Panniculitis (Chapter 100)

Predominantly Septal paniculitidies
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Terms in this set (51)
Predominantly Septal paniculitidies
• Erythema nodosum Erythema nodosum migrans (subacute nodular migratory panniculitis)
• Panniculitis of morphea/scleroderma
• Alpha-1 antitrypsin deficiency panniculitis
Lobular and mixed septal-lobular panniculitidies
• With vasculitis involving septal veins or arteries, lobular venules or small veins Erythema induratum (nodular vasculitis)
• With necrosis as an early finding Pancreatic panniculitis • With needle-shaped clefts within lipocytes Sclerema neonatorum Subcutaneous fat necrosis of the newborn Post-steroid panniculitis
• Associated with autoimmune connective tissue disease Lupus erythematosus panniculitis (lupus profundus) Panniculitis of dermatomyositis
• Lipodystrophic panniculitis (see Ch. 101) Lipoatrophy Lipohypertrophy
• Traumatic panniculitis, including factitial panniculitis Cold panniculitis (popsicle panniculitis, Haxthausen disease) Sclerosing lipogranuloma (including grease gun granuloma) Panniculitis due to other injectable substances Panniculitis due to blunt trauma
• Lipodermatosclerosis
• Infection-induced panniculitis
• Malignancy-related panniculitis-like infiltrates Subcutaneous panniculitis-like T-cell lymphoma (see Ch. 120) Other lymphomas with involvement of subcutaneous tissues
Erythema Nodosa
- how common,
Introduction
Erythema nodosum is the best known of the various forms of panniculitis, as well as the most common. It typically presents as an acute eruption of tender, erythematous, subcutaneous nodules in the pretibial areas bilaterally. It is widely regarded as a delayed hypersensitivity response to a variety of antigenic challenges1 , although the mechanisms of its development are more complex than this statement would indicate. Histopathologically, it is the prototype of a "septal" panniculitis. Identification and treatment of the underlying disorder, if found, is of primary importance, but therapy directed toward the lesions themselves is also an option, especially when idiopathic.

History
At the beginning of the eighteenth century, Robert Willan gave the first clear description of erythema nodosum, and he provided its name in his famous work, On Cutaneous Disease
Erythema Nodosa
- who is most commonly affected
- Pathophysiology? What type of immune response is implicated
- What specific immune cell is prevalent in early disease
- what about late disease? what immune factor plays a role here
Erythema nodosum can occur at any age, in both sexes, and in all racial groups. It is more common among women and is more frequently observed during the second through fourth decades of life4,5. The relative ranking of underlying causes may vary according to geographic location; for example, in areas where Coccidioides immitis is endemic or regions where Behçet disease is more prevalent

Erythema nodosum has been considered a delayed hypersensitivity response to a variety of antigenic stimuli, including bacteria, viruses and chemical agents1,6. Llorente et al.7 observed expression of mRNA for Th1 cytokines (interferon-γ, interleukin-2) in the skin lesions and peripheral blood of patients with erythema nodosum, and a Th1 pattern of cytokine synthesis is associated with delayed-type hypersensitivity reactions. However, a complex series of intermediate steps is involved in the development of these lesions. A variety of adhesion molecules and inflammatory mediators appear to be associated with erythema nodosum. For example, in erythema nodosum lesions, vascular cell adhesion molecule-1 (VCAM-1; CD106), platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31), HLA-DR and E-selectin are expressed on endothelial cells, while intercellular adhesion molecule-1 (ICAM-1; CD54), very late antigen-4 (VLA-4), L-selectin and HLA-DR are expressed by inflammatory cells (see Ch. 102)8 . Neutrophils are often numerous in early lesions, and it has been shown that a higher percentage of circulating neutrophils in patients with erythema nodosum leads to the production of reactive oxygen intermediates; these intermediates, in turn, may provoke inflammation and tissue damage9 . Support for a pathogenic role for these cells and molecules is provided by studies on the effects of colchicine. This inhibitor of neutrophil chemotaxis has been shown to diminish L-selectin expression on the neutrophil surface, inhibit E-selectin mediated endothelial adhesiveness for neutrophils, and diminish stimulated expression of ICAM-1 on the endothelium8 . Additional indirect evidence for the role of inflammatory cells and mediators includes reports of erythema nodosum following treatment with granulocyte colony-stimulating factor11, and improvement (as well as flares) of erythema nodosum lesions with administration of tumor necrosis factor (TNF) inhibitors12. Erythema nodosum, especially in its chronic phase, is characterized by granuloma formation and TNF is known to play a role in granuloma formation. A link between deregulation of TNF-α production and granuloma formation is further supported by the strong correlation of a polymorphism in the promoter region of the gene that encodes TNF-α and the development of sarcoidosis-associated erythema nodosum13. A wide range of precipitating factors has been linked with erythema nodosum. Infectious causes are common, particularly upper respiratory infections (both streptococcal and non-streptococcal). Other commonly reported causes are listed in
Erythema Nodosa
- Name causes for erythema Nodosum
1) Idiopathic: Still the largest single category, accounting for a third to a half of cases
2) Streptococcal infections, especially of the upper respiratory tract The largest single infectious cause
3) Other infections: Viral upper respiratory tract infections Bacterial gastroenteritis - Yersinia > Salmonella, Campylobacter Overall, infection may account for a third or more of cases
4) Coccidioidomycosis Erythema nodosum is associated with a lower incidence of disseminated disease
5) Drugs* Especially estrogens and oral contraceptive pills; also sulfonamides, penicillin, bromides, iodides; occasionally, TNF inhibitors, BRAF inhibitors^
6) Sarcoidosis** 10-20% of cases in some series
7) Inflammatory bowel disease Crohn disease has a stronger association with erythema nodosum than does ulcerative colitis

NODOSUM
- No = idiopathic
- Drugs
- Oral Contraceptives
- Sarcoid
- UC, crohns, bichets
- Micor: TB, Viral, strep
-Clinical Features of EN
-EN is a good prognostic indicator for which underlying conditions?
- How long until lesions resolve? what % of cases recur?
- What is erythema nodosum migrans?
Erythema nodosum presents with bilateral, tender, erythematous nodules. These arise in crops and clearly the most common site is the shins (Fig. 100.2). Other locations are occasionally involved, particularly the thighs and forearms4 . Nodules may also appear on the trunk, neck and face3 , but this is sufficiently rare that development of lesions in these locations should prompt consideration of other diagnoses. Unlike other forms of panniculitis, ulceration is not a feature of erythema nodosum. Systemic symptoms may occur that are not necessarily related to a specific coexisting systemic disorder; these include arthritis, arthralgia, fever and malaise3 . Because of its close association with a variety of disorders and infections, erythema nodosum is an important skin sign of systemic disease. For example, its development may precede or accompany a flare of inflammatory bowel disease15. It may also have some value as a prognostic indicator in certain disorders. For example, erythema nodosum is associated with a protective effect against disseminated disease in patients with coccidioidomycosis, and it is closely aligned with a more benign and self-limited form of sarcoidosis1,16. Nevertheless, a significant percentage of cases - more than one-third - have no known disease association, even when followed for a year or more5 . Clinical or laboratory data that tend to predict that the development of erythema nodosum may be secondary to a systemic disease are listed in Table 100.4. Erythema nodosum lesions usually last a few days or weeks and then slowly involute, without scar formation. Discoloration suggestive of a bruise may be seen as the erythema subsides. More chronic forms do occur, some of which show a tendency toward migration or centrifugal spread; the latter have been termed subacute nodular migratory panniculitis or erythema nodosum migrans (see below). Up to one-third of cases of erythema nodosum recur. Annual recurrences are particularly common among idiopathic cases
Erythema Nodosa Pathology
- key histologic features?
Erythema nodosum is the prototypic septal panniculitis (Fig. 100.3), but this should not be taken to imply that histopathologic changes are entirely confined to subcutaneous septa17. Biopsy specimens of early lesions tend to show edematous septa and mild lymphocytic infiltrates. Of note, neutrophils may predominate in early lesions8 , and a variant with a predominance of eosinophils has been reported18,19. True vasculitis of the type seen in leukocytoclastic vasculitis is not observed, and erythema nodosum is not generally regarded as a vasculitic process. However, "secondary" vasculitis may be observed in lesions when they contain relatively heavy, mixed, or neutrophil-rich inflammatory infiltrates. Erythema nodosum-like lesions in Behçet disease may demonstrate leukocytoclastic or lymphocytic vasculitis involving subcutaneous venules or muscular veins; the latter changes are prone to occur in patients with more severe forms of Behçet disease20. In early lesions, one may also find Miescher microgranulomas, a characteristic if not pathognomonic feature of erythema nodosum. These are small collections of macrophages, found within septa or at a septal-lobular interface, that tend to surround neutrophils or small cleft-like spaces3 . Reported variations in the frequency of these granulomas in erythema nodosum3,21 may result in part from differences in definition, in the acceptance of subtle changes, and in the rigor of the search. In older lesions, Miescher microgranulomas may feature epithelioid and multinucleated giant cells (Fig. 100.3, inset). As lesions progress, the septa become widened and contain a mixed, partly granulomatous infiltrate. These cells infiltrate the periphery of fat lobules in a lace-like configuration. The extent of lobular involvement may vary, and in some cases can be prominent8 . Nevertheless, in the case of a lobular panniculitis without the characteristic septal changes, a diagnosis of erythema nodosum should be made with caution. Frequently, there is also a mild to moderate perivascular lymphocytic infiltrate in the overlying dermis. In later stages, the septa become fibrotic, partially replacing the fat lobules. Residual granulomas and lipophages can be observed, and a degree of vascular proliferation
may be present3 . Over the long term, a remodeling process takes place that usually results in minimal residual scarring3 .
Differential Diagnosis of EN
Differential diagnosis The clinical scenario of an acute eruption of tender subcutaneous nodules over both shins of a young person is highly characteristic of erythema nodosum. However, when lesions are few in number, are located in sites other than the lower legs, or are of longer duration (>6 weeks), erythema nodosum can be difficult to distinguish from other forms of panniculitis. Lesions of erythema induratum (nodular vasculitis) can resemble those of erythema nodosum, but they tend to occur on the posterior aspect of the lower legs and may ulcerate. Ulceration is also a feature of pancreatic panniculitis, which occurs more frequently in other locations (although still favoring the lower legs), is more likely to be accompanied by arthritis and serositis, and is associated with elevated serum amylase and lipase levels. Histopathologically, the picture of a predominantly septal panniculitis usually limits the differential diagnosis and tends to exclude those conditions that are chiefly lobular or mixed. Pancreatic panniculitis may show predominantly septal changes in its earliest stages22, but eventually, these lesions exhibit the characteristic fat necrosis, with saponification and "ghost cell" formation. Infectioninduced panniculitis can sometimes mimic erythema nodosum, but there are often more extensive neutrophilic infiltrates, cellular necrosis (including sweat gland necrosis), vascular proliferation, and hemorrhage
Treatment of EN
- what are some drug options?
Treatment Treatments most often recommended for uncomplicated erythema nodosum include bed rest, salicylates, and nonsteroidal antiinflammatory drugs (NSAIDs; Table 100.5) 2,15. Potassium iodide has been used with success, with adult dosages ranging from 450 to 1500 mg/day (Table 100.6) 24. Improvement can be seen within 2 weeks. Potassium iodide may work through inhibition of cell-mediated immunity, as well as via inhibition of neutrophil chemotaxis and suppression of neutrophil-generated oxygen intermediates2 . In light of this treatment response, reports of erythema nodosum triggered by potassium iodide seem contradictory. Treatment of erythema nodosum is influenced by underlying conditions. Thus, colchicine is useful in management of erythema nodosum that accompanies Behçet disease8 . Various treatments for inflammatory bowel disease are also effective in managing coexistent erythema nodosum12,25. Both etanercept and infliximab have been reported to be effective in treating erythema nodosum25,26, but paradoxically both have been noted to produce erythema nodosum as a cutaneous side effect27,28. In case reports, adalimumab has led to improvement of refractory chronic erythema nodosum29. Additional systemic therapies are listed in
More EN Treatment
- what should be done in all patients
- first, second, and third line treatments
In all patients Discontinue possible causative medications Diagnose and treat underlying cause Bed rest and leg elevation Compression

First-line Nonsteroidal anti-inflammatory medications (3)* Salicylates Potassium iodide (2) (see Table 100.6)

Second-line** Colchicine (3) Infliximab (3) Hydroxychloroquine (3) Adalimumab (3) Etanercept Mycophenolate mofetil (3)

Third-line** Systemic corticosteroids (3) Thalidomide (3) Cyclosporine (3) Dapsone (3)
Subacute Nodular Migratory Panniculitis - clinical presentation, similar to what condition - Causes for disease?■ Nodules on the lower extremities that migrate or undergo centrifugal spread, with central clearing ■ Often unilateral ■ Most cases are idiopathic; occasionally associated with streptococcal infection or thyroid disease ■ More chronic course than typical erythema nodosum Clinical features This condition was first described by Bafverstedt in 195430 and was named subacute nodular migratory panniculitis by Vilanova and Piñol Aguade in 195631. Some of its clinical and microscopic characteristics are similar to chronic erythema nodosum, and it is believed by many to represent a variant of the latter3,30. However, others consider it to be a separate disorder32. Subacute nodular migratory panniculitis is seen predominantly in women, is often unilateral, and is characterized by nodules that migrate or expand in a centrifugal manner (with central clearing)3 and may assume a yellowish or morpheaform appearance33. Lesions tend to be less tender than those of classic erythema nodosum. There may be few, if any, associated systemic symptoms30, though arthralgias have been reported and the ESR may be elevated31. Most cases are idiopathic, but some are associated with streptococcal infection (as evidenced by elevated antistreptolysin O and anti-DNase B titers) or thyroid disease3Pathology and Treatment - what is seen histologically? - treatment?Pathology - Microscopically, the changes are those of a chronic septal panniculitis33. However, in contrast to more classic forms of chronic erythema nodosum, subacute nodular migratory panniculitis shows greater septal thickening, more prominent granulomatous inflammation along the borders of widened subcutaneous septa, absence of phlebitis, and rare hemorrhage32. Treatment - Untreated, subacute nodular migratory panniculitis can last for months or years. However, treatment with potassium iodide is usually effective, resulting in clearing of lesions within several weeksMorphea/scleroderma panniculitis - what cells predominate histologically? what is seen in later stagesClinical features Both morphea and scleroderma (systemic sclerosis) can affect the subcutaneous fat (Table 100.7), which is the primary site of involvement in deep morphea (morphea profunda)34. Subcutaneous extension also occurs in variants such as disabling pansclerotic morphea of childhood, generalized morphea, and linear morphea. In addition, eosinophilic fasciitis can involve the subcutaneous fat as well as the fascia35. These syndromes may be associated with peripheral eosinophilia, polyclonal gammopathy, and serologic abnormalities35,36. Fleischmajer et al.37 proposed that the sclerosing process in scleroderma is initiated by the changes that take place in the subcutis. Pathology Table 100.7 outlines the microscopic changes in morphea- and scleroderma-associated septal panniculitis (Fig. 100.4). Lymphocytes and plasma cells predominate35,38,39, although macrophages and eosinophils may be present. In some cases, the number of plasma cells is striking38. In late stages of morphea, the subcutis is largely replaced by hyalinized connective tissue, very often accompanied by changes of lipoatrophy. Differential diagnosis The combination of septal panniculitis with lymphoplasmacytic predominance and dermal and subcutaneous sclerosis is unique, and this helps to separate morphea/scleroderma panniculitis from other septal forms of panniculitis. Differentiation among the several variants outlined above is more difficult, requiring clinical data for accurate classification. Sclerosis with lesser degrees of subcutaneous inflammation characterizes scleroderma, while a predominance of fascial involvement with extension into the subcutis is more typical of eosinophilic fasciitis.Alpha 1 antitrypsin Deficiency Panniculitis - clinical features - most severe diseases are homozygous for what mutation - key histologic findings■ Erythematous, painful, subcutaneous nodules or plaques that often ulcerate and drain ■ Associated with alpha-1 antitrypsin deficiency; patients with the most severe disease are homozygotes for the Z allele of the SERPINA1 gene (PiZZ) ■ A characteristic histologic finding is liquefactive necrosis of the dermis and subcutaneous septa, but lobular or mixed septal- lobular changes with neutrophils may occur Introduction Alpha-1 antitrypsin deficiency is a well-established, but uncommon, cause of panniculitis. The most severely affected individuals, with markedly decreased levels of the protease inhibitor, are most prone to the development of ulcerating neutrophilic panniculitis. Recognition of the disorder is important not only in the selection of appropriate therapy, but also in addressing other systemic manifestations of the disease and in dealing with its genetic aspects. History Alpha-1 antitrypsin deficiency is an inborn error of metabolism that was first delineated by Eriksson and others in the early 1960s40. In 1972, Warter and colleagues identified members of a family with alpha-1 antitrypsin deficiency and "Weber-Christian syndrome". Subsequent investigations linked the clinical and microscopic findings to known effects of proteinase inhibitor deficiency. Epidemiology No apparent racial or geographic prevalence has been noted for alpha-1 antitrypsin deficiency panniculitis. The incidence of the disease is approximately equal in men and women41,42. Age of onset ranges from infancy to the eighth decade of lifePathogenesis of alpha 1 antitrypsin - what is alpha 1 antitrypsin? where is it made? - gene responsible for producing it? how many types of this gene? - what organs are affected by deficiency? - what events may trigger disease?Pathogenesis Alpha-1 antitrypsin, a glycoprotein produced in the liver, is the most abundant circulating serine protease inhibitor (serpin). The more than 120 different alleles of the gene that encodes this protein (SERPINA1; formerly known as PI) are divided into categories based upon the electrophoretic mobility of their protein products (M = medium, S = slow, Z = very slow). The most common protease inhibitor (Pi) phenotype is MM (homozygous for M alleles), which is associated with normal serum levels of alpha-1 antitrypsin (100-200 mg/dl)43. Heterozygotes with one copy of the S or Z allele have mild to moderate deficiencies of the inhibitor (PiMS and PiMZ; prevalences of 1-3% in Caucasian populations). Patients who are homozygous for the Z allele (PiZZ; prevalence of 1 : 150-1 : 5000 in Caucasian populations) or whose genotype is the rare PiZnull have severe alpha-1 antitrypsin deficiency, with serum levels in the range of 20-45 mg/dl. In these individuals, most of the aberrant alpha-1 antitrypsin protein accumulates in the endoplasmic reticulum of hepatocytes, and the small amounts that enter the circulation have decreased function and a tendency to form inactive polymers that may stimulate neutrophil chemotaxis44. Of note, Z-type polymers have been detected in the skin of a patient with alpha-1 antitrypsin deficiency panniculitis, further suggesting a possible proinflammatory role45. Alpha-1 antitrypsin acts upon a wide range of proteolytic enzymes that play a direct role in degradation of tissues, including trypsin, collagenase, and elastase46. It also has important effects on immune function, e.g. inhibition of membrane-bound serine proteases involved in the activation of lymphocytes and macrophages47. It may also inhibit complement activation, both through a direct effect on complement related proteases48 and by inhibiting the neutrophil proteases that activate enzymes of the complement system49. In addition to panniculitis, the consequences of alpha-1 antitrypsin deficiency include chronic liver disease with cirrhosis (resulting from retention of the aberrant protein within the liver), emphysema, pancreatitis, membranoproliferative glomerulonephritis, rheumatoid arthritis, c-ANCA (cytoplasmic antineutrophil cytoplasmic antibody)-positive vasculitis, other cutaneous vasculitides such as Henoch-Schönlein purpura, and angioedema (resulting from deficiency of the protease inhibitor)41,49. The initiating event in individuals who develop panniculitis is not always clear; trauma appears to play a role in some patients. Postpartum flares of the disease have been reported in genetically susceptible individuals. This is attributed to the estrogen-promoted increase in proteinase inhibitor levels during pregnancy, followed by a precipitous decline to subnormal levels postpartum50. Absence of the alpha-1 antitrypsin protease inhibitor results in activation of lymphocytes and macrophages, lack of restraint upon the complement cascade, release of chemotactic factors, accumulation of neutrophils with release of their proteolytic enzymes, and consequent attack upon fat and nearby connective tissues44,46. The subcutis may be particularly vulnerable to this process, since fatty acids make nearby elastin more susceptible to proteolytic degradation4Alpha 1 - clinical presentation, systemic symptoms - Pathology findingsClinical features Large, erythematous to purpuric, tender nodules or plaques appear in a variety of sites (Fig. 100.5), especially the lower trunk and proximal extremities (flanks, buttocks and thighs)41,44,46. Ulcers develop that may be deep and necrotic, accompanied by an oily discharge42,44,46. Migration of lesions has been reported41. A history of antecedent trauma can be elicited in approximately one-third of patients42. Panniculitis may be accompanied by fever, pleural effusions and pulmonary emboli42. The clinical course of the panniculitis is often prolonged, and lesions are resistant to immunosuppressive therapy. Healing is accompanied by scarring and subcutaneous atrophy42. The most severe manifestations arise in those with profound proteinase inhibitor deficiency (PiZZ), although the panniculitis can also occur in heterozygotes Pathology Descriptions of the pathology of alpha-1 antitrypsin deficiency panniculitis have varied. Early, there is a neutrophilic panniculitis, followed rapidly by necrosis and destruction of fat lobules46. Splaying of neutrophils between collagen bundles in the reticular dermis has been described as an early clue to the diagnosis51. Dissolution of dermal collagen, with resultant liquefactive necrosis and separation of fat lobules from adjacent septa, is a principal change in most cases52. Another characteristic feature is the presence of "skip areas" of normal fat adjacent to foci of severe necrotizing panniculitis46. Chronic inflammation and hemorrhage may be present at the periphery of areas of involvement46. Most authors have not found evidence for primary leukocytoclastic vasculitis, although there may be evidence for lymphocytic vasculitis, secondary vasculitis in areas of heavy neutrophilic infiltration, or thrombosis46. In individuals with intermediate levels of protease inhibitor deficiency, lipophage and giant cell accumulation may be prominent46. Lesions heal with scarring and obliteration of fat lobules. Views differ on whether alpha-1 antitrypsin deficiency panniculitis should be regarded as a primarily septal or lobular panniculitis. Clearly, involvement of fat lobules can be significant, and, as a result, there are authors who have labeled the process a lobular panniculitis. On the other hand, some descriptions have emphasized early septal inflammation, collagenolysis of the fibrous septa (Fig. 100.6) 52, and the prominent septal fibrosis in late-stage lesionsDdx and Treatment - differentials to consider? - most effective treatment? other options?Differential diagnosis Clinically, the degrees of inflammation, ulceration and drainage associated with alpha-1 antitrypsin deficiency panniculitis may actually elicit a differential diagnosis more focused upon ulcerative skin disorders (see Fig. 105.1). Ulcers associated with alpha-1 antitrypsin deficiency generally lack the necrotic, "undermined" borders associated with pyoderma gangrenosum46. Tissue culture to exclude infection-induced panniculitis may be required. Entities in the microscopic differential diagnosis include traumatic (factitial) panniculitis, infection-induced panniculitis, pancreatic panniculitis, and erythema induratum (nodular vasculitis)46. Each of these can be associated with infiltrates that include neutrophils and varying degrees of necrosis, yet each has other distinct findings (see below). In the appropriate clinical setting, subcutaneous Sweet syndrome and neutrophilic panniculitis in patients with rheumatoid arthritis or inflammatory bowel disease may represent additional diagnostic considerations Treatment Treatments that are usually ineffective include corticosteroids and other immunosuppressants, cytotoxic agents, colchicine, danazol, and hydroxychloroquine41,46. Doxycycline is sometimes effective, particularly in mild cases; one suggested dosage schedule is 200 mg twice daily for 3 months48,53. Dapsone may also be beneficial in mild cases, by suppressing neutrophil migration and inhibiting oxidation reactions induced by myeloperoxidase41. Reduction of alcohol intake has also been recommended, since ethanol (as a hepatotoxin) may precipitate alpha-1 antitrypsin-associated hepatitis49. The most effective therapeutic intervention is replacement of alpha-1 antitrypsin via intravenous infusions. Dosages are generally 60 mg/kg per week, administered over a period of 3 to 7 weeks41,42. Improvement is relatively rapid, in that clearing of the panniculitis can occur after three weekly doses41. Recurrences are possible when alpha-1 antitrypsin levels fall below 50 mg/dl41, but these typically respond to further replacement therapy. Other successful therapies include plasma exchange and liver transplantation (in appropriate clinical circumstances). There is evidence that autophagy-enhancing drugs, such as carbamazepine, may reduce systemic manifestations, including hepatic fibrosis54, and clinical trials are currently underwayErythema Induratum - characterized by what? - what is a possible other term? - Association with what infectious etiology - most commonly seen in whom?Introduction Erythema induratum is a condition characterized by nodules on the lower extremities, which may ulcerate and drain. Originally regarded as a tuberculid, its relationship to tuberculosis in a subset of patients has been solidified by more recent studies that have detected mycobacterial DNA in cutaneous lesions. History Erythema induratum was first described by Ernest Bazin in 1861. It was generally regarded as a tuberculid because of a strong association with tuberculosis, although Koch's postulates could not be fulfilled. In 1945, Montgomery and colleagues proposed the term nodular vasculitis for cases with similar clinical and pathologic features that were not of tuberculous origin. Since the early 1970s, erythema induratum and nodular vasculitis have generally been considered as synonyms referring to a clinicopathologic entity with several possible causes, one of which is tuberculosis. The detection of mycobacterial DNA in cutaneous lesions has confirmed a tuberculous origin in some patients56. There are certain clinicians, however, who prefer to use the term nodular vasculitis when referring to individuals with a non-tuberculous etiology. Epidemiology In erythema induratum, an overwhelming female predominance is observed, but men can also develop the disease57. There is no apparent racial predilection, and although there is a wide age range among affected patients, the mean is between 30 and 40 years57. Erythema induratum of tuberculous etiology occurs more frequently in populations with a high prevalence of tuberculosis.Erythema Induratum - what type of immune response? - possible triggers - clinical features, most common locationPathogenesis As mentioned previously, some cases have been strongly associated with Mycobacterium tuberculosis infection. This can be substantiated by the detection of mycobacterial DNA in skin lesions by PCR56,58,59, with specific primers used to distinguish M. tuberculosis complex DNA from that of other mycobacterial pathogens59. Non-tuberculous cases have been related to other infectious agents (e.g. Nocardia23, hepatitis C virus60) or to drugs (e.g. propylthiouracil61). There is a report of erythema induratum being induced by a tuberculin skin test. Although it has been suggested that erythema induratum results from an immune complex-mediated vasculitis57, most investigators believe that the process represents a type IV, cell-mediated response to an antigenic stimulus62. Biopsy specimens show a predominance of T lymphocytes, macrophages and dendritic cells, including Langerhans cells57,63,64. One study of peripheral blood mononuclear cells from a patient with erythema induratum and active tuberculosis showed a high proliferative response to purified protein derivative (PPD) and marked production of interferon-γ, suggesting a pathogenic role for these PPD-specific T cells in a delayed hypersensitivity response to mycobacterial antigens65. Clinical features Erythema induratum is characterized by tender, erythematous to violaceous nodules and plaques that most often develop on the lower legs, especially the calves63,64. Lesions have also been reported on the feet, thighs, buttocks and arms57. An annular arrangement of nodules has been described in M. tuberculosis-related cases66. Ulceration can occur (Fig. 100.7). Lesions are persistent, tend to heal with scarring, and are prone to recurrence57,63,67. In erythema induratum associated with M. tuberculosis, there may be clinical and radiographic evidence for active tuberculosis, positive skin tests to PPD, or a positive interferon-gamma release assay such as the QuantiFERON®-TB Gold In-Tube test68. In addition, other tuberculids, e.g. papulonecrotic, may be present. Clinical differences between tuberculous and non-tuberculous cases are minor.Erythema induratum pathology - what type of panniculitis? - differential diagnosis - treatmentPathology Erythema induratum is generally described as a lobular or mixed septal/lobular panniculitis. Inflammation is mixed, and can include neutrophils, lymphocytes, macrophages and multinucleated giant cells (Fig. 100.8A). Vasculitis is identifiable in the vast majority of cases, and most frequently involves veins or arteries of connective tissue septa and small venules of the fat lobules69 (Fig. 100.8B). It may be predominantly neutrophilic63, lymphocytic67, or granulomatous. Necrosis with a coagulative or caseous appearance may be present, sometimes with palisading granulomas63. Necrosis has been described in both tuberculous and non-tuberculous cases, and the incidence and degree of necrosis are greater in those cases that are positive for M. tuberculosis DNA by PCR methods58. However, this finding is absent in over half of cases. Differential diagnosis Infection-induced panniculitis tends to show a more prominent neutrophilic component, granular basophilic necrosis, sweat gland necrosis and proliferation of small vessels, and organisms may be identified on special staining. Lupus panniculitis tends to be less granulomatous, has a prominent lymphoplasmacellular infiltrate, may show mucin deposits, and sometimes has overlying epidermal and dermal changes typical for lupus erythematosus. Both polyarteritis nodosa and thrombophlebitis tend to show inflammation limited to the immediate perivascular zone, in contrast to the extensive lobular panniculitis often encountered in erythema induratum. Histologically, perniosis can be difficult to distinguish from erythema induratum, but there is typically a history of cold exposure63, and on microscopic examination prominent involvement of dermal vessels is often observed, with "fluffy edema" of their walls. Treatment Treatment should be directed at the underlying cause, if found. This includes multi-drug antituberculous therapy66 (see Ch. 75) and discontinuing possible inciting medications. Therapeutic options for nontuberculous erythema induratum include NSAIDs, corticosteroids, tetracyclines, potassium iodide, and mycophenolate mofetil70. Supportive care is similar to that for erythema nodosumPancreatic Panniculitis - associated with what pancreatic disorders ? - key histofinding - occurs in what% of patients with pancreatic conditions?■ Subcutaneous nodules, sometimes accompanied by fever, arthritis or abdominal pain ■ Associated with pancreatic disorders, including acute and chronic pancreatitis and pancreatic carcinoma ■ Mixed septal/lobular panniculitis featuring "ghost cell" formation and the deposition of basophilic material due to saponification of fat by calcium salts ■ Treatment primarily directed towards the underlying pancreatic disorder Introduction Pancreatic panniculitis is an unusual complication of pancreatic disease. In addition to the symptoms associated with fat necrosis, its chief importance is as a sign of a significant systemic disorder, particularly because the panniculitis may be recognized prior to detection of the underlying pancreatic disease. History Chiari first described pancreatic panniculitis in 1883. By 1999, fewer than 100 cases had been reported71,72. Since then, an additional 90 publications have appeared, primarily as case reports. Epidemiology Panniculitis develops in up to 2% of patients with pancreatic disorders73. No geographic, racial or gender predilections have been reported.Pancreatic Panniculitis - what is implicated?Pathogenesis: There is considerable evidence that the enzymes lipase, amylase and trypsin are involved in producing the lesions of pancreatic panniculitis71. Elevated enzyme levels have been detected in the blood urine71, and skin lesions, even in the absence of detectable pancreatic disease. Lipase has the clearest relationship with the panniculitis, with a number of patients having elevated serum lipase levels but normal amylase levels72. Utilizing an anti-pancreatic lipase monoclonal antibody, positive intracellular adipocyte staining was observed in a biopsy of lesional skin74. Amylase levels, when elevated, tend to peak 2-3 days after eruption of the skin lesions and return to normal 2-3 days after regression of the lesions. Trypsin and perhaps amylase may act by promoting increased permeability of vessel walls, thereby permitting lipase to hydrolyze neutral fat to form glycerol and free fatty acids, with resulting fat necrosis and inflammation72,73. Venous stasis may promote this process, possibly explaining the predilection for the lower extremities. Elevated enzyme levels may not be the complete explanation for the changes of pancreatic panniculitis75; immunologic factors probably also play a roleClinical Features of pancreatic panniculitis - what is schmids triad? clinical significance? -Clinical features Subcutaneous nodules develop in association with acute or chronic pancreatitis, pancreatic carcinoma (acinar cell > other types [e.g. neuroendocrine carcinomas]), pancreatic pseudocysts, pancreas divisum, or traumatic pancreatitis72,76. The possibility of a pancreaticoportal fistula should be considered when panniculitis develops in individuals with chronic pancreatitis, and in some of these patients, an acinar cell carcinoma can also be found. Panniculitis may precede detection of pancreatic disease by 1-7 months73, and in the case of pancreatic carcinoma, its onset may signal the presence of metastatic disease72,73. In pancreatic panniculitis, subcutaneous nodules develop, frequently on the legs but also on the anterior trunk, arms (Fig. 100.9), and scalp72,73. Erythematous, edematous, sometimes painful lesions arise singly or in crops, and they may migrate. They can become fluctuant and ulcerate, discharging an oily material72. Panniculitis may also involve visceral fat, including the omentum and preperitoneal fat72. Associated findings include fever, abdominal pain, inflammatory polyarthritis, ascites and pleural effusions72. The association of subcutaneous nodules, polyarthritis and eosinophilia is known as Schmid's triad, and it is associated with a poor prognosis. Some patients have radiographic evidence of multiple lytic areas involving the cortical bone near large joints. Cutaneous lesions may involute within a period of weeks, leaving hyperpigmented scars. In acute pancreatitis, the panniculitis resolves as the acute inflammatory phase passes72. However, lesions may also persist and expand until the underlying pancreatic abnormality has been treated.More Pancreatic Panniculitis - what type of panniculitis is this? - key histo-findings? - treatment? what can help?Pancreatic panniculitis may begin as a septal panniculitis22, but with progression, the lesion takes on the appearance of a lobular or mixed septal/lobular process. Even in early stages, fat necrosis with liquefaction and microcyst formation is observed71,75. Lipocytes lose their nuclei and develop thick, shadowy walls, forming the characteristic "ghost cells". Saponification of fat by calcium salts results in deposition of granular or homogeneous basophilic material (Fig. 100.10). Neutrophils, occasional eosinophils, macrophages, and multinucleated giant cells are sometimes present and may encroach upon the septa. Fibrosis and lipoatrophy are seen in late stages as the process resolves. Differential diagnosis Clinically, the nodules of pancreatic panniculitis can resemble those of a number of other forms of panniculitis. Ulceration and discharge would argue against erythema nodosum, and an association with fever, polyarthritis and/or abdominal pain should raise suspicion of associated pancreatic disease. Serum amylase and lipase levels, if elevated, may also be helpful. Histologic evidence of "ghost cell" formation and saponification of fat distinguishes pancreatic panniculitis from other panniculitides, with the exception of ghost cell formation in mucormycosis panniculitis. Eosinophilic "hyaline necrosis" is seen in lupus panniculitis, rather than the granular or homogeneous basophilic necrosis typical of pancreatic panniculitis. Treatment Although supportive measures such as compression and elevation can be helpful, effective management of pancreatic panniculitis is dependent upon treatment of the underlying pancreatic disease. In chronic pancreatitis, a pancreatic duct stent can be used to relieve obstruction, or, if a fistula or cyst is involved, biliary bypass surgery can be undertaken if simple drainage measures are unsuccessful. Octreotide, a synthetic somatostatin-like polypeptide, can be used to inhibit pancreatic enzyme production72. Resection of pancreatic cancer may be followed by regression of the panniculitis.Sclerema Neonatorum - arises in whom? describe skin - key histo finding - associated issues - Pathogenesis■ Arises in premature infants ■ Skin is diffusely cold, rigid, and board-like ■ Microscopically, needle-shaped clefts are present within lipocytes and there is minimal inflammation ■ Affected infants are often hypothermic and may have a variety of other medical problems; early death is common History Uzembenzius first recognized sclerema neonatorum in 1722, although the classic description is usually attributed to Underwood (1784). Ballantyne provided an early description of the histopathologic changes, and Knopfelmacher noted the presence of needle-shaped crystals in subcutaneous tissue in 1897. Epidemiology Sclerema neonatorum presents most often in premature, debilitated infants, usually during the first week of life. There is a slight male predominance, with no substantial gender differences in death rates78. Pathogenesis In infants who develop sclerema, crystallization and hardening of fat occur in the setting of an increased saturated : unsaturated fatty acid ratio and a defective ability to mobilize fatty acids. Precipitating factors are listed inSclerema Neonatorum - clinical features - key histo findings - key differentials - TreatmentsClinical features The clinical features are outlined in Table 100.877-79. Rapid hardening of the subcutaneous tissues leads to firm, rigid skin over most of the body. Low birth weight and hypothermia as well as hemorrhagic phenomena portend a particularly poor prognosis78. Pathology Table 100.8 outlines the microscopic features. Inflammation is usually sparse, and most of the needle-shaped clefts are found within lipocytes rather than within giant cells (Fig. 100.11) 77,79. At a later stage, thickened connective tissue bands may be the only histologic finding79. Differential diagnosis In contrast to sclerema neonatorum, subcutaneous fat necrosis of the newborn is a localized process with a favorable prognosis; histologically, the latter is distinguished by more prominent inflammation and localization of needle-shaped clefts within giant cells. Scleredema neonatorum is a condition seen in premature infants with congenital heart disease. In this disorder, the skin is distended and wax-like, and on biopsy the dermis appears edematous, with increased amounts of mucin77. Other conditions that can present with diffusely indurated skin in the neonatal period include stiff skin syndrome (usually favoring the trunk, buttocks and thighs), restrictive dermopathy, and Hutchinson- Gilford progeria. While subcutaneous needle-shaped clefts are generally observed in infants and children, radially arranged needle-shaped clefts (resembling those of sclerema neonatorum) were recently reported in an adult with gemcitabine-related thrombotic microangiopathy80; however, these crystals were quite small. Treatment Attempts to treat this disorder are disappointing78. Management includes treatment of sepsis, ventilatory support, correction of fluid and electrolyte imbalances, and maintenance of body temperature77,81. Exchange transfusions may be of value in selected instances77,81. Systemic corticosteroids are of questionable utilitySubcutaneous Fat Necrosis of the Newborn - clinical features, occurs in whom and when - associated lab abnormalities - key histo-findings - prognosis - how does it differ from sclerema neonatorum - pathogenesis■ Development of one or more mobile, firm, subcutaneous nodules or plaques during the newborn period ■ Sometimes associated with hypercalcemia or thrombocytopenia ■ Granulomatous lobular panniculitis with needle-shaped clefts within lipocytes and giant cells ■ Prognosis is usually favorable; spontaneous resolution is common Introduction In contrast to sclerema neonatorum, subcutaneous fat necrosis is a localized process. Although complications can arise, particularly in relation to hypercalcemia, most cases resolve spontaneously. History At the beginning of the twentieth century, Fabyan described "abscesses" that spontaneously resorbed, and he provided the first microscopic description of subcutaneous fat necrosis. Epidemiology Subcutaneous fat necrosis of the newborn typically occurs in full-term neonates during the first 2 to 3 weeks of life Pathogenesis It is believed that a variety of stresses imposed upon fetal fat, with its high ratio of saturated : unsaturated fatty acids, results in crystallization, adipocyte injury, and granulomatous inflammation. Hypothermia is one potential eliciting factor, as illustrated by cases of subcutaneous fat necrosis that developed following hypothermic cardiac surgery and the use of cooling blankets83-85. Other proposed causes are listed in Table 100.877,82,84. The role of birth trauma has been questioned, since many cases have occurred in infants delivered by cesarean sectionMore Subcutaneous fat necrosis of the newborn - clinical presentation - associated labs? why? - Path findings? stain that may helpClinical features The clinical features are outlined in Table 100.8. Smooth, circumscribed, mobile, red to violaceous, subcutaneous nodules or plaques develop, sometimes in a symmetrical fashion77,82 (Fig. 100.12). The areas of fat necrosis can be detected by CT86 and MRI87. Some patients develop hypercalcemia or thrombocytopenia, and the former may appear 1-4 months after the onset of the skin lesions84. It is believed that the hypercalcemia results from extrarenal production of 1,25-dihydroxyvitamin D3 (calcitriol) by activated macrophages (expressing 1-α-hydroxylase) within areas of granulomatous panniculitis. This stimulates calcium absorption from the gut and mobilization from the bones82,88. The mechanism for thrombocytopenia may be local sequestration in the subcutis, as studies have shown normal bone marrow cellularity and resolution of the thrombocytopenia as the inflammatory process resolves89. Spontaneous resolution of lesions is the rule, but some patients develop residual lipoatrophy. Deaths have been reported in those with associated hypercalcemia89. Pathology The microscopic changes are outlined in Table 100.8. They include a predominantly lobular panniculitis with mixed cellularity (Fig. 100.13). Needle-shaped clefts are observed within both lipocytes and giant cells (Fig. 100.13, inset). The crystals are doubly refractile and stain with oil red O77. Occasionally, however, needle-shaped clefts are not evident in otherwise typical cases. Eosinophilic granules are sometimes found within multinucleated giant cells; their origin is not entirely certain, but they may be derived from degranulating eosinophils9Fat necrosis of the newborn - how is it different from sclerema neonatorum and post steroid fat necrosis? - TreatmentDifferential diagnosis The extensive cutaneous involvement in sclerema neonatorum is usually distinguishable from the localized, self-limited process of subcutaneous fat necrosis; histologically, inflammation in sclerema is minimal. Post-steroid panniculitis is microscopically indistinguishable from subcutaneous fat necrosis, but it arises in a different clinical setting (see below). Treatment Since many lesions resolve spontaneously, the emphasis is on supportive care. Systemic corticosteroids may be indicated to control the inflammation in severe cases77. Serial monitoring of calcium levels (for at least 4 months) is recommended. Hypercalcemia is managed by hydration, dietary restriction of both calcium and vitamin D, calcium-wasting diuretics (e.g. furosemide), calcitonin, and bisphosphonates (e.g. etidronate, pamidronate)82,84,91. Corticosteroids may be helpful in managing hypercalcemia, by interfering with the metabolism of vitamin D to calcitriol, and by inhibiting calcitriol production by macrophagesPost steroid Panniculitis - cause, when do lesions resolve, key path findings - Occurs in whom? - pathophysiology■ A rare complication of rapid withdrawal of systemic corticosteroids ■ Subcutaneous nodules develop on the cheeks, arms and trunk ■ Lesions resolve spontaneously, or when corticosteroids are readministered ■ Microscopically, granulomatous lobular panniculitis with needleshaped clefts within both lipocytes and giant cells History In 1956, Smith and Good92 reported 11 children with acute rheumatic fever who were treated with large doses of corticosteroids that were rapidly tapered. Five children developed pruritic, erythema nodosumlike lesions. Epidemiology Post-steroid panniculitis is typically a disorder of children. It occurs in an older age group than either sclerema neonatorum or subcutaneous fat necrosis of the newborn, with reported ages ranging from 20 months to 14 years93. Occasionally, the disorder occurs in adults94,95. Pathogenesis Post-steroid panniculitis occurs after rapid withdrawal of systemic corticosteroids that have been administered either orally or intravenously. For patients who had received prednisone, cumulative dosages ranged from 2000 to 6000 mg93. The precise mechanism by which the panniculitis arises is not known.Post Steroid - timing of onset and resolution - Histology? identical to whom? - TreatmentClinical features Patients who have developed this form of panniculitis received corticosteroid therapy for a variety of conditions92-96, including those listed in Table 100.8. Lesions appear 1 to 40 days after rapid corticosteroid withdrawal and disappear spontaneously over a period of months to a year96. Pathology Microscopic changes are outlined in Table 100.896. Needle-shaped clefts, some with a "starburst" pattern, can be identified within lipocytes or giant cells Differential diagnosis A less nodular presentation involving the cheeks can mimic nonpanniculitic disorders such as erythema infectiosum, atopic dermatitis, lupus erythematosus, or facial cellulitis. The microscopic changes in these conditions would be quite different from those of post-steroid panniculitis. Cold panniculitis has clinical and microscopic similarities, but the history of cold exposure and the lack of needle-shaped clefts on biopsy permit distinction. The microscopic changes of poststeroid panniculitis are virtually identical to those of subcutaneous fat necrosis of the newborn, although calcification and hemorrhage are more commonly observed in the latter condition. Clinical history allows distinction. Treatment Since spontaneous resolution is the rule, treatment is usually unnecessary. Readministration of corticosteroids followed by a more gradual taper may be helpfulLupus Panniculitis - accounts for what % of cuteanous lupus - usually seen in whomHistory Kaposi first described the clinical characteristics of lupus panniculitis in 1869. In 1940, it was recognized as a manifestation of lupus erythematosus (LE) by Irgang. Lupus panniculitis was firmly established as a specific subtype of LE in a 1956 paper by Arnold97. Epidemiology Lupus panniculitis constitutes a small subset of all cases of cutaneous LE, representing 2-3% of this group98. It usually occurs in adults, with a median age of onset of 30-40 years99. Children can also develop lupus panniculitis, and an association with neonatal lupus has been described97. There is a predominance among women, with a female : male ratio ranging from 2 : 1 to 4 : 136,99. Sometimes there is a family history of either LE or another autoimmune connective tissue disease98. Pathogenesis The autoimmune basis of lupus panniculitis is thought to be similar to that of other types of LE (see Ch. 41). The cells comprising the infiltrates of lupus panniculitis are T lymphocytes and macrophages100. Lupus panniculitis, often with a childhood onset and widespread distribution, has been described in patients with partial C4 deficiency101. This complement deficiency causes defective opsonization of immune complexes, which may play a role in the pathogenesis of the disease101. Immunohistochemical analysis has shown an interferon-driven Th1- biased immune response in active lesions of lupus panniculitis; this may result in recruitment of cytotoxic CXCR3-positive lymphocytesClinical Features of Lupus Panniculitis - morphology? typically found on what areas of the body - more likely to occur with what other forms of lupus - what % of patients meet criteria for systemic LE - what anti-bodies may be presentClinical features Lupus panniculitis is characterized by tender subcutaneous nodules and plaques that may arise in crops (see Table 100.7). A history of trauma can sometimes be elicited. Lesions tend to develop on the face, upper arms, hips and trunk (Fig. 100.14). Linear scalp lesions are common among, but not restricted to, East Asian populations103. The lack of involvement of the distal extremities is noteworthy99. Changes in the overlying skin range from a light pink color to those of discoid LE, i.e. scaling, follicular plugging, dyspigmentation, telangiectasias, atrophy and scarring. At times, findings of discoid LE are too subtle to be recognized clinically but can be seen on microscopic examination of biopsy specimens. The overlying skin may also be "tethered" to the subcutaneous nodule or plaque, creating a surface depression, and ulceration occasionally occurs. Lupus panniculitis has a chronic, relapsing clinical course104. It usually eventuates in subcutaneous atrophy, which can be disfiguring (see Chs 41 & 101). Lupus panniculitis often occurs prior to other manifestations of LE and in the absence of other autoimmune connective tissue diseases99. For example, lesions of discoid LE have developed up to 10 years after the appearance of the panniculitis. However, manifestations of systemic LE or discoid LE can also occur long before or simultaneously with the panniculitis36. There is a closer relationship of lupus panniculitis to other forms of chronic cutaneous LE (e.g. discoid LE) than to systemic LE. Coexistent discoid lesions are observed in at least one-third of patients, whereas only 10-15% meet the diagnostic criteria for systemic LE99,105. Most individuals in the latter group have relatively mild systemic manifestations, usually arthralgias or Raynaud phenomenon98. It is common for patients to have low-titer antinuclear antibodies; they can also have other circulating autoantibodies (e.g. anti-dsDNA, antiRNP), leukopenia, hypocomplementemia, and an elevated ESRPathology of lupus panniculitis - lobular or septal? - Dif findings?Pathology Lupus panniculitis is a predominantly lobular process with a variable degree of inflammation (Fig. 100.15A). Nodular aggregates of lymphocytes are often present (Fig. 100.15B). The characteristic microscopic changes, e.g. hyaline necrosis of the fat lobules, are outlined in Table 100.7 (Fig. 100.15C). Granulomas can occur and tend to encroach upon the septa, but they are usually not prominent. Other features include lymphocytic vasculitis and mucin or calcium deposition. The subcutaneous findings alone are considered sufficiently characteristic to permit a diagnosis of lupus panniculitis. However, overlying epidermal or dermal changes of discoid LE occur in one-half to two-thirds of cases and are also helpful diagnostically 100,105,106. With direct immunofluorescence, a positive lupus band can be identified in the overlying skin in a high percentage of cases, even in those where the histopathologic changes are nonspecific1Lupus paniculitis ddx - how can it be distinguished from EN or erythema induratum? - Most important differential? - TreatmentDifferential diagnosis Clinically, lesions of lupus panniculitis can resemble other forms of panniculitis. The rarity of involvement of the distal extremities helps to distinguish it from conditions such as erythema nodosum and erythema induratum. It should also be remembered that other forms of subcutaneous inflammation may occur in patients with LE, including erythema nodosum, thrombophlebitis, pancreatic panniculitis, and juxta-articular, rheumatoid nodule-like lesions. Microscopically, lupus panniculitis can resemble the panniculitis associated with morphea and dermatomyositis (see Table 100.7), traumatic panniculitis (which often has evidence of foreign material) and, in its later stages, localized lipoatrophy due to other etiologies98,104. The most important entity in the differential diagnosis is subcutaneous panniculitis-like T-cell lymphoma, as there can be considerable histopathologic overlap between the two disorders. The distinguishing features are outlined in Table 100.9. It should be noted, however, that changes such as vacuolar alteration of the basilar layer and dermal mucin deposition have been reported in panniculitis-like T-cell lymphoma107. To complicate matters further, features of both disorders can be present in the same biopsy specimen108. Treatment Antimalarials are frequently used to treat lupus panniculitis, and they produce improvement in most patients99. Addition of a second antimalarial may prove useful in patients who do not respond to a single agent104. In view of the chronic, relapsing nature of the disease, treatment may be required for several years98. Systemic corticosteroids, when used, are often restricted to initial phases of the disease98. Other systemic therapies include dapsone, mycophenolate mofetil, cyclophosphamide, thalidomide, and IVIg Overlying discoid lesions, if present, can be treated with potent topical or intralesional corticosteroidsPanniculitis of Dermatomyositis - is it common in dermatomyositis, timing related to classic dermatomyositis findings - key histo findings■ An uncommon manifestation of dermatomyositis ■ More frequently, incidental microscopic changes of panniculitis (in the absence of clinical lesions) are observed ■ Can precede or follow other manifestations of dermatomyositis ■ Microscopically, it is a lobular or mixed panniculitis with lymphoplasmacytic predominance ■ Usually responds to therapy Clinical features The characteristic lesions are persistent, indurated, painful plaques and nodules that may ulcerate and lead to lipoatrophy (see Table 100.7) 110. They can arise in the setting of established dermatomyositis110 or represent the first manifestation of the disease111. In affected individuals, the other clinical and laboratory features as well as the incidence of malignancy appear to be similar to those of dermatomyositis patients without panniculitis110. Partial or generalized lipoatrophy without preceding clinical lesions of panniculitis (occasionally accompanied by increased abdominal fat) occurs in up to one-quarter of patients with juvenile dermatomyositis, and it is often associated with metabolic abnormalities such as hypertriglyceridemia and insulin resistancePanniculitis of Dermatomyositis - what is an important differential and how might they be distinguished histologically? - treatmentPathology The microscopic features are outlined in Table 100.7. Lymphocytic vasculitis has been described, and fat necrosis has been noted in several reports110. Membranocystic changes have been observed in some cases (see section on lipodermatosclerosis), and lesions with these changes may be particularly resistant to therapy110. Calcification is variable and is an expected finding in cases of dermatomyositis associated with calcinosis of deep soft tissues and skeletal muscle35. Vacuolar alteration of the basal layer of the overlying epidermis has been described110, and the dermis may be edematous or mucinous with perivascular lymphocytic inflammation112. Direct immunofluorescence is reported to be negative for deposits along the dermal-epidermal junction110, although immunoreactants have been detected in vessel walls Differential diagnosis Lupus panniculitis is more likely to show hyaline necrosis and lymphoid nodules, but clinical and laboratory findings may be needed to make a distinction. Overlying poikilodermatous changes can occur in both diseases, but lupus is more likely to show appendageal involvement and is associated with positive basement membrane zone fluorescence. Treatment Good responses to therapy have generally been reported112, and treatments include prednisone, methotrexate, azathioprine, cyclosporine, and IVIg110-112. Panniculitis lesions have shown variable responses to hydroxychloroquine. Residual facial lipoatrophy has been successfully treated with hyaluronic acid and poly-L-lactic acid dermal fillers.Traumatic Panniculitis - triggers for traumatic panniculitis - children most at risk for what?■ Inflammation in the subcutis resulting from external injury ■ The injurious event may be accidental, purposeful or iatrogenic, and it may be a manifestation of an underlying psychiatric disturbance ■ A variety of histopathologic changes are observed, depending upon the inciting agent ■ Identification of foreign material is of greatest help in diagnosis Introduction Extrinsic injury of varying types can produce panniculitis. There are four broad categories: cold panniculitis (Haxthausen disease), sclerosing lipogranuloma, panniculitis due to other injectable substances or therapies (e.g. megavoltage radiation), and panniculitis due to blunt trauma. History Lemez described cold panniculitis in 1928, when he noted that newborns and infants up to 6 months of age were particularly susceptible to cold injury, as demonstrated by the production of a subcutaneous nodule following application of an ice cube113. In 1941, Haxthausen described a condition occurring in small children a few days after exposure to cold, consisting of firm infiltrated nodules of the cheeks and chin. A similar type of cold injury due to popsicles was reported by Epstein and Oren in 1970114. Injection of foreign lipid material into the skin for cosmetic or other purposes has been performed for centuries115. In 1950, Smetana and Bernhard reported 14 cases of what they termed sclerosing lipogranuloma of the male genitalia. They believed it was an endogenous process, but subsequent studies demonstrated the presence of mineral oil in similar cases115. Epidemiology Infants and small children are most at risk for cold panniculitis. A form of the disease also occurs on the thighs of young women who are equestrians116. Sclerosing lipogranuloma of the male genitalia is seen mostly in young adults117. A sclerosing, pseudosclerodermatous panniculitis has been reported following megavoltage radiation for metastatic carcinoma118 and as a radiation recall reaction after cyclophosphamide therapyTraumatic Panniculitis - cold physiology favors whom? - what oils have been implicated - factitial causes, medication causesPathogenesis Cold injury to fat favors small children, due in part to the previously discussed characteristics of their fat120. Cold injury is also related to fluctuations in blood flow that occur with declining temperatures (the "hunting phenomenon"), ice crystal formation, and the changes that occur with thawing120. Injections of oils (and associated impurities) are known for producing subcutaneous inflammation. Substances include mineral oil (paraffin) as well as camphor, cottonseed, and sesame oils. Even medical grade silicone may contain impurities, and since encapsulation of this material is desirable when used for cosmetic purposes, fibrosis-inducing substances such as olive oil or castor oil are often added115. Injected substances responsible for factitial panniculitis have included milk, feces, and a host of other substances. Panniculitis has been produced by numerous therapeutic agents, such as meperidine, morphine, pentazocine, phytonadione (vitamin K)121, glatiramer acetate, interferon-β, interleukin-2122, and vaccines (e.g. tetanus), as well as substances that have been used for tissue augmentation such as bovine collagen123 or poly-L-lactic acid. More recently, panniculitis due to "mesotherapy" (injection of substances such as phosphatidylcholine to treat localized fat accumulations; see Ch. 156)124 and electroacupuncture125 have been described. In addition to the foreign body response elicited by many of these agents, other immune mechanisms may also be involved. With blunt trauma, granulomas contain material that may be derived from the breakdown of erythrocyte membranesTraumatic Panniculitis - cold panniculitis presentation - what is texier disease - what to look for on path?Clinical features In cold panniculitis (including popsicle panniculitis), erythematous, firm nodules develop, particularly on the cheeks and chin120. In equestrian cold panniculitis, erythematous to violaceous, tender plaques appear on the thighs following exposure to cold while wearing tightfitting clothing (Fig. 100.16) 116. In lipogranuloma, nodules are sometimes migratory and can be accompanied by varying degrees of swelling, erythema, abscess formation, lymphangitis, and fibrosis115. The term sclerosing lipogranuloma often refers to lesions arising on the male genitalia due to self-injection of oily materials (see Ch. 94). There has also been a report of a sclerosing lipogranuloma that apparently resulted from topical application of vitamin E cream127. In several Japanese patients, Y-shaped induration of the scrotum (in which exogenous lipids could not be detected) was described as eosinophilic sclerosing lipogranuloma128. Patients with sclerosing lipogranuloma frequently deny self-injection, making diagnosis difficult. Another variant of lipogranuloma is the grease gun granuloma, which results from accidental firing of the grease gun used by mechanics. This results in formation of a verrucous nodule, often on the dorsum of the hand129. Inflamed nodules with varying degrees of pain and fibrosis have been observed in other forms of panniculitis due to injection, with the distribution of lesions sometimes providing a clue to their cause. A dramatic example of this is Texier disease, a panniculitis due to phytonadione (vitamin K) injections. In this disorder, sclerotic lesions with lilac-colored borders form on the buttocks and thighs, in a configuration resembling a "cowboy gunbelt and holster"121. Lesions due to blunt trauma often have an ecchymotic character and involve locations such as the shin, arm or hand126. Hypertrichosis may also be present, possibly the consequence of local hyperemia or angiogenesis130. Pathology Table 100.10 outlines the microscopic changes in various forms of traumatic panniculitis117-119,129-133. In addition, sclerosing lipogranuloma is discussed in Chapter 94. - Look for "CENTRAL NIDUS" of inflammation or foreign bodiestreatment of traumatic panniculitisDifferential diagnosis In cold panniculitis, the absence of needle-shaped clefts in lipocytes and location of the most intense inflammation near the dermal- subcutaneous interface help to distinguish this condition from subcutaneous fat necrosis of the newborn. In sclerosing lipogranuloma and related lipogranulomas, distinctive large vacuoles are found in the dermis and subcutis (Fig. 100.17). Radiographs are sometimes useful in differentiating lipogranulomas from silicone granulomas, since only the latter are radio-opaque134. Mineral oil in non-processed tissue can be identified by infrared spectrophotometry129. Panniculitis due to injectable substances can be diagnosed when foreign material (often identified by polarization microscopy) is present. Cosmetic fillers have distinctive histologic features (see Fig. 94.10), and they can be identified by cutaneous sonography135. Cases with acute inflammation and necrosis may resemble infection-induced panniculitis, and, in fact, infection may accompany injection panniculitis136; special stains and cultures for organisms (including atypical mycobacteria) are useful in this regard. Sclerosing traumatic panniculitis (e.g. due to phytonadione or pentazocine injections) may resemble morphea clinically, but would not present as a septal panniculitis histologically. Treatment Treatment of these disorders should focus on removal of the inciting stimulus and eradication of any associated infection. Intralesional or systemic corticosteroids can be helpful in controlling the inflammation, and they have been used in the management of sclerosing lipogranuloma115 and granulomatous panniculitis due to other injected substances123. Surgical excision may also be an option for sclerosing lipogranulomaLipodermatosclerosis - favors what area of the body, describe chronic and acute phases - usually develops in the setting of what? - most patients are?■ Favors the medial aspect of the lower extremities above the malleolus ■ Acute phase with erythema, warmth and tenderness, which may be misdiagnosed as infectious cellulitis ■ Chronic phase with induration and red-brown to violet-brown discoloration ■ Usually develops in the setting of chronic venous insufficiency ■ Both septal and lobular panniculitis; lipomembranous changes are common, particularly in chronic lesions Introduction Erythema, induration and pigmentary changes have long been known to be associated with venous insufficiency. Because of the variety of clinical appearances and histopathologic findings that can occur at different stages of the disease, a number of diagnostic terms have been employed to explain the changes. Recently, the various manifestations of this panniculitis have been consolidated under the heading of lipodermatosclerosis or sclerosing panniculitis Most patients are women over the age of 40 years, but appearance after the age of 75 years has also been reportedLDS Pathogenesis - key cause? - increased expression of what factors have been seen?Pathogenesis There is considerable evidence for venous insufficiency in patients with lipodermatosclerosis140, and fibrinolytic abnormalities are also present in these individuals. Venous hypertension leads to a compromised ability to reduce foot vein pressure during exercise. This results in increased capillary permeability, which causes leakage of fibrinogen, its polymerization to form fibrin cuffs around vessels, impedance of oxygen exchange, and tissue anoxia (see Ch. 105)139. Pericapillary fibrin deposits can be seen in uninvolved, clinically normal extremities of patients with healed venous ulcers of the opposite extremity, suggesting that this abnormality precedes the clinical changes of lipodermatosclerosis141. There may also be an abnormal regulation of angiogenesis within lesions of lipodermatosclerosis. In particular, increased expression of vascular endothelial growth factor receptor 1 (VEGFR-1), which can act as a negative regulator of VEGF-mediated angiogenesis, has been observed, along with increased expression of angiopoietin-2 (Ang-2)142. Additional factors contributing to the pathogenesis of lipodermatosclerosis may include protein C and S deficiencies143, local stimulation of collagen synthesis139, including an increased number of cells expressing procollagen type 1 mRNA144, and obesityClinical findings Path findingsClinical features The acute phase of lipodermatosclerosis presents with pain, warmth, erythema and some induration (Fig. 100.18), most often initially on the medial lower leg above the malleolus. Other dependent sites such as the lower aspect of the abdominal pannus can also develop lipodermatosclerosis. At this point, the changes are relatively diffuse139. In the chronic phase, there is marked sclerosis of the dermis and subcutis, resulting in induration that is more sharply demarcated from adjacent normal skin. Hyperpigmentation due to hemosiderin deposition may also be present138. These features give the affected leg the appearance of an inverted wine bottle145. Pathology Early lesions show mid-lobular ischemic necrosis, a lymphocytic infiltrate in the septa that rims the fat lobules, variable degrees of capillary congestion and thrombosis, and hemorrhage with hemosiderin deposition. With progression, septal thickening, hyaline sclerosis involving lipocytes, lipophage formation, and mixed inflammatory cell infiltrates appear138. Advanced lesions show marked septal sclerosis and membranocystic change in the face of a marked reduction in inflammation. Membranocystic change is a key feature in lipodermatosclerosis146. This consists of thickened, undulating membranes that form cysts and papillary configurations (Fig. 100.19). The membranes are believed to result from degenerated cell membranes of lipocytes and/or macrophages. The material comprising the membranes is ceroid, an oxidation product of unsaturated fatty acids147. Short, frayed elastic fibers can be present within the subcutaneous septa, and these may be calcified, features that resemble pseudoxanthoma elasticum148. By phosphotungstic acid-hematoxylin stain or by immunofluorescent methods, pericapillary fibrin can also be demonstrated in lesions of lipodermatosclerosis146. Dermal changes include fibrosis, tortuous thick-walled veins, and superficial and deep perivascular inflammation138. Biopsy should be avoided if the diagnosis is obvious, since poor wound healing and ulceration frequently result. When necessary, a thin elliptical excision should be obtained from the margin of a lesionLDS ddx and treatment - mainstays of treatment - what drug is go to? side effects of this medication - other med to considerDifferential diagnosis Difficulties in clinical diagnosis arise most often in early lesions, when the process is more diffuse and erythematous. At this stage, consideration is often given to cellulitis, erythema nodosum, or erythema induratum138,139,145. Persistence of a lesion, association with stasis changes, and lack of response to antimicrobials suggest the correct diagnosis, perhaps aided by studies of venous function140. As induration develops and progresses, differentiation from morphea and scleromyxedema may be necessary. In morphea, subcutaneous involvement is predominantly septal, and lipophagic and lipodystrophic changes are not as prominent as they are in lipodermatosclerosis138. Membranocystic changes, when present, can be of great diagnostic help; however, these findings can occur in a variety of other conditions, including lupus and dermatomyositis panniculitis, liposarcoma, erythema nodosum, and diabetic dermopathy147. Treatment Leg elevation and consistent compression therapy are the mainstays of treatment for lipodermatosclerosis139. Traditional anti-inflammatory therapies are usually ineffective in this condition138, although intralesional corticosteroids (e.g. triamcinolone 5-10 mg/cc) may be of benefit when used in conjunction with compression therapy. Good results were reported with the anabolic steroid stanozolol139, especially in the earlier phases of the disease, but this medication is no longer commercially available. As a result, danazol has been used (successfully) as a substitute149. Anabolic steroids enhance fibrinolysis, and they can reduce pain, extent of involvement, and induration of the skin. However, side effects of sodium retention, lipid profile abnormalities, hepatotoxicity, and virilization in women do limit their use. Oxandrolone, an anabolic steroid with less hepatotoxicity and fewer androgenic effects, represents another therapeutic option Other reported treatments include ultrasound, pentoxifylline, fasciotomy, and phlebectomyInfection induced panniculitis - occur more commonly in patients with what comorbidities? - methods of innoculation?■ A wide variety of infectious agents has been reported to produce panniculitis ■ Some degree of immunosuppression is common, but not invariable ■ Histopathologic findings vary, but often include mixed septal/ lobular panniculitis, neutrophilic infiltration, hemorrhage and necrosis ■ Special staining and culture of drainage and tissue can provide a definitive diagnosis Introduction Panniculitis can result from a distant focus of infection (a classic example being erythema nodosum) or panniculitis can be directly induced by an infectious agent. The latter can produce a variety of clinical and microscopic appearances, although there are some features that infection-induced lesions have in common, regardless of the etiologic agent Epidemiology There appears to be no age, gender or racial predilection among cases of infection-induced panniculitis. Many of these patients are immunosuppressed23 or have predisposing medical conditions such as diabetes mellitus151. Pathogenesis In this group of disorders, infectious agents are considered to be directly responsible for the panniculitis. Examples of reported microorganisms to date are listed in Table 100.1123,151-165b. Involvement of the subcutis can result from direct inoculation or septicemia. Other potential modes of spread include transfascial from an enteric source, in the case of abdominal panniculitis158, or via "persorption", a proposed mechanism by which Candida migrates across intact endothelium from the gut to a subcutaneous site159. Immunosuppression is common, but not invariable, among individuals with infection-induced panniculitis.Infectious panniculitis - path findings - possible organisms?Clinical features Patients develop local swelling and erythema. There may be one or more fluctuant nodules that ulcerate and drain. Lesions on the legs and feet are common, but other sites of involvement include the gluteal region, abdomen, axillae, arm or hand. Underlying conditions include diabetes mellitus, leukemias or solid tumors, autoimmune connective tissue disease, AIDS, and organ transplantation. Pathology Individual cases can mimic other primary forms of panniculitis. Common changes (regardless of the infectious agent) include a mixed septal/lobular panniculitis, neutrophilic infiltration, vascular proliferation, hemorrhage, and necrosis that involves lipocytes, inflammatory cells and eccrine sweat coils23 (Fig. 100.20). In Q fever due to Coxiella burnetii, there may be a "doughnut-like" granulomatous lobular panniculitis, in which fibrin and inflammatory cells form a ring around a central clear space; similar changes have been found in the liver and bone marrow of patients with Q fever Bacteria Staphylococcus aureus Group A Streptococcus Pseudomonas aeruginosa Brucella melitensis Nocardia asteroides Tropheryma whipplei (causative agent of Whipple disease) Mycobacteria M. tuberculosis M. marinum, M. avium-intracellulare, M. chelonae, M. fortuitum, M. ulcerans Coxiella C. burnetii Borrelia B. burgdorferi Fungi Blastomyces dermatitidis, Histoplasma capsulatum Microsporum spp. (including M. canis) Candida spp. (including C. albicans) Cryptococcus neoformans Aspergillus spp. (including A. flavus), Mucor or related zygomycetes, Fusarium spp., Aureobasidium pullulans Helminths & protozoa Nematodes (Gnathostoma spp.) Trematodes (Fasciola hepatica, Schistosoma spp.)ddx and treatment of infection induced panniculitisDifferential diagnosis Fluctuant, ulcerating nodules also occur in pancreatic panniculitis, traumatic panniculitis, and alpha-1 antitrypsin deficiency panniculitis. Clinical and laboratory data can usually permit distinction. As noted previously, traumatic panniculitis may be accompanied by infection. Examples of infection-induced panniculitis with predominantly septal involvement or vasculitis could be confused with acute erythema nodosum or erythema induratum, respectively. Panniculitis due to mucormycosis may feature "ghost cells" and granular calcium deposits and thus resemble pancreatic panniculitis; it can also mimic gouty panniculitis due to the presence of intracellular crystalline deposits162. Special stains for organisms and cultures of drainage and tissue are keys to the diagnosis. In one study, special stains were positive for organisms in 14 of 15 cases23. Treatment Treatment consists of appropriate antimicrobial therapy. Surgery may be indicated for isolated lesions caused by grain-forming fungi or bacteria, such as mycetoma or botryomycosis153. A more radical surgical approach has been used successfully in treating abdominal panniculitis due to enteric bacteriaCytopathic Histiocytic panniculitis - refers to what? what are the implicated cells called? - The vast majority of these patients have what? - genes that encode for what have been implicated?The term "cytophagic histiocytic panniculitis" (CHP) has been used to describe subcutaneous nodules or plaques that on histiologic examination show infiltrates of macrophages containing erythrocytes, lymphocytes and/or karyorrhectic debris, i.e. exhibiting hemophagocytosis (Figs 100.21 & 100.22) 166. These macrophages with cytophagic activity have been referred to as "bean bag" cells. With the advent of immunophenotyping and genetic techniques, it has become apparent that the vast majority of patients have lymphoma, with atypical lymphoid cells also present within the panniculus167. In general, the lymphomas represent subcutaneous involvement of primary cutaneous γ/δ T-cell lymphoma or EBV-associated extranodal NK/T-cell lymphoma, nasal type (see Ch. 120)168. Occasionally, patients have subcutaneous panniculitis-like T-cell lymphoma, and, rarely, no lymphoma169. Individuals in the latter group may still have a fatal course due to a hemophagocytic syndrome that involves the liver, spleen and bone marrow (leading to pancytopenia). Mutations in a number of genes can predispose individuals to the development of hemophagocytic syndrome, including that which encodes perforin (see Table 91.1). Of note, a child with microscopic findings of CHP but no evidence of lymphoma was found to have a heterozygous nonsense mutation in the gene that encodes perforinMalignant subcutaneous infiltratesMalignant infiltrates may involve the subcutis, mimicking the clinical and microscopic appearance of panniculitis. The best known of these is subcutaneous panniculitis-like T-cell lymphoma (see Ch. 120). While cytophagia can be seen in the latter disorder, it is particularly characteristic of subcutaneous involvement of primary cutaneous γ/δ T-cell lymphoma and EBV-associated extranodal NK/T-cell lymphoma, nasal type (see above). Other lymphomas (e.g. B-cell), leukemias, and metastatic solid tumors may infiltrate the subcutis. For example, a case of melanophagic panniculitis that obscured foci of metastatic melanoma has been reported171. Obviously, clinical information is crucial in such cases. Histopathologic clues include the recognition of significant pleomorphism or monotony among infiltrating cells in the subcutis, infiltration between collagen bundles of the dermis or around adnexal structures, and supporting immunohistochemical studies. Of note, the diagnosis of subcutaneous panniculitis-like T-cell lymphoma can sometimes be elusive as the initial impression may be lupus panniculitis (see Table 100.9) or even a nonspecific panniculitis with lipomembranous changesUnusual Forms of Panniculitislists several more recently described or unusual forms of panniculitis155,173-182. When a patient presents with panniculitis that is not readily classifiable, it may be worthwhile to consider these alternative diagnoses. Several of them probably do not actually represent distinct entities but rather, overarching terms that include established forms of panniculitis. For example, plasma cell panniculitis could include not only morphea and postirradiation pseudosclerodermatous panniculitis but also other autoimmune connective tissue diseases or infectious diseases. The fasciitis-panniculitis syndrome is a term that has appeared from time to time, primarily in the non-dermatology literature. While sometimes discussed as if it were a single entity, fasciitis-panniculitis syndrome has been used to include eosinophilic fasciitis, morphea profunda, lupus panniculitis, lipodermatosclerosis, and a variety of other conditions. Sweet syndrome and Lyme disease are established entities that can occasionally have panniculitis as a significant finding. Two other more recently described conditions, atypical lymphocytic lobular panniculitis and panniculitic bacterid, may require further study and experience before being widely accepted as distinct entities. No doubt this list will change as disease mechanisms are better understood and disorders are reclassified or absorbed into other classification schemes.