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.     

Panniculitis. Part II. Mostly lobular panniculitis

The second part of our review of panniculitis summarizes the clinicopathologic features of the mostly lobular panniculitides. Erythema induratum of Bazin (nodular vasculitis) represents the most common variant of lobular panniculitis with vasculitis, although controversy persists about the nature of the involved vessels. Mostly lobular panniculitides without vasculitis comprise a series of disparate disorders. These include sclerosing panniculitis that results from chronic venous insufficiency of the lower extremities; panniculitis with calcification of the vessel walls such as calciphylaxis and oxalosis; and inflammatory diseases with crystals within the adipocytes such as sclerema neonatorum, subcutaneous fat necrosis of the newborn, and poststeroid panniculitis. Connective tissue diseases, such as systemic lupus erythematosus and dermatomyositis, pancreatic diseases, and alpha(1)-antitrypsin deficiency may also show a mostly lobular panniculitis with characteristic histopathologic features. Lobular panniculitis may also be an expression of infections, trauma, or factitial causes involving the subcutaneous fat. Lipoatrophy refers to a loss of subcutaneous fat due to a previous inflammatory process involving the subcutis, and it may be the late-stage lesion of several types of panniculitis. In contrast, lipodystrophy means an absence of subcutaneous fat with no evidence of inflammation and often the process is associated with endocrinologic, metabolic, or autoimmune diseases. Finally, cytophagic histiocytic panniculitis is the term that has been used to describe two different processes: one is inflammatory, a lobular panniculitis, and the other one is neoplastic, a subcutaneous T-cell lymphoma. The only common feature of these two different processes is the presence of cytophagocytosis in the lesions. (J Am Acad Dermatol 2001;45:325-61.) 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 lobular panniculitides.     

Cutaneous manifestations in patients with microscopic polyangiitis: two case reports and a minireview

Microscopic polyangiitis is a systemic small vessel vasculitis, which often has cutaneous and musculoskeletal features. Microscopic polyangiitis is a member of the family of anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitides and is strongly associated with anti-myeloperoxidase (MPO)-ANCA. Titres of MPO-ANCA may reflect disease activity and play a pathogenic role. Patients with microscopic polyangiitis usually present with erythematous macules on the extremities as the first cutaneous manifestation. Skin biopsy specimens from the erythema reveal small-sized vessels that are infiltrated with neutrophils, consistent with leukocytoclastic vasculitis, in the deep dermis to the subcutaneous fat tissue. The cutaneous involvement is present at an early stage of microscopic polyangiitis with other non-specific symptoms, such as arthralgias and myalgias. The initial cutaneous manifestations are important in early diagnosis of possible ANCA-associated vasculitides with elevated ANCA titres.     

Diffuse lower limb lipoatrophy

Lipoatrophic panniculitis is the term used to describe those panniculitides in which atrophy of the subcutaneous fat is the main residual lesion. They can be classified as primary or secondary. Primary lipoatrophic panniculitis is idiopathic, whereas secondary lipoatrophic panniculitides include those because of infection, malignancy, pancreatic disorders or connective tissue diseases. Usually, these entities are characterized by the appearance of tender, erythematous nodules or plaques that resolve leaving one or several localized areas with loss of subcutaneous fat. We report a 76-year-old female who developed diffuse and symmetric lipoatrophy of lower limbs after an extensive inflammatory process affecting both extremities from thighs to ankles. Histopathologic assessment revealed a lobular panniculitis with a lymphohistiocytic infiltrate, foamy macrophages and lipophagic granuloma formation. The most striking feature in our patient was the clinical presentation as a symmetrical diffuse inflammatory process resulting in lipoatrophy of the lower limbs.     

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.     

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.     

Anatomy and histology of normal subcutaneous fat, necrosis of adipocytes, and classification of the panniculitides

The panniculitides comprise a group of heterogeneous inflammatory diseases that involve the subcutaneous fat. Histopathologic study is required for the specific diagnosis of these disorders, because different panniculitides usually show the same clinical appearance, which consists of erythematous nodules on the lower extremities. The histopathologic study of panniculitis is difficult, however, because of an inadequate clinicopathologic correlation and the changing evolutive nature of the lesions. Some cutaneous lymphomas may simulate panniculitis, both from clinical and histopathologic points of view, and for that reason are included in this article despite the fact that they are not inflammatory processes but authentic lymphocytic neoplasms involving subcutaneous tissue.     

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.     

Peripheral T-cell lymphoma involving subcutaneous tissue

The peripheral T-cell lymphomas, presumably derived from various immunocompetent peripheral T-cell system components, form a heterogeneous group of non-Hodgkin's lymphomas. We describe two patients with peripheral T-cell lymphoma primarily involving subcutaneous tissue. They presented with multiple subcutaneous nodules. Skin biopsy specimens in both patients demonstrated a lobular subcutaneous infiltrate. The infiltrate consisted of small and medium-sized atypical lymphoid cells. Both patients had a protracted clinical course before they were diagnosed as having malignant lymphoma. We detected latent Epstein-Barr virus infection in the skin lesions of case 2. Latent Epstein-Barr virus infection might be related to the development of this variant of peripheral T-cell lymphoma.     

A case of angiolymphoid hyperplasia with eosinophilia (ALHE) of the upper lip

Angiolymphoid hyperplasia with eosinophilia (ALHE) is clinically characterized by intradermal or subcutaneous papules and/or nodules usually occurring in young adults. Lesions in the oral mucosa are extremely rare. We report a case and review the literature of ALHE cases involving the oral mucosa. A 40-year-old man presented with a painless, 20 x 20 mm, submucosal nodule on the upper lip. Histological examination of lip biopsy specimens revealed an increase in many small vessels. The vascular walls consisted of prominent endothelial cells with a histiocytoid appearance, which protruded into the lumen. Many eosinophils and lymphocytes were also seen around the vessels. The diagnosis of ALHE was made from the above findings.     

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.     

Panniculitis in children

The panniculitides include a group of disorders of varied etiology that manifest as inflamed nodules in the subcutaneous tissue. They are rarely seen in infants and children. The panniculitides of the newborn represent a unique response of the infant's fat to different injuries, and are a specific type of panniculitis that is only seen in neonates and very young infants. These specific panniculitides of children include subcutaneous fat of the newborn, poststeroid panniculitis, sclerema neonatorum, and cold panniculitis. This article reviews in detail the specific types of panniculitis of the newborn and discusses the pediatric aspects of the panniculitis that is often seen in adults.     

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.     

Cutaneous Polyarteritis Nodosa in a Child

Abstract: Cutaneous polyarteritis nodosa (CPAN) is a benign form of vasculitis of small and medium-size arteries with a recurrent but benign course without systemic involvement. This entity is very rare in children, with about 45 cases described in the literature we reviewed. Herein we report a 10-year-old girl with typical CPAN. Trigger factors such as streptococcal infection were not detected. Of four episodes over the last 2 years, only one required treatment with a moderate-sized oral dose of prednisone. In diagnosing CPAN, it is necessary to rule out systemic polyarteritis nodosa, which is also rare in children, as well as other panniculitides and vasculitides.     

Classification of vascular disorders in the skin and selected data on new evaluation and treatment

Cutaneous vascular disorders are common. They include arteries, veins, and lymphatic vessels, or a mixture of them. In this review, we discuss classification, new developments in understanding and treatment of vascular diseases. We focus on infantile hemangiomas and drug therapy, vasculitides with new vasculitic syndromes, yellow nail syndrome and localized lymphatic malformations. Benign cutaneous vascular lesions may be a sign of severe internal diseases. In many cases multidisciplinary treatment is important. The dermatologist can often act as a pilot for these patients.     

Vascular calcification in dermatopathology

Calcification in cutaneous blood vessels is an uncommon finding in biopsies submitted for dermatopathological examination. Of 14 biopsy specimens showing the phenomenon that was studied by us, the greater number was from women who had a combination of severe diabetes, hypertension, and atherosclerosis. Unusual clinical syndromes as the bases for the vascular calcification were hyperthyroidism in three patients and arteritis in two patients. Three patients died as a consequence of massive cutaneous infarction and sepsis, probably stemming from cutaneous vascular calcification. Vascular calcification in biopsy of skin may result from metabolic, inflammatory, or degenerative diseases of blood vessels.     

Perinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris

Minocycline is an oral antibiotic widely used for the long-term treatment of acne vulgaris. Unusual side effects of this medication include two overlapping autoimmune syndromes: drug-induced lupus and autoimmune hepatitis. In addition, in a few patients livedo reticularis or subcutaneous nodules have developed in association with arthritis and serum perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) during long-term minocycline therapy. We report the cases of two young women receiving long-term minocycline therapy (>3 years) in whom P-ANCA-positive cutaneous polyarteritis nodosa developed. Both patients presented with a violaceous reticulated pattern on the lower extremities. Histologic examination of biopsy specimens from a reticulated area and a subcutaneous nodule showed necrotizing vasculitis of medium-sized arteries in the deep dermis, consistent with the diagnosis of polyarteritis nodosa. The cutaneous lesions rapidly resolved on discontinuation of minocycline and initiation of prednisone therapy. A high index of suspicion and testing for antineutrophil cytoplasmic antibody in addition to the standard antinuclear antibody panel can facilitate diagnosis of minocycline-related autoimmune disorders.     

An approach to the patient with retiform purpura

Retiform purpura consists of branching purpuric lesions caused by a complete blockage of blood flow in the dermal and subcutaneous vasculature. The differential diagnosis for retiform purpura is broad, including vasculitides of the small and medium vessels as well as microvascular occlusion due to thrombotic, infectious, and embolic phenomena. Determining the etiology of this important dermatologic sign can be a diagnostic challenge; however, an organized approach can improve the speed and accuracy of diagnosis and identify an effective treatment. This review focuses on early recognition, evaluation, and treatment of hospitalized patients with retiform purpura. Specifically, vasculitis, protein C and S deficiencies, heparin necrosis, warfarin necrosis, antiphospholipid antibody syndrome, disseminated intravascular coagulation, cryoglobulinemia, calciphylaxis, and cholesterol embolization syndrome will be discussed in detail. These conditions are commonly seen in consultative dermatology and can have multiorgan involvement, complicated laboratory evaluation, and long-term therapeutic implications.     

Three-dimensional analysis of a calciphylaxis plaque: clues to pathogenesis

BACKGROUND: Calciphylaxis is a rare, life-threatening disorder associated with chronic renal failure, presenting with ulcerating plaques leading to death by sepsis in 60% of patients. Calcification of subcutaneous arterioles, thromboses, and extravascular calcification have been demonstrated in incisional biopsy specimens. However, the sequence of these pathologic events is unknown. OBJECTIVE: We examined a calciphylaxis plaque to document the wave of pathologic change from its center to its periphery. METHODS: A calciphylaxis plaque was excised postmortem from a female patient. It was examined histologically along 12 radii from the center of the lesion to its periphery. RESULTS: Calcification of small subcutaneous vessels was present in all histologically abnormal sections and extended further peripherally than extravascular calcification by up to 3.0 cm and further than subcutaneous thrombosis by up to 1.5 cm. CONCLUSION: Vascular mural calcification is an early and essential process in the development of a calciphylaxis plaque.     

Cutaneous vasculitis: a review

As the skin is commonly involved in systemic vasculitic disorders as well as those hypersensitivity states whose expression is largely skin-confined, cutaneous vasculitic lesions offer a window to diagnosis and a ready source of accessible tissue for biopsy. In this review, we discuss the pathologic manifestations of chronic vasculitic syndromes such as granuloma faciale and erythema elevatum diutinum; IgA-associated vasculitis including Henoch-Schonlein purpura; vasculitis seen in the setting of cryoglobulinemia and hypergammaglobulinemia of Waldenstrom, hereditary deficiencies of complement, and IgA deficiency; those leukocytoclastic vasculitides resulting from hypersensitivity reactions to drug, chemical and foodstuff ingestion; and those vasculitides seen in patients with systemic diseases such as polyarteritis nodosa, rheumatoid arthritis, mixed connective tissue disease, systemic lupus erythematosus, Sjogren's syndrome, relapsing polychondritis, Behcet's disease, Wegener's granulomatosis, and allergic granulomatosis of Churg and Strauss.