Panniculitis

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Panniculitis

Carrie Ann R. Cusack and Matthew Fanelli

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Panniculitis is a term used to describe the different inflammatory diseases of the subcutaneous fat. The subcutaneous fat is derived embryologically from mesenchymal cells. It is this mesenchyme which gives rise to adipocytes, or fat cells. A cohesive collection of fat cells, termed a microlobule, makes up the basic unit of the subcutaneous tissue. When these microlobules are grouped together, they make up the individual lobules of the subcutaneous layer of skin. Lobules are separated from each other by fibrous septae. It is within these septae that the main arteries and veins that supply the fat tissue are located. Classically, the panniculitides have been defined by knowledge of this basic architecture of the subcutaneous tissue. Most classifications define them based on whether the inflammation is located in the lobules or in the fibrous septae. In reality, none of the panniculitides have their inflammation located solely in the septae or solely in the lobules. It is more correct to describe them as predominantly septal or predominantly lobular panniculitides. Based on this classification, we can better separate the individual disease processes.

The characteristic septal panniculitis is erythema nodosum, which is also the most common panniculitis. The majority of other panniculitides are predominantly lobular. However, some other rarer panniculitides have predominantly septal inflammation, such as subacute nodular migratory panniculitis, panniculitis of morphea/scleroderma, and α1-antitrypsin deficiency panniculitis. Within the lobular panniculitides, a further division can be made based on the presence of vasculitis. The main lobular panniculitis with vasculitis is erythema induratum, or more aptly termed, nodular vasculitis. Rarer vasculitic panniculitides occur in the setting of leprosy with erythema nodosum leprosum and Lucio phenomenon. The remaining lobular panniculitides are not associated with vasculitis, but can be associated with systemic disease. Subtypes include lupus panniculitis, pancreatic panniculitis, cytophagic histiocytic panniculitis, panniculitis of dermatomyositis, infectious panniculitis, sclerosing panniculitis/lipodermatosclerosis, oxalosis, and those with needle-shaped clefts (sclerema neonatorum and subcutaneous fat necrosis of the newborn).

In previous editions of this book, as well as in much of the older literature, Weber–Christian disease (WCD) has been described. This was defined loosely as a lobular panniculitis without vasculitis which also displayed non-specific systemic features. This was a diagnosis of exclusion which essentially lumped together all panniculitides that did not fit into one of the more specific diagnoses. This term has recently fallen out of favor. Many of the cases originally defined as WCD have been reclassified since newer panniculitides, such as nodular vasculitis, α1-antitrypsin panniculitis, and pancreatic panniculitis, were separated as specific diseases. In a report by White and Winkelmann, they reviewed 30 previously diagnosed cases of WCD and found that, in all cases, a more specific diagnosis could be found. Therefore, we will not include WCD in our classification for panniculitides in this chapter.

Management strategy

Many studies can be performed in evaluating panniculitides; however, none is more important than the skin biopsy. Therefore, it is extremely important that the biopsy includes a substantial portion of the subcutaneous fat. A punch biopsy alone is not enough. And while a double punch biopsy technique is better, the best way to get a sample of the subcutaneous tissue is through an excisional biopsy that extends through the subcutis, or a narrow incisional biopsy that includes a significant amount of fatty tissue. If an infectious cause of the panniculitis is suspected, a small piece of this biopsy should be sent for Gram staining as well as culture for bacteria, mycobacteria, and fungi. If a mycobacterial infection is in consideration, the specimen should be grown at 24, 30, 37, and 42°C.

Lupus panniculitis, also known as lupus profundus, makes up only a small portion of cutaneous lupus erythematosus, comprising only 2–3%. In many instances, it is the first cutaneous sign of lupus erythematosus, preceding many other features. It is associated mainly with discoid lupus erythematosus (DLE), occurring in more than one-third of cases of DLE. Lesions of DLE often are present in the skin overlying the lesions of lupus profundus. Lupus panniculitis occurs in approximately 10–15% of patients with systemic lupus erythematosus (SLE), which tends to have a chronic course with few systemic manifestations, usually arthralgias. The distribution of these lesions can be helpful in making the diagnosis as they are typically located on the face, trunk, and proximal extremities, in contrast to erythema nodosum. Laboratory studies should include antinuclear antibody (ANA), dsDNA, ssDNA, SSA, SSB, complement levels, complete blood count (CBC), and a chemistry panel. On biopsy, it shows a predominantly lobular inflammation of T lymphocytes and macrophages. A biopsy for direct immunofluorescence (DIF) should be performed to confirm the diagnosis in cases where the histopathology is not specific. In a high majority of cases, a linear deposition of C3 and IgM is present along the dermoepidermal junction in the overlying skin. First-line therapy for lupus profundus consists of systemic antimalarial agents as well as sunscreen use. The addition of a second antimalarial agent has proven helpful in patients who are resistant to just one agent. In addition, systemic corticosteroids can also be used first line; however, they are usually effective only in the early phases of disease.

Nodular vasculitis includes both tuberculous and non-tuberculous causes. The tuberculous form is referred to as erythema induratum (of Bazin). Non-tuberculous etiologies include other infectious agents such as Nocardia or hepatitis C virus and medications such as propylthiouracil. The non-tuberculous form has sometimes been referred to as erythema induratum of Whitfield. Clinically, lesions appear on the posterior legs of middle-aged women, and present as painful, erythematous nodules. In making the diagnosis, mycobacterial culture as well as polymerase chain reaction (PCR) of mycobacterial DNA should be ordered. Purified protein derivative as well as Quantiferon-TB Gold test can be helpful in making the diagnosis caused by tuberculosis. On biopsy, it is typically a lobular panniculitis with a mixed inflammation, comprising lymphocytes and neutrophils. The key is identifying vasculitis as well, as the majority of cases show inflammation of either arteries or veins. Treatment includes multi-drug anti-tuberculous agents in cases caused by tuberculosis, and other antibiotics in cases of other infectious etiologies. Other effective therapies include potassium iodide, colchicine, and corticosteroids.

Pancreatic panniculitis can occur in many different pancreatic disorders that cause tissue necrosis. This includes acute or chronic pancreatitis, pancreatic carcinoma, with acinar cell being the main type, pancreas divisum, and pancreatic pseuodocysts. It occurs in about 2–3% of all cases of pancreatic diseases. The presence of panniculitis may precede the detection of pancreatic disease, and warrants an investigation for potential etiologies. It may be a harbinger of metastasis in cases of pancreatic carcinoma. Lesions consist of subcutaneous nodules that usually occur on the legs (around the ankles and knees predominantly) but can occur in any location. They may or may not be painful, but the majority of lesions ulcerate, discharging an oily brown substance. Histopathology shows fat necrosis and the formation of ‘ghost cells’ is classic. Amylase and, more specifically, lipase are elevated in pancreatic panniculitis and should be ordered. A CBC should be ordered as well, as eosinophilia may be present in 60% of cases. Imaging with MRI can identify a pancreatic malignancy. Treatment involves treating the underlying pancreatic inflammation. Octreotide has also been helpful.

Cytophagic histiocytic panniculitis is defined based on the presence of hemophagocytosis on histopathology. There are characteristic ‘bean-bag cells’ which are macrophages that engulf lymphocytes, neutrophils, and erythrocytes. The vast majority of cases are caused by a lymphoma. The main types are Epstein-Barr virus associated extranodal NK/T-cell lymphoma, and primary cutaneous gamma/delta T-cell lymphoma. Clinically, painful subcutaneous nodules are present. Patients may have a prolonged clinical course that may involve fever, hepatosplenomegaly, and pancytopenia secondary to hemophagocytosis of the bone marrow. Treatment consists of treating any underlying malignancy, possibly with a bone marrow transplant. In cases where lymphoma has not been identified, cyclosporin has been effective.

α1-Antitrypsin deficiency panniculitis occurs in patients with a severe deficiency of this enzyme, a protease inhibitor. There are many different alleles of the gene that encodes this protein, with the most common being the M allele. The most common phenotype for the protease inhibitor (Pi) is PiMM. Patients with the S or Z allele may exhibit a mild deficiency in the enzyme. Patients with the phenotype PiZZ have the most severe enzyme deficiency, and it is typically these patients who manifest the panniculitis. Inflammation in the subcutaneous fat occurs because lipase, elastase, and other enzymes are not neutralized. These patients have painful, often purpuric nodules that ulcerate and drain. On pathology, there is usually focal necrosis of the fat lobules with a predominantly neutrophilic inflammation. An elastic stain of the biopsy may be helpful to show the reduced elastic tissue. Gene phenotyping helps determine an enzyme mutation. The most effective treatment is enzyme replacement through intravenous injections. Other treatments include dapsone, colchicine, and liver transplantation to permanently replace the missing enzyme.

Panniculitis can also occur in infants. The two main types are sclerema neonatorum and subcutaneous fat necrosis of the newborn. They both are characterized histologically by needle-shaped clefts within lipocytes. In sclerema neonatorum, an extremely rare condition, the skin becomes hardened on the buttocks or thighs, and then rapidly spreads in the first few days of life, causing immobility. Death typically occurs in a few days. Treatment for this condition is disappointing. It involves supportive care, treating any underlying condition, and exchange transfusions. The prognosis for subcutaneous fat necrosis of the newborn, on the other hand, is good. It involves full-term infants in contrast to the premature newborns in sclerema neonatorum. Clinically, this condition consists of localized, indurated plaques involving the trunk that form during the first few weeks of life. Most lesions resolve spontaneously, so treatment involves supportive care. It may be complicated by hypercalcemia, in which case, treatment for this may be needed.

Lipodermatosclerosis, or sclerosing panniculitis, is a condition that usually develops in patients with chronic venous insufficiency. It is classically located on the medial lower legs in middle-age women. It has been described as looking like an “inverted champagne bottle.” Histologically there is ischemia and necrosis of the central fat lobule, and there are characteristic lipomembranous changes. Treatment involves correcting the venous insufficiency with compression stockings and leg elevation. Stanozolol has also been helpful.

Panniculitis can also occur in the setting of other connective tissue diseases such as dermatomyositis and morphea/scleroderma. In morphea, usually there is a septal panniculitis with a plasma lymphocytic cell infiltrate. Indurated plaques appear on the trunk and extremities. In dermatomyositis, the panniculitis is more lobular and the inflammation is primarily lymphocytic. Clinically, there are tender, indurated plaques that may ulcerate and heal with atrophy. Treatment of both conditions involves treating the underlying connective tissue disease.

The physical forms of panniculitis, such as those resulting from cold exposure, foreign body, or factitious causes, usually resolve by removal of the offending trigger or surgical removal of the foreign body. This is similar to panniculitis caused by silicone or paraffin that has been used for cosmetic purposes. There are also forms of panniculitis associated with chronic renal failure, with the main ones being calciphylaxis and oxalosis. Calciphylaxis can be very severe and cause large areas of necrosis. Treatment involves parathyroidectomy, sodium thiosulfate, binding agents, or renal transplantation. Oxalosis is a crystalline deposit panniculitis. Calcium oxalate crystals typically are deposited on the palmar fingers, among other locations. Treatment for this is renal transplantation as well.

Lupus panniculitis

First-line therapies

imageAntimalarials E
imageSystemic or intralesional corticosteroids E

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