Panniculitis. Part I. Mostly septal panniculitis.

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.     

Normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides

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 erythematous nodules on the lower extremities. However, the histopathologic study of panniculitis is difficult because of an inadequate clinicopathologic correlation and the changing evolutive nature of the lesions. In addition, large scalpel incisional biopsies are required. From histopathologic point of view, all panniculitides are somewhat mixed because the inflammatory infiltrate involves both the septa and lobules. However, nearly always the differential diagnosis between a mostly septal and a mostly lobular panniculitis is straightforward at scanning magnification on the basis of the structures more intensely involved by the inflammatory infiltrate. Mostly septal panniculitides with vasculitis are actually more vasculitis than panniculitis and include superficial thrombophlebitis and cutaneous polyarteritis nodosa. Mostly septal panniculitides with no vasculitis include erythema nodosum, necrobiosis lipoidica, deep morphea, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. Mostly lobular panniculitis with vasculitis is only represented by erythema induratum of Bazin. In contrast, mostly lobular panniculitides without vasculitis comprise a large series of disparate disorders, including sclerosing panniculitis, calciphylaxis, sclerema neonatorum, subcutaneous fat necrosis of the newborn, poststeroid panniculitis, lupus erythematosus profundus, pancreatic panniculitis, alpha(1)-antitrypsin deficiency panniculitis, subcutaneous Sweet syndrome, infective panniculitis, factitial panniculitis, lipodystrophy, traumatic panniculitis, subcutaneous sarcoidosis, and sclerosing postirradiation panniculitis. Finally, some cutaneous lymphomas may simulate panniculitis, both from clinical and histopathologic points of view and, for that reason, they will be included in this review, although they are not inflammatory processes, but authentic lymphocytic neoplasms involving subcutaneous tissue.     

Nodular vasculitis - a novel cutaneous manifestation of autoimmune colitis

Panniculitis in association with autoimmune colitis (AC) is mostly confined to reports of erythema nodosum (EN) and Crohn's disease. We expand the repertoire of panniculitides associated with autoimmune bowel disease through a unique case report of nodular vasculitis (NV) that developed in parallel fashion to flares of ulcerative colitis (UC). A 51-year-old woman with a clinical history of surgically treated UC developed lesions on the lower legs that were initially diagnosed and treated as EN. Two years later, during a clinical exacerbation of UC, she developed similar lesions that on biopsy examination showed features consistent with NV. While treatment with antibiotics resulted in amelioration of both bowel symptoms and leg lesions, cessation of the same resulted in recurrence of both. This report implies an association between NV and UC.     

Histopathologic spectrum of erythema nodosum

Erythema nodosum (EN) is the most common panniculitis and histologically represents the prototype of a septal panniculitis. However, the histologic findings can be quite variable. We describe four patients with EN who each underwent two consecutive biopsies. In each case, the first biopsy showed histopathologic features that fall outside the usual spectrum of disease. Two cases showed predominantly neutrophilic infiltrates with focal suppuration as well as vasculitis of medium-sized arteries. The areas of suppuration were more extensive in the first case prompting special stains for microorganisms that were all negative. The third case demonstrated a lobular panniculitis with a predominantly lymphohistiocytic infiltrate. Special stains were negative in this case as well. The fourth case revealed vasculitis of a medium sized artery, small vessel vasculitis, and a mixed septal and lobular panniculitis with a polyclonal population of atypical lymphocytes. In all patients, the clinical course and the subsequent biopsy were classic for EN. We conclude that lobular neutrophilic panniculitis with suppuration, small vessel vasculitis, and even medium vessel arteritis may rarely occur in EN. There are few clues in these unusual cases that allow for a specific diagnosis from the start, and often, a second biopsy is required.     

Erythema induratum (nodular vasculitis) associated with Crohn's disease: a rare type of metastatic Crohn's disease

We herein report a patient with erythema induratum/nodular vasculitis (EI/NV) associated with Crohn's disease (CD), which is considered to be a rare type of metastatic CD. A 54-year-old woman, who had a history of CD, presented with erythematous nodules on her legs. The histopathological features of the skin biopsy revealed a granulomatous, mixed septal and lobular panniculitis, which was characterized by many discrete epithelioid cell granulomas (necrobiotic/necrotizing-type and sarcoidal type), necrosis of the adipocytes, and granulomatous phlebitis in the muscular wall of a subcutaneous vein. A review of the pertinent literature and the presented case suggested the following: (1) panniculitis associated with CD may be either an erythema nodosum type or an EI/NV type; (2) so far, the reported cases of metastatic CD or granulomatous vasculitis in CD rarely presented with granulomatous panniculitis without dermal involvement, and most cases showed histopathological features that were similar to or indistinguishable from those of EI/NV; and (3) the finding of granulomatous vasculitis (especially the presence of discrete epithelioid cell granulomas involving the veins or venules) may be a characteristic feature of EI/NV associated with CD, in contrast to the finding of acute vasculitis, which is typically present in patients with EI/NV due to causative factors other than CD.     

Subcutaneous pseudomembranous fat necrosis: new observations

BACKGROUND: Pseudomembranous fat necrosis is a peculiar manifestation of necrosis of adipose tissue characterized by formation of pseudocystic cavities lined by crenulated membranes. The underlying mechanism for the formation of pseudomembranes is unknown and numerous hypotheses have been proposed. Despite divergent interpretations, most authors consider necrotic fat cells to be the anatomic substrate for the formation of pseudomembranes. METHODS: A total of 341 panniculitides were reviewed for the presence of pseudomembranous fat necrosis. The specific diagnoses were established after correlation of all available clinical and laboratory data with the histopathology. Special attention was given to the time in the evolution of the disease when the biopsy was taken. Additional immunohistochemical studies were performed in 12 cases. RESULTS: Thirty of 341 cases of different types of panniculitides were found to show pseudomembranous fat necrosis, namely: 10 of 15 cases of sclerosing panniculitis (lipodermatosclerosis), 6 of 95 cases of erythema nodosum, 7 of 34 cases of traumatic panniculitis, 1 of 7 cases of lupus panniculitis, 1 of 20 cases of erythema induratum Bazin (nodular vasculitis), 1 of 9 cases of necrobiosis lipoidica, 1 of 4 cases of sclerotic lipogranuloma, 1 of 9 cases of infectious panniculitis (erysipelas), 1 of 2 cases of pancreatic panniculitis, and 1 of 4 cases of subcutaneous sarcoidosis. Pseudomembranous fat necrosis labelled strongly for the histiocytic markers CD68 and lysozyme. CONCLUSIONS: Our series provides data suggesting that pseudomembranous fat necrosis represents a dynamic process that varies according to the evolution of the lesion at the time of the biopsy. In biopsies taken from early foci of panniculitides pseudomembranes show vescicular or picnotic nuclei. Later, pseudomembranes retain their crenulated appearance but lack nuclear elements. Furthermore, we present histopathologic, histochemical, and immunohistochemical evidence that pseudomembranous fat necrosis results from the interaction of residual products of disintegrated fat cells and macrophages. Histiocytic markers such as CD68 and lysozyme may be used as reliable tools in order to detect pseudomembranes in panniculitides.     

Panniculitis

The classification of inflammatory disorders of the subcutaneous tissue has mystified dermatologists for decades. Overlapping clinical and histologic features, and a lack of specific treatments have added to the confusion. This article initially classifies the various panniculititides by their primary histopathologic pattern: (1) septal panniculitis without vasculitis, (2) septal panniculitis with vasculitis, (3) lobular panniculitis without vasculitis, and (4) lobular panniculitis with vasculitis. Subsequently, we describe the key clinical findings in the most important forms of panniculitis. We begin with the most common form of panniculitis, erythema nodosum. Indeed, in many patients suspected of having panniculitis, a worthwhile question to consider initially might be, "Is this, or is this not, erythema nodosum?" before engaging in an elaborate (and expensive) exercise in differential diagnosis.     

Subcutaneous sweet syndrome

Neutrophilic panniculitis encompasses a heterogeneous group of diseases histopathologically characterized by an inflammatory infiltrate in the subcutaneous fat mainly composed of mature neutrophils. This group of panniculitides includes alpha(1)-antitrypsin deficiency, infectious panniculitis, factitious panniculitis, subcutaneous Sweet syndrome, neutrophilic/pustular panniculitis associated with rheumatoid arthritis, erythema nodosum-like lesions of Beh?et disease, bowel bypass panniculitis, and iatrogenic panniculitis. This article reviews subcutaneous Sweet syndrome, which is a rare idiopathic panniculitis characterized by a dense neutrophilic infiltrate in the subcutis and is often related to hematologic malignancies. The relationship of subcutaneous Sweet syndrome and erythema nodosum is discussed as well as the differential diagnosis with other neutrophilic panniculitis.     

Lipodermatosclerosis: a clinicopathologic study of 17 cases and differential diagnosis from erythema nodosum

Background: The clinical manifestations of lipodermatosclerosis (LDS) may mimic cellulitis and various panniculitides. Methods: To better characterize the histopathologic changes of LDS, we reviewed the clinicopathologic findings of 26 cases with a pathologic diagnosis consistent with LDS. A final diagnosis of LDS was made in 17 cases based on the clinicopathological correlation. As some cases manifested erythema nodosum (EN)-like lesions, 14 specimens of EN were reviewed to identify features for differential diagnosis. Results: Microscopically, the acute LDS lesions were characterized by patchy hemorrhage, ischemic fat necrosis with lipophages or hyalinization in the fat lobules. As the disease progressed to the subacute and chronic stages, lipomembranous or membranocystic fat necrosis, septal fibrosis and background venous stasis in the dermis became more pronounced. In contrast, EN typically displayed minimal venous stasis and membranocystic fat necrosis. Conclusions: LDS may manifest as EN-like lesions. Therefore LDS should be included in the differential diagnosis of EN. Clinicopathologic correlation is essential for diagnosis. Differentiating the acute LDS from the early EN is more difficult. A constellation of the findings of septal/lobular panniculitis, hemorrhage in the subcutaneous tissue, and lipophages and/or ischemic fat necrosis in the fat lobules favors the diagnosis of acute LDS.     

Panniculitis in tuberculosis: a clinicopathologic study of nodular panniculitis associated with tuberculosis

Background Certain types of panniculitis, erythema induratum of Bazin and erythema nodosum, have been well documented as tuberculids. Many histopathologic diagnoses of panniculitis have been reported in tuberculosis patients. This study investigates the correlation between underlying tuberculosis and clinicopathologic findings of panniculitis.
Methods We retrospectively reviewed the clinical files of histologic-proven panniculitis cases at the Dermatologic Clinic, Siriraj Hospital from January 1992 to December 1995; only cases with active tuberculous foci were analyzed.
Results The incidence of panniculitis caused by tuberculosis was 8.2%. The ratio of men to women was 1 : 1. The mean age of onset was 35.3 years. The average duration of the nodules was 35.5 days. There was a history of contact tuberculosis in 16.6%. Constitutional symptoms and a strongly positive purified protein derivative (PPD) reaction were found in 66.6%. Chest roentgenograms were abnormal in 83.3%. The erythrocyte sedimentation rate was elevated in all tested cases. The histopathologic diagnoses were nodular vasculitis (33.3%), erythema nodosum (50%), and cutaneous periarteritis nodosa (16.4%). The panniculitis lesion responded to standard antituberculous regimens in 4.6 weeks, on average, with residual hyperpigmentation.
Conclusions In panniculitis patients, clues for the investigation of tuberculosis included constitutional symptoms, elevated erythrocyte sedimentation rate, and abnormal chest roentgenograms. Histopathologic changes of panniculitis did not seem to correlate with underlying tuberculosis. The clinician should be aware of the tuberculosis, however, and should carefully search for active foci in all panniculitis patients.     

Erythema Nodosum in Children: A Study of 27 Patients

Abstract: Erythema nodosum (EN) seems to occur in children more rarely than in adults. It still remains the most frequent acute panniculitis, for which the diagnosis is almost always clinical. In a retrospective study of 27 pediatric patients, we have attempted to clarify the clinical spectrum and prognosis of this disease and discuss the differential diagnosis of nodular eruptions on the lower limbs of children. In almost half the patients of our series, the cause of EN remained undetermined. Streptococ-cal infections (usually of the pharynx) were the most common cause of EN in children (22% of patients in our series), followed by Yersinia infection in about 15% of patients. Tuberculosis, an important cause in the past, was never found, but must always be excluded. A benign course was noted in all patients. Erythema nodosum is easily recognized clinically, but other subcutaneous lesions, especially nodular vasculitis and Schönlein-Henoch purpura, have to be excluded by pathologic study, in cases of atypical presentation or long duration.     

Panniculitis in childhood

Panniculitis refers to disorders with inflammation of the subcutaneous fat. Such inflammation can be primary or can be a reaction pattern induced by a systemic process. Some types of panniculitis are seen more commonly or exclusively in children. These include erythema nodosum, subcutaneous fat necrosis of the newborn, sclerema neonatorum, poststeroid panniculitis, and cold panniculitis. The most typical clinical finding is tender, erythematous subcutaneous nodules. Clinical clues can aid in the diagnosis of the panniculitides, but pathology is often necessary to confirm the diagnosis. In general, the pediatric panniculitides are treated with supportive care and management of any underlying disorders, but certain types such as infectious panniculitis and malignancy‐related panniculitis require more specific therapies.     

Inflammatory Nodules of the Lower Legs: A Clinical and Histological Analysis of 134 Cases in Korea

We analysed 134 Korean cases with inflammatory nodules of the lower legs on the basis of clinicopathological findings, responsiveness to various therapeutic agents, and clinical course. There were 53 cases of erythema induratum (EI), 18 of erythema nodosum (EN), 40 of EN-like lesions of Behçet's disease, 15 of other entities, including superficial migratory thrombophlebitis, cutaneous periarteritis nodosa, sarcoidosis, malignant lymphoma, Churg-Strauss syndrome, and parasitosis, and eight unclassified cases. The unclassified group was composed of a spectrum of diseases with clinicopathologic features ranging between those typical of EN and EI. The present study revealed that the profiles of diseases featuring inflammatory nodules of the lower legs in Korea differed from those found in other areas. These geographic and demographic differences should be kept in mind when managing a patient with inflammatory nodules of the lower legs.     

Erythema nodosum

Erythema nodosum is the most frequent clinico-pathological variant of the panniculitides. The disorder is a cutaneous reaction consisting of inflammatory, tender, nodular lesions, usually located on the anterior aspects of the lower extremities. The process may be associated with a wide variety of diseases, being infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies the most common associated conditions. The typical eruption consists of a sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the shins, ankles and knees. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish, and finally they exhibit a yellow or greenish appearance taking on the look of a deep bruise. Ulceration is never seen and the nodules heal without atrophy or scarring. Some clinical variants of erythema nodosum have been described under different names, including erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum, but probably they are just clinical variants which may all be included within the spectrum of erythema nodosum. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal anti-inflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.     

Nodules on the legs. A clinical, histological and immunohistological study of 82 patients representing different types of nodular panniculitis.

Eighty-two cases of nodular panniculitis of the legs were examined clinically, histologically and immunohistologically. Clinically the cases could be divided into four groups: typical erythema nodosum (ENty) (35 cases), erythema nodosum migrans (ENmi) (11 cases), erythema induratum (EI) (11 cases) and the remaining 25 cases not consistent with the others as "non-definite panniculitis" (NDP). The main histological categories were septal panniculitis and lobular panniculitis, the former including erythema nodosum, both typical and migrans, the latter EI and NDP. Lobular panniculitis was divided into three subgroups in which the most prominent histological features were epithelioid cell granuloma, vasculitis and palissading granuloma, respectively. Immunoglobulins in the vessel walls were found in 5 of the 46 cases of erythema nodosum, in 19 of the 36 EI and NDP cases and, in the histological groups in 4 of the 43 cases of septal panniculitis and in 19 of the 35 cases of lobular panniculitis, respectively. Fibrin was found in the walls of the papillary capillaries and deep dermal vessels in the majority of cases of lobular panniculitis. In EI and NDP the follow-up time was 40 months, on average. Twenty-two patients were treated with antituberculous drugs, 15 became symptomless, as did 5 of the 12 patients who were not treated at all.     

Skin lesions in human yersiniosis

Various types of skin manifestations of human yersiniosis were examined with routine histological and immunohistological methods. The biopsy material consisted of sixteen cases of erythema nodosum, eight cases of erythema multiforme, and one case of erythema figuratum. The principal histopathological changes in erythema nodosum were septal or diffuse, mild panniculitis and in seven cases also necrotizing vasculitis in small, medium-sized or large arteries. Perivascular lymphocytic infiltration without vasculitis was the most prominent feature in erythema figuratum. By using a polyvalent conjugate, immunoglobulins in vessel walls in the dermis were found in two cases of EM. The rapid course of the skin eruptions and the frequency of necrotizing vasculitis in arteries fit the changes seen in an experimental Arthus reaction, in which necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction.     

Exploring the combination of SSKI and topical heparin in a case of erythema nodosum migrans

Erythema nodosum migrans (subacute nodular migratory panniculitis) is an uncommon type of panniculitis characterized by migrating subcutaneous nodules or plaque on the lower extremity. There are a very few cases of Erythema nodosum migrans reported and thus its appropriate treatment modality is not defined. We describe a case of a 30‐year‐old male with idiopathic erythema nodosum migrans which was manifest centrifugally spreading, slightly morpheaform erythematous plaque on the lower left leg. The patient was diagnosed initially and treated as a case of furunculosis with poor clinical response. The skin biopsy showed features consistent with subacute nodular panniculitis. Saturated Solution of Potassium Iodide along with topical Heparin successfully treated the patient, when the conventional treatment modalities failed. In a morpheaform centrifugally expanded plaque, erythema nodosum migrans should be kept in mind in the differential diagnosis, especially in the lower extremities in cases of unknown etiology.     

Erythema nodosum

Erythema nodosum is the most frequent clinicopathologic variant of panniculitis. The process is a cutaneous reaction that may be associated with a wide variety of disorders, including infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified.     

Poststeroid panniculitis

Poststeroid panniculitis (PSP) is a rare complication of systemic corticosteroid therapy. Clinically, erythematous nodules and indurated plaques develop on the cheeks of children within days or weeks following rapid systemic steroid tapering or cessation. The clinical differential diagnosis of childhood cheek erythema is broad. However, PSP can be identified by clinical history and, if necessary, with a biopsy. Histologically, PSP presents as lobular panniculitis with a mixed inflammatory infiltrates without vasculitis. Needle-shaped clefts within adipocytes are characteristic. The histological differential diagnosis of adipocytes containing needle-shaped crystals is limited. We describe a case of poststeroid panniculitis and discuss the clinicopathological features and pertinent differential diagnoses.     

Panniculitis: definition of terms and diagnostic strategy

Inflammation of the subcutaneous tissue represents a dynamic process that shows different histopathologic findings at different stages of development; therefore, the stage of evolution of a lesion at the time of biopsy influences the microscopic appearance significantly. Furthermore, location and type of inflammation may vary among different examples of the same panniculitis independent of the stage of evolution. For these reasons, the histopathologic diagnosis of panniculitides is often difficult. Currently, the most common approach to diagnosis is differentiation between predominantly septal and predominantly lobular panniculitis, followed by the distinction between lesions with and without vasculitis. Although these criteria are important for diagnosis, they are often insufficiently specific. To determine an alternative method of diagnosis, 329 cases of panniculitis were histopathologically analyzed using the following parameters: location and type of inflammatory infiltrate within and around the subcutaneous tissue, presence or absence of fat necrosis, type of necrosis, presence or absence of vascular changes, and presence or absence of associated findings (e.g., hemorrhage, sclerosis). On the basis of the results of this study and of an extensive review of the literature, tables of histopathologic findings for the diagnosis of panniculitides are presented.