Panniculitis. Part I. Mostly septal panniculitis

CONTINUING

MEDICAL EDUCATION

Panniculitis. Part I. Mostly septal panniculitis Luis Requena, MD,a and Evaristo Sánchez Yus, MDb Madrid, Spain The panniculitides represent a group of heterogeneous inflammatory diseases that involve the subcutaneous fat. The specific diagnosis of these diseases requires histopathologic study because different panniculitides usually show the same clinical appearance, which consists of subcutaneous erythematous nodules on the lower extremities. However, the histopathologic study of panniculitis is difficult because of an inadequate clinicopathologic correlation, and the changing evolutionary nature of the lesions means that biopsy specimens are often taken from late-stage lesions, which results in nonspecific histopathologic findings. In addition, large-scalpel incisional biopsies are required. However, we believe that by obtaining appropriate biopsy specimens and with adequate clinicopathologic correlation, a specific diagnosis may be rendered in most cases of panniculitis. It must be accepted that all panniculitides are somewhat mixed because the inflammatory infiltrate involves both the septa and lobules; however, in general the differential diagnosis between a mostly septal and a mostly lobular panniculitis is straightforward at scanning magnification. Mostly septal panniculitides with vasculitis include leukocytoclastic vasculitis involving the small blood vessels of the septa; superficial thrombophlebitis resulting from inflammation and subsequent thrombosis of large veins of the septa; and cutaneous polyarteritis nodosa, which is a vasculitis involving arteries and arterioles of the septa of subcutaneous fat with few or no systemic manifestations. Often septal panniculitides with no vasculitis are the consequence of dermal inflammatory processes extending to the subcutaneous fat, such as necrobiosis lipoidica, scleroderma, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. However, in other cases, the inflammatory process is primarily located in the fibrous septa of the subcutis with or without involvement of the overlying dermis. The most frequently seen septal panniculitis is erythema nodosum, which, in fully developed lesions, is characterized histopathologically by Miescher’s radial granulomas in the septa. (J Am Acad Dermatol 2001;45:163-83.)

Learning objective: At the completion of this learning activity, participants should be familiar with the pathogenesis, clinical manifestations, histopathologic findings, and treatment options for the most frequent variants of the septal panniculitides.

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he panniculitides are a group of heterogeneous inflammatory diseases involving the subcutaneous fat. Traditionally, the histopathologic study of the panniculitides has been considered one of the most difficult subjects in dermatopathology. The reasons for the relative unpopularity of the panniculitides are varied. First, the lesions show a disappointing clinical monotony. The most disparate processes involving the subcutaneous fat have the same clinical morphology presenting as erythematous nodules generally located on the lower limbs. Therefore the clinical findings are often not helpful in

From the Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma,a and Department of Dermatology, Hospital Clínico San Carlos, Universidad Complutense.b Reprints not available from authors. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/2/114736 doi:10.1067/mjd.2001.114736

the differential diagnosis among the different inflammatory conditions involving the subcutis. In addition to this clinical nonspecificity, there is an issue relative to the depth of the lesions. Sometimes specimens sent to the dermatopathology laboratories with a clinical diagnosis of panniculitis contain no subcutaneous fat at all. Inadequate specimens are usually obtained when a resident in early training performs the procedure; because of inexperience, the resident is afraid to obtain a sufficiently deep cutaneous biopsy specimen. Although trephine punches have been proposed for biopsies of panniculitides,1 an incisional biopsy with a larger scalpel that extends through the subcutaneous fat is preferred. However, pathologists and dermatopathologists also share some responsibility for the fact that panniculitides are considered to be the “ugly duckling” of dermatopathology. Too often, a dermatopathologic report of a panniculitis is signed out with the diagnosis of septal panniculitis or lobular panniculitis, or, even worse, mixed panniculitis, so 163

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Table I. Histopathologic classification of the panniculitides Mostly septal panniculitides With vasculitis Small vessels Venules Large vessels Veins Arteries No vasculitis Lymphocytes and plasma cells mostly With granulomatous infiltrate in septa No granulomatous infiltrate in septa Histiocytes mostly Granulomatous infiltrate With mucin in center of palisaded granulomas With fibrin in center of palisaded granulomas With large areas of degenerated collagen, foamy histiocytes, and cholesterol clefts Without mucin, fibrin, or degeneration of collagen, but with radial granulomas in septa Mostly lobular panniculitides With vasculitis Small vessels Venules

Large vessels Arteries No vasculitis Few or no inflammatory cells Necrosis at center of lobule With vascular calcification With needle-shaped crystals in adipocytes Lymphocytes predominant With superficial and deep perivascular dermal infiltrate With lymphoid follicles, plasma cells, and nuclear dust of lymphocytes With lymphocytes and plasma cells Neutrophils predominant Extensive fat necrosis with saponification of adipocytes With neutrophils between collagen bundles of deep reticular dermis With bacteria fungi or protozoa identifiable by specialized stains With foreign bodies Histiocytes predominant (granulomatous) No crystals in adipocytes

With crystals in histiocytes or adipocytes

With cytophagic histiocytes With sclerosis of the septa

Leukocytoclastic vasculitis Superficial thrombophlebitis Cutaneous polyarteritis nodosa

Necrobiosis lipoidica Scleroderma

Subcutaneous granulosa annulare Rheumatoid nodule Necrobiotic xanthogranuloma Erythema nodosum

Erythema nodosum leprosum Lucio’s phenomenon Neutrophilic lobular (pustular) panniculitis associated with rheumatoid arthritis Erythema induratum of Bazin Crohn’s disease

Sclerosing panniculitis Calciphylaxis Oxalosis Sclerema neonatorum Cold panniculitis Lupus panniculitis (lupus erythematosus profundus) Panniculitis in dermatomyositis Pancreatic panniculitis α1-Antitrypsin deficiency Infective panniculitis Factitial panniculitis Subcutaneous sarcoidosis Traumatic panniculitis Lipoatrophy Subcutaneous fat necrosis of the newborn Poststeroid panniculitis Gout panniculitis Crystal-storing histiocytosis Cytophagic histiocytic panniculitis Postirradiation pseudosclerodermatous panniculitis

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Table I. Cont’d Disorders erroneously considered as specific variants of panniculitis Weber-Christian disease Rothmann-Makai disease Lipomembranous or membranocystic panniculitis Eosinophilic panniculitis

that the report communicates little or nothing to the clinician. Dermatopathologists must recognize that a diagnosis of septal or lobular panniculitis is just the first step in the diagnostic process. After that initial classification, efforts should be made to look for the characteristic histopathologic findings that allow for a more specific final diagnosis in the language of clinical dermatology. Another difficulty for the specific diagnosis of panniculitides results from the evolutionary nature of the lesions. Like other inflammatory diseases of the skin, panniculitides constitute dynamic processes in which both the composition and the distribution of the inflammatory infiltrate cells change within the course of a few days. Biopsy specimens from panniculitis are often taken from late-stage lesions because of inadequate clinicopathologic correlation and they show nonspecific findings. Clinicians are often reluctant to perform deep excisional biopsies for diagnosis of panniculitic disorders because they are unable to obtain an adequate histopathologic diagnosis and because of poor healing of large biopsy incisions on the lower legs of women. Some authors believe that “the histologic septal-lobular dichotomy is sometimes diagnostically useful, but more often there is a mixed picture that adds to interpretative difficulties.”2 (page 1615) We think that this is an overly pessimistic view of the histopathology of panniculitides and that, with an appropriate biopsy, a specific diagnosis can usually be made. First, it is necessary to accept that all panniculitides are mixed panniculitis because all have an inflammatory infiltrate involving both the septa and the lobules of the subcutaneous fat. However, the inflammatory infiltrate is more abundant in one of these two components of the subcutaneous fat; therefore diagnosis of a mostly septal or mostly lobular panniculitis can be rendered without difficulty at scanning magnification. The second step in the histopathologic diagnosis is to assess whether vasculitis is or is not present. If it is, the size and nature of the involved blood vessel must be determined. The third step should be to identify the nature of the cells present in the inflammatory infiltrate and, finally, to look for additional histopathologic features that allow a specific diagnosis of the disease involving the subcutaneous fat.

Another problem for histopathologic diagnosis of panniculitides results from the fact that the necrosis of adipocytes has a different appearance from the necrosis of other cells.3 In classic pathology, changes in nuclei, namely, pyknosis, karyorrhexis, and karyolysis, are signs of cellular necrosis. In contrast, necrotic adipocytes, regardless of cause, may appear as either anucleated cells or with complete disintegration of the cellular structure. The most common type of fat necrosis is the so-called lipophagic necrosis, which consists of foamy macrophages laden with the lipid products released from dead adipocytes. These lipophages exhibit a large pale microvacuolated or granular cytoplasm. Liquefactive fat necrosis is another type of necrosis of adipocytes that produces granular wisps of amphophilic detritus. Hyalinizing fat necrosis results in mummified adipocytes with glassy homogeneous proteinaceous material within their cytoplasm that effaces their architecture. Membranous fat necrosis is a late-stage necrosis of adipocytes that appears as a leathery eosinophilic or amphophilic rim of collapsed cellular organelles. When membranous fat necrosis is extensive, fat microcysts devoid of cell structures appear. Ischemic fat necrosis is mostly seen at the center of the involved lobules; at first the changes are subtle, appearing as small adipocytes at the center of the lobule, many of them as anucleated cells. Later stages of ischemic necrosis are also characterized by lipophagic necrosis. The purpose of this review is to present a comprehensive clinicopathologic overview of the panniculitides. Emphasis is placed on the characteristic histopathologic features for specific diagnosis and short comments about the treatment for each entity are included. In this report we use the classification system and the algorithmic method for histopathologic diagnosis proposed by Ackerman et al,4 although with some modifications. Our classification of the panniculitides is presented in Table I. Of course, we accept in advance that the classification proposed in Table I is imperfect. From an academic point of view it is probably inaccurate to include some inflammatory skin diseases among the panniculitides. These skin diseases involve the dermis more often than subcutaneous fat (eg, granuloma annulare, necrobiosis lipoidica, sarcoidosis), and some authors

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advocate that these disorders are not authentic panniculitides, but rather a deep extension of the dermal inflammatory process to the subcutaneous fat. Authors who support this view classify the panniculitides as authentic or primary panniculitides (ie, erythema nodosum, erythema induratum of Bazin), when the inflammatory process is characteristic and involves primarily the subcutaneous fat. When the inflammatory infiltrate extends from the deeper dermis into the subcutis, the processes are classified as pseudo or secondary panniculitides. However, although these arguments are correct, it is also true that in authentic or primary panniculitides, such as erythema nodosum and erythema induratum of Bazin, the inflammatory process mostly involves the subcutaneous fat but also always has an accompanying deep dermal perivascular inflammatory infiltrate. Therefore the use of dermal involvement as a criterion to separate authentic from pseudo panniculitides is futile. Furthermore, sometimes inflammatory disorders characteristic of the dermis, such as granuloma annulare, appear only in the subcutaneous fat with no dermal participation; therefore those cases should be considered as authentic panniculitides. Regardless of the classification system, which is just a working aid, the most important point is to identify those histopathologic features that result in specific diagnosis of the panniculitic disorder. In difficult cases, it may be helpful to take more than one biopsy specimen from lesions at different stages of evolution. In our experience, with appropriate specimens, adequate clinicopathologic correlation, and pertinent histopathologic study a specific diagnosis may be rendered in most cases of panniculitis. Usually, special stains and immunohistochemistry are not necessary for diagnosis, and the “gold standard” technique is deeper sections through the block stained with hematoxylin-eosin. Sometimes, however, special stains, polarization of sections, or cultures of the tissue for bacteria or fungi are useful in making a specific diagnosis. Elastic tissue stain is probably the most frequently requested special stain in biopsy specimens of panniculitis with large-vessel vasculitis used to study the nature of the involved vessel. With experience, a distinction can usually be made between artery and vein in large-vessel vasculitis involving the subcutaneous fat with hematoxylineosin stain used to distinguish the histopathologic characteristics of the involved vessel wall.5

HISTOLOGY OF THE SUBCUTANEOUS FAT Subcutaneous fat is organized into lobules of lipocytes separated by thin septa of connective tissue. The separation between reticular dermis and subcutaneous fat is not a straight line. Prolongations of subcutis ascend to the dermis surrounding the

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eccrine and apocrine coils, and consequently the boundary between dermis and subcutaneous fat is often a corrugated line. The thickness of the subcutaneous fat varies from one part of the body to another, with a thinner subcutis in areas of lax skin, such as the eyelids and scrotum, and thicker in the hips and buttocks. There are also sexual differences in the deposition of fat, and an increased thickness of the subcutis results in the rounded contours of the female torso. The fat cells or lipocytes considered as individual cells are large, which, with hematoxylin-eosin stain, appear as empty cells with signet-ring morphology; this is due to the fact that the flat spindle nucleus is displaced by a single, large intracytoplasmic vacuole, which contains fat. The septa that divide the subcutaneous fat into lobules are thin and composed of collagen and reticulin fibers. These septa house the blood and lymphatic vessels as well as the nerves. Arteries and veins of the subcutis run along the septa. Each individual lobule is supplied by an arteriole branching from the septa to form capillaries into the lobule, and a capillary network surrounds each adipocyte. Postcapillary venules meet in veins that also run along the septa. In each microlobule, the arteriole occupies a central position, whereas the venule runs along the periphery. The blood supply of each microlobule is terminal, meaning that there are no capillary connections between adjacent microlobules or between dermis and subcutaneous fat. This peculiar structure of the blood supply in subcutaneous fat explains why large-vessel vasculitis involving the septal vessels is usually accompanied by little inflammation of the fat lobules, whereas when the vasculitis involves small blood vessels, there is extensive necrosis of the adipocytes with centrilobular infarct and dense inflammatory infiltrate within the lobule. The septa of the subcutaneous fat also contain abundant lymphatic vessels that come from the dermis and transverse the subcutis, first, parallel to the surface of the skin and then vertically penetrating the deep fascia and draining into the regional lymph nodes. In panniculitis with large-vessel vasculitis it is mandatory to differentiate whether the involved vessel is artery or vein. A peculiarity of the veins in the subcutaneous fat of the lower limbs is that they often exhibit an “arterial” appearance because they have a thick muscular layer.5 However, with hematoxylineosin staining, the venous nature of these vessels may be determined because the middle layer of the subcutaneous veins is composed of several muscular fascicles separated by tiny unstained elastic fibers, whereas arteries show a more compact muscular layer. In classic pathology, many authors continue to promote the misleading notion that arteries of the

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subcutaneous fat of the lower legs have a thicker muscular layer than veins; however, this is not necessarily true because often veins show thicker muscular layers than arteries. In difficult cases, elastic tissue stain allows definite discrimination between artery and vein. Arteries have a well-formed, thick internal elastic lamina, whereas veins show a less evident internal elastic lamina and have tiny elastic fibers interspersed between muscular fascicles of the middle layer of the vessel wall.

MOSTLY SEPTAL PANNICULITIS WITH VASCULITIS Leukocytoclastic vasculitis Usually, cutaneous leukocytoclastic vasculitis involves the postcapillary venules of the superficial plexus, and consequently, the necrosis of endothelial cells, fibrin deposition, neutrophils, and nuclear dust are seen within the walls of the venules of the papillary dermis. However, in some instances the lesions of cutaneous leukocytoclastic vasculitis appear in the form of subcutaneous erythematous nodules (Fig 1); in other words, they show the clinical appearance of panniculitis. Histopathologic study of these lesions demonstrates thickened septa with features of

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Fig 1. Erythematous nodules on the ankle of a patient with leukocytoclastic vasculitis.

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Fig 2. Histopathologic features of leukocytoclastic vasculitis as a septal panniculitis. A, At scanning magnification inflammation is seen at the septa and periphery of the fat lobule (arrow indicates the area enlarged in B). B, Higher magnification demonstrated necrosis of the small blood vessel walls of the septa. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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leukocytoclastic vasculitis involving the small blood vessels (Fig 2). There is no involvement of the dermal blood vessels. Usually, there is little or no inflammatory infiltrate at the adjacent fat lobule. The mechanism responsible for leukocytoclastic vasculitis involving only the small blood vessels of the subcutaneous septa is uncertain. As in other forms of cutaneous leukocytoclastic vasculitis, treatment of patients with subcutaneous leukocytoclastic vasculitis should be focused on the precipitating event. Withdrawal of the medication or treatment of the infections or any other underlying disease results in resolution of the cutaneous lesions. Relative rest and local measures are required for management of cutaneous ulcers secondary to leukocytoclastic vasculitis. Superficial thrombophlebitis Superficial thrombophlebitis presents with erythematous, tender subcutaneous nodules arranged in a linear fashion, with a cordlike thickening of the subcutis along the involved vein and it is usually located on the lower limbs (Fig 3). Although a hypercoagulable stage, either primary6 or secondary,7 should be investigated, venous insufficien-

Fig 3. Superficial thrombophlebitis. Erythematous nodules in linear arrangement with cordlike thickening of the subcutis along the involved vein.

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A

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Fig 4. Histopathologic features of superficial thrombophlebitis. A, Low-power view shows thrombosis of a large vessel within thickened septa. B, Higher magnification demonstrated that the involved vessel had several muscular fascicles in its wall. C, Elastic tissue stain demonstrated that the involved vessel had tiny elastic fibers between the muscular layers, but internal elastic lamina was lacking, confirming that it was a vein. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×100. C, Orcein stain; original magnification ×100.)

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cy of the lower extremities is usually the only precipitating factor. Characteristically, the location of the nodules changes from one day to another because multiple segments of the vein may be involved. Hence the term migratory is applied to describe this disorder. In classic literature, emphasis was placed on the paraneoplastic character of superficial migratory thrombophlebitis (Trousseau sign),8 and internal malignancy was always suspected, although it could seldom be demonstrated. In some cases thrombophlebitis precedes the diagnosis of malignancy and the most frequent underlying reported malignant neoplasms include carcinomas of the pancreas, stomach, lung, prostate, colon, ovary, and bladder.9-12 Patients with Behçet syndrome may also have superficial migratory thrombophlebitis in the lower extremities as one of the main clinical features; in these patients the thrombophlebitic process may involve not only the subcutaneous veins,13 but also the deeper veins of the brain, liver, or lungs.14,15 Histopathologically, cutaneous lesions of superficial migratory thrombophlebitis involve large veins of the septa in the upper subcutis (Fig 4). The affected vessel appears with luminal thrombosis and with inflammatory infiltrate within its wall. In early lesions the inflammatory cell infiltrate is mostly composed of neutrophils, whereas in later stages there are lymphocytes, histiocytes, and occasional multinucleated giant cells. A striking feature is that, despite the intense damage of the involved vein with dense inflammatory infiltrate in its wall and with marked septal thickening, there is little or no involvement of the adjacent fat lobule, and the process is more vasculitic than panniculitic. The differential diagnosis for superficial migratory thrombophlebitis is cutaneous polyarteritis nodosa. In contrast to superficial thrombophlebitis, cutaneous polyarteritis nodosa is a benign form of polyarteritis nodosa in which the involved vessel is an artery of the subcutaneous septa. The process is more inflammatory than thrombotic, with prominent fibrinoid necrosis of the tunica intima. In doubtful cases elastic tissue stain solves the problem because in cutaneous polyarteritis nodosa the involved artery shows prominent internal elastic lamina, whereas in superficial thrombophlebitis the damaged vessel is a vein with little or no discernible internal elastic membrane. Malignancy should be ruled out in patients with superficial migratory thrombophlebitis. Treatment of cutaneous lesions is otherwise conservative. Exercise is a good prophylactic and in acute episodes use of a stocking or bandage on the involved leg is helpful. Patients with chronic venous insufficiency of the lower limbs should ask for consultation with a vascu-

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lar surgeon. In chronic and recurrent cases, especially those associated with malignancy, heparin and fibrinolytic drugs may be used. Cutaneous polyarteritis nodosa Cutaneous polyarteritis nodosa is a vasculitis involving the arteries and arterioles of the septa of the subcutaneous fat with little or no evidence of systemic disease.16 The cutaneous form of polyarteritis nodosa should be distinguished from the cutaneous involvement in patients with systemic polyarteritis nodosa, which occurs in approximately 10% to 15% of cases and consists of purpuric papules of leukocytoclastic vasculitis involving the upper dermis and sometimes ulceration of the lower extremities.17 Clinically, the lesions of cutaneous polyarteritis nodosa can present as bilateral tender erythematous nodules, livedo reticularis, and ulceration of the lower limbs (Fig 5). Usually there are mild constitutional symptoms, with low-grade fever, arthralgias, myalgias, malaise, and fatigue.18 The absence of systemic involvement is characteristic, and, although the course may be prolonged, the prognosis is good. However, in some series a small portion of patients develop mild renal involvement, serologic evidence of hepatitis B infection,19 cryoglobulinemia,19 or peripheral neuropathy.20 Patients with ulcerated lesions have a more prolonged course and frequently show associated neuropathy.20 In contrast to systemic polyarteritis nodosa, laboratory evidence of immunologic abnormalities (antinuclear antibody, antineutrophil cytoplasm antibody, rheumatoid factor, cryoglobulins, or decreased complement level) is lacking in patients with cutaneous polyarteritis nodosa.20 Histopathologically, lesions of cutaneous polyarteritis nodosa show vasculitis involving mediumsized arteries and arterioles at the septa of the upper subcutis. The involved vessel appears with a thickened wall and in the early stages an inflammatory infiltrate composed predominantly of neutrophils is seen within its wall. Characteristically, the tunica intima of the involved artery exhibits an eosinophilic ring of fibrinoid necrosis, giving a targetlike appearance to the vessel (Fig 6). The composition of the inflammatory infiltrate varies with time, and in later stage lesions there is a greater proportion of mononuclear cells, particularly lymphocytes and histiocytes. Although luminal thrombi may be present, they are less frequent than in lesions of superficial thrombophlebitis. Additional characteristic features of cutaneous polyarteritis nodosa are the segmental involvement of the arteries and the coexistence of lesions at different stages of development in the same patient. In contrast to systemic polyarteritis nodosa, lesions of cutaneous polyarteritis nodosa have no predilection for involvement of the bifurcation of the arteries.

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Fig 5. Cutaneous polyarteritis nodosa. Erythematous nodules and livedo reticularis on the posterior aspect of the leg.

Direct immunofluorescence studies of lesions of cutaneous polyarteritis nodosa have shown IgM and complement deposition in the involved vessel walls.21 As in superficial thrombophlebitis, lesions of cutaneous polyarteritis nodosa show little or no involvement of the adjacent fat lobule, and the process is exclusively a septal arteritis. Evaluation of the response to treatment of patients with cutaneous polyarteritis nodosa is difficult because the course of the disease fluctuates. Mild cases may be managed with nonsteroidal antiinflammatory drugs or low doses of prednisone (20 mg/d).20 In patients with acute flares of cutaneous polyarteritis nodosa associated with documented bacterial infections, a long course of treatment with antibiotics may be helpful.

MOSTLY SEPTAL PANNICULITIS WITHOUT VASCULITIS Necrobiosis lipoidica The palisading granulomatous process of necrobiosis lipoidica may extend from the deep dermis into the upper part of the connective tissue of the subcutaneous septa, resulting in septal panniculitis. The involvement of the subcutis in necrobiosis lipoidica is always a deep extension of the dermal process, and there are no descriptions of necrobiosis lipoidica involving only subcutaneous fat. Clinically, the lesions consist of yellow-brown, indurated plaques with an atrophic and slightly

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depressed center and a well-defined raised erythematous edge that radially enlarges (Fig 7). The legs, particularly the shins, are the most common sites of involvement with symmetric and bilateral distribution, but lesions may also occur in other areas. Classically, necrobiosis lipoidica has been related to diabetes mellitus, but it is not exclusive to persons with diabetes. However, in a series of patients with necrobiosis lipoidica, some nondiabetic patients had a family history of diabetes mellitus or they showed abnormal results when they were studied with standard oral glucose or cortisone glucose tolerance tests. Therefore nondiabetic patients with necrobiosis lipoidica should be considered likely to develop diabetes mellitus.22 Histopathologically lesions of necrobiosis lipoidica involve the full thickness of the dermis and, often, the subcutaneous fat. The subcutaneous involvement of necrobiosis lipoidica consists of palisading granulomas with histiocytes surrounding areas of degenerated collagen within widened septa. Although lesions of necrobiosis lipoidica usually show no vasculitis, rarely, the small blood vessels of the deeper dermis show features of necrotizing thrombotic vasculitis with neutrophilic and lymphocytic infiltrates within the vessel walls.22 The most characteristic feature supporting a diagnosis of necrobiosis lipoidica as the cause of an inflammatory process involving the subcutis is the coexistence of similar lesions in the dermis, with alternating horizontal bands of inflammatory cells and fibrosis involving the full thickness (Fig 8). Early lesions of necrobiosis lipoidica involving the subcutaneous fat present with an inflammatory infiltrate composed predominantly of neutrophils scattered within the septa.23 In later lesions, lymphocytes and plasma cells, sometimes with lymphoid follicle formation, are present in the thickened septa.24 In old atrophic lesions the inflammatory infiltrate decreases, persisting only small granulomas with frequent multinucleated giant cells that replace the septa surrounding areas of fibrotic and degenerated collagen. The dramatic thickening of the septa results in the small size of the fat lobules. Immunofluorescence studies in early lesions of necrobiosis lipoidica demonstrated IgM and complement depositions in the walls of the blood vessel of necrobiotic areas, and in some cases IgM, complement, and fibrin along the dermoepidermal junction.25 Lesions of necrobiosis lipoidica are usually asymptomatic, and, except for ulceration, they are only of cosmetic importance. In persons with diabetes, treatment of diabetes does not prevent the growth of the lesions of necrobiosis lipoidica. Some clearing of lesions of necrobiosis lipoidica has been reported

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A

B

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Fig 6. Histopathologic features of cutaneous polyarteritis nodosa. A, Scanning power shows involvement of large vessel in the septa of subcutaneous fat (arrow indicates area enlarged in B). B, Higher magnification demonstrates fibrinoid necrosis of the tunica intima and neutrophilic infiltrate involving full thickness of vessel wall. C, Elastic tissue stain of involved vessel shows necrosis of the tunica intima and well-developed internal elastic lamina (arrows), confirming that it was an artery. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200. C, Orcein stain; original magnification ×200.)

with locally injected steroids,26 orally administered aspirin and dipyridamole,27 or pentoxifylline.28 Scleroderma Scleroderma may also extend into the septa of subcutaneous fat from the deep dermis, but sometimes the process is entirely a panniculitis with no involvement of the epidermis, cutaneous adnexa, or dermis. Clinically, lesions of subcutaneous morphea appear as indurated plaques or nodules that remain stable or enlarge progressively and often heal with subcutaneous atrophy and residual hyperpigmenta-

tion (Fig 9). They have a predilection for the shoulders, upper arms, and trunk.29-31 The most characteristic histopathologic finding in deep morphea is the presence of a marked fibrous thickening of the septa of subcutaneous fat (Fig 10). As a consequence of thickening, collagen also replaces the fat normally present around the eccrine coils and below them, giving the misimpression that sweat glands have ascended into the dermis. When the sclerotic process involves both dermis and subcutis, the full thickness of the specimen appears homogeneously eosinophilic. The spaces between

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Fig 7. Necrobiosis lipoidica involving the skin of the knee.

collagen bundles disappear, with atrophy of the adnexal structures, blood vessels, and nerves; only the muscle fibers of arrectores pilorum remain. Inflammatory infiltrate is only present in active lesions and it consists of aggregations of lymphocytes surrounded by plasma cells at the junction of the thickened septa and the fat lobules. Plasma cells may also be present arranged interstitially between the sclerotic collagen bundles.32-35

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Eosinophilic fasciitis, also named Shulman’s syndrome, is regarded as a variant of scleroderma by most authors.36-43 Clinically the process is characterized by a sudden onset, sometimes occurring after intense physical activity. The lesions consist of a symmetric induration of the skin and subcutaneous tissues of the limbs. Usually, there is a gradual improvement of the lesions, even without any treatment, and the majority of the affected patients experience complete recovery after some years.39 Histopathologically, lesions of eosinophilic fasciitis are quite similar to those of subcutaneous scleroderma. They show edema and thickening of the interlobular fibrous septa of the subcutaneous fat and the deep fascia. Both the septa and the fascia show inflammatory infiltrate of lymphocytes, histiocytes, plasma cells, and an abundant number of eosinophils.40,41 Occasionally lymphoid follicles are also present within the widened septa. Lesions of eosinophilic fasciitis extend deeply, involving the underlying fascia, but in contrast to scleroderma, which usually shows no inflammatory infiltrate, eosinophilic fasciitis is characterized by a conspicuous infiltration of eosinophils in the fascia.42-44 Cutaneous lesions with clinicopathologic changes similar or identical to those of eosinophilic fasciitis have been described in patients with the Spanish oiltoxic syndrome,45 the eosinophilia-myalgia syndrome induced by L-tryptophan,46 in late-stage lesions of cutaneous graft-versus-host disease,47 in brucellosis,48 and as a paraneoplastic manifestation.49 Treatment of subcutaneous scleroderma is the same as that of scleroderma in general. Although usually there is poor response to the treatment and the lesions progress slowly toward sclerosis and atrophy of the involved areas, there are some reports

B Fig 8. Histopathologic features of necrobiosis lipoidica. A, Scanning power shows alternating horizontal bands of inflammatory infiltrate and fibrosis involving full thickness of the dermis and extending into the subcutaneous fat. Note small collections of lymphocytes at periphery of the fat lobules. B, Higher magnification shows thickened and fibrotic septa with lymphocytes and plasma cells between collagen bundles. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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describing resolution or some clearing of the lesions with locally injected triamcinolone. Penicillamine has been also associated with resolution in some cases, but there is a risk of renal damage.50 Subcutaneous granuloma annulare Subcutaneous granuloma annulare is an uncommon clinicopathologic variant of granuloma annulare that appears more frequently in children and young adults.51,52 The lesions consist of subcutaneous nodules, with no inflammatory appearance at the skin surface, most commonly located on the head, hands, buttocks, and the anterior aspect of the lower legs (Fig 11). Usually, subcutaneous granuloma annulare is an authentic and exclusive panniculitic process with no dermal participation, although in 25% of the cases lesions of subcutaneous granuloma annulare coexist with the classic findings of granuloma annulare in the dermis.53 The histopathologic changes found in subcutaneous or deep granuloma annulare consist of areas of necrobiosis with peripheral palisading granulomas involving the septa of the subcutis (Fig 12). Usually the area of necrobiosis in subcutaneous granuloma annulare is larger than in the dermal counterpart. The central necrobiotic areas contain increased

A

Fig 9. Morphea involving the subcutaneous fat.

amounts of connective tissue mucin and nuclear dust from neutrophils between the degenerated collagen bundles. The peripheral ring is composed of epithelioid histiocytes arranged in a palisaded fashion, and multinucleated giant cells may also be present.54,55 Eosinophils are more common in subcutaneous granuloma annulare than in the superficial counterpart.56 The so-called incomplete or interstitial histopathologic variant of granuloma annulare is

B Fig 10. Histopathologic features of subcutaneous morphea. A, Scanning power shows thickened septa of the subcutaneous fat. B, Higher magnification shows sclerotic collagen bundles at the septa and small collections of lymphocytes and plasma cells at periphery of the fat lobule. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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an unpredictable course; therefore evaluation of the response to treatment is difficult.

Fig 11. Subcutaneous granuloma annulare. Nodules on the anterior aspect of the legs in an adolescent girl.

characterized by interstitially arranged histiocytes between collagen bundles with no areas of necrobiosis. This has yet to be described in subcutaneous granuloma annulare, and all reported patients with deep forms of granuloma annulare showed the palisading necrobiotic pattern.57 As in other variants of granuloma annulare, lesions of subcutaneous granuloma annulare follow

A

Rheumatoid nodule Approximately 20% of patients with rheumatoid arthritis have rheumatoid nodules in the vicinity of the joints. Those patients with rheumatoid arthritis and rheumatoid nodules present with more aggressive forms of the disease. Rheumatoid nodules appear as deeply situated nodules, with a firm consistency on palpation, and no changes of the skin surface. Their size ranges from millimeters to centimeters and the lesions persist for months or years. Rheumatoid nodules have a predilection for the elbows (Fig 13) and fingers.58 A rare variant of multiple rheumatoid nodules involving the fingers with little or no articular disease is named rheumatoid nodulosis.59-61 Lesions identical to rheumatoid nodules have been described in children with rheumatoid fever, although these nodules last only briefly and eventually involute.62 Rheumatoid nodules have also been reported in patients with systemic lupus erythematosus.63 Histopathologically, large areas of necrobiosis surrounded by palisaded granulomas involving the dermis and subcutaneous fat (Fig 14) characterize

B

Fig 12. Histopathologic features of subcutaneous granuloma annulare. A, Scanning power shows nodular infiltrate at junction between the deep dermis and the subcutaneous fat. B, Higher magnification demonstrates that the nodular infiltrate consisted of histiocytes in a palisade around a focus of degeneration of collagen and mucin. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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rheumatoid nodule. The central necrobiotic area appears as an eosinophilic granular or fibrillary material containing fibrin.64 At the periphery of the necrobiotic areas there are elongated histiocytes in a palisaded arrangement. Multinucleated giant cells may also be present. In contrast with subcutaneous granuloma annulare, which usually exhibits a pale and mucinous center with a tendency to be basophilic, the central necrobiotic areas of rheumatoid nodules appear homogeneous and eosinophilic.54 Old rheumatoid nodules show extensive fibrosis in which necrobiotic areas persist. Usually, rheumatoid nodules are asymptomatic and surgical excision is only indicated in ulcerated or painful lesions. Necrobiotic xanthogranuloma Kossard and Winkelmann65 described this rare disorder in 1980; since then approximately 50 cases have been reported in the literature. Necrobiotic xanthogranuloma is characterized by the presence of multiple, large, indurated plaques, with yellow-violaceous coloration (Fig 15) that are sharply demarcated and show a tendency to ulceration. Often, a yellowish hue and telangiectasia are seen in the

A

Fig 13. Rheumatoid nodule involves elbow of patient with rheumatoid arthritis.

B

Fig 14. Histopathologic findings in rheumatoid nodule. A, Scanning power shows large areas of degeneration of collagen involving the deeper dermis and extending into the septa of the subcutaneous fat. B, Higher magnification demonstrates that center of palisaded granuloma contained fibrin. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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Fig 15. Necrobiotic xanthogranuloma involving scalp of patient with multiple myeloma.

patients are seen with necrobiotic xanthogranuloma and no hematologic abnormalities.69 The clinical course of the disorder is chronic and progressive. The distinctive histopathologic changes of necrobiotic xanthogranuloma are seen both in the deeper dermis and in the subcutaneous fat. They consist of large areas of necrobiosis alternating with granulomatous inflammation. Characteristically, histiocytes, many of them with foamy cytoplasm, and multinucleated giant cells, some of them of Touton type, are also present.66 In some cases, numerous cholesterol crystals are seen in the center of degenerated collagen areas (Fig 16). Other less constant changes described in lesions of necrobiotic xanthogranuloma include the presence of lymphoid follicles, sometimes with germinal center formation, aggregations of plasma cells, and eosinophils. Treatment of patients with necrobiotic xanthogranuloma is generally directed to the associated paraproteinemia. Melphalan with or without associated prednisolone has resulted in the temporary clearing of cutaneous lesions.70 In another patients, plasmapheresis reduced the level of circulating monoclonal IgG, resulting in healing of cutaneous ulcers of necrobiotic xanthogranuloma on the lower extremities.71

plaques. There is a predilection toward the periorbital region of the face, although other areas may also be involved. Usually necrobiotic xanthogranuloma appears in patients with paraproteinemia, mostly of IgG κ type, and cases associated with multiple myeloma and other lymphoproliferative disorders have also been recorded.66-68 Less frequently,

Erythema nodosum Erythema nodosum is the most common type of panniculitis and is the paradigm of predominantly septal panniculitis. This process can occur at any age, but most cases appear between the second and fourth decades of life; its incidence peaks between 20 and 30 years of age. Several studies have demonstrated that erythema nodosum occurs 3 to 6 times more frequently in women than in men. The typical

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B Fig 16. Histopathologic features of necrobiotic xanthogranuloma. A, Scanning power demonstrates inflammatory process involving full thickness of the dermis and extending into the subcutaneous fat (arrow indicates area enlarged in B). B, Higher magnification shows degeneration of collagen bundles and numerous cholesterol clefts surrounded by histiocytes and multinucleated giant cells. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

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eruption is quite characteristic and consists of a sudden onset of symmetric, tender, erythematous, warm nodules and raised plaques usually located on the knees, shins (Fig 17), and ankles. Often the lesions are bilaterally distributed. In rare instances, more extensive lesions may appear, involving the neck, extensor aspects of the arms, thighs, and even the face. At first, the nodules are bright red and are slightly raised. Within a few days, they become flat and turn a livid red or purplish hue. 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. These are the two clinical features that distinguish erythema nodosum from erythema induratum of Bazin–nodular vasculitis. Usually acute bouts of erythema nodosum are associated with a fever of 38°C to 39°C, fatigue, malaise, arthralgia, headache, cough, abdominal pain, vomiting, or diarrhea. Episcleral lesions and phlyctenular conjunctivitis may also accompany the cutaneous lesions. The eruption generally lasts from 3 to 6 weeks, but persistence beyond this time is not unusual and recurrences are frequent. Some clinical variants of erythema nodosum have been described under different names. These variants include erythema nodosum migrans,72-75 subacute nodular migratory panniculitis of Vilanova and Piñol,76,77 and chronic erythema nodosum.78 Erythema nodosum migrans was reported by Bafverstedt72 in 1954 as an entity clinically different from classic erythema nodosum, but with identical histopathologic findings. The lesions were unilateral, and they consisted of erythematous plaques that extended peripherally and healed at the center. In 1973 Hannuksela73 described 438 patients with subcutaneous nodules on the lower extremities; of these, 56 had features that were interpreted as erythema nodosum migrans. Similar cases appeared in the literature shortly afterward.74,75 The term subacute nodular migratory panniculitis was coined by Vilanova and Piñol76 in 1956 for a variant of septal panniculitis that they considered to be clinical and histopathologically different from erythema nodosum. This opinion was supported by Perry and Winkelmann77 in 1964. Fine and Meltzer78 favored the name chronic erythema nodosum as the best denomination for lesions previously described as erythema nodosum migrans or subacute nodular migratory panniculitis. However, more recently, some authors75 still believe that erythema nodosum migrans and chronic erythema nodosum are two different clinicopathologic entities. These authors stud-

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ied 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 of 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.75 In our opinion, these histopathologic differences do not separate erythema nodosum migrans from chronic erythema nodosum and are probably expressions of a different stage of evolution of lesions rather than two different entities. Currently, most authors believe that erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum are clinical variants that may all be included within the spectrum of erythema nodosum.3 A review of the literature reveals that the list of etiologic factors that can lead to erythema nodosum is long and varied, including infections, drugs, malignant diseases, and a wide group of miscellaneous conditions (Table II).79-135 Although there are considerable geographic variations related to endemic infections, streptococcal infections are the most frequent etiologic factor for erythema nodosum in children, whereas drugs, sarcoidosis, and inflammatory diseases of the bowel are the most commonly associated disorders in adults. In some countries, erythema nodosum and bilateral hilar adenopathy are frequently seen as early manifestations of sarcoidosis (Löfgren’s syndrome). In adults, erythema nodosum associated with enteropathies often correlates with a flare of the disease. In many patients with Behçet’s disease, lesions develop that clinically resemble those of erythema nodosum. A recent study, however, demonstrated that these lesions are histopathologically characterized by a mostly lobular panniculitis with the frequent finding of leukocytoclastic or lymphocytic vasculitis.136 In other words, patients with Behçet’s disease show a panniculitis different from that of erythema nodosum. Erythema nodosum is considered to be a hypersensitivity response to many inciting factors. The variability of possible antigenic stimuli that can induce erythema nodosum

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Fig 17. Erythema nodosum involving anterior aspect of the legs of a young woman.

A

indicates that this disorder is a cutaneous reactive process and that the skin has limited responses to different provoking agents. 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. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions, edema, hemorrhage, and neutrophils (Fig 18) 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 so-called Miescher’s radial granulomas,137-139 which consist of small, well-defined nodular aggregations of small histiocytes around a central stellate or banana-shaped cleft (Fig 19). The nature of the central cleft is unknown, and our immunohistochemical and ultrastructural studies of cases of Miescher’s radial granulomas have failed to demonstrate endothelial or other cellular lining of these

B Fig 18. Histopathologic features in early erythema nodosum. A, Scanning power shows thickened septa with inflammatory infiltrate. B, Higher magnification demonstrates that the inflammatory infiltrate of the septa was mostly composed of neutrophils. (A and B, Hematoxylineosin stain; original magnifications: A, ×20; B, ×400.)

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A

B Fig 19. Histopathologic features in fully developed lesions of erythema nodosum. A, Scanning power shows sparse inflammatory infiltrate involving mostly the septa of the subcutaneous fat (arrow indicates area enlarged in B). B, Higher magnification demonstrates presence of Miescher’s radial granulomas at the septa. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×200.)

clefts. 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 keep in their cytoplasm a stellate central cleft reminiscent of those centers of Miescher’s radial granuloma. 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 sought to make a specific diagnosis.139 Although 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’s syndrome, erythema induratum of Bazin, Behçet’s disease, and necrobiosis lipoidica.3 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.140 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.

With time, the lesions resolve without atrophy or scarring of the involved septa. 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 indomethacin141 or naproxen,142 may be helpful to enhance analgesia and resolution. 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 3 times per day, has been reported to be useful.143-145 The mechanism of action of potassium iodide in erythema nodosum is unknown, but it appears to cause heparin release from mast cells and 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.146 On the other hand, potassium iodide also inhibits neutrophil chemotaxis.147 Potassium iodide is contraindicated during pregnancy because it can produce a goiter in the fetus. 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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Table II. Etiologic factors in erythema nodosum Infections Bacterial infections Streptococcal infections79 Tuberculosis80 Yersinia infections81 Salmonella infections82 Campylobacter infections83 Brucellosis84 Tularemia85 Atypical mycobacterial infections86 Chancroid86 Meningococcemia86 Corynebacterium diphtheriae infections86 Cat-scratch disease87 Propionibacterium acnes88 Shigella infections89 Gonorrhea90 Syphilis91 Leptospirosis92 Q fever93 Lymphogranuloma venereum94 Chlamydia psittaci infections95 Mycoplasma pneumoniae infections96 Viral infections Infectious mononucleosis97 Hepatitis B98 Milker’s nodules99 Orf100 Herpes simplex86 Measles100 Cytomegalovirus infections101 Fungal infections Dermatophytes102 Blastomycosis103 Histoplasmosis104 Coccidioidomycosis105 Sporotrichosis86 Aspergillosis106 Protozoal infections Toxoplasmosis107 Ancylostomiasis86 Amebiasis108 Giardiasis108 Ascariasis109

Many colleagues contributed clinical photographs, histopathologic slides, or other material for this review. We are grateful to the following clinicians and pathologists: A. Bernard Ackerman, MD (United States); Adolfo Aliaga, MD (Spain); J. Andrew Carlson, MD (United States); Carlos Díaz, MD (Germany); Heinz Kutzner, MD (Germany); Arno Rutten, MD (Germany); Omar Sangueza, MD (United States); and H. Peter Soyer, MD (Austria). Catherine Sangueza read and corrected the manuscript. REFERENCES 1. Tok J, Abrahams I, Ravits MA, Silvers DN. Surgical pearl: the trephine punch for diagnosing panniculitis. J Am Acad Dermatol 1996;35:980-1.

Drugs Sulfonamides110 Bromides111 Iodides111 Oral contraceptives112 Minocycline113 Gold salts114 Penicillin115 Salicylates115 Chlorothiazides100 Phenytoin100 Aminopyrine86 Arsphenamine86 Hepatitis B vaccine115 Nitrofurantoin86 Pyritinol90 D-Penicillamine116 Thalidomide117 Isotretinoin118 Interleukin 2119 Malignant diseases Hodgkin’s disease120 Non-Hodgkin’s lymphoma121 Leukemia122 Sarcoma90 Renal carcinoma119 Postradiotherapy for pelvic carcinoma123 Miscellaneous conditions Sarcoidosis124 Ulcerative colitis125 Colon diverticulosis90 Crohn’s disease126 Behçet’s syndrome127 Reiter’s syndrome128 Sweet’s syndrome129 Pregnancy130 Takayasu’s arteritis131 IgA nephropathy132 Chronic active hepatitis133 Granulomatous mastitis134 Vogt-Koyanagi disease135 Sjögren’s syndrome135

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nosis and immunohistochemical findings. Ann Rheum Dis 1993;52:625-6. Ginsberg MH, Genant HK, Yu TF, McCarthy DJ. Rheumatoid nodulosis: an unusual variant of rheumatoid disease. Arthritis Rheum 1975;18:49-58. Couret M, Combe B, Van Thoai CH, Leroux JL, Blatman F, Sany J. Rheumatoid nodulosis: report of two cases and discussion of diagnostic criteria. J Rheumatol 1988;15:1427-30. Lagier R, Gerster JC. Palmar rheumatoid nodulosis of the fingers. Clin Rheumatol 1995;14:592-3. Benneth GA, Zeller JW, Bauer W. Subcutaneous nodules of rheumatoid arthritis and rheumatoid fever. Arch Pathol 1940;30:70-89. Schofield JK, Cerio R, Grice K. Systemic lupus erythematosus presenting with rheumatoid nodules. Clin Exp Dermatol 1992;17:53-5. Aherne MJ, Bacon PA, Blake DR, Gallagher PJ, Jobes DB, Morris CJ, et al. Immunohistochemical findings in rheumatoid nodules. Virchows Arch A Pathol Anat Histopathol 1985;407:191-202. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma. Australas J Dermatol 1980;21:85-8. Finan MC,Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol 1987;14: 92-9. Mehregan DA, Winkelmann RK. Necrobiotic xanthogranuloma. Arch Dermatol 1992;128:94-100. Hafner O, Witte T, Schmidt RE, Vakilzadeh F. Nekrobiotisches xantogranulom bei IgG-kappa-plasmozytom und Quincke odem. Hautarzt 1994;45:339-43. Dupré A, Viraben DA. Necrobiotic xanthogranuloma: a case without paraproteinemia but with transepithelial elimination. J Cutan Pathol 1988;15:116-9. Macfarlane AW, Verbov JL. Necrobiotic xanthogranuloma with paraproteinaemia. Br J Dermatol 1985;113:339-43. Finelli LG, Ratz JL. Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma. J Am Acad Dermatol 1987;17: 351-4. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1954;34:181-93. Hannuksela M. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1973;3(suppl 7):1-64. Rostas A, Lowe S, Smout MS. Erythema nodosum migrans in a young man. Arch Dermatol 1980;116:325-30. De Almeida Prestes C, Winkelmann RK, Su WPD. Septal granulomatous panniculitis: comparison of the pathology of erythema nodosum migrans (migratory panniculitis) and chronic erythema nodosum. J Am Acad Dermatol 1990;22: 477-83. Vilanova X, Piñol Aguade J. Hypodermyte nodulaire subaigue migratice. Ann Dermatol Syphiligr 1956;83:369-404. Perry HO, Winkelmann RK. Subacute nodular migratory panniculitis. Arch Dermatol 1964;89:170-9. Fine RM, Meltzer HD. Chronic erythema nodosum. Arch Dermatol 1969:100:33-8. Favour CB, Sosman MC. Erythema nodosum. Arch Intern Med 1947;80:435-53. Simila S, Pietilla J. The changing etiology of erythema nodosum in children. Acta Tuberc Scand 1965;46:159-68. Debois J, Vandepitte J, Degreef H. Yersinia enterocolitica as a cause of erythema nodosum. Dermatologica 1978;156:65-78. Scott BB. Salmonella gastroenteritis: another cause of erythema nodosum. Br J Dermatol 1980;102:339-40. Ellis ME, Pope J, Mokashi A, Dunbar E. Campylobacter colitis associated with erythema nodosum. Br Med J 1982;285:937. Perez Arellano JL, Martinez Martinez LM, Fernandez Lopez E, Luna Rodrigo G. Eritema nudoso y brucelosis. Med Clin (Barc) 1988;90:81.

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85. Kleibl K. Erythema nodosum rapricinene yersinia pseudotuberculosis. Cesk Dermatol 1971;46:74-6. 86. White JM Jr. Erythema nodosum. Dermatol Clin 1985;3:119-27. 87. Sundaresh KV, Madjar DD, Camisa C, Carvallo E. Cat-scratch disease associated with erythema nodosum. Cutis 1986;38:317-9. 88. Williamson DM, Cunliffe WJ, Gatecliff M, Scott DG. Acute ulcerative acne (acne fulminans) with erythema nodosum. Clin Exp Dermatol 1977;2:351-4. 89. Tami LF. Erythema nodosum associated with Shigella colitis. Arch Dermatol 1985;121:590. 90. Hannuksela M. Erythema nodosum. Clin Dermatol 1986;4: 88-95. 91. Alinovi A, Lui P, Benoldi D. Syphilis: still a cause of erythema nodosum. Int J Dermatol 1983;22:310-1. 92. Derham RJL, Owens GG, Wooldridge MAW. Leptospirosis as a cause of erythema nodosum. Br Med J 1976;2:403-4. 93. Conget L, Mallolas J, Mensa J, Rovira M. Erythema nodosum and Q fever. Arch Dermatol 1987;123:867. 94. Kousa M, Saikku P, Kanerva L. Erythema nodosum in chlamydial infections. Acta Derm Venereol (Stockh) 1980;60:319-22. 95. Palmer JR. Psittacosis in man: recent developments in the UK: a review. Proc R Soc Med 1982;75:262-7. 96. Teyssandier R, Guidet B, Pinta B, Offenstadt G. Pneumopathie á mycoplasma pneumoniae avec anémie grave et érythème noueux. Presse Med 1985;14:1613. 97. Bodansky HI. Erythema nodosum and infectious mononucleosis. Br Med J 1979;2:1263. 98. Maggiore G, Grifeo S, Marzani MD. Erythema nodosum and hepatitis B virus (HBV) infection. J Am Acad Dermatol 1983;9: 602-3. 99. Kuokkanan K, Launis J, Mortinnen A. Erythema nodosum and erythema multiforme associated with milker’s nodules. Acta Derm Venereol (Stockh) 1976;56:69-72. 100. Anderson PC. Erythema nodosum. In: Demis JE, editor. Clinical dermatology. Vol 2. Philadelphia: Lippincott; 1990. p. 7-13. 101. Spear JB, Kessler HA, Dworin A, Semel J. Erythema nodosum associated with acute cytomegalovirus mononucleosis in an adult. Arch Intern Med 1988;148:323-4. 102. Martínez Roig A, Llorens Teral J, Torres JM. Erythema nodosum and kerion on the scalp. Am J Dis Child 1982;13:440-2. 103. Miller DD, Davies SF, Sarosi GA. Erythema nodosum and blastomycosis. Arch Intern Med 1982;142:1839. 104. Ozols II,Wheat LJ. Erythema nodosum in an epidemic of histoplasmosis in Indianapolis. Arch Dermatol 1981;117:709-12. 105. Dickson EC. Erythema nodosum. JAMA 1937;109:36. 106. Miranda M, Fonseca E, Maza P. Eritema nodoso: estudio de 133 casos. An Med Intern 1985;2:433-8. 107. Longmore HJA. Toxoplasmosis and erythema nodosum. Br J Med 1977;1:490. 108. Harries AD, Taylor J. Erythema nodosum associated with invasive amoebiasis and giardiasis. Br J Dermatol 1986;114:394. 109. De Paz Arranz S, Pérez Pimiento A, Santaolalla Montoya M, Trampal Gonzalez A, Rodriguez Mosquera M. Eritema nudoso asociado a infección por Ascaris lumbricoides. Actas Dermosifiliogr 1999;90:384-5. 110. Beurey J, Jeandidier P, Bermont A. Les complications dermatologiques des traitments antidiabetiques. Ann Dermatol Syphiligr 1966;93:13-42. 111. Eng AM, Aronson IK. Dermatopathology of panniculitis. Semin Dermatol 1984;3:1-13. 112. Salvatore MA, Lynch PJ. Erythema nodosum, estrogens, and pregnancy. Arch Dermatol 1980;116:557-8. 113. Bridges AJ, Graziano FM, Calhoun W, Reizner GT. Hyperpigmentation, neutrophilic alveolitis, and erythema nodosum resulting from minocycline. J Am Acad Dermatol 1990;22:959-62. 114. Stone RL, Claflin A, Penneys NS. Erythema nodosum following

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115. 116.

117.

118.

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121.

122. 123.

124. 125. 126. 127.

128. 129.

130.

131.

gold sodium thiomalate therapy. Arch Dermatol 1973;107: 602-4. Di Giusto CA, Bernhard JD. Erythema nodosum provoked by hepatitis B vaccine. Lancet 1986;2:1042. Grauer JL, Fonteille J, Zaski JP, Gintz B, Phelip X, Cabanel G. Erythéme noueux et hépatite cholestatique au cors d’un traitment par D pénicillamine. Presse Med 1983;12:1997. Viraben R, Dupre A. Erythema nodosum following thalidomide therapy for Behçet disease. Dermatologica 1988;176: 107. Kellett JK, Beck MH, Chalmers RJE. Erythema nodosum and circulating immunocomplexes in acne fulminans after treatment with isotretinoin. Br Med J 1985;290:820. Weinstein A, Bujak D, Mittelman A, Davidian M. Erythema nodosum in a patient with renal cell carcinoma treated with interleukin 2 and lymphokine-activated killer cells. JAMA 1987;258:3120-1. Reynolds NJ, Kennedy CTC. Erythema nodosum and cutaneous vasculitis associated with recurrence of Hodgkin’s disease. Br J Dermatol (Suppl) 1990;123:101-2. Parodi A, Costari R, Rebora A. Erythema nodosum as the presenting symptom of gastric centro-follicular lymphoma. Int J Dermatol 1989;28:336-7. Sumaya CV, Babu S, Reed RJ. Erythema nodosum-like lesions of leukemia. Arch Dermatol 1974;110:415-8. Ryan TJ. Cutaneous vasculitis. In: Champion RH, Burton JL, Ebling FJG, editors. Textbook of dermatology. 5th ed. Oxford: Blackwell Scientific Publications; 1992. p. 1893-961. James DG, Neville E, Diltzbach LE. A worldwide review of sarcoidosis. Ann N Y Acad Sci 1976;278:321-34. Sams WM, Winkelmann RK. The association of erythema nodosum with ulcerative colitis. South Med J 1968;61:676-9. McCallum DI, Kinmont PDC. Dermatological manifestations of Crohn’s disease. Br J Dermatol 1968;80:1-8. Behçet R. Immunological studies on aphthous ulcer and erythema nodosum-like eruptions in Behçet disease. Br J Dermatol 1985,113:303-12. McMillan A. Reiter’s disease in a female, presenting as erythema nodosum. Br J Vener Dis 1975;51:345-7. Blaustein A, Moreno A, Noguera J, de Moragas JM. Septal granulomatous panniculitis in Sweet’s syndrome. Arch Dermatol 1985;121:785-8. Bombardieri S, Dimunno O, Dipunzio C, Pasero G. Erythema nodosum associated with pregnancy and oral contraceptives. Br Med J 1977;1:1509-10. Acha Arrieta V, Fuertes Perez J, Gonzalez de Zarate P, Aguirre Errasti C. Eritema nudoso y arteritis de células gigantes. Med Clin (Barc) 1987;88:171-2.

132. Dux S, Grosskopf I, Rosenfeld JB. Recurrent erythema nodosum arthritis and IgA nephropathy. Dermatologica 1988; 176:293-5. 133. Cervia M, Parodi A, Rebora A. Chronic active hepatitis and erythema nodosum. Arch Dermatol 1982;118:878. 134. Adams DH, Hubscher SG, Scott DGI. Granulomatous mastitis: a rare cause of erythema nodosum. Postgrad Med J 1987;63: 581-2. 135. Gouet D, Anquez M, Risse JF, Becq-Giraudon B. Association d’une maladie de Vogt-Koyanagi d’un syndrome de Gougerot-Sjögren et d’un érythéme noueux. Presse Med 1984;13:624. 136. Kim B, LeBoit PE. Histopathologic features of erythema nodosum-like lesions in Behçet disease: a comparison with erythema nodosum focusing on the role of vasculitis. Am J Dermatopathol 2000;22:379-90. 137. Miescher G. Zur Histologie des Erythema nodosum. Acta Derm Venereol (Stockh) 1947;27:447-68. 138. Miescher G. Zur Frage der Radiärknötchen beim Erythema nodosum. Arch Dermatol Syphil 1951;193:251-6. 139. Sanchez Yus E, Sanz Vico MD, de Diego V. Miescher’s radial granuloma: a characteristic marker of erythema nodosum. Am J Dermatopathol 1989;11:434-42. 140. White WL, Hitchcock MG. Diagnosis: erythema nodosum or not? Semin Cutan Med Surg 1999;18:47-55. 141. Ubogy Z, Persellin RM. Suppression of erythema nodosum by indomethacin. Acta Derm Venereol (Stockh) 1982;62:265-7. 142. Lehman CW. Control of erythema nodosum with naproxen. Cutis 1980;96:383-5. 143. Schulz EJ, Whiting DA. Treatment of erythema nodosum and nodular vasculitis with potassium iodide. Br J Dermatol 1976; 94:75-8. 144. Miyachi Y, Niwa Y. Effects of potassium iodide, colchicine and dapsone on the generation of the polymorphonuclear leukocyte-derived oxygen intermediates. Br J Dermatol 1982;107: 209-14. 145. Hori T, Imamura S, Danno K, Ofuji S. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol 1981;117:29-31. 146. Bondi EE, Lazarus GS. Panniculitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. 3rd ed. New York: McGraw-Hill; 1987. p. 1131-51. 147. Honma K, Saga K, Onodera H, Takahashi M. Potassium iodide inhibits neutrophil chemotaxis. Acta Derm Venereol (Stockh) 1990;70:247-9.

Answers to CME examination Identification No. 801-108

August 2001 issue of the Journal of the American Academy of Dermatology

Questions 1-30, Requena L, Sánchez Yus E. J Am Acad Dermatol 2001;45:163-83. 1. 2. 3. 4. 5. 6.

a e b c c c

7. 8. 9. 10. 11. 12.

a b e d d d

13. 14. 15. 16. 17. 18.

e c a b a d

19. 20. 21. 22. 23. 24.

d e d b a e

25. 26. 27. 28. 29. 30.

d c e e e a

Answer sheets are bound into the Journal for US, Canadian, and life members. Request additional answer sheets from American Academy of Dermatology, Member Services Department, PO Box 4014, Schaumburg, IL 60168-4014. Phone 847-330-0230; E-mail: [email protected]

CME examination Identification No. 801-108

Instructions for Category I CME credit appear in the front advertising section. See last page of Contents for page number.

Questions 1-30, Requena L, Sánchez Yus E. J Am Acad Dermatol 2001;45:163-83.

Directions for questions 1-30: Give single best response. 1. The blood vessels most commonly involved by cutaneous leukocytoclastic vasculitis are the a. postcapillary venules of the superficial dermis b. venules of deep reticular dermis c. veins of the septa of the subcutaneous fat d. arteries of the septa of the subcutaneous fat e. none of the above 2. Each of the following diseases has been associated with superficial thrombophlebitis except a. venous insufficiency of the lower extremities b. carcinoma of the stomach c. Behçet’s syndrome d. carcinoma of the pancreas e. Reiter’s syndrome 3. Superficial thrombophlebitis of the lower extremities associated with thrombophlebitis of the veins of brain, liver, and lung has been described in patients with a. Reiter’s syndrome b. Behçet’s syndrome c. Sweet’s syndrome d. Crohn’s disease e. Sjögren’s syndrome 4. Cutaneous lesions of superficial migratory thrombophlebitis are histopathologically characterized by luminal thrombosis involving a. venules of the superficial dermis b. arterioles of the reticular dermis c. veins of the septa of subcutaneous fat d. arteries of the septa of subcutaneous fat e. none of the above 5. Clinical manifestations of cutaneous polyarteritis nodosa include each of the following except a. cryoglobulinemia b. peripheral neuropathy c. lung involvement d. arthralgias e. fever 16/2/116908

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6. Neuropathy is more frequently seen in patients with cutaneous polyarteritis nodosa and a. chronic course b. involvement of the upper extremities c. ulcerated lesions d. serologic evidence of hepatitis B infection e. none of the above 7. Lesions of cutaneous polyarteritis nodosa are histopathologically characterized by vasculitis involving the a. arteries of the septa of subcutaneous fat b. arteries of the lobules of subcutaneous fat c. veins of the septa of subcutaneous fat d. arterioles of the superficial dermis e. none of the above 8. Involvement of the subcutaneous fat in lesions of necrobiosis lipoidica a. is always present b. results from a deep extension of the dermal process c. may be seen without dermal involvement d. is only seen in diabetic patients e. none of the above 9. Some clearing of the cutaneous lesions of necrobiosis lipoidica has been described after treatment with each of the following drugs except a. intralesional corticosteroids b. aspirin c. dipyridamole d. pentoxifylline e. dapsone 10. The most frequently involved cutaneous areas in deep morphea are a. face and neck b. hands and feet c. buttocks and lower back d. shoulders, upper arms, and trunk e. scalp and forehead 11. Each of the following histopathologic features has been described in scleroderma involving the subcutaneous fat except a. thickening of the septa of the subcutaneous fat

J AM ACAD DERMATOL VOLUME 45, NUMBER 2

b. aggregations of lymphocytes surrounded by plasma cells at the junction of the septa and the fat lobules c. plasma cells between collagen bundles of the septa of the subcutaneous fat d. mucin between collagen bundles of the septa of the subcutaneous fat e. collagen replacing fat normally present around and below eccrine sweat coils 12. Each of the following statements is true for eosinophilic fasciitis except a. sudden onset b. occasionally, the process appears after intense physical activity c. there is gradual improvement of the lesions d. the lesions consist of asymmetric induration of the skin of the limbs e. histopathologically, the lesions show sclerotic septa of the subcutaneous fat with an abundance of eosinophils 13. Each of the following disorders may show lesions similar to those of eosinophilic fasciitis except a. Spanish oil-toxic syndrome b. eosinophilia-myalgia syndrome induced by L-tryptophan c. late-stage lesions of cutaneous graft-versus-host disease d. brucellosis e. sarcoidosis 14. Each of the following statements is true for subcutaneous granuloma annulare except a. it is more frequent in children and young adults b. the lower legs, hands, head, and buttocks are the most frequent locations of the lesions c. subcutaneous granuloma annulare does not coexist with dermal granuloma annulare d. the histopathologic pattern is a palisaded necrobiotic granuloma e. the interstitial pattern has not been described in subcutaneous granuloma annulare 15. From a histopathologic point of view, lesions of subcutaneous granuloma annulare a. show larger areas of necrobiosis than in the dermal granuloma annulare b. increased amounts of fibrin are seen in the center of necrobiotic areas c. features of vasculitis are usually seen d. eosinophilis are less frequently seen than in dermal granuloma annulare e. none of the above 16. Each of the following statements is true for rheumatoid nodule except a. approximately 20% of patients with rheumatoid arthritis have rheumatoid nodules b. rheumatoid nodulosis is associated with severe articular disease c. rheumatoid nodules have predilection by fingers and elbows

CME examination 185

d. patients with rheumatoid arthritis and rheumatoid nodules present more aggressive forms of the disease e. rheumatoid nodules have been described in patients with systemic lupus erythematosus 17. From a histopathologic point of view, lesions of rheumatoid nodule consist of palisaded necrobiotic granuloma with a. abundant fibrin in the center b. abundant mucin in the center c. cholesterol crystals in the center d. multinucleated giant cells in the center e. none of the above 18. The most frequently involved cutaneous areas in necrobiotic xanthogranuloma are a. palms and soles b. lower limbs c. upper limbs d. periorbital areas of the face e. elbows and knees 19. Each of the following statements is true in patients with necrobiotic xanthogranuloma except a. association with paraproteinemia b. association with multiple myeloma c. cases of necrobiotic xanthogranuloma have been described with no hematologic abnormalities d. cholesterol crystals are seen within the lumina of blood vessels e. treatment with melphalan resulted in temporary clearing of the cutaneous lesions 20. Erythema nodosum a. occurs more frequently in men than in women b. has a peak incidence between 20 and 30 years c. shins, ankles, and knees are the most frequently involved areas d. the onset of cutaneous lesions is usually associated with fever, malaise, and arthralgia e. b, c, and d are correct 21. Although Miescher’s radial granuloma is the most characteristic histopathologic feature of lesions of erythema nodosum, it has also been described in lesions of the following types of panniculitis except a. Sweet’s syndrome b. erythema induratum of Bazin c. Behçet’s syndrome d. subcutaneous granuloma annulare e. necrobiosis lipoidica 22. Acute bouts of erythema nodosum are usually associated with each of the following manifestations except a. fever b. choluria c. diarrhea d. episcleral lesions e. arthralgia 23. Each of the following statements is true in so-called erythema nodosum migrans except a. lesions are bilateral

186 CME examination

b. lesions consist of erythematous plaques that extend peripherally c. lesions heal at the center d. the most frequently involved sites are the lower limbs e. none of the above 24. Each of the following drugs has been related with the onset of erythema nodosum except a. penicillin b. oral contraceptives c. minocycline d. isotretinoin e. dapsone 25. Each of the following infections has been associated with erythema nodosum except a. tuberculosis b. hepatitis B c. leptospirosis d. parvovirus infections e. cytomegalovirus infections 26. Each of the following malignant neoplasms has been associated with erythema nodosum except a. Hodgkin’s lymphoma b. non-Hodgkin’s lymphoma c. choriocarcinoma of the testis d. leukemia e. renal carcinoma 27. Each of the following diseases has been associated with erythema nodosum except a. sarcoidosis b. ulcerative colitis

J AM ACAD DERMATOL AUGUST 2001

c. Crohn’s disease d. Behçet’s disease e. pustular psoriasis 28. From a histopathologic point of view, each of the following statements is true in erythema nodosum except a. it is a mostly septal panniculitis b. Miescher’s radial granulomas are usually seen c. septa of subcutaneous fat are thickened d. neutrophils are the predominant inflammatory cells in early lesions e. vasculitis in small blood vessels of the septa is a frequent finding 29. Each of the following statements is true in erythema nodosum except a. in early lesions, the septal thickening results from edema and hemorrhage b. in late lesions, the septal thickening results from fibrosis and periseptal formation of granulation tissue c. Miescher’s radial granulomas are usually seen d. vasculitis is a rare finding e. lesions resolve with atrophy and scarring 30. Each of the following drugs has been demonstrated to be effective therapy for erythema nodosum except a. dapsone b. indomethacin c. naproxen d. aspirin e. potassium iodide

AMERICAN BOARD OF DERMATOLOGY EXAMINATION DATES In 2001, the Certifying Examination of the American Board of Dermatology (ABD) will be held at the Holiday Inn O’Hare International in Rosemont, Illinois on Oct 14 and 15, 2001. The next examination for subspecialty certification in Dermatopathology will be held in Tampa, Florida on Friday, Nov 16, 2001. The next examination for subspecialty certification in Clinical and Laboratory Dermatological Immunology will be held in Rosemont, Illinois, on Oct 12, 2001. The next Recertification Examination of the ABD will be mailed to approved candidates on June 1, 2001. A certification process is being developed for the subspecialty of Pediatric Dermatology. It is anticipated that the first examination will be administered in 2002 or 2003. Further details about the examination will be available from the Board office. For further information about these examinations, please contact: Antoinette F. Hood, MD Executive Director, American Board of Dermatology Henry Ford Hospital 1 Ford Place Detroit, MI 48202-3450 Telephone: (313)874-1088 Fax: (313)872-3221