Panniculitis

10 Panniculitis Terence J, Ryan, DM, FRCP

From the Department of Dermatology, The Slade Hospital, Headington, Oxford, United Kingdom

In a recent editorial review of panniculitis, Patterson 1 emphasized the recent progress in our understanding of panniculitis, but prefaced this with the following: "It is not unusual at medical meetings to encounter physicians, both clinicians and pathologists, who express frustration over disorders of the subcutaneous fat. It is interesting to speculate on the reasons for this relative unpopularity of panniculitis. Despite the admitted importance of subcutaneous fat as a mechanical cushion and as a metabolic and thermal regulator, many people in our society spend inordinate amounts of time and money trying to get rid of it! The depth of the subcutis, when compared to that of the other compartments of skin (ie, the epidermis and dermis) may lend it an aura of "remoteness" for some dermatologists. There is a daunting clinical sameness to the panniculitides, since many of them at some stage in their development present as erythematous subcutaneous nodules that are frequently located on the legs. Things are little better for the dermatopathologist. Predictably, these conditions begin with acute inflammation, are followed by a granulomatous stage featuring foamy macrophages, and then resolve with varying degrees of fibrosis. The histologic septal-lobular dichotomy is sometimes diagnostically useful, but more often there is a mixed picture that adds to interpretative difficulties." The term panniculitis is used for a number of inflammatory conditions affecting the subcutaneous adipose tissue and includes the direct consequence of trauma to fat cells, biochemical injury such as occurs in pancreatitis, alphal antitrypsin (alpha1 protease inhibitor) deficiency or calciphylaxis, as well as the commonest cause, which is infection (Table 10-1). The clinical syndromes include erythema nodosum and some forms of nodular vasculitis in which the damage to the fat is probably secondary to a primary injury to the microvascular system rather than to the adipose tissue. The first significant description of panniculitis was that of erythema nodosum by Robert Willan, 2 as follows: "In the erythema nodosum, many of the red patches are large and rounded. The central part of them are very gradually elevated, and on the sixth or seventh day, form hard and painful protuberances, which are often taken for imposthumes, but from the seventh to the tenth, they constantly soften and subside, without ulceration. On the eighth or ninth day, the red color changes to bluish or livid, and the affected limb appears as if it had been severely bruised. This appearance remains for a week or 10 days, when the cuticle begins to separate in scurf. 120

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"The erythema nodosum usually affects the fore part of the legs. I have only seen it in females, most of whom were servants. It is preceded by irregular shiverings, nausea, headache and fretfulness, with a quick unequal pulse and a whitish fur on the tongue. These symptoms continue for a week, or more, but they usually abate on the appearance of the erythema, so that in the latter stages of the disease, the only sensations of uneasiness are languor, thirst, and disrelish for food." The next most signfieant description of panniculitis was erythema induratum by Bazin, 3 as follows: "...red indurated plaques from which, with digital pressure, the redness disappears momentarily, soon to return. One feels an induration on the skin and in the skin which reaches more or less deeply into the subcutaneous tissues. The redness, which is more or less dark, quite often violaceous and more marked in the centre, blends insensibly at the periphery with the normal colour of the skin. There is no itching in these plaques; digital pressure on them causes scarcely any pain. "This affection is observed commonly on the leg, more often perhaps in females than males. I have often found it on the legs of young laundresses, young women with all the a t t r i b u t e s of scrofulous corpulence and ruddiness. Its site of predilection is the lateral and lower part of the leg. At times one sees it located a little about the heel, along the achilles tendon. Finally, one may see it on the face, and I have seen it alternating with scrofulus opththalmia in that region." Kussmaul and Meier" described periarteritis nodosa, another pattern of deep dermal inflammation. Their first patient developed palpable rather than visible subcutaneous nodules on his trunk, Many years later, LindbergS, 6 described two patients with subcutaneous nodules whom he observed for 4 and 9 years, respectively, and emphasized a cutaneous form of the disease with a good prognosis. During the past 150 years, subcutaneous nodules involving the deep dermis and adipose tissue were most often described in association with other dermal elements such as purpura and urticaria. (;ougerot

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TABLE 10-1. Classification of Panniculitis (Lipogranuloma)

Primary Lobular Initiated within the fat cell Major trauma causing rupture Severe cold Calcification--hyperparathyroidism, calciphylaxis Pancreatic enzyme digestion Acute withdrawal of corticosteroids Other drugs Failure of interstitial clearance of lipid (may be initiated by minor degrees of: Alpha I antitrypsin deficiency, Idiopathic nodular panniculitis (lipogranuloma) Lymphoma and leukemia or neoplasia Infection within the Iobule--bacterial, fungal, or parasitic. Secondary Dermal and/or septal, including vascular (hypodermatitis) Infection--Bacterial, fungal or parasitic (cellulitis) Oil innoculation (paraffinoma, siliconoma) Vasculitic Microvascular-Soluble immune complexes may spare the vessel wall and localize in the interstitium); lupus erythematosus, dermatomyositis, and scleroderma Venous--Thrombophlebitis, liposclerosis Lymphatic--Lymphoedema Arterial Fat Atrophy Insulin, corticosteroid Granuloma necrobiosis Granuloma annulare, necrobiosis lipoidica, rheumatic nodules

described a chronic indeterminate septacemia with endocarditis c h a r a c t e r i z e d by d e r m a l nodules, e r y t h e m a t o p a p u l a r elements, and purpura. 7 Linked to these descriptions was the belief that infection was the principal cause of these disorders; the most important of infections was tuberculosis, which could explain both erythema nodosum and erythema induratum, but during the first

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Terence J. Ryan

50 years of this century, septacemia gradually became replaced by allergides. Bazin, ,~ of course, described the relationship to tuberculosis at a time when the mycobacterium was not even isolated, and it was later authors, Audry s and Galloway2,1° who doubted the tuberculous etiology of erythema induratum. Whitfield 1~ blamed the condition on cold and fatness of the legs. It was Montgomery, O'Leary, and Barker 12 who introduced the term 'nodular vasculitis,' partly in a negative sense, as it was applied to patients who clearly did not have t u b e r c u l o s i s , chilblains, e r y t h e m a nodosum, thrombophlebitis, or other changes due to chronic venous stasis. They saw the condition partly from a histopathologic standpoint: vasculitis with varying degrees of thickening and obliteration of veins and arteries, and with fibrosis, collections of foreign body giant cells and atrophy, involving the fat but without forming definite tubercles. Montgomery 13 later reviewed the progress of his concept and wished it to be preserved, albeit, as a rather vague entity, for it was of value in distinguishing the clearly defined conditions from those chronic inflammatory nodules of the legs due to "other causes." On clinical as well as histologic grounds, Fine and Meltzer H p r e f e r r e d to g r o u p nodular vasculitis, erythema induratum, and a chronic condition related to e r y t h e m a nodosum known as subacute nodular migratory panniculitis, under the single term "chronic erythema nodosum." Wilkinson ~ also reviewed the vascular basis of some nodular eruptions of the legs and did so in a helpful way because it was emphasized in some patients that the major factor was a reaction to cold, while in others it was a combination of cold and tuberculosis, and yet in others, phlebitis and thrombosis was predominant. In a few eases, hypertension was important. Thus began a period during which English writers searched for a more mechanistic classification, embracing thrombosis, stasis, cold, hypertension, bacterial infection, and allergy. The involvement of fat in inflammation was the basis of a further nosological debate.

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Weber-Christian Disease or Relapsing Febrile Nodular Nonsuppurative Panniculitis For almost 100 years it has been recognized that inflammatory conditions of the fat may be recurrent and may be associated with fever, and since some of these cases never produced a break in the surface continuity of epithelium, they were called nonsuppurative. While early cases were described without fever by Pfeifer in 19281~ and by Gilchrist and Ketron in 1916y the first authorative account was given by ParkesWeber in 1925 is who described relapsing nodular nonsuppurative panniculitis. It was Christian in 1928 who added the t e r m "febrile." In a classic monograph concerning rare diseases, Alice Carleton, 2° the dermatologist in Oxford at that time, reviewed the first 48 eases of this condition. She pointed out that the number of nodules could range from one to 20, affecting almost any part of the body. She also pointed out that they could be febrile or afebrile, painful or nonpainful, suppurative or n o n s u p p u r a t i v e , with i n t e r v a l s between eruptions ranging from a few days to several years. With regard to etiology, a wide range of infections could trigger the disorder, as could drugs. Alice Carleton put forward a classification of panniculitis that included: 1) secondary panniculitis adjacent to a phlebitis or tumor; 2) traumatic panniculitis due to mechanical injury, which included t r a u m a , cold, or subcutaneous injections of various chemicals, and she included bacterial causes. In all the above, the panniculitis was regarded as secondary and she differentiated a primary or spontaneous panniculitis that included the WeberChristian disease from a condition described by Rothmann-Maka,21, 22 and later by Baumgartner and Riva, 23 which were thought to be more common t h a n t h a t of W e b e r Christian's disease. In the Rothmann-Makai disorder the onset could be sudden, but the course was continuous and uninterrupted, low-grade, and without fever, and thus it was described as a disorder with a somewhat different rhythm to that of Weber-Christian

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Panniculitis

123

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F,a. 10-1. (Top, left): Erythematous nodule. Ifacute, symmetrical, and tender, would be labelled as erythema nodosum. If chronic, unilateral, and nontender, would be labelled as chronic panniculitis, nodular vasculitis, etc. (Top, center): A migrating or slowly spreading form of erythema nodosum or a panniculitis. (Top, right): A localized persistent nontender nodule variously labelled as panniculitis or nodular vasculitis. (Bottom,

left): A more diffusely spreading form of chronic erythema nodosum or panniculitis lasting many weeks. (Bottom, center): A nodular and ischemic form of panniculitis; in this case, associated with hyperparathyroidism and renal disease. (Bottom, right): A suppurative chronic form of panniculitis.

disease. Since this review, many authors have shown no confidence in the view that these disorders are distinct entities, and in this monograph we believe that the early deserip~ tions of panniculitis are of historical interest only and that it is not helpful to perpetuate such terms. Throughout m a n y subsequent descriptions, the overlap and variability of presentations are emphasized. The Rothmann-Makai syndrome is possibly worth noting for its absence of systemic symptoms occurring on the legs of children; 24 however, original descriptions by both these authors included virtually the entire spectrum of pannieulitis (Fig. 10-1). As panniculitis is often associated with thrombophlebitis, and sometimes also with arterial changes, it can be seen why Pierini, Abulafia, and Wainsfield 2'~ were prepared to group e r y t h e m a i n d u r a t u m , p e r i a r t e r i t i s nodosa, and idiopathic lipogranulomatous hypodermatitis (chronic e r y t h e m a nodosum renamed) in the same histological group. Moveover, when such patients are febrile, the disease has sometimes been reclassified by

some as Weber-Christian's nonsuppurative panniculitis. Even autoerythrocytic sensitization, otherwise known as psychogenic purpura, has been discussed under pannieulitis in the textbook by Pinkus and Mehregan. 26 One of the most recent reviews of pannieulitis, 27 based on a series of 121 patients, m e n t i o n e d n e i t h e r W e b e r - C h r i s t i a n nor Rothmann-Makai. In his classification, he retained e r y t h e m a nodosum as a recognizable entity in a larger group and studied separately 21 patients in whom infection, collagen v a s c u l a r disease, and p a n e r e a t i t i s were recognized as well as two other sub groups of eosinophilie histioeytosis and e r y t h e m a i n d u r a t u m . A b u l a f i a ~ has g i v e n m u c h thought to the problem of pannieulitis and has a sensible c l a s s i f i c a t i o n spoiled by overloading it with dermatologic jargon. According to his classification, the differential diagnosis of nodules in the deep dermis or subcutaneous tissue can be simply divided into four subgroups of pannieulitis, vaseulitis, disorders of connective tissue, or deep and specific infections. The disorders of eonnee-

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Terence J. Ryan

tive tissue with which he is concerned include the rheumatoid nodule, granuloma annulare, necrobiosis lipoidiea and scleroderma, and the deep and specific infections include tuberculosis, syphilis, and deep fungal infections. He points out that acute fat necrosis may be a consequence of a compromised circulation, whereas in chronic or slowly dying adipose, the tissue blood supply is preserved. He suggests that some of the histopathological confusion is due to factors such as whether the fat is normal or crystallized and whether the fat can be speedily digested. When fat cannot be removed, fibrosis or sclerosis confines and eventually replaces it. Abulafia notes that granulation tissue in the septa accompanies atrophy of the adipose tissue that, in view of the relationship of blood supply to lipid deposition described in the first chapter, is to be expected.

Acute Panniculitis Forstrom and Winkelmann 29described the clinical histopathological features of 34 cases of acute panniculitis. Fifteen of these had clinical findings of erythema nodosum; six had infectious lesions; and five had a WeberChristian-like condition with r e c u r r e n t febrile suppurative or nonsuppurative nodular eruptions; three of the five had amylase and lipase enzyme abnormalities with or without pancreatic disease. Five additional patients had acute panniculitis that would be termed erythema induratum or nodular vasculitis by most clinicians. Two patients had limited traumatic panniculitis and one patient had vasculitis. Concerning the etiologic factors, the authors pointed out that trauma played some part in all forms of acute panniculitis. Thus, even in the erythema nodosum, some nodules had occurred following local trauma. Either this is due to the release of fat into the interstitium, or as Ryan 3° pointed out, commonly in the vascular bed trauma is a localizing factor for circulating immune complexes, and also trauma can exhaust the vascular bed of its repair mechanisms so that it is less able to cope with a subsequent injury from immune complexes.

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Forstrom and Winkelmann's studies tended to separate off those cases of panniculitis in whom a clear infective etiology could be detected, such as one case of pericholangiolitic hepatitis, and another with abscesses of skin following a contact dermatitis, and yet another who had infected varicose ulcers of the legs. They also included a 14-year-old boy who had widespread septic lesions and who died of pneumonia and staphylococcal sepis. These same authors used the term "erythema induratum" and "nodular vasculitis" synonymously, and in their studies the evidence for tuberculosis was minimal or absent. The five patients who had recurrent febrile inflammatory and subcutaneous masses, and were termed "acute Weber-Christian disease," included two patients with pancreatic disease and one with chronic symptomatic cholecystitis. The localization of lesions by trauma was again reported. In the cases of erythema nodosum, the authors once again emphasized the high incidence of thrombophlebitis as an associated feature. Hemorrhage into the tissues was also a common finding. In the cases of Weber-Christian-llke panniculitis, the authors emphasized the literature devoted to a factitial pannieulitis. In later papers, Winkelmann has reinterpreted Weber-Christian disease as an alpha1 antitrypsin deficiency (see below). An understanding of panniculitis should be based on the clearly recognized mechanism of trauma and other forms of injury to fat or to the capillaries that supply it that releases fat into the interstitium, and on the role of proteases and the monocytic macrophage system in partnership with lymphatics in the clearance of fat. There is a significant increase in our understanding of panniculitis as a result of recognizing alpha1 antitrypsin deficiency, understanding the concept of calciphylaxis, or the role of cold as in fat necrosis of the newborn, as well as the role of infection and immune complex disease in erythema nodosum that follows a streptococcal sore throat or the erythema nodosum/ erythema induratum overlap of tuberculosis. It is reasonable also to consider the panniculitis of erthema nodosum leprosum, the

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Panniculitis

nodular migratory eosinophilie pannieulitis of gnathostomiasis, as well as the role of the pancreas and of autoimmune disease, such as lupus erythematosus. Trauma

Early studies of Maximov '~1 and Sabin ae first established that injury to the subcutaneous tissues attracted inflammatory cells from the blood stream, as well as activated resident cells. They described the influx of neutrophils and the conversion of the monoeyte into an epithelioid cell. The response to the inoculation of fat was shown to depend on the solubility of the fat in water and the capacity of the tissues to break down the molecule into diffusible material. Early studies showed that less-soluble cerebrosides from the brain and several vegetable oils, as well as tuberculins, stimulated epithelioid cell formation.ae, :~'~ Gray 36 e x a m i n e d biopsy m a t e r i a l from subcutaneous tissues of guinea pigs following the inoculation of a 1% solution of various synthetic triglyeerides and also of saline. The inoculations were at several different sites. In normal tissues, fibroblasts made up about two-thirds of the resident cells, whereas professional phagocytic cells made up about 25% of the cells and other cells like the mast cell, 0.1-1%. In normal tissues, neutrophils were never seen. After the inoculation of triglyeerides, the first observable change was dilatation of blood vessels and filling of the vessels with leucocytes. Phagocytosis by all resident cells occurred within a few hours and was followed by ingestion of white and red cells leaking from the blood vessels. Resolution occurred in about 2 to 3 weeks when tributyrin was injected. With several other triglyeerides, epithelioid cells developed as early as 12 hours after the inoculation and giant cells could be seen within 3 days. The degree of extravasation of red cells might relate to the activation of fibrinolysis that is more obvious with some fatty acids than with others, a: Certainly in these early studies, some fatty acids produced considerable extravasation of blood, whereas others produced none. The number and predominance of epithelioid

125

TABLE 10-2.Trauma and the Host. Abrupt rupture of fat cells _+ hemorrhage Cold Inoculations Insect bites Calciphylaxis Aggravating host factors Alpha1 antitrypsin deficiency Gravitational stasis Diabetes mellitus Hypertension Steroid withdrawal Bacterial allergy Drugs

cells peaked at about 12 days with the various fatty acids other than tributyrin. Ultimate resolution took place more or less at the same time after a few weeks. T r i l a u r i n and tristearin are both solid at body temperature and more indigestible, and thus not surprisingly therefore, giant cells developed within about 4-5 days and were most numerous at 14 days. With these agents there was very little extravasation of red cells. It is important to note that even the injection of saline could introduce neutrophils within 2 to 4 hours, leading to some refraetile droplets released from fat cells being taken up by the resident phagocytes within about 4 days, as in lymphoedema (see Chapter 3 and see Fig. 1013, page 139). Table 10-2 lists traumatic causes of pannicuulitis. B l o o d Vessels a n d L y m p h a t i c s

To understand panniculitis it is necessary to reflect on the relationship between the blood supply and lymphatic drainage to the fat cell when either or both are injured. As described in Chapters 1 and 3, the fat lobule has a rich capillary blood supply, virtually no lymphatic drainage within the lobule, and a rather minimal interstitium. It is inconceivable that fat could be injured without the capillary being affected, and it is equally inconceivable that damage to capillaries could avoid affecting the fat cells. Athough the fat lobule is circumscribed, this is not because it is bounded by a well-defined

126

Clinics in Dermatology

Terence J. Ryan

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capsule, but because of the pattern of the blood vessels around and within which adipocytes are formed during development. Between the fat lobules, the so-called septa carry the larger supplying and draining vessels, including the lymphatics, and these are surrounded by connective tissue resisting distortion and holding the fat in place. As seen in Figure 10-1, however, when one injects a dye into the dermis, it spreads not only into the septa but, after a very slight delay, into the outer regions of the fat lobules. There is thus no barrier" to the flow of protein-bound materials and the adipose tissue's interstitium is continuous with that of the dermis. Conversely, when material leaks out of the highly permeable capillaries within the normal fat lobule, it has no difficulty in finding its way into the septa, and probably the direction of flow within the interstitium is outward from the lobule into the septa. For this reason it is not surprising that when there is an inflammatory process that involves either the lobule or the septa, the outer edge of the fat lobule is inevitably involved. The arteries and veins of the panniculus

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are housed within the major septa. 3~ The arteries are small and muscular, where the veins are slightly larger (Fig. 10-2). The lymphatics may be even larger and within the septa contain smooth muscle and connective tissue cells. For these reasons it is not always easy to differentiate between the vessels in the septa, and especially when they are inflamed, it may become difficult to distinguish between a lymphatic and a vein. indeed, a highly inflamed lymphatic trunk that contains an elastic tissue network, may be mistaken for an artery (Fig. 10-3). It is important to realize that each fat lobule is an end organ; that is, it has a network of capillaries supplied by a single arteriole. It is also well recognized that the venular compartment of the capillary system tends to lie on the outside of the microlobule. The significance of this is that in inflammatory states in which the venule is p r i m a r i l y affected, r a t h e r than other areas in the vascular bed, most of the inflammatory state inevitably is seen on the other aspect of the lobule. If such an inflammatory state leads to impairment of flow through the venous

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327

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system, it inevitably impairs the inflow through the arteriole, which may lead to an acute ischemic necrosis of the entire fat lobule. There is a tradition throughout the history of the histopathological e x a m i n a t i o n of panniculitis to divide inflamatory disease into septal and lobular, depending where most of the inflammatory cells are found. It is usually emphasized that there is some overlap in these

FIG. 10-3. Large lymphatics from the dorsum of the foot showing transmural thickening of the vessel wall, with abundant fibrosis in the tunica media. The lymphatic on the left also demonstrates prominant cuboidal metaplasia of ordinarily flat endotheliumlining the luminal surface. (Photograph courtesy of I.O. Rada and N. Tudose, Timisiara, Romania).

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patterns. Indeed, it is difficult to see how such overlap can be avoided. Just as it was noted that even a little saline injected into a fat lobule may result in early accumulation of neutrophils, so throughout the literature of panniculitis, neutrophils are regarded as an early phenomenon, followed by lymphocytes and eventually, histiocytes, and fibroblasts. Ackerman :~s emphasized how in septal panniculitis, a vasculitis may be present and this

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Terence J. Ryan

may be in the small vessels, leucoeytoelastic vasculitis, or in large vessels, subcutaneous polyarteritis nodosa. He includes erythema nodosum as a condition that is without vaseulitis. This kind of classification of pathogenesis is not particularly helpful since it is difficult to believe that e r y t h e m a nodosum is not in some way a mierovaseular injury, and with respect to subcutaneous polyarteritis nodosa, it is difficult not to be confused by the frequent problem of thrombophlebitis and lymphangitis that occurs in the septa of the lower legs, where that condition is most commonly described. In trying to understand the concept of erythema nodosum, it may be relevant to consider the observations of Waksmana% 4° that immunological phenomena induce a wide range of patterns of inflammation, and these patterns are determined more by the configuration of the venous system than by any other factor. Throughout the literature on blood-borne noxious agents, immune complexes, bacteria, and viruses, it is accepted that the most likely site for vessel injury is in the capillary venules, where flow is slow and the vessels are most permeable. More proximal arterial damage occurs when there is vasos~asm, as in hypertension, or platelet aggregation, or coagulation as well as by any embolie phenomenon. As indicated in Chapter 3, the capillary venules of the fat lobule are e x t r e m e l y p e r m e a b l e and fluoreseenelabelled protein-bound materials in experimental systems, such as the hamster cheek pouch, revealed that the maximal permeability is often near fat cells. For this reason, one can suppose that the fat lobule will be a locus minores resistantiae, where soluble immune complexes will be deposited. This matters very little if they can be instantly removed and detoxieated. Thus, as explained elsewhere, the interstitium in the adipose tissue itself has very few maerophages, and there is no lymphatic system. In the fat lobule in healthy nonobese areas, it is probable that little damage may occur as maeromoleeules may travel by diffusion to the lymphatics and maerophages in the septa. It is more than conceivable, however, that in a site such as

the leg a combination of factors may contribute, especially in the obese, to a chronic inflammatory response within the fat lobule. Gravitational factors affecting blood flow will encourage the deposition of hematogenous agents betwen the fat cells. Exhaustion of the capillary endothelial systems for dealing with coagulation or thrombosis will interfere with the capacity of the vessel to repair itself from minor injuryY In a larger fat lobule, especially in aging fat, the gradual widening of the interstitium will lead to greater impairment of clearance of injurious agents, the distances become too great for simple diffusion within the interstitium. In the lower leg, the thermoregulatory and insulatory effects of adipose tissue will be influenced by cooling, and the effects of cold will further contribute to the localization of disease. The theory of lipodermatoselerosis41 has included observations on the deposition of fibrin within the tissues and the gradual exhaustion of the fibrinolytie system. They suggested that this interfered with the oxygenation of the tissues simply by impairing diffusion. Others have pointed out that cuffing of vessels leads to increased stiffness that may impair vasodilatation and blood flow ,~° (Fig. 10-4), and Tooke4e has produced evidence that some monoeytes may have difficulty in transversing such stiffened vessels, and this too will interfere with the processes of repair.

Venous Stasis Erthema nodosum and erythema induraturn are conditions that mostly affect the lower leg, and gravitational factors affecting the venous system would seem to play some part in this. Indeed, when a pannieulitis is generalized, it is then that one should look for systemic factors rather than local factors as an explanation. Biochemical diseases, like alpha, antitrypsin deficiency or severe septaeemie conditions, are not nearly so commonly localized to the lower leg. Children and adults spend as much as 10 hours per day sitting 4:~ and this posture also slows the circulation in the legs. 44The overall

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Panniculitis

effect is for venous hypertension in the leg to cause a gradual dilatation of the smaller veins and venules, and it discourages the normal emptying of the capillaries while encouraging congestion of those parts of the skin that are rich in venules. The consequences of leakage and the impairment of flow, particularly of white cells (Fig. 10-5A), are all part of the story of venous disorders of the leg. The features of the special vulnerability of the venous system have been summarized by Hauck 4'~as follows: 1. As the vessels dilate, the blood flow through them inevitably slows; under such circumstances red cells clump together and it becomes more difficult for blood to pass through channels (Fig. 7-4, page 91 and Fig. 10-6), 2. Normal plasma concentration of fibrinogen influencing the postcapillary tendency to red cell aggregation. 3. Normally plasma leaks from blood as it flows through the far end of the capillaries and the small vessels of the venous tree. As this portion is lost, the blood becomes concentrated, contains relatively more fibrinogen, and develops an unstable flow--in fact, it can become very sluggish or stop--even in normal conditions. Thus these small vessels beyond capillaries do not make a very good job of letting the blood through or keeping it in good shape. Moveover, they do not control a proper distribution of fluid between and within the vessels. When several factors work together to encourage intravascular clotting, endothelial injury of a considerable rise in blood viscosity, the blood flow in the mierovaseular system of the skin often ceases long enough to cause isehemie necrosis. This is seen in a number of skin deseases, including chilblains and other forms of perniosis, collagen diseases such as seleroderma, rheumatoid arthritis, lupus erythematosus, and dermatomyositis, and other disorders classified as vasculitis. Whenever there is stasis in the capillary bed, blood tends to be diverted through alternative or preferential channels. Even in normal tissues there are ample anastomoses to take on such a shunting role; they merely

129

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FIG. 10-6. Flow through a capillary bed such as that of adipose tissue may become so reduced in inflammatory states that the supplying arterial suffers from hypoxia, disintegrates, and ischemic necrosis of a Iobule is a consequence.

have to dilate to become significant. Persistent stasis and ischemia invariably encourage an increase in the number of actively shunting vessels. Some of these may be newly formed vessels, but much depends on whether the affected area also has some stimulus to angiogenesis. The stasis seen in carcinomatous tissue is usually associated with very considerable new vessel formation, stimulated probably by metabolic demands and by the irritation of various by-products and growth factors. Any endothelial injury in association with coagulation seems to result in endothelial proliferation, provided that complete infarction does not occur. Such granulation tissue is seen most commonly in the septa of adipose tissue. In allograft rejection, venous block is more usual and damaging than is arterial occlusion, and the distribution of autoallergic lesions depends on the distribution of veins in the affected organs29 Species variation in the morphology of lesions due to tuberculin inoculation can be explained by differences in venous pattern. Delayed hypersensitivity reactions, as a class, can be expressed only where veins and venules are numerous. Waksman 4° illustrated that when the dermis is poorly endowed with venules, then hypersensitivity reactions present in the adipose tissue in a clinical pattern similar to erythema nodosum. It seems at least possible that the

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frequency with which the shin is a site for erythema nodosum might have something to do with both gravitational stasis and the relative paucity of vessels in the upper dermis at that site. One important contribution made by veins, as distinct from arteries, is the greater degree to which fibrinolysis is activated by their endothelium46, 47 Cuffing a limb with a sphygmomanometer temporarily increases fibrinolysis in it, 48 but it may be reduced in areas of prolonged stasis. Thus fibrinolytie activity is lower in the legs than in the arms. 49 Nevertheless, transient venous occlusion or prolonged elevation restores the activity in the legs to levels found in the arms. Less activator than normal is found in the endothelium of veins predisposed to thrombosiss° or to vaseulitis. 51Isaaeson at al. 52studied local fibrinolysis in the arm veins of 11 patients suffering from pannieulitis of the lower leg. In four patients, no spontaneous fibrinolytie activity could be demonstrated in the blood taken from the arm, and in another five patients, venous stasis-enhaneed blood fibrinolysis was diminished. Histoehemieal estimation of the fibrinolytie activity of the venous walls revealed markedly low values for the arms of six patients, and in three patients samples were obtained from superfieial leg veins. Fibrinolytie activity was reduced in two of these. Following observations on skin surfaet lipids 37 (in unpublished studies by Dawber and Ryan) of the effect of a wide range of saturated and unsaturated fatty acids added to a fibrin plate, it was clear that fibrinolysis might depend on the particular mix of fatty acids released from lipid breakdown.

Clinics in Dermatology

heterogenous vascular patterns predisposing to inhomogeneity within the vascular system. Such inhomogeneity predisposes to ischemia, and a damaged capillary bed often may ultimately impair flow through the incoming "end" artery, which, as a consequence, may itself suffer from ischemic changes. In all inflammatory states involving blood vessels, there is a spectrum ranging from a simple increase in permeability to a gradual increase in leucocytoclasia, and there comes a point in the spectrum when flow ceases and ischemic necrosis quickly follows. The clinical spectrum that one may observe in fat ranges from angioedema, such as the pattern of tender edema featured in pressure urticaria, through the clinical picture of erythema nodosum in its acute and chronic forms to the chronic granulomatous phase, and finally, the acute ischemic necrosis that leads to death of fat. The factors determining which part of the spectrum presents clinically are complex and clinical overlap occurs so that not all lesions behave in the same way in the same patient. Even with a common trigger like tuberculosis or a hemolytic sore throat, the clinical acuteness or chronieity may be a variable. The role of immune complexes should be thought of in terms of the factors determining antigen release and antibody response, as well as clearance determined in part by the complete activation of complement. Paraproteinemia and deficiency of various components of the complement cascade can account for panniculitis, as in the cases of IgG1 Kappa paraproteinemia and C1 inhibitor deficiency described by Widmann and Schifferli.53 Lupus panniculitis has been reviewed by Winkelmann and Peters 54 (see below).

Vasculitis versus Panniculitis The Role of Infection The debate as to whether some inflammatory states of subcutaneous tissues are due to a primary vascular injury or a primary fat injury is naive. Within the fat lobule, all the factors encouraging vaseulitis can be found. These include impairment of flow, excess permeability, exhaustion of repair mechanisms, and angiogenesis with new

Throughout the history of panniculitis and of the diseases listed above, the role of infection has been a predominant feature. Ryan,3° in his discussion of mierovaseular injury, reviewed a literature that indicated how erythema nodosum could be a consequenceofalmostanyinfeetion.Morereeently,

October-December 1989 Volume 7 Number 4

Panniculitis

Moragas 27 has also re-emphasized the role of infection in all forms of panniculitis. Rudzki et al., ~5reviewing the role of bacterial allergy in skin disease, gives some two dozen references to the concept of foci of infection. Several of these are sources of other references to what was at one time of major interest to the medical profession that has been forgotten because of greater interest in immunology. These authors refer to 20 or so additional reports of remissions of disease following surgical removal or spontaneous clearance of loci of infection or following a course of antibiotics. These reports coincide with a period in which the use of autologous vaccines had been associated with an increased incidence of fulminant vasculitis. Rudzki et al. 5~ tested 1,977 individuals with streptococci antigens and 779 individuals with staphyloccocal antigens. They were able to induce erythema nodosum-like lesions in 19 subjects, allergic vasculitis in 12, and urticaria in three. They emphasized that such reactions could be provoked only at the height of active disease and were rarely seen during remission. These tests were more likely to be positive when there was gross infection, probably because the tissues were in some way altered or "prepared" by such infection. Vasculitis was the commonest disease pattern associated with positive skin tests, and it seemed that the vascular system is the locus minoris resistentiae for bacterial hypersensitivity. The ability of skin vessels to react to skin tests is transient and often expires after active disease has subsided. Rostenberg, 5~ in an article that drew the attention of dermatologists to a number of diseases that could be explained by the Swartzmann phenomenon, also referred to changes and reactivity at the height of the disease. Winkelmann and Ditto '~7 also described allergic vasculitis following the inoculation of bacterial antigen. The particular role of the streptococcus in nodular vasculitis has been demonstrated by the results of intradermal tests, passive transfer tests, and lymphocyte transformation in 20 patients studied by Ky et alY Parish 59 stated "after infection, many persons form antibody to

131

bacterial antigen capable of forming tissue damaging complexes, but vasculitis may only occur in those in whom sufficient antigens released into the blood to form complexes and whose tissues are 'prepared' for the penetration of the complexes into the vessel walls." Parish observed that patients with vasculitis had less circulating antibody to bacterial antigen, particularly to streptococcal protein and lipopolysaccharide cellular antigen, as did patients recovering from similar infections with that of vasculitis. It is now recognized that antibody excess is associated with soluble immune complexes that are less harmful to the tissues. Parish and Rhodes G° were the first to detect streptococcal antigen in vasculitis, and in nodular vasculitis in particular. They found streptococcal antigen in 14 of 80 cases of vasculitis, and in four cases of erythema nodosum. Wilkinson 15 found active infection in nine of 28 cases of nodular vasculitis; in three of these, resolution followed treatment of a streptococcal throat infection, and in four, the vasculitis was related to a symptomless dental abscess and cleared after the tooth had been extracted. This situation was also emphasized by Duperrat and Monfort~1and Vilanova. 62 It was mycobacterial infections that had been most consistently proven to be the cause of nodular vasculitis. In the United Kingdom, this has become much rarer than is currently the case in the developing world where both tuberculosis and leprosy account for recurrent erythema nodosum. The debate as to whether one should treat all cases of nodular vasculitis with antituberculous t herapy remains unresolved. 63-6~ This latter study of 90 patients (eight of whom had erythema nodosum, 44 had erythema induratum, and 38 had other forms of panniculitis), tuberculosis was proven in 31 of these. G n a t h o s t o m i a s i s 67

Gnathostoma is a form of larvae migrans that characteristically migrates through the subcutaneous tissues and produces a wellmarked eosinophilic reaction. It is common in Equador and Southeast Asia where fish

132

Terence J. Ryan

may be eaten in its raw or partially cooked state. A panniculitis presents as an erythematous edematous migratory plaque. Around the third to sixth day of infestation, eosinophils begin to increase. Initially, there may be a patchy, mixed, cellular reaction, including leucocytoclasis and foci of lymphoid cells, but by the seventh to eleventh day, the adipose tissue is completely infiltrated by eosinophils and only a small percentage of lymphocytes. The eosinophils are found between the adipocytes and in the septa. There is usually edema and there may be hemorrhage. There may be collections of eosinophilic material of the flame type described in Well's syndrome (Fig. 10-8). By the twelfth to fifteenth day, the eruption is beginning to resolve and with no necrosis, and there is complete recovery without fibrosis. Occasionally the larvae may be found within the adipose tissue, usually at sites where there is some hemmorrhage. The presence of an accompanying blood eosinophilia is an important accompanying sign of larvae migrans infection.

The Effect of Cold on Skin Circulation In certain areas of the skin, especially over fat pads, the skin can be cooled on a chilly day by the application of a glass vessel containing water at 20 ° C, and such cooling persists for as long as 1 hour 6s (quoted by Haxthausen). ~9 Haxthausen emphasized that the fat arms and legs of women were subject to repetitive cooling effects. The skin is often red, cyanosed, and traversed by numerous small dilated venules, and it is cool. The lower leg and outer aspect of the upper arm are most affected by these changes, 69and several groups of workers cited by him have emphasized that the capillary changes of perniosis are associated with vasoconstriction of arteries and veins. Chilblains (Fig. 10-8) have the histology of vasculitis, the principal feature being dilated congested vessels, endothelial proliferation, and infiltration by white cells. Kyrle, 7° however, observed similar changes even in the skin surrounding chilblains. The subcutaneous tissues tend to be thickened, and the

Clinics in Dermatology

superficial capillaries are widely dilated, aneurysmal, and inclined to angiokeratomous changes. Dittrich 71found that cold affects the veins more than the arteries, and that they tend to be thickened. The blood in these dilated superficial vessels is almost stationary. Perniosis is a general term useful in describing changes that have a common etiology and pathogenesis. The tendency is for arteries and veins to contract and for capil-laries to dilate, and this results in the blood being trapped in the capillary bed, through which it flows sluggishly. Haxthausen 6',~ suggested that in this situation there is a lowering of nutrition in the skin and a greater' opportunity for microembolism. He listed the localization of tuberculosis, leprosy, and syphilis at such sites. Chilblains are seen on the thighs of plump girls riding horses on cold mornings, especially if tight pants are worn. It is a common occurrence in the UK. In the USA, it has been called "Equestrian cold panniculitis. ''72 The authors emphasize the venular nature of the, disorder, especially in the septa of the fat. In neurovascular bundles an inflamed vein was regularly identified adjacent to a completely normal small muscular artery.

Nodular Lesions Associated with Cold Exposure Wilkinson 15described three groups of such

patients: 1) Young obese women, otherwise healthy; 2) Young or middle-age women, immobilized by rheumatoid arthritis or poliomyelitis; 3) Menopausal women with Raynaud's phenomenon and acrocyanosis. Jepson 73 described a group of middle-aged females with rheumatoid disease who also had cold hands and who developed painless nodules of the lower legs after exposure to cold; these initially were bright pink and later purplish, and were annular or serpiginous in shape. There could also be cayenne pepper spots, seen microscopically to be dilated capillary tufts; in addition, follicular perniosis and hypertrichosis were present.

October-December 1989 Volume 7 Number 4

FIG. 10-8. Cold-induced

Panniculitis

injury

is

133

usually

associated with acral tissues that are well covered by fat. A Thick ankles of erythrocyanotic and perniotic legs. B The plump upper arms of a patient with mild perniosis. C In the mini-skirt era, increased fat deposition immediately above the knee coincided with an increased localization of vasculitic disorders at that site in the winter.

The inflammatory reaction to fat depends on the ease at which it can be cleared and this in turn depends on solubility. Animal fat becomes solid when cooled, and the melting point depends on the ratio of saturated to unsaturated fatty acids. It is a feature of the immature newborn and of the elderly that the ratio is tipped in favor of a higher melting point so that relatively minor degrees of cooling can lead to crystalization. This in p a r t i c u l a r explains the subcutaneous fat necrosis of the newborn. The t e m p e r a t u r e of the skin depends so much on its blood supply, and it is perhaps not surprising that the sick child with e x t r e m e hypoperfusion of the peripheries and the skin may develop diffuse generalized hardness of the fat known as selerma neonatorum. 74

Sclerema Neonatorum a n d S u b c u t a n e o u s Fat Necrosis of the N e w b o r n

Cooling is a stimulus for the burning of fat, so that within the first 6 hours of life, serum lipids rapidly rise. In p r e m a t u r e or debilitated infants this does not occur. The biochemical composition of fat of the newborn contains more palmitic and stearic acid and less oleic acid than in adults. The former are saturated and latter is a monounsaturated fatty acid. A very small change in the relative proportion of these acids alters the melting point of neutral fat. Cooling of the skin leads to crystallization. Such cooling may occur more readily in the p r e m a t u r e infant or in babies suffering from major infections, dehydration,

f134

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Terence J. Ryan

FiG. 10-9. Sclerema neonatorum is a condition of the first week of life in which fat solidifies in the cold and histologically reveals needle-shaped clefts and crystals. (From Fretzin and Arias 1987, used with permission.)

or other stresses. Sclerema neonatorum is a condition that was first described in the 18th century. 75Important reviews were by Hughes and Hammon 7G and Underwood. 77 It was KnopfelmacheV s who recognized the characteristic needle-shaped crystals. The condition appears around the third or fourth day after birth, or less commonly, later during the first 6 weeks of life. The skin develops a boardlike stiffness due to rapid solidification of subcutaneous fat. It often begins in the lower extremities and spreads upward. The skin seems greatly thickened, firm, and tethered. Histologically, the adipose tissues contain needle-shaped clefts in radial array (Fig. 109). This reaction in the fat excites a relatively sparce inflammatory reaction. The disorder is usually fatal, children often dying of septacemia. There is some evidence that steroids may be beneficial and there were r e p o r t s of i m p r o v e m e n t with e x c h a n g e transfusion. The disorder has to be distinguished from the subcutaneous fat necrosis of the newborn that appears during the first weeks of life. This was first described by Cruse 79 in Russia and often first appears on the cheeks. It is more patchily nodular than the board-like stiffness of sclerema. In general, the children are less premature or generally diseased than in sclerema. The nodules begin as edematous and erythematous or violaceus lesions, and

may become fluctuant with actual fat necrosis, and eventually, there may be calcification. The actual etiology of the condition is unknown, but exposure to cold is one cause, s° It is important to exclude other causes of panniculitis, such as hypercalcemia or alpha1 anti-trypsin deficiency. Histology shows fat crystallization with a nonspecific inflammatory infiltrate of lymphocytes, histiocytes, and even foreign body giant cells. The clinical appearance is similar to that of poststeroid panniculitis which also often affects the face.

Popsicle Panniculitis This was described by Epstein and Oren 81 and is a form of panniculitis of the cheeks of children, usually unilateral, occurring in summertime as a result of sucking ice cubes or popsicles.

Poststeroid Panniculitis This is a condition that occurs following rapid reduction in steroid administration for diseases such as rheumatic fever, leukaemia or the nephrotic syndrome. The histology is similar to that in subcutaneous fat necrosis with needle-shaped clefts and crystallization. Nodules are usually asymptomatic, s2 Localized atrophy is also a feature (Fig. 8-2).

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Panniculitis

f135

Calcifying Panniculitis with Renal Failure--A Tissue Calciphylaxis Syndrome

a biopsy revealed urate crystals within the adipose tissue (Fig. 10-12 A, B).

Anderson et al s3 described a patient with calcifying panniculitis with fat and skin necrosis associated with uremia and hyperparathyroidism. More recently, Laurent et al. s4 have reviewed the phenomenon of calcifying panniculitis with renal failure. They reported a 64-year-old obese diabetic woman who presented with hard and tender nodules in the deep dermis of her abdomen and thighs. These nodules later extensively necrosed. The patient had been discharged from hospital a month earlier following prolonged treatment for renal failure and secondary hyperparathyroidism. During that time, the fat of her abdomen and thighs had been injected with subcutaneous heparin in its calcium salt form and sulphate of tobramicine that contained a calcium chelator. A biopsy of the fat showed extensive calcification in the spaces between the fat cells and in the adventitia of the blood vessels, confirmed by later microscopy (Fig. 10-10). The calcification was particularly prominant around the mitochondria of many cells. The authors referred to the work of Selyes4-89 who showed that hyperparathyroidism, or the administration of vitamin D, sensitized animals so that if they were then subjected to trauma or the injection of metallic salts or albumin, calcification of the tissues was a consequence. Much of the damage that is done by such calcification is a consequence of ischemic necrosis due to the now wellrecognized calicification of the vascular system in, for instance, chronic renal insufficieny with hyperparathyroidism (Fig. 1011). But in these cases of calcifying panniculitis, damage to fat by calcium deposits within the adipocytes, especially around their mitochondria, may induce this inflammatory response that leads to the tissue necrosis.

Alphal antitrypsin--Alphal Protease Inhibitor Deficiency

Gouty panniculitis Le Boit9° described a male patient with three subcutaneous painful nodules in whom

Important for the understanding of panniculitis was the observation that alpha1 antitrypsin deficiency may be associated with a panniculitis? 1-1°1 When small blood vessels or fat cells are damaged, processes such as fibrinolysis, blood coagulation, and phagocytosis are activated, and fine controls, which include inhibition of proteases, are important if inflammatory reactions are to be quickly resolved. Apha, antitrypsin is a serine protease inhibitor (recently renamed as alpha1 protease inhibitor) that can inhibit trypsin, kallikrein, collagenase, elastase, thrombin, and leukocytic enzymes. It may interact with C3 and prevent opsonisation.'03, ,o4 Alpha, protease inhibitor is also important for the suppression of activation of lymphocytes and all phagocytic cells, and it is not surprising therefore that it is signficant in the pathogenesis of panniculitis. '°2 The understanding of alpha, protease inhibitor deficiency may shed light on the subcutaneous fat necrosis of the newborn, since in the newborn control of proteases may be defective. The t r e a t m e n t of alpha~ protease inhibitor deficiency panniculitis has been reviewed by Pittelkow. ~°~ In this review, the authors state that 21 cases of panniculitis have been described since 1972 and the initial episode of panniculitis could occur in any age group. Relevant to Weber-Christian disease, it is important that in 13 of the first 21 reported cases, fever was an accompanying feature. The authors described how alpha, proteinase inhibitor concentrate can result in marked clinical improvement and eventual healing. They also point out that dapsone is an effective therapy in those who are unresponsive to oral corticosteriods and immunosuppressive agents, possibly through an antioxidant effect because alpha1 proteinase inhibitor is easily oxydized,lo6 The laboratory evaluation demonstrated markedly decreased

136

Clinics in Dermatology

Terence J. Ryan

FIG. 10-10 A. Calcifying panniculitis associated with renal deficiency. Calcium deposits in the space between the adipose cells (X 2,400). Insert--Needlelike crystals of calcium apatite (X 14,000). (From Laurent et al, 1987.) r :

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levels of serum alpha1 antitrypsin, ranging from 0.2-0.4 g/1 (normal range more than 1.5 g/l) for their laboratory. Treatment with their concentrate (obtained from Cutter biologicals) consisted of 60 mg/K weekly by intravenous infusion. Maintenance therapy with dapsone prevented recurrences. S u e t al 1°2 emphasize that neither the "ghost-like" cells nor the calcification of pancreatic disease are a feature of alpha1 proteinase inhibitor deficiency. Giant cells are also mostly not a feature, whereas neutrophils are prominant. All this is to be expected in a disease where proteolysis is activated.

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This was first described by Chiari ~°7 and a few years later by Hansemann. 1°8 The skin lesions begin on the legs, and more rarely on the buttocks or trunk, as painless and sometime spainful erythematous subcutaneous nodules. The pancreatitis, which may be due to a carcinoma, is often asymptomatic. The rapid uptake of fat by macrophages gives rise to the nonspecific picture of foam cell~,; (Fig. 10-13). It was Szymanski and Bluefarb 1°9 who described pathognomonic histo-

October-December 1989 Volume 7 Number 4

Panniculitis

137

FiG. 10-11. Calcification of the walls of blood vessels occurs in hyperparathyroidism secondary to chronic renal insufficiency. The subcutaneous adipose tissue is the focus of the ischemic necrosis.

pathological findings of subcutaneous focal fat necrosis in which there were "ghost-like" cells with thick shadowy walls and no nuclei; large areas of calcification are seen (Fig. 1014). Hughes et al, u° reviewing 36 cases of pancreatitis and 17 cases of carcinoma of the pancreas in the literature associated with subcutaneous fat necrosis, noted the male preponderance and a signficant association with alcoholism. They emphasized that the patients presenting complaint is often unrelated to abdominal symptoms, the chief complaints being skin nodules 65% and joint pain 35%, particularly of the ankles. They referred to damaged synnovial tissue and to lytic bone lesions. They also emphasized the high incidence of an acinous type of pancreatic carcinoma. Forstrom and Winklelmann 6~; examined biopsy specimens for amylase and lipid, and found these raised even when the urinary amylase level was normal. Normal skin from three control subjects showed no amylase or lipase activity. Panapokke ~'~ injected lipase, amylase, and trypsin separately into fat without any ill effect, but when they injected them together, a lesion was evoked.

Fibrosis

In Chapter 9, some of the fibrotic changes t h a t occur as a g e - r e l a t e d and possibly endocrine-associated disorders of the adipose tissue of the breast and thighs are described. Some similar changes have been labelled lipomembranous or membranocytic and were described in panniculitis. Originally, Nasu et a1112noticed such changes in the skin and bone marrow of a patient with pseudanophylic leucodystrophy of the cerebrum, but it was also d e s c r i b e d in the adipose tissue of diabetics; 1~:~ in ischemic necrosis of the legs 114,1,~from arterial disease; and by Poppiti et al '~6 who recognized the changes as of many causes. Alegre et ab 17 believe that it represents a form of fat necrosis that can be observed with venous liposclerosis as part of a local or systemic ischemic and hemorrhagic inflammatory process. We prefer to downgrade the term and suggest that it is a banal process of fibrosis of the adipose tissue that should not be equated with panniculitis in particular (Fig. l0 15 A, B). Alegre et al, '17 reviewing 1806 biopsies of

Terence J. Ryan

138

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Clinics in Dermatology

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subcutaneous tissues, found only 13 specimens with membranocystic changes. It is probable that this relatively normal event is obscured by the more intense pathological states encompassed in their study.

Cytophagic Histiocytic Panniculitis Crotty and Winkelmann us reviewed five cases of panniculitis in which a principal

FIG. 10-12. S u b c u t a n e o u s painful nodule in a patient with gout. A Biopsy revealed urate crystals. B The characteristic crystals shown up by polarized light (photograph courtesy of Leboit).

histologie feature was the phagocytosis of red cells and lymphocytes by histiocytes infiltrating the adipose tissue. They stated: "some histiocytes are so stuffed with cells and cell particles that they are well called 'bean bag cells.'" The histiocytes are otherwise benign but are found infiltrating liver, spleen, lymph node, and marrow as well as other organs. In all five patients, the panniculitis was the presenting or major clinical feature, but one

October-December f1989 Volume 7 Number 4

139

Panniculitis

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of fat by macrophages occurs especially in conditions such as pancreatitis in which the lipid is massively released from the adipocyte. Macrophages become distended with a foamy cytoplasm and become known as foam cells.

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patient had been ill with recurrent fever and leucopenia for at least 10 years. The patients developed a bleeding diathesis, mucous membrane ulceration, fever, and progressive liver dysfunction before dying from hemorrhage or pneumonia. The authors concluded that cytophagic panniculitis and other regional histiocytosis may represent a proportion of the spectrum of histiocytic disease that includes malignant histiocytosis, adult histiocytosis X, familial hemophagocytic reticulosis, and viral associated hemophagocytic syndrome. Aronson et al, 119 reviewing fatal panniculitis, described four further cases of this syndrome and speculated how macrophages might be activated by lipid. They quote Jaffe et a112° who suggested that erythrophagocytosis in T-cell lymphoma might be secondary to lymphokines produced by neoplastic T cells; however, it was noted as a nonspecific feature of the inoculation of triglyeerides.36 In a recent review from the Mayo Clinic, the authors gave the impression that histiocyte cytophagic panniculitis is a disease entity. Because both local and systemic coagulation defects are common associations of panniculitis, however, and phagocytosis of red cells occurs wherever red cells are extravasated, as described by early authors injecting 'fat' into the tissues, one of us (TJR) believes histiocytic cytophagocytosis is nonspecific and does not justify delineation.

The Mayo Clinic article finds virtually no other consistent factor present to support such delineation and no estimation of important phenomenon such as alpha1 antiproteinase deficiency is given.

Supressor T-cell Panniculitis Solomon et a1121described panniculitis and fever in a 3 1/2-year-old girl in whom the pathology was confined to the fat lobules. Fat cells were infiltrated by suppressor eytotoxie OK T8 lymphoeytes, while the circulating lymphoeytes were normal. They could find no etiological factor in spite of an extensive search. They pointed out that suppressor T cells are very sensitive to steroid therapy and the lesions disappeared promptly on 40 mg/ M2 of prednisone. They postulated an autoimmune reaction directed against the adipoeyte.

Helper T-cell Panniculitis The role of the lymphocyte in the destruction of adipocytes is discussed by Honma 122 in a study of erythema nodosum-like lesions in 18 patients with Beh(iet's disease. They postulate more easy access of the lymphocyte into the interstitial space between adipoeytes and its basement lamina (see p 80, Fig. 3-

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OctoberLDecember f1989 Volume 7 Number 4

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FIG. 10-15. Fibrosis is a nonspecific consequence of inflammation of fat. It begins as a widening of the septa and gradual replacement of the periphery of the fat Iobule, usually as the consequence of the organization of protein and other macromolecules. Two examples from lymphedema--A Septal fibrosis; B Complete replacement of adipose tissue in a case of African elephantiasis. (Previously published by Ryan, 1975.)

3; also Fig. 10-16 and Chapter 16). Interaction between lymphocyte and macrophage causes phagocytosis of the fat by the macrophage and gradual loss of fat and collapse of the adipocyte (Fig. 10-17). They believe this to be a helper T-cell syndrome activating macrophage phagocytosis, and hence the excess production of lysosomal enzymes and oxygen intermediates• As described above, such oxygen intermediates are believed to inhibit alpha: antitrypsin. Billings :2,~ also suggested a similar pathogenesis for the slowly developing inflammatory nodules that expand annually, leaving central lipoatrophy that they observed in three children who had insulin-dependant diabetes mellitus, Hashimoto thyroiditis, seronegative rheumatoid arthritis, hepatomegaly, hyperglycemia, and insulin resistance with hypertriglyceridemia.

Lupus Profundus It was Kaposi 124 who first described subcutaneous nodules in lupus erythematosus, and this was well described by Arnold 12'~in a commentary on lupus erythematosus profundus. Most commonly it is diagnosed in association with discoid lupus erythematosus. The histopathology is a lymphocytic infiltration of the fat that may progress to fat necrosis and calcification• The fibrosis, which is associated, shows necrobiosis and hyalinization of the collagen. The diagnosis is favored if the typical serologic findings, which range through the spectrum of lupus erythematosus and the immunofluorescent findings of linear IgG and complement in the overlying epidermal bsement lamina, can be detected. ~ It should be thought of in every asymmetrical localized subcutaneous atrophy.:2%12~

Clinic:~ in

Terence J. Ryan

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Eosinophilic Cellulitis After several preliminary papers, Wells '29 brought together his experience of 12 cases in which cutaneous swellings erupt suddenly or evolve over two days, which may be single or multiple and have the appearance of cellulitis with redness and edema. Some of the lesions evolve to stiffening of the skin, reminiscent of morphea with a color that is a characteristic

greenish gray. The characteristic feature is edema and deposition of fibrin between connective tissue fibers with a massive infiltration of eosinophils. Linear microscopic deposits of brightly eosinophilic material are described as flame figures (Fig. 10-18). While Wells described predominantly a dermal syndrome, Winkelmann and Frigas 12s described an eosinophilic panniculitis. They write about 18 patients in which 32 specimens

October-December 1989 Volume 7 Nutuber 4

Panniculitis

143

FIG, 10-16. Erythema nodosum infiltration of lymphoctyes between the cells follows an earlier protein edema. The adipocytes quickly lose their lipid content so that consequently the adipose tissue shows a greater variety of adipocyte size and replacement.

are examined and an eosinophilic infiltrate was observed in the fat with more than 25 eosinophils per high-power field. Neither they nor Wells suggest that this is a specific entity, and they imply that there is an overlap with Well's syndrome, as well as other forms of vaseulitis, the eosinophilic infiltration being nonspeeific and of multiple etiology. They do, however, suggest that it is a manifestation that is steroid responsive.

involved. Inevitably, there is an inflammatory state involving blood vessels and the condition can only be diagnosed in the stages at which it is clear that there is dissolution of the fat cells to a degree that is greater than can be explained by damage to the blood vessel. There is usually loss of nuclear staining, and "ghosts" of fat cells include a varying degree of calcification in the peripheries of the cell.

Nodular Cystic Fat Necrosis Lobular Panniculitis U n d e r c e r t a i n c i r c u m s t a n c e s such as t r a u m a , calciphylaxis, and pancreatitis, damage to the fat is distinctly primary, so that materials leak into the interstitium of the adipose tissue and the capillary venous system, and eventually the septa are only secondarily

H u r t and Santa Cruz 131 described five patients with a distinct post-traumatic subcutaneous nodular lesions suggestive of a mobile-encapsulated lipoma, but actually being a nodule cystic fat necrosis (Fig. 1019). Nodules presented in the subcutaneous tissue over the elbow or hip and fully

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FIG. 10-19. Encapsulation of fat in the condition nodule cystic fat necros,s. It shows normal adipose tissue in the center of the lesion, but in the peripheries there are necrotic and "ghost-like" cells adjacent to a well-defined capsule. (Photograph courtesy of Hurt.)

developed lesions with totally or nearly totally encapsulated by thin fibrous tissue, all contain well-preserved outlines of enucleated adipocytes, and there was no inflammation or saponification, but there were areas of partially encapsulated nodules and calcification. They suggest that it is due to trauma with rapid vascular insufficiency and subsequent fibrous capsule formation, but recognize that some cases have no previous history of trauma. They suggest the lesion must be histologically distinguished from lipoma, and hence it is placed in this chapter on panniculitis. The similarity to the descriptions of the development of lipoma at pressure points discussed in Chapter 8, however, is worth noting.

Associated Liver Disease Lipodystrophies and pannieulitis are commonly associated with liver disease. The exact

cause of this may be uncertain, but it should be recognized that alpha1 antitrypsin deficiency contributes to liver disorders, and that many of the infections that contribute to panniculitis, such as virus disease or toxoplasmosis, also may affect the liver. One should recognize systemic lupus erythematosus, and also the damage that can be done to the liver by raised blood levels of fatty acids due to destruction of adipose tissue.

Associations with Neurological Disease This is rare but it is described and reviewed by Alegre et al 1~2 in their discussion of panniculitis in childhood. Presentation of a neurological syndrome i n association with panniculitis should alert one to hepatic encephalopathy, or to the possibility of vasculitis or systemic lupus ereythematosus and to the various viruses or organisms such as toxoplasmosis, which directly infect the brain.

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Disseminated Intravascular Coagulation Although not well documented in the literature, purpura fulminans due to disseminated intravaseular coagulation frequently involves the subcutaneous adipose tissue. The release of lipid from adipose tissue is both a consequence and a contributing factor to disseminated intravascular coagulation, and the terminal event in many eases of severe pannieulitis is hemorrhage or thrombosis.

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34. Tomkins EH. Qualitative differences in the reaction of the large phagocytic mononuclear cells to subcutaneous injections of the phosphatides and cerebrosides of beef brains. Anat Rec. 1939;73:52. 35. Tomkins EH. A comparison between the reactions of the large phagocytic mononuclear cells to subcutaneous injections of individual lipids and to mixtures of the same lipids. South Meal J. 1940;33:154-159. 36. Gray ME. A s u p r a v i t a l s t u d y of the cells of s u b c u t a n e o u s tissue in g u i n e a pigs, following injections of synthetic triglycerides. Am J Anat. 1940;67:361-391. 37. Dawber RPR, Nishioka K, Ryan TJ. Fibrinolytic activity of skin surface lipids (letter). Lancet: 1971;1:193. 38. Ackerman AB. Histologic diagnosis of inflammatory skin disease. Philadelphia: Lea & Febiger, 1978:1 863. 39. Waksman BH. The pattern of rejection in rat skin homografts and its relation to the vascular network. Lab Invest. 1960;12:46-48. 40. Waksman BH. The distribution of experimental autoallergic lesions. Its relation to the distribution of small veins. Am J Pathoh 1960;37:673-93. 41. Browse NL, Burnand KG. The cause of venous ulceration. Lancet. 1982:2:243 245.

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71. Dittrich O. Uber frosstchaden. Archly fur Dermatololgie und Syphilis. 1929;157:1-27. 72. Beacham BE, Cooper PH, Buchanan CS, et al. Equestrian cold panniculitis in women. Arch Dermatol. 1980;116:1025 1027. 73. Jepson RP. Raynauds' phenomenon--a review of the clinical problem. Ann R Coll Surg Engl. 1951;9:3551. 74. Fretzin DF, Arias AM. Sclerema neonatorum and subcutaneous fat necrosis of the new born. Pediatr Dermatol. 1987;4:112 122. 75. Uzembenzius JA. Partus Octimistris vivis, frigidus et rididus. Emphemerides Academia Caesareo Leopoldinse Carolinae Naturae Cutiosorum. 1722;9:62-64. 76. Hughes WE, Hammond ML. Sclerema Neonatorum. J Pediatri. 1948;32:676 692. 77. Underwood M. A treatise on disease of children. Philadelphia: WB Saunders, 1973;110. 78. Knopfelmacher W. Untersuchungen uber das Fett in Sanglingsalten und uber das Fettscleren. Jahrb Kinderheilkd; 1978;45:177-203. 79. Cruse P. Ein fall von sclerodermie (sogenannt sclerodermis adultorum bei saighing, St Petersburg). Ztschr: 1875;5:306-309. 80. Taib A, Douard D, Maleville J. Subcutaneous fat necrosis and brown fat deficiency. J Am Acad Dermatol: 1987;16:624-625. 81. Epstein EH Jr, Oren ME. Popsicle panniculitis. N Engl J Med. 1970;282:996-997. 82. Silverman RA, Newman MD, Levine MJ, et al. Posteroid panniculitis: a case report, Pediatr Dermatol: 1988;2:92-93. 83. Anderson DC, Stewart WK, Piercy DM. Calcifying panniculitis with fat and skin necrosis in a case of uraemia with autonomous hyperparathyroidism. Lancet: 1968;2:323-325. 84. Laurent R. Thiery F, Saint-Hillier Y, et al. Panniculite calcifiante associee a une insuffisance renale: Un syndrome de calciphylaxie tissulaire. Annales Dermatologie et Venereologie. 1987;114:1073-1081. 85. Selye H, Jean P, Veilleix R. Role of local trauma in production of cutaneous calcinoisis by dihydrotachysterol. Proceedings of the Society for Experimental Biology and Medicine. 1960;104:409-410. 86. Selye H, Sister Adrian Marie, Jean P. Systemic and topical factors involved in the production of experimental cutaneous calcinosis. J Invest Dermatol. 1961;37:7-12. 87. Selye H, Nielsen K. Histogenesis of experimental cutaneous caleinosis. Acta Morphol Hung. 1961;10:327. 88. Selye H. Calciphylaxis. Chicago: Chicago University Press, 1962:1-552. 89. Selye H, Gabbiani G, Tuchneber B. Calciphylaxis and the parathyroid glands. Rec Prog Horm Res. 1964;20:33-58. 90. Le Bolt PE, Schneider S. Gout presenting as lobular panniculitis. Am J Dermatopathol. 9:334-338.

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Address for correspondence: Terence J. Ryan, DM, FRCP, Department of Dermatology, The Slade Hospital, Headington, Oxford 0X3 7JH, United Kingdom.