Chapter 70. Panniculitis

Inflammation in subcutaneous fat often poses a diagnostic problem for clinician and pathologist alike, since the clinical and histopathological findings in the various inflammatory disorders of adipose tissue (AT) have overlapping features. Specificity in diagnosis is potentially difficult since similar clinical presentations are sometimes associated with disparate histopathological features. Diagnostic problems may also relate to the corollary observation that a range of clinical presentations may have similar histopathologic findings.

There is no universally accepted classification of panniculitis, but from the point of view of many pathologists, a useful classification begins by dividing panniculitis into septal and lobular forms, “septal” signifying inflammation confined predominantly to the septa, and “lobular” indicating inflammation predominantly involving the fat lobule itself. The septal form has been most classically associated with erythema nodosum (EN) and the lobular form with all or most other types of panniculitides. But even this beginning point has not been proven adequate since lobular granulomatous panniculitis may be seen in clinically classic EN,1 and lobular panniculitides may have mixed lobular and septal inflammation.2 This classification has been expanded by making note of the presence or absence of vasculitis in the septa or lobules,3 by the composition of the inflammatory infiltrate, and by additional specific features when present (Fig. 70-1).

Since diverse clinical conditions may be expressed by similar histopathologic features, and the spectrum of histopathologic features in EN and other panniculitides may be variable,4 it may not be possible to make a specific diagnosis of panniculitis based on histopathology alone. This necessitates correlation with clinical features, including location of lesions, systemic symptoms, laboratory findings, and etiological factors. A significant aid to success in the diagnosis of inflammation in AT is obtaining a tissue sample that will adequately represent the histopathologic changes in the lesion. This can only be done with large excisional biopsies, as small punch biopsies are unlikely to obtain adequate AT, and the inflammatory infiltrate can be missed. An additional consideration is that inflammation in AT is not a static process, and as samples taken at different stages of an evolving lesion will present with different histopathologic features, more than one biopsy may be necessary to come to a conclusive diagnosis.

Under the best of circumstances, with optimal histopathologic sampling and clinical correlation, there may be no specific etiology for many inflammatory reactions in AT. But even with a specific diagnosis or etiology, underlying questions remain. Why were the inflammatory cells accumulating in the AT? What were they doing there?

One of the characteristics of certain types of panniculitides is the preferential localization, such as the pretibial areas for EN, the calf for erythema induratum (EI), and the upper arms, shoulders, and face for lupus panniculitis. Location of panniculitis is a helpful adjunct for differential diagnosis of inflammation in AT and the question of why that occurs may be traced to the origin of the adipocyte regions from different areas of the mesoderm and the varying gene expression in different fat depots.25 The differences in gene expression between fat depots are large, up to 1,000-fold, and appear to be intrinsic, autonomous, and independent of the tissue microenvironment.25 Different AT depots may also contain variable percentage of adipocytes of different developmental origins,25 including brown AT (BAT) that has been observed to be present in white AT depots.25,26

The role of AT in innate immunity, inflammation, adaptive immunity, and energy homeostasis places the adipocyte itself centrally in the inflammatory disorders that affect it. The presence of adipocyte transmembrane PRRs, TLRs, and cytosolic PRRs, NLRs, and RLRs and receptors for interaction with macrophages and lymphocytes, as well as production and secretion of multiple cytokines and adipokines reflect the role of the adipocyte in protecting the host from infectious disease and other environmental dangers. The complex interweaving of the adipocyte's role in such numerous and varied spheres may lead to complications should there be a genetic or acquired functional abnormality and/or molecular perturbations, and this may in some instances result in the inflammatory process known as panniculitis.

Nodular lesions of the legs may represent EN, EI, nodular vasculitis (NV), cutaneous polyarteritis nodosa, or nodules related to vascular disorders. Diagnosis of these disorders often presents difficulties because their clinical manifestations as well as histopathological findings may overlap. In order to diagnose lesions of the leg, one needs information on the typical as well as unusual manifestations of each disorder, the associated diseases and conditions, and the histopathological presentation.

Erythema Nodosum

Epidemiology

EN may occur in both genders, at any age from childhood to 70 years of age, but is more common in young women in the second to fourth decades of life.27 There is no gender difference in childhood cases. Prevalence varies from 2.4 per ten thousand population to 52 per million population, and in patient population from 0.38% to 0.5% of patients seen in clinics in Spain and England, respectively.28,29

Etiology and Pathogenesis

EN is a panniculitis that has been reported in association with infections (bacteria, viruses, fungi, and protozoa), medications (antibiotics, oral contraceptives, halides), malignancies (most often leukemias or lymphomas), autoimmune diseases, and other inflammatory disorders, especially sarcoidosis and inflammatory bowel disease (see eTables 70-0.1 and 70-0.2). Geographical variations in infectious etiology occur, but streptococcal upper respiratory infections are the most common infectious etiologic factors and the most common causes in childhood.30 Tuberculosis was a common etiology in the past, and though less frequent now, must always be excluded. Half of all EN cases are idiopathic, without specific etiology, even though in many a viral cause may be suspected.30

EN is considered to be a hypersensitivity reaction to the various etiologic factors, but the pathophysiological mechanism of the disorder is not yet understood. Early studies have shown the presence of IFNγ and IL-2, activation of leukocytes, 31 and upregulation of various adhesion molecules,32,33 and genetic polymorphism in TNF-α promoter, MIF (macrophage migration inhibitory factor), or RANTES (regulated upon activation, normal T-cell expressed, and secreted).34–36 More recent information identifies AT as an immune organ and adipocytes as cells of the innate immune system, with primary responsibilities and capabilities of activating inflammatory systems and the adaptive immune system to destroy pathogens37 (see Section “Introduction”). Historically, the primary function of the adipocyte was thought to be protective. However, excessive adipocyte production and secretion of multiple proinflammatory adipokines and adipocytokines is associated with obesity, cardiovascular disease, hypertension, and diabetes.37 In contrast, the inflammatory reaction of EN is associated with a more limited coccidiomycosis infection38 and with a less severe and shorter duration of sarcoidosis,38 especially in those carrying the HLA-DRB1*03-positive leukocyte antigen,39 which belongs to the “8.1 ancestral haplotype” genes associated with a wide range of immunopathologic diseases.40 Therefore, it is possible that, especially in AT, certain genetic mutations associated with enhanced inflammatory reactions may confer resistance to certain pathogens, and this may explain the observation that EN, whether in association with coccidiomycosis or sarcoidosis, may be protective against disease dissemination.38,39

Clinical Features

EN most commonly presents with an acute onset of tender, painful, erythematous, warm nodules and plaques on the anterior and at times the lateral aspect of both lower legs and ankles (Fig. 70-2). Other sites may also be involved, including forearms, thighs, and rarely the trunk or even the face, especially in children.41,42 The nodules may persist a few days or weeks, may become confluent, and evolve from an erythematous or purple-like hue to a bruise-like pigmentation called erythema contusiforme if hemorrhage is present in the AT. The eruption usually lasts from 3 to 6 weeks, with new lesions appearing for up to 6 weeks, but it may persist longer and may recur.42 The lesions do not ulcerate, and they resolve without atrophy or scarring.

Systemic symptoms such as fever, fatigue, malaise, arthralgia, arthritis, and headache are common. Abdominal pain, vomiting, diarrhea, and cough are less frequent.30,42 Ocular manifestations may accompany the cutaneous lesions.42 Tonsillitis/pharyngitis/upper respiratory infection (URI) preceded the onset in 20%–30% in two series29,30 and prodromal symptoms may appear 1–3 weeks prior to lesional onset, at which time symptoms may become exacerbated.43

Laboratory abnormalities may include a high ESR, positive throat culture, or high ASO titer in those with a streptococcal etiology and leukocytosis. A positive PPD must be evaluated in the context of prevalence of tuberculosis in the geographical area. Chest X-ray will rule out pulmonary infectious or noninfectious disease (sarcoidosis), and serology or culture for various infectious diseases as well as other testing may be warranted in the appropriate setting (see eTables 70-0.1 and 70-0.2).

Histopathology

Histopathologically, EN is considered the prototype of septal panniculitis, although lobular inflammation may additionally be present. The composition of the inflammatory infiltrate varies according to lesional age, with the earliest lesions demonstrating septal edema, extravasated red blood cells, and scattered neutrophils. More fully developed lesions of EN show widening of the septa and early fibrosis, along with a septal infiltrate that includes lymphocytes, histiocytes, neutrophils, and eosinophils.27,42,44 There may be extension of the infiltrate into adjacent fat lobules, but centrilobular necrosis of adipocytes is not seen.27,41,42 Late-stage lesions show widened and fibrotic septa, often containing granulomas (Fig. 70-3A). The fibrosis and inflammation may encroach upon and partially efface fat lobules. Occasionally, predominantly polymorphonuclear cells may be present in typical EN,45 but this is considered to be part of the early phase of inflammation.27,41,42

Miescher's granuloma, a discrete micronodular aggregate of small histiocytes around a central stellate cleft27,42 (Fig. 70-3B), is considered characteristic of early EN by some, but is not universally found in EN,41,44 and has been described in other types of panniculitis.41 The picture of Miescher's granuloma also evolves, as in later-stage lesions, some aggregates of larger histiocytes and multinucleated giant cells retain a central cleft. An overlying superficial and deep perivascular dermal infiltrate is frequently present in EN.41 Lipomembranous changes have been described in late stages of EN.27,42 Although by definition, vasculitis is characteristically absent in EN, thrombophlebitis has been emphasized by some as a feature in early EN,1 and medium vessel arteritis may rarely occur.4

Differential Diagnosis

Differential diagnosis includes cellulitis, infection-induced panniculitis, acute lipodermatosclerosis (LDS), EI/NV, which tends to appear on the calves and ulcerate, other vasculitides which must be differentiated histopathologically, and pancreatic panniculitis, which may occur anywhere on the leg, ulcerate and drain, and which is accompanied by an increase in serum lipase and amylase.

Treatment

Treatment of EN primarily focuses on treatment or removal of the etiologic factor. Suspected medications should be discontinued, underlying infections sought and treated if possible, and associated inflammatory disorders or malignancies sought and appropriately treated. The disorder may persist for months before remission, and recurrence is possible, especially if the etiology is unknown.46 Additional management options include bed rest and leg elevation, aspirin, nonsteroidal anti-inflammatory agents (avoided with IBD). Supersaturated potassium iodide solution (SSKI), 2–10 drops (1 drops = 0.03 mL = 30 mg) three times per day in water or orange juice has been useful, but individuals with thyroid disorders and on certain medications may be at risk for hypothyroidism and goiter as well as toxicity reactions of high potassium involving the heart and lungs.47 SSKI is contraindicated in pregnancy. Other medications that have been used to treat EN include colchicine (especially for Behcet's disease),48 corticosteroids (rarely used, especially since an underlying infection must be ruled out), etanercept,49 and infliximab for IBD-associated EN.50

Erythema Induratum and Nodular Vasculitis

Epidemiology and Clinical Findings

EI is an inflammatory panniculitis, most commonly presenting with ulcerated nodules on the calves, and frequently associated with MTB infection. A similar disorder, without ulceration appearing in calves and other lower extremity sites was subsequently described without MTB association and was called NV. However, with patients presenting with different features in either the same flare or in preceding or subsequent flares, multiple studies have concluded that the clinical and pathological features of the two nodular leg syndromes are so similar that it is impossible to separate them.51–54 Therefore, at this time the terms are most often used interchangeably. But some still prefer to use EI to denote the MTB-associated panniculitis, and NV for those without MTB association despite the otherwise identical features, to emphasize the need for antituberculosis therapy in the former cases.55

EI/NV is seen most commonly in young to middle-aged women, presenting as recurrent erythematous to violaceous nodules and deep plaques on the lower legs that may be tender, or only tender to pressure52 (Fig. 70-4). Some lesions may heal without scarring, but often ulceration leads to scarring.52 Surface changes include crusting of the ulcers and a surrounding collarette of scale (Fig. 70-5). The histology is shown in Fig. 70-6. The posterior leg calf region is the most frequent location, but lesions may also appear in the anterolateral areas of the legs, the feet, thighs, and rarely the arms and face.51 EI lesions develop more frequently during winter, and EI is commonly associated with obesity and venous insufficiency of varying degree and manifestation.52

Etiology and Pathogenesis

Pathology

Course

EI/NV can have a protracted course with recurrent episodes over years.52,53 Patients with EI/NV are for the most part in fairly good health, except for the associated diseases, without the symptoms usually associated with EN. There has been one case report of membranous glomerulonephritis associated with EI/NV72 and one case of painful peripheral neuropathy in an initially MTB skin test negative patient who was later found to have MTB-positive culture of cervical lymph node.73

Treatment

In patients with positive MTB cultures, positive skin test or Quantiferon gold test for MTB, treatment with triple agent antituberculosis therapy is indicated. Patients with hepatitis B or C should receive appropriate intervention for that disorder. Other infectious etiologies including fungi, parasites, and viruses should be sought and treated, if present. Medications that may have incited EI should be discontinued.

Anti-inflammatory treatments that have been used in EI/NV not associated with MBT include super saturated potassium iodide (SSKI), nonsteroidal anti-inflammatory agents (NSAIDS), colchicine, antimalarials, corticosteroids,55 gold74 as well as bed rest or leg elevation, and treatment of venous insufficiency with compression and pentoxifylline. Other treatments that have been used include tetracycline and mycophenolate mofetil.75 If immunosuppressive agents are used, continued monitoring for possible infectious etiology is recommended.

LDS (synonyms: sclerosing panniculitis, hypodermitis sclerodermiformis, chronic panniculitis with lipomembranous changes, sclerotic atrophic cellulitis, venous stasis panniculitis) is a form of sclerosing panniculitis involving the lower legs.

Epidemiology

LDS is the most common form of panniculitis, seen by clinicians far more frequently than EN, which has the next highest incidence. LDS occurs in association with venous insufficiency, mostly in overweight women over the age of 40.76,77 In a review of 97 patients with LDS, 87% were female with a mean age at diagnosis of 62 years; 85% of patients were overweight (BMI >30); and 66% were obese (BMI >34).78 Comorbidities included hypertension (41% of patients), thyroid disease (29%), diabetes mellitus (21%), prior history of lower extremity cellulitis (23%), deep vein thrombosis (19%), psychiatric illness (13%), peripheral neuropathy (8%), and atherosclerosis obliterans (5%).78 Due in part to its placement in the ICD9 classification under “Venous insufficiency with inflammation,” and its designation by various medical names (see list of synonyms for LDS above), precise data for prevalence of LDS are not available. With increasing rates of obesity in the United States and the aging of the baby boomer generation, a corresponding increase in incidence and prevalence of LDS will likely follow.

Etiology and Pathogenesis

Most patients with LDS are female and also have in common venous hypertension and a higher than normal BMI. Additional associated features that have been sought as pathogenetic factors in LDS include the following: elevated hydrostatic pressure-induced increased vascular permeability secondary to downregulation of tight junctions79,80 with extravascular diffusion of fibrin78; microthrombi81; abnormalities in protein S and protein C82; hypoxia83; damage to endothelial cells by inflammatory cells84; upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), leukocyte function-associated antigen 1 (LFA-1), platelet- and endothelial-derived factors85; and inflammation with wound healing and local collagen stimulation leading to fibrosis and further vascular and lymphatic damage.78 The fibrosis is accompanied by increased transforming growth factor-β 1 (TGF-β1) gene and protein expression86 as well as an increase in procollagen type 1 gene expression.87

Hypoxia in AT induces chronic inflammation with macrophage infiltration and inflammatory cytokine expression.88 The adipocyte plays a significant role in extracellular tissue remodeling. For this task, the adipocyte produces multiple matrix metalloproteinases (MMPs) as well as tissue inhibitors of metalloproteinases (TIMPs) and other tissue proteases needed during tissue remodeling,89 all of which may significantly contribute to the tissue remodeling seen in LDS. Recent studies have linked expansion of AT (as seen in obesity) to resultant hypoxia, causing an increase in hypoxia-inducible factor 1α (HIF1α) expression.90 This stimulates multiple extracellular factors, including collagen I and III, as well as other components involved in remodeling the extracellular matrix, leading to fibrosis as the end result.91

A theory regarding an infectious pathogenesis of LDS was advocated by Cantwell and colleagues, who reported the presence of unusual acid-fast bacteria that could not be grown in culture in biopsies of several patients with LDS.92 This 1979 article dealt with the controversial issue of pleomorphic, nonrod-shaped, acid-fast bacteria being responsible for disease. It is widely accepted that other infections associated with repeated episodes of cellulitis cause lymphatic damage and subsequent changes in the AT.77 Particularly in the light of more recent discoveries that adipocytes are cells of the innate immune system and possible reservoirs of infectious organisms of all types, the role of infection as a contributing factor to LDS should be reconsidered and explored, perhaps in an analogous manner to that of the process leading to evidence of MTB DNA and dormant MTB in AT of the legs in EI.58,67

Clinical Findings

LDS has an acute inflammatory stage and a chronic fibrotic stage with a spectrum of intermediate77 and overlapping presentations. In patients presenting with the acute form (Fig. 70-7A), very painful, poorly demarcated, cellulitis-like erythematous plaques to purple somewhat edematous indurated plaques or nodules are seen on the lower legs, most commonly on the lower anteromedial calf area.77,93 Scaling may be present in some. The pain can be so intense that patients may not even tolerate a sheet while in bed. In this stage, patients are frequently diagnosed as having EN, cellulitis, or thrombophlebitis,77,93 and compression may not be tolerated. The acute form may last a few months or even a year.93 Although patients in this acute phase may present without obvious signs of venous disease,77 vascular studies show venous insufficiency in the majority.93 In the remaining group of LDS patients with normal venous studies, most have a high BMI, and given that obesity is usually associated with inactivity, these patients may not exert enough calf muscle contraction to maintain normal venous pressure in the lower extremities78; also, obesity is frequently associated with arterial hypertension.

The chronic form of LDS may or may not be preceded by a clinically obvious acute form.77 Chronic LDS features indurated to sclerotic, depressed, hyperpigmented skin (Fig. 70-7B). These findings occur on the lower portion of the lower leg, predominantly but not limited to the medial aspect, or in a stocking distribution. This is described as having an “inverted champagne bottle” or a “bowling pin” appearance.76,77,93

Although some patients may not describe associated pain or tenderness,93 pain is the most frequent symptom reported by others.78 Most of the patients are obese or overweight and have hypertension and evidence of venous abnormalities, but only rarely obstruction.78 Unilateral involvement is seen in 55%, localized plaque in 51%, and ulceration in 13% of cases78 (Fig. 70-8). Dermatosclerosis in patients with systemic sclerosis has been associated with pulmonary infarction and hypertension secondary to leg thrombi.94

Diagnostic tests to evaluate peripheral vascular disease should include ankle brachial index for arterial evaluation. Also indicated are venous tests: Dopplers to detect thrombi as well as color duplex sonography to detect direction of flow and presence of venous reflux.93 If the clinical findings are characteristic, biopsy of LDS is usually discouraged, due to the high incidence of subsequent development of ulcers at the biopsy site.77 But if necessary for diagnosis, a thin elliptical excision from the margin of an erythematous and indurated area, closed primarily with sutures, is recommended.77

Dermatopathology

Histopathologic findings reflect the evolution of the disease. Dermal stasis changes are present at any stage, and these include a variable degree of proliferation of capillaries and venules, small thick-walled blood vessels, extravasated erythrocytes, hemosiderin-laden macrophages, lymphohistiocytic inflammation, and fibrosis.53,95

In the subcutis, early lesions of LDS show a sparse infiltrate of lymphocytes in the septa, accompanied by central lobular ischemic fat necrosis; the latter is recognized by the presence of pale-staining, small anucleate adipocytes. Capillary congestion is also observed within fat lobules; this may be accompanied by endothelial cell necrosis, thrombosis, red cell extravasation, and hemosiderin deposition.53,95 Septal fibrosis and small foci of lipomembranous fat necrosis and fat microcysts have also been described to occur in acute lesions.95 In lipomembranous or membranocystic change, small pseudocystic spaces are formed within necrotic fat. The spaces are lined by a hyaline eosinophilic material believed to be the residue of disintegrated adipocytes and their interaction with macrophages.96 This distinctive membranous lining is highlighted by periodic acid-Schiff (PAS) staining and may present an arabesque pattern, with intricate undulating papillary and crenulated projections into the cystic spaces. However, membranocystic changes are not exclusive to LDS and may be found in any type of panniculitis.53,97

With progression of LDS, the spectrum of histopathologic changes encompasses increasing degrees of membranocystic fat necrosis, septal fibrosis, and thickening; an inflammatory infiltrate comprising lymphocytes, histiocytes, and foamy macrophages; and partial to extensive atrophy of fat lobules.53,77,95 Advanced lesions show septal sclerosis most prominently, with marked atrophy of fat lobules secondary to lipophagic fat necrosis, accompanied by microcystic and lipomembranous change and a marked reduction in inflammation.53,95 The most severe LDS shows marked fibrosis and sclerosis in the AT layer with little inflammation.77 In late stages, with fibrous thickening of the lower dermis and replacement of the subcutis by sclerosis, a punch biopsy of involved skin may not produce any subcutaneous fat.98

Treatment

Compression therapy is the major universally recommended treatment for LDS.77,78 Higher compression gradient (30–40 mm Hg) may be more effective, but lower class compression (15–20 mm Hg or 20–30 mm Hg) may be associated with higher rate of compliance, especially in the elderly, and has been shown to be effective in decreasing edema.99 One mechanism by which compression improves venous return and decreases edema is via tightening of vascular tight junctions, significantly elevating expression of tight junction proteins and inhibiting permeability of fluid into the perivascular tissue, thereby preventing progression of venous insufficiency.79,80 Stockings must be worn all day and not removed until bedtime, since even a few days without compression may lead to recurrence of the edema and inflammation.99

Stanazolol has been shown to be effective in LDS, with decrease in pain, erythema, and induration.77,100 Patients tolerated the treatment well, but potential side effects of this treatment include hepatotoxicity, and this may preclude its widespread use. In the United States, this drug is no longer distributed. Other anabolic steroids such as oxandrolone and danazol have also been used.101,102 Pentoxifylline has been successfully used in LDS cases with and without associated ulceration. A Cochrane Database System review of 12 trials involving 864 patients in 2007 concluded the drug was a useful adjunct to compression for treating venous ulcers and may be effective in the absence of compression.103 Other treatments for chronic venous insufficiency include horse chestnut seed extract,104,105 oxerutin,106,107 and flavonoid fraction.108

Ultrasound therapy was reported in two studies as being successful in reducing and even resolving hardness, tenderness, and erythema.109,110 Readily available through physical therapy departments, it is a simple and safe treatment of a painful and refractory condition and may be used along with Grade-2 compression therapy.109,110

Prevention

Since being overweight and obese are common conditions among affected patients, efforts to reduce weight are prudent.

Epidemiology

Infection-induced panniculitis (Infectious panniculitis, infective panniculitis) is panniculitis directly caused by an infectious agent.62 AT infection can be due to bacteria, mycobacteria, fungi, protozoa, and viruses.53,62,111 Primary infections produced by direct inoculation at a wound site (injury, surgical procedure, catheter, injection, acupuncture) usually result in a single lesion which may enlarge and spread locally.53,62,111 Secondary infections caused by sepsis and hematogenous spread may manifest as single or multiple lesions.53,62,111 In immunosuppressed patients, microorganisms may be numerous and identified on routine histopathology or special stains. In immunocompetent patients, microorganisms may be sparse and not seen on either routine histopathology or special stains, requiring positive cultures or serological studies for identification.53,62,111 Recent reports of infectious etiologies in association with various autoimmune disorders include Staphylococcus aureus panniculitis with juvenile dermatomyositis (DM),112 Mycobacterium- and Histoplasma-associated panniculitis with rheumatoid arthritis,113,114 and diffuse fusariosis with acute lymphobastic leukemia (ALL).115

Etiology and Pathogenesis

Clinical Findings

The clinical appearance of infectious panniculitis varies from fluctuant- or abscess-type lesions with purulent discharge and ulcerations to nonspecific erythematous firm nonfluctuant subcutaneous plaques and nodules, purpuric plaques, and EN-type lesions.62,111,129 Deep nodules or plaques may not always appear fluctuant, and pustules, fluctuant papules, and ulcers can be superimposed on top of the nodules.111 The most common sites of infection are the legs and feet, but upper extremities, trunk, and face may also be involved.62,111 Immunosuppression of varying etiology is the most frequent, but not universal, association.53,62,111 Immunosuppression is associated with more widespread abscess-type lesions containing nontuberculous mycobacteria, whereas in immunocompetent patients, granulomas are more commonly seen.111,130 Fungal infections occur in the following clinical settings: (1) localized environmentally injected panniculitis of mycetoma, chromoblastomycosis, and sprorotrichosis; or (2) panniculitis associated with systemic disseminated fungal infection that may be seen in individuals with normal immune functions, or with opportunistic fungal infection seen in immune compromised individuals.111,129 Clinical features vary with the setting, the infective organism and the underlying state of the individual's immunocompetence or immunosuppression.111,129

Histopathology

Evaluation of panniculitis for infections should include histopathologic studies with special stains for all types of organisms as well as culture and sensitivity testing of biopsy material. In the immunosuppressed patient, microorganisms may be numerous and more readily identified, but in immunocompetent patients, microorganisms may not be seen on either routine histopathology or special stains, requiring positive cultures or serological studies for identification.53,62,111 The anti-Bacille Calmette-Guérin (BCG) polyclonal antibody immunostain cross-reacts with many bacteria, mycobacteria, and fungi with minimal background staining and is advocated as a good screening tool for detection of microorganisms in paraffin-embedded tissue specimens when conventional stains are negative.53,111,131 Molecular PCR techniques have been utilized with mycobacterium infections.56–58,122 Histopathologic features may vary with the organism and its virulence, the host immune status, and the duration of the lesion at time of biopsy.62 Classified by some as a mostly lobular panniculitis,53 infection-induced panniculitis often presents a mixed septal and lobular pattern, and a predominantly septal, EN-like neutrophilic panniculitis has also been reported to occur in cases of bacterial as well as fungal etiology.62 The superficial dermis is the epicenter of inflammation in infections acquired by direct inoculation or by an indwelling catheter, in contrast to more deeply seated infections secondary to hematogenous spread involving the deep reticular dermis and subcutaneous fat.53

Generally, in a typical case, the subcutaneous fat contains a dense infiltrate of neutrophils and some admixed lymphocytes and macrophages, often with extension into the overlying dermis and with abscess formation a common finding.62,111 Patterson et al additionally noted distinctive subcutaneous features in the majority of 15 reported cases of infection-induced panniculitis of bacterial, atypical mycobacterial and fungal origin, independent of the particular causative microorganism. These features included hemorrhage, vascular proliferation, foci of basophilic necrosis, and sweat gland necrosis. Overlying changes such as parakeratosis, acanthosis, and spongiosis were seen in all cases in which the epidermis was available for examination. All 15 cases also had dermal findings, most commonly upper dermal edema, a diffuse and perivascular inflammatory infiltrate, often with prominent neutrophils, proliferation of thick-walled vessels, and focal or diffuse hemorrhage.62 With observation of any of these enumerated features, special stains for bacteria, mycobacteria, and fungi are imperative, and additional immunohistochemistry or PCR amplification techniques may be necessary.

Other histopathologic changes may point toward a more particular etiology. Suppurative granulomas formed by epithelioid histiocytes surrounding aggregated neutrophils may occur in panniculitis caused by atypical mycobacteria.53 Caseating granulomas, though rarely seen, raise suspicion for tuberculous panniculitis.111 A case of panniculitis secondary to CMV has been reported as a mostly septal panniculitis with many CMV inclusions contained within endothelial cells.132

Differential Diagnosis

Differential diagnosis includes α1-antitrypsin (α1AT) panniculitis, pancreatic panniculitis, traumatic, and factitial panniculitis. It is important to recall that presence of one of the above diagnostic types of panniculitis does not exclude infection, as in the case of α1AT panniculitis associated with lymph node histoplasmosis.133

Treatment

Treatment will vary and depend on the suspected or known organisms and their cultures and sensitivities. In cases involving bacteria such as MTB and parasites such as T. cruzi, their known capability to remain dormant in AT necessitates the use, for adequate treatment durations, of appropriate antibiotics, selected for their abilities to affect nonreplicating organisms.67,121

α1-ANTITRYPSIN-DEFICIENCY PANNICULITIS AT A GLANCE

• Clinical
  • ZZ-, MZ-, MS-, and SS-phenotype-associated panniculitis rare, with higher percentage (>60%) in ZZ cases; low levels of α1-antitrypsin are associated with emphysema, hepatitis, cirrhosis, vasculitis, and angioedema.
  • Subcutaneous nodules mostly located on the lower abdomen, buttocks, and proximal extremities.
  • Frequent ulceration and isomorphic phenomenon.
• Histopathology
  • Mostly lobular panniculitis without vasculitis.
  • Necrosis of fat lobules with a dense inflammatory infiltrate of neutrophils.
  • Splaying of neutrophils between collagen bundles of deep reticular dermis.
  • Large areas of normal fat adjacent to necrotic adipocytes.
• Treatment
  • Dapsone, doxycycline.
  • Homozygous ZZ patients with severe forms of the disease: supplemental intravenous infusion of exogenous α1-proteinase inhibitor concentrate or α1-antitrypsin produced by genetic engineering; liver transplantation.

Etiology and Pathogenesis

α1AT is a glycoprotein that accounts for 90% of the total serum serine protease inhibitor capacity in humans.134 It is produced and secreted mainly by hepatocytes, but also in small amounts by monocytes/macrophages and neutrophils,135–137 and is known to inhibit trypsin, chymotrypsin, leukocyte elastase, kallikrein, collagenase, plasmin, and thrombin among other proteases.134 α1AT may also help regulate protease stimulated activation of lymphocytes, phagocytosis by macrophages and neutrophils, and complement activation.138–141 It is an acute phase reactant, increased in times of stress.

α1AT deficiency is inherited as a codominant disorder, and more than 100 alleles have been identified.142,143 The α1AT phenotypes are classified according to gel electrophoresis migration/mobility as F (fast), M (medium), S (slow), and Z (very slow), but null variants that do not produce any α1AT and patients may have dysfunctional α1AT with normal levels.144 Homozygous MM, the most common phenotype, is associated with normal levels of α1AT, whereas those homozygous for ZZ have low levels at 10%–15% of normal, and those heterozygous for S or Z allele have levels in between. MS heterozygous individuals may have low normal serum levels.145 Due to the complex nature of these proteins, combination protein levels, or phenotyping and genotyping, have been recommended.144 Estimated prevalence of α1AT deficiency in Caucasians is 1 per 3,000–5,000 in the United States, with incidence in Caucasian newborns similar to that of cystic fibrosis.144

Clinical Findings

α1AT deficiency is most commonly associated with pulmonary and hepatic disease, leading to chronic obstructive pulmonary disease (COPD), hepatic cirrhosis, or hepatocellular carcinoma144; the ZZ genotype is at highest risk. There is no association of the null variant with hepatic disease, as it is the accumulation of polymerized α1AT in the liver that induces damage, and accumulation does not occur in this variant.144 The exact mechanism of injury is still controversial.144

Panniculitis uncommonly occurs in α1AT deficiency. Less than 50 cases have been reported146,147 in ZZ, MZ, MS, and SS phenotypes, with higher percentage (>60%) of ZZ cases as well as higher incidence in women (65%).146 Presenting in an age range from childhood (infancy) to the elderly, panniculitis is most frequently seen between ages 30 and 60.146,148 Patients present with painful erythematous nodules and plaques, but early lesions may have a cellulitic or fluctuant abscess-type appearance (Fig. 70-9A). Lesions may ulcerate and discharge an oily material or serosanguineous discharge9 (Fig. 70-9B) and resolve with atrophic scars.53 The lesions appear most commonly on the lower trunk (buttocks) (Fig. 70-10) and proximal extremities, but lower legs and other sites may be affected.53,146,150 As trauma or excessive activity may precede the onset of lesions in a third of patients,53,146 debridement is discouraged.53 α1AT panniculitis has occurred in patients with such conditions as hypothyroidism, mixed connective tissue disease, lymphoproliferative disorders, and infections, including a focus of histoplasmosis in a lymph node.133,149 Therefore, the presence of α1AT deficiency in association with panniculitis should not preclude a search for infection or other underlying medical problems such as autoimmune disorders, malignancies, or infections, since they may coexist. Cutaneous and subcutaneous necrosis can develop rapidly. Extensive involvement with α1AT panniculitis can be life threatening, and fatal cases have been reported.148,151,152 Erythrophagocytosis was noted in the biopsy of one of the patients with fatal panniculitis.153

Possible mechanisms leading to the development of α1AT panniculitis include lack of interference with the various proteases that lead to activation of lymphocytes, macrophages, complement, and lysis and destruction of connective tissue at sites of inflammation. Trauma to adipocytes may result in their activation, with release of the various adipokines and cytokines that are chemotactic to inflammatory cells, whose released proteases are unopposed due to absence of the α1AT, leading to severe damage in involved tissue.154,155 Animal models of soft tissue injury show elevated levels of IL-6 and MCP-1 and increased systemic inflammatory mediators.154

Pathology

Histopathologic findings vary with the age and type of lesion biopsied. Early in their development, nodular lesions may reveal edema and degeneration of adipocytes, with ruptured and collapsed cell membranes and a perivascular mononuclear infiltrate.153 Also reported at this stage is a mild infiltrate of neutrophils and macrophages in septa and lobules, with foci of early necrosis of subcutaneous fat. This may be accompanied by splaying of neutrophils between collagen bundles throughout the overlying reticular dermis, considered an early and distinctive diagnostic clue.156 More advanced lesions have masses of neutrophils and histiocytes associated with necrosis and replacement of fat lobules (Figs. 70-11A and 70-11B). A focal pattern of involvement is another distinguishing feature that may be appreciated, manifested by large areas of normal fat in immediate proximity to necrotic septa and fat lobules.157 Liquefactive necrosis and dissolution of dermal collagen may be accompanied by ulceration, and degeneration of elastic tissue may lead to septal destruction and the appearance of “floating” necrotic fat lobules.149,158 A rare occurrence is an exclusively septal pattern of mixed inflammatory infiltrate with a predominance of neutrophils.146,158 Neutrophils and necrotic adipocytes are less prevalent in late stage lesions, with replacement by lymphocytes, foamy histiocytes, and variable amount of fibrosis within fat lobules.149,159

Differential Diagnosis

Differential diagnosis of α1AT panniculitis includes other panniculitides that may ulcerate and drain such as the spectrum of infections, factitial disease, EI, and pancreatic panniculitis. Subcutaneous Sweet syndrome, rheumatoid arthritis, and myelodysplasia-associated neutrophilic panniculitis do not usually drain and ulcerate.160,161

Treatment

Many medications have been used in the treatment of α1AT deficiency panniculitis including colchicine, antimalarials, steroids, immunosuppressive agents, cytotoxic agents, dapsone, doxycyline, plasma infusion and plasma exchange, intravenous α1AT replacement therapy, and liver transplantation.148,150,162–167 Steroids, immunosuppressives, and cytotoxic agents were the least successful treatment options. Doxycycline and especially dapsone were very helpful in mild to moderate cases, but severe panniculitis required A1P replacement therapy.148,149,159,167 Panniculitis resolved with liver transplantation,168 and panniculitis acquired after liver transplantation was successfully treated with retransplantation.169

Epidemiology

Panniculitis in association with pancreatic disease is a rare occurrence, developing in 2%–3% of all patients with pancreatic disorders and appearing in the setting of acute or chronic pancreatitis, pancreatic carcinoma, or pancreatic pseudocysts.170–172 Although pancreatitis is most commonly due to alcohol abuse, cholelithiasis, or pancreatic calculi, medications and viral infections are also known etiologic factors.173,174 The cutaneous panniculitis may precede the diagnosis of the associated pancreatic disease by weeks to months in up to 45% of patients.170,173 Mono- or oligoarticular arthritis secondary to periarticular fat necrosis may be present in over half of patients.170 This triad of pancreatic disease, panniculitis, and polyarthritis may occur with either pancreatitis or pancreatic carcinoma.175 and is seen in less than 1% of pancreatitis patients172; joint disease may precede the diagnosis of pancreatic disorder.175 Abdominal symptoms may be mild or absent.175 Pancreatic panniculitis may also be seen in association with pancreatitis following renal or pancreas renal transplant,176,177 with SLE,178 and with hemophagocytic syndrome (HPS).179 Panniculitis associated with pancreatic disease may be fatal,170,172,180 with a mortality rate of up to 24% in one series175 and mortality rates of 100% in those with pancreatic carcinoma and 42% of 19 patients with pancreatitis in another series.181

Etiology and Pathogenesis

Pancreatic panniculitis has generally been attributed to release of pancreatic enzymes such as lipase, amylase, and trypsin into the circulation, promoting vascular permeability, leading to release of fatty acids from adipocytes and subsequent fat necrosis.172,182 However, there are reports of normal serum levels of pancreatic enzymes in association with typical pancreatic pannicultis.170 Additionally, incubation of normal AT with amylase and lipase and with pancreatitis patient serum high in those enzymes failed to induce fat necrosis in vitro,183 leading to suggestions that other mechanisms may be involved in the development of pancreatic panniculitis. Since many of the lesions appear on lower legs, these mechanisms may include venous hypertension, but likely also involve adipocyte generated cytokines and adipokines related to effects of high levels of free fatty acids170; resistin and leptin have been shown to be potential markers of extrapancreatic fat necrosis.184

Clinical Findings

The cutaneous lesions appear most frequently on the lower legs, especially the periarticular areas,170 but are also found on the arms, thighs, and trunk.170 Lesions often appear in crops, although single nodule pancreatic panniculitis also occurs.185 The lesions are ill-defined erythematous to red–brown edematous tender nodules, which in mild cases may involute and resolve with atrophic hyperpigmented scars,170 may have central “softer” areas or may become fluctuant, abscess-like, and drain oily material similar to lesions of α1AT deficiency panniculitis (Fig. 70-12A).170

Extracutaneous manifestations include periarticular fat necrosis with concomitant arthritis,170 painful medullary fat necrosis in bone,172 and pleural effusions and serositis.172,181 The presence of pleural effusions, alone or with arthritis, is associated with a high mortality rate.181 Eosinophilia may be seen in both pancreatitis- and pancreatic malignancy-associated pannicultis,181 and a pancreatic tumor in association with panniculitis, polyarthritis, and eosinophilia (Schmid's triad) imparts a poor prognosis.186

Histopathology

Fully developed lesions of pancreatic panniculitis demonstrate lobular fat necrosis with distinctive qualities (Fig. 70-12B). Adipocytes lose their nuclei but maintain peripheral outlines, forming characteristic “ghost cells” (Fig. 70-12C). With saponification, calcification occurs, producing fine granular basophilic deposits within and around individual necrotic adipocytes. The ghost cells are frequently aggregated in small clusters at the center of fat lobules, with a peripheral inflammatory infiltrate of neutrophils.53 In older lesions, necrosis and ghost cells are less evident, replaced by foamy histiocytes, multinucleated giant cells, lymphocytes, and eventually, fibrosis.53,98 Of note, pancreatic panniculitis has been reported to originate as a septal inflammatory process similar to EN in its earliest manifestation,187 and findings mimicking pancreatic panniculitis have been documented at the site of subcutaneous interferon β injections in the course of treatment of multiple sclerosis.188

Treatment is supportive and directed at the underlying pancreatic disorder. Since patients may not have abdominal symptoms, pancreatic panniculitis should be considered in the differential diagnosis of any panniculitis. Resolution of the lesions occurs with specific surgical treatment appropriate to the underlying disorder.173,175,189 Ocreotide, a somatostatin analog, and plasmapheresis have also been associated with resolution of pancreatic panniculitis.190,191

Epidemiology

Lupus erythematosus panniculitis (LEP) is a rare variant of lupus erythematosus (LE), which primarily affects the subcutaneous AT.192,193 LEP may appear as the sole manifestation of LE or may occur prior to or after the onset of discoid lupus erythematosus (DLE) or systemic lupus erythematosus (SLE).194,195 The incidence of SLE in patients with LEP has been reported to range from 10% to 41%, with the highest incidence seen in a Japanese series of 44 cases193,195,196; LEP occurs in only 1%–5% of patients with SLE.192,193 Although rare, LEP occurs worldwide, more frequently among women than men, with a female to male ratio of about 4:1.193,195,197 LEP is most common between the ages of 30 and 60, but may rarely be seen in childhood or even as neonatal lupus.53,193,194,198 When present in association with SLE, LEP tends to occur in SLE cases of lesser severity.195,197 There are a few case reports of LEP in more than one family member, or of family members with SLE unaccompanied by LEP.192,193 Patients with LEP may also have other autoimmune disorders such as Sjögren's syndrome and rheumatoid arthritis.192,193

Etiology and Pathogenesis

While a complete understanding of why LEP develops is still lacking, the innate immune system has been recently recognized to play a significant role in the development of SLE. Adipocytes are important cells of the innate immune system and function in pathogen recognition, activation of adaptive immunity, and as a reservoir for various microbes. All TLRs are expressed in AT. Adipocytes themselves express TLR1, 2, 3, 4, and 6, whereas TLR5, 7, 8, 9, and 10 are expressed on the nonadipocyte stromovascular fraction of AT.199 The reasons for “lupus panniculitis” may vary from genetic polymorphism of TLRs leading to inappropriate activation of innate immune systems (especially of the type 1 interferon system),200 to inappropriate interactions of adipocytes with inflammatory cells, to immune responsiveness against microbial and nonmicrobial antigens within AT. The localization of LEP to specific fat depots may be a clue to the functions of those adipocytes, or to a specific genetic aberration, or to the type of lymphocytes that are attracted to those AT depots.

In SLE, TLR7 and TLR9 recognize RNA and DNA patterns, respectively, and appear to provide a mechanism for recognition of self-DNA or self-RNA, with subsequent activation of the adaptive immune system and production of autoantibodies to nucleic acids and proteins bound to nucleic acids.201–205 Inhibitors of TLR7 and TLR9 can prevent disease in mouse models of autoimmunity,203 although deletion of TLR9 may enhance disease in some experimental models.206 Both receptors have been suggested as therapeutic targets.203,205,206 Genetic variations in TLR9 receptor has been shown to predispose to SLE in a Japanese series207 and regression of SLE was seen in a patient who developed an acquired TLR7 and TLR9 defect and antibody deficiency.208 SLE occurs much more commonly in women, and both TLR7 and TLR8 are encoded on the X chromosome, adding another layer of disease association.209 In addition, hydroxychloroquine, the most common treatment for all variants of SLE and LEP, has been shown to block intracellular TLRs in vitro.210

Clinical Findings

LEP lesions may be tender and painful and usually appear on the upper arms (lateral aspect), shoulders, face, scalp, hips, buttocks, breasts, and rarely on the lower extremities (Fig. 70-13).193–195 Orbital/ocular involvement may present with periorbital edema.211,212 The lesions are deep subcutaneous nodules without any surface changes, or with surface changes including erythema and DLE features such as atrophy, hyperkeratosis, hyper- or hypopigmentation, telangiectasia, follicular plugging, and focal ulceration and necrosis.193,194 The shoulder and arm sites are frequently associated with surface DLE lesions.193 Incidence of ulceration varies from <7% (of 44 Japanese cases)195 to 28% of 40 US cases.197 Individual lesions may enlarge and/or coalesce to involve large areas with atrophy.193 Areas of ongoing indurated panniculitis may coexist with DLE, subcutaneous atrophy, and bizarre scar formation.193 LEP resolves with depressed lipoatrophic areas that may involve much of the upper arms, shoulder, or buttock.193,194 Facial involvement may result in noticeably atrophic malar areas with severe cosmetic alterations. LEP is a chronic inflammatory disorder with yearly or periodic flares or long remissions.193 Lesions may appear at sites of trauma, including injections and surgical sites.193,194 Average disease duration is 6 years, with a range of less than 1 year to 38 years.197

Serological findings may be normal194 or abnormal.193,195 Patients without associated SLE may have low positive ANA titers and those with SLE tend to have higher positive titers.195 C4 deficiency may be found.194,213 Other laboratory findings in some patients may include rheumatoid factor, false positive Venereal Disease Research Laboratory (VDRL), specific ANAs, leucopenia, anemia, or thrombocytopenia.193

Histopathology

Findings may vary, with features of DLE in about 20%–30% of cases. These features include vacuolar alteration of the basal cell layer, thickened basement membrane,53,193,195 mucin deposition between dermal collagen bundles,53,193,195 and a superficial and deep perivascular inflammatory infiltrate of lymphocytes.53 Findings of basement membrane thickening or liquefaction degeneration and/or pigment incontinence may be noted in significant percentages of LEP patients without clinical epidermal changes.195 The AT shows a mostly lobular or mixed lobular and septal panniculitis, with lymphocytes, often with formation of lymphoid follicles (some with germinal centers), variable hyaline fat necrosis,53,195 hyalinized, and sclerotic septal collagen bundles associated with an interstitial infiltrate of lymphocytes and plasma cells53; occasional lymphocytic vasculitis in small blood vessels of fat lobules, presence of eosinophils in the inflammatory infiltrate in some cases,53 and membranocystic changes in some late stage lesions.53 Calcification and/or fibrin thrombi may also be noted in 10% of cases.195

In cases with only AT involvement and without other features specific for DLE or SLE, differentiation from subcutaneous T-cell lymphoma, although essential, can be very difficult. There are reports of a spectrum of subcutaneous lymphoid dyscrasias, with lesions originally diagnosed as LEP progressing to indeterminate lymphocytic lobular panniculitis and eventuating in a subsequent diagnosis of subcutaneous panniculitis-like T-cell lymphoma (SPTL).214 There may also be epidermal involvement in SPTL,215–217 making the distinction even more difficult; in two cases initially thought to be LEP, one with subcutaneous leg nodules demonstrating biopsy changes of interface vacuolar alteration and mucin deposition,218 and the other with vacuolar interface changes,219 the final diagnosis was fatal SPTL. Multiple wedge biopsies may be necessary to differentiate the αβ TCR-SPTL (SPTL-AB) or the more ominous γδ TCR (SPTL-GD) subcutaneous lymphoma from benign LEP.214,216,217 Hemophagocytocytic syndrome has been reported in SLE with panniculitis,220 but is more common in patients with SPTL-AB and SPTL-GD.216

Direct immunofluorescence biopsies are very helpful in the diagnosis of LEP, with positive findings in almost all SLE-associated LEP, and a high percentage of positive findings in LEP alone.193,195 Blood vessel deposition of immunoglobulins and complement varies.193,195 In those cases in which the histopathology does not provide a specific diagnosis, immunofluorescence biopsies may demonstrate the essential features for diagnosis.193

Immunhistochemical studies of LEP show a predominance of lymphocytes, with both αβT helper (CD4+) and cytotoxic (CD8+) lymphocytes mixed with (CD20+) B cells and plasma cells.196

Polyclonal findings are seen upon analysis of the TCR-γ gene,196 although there are additional reports that LEP can also show clonality, respond to antimalarials or corticosteroids, and not progress to clinical lymphoma, suggesting that some cases of LEP may represent an abortive lymphoid dyscrasia.221

In one study of biopsies from six patients with active LEP, high levels of type I interferon marker MxA were found in the epidermis and infiltrate of inflamed LEP lesions, along with numerous CD123+ cells with plasmacytoid morphology and expression of interferon inducible protein (IP10)/CXCL10. Sixty to ninety percent of the infiltrating cells in the lobular infiltrates comprised cytotoxic CXCR3+ lymphocytes expressing granzyme B and Tia1, leading to the conclusion that a type 1 interferon-driven immune response was present in active LEP lesions.222

In addition to SPTL, the differential diagnosis of LEP includes panniculitis associated with DM or morphea, as well as other panniculitides that may occur in patients with SLE such as pancreatic panniculitis and EN.

Treatment

Treatment is challenging and difficult, and there are no easily verifiable assessment tools to judge response to therapy other than clinical assessment of erythema, induration, and tenderness.223 Antimalarials are usually the first-line treatment for LEP193,194,197,224 and may be the only medications needed.193,224 When monotherapy with hydroxychloroquine is ineffective, combination with quinacrine has been used successfully.194,225 Antimalarials have a lesser effect in smokers,226–228 requiring at least 3 months to show effectiveness.194 Antimalarials interfere with inflammatory cytokines229 as well as TLRs.210 The effect of cigarette smoking on antimalarial treatment in LE still needs to be better defined, since cigarette smoke may both attenuate and enhance different aspects of the immune system and, in the airways, is considered able to suppress innate immune response to infections.230,231

Corticosteroids are effective and useful if the disease is active and severe.193,195,232 Corticosteroids may be used short term during the period of antimalarial initiation, but long-term use is generally avoided due to the chronic nature of LEP. Intralesional steroids are not recommended currently since they are traumatic and may induce atrophy. Other treatments include dapsone,233 thalidomide,223,234 cyclosporine,235 methotrexate,236 intravenous immunoglobulin (IVIG)236 and rituximab.237

Epidemiology

Clinical signs of panniculitis in association with DM are very rare, despite histopathological findings of focal nonspecific panniculitis in 9% (5/55) of biopsy specimens from patients with Diabetes Mellitus (DM).193,238 In a 2009 literature review of clinical panniculitis with nodular and plaque lesions in DM patients, 24 cases were identified, including six in children.239

Clinical Findings

Panniculitis associated with DM presents as painful indurated erythematous nodules and plaques on the arms, buttocks, thighs, and abdomen; these may ulcerate and result in lipoatrophy.240,241 The nodules and plaques usually present in association with the characteristic cutaneous manifestations of DM. They are rarely the sole manifestation.53,242 Juvenile DM is also known to result in lipoatrophy without preceding clinical panniculitis lesions.

Histopathology

Histopathological features are similar to those of lupus panniculitis,53 consisting of a mostly lobular panniculitis, or mixed lobular and septal panniculitis, with lymphocytic and plasma cell infiltrates, hyaline sclerosis and fibrosis of septal collagen bundles, progressive replacement of the fat by fibrosis, and calcification in 25% of cases.53,193,239 Lesions may be associated with vacuolar alteration of the dermal–epidermal junction, and late features may include membranocystic change.53 Dermal findings include mucin deposition or edema with perivascular lymphocytic inflammation.243

Differential Diagnosis

The main differential diagnoses are cellulitis, infection-associated panniculitis, and lupus panniculitis, which can be distinguished by a combination of clinical, laboratory, and histological findings.

Clinical Course

The panniculitis may precede, occur with, or appear late in the disease course,240 and subsides and flares with the overall DM activity.244 Infection can cause worsening of the panniculitis. Three patients have had infection associated with the panniculitis, two with S. aureus [including an immunosuppressed adolescent with both methicillin-resistant S. aureus (MRSA) and Acinetobacter baumanii] and one with Mycobacterium chelonae.239 Membranocystic changes indicated a worse prognosis.239

Treatment

As in therapy for DM, treatment for DM-associated panniculitis consists of corticosteroids alone,239 or corticosteroids and methotrexate,242,244 or other immunosuppressive therapies such as azathioprine, cyclosporine, or IVIG.240 Response of panniculitis in juvenile DM to hydroxychloroquine has been variable.245 Patients with cutaneous calcification may benefit from treatment with IVIG.246 Infection should be aggressively sought and identified prior to increasing immunosuppressive therapy; concurrent infection may require antibiotic therapy and reduction in immunosuppression.239

Panniculitis may also occur in patients with morphea (see Chapter 64) or systemic sclerosis (see Chapter 157).

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Histopathological Findings

Prognosis/Clinical Course

Treatment

Epidemiology

Subcutaneous fat necrosis of the newborn (SCFN) is a rare panniculitis that occurs in the first few weeks of life. It presents in full-term newborns with a preceding history of perinatal problems, including meconium aspiration, asphyxia, hypothermia (e.g., for cardiac surgery or ice pack application for supraventricular tachycardia), hypoxemia, seizures, sepsis, preeclampsia, factors requiring cesarean section, forceps delivery, severe neonatal anemia, maternal cocaine use, and/or failure to thrive.279–287 SCFN may be complicated by hypercalcemia, and rarely, by hypertriglyceridemia, hypoglycemia, thrombocytopenia, and anemia.282–284

Etiology and Pathogenesis

The cause in not known, but hypothermia or hypoxia is presumed to be involved. Possible explanations have included a biochemical defect in the composition or metabolism of neonatal fat, leading to crystallization, fat necrosis, and subsequent inflammation after cold stress.283,288 The hypercalcemia may be related to increased levels of 25-hydroxyvitamin D3–1α hydroxylase within the granulomatous infiltrate of lesions.289 Another explanation takes into account the presence of BAT in neonates along with its main function, which is to rapidly convert fat stores to heat under conditions of cold stress.290 BAT is widely distributed in the early years of life. At its maximal size relative to body weight at birth, when nonshivering heat generation is most needed, the presence and function of BAT relates to the immaturity of the heat regulating mechanism, providing the young with a “thermogenic jacket.”25,290 The BAT cells leak hydrogen ions across the inner membrane of the mitochondria to generate heat instead of creating ATP for other metabolic processes.291 The mechanism is complex, and uses uncoupling protein isoform 1 (UCP1), found specifically in BAT, cytosolic fatty acids, and Ca2+ ions.292

Clinical Findings

Lesions are sharply demarcated, erythematous to violaceous, firm, indurated nodules, or plaques located on the back, shoulders, arms, buttocks, thighs, or face, but usually not on the anterior trunk279,283 (Fig. 70-15A). In one case, MRI findings consistent with fat necrosis were seen in the abdominal wall as well as in the fat surrounding the liver, spleen, and a kidney.293 The subcutaneous nodules range in size from several millimeters to up to 11 cm in greatest dimension,280,294 may be single or multiple, and may be of irregular shape, although usually well defined.280 Rarely, fluctuant nodules may drain an oily or chalky white material.294 Lesions are not warm to touch280 and may vary from entirely painless280 to those requiring morphine for control of pain.284

Histopathology

Characteristically, SCFN is a mostly lobular panniculitis (Fig. 70-15B), with focal necrosis of the fat lobule and a dense inflammatory infiltrate of lymphocytes, histiocytes, and foreign body giant cells; a few eosinophils may insinuate between the fat cells. Many adipocytes retain their cellular outlines, but contain fine eosinophilic strands and granules as well as needle-shaped clefts in radial array53,98,283,295 (Fig. 70-15C). On frozen section, these clefts are occupied by doubly refractile crystals, representing triglycerides. Similar clefts and crystals may also be seen within the cytoplasm of the multinucleated giant cells.53,98,282,295 Late stage lesions may demonstrate fibrosis and calcified areas within fat lobules; the latter may also be seen radiographically.53,280

Differential Diagnosis

Differential diagnoses include cellulitis, erysipelas, and cold panniculitis (if cold-induced).285,286 In contrast to SCFN, the histopathology of cold panniculitis does not feature the presence of needle-shaped clefts within the subcutaneous AT.286 Other childhood panniculitides with the histologic finding of needle-shaped clefts in subcutaneous fat include sclerema neonatorum, which manifests with diffuse skin hardening in stressed infants,296 and poststeroid panniculitis.297–299 Only one infant with the clinical findings of both the diffuse hardening of the skin of sclerema and the violaceous nodules of SCFN has been described.300 Poststeroid panniculitis occurs in children, usually within 10 days (range, 1–40 days) after rapid cessation of high-dose systemic corticosteroid therapy.297,298

Clinical Course

SCFN is usually a benign process with an uncomplicated course and excellent prognosis. Lesions regress in a few weeks to 6 months, with some eventuating in atrophy.283,284,293 However, there are several metabolic complications that may occur during and even after resolution of the panniculitis.283 These include hypercalcemia,280,282,284,293,294 thrombocytopenia,282,283 hypertriglyceridemia, which appears to be related to the fat necrosis283,284 and anemia.283 Hypercalcemia may be asymptomatic and uncomplicated,281,284 or may become symptomatic, with failure to thrive, irritability, fever, vomiting, hypotonia, seizures, polyuria and polydypsia, and even death.280,294 Soft tissue calcification may occur and resolve without evidence of hypercalcemia,280 or calcium may deposit in the kidneys and cardiovascular system.282–284 The hypercalcemia may have a delayed onset up to 6 months after appearance of the skin lesions; therefore, serial monitoring of serum calcium levels is necessary.283,284

Treatment

SCFN nodules resolve spontaneously, and treatment should be conservative in most cases, except for fluctuant lesions that may benefit from aspiration to prevent rupture, infections, necrosis, and scarring.282,283 Serum calcium should be monitored with serial calcium determinations. If hypercalcemia is present, management by a pediatric endocrinologist will include hydration, use of the calcium wasting diuretic furosemide, and a low calcium and vitamin D diet.283,294 The diuretics that increase calcium excretion may also induce dehydration, requiring careful monitoring. If these measures are insufficient to control hypercalcemia, systemic glucocorticoids are used, as they interfere with vitamin D metabolism and inhibit active vitamin D production by the macrophages in the inflamed AT279,283,294; however, nephrocalcinosis may still develop in spite of response to systemic steroids.301 First and second generation bisphosphonates, including etidronate,302,303 clodronate,304 and pamidronate,305 have been used to treat hypercalcemia in SCFN. However, nephrocalcinosis may develop, despite a rapid response to pamidronate.306 The degree and duration of hypercalcemia and hypercalciuria may be the important factor in development of nephrocalcinosis; this calls for close early monitoring and recognition of hypercalcemia, since rapid therapeutic intervention to lower serum and urine calcium may be the best treatment modality for prevention of dystrophic calcification.306

Factitial panniculitis is a reaction in AT induced by external factors, usually injection of foreign materials. This may be iatrogenic due to injection of medications or cosmetic fillers, or secondary to cupping and acupuncture,320 or other means of trauma (accidental or deliberate). Factitial panniculitis is also associated with self-induced injections of various substances due to psychiatric disorder. History obtained from patients of injections of therapeutic agents or cosmetic fillers aids the diagnosis. Self-inflicted factitial panniculitis due to substances that may not necessarily leave a recognizable clinical or histopathologic footprint may be difficult to diagnose and requires a high index of suspicion.53,320–322 Factitial lesions present a spectrum of clinical findings, from papules and nodules to erosions or ulcerations with perfect round or angulated appearance322 (Fig. 70-16). Lesions due to blunt trauma will often be ecchymotic, show organized hematomas and hemosiderin deposits.322 Injections of various oily substances will lead to foreign body reactions with foamy histiocytes and pseudocystic spaces.53,322 Injection of medication and various other substances such as acids, milk, mustard, acids, alkalis, infected/contaminated materials, urine, and feces have been reported.53,322 Early lesional histopathology is usually predominantly neutrophilic, and later may show a granulomatous infiltrate.53,234 Due to the presence of macrophages and lymphocytes in AT, as well as the adipocyte's role as an innate immune cell producing multiple cytokines, materials injected into AT are treated as a foreign agent, with an inflammatory immune response with or without associated fat necrosis.53,234 Patients with self-induced factitial panniculitis suffer from mental illness and require psychiatric care.53,234 If iatrogenic, the causative action must cease. Surgical excision of the injected materials may be necessary.320,322