodosum

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New Observations in the Histopathology of Erythema Nodosum THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 65:441- 446, 1975 Vol. 65, No.5 Copyright © 1975 by The Williams & Wilkins Co. Print ed in U.S.A. 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
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