Erythema nodosum is an acute, painful, erythematous, nodular eruption. The nodules, which range from 1 to 5 cm or more in diameter, are usually situated on the anterior aspect of the lower legs; more rarely, they occur on the arms, soles,^{14.15. and 16.} or trunk. There may be associated fever, malaise, and arthralgia. The lesions subside after a period of approximately 2–6 weeks or so. Up to one-third of cases may recur. Erythema nodosum usually occurs in young adults, but childhood cases occur. ¹⁷ Encapsulated fat necrosis (‘mobile encapsulated lipoma’) is a rare complication (see p. 474). ¹⁸ Erythema nodosum may be associated with sarcoidosis, ⁴ Sweet’s syndrome,^{19. and 20.} Behçet’s disease,^{21.22. and 23.} celiac disease, ²⁴ inflammatory bowel disease, intestinal bypass syndrome, ²⁵ eosinophilic esophagitis, ²⁶ carcinomas,^{27. and 28.} carcinoid tumor, ²⁹ leukemia, ³⁰ lymphoma,^{31.32. and 33.} hairy cell leukemia, ³⁴ tularemia³⁵ or with streptococcal, ⁴ staphylococcal, ³⁶ meningococcal, ³⁷ campylobacter, ³⁸ giardia, ³⁹ salmonella, ⁴⁰ histoplasma, ⁴ mycoplasma,^{41. and 42.} chlamydial, ⁴³ mycobacterial,^{44. and 45.} dermatophyte, ⁴⁶ sporotrichosis, ⁴⁷ human immunodeficiency virus, ⁴⁸ or yersinia^{49. and 50.} infections. Various drugs have been incriminated, ⁵¹ including isotretinoin, ⁵² sulfonamides, penicillin, ciprofloxacin, ⁵³ minocycline, ⁵⁴ leukotriene-modifying drugs such as zileuton, ⁵⁵ azathioprine, ⁵⁶ salicylates, iodides, gold salts, echinacea, ⁵⁷ hepatitis B vaccine, ⁴¹ capecitabine, ⁵⁸ and also oral contraceptives. ⁵⁹ The triad of erythema nodosum, bilateral hilar lymphadenopathy, and polyarthralgia (Lofgren syndrome) represents an acute, benign, and usually self-limiting form of sarcoidosis. ⁶⁰ It is said to be the most common form of sarcoidosis in Spain. The erythema nodosum is present at the onset in most cases. ⁶⁰ Radiotherapy may also trigger the onset of erythema nodosum.^{61. and 62.} In about one-third of cases the etiology is obscure.

The pathogenesis of erythema nodosum is unknown but it may represent an allergic response to infection or systemic disease. Reactive oxygen intermediates, released by primed neutrophils, may play a role in the pathogenesis. ⁶³

In erythema nodosum migrans (subacute nodular migratory panniculitis), a centrifugally enlarging plaque with central clearing develops on the lower leg. It is usually solitary, but several lesions may exist.^{64.65.66.67.68. and 69.}

In chronic erythema nodosum there are non-ulcerated lesions located mainly on the legs which may persist for years. There is no migratory tendency. ⁷⁰

Treatment for erythema nodosum includes non-steroidal anti-inflammatory drugs, corticosteroids, and potassium iodide. Chronic cases have been successfully treated with infliximab⁷¹ and with adalimumab. ⁷⁰

In necrobiosis lipoidica the necrobiotic and granulomatous process, followed by fibrosis, may extend from the dermis into the subcutaneous septa, producing marked widening of these structures, which encroach on the fat lobules. This condition is considered further in Chapter 7, page 181.

In scleroderma and its localized cutaneous variants (morphea) there may be extension of the process from the dermis into the subcutaneous fat. There is marked fibrous thickening of the septa, and often lymphoid collections are present at the junction of the thickened septa and the fat lobules. ⁷⁹

There are variants of morphea in which only the subcutaneous fat and/or fascia are involved. The terms subcutaneous morphea and morphea profunda are often used interchangeably for these variants, although morphea profunda has been proposed as the appropriate diagnosis when both fat and fascia are involved and subcutaneous morphea for cases with involvement of fat only (see p. 306). A panniculitis usually accompanies the fasciitis associated with eosinophilic fasciitis. ⁸⁰ Septal fibrosis and hyalinization are obvious features. There are often small lymphoid collections but not lymphoid follicles with germinal centers. Plasma cells are usually present. They were the predominant cell type in two siblings with the disease. ⁸¹

A case of linear scleroderma with an intense plasma cell infiltrate in the dermis and subcutaneous fat has been reported. ⁸² Nodular aggregates of plasma cells were present in the fat lobules and the thickened interlobular septa. Scleroderma is considered further in Chapter 11 (pp. 304–310).

Erythema induratum and nodular vasculitis were originally regarded as one entity. However, it has been the practice for the last 50 years or so to recognize two variants – one of presumptive tuberculous origin (erythema induratum, Bazin-type) and the other of non-tuberculous origin, known as nodular vasculitis or erythema induratum, Whitfield-type. ³ The tuberculous group was regarded as a tuberculid (see p. 559) on the basis of the persistent failure to culture Mycobacterium tuberculosis from lesional tissue or to see organisms on acid-fast stains. The tuberculous origin of the Bazin subtype was assumed on the basis of strongly positive reactions with the Mantoux test, the presence of active tuberculosis in other organs in some cases, and the favorable response of the skin lesions to antituberculous therapy.^{83.84.85.86.87. and 88.}

The advent of PCR-based methods has led to the detection of mycobacterial DNA in from 30 to 80% of cases of erythema induratum–nodular vasculitis, defined on the basis of clinical presentation and a lobular granulomatous panniculitis on histology.^{89.90.91.92.93. and 94.} However, a study of 10 cases in 2005, failed to demonstrate Mycobacterium of any species by PCR techniques. ⁹⁵ As no significant differences have been consistently demonstrated between cases with detectable mycobacterial DNA and those without, it does not seem tenable to continue the separation of erythema induratum and nodular vasculitis. ⁹⁶ After all, erythema nodosum has multiple etiologies (including tuberculosis), and it is considered as one condition.^{44. and 97.} Thus the wheel has turned full circle and once again there is a single (composite) entity. It has been suggested that patients presenting with this disease should have an ELIspot (T-SPOT.TB) assay for detecting active or latent tuberculous disease. ⁹⁸

Erythema induratum–nodular vasculitis is characterized by recurrent crops of tender erythematous nodules, usually with a predilection for the calves, although the shins are sometimes involved as well. The nodules may coalesce to form one or more plaques. Uncommonly, lesions may develop in other sites such as the buttocks and arms. Although it was originally regarded as a disease of young adult females, a wide range of ages can be affected. Lesions occasionally ulcerate; they may heal with scarring. ⁹⁹

Erythema induratum–nodular vasculitis appears to be a disease of diverse etiologies, mycobacterial infection being one of them. Presumably other infections may be involved. To date, only hepatitis C has been incriminated.^{100.101. and 102.} An association with ulcerative colitis has been reported. ¹⁰³ Both erythema nodosum and a lobular panniculitis with vasculitis can be produced by brucellosis. ¹⁰⁴ A paraneoplastic presentation has also been suspected. ¹⁰⁵ The pathogenesis appears to involve a delayed hypersensitivity or Arthus-type reaction. Host responses may perpetuate the disease even after the infection has been cleared. ⁹⁰

In cases suspected of having a tuberculous etiology, antituberculous therapy should be given. ⁸⁸

Subcutaneous fat necrosis of the newborn is a self-limited condition, present at birth or appearing in the first few days of life.^{111.112. and 113.} It is characterized by indurated areas and distinct nodules with a predilection for the cheeks, shoulders, buttocks, thighs, and calves. ¹¹⁴ Sometimes only solitary lesions are discernible. Lesions may be painful. Subcutaneous atrophy is a common complication. ¹¹⁵ Hypercalcemia has been reported in some cases.^{116.117.118.119. and 120.} Thrombocytopenia, hypoglycemia, and hypertriglyceridemia may also develop. ¹²¹ Lactic acidosis, and hyperferritinemia were each present in one case.^{122. and 123.} Obstetrical trauma, hypothermia, asphyxia, and anemia have been incriminated in the etiology. ¹²⁴ A recent study from Paris added failure to thrive, forceps delivery, macrosomia, and exposure to active or passive smoking during pregnancy. ¹¹⁵ Cases have been reported after hypothermic cardiac surgery,^{125. and 126.} prostaglandin E administration, and maternal exposure to cocaine or calcium channel blockers.^{127. and 128.} It has been suggested that trauma to fragile adipose tissue low in oleic acid and with a compromised circulation, followed by the release of hydrolases, leads to the breakdown of unsaturated fatty acids. ¹¹¹ It should be remembered that infant fat already has a greater ratio of saturated to unsaturated fatty acids than exists in adult fat.

Sclerema neonatorum has a pathogenetic relationship to subcutaneous fat necrosis of the newborn and was at one stage regarded as a diffuse form of the latter. ¹³⁴ It is also characterized by intracellular microcrystallization of triglyceride in the subcutaneous and sometimes also in the visceral fat of preterminal neonates. Sclerema neonatorum produces wax-like, hard skin which is also dry and cold. It is rarely seen these days, presumably because of improved neonatal care.

Panniculitis may occur following exposure to severe cold, particularly in infants.^{135.136.137. and 138.} It has occurred in older children and on the thighs of women who have ridden horses in cold weather.^{139. and 140.} In the latter instance it has been suggested that tight pants may restrict the blood supply, contributing to the injury. The lesions are indurated, somewhat tender plaques and nodules.

The diagnosis of Weber–Christian disease has engendered more confusion in dermatopathology than practically any other.^{142.143.144.145.146.147.148.149.150.151.152.153.154.155.156. and 157.} It has been applied by some to all cases of panniculitis with systemic symptoms or to all cases of fatal panniculitis with visceral involvement. ¹⁴³ The term ‘Weber–Christian disease’ has been a convenient ‘pigeon hole’ for undiagnosable cases of panniculitis. ¹⁵⁸

Weber–Christian disease was defined in the past as a rare disorder with recurrent subcutaneous nodules and plaques with a predilection for the extremities and buttocks, commonly associated with fever. ¹⁵⁴ It was said to have a short self-limited course or follow an unremitting course with a fatal outcome and visceral involvement.^{151.155. and 156.}

In a review of 30 cases diagnosed as Weber–Christian disease at the Mayo Clinic, White and Winkelmann were able to reclassify the cases as other entities, such as erythema nodosum, factitial panniculitis, cytophagic histiocytic panniculitis, and post-phlebitic syndrome. ¹⁵⁹The diagnosis should no longer be used.

The term Rothman–Makai syndrome was regarded as a rare variant of Weber–Christian disease, but without the fever and systemic symptoms. Despite a recent case report, this entity is thought to no longer exist. ¹⁶⁰

α₁-Antitrypsin deficiency (OMIM 107400) is a genetic disorder characterized by low serum levels of α₁-antitrypsin. The gene (PI) encoding this protease inhibitor is situated at 14q32.1. There are at least 90 allelic variants of this condition. Twenty-eight of the 40 cases (70%) of panniculitis in which the phenotype had been determined (up to 2004) had the ZZ phenotype, but other phenotypes have been involved.^{157.161.162. and 163.} Panniculitis may be an early sign of this deficiency, but most cases present during the third and fourth decades. ¹⁶⁴ The lesions begin as tender, erythematous, indurated, subcutaneous nodules that may be widely disseminated on the trunk, particularly the buttocks, or on extremities, especially the proximal limbs.147.^{149.162. and 164.} They may be precipitated by childbirth, and by trauma, including cryotherapy.^{165. and 166.} It has been associated with the extravasation of clarithromycin. ¹⁶⁷ Spontaneous ulceration with discharge of an oily fluid may occur. Ulceration is uncommon in the other panniculitides.

Different treatments have been used to control the cutaneous lesions, such as corticosteroids, dapsone, cyclophosphamide, colchicine, and doxycycline. ¹⁶⁸ Two more recent therapies have included plasma exchange or a purified concentrate of α₁-antitrypsin (Prolastin^®).^{168.169. and 170.}

Winkelmann and colleagues coined the term ‘cytophagic histiocytic panniculitis’ over 25 years ago for a usually fatal syndrome which included a chronic and recurring panniculitis with an infiltrate of cytophagic histiocytes with eventual multisystem involvement, terminating usually with a hemorrhagic diathesis resulting from the hemophagocytic syndrome.^{145.175.176.177.178.179.180.181.182.183.184.185. and 186.} Other cases have been included in the past with systemic Weber–Christian disease. ¹⁴⁴ The current status of this condition is controversial. Two distinct entities appear to be included under this ‘umbrella’ term: subcutaneous panniculitis-like T-cell lymphoma (see below); and an authentic panniculitis for which the term cytophagic histiocytic panniculitis still applies. In the latter group are several patients in whom the disease has not progressed to overt lymphoma after prolonged follow-up (41 years in one case).^{187. and 188.} Furthermore, monoclonal T-cell populations cannot be detected in these cases, although parallels have been drawn with large plaque parapsoriasis in which this may also occur. ¹⁸⁹ It is possible that isolated cases represent a manifestation of a non-neoplastic, infection-associated hemophagocytic syndrome.^{189.190. and 191.} Fatal cases still occur in the presumptive non-lymphoma group. ¹⁹²

The disease, as originally described, consists of ulcerating nodules or plaques, sometimes painful, with a predilection for the legs and forearms. Other sites are often involved in established cases. It affects mostly middle-aged or elderly individuals.

Panniculitis-like T-cell lymphoma is a rare form of cutaneous lymphoma; over 150 cases have now been reported.^{194.195.196.197. and 198.} Affected individuals present with multiple subcutaneous tumors or plaques, often associated with constitutional symptoms. Unusual presentations include patches of alopecia¹⁹⁹ and venous stasis-like ulceration. ²⁰⁰ Most cases occur in adults but children can be affected.^{201. and 202.} Sometimes a cytokine-induced hemophagocytic syndrome develops.^{188. and 194.} The disease is indolent in some,^{195. and 199.} but it may run a rapid course. Most cases have the phenotype of cytotoxic T cells and are derived from αβ T cells. ²⁰³ A case purporting to have resulted from previous chemotherapy has been reported. ²⁰⁴ Another case developed in a cardiac allograft recipient. ²⁰⁵

A panniculitis has also been reported in association with a lymphoma composed of natural killer cells. ²⁰⁶ An association with Epstein–Barr virus is common in these CD56⁺, nasal-type lymphomas.^{194.207. and 208.} They have an aggressive course, often terminating with a fatal hemophagocytic syndrome. ²⁰⁹ This variant is derived from γδ T cells. ²¹⁰ They bear a plasmacytoid dendritic cell phenotype. ²¹¹

These types of cutaneous lymphoma are considered further in Chapter 41 (p. 984).

Pancreatic panniculitis manifests as painful or asymptomatic subcutaneous nodules or indurated plaques on the thighs, buttocks, lower trunk or distal extremities, usually the lower. The lesions are associated with acute pancreatitis^{221.222.223.224.225.226. and 227.} or, less commonly, pancreatic carcinoma,^{228. and 229.} either of which may be asymptomatic.^{230.231. and 232.} Pancreatic panniculitis has been reported in a 4-year-old child with the nephrotic syndrome. ²³³ It has also been associated with low-grade pancreatitis in a patient with a pancreas divisum. ²³⁴ There may also be polyserositis, arthritis, eosinophilia, or rarely a leukemoid reaction. The pancreatic carcinoma, when present, is often of acinic type, although panniculitis has also been reported in association with an islet cell carcinoma.^{235.236.237.238. and 239.}

Lesions probably result from the local action of blood-borne pancreatic lipase and trypsin, although other factors may also be involved.230. ^{and 240.} Cases have been reported without pancreatic disease, but with circulating lipase or amylase of uncertain origin. ²⁴¹

Lupus panniculitis (sometimes referred to as lupus (erythematosus) profundus) is a chronic, recurrent panniculitis with a predilection for the proximal extremities, trunk, or lower back: it is a complication in approximately 1–3% of patients with cutaneous lupus erythematosus, both systemic and discoid forms.^{244.245.246.247. and 248.} Rare sites of involvement in Western populations include the scalp²⁴⁹ and the earlobe. ²⁵⁰ The face and scalp are common sites of involvement in Asians. ²⁵¹ There is a female predominance. While most cases develop in middle-aged adults, onset in childhood has been reported.^{252.253.254. and 255.} The lesions present as subcutaneous nodules or indurated plaques, although large, painful, indolent ulcers may develop.^{256. and 257.} Lipoatrophy may result. This was accompanied by localized hypertrichosis in one case. ²⁵⁸ The panniculitis may precede, accompany, or follow the development of the associated lupus erythematosus; ²⁴⁷ in nearly half of the cases no associated lupus subtype or autoimmune disease is present.^{259. and 260.} Accordingly, lupus panniculitis should be regarded as a unique entity within the lupus spectrum. ²⁵⁹ It has been suggested that a type I interferon driven immune response may be responsible for the lesions. ²⁶¹ The lobular panniculitis is dominated by cytotoxic CXCR3⁺ lymphocytes. ²⁶¹

A panniculitis mimicking lupus panniculitis has been reported in a case of malignant atrophic papulosis (Degos’ disease); ²⁶² many pathologists now regard malignant atrophic papulosis as being part of the ‘lupus spectrum’. A lupus-like lobular panniculitis may develop at the injection site of glatiramer acetate, used in the treatment of multiple sclerosis. ²⁶³

Treatment options include corticosteroids, cyclosporine (ciclosporin), dapsone, and antimalarials such as hydroxychloroquine.^{255. and 264.} Topical treatment with potent corticosteroids may be used for localized lesions.

Connective tissue panniculitis is extremely rare. ²⁷¹ It tends to occur in female adults and children. It is characterized by multiple nodules and plaques on the trunk and lower limbs.^{271. and 272.} Low-titer antinuclear antibodies are usually present. Cases followed by lipoatrophy have been included as a variant;273.^{274.275. and 276.} this may be the natural course of the disease. Other autoimmune diseases or a family history of autoimmune disease may be present. ²⁷¹

Poststeroid panniculitis is a rare complication of systemic corticosteroid therapy. It is characterized clinically by the development, usually on the cheeks, of multiple subcutaneous nodules within days or weeks of the withdrawal of steroid therapy.^{278. and 279.} It usually occurs when the steroid is abruptly tapered or stopped. The lesions heal without scarring.

Subcutaneous sarcoidosis is an uncommon form of sarcoidosis that presents with subcutaneous nodules, principally on the extremities. It constituted 2.2% of the cases of cutaneous sarcoidosis on file at the Mayo Clinic. ²⁸⁰ This entity should not be confused with the erythema nodosum that may be associated with sarcoidosis, particularly in cases of Lofgren syndrome (see p. 460). Sarcoidosis is discussed further in Chapter 7, pp. 171–173).

The term ‘lipodystrophy’ has traditionally been used for primary, idiopathic atrophy of subcutaneous tissue, whether total, partial, or localized. ²⁸² It has been distinguished from the secondary lipoatrophy that may follow certain panniculitides such as lupus panniculitis, connective tissue panniculitis, and subcutaneous morphea.^{274.282.283.284. and 285.} Lipoatrophy may be a diagnostically challenging presentation of T-cell lymphoma. ²⁸⁶ The term ‘lipodystrophy’ is also used for the lipoatrophy (and the rare lipohypertrophy) that may follow the repeated injection of insulin into the subcutis by diabetics. ²⁸⁷ The term ‘corticosteroid-induced lipodystrophy’ has been used for the morphological changes that follow the use of corticosteroids. ²⁸⁸ Adipose tissue accumulates in the face (‘moon’ face), the dorsocervical region (‘buffalo hump’), the supraclavicular area, and the abdomen. ²⁸⁸ It has been suggested that lipedema, characterized by the abnormal deposition of subcutaneous fat in the legs (associated with edema), is a lipodystrophy. ²⁸⁹ The three major categories of lipodystrophy will be considered further, followed by a discussion on lipedema.

A lipodystrophy can be seen in patients with the acquired immunodeficiency syndrome (AIDS). Three clinical settings appear to be involved. The most common variant, characterized by the presence of peripheral lipoatrophy and central adiposity, can develop following the use of protease inhibitor therapy.^{354.355.356.357. and 358.} Clinically evident lipodystrophy usually begins 2–14 months after the commencement of therapy. The changes include loss of fat from the arms, buttocks, thighs, and legs, leading to prominence of veins and muscles, particularly on the legs. ³⁵⁹ Loss of the buccal fat pad gives a cachectic appearance. ³⁵⁶ The accompanying lipohypertrophy includes central obesity, enlargement of the dorsocervical fat pad (‘buffalo hump’), and deposition of abdominal fat. Indinavir is the protease inhibitor most often implicated. Resolution of the lipodystrophy usually occurs on discontinuation of the therapy. ³⁵⁴ It has been suggested that protease inhibitors bind to proteins that regulate lipid metabolism. Dysregulation of peroxisome function also occurs. ³⁶⁰

A similar lipodystrophy has been reported with the use of reverse transcriptase inhibitors. It has been suggested that these cases may in some way be related to suppression of HIV replication. ³⁵⁷

Finally, a third group of HIV-related cases appears to exist. Some patients with AIDS develop a facial lipoatrophy; not all have been on protease or reverse transcriptase inhibitor therapy.

Autologous fat grafts for the enhancement of facial contours have met with high patient satisfaction rates. ³⁶¹ Polylactic acid implants are another successful strategy. ³⁶²

Gynoid lipodystrophy, better known as cellulite, is an alteration of the topography of the skin that occurs mainly in women on the buttocks, thighs, and abdomen. ³⁶³ It gives the skin a dimpled (‘orange peel’, ‘quilted’, ‘mattress’) appearance.^{364. and 365.} It is very common in obese patients, although it differs from obesity both structurally and mechanistically.^{363. and 366.} Four grades of clinicopathological severity have been defined. ³⁶³

The pathogenesis of gynoid lipodystrophy is complex and still being elucidated but it includes alterations in the composition and the amount of fat in adipocytes, changes in the microcirculation of the subcutis, and hyperpolymerization in the connective tissue of the fat septa. ³⁶³ These changes appear to be influenced by hormonal and psychosomatic factors as well as by race, sedentary lifestyle, and an inherent predisposition. ³⁶³ Cellulite appears to predispose to earlier skin aging changes. ³⁶⁷

The term ‘membranous lipodystrophy’ was originally applied to a sudanophilic sclerosing leukoencephalopathy in which cystic degeneration of the marrow of long bones also occurred. ³⁶⁸ The fat showed a characteristic lipomembranous (membranocystic) change (see below). The term has since been applied to a varied group of panniculitides in which this same lipomembranous change occurs. The term pseudomembranous fat necrosis is also used. ³⁶⁹ There are several cases in the literature where this change has been found as a primary phenomenon in the subcutaneous fat of the skin; it has therefore been proposed that such cases should be designated primary membranous lipodystrophy to distinguish them from the cases in which it is merely an incidental histological feature – secondary membranous lipodystrophy.^{370.371. and 372.} Diseases in this latter category include erythema nodosum,^{269. and 373.} morphea profunda, ³⁶⁸ lupus panniculitis, traumatic fat necrosis, insulin lipoatrophy, ³⁷⁴ the panniculitis of Behçet’s syndrome, encapsulated fat necrosis, and the panniculitis of dermatomyositis.^{369. and 375.} Membranous lipodystrophy also occurs in association with circulatory disturbances, particularly diabetic microangiopathy and venous insufficiency; vasculitis-induced lesions are rare. ³⁷⁶ As lipodermatosclerosis also occurs in a setting of venous insufficiency, it is perhaps not surprising that lipomembranous change is common in lipodermatosclerosis. ³⁷⁷

It seems likely that membranous lipodystrophy will eventually be regarded as synonymous with lipomembranous (membranocystic) change – a histological change rather than a disease sui generis.

Criticisms notwithstanding, ³⁸¹‘lipodermatosclerosis’ is still the preferred term for an entity characterized by circumscribed, indurated, often inflammatory plaques on the lower extremities. In a series of 97 patients reviewed at the Mayo Clinic, 84 were women, and the mean age was 62 years. ³⁸² Lesions were bilateral in nearly half of the cases. The condition is usually associated with venous insufficiency, arterial ischemia, or previous thrombophlebitis.^{259. and 383.} One case developed during therapy with gemcitabine, ³⁸⁴ and another as a form of radiation recall dermatitis. ³⁸⁵ It may also complicate chronic lymphedema. There may also be mottled hyperpigmentation related to venous stasis. ³⁸⁶ Sometimes the clinical appearances mimic a cellulitis. Similar lesions have been reported as sclerosing panniculitis³⁸⁷ and hypodermitis sclerodermiformis. So-called ‘lipomembranous’ (membranocystic) change is frequently seen on histology, thus this condition has also been regarded as a membranous lipodystrophy (see above) or simply called lipomembranous (membranocystic) fat necrosis. ²⁶⁹

Lipodermatosclerosis appears to be a consequence of ischemia and venous stasis. Venous insufficiency was thought to be present in a case in a 15-year-old girl. ³⁸⁸ There is abnormally low plasma fibrinolytic activity in these patients, as well as low levels of proteins C and S. ³⁸⁹ However, fibrinolytic activity is increased in affected tissues and this is associated with elevated levels of urokinase-type plasminogen activator (uPA). ³⁹⁰ In addition, there is elevated matrix turnover, although the significance of this finding is uncertain. ³⁹¹ Sclerosis is also a feature. ³⁹² There is a significant increase in the number of dermal fibroblasts undergoing proliferation, and an increase in the number of cells expressing procollagen type 1 mRNA. ³⁹³ Ultrasound investigations have shown that the edema fluid in this condition is predominantly in the upper dermis in contrast to the deep dermal location of the fluid in chronic heart failure. ³⁹⁴ Magnetic resonance imaging (MRI) can be used as a diagnostic tool in this condition. ³⁹⁵ As light compression appears to enhance the removal of edema fluid, compression stockings have been used in the treatment of lipodermatosclerosis. ³⁹⁶ Other therapies used have included stanozolol combined with compression therapy, surgical correction of venous disease, pentoxifylline, and intralesional triamcinolone. ³⁹⁷

The clinical manifestations of self-induced panniculitis will depend on the nature and site of the insult. Factitial panniculitis may follow injections of all manner of substances, including milk, urine, feces, oils (oleoma), and drugs, into the subcutaneous fat. Reports have included the injection of procaine povidone, ³⁹⁸ meperidine (pethidine), ³⁹⁹ sesame oil, ⁴⁰⁰ and pentazocine. ⁴⁰¹ A case masquerading as pyoderma gangrenosum has been reported. ⁴⁰² Sclerosing lipogranuloma (paraffinoma) is a special form of factitial panniculitis resulting from the injection of lipid, often paraffin, into the subcutaneous tissue, ⁴⁰³ particularly in an attempt to produce enlargement of the penis and even the breasts.^{404. and 405.} Other oils and silicones have been involved.^{406.407. and 408.} The lesion presents as a painful rubbery induration of the involved area. Fistulas and ulceration are common. ⁴⁰⁹ Oil cysts developed after the regular subcutaneous injections of interferon-α and interleukin-2 for metastatic melanoma. However, as the injectable solutions are water based, it was postulated that the injection of these cytokines may have led to a focal liponecrosis with resulting fat cysts. ⁴¹⁰ Mesotherapy injections for ‘cellulite’ produced a granulomatous panniculitis with some fat cysts. ⁴¹¹

A localized panniculitis has also been reported following the subcutaneous injection of glatiramer acetate in the treatment of multiple sclerosis.^{263. and 412.} Transient reactions and pain are not uncommon complications, but more persistent lesions occur.

The term pseudosclerodermatous panniculitis was used by Winkelmann and colleagues in 1993 to describe four cases of women with breast cancers who received megavoltage radiotherapy. ⁴¹³ Further cases have since been described. ⁴¹⁴ All patients developed progressive induration of the subcutaneous tissues in the irradiated area. In one series, the interval between radiotherapy and the development of the induration varied from 4 to 8 months. ⁴¹⁴

Subcutaneous fat necrosis may follow trauma, particularly to the shins. Focal liquefaction of the injured fat often follows and this is sometimes discharged through a surface wound. Some cases of traumatic fat necrosis have a factitial origin, so there is obvious overlap with factitial panniculitis. ⁴¹⁵

Encapsulated fat necrosis is the preferred designation for the small mobile nodules that may develop in the subcutis; they often follow trauma.^{417. and 418.} These lesions have also been called ‘mobile encapsulated lipoma’ and ‘nodular-cystic fat necrosis’. ⁴¹⁹

The lesions, which are usually solitary, are whitish-yellow in color, and measure 3–20 mm in diameter. ⁴¹⁷ An unusually large case, measuring 18 cm in longest diameter, has been reported in an elderly female with morbid obesity. ⁴²⁰ Encapsulated fat necrosis has also been reported in a patient with sarcoidosis. ⁴²¹

Various infections and infestations may result in a lobular or mixed lobular and septal panniculitis.^{4. and 423.} These include candidiasis, ³⁷⁰ cryptococcosis, mycetoma, actinomycosis, nocardiosis, chromomycosis, sporotrichosis, and histoplasmosis,424. ^{and 425.} infections with Mycobacterium marinum, ⁴²⁶M. chelonae, ⁴²⁷M. ulcerans, M. fortuitum, M. tuberculosis, ⁴²⁸M. leprae (erythema nodosum leprosum – see p. 566), M. avium-intracellulare, ⁴²⁹Neisseria menigitidis and other bacteria,^{423. and 430.} bites of ticks, ⁴³¹ and of the brown recluse spider (Loxosceles reclusa), ⁵¹ and metazoal infestations (myiasis, cysticercosis, sparganosis, and infestations by some other helminths). Most cases of infection-induced panniculitis occur in patients who are immunosuppressed. ⁴²³ Two subcutaneous nodules developed in a patient with chronic myeloid leukemia who contracted Q fever. ⁴³²

Neutrophilic panniculitis presents with multiple, often painful, subcutaneous nodules on the legs, arms, and trunk. Between 10 and 20 nodules may be present. ⁴³⁴ The lesions are erythematous and deep on palpation. They tend to last about 15 days. ⁴³⁴ While an infective cause should always be considered in the presence of a neutrophilic panniculitis, other etiologies do exist.^{435. and 436.} In the early stages of many of the panniculitides, neutrophilic infiltration occurs. Examples include erythema nodosum, Behçet’s disease, pancreatic panniculitis, and factitial panniculitis. Other causes of neutrophilic panniculitis include rheumatoid arthritis, ⁴³⁵ including the juvenile form, ⁴³⁷ Sweet’s syndrome,^{438. and 439.} and Crohn’s disease. ⁴⁴⁰ Myelodysplastic syndromes⁴⁴¹ seem to be significantly associated with a neutrophilic panniculitis. A neutrophilic lobular panniculitis has been reported in a patient with acute promyelocytic leukemia treated with all-trans-retinoic acid. ⁴⁴²