Panniculitis — Septal & Lobular

• Panniculitis is diagnostically challenging for dermatologists and pathologists.
• Terminology is difficult: same disorder given different names (e.g., nodular vasculitis and erythema induratum); new terms introduced, old ones abandoned.
• Clinically, many forms with diverse etiologies resemble one another — tender, erythematous, subcutaneous nodules.
• Some panniculitides (e.g., erythema nodosum) are a manifestation of many different disease processes.
• Even when the type of panniculitis is identified correctly, further investigation is required to find the underlying cause.
• Pathologically, subcutaneous fat responds to varied insults in a limited number of ways — histopathologic differences may be subtle.
• Management typically requires two therapeutic goals:
• Specific treatment of the panniculitis.
• Treatment of the underlying illness.
• Classification categories are determined partly by:
• Clinical characteristics such as anatomic location.
• Histopathology.
• Etiology.
• Septal vs lobular panniculitis are largely artificial constructs — no purely septal or purely lobular panniculitis exists.
• Biopsy technique is critical: specimen must include a generous portion of subcutaneous fat.
• Excisional biopsies extending through the subcutis, or narrow incisional biopsies incorporating a broad expanse of subcutaneous fat, are preferable to punch biopsies.

• Erythema nodosum — pretibial areas.
• Erythema induratum — posterior calves.
• Lupus panniculitis — face, upper arms.
• Alpha-1 antitrypsin deficiency panniculitis — lower trunk/proximal extremities.
• Lipodermatosclerosis — medial lower leg above malleolus.

Mostly SEPTAL, WITHOUT vasculitis:

• No inflammatory cells (lipoatrophy residua — see Ch. 101).
• Lymphocytes and plasma cells → Erythema nodosum (EN), EN migrans.
• Sclerosis of the septa → Postirradiation panniculitis.
• α1-antitrypsin deficiency† (some authors classify as mostly septal) → Alpha-1 antitrypsin deficiency panniculitis.

Mostly SEPTAL, WITH vasculitis:

• Large vessels (veins): mucin → Superficial thrombophlebitis.
• Small vessels (venules)*: fibrin → Cutaneous PAN.

Mostly LOBULAR, WITHOUT vasculitis:

• Cholesterol clefts → Necrobiosis lipoidica.
• Histiocytes/granulomas → Deep morphea, Subcutaneous GA, Rheumatoid nodule, Necrobiotic xanthogranuloma.
• Necrosis at center of fat lobule, lipomembranous change → Sclerema neonatorum, Fat necrosis of the newborn, Post-steroid panniculitis, Gout panniculitis, Crystal-storing histiocytosis^^.
• Vascular calcification, needle-shaped crystals in adipocytes → Calciphylaxis, Oxalosis.
• Lymphocytes, lymphoid follicles, plasma cells → Pancreatic panniculitis, Lupus panniculitis, Panniculitis of dermatomyositis, Cold panniculitis, Lipodermatosclerosis.
• Neutrophils, necrosis and saponification of adipocytes → Pancreatic panniculitis.
• Neutrophils between collagen bundles, bacteria/fungi/protozoa, foreign bodies → Infective panniculitis, Facticial panniculitis.
• Histiocytes with cytophagocytosis → Cytophagic histiocytic panniculitis.
• Crystals → Infective panniculitis.

Mostly LOBULAR, WITH vasculitis:

• Large vessels (arteries and veins) → Erythema induratum.
• Neutrophilic lobular panniculitis^ → Lucio phenomenon, Erythema nodosum leprosum.

Footnotes:

• \*Rarely, small vessel vasculitis (leukocytoclastic vasculitis) affects postcapillary venules of septa while sparing superficial dermal plexus.
• \\Lipoatrophy without inflammatory cells can represent residua of several panniculitides (see Ch. 101).
• †Some authors describe α1-antitrypsin deficiency panniculitis as mostly septal.
• ^A manifestation of subcutaneous Sweet syndrome and inflammatory bowel disease.
• ^^In most patients associated with monoclonal gammopathy.
• Drug-induced panniculitis can be primarily septal OR lobular.
• Leukemia cutis/lymphoma cutis may mimic panniculitis (e.g., subcutaneous panniculitis-like T cell lymphoma).
• Subcutaneous nodules of ANCA-associated vasculitides can contain extravascular necrotizing granulomas.
• GA = granuloma annulare; PAN = polyarteritis nodosa.

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Synonyms: Erythema contusiformis; Erythema nodosum migrans (variant form)

• Tender, erythematous, subcutaneous nodules.
• Usually distributed symmetrically, favoring pretibial areas; occasionally elsewhere.
• In later stages, lesions acquire a bruise-like appearance.
• May be accompanied by fever, arthralgias, malaise.
• Associated with a wide variety of systemic disorders.

• Best known and most common form of panniculitis.
• Acute eruption of tender erythematous subcutaneous nodules, pretibial, bilateral.
• Widely regarded as a delayed hypersensitivity response to a variety of antigenic challenges, though mechanisms are more complex.
• Histopathologic prototype of "septal" panniculitis.
• Identification and treatment of underlying disorder is primary; symptomatic therapy also an option, especially if idiopathic.

• Robert Willan gave the first clear description of EN at the beginning of the eighteenth century; named it in his work On Cutaneous Disease.

• Can occur at any age, both sexes, all racial groups.
• More common among women; most frequent in the 2nd–4th decades of life.
• Relative ranking of causes varies geographically (e.g., areas endemic for Coccidioides immitis, or high Behçet disease prevalence).

• Considered a delayed hypersensitivity response to varied antigenic stimuli (bacteria, viruses, chemical agents).
• Th1 cytokine pattern (IFN-γ, IL-2 mRNA) observed in skin lesions and peripheral blood — consistent with delayed-type hypersensitivity.
• Adhesion molecules/inflammatory mediators involved:
• Endothelial cells express VCAM-1 (CD106), PECAM-1 (CD31), HLA-DR, E-selectin.
• Inflammatory cells express VLA-4, L-selectin, HLA-DR.
• Neutrophils numerous in early lesions; higher percentage circulating neutrophils → increased reactive oxygen intermediates → inflammation/tissue damage.
• Colchicine supports pathogenic role of neutrophils/molecules:
• Diminishes L-selectin expression on neutrophil surface.
• Inhibits E-selectin-mediated endothelial adhesiveness for neutrophils.
• Diminishes stimulated ICAM-1 expression on endothelium.
• Additional indirect evidence:
• EN reported following G-CSF treatment.
• EN improvement (and flares) with TNF inhibitors.
• Chronic EN characterized by granuloma formation; TNF plays a role in granuloma formation.
• Strong correlation between a TNF gene promoter polymorphism and sarcoidosis-associated EN.
• Wide range of precipitating factors — infectious causes common, particularly upper respiratory infections (streptococcal and non-streptococcal).

Most common:

• Idiopathic — largest single category, 1/3 to 1/2 of cases.
• Streptococcal infections, especially upper respiratory tract — the largest single infectious cause.
• Other infections: viral URI; bacterial gastroenteritis — Yersinia > Salmonella, Campylobacter. Overall, infection may account for 1/3 or more of cases.
• Coccidioidomycosis — EN associated with lower incidence of disseminated disease.
• Drugs.
• Sarcoidosis* — 10%–20% of cases in some series.
• Inflammatory bowel disease — Crohn disease has a stronger association than ulcerative colitis.

Uncommon:

• Infections: Brucella melitensis, Chlamydophila† pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Mycobacterium tuberculosis, Histoplasma capsulatum, Hepatitis B virus‡.
• Neutrophilic dermatoses: Behçet disease (EN-like lesions more closely resemble erythema induratum/nodular vasculitis), Sweet syndrome.
• Acne fulminans, including isotretinoin-associated.
• Pregnancy.

Rare:

• Granulomatous mastitis, pernicious anemia, diverticulitis.
• Infections: Neisseria gonorrhoeae, N. meningitidis, Escherichia coli, Bartonella henselae, Bordetella pertussis, Treponema pallidum, dermatophytes (kerion), Blastomyces dermatitidis, HIV, COVID-19, giardiasis, amoebiasis (abscesses).
• Erythema nodosum leprosum — a different disease, characterized by cutaneous small vessel vasculitis.
• MonoMAC syndrome (GATA2 mutations).
• Malignancy, most often acute myelogenous leukemia, Hodgkin disease — may overlap with Sweet syndrome.
• Lupus erythematosus — one of several forms of panniculitis reported in LE, in addition to lupus panniculitis.

Footnotes:

• \*Löfgren syndrome: acute, spontaneously resolving sarcoidosis — EN + hilar lymphadenopathy + fever + polyarthritis + uveitis.
• †Previously referred to as Chlamydia.
• ‡EN secondary to hepatitis B vaccine also reported.

• Lesions can develop at multiple sites; distinguish from panniculitis at injection sites of medications: glatiramer acetate, interferon-β, phytonadione (vitamin K), interleukin-2, heparin (eosinophilic panniculitis), pentazocine, vaccines (e.g., tetanus).
• Additional causes of multiple lesions: G-CSF, NSAIDs, abatacept, carbamazepine, leukotriene inhibitors, proton pump inhibitors.

• Bilateral, tender, erythematous nodules arising in crops.
• Most common site: shins.
• Other locations occasionally: thighs, forearms; rarely trunk, neck, face (development in these locations should prompt consideration of other diagnoses).
• Ulceration is NOT a feature of erythema nodosum (unlike other panniculitides).
• Systemic symptoms may occur (not necessarily linked to a coexisting systemic disorder): arthritis, arthralgia, fever, malaise.
• Important skin sign of systemic disease — development may precede or accompany a flare of IBD.
• Prognostic value: associated with a protective effect against disseminated disease in coccidioidomycosis; closely aligned with a more benign, self-limited form of sarcoidosis.
• >1/3 of cases have no known disease association even when followed for a year or more.
• Lesions usually last a few days to weeks, then slowly involute without scar formation.
• Discoloration suggestive of a bruise seen as erythema subsides.
• More chronic forms show tendency toward migration/centrifugal spread → termed subacute nodular migratory panniculitis or erythema nodosum migrans.
• Up to 1/3 of cases of EN recur; annual recurrences particularly common among idiopathic cases.

• Synovitis.
• Diarrhea* (check fecal blood/WBC, stool culture, ova and parasites if indicated, fecal calprotectin).
• Abnormal chest X-ray.
• Preceding upper respiratory tract infection.
• Elevated antistreptolysin O and/or anti-DNase B titers.
• Positive tuberculin skin test or interferon-gamma release assay (e.g., QuantiFERON-TB Gold In-Tube Plus, T-SPOT.TB test).
• Additional evaluation: viral hepatitis panel; serum β-hCG in women of child-bearing age.

• Prototypic septal panniculitis — not entirely confined to septa though.
• Early lesions: edematous septa, mild lymphocytic infiltrates.
• Neutrophils may predominate in early lesions; a variant with eosinophil predominance has been reported.
• True vasculitis (leukocytoclastic type) is NOT observed — EN is not generally regarded as a vasculitic process.
• "Secondary" vasculitis may occur with heavy, mixed, or neutrophil-rich infiltrates.
• EN-like lesions in Behçet disease may show leukocytoclastic or lymphocytic vasculitis of subcutaneous venules/muscular veins — more common in severe Behçet disease.
• Miescher microgranulomas: characteristic (not pathognomonic) — small collections of macrophages or "histiocytoid cells" (neutrophil precursors) within septa or septal–lobular interface, surrounding neutrophils or cleft-like spaces.
• Older lesions: Miescher microgranulomas may feature epithelioid and multinucleated giant cells.
• As lesions progress: septa widen, mixed partly granulomatous infiltrate infiltrates fat lobule periphery in a lace-like configuration.
• Lobular involvement can be prominent — but a purely lobular panniculitis without septal changes should make EN diagnosis cautious.
• Frequently mild-moderate perivascular lymphocytic infiltrate in overlying dermis.
• Later stages: septa become fibrotic, partially replacing fat lobules; residual granulomas and lipophages; vascular proliferation may be present.
• Long term: remodeling → minimal residual scarring.

• Acute eruption of tender nodules over both shins in a young person = highly characteristic.
• Difficult to distinguish when lesions are few, non-lower-leg location, or >6 weeks duration.
• Erythema induratum (nodular vasculitis): resembles EN but tends to occur on posterior lower legs, may ulcerate.
• Pancreatic panniculitis: also ulcerates; other locations (though still favors lower legs); more likely arthritis/serositis; elevated serum amylase/lipase.
• Histopathologically, predominantly septal pattern usually excludes chiefly lobular/mixed conditions.
• Pancreatic panniculitis may show predominantly septal changes early, but eventually shows fat necrosis with saponification and "ghost cell" formation.
• Infection-induced panniculitis can mimic EN, but shows more extensive neutrophilic infiltrates, cellular necrosis (including sweat gland necrosis), vascular proliferation, hemorrhage.

• In all patients: discontinue possible causative medications; diagnose and treat underlying cause; bed rest and leg elevation; compression.
• First-line:
• NSAIDs (evidence level 3)* — *may trigger a flare of IBD.
• Salicylates.
• Potassium iodide (evidence level 2).
• Second-line† (immunosuppressives only if underlying infection excluded/treated):
• Colchicine (3)‡ — helpful for EN associated with Behçet disease.
• Infliximab (3)¶ — helpful for EN associated with IBD.
• Hydroxychloroquine (3)§ — helpful for chronic EN.
• Adalimumab (3)§.
• Etanercept (3).
• Mycophenolate mofetil (3).
• Third-line†:
• Systemic corticosteroids (3).
• Thalidomide (3)^ — may transiently exacerbate EN associated with Behçet disease.
• Cyclosporine (3).
• Dapsone (3).
• Evidence key: (1) prospective controlled trial; (2) retrospective study or large case series; (3) small case series or individual case reports.
• Potassium iodide — improvement within 2 weeks; may work via inhibition of cell-mediated immunity, inhibition of neutrophil chemotaxis, suppression of neutrophil-generated oxygen intermediates. (Note: EN triggered by potassium iodide has also been reported, seemingly contradictory.)
• Treatment influenced by underlying condition: colchicine useful for Behçet-associated EN; IBD treatments effective for coexistent EN.
• Etanercept and infliximab: both effective in treating EN, but paradoxically both can also produce EN as a cutaneous side effect.
• Adalimumab: case reports show improvement of refractory chronic EN.

• Saturated solution of potassium iodide (SSKI): 1000 mg/ml.
• Droppers calibrated for: 0.3 ml (300 mg)* and 0.6 ml (600 mg).
• Adults/older children: common dose = 300 mg TID po; starting dose = 150–300 mg TID.
• Infants/young children: common dose = 150 mg TID po.
• Adult dosages overall range 450–1500 mg/day.
• Dilute in water/juice to minimize bitter aftertaste.
• Crystallization may occur with cold; rewarming and shaking dissolves crystals; discard if solution turns yellow–brown.
• Side effects — Acute: nausea, bitter eructation, excessive salivation, urticaria, angioedema, cutaneous small vessel vasculitis.
• Side effects — Chronic: enlargement of salivary and lacrimal glands, acneiform eruption, iododerma, hypothyroidism, hyperkalemia, occasionally hyperthyroidism.
• *0.3 ml = 10 drops from the calibrated dropper.

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*Less often than in lupus panniculitis.

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Synonyms: Erythema nodosum migrans; Chronic erythema nodosum

• Nodules on lower extremities that migrate or undergo centrifugal spread, with central clearing.
• Often unilateral.
• Most cases idiopathic; occasionally associated with streptococcal infection or thyroid disease.
• More chronic course than typical EN.

• First described by Bafverstedt in 1954; named "subacute nodular migratory panniculitis" by Vilanova and Piñol Aguade in 1956.
• Some clinical/microscopic characteristics resemble chronic EN — believed by many to be a variant; others consider it a separate disorder.
• Predominantly seen in women, often unilateral.
• Nodules migrate or expand centrifugally with central clearing; may assume yellowish or morpheaform appearance.
• Lesions less tender than classic EN.
• Few, if any, associated systemic symptoms; arthralgias reported; ESR may be elevated.
• Most cases idiopathic; some associated with streptococcal infection (elevated ASO/anti-DNase B) or thyroid disease.

• Chronic septal panniculitis.
• In contrast to classic chronic EN: greater septal thickening, more prominent granulomatous inflammation along borders of widened septa, absence of phlebitis, rare hemorrhage.

• Untreated: can last months to years.
• Potassium iodide usually effective — clearing within several weeks.

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(See also Chs. 43 & 44.)

• Both morphea and systemic sclerosis can affect subcutaneous fat.
• Primary site of involvement in deep morphea (morphea profunda).
• Subcutaneous extension also occurs in: disabling pansclerotic morphea of childhood, generalized morphea, linear morphea.
• Eosinophilic fasciitis can involve subcutaneous fat as well as fascia.
• May be associated with peripheral eosinophilia, polyclonal gammopathy, serologic abnormalities.
• Proposed that sclerosing process in systemic sclerosis is initiated by changes taking place in the subcutis.

• Table 100.7 outlines microscopic changes.
• Lymphocytes and plasma cells predominate (macrophages/eosinophils may be present); plasma cell numbers can be striking in some cases.
• Late morphea: subcutis largely replaced by hyalinized connective tissue, often with lipoatrophy.

• Septal panniculitis with lymphoplasmacytic predominance + dermal/subcutaneous sclerosis is unique — separates it from other septal forms.
• Differentiation among the variants requires clinical data.
• Sclerosis with lesser subcutaneous inflammation = systemic sclerosis.
• Predominance of fascial involvement with subcutis extension = more typical of eosinophilic fasciitis.

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Synonym: Alpha-1 protease (proteinase) deficiency panniculitis

• Erythematous, painful, subcutaneous nodules or plaques that often ulcerate and drain.
• Associated with alpha-1 antitrypsin deficiency; most severe disease in homozygotes for the Z allele of SERPINA1 (PiZZ).
• Characteristic histopathology: liquefactive necrosis of dermis and subcutaneous septa; lobular or mixed septal-lobular changes with neutrophils may occur.

• Well-established but uncommon cause of panniculitis.
• Most severely affected (markedly decreased protease inhibitor levels) most prone to ulcerating neutrophilic panniculitis.

• Alpha-1 antitrypsin deficiency first delineated by Eriksson and others in the early 1960s.
• 1972: Warter and colleagues identified family members with the deficiency and "Weber–Christian syndrome."
• Subsequent investigations linked clinical/microscopic findings to known effects of proteinase inhibitor deficiency.

• In US: occurs most commonly in White, followed by Hispanic and Black individuals.
• Incidence of panniculitis approximately equal in men and women.
• Age of onset: infancy to the 8th decade of life.

• Alpha-1 antitrypsin: glycoprotein produced in liver; most abundant circulating serine protease inhibitor (serpin).
• >120 different alleles of gene (SERPINA1, formerly PI); divided by electrophoretic mobility: M = medium, S = slow, Z = very slow.
• MM (homozygous M): most common Pi phenotype; normal serum levels (100–200 mg/dl).
• Heterozygotes (PiMS, PiMZ): mild-moderate deficiency; prevalence 1%–3% in White populations.
• PiZZ (prevalence 1:150–1:5000 in White populations) or rare PiZnull: severe deficiency; serum levels 20–45 mg/dl.
• Aberrant protein accumulates within hepatocyte endoplasmic reticulum; small amounts entering circulation have decreased function and tendency to form inactive polymers that may stimulate neutrophil chemotaxis.
• Z-type polymers detected in skin of a patient with the panniculitis — suggests proinflammatory role.
• Alpha-1 antitrypsin acts on trypsin, collagenase, elastase; inhibits membrane-bound serine proteases (lymphocyte/macrophage activation); may inhibit complement activation directly and via inhibiting neutrophil proteases.
• Other consequences of deficiency: chronic liver disease/cirrhosis, emphysema, pancreatitis, membranoproliferative glomerulonephritis, rheumatoid arthritis, c-ANCA-positive vasculitis, other cutaneous vasculitides (e.g., Henoch–Schönlein purpura), angioedema.
• Initiating event unclear; trauma plays a role in some patients.
• Postpartum flares reported — attributed to estrogen-promoted increase in proteinase inhibitor during pregnancy followed by precipitous postpartum decline.
• Absence of inhibitor → activation of lymphocytes/macrophages, lack of complement restraint, release of chemotactic factors, neutrophil accumulation with proteolytic enzyme release, attack on fat and connective tissue.
• Subcutis particularly vulnerable — fatty acids make nearby elastin more susceptible to proteolytic degradation.

• Large, erythematous to purpuric, tender nodules/plaques, especially lower trunk and proximal extremities (flanks, buttocks, thighs).
• Ulcers develop — deep, necrotic, with oily discharge.
• Antecedent trauma elicited in ~1/3 of patients.
• May be accompanied by fever, pleural effusions, pulmonary emboli.
• Clinical course often prolonged; lesions resistant to immunosuppressive therapy.
• Healing accompanied by scarring and subcutaneous atrophy.
• Most severe manifestations in PiZZ, but can also occur in heterozygotes.

• Early: neutrophilic panniculitis, followed rapidly by necrosis/destruction of fat lobules.
• Splaying of neutrophils between collagen bundles in reticular dermis — early clue to diagnosis.
• Dissolution of dermal collagen with liquefactive necrosis and separation of fat lobules from adjacent septa — principal change in most cases.
• Characteristic "skip areas" of normal fat adjacent to foci of severe necrotizing panniculitis.
• Chronic inflammation and hemorrhage may occur at periphery.
• Most authors: no evidence for primary leukocytoclastic vasculitis, though lymphocytic vasculitis, secondary vasculitis in heavily neutrophilic areas, or thrombosis may occur.
• Intermediate deficiency levels: lipophage/giant cell accumulation may be prominent.
• Lesions heal with scarring and obliteration of fat lobules.
• Debate whether primarily septal or lobular — significant fat lobule involvement argues lobular; early septal inflammation, collagenolysis of fibrous septa, and prominent late septal fibrosis argue septal.

• Ulcers lack the necrotic, "undermined" borders of pyoderma gangrenosum.
• Tissue culture needed to exclude infection-induced panniculitis.
• Microscopic differential: traumatic (factitial) panniculitis, infection-induced panniculitis, pancreatic panniculitis, erythema induratum (nodular vasculitis).
• In appropriate setting: subcutaneous Sweet syndrome, drug-induced panniculitis, neutrophilic panniculitis of rheumatoid arthritis/IBD (IBD can be clinically silent) — additional considerations.
• When no underlying disorder found: term idiopathic neutrophilic lobular panniculitis applies.

• Usually ineffective: corticosteroids and other immunosuppressants, cytotoxic agents, colchicine, danazol, hydroxychloroquine.
• Doxycycline sometimes effective in mild cases — e.g., 200 mg twice daily for 3 months.
• Dapsone may be beneficial in mild cases (suppresses neutrophil migration, inhibits myeloperoxidase-induced oxidation).
• Reduce alcohol intake (ethanol as hepatotoxin may precipitate alpha-1 antitrypsin-associated hepatitis).
• Most effective: IV replacement of alpha-1 antitrypsin, dosage 60 mg/kg/week, over 3–7 weeks.
• Improvement relatively rapid — clearing can occur after 3 weekly doses.
• Recurrences possible when levels fall <50 mg/dl; typically respond to further replacement.
• Other successful therapies: plasma exchange, liver transplantation (appropriate circumstances).
• Autophagy-enhancing drugs (e.g., carbamazepine) may reduce systemic manifestations including hepatic fibrosis.
• Most recently: fazirsiran, an RNA interference therapy, has led to hepatic improvement.

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Synonyms: Nodular vasculitis; Erythema induratum of Bazin or Bazin disease (tuberculous etiology); Erythema induratum of Whitfield (non-tuberculous etiology)

• Erythematous nodules/plaques, usually on posterior lower legs of young to middle-aged women.
• Ulceration and drainage may occur.
• Microscopic features of lobular or mixed panniculitis with vasculitis involving arteries or veins.
• Classically associated with tuberculosis, but similar lesions can be idiopathic or induced by other infectious agents/drugs.

• Characterized by nodules on lower extremities, which may ulcerate and drain.
• Originally regarded as a tuberculid; detection of mycobacterial DNA in cutaneous lesions in a subset supports relationship to TB, at least in a proportion of cases.

• First described by Ernest Bazin in 1861.
• Generally regarded as a tuberculid due to strong TB association, though Koch's postulates could not be fulfilled.
• 1945: Montgomery and colleagues proposed term "nodular vasculitis" for non-tuberculous cases.
• Since early 1970s, erythema induratum and nodular vasculitis considered synonyms for a clinicopathologic entity with several possible causes (TB being one).
• Some clinicians prefer "nodular vasculitis" for non-tuberculous etiology.

• Overwhelming female predominance; men can also be affected.
• No apparent racial predilection.
• Wide age range; mean 30–40 years.
• Tuberculous etiology occurs more frequently in populations with high TB prevalence.

• Some cases strongly associated with M. tuberculosis infection — substantiated by mycobacterial DNA detection via PCR (specific primers distinguish M. tuberculosis complex from other mycobacteria).
• Non-tuberculous cases related to other infectious agents (e.g., Nocardia, hepatitis C virus) or drugs (e.g., propylthiouracil).
• Report of erythema induratum induced by a tuberculin skin test.
• Most investigators believe it represents a type IV, cell-mediated response to an antigenic stimulus (not immune complex-mediated vasculitis, as previously suggested).
• Biopsies show predominance of T lymphocytes, macrophages, dendritic cells (including Langerhans cells).
• Study of PBMCs from a patient with EI and active TB: high proliferative response to PPD, marked IFN-γ production — suggests pathogenic role for PPD-specific T cells in delayed hypersensitivity to mycobacterial antigens.

• Tender, erythematous to violaceous nodules and plaques, most often on lower legs, especially calves.
• Also reported on feet, thighs, buttocks, arms.
• Annular arrangement described in M. tuberculosis-related cases.
• Ulceration can occur; lesions persistent, heal with scarring, prone to recurrence.
• TB-associated cases: may show clinical/radiographic evidence of active TB, positive PPD, or positive interferon-gamma release assay (e.g., QuantiFERON-TB Gold Plus).
• Other tuberculids (e.g., papulonecrotic) may be present.
• Clinical differences between tuberculous and non-tuberculous cases are minor.

• Generally described as lobular or mixed septal/lobular panniculitis.
• Inflammation mixed: neutrophils, lymphocytes, macrophages, multinucleated giant cells.
• Vasculitis identifiable in vast majority of cases — most frequently involves veins or arteries of connective tissue septa and small venules of fat lobules.
• May be predominantly neutrophilic, lymphocytic, or granulomatous.
• Necrosis (coagulative or caseous) may be present, sometimes with palisading granulomas.
• Necrosis described in both TB and non-TB cases; incidence/degree of necrosis greater in PCR-positive M. tuberculosis DNA cases — but absent in over half of cases.

• Infection-induced panniculitis: more prominent neutrophilic component, granular basophilic necrosis, sweat gland necrosis, small vessel proliferation, organisms identifiable on special stains.
• Lupus panniculitis: less granulomatous, prominent lymphoplasmacellular infiltrate, may show mucin deposits, frequently overlying epidermal/dermal LE changes.
• Polyarteritis nodosa and thrombophlebitis: inflammation limited to immediate perivascular zone (contrast to extensive lobular panniculitis of erythema induratum).
• Perniosis: can be difficult to distinguish histologically; typically history of cold exposure; prominent dermal vessel involvement with "fluffy edema" of walls.

• Direct treatment at underlying cause if found: multi-drug antituberculous therapy (Ch. 75); discontinue inciting medications.
• Nontuberculous EI: NSAIDs, corticosteroids, tetracyclines, potassium iodide, mycophenolate mofetil.
• Supportive care similar to erythema nodosum.

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Synonyms: Pancreatic fat necrosis; Enzymatic panniculitis

• Subcutaneous nodules, sometimes with fever, arthritis, or abdominal pain.
• Associated with pancreatic disorders: acute and chronic pancreatitis, pancreatic carcinoma.
• Mixed septal/lobular panniculitis featuring "ghost cell" formation and deposition of basophilic material due to saponification of fat by calcium salts.
• Treatment primarily directed at underlying pancreatic disorder.

• Unusual complication of pancreatic disease.
• Panniculitis may be recognized prior to detection of underlying pancreatic disease.
• PPP syndrome: pancreatitis + panniculitis + polyarthritis.

• First described by Chiari in 1883.
• By 1999: fewer than 100 cases reported.
• Since then, ~100 additional patients described, primarily case reports.

• Panniculitis develops in up to 2% of patients with pancreatic disorders.
• No geographic, racial, or sex predilections.

• Enzymes lipase, amylase, trypsin involved in producing lesions.
• Elevated enzyme levels detected in blood, urine, and skin lesions, even absent detectable pancreatic disease.
• Lipase has the clearest relationship: patients may have elevated serum lipase but normal amylase.
• Anti-pancreatic lipase monoclonal antibody: positive intracellular adipocyte staining in lesional skin.
• Amylase, when elevated, peaks 2–3 days after eruption, returns to normal 2–3 days after regression.
• Trypsin (and perhaps amylase) may promote increased vessel wall permeability, allowing lipase to hydrolyze neutral fat → glycerol + free fatty acids → fat necrosis and inflammation.
• Venous stasis may promote this process — explains lower extremity predilection.
• Elevated enzyme levels may not fully explain changes — immunologic factors probably also play a role.

• Nodules develop with: acute or chronic pancreatitis, pancreatic carcinoma (acinar cell > other types, e.g., neuroendocrine carcinomas), pancreatic pseudocysts, pancreas divisum, traumatic pancreatitis, drug-induced panniculitis (e.g., azathioprine).
• Consider pancreaticoportal fistula when panniculitis develops with chronic pancreatitis — acinar cell carcinoma can also be found.
• Panniculitis may precede detection of pancreatic disease by 1–7 months; in pancreatic carcinoma, onset may signal metastatic disease.
• Nodules frequently on legs, also anterior trunk, arms, scalp.
• Erythematous, edematous, sometimes painful lesions, singly or in crops; may become fluctuant and ulcerate, discharging oily material.
• Panniculitis may also involve visceral fat (omentum, preperitoneal fat).
• Associated findings: fever, abdominal pain, inflammatory polyarthritis, ascites, pleural effusions.
• Schmid's triad: subcutaneous nodules + polyarthritis + eosinophilia — associated with poor prognosis.
• Some patients: radiographic evidence of multiple lytic areas near large joints (cortical bone).
• Cutaneous lesions may involute within weeks, leaving hyperpigmented scars.
• In acute pancreatitis, panniculitis resolves as acute phase passes; may also persist and expand until underlying abnormality treated.

• May begin as septal panniculitis, but with progression becomes lobular or mixed septal/lobular.
• Even early: fat necrosis with liquefaction and microcyst formation.
• Lipocytes lose nuclei, develop thick shadowy walls → characteristic "ghost cells".
• Saponification of fat by calcium salts → granular/homogeneous basophilic material.
• Neutrophils, occasional eosinophils, macrophages, multinucleated giant cells may encroach upon septa.
• Fibrosis and lipoatrophy in late stages.

• Ulceration/discharge argues against EN.
• Fever, polyarthritis, and/or abdominal pain should raise suspicion for pancreatic disease.
• Serum amylase/lipase levels helpful if elevated.
• "Ghost cell" formation and saponification distinguishes it from other panniculitides — except ghost cell formation in mucormycosis panniculitis.
• Eosinophilic "hyaline necrosis" = lupus panniculitis (vs granular/homogeneous basophilic necrosis of pancreatic panniculitis).

• Supportive: compression, elevation.
• Effective management depends on treating underlying pancreatic disease.
• Chronic pancreatitis: pancreatectomy is curative but rarely performed (potential complications).
• Fistula/cyst: minimally invasive drainage techniques initially.
• Somatostatin analogues (e.g., octreotide) to inhibit pancreatic enzyme production.
• Resection of pancreatic cancer may be followed by regression of panniculitis.

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• All three characterized histologically by needle-shaped clefts within lipocytes.
• Infant subcutaneous fat is prone to crystal formation: higher content of saturated fatty acids (palmitic, stearic acid), relatively lower unsaturated fatty acids (e.g., oleic acid).
• Increased saturated:unsaturated ratio → higher melting point of stored fat → promotes crystallization under certain conditions.
• Microsized crystals (type A): apparently do not produce inflammatory response; common (widely dispersed) in healthy infants ≤6 months, more numerous in sclerema neonatorum.
• Larger, type B crystals (arranged in rosettes): capable of eliciting granulomatous response; most often seen in subcutaneous fat necrosis of the newborn and post-steroid panniculitis.
• Crystallization and defects in fat mobilization account for clinical findings.

Key Features

• Arises in premature infants.
• Skin diffusely cold, rigid, board-like.
• Needle-shaped clefts within lipocytes; minimal inflammation microscopically.
• Affected infants often hypothermic, may have various medical problems; early death is common.

History

• First recognized by Uzembenzius in 1722; classic description usually attributed to Underwood (1784).
• Ballantyne provided early description of histopathologic changes.
• Knopfelmacher noted needle-shaped crystals in subcutaneous tissue in 1897.

Epidemiology

• Presents most often in premature, debilitated infants, usually during the first week of life.
• Slight male predominance; no substantial sex difference in death rates.

Pathogenesis

• Crystallization/hardening of fat occurs with increased saturated:unsaturated fatty acid ratio and defective fatty acid mobilization.
• Precipitating factors listed in Table 100.8.

Clinical Features

• Rapid hardening of subcutaneous tissues → firm, rigid skin over most of body.
• Low birth weight, hypothermia, hemorrhagic phenomena → particularly poor prognosis.

Pathology

• Inflammation usually sparse.
• Most needle-shaped clefts found within lipocytes rather than giant cells.
• Later stage: thickened connective tissue bands may be only histologic finding.

Differential Diagnosis

• Vs subcutaneous fat necrosis of the newborn: latter localized, favorable prognosis, more prominent inflammation, clefts within giant cells.
• Scleredema neonatorum: seen in premature infants with congenital heart disease; skin distended, wax-like; dermis edematous with increased mucin.
• Other conditions with diffusely indurated neonatal skin: stiff skin syndrome (favors trunk, buttocks, thighs), restrictive dermopathy, Hutchinson–Gilford progeria.
• Radially arranged needle-shaped clefts (resembling sclerema) reported in an adult with gemcitabine-related thrombotic microangiopathy (crystals quite small).

Treatment

• Results generally disappointing.
• Management: treat sepsis, ventilatory support, correct fluid/electrolyte imbalances, maintain body temperature.
• Exchange transfusions may be of value in selected instances.
• Systemic corticosteroids of questionable utility.

Key Features

• Development of one or more mobile, firm, subcutaneous nodules/plaques during newborn period.
• Sometimes associated with hypercalcemia or thrombocytopenia.
• Granulomatous lobular panniculitis with needle-shaped clefts within lipocytes AND giant cells.
• Prognosis usually favorable; spontaneous resolution common.

Introduction

• In contrast to sclerema, this is a localized process; most resolve spontaneously (complications relate to hypercalcemia).

History

• At beginning of 20th century, Fabyan described "abscesses" that spontaneously resorbed, provided first microscopic description.

Epidemiology

• Typically occurs in full-term neonates during the first 2–3 weeks of life.

Pathogenesis

• Stresses on fetal fat (high saturated:unsaturated ratio) → crystallization, adipocyte injury, granulomatous inflammation.
• Hypothermia is a potential eliciting factor — cases following hypothermic cardiac surgery, cooling blankets.
• Other proposed causes in Table 100.8.
• Role of birth trauma questioned — many cases occurred after cesarean section.

Clinical Features

• Circumscribed, erythematous, indurated subcutaneous nodules/plaques, sometimes symmetrical.
• Areas of fat necrosis detectable by ultrasonography, CT, MRI.
• Hypercalcemia (onset usually within 2 months) — more common in higher birth weight infants.
• Believed hypercalcemia results from extrarenal production of 1,25-dihydroxyvitamin D3 (calcitriol) by activated macrophages (expressing 1-α-hydroxylase) within granulomatous panniculitis areas — stimulates calcium absorption from gut and mobilization from bones.
• Thrombocytopenia — mechanism may be local sequestration in subcutis (normal bone marrow cellularity, resolves as inflammation resolves).
• Spontaneous resolution is the rule; some develop residual lipoatrophy.
• Deaths reported in those with associated hypercalcemia.

Pathology

• Predominantly lobular panniculitis with mixed cellularity.
• Needle-shaped clefts within both lipocytes and giant cells (Fig. 100.14 inset).
• Crystals doubly refractile, stain with oil red O.
• Occasionally clefts not evident in otherwise typical cases.
• Eosinophilic granules sometimes within multinucleated giant cells — may derive from degranulating eosinophils.

Differential Diagnosis

• Sclerema neonatorum: extensive vs localized, minimal inflammation.
• Post-steroid panniculitis: microscopically indistinguishable, but arises in different clinical setting.

Treatment

• Emphasis on supportive care since many lesions resolve spontaneously.
• Systemic corticosteroids may be indicated in severe cases.
• Serial calcium monitoring for at least 2 months after skin lesion resolution.
• Hypercalcemia management: hydration, dietary restriction of calcium and vitamin D, calcium-wasting diuretics (e.g., furosemide), calcitonin, bisphosphonates (e.g., etidronate, pamidronate).
• Corticosteroids may help hypercalcemia by interfering with vitamin D metabolism to calcitriol and inhibiting macrophage calcitriol production.

Key Features

• Rare complication of rapid withdrawal of systemic corticosteroids.
• Subcutaneous nodules on cheeks, arms, trunk.
• Lesions resolve spontaneously, or with corticosteroid readministration.
• Microscopically: granulomatous lobular panniculitis with needle-shaped clefts within both lipocytes and giant cells.

History

• 1956: Smith and Good reported 11 children with acute rheumatic fever treated with large-dose corticosteroids rapidly tapered — 5 children developed pruritic, EN-like lesions.

Epidemiology

• Typically a disorder of children; reported ages 20 months to 14 years; occasionally occurs in adults.

Pathogenesis

• Occurs after rapid withdrawal of systemic corticosteroids (oral or IV).
• Cumulative prednisone dosages ranged 2000–6000 mg.
• Precise mechanism not known.

Clinical Features

• Developed for a variety of underlying conditions (leukemia, cerebral edema, nephrotic syndrome, secretory diarrhea, acute rheumatic fever; also COPD and Sjögren syndrome in adults).
• Lesions appear 1–40 days after rapid corticosteroid withdrawal (usually within 10 days).
• Disappear spontaneously over months to a year.

Pathology

• Needle-shaped clefts, some with "starburst" pattern, within lipocytes or giant cells.

Differential Diagnosis

• Less nodular cheek presentation can mimic erythema infectiosum, atopic dermatitis, lupus erythematosus, facial cellulitis (microscopic changes distinguish).
• Cold panniculitis: clinical/microscopic similarities, but history of cold exposure and lack of needle-shaped clefts distinguish.
• Microscopically virtually identical to subcutaneous fat necrosis of the newborn, but calcification/hemorrhage more common in the latter; clinical history distinguishes.

Treatment

• Spontaneous resolution is the rule; treatment usually unnecessary.
• Readministration of corticosteroids followed by more gradual taper may help.

*Usually within 10 days.

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Synonyms: Lupus profundus; Subcutaneous lupus erythematosus

• Tender subcutaneous nodules/plaques arising on face, proximal extremities, hips, trunk.
• Associated with discoid LE in at least 1/3 of patients; less often with systemic LE (10%–15%).
• Often precedes onset of other lupus manifestations.
• Characteristic microscopy: lobular panniculitis with hyaline necrosis, predominantly lymphoplasmacytic infiltrate; nodular lymphocyte aggregates common.
• Overlying epidermal/dermal changes of LE frequently present.

• Clinical characteristics first described by Kaposi in 1869.
• 1940: recognized as a manifestation of LE by Irgang.
• Firmly established as specific LE subtype in 1956 by Arnold.

• Small subset of cutaneous LE, representing 2%–3% of that group.
• Usually adults; median age of onset 30–40 years.
• Children can develop it; association with neonatal lupus described.
• Female predominance, F:M ratio 2:1 to 4:1.
• Sometimes family history of LE or another autoimmune connective tissue disease.

• Autoimmune basis thought similar to other LE types (see Ch. 41).
• Infiltrates comprised of T lymphocytes and macrophages.
• Childhood-onset, widespread lupus panniculitis described with partial C4 deficiency — causes defective opsonization of immune complexes, may play pathogenic role.
• Immunohistochemistry shows interferon-driven Th1-biased immune response in active lesions — may result in recruitment of cytotoxic CXCR3+ lymphocytes.

• Tender subcutaneous nodules/plaques, may arise in crops.
• History of trauma sometimes elicited.
• Develops on face, upper arms, hips, trunk.
• Linear scalp lesions more common (not restricted to) East Asian populations.
• Lack of involvement of distal extremities is noteworthy.
• Overlying skin: light pink color to discoid LE changes (scaling, follicular plugging, dyspigmentation, telangiectasias, atrophy, scarring); subtle findings may only be seen on microscopy.
• Overlying skin may be "tethered" to subcutaneous nodule/plaque → surface depression; ulceration occasionally occurs.
• Chronic, relapsing course; usually eventuates in subcutaneous atrophy (can be disfiguring; see Ch. 41 & 101).
• Often occurs prior to other LE manifestations, and in the absence of other autoimmune connective tissue disease — discoid LE lesions may develop up to 10 years after appearance of panniculitis.
• Manifestations of systemic/discoid LE can also occur long before or simultaneously.
• Closer relationship to other forms of chronic cutaneous LE (e.g., discoid LE) than to systemic LE.
• Coexistent discoid lesions in at least 1/3 of patients; only 10%–15% meet diagnostic criteria for systemic LE.
• Most in the systemic LE group have relatively mild manifestations (arthralgias or Raynaud phenomenon).
• Common to have low-titer ANA; other autoantibodies possible (anti-dsDNA, anti-RNP); leukopenia, hypocomplementemia, elevated ESR.

• Predominantly lobular process with variable inflammation.
• Nodular aggregates of lymphocytes, usually B cells, often present, as are variably large clusters of CD123+ plasmacytoid dendritic cells.
• Characteristic: hyaline necrosis of fat lobules — outlined in Table 100.7.
• Granulomas can occur, tend to encroach septa, usually not prominent.
• Other features: lymphocytic vasculitis, mucin or calcium deposition.
• Subcutaneous findings alone can be sufficiently characteristic for diagnosis.
• Overlying epidermal/dermal changes of discoid LE occur in 1/2 to 2/3 of cases and help diagnostically.
• Direct immunofluorescence: positive lupus band in overlying skin in a high percentage of cases, even with nonspecific histopathology.

• Rarity of distal lower extremity involvement helps distinguish from EN and erythema induratum.
• Remember other forms of subcutaneous inflammation in LE patients: erythema nodosum, thrombophlebitis, pancreatic panniculitis, juxta-articular rheumatoid nodule-like lesions.
• Microscopically resembles morphea/dermatomyositis panniculitis, traumatic panniculitis (often has foreign material), and later-stage localized lipoatrophy of other etiologies.
• Most important DDx: subcutaneous panniculitis-like T cell lymphoma (SPTCL) — significant histopathologic overlap.
• Note: vacuolar alteration of basilar layer and dermal mucin deposition have been reported in SPTCL too.
• Overlapping features reported — probably represent "atypical" lupus panniculitis.

Clinical features:

Microscopic and laboratory features:

HSCT = hematopoietic stem cell transplant; MxA = human myxovirus resistance protein 1; TCR = T cell receptor.

• Antimalarials frequently used, produce improvement in most patients; adding a second antimalarial may help non-responders.
• Given chronic, relapsing nature, treatment may be required for several years.
• Systemic corticosteroids, when used, often restricted to initial phases.
• Other systemic therapies: dapsone, immunosuppressives (e.g., mycophenolate mofetil), thalidomide, IVIg, rituximab.
• Overlying discoid lesions: potent topical or intralesional corticosteroids.

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• Uncommon manifestation of dermatomyositis.
• More frequently, incidental microscopic panniculitis changes (without clinical lesions) are observed.
• Can precede or follow other dermatomyositis manifestations.
• Microscopically: lobular or mixed panniculitis with lymphoplasmacytic predominance.
• Usually responds to therapy.

• Uncommon but established clinical manifestation; microscopic involvement without overt clinical panniculitis more frequently observed.

• Persistent, indurated, painful plaques and nodules; may ulcerate and lead to lipoatrophy.
• Arise in established dermatomyositis or as initial manifestation.
• Other clinical/laboratory features and malignancy incidence similar to dermatomyositis without panniculitis.
• Partial or generalized lipoatrophy without preceding panniculitis lesions (occasionally with increased abdominal fat) occurs in up to 1/4 of patients with juvenile dermatomyositis, often with hypertriglyceridemia and insulin resistance (see Ch. 101).

• Microscopic features outlined in Table 100.7.
• Lymphocytic vasculitis has been described; fat necrosis noted in several reports.
• Membranocystic changes observed in some cases (see lipodermatosclerosis section) — lesions with these changes may be particularly resistant to therapy.
• Calcification variable — expected finding when associated with calcinosis of deep soft tissues and skeletal muscle.
• Vacuolar alteration of basal layer of overlying epidermis described; dermis may be edematous/mucinous with perivascular lymphocytic inflammation.
• Direct immunofluorescence reported negative for BMZ deposits, although immunoreactants detected in vessel walls.

• Lupus panniculitis more likely to show hyaline necrosis and lymphoid nodules; clinical/laboratory findings may be needed for distinction.
• Overlying poikilodermatous changes occur in both, but lupus more likely to show appendageal involvement and positive BMZ fluorescence.

• Good responses generally reported.
• Treatments include: prednisone, methotrexate, azathioprine, JAK inhibitors, cyclosporine, IVIg.
• Variable response to hydroxychloroquine.
• Residual facial lipoatrophy successfully treated with hyaluronic acid and poly-L-lactic acid dermal fillers.

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• Inflammation in the subcutis from external injury.
• Injurious event may be accidental, purposeful, or iatrogenic, may be a manifestation of underlying psychiatric disturbance.
• Variety of histopathologic changes depending on inciting agent.
• Identification of foreign material is of greatest help in diagnosis.

• Four broad categories:
• Cold panniculitis (Haxthausen disease).
• Sclerosing lipogranuloma.
• Panniculitis due to other injectable substances or therapies (e.g., megavoltage radiation).
• Panniculitis due to blunt trauma.

• Lemez described cold panniculitis in 1928 — newborns/infants up to 6 months especially susceptible, demonstrated by subcutaneous nodule following ice cube application.
• 1941: Haxthausen described a condition in small children a few days after cold exposure — firm infiltrated nodules of cheeks/chin.
• Similar cold injury due to popsicles reported by Epstein and Oren in 1970.
• Injection of foreign lipid material for cosmetic purposes performed for centuries.
• 1950: Smetana and Bernhard reported 14 cases of "sclerosing lipogranuloma of the male genitalia"; believed endogenous, but later studies demonstrated mineral oil.

• Infants and small children most at risk for cold panniculitis.
• Form also occurs on thighs of young women who are equestrians.
• Sclerosing lipogranuloma of male genitalia — mostly young adults.
• Sclerosing, pseudosclerodermatous panniculitis reported after megavoltage radiation for metastatic carcinoma and as a radiation recall reaction after cyclophosphamide.

• Cold injury to fat favors small children due to fat characteristics discussed above.
• Related to fluctuations in blood flow with declining temperatures ("hunting phenomenon"), ice crystal formation, thawing changes.
• Injected oils (and impurities) known to produce subcutaneous inflammation: mineral oil (paraffin), camphor, cottonseed, sesame oils.
• Even medical grade silicone may contain impurities; fibrosis-inducing substances (olive oil, castor oil) often added for encapsulation.
• Substances causing factitial panniculitis: milk, feces, and others.
• Panniculitis produced at injection sites by: pentazocine, phytonadione (vitamin K), glatiramer acetate, interferon-β, interleukin-2, heparin, vaccines (e.g., tetanus), tissue augmentation substances (bovine collagen, poly-L-lactic acid).
• More recently: panniculitis due to "mesotherapy" (phosphatidylcholine, deoxycholate; see Ch. 156) and electroacupuncture.
• Blunt trauma: granulomas may contain material derived from breakdown of erythrocyte membranes.

• Cold panniculitis (including popsicle panniculitis): erythematous, firm nodules, particularly cheeks/chin.
• Equestrian cold panniculitis: erythematous to violaceous, tender plaques on thighs after cold exposure while wearing tight clothing. Term suggested to be more accurately called "equestrian perniosis" since infiltrate is primarily dermal.
• Lipogranuloma: nodules sometimes migratory, with swelling, erythema, abscess formation, lymphangitis, fibrosis.
• Sclerosing lipogranuloma: typically male genitalia due to self-injection of oily materials (see Ch. 94).
• Report of sclerosing lipogranuloma from topical vitamin E cream.
• Eosinophilic sclerosing lipogranuloma: Y-shaped scrotal induration in Japanese patients, no exogenous lipids detectable.
• Patients frequently deny self-injection — diagnosis difficult.
• Grease gun granuloma: from accidental firing of mechanic's grease gun → verrucous nodule, often dorsum of hand.
• Inflamed nodules with varying pain/fibrosis in other injection-related panniculitides; distribution can provide clue.
• Texier disease: panniculitis due to phytonadione (vitamin K) injections — sclerotic lesions with lilac-colored borders on buttocks/thighs, resembling a "cowboy gunbelt and holster" configuration.
• Blunt trauma lesions: often ecchymotic, at shin, arm, hand.
• Hypertrichosis may be present (possibly from local hyperemia/angiogenesis).

*Especially with phytonadione (vitamin K) and pentazocine injections; lipid-containing vacuoles, fat necrosis, foam cells, thrombosis, and endarteritis also observed in the latter.

• Cold panniculitis: absence of needle-shaped clefts and most intense inflammation near dermal–subcutaneous interface distinguish from subcutaneous fat necrosis of the newborn.
• Sclerosing lipogranuloma: distinctive large dermal/subcutaneous vacuoles.
• Mineral oil in non-processed tissue identified by infrared spectroscopy or mass spectrometry.
• Foreign material (often via polarization microscopy) diagnostic for injectable substance panniculitis.
• Cosmetic fillers have distinctive histologic features; silicone distinguished from other fillers by cutaneous ultrasonography.
• Cases with acute inflammation/necrosis may resemble infection-induced panniculitis; infection may accompany injection panniculitis — special stains/cultures (including atypical mycobacteria) useful.
• Sclerosing traumatic panniculitis (e.g., phytonadione or pentazocine injections) may resemble morphea clinically, but would not present as septal panniculitis histologically.

• Focus on removal of inciting stimulus and eradication of associated infection.
• Intralesional or systemic corticosteroids can help control inflammation (used for sclerosing lipogranuloma and granulomatous panniculitis due to other injected substances).
• Surgical excision may be an option for sclerosing lipogranuloma.

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Synonyms: Sclerosing panniculitis; Hypodermitis sclerodermiformis; Chronic panniculitis with lipomembranous changes

• Favors medial aspect of lower extremities above the malleolus.
• Acute phase: erythema, warmth, tenderness — may be misdiagnosed as infectious cellulitis.
• Chronic phase: induration, red–brown to violet–brown discoloration.
• Usually develops in setting of chronic venous insufficiency.
• Both septal and lobular panniculitis; lipomembranous changes common, particularly in chronic lesions.

• Erythema, induration, pigmentary changes long known to be associated with venous insufficiency.
• Variety of terms consolidated under lipodermatosclerosis or sclerosing panniculitis.

• 1955: Huriez drew attention to a related indurated lesion, termed hypodermitis sclerodermiformis.

• Most patients women over age 40; appearance after age 75 also reported.

• Considerable evidence for venous insufficiency; fibrinolytic abnormalities also present.
• Venous hypertension → compromised ability to reduce foot vein pressure during exercise → increased capillary permeability → fibrinogen leakage, polymerization to form fibrin cuffs around vessels → impedance of oxygen exchange, tissue anoxia (see Ch. 105).
• Pericapillary fibrin deposits seen in uninvolved, clinically normal extremities of patients with healed venous ulcers of the opposite extremity — suggests abnormality precedes clinical changes.
• Abnormal regulation of angiogenesis: increased VEGFR-1 (negative regulator of VEGF-mediated angiogenesis) and angiopoietin-2 (Ang-2) expression.
• Additional factors: protein C and S deficiencies, local stimulation of collagen synthesis (increased cells expressing procollagen type 1 mRNA), obesity.

• Acute phase: pain, warmth, erythema, some induration, most often initially on medial lower leg above malleolus.
• Other dependent sites: lower abdominal pannus.
• Chronic phase: marked sclerosis of dermis/subcutis, sharply demarcated induration.
• Brown discoloration due to hemosiderin deposition.
• Gives affected leg the appearance of an "inverted wine bottle."

• Early lesions: mid-lobular ischemic necrosis, lymphocytic infiltrate in septa rimming fat lobules, variable capillary congestion/thrombosis, hemorrhage with hemosiderin deposition.
• With progression: septal thickening, hyaline sclerosis of lipocytes, lipophage formation, mixed inflammatory infiltrates.
• Advanced lesions: marked septal sclerosis and membranocystic change with marked reduction in inflammation.
• Membranocystic change — key feature: thickened, undulating membranes forming cysts and papillary configurations; believed to derive from degenerated cell membranes of lipocytes/macrophages; material is ceroid (oxidation product of unsaturated fatty acids).
• Short, frayed elastic fibers within subcutaneous septa, may be calcified — resemble pseudoxanthoma elasticum.
• Myospherulosis: foreign-body granulomatous reaction to lipid-containing material and blood, described in lipodermatosclerosis lesions.
• Pericapillary fibrin demonstrable by phosphotungstic acid–hematoxylin stain or immunofluorescence.
• Dermal changes: fibrosis, tortuous thick-walled veins, superficial/deep perivascular inflammation.
• Biopsy should be avoided if diagnosis obvious — poor wound healing/ulceration frequently result. If needed, thin elliptical excision from margin of lesion.

• Early diffuse erythematous stage: consider infectious cellulitis, EN, erythema induratum.
• Persistence, association with stasis changes, lack of antimicrobial response suggest correct diagnosis; venous function studies may aid.
• As induration progresses: differentiate from morphea and scleromyxedema.
• Morphea: subcutaneous involvement predominantly septal; lipophagic/lipodystrophic changes not as prominent.
• Membranocystic changes: helpful diagnostically but can occur in lupus/dermatomyositis panniculitis, liposarcoma, EN, diabetic dermopathy.

• Leg elevation and consistent compression therapy are mainstays.
• Traditional anti-inflammatory therapies usually ineffective.
• Intralesional corticosteroids (e.g., triamcinolone 5–10 mg/cc) may help combined with compression therapy.
• Anabolic steroid stanozolol — good results, especially earlier phases; no longer commercially available.
• Danazol used successfully as substitute.
• Anabolic steroids enhance fibrinolysis, reduce pain/extent/induration; side effects: sodium retention, lipid abnormalities, hepatotoxicity, virilization in women limit use.
• Oxandrolone: anabolic steroid with less hepatotoxicity/fewer androgenic effects — alternative option.
• Other reported treatments: ultrasound, pentoxifylline, fasciotomy, phlebectomy.

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Synonym: Infective panniculitis

• Wide variety of infectious agents reported to produce panniculitis.
• Some degree of immunosuppression common, but not invariable.
• Histopathologic findings vary, often include mixed septal/lobular panniculitis, neutrophilic infiltration, hemorrhage, necrosis.
• Special staining and culture of drainage/tissue provide definitive diagnosis.

• Panniculitis can result from a distant focus of infection (classic example: EN) or be directly induced by an infectious agent.

• Most early studies of deep skin infections did not focus on subcutaneous fat changes.
• 1989: Patterson et al. studied 15 cases of infection-induced panniculitis, emphasizing histopathologic features.

• No age, sex, or racial predilection.
• Many patients immunosuppressed or have predisposing conditions (e.g., diabetes mellitus).

• Infectious agents directly responsible for the panniculitis.
• Subcutis involvement via direct inoculation or septicemia.
• Other spread modes: transfascial from enteric source (abdominal panniculitis); "persorption" — proposed mechanism by which Candida migrates across intact endothelium from gut to subcutaneous site.
• Immunosuppression common but not invariable.

• Local swelling and erythema; one or more fluctuant nodules that ulcerate and drain.
• Common sites: legs and feet; also gluteal region, abdomen, axillae, arm, hand.
• Underlying conditions: sepsis, diabetes mellitus, leukemias/solid tumors, autoimmune connective tissue disease, AIDS, organ transplantation.

• Can mimic other primary forms of panniculitis.
• Common changes (regardless of agent): mixed septal/lobular panniculitis, neutrophilic infiltration, vascular proliferation, hemorrhage, necrosis involving lipocytes, inflammatory cells, and eccrine sweat coils.
• Q fever (Coxiella burnetii): "doughnut-like" granulomatous lobular panniculitis — fibrin and inflammatory cells forming a ring around a central clear space (similar changes in liver, bone marrow).
• Stenotrophomonas maltophilia (previously Pseudomonas maltophilia): phagocytosis of bacteria → foamy histiocytes with cytoplasm filled with bluish, granular material.

• Bacteria: Staphylococcus aureus, Group A Streptococcus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Brucella melitensis, Nocardia asteroides, Tropheryma whipplei (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.).

• Fluctuant, ulcerating nodules also occur in pancreatic panniculitis, traumatic panniculitis, alpha-1 antitrypsin deficiency panniculitis — clinical/lab data usually permits distinction.
• Traumatic panniculitis may be accompanied by infection.
• Predominantly septal or vasculitic infection-induced cases could be confused with acute EN or erythema induratum.
• Mucormycosis panniculitis: may feature "ghost cells" and granular calcium deposits (resembles pancreatic panniculitis); can also mimic gouty panniculitis (intracellular crystalline deposits).
• Special stains for organisms and cultures are key to diagnosis — in one study, special stains positive for organisms in 14 of 15 cases.

• Appropriate antimicrobial therapy.
• Surgery may be indicated for isolated lesions from grain-forming fungi or bacteria (mycetoma, botryomycosis).
• More radical surgical approach used successfully for abdominal panniculitis due to enteric bacteria.

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• Term used for subcutaneous nodules/plaques showing infiltrates of macrophages containing erythrocytes, lymphocytes, and/or karyorrhectic debris (i.e., exhibiting hemophagocytosis).
• These macrophages with cytophagic activity referred to as "bean bag" cells.
• With immunophenotyping/genetic techniques: vast majority of patients have lymphoma, with atypical lymphoid cells also present within the panniculus.
• In general, 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).
• Occasionally patients have subcutaneous panniculitis-like T cell lymphoma; rarely, no lymphoma.
• Individuals without lymphoma may still have a fatal course due to a hemophagocytic syndrome involving liver, spleen, bone marrow (→ pancytopenia).
• Mutations in a number of genes can predispose to hemophagocytic syndrome, including the gene encoding perforin.
• A child with microscopic CHP but no lymphoma evidence was found to have a heterozygous nonsense mutation in the perforin gene.

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• Malignant infiltrates may involve the subcutis, mimicking panniculitis clinically and microscopically.
• Best known: subcutaneous panniculitis-like T cell lymphoma (see Ch. 120).
• Cytophagia can be seen in SPTCL but is particularly characteristic of subcutaneous involvement of primary cutaneous γ/δ T cell lymphoma and EBV-associated extranodal NK/T cell lymphoma, nasal type.
• Other lymphomas (e.g., B cell), leukemias, metastatic solid tumors may infiltrate the subcutis — clinical information crucial.
• Histopathologic clues: significant pleomorphism or monotony among infiltrating cells, infiltration between dermal collagen bundles or around adnexal structures, supporting immunohistochemical studies.
• Diagnosis of SPTCL can be elusive — initial impression may be lupus panniculitis or even a nonspecific panniculitis with lipomembranous changes.

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• Table 100.12 lists several more recently described or unusual forms.
• Ever-expanding list of drugs causing panniculitis, especially with immune/targeted therapies.
• When panniculitis is not readily classifiable, consider these alternatives.
• Several probably do not represent distinct entities but overarching terms including established forms:
• Plasma cell panniculitis: could include morphea, postirradiation pseudosclerodermatous panniculitis, other autoimmune connective tissue diseases, or infectious diseases.
• Fasciitis–panniculitis syndrome: term from non-dermatology literature — includes eosinophilic fasciitis, morphea profunda, lupus panniculitis, lipodermatosclerosis, and other conditions.
• Sweet syndrome and Lyme disease are established entities that can occasionally feature panniculitis significantly.
• Atypical lymphocytic lobular panniculitis and panniculitic bacterid are more recently described conditions requiring further study before wide acceptance as distinct entities.

*Neutrophilic panniculitis also may precede the lipodystrophy of proteasome-associated autoinflammatory syndrome/CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome.

AML = acute myelogenous leukemia; TNF = tumor necrosis factor.

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• Subcutaneous tissue (subcutis) = predominantly fat cells embedded in a connective tissue framework.
• Present almost universally over the body surface between the skin and the deep fascia; in the normal state constitutes about 10% of body weight.
• Forms a specialised, closely regulated METABOLIC RESERVE capable of storing or rapidly releasing energy — typically providing sufficient for about 40 DAYS' requirements.
• Acts as an INSULATING LAYER against heat loss and a PROTECTIVE CUSHION against external injury; provides structural support to overlying skin and has a COSMETIC function (e.g. contours of the face).
• Subcutaneous fat is ABSENT from the EYELIDS and the MALE GENITALIA.
• Sexual differences in distribution: increased thickness gives the rounded contours of the female trunk, breasts, hips, pubis and thighs.
• Also varies in thickness with race, age, and endocrine and nutritional status.
• BROWN FAT has a very important THERMOREGULATORY role, acting by INCREASING THE BASAL METABOLIC RATE — particularly important in infancy; heat production in response to cold exposure is MAXIMAL IN NEONATES, who have large quantities of brown fat.

• The first fat-containing cell, the PRE-ADIPOCYTE, appears in the mesenchyme around the 14TH WEEK of fetal life.
• The primitive mesenchymal cell forming the determined pre-adipocyte is also capable of maturing to form a FIBROCYTE, MYOCYTE, CHONDROCYTE or OSTEOBLAST.
• Pre-adipocytes can terminally differentiate into either BROWN or WHITE adipocytes.

Brown fat

• A special type of GRANULAR fat differing from white fat in DISTRIBUTION, HISTOLOGY and FUNCTION.
• MULTILOCULAR and metabolically very active with MANY MITOCHONDRIA — capable of transferring energy from food to produce HEAT.
• Has a much GREATER CAPILLARY NETWORK than white fat (partly responsible for the brown colour), so heat can be rapidly transferred into the circulation.
• Most prominent in the NECK and UPPER THORAX of the fetus; may be homologous to the HIBERNATING GLAND FAT found in some animals.
• Now known to PERSIST INTO ADULT LIFE, and may have a role in PREVENTING OBESITY.
• Warm patches develop in the skin 1 h after taking EPHEDRINE orally — these may indicate the site of thermogenic brown fat.
• Brown and white fat may be distinguished using ¹⁸F fluorodeoxyglucose PET (FDG-PET).
• Brown fat adipocyte mitochondria UNIQUELY EXPRESS UNCOUPLING PROTEIN 1 (UCP-1), allowing confirmation that brown fat is present in ADULT WHITE FAT DEPOTS in variable amounts, and that TRANSDIFFERENTIATION from white to brown adipocytes can occur.
• Development begins at the 20TH WEEK of gestation, reaches its MAXIMUM AT BIRTH, then diminishes — no large collections of brown fat in the adult, though FDG-PET suggests some adults have SUPRACLAVICULAR areas of brown fat.
• Evidence for cold induction by brown fat as an adaptive response in humans is at present EQUIVOCAL.

White fat

• White fat adipocytes are the LARGEST CONNECTIVE TISSUE CELLS IN THE BODY, with a diameter of UP TO 100 μm.
• Much of their differentiation occurs SOON AFTER BIRTH.
• Mature adipocyte has a characteristic SIGNET-RING appearance — the flat, oval nucleus is displaced to the side by a SINGLE, LARGE, INTRACELLULAR, FAT-CONTAINING VACUOLE, surrounded by PERILIPIN.
• Originally thought an inert store, but the white adipocyte has a huge array of functions, secreting ADIPOKINES affecting lipid and glucose metabolism, endocrine functions, blood pressure control, coagulation, fibrinolysis, angiogenesis and inflammation.

• Forms a TRUE ORGAN as regards both structure and function.
• Groups of adipocytes arranged in LOBULES, each measuring approximately 1 cm in diameter, separated by INTERLOBULAR SEPTA composed of COLLAGEN and RETICULIN fibres.
• Each lobule subdivided into 1 mm diameter MICROLOBULES = the FUNCTIONAL UNIT of the subcutaneous fat.
• Each microlobule = a group of adipocytes arrayed around a CENTRAL ARTERIOLE, surrounded by capillaries and postcapillary venules.
• Arteries and veins of the subcutis run ALONG THE SEPTA.
• Each individual fat lobule is supplied by a small muscular artery (250–500 μm diameter) branching from the septa to form arterioles (up to 100 μm diameter) supplying every individual microlobule; each arteriole branches into a capillary network surrounding each individual adipocyte.
• Subcutaneous fat also contains a RICH LYMPHATIC PLEXUS receiving vessels from the dermis; these traverse the subcutaneous layer PARALLEL TO THE SKIN SURFACE for some distance before penetrating the deep fascia and draining into regional lymph nodes.
• Both white and brown fat are innervated by NORADRENERGIC fibres of the SYMPATHETIC nervous system and PARASYMPATHETIC fibres.
• Adipocytes may comprise ONLY 25% of the total cell population of a lobule; the remainder — the STROMA–VASCULAR FRACTION — are macrophages, fibroblasts, mast cells, pericytes, endothelial cells and pre-adipocytes, enabling considerable CROSS-TALK between cells by locally secreted cytokines including LEPTIN and ADIPONECTIN.
• Approximately 20% of fat tissue occurs INTERNALLY — mediastinal and retroperitoneal tissues, mesentery, bone marrow, and in and around individual organs including blood vessels.
• DEPOT-SPECIFIC differences occur:
• Increases in subcutaneous UPPER BODY and VISCERAL fat are associated with INCREASED cardiovascular and metabolic risk, but increases in GLUTEO-FEMORAL subcutaneous fat are NOT.
• Perivascular adipose tissue shows INCREASED ANGIOGENESIS compared with subcutaneous fat.
• Some genetic lipodystrophy patients lose PERIPHERAL fat but FAT PADDING FOR ABSORPTION OF MECHANICAL PRESSURE IS MAINTAINED — further evidence for depot-specific differences.
• Superficial fascia divides subcutaneous fat into two compartments — SUPERFICIAL and DEEP:
• SUPERFICIAL (areolar) layer: fat mass compartmentalised into lobules by VERTICAL and OBLIQUE fibrous septal planes and bands. Fairly constant.
• DEEP (lamellar) layer: septae more HORIZONTALLY positioned. More variable, with an increase in fat mass accumulating between the split horizontal septae.
• In FEMALES, subcutaneous fat is most abundant in the gluteo-femoral region and breasts = GYNAECOID distribution.
• In MALES, the ANDROID distribution predominates — shoulders and upper arms, neck and lumbo-sacral area.

Energy homeostasis

• A major function of white adipose tissue is to store energy at times of calorie excess and release it when needed.
• The role of the AUTONOMIC NERVOUS SYSTEM is well established, being particularly important for RAPID energy need compared with the slower control exerted by NEUROENDOCRINE factors.
• A DECREASE in PARASYMPATHETIC activity results in INCREASED LIPOLYSIS, as does an INCREASE in SYMPATHETIC activity — the opposites stimulating lipogenesis.
• Hormones affecting energy metabolism of fat cells: insulin, cortisol, norepinephrine (noradrenaline) and several pituitary hormones — somatotrophin, ACTH, thyrotrophin, lipotrophin and natriuretic peptide.
• Fats within adipocytes are predominantly TRIGLYCERIDES (triacylglycerols) — especially those of PALMITIC and STEARIC acids and the unsaturated OLEIC acid.
• ALL the fatty acids have an EVEN number of carbon atoms — predominantly C16 and C18, with a few C14 and C12.
• Adipose tissue contains 10–30% WATER, a small proportion of lipochromes, and less than 2% cholesterol.
• Fat-soluble substances present in varying amounts: fat-soluble vitamins; traces of chlorinated hydrocarbons (e.g. aldrin, dieldrin) ingested with the diet; and drugs such as ACITRETIN.
• Adipose tissue in vitro has a metabolic rate SIMILAR TO KIDNEY tissue, and approximately HALF that of LIVER.
• Approximately HALF the triglyceride in the adipose tissue of rats and mice is catabolised and reconstituted in the course of a week or so.

Lipogenesis

• Fat enters the adipocyte as FATTY ACIDS, having been converted from lipoproteins by the extracellular enzyme LIPOPROTEIN LIPASE.
• Fatty acids combine with coenzyme A, using the energy of ATP, to form acetyl coenzyme A compounds; some are oxidised to regenerate ATP, but most are converted to TRIGLYCERIDE by combination with GLYCEROL-3-PHOSPHATE derived from GLUCOSE.
• The adipocyte is one of the FEW cells to express the INSULIN-DEPENDENT GLUCOSE TRANSPORTER RECEPTOR 4 (GLUT-4), mediating passage of glucose into the cell and facilitating triglyceride formation via de novo lipogenesis — the latter providing only a SMALL contribution to the pool.
• At the same time, INSULIN INHIBITS hydrolysis and breakdown of triglyceride, conserving the energy store.

Lipolysis

• Triglyceride is hydrolysed in the adipocyte, converted to NON-ESTERIFIED FATTY ACIDS (NEFAs) and GLYCEROL — the rate-limiting enzyme being HORMONE-SENSITIVE LIPASE (HSL).
• NEFAs are conveyed in the blood to tissues such as LIVER and MUSCLE, in which fatty acid oxidation readily takes place — the essential part being oxidation in the MITOCHONDRIA of the long-chain fatty acids.
• Glycerol reacts with ATP to form glycerol phosphate, oxidised to glyceraldehyde-3-phosphate, which may be converted to glycogen by reversal of glycolysis, or to pyruvate.
• SKELETAL MUSCLE readily oxidises fatty acids, but GLUCOSE, IF AVAILABLE, IS PREFERENTIALLY USED. In CARDIAC MUSCLE, FATTY ACIDS ARE A MAJOR SOURCE OF ENERGY.
• Lipolysis is regulated predominantly through INSULIN and CATECHOLAMINES — the latter, elevated during a sudden energy demand, bind to β-ADRENERGIC RECEPTORS and activate HSL through the classic AMP–PKA pathway.

Role of leptin

• An adipokine involved in energy homeostasis that may have evolved to help adaptation FROM THE STARVED TO THE ADEQUATELY NOURISHED STATE rather than to prevent obesity.
• A product of the ob gene; a 16 kDa polypeptide comprising 167 AMINO ACIDS, with structural homology similar to other cytokine proteins such as TNF-α and IL-6.
• Secreted by ADIPOCYTES predominantly, but also by the STOMACH, aiding immediate appetite control.
• Leptin receptors are present in the hypothalamus, on adipocytes, skeletal muscle, liver, pancreatic β cells, ovary and endometrium.
• Main effect is via the SATIETY CENTRES in the HYPOTHALAMUS: if excess energy is being stored, rising leptin levels stimulate the satiety centres to REDUCE APPETITE; during starvation LOW leptin levels STIMULATE appetite.
• Circulating levels correlate with increasing BMI but have LITTLE EFFECT on the satiety centres — indicating an apparent LEPTIN RESISTANCE.
• Also influences neuroendocrine and reproductive functions, insulin secretion and blood pressure.
• Patients with CONGENITAL LEPTIN DEFICIENCY (Ch 72) have gross obesity, hyperphagia, delayed pubertal development, abnormal T-cell number and function, and altered thyroid and growth hormone function.
• Leptin also has a role in immune function and inflammation; increased expression in CHONDROCYTES — may have a part in articular degenerative disease.

Adipogenesis

• Recruitment from multipotent stem cells in the mesenchyme and stroma–vascular tissue, proliferation of pre-adipocytes followed by differentiation into mature fat cells.
• Major transcriptional factors: peroxisome proliferator-activated receptor γ (PPAR-γ) and the CCAAT enhancer binding proteins (C/EBPs).
• Contribution towards enlargement of the fat organ is uncertain but seems MAXIMAL BEFORE AND AROUND BIRTH before diminishing, then possibly continuing at a LOW RATE throughout adult life.
• Glucocorticoids, growth hormone and insulin stimulate cells to terminal differentiation; when mature fat cells reach a certain size, recruitment occurs so the fat organ enlarges through HYPERPLASIA (increased NUMBERS of cells) rather than HYPERTROPHY (increase in SIZE of cells).
• Control of this hyperplastic response may come from local adipocytes through PARACRINE effects involving local growth factors.
• The local EXTRACELLULAR MATRIX also changes — supported by the fact that fat tissue repair is IMPROVED if elements of this matrix are included with the donor adipocytes.

Insulin sensitivity

• Insulin secretion, stimulated by raised blood glucose after meals, has TWO MAJOR EFFECTS: it facilitates glucose uptake into most cells (liver, skeletal muscle and adipocytes) and it suppresses glucose output by the liver.
• INSULIN RESISTANCE occurs when a target organ fails to respond normally → HYPERINSULINAEMIA.
• Effect may be incomplete suppression of hepatic glucose output and/or impaired insulin-mediated glucose uptake in peripheral tissues.
• If increased insulin secretion CANNOT prevent hyperglycaemia, TYPE 2 DIABETES results.

Adiponectin

• A 30 kDa protein composed of 244 amino acids with structural similarity to BOTH COLLAGEN and COMPLEMENT C1q; currently thought to be secreted EXCLUSIVELY by adipocytes.
• Has autocrine/paracrine effects locally as well as endocrine effects distantly.
• Locally it can promote pre-adipocytes to become mature fat cells, which with increasing cell size DOWNREGULATE their adiponectin secretion to exert feedback control.
• Adiponectin receptor-activated AMPK (AMP-activated protein kinase) likely leads to enhanced insulin signalling and therefore insulin sensitivity.
• If BMI is elevated, adiponectin expression is REDUCED in VISCERAL adipose tissue (VAT) adipocytes compared with SUBCUTANEOUS (SAT).
• Serum adiponectin levels FALL with WEIGHT GAIN and RISE with WEIGHT LOSS.
• Exerts PROTECTIVE ANTI-INFLAMMATORY effects:
• Local: inhibiting secretion of IL-6, IL-8, macrophage inflammatory protein 1 and monocyte chemotactic protein 1.
• Distant: direct action on monocytes/macrophages, endothelial cells, hepatocytes and muscle cells, and indirectly by inhibition of TNF-α production.
• PARADOX: in obesity, macrophages in VAT generate TNF-α that SUPPRESSES adiponectin secretion; low adiponectin promotes inflammation, generating a SELF-SUSTAINING LOOP — so in obesity, adiponectin levels are INVERSELY correlated with inflammatory markers.
• In AUTOIMMUNE states (rheumatoid arthritis, SLE), adiponectin levels are RAISED, POSITIVELY correlating with inflammatory markers.
• Suggested that the adiponectin system evolved as a mechanism for ADAPTATION TO STARVATION, a CATABOLIC state — hence raised in other catabolic states such as autoimmune disease and inflammatory bowel disease — and did NOT evolve as a protective device against insulin resistance.

Other adipokines

• The stroma–vascular tissue is responsible for a variety of cytokines. Macrophages secrete TNF-α, IL-1, IL-6, IL-8, IL-10, MCP-1, macrophage migration inhibitory factor (MIF), angiotensinogen, and endothelial and vascular growth factors.
• As well as affecting energy homeostasis, insulin sensitivity and adipocyte differentiation, the fat organ influences inflammation, immune function, vascular inflammation and neoangiogenesis — lending credence to the concept of the FAT ORGAN BEING AN ENDOCRINE ORGAN IN ITS OWN RIGHT.

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• Inflammatory diseases involving the subcutaneous fat comprise a heterogeneous group named generically PANNICULITIS.
• Classically considered DIAGNOSTICALLY CHALLENGING for both clinicians and dermatopathologists — reasons:

1. Subcutaneous tissue is TOO DEEP to be visible to the examining eye.
2. Cutaneous lesions usually show a DISAPPOINTING MONOTONY — completely different diseases show the same clinical morphology, namely REDDISH NODULES located preferentially on the LOWER EXTREMITIES.
3. LARGE INCISIONAL BIOPSIES are necessary — diagnosis is based on correct evaluation of the PATTERN of the inflammatory infiltrate and the INVOLVEMENT OF BLOOD VESSELS. The specimen MUST include a FAT LOBULE AND ITS SURROUNDING CONNECTIVE TISSUE SEPTA; many dermatologists perform superficial or small biopsies which are NOT diagnostic.
4. Subcutaneous fat has a LIMITED RANGE OF RESPONSES — a variety of insults of entirely different aetiologies may produce VERY SIMILAR histopathological changes.
5. Panniculitides are DYNAMIC processes — both the distribution and composition of the inflammatory cells may change rapidly over the course of a few days; biopsies from LATE or RESOLVING lesions, especially in predominantly lobular panniculitis, may show COMPLETELY NON-SPECIFIC findings.

• Despite pitfalls, serial sections of an adequate biopsy enable classification in MOST cases as either a PREDOMINANTLY SEPTAL or a PREDOMINANTLY LOBULAR panniculitis — an INITIAL DESCRIPTIVE WORKING CLASSIFICATION only.
• Diagnostic steps:

1. Septal vs lobular.
2. Assess whether VASCULITIS is present and, if so, the SIZE AND NATURE of the involved blood vessels.
3. Identify the COMPOSITION of the inflammatory infiltrate, the TYPE OF ADIPOCYTE NECROSIS, and additional histopathological features.

• There is probably NO individual cell of the human body with a BETTER VASCULAR SUPPLY than the ADIPOCYTE.
• In each microlobule, the ARTERIOLE occupies a CENTRAL position, whereas the VENULE runs along the PERIPHERY.
• Consequently:
• Interference with the ARTERIAL supply → DRAMATIC NECROTIC CHANGES WITHIN THE FAT LOBULE (predominantly LOBULAR panniculitis).
• VENOUS disorders → alterations in the SEPTAL and PARASEPTAL areas (predominantly SEPTAL panniculitis).
• LARGE-VESSEL vasculitis involving septal vessels is usually accompanied by LITTLE inflammation of the fat lobules, whereas vasculitis involving SMALL blood vessels of the lobule usually causes EXTENSIVE NECROSIS of the CENTRILOBULAR adipocytes and a DENSE inflammatory response.
• In contrast with the dermal vascular network, the blood supply of each subcutaneous microlobule is TERMINAL — there are NO vascular connections between adjacent microlobules or between dermis and subcutaneous fat.
• Normal septa are THIN, from 200 to 300 μm, composed mostly of collagen bundles and thin elastic and reticulin fibres.
• Mature normal adipocytes have a diameter up to 100 mm; in H&E sections appear as empty cells with SIGNET-RING morphology — the lipid dissolves in routine processing. Frozen sections and OIL RED O or SUDAN B demonstrate the lipid but are NOT necessary for diagnostic purposes.
• Perivascular adipocytes are powerful ENDOCRINE cells capable of responding to metabolic changes and transducing signals to adjacent vessels; regulate vascular function and play a role in inflammation and vasoreactivity.
• Normal subcutaneous fat contains T LYMPHOCYTES located BETWEEN adipocytes of the fat lobule — they DIFFER from those of other tissues and VARY between different regions of the body.
• CYTOTOXIC T LYMPHOCYTES PRECEDE the accumulation of MACROPHAGES during inflammation of the fat lobule; in vitro co-cultures show a VICIOUS CYCLE in which adipocytes ACTIVATE cytotoxic T lymphocytes with subsequent recruitment and activation of macrophages.
• Human adipocytes express the inflammatory receptor CD40, contributing to intercellular cross-talk with lymphocytes; co-cultures show UPREGULATION of IL-6, MCP-1 and PAI-1, but DOWNREGULATION of LEPTIN and ADIPONECTIN.
• Immunohistochemistry: adipocytes express S-100 PROTEIN (staining around the PERIPHERY of the cell) and VIMENTIN.
• In contrast with the MULTIVACUOLATED cytoplasm of SEBOCYTES and FOAMY HISTIOCYTES, which express ADIPOPHILIN, the SINGLE LARGE cytoplasmic vacuole of the adipocyte is ADIPOPHILIN NEGATIVE.

• A peculiarity of the VEINS in the subcutaneous fat of the LOWER LIMBS is that they have a THICK MUSCULAR LAYER, conferring an "ARTERIAL" appearance.
• On H&E: the middle layer of subcutaneous VEINS is composed of SEVERAL MUSCULAR FASCICLES SEPARATED BY TINY UNSTAINED ELASTIC FIBRES, whereas ARTERIES show a MORE COMPACT muscular layer.
• Many authors continue to promote the MISLEADING notion that arteries of the lower legs have a thicker muscular layer than veins — IN FACT VEINS OFTEN HAVE A THICKER MUSCULAR LAYER THAN ARTERIES.
• ELASTIC TISSUE STAINING allows definite discrimination: ARTERIES have a WELL-DEMARCATED, THICK AND SHARP INTERNAL ELASTIC MEMBRANE, whereas VEINS have an ILL-DEFINED, THIN, MULTILAYERED internal elastic lamina with tiny elastic fibres interspersed between muscular fascicles.
• Some authors believe that when inflammation is present within and around the wall, ALL studied histological features become LESS RELIABLE, and that the interobserver reliability of distinguishing arteritis from thrombophlebitis is LOW.

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WITH vasculitis

• VEINS → Superficial migratory thrombophlebitis
• ARTERIES → Cutaneous polyarteritis nodosa (cutaneous arteritis)

NO vasculitis

• Lymphocytes and plasma cells predominantly:
• WITH granulomatous infiltrate in septa → Necrobiosis lipoidica
• NO granulomatous infiltrate in septa → Deep morphoea
• Histiocytes predominantly (granulomatous):
• With MUCIN in centre of palisaded granulomas → Subcutaneous granuloma annulare
• With FIBRIN in centre of palisaded granulomas → Rheumatoid nodule
• With LARGE AREAS OF DEGENERATE COLLAGEN, FOAMY HISTIOCYTES and CHOLESTEROL CLEFTS → Necrobiotic xanthogranuloma
• WITHOUT mucin, fibrin or degeneration of collagen, but with RADIAL GRANULOMAS in septa → Erythema nodosum

WITH vasculitis

• SMALL vessels: VENULES → Erythema nodosum leprosum; Erythema induratum of Bazin
• LARGE vessels: ARTERIES → Erythema induratum of Bazin

NO vasculitis

• Few or no inflammatory cells:
• Necrosis at the centre of the lobule → Sclerosing panniculitis (lipodermatosclerosis)
• With VASCULAR CALCIFICATION → Calcific uraemic arteriolopathy (calciphylaxis)
• LYMPHOCYTES predominant:
• With superficial and deep perivascular DERMAL infiltrate → Cold panniculitis
• With LYMPHOID FOLLICLES, PLASMA CELLS, clusters of PLASMACYTOID DENDRITIC CELLS and NUCLEAR DUST of lymphocytes → Lupus panniculitis; Panniculitis associated with dermatomyositis
• NEUTROPHILS predominant:
• Extensive fat necrosis with SAPONIFICATION of adipocytes → Pancreatic panniculitis
• With neutrophils BETWEEN COLLAGEN BUNDLES of deep reticular dermis → α1-antitrypsin deficiency panniculitis
• With BACTERIA, FUNGI or PROTOZOA → Infective panniculitis
• With FOREIGN BODIES → Factitious panniculitis
• Neutrophilic lobular panniculitis → Subcutaneous Sweet syndrome; Drug-induced (checkpoint inhibitor drugs) panniculitis
• HISTIOCYTES predominant (granulomatous):
• NO crystals in adipocytes → Subcutaneous sarcoidosis; Traumatic panniculitis
• WITH CRYSTALS in histiocytes or adipocytes → Subcutaneous fat necrosis of the newborn; Poststeroid panniculitis; Sclerema neonatorum; Gouty panniculitis; Fungal panniculitis due to zygomycosis, mucormycosis and aspergillosis
• With CYTOPHAGIC HISTIOCYTES → Cytophagic histiocytic panniculitis; subcutaneous γ/δ T-cell lymphoma; some cases of subcutaneous panniculitis-like T-cell lymphoma (included because they may MIMIC panniculitis both clinically and histopathologically, although characterised by a NEOPLASTIC proliferation rather than an authentic panniculitic process)
• With SCLEROSIS OF THE SEPTA → Sclerosing postirradiation panniculitis

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• The appearance of necrotic adipocytes is POLYMORPHOUS and DIFFERENT from other necrotic cells.
• In classic histopathology, PYKNOSIS, KARYORRHEXIS and KARYOLYSIS are signs of cellular necrosis. In contrast, necrotic adipocytes — REGARDLESS OF AETIOLOGY — show GREAT VARIABILITY and may appear as anucleate cells or with complete disintegration of cellular structure.
• Often the ONLY sign of necrosis is the LACK OF NUCLEI, dead fat cells appearing as round empty bags with NO inflammatory infiltrate among them.

• The MOST FREQUENT type. Replacement of necrotic adipocytes by FOAMY MACROPHAGES formed by engulfment of lipid released from dead adipocytes.
• Lipophages have large, pale, microvacuolated or granular-like cytoplasm and round, central, VESICULAR nuclei.
• Lipophagic granulomatous inflammation is ENTIRELY NON-SPECIFIC — many lobular panniculitides show this at LATE or RESOLVING stages.
• Usually seen in LIPODERMATOSCLEROSIS and TRAUMATIC panniculitis, but may also be present in erythema nodosum and erythema induratum of Bazin.

• A MORE SPECIFIC pattern — more often seen in α1-ANTITRYPSIN DEFICIENCY panniculitis and in PANCREATIC panniculitis.
• Necrotic adipocytes appear as GRANULAR WISPS OF AMPHOPHILIC DETRITUS; cellular structures no longer evident.

• A SPECIFIC type of liquefactive fat necrosis characteristically observed in PANCREATIC panniculitis.
• Due to SAPONIFICATION of the adipocyte lipid contents by PANCREATIC LIPASE, with secondary deposition of CALCIUM SALTS → "GHOST ADIPOCYTES" — adipocytes with NO nuclei and GRANULAR BASOPHILIC cytoplasm.

• Characteristically observed in LUPUS PANNICULITIS and panniculitis associated with DERMATOMYOSITIS.
• Necrotic adipocytes appear as MUMMIFIED ANUCLEATED CELLS surrounded by GLASSY HOMOGENEOUS PROTEINACEOUS MATERIAL, effacing the architecture of the fat lobule.

• A LATE-STAGE and NON-SPECIFIC type: a LEATHERY EOSINOPHILIC or AMPHOPHILIC RIM of collapsed cellular organelles with a CRENULATED or ARABESQUE appearance.
• PAS and SUDAN III staining POSITIVE.
• When extensive → formation of CYSTIC STRUCTURES devoid of cellular components, lined by hyaline-crenulated membrane.
• Membranous and membrano-cystic fat necrosis are ALMOST ALWAYS seen in LIPODERMATOSCLEROSIS, but may also be seen in late-stage lesions of several types of panniculitis.

• More frequently seen at the CENTRE of fat lobules; characterised by PALLOR of adipocytes, which are SMALLER than normal due to severe impairment of blood supply.
• Later stages also show lipophagic granulomas.
• Frequently seen in ERYTHEMA INDURATUM OF BAZIN, but also in calcific uraemic arteriolopathy (calciphylaxis), infectious panniculitis and cutaneous polyarteritis nodosa.

• Results from necrosis of adipocytes intermingled with NUCLEAR DUST of NEUTROPHILS and GRANULAR BASOPHILIC MATERIAL, which represent AGGREGATIONS OF BACTERIA.
• Characteristically seen in cases of INFECTIOUS panniculitis.

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• Classically used for predominantly LOBULAR panniculitis WITHOUT vasculitis with systemic manifestations including FEVER and involvement of VISCERAL fat tissue.
• Synonyms used: idiopathic nodular panniculitis; nodular panniculitis; relapsing febrile non-suppurative nodular panniculitis.
• Many cases were later RECLASSIFIED when erythema induratum of Bazin (nodular vasculitis), pancreatic panniculitis and α1-antitrypsin deficiency panniculitis were separated as specific diseases.
• White and Winkelmann reviewed 30 cases previously diagnosed as Weber–Christian disease at the Mayo Clinic; MOST could be reclassified:
• 12 cases as ERYTHEMA NODOSUM
• 6 cases as SUPERFICIAL THROMBOPHLEBITIS (STP)
• 5 cases as FACTITIOUS panniculitis
• 3 cases as TRAUMATIC panniculitis
• Individual cases as CYTOPHAGIC HISTIOCYTIC PANNICULITIS, subcutaneous "PANNICULITIC" LYMPHOMA and SUBCUTANEOUS INVOLVEMENT BY LEUKAEMIA
• The term SHOULD BE ABANDONED.

• Used previously for relapsing nodular panniculitis similar to Weber–Christian disease but with NO FEVER or other systemic manifestations. Also obsolete — should no longer be used.

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• Inflammation and THROMBOSIS of the SUPERFICIAL VEINS, presenting as painful induration with red areas of skin, often in a LINEAR OR BRANCHING configuration forming CORDS (Chapter 101).
• Results from a HYPERCOAGULABLE STATE, either PRIMARY or SECONDARY.
• In the MAJORITY of cases, VENOUS INSUFFICIENCY of the lower extremities is the ONLY precipitating factor.

Primary hypercoagulable states

• Antiphospholipid syndrome
• Deficiencies of: protein C; protein S; heparin cofactor II; antithrombin III; factor XII; tissue plasminogen activator; factor V Leiden

Secondary hypercoagulable states

• Paraneoplastic superficial migratory thrombophlebitis (TROUSSEAU SYNDROME)
• Behçet syndrome
• Buerger disease
• Pregnancy
• HIV-associated immune reconstitution syndrome (IRIS)
• Secondary syphilis
• Infectious suppurative thrombophlebitis in children due to Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa or fungi
• Oral contraceptive pills
• Sepsis, intravenous injections or catheterisations
• Complications of venous sclerotherapy

• Lesions involve LARGE VEINS OF THE SEPTA in the UPPER subcutaneous tissue.
• The affected vein exhibits LUMINAL THROMBOSIS and an inflammatory infiltrate WITHIN ITS WALL.
• EARLY lesions: infiltrate composed mostly of NEUTROPHILS. LATER stages: lymphocytes, histiocytes and occasional multinucleated giant cells — granulomatous infiltration participates in the RECANALISATION of the thrombus.
• A STRIKING FEATURE: despite intense damage to the vein with dense infiltrate and marked septal thickening, there is LITTLE OR NO INVOLVEMENT OF THE ADJACENT FAT LOBULE — the process is MORE VASCULITIC THAN PANNICULITIC.
• INTRAMURAL MICROABSCESSES in the wall of the involved vein have been described as CHARACTERISTIC OF STP ASSOCIATED WITH BUERGER DISEASE.

• Patients should be investigated to rule out hypercoagulable states, paraneoplastic processes (TROUSSEAU SIGN) and BEHÇET DISEASE — although BY FAR the most common cause is CHRONIC VENOUS INSUFFICIENCY of the lower limbs.
• Main histopathological differential: CUTANEOUS POLYARTERITIS NODOSA:
• Cutaneous PAN involves the SMALL ARTERIES AND ARTERIOLES of the subcutaneous septa; the process is MORE INFLAMMATORY THAN THROMBOTIC, with prominent FIBRINOID NECROSIS of the TUNICA INTIMA resulting in the "TARGET-LIKE" ARTERITIS — an eosinophilic ring of fibrinoid necrosis replacing the intima.
• ELASTIC TISSUE STAIN usually resolves uncertainty: in cutaneous PAN the involved artery shows a SHARP AND PROMINENT internal elastic lamina, whereas in STP the damaged vessel is a VEIN with LITTLE OR NO DISCERNIBLE internal elastic membrane.
• Some authors note that with inflammation present, identification of the internal elastic lamina is less reliable EVEN WITH ELASTIC STAINS, and that the SMOOTH MUSCLE PATTERN has the HIGHEST sensitivity and specificity for distinguishing arteries from veins.
• NODULAR GRANULOMATOUS PHLEBITIS — a recently described type of TUBERCULID — may clinically resemble STP, but is histopathologically characterised by TUBERCULOID GRANULOMAS AND MULTINUCLEATE GIANT CELLS involving the WALLS OF THE VEINS of subcutaneous tissue.

• Conservative, with application of a SUPPORT STOCKING.
• In chronic and recurrent cases, especially those associated with MALIGNANCY: heparin and fibrinolytic drugs.
• Patients with a HIGH RISK OF PULMONARY EMBOLISM should receive FONDAPARINUX 2.5 mg/day SUBCUTANEOUSLY FOR 45 DAYS.
• PHLEBECTOMY may be necessary in recurrent cases due to LARGE VARICOSITIES.

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• A cutaneous vasculitis of poorly understood aetiology affecting the SUBCUTANEOUS ARTERIES AND ARTERIOLES.
• In contrast to SYSTEMIC polyarteritis nodosa, there is LITTLE OR NO EVIDENCE OF SYSTEMIC DISEASE (Chapter 100).
• So-called MACULAR LYMPHOCYTIC ARTERITIS is now considered by most authors a MILD VARIANT characterised by MACULAR rather than NODULAR lesions.

• Serum is usually NEGATIVE for both MPO-ANCA (p-ANCA) and PR3-ANCA (c-ANCA) by DIRECT ELISA and CAPTURE ELISA, but 84% of patients reveal p-ANCA POSITIVITY by INDIRECT IMMUNOFLUORESCENCE.
• Serum ANTI-LAMP-2 (antilysosomal-associated membrane protein 2) antibody levels are SIGNIFICANTLY ELEVATED in p-ANCA-positive patients — suggesting anti-LAMP-2 antibodies might play an important role in pathogenesis.
• IgG antiphosphatidylserine–prothrombin complex (anti-PS/PT) antibodies and/or IgG anticardiolipin antibodies also detected in the serum of some patients.
• A recently identified, GENETICALLY DETERMINED form: loss-of-function mutation in the ADENOSINE DEAMINASE TYPE 2 gene (ADA2 DEFICIENCY) — linked to AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET disease with features similar to classic PAN; shows considerable variability in severity, ranging from CUTANEOUS to SYSTEMIC vasculopathy.

• Vasculitis involving MEDIUM-SIZED ARTERIES AND ARTERIOLES at the SEPTA of the UPPER SUBCUTIS.
• Direct immunofluorescence demonstrates IgM AND COMPLEMENT deposition in the involved vessel walls and CONSISTENT ABSENCE OF IgG.
• The involved vessel has a THICKENED WALL with an inflammatory infiltrate whose composition varies with the stage:
• EARLY: neutrophilic infiltrate and LEUKOCYTOCLASIS; in some cases EOSINOPHILS may be prominent.
• Characteristically: the INTIMA exhibits an EOSINOPHILIC RING OF FIBRINOID NECROSIS, giving a TARGET-LIKE appearance.
• OLDER lesions: LYMPHOCYTES predominant.
• STILL LATER: FIBROSIS of the ENTIRE THICKNESS of the vessel wall, leading to OBLITERATION of its lumen.
• A rare complication is the formation of PERIOSTEAL NEW BONE beneath the cutaneous lesions.
• Luminal thrombi may be present but are LESS FREQUENT than in STP.
• Arterial involvement is often SEGMENTAL — SERIAL SECTIONS throughout the entire specimen are required to demonstrate the pathology.
• As in STP, there is LITTLE OR NO INVOLVEMENT OF THE ADJACENT FAT LOBULE — the process is EXCLUSIVELY A SEPTAL ARTERITIS.

• Usually follows a BENIGN clinical course.
• TOPICAL or INTRALESIONAL corticosteroids helpful in localised areas; extensive disease may warrant SYSTEMIC corticosteroids.
• Symptomatic relief with NSAIDs.

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• Degenerated dermal collagen surrounded by a granulomatous inflammatory response producing shiny, red-brown or yellowish plaques, particularly on the SHINS; may ULCERATE. Associated with diabetes in the majority but not all cases, the onset of which it may PRECEDE (Chapter 95).
• It MAY involve the subcutis but DOES NOT CAUSE A TRUE PANNICULITIS — the palisading granulomatous process involving the subcutis is ALWAYS A DEEP EXTENSION OF THE DERMAL PROCESS; there are NO descriptions of necrobiosis lipoidica involving ONLY subcutaneous fat.

• Lesions involve the FULL THICKNESS OF THE DERMIS and often extend to the superficial subcutaneous tissue causing a SEPTAL panniculitis.
• PALISADING GRANULOMAS with histiocytes surrounding areas of DEGENERATE COLLAGEN within WIDENED SEPTA.
• The MOST CHARACTERISTIC feature supporting the diagnosis is the COEXISTENCE OF SIMILAR LESIONS IN THE DERMIS, with ALTERNATING HORIZONTAL BANDS OF INFLAMMATORY CELLS AND FIBROSIS involving the ENTIRE DERMIS.
• EARLY lesions: infiltrate composed predominantly of NEUTROPHILS scattered within the septa.
• LATER lesions: histiocytes, lymphocytes and PLASMA CELLS, sometimes with LYMPHOID FOLLICLE formation.
• Multinucleated giant cells involving the septa are sometimes prominent — histopathological findings then RESEMBLE ERYTHEMA NODOSUM; differential diagnosis is STRAIGHTFORWARD because in erythema nodosum there are NO significant DERMAL changes other than a perivascular lymphocytic infiltrate.
• CHRONIC longstanding lesions: dermis and superficial subcutis replaced by HORIZONTAL FIBROSIS with SCLEROTIC COLLAGEN BUNDLES ARRANGED PARALLEL TO THE EPIDERMIS, scattered with plasma cells — closely resembling MORPHOEA. Features of necrobiosis are NO LONGER EVIDENT and elastic tissue stains demonstrate a DRAMATIC LOSS OF ELASTIC FIBRES.
• Some authors postulate that the finding of VASCULITIS AND LEUKOCYTOCLASIS is INDICATIVE OF AN UNDERLYING SYSTEMIC DISEASE.
• MEMBRANOUS FAT NECROSIS described in late-stage lesions extending to the subcutis.
• Direct immunofluorescence has demonstrated IgM and complement in the blood vessels of some lesions, suggesting an immune complex vasculitis — but extensive histopathological studies identified vascular involvement in ONLY 30% of cases.
• GLUT-1 immunohistochemical expression in areas of sclerotic collagen raises the possibility that a disturbance in GLUCOSE TRANSPORT BY FIBROBLASTS contributes to histogenesis.

• There is NO effective treatment. SPONTANEOUS REMISSION after several years occurs RARELY.
• Most commonly used: potent topical corticosteroids (including under occlusion) and intralesional corticosteroids for early lesions.
• Topical tacrolimus 0.1% ointment has led to improvement in some cases.
• Pentoxifylline, stanozolol, nicofuranose and ticlopidine hydrochloride tried with variable results.
• Additional anti-inflammatory drugs beneficial in anecdotal cases: antimalarials, niacinamide, mycophenolate mofetil, doxycycline, colchicine, methotrexate, thalidomide, TNF-α inhibitors and ciclosporin.
• Improvement also achieved with topical UVA1 and PUVA phototherapy.

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• A group of related diseases affecting principally skin and subcutaneous tissue, characterised by variable FIBROSIS, SCLEROSIS and CUTANEOUS ATROPHY.
• Three closely related processes are included: MORPHOEA PROFUNDA, EOSINOPHILIC FASCIITIS and DISABLING PANSCLEROTIC MORPHOEA OF CHILDREN (Chapter 55).
• Although classic morphoea often extends from the deep dermis to the subcutis, morphoea is SOMETIMES AN ENTIRELY PANNICULITIC PROCESS with NO involvement of the epidermis, cutaneous adnexa or dermis — known variously as morphoea profunda, NODULAR SCLERODERMA or KELOIDAL SCLERODERMA.

• MARKED FIBROUS THICKENING OF THE SEPTA of subcutaneous fat.
• As a consequence, collagen also REPLACES THE FAT normally present around and below the ECCRINE COILS, giving the MISLEADING IMPRESSION THAT THE SWEAT GLANDS HAVE ASCENDED INTO THE DERMIS.
• When the sclerotic process involves both dermis and subcutis, the full thickness of the specimen appears HOMOGENEOUSLY EOSINOPHILIC.
• Inflammatory infiltrate is present ONLY IN ACTIVE LESIONS — aggregates of LYMPHOCYTES surrounded by PLASMA CELLS at the INTERFACE between the thickened septa and the fat lobules; plasma cells may also be arranged interstitially between sclerotic collagen bundles.
• Active lesions of DEEP morphoea usually show a DENSER infiltrate than DERMAL morphoea.

Eosinophilic fasciitis (Shulman syndrome)

• Regarded as a variant of deep morphoea in which the thick, sclerotic septa AND THE FASCIA show an infiltrate of lymphocytes, histiocytes, plasma cells and ABUNDANT NUMBERS OF EOSINOPHILS.
• EARLY stages: oedema and infiltration by eosinophils, lymphocytes and plasma cells between the collagen bundles of the connective tissue septa AND SUBCUTANEOUS FASCIA; lymphoid aggregates may be present.
• LATER stages: fibrosis and hyalinisation.
• The presence of EOSINOPHILS IN THE BLOOD AND FASCIA and a FOCAL LOSS OF CD34 STAINING are MORE SUGGESTIVE OF EOSINOPHILIC FASCIITIS than deep morphoea.

Disabling pansclerotic morphoea in children

• An AGGRESSIVE clinical variant appearing BEFORE 14 YEARS OF AGE — although adult onset has also been described.
• Involves not only the full thickness of the skin, but also the SUBCUTANEOUS TISSUES, MUSCLE AND BONE.
• Histopathology: SCLEROTIC REPLACEMENT of the full thickness of the dermis and subcutaneous fat, extending to the underlying FASCIA; in active lesions a variable infiltrate of LYMPHOCYTES and PLASMA CELLS between the sclerotic collagen bundles.

• In patients with progressive disease and disseminated forms, SYSTEMIC therapy is indicated.
• Most commonly used: COMBINATIONS OF PULSED INTRAVENOUS AND/OR ORAL STEROIDS WITH METHOTREXATE as the FIRST LINE treatment.

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• A rare clinicopathological variant of granuloma annulare characterised by subcutaneous nodules that may appear alone or in association with the classic dermal papular lesions.
• Typically presents in CHILDREN OR YOUNG ADULTS (Chapter 95).

• Proposed mechanisms: an IMMUNOGLOBULIN-MEDIATED VASCULITIS for the necrobiotic areas (although direct immunofluorescence FAILED to demonstrate immune deposits within the vessel walls); a CELL-MEDIATED immune response with increased HELPER/INDUCER T CELLS and CD1a-POSITIVE LANGERHANS CELLS; a Th1 inflammatory reaction with IFN-γ-producing lymphocytes eliciting MATRIX DEGRADATION; increased collagen synthesis; and elastic tissue degeneration.
• Inflammatory cells release cytokines including MACROPHAGE INHIBITOR FACTOR, causing histiocytes to accumulate in the necrobiotic areas and release LYSOSOMAL ENZYMES resulting in degenerate connective tissue.
• Usually a TRUE PANNICULITIC process with NO dermal involvement, although in 25% of patients subcutaneous nodular lesions COEXIST with the classic presentation of superficial papules.
• In rare instances may extend to involve DEEPER SOFT TISSUES, producing a DESTRUCTIVE ARTHRITIS AND LIMB DEFORMITY.

• Areas of BASOPHILIC DEGENERATION of collagen bundles with PERIPHERAL PALISADING GRANULOMAS involving the CONNECTIVE TISSUE SEPTA of the subcutis.
• Usually the areas of collagen degeneration are LARGER than in the dermal counterpart.
• Central necrobiotic areas contain increased CONNECTIVE TISSUE MUCIN and NUCLEAR DUST FROM NEUTROPHILS between the degenerated collagen bundles.
• ELASTIC TISSUE IS USUALLY ABSENT within the foci of degenerate collagen.
• Peripheral ring composed of epithelioid histiocytes in a PALISADE fashion; multinucleated giant cells may be seen.
• EOSINOPHILS are MORE COMMON in SUBCUTANEOUS granuloma annulare than in the dermal superficial lesions.
• The INTERSTITIAL histopathological variant (histiocytes interstitially arranged between collagen bundles, with mucin deposition but NO areas of degenerate collagen) — MORE FREQUENT than the necrobiotic one in DERMAL lesions — HAS YET TO BE DESCRIBED IN SUBCUTANEOUS granuloma annulare; all reported patients with deep forms showed the CLASSIC PALISADING NECROBIOTIC pattern.
• Immunohistochemistry: intense expression of CD68/PGM1 in the histiocytic population and variable LYSOZYME; T-cell markers (CD3, CD4, CD8) mainly in the perivascular lymphocytic infiltrate, with CD4+ predominating over CD8+.

• RHEUMATOID NODULE: in contrast to subcutaneous GA, which exhibits a PALE AND MUCINOUS centre with a tendency to be BASOPHILIC, the central necrobiotic areas of rheumatoid nodules appear HOMOGENEOUS AND EOSINOPHILIC WITH ABUNDANT FIBRIN DEPOSITS. Sometimes the differential may be IMPOSSIBLE on histopathological grounds alone. OLD rheumatoid nodules may show extensive FIBROSIS in which necrobiotic areas persist.
• NECROBIOSIS LIPOIDICA: involves the FULL THICKNESS of the dermis, subcutaneous involvement being just a deep extension. PLASMA CELLS, aggregations of histiocytes and multinucleated giant cells are MORE COMMON in necrobiosis lipoidica. In late stages there is extensive fibrosis and degenerate collagen is NO LONGER SEEN.
• EPITHELIOID SARCOMA (Ch 136): a NEOPLASTIC process in which central areas of degenerate collagen are surrounded by epithelioid cells with HYPERCHROMATIC AND PLEOMORPHIC nuclei, some showing ATYPICAL MITOTIC FIGURES.
• Immunohistochemistry: the neoplastic cells express LOW- AND HIGH-MOLECULAR-WEIGHT CYTOKERATINS, EPITHELIAL MEMBRANE ANTIGEN and CD34; furthermore, their nuclei show NO EXPRESSION OF INTEGRASE INTERACTOR 1.

• Because lesions may regress spontaneously, assessment of treatment efficacy is difficult.
• INTRALESIONAL CORTICOSTEROIDS are the FIRST CHOICE for solitary symptomatic lesions.

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• One of the EXTRA-ARTICULAR manifestations of RHEUMATOID ARTHRITIS.
• Usually found in proximity to JOINTS or EXTENSOR SURFACES and other areas subjected to MECHANICAL PRESSURE; can also develop elsewhere, including in the PLEURA and MENINGES.
• Nodules vary in size and consistency and are RARELY symptomatic (Chapter 155).

• Pathogenesis remains UNKNOWN.
• Because lesions develop at sites of trauma and pressure, MECHANICAL FACTORS have been postulated.
• Genetic factor: patients with HLA-DRB1 present with SEVERE rheumatoid arthritis and FREQUENT rheumatoid nodules, whereas those with HLA-DRw2 have MILD articular disease and INFREQUENT nodules.
• MICROCHIMERISM has been demonstrated in ALMOST 50% of cases of rheumatoid nodules in RA patients — since microchimerism is genetically disparate, it may serve as an ALLOGENEIC STIMULUS OR ALLOGENEIC TARGET.
• Pro-inflammatory cytokines and cell adhesion molecules are VERY SIMILAR in rheumatoid nodules and the SYNOVIAL LINING in rheumatoid joints.
• Cytokine profile within the nodule: presence of IFN-γ, but NOT IL-2, and prominent expression of IL-1β and TNF-α together with IL-12, IL-18, IL-15 and IL-10 — supporting that nodule formation is DRIVEN BY Th1 LYMPHOCYTES.
• An IMMUNE COMPLEX-mediated mechanism also postulated: IgG and IgM detected by direct immunofluorescence in the VESSEL WALLS, suggesting a vasculitic process.
• Mechanism for central collagen degeneration unknown. Although APOPTOSIS has been demonstrated throughout the entire nodule, it seems that PROTEASES, COLLAGENASES and other chemotactic factors (e.g. GM-CSF and FIBRONECTIN) secreted by lesional MONOCYTES AND MACROPHAGES are the MAIN FACTORS inducing collagen degeneration, mucin deposition and palisading granuloma formation.

• Varies with the AGE of the lesion.
• EARLY: microscopic features of GRANULATION TISSUE surrounded by MONONUCLEAR CELLS AND FIBROBLASTS.
• LATER: central area of degenerate collagen ADMIXED WITH FIBRINOID MATERIAL, surrounded by a PALISADE OF ELONGATED MONONUCLEAR HISTIOCYTES.
• The inner central degenerated zone appears as INTENSELY EOSINOPHILIC AMORPHOUS, GRANULAR OR FIBRILLARY MATERIAL containing COLLAGEN FIBRILS, FIBRIN AND CELLULAR DEBRIS.
• Multinucleated giant cells, T lymphocytes, plasma cells, mast cells and eosinophils may be seen at the periphery.
• Uncommonly, features of ACUTE VASCULITIS described in surrounding vessels; sometimes a necrotic blood vessel with nuclear debris and sparse neutrophils at the CENTRE of necrobiotic areas — probably representing SECONDARY vasculitis.
• In rare instances, SUPERFICIAL nodules may PERFORATE THE EPIDERMIS.
• LONGSTANDING nodules exhibit EXTENSIVE FIBROSIS in which CLEFTS AND CYSTIC DEGENERATION appear due to LIQUEFACTIVE DEGENERATION of the contents.

• Development of NEW PAINFUL rheumatoid nodules in patients with CHRONIC RA under treatment with METHOTREXATE.
• New nodules develop preferentially on the HANDS, FEET AND EARS.
• Individual susceptibility: develops more frequently in patients with HLA-DRB1 and SEROPOSITIVE RA.
• Genetically predisposed patients appear to be PROTECTED by CONCOMITANT ADMINISTRATION of HYDROXYCHLOROQUINE, D-PENICILLAMINE, COLCHICINE or SULFASALAZINE.
• Pathogenesis unknown, although an ADENOSINE A1 RECEPTOR promotion of MULTINUCLEATED GIANT CELL FORMATION by human monocytes has been postulated.
• NOT exclusively related to METHOTREXATE — identical lesions reported with azathioprine, etanercept, infliximab, leflunomide and tocilizumab.
• NOT found exclusively in RA — similar lesions described in PSORIATIC ARTHRITIS and SYSTEMIC LUPUS ERYTHEMATOSUS; also in SEROPOSITIVE, POLYARTHRITIC-ONSET JUVENILE rheumatoid arthritis after methotrexate.
• In all these patients the condition causes MINIMAL SYMPTOMS and REGRESSES after methotrexate is withdrawn; it RECURS when methotrexate is reintroduced.

• Palisading necrobiotic granulomas have been classified into "BLUE" and "RED" granulomas according to the colour of the central area on H&E:
• BLUE granulomas: BASOPHILIC centre due to MUCIN deposition and the presence of NEUTROPHILS AND NUCLEAR DUST — usually SUBCUTANEOUS GRANULOMA ANNULARE.
• RED granulomas: EOSINOPHILIC necrobiotic central area due to FIBRIN deposition — predominantly RHEUMATOID NODULES.
• Necrobiosis lipoidica usually shows a MORE FIBROTIC pattern and the process ALWAYS INVOLVES THE DERMIS.

• Cutaneous nodules often wax and wane with treatment of the associated RA.
• RITUXIMAB has proved to be a beneficial treatment.
• Intralesional corticosteroids may be indicated in solitary symptomatic lesions.
• It must be remembered that some drugs — including METHOTREXATE and ANTI-TNF agents — may EXACERBATE the lesions (accelerated rheumatoid nodulosis).

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• A rare histiocytic disorder causing PROGRESSIVE DESTRUCTION of the involved cutaneous and extracutaneous tissues.
• Most commonly presents as multiple, indurated, YELLOW-RED or VIOLACEOUS plaques or nodules, preferentially involving PERIORBITAL skin.
• PARAPROTEINAEMIA is detected in 82.1% of patients — MOST OFTEN IgG-κ — and a MALIGNANT CONDITION in 25.1%, most often MULTIPLE MYELOMA (Chapter 135).

• Poorly understood. Proposed mechanisms:
• The monoclonal paraprotein BEHAVES AS A LIPOPROTEIN, binding to MONOCYTE LIPOPROTEIN RECEPTORS to form xanthomas.
• Intracellular accumulation of lipoprotein-derived lipids in skin macrophages may result from activation of monocytes, with both the paraprotein and immune complexes inducing granuloma formation.
• The central areas of necrobiosis may be the consequence of ISCHAEMIA.
• An increase in circulating MACROPHAGE COLONY-STIMULATING FACTOR (M-CSF) activates monocytes and favours accumulation of large amounts of lipid and xanthoma formation.
• Finding of Borrelia organisms in SIX OF SEVEN cases using FOCUS-FLOATING MICROSCOPY has led some authors to propose an INFECTIOUS aetiology.

• NOT a true panniculitis but a DEEPER EXTENSION OF A PREDOMINANTLY DERMAL PROCESS.
• Diffuse involvement of the DERMIS by FOAMY HISTIOCYTES and some TOUTON-LIKE MULTINUCLEATED GIANT CELLS; from the dermis the infiltrate extends through the connective tissue septa of the subcutis and underlying soft tissues.
• Areas of degenerate collagen bundles and CHOLESTEROL CLEFTS are often seen within the diffuse infiltrate.
• A PALISADING GRANULOMA of epithelioid histiocytes is present, AT LEAST FOCALLY, around the areas of degenerate collagen.
• LYMPHOID AGGREGATES, sometimes with GERMINAL CENTRE formation, and NUMEROUS PLASMA CELLS at the periphery are often seen around the deeper areas of collagen degeneration.
• Although the infiltration is diffuse, some cases exhibit a MULTINODULAR pattern.
• Immunohistochemistry: histiocytes and foamy macrophages express LYSOZYME, CD68, CD163 and CD11b; in one case intense histiocytic expression of CD10.
• Although frequently associated with paraproteinaemia, the SKIN LESIONS REPRESENT REACTIVE INFLAMMATION because the PLASMA CELLS in the cutaneous lesions are POLYCLONAL.
• VASCULITIS is not usually seen, although some lesions may show leukocytoclasis and thrombosis.
• TRANSEPIDERMAL and TRANSFOLLICULAR ELIMINATION of degenerate collagen and cholesterol clefts reported.
• Reports of granuloma annulare with subsequent evolution into necrobiosis lipoidica or necrobiotic xanthogranuloma raise the possibility of a general granulomatous process accompanying paraproteinaemia.
• Coexistence of NORMOLIPAEMIC PLANE XANTHOMA and necrobiotic xanthogranuloma in the same patient suggests these represent part of a SPECTRUM of xanthomatous dermal reactions associated with paraproteinaemia.

• Subcutaneous granuloma annulare: occurs mainly in CHILDREN and does NOT tend to ULCERATE; MUCIN deposits evident at the centre of degenerate collagen; LYMPHOID FOLLICLES AND CHOLESTEROL CLEFTS ARE ABSENT.
• Necrobiosis lipoidica: may extend to subcutaneous tissue, making the differential challenging — however XANTHOMATISATION, LYMPHOID FOLLICLES AND CHOLESTEROL CLEFTS ARE LESS FREQUENTLY SEEN.
• Juvenile xanthogranuloma and deep xanthomas: do NOT show LARGE AREAS OF DEGENERATE COLLAGEN.

• Due to rarity there is NO consensus regarding optimal treatment.
• Therapies directed to the associated paraproteinaemia have shown variable cutaneous response.
• MELPHALAN, with or without PREDNISOLONE, achieved temporary improvement.
• Intralesional corticosteroids, chlorambucil, IFN-α, cyclophosphamide, methotrexate, hydroxychloroquine, azathioprine, intravenous immunoglobulin and thalidomide used in isolated cases with variable results.
• More aggressive therapies — RADIOTHERAPY and CARBON DIOXIDE LASER — should be considered in individual cases.

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• THE MOST COMMON PANNICULITIS. Usually ACUTE onset and SELF-LIMITED course.
• Sudden eruption of several RED, TENDER, NON-ULCERATING nodules and plaques, typically located on the SHINS.
• Normally resolves SPONTANEOUSLY WITHOUT ULCERATION, SCARRING OR ATROPHY, but RECURRENT episodes are common.
• A cutaneous REACTIVE PROCESS triggered by a wide variety of infectious and inflammatory disorders and, less commonly, by malignant neoplasms and medications.
• The MOST COMMON triggers are BACTERIAL INFECTIONS, SARCOIDOSIS and INFLAMMATORY BOWEL DISEASE.

• Population prevalence in a semirural area of England over a 2-year period: 2.4 CASES PER 1000 POPULATION PER YEAR.
• Accounted for about 0.5% of new cases seen in departments of dermatology in England, and about 0.38% of all patients seen in a department of internal medicine in Spain.
• Average annual incidence of BIOPSY-PROVEN erythema nodosum in persons aged ≥14 years at a hospital in NORTHWESTERN SPAIN: 52 CASES PER MILLION population served — almost certainly an UNDERESTIMATE as only biopsy-confirmed cases were included.
• MOST cases occur within the FIRST HALF OF THE YEAR — probably due to increased frequency of STREPTOCOCCAL infections in this period.
• NO difference in incidence between URBAN and RURAL areas.
• Familial cases are usually attributable to infection; simultaneous occurrence in MONOZYGOTIC TWIN SISTERS has been reported.
• Age: may occur at any age, but MOST cases appear between the SECOND AND FOURTH DECADES, with the PEAK between 20 and 30 years — probably due to the high incidence of SARCOIDOSIS at this age.
• Sex: occurs THREE TO SIX TIMES MORE FREQUENTLY IN WOMEN than in men — although the incidence BEFORE PUBERTY is approximately EQUAL in both genders.
• Associated diseases: concomitant presentation of SWEET SYNDROME and erythema nodosum repeatedly reported.
• Simultaneous occurrence associated with sarcoidosis, throat infection, acute myelogenous leukaemia and Crohn disease.
• Described in UP TO 15–30% of patients in some series of biopsy-proven erythema nodosum — suggesting a COMMON UNDERLYING PATHOGENETIC MECHANISM for both processes.

(Most well-documented associations shown in bold in the source.)

BACTERIAL INFECTIONS: Atypical mycobacterial infections; Bartonella henselae; Borrelia burgdorferi; Boutonneuse fever; Brucellosis; Campylobacter; Cat-scratch disease; Chancroid; Chlamydia psittaci; Chlamydophila pneumoniae; Corynebacterium diphtheriae; Escherichia coli; Gonorrhoea; Klebsiella pneumoniae; Leprosy; Leptospirosis; Lymphogranuloma venereum; Melioidosis; Meningococcaemia; Moraxella catarrhalis; Mycoplasma pneumoniae; Pasteurella pseudotuberculosis; Propionibacterium acnes; Pseudomonas aeruginosa; Q fever; Rickettsiae; Salmonella; Shigella; Staphylococcus xylosus; STREPTOCOCCAL INFECTIONS; Syphilis; TUBERCULOSIS; Tularaemia; Yersinia

VIRAL INFECTIONS: COVID-19; Cytomegalovirus; Epstein–Barr virus after living-donor liver transplantation; Hepatitis B; Hepatitis C; Herpes simplex; HIV; Infectious mononucleosis; Measles; Orf; Parvovirus B19; Varicella

FUNGAL INFECTIONS: Aspergillosis; Blastomycosis; Coccidioidomycosis; Dermatophytes; Histoplasmosis; Sporotrichosis

PROTOZOAL INFECTIONS: Amoebiasis; Ascariasis; Giardiasis; Hookworm infestation; Hydatidosis; Sparganum larva; Toxoplasmosis; Trichomoniasis; Visceral larva migrans

DRUGS (selected): acetaminophen; actinomycin-D; all-trans retinoic acid; aminopyrine; amiodarone; amoxicillin; ampicillin; antimony; arsphenamine; azathioprine; BRAF inhibitors; bromides; busulfan; cabergoline; capecitabine; carbamazepine; carbenicillin; carbimazole; cefdinir; certolizumab; chlordiazepoxide; chlorotrianisene; chlorpropamide; ciprofloxacin; clomiphene; codeine; cotrimoxazole; D-penicillamine; dabrafenib and trametinib; dapsone; diclofenac; dicloxacillin; diethylstilbestrol; disopyramide; echinacea herbal therapy; enoxacin; erythromycin; etanercept; everolimus; fluoxetine; furosemide; glatiramer acetate; glucagon; gold salts; granulocyte colony-stimulating factor; hepatitis B vaccine; HPV vaccine; hydralazine; ibuprofen; imatinib mesylate; indomethacin; infliximab; interleukin-2; iodides; ipilimumab; isotretinoin; leukotriene modifying agents (zileuton, zafirlukast); levofloxacin; lidocaine; meclofenamate; medroxyprogesterone; meprobamate; mesalamine; methicillin; methimazole; methyldopa; mezlocillin; minocycline; naproxen; nifedipine; nitrofurantoin; nivolumab; norethindrone acetate/ethinyl estradiol/ferrous fumarate; oestrogens; ofloxacin; olaparib; omeprazole; ORAL CONTRACEPTIVES; oxacillin; paroxetine; penicillin; phenylbutazone; phenytoin; piperacillin; progestins; propylthiouracil; pyritinol; rabies vaccine; serotonin reuptake inhibitors; sparfloxacin; streptomycin; sulfamethoxazole; sulfasalazine; sulfisoxazole; SULFONAMIDES; thalidomide; ticarcillin; trimethoprim; typhoid vaccination; valproate; vedolizumab; verapamil

MALIGNANT DISEASES: adenocarcinoma of the colon; carcinoid tumour; carcinoma of the uterine cervix; hepatocellular carcinoma; Hodgkin disease; leukaemia; lung cancer; myelodysplastic syndrome; non-Hodgkin lymphoma; pancreatic carcinoma; parathyroid carcinoma; post-radiotherapy for pelvic carcinoma; renal carcinoma; sarcoma; stomach cancer

MISCELLANEOUS DISEASES: acne fulminans; acupuncture therapy and flu-like infection; adult-onset Still disease; ankylosing spondylitis; antiphospholipid antibody syndrome; autoimmune atrophic gastritis; BEHÇET DISEASE; breast abscesses; chronic active hepatitis; coeliac disease; colon diverticulosis; CROHN DISEASE; cryopyrin-associated periodic syndrome; diverticulitis; eosinophilic oesophagitis; exercise; GATA-2 deficiency; granulomatosis with polyangiitis; granulomatous mastitis; IgA nephropathy; immune-mediated necrotising myopathy; intestinal bypass syndrome; jellyfish sting; Kawasaki disease; large-vessel giant cell arteritis; lupus erythematosus; polyarteritis nodosa; pregnancy; primary biliary cirrhosis; radiotherapy; reactive arthritis; relapsing polychondritis; rheumatoid arthritis; SARCOIDOSIS; Sjögren syndrome; smoke inhalation in a house fire; Sweet syndrome; SLE-like syndrome due to C4 deficiency; Takayasu arteritis; ULCERATIVE COLITIS; Vogt–Koyanagi disease; Whipple disease

• Aetiological factors show considerable GEOGRAPHICAL VARIATION related to specific ENDEMIC INFECTIONS.
• In EUROPE: streptococcal infections, sarcoidosis and inflammatory bowel disease are important causes.
• In a significant percentage of cases (RANGING BETWEEN 37% AND 60% in reported series), the aetiology CANNOT BE DETERMINED despite extensive clinical and laboratory investigation.
• STREPTOCOCCAL: a previous upper respiratory infection by GROUP A β-HAEMOLYTIC Streptococcus is a frequent cause in children and young adults.
• Nodules usually develop 2–3 WEEKS AFTER the throat infection, accompanied by elevation of the ANTISTREPTOLYSIN O (ASO) TITRE.
• By the time cutaneous lesions appear, THROAT SWAB CULTURES USUALLY FAIL TO DETECT MICROORGANISMS.
• TUBERCULOSIS: a common cause in areas of HIGH ENDEMICITY — used to apply to many parts of Europe but NO LONGER does so.
• Presents mainly in CHILDREN at the time of PRIMARY PULMONARY INFECTION and CONCOMITANT WITH THE CONVERSION OF THE TUBERCULIN TEST.
• MEDICATIONS: real pathogenetic role difficult to establish with confidence.
• Historically SULFONAMIDES, BROMIDES and ORAL CONTRACEPTIVE PILLS were most commonly associated.
• ORAL CONTRACEPTIVE PILLS have become a RARE cause since their OESTROGEN CONTENT WAS GREATLY REDUCED.
• Where EN arises in patients receiving antibiotics for infections, it is difficult to discern whether the reaction is due to the ANTIBIOTIC or the INFECTIOUS process.
• SARCOIDOSIS: one of the commonest disorders associated with EN in adults.
• Hilar adenopathy + arthritis around the ankles + erythema nodosum = LÖFGREN SYNDROME.
• However, EN and BILATERAL HILAR ADENOPATHY do NOT occur EXCLUSIVELY in sarcoidosis — also seen in lymphomas, tuberculosis, streptococcal infections, coccidioidomycosis, histoplasmosis and acute infections by Chlamydophila pneumoniae.
• INFLAMMATORY BOWEL DISEASE: in adults, EN is often associated with a FLARE — although the eruption may sometimes PRECEDE the bowel disease. CROHN DISEASE is MORE frequently associated than ULCERATIVE COLITIS.
• Most probably EN results from IMMUNE COMPLEX DEPOSITION IN AND AROUND VEINS of the connective tissue septa of the subcutis.
• Supported by demonstration of CIRCULATING IMMUNE COMPLEXES, COMPLEMENT ACTIVATION and DEPOSITS OF IMMUNOGLOBULINS in the blood vessel walls of the septa.
• However, some investigators FAILED to demonstrate circulating immune complexes, and a TYPE IV DELAYED HYPERSENSITIVITY reaction has been proposed.
• REACTIVE OXYGEN INTERMEDIATES (ROIs): patients have a FOURFOLD HIGHER percentage of ROIs produced by activated neutrophils in peripheral blood compared with healthy volunteers.
• The percentage of ROI-producing cells CORRELATES WITH CLINICAL SEVERITY; ROIs may act by oxidative tissue damage and by promoting tissue inflammation.
• Genetic polymorphisms:
• Patients with SARCOIDOSIS-associated EN secrete an UNCOMMON TNF-α II due to a nucleotide exchange (G→A) at position −308 in the human TNF-α gene promoter — patients with EN WITHOUT underlying sarcoidosis do NOT have this anomaly.
• Polymorphism of the macrophage MIF gene at position −173 is associated with a significantly increased risk of DEVELOPING SARCOIDOSIS in patients with EN.
• CYTOKINES: pro-inflammatory pattern (both infectious and non-infectious related) characterised by RAISED IL-6 SERUM CONCENTRATIONS.
• HIGH expression of Th1 cytokines (IL-2 and IFN-γ) demonstrated in most skin lesions and in peripheral blood — a POLARISED Th1 IMMUNE RESPONSE occurs REGARDLESS of the wide variety of provoking agents.
• ADIPOCYTES play an important role in ACTIVATING inflammatory and adaptive immune systems, destroying pathogens through secretion of multiple ADIPOKINES and ADIPOCYTOKINES — this may explain why BOTH COCCIDIOIDOMYCOSIS AND SARCOIDOSIS appear LESS SEVERE and of SHORTER DURATION in patients who develop EN, especially if they are carriers of the HLA-DRB1\03-POSITIVE leukocyte antigen.

• THE PROTOTYPE OF A PREDOMINANTLY SEPTAL PANNICULITIS WITHOUT VASCULITIS.
• Connective tissue septa appear THICKENED AND OEDEMATOUS, infiltrated by inflammatory cells mainly at the INTERFACE between the septa and the fat lobule.
• Usually a mild superficial and deep perivascular infiltrate of predominantly LYMPHOCYTES in the overlying dermis.
• EARLY lesions (<48 h): oedema and haemorrhage at the septa and numerous NEUTROPHILS arranged INTERSTITIALLY between collagen bundles.
• In some early lesions most cells are "HISTIOCYTOID" cells — in fact IMMATURE NEUTROPHILS similar to those in histiocytoid Sweet syndrome.
• If the infiltrate extends to the periphery of the fat lobule surrounding individual adipocytes in a LACE-LIKE fashion, the process may be MISINTERPRETED as a predominantly lobular panniculitis — HOWEVER, in contrast with a TRUE lobular panniculitis, NECROSIS OF THE ADIPOCYTES AT THE CENTRE OF THE FAT LOBULE IS NEVER SEEN IN ERYTHEMA NODOSUM.
• In rare instances EOSINOPHILS may be numerous in early lesions — this does NOT correlate with any specific aetiological factor.
• HISTOPATHOLOGICAL HALLMARK: MIESCHER RADIAL GRANULOMAS — small, well-defined NODULAR AGGREGATES of small HISTIOCYTOID CELLS around a CENTRAL STELLATE or BANANA-SHAPED CLEFT.
• The nature of the central cleft is UNKNOWN; although some considered them lymphatic spaces, immunohistochemical and ultrastructural studies FAILED to demonstrate any ENDOTHELIAL CELL LINING.
• EARLY lesions: granulomas scattered in the septa, surrounded by NEUTROPHILS.
• OLDER nodules: histiocytic cells group to form MULTINUCLEATED GIANT CELLS, many of which STILL RETAIN the stellate central cleft.
• Sometimes conspicuous; occasionally SERIAL SECTIONS are required — if carefully sought they can be found in ALMOST ALL STAGES, and such a search should ALWAYS be undertaken to establish a specific diagnosis.
• Some authors consider similar granulomas may be found in SUBCUTANEOUS SWEET SYNDROME, ERYTHEMA INDURATUM OF BAZIN, BEHÇET DISEASE and NECROBIOSIS LIPOIDICA.
• Recent immunohistochemistry: cells around the central clefts express MPO, similar to the small, elongated, twisted-appearing mononuclear cells in histiocytoid Sweet syndrome — demonstrating these are IMMATURE MYELOID CELLS, providing a LINK BETWEEN ERYTHEMA NODOSUM AND SWEET SYNDROME.
• LATE-STAGE lesions: SEPTAL FIBROSIS and PERISEPTAL GRANULATION TISSUE, partially replacing the fat lobules, with an infiltrate of lymphocytes, histiocytes and multinucleated giant cells.
• Despite this fibrotic process, it is STRIKING that erythema nodosum RESOLVES COMPLETELY after some weeks or months.
• VASCULITIS is NOT normally seen at ANY stage, although in rare cases a necrotising small-vessel vasculitis with fibrinoid necrosis of the small vessels in the septa has been described.
• In a detailed study of 79 cases, TRUE LEUKOCYTOCLASTIC VASCULITIS WAS NOT FOUND.
• Cases described as "EN with lobular neutrophilic panniculitis and vasculitis involving medium-size arteries" are BETTER INTERPRETED AS EXAMPLES OF STP, because the involved vessels were MEDIUM-SIZE VEINS rather than arteries.
• Ultrastructural studies have ALSO failed to demonstrate true vasculitis.
• LIPOMEMBRANOUS or MEMBRANOCYSTIC panniculitis and ENCAPSULATED FAT NECROSIS ("mobile encapsulated lipoma") may be seen in late-stage lesions.

• Sudden onset of SYMMETRICAL, BILATERAL, TENDER, RED, WARM nodules and RAISED PLAQUES usually involving the SHINS, ANKLES and KNEES.
• Nodules range from 1 to 5 cm or more in diameter and may become CONFLUENT resulting in red plaques.
• Occasionally lesions appear in other areas — thighs, extensor aspects of the arms, neck and even the FACE.
• Evolution of colour:
• EARLY: bright red, raised slightly above the skin.
• After a few days: flat, with a LIVID RED OR PURPLISH colour.
• Finally: YELLOW OR GREENISH appearance, often taking on the look of a DEEP BRUISE — hence the classic name "ERYTHEMA CONTUSIFORMIS".
• Nodules NEVER ULCERATE and lesions regress WITHOUT ATROPHY OR SCARRING.
• Acute bouts often associated with fever of 38–39°C, fatigue, malaise, arthralgia, headache, abdominal pain, vomiting, cough or diarrhoea.
• EPISCLERAL lesions and PHLYCTENULAR CONJUNCTIVITIS may also accompany the cutaneous lesions.
• Rare associated manifestations: lymphadenopathy, hepatomegaly, splenomegaly and pleuritis.
• The eruption persists for 3–6 WEEKS and regresses leaving NO RESIDUAL MARKS. RECURRENCES ARE COMMON.
• Duration in CHILDREN is SHORTER than in adults, and ARTHRALGIAS AND FEVER ARE LESS FREQUENT in paediatric cases.

• ERYTHEMA NODOSUM MIGRANS, SUBACUTE NODULAR MIGRATORY PANNICULITIS OF VILANOVA AND PIÑOL, and CHRONIC ERYTHEMA NODOSUM are now all thought to be expressions of DIFFERENT STAGES OF THE EVOLUTION of erythema nodosum rather than SEPARATE ENTITIES.
• In CHILDREN, a RARE variant characterised by UNILATERAL RED NODULES involving the PALMS OR SOLES appearing AFTER PHYSICAL ACTIVITY — histopathology shows features of classic erythema nodosum.

• Patients with BEHÇET DISEASE may present with eruptions clinically resembling EN.
• However, histopathology demonstrates these are NOT erythema nodosum but show a PREDOMINANTLY LOBULAR panniculitis with LEUKOCYTOCLASTIC OR LYMPHOCYTIC VASCULITIS.
• Furthermore, the frequency of THROMBOPHLEBITIS is HIGHER in the EN-like lesions of Behçet disease compared with idiopathic EN.

• A rational, COST-EFFECTIVE diagnostic approach should be initiated.
• Complete clinical history: previous diseases, medications, foreign travel, pets and hobbies, and possible familial cases.
• Initial laboratory investigations: complete blood count, erythrocyte sedimentation rate, ASO titre, urinalysis, throat culture, intradermal tuberculin test and/or chest X-ray.
• When the aetiology is unclear: serological tests for those bacterial, viral, fungal or protozoal infections MOST PREVALENT IN THE AREA.
• Tuberculin test results must be evaluated in the context of LOCAL PREVALENCE — where TB is endemic, a significant percentage of HEALTHY ADULTS show POSITIVE results. A STRONGER relationship with tuberculosis may be established using an IFN-γ RELEASE ASSAY.
• When clinical and laboratory findings are characteristic, a TENTATIVE diagnosis may be established — but DIAGNOSTIC CONFIRMATION REQUIRES BIOPSY.

• Most cases regress SPONTANEOUSLY in 3–4 WEEKS, but RELAPSES are common.
• Recurrent episodes are MORE FREQUENT in patients with IDIOPATHIC erythema nodosum and EN associated with STREPTOCOCCAL upper respiratory tract infections.
• Complications are uncommon — described: RETROBULBAR OPTIC NERVE NEURITIS during the acute episode; and EN coexisting with erythema multiforme, lichen planus and concomitant REACTIVATION OF HEPATITIS C VIRAL REPLICATION.
• Treatment primarily includes IDENTIFICATION AND MANAGEMENT OF THE UNDERLYING CAUSE, especially if infectious.
• Limiting physical exercise and BED REST should be recommended.
• ASPIRIN and other NSAIDs — e.g. indometacin 100–150 mg daily or naproxen 500 mg daily — are helpful for pain and for hastening resolution.
• NSAIDs are CONTRAINDICATED in patients with INFLAMMATORY BOWEL DISEASE.
• In more persistent cases: POTASSIUM IODIDE 400–900 mg daily, or a saturated solution of potassium iodide, 2–10 DROPS in water or orange juice THREE TIMES PER DAY.
• Mechanism unknown, but it probably induces MAST CELLS to release HEPARIN, which suppresses delayed hypersensitivity reactions — supported by the reported response to HEPARINOID OINTMENT UNDER OCCLUSION. Potassium iodide also INHIBITS NEUTROPHIL CHEMOTAXIS.
• POTASSIUM IODIDE IS CONTRAINDICATED DURING PREGNANCY because it may induce GOITRE IN THE FETUS.
• SEVERE HYPOTHYROIDISM secondary to exogenous iodide intake has also been described in EN patients treated with potassium iodide.
• SYSTEMIC CORTICOSTEROIDS are NOT usually indicated and SHOULD NOT BE COMMENCED UNLESS AN INFECTIOUS AETIOLOGY HAS BEEN EXCLUDED.
• When administered, prednisolone 40 mg/day is followed by resolution of the nodules in a FEW DAYS.
• Intralesional triamcinolone acetonide 10 mg/mL into the centre of the nodules may help in solitary persistent lesions.
• Some patients respond to COLCHICINE 0.6–1.2 mg twice a day and to HYDROXYCHLOROQUINE 200 mg twice a day.
• Cases have responded to anti-TNF biological agents — ETANERCEPT, ADALIMUMAB and INFLIXIMAB in patients treated with these drugs for inflammatory bowel disease.
• PARADOXICALLY, HOWEVER, ETANERCEPT AND INFLIXIMAB HAVE BEEN REPORTED TO PRODUCE ERYTHEMA NODOSUM AS A CUTANEOUS SIDE EFFECT.

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• A TYPE II LEPROSY REACTION characterised by a NECROTISING VASCULITIS involving SMALL- TO MEDIUM-SIZE VESSELS of the DEEP DERMIS AND SUBCUTIS.
• Provoked by an IMMUNE COMPLEX-MEDIATED response to the RELEASE OF MYCOBACTERIAL ANTIGENS FROM EFFETE BACILLI in patients with MULTIBACILLARY leprosy (LEPROMATOUS and BORDERLINE LEPROMATOUS), usually AFTER INITIATION OF TREATMENT (Chapter 28).
• Type II reactions are due to formation and deposit of IMMUNE COMPLEXES in association with EXCESSIVE HUMORAL REACTION — tissue expression of cytokines is mostly IL-4 and IL-10.
• During this reaction patients show an INCREASED CD4/CD8 RATIO due to an increase in T-helper and a decrease in T-suppressor lymphocytes, accompanied by a specific increase in Th2 lymphocytes, which induce plasma cell proliferation and release of immunoglobulins.
• Patients show a TEMPORARY RECOVERY OF LANGERHANS CELL ANTIGEN-PRESENTING FUNCTION, which is DIRECTLY PROPORTIONAL TO THE SEVERITY of the leprosy reaction.
• THE TERM "ERYTHEMA NODOSUM LEPROSUM" IS INADEQUATE because it may be confused with true erythema nodosum (the prototype of septal panniculitis WITHOUT vasculitis) — erythema nodosum leprosum is a PREDOMINANTLY LOBULAR PANNICULITIS WITH VASCULITIS involving the LARGE VESSELS of the subcutis.

• EARLY nodules: oedema of the PAPILLARY DERMIS and a NEUTROPHILIC infiltrate with NECROTISING VASCULITIS.
• Although mostly centred in the dermis, it may extend to subcutaneous tissue as a predominantly LOBULAR panniculitis with vasculitis involving vessels of the subcutis.
• LATER stages: LYMPHOHISTIOCYTIC infiltrate in which FOAMY MACROPHAGES WITH NUMEROUS MYCOBACTERIA are seen within the fat lobule (Ziehl–Neelsen positive).

• An UNCOMMON variant of type II leprosy reaction with a UNIQUE clinical morphology.
• Occurs ALMOST EXCLUSIVELY in MEXICAN AND CENTRAL AMERICAN patients with UNTREATED, DIFFUSELY INFILTRATED, NON-NODULAR LEPROMATOUS leprosy.
• Characterised by MULTIPLE HAEMORRHAGIC NECROTIC SKIN INFARCTS.
• DOES NOT result in panniculitis and SUBCUTANEOUS TISSUE IS NOT USUALLY INVOLVED — histologically there is a NECROTISING VASCULITIS involving the SUPERFICIAL AND MID DERMIS.

• Difficult to treat. Often requires systemic therapy with HIGH-DOSE CORTICOSTEROIDS (80 mg/day, tapered down RAPIDLY) or THALIDOMIDE (400 mg/day).
• Improvement also described with CLOFAZIMINE (300 mg/day).

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• Synonyms: nodular vasculitis; Bazin disease; erythema induratum of Whitfield.
• A CHRONIC, RECURRENT, REACTIVE disorder characterised by subcutaneous nodules located preferentially on the POSTERIOR ASPECTS OF THE LOWER LEGS OF ADULT WOMEN.
• Nodules commonly develop AFTER EXPOSURE TO COLD and may BREAK DOWN TO FORM IRREGULAR ULCERS (Chapter 27).
• Historically regarded as a TUBERCULID linked to a DISTANT FOCUS OF TUBERCULOSIS — when this is the case, referred to as erythema induratum of BAZIN.
• M. tuberculosis is NOT implicated in all cases — the terms erythema induratum of WHITFIELD and NODULAR VASCULITIS have been used to differentiate such cases.
• No significant clinicopathological differences have been consistently demonstrated between tuberculosis-related and non-related cases. Most authors now consider them a SINGLE REACTIVE PROCESS provoked by a number of different mechanisms, ONE OF WHICH IS ACTIVE TUBERCULOSIS.

• Chronic hepatitis C; ulcerative colitis; brucellosis; paraneoplastic process; Nocardia infections; propylthiouracil; systemic lupus erythematosus; pneumonia due to Chlamydophila pneumoniae; BCG vaccination; aortic valve stenosis; hepatitis B; Crohn disease; leukaemia; rheumatoid arthritis; hypothyroidism; cold weather; chronic venous insufficiency; tumour necrosis factor antagonist therapy; Takayasu arteritis; lung adenocarcinoma; cobimetinib and vemurafenib therapy

• THE PROTOTYPE OF A PREDOMINANTLY LOBULAR PANNICULITIS WITH VASCULITIS — but the picture and infiltrate composition greatly depend on the STAGE at which the biopsy was taken.
• EARLY stages: fat lobules punctuated throughout by DISCRETE COLLECTIONS OF INFLAMMATORY CELLS, mostly NEUTROPHILS; there may be EXTENSIVE NECROSIS of the adipocytes.
• Necrotic adipocytes elicit a response from histiocytes, which phagocytose lipid and become LIPOPHAGES.
• FULLY DEVELOPED lesions: epithelioid and foamy histiocytes, LANGHANS-type or FOREIGN-BODY multinucleated giant cells, and lymphocytes contribute to the GRANULOMATOUS appearance.
• When INTENSE VASCULAR DAMAGE occurs, LARGE AREAS OF CASEOUS NECROSIS appear and the lesions show ALL the histopathological attributes of a TUBERCULOID GRANULOMA.
• HOWEVER, stains for acid-fast bacilli (ZIEHL–NEELSEN or FITE) and immunohistochemical stains for mycobacteria are NEGATIVE.
• Caseous necrosis may extend to the overlying dermis and secondarily involve the epidermis with ULCERATION and DISCHARGE OF LIQUEFIED NECROTIC FAT.
• Previously, TUBERCULOID GRANULOMAS AROUND THE ECCRINE COILS were regarded as suggestive of a tuberculous aetiology — but these findings may ALSO be seen in NON-TUBERCULOUS cases.
• CONTROVERSY over whether VASCULITIS is a REQUIRED criterion, and over the nature of the vessels involved — disagreement as to whether arteries, veins, or both are affected.
• In a recent LARGE STUDY of 101 skin biopsies from 86 patients, VASCULITIS was present in 90% of cases.

Vascular involvement in erythema induratum (Segura et al. 2008)

• Small VENULES of the FAT LOBULE — 46.5% of cases
• BOTH large veins of the connective tissue septa AND small venules of the fat lobule — 12.8%
• ONLY large veins of the connective tissue septa — 11.8%
• Large veins and ARTERIES of the septa AND small venules of the fat lobule — 9.9%
• Large veins and arteries of the connective tissue septa — 8.9%
• NO evidence of vasculitis — 9.9%

• Although vasculitis is demonstrable in the majority, some cases with ALL other clinicopathological attributes lack it despite careful search — therefore ITS PRESENCE SHOULD NOT BE CONSIDERED AN ESSENTIAL CRITERION for histopathological diagnosis.

• The relationship has been controversial because MYCOBACTERIA CANNOT BE CULTURED FROM THE CUTANEOUS LESIONS.
• Indirect evidence:
• STRONG HYPERSENSITIVITY REACTION TO TUBERCULIN.
• Presence of concomitant ACTIVE DISTANT (usually PULMONARY) tuberculous infection.
• Occasional COEXISTENCE in the same patient of erythema induratum and ANOTHER TUBERCULID.
• Frequent PERSONAL OR FAMILY HISTORY of tuberculosis.
• Favourable response to ANTITUBERCULOUS CHEMOTHERAPY.
• Suggested that ADIPOSE TISSUE might constitute a RESERVOIR where the M. tuberculosis bacillus could PERSIST for long periods and AVOID BOTH KILLING BY ANTIMICROBIALS AND RECOGNITION BY THE HOST IMMUNE SYSTEM.
• It has, however, NEVER been possible to ISOLATE M. tuberculosis from lesions.
• PCR studies have demonstrated M. tuberculosis DNA in cutaneous lesions with frequencies ranging from 25% to 77%.
• However, in a SPANISH study from a region with HIGH TB prevalence, M. tuberculosis DNA was detected by PCR in ONLY 14% of cases.
• Other investigators FAILED to demonstrate DNA from M. tuberculosis or ANY other mycobacterium — supporting other triggers than tuberculosis.
• Suggested that erythema induratum results from an IMMUNE COMPLEX-MEDIATED VASCULITIS, but MOST authors believe it results from a TYPE IV CELL-MEDIATED response to an antigenic stimulus.
• Supporting delayed hypersensitivity: the presence of an abundant number of S-100-POSITIVE DENDRITIC CELLS within the granulomatous infiltrate, probably presenting antigens to T cells.
• The presence in lesional skin of M. tuberculosis DNA BUT NOT VIABLE TUBERCULOUS BACILLI suggests erythema induratum is a HYPERSENSITIVITY REACTION TO FRAGMENTS OF TUBERCULOUS BACILLI.

• Where positive QuantiFERON-TB Gold in Tube® (QFT-GIT) or PCR have demonstrated M. tuberculosis DNA, FULL SPECIFIC ANTITUBERCULOUS THERAPY should be given according to current guidelines for systemic tuberculosis.
• NO MONOTHERAPY should be administered (as recommended in the past) because DRUG RESISTANCE IS LIKELY TO DEVELOP.
• In patients with NEGATIVE QFT-GIT or PCR: simple measures such as RESTING, NSAIDs and COMPRESSION BANDAGING may be helpful.
• As in erythema nodosum, POTASSIUM IODIDE 400–900 mg daily, or a saturated solution 2–10 drops in water or orange juice three times per day, may be administered in more persistent cases.

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• A relatively COMMON form of LONG-TERM CHRONIC panniculitis associated with CHRONIC VENOUS INSUFFICIENCY, typically affecting the lower extremities of MIDDLE-AGED OR ELDERLY WOMEN.
• Manifested as DIFFUSE SCLEROSIS AND PIGMENTATION of the skin and subcutaneous tissue (Chapter 101).

• Clinicians are often RELUCTANT TO BIOPSY because it is NOT UNUSUAL TO INDUCE A CHRONIC ULCER WITH POOR HEALING at the biopsy site — most biopsies are thus obtained in later stages.
• EARLY stages: sparse lymphocytic infiltrate in the SEPTA and areas of ISCHAEMIC NECROSIS at the CENTRE of the fat lobules (small, pale, ANUCLEATE adipocytes).
• Small blood vessels of the fat lobule appear CONGESTED, with EXTRAVASATED ERYTHROCYTES, HAEMOSIDERIN DEPOSITS and NECROSIS OF ENDOTHELIAL CELLS.
• FULLY DEVELOPED lesions: septa show MARKED THICKENING AND FIBROSIS; lobules appear ATROPHIC, often with LIPOPHAGIC GRANULOMAS at their periphery. Infiltrate = lymphocytes, histiocytes and foamy macrophages. Blood vessels appear PROMINENT in the septa at ALL stages.
• LATE-STAGE lesions: infiltrate sparse or absent; septal sclerosis prominent; fat lobules atrophic, with MICROCYSTS and FOCAL LIPOMEMBRANOUS (MEMBRANOCYSTIC) CHANGES.
• Cystic structures lined by a LIPOMEMBRANE appearing as FEATHERY AMORPHOUS EOSINOPHILIC MATERIAL, sometimes with a CRENELLATED OR ARABESQUE PATTERN.
• The thickened undulating membrane is PAS POSITIVE, stains for SUDAN BLACK and LUXOL FAST BLUE, and expresses immunoreactivity for CD68 and LYSOZYME — suggesting the contribution of these macrophage-derived enzymes in its histogenesis.
• Pseudomembranous/membranocystic changes involving the DERMIS described as a clue for EARLY lesions — NOT specific, as they occur in longstanding lesions of various septal and lobular panniculitides.
• CALCIFICATION and ELASTIC TISSUE DEGENERATION, sometimes with fragmented and calcified elastic fibres RESEMBLING THOSE OF PSEUDOXANTHOMA ELASTICUM (PXE), may be seen in longstanding lesions.
• These PXE-like fibres are POSITIVE for BOTH von KOSSA and VERHOEFF–VAN GIESON stains and may develop METAPLASTIC OSSIFICATION.
• NOT specific — also described in uraemic and non-uraemic calcific arteriolopathy (calciphylaxis), erythema nodosum, granuloma annulare, morphoea profunda and nephrogenic systemic fibrosis.
• Overlying SUPERFICIAL DERMIS shows VENOUS STASIS changes — lobules of capillaries and venules of slightly thick-walled vessels, with extravasated erythrocytes and haemosiderin deposition.
• Increased MELANIN pigment along the basal layer and within MELANOPHAGES in the superficial dermis contributes to the characteristic hyperpigmentation.
• Differential: panniculitis of scleroderma and deep morphoea show predominantly SEPTAL panniculitis; although lipodystrophy and lipophagic changes adjacent to the septa may be seen, they are NOT prominent, and they do NOT show STASIS changes in the superficial dermis.

Vascular disorders: venous insufficiency (lipodermatosclerosis); arteriosclerosis; thromboangiitis obliterans; thrombophlebitis; diabetes

Connective tissue/autoimmune disease: lupus panniculitis/discoid lupus erythematosus; morphoea/scleroderma; CREST syndrome; dermatomyositis-associated panniculitis; vasculitis; Behçet disease

Inflammatory panniculitis: erythema nodosum; erythema induratum; traumatic panniculitis; necrobiosis lipoidica; pancreatic panniculitis; factitial panniculitis; nodular fat necrosis

Infections: atypical mycobacteria; erysipelas

Neoplastic panniculitis: subcutaneous panniculitis-like T-cell lymphoma

Miscellaneous: splinter granuloma; chemotherapy for leukaemia; chemotherapy for breast cancer; testicular torsion; subcutaneous elemental mercury injections; mature cystic teratomas of the ovary; myospherulosis; breast after radiotherapy

• The aetiological role of VENOUS HYPERTENSION is UNDISPUTED.
• Venous hypertension increases capillary permeability → leakage of FIBRINOGEN and its polymerisation to form FIBRIN RINGS around vessels, with impedance of oxygen exchange and TISSUE ANOXIA.
• Other factors: trauma and recurrent episodes of CELLULITIS.
• In a study of 128 patients with systemic sclerosis, patients with sclerosing panniculitis had PULMONARY HYPERTENSION at a significantly HIGHER incidence — the authors suggested that THROMBOSIS caused by venous hypertension of the leg may be the main cause of pulmonary hypertension in such patients.
• Other findings of possible pathogenetic relevance: increased PLASMINOGEN ACTIVATION; increased expression of VEGFR-1 and ANGIOPOIETIN 2 (Ang-2); deficiencies of PROTEIN C AND S; and local INCREASED SYNTHESIS OF COLLAGEN.

• Because initial stages involve only ONE leg, it may be confused clinically with BACTERIAL CELLULITIS or ERYSIPELAS — although in the latter there is accompanying HEAT ON PALPATION, FEVER or other systemic symptoms.
• Early lesions may also MIMIC ERYTHEMA NODOSUM.
• In longstanding lesions, the differential is with other sclerodermiform processes — but the ABSENCE of DERMAL SCLEROSIS histopathologically, the peculiar distribution affecting only the DISTAL part of one or both legs, and the presence of features of CHRONIC VENOUS STASIS exclude morphoea, scleroderma and acrodermatitis chronica atrophicans.
• A RARE case of SARCOIDOSIS clinically mimicked sclerosing panniculitis.
• Management: there is NO effective treatment.
• COMPRESSION BANDAGING may achieve transitory results in EARLY cases; in more chronic cases, MULTILAYER LYMPHOEDEMA COMPRESSION BANDAGING is a better therapy.
• Improvement reported with the anabolic steroid STANOZOLOL, mostly in earlier stages — but this medication is NO LONGER COMMERCIALLY AVAILABLE.
• DANAZOL successfully administered as a substitute — may cause SEVERE side effects including SODIUM RETENTION, LIPID PROFILE ABNORMALITIES, HEPATOTOXICITY and VIRILISATION IN WOMEN.
• OXANDROLONE is an anabolic steroid with LESS androgenic effects and hepatotoxicity.
• Other therapies with variable results: ultrasound, pentoxifylline, fasciotomy and phlebectomy.

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• Strongly associated with END-STAGE CHRONIC KIDNEY DISEASE and RENAL TRANSPLANTATION, particularly in DIABETICS — although a small proportion arise in the ABSENCE of renal disease.
• Typically presents as IRREGULAR, EXQUISITELY TENDER patches of MOTTLED, DUSKY, LIVEDOID RED skin with PALE GREYISH AREAS OF DEVITALISATION, progressing to FULL-THICKNESS INFARCTION with NECROTIC ULCERATION.
• Changes commonly extend DEEPLY into subcutaneous fat. Most common areas: LOWER EXTREMITIES and ABDOMEN; may also involve other areas including the GENITALIA (Chapter 59).

• Three-dimensional studies show VASCULAR MURAL CALCIFICATION as an EARLY feature, probably PRECEDING ENDOVASCULAR FIBROSIS.
• Presence of MATRIX Gla PROTEIN, OSTEOPONTIN and BONE MORPHOGENIC PROTEIN 2 (BMP-2) in pathologically calcified arteries.
• In involved skin: significant UPREGULATION of BMP-2, its target gene RUNX2, and its indirect antagonist SCLEROSTIN, as well as increased expression of INACTIVE UNCARBOXYLATED MATRIX Gla PROTEIN (Glu-MGP).
• Upregulation of osteogenesis-associated markers accompanied by increased expression of OSTEOPONTIN, FIBRONECTIN, LAMININ and COLLAGEN I — indicating EXTENSIVE REMODELLING of the subcutaneous extracellular matrix.
• Electron dispersive X-ray analysis revealed CALCIUM/PHOSPHATE ACCUMULATIONS in the subcutis.
• Widespread MEDIAL calcification in cutaneous arterioles is associated with DESTRUCTION OF THE ENDOTHELIAL LAYER and PARTIAL EXFOLIATION of endothelial cells.
• CD31 immunostaining reveals aggregates of ENDOTHELIAL CELLS contributing to INTRALUMINAL OBSTRUCTION and consequent malperfusion → ulcerative necrosis.
• These data indicate vascular calcification in calciphylaxis is an ACTIVE OSTEOGENIC PROCESS involving upregulation of BMP-2 signalling, HYDROXYAPATITE deposition and extensive matrix remodelling.
• MATRIX Gla PROTEIN IS VITAMIN K DEPENDENT AND INHIBITS VASCULAR CALCIFICATION — THEREFORE ORAL ANTICOAGULANT THERAPY WITH WARFARIN, A VITAMIN K ANTAGONIST, FAVOURS VASCULAR CALCIFICATION IN THESE PATIENTS.
• Other recognised triggering factors: low levels of albumin, arterial hypertension, obesity, administration of systemic corticosteroids, vitamin D supplementation, blood transfusions, oral phosphate binders, metallic salts, calcitriol, local trauma, UV light treatment, malnutrition with weight loss, and insulin injections.

• The MOST CHARACTERISTIC finding = SMALL AND MEDIUM-SIZED VESSEL CALCIFICATION — small arteries, arterioles and venules may be involved.
• Vascular calcification is usually EXTENSIVE within the vessel walls, often exhibiting a CONCENTRIC, CIRCUMFERENTIAL, RING-LIKE pattern.
• Detailed studies show the EARLIEST sites of calcification are the MEDIA and/or INTIMA of CUTANEOUS ARTERIOLES.
• Calcification in arterioles of deeper reticular dermis or subcutis is usually evident with H&E, but VON KOSSA stain may help highlight these deposits.
• Involved vessels sometimes show LUMINAL THROMBOSIS; they develop INTIMAL HYPERPLASIA with ENDOVASCULAR ENDOTHELIAL PROLIFERATION and INTIMAL FIBROSIS, resulting in ISCHAEMIA.
• Secondary ischaemic changes: epidermal ulceration and degeneration of dermal collagen.
• FOCAL LOBULAR PANNICULITIS is frequently seen, although some biopsies show few/no inflammatory infiltrate adjacent to the calcified vessel. Some authors have described a predominantly SEPTAL panniculitis.
• Since vascular calcification may be seen in other disorders, ADDITIONAL FEATURES may be needed to support the diagnosis:
• Interstitial deposition of calcium in the dermis
• FINE calcium deposits IN AND AROUND THE ADIPOCYTES
• EPIDERMAL and HAIR FOLLICLE calcification
• PERINEURAL calcium deposits
• CALCIFIED ELASTIC FIBRES with a PXE-LIKE appearance
• Association with DIFFUSE DERMAL ANGIOMATOSIS
• PERIECCRINE CALCIUM DEPOSITION reported as a HIGHLY SPECIFIC histopathological finding

• Renal failure and hyperparathyroidism
• Atherosclerosis; liver disease (alcoholic cirrhosis); Crohn disease
• Malignancies: metastatic breast carcinoma; cholangiocarcinoma; malignant melanoma; osteosclerotic myeloma; chronic myelomonocytic leukaemia
• Rheumatoid arthritis on long-term steroid and methotrexate treatment
• Protein S deficiency; AIDS; antiphospholipid antibody syndrome; POEMS syndrome
• As an INCIDENTAL histopathological finding: calcinosis cutis secondary to injections; sclerosing panniculitis (lipodermatosclerosis); erythema induratum; leukocytoclastic vasculitis; traumatic ulcer; basal cell and squamous cell carcinomas; scars

• METASTATIC cutaneous calcification is a rare phenomenon involving dermis and subcutis, affecting predominantly uraemic patients with COMBINED HYPERPHOSPHATAEMIA AND HYPERCALCAEMIA, often with hyperparathyroidism (Ch 59).
• Presents as FIRM PAPULES, NODULES OR PLAQUES, particularly around LARGE JOINTS or FLEXURAL sites.
• UNLIKE CALCIPHYLAXIS, METASTATIC CUTANEOUS CALCIFICATION DOES NOT LEAD TO TISSUE NECROSIS.
• Histopathologically, deposits appear BLUE with H&E and BLACK with von KOSSA, seen in dermis and subcutis with variable surrounding inflammatory infiltrate — BUT THE VESSEL WALLS ARE SPARED.

• Identify and address precipitating factors — calcium supplementation and vitamin D intake.
• In end-stage renal insufficiency: INCREASE FREQUENCY AND DURATION OF DIALYSIS, plus a LOW PHOSPHATE DIET and PHOSPHATE BINDERS.
• CINACALCET or ETELCALCETIDE may be administered in hyperparathyroidism; PARATHYROIDECTOMY should be RESERVED for those who FAIL TO RESPOND.
• Multiple reported cases of successful use of SODIUM THIOSULFATE: for patients on haemodialysis, the proposed INTRAVENOUS dose is 25 g THRICE WEEKLY (during the LAST HOUR of haemodialysis).
• Although VERY PAINFUL, INTRALESIONAL sodium thiosulfate is beneficial and should be kept until RESOLUTION OF ERYTHEMA AND PURPURA.
• Extensive ulcerations: INTENSIVE WOUND CARE.
• SURGICAL DEBRIDEMENT is usually followed by improvement and SIGNIFICANTLY BETTER LONG-TERM SURVIVAL — although there are ALSO reports of the ONSET OF NEW LESIONS AND WORSENING after surgical debridement.
• Isolated cases improved with HYPERBARIC OXYGEN therapy.

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• Injury to subcutaneous fat induced by exposure to cold — either ENVIRONMENTAL or as COLD OBJECTS APPLIED TO THE SKIN (e.g. ICE PACKS).
• INFANTS are particularly susceptible; not uncommon in children in regions subject to LOW TEMPERATURES.

• HOCHSINGER (1902): originally described as SUBMENTAL nodules and plaques in children after cold exposure.
• LEMEZ (1928): demonstrated INFANTS are MORE SUSCEPTIBLE to fat necrosis by cold exposure than adults.
• HAXTHAUSEN (1941): similar cases on the CHEEKS of infants; named it "ADIPONECROSIS E FRIGORE".
• ADAMS et al. (1954): clarified pathogenesis — PIGS fed a diet RICH IN SATURATED FATTY ACIDS showed HIGHER cold susceptibility due to the HIGHER RATIO OF SATURATED TO UNSATURATED FATTY ACIDS, resulting in an ELEVATED FREEZING POINT OF FAT.
• HIRSCH (1965): confirmed that SATURATED fats SOLIDIFY AT A HIGHER TEMPERATURE than unsaturated fats.
• SOLOMON and BEERMAN (1963): panniculitis in a 28-year-old JAMAICAN WOMAN within HOURS of cold exposure, lesions readily inducible with local applications of ICE.
• ROTMAN: similar cases involving the cheeks in two infants of 5 and 8 months.
• "POPSICLE PANNICULITIS" — on the cheeks of children a few hours after eating ICE LOLLIES.
• DUNCAN et al. (1966): most extensive histopathological study — serial biopsies after exposing the child's skin to ICE for 2–4 min. Increased duration of ice exposure was required as the child aged, and the reaction NO LONGER OCCURRED AT THE AGE OF 22 MONTHS.

• A predominantly LOBULAR panniculitis, although a variable SEPTAL component is usually present.
• Inflammation is DENSER in the LOWER RETICULAR DERMIS and DERMAL–HYPODERMAL INTERFACE — the process is MORE A DERMATITIS THAN A PANNICULITIS.
• Infiltrate composed mostly of LYMPHOCYTES and some HISTIOCYTES involving the fat lobules.
• Overlying dermis shows a superficial and deep perivascular lymphocytic infiltrate WITH NO VASCULITIS.
• Blood vessels of both septa and fat lobules may exhibit ENDOTHELIAL SWELLING and INTRAMURAL OEDEMA, but there are NO fibrin deposits or nuclear dust as in TRUE vasculitis.
• INTERSTITIAL MUCIN deposition may also be seen, with a picture closely resembling LUPUS PANNICULITIS.

Duncan et al. "lives of lesions" — serial biopsies in a 6-month-old infant after ice cube application to the buttocks

• 30 min, 6 h: no changes described.
• 24 h: EARLIEST changes — mild perivascular lymphohistiocytic infiltrate mostly at the dermal–hypodermal interface, WITHOUT associated fat necrosis.
• 48 and 72 h: MORE INTENSE — denser MIXED infiltrate of lymphocytes, scattered neutrophils, histiocytes and foamy macrophages mostly involving the fat lobule; features of adipocytic necrosis evident as LIPOPHAGIC GRANULOMAS surrounding small cystic spaces.
• The reaction progressively increased over the next 2–3 days, then slowly decreased to REGRESS COMPLETELY BY 2 WEEKS. Subcutaneous nodules regressed leaving NO residual lesion.
• In ADULTS, findings are similar to those of PERNIOSIS — variable oedema of the superficial dermis and a superficial and deep dermal perivascular lymphocytic infiltrate that may extend to underlying fat lobules, but subcutis involvement is usually NOT prominent.

Neonatal and infantile cold panniculitis

• Neonates are particularly susceptible because subcutaneous fat in newborns is RICH IN SATURATED FATTY ACIDS — particularly PALMITIC and STEARIC acids — which have a HIGHER FREEZING POINT than unsaturated fatty acids, so a SMALL DECREASE in temperature may result in CRYSTALLISATION of subcutaneous fat.
• Risk in neonates may be INCREASED by COOLING for management of BIRTH ASPHYXIA or for infants undergoing CARDIAC SURGERY.
• Also reported in neonates administered ICE PACKS to control NEONATAL SUPRAVENTRICULAR TACHYCARDIA.
• Over the first 2 YEARS of life the subcutaneous fat rapidly becomes LESS SATURATED, with an INCREASE IN OLEIC ACID content and a consequent LOWERING OF THE FREEZING POINT and lessening of the risk.
• In young children the most commonly involved areas are the CHEEKS AND CHIN, because they are rich in subcutaneous fat and normally MORE EXPOSED to cold.
• Lesions = INDOLENT RED OR VIOLACEOUS INDURATED PLAQUES OR NODULES with NO systemic manifestations. The child is otherwise HEALTHY and lesions REGRESS WITHOUT TREATMENT within WEEKS.

Cold panniculitis in adults (equestrian chilblain)

• Adult patients are typically OBESE and PREDOMINANTLY FEMALE.
• Most commonly affected areas: LATERAL UPPER THIGHS and GLUTEAL REGION.
• Distribution postulated to be due to TIGHT-FITTING CLOTHING compromising blood flow in the upper lateral thighs, rendering ischaemic fat more susceptible to cold injury.
• A MORE PLAUSIBLE explanation: the skin and immediately subjacent fat is INSULATED FROM CORE BODY TEMPERATURE by a THICK LAYER OF INTERVENING FAT; tight-fitting clothing offers little protection from low external temperature, and lesions are usually accompanied by some degree of VASODILATATION as one would expect with perniosis.
• Suggested that a diet rich in SATURATED FATTY ACIDS would result in subcutaneous fat SIMILAR TO THAT OF A NEWBORN.
• Some patients have CRYOFIBRINOGENAEMIA, probably predisposing them.
• "EQUESTRIAN CHILBLAIN" or HORSE RIDER'S PERNIO: healthy adult women with lesions involving the lateral upper thighs after PROLONGED HORSE-RIDING IN COLD WEATHER — may be regarded as a FORM OF PERNIOSIS.
• Symptoms more pronounced in OLDER women and aggravated by HEAVY SMOKING, WEARING TIGHT RIDING CLOTHES and LONGER RIDING TIMES.
• Similar cases in obese women engaged in CYCLING and MOTORCYCLING in humidity and wind, or riding on OPEN, SLOW-MOVING VEHICLES.
• "ICE PACK DERMATOSIS": prolonged direct application of ice, described on the LOWER BACK of adults using ice packs for CHRONIC LOW BACK PAIN.

• In CHILDREN: subcutaneous fat necrosis of the newborn; sclerema neonatorum; lupus panniculitis; poststeroid panniculitis.
• In ADULTS: lupus erythematosus tumidus; perniosis; frostbite.
• Subcutaneous fat necrosis of the newborn — appears in the FIRST DAYS of life; predilection for thighs, buttocks, cheeks, back and arms; may be associated with symptomatic HYPERCALCAEMIA, and with hypothermia, obstetric trauma, maternal diabetes and maternal pre-eclampsia. Histopathology: LOBULAR panniculitis with a mostly HISTIOCYTIC infiltrate including MULTINUCLEATE GIANT CELLS, and adipocytes and histiocytes containing NEEDLE-SHAPED CLEFTS from LIPID CRYSTALLISATION.
• Sclerema neonatorum — extremely rare; PREMATURE or DEBILITATED children developing DIFFUSE BOARD-LIKE STIFFNESS due to generalised fat necrosis; appeared in the first days after birth and was usually FATAL. Histology: adipocytes contain NEEDLE-SHAPED CLEFTS IN RADIAL ARRAYS with NO INFLAMMATORY RESPONSE. No recent reports — likely disappeared where proper neonatal facilities exist.
• Lupus panniculitis — rare in children; the few paediatric cases do not differ significantly from adults. Histopathology: mostly LOBULAR panniculitis with LYMPHOCYTES AND PLASMA CELLS, LYMPHOID AGGREGATES with GERMINAL CENTRE formation, and SCLEROTIC COLLAGEN BUNDLES at connective tissue septa. The process is CHRONIC, and longstanding lesions show HYALINE NECROSIS of the fat lobule — NOT seen in the more ACUTE and SELF-RESOLVING cold panniculitis.
• Poststeroid panniculitis — occurs in children receiving high doses of systemic corticosteroids when the dose is RAPIDLY DECREASED OR SUDDENLY WITHDRAWN; small painful nodules on the CHEEKS AND POSTERIOR NECK — the areas in which corticosteroid therapy has induced FAT DEPOSITION. Histopathology IDENTICAL to subcutaneous fat necrosis of the newborn.
• Chilblains — bluish macules, papules and plaques involving mostly acral areas, but also thighs and buttocks. Picture may be very similar, although chilblains usually show oedema of the PAPILLARY dermis, the lymphocytic infiltrate is mostly arranged AROUND ECCRINE COILS, and some cases show LYMPHOCYTIC VASCULITIS in dermal vessels. Extension to subcutaneous fat is UNCOMMON in chilblains, except in lesions on thighs and buttocks.
• Lupus erythematosus tumidus — may be very similar, although usually NO oedema in the superficial dermis and INTERSTITIAL MUCIN DEPOSITS are often prominent.
• Frostbite — EARLY: reddish and oedematous plaques, may be PAINFUL OR ANAESTHETIC. FULLY DEVELOPED SEVERE: blistering and necrosis. Histopathology: SUBEPIDERMAL OEDEMA with blister formation, NECROSIS OF EPIDERMAL KERATINOCYTES, and a superficial and deep perivascular lymphocytic infiltrate involving the FULL THICKNESS of the dermis.

• Treatment is NOT usually required — the condition resolves spontaneously.
• PREVENTION in children: avoid cold exposure and DIRECT CONTACT WITH ICE PRODUCTS.
• For EQUESTRIAN cold panniculitis in adult women: use of LOOSE, WARM CLOTHING when riding, avoiding tight-fitting clothes and, where possible, cold exposure.
• NIFEDIPINE HAS BEEN SHOWN TO BE INEFFECTIVE.
• In one case a DRAMATIC RESPONSE TO TETRACYCLINE was observed, which was ALSO EFFECTIVE PROPHYLACTICALLY.

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• Synonyms: lupus erythematosus profundus; subcutaneous lupus erythematosus.
• Characterised by DESTRUCTIVE INFLAMMATION OF SUBCUTANEOUS FAT (Chapter 51).

• A predominantly LOBULAR panniculitis in which, in ACTIVE lesions, the infiltrate involves mainly the fat lobule.
• Some authors find difficulty classifying it as lobular because of the prominent SEPTAL component — however the septal component consists of THICKENING AND SCLEROSIS of collagen bundles, whereas MOST OF THE INFILTRATE IS IN THE FAT LOBULE.
• ACTIVE lesions: predominantly LYMPHOCYTIC panniculitis with NUMEROUS PLASMA CELLS.
• LONGSTANDING lesions: HYALINE NECROSIS of the fat lobule with little or no infiltrate, and replacement by DIFFUSE EOSINOPHILIC GLASSY REMNANTS of adipocytes.
• LYMPHOID AGGREGATES, sometimes with GERMINAL CENTRE FORMATION, frequently seen in the septa or at the periphery of the fat lobules.
• Although characteristic, these lymphoid follicles are NOT PATHOGNOMONIC — also seen in deep morphoea, erythema nodosum, erythema induratum, necrobiosis lipoidica, panniculitis associated with dermatomyositis and necrobiotic xanthogranuloma.
• Additional findings: calcification, interstitial MUCIN deposition, and features of DISCOID LUPUS ERYTHEMATOSUS in the overlying epidermis.
• An UNCOMMON but DISTINCTIVE feature is the presence of NUCLEAR DUST within the infiltrate.
• EOSINOPHILS are NOT usually prominent — but in contrast with OTHER forms of cutaneous lupus, in which eosinophils are CHARACTERISTICALLY ABSENT, the infiltrate of LUPUS PANNICULITIS MAY CONTAIN SOME EOSINOPHILS.
• Longstanding and residual lesions may show LIPOMEMBRANOUS changes.
• LYMPHOCYTIC VASCULITIS described with variable frequency — lymphocytes in and around the vessel walls, mural FIBRIN deposition, LUMINAL THROMBOSIS and NUCLEAR DUST. Some authors consider that HYALINE NECROSIS of the fat lobule results from the ISCHAEMIC process secondary to this lymphocytic vasculitis.
• Histopathological features of DISCOID LUPUS at the dermal–epidermal junction described in 20% to 75% of cases:
• Epidermal atrophy with hyperkeratosis; follicular plugging; VACUOLAR ALTERATION of the basal layer; BASEMENT MEMBRANE THICKENING.
• Additional: interstitial mucin deposition, telangiectasia, and superficial and deep perivascular dermal lymphocytic infiltrate.
• CALCIFICATION is frequent in chronic lesions — individual calcification of ELASTIC FIBRES or LARGE MASSES OF CALCIUM within the lobules and septa.
• Direct immunofluorescence: the LUPUS BAND TEST at the dermal–epidermal junction is OFTEN POSITIVE; additional findings — IgG deposition at the PERIPHERY OF ADIPOCYTES and AROUND THE VESSELS.
• Immunohistochemistry: infiltrate composed mostly of T lymphocytes, with a SLIGHT PREPONDERANCE OF CD4 OVER CD8; ALL show α/β immunophenotype; small aggregates of B lymphocytes at the periphery of the lymphoid aggregates.
• PCR for TCRγ gene rearrangement demonstrates a POLYCLONAL nature in MOST cases.
• Because of the presence of CYTOTOXIC CXCR3+ LYMPHOCYTES in the fat lobules, suggested that lupus panniculitis may be due to a TYPE I INTERFERON Th1-DRIVEN IMMUNE RESPONSE.

• INDURATED PLAQUES that RESOLVE WITH LOCALISED LIPOATROPHY.
• Depending on the intensity of inflammation, a patient may FIRST PRESENT WITH LIPOATROPHY RATHER THAN INDURATION.
• Overlying skin may show changes of chronic cutaneous lupus erythematosus.
• Most commonly affected: FACE, UPPER ARMS, UPPER TRUNK, BREASTS, BUTTOCKS and THIGHS.

• PANNICULITIS ASSOCIATED WITH DERMATOMYOSITIS shares IDENTICAL histopathological findings.
• Also includes: cold panniculitis; deep morphoea; persistent nodules after injection of vaccines containing ALUMINIUM; panniculitis at injection sites of GLATIRAMER ACETATE; and SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA (SPTCL).
• DEEP MORPHOEA may also display lymphoid nodules at the septa, but the process involves EXCLUSIVELY THE SEPTA and the FAT LOBULE IS SPARED.
• ALUMINIUM-CONTAINING VACCINE injection-site nodules: similar features including hyaline necrosis and lymphoid aggregates, but the diagnosis is suspected by the presence of HISTIOCYTES CONTAINING FINE BASOPHILIC GRANULES OF ALUMINIUM and ABUNDANT EOSINOPHILS. Unlike lupus panniculitis, the infiltrate is CENTRED AROUND AN AREA OF DEGENERATED COLLAGEN representing the SITE OF INJECTION.
• GLATIRAMER ACETATE injection-site panniculitis (daily injections for multiple sclerosis): mostly LOBULAR panniculitis with LIPOPHAGIC GRANULOMAS; scattered neutrophils and eosinophils in septa and lobules; septa widened and fibrotic with MANY LYMPHOID FOLLICLES showing GERMINAL CENTRE formation.
• Immunohistochemistry: lobule infiltrate = CD68-positive histiocytes and SUPPRESSOR/CYTOTOXIC T lymphocytes; lymphoid follicles in the septa mainly B LYMPHOCYTES.
• The clinical history with lesions localised ONLY AT INJECTION SITES rules out lupus panniculitis.

The most difficult differential — SPTCL

• SPTCL is a peculiar α/β T-cell lymphoma, usually CD8+, involving subcutaneous fat WITHOUT epidermal and/or dermal involvement, mimicking a panniculitic process (Chapter 139).
• Magro et al. reviewed 32 cases of lymphocytic lobular panniculitis, classifying them into THREE groups: lupus panniculitis; SPTCL; and a third group with INTERMEDIATE features named "INDETERMINATE LYMPHOCYTIC LOBULAR PANNICULITIS" (more recently proposed as "ATYPICAL LYMPHOCYTIC LOBULAR PANNICULITIS").
• The third group showed involvement by atypical lymphocytes with PLEOMORPHIC AND HYPERCHROMATIC NUCLEI, DELETION of one or more PAN-T-CELL MARKERS (CD3, CD5 and/or CD7) and MONOCLONAL TCRγ gene rearrangement by PCR.
• Introduced the concept of "SUBCUTANEOUS LYMPHOID DYSCRASIA" to encompass overlapping cases.
• Pincus et al. (5 patients) and Bosisio et al. (11 patients) described SPTCL patients also exhibiting features of LUPUS ERYTHEMATOSUS.
• Attributes indicating SPTCL: infiltrate of lymphocytes with pleomorphic nuclei involving subcutaneous lobules with a CYTOTOXIC T-CELL (CD3/CD8/βF1) immunophenotype; HIGH proliferation rate; MONOCLONAL TCRγ gene rearrangement in most cases.
• Manifestations of lupus: subcutaneous nodules healing with lipoatrophy on the FACE; serological and/or extracutaneous end-organ abnormalities; VACUOLAR CHANGE at the dermal–epidermal interface; interstitial MUCIN in the reticular dermis; clusters of CD20+ B cells partially arranged within GERMINAL CENTRES; a few small clusters of CD123+ PLASMACYTOID DENDRITIC CELLS within the adipose tissue; and a POSITIVE direct immunofluorescence test on clinically UNINVOLVED AND LESIONAL skin.
• Conclusion: SOME patients show OVERLAP between SPTCL and lupus panniculitis, and PATIENTS WITH LUPUS PANNICULITIS SHOULD BE MONITORED FOR POSSIBLE EVOLUTION INTO SPTCL.
• More recently proposed that these "overlapping" cases represent examples of LUPUS PANNICULITIS WITH FOCAL ATYPICAL LYMPHOID INFILTRATES rather than TRUE subcutaneous panniculitis T-cell lymphomas.

The MOST USEFUL CRITERIA for distinguishing LUPUS PANNICULITIS from SPTCL — presence in lupus panniculitis of:

• EPIDERMAL involvement
• Superficial and deep PERIVASCULAR LYMPHOCYTIC INFILTRATE in the DERMIS
• LYMPHOID FOLLICLES with REACTIVE GERMINAL CENTRES
• A MIXED infiltrate with NUMEROUS PLASMA CELLS
• Clusters of B LYMPHOCYTES
• Clusters of CD123+ PLASMACYTOID DENDRITIC CELLS
• LOW PROLIFERATIVE INDEX in lymphocytes
• FEW OR NO lymphocytes with immunohistochemical positivity for c-MYC
• POLYCLONAL TCRγ rearrangement

• ORAL ANTIMALARIAL drugs usually IMPROVE cutaneous lesions.
• Isolated lesions may be handled with intralesional corticosteroids.
• SYSTEMIC corticosteroids are MORE EFFECTIVE IN EARLY PHASES of the disease.
• Other systemic therapies with variable results: dapsone, mycophenolate mofetil, cyclophosphamide, thalidomide and intravenous immunoglobulins.
• In FACIAL residual lesions of lipoatrophy, cosmetic improvement may be achieved with INTRALESIONAL FILLERS — ALTHOUGH THESE INJECTIONS MAY BE FOLLOWED BY REACTIVATION OF APPARENTLY NON-ACTIVE LESIONS.

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• Panniculitis is LESS FREQUENT in dermatomyositis than in LUPUS ERYTHEMATOSUS and SYSTEMIC SCLEROSIS.
• In a series of 55 adult patients with dermatomyositis and cutaneous lesions studied histopathologically, panniculitis was found in ONLY FIVE cases.
• Also described in JUVENILE dermatomyositis. When the inflammation settles it leaves areas of LIPOATROPHY.
• In some patients panniculitis is associated with other characteristic cutaneous lesions; in others panniculitis is the ONLY cutaneous manifestation.
• There is a report of a patient presenting with panniculitis and VESICULO-BULLOUS skin lesions but NO evidence of MUSCLE involvement (Chapter 52).

• Similar to LUPUS PANNICULITIS: a predominantly LOBULAR panniculitis with LYMPHOCYTES AND PLASMA CELLS among the adipocytes.
• Septal collagen bundles show HYALINE SCLEROSIS, with progressive replacement of fat with fibrous tissue.
• Additional findings: thickening of the blood vessels of the fat lobule; NEUTROPHILIC VASCULITIS with FIBRINOID NECROSIS or LYMPHOCYTIC VASCULITIS involving the ARTERIOLES of the septa; and CALCIFICATION.
• LYMPHOID FOLLICLES, with or without reactive germinal centre formation, also described — LESS FREQUENT than in lupus panniculitis or deep morphoea.
• As in lupus panniculitis, there may be VACUOLAR CHANGE at the dermal–epidermal junction and, in late stages, MEMBRANOCYSTIC changes.
• Direct immunofluorescence reported in only THREE cases: negative in one; the second had deposits of IgM, C3 and FIBRINOGEN in dermal blood vessel walls but NOT at the dermal–epidermal junction; the third showed C3 at the basement membrane zone and around dermal blood vessels, but in the SUBCUTANEOUS FAT ONLY DEPOSITS OF FIBRINOGEN.
• As with lupus panniculitis, patients seem to be a SUBGROUP WITH A GENERALLY GOOD PROGNOSIS AND NO OBVIOUS INCREASE IN THE INCIDENCE OF MALIGNANCY — malignancy has been reported in ONLY ONE patient.
• MORE COMMON than pure dermatomyositis-associated panniculitis is panniculitis occurring in association with CALCIFICATION of the MUSCLE AND DEEP TISSUE — in these cases the fat lobule shows lipophagic granulomas, calcification and various degrees of acute and chronic inflammation.

• There is a CLEAR DISCORDANCE between response of the MUSCLE disease to therapy and response of the SKIN disease.
• Cutaneous lesions of dermatomyositis-associated panniculitis respond BETTER to immunosuppressive therapy than OTHER cutaneous lesions of dermatomyositis.
• If MUSCLE disease is confirmed, SYSTEMIC CORTICOSTEROID therapy should be initiated in doses aimed at CONTROL OF THE MYOSITIS.
• In AMYOPATHIC dermatomyositis, systemic corticosteroids are NOT traditionally utilised.
• ORAL ANTIMALARIAL drugs are LESS EFFECTIVE in dermatomyositis-associated panniculitis than in LUPUS panniculitis.
• Other treatments used: low-dose weekly methotrexate, mycophenolate mofetil, intravenous immunoglobulins, dapsone, tofacitinib and thalidomide.
• In contrast with lupus panniculitis, the FACE is usually SPARED and NO COSMETIC FILLERS are usually necessary for lipoatrophic residual lesions.

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• Synonym: enzymatic fat necrosis.
• Originally described by CHIARI in 1883; the first case in the English literature reported by SZYMANSKI AND BLUEFARB in 1961.
• Uncommon — appears in ONLY ABOUT 2–3% of all patients with pancreatic disease, although incidence is HIGHER among MALES WITH ALCOHOLISM.

• Pathogenesis remains unclear, but release of pancreatic enzymes — LIPASE, TRYPSIN and AMYLASE — seems to be the most important aetiological factor.
• TRYPSIN may INCREASE THE PERMEABILITY of the microcirculation within the LYMPHATIC vessels, allowing lipase and amylase to enter the peripheral circulation.
• Within the fat lobules these enzymes HYDROLYSE NEUTRAL FAT to form GLYCEROL AND FREE FATTY ACIDS, resulting in adipocyte necrosis and an inflammatory response.
• Supported by: elevated enzyme levels in blood, urine and skin lesions EVEN IN THE ABSENCE of detectable pancreatic disease; and positive INTRACELLULAR immunostaining of adipocytes with a monoclonal antibody to PANCREATIC LIPASE.
• HOWEVER, other factors must also play a role:
• Clear DISCREPANCY between the SMALL number of cases and the GREAT number of patients with pancreatitis and pancreatic carcinoma who have INCREASED SERUM ENZYMES BUT NO PANNICULITIS.
• Conversely, some patients with pancreatic panniculitis have had NORMAL serum levels of ALL pancreatic enzymes.
• In vitro investigations have FAILED to reproduce pancreatic panniculitis when normal human fat was incubated with serum of patients with high levels of pancreatic lipase, trypsin and amylase.
• Other proposed mechanisms: vascular damage; immune complexes; and ADIPOCYTE-GENERATED CYTOKINES AND ADIPOKINES released in response to high levels of free fatty acids.
• RESISTIN and LEPTIN have been shown to be POTENTIAL MARKERS OF EXTRAPANCREATIC FAT NECROSIS.

• ALMOST PATHOGNOMONIC: a predominantly LOBULAR panniculitis WITHOUT vasculitis.
• Some authors propose the EARLIEST feature is a predominantly SEPTAL panniculitis resulting from ENZYMATIC DAMAGE TO ENDOTHELIAL CELLS lining septal blood vessels, allowing pancreatic enzymes to cross from blood to fat lobules.
• EARLY states: predominantly NEUTROPHILIC infiltrate, with occasional EOSINOPHILS and, as the MOST CHARACTERISTIC finding, GHOST ADIPOCYTES resulting from COAGULATIVE adipocyte necrosis.
• Ghost adipocytes LOSE THEIR NUCLEI and show FINELY GRANULAR AND BASOPHILIC material within their cytoplasm BECAUSE OF CALCIFICATION.
• Often GROUP IN SMALL CLUSTERS AT THE CENTRE of the fat lobule, whereas the NEUTROPHILIC infiltrate is at the PERIPHERY.
• DYSTROPHIC CALCIFICATION in ghost adipocytes results from the HYDROLYTIC ACTION of pancreatic enzymes with subsequent CALCIUM DEPOSITION — a process known as SAPONIFICATION.
• Often ADJACENT LOBULES show a DIFFERENT STAGE in the histopathological evolution.
• LATE stages: fat necrosis and ghost adipocytes less evident; infiltrate more GRANULOMATOUS, containing FOAMY HISTIOCYTES, MULTINUCLEATE GIANT CELLS and HAEMOSIDERIN DEPOSITS. Residual lesions show FIBROSIS and LIPOATROPHY.
• GHOST ADIPOCYTES ARE VERY CHARACTERISTIC BUT NOT PATHOGNOMONIC — similar findings in MUCOCUTANEOUS MUCORMYCOSIS and CUTANEOUS ASPERGILLOSIS.
• Fungi of the family MUCORACEAE produce remarkable amounts of EXTRACELLULAR LIPASES — likely the ghost adipocytes result from the local effect of these lipases.

• Most, although not all, patients show ELEVATED serum AMYLASE, LIPASE or TRYPSIN — often ONE enzyme is within normal levels while the OTHERS are elevated.
• There is NO CORRELATION between the SERUM LEVELS of pancreatic enzymes and the SEVERITY of cutaneous lesions.
• In rare instances, patients may show HIGH serum PANCREATIC LIPASE with NO EVIDENCE OF UNDERLYING PANCREATIC DISEASE.
• A LEUKAEMOID REACTION and EOSINOPHILIA in peripheral blood are also common — particularly in patients with PANCREATIC CARCINOMA.
• Other tumour markers such as CARCINOEMBRYONIC ANTIGEN or Ca 19.9 are often elevated.

• TENDER, RED OR RED-BROWN NODULES that may SPONTANEOUSLY ULCERATE, DRAINING AN OILY BROWN, STERILE AND VISCOUS MATERIAL resulting from liquefactive necrosis of adipocytes.
• Predilection for the DISTAL parts of the LOWER EXTREMITIES, mostly AROUND THE ANKLES. VENOUS STASIS may promote this process.
• Lesions in other areas — knees, thighs, buttocks, arms, abdomen, chest and scalp — may also be seen.
• ULCERATION AND FISTULISATION of necrotic fat to the skin surface are frequent, but may also occur in other panniculitides.
• Panniculitis associated with PANCREATIC CARCINOMA tends to be MORE PERSISTENT, with MORE FREQUENT RECURRENCES and a GREATER TENDENCY TO ULCERATION, FISTULISATION and INVOLVEMENT OF AREAS BEYOND THE LOWER EXTREMITIES than that related to inflammatory pancreatic disease.
• Cases with a SINGLE cutaneous nodule have also been reported.
• The association of PANNICULITIS with FEVER, POLYARTHRITIS and ABDOMINAL PAIN should raise suspicion of PANCREATIC DISEASE.

Extracutaneous enzymatic fat necrosis

• Not confined to subcutaneous fat — patients often have other foci of fat necrosis.
• PERIARTICULAR fat involvement may cause a MONO- OR OLIGOARTICULAR ARTHRITIS, which may be symmetrical and can be intermittent, migratory or persistent — the PANCREATITIS, PANNICULITIS AND POLYARTHRITIS syndrome (PPP SYNDROME).
• Usually involves the small joints of the HANDS, WRISTS AND FEET, but also larger joints — elbows, knees and ankles.
• Aspiration yields a CREAMY, PURULENT, STERILE FLUID with a FEW WHITE CELLS.
• Joint fluid may contain LIPID CRYSTALS with increased AMYLASE, LIPASE, FREE FATTY ACIDS, TRIGLYCERIDES and CHOLESTEROL.
• In rare instances may progress to CHONDRONECROSIS AND OSTEONECROSIS.
• Other extrapancreatic sites rarely cause symptomatology, but autopsies of patients with pancreatic carcinoma and panniculitis have demonstrated FAT NECROSIS IN ABDOMINAL FAT AND BONE MARROW.
• Radiological images are characteristic: OSTEOLYTIC lesions, MOTH-EATEN BONE DESTRUCTION and PERIOSTITIS of involved bone of the extremities, due to extensive areas of BONE MARROW FAT NECROSIS and TRABECULAR BONE DESTRUCTION.
• The association of PANNICULITIS, POLYARTHRITIS AND EOSINOPHILIA in a patient with PANCREATIC CANCER is known as the SCHMID TRIAD and USUALLY CARRIES A POOR PROGNOSIS.

Skin lesions as the first sign

• Skin lesions may be the FIRST SIGN of pancreatic disease — an important diagnostic clue.
• Several reports where cutaneous nodules PRECEDED the detection of pancreatic carcinoma by several MONTHS; development of panniculitis may also PREDICT PROGRESSIVE OR METASTATIC MALIGNANT DISEASE.
• HOWEVER, the MOST FREQUENT underlying associated pancreatic disease is NOT pancreatic carcinoma, but ACUTE or CHRONIC PANCREATITIS caused by ALCOHOL ABUSE, TRAUMA or CHOLELITHIASIS. After acute and chronic pancreatitis, PANCREATIC CARCINOMA is the NEXT most common cause.

Acute or chronic pancreatitis: secondary to alcohol abuse; trauma; cholelithiasis; pancreatic pseudocyst; acute fatty liver of pregnancy and pancreatitis

Malignancy: acinar cell pancreatic carcinoma; islet cell pancreatic carcinoma; acinar cell pancreatic cystadenocarcinoma; liver carcinoma; adenocarcinoma of unknown origin; cancer-associated fasciitis–panniculitis syndrome; pancreatic adenosquamous carcinoma; pancreatic neuroendocrine carcinoma

Postprocedural: following renal or simultaneous pancreas and kidney transplantation; after endoscopic retrograde cholangiopancreatography

Pancreatic anomalies: vascular pancreatic fistulae; pancreas divisum

Miscellaneous: systemic lupus erythematosus; association with HIV infection and haemophagocytic syndrome; hypertriglyceridaemia and nephrotic syndrome; sulindac therapy; following L-asparaginase treatment for acute lymphoblastic leukaemia

• Clinically: erythema induratum, α1-antitrypsin deficiency panniculitis and infectious panniculitis — histopathology usually resolves any doubt by finding GHOST ADIPOCYTES in the SAPONIFIED fat lobule.
• Lobular panniculitis at the site of subcutaneous IFN-β injections for multiple sclerosis may HISTOLOGICALLY MIMIC pancreatic panniculitis.
• Management: treatment should be DIRECTED TO THE UNDERLYING PANCREATIC DISEASE — cutaneous lesions usually heal once the acute inflammatory pancreatic process has resolved or the pancreatic anomaly has been SURGICALLY CORRECTED.
• OCTREOTIDE (somatostatin analogue inhibiting pancreatic enzyme production) reported to result in significant improvement in SOME but NOT ALL patients with pancreatic carcinoma.
• CORTICOSTEROIDS, NSAIDs and IMMUNOSUPPRESSIVE DRUGS are USUALLY NOT EFFECTIVE.

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• A genetic disorder manifesting as PULMONARY EMPHYSEMA, LIVER CIRRHOSIS and, RARELY, CUTANEOUS PANNICULITIS.
• Characterised by LOW serum levels of α1-antitrypsin, THE MAIN PROTEASE INHIBITOR IN HUMAN SERUM.
• WARTER et al. (1972) first described panniculitis in association with the deficiency, considering it a manifestation of FAMILIAL WEBER–CHRISTIAN DISEASE.
• RUBINSTEIN et al. (1977) described the first TWO cases as a SPECIFIC manifestation of this AUTOSOMAL RECESSIVE INBORN ERROR OF METABOLISM.
• Epidemiology: RARE, with a FEMALE preponderance of 71%; age of presentation ranging from 7 to 73 years, MEAN 39.7 years — children may also be affected.

• α1-antitrypsin is the MOST IMPORTANT SERINE PROTEASE INHIBITOR produced in the LIVER.
• Principal function is to INHIBIT TRYPSIN activity, but it also potently inhibits CHYMOTRYPSIN, PLASMIN, THROMBIN, NEUTROPHILIC ELASTASE, PANCREATIC ELASTASE, SERINE PROTEASES, COLLAGENASE, FACTOR VIII, KALLIKREIN, UROKINASE and CATHEPSIN G.
• May also INHIBIT COMPLEMENT ACTIVATION — both directly on complement-related proteases and by inhibiting the neutrophil proteases that activate complement enzymes.
• Thought to help regulate PROTEASE-STIMULATED ACTIVATION OF LYMPHOCYTES and PHAGOCYTOSIS by macrophages and neutrophils.
• An ACUTE PHASE REACTANT released in stress situations.
• Structure: 394 AMINO ACIDS organised into THREE β SHEETS and NINE α HELICES; the active site is a REACTIVE CENTRAL LOOP composed of 20 AMINO ACIDS, which on contact with a serine protease induces conformational changes INACTIVATING BOTH α1-antitrypsin AND protease.
• Gene: SERPINA 1 (formerly PI), located at 14q32.1. MORE THAN 120 ALLELIC VARIANTS described to date.
• Alleles defined by protein isoelectrophoretic mobility:
• PiM (M = MEDIUM mobility) — the most frequent allele; homozygous PiMM phenotype with NORMAL serum levels (120–200 mg/dL).
• PiS (S = SLOW mobility) and PiZ (Z = VERY SLOW mobility) — each caused by a SINGLE NUCLEIC ACID SUBSTITUTION; considered involved in pathological manifestations.
• In the Z variant, GLUTAMIC ACID REPLACES LYSINE AT POSITION 342.
• Homozygosity for the Z allele (PiZZ) → VERY LOW serum levels (20–45 mg/dL).
• Heterozygous PiMZ or PiMS → MODERATE reduction.
• A NULL ALLELE variant — no apparent gene alteration but NO DETECTABLE mRNA produced; in individuals homozygous for Pi null/null, serum α1-antitrypsin is NOT DETECTABLE AT ALL.
• Heterozygosity for pathogenic mutations (PiMS, MZ, SZ) estimated in ABOUT 10% of the general population, with 2% heterozygous for the Z allele.
• Prevalence of the homozygous PiZZ phenotype is ONLY ABOUT 1 IN 3500 in NORTHERN EUROPEAN populations.
• In heterozygous carriers of S or Z, production and function are apparently NORMAL but only a SMALL amount enters the circulation from the liver — both mutations result in a HIGH TENDENCY FOR THE PROTEIN TO POLYMERISE, especially in the Z variant.
• Z-type α1-antitrypsin POLYMERS have been detected IN LESIONAL SKIN, supporting the inflammatory pathogenesis and the potential PRO-INFLAMMATORY ROLE OF POLYMERS.
• In situations causing TISSUE INJURY — SMOKING for emphysema, TRAUMA for panniculitis, HEPATOTOXINS for cirrhosis — the deficiency results in:
• UNCONTROLLED ACTIVATION OF LYMPHOCYTES AND MACROPHAGES
• A LACK OF INHIBITION OF THE COMPLEMENT CASCADE including C3a–C5a NEUTROPHILIC CHEMOTACTIC FACTORS
• ACCUMULATION OF NEUTROPHILS with RELEASE OF PROTEOLYTIC ENZYMES and SECONDARY TISSUE DAMAGE
• The SPECIAL SUSCEPTIBILITY OF SUBCUTANEOUS FAT to proteolytic degradation when NOT protected by α1-antitrypsin is due to its HIGH FATTY ACID CONTENT — FATTY ACIDS MODIFY ELASTIN CONFORMATION and render fat MORE SUSCEPTIBLE to proteolytic degradation.
• MOST SEVERE in HOMOZYGOUS PiZZ individuals, but can also develop in heterozygotes with PiMS, PiMZ and PiSZ genotypes and in homozygotes with PiSS and PiM1M1 genotypes — suggesting factors OTHER than α1-antitrypsin deficiency may be involved.
• Some authors believe there are patients with the phenotypic features but NORMAL SERUM LEVELS who develop panniculitis because of mutations that DO NOT INDUCE POLYMERISATION but AFFECT THE REACTIVE CENTRE LOOP, resulting in NON-FUNCTIONAL PROTEIN.

• A predominantly LOBULAR panniculitis with NO vasculitis.
• In EARLY stages, the presence of NEUTROPHILS extending into the LOWER RETICULAR DERMIS in an INTERSTITIAL pattern BETWEEN COLLAGEN BUNDLES ("SPLAYING OF NEUTROPHILS") has been proposed as a specific clue — HOWEVER this is a NON-SPECIFIC finding that may be found in ANY neutrophilic lobular panniculitis.
• A MORE SPECIFIC finding is the FOCAL NATURE OF THE DAMAGE, with LARGE CLUSTERS OF NORMAL ADIPOCYTES ADJACENT TO AREAS OF NECROSIS and dense neutrophilic and histiocytic infiltrates.
• Occasionally the intense neutrophilic infiltrate causes COLLAGENOLYSIS AND ELASTIC TISSUE DESTRUCTION at the connective tissue septa, and then NECROTIC FAT LOBULES APPEAR TO BE "FLOATING" AND SURROUNDED BY NEUTROPHILS.
• TRANSEPIDERMAL ELIMINATION of liquefied dermis may occur as a secondary phenomenon.
• LATE-STAGE lesions: neutrophils and necrotic adipocytes less evident; picture dominated by NON-SPECIFIC LIPOPHAGIC GRANULOMAS replacing fat lobules. Some macrophages may engulf NUCLEAR DUST of neutrophils, and DYSTROPHIC CALCIFICATION may develop.
• Direct immunofluorescence has revealed deposits of complement C3 and IgM around the dermal blood vessels — of UNCERTAIN SIGNIFICANCE.

• Absence or significantly REDUCED levels of α1-GLOBULIN on PLASMA PROTEIN ELECTROPHORESIS and abnormally reduced levels of α1-antitrypsin.
• Sometimes an isoelectrophoretic mobility study may demonstrate an ABNORMAL PHENOTYPE with NORMAL SERUM LEVELS.
• Therefore α1-antitrypsin levels measured OUTSIDE OF THE ACUTE PHASE (it is an ACUTE-PHASE REACTIVE PROTEIN that may be ELEVATED in inflammation), as well as α1-antitrypsin PHENOTYPING AND GENOTYPING, should be requested in suspicious cases.
• In chronic cases, NORMOCYTIC NORMOCHROMIC ANAEMIA and HYPOALBUMINAEMIA are frequently found.

• Panniculitis is the MOST IMPORTANT dermatological manifestation.
• Inflammation of subcutaneous fat MAY BE THE FIRST SIGN, although nodules usually appear when other manifestations have already developed.
• RED NODULES AND PLAQUES mainly located on the TRUNK and around the SHOULDERS AND HIPS; the head and extremities may sometimes be involved.
• The EARLIEST lesions RESEMBLE CELLULITIS and show a tendency to ULCERATE and EXUDE OILY MATERIAL derived from necrotic adipocytes.
• Healing leaves ATROPHIC SCARS. A CHRONIC RELAPSING COURSE IS CHARACTERISTIC.
• Antecedent TRAUMA at the site, SURGICAL DEBRIDEMENT, CRYOSURGERY or INJECTIONS can PRECIPITATE NEW LESIONS.
• POSTPARTUM FLARES attributed to an oestrogen-stimulated INCREASE in proteinase inhibitor levels during pregnancy, followed by a PRECIPITOUS DECLINE to SUBNORMAL levels postpartum.
• Uncommon associated cutaneous manifestations: VASCULITIS and ACQUIRED ANGIOEDEMA.
• Visceral extension is uncommon, but involvement of PERINEPHRIC fat as well as HEPATIC AND SPLENIC STERILE ABSCESSES has been reported.

• Other neutrophilic panniculitides with a tendency to ULCERATION AND FISTULA FORMATION: early stages of erythema induratum, pancreatic panniculitis, factitial panniculitis and infective panniculitis.
• When neutrophilic lobular panniculitis is found WITHOUT indications of other specific diagnoses, MEASUREMENT OF SERUM α1-ANTITRYPSIN AND ELECTROPHORETIC MOBILITY STUDIES SHOULD BE UNDERTAKEN.

• Systemic manifestations: PANACINAR EMPHYSEMA; NEONATAL HEPATITIS; CIRRHOSIS and LIVER DISEASE resulting from RETENTION OF THE ABNORMAL POLYMERISED PROTEIN WITHIN THE LIVER; PANCREATITIS; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; c-ANCA-POSITIVE VASCULITIS; and ANGIOEDEMA.
• APPROXIMATELY 50% OF ZZ PATIENTS WILL DIE FROM EMPHYSEMA-RELATED COMPLICATIONS and 10% WILL DEVELOP LIVER DISEASE.
• The MZ phenotype is associated with a SLIGHTLY HIGHER RISK OF BOTH LUNG AND LIVER DISEASE.
• NO increased likelihood of either lung or liver disease is seen in MS patients.
• The NULL/NULL phenotype is usually accompanied by EMPHYSEMA BUT NO LIVER DISEASE, because there is NO α1-antitrypsin synthesis and ACCUMULATION IN THE LIVER CANNOT THEREFORE OCCUR.

• AVOID trauma and surgical debridement, as well as SMOKING or exposure to HEPATOTOXINS. Reduction of ALCOHOL intake should be recommended.
• Corticosteroids, immunosuppressive drugs, colchicine, danazol and antimalarials have shown POOR OR NO RESPONSE.
• FIRST LINE: DOXYCYCLINE or MINOCYCLINE 200 mg daily for AT LEAST 3 MONTHS — may be effective in mild cases, as TETRACYCLINES have ANTICOLLAGENASE ACTIVITY which may partly RE-ESTABLISH PROTEASE–ANTIPROTEASE HOMEOSTASIS.
• DAPSONE also effective because it INHIBITS THE MIGRATION OF NEUTROPHILS.
• For SEVERE cases with liver and lung involvement, the BEST option is REPLACEMENT of α1-antitrypsin using HUMAN POOLED PLASMA from normal donors (Prolastin®).
• INTRAVENOUS infusions at 60–100 mg/kg PER WEEK, depending on severity, over a period of 3–7 WEEKS.
• RECURRENCE after discontinuation is COMMON, but there is a GOOD RESPONSE TO REINFUSION.
• Other interventions: PLASMA EXCHANGE and LIVER TRANSPLANTATION.
• In one patient, α1-antitrypsin deficiency panniculitis APPEARED AFTER LIVER TRANSPLANT and was successfully treated with RETRANSPLANT.
• The role of GENETIC ENGINEERING in producing α1-antitrypsin is being investigated.

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• A predominantly LOBULAR NEUTROPHILIC panniculitis WITHOUT vasculitis — although in some cases small-vessel vasculitis has been described.
• Additional features suggestive of an INFECTIVE aetiology: HAEMORRHAGE; PROLIFERATION OF VESSELS; FOCI OF BASOPHILIC NECROSIS; and NECROSIS OF SWEAT GLANDS.
• Special stains — GRAM, PAS, ZIEHL–NEELSEN and METHENAMINE-SILVER — as well as TISSUE CULTURES should be performed.
• Rarely may RESEMBLE SPTCL — as reported in a case due to Borrelia burgdorferi where the lobular infiltrate was composed of atypical lymphocytes with cytotoxic immunophenotype; aetiology proven by positive PCR, serology and favourable response to antibiotics.
• MYCOBACTERIAL panniculitis: varies with organism and immune state — usually a neutrophilic lobular panniculitis, but often contains SUPPURATIVE GRANULOMAS or frank TUBERCULOID GRANULOMAS. CASEOUS NECROSIS is SUGGESTIVE of TUBERCULOUS panniculitis.
• Q FEVER due to Coxiella burnetii: a "DOUGHNUT-LIKE" LOBULAR GRANULOMATOUS panniculitis, similar to changes found in the liver and bone marrow.
• GHOST ADIPOCYTES reminiscent of PANCREATIC panniculitis documented in MUCORMYCOSIS and ASPERGILLOSIS.
• Different patterns according to INOCULATION ROUTE:
• PRIMARY cutaneous infections (direct physical inoculation, or at the site of an occlusive dressing over an indwelling catheter): the EPICENTRE of inflammation is the SUPERFICIAL DERMIS, and thrombosed vessels DO NOT contain intravascular organisms.
• SECONDARY cutaneous infections (direct extension to the chest wall in pulmonary infections, or haematogenous dissemination): the epicentre is MORE DEEPLY SEATED, involving only the DEEP RETICULAR DERMIS AND SUBCUTANEOUS FAT; blood vessels are THROMBOSED AND DILATED WITH MASSES OF ORGANISMS EXPANDING THEIR LUMINA.
• In IMMUNOSUPPRESSED patients, microorganisms are NUMEROUS and easily identified with H&E or special stains. In IMMUNOCOMPETENT patients they are SPARSE and may be DIFFICULT TO DETECT — diagnosis may be established ONLY FROM CULTURE.
• ANTI-BCG ANTIBODY immunohistochemical staining was proposed as a helpful screening tool because this polyclonal antibody showed cross-reactivity with many bacteria, mycobacteria and fungi with minimal background staining.
• HOWEVER, due to OVERPURIFICATION by the manufacturer in recent years, anti-BCG antibody NO LONGER has the original wide sensitivity, and currently should be RESTRICTED TO THE SEARCH FOR MYCOBACTERIA in formalin-fixed and paraffin-embedded samples.
• PCR-based methods are also available to test formalin-fixed tissue for specific agents.

• BACTERIA: Streptococcus pyogenes; Staphylococcus aureus; Pseudomonas spp.; Klebsiella; Nocardia spp.; Brucella; Borrelia burgdorferi.
• Cutaneous lesions in patients with sepsis due to Stenotrophomonas maltophilia may show a lobular panniculitis with MACROPHAGES ENGULFED BY MICROORGANISMS.
• MYCOBACTERIA: most cases reported have been caused by NON-TUBERCULOUS mycobacteria, especially RAPIDLY GROWING mycobacteria such as M. chelonae and M. fortuitum, and less frequently SLOW-GROWING mycobacteria such as M. avium intracellulare complex and M. marinum.
• EXCEPTIONAL cases due to M. tuberculosis; panniculitis caused by M. leprae is EXTREMELY RARE.
• M. ulcerans causes a well-defined clinicopathological entity known as BURULI ULCER, which involves PREDOMINANTLY SUBCUTANEOUS FAT.
• WHIPPLE DISEASE (Tropheryma whippelii): specific cutaneous involvement is EXTREMELY RARE — described cases presented subcutaneous nodules on the LEGS, histopathologically a mostly SEPTAL panniculitis with infiltration of the septa by FOAMY MACROPHAGES CONTAINING PAS-POSITIVE INTRACELLULAR GRANULES.
• In some patients, ERYTHEMA NODOSUM-LIKE lesions appeared in TREATED Whipple disease as a sign of IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME.
• FUNGAL infections — TWO main categories:

1. Panniculitis in the setting of a DISSEMINATED fungal infection — most common: Candida spp.; Aspergillus spp.; Fusarium spp.; Histoplasma capsulatum.
2. CLASSIC SUBCUTANEOUS MYCOSIS — most common: SPOROTRICHOSIS (Sporothrix schenckii); EUMYCETOMA (Madurella mycetomatis); CHROMOBLASTOMYCOSIS caused by pigmented fungi — most common being Phialophora verrucosa, Fonsecaea pedrosoi, F. compacta and Cladophialophora carrionii.

• Uncommon subcutaneous fungal infections: phaeohyphomycosis, lobomycosis, rhinosporidiosis and subcutaneous zygomycosis.
• Also described: SEPTAL panniculitis caused by CYTOMEGALOVIRUS infection (many CMV inclusions in endothelial cells) in an immunosuppressed patient; and neutrophilic lobular panniculitis due to ACANTHAMOEBIASIS in a patient with AIDS.

• With the exception of the CLASSIC SUBCUTANEOUS MYCOSES, most infective panniculitides occur in IMMUNOSUPPRESSED patients and are UNCOMMON in immunocompetent hosts.
• BACTERIAL panniculitis may appear in the setting of SEPTICAEMIA, as the consequence of DIRECT INOCULATION, or by DIRECT SPREAD from an underlying infection.
• In sepsis, solitary or multiple nodules and abscesses appear from haematogenous dissemination. Constitutional symptoms are often ABSENT, but the general condition of the patient is IMPAIRED by the underlying disease.
• MYCOBACTERIAL infections:
• IMMUNOCOMPROMISED patients: lesions tend to be WIDESPREAD due to haematogenous dissemination; SPOROTRICHOID SPREAD is not uncommon; spread to internal organs may occur.
• IMMUNOCOMPETENT patients: infection is usually LOCALISED AND RELATED TO TRAUMA — penetrating injury, surgical procedures, ACUPUNCTURE, injections or POSTEPILATION FOLLICULITIS.
• FUNGAL panniculitis in immunosuppressed patients with disseminated infection: multiple, reddish, subcutaneous nodules, pustules or FLUCTUANT ABSCESSES.
• SUBCUTANEOUS MYCOSES: the fungus enters the skin from SOIL, PLANTS OR WOOD via a PENETRATING INJURY; lesions localised mostly to EXPOSED areas — face, hands, arms or feet.
• Consist of a SOLITARY PAINLESS NODULE that SPREADS SLOWLY; with time secondary nodules and papules may develop in adjacent skin, accompanied by SINUSES EXUDING A SEROUS OR OILY DISCHARGE.

• Appropriate ANTIMICROBIAL therapy.
• SURGICAL EXCISION may be necessary for isolated lesions due to GRAIN-FORMING FUNGI OR BACTERIA, such as MYCETOMA or BOTRYOMYCOSIS.

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• Results from EXTERNAL INJURY to subcutaneous fat. Aetiological factors: MECHANICAL TRAUMA, CHEMICAL SUBSTANCES and THERMAL INJURY; reasons may be ACCIDENTAL, INTENTIONAL or IATROGENIC.
• Often a manifestation of underlying PSYCHIATRIC DISORDERS; in other instances it results from iatrogenic injections of drugs or immunisation agents.

• Varies with the causal agent. EARLY lesions usually show a predominantly NEUTROPHILIC LOBULAR panniculitis with SEVERE FAT NECROSIS and an INTENSE inflammatory infiltrate.
• EOSINOPHILS may be abundant — especially in panniculitis arising at the site of CANCER VACCINES, and in SCLEROSING LIPOGRANULOMAS OF THE GENITALIA.
• SUPERIMPOSED INFECTION often complicates self-induced panniculitis.
• FULLY DEVELOPED: granulomatous infiltrates involving the fat lobule. LONGSTANDING: lipophagic granulomas and surrounding fibrosis.
• In some cases POLARISED LIGHT will reveal the BIREFRINGENT FOREIGN BODIES responsible.
• In panniculitis due to INJECTED SUBSTANCES, the DERMIS IS ALSO INVOLVED — a CLUE to the correct diagnosis.

Specific histopathological signatures

• PARAFFINOMA: a predominantly LOBULAR panniculitis in which the subcutaneous fat exhibits a "SWISS-CHEESE" appearance, with cystic spaces of variable size and shape surrounded by FOAMY HISTIOCYTES AND MULTINUCLEATED GIANT CELLS; intense FIBROSIS with SCLEROTIC COLLAGEN BUNDLES surrounding the cystic spaces.
• Similar findings described in the penis following a GREASE GUN INJURY.
• Exogenous oils may be highlighted by OIL RED O and OSMIUM TETROXIDE.
• SILICONE implants: findings vary with the FORM of injected silicone.
• SOLID ELASTOMER silicone induces an EXUBERANT FOREIGN-BODY GRANULOMATOUS reaction, whereas silicone OIL and GEL induce a SPARSER inflammatory response.
• Silicone particles appear as groups of ROUND, EMPTY VACUOLES of different sizes between collagen bundles or within macrophages. Silicone particles are NOT BIREFRINGENT under polarised light, but sometimes TRANSLUCENT ANGULATED FOREIGN BODIES representing IMPURITIES in the silicone are also found.
• POLYMETHYLSILOXANE fillers: irregularly shaped cystic spaces containing TRANSLUCENT, JAGGED "POPCORN", NON-BIREFRINGENT particles of varying size dispersed in a SCLEROTIC STROMA, surrounded by abundant multinucleated foreign-body giant cells.
• COLLAGEN-BASED cosmetic fillers containing POLYMETHYLMETHACRYLATE MICROSPHERES: nodular or diffuse granulomatous infiltrate surrounding ROUNDED VACUOLES OF SIMILAR SHAPE AND SIZE, WHICH MIMIC NORMAL ADIPOCYTES and correspond to the implanted microspheres.
• PHOSPHATIDYLCHOLINE-containing substances injected into lipomas: EARLY — neutrophilic infiltration with PARTIALLY DESTROYED FAT CELLS. LATE — infiltration of T lymphocytes and macrophages with FOAMY HISTIOCYTES, accompanied by THICKENED SEPTA and PSEUDOCAPSULE FORMATION surrounding the inflamed area.
• ALUMINIUM at hyposensitisation vaccine injection sites: abundant LYMPHOID FOLLICLES in the subcutis with GERMINAL CENTRE formation. May mimic LUPUS PROFUNDUS, PSEUDOLYMPHOMA or DEEP MORPHOEA — but the ABUNDANT EOSINOPHILS and the identification of characteristic HISTIOCYTES WITH BASOPHILIC GRANULAR CYTOPLASM are the KEY DISTINCTIVE FEATURES. These macrophages contain lysosomes filled with ALUMINIUM SALTS demonstrable with X-RAY DISPERSION MICROANALYSIS.
• PENTAZOCINE panniculitis: SCLERODERMOID PLAQUES resulting from THROMBOSIS OF SMALL VESSELS, ENDARTERITIS, GRANULOMATOUS INFLAMMATION, LIPOPHAGIC GRANULOMAS and PRONOUNCED FIBROSIS of dermis and subcutaneous fat.
• VITAMIN K injections: prominent SCLEROSIS of the collagen bundles of the connective tissue septa and an infiltrate of lymphocytes, mast cells and plasma cells, raising differential diagnosis with MORPHOEA. In contrast with deep morphoea, VITAMIN K1 PANNICULITIS USUALLY ALSO INVOLVES THE FAT LOBULE with LIPOPHAGIC GRANULOMAS.
• POVIDONE panniculitis: granulomatous infiltration of the fat lobule with FOCAL HAEMORRHAGE AND NECROSIS; many macrophages contain GREY-BLUE FOAMY MATERIAL in their cytoplasm, POSITIVE for CONGO RED and CHLORAZOL-FAST PINK.
• EXTRAVASATION of CYTOTOXIC DRUGS: lobular panniculitis, ABUNDANT ADIPOCYTE NECROSIS WITH LITTLE INFLAMMATORY INFILTRATE, together with epidermal lesions attributable to DIRECT CYTOTOXICITY. More chronic cases show MARKED FIBROSIS and LIPOMEMBRANOUS changes.
• GLATIRAMER ACETATE injections: predominantly LOBULAR panniculitis with LIPOPHAGIC GRANULOMAS and scattered NEUTROPHILS AND EOSINOPHILS both in the septa and in the fat lobules; septa widened and fibrotic with MANY LYMPHOID FOLLICLES, some with REACTIVE GERMINAL CENTRES.
• Immunohistochemistry: lobule infiltrate = CD68-positive histiocytes and suppressor/cytotoxic T lymphocytes; lymphoid follicles in septa mainly B lymphocytes.
• REPEATED TRAUMA: ORGANISING HAEMATOMAS, FOCAL GRANULOMAS and HAEMOSIDERIN DEPOSITION.

• Injectable FILLER AGENTS are now widespread in aesthetic dermatology and plastic surgery.
• BIODEGRADABLE or RESORBABLE agents may induce severe complications but usually DISAPPEAR SPONTANEOUSLY in a few months.
• SLOWLY BIODEGRADABLE or NON-RESORBABLE fillers may give rise to SEVERE reactions with LITTLE OR NO tendency to spontaneous improvement; may appear SEVERAL YEARS after injection, when the patient does not remember which product was injected.
• Previously: subcutaneous injection of OILY MATERIALS including MINERAL OIL (PARAFFIN) or VEGETABLE OILS (COTTONSEED and SESAME oils) — used to augment the size of BREASTS or GENITALIA, often inducing PARAFFINOMA or SCLEROSING LIPOGRANULOMA.
• Most such fillers have now been ABANDONED by medical professionals, although complications may appear a LONG TIME after injections — EVEN 30 YEARS LATER.
• Currently used fillers — bovine collagen, silicone, polymethylmethacrylate microspheres (Artecoll®), polymethylsiloxane (Bioplastique®) and hydroxyethylmethacrylate particles in hyaluronic acid (Dermalive®) — are better tolerated but may also sometimes induce factitious panniculitis.
• Lipostabil® (a phosphatidylcholine-containing substance) — popular for treatment of localised fat accumulation and lipomas, causing factitious panniculitis of the injected fat tissue.
• MESOTHERAPY injections to reduce thickness of hypertrophic subcutaneous fat produce a granulomatous panniculitis with some CYSTIC FAT NECROSIS.

Medications causing panniculitis at the sites of injection

• Pethidine; pentazocine; methadone; povidone; gold salts (aurothioglucose); phytomenadione (vitamin K1); glatiramer acetate (multiple sclerosis); tetanus antitoxoid vaccination and antihepatitis vaccines; hyposensitisation vaccination with vaccines containing ALUMINIUM; anticancer vaccines such as GANGLIOSIDES for melanoma and CARCINOEMBRYONIC ANTIGEN and MUCIN-1 (MUC1) for pancreatic cancer; interferon β; granulocyte colony-stimulating factor; interleukin 2

• Extravasation of CYTOSTATIC agents during antineoplastic chemotherapy presents as a SEVERE panniculitis.
• CUPPING and ACUPUNCTURE techniques for pain relief may induce factitious panniculitis on the limbs.
• Patients with PSYCHIATRIC DISORDERS may present with self-inflicted panniculitis due to subcutaneous injections of acids, alkalis, farming products, mustard, milk, microbiologically contaminated material, urine and faeces.
• Exact mechanisms uncertain, but VASOCONSTRICTION with tissue ischaemia at injection sites, a LOCAL INFLAMMATORY RESPONSE elicited by direct contact, IMMUNE MECHANISMS and TRAUMA due to repeated injections may be implicated.

• Self-induced factitious panniculitis usually occurs in young adults or middle-aged women with a history of DRUG ADDICTION or PSYCHIATRIC DISORDERS (Ch 84).
• Lesions tend to be LOCALISED TO AREAS EASILY ACCESSIBLE TO THE HANDS — BUTTOCKS AND THIGHS — usually SOLITARY OR FEW; when multiple they tend to be GROUPED.
• The clinical appearance is BIZARRE and suspicions should be raised when they DO NOT FIT WITH ANY WELL-DEFINED DERMATOSIS.
• Lesions due to BLUNT TRAUMA often appear BRUISED and frequently involve the ARM OR HAND.
• SECRETAN SYNDROME (l'oedème bleu): a particular presentation of self-induced traumatic panniculitis — a FACTITIOUS OEDEMA OF THE HAND caused by frequent application of a TOURNIQUET or repeated trauma. Chronic and recurrent course, leading to PROGRESSIVE FIBROSIS OF THE DORSUM OF THE HAND.
• Self-inflicted injections with CONTAMINATED MATERIAL produce an ACUTE SUPPURATIVE panniculitis, often with SYSTEMIC SYMPTOMS.
• EARLY lesions: inflammatory nodules and plaques secondary to fat necrosis and suppuration; some cases show ABSCESS FORMATION AND LYMPHANGITIC SPREAD.
• A case masquerading as FLORID PYODERMA GANGRENOSUM was reported in a depressed woman.
• Risk of progression to GRANULOMATOUS INFLAMMATION AND FIBROSIS in longstanding lesions.
• SCLEROSING LIPOGRANULOMA: factitious lesions of the MALE GENITALIA secondary to injections of LIQUID PARAFFIN intended to augment the size of the penis. Often these patients DENY previous injections, making diagnosis difficult.
• Similar lesions may appear in EYELIDS, LIPS or GLUTEAL region after injection of LIQUID SILICONE.
• PENTAZOCINE abuse (patients with chronic pain or addiction): repeated injections may induce panniculitis AND MYOSITIS; presents as multiple NODULO-ULCERATIVE lesions of LONG DURATION located BILATERALLY on the BUTTOCKS AND SHOULDERS, slowly progressing to fibrosis resulting in SCLERODERMOID PLAQUES extending to the underlying FASCIA AND MUSCLE.
• TEXIER DISEASE: iatrogenic panniculitis due to vitamin K1 injections — EARLY lesions have an ECZEMATOUS appearance, but LONGSTANDING reactions MIMIC MORPHOEA.
• PROCAINE POVIDONE was used to treat chronic pain with local infiltrations. Povidone is a synthetic product now widely used in HAIR SPRAYS and as a dispersing/suspending agent in drugs such as procaine and hormones.
• Povidone polymers CANNOT BE EXCRETED BY THE KIDNEY and are PHAGOCYTISED AND STORED PERMANENTLY IN MACROPHAGES → "POVIDONE STORAGE DISEASE".
• In addition to panniculitis, povidone may cause PULMONARY LESIONS, LYMPHADENOPATHY and VISCEROMEGALY.
• Subcutaneous extravasation of CYTOTOXIC agents causes SEVERE, PAINFUL, NECROTIC reactions of the subcutis and underlying muscles, which may DISABLE A PATIENT FOR MONTHS — RED-BROWN PAINFUL OEDEMA evolving into NECROTIC PLAQUES healing with SCLEROTIC, INDURATED SCARS which may become BOUND TO UNDERLYING MUSCLE AND BONE.

• EARLY lesions should be treated with SYSTEMIC ANTIBIOTICS to cover a wide spectrum of microorganisms.
• If ARTEFACT is suspected, the affected area may be OCCLUDED FOR A WEEK WITH A BANDAGE — IMPROVEMENT WOULD SUPPORT A SUSPICION OF SELF-INDUCED FACTITIOUS PANNICULITIS, for which appropriate social and psychiatric care should be offered. Regrettably, these offers are usually REJECTED by patients.
• Panniculitis secondary to COSMETIC FILLERS usually requires INTRALESIONAL STEROIDS and, if possible, REMOVAL OF THE IMPLANTED MATERIAL.
• Panniculitis secondary to injection of DRUGS usually requires only SUPPORTIVE CARE and WITHDRAWAL of the responsible drug.

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• Incorporates a range of different panniculitides in which the fat lobule infiltrate is mostly composed of NEUTROPHILS.
• According to Cohen, "neutrophilic lobular panniculitis is NOT A DISTINCT ENTITY but has a CONCISE PATHOLOGIC DESCRIPTION of specific changes in the subcutaneous fat observed in association with several conditions".
• AN INFECTIOUS AETIOLOGY MUST ALWAYS BE RULED OUT before making the histopathological diagnosis.

• Alpha-1 antitrypsin deficiency panniculitis
• Pancreatic panniculitis
• Infective panniculitis
• Factitious panniculitis
• Neutrophilic lobular panniculitis / subcutaneous Sweet syndrome
• Neutrophilic/pustular panniculitis of rheumatoid arthritis
• Erythema nodosum-like lesions of Behçet disease
• Bowel bypass dermatosis
• Iatrogenic neutrophilic panniculitis
• Drug-induced neutrophilic panniculitis
• Neutrophil-rich lupus panniculitis
• Neutrophilic variant of subcutaneous fat necrosis of the newborn

• Sweet syndrome (acute febrile neutrophilic dermatosis) — acute onset of OEDEMATOUS, RED PAPULES AND PLAQUES, often with FEVER AND MALAISE; first described by SWEET in 1964.
• Classic histopathology: oedema of the PAPILLARY dermis and a DENSE BAND-LIKE infiltrate of NEUTROPHILS involving mostly the SUPERFICIAL DERMIS, with NO vasculitis.
• Subcutaneous involvement in CLASSIC Sweet syndrome is NOT RARE — described with frequencies ranging from 25% TO 50% of cases.
• A diagnosis of SUBCUTANEOUS Sweet syndrome should be made ONLY in cases in which the neutrophilic infiltrate involves EXCLUSIVELY the subcutaneous tissue with FEW OR NO NEUTROPHILS IN THE DERMIS.
• Cullity et al. were the first to use the terms "SWEET'S PANNICULITIS" or "ACUTE FEBRILE NEUTROPHILIC PANNICULITIS".
• Most cases show a neutrophilic LOBULAR panniculitis, although in rare instances a SEPTAL component may be predominant. To date, only 27 well-documented cases have been reported.
• Features supporting the relationship to Sweet syndrome:
• In some cases, subcutaneous Sweet syndrome was FOLLOWED BY CLASSIC DERMAL Sweet syndrome.
• Another patient presented SIMULTANEOUSLY with classic Sweet syndrome and Sweet panniculitis.
• As in classic Sweet syndrome, many patients had associated MYELODYSPLASTIC SYNDROMES and HAEMATOLOGICAL NEOPLASMS, and lesions showed an EXCELLENT RESPONSE to SYSTEMIC CORTICOSTEROIDS.
• Histopathology: dense infiltrate of MATURE NEUTROPHILS involving subcutaneous tissue — may involve septa, lobules or both, but in most cases the LOBULAR component predominates.
• VASCULITIS is usually ABSENT in all cases, but in TWO patients LEUKOCYTOCLASIA was noted.
• THE DERMIS IS, BY DEFINITION, SPARED IN ALL PATIENTS. Occasionally some mononuclear cells may be found.
• Rarely, infiltration of MYELOPEROXIDASE-POSITIVE IMMATURE GRANULOCYTES has been described — representing the SUBCUTANEOUS COUNTERPART of the so-called HISTIOCYTOID SWEET SYNDROME.
• SUMMARY — Sweet syndrome may involve subcutaneous tissue with TWO DIFFERENT PATTERNS:

1. A mostly SEPTAL panniculitis with occasionally granulomatous infiltrate, as in CLASSIC ERYTHEMA NODOSUM associated with Sweet syndrome.
2. A NEUTROPHILIC infiltrate mostly involving the FAT LOBULES, as in SUBCUTANEOUS SWEET SYNDROME.

• Clinical features: median age of onset during the SIXTH DECADE, but appears NOT to show the FEMALE PREPONDERANCE of classic Sweet syndrome.
• Lesions consist of RED NODULES or PLAQUES; often TENDER OR PAINFUL.
• Frequently preceded or accompanied by SYSTEMIC SYMPTOMS such as FEVER AND MALAISE; LEUKOCYTOSIS found in several patients.
• Most frequent locations: LOWER EXTREMITIES, followed by UPPER EXTREMITIES, TRUNK and HEAD.
• In one patient lesions were associated with all-trans-retinoic acid chemotherapy for PROMYELOCYTIC LEUKAEMIA; another presented with associated DACRYOADENITIS; another developed the condition when administered PEGYLATED G-CSF.
• Management: most patients show a DRAMATIC RESPONSE TO SYSTEMIC CORTICOSTEROIDS such as PREDNISOLONE. DAPSONE has also been administered successfully in one patient.

• "ERYTHEMA NODOSUM-LIKE" lesions occur in APPROXIMATELY 30% of patients with Behçet disease.
• Consist of nodules on the LOWER extremities, and sometimes also on the ARMS, IDENTICAL to those of classic erythema nodosum.
• HOWEVER, histopathology demonstrates involvement of BOTH the SEPTA AND FAT LOBULES, with NECROTISING LEUKOCYTOCLASTIC VASCULITIS involving the ARTERIOLES AND VENULES.
• In some cases NEUTROPHILIC ABSCESSES are found within the fat lobules; a variable degree of FAT NECROSIS is NEARLY ALWAYS PRESENT.
• Therefore the histopathological findings RULE OUT erythema nodosum, and the VASCULITIS COMPONENT allows SUBCUTANEOUS SWEET SYNDROME to be ruled out.

• Several cases of neutrophilic (pustular) panniculitis described.
• Subcutaneous nodules mostly located on the LOWER extremities with a TENDENCY TO FORM DRAINING FISTULAE WITH A YELLOWISH DISCHARGE.
• Histopathology: lobular infiltrate of NEUTROPHILS accompanied by LYMPHOCYTES, MACROPHAGES and MULTINUCLEATE GIANT CELLS. FAT NECROSIS found in NEARLY ALL cases; LEUKOCYTOCLASTIC VASCULITIS described in some.

• Characterised by RECURRENT FEVER, ARTHRALGIA and SKIN LESIONS after INTESTINAL BYPASS or BARIATRIC SURGERY.
• Most frequent skin lesions: RED PAPULES or VESICULOPUSTULES.
• LOBULAR NEUTROPHILIC PANNICULITIS with tender subcutaneous nodules on the lower extremities has, however, RARELY been described.

• In addition to drug-induced erythema nodosum and panniculitis at injection sites, some recently introduced drugs may induce NEUTROPHILIC SEPTAL OR LOBULAR PANNICULITIS BEYOND THE SITES OF INJECTION, with red subcutaneous nodules mostly involving the UPPER AND LOWER LIMBS.
• Usually appear after an AVERAGE OF 30 DAYS from the onset of treatment.
• Often associated with SYSTEMIC SYMPTOMS such as FEVER OR ARTHRALGIA.
• Lesions are usually MILD and DO NOT REQUIRE WITHDRAWAL of the responsible drug.

Drug-induced panniculitis

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• Synonym: Darier–Roussy sarcoid.
• Minimal DERMAL involvement is acceptable for the histopathological diagnosis, but it is considered a specific clinicopathological variant involving EXCLUSIVELY the subcutaneous fat.
• Should be DIFFERENTIATED from NODULAR DERMAL lesions of sarcoidosis with DEEP EXTENSION into the subcutaneous tissue.
• Mostly associated with SYSTEMIC sarcoidosis, although with an INDOLENT AND NON-AGGRESSIVE form of the disease.
• The MOST FREQUENT subcutaneous disorder associated with sarcoidosis is NOT subcutaneous sarcoidosis, but CLASSIC ERYTHEMA NODOSUM.
• Epidemiology: the LEAST COMMON specific cutaneous manifestation of sarcoidosis — frequency ranging in different series between 1.4% and 6% of patients with systemic sarcoidosis; represents 11.76% of specific cutaneous lesions (Chapter 96).

• NON-CASEATING GRANULOMAS involving FAT LOBULES.
• At low-power, appears as a predominantly LOBULAR panniculitis with MINIMAL OR NO SEPTAL involvement.
• Sarcoidal granulomas in subcutaneous tissue are usually SMALL, UNIFORM IN SIZE and mainly composed of EPITHELIOID HISTIOCYTES, with LIMITED numbers of MULTINUCLEATE GIANT CELLS and a SPARSE LYMPHOCYTIC component.
• FIBROSIS is a FREQUENT finding and, although it may be INTENSE, it is NOT associated with PULMONARY FIBROSIS or with LONG-TERM PERSISTENCE OF SYSTEMIC SARCOIDOSIS ACTIVITY.
• Occasionally SMALL FOCI OF EOSINOPHILIC NECROSIS may appear in the centre of regressing sarcoid granulomas, raising the differential diagnosis of TUBERCULOSIS; in RARE instances, CASEATING NECROSIS may be EXTENSIVE.
• Development of CALCIFICATION in these granulomas has also been reported.
• FOREIGN REFRACTILE PARTICLES under polarised light have been detected in some cases — and THIS FINDING SHOULD NOT EXCLUDE THE DIAGNOSIS.

• CORTICOSTEROIDS — topical, intralesional or systemic — are the MAINSTAY of therapy.
• For EXTENSIVE lesions, the usual dose is 0.5–1 mg/kg/day for 4–6 WEEKS, followed by a SLOW TAPER.
• For SOLITARY cutaneous lesions, topical or intralesional corticosteroids may suffice.
• Alternative non-steroidal systemic medications: hydroxychloroquine (200–400 mg/day); chloroquine (250–500 mg/day); minocycline (200 mg/day); methotrexate (10–25 mg weekly); thalidomide (50–300 mg/day).
• Improvement of BOTH systemic and cutaneous sarcoidosis observed with TNF-α inhibitors, including INFLIXIMAB and ADALIMUMAB.

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• Damage to subcutaneous tissue induced by PHYSICAL AND CHEMICAL AGENTS — trauma, cold, electricity or chemicals.
• In general, there is NO DIRECT RELATIONSHIP between the SEVERITY OF THE INJURY and the SEVERITY OF THE RESULTANT PANNICULITIS — EVEN MINOR TRAUMA OFTEN CAUSES NODULES OF PANNICULITIS ON THE SHINS.

• NOT SPECIFIC.
• EARLY lesions: intense HAEMORRHAGE and an infiltrate mostly of lymphocytes and macrophages arranged around SEPTAL VESSELS.
• FULLY DEVELOPED: CYSTIC AREAS OF FAT NECROSIS surrounded by histiocytes; LIPOPHAGIC GRANULOMAS scattered with HAEMOSIDEROPHAGES; and some neutrophils and eosinophils.
• LATE lesions: FIBROTIC REPLACEMENT of the fat lobule with RESIDUAL CYSTIC FAT NECROSIS surrounded by MACROPHAGES and FOREIGN-BODY MULTINUCLEATE GIANT CELLS.
• LIPOMEMBRANOUS changes are also COMMON in late-stage lesions. DYSTROPHIC CALCIFICATION may appear in longstanding nodules.
• SEMICIRCULAR ATROPHY: biopsy shows inflammatory perivascular changes in EARLY lesions.
• NODULAR–CYSTIC FAT NECROSIS: extensive necrosis of the fat lobules with CYSTIC FAT NECROSIS and LIPOMEMBRANOUS changes, and — as the MOST CHARACTERISTIC finding — a THICK, EOSINOPHILIC, PERIPHERAL, FIBROTIC PSEUDOCAPSULE with HYALINE APPEARANCE encircling the nodule and separating it from surrounding tissues.

• A specific form is COMMON IN WOMEN WITH LARGE PENDULOUS BREASTS — LARGE BREAST MASSES can form and MAY BE MISINTERPRETED AS BREAST CANCER.
• SEMICIRCULAR LIPOATROPHY — probably induced by REPEATED MICROTRAUMA (Chapter 98).
• Generally ADULT WOMEN develop HORIZONTAL BAND-LIKE OR CIRCULAR DEPRESSIONS around the ANTEROLATERAL aspects of the THIGHS.
• Lipoatrophy develops over SEVERAL WEEKS WITHOUT SYMPTOMS.
• Trauma is the most probable cause because the affected areas are vulnerable to REPETITIVE TRAUMA FROM SITTING AT DESKS AND TABLES.
• POST-TRAUMATIC panniculitis may present as a solitary nodule or multiple subcutaneous nodules caused by traumatic SEPARATION and consequent DEVASCULARISATION of pieces of subcutaneous fat from its blood supply.
• The resultant WALLING OFF of the necrotic fat by FIBROUS TISSUE results in ENCAPSULATED FAT NECROSIS, otherwise termed NODULAR CYSTIC FAT NECROSIS or MOBILE ENCAPSULATED LIPOMA.
• ELECTRICAL INJURIES appear at the POINT OF CONTACT OF DIFFERENT ELECTRODES, causing SKIN BURNS with SUPERFICIAL SUBCUTANEOUS involvement.
• Management: usually a SELF-LIMITING disorder with CONSIDERABLE IMPROVEMENT OVER TIME.

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• Initially reported by SHELLEY and IZUMI in 1970, who coined the expression "ANNULAR ATROPHY OF THE ANKLES".
• Since then only a handful of cases reported, some under the heading of CONNECTIVE TISSUE PANNICULITIS.
• A recently published small series proposed the term "RECURRENT LIPOATROPHIC PANNICULITIS IN CHILDREN" as the best name.

• In all except one reported case, a mainly LOBULAR inflammation with predominance of HISTIOCYTES, LIPOPHAGIC GRANULOMAS and a smaller number of lymphocytes, neutrophils, plasma cells and eosinophils.
• NEUTROPHILS AND MYELOID CELLS are MORE PROMINENT IN EARLY lesions, whereas MACROPHAGES PREDOMINATE IN LATE stages, leading to LIPOPHAGIA AND LIPOATROPHY.
• Immunohistochemistry: positive MYELOPEROXIDASE staining around necrotic adipocytes in EARLY stages and CD68/PGM1 macrophages in LATE stages. INTENSE STAT1 STAINING observed in the inflammatory infiltrate.
• One reported case was remarkable for the RELATIVE ABUNDANCE OF LYMPHOCYTES, some MILDLY ATYPICAL — immunohistochemistry showed most lymphocytes positive for CD3 and CD7, with only occasional CD20+ B lymphocytes, and approximately EQUAL numbers of CD4 and CD8 cells; PCR for B- and T-cell clonality yielded POLYCLONAL results.
• The authors concluded that their findings of a mostly LYMPHOCYTIC panniculitis were due to a biopsy performed at an EARLIER STAGE of evolution.
• The PARTIAL "RIMMING" of necrotic adipocytes by lymphocytes, as well as the relatively HIGH PROLIFERATIVE ACTIVITY disclosed by MIB-1, raised the differential diagnosis of SPTCL — but the other immunohistochemical results and PCR studies RULED OUT that diagnosis.

• Many reported patients are CHILDREN with ANTINUCLEAR ANTIBODIES, AUTOIMMUNE CONDITIONS OR BOTH — the disorder has been included under CONNECTIVE TISSUE PANNICULITIS, together with morphoea, lupus panniculitis and dermatomyositis.
• The characteristic ANNULAR OR SEMICIRCULAR involvement of the ANKLES makes this a DISTINCTIVE condition with FEW IF ANY differential diagnoses.
• Lesions are TENDER, and the onset of subcutaneous nodules is accompanied by FEVER, MALAISE and ARTHRALGIA OF THE ANKLES.
• RED NODULES AND PLAQUES RESOLVE WITH ANNULAR SCALING, LEAVING LIPOATROPHY AROUND THE ANKLES.
• In some cases lesions may extend to other areas of the lower and upper limbs and EVEN THE FACE may be involved. LIPOATROPHY is the characteristic RESIDUAL lesion.
• Laboratory abnormalities: increased ACUTE PHASE REACTANTS; LEUKOCYTOSIS with MILD NEUTROPHILIA; MICROCYTIC ANAEMIA; and ELEVATED LIVER ENZYMES.
• The clinicopathological presentation SHARES FEATURES WITH OTHER AUTOINFLAMMATORY DISORDERS.

• Symptomatic treatment with NSAIDs provides ANALGESIA and helps RESOLUTION.
• ORAL PREDNISOLONE usually leads to MARKED IMPROVEMENT, but some cases have RECURRED ON TAPERING — then hydroxychloroquine, methotrexate and azathioprine have been administered with good effect.
• RESIDUAL LIPOATROPHY OF THE ANKLES TENDS TO IMPROVE SLOWLY WITH TIME.
• In a recent small series of FIVE cases, ALL patients improved with a COMBINED THERAPY OF METHOTREXATE AND CORTICOSTEROIDS.

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• Pathogenesis is UNKNOWN.
• Perinatal complications recorded in many cases: Rh factor incompatibility, MECONIUM ASPIRATION, umbilical cord prolapse, placenta praevia, BIRTH ASPHYXIA, seizures, congenital heart disease, intestinal perforation, HYPOTHERMIA, sepsis, anaemia, OBSTETRIC TRAUMA, GESTATIONAL DIABETES, PRE-ECLAMPSIA or MATERNAL ABUSE OF DRUGS — but in many instances there is NO history or any other associated anomaly.
• Suggested that LOCALISED AND TRANSIENT HYPOXIA may be an aetiological factor.
• COLD may also play a role — several reports in children who had CARDIAC SURGERY with lesions appearing after cutaneous applications of ICE to induce HYPOTHERMIA.
• Also described after WHOLE BODY COOLING in an infant with POLYCYTHAEMIA AND HYPOCALCAEMIA, and in newborns after hypothermia treatment of HYPOXIC ISCHAEMIC ENCEPHALOPATHY.
• Another important predisposing factor may be the particular subcutaneous fat composition in neonates — a relatively high concentration of SATURATED fatty acids compared with UNSATURATED, resulting in a HIGHER MELTING POINT and a greater propensity to undergo CRYSTALLISATION under cold temperatures.
• Suggested that newborns might have a TRANSITORY PROTEASE INHIBITOR DEFICIENCY DUE TO LIVER IMMATURITY, similar to α1-antitrypsin deficiency — HOWEVER the histopathological findings are ENTIRELY DIFFERENT from those of α1-antitrypsin deficiency panniculitis, which MILITATES AGAINST this theory.
• Other authors propose it is a DISORDER OF BROWN FAT, which is present in the most frequently involved areas.
• Also described after the administration of PROSTAGLANDIN E1 for the treatment of CONGENITAL HEART DISEASE — supporting some pathogenic role of prostaglandin E1.
• APPROXIMATELY 25% of infants present with HYPERCALCAEMIA for unknown reasons — MORE FREQUENT in infants with EXTENSIVE lesions and when the TRUNK is involved.
• The origin is not known, but INCREASED CALCIUM ABSORPTION due to EXTRARENAL HYPERPRODUCTION OF 1,25-DIHYDROXYVITAMIN D3 (CALCITRIOL) has been detected in several granulomatous processes including sarcoidosis and this condition.
• ELEVATED PARATHORMONE levels detected in some cases, but AUTOPSY STUDIES FAILED TO REVEAL ANY PARATHYROID HYPERPLASIA.
• ELEVATED URINARY EXCRETION OF PROSTAGLANDIN E1 suggests INCREASED CALCIUM RESORPTION FROM BONE as the explanation.

• A predominantly LOBULAR panniculitis, with a DENSE infiltrate of LYMPHOCYTES, HISTIOCYTES, LIPOPHAGES, MULTINUCLEATE GIANT CELLS and sometimes EOSINOPHILS interspersed among the adipocytes.
• A NEUTROPHILIC variant MIMICKING INFECTIVE PANNICULITIS has been described, which probably corresponds to EARLY stages.
• Many adipocytes are replaced by cells with FINELY EOSINOPHILIC GRANULAR CYTOPLASM containing DOUBLY REFRACTILE, NARROW, NEEDLE-SHAPED CLEFTS RADIALLY ARRANGED, which represent TRIGLYCERIDE CRYSTALLISATION within adipocytes and STAIN WITH OIL RED O.
• Some of these refractile clefts may also be found within the cytoplasm of MULTINUCLEATE GIANT CELLS, which may also contain EOSINOPHILIC GRANULES — their origin from DEGRANULATING EOSINOPHILS has been postulated.
• FIBROTIC OBLITERATION OF SMALL ARTERIOLES and CALCIUM DEPOSITS in necrotic fat also described.
• LATE-STAGE: SEPTAL FIBROSIS, with areas of CALCIFICATION and LIPOATROPHY appearing within the fat lobule.
• Adipocytes containing radially arranged needle-shaped clefts have ALSO been found during AUTOPSY STUDIES in VENTILATOR-ASSOCIATED TRACHEOBRONCHITIS.
• In some cases the diagnosis was established using TOUCH PREPARATION (pressing a fresh biopsy against a glass slide) and FINE-NEEDLE ASPIRATION techniques.

• Multiple, SYMMETRICALLY DISTRIBUTED, INDURATED, SMOOTH, NON-PITTING, MOBILE subcutaneous RED or VIOLACEOUS nodules or plaques appearing in the FIRST FEW WEEKS OF LIFE.
• Most common locations: SHOULDERS AND BUTTOCKS; also face, thighs, back and distal areas of the extremities. These lesions tend to SPARE THE ANTERIOR TRUNK.
• In rare instances the nodules may ULCERATE, DISCHARGE THEIR OILY CONTENTS and heal leaving ATROPHIC SCARS.
• Confluence of the nodules results in EXTENSIVE RED INDURATED PLAQUES.

• Most children remain otherwise HEALTHY, but APPROXIMATELY 25% develop complicating HYPERCALCAEMIA.
• The hypercalcaemia MAY PERSIST FOR SEVERAL WEEKS AFTER THE SUBCUTANEOUS LESIONS HAVE REGRESSED — requiring CALCIUM LEVELS TO BE MONITORED and ASSOCIATED ENDOCRINOLOGICAL DISORDERS TO BE RULED OUT.
• Other reported laboratory anomalies: TRANSIENT THROMBOCYTOPENIA (probably due to PLATELET SEQUESTRATION); HYPOGLYCAEMIA due to MATERNAL DIABETES; and HYPERTRIGLYCERIDAEMIA.
• In RARE instances the condition may be FATAL, particularly when VISCERAL FAT IS INVOLVED.
• NEPHROCALCINOSIS persisting SEVERAL YEARS after resolution of the skin nodules reported as a rare complication.

• In most children TREATMENT IS NOT REQUIRED because the problem tends to RESOLVE SPONTANEOUSLY.
• The MAIN GOALS are the DETECTION AND TREATMENT OF HYPERCALCAEMIA, with AVOIDANCE OF CALCIUM AND VITAMIN D3.
• ETIDRONATE, a bisphosphonate that decreases bone resorption of calcium, has been helpful — should be used as a SECOND LINE drug because its effects on BONE PRODUCTION, GROWTH PLATES AND MINERALISATION IN INFANTS ARE AS YET UNKNOWN.
• PAMIDRONATE is also helpful and may REDUCE THE RISK OF NEPHROCALCINOSIS.
• CALCITONIN and CITRATE may be used as second line therapy for resistant cases.

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• In 1956, SMITH and GOOD reported 11 children with ACUTE RHEUMATIC FEVER receiving high doses of corticosteroids with RAPID TAPER, of whom FIVE developed RED SUBCUTANEOUS NODULES.
• A rare panniculitis of CHILDREN AND INFANTS on PROLONGED systemic corticosteroid treatment, related to a RAPID DECREASE or SUDDEN WITHDRAWAL of steroid therapy.
• Only about 20 cases described in the literature.
• Develops in an OLDER age group than SCLEREMA NEONATORUM and SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN — reported ages ranging from 20 MONTHS TO 14 YEARS.
• Although mostly seen in children, there are a few reported cases in ADULTS — in one adult patient the lesions involved the arms and legs and were PAINLESS.

• IDENTICAL to those of SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN: a mostly LOBULAR panniculitis with an infiltrate of FOAMY HISTIOCYTES AND LYMPHOCYTES involving the fat lobules.
• Often DOUBLY REFRACTILE NARROW NEEDLE-SHAPED CLEFTS RADIALLY ARRANGED are found within the cytoplasm of some histiocytes and necrotic adipocytes — although USUALLY NOT AS NUMEROUS as in subcutaneous fat necrosis of the newborn.

• Lesions vary in size from 0.5 to 4 cm and consist of ASYMPTOMATIC FIRM SUBCUTANEOUS NODULES, often with overlying REDNESS.
• Tend to be LOCALISED IN THOSE AREAS WHERE THERE IS THE GREATEST ACCUMULATION OF FAT FROM STEROID THERAPY — the FACE, ARMS and POSTERIOR NECK.
• Usually appear 1–10 DAYS AFTER THE CESSATION of high doses of systemic corticosteroids.
• Underlying disorders treated with high-dose corticosteroids have been varied: rheumatic fever, leukaemia, nephrotic syndrome, acute exacerbation of chronic obstructive pulmonary disease, erythema nodosum leprosum, autoimmune enteropathy, Sjögren syndrome and brain tumours.
• Different oral or intravenous corticosteroid drugs, including PREDNISOLONE and DEXAMETHASONE, have been associated.
• Usually, REINSTITUTION of corticosteroid administration induces improvement — although some authors believe this is NOT NECESSARY for its resolution.

• Lesions usually disappear GRADUALLY WITHOUT RESIDUAL SCARRING over the course of WEEKS OR MONTHS, EVEN WITHOUT RESUMING STEROID THERAPY — therefore NO TREATMENT IS USUALLY NECESSARY.
• However, READMINISTRATION of high doses of systemic corticosteroid and a SLOWER AND MORE GRADUAL DECREASE of the dose is followed by FASTER IMPROVEMENT AND RESOLUTION.

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• An uncommon condition typically affecting GRAVELY ILL, PRETERM NEONATES in the FIRST WEEK OF LIFE.
• Manifests as DIFFUSE HARDENING of skin and subcutaneous tissue such that THE SKIN CANNOT BE PITTED OR PICKED UP AND PINCHED INTO A FOLD.
• Histologically there is MINIMAL INFLAMMATION with EXTENSIVE FAT NECROSIS. Associated with a HIGH MORTALITY (Chapter 114).

• A STRIKING CONTRAST at low power between the SEVERE DAMAGE in the subcutaneous fat and the SPARSE INFLAMMATORY RESPONSE.
• Most fat lobules appear replaced by AMPHOPHILIC GRANULAR DETRITUS, and the cellular structures of the adipocytes are NO LONGER EVIDENT.
• SURPRISINGLY, there is SPARSE OR NO INFLAMMATORY INFILTRATE despite the intense fat necrosis.
• The MOST CHARACTERISTIC feature: RADIALLY ARRANGED NEEDLE-SHAPED REFRACTILE CLEFTS in adipocytes and, occasionally, in the FEW multinucleate giant cells — resulting from crystallisation of the lipid contents.
• X-RAY DIFFRACTION studies have demonstrated the clefts are due to CRYSTALLISATION OF TRIGLYCERIDES.
• In LATE-STAGE lesions, THICKENED CONNECTIVE TISSUE SEPTA may be the ONLY anomaly.

• Extremely uncommon; almost ALWAYS appears during the FIRST WEEK OF LIFE, although also reported in infants born preterm with low birth weight who developed it later.
• In most cases a GRAVE illness, associated with a MORTALITY OF UP TO 75%.
• Most case series date from 40 OR MORE YEARS AGO; NOW the process is VERY UNCOMMON, probably due to BETTER NEONATAL CARE.
• PREMATURITY and PLACENTAL INSUFFICIENCY proposed as pathogenetic factors.
• Affected infants are ALMOST ALWAYS SEVERELY ILL from conditions such as septicaemia or other disseminated infections, congenital heart disease, pneumonia, diarrhoea, dehydration, intestinal obstruction or other congenital developmental defects.
• In a multivariate analysis of risk factors in preterm neonates in BANGLADESH, the main risk factors were LOWER MATERNAL EDUCATION, SIGNS OF JAUNDICE and POOR FEEDING ON ADMISSION — although the diagnosis in that study was NOT histopathologically confirmed.
• COLD INJURY proposed as an aetiological factor, but DOES NOT APPEAR TO BE IMPORTANT IN MOST CASES.
• LIPOLYTIC IMMATURITY in preterm infants and the DIFFERENT COMPOSITION of subcutaneous fat in newborns — a HIGHER PROPORTION OF SATURATED (PALMITIC and STEARIC) TO UNSATURATED (OLEIC) FATTY ACIDS — may also be predisposing, favouring SOLIDIFICATION of subcutaneous fat if there is a fall in temperature as a result of PERIPHERAL CIRCULATORY COLLAPSE.
• Characterised by INCREASED BLOOD LIPID PEROXIDATION and DIMINISHED SUPEROXIDE DISMUTASE ACTIVITY, raising the possibility that FREE RADICALS may also play some role.
• Clinically: infants typically appear SEVERELY ILL FROM BIRTH; during the first days of life they develop GENERALISED WOODY INDURATION OF THE SKIN.
• Usually BEGINS ON THE BUTTOCKS AND THIGHS but RAPIDLY EXTENDS to involve ALMOST THE ENTIRE SKIN SURFACE WITH THE EXCEPTION OF THE PALMS, SOLES AND GENITALIA.
• Involved skin has a HARD CONSISTENCY, is NON-PITTING and COLD TO THE TOUCH; YELLOWISH WHITE in colour, often with PURPLISH MOTTLING.
• IMMOBILITY OF THE EXTREMITIES; the FACE shows a MASK-LIKE EXPRESSION.
• Prognosis is POOR and most affected infants DIE WITHIN A FEW DAYS. However, IF THE INFANT SURVIVES, THE SKIN RECOVERS ITS NORMAL APPEARANCE and there are NO LONG-TERM COMPLICATIONS SUCH AS CALCIFICATION.

• The MAIN differential is SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN — important because they represent TWO DISTINCTIVE clinicopathological processes with VERY DIFFERENT PROGNOSES.
• There is a single reported case of coexistence in the same infant, but that is DOUBTFUL because histopathological study was LACKING.
• Usually straightforward: subcutaneous fat necrosis of the newborn is a LOCALISED AND SELF-HEALING process, DOES NOT DEVELOP IN THE FIRST DAYS OF LIFE, and has characteristic histopathology of a DENSE HISTIOCYTIC INFILTRATE in the fat lobules with radially arranged needle-shaped refractile clefts within adipocytes AND histiocytes.
• Histopathological changes SIMILAR to sclerema neonatorum have been described in a patient with GEMCITABINE-ASSOCIATED LIVEDOID THROMBOTIC MICROANGIOPATHY — biopsy showed small-vessel occlusion by INTRAVASCULAR FIBRIN AND LEUKOCYTES, VESSEL WALL THICKENING and ENDOTHELIAL CELL SWELLING, and some structures arranged radially with needle-shaped clefts.
• SHOULD NOT BE CONFUSED WITH SCLEROEDEMA NEONATORUM — an entirely different process seen in PREMATURE infants with CONGENITAL HEART DISEASE, characterised by DISTENDED SKIN WITH WAX-LIKE APPEARANCE resulting from DERMAL OEDEMA WITH INCREASED AMOUNTS OF MUCIN.

• Mainly directed to the UNDERLYING DISEASE.
• SYSTEMIC CORTICOSTEROIDS HAVE BEEN DEMONSTRATED NOT TO BE EFFECTIVE.
• REPEATED EXCHANGE TRANSFUSIONS may SUBSTANTIALLY REDUCE MORTALITY — but the diagnosis in those cases was NOT histopathologically confirmed.
• INTRAVENOUS IMMUNOGLOBULINS were used in a newborn with sclerema neonatorum and sepsis, with transitory improvement of the skin induration, but the patient DIED OF RESPIRATORY FAILURE.

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• Panniculitis is a VERY UNCOMMON complication of TOPHACEOUS GOUT (Chapter 155).
• Histopathology: a LOBULAR, sometimes NEUTROPHILIC, panniculitis with deposition of NEEDLE-SHAPED REFRACTILE CRYSTALS WITHIN ADIPOCYTES.
• Frequently HISTIOCYTES AND MULTINUCLEATE GIANT CELLS FORM A PALISADE AROUND THE URATE CRYSTALS.
• ULTRASOUND SCANS may be helpful for DIAGNOSIS AND MONITORING.
• Clinical features: usual presentation consists of PAINFUL ULCERATING NODULES ON THE LOWER LEGS.
• In most reported cases patients had ALREADY SUSTAINED SEVERE JOINT DAMAGE by the time panniculitis manifested — but in some cases PANNICULITIS MAY BE THE FIRST MANIFESTATION OF HYPERURICAEMIA.
• One patient also had involvement of BONE MARROW FAT.
• Management: usual systemic drugs for gouty tophi — COLCHICINE, ALLOPURINOL and FEBUXOSTAT — BLOCK URIC ACID PRODUCTION, BUT HAVE LITTLE OR NO EFFECT IN CUTANEOUS AND SUBCUTANEOUS TOPHI.
• Symptomatic lesions may improve with NSAIDs.

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• A predominantly LOBULAR panniculitis with FINE NEEDLE-SHAPED REFRACTILE CRYSTALS WITHIN ADIPOCYTES has been described in subcutaneous fungal infections including ZYGOMYCOSIS, MUCORMYCOSIS and ASPERGILLOSIS (Chapter 32).
• The presumed URATE CRYSTALS are SIMILAR to those found in GOUTY PANNICULITIS, but THE MECHANISM BY WHICH THEY ARE FORMED IS UNKNOWN.

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• CYTOPHAGIC HISTIOCYTIC PANNICULITIS was introduced to describe a rare entity characterised by subcutaneous nodules containing LOBULAR INFILTRATES OF MACROPHAGES WHICH HAD PHAGOCYTOSED LYMPHOCYTES, ERYTHROCYTES AND NUCLEAR DEBRIS.
• With modern immunohistochemistry and genetic techniques, MOST patients found to have cytophagic histiocytic panniculitis have ONE OF TWO TYPES OF PRIMARY LYMPHOMA affecting the subcutaneous tissue:
• SPTCL — a HOMOGENEOUS entity with an α/β+ T-cell phenotype, INDOLENT biological behaviour and GOOD prognosis.
• Primary cutaneous γ/δ T-cell lymphoma — patients are MORE HETEROGENEOUS and show a VERY AGGRESSIVE clinical course with POOR prognosis (Chapter 139).
• Although most cases represent one of the subcutaneous lymphomas, there is STILL A GROUP OF PATIENTS in whom a definitive diagnosis of lymphoma CANNOT be made and in whom molecular studies FAIL to demonstrate monoclonal rearrangements.
• Nevertheless, the prognosis within this group is OFTEN POOR, with PANCYTOPENIA and FATAL OUTCOME from HAEMOPHAGOCYTIC SYNDROME involving LIVER, SPLEEN and BONE MARROW.

• SPTCL and cytophagic histiocytic panniculitis may be INDISTINGUISHABLE — only after IMMUNOHISTOCHEMICAL AND MOLECULAR STUDIES can they be differentiated.
• At low power BOTH mimic a predominantly LOBULAR panniculitis.
• The fat lobule is involved by SMALL AND MEDIUM-SIZED ATYPICAL LYMPHOCYTES with HYPERCHROMATIC NUCLEI; numerous MACROPHAGES intermingled.
• A characteristic finding in favour of SPTCL: SPARING OF THE EPIDERMIS AND DERMIS.
• In some areas, atypical lymphocytes are arranged in a CIRCLE AROUND NECROTIC ADIPOCYTES ("RIMMING") — although this rimming is NOT ENTIRELY SPECIFIC for SPTCL and may also be seen in other lymphoid processes involving subcutaneous fat.
• Macrophages with CYTOPHAGIC ACTIVITY containing lymphocytes, neutrophils and nuclear debris within their cytoplasm — the so-called "BEAN BAG" CELLS — are a frequent finding in BOTH processes. FOAMY HISTIOCYTES are also frequently found in areas of fat necrosis.

• Lymphocytes involving the fat lobules have a TCR-α/β+, CD3+, CD4–, CD8+, TIA-1+ (T-cell intracellular antigen 1), PERFORIN+, GRANZYME B+, CD30– T-cell immunophenotype.
• NO evidence of EBV infection — either by PCR amplification for EBV-encoded RNA and EBV DNA or by immunohistochemical staining for LATENT MEMBRANE PROTEIN 1.
• As a consequence of its α/β+ T-cell phenotype, SPTCL expresses βF1 but is NEGATIVE for TCRγ and TCRδ — IN CONTRAST with primary cutaneous γ/δ+ T-cell lymphoma and other lymphoproliferative processes involving subcutaneous fat.
• MONOCLONAL REARRANGEMENT of γ or β genes can usually be detected in SPTCL by molecular analysis, whereas these rearrangements are NOT found in patients with CYTOPHAGIC HISTIOCYTIC PANNICULITIS.

• RARE, accounting for LESS THAN 1% of all primary cutaneous T-cell lymphomas, with EQUAL incidence in both genders, preferentially involving adult patients — although cases are also described in CHILDREN.
• Patients present with RED SUBCUTANEOUS NODULES that may GROUP INTO LARGE PLAQUES, typically involving the LOWER EXTREMITIES.
• A COMMON feature consists of areas of LIPOATROPHY WHEN THE LESIONS RESOLVE.
• Less commonly may involve the TRUNK, HEAD or UPPER EXTREMITIES.
• APPROXIMATELY 50% OF PATIENTS HAVE "B" SYMPTOMS — FEVER, FATIGUE and WEIGHT LOSS.
• CYTOPENIA and ELEVATION OF LIVER ENZYMES are frequently found, but a FRANK HAEMOPHAGOCYTIC SYNDROME IS RARE.

• CONSERVATIVE IMMUNOSUPPRESSIVE REGIMENS based on SYSTEMIC CORTICOSTEROIDS AND CICLOSPORIN may be effective in patients WITHOUT an associated HAEMOPHAGOCYTIC SYNDROME.
• In patients presenting with SOLITARY lesions, LOCAL RADIOTHERAPY MAY SUFFICE.

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• Synonym: postradiotherapy panniculitis.
• A rare clinicopathological variant appearing MONTHS OR YEARS AFTER RADIOTHERAPY in the IRRADIATED SKIN; lesions consist of subcutaneous INDURATED NODULES.
• In 1993 WINKELMANN et al. described the FIRST FOUR CASES of "pseudosclerodermatous panniculitis after irradiation"; since then only 10 ADDITIONAL cases have been published.

• A predominantly LOBULAR panniculitis with NECROSIS OF THE ADIPOCYTES AT THE CENTRE of the fat lobule and dense inflammatory infiltrates composed mainly of FOAMY HISTIOCYTES.
• The MOST CHARACTERISTIC features in the subcutaneous tissue: LIPOPHAGIC GRANULOMAS involving the PERIPHERY of the fat lobules, and THICKENING AND SCLEROSIS of the connective tissue SEPTA.
• These findings may or may not be accompanied by DERMAL CHANGES SECONDARY TO RADIOTHERAPY: SCLEROSIS of the PAPILLARY dermis; ATYPICAL STAR-SHAPED FIBROBLASTS scattered among dermal collagen bundles; and DILATED THROMBOSED BLOOD VESSELS with ENDOTHELIAL CELL SWELLING and HYALINE SCLEROSIS of their walls.

• Presents as an INDURATED, ASYMPTOMATIC subcutaneous NODULE OR PLAQUE with LITTLE OR NO CHANGE in the epidermis and dermis at the site of previous radiotherapy.
• The MOST COMMON location is the ANTERIOR CHEST WALL following treatment for BREAST CANCER — however it may appear in any previously irradiated area.
• The interval between the radiotherapy and presentation varies from MONTHS TO SEVERAL YEARS.

• Other diseases showing a septal or lobular panniculitis with sclerosis of the connective tissue septa: DEEP MORPHOEA and LUPUS PANNICULITIS.
• DEEP MORPHOEA: histopathologically a SEPTAL panniculitis WITHOUT significant lobular involvement, with sclerotic collagen bundles and aggregates of LYMPHOCYTES AND ESPECIALLY PLASMA CELLS at the interface between the septa and the fat lobules. In contrast with sclerosing postirradiation panniculitis, deep morphoea does NOT show LOBULAR involvement and the inflammatory cells within the thickened septa are MAINLY PLASMA CELLS.
• LUPUS PANNICULITIS: a mostly LOBULAR panniculitis with SCLEROTIC SEPTA, but in contrast with sclerosing postirradiation panniculitis, the infiltrate involving the lobules is MOSTLY composed of LYMPHOCYTES AND PLASMA CELLS.

• Treatment is NOT REQUIRED.
• Biopsy and subsequent histopathological study are ONLY performed when the possibility of a SUBCUTANEOUS METASTASIS from the previously excised and/or irradiated BREAST CANCER is raised.

• Inflammation in subcutaneous fat (adipose tissue, AT) is a diagnostic problem: clinical and histologic findings overlap
• No universally accepted classification; useful pathologic start = septal vs lobular, then presence/absence of vasculitis, composition of infiltrate, and additional specific features
• Septal prototype = erythema nodosum (EN); lobular = most other panniculitides
• Diagnosis needs clinicopathologic correlation (site, systemic symptoms, labs, etiology)
• Large excisional biopsy required; punch biopsies inadequate; more than one biopsy may be needed as lesions evolve
• Lipodermatosclerosis (LDS) = most common panniculitis; EN is next
• AT is an immune organ; adipocytes are innate immune cells — a recurring theme in pathogenesis

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• Diagnostic difficulty:
• Similar clinical presentations may have disparate histopathology
• A range of clinical presentations may share similar histopathology
• Septal = inflammation confined predominantly to septa; lobular = predominantly involving the fat lobule
• Septal/lobular division alone not adequate:
• Lobular granulomatous panniculitis may be seen in clinically classic EN
• Lobular panniculitides may have mixed lobular and septal inflammation
• Expanded classification: presence/absence of vasculitis (septa or lobules), composition of infiltrate, specific features
• Spectrum of histopathology in EN and others is variable → may not be possible to diagnose on histopathology alone
• Biopsy:
• Only large excisional biopsies adequately sample AT; small punch biopsies likely miss AT and infiltrate
• Inflammation in AT is not static → different stages show different features → more than one biopsy may be necessary
• Even with optimal sampling, no specific etiology for many reactions; open questions: why inflammatory cells accumulate in AT and what they do there

• Note: flowchart was column-scrambled in extraction; branches rebuilt from the order of terms and standard septal/lobular logic
• Mostly septal
• With vasculitis
• Small vessels (venules) → Leukocytoclastic vasculitis
• Large vessels: veins → Superficial thrombophlebitis; arteries → Cutaneous polyarteritis nodosa
• Without vasculitis
• Lymphocytes and plasma cells → Deep morphea
• Histiocytes, granulomatous infiltrate:
• Radial granulomas in septa → Erythema nodosum
• Mucin → Subcutaneous granuloma annulare
• Fibrin → Rheumatoid nodule
• Cholesterol clefts → Necrobiotic xanthogranuloma
• (granulomatous, septal) → Necrobiosis lipoidica
• Mostly lobular
• With vasculitis
• Small vessels (venules) → Erythema induratum of Bazin / Nodular vasculitis
• Others with vasculitis → Erythema nodosum leprosum, Lucio phenomenon
• Without vasculitis
• No inflammatory cells:
• Vascular calcification → Calciphylaxis
• Crystals → Oxalosis
• Needle-shaped crystals in adipocytes → Sclerema neonatorum
• Lymphocytes:
• Lymphoid follicles and plasma cells → Lupus panniculitis
• Superficial & deep perivascular infiltrate → Cold panniculitis
• Necrosis at the center of fat lobule (stasis) → Sclerosing panniculitis (LDS)
• Neutrophils:
• Saponification of adipocytes → Pancreatic panniculitis
• Neutrophils between collagen bundles → α1-antitrypsin deficiency
• Bacteria, fungi, protozoa → Infectious panniculitis
• Foreign bodies → Factitial panniculitis
• No specific feature → Neutrophilic lobular panniculitis
• Histiocytes:
• Granulomatous infiltrate → Subcutaneous sarcoidosis
• Cytophagocytosis → Cytophagic panniculitis
• Needle-shaped crystals in adipocytes → Fat necrosis of the newborn, Poststeroid panniculitis
• Crystals (needle-shaped/urate) → Gout panniculitis; crystals in histiocytes → Crystal storing histiocytosis
• No crystals → Traumatic panniculitis, Lipoatrophy
• Sclerosis of the septa → Postirradiation panniculitis
• Uncertain placements in reconstruction: exact cell-type branch for neutrophilic lobular panniculitis, traumatic panniculitis, lipoatrophy, crystal storing histiocytosis, Lucio phenomenon/ENL (small vs large vessels), and necrobiosis lipoidica feature label

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• Preferential localization aids differential diagnosis:
• Pretibial → EN
• Calf → erythema induratum (EI)
• Upper arms, shoulders, face → lupus panniculitis
• Explanation: adipocyte regions derive from different areas of mesoderm; varying gene expression in different fat depots
• Gene-expression differences between depots up to 1,000-fold; intrinsic, autonomous, independent of microenvironment
• Depots contain variable percentages of adipocytes of different developmental origins, including brown AT (BAT) within white AT depots
• AT roles: innate immunity, inflammation, adaptive immunity, energy homeostasis → adipocyte central to its inflammatory disorders
• Adipocytes carry transmembrane PRRs (TLRs), cytosolic PRRs (NLRs, RLRs), receptors for macrophage/lymphocyte interaction; produce and secrete multiple cytokines and adipokines
• Genetic or acquired functional abnormality / molecular perturbation → may result in panniculitis

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• May represent EN, EI, nodular vasculitis (NV), cutaneous polyarteritis nodosa, or nodules of vascular disorders
• Clinical and histologic findings overlap → need typical and unusual manifestations, associations, and histopathology

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• Clinical: symmetric, tender, erythematous, warm nodules and plaques on anterior lower extremities; may become confluent
• Acute onset; no ulceration or scarring; more common in women
• Fever, fatigue, arthralgias, arthritis, headache common
• Lasts 3–6 weeks, new lesions for up to 6 weeks
• Histopathology: mostly septal panniculitis without vasculitis; thickened septa with inflammatory cells; neutrophils early, histiocytes and Miescher granulomas late
• Treatment: treat associated disorder; bed rest, aspirin, NSAIDs; systemic corticosteroids rarely indicated

• Both genders, any age from childhood to 70 years; more common in young women, 2nd–4th decades
• No gender difference in childhood
• Prevalence: 2.4 per 10,000 population to 52 per million population
• Clinic patients: 0.38% (Spain) to 0.5% (England)

• Associations (70-0.2 online):
• Infections: bacteria, viruses, fungi, protozoa
• Medications: antibiotics, oral contraceptives, halides
• Malignancies: most often leukemias or lymphomas
• Autoimmune diseases; other inflammatory disorders, especially sarcoidosis and inflammatory bowel disease
• Streptococcal upper respiratory infections = most common infectious cause and most common cause in childhood (geographic variation exists)
• Tuberculosis: common in past; less frequent now but must always be excluded
• Half of all EN cases are idiopathic (viral cause often suspected)
• Considered a hypersensitivity reaction; mechanism not understood
• IFNγ and IL-2, leukocyte activation, upregulated adhesion molecules
• Genetic polymorphisms: TNF-α promoter, MIF (macrophage migration inhibitory factor), RANTES
• AT = immune organ; adipocytes = innate immune cells that activate inflammatory and adaptive immunity to destroy pathogens
• Excess proinflammatory adipokines linked to obesity, cardiovascular disease, hypertension, diabetes
• Protective role: EN associated with more limited coccidioidomycosis and less severe, shorter sarcoidosis
• Especially with HLA-DRB1*03, part of the "8.1 ancestral haplotype" (wide range of immunopathologic diseases)
• Enhanced inflammatory genes may confer resistance to pathogens → EN may protect against dissemination

• Acute onset of tender, painful, erythematous, warm nodules and plaques on anterior (at times lateral) lower legs and ankles, bilateral
• Other sites: forearms, thighs; rarely trunk or face, especially in children
• Nodules persist days–weeks; may become confluent
• Color evolves from erythematous/purple to bruise-like = erythema contusiforme (if hemorrhage in AT)
• Eruption lasts 3 to 6 weeks, new lesions up to 6 weeks; may persist longer and may recur
• Do NOT ulcerate; resolve without atrophy or scarring
• Systemic: fever, fatigue, malaise, arthralgia, arthritis, headache common; abdominal pain, vomiting, diarrhea, cough less frequent; ocular manifestations may occur
• Tonsillitis/pharyngitis/URI preceded onset in 20%–30% (two series)
• Prodromal symptoms 1–3 weeks before lesion onset; may exacerbate then

• High ESR, positive throat culture or high ASO (streptococcal), leukocytosis
• Positive PPD interpreted in context of local TB prevalence
• Chest X-ray: rule out pulmonary infection or sarcoidosis
• Serology/culture and other tests as indicated

• Prototype of septal panniculitis; lobular inflammation may also be present
• Earliest: septal edema, extravasated RBCs, scattered neutrophils
• Fully developed: widened septa, early fibrosis, septal infiltrate of lymphocytes, histiocytes, neutrophils, eosinophils
• Extension into adjacent lobules possible, but NO centrilobular necrosis of adipocytes
• Late: widened fibrotic septa, often with granulomas; may partially efface lobules
• Predominantly polymorphonuclear infiltrate occasionally → part of early phase
• Miescher's granuloma: discrete micronodular aggregate of small histiocytes around a central stellate cleft
• Considered characteristic of early EN by some; not universally found; also seen in other panniculitides
• Evolves: later aggregates of larger histiocytes and multinucleated giant cells retain central cleft
• Superficial and deep perivascular dermal infiltrate frequent
• Lipomembranous changes in late EN
• Vasculitis absent by definition; but thrombophlebitis emphasized by some in early EN; medium-vessel arteritis rarely

• Cellulitis; infection-induced panniculitis; acute LDS
• EI/NV: tends to appear on calves and ulcerate
• Other vasculitides (differentiate histologically)
• Pancreatic panniculitis: anywhere on leg, ulcerates and drains, ↑ serum lipase and amylase

• Primarily treat/remove etiologic factor: stop suspected drugs; seek and treat infections, inflammatory disorders, malignancies
• May persist months; recurrence possible, especially if etiology unknown
• Bed rest, leg elevation, aspirin, NSAIDs (avoid with IBD)
• SSKI (supersaturated potassium iodide): 2–10 drops three times per day in water or orange juice (1 drop = 0.03 mL = 30 mg)
• Risks: hypothyroidism and goiter (thyroid disorders, certain medications); hyperkalemia toxicity (heart, lungs)
• Contraindicated in pregnancy
• Others: colchicine (especially Behçet's), corticosteroids (rarely; exclude infection first), etanercept, infliximab for IBD-associated EN

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• Clinical: erythematous subcutaneous nodules and plaques of lower legs; calves common, also anterolateral legs, feet, thighs; rarely elsewhere
• Associated with venous insufficiency; more frequent in middle-aged women
• Often ulceration and scarring, especially calves; chronic course
• Seek infectious etiology: bacterial (especially Mycobacterium tuberculosis, MTB), fungal, protozoal, viral
• Histopathology: mostly lobular or mixed lobular and septal panniculitis with vasculitis in 90%
• Extensive necrosis of adipocytes at center of lobule
• Infiltrate: neutrophils early; epithelioid histiocytes and multinucleated giant cells in developed lesions
• Vasculitis of small veins and venules of fat lobule
• Treatment: positive MTB microbiology, serology, Mantoux, or MTB DNA → full course of triple-agent antituberculosis therapy; other proven/suspected infection → treat it
• Otherwise: potassium iodide, other anti-inflammatories, supporting bandages, support hose, leg elevation, bed rest

• EI: inflammatory panniculitis, ulcerated nodules on calves, frequently associated with MTB
• NV: similar disorder without ulceration, calves and other leg sites, without MTB association
• Features in same or different flares overlap → studies conclude the two are impossible to separate → terms used interchangeably
• Some prefer EI = MTB-associated, NV = non-MTB to emphasize need for antituberculosis therapy
• Most common in young to middle-aged women
• Recurrent erythematous to violaceous nodules and deep plaques on lower legs; tender or only tender to pressure
• Some heal without scarring, but ulceration often leads to scarring
• Surface: crusted ulcers with surrounding collarette of scale
• Histology: mostly lobular panniculitis; extensive adipocyte necrosis and necrotizing vasculitis of small venules in lobule
• Posterior calf = most frequent site; also anterolateral legs, feet, thighs; rarely arms, face
• More frequent in winter; associated with obesity and venous insufficiency

• Protracted, recurrent episodes over years
• Patients generally in fairly good health apart from associated diseases; lack EN-type systemic symptoms
• Single reports: membranous glomerulonephritis; painful peripheral neuropathy in initially MTB skin-test-negative patient later found MTB-positive cervical lymph node culture

• Positive MTB culture, skin test, or QuantiFERON gold → triple-agent antituberculosis therapy
• Hepatitis B or C → appropriate intervention
• Seek and treat fungi, parasites, viruses; discontinue inciting medications
• Non-MTB EI/NV anti-inflammatories: SSKI, NSAIDs, colchicine, antimalarials, corticosteroids, gold
• Bed rest/leg elevation; venous insufficiency → compression and pentoxifylline
• Others: tetracycline, mycophenolate mofetil
• With immunosuppressives → continued monitoring for infectious etiology

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• Synonyms: sclerosing panniculitis, hypodermitis sclerodermiformis, chronic panniculitis with lipomembranous changes, sclerotic atrophic cellulitis, venous stasis panniculitis
• A form of sclerosing panniculitis of the lower legs

• Clinical: indurated plaques of wood-like consistency on lower legs; acute and chronic changes; pain frequent
• Chronic venous insufficiency, higher than normal BMI, female, arterial hypertension, arterial ischemia, thrombophlebitis episodes
• Pulmonary hypertension in patients with systemic sclerosis and sclerosing panniculitis
• Histopathology: stasis background; mostly lobular panniculitis without vasculitis
• Ischemic necrosis at center of fat lobule
• Thickened, fibrotic septa, atrophy of subcutaneous fat; marked fibrosis and sclerosis in late severe cases
• Frequent membranocystic changes
• Treatment: compression stockings, ultrasound therapy, pentoxifylline; anabolic steroids in some

• Most common form of panniculitis — far more frequent than EN (next highest)
• Associated with venous insufficiency; mostly overweight women over 40
• Review of 97 patients:
• 87% female; mean age at diagnosis 62 years
• 85% overweight (BMI >30); 66% obese (BMI >34)
• Comorbidities: hypertension 41%, thyroid disease 29%, diabetes mellitus 21%, prior lower-extremity cellulitis 23%, DVT 19%, psychiatric illness 13%, peripheral neuropathy 8%, atherosclerosis obliterans 5%
• Precise prevalence unavailable (ICD-9 placement under "Venous insufficiency with inflammation"; multiple names)
• Rising obesity and aging baby boomers → expected increase in incidence/prevalence

• Common: female, venous hypertension, higher BMI
• Proposed factors:
• Elevated hydrostatic pressure → ↑ vascular permeability from downregulated tight junctions → extravascular fibrin
• Microthrombi; protein S and protein C abnormalities; hypoxia
• Endothelial damage by inflammatory cells
• Upregulated ICAM-1, VCAM-1, LFA-1, platelet- and endothelial-derived factors
• Inflammation + wound healing + collagen stimulation → fibrosis → further vascular and lymphatic damage
• Fibrosis: ↑ TGF-β1 gene and protein expression; ↑ procollagen type 1 gene expression
• AT hypoxia → chronic inflammation, macrophage infiltration, cytokines
• Adipocyte remodels ECM: produces MMPs, TIMPs, other proteases
• AT expansion (obesity) → hypoxia → ↑ HIF1α → collagen I and III and other ECM factors → fibrosis
• Infectious hypothesis: Cantwell (1979) — unusual pleomorphic, non-rod-shaped acid-fast bacteria (not culturable) in LDS biopsies (controversial)
• Recurrent cellulitis causes lymphatic damage and AT changes (widely accepted)
• Role of infection should be reconsidered, analogous to MTB DNA / dormant MTB in leg AT in EI

• Acute inflammatory stage and chronic fibrotic stage, with intermediate/overlapping forms
• Acute (Fig. 70-7A per text):
• Very painful, poorly demarcated, cellulitis-like erythematous to purple, somewhat edematous indurated plaques or nodules
• Most common on lower anteromedial calf; scaling in some
• Pain may be so intense patients cannot tolerate a bed sheet
• Often misdiagnosed as EN, cellulitis, thrombophlebitis; compression may not be tolerated
• Lasts a few months to a year
• May lack obvious venous disease, but vascular studies show venous insufficiency in the majority
• Normal venous studies → most have high BMI (inactivity → inadequate calf muscle pump); obesity also linked to arterial hypertension
• Chronic (may or may not follow obvious acute form):
• Indurated to sclerotic, depressed, hyperpigmented skin (Fig. 70-7B per text)
• Lower portion of lower leg, predominantly medial, or stocking distribution
• "Inverted champagne bottle" / "bowling pin" appearance
• Some report no pain, but pain = most frequent symptom in others
• Most obese/overweight, hypertensive, with venous abnormalities but rarely obstruction
• Unilateral 55%, localized plaque 51%, ulceration 13%
• Dermatosclerosis in systemic sclerosis: associated with pulmonary infarction and hypertension from leg thrombi
• Note: figure legend text labels Fig. 70-7A as sclerotic hyperpigmented chronic LDS and 7B as acute-on-chronic with ulceration (legend and body text differ)

• Ankle brachial index (arterial)
• Venous: Dopplers (thrombi); color duplex sonography (flow direction, venous reflux)
• Biopsy discouraged if clinically characteristic → high incidence of ulcers at biopsy site
• If needed: thin elliptical excision from the margin of erythematous indurated area, closed primarily with sutures

• Dermal stasis changes at any stage: proliferation of capillaries and venules, small thick-walled vessels, extravasated RBCs, hemosiderin-laden macrophages, lymphohistiocytic inflammation, fibrosis
• Early subcutis: sparse septal lymphocytes + central lobular ischemic fat necrosis (pale-staining, small anucleate adipocytes)
• Capillary congestion in lobules ± endothelial necrosis, thrombosis, RBC extravasation, hemosiderin
• Septal fibrosis, small foci of lipomembranous fat necrosis and fat microcysts also in acute lesions
• Lipomembranous (membranocystic) change:
• Small pseudocystic spaces in necrotic fat, lined by hyaline eosinophilic material (residue of disintegrated adipocytes and macrophage interaction)
• Lining highlighted by PAS; may show an arabesque pattern (undulating papillary, crenulated projections)
• NOT exclusive to LDS — may be found in any panniculitis
• Progression: increasing membranocystic necrosis, septal fibrosis/thickening, infiltrate of lymphocytes, histiocytes, foamy macrophages, partial to extensive lobular atrophy
• Advanced: septal sclerosis most prominent, marked lobular atrophy (lipophagic fat necrosis), microcystic/lipomembranous change, markedly reduced inflammation
• Most severe: marked fibrosis and sclerosis with little inflammation
• Late: lower dermis fibrous thickening, subcutis replaced by sclerosis → punch biopsy may contain no subcutaneous fat

• Compression = major universally recommended treatment
• Higher gradient 30–40 mm Hg may be more effective
• Lower class 15–20 or 20–30 mm Hg → better compliance (especially elderly); effective in reducing edema
• Mechanism: tightens vascular tight junctions, ↑ tight-junction proteins, ↓ permeability → prevents progression of venous insufficiency
• Wear all day until bedtime; even a few days without may cause recurrence of edema/inflammation
• Stanozolol: ↓ pain, erythema, induration; well tolerated; risk hepatotoxicity; no longer distributed in the US
• Other anabolic steroids: oxandrolone, danazol
• Pentoxifylline: successful with or without ulceration
• Cochrane review (2007): 12 trials, 864 patients → useful adjunct to compression for venous ulcers; may work without compression
• Other chronic venous insufficiency treatments: horse chestnut seed extract, oxerutin, flavonoid fraction
• Ultrasound therapy (two studies): reduced/resolved hardness, tenderness, erythema; simple, safe, via physical therapy; use with Grade-2 compression

• Weight reduction prudent (overweight/obesity common)

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• Clinical: wide variety of agents — bacteria, fungi, parasites, viruses; AT may serve as reservoir
• Primary inoculation or hematogenous spread; patients may be immunosuppressed
• Erythematous plaques, nodules, abscesses, ulcers with purulent discharge
• Histopathology: suppurative granulomas within fat lobule
• Primary cutaneous infection → epicenter superficial dermis; secondary → deep reticular dermis and subcutaneous fat
• Special stains, cultures, serology necessary
• Treatment: appropriate antimicrobials per susceptibility testing

• Synonyms: infectious panniculitis, infective panniculitis — panniculitis directly caused by an infectious agent
• Agents: bacteria, mycobacteria, fungi, protozoa, viruses
• Primary: direct inoculation (injury, surgery, catheter, injection, acupuncture) → usually single lesion, enlarges/spreads locally
• Secondary: sepsis/hematogenous → single or multiple lesions
• Immunosuppressed: organisms numerous, seen on routine/special stains
• Immunocompetent: organisms sparse, may need cultures or serology
• Reported with autoimmune disorders:
• Staphylococcus aureus panniculitis with juvenile dermatomyositis
• Mycobacterium- and Histoplasma-associated panniculitis with rheumatoid arthritis
• Diffuse fusariosis with acute lymphoblastic leukemia

• Range: fluctuant/abscess lesions with purulent discharge and ulceration → nonspecific firm nonfluctuant plaques/nodules, purpuric plaques, EN-type lesions
• Deep nodules may not seem fluctuant; pustules, fluctuant papules, ulcers may be superimposed
• Most common sites: legs and feet; also upper extremities, trunk, face
• Immunosuppression = most frequent (not universal) association
• Immunosuppressed → widespread abscess-type lesions with nontuberculous mycobacteria
• Immunocompetent → granulomas more common
• Fungal settings:
• (1) Localized environmentally injected: mycetoma, chromoblastomycosis, sporotrichosis
• (2) Systemic disseminated fungal infection (normal immunity) or opportunistic infection (immunocompromised)
• Features vary with setting, organism, immune status

• Evaluate with special stains for all organisms plus culture and sensitivity of biopsy material
• Anti-BCG polyclonal antibody immunostain: cross-reacts with many bacteria, mycobacteria, fungi, minimal background → good screening tool in paraffin tissue when conventional stains negative
• PCR used for mycobacteria
• Features vary with organism, virulence, host immunity, lesion duration
• Classified by some as mostly lobular, but often mixed septal and lobular; predominantly septal EN-like neutrophilic panniculitis reported with bacterial and fungal causes
• Superficial dermis epicenter: direct inoculation or indwelling catheter; deep reticular dermis/subcutis: hematogenous
• Typical: dense neutrophilic infiltrate in fat with lymphocytes and macrophages, extension into dermis, abscess formation common
• Patterson et al (15 cases; bacterial, atypical mycobacterial, fungal) — features independent of organism, in majority:
• Subcutis: hemorrhage, vascular proliferation, foci of basophilic necrosis, sweat gland necrosis
• Epidermis (all evaluable cases): parakeratosis, acanthosis, spongiosis
• Dermis (all 15): upper dermal edema, diffuse and perivascular infiltrate often with prominent neutrophils, thick-walled vessel proliferation, focal or diffuse hemorrhage
• Any of these → special stains imperative; possibly IHC or PCR
• Clues:
• Suppurative granulomas (epithelioid histiocytes around neutrophils) → atypical mycobacteria
• Caseating granulomas (rare) → tuberculous panniculitis
• CMV panniculitis: mostly septal, many CMV inclusions in endothelial cells

• α1-antitrypsin panniculitis, pancreatic, traumatic, factitial panniculitis
• One of these diagnoses does NOT exclude infection (e.g., α1AT panniculitis with lymph node histoplasmosis)

• Depends on organism, cultures, sensitivities
• MTB and parasites such as T. cruzi can remain dormant in AT → adequate duration of antibiotics able to affect nonreplicating organisms

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• Clinical: ZZ-, MZ-, MS-, SS-phenotype panniculitis rare; higher percentage (>60%) in ZZ
• Low α1AT associated with emphysema, hepatitis, cirrhosis, vasculitis, angioedema
• Nodules mostly on lower abdomen, buttocks, proximal extremities
• Frequent ulceration and isomorphic phenomenon
• Histopathology: mostly lobular without vasculitis; necrosis of fat lobules with dense neutrophilic infiltrate
• Splaying of neutrophils between collagen bundles of deep reticular dermis
• Large areas of normal fat adjacent to necrotic adipocytes
• Treatment: dapsone, doxycycline
• Severe homozygous ZZ: IV α1-proteinase inhibitor concentrate or recombinant α1AT; liver transplantation

• α1AT: glycoprotein = 90% of total serum serine protease inhibitor capacity
• Produced mainly by hepatocytes; small amounts by monocytes/macrophages and neutrophils
• Inhibits trypsin, chymotrypsin, leukocyte elastase, kallikrein, collagenase, plasmin, thrombin, others
• May regulate protease-stimulated lymphocyte activation, phagocytosis, complement activation
• Acute phase reactant
• Inheritance: codominant; >100 alleles
• Phenotypes by gel electrophoresis mobility: F (fast), M (medium), S (slow), Z (very slow)
• Null variants produce no α1AT; some have dysfunctional α1AT with normal levels
• MM = most common, normal levels; ZZ = 10%–15% of normal; S or Z heterozygotes intermediate; MS may be low normal
• Recommend combined protein levels, phenotyping and genotyping
• Prevalence in US Caucasians: 1 per 3,000–5,000; newborn incidence similar to cystic fibrosis

• Mostly causes COPD, hepatic cirrhosis, hepatocellular carcinoma; ZZ highest risk
• Null variant: NO hepatic disease (liver damage from accumulated polymerized α1AT, which doesn't occur in null); exact injury mechanism controversial
• Panniculitis uncommon: <50 cases reported (ZZ, MZ, MS, SS); >60% ZZ; women 65%
• Age: infancy to elderly; most often 30–60 years
• Painful erythematous nodules and plaques; early lesions may be cellulitic or fluctuant abscess-like
• Ulcerate and discharge oily or serosanguineous material → atrophic scars
• Sites: lower trunk (buttocks), proximal extremities; lower legs/others possible
• Trauma or excessive activity precedes onset in one-third → debridement discouraged
• Reported with hypothyroidism, MCTD, lymphoproliferative disorders, infections (histoplasmosis in lymph node) → α1AT deficiency should not preclude search for infection, autoimmune disease, malignancy
• Rapid cutaneous/subcutaneous necrosis; extensive disease life-threatening; fatal cases reported
• Erythrophagocytosis in biopsy of one fatal case
• Mechanism: unopposed proteases → activation of lymphocytes, macrophages, complement, connective tissue destruction; trauma activates adipocytes → chemotactic adipokines/cytokines → unopposed proteases → severe damage
• Animal soft-tissue injury models: ↑ IL-6, MCP-1, systemic inflammatory mediators

• Early: edema, adipocyte degeneration (ruptured/collapsed membranes), perivascular mononuclear infiltrate; mild neutrophils/macrophages in septa and lobules; foci of early fat necrosis
• Splaying of neutrophils between collagen bundles of reticular dermis = early, distinctive diagnostic clue
• Advanced: masses of neutrophils and histiocytes with necrosis and replacement of lobules
• Focal pattern: large areas of normal fat immediately next to necrotic septa/lobules
• Liquefactive necrosis, dissolution of dermal collagen ± ulceration; elastic degeneration → septal destruction → "floating" necrotic fat lobules
• Rare: exclusively septal mixed, neutrophil-predominant infiltrate
• Late: fewer neutrophils/necrotic adipocytes; lymphocytes, foamy histiocytes, fibrosis

• Other ulcerating/draining panniculitides: infections, factitial, EI, pancreatic
• Do NOT usually drain/ulcerate: subcutaneous Sweet syndrome, rheumatoid arthritis- and myelodysplasia-associated neutrophilic panniculitis

• Used: colchicine, antimalarials, steroids, immunosuppressives, cytotoxics, dapsone, doxycycline, plasma infusion/exchange, IV α1AT replacement, liver transplantation
• Least successful: steroids, immunosuppressives, cytotoxic agents
• Doxycycline and especially dapsone: very helpful in mild to moderate cases
• Severe: A1P (α1-proteinase inhibitor) replacement therapy
• Resolved with liver transplantation; panniculitis after transplant treated with retransplantation

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• Clinical: erythematous subcutaneous nodules that often ulcerate spontaneously; lower extremities (ankles, knees) most frequent
• Pancreatitis-associated lesions regress; carcinoma-associated persist; may be fatal
• Histopathology: mostly lobular, no vasculitis; intense necrosis at center of lobule; ghost adipocytes with finely granular basophilic intracytoplasmic material
• Treatment: treat pancreatic disease; octreotide; plasmapheresis

• Develops in 2%–3% of all patients with pancreatic disorders: acute or chronic pancreatitis, pancreatic carcinoma, pseudocysts
• Pancreatitis causes: alcohol, cholelithiasis, pancreatic calculi; also medications and viral infections
• Panniculitis precedes pancreatic diagnosis by weeks–months in up to 45%
• Mono-/oligoarticular arthritis (periarticular fat necrosis) in over half
• Triad: pancreatic disease + panniculitis + polyarthritis — with pancreatitis or carcinoma; <1% of pancreatitis patients; joint disease may precede diagnosis
• Abdominal symptoms may be mild or absent
• Also with pancreatitis after renal or pancreas-renal transplant, SLE, hemophagocytic syndrome (HPS)
• Mortality: up to 24% in one series; another: 100% with carcinoma and 42% of 19 with pancreatitis

• Attributed to circulating lipase, amylase, trypsin → ↑ vascular permeability → fatty acid release → fat necrosis
• BUT: normal enzyme levels reported in typical cases; in vitro incubation of AT with amylase/lipase or high-enzyme patient serum failed to induce fat necrosis
• Other mechanisms: venous hypertension (lower legs), adipocyte cytokines/adipokines from high free fatty acids
• Resistin and leptin: potential markers of extrapancreatic fat necrosis

• Most on lower legs, especially periarticular; also arms, thighs, trunk
• Often in crops; single-nodule form also occurs
• Ill-defined erythematous to red–brown edematous tender nodules
• Mild → involute with atrophic hyperpigmented scars
• May have central "softer" areas, become fluctuant, abscess-like, drain oily material (like α1AT)
• Extracutaneous: periarticular fat necrosis with arthritis, painful medullary fat necrosis in bone, pleural effusions and serositis
• Pleural effusions (alone or with arthritis) → high mortality
• Eosinophilia in pancreatitis- and malignancy-associated cases
• Schmid's triad: pancreatic tumor + panniculitis + polyarthritis + eosinophilia → poor prognosis

• Lobular fat necrosis
• "Ghost cells": adipocytes lose nuclei but keep peripheral outlines
• Saponification → calcification → fine granular basophilic deposits in/around necrotic adipocytes
• Ghost cells in small clusters at lobule center, with peripheral neutrophilic infiltrate
• Older: fewer ghost cells; foamy histiocytes, multinucleated giant cells, lymphocytes, eventually fibrosis
• Earliest may be septal, EN-like
• Mimic: subcutaneous interferon β injection sites (multiple sclerosis)

• Supportive; directed at underlying pancreatic disorder
• No abdominal symptoms possible → consider in differential of ANY panniculitis
• Resolution with specific surgical treatment of underlying disorder
• Octreotide (somatostatin analog) and plasmapheresis associated with resolution

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• Clinical: erythematous nodules on face, shoulders, upper arms, scalp, chest, buttocks; rarely lower extremities
• Persistent lipoatrophy in regressed lesions
• Histopathology: mostly lobular, no vasculitis (lymphocytic vasculitis occasionally)
• Lobular lymphocytic infiltrate, plasma cells in many, eosinophils sometimes
• Lymphoid follicles with germinal centers often
• Sclerotic collagen bundles in septa
• Hyaline necrosis and atrophy of entire lobule late
• DLE interface changes in 20%–30% (interface changes may rarely accompany SPTL)
• Treatment: antimalarials, thalidomide; active severe → short oral corticosteroid courses; dapsone, cyclosporine, methotrexate, IVIG, rituximab

• Rare LE variant primarily affecting subcutaneous AT
• Sole manifestation of LE, or before/after DLE or SLE
• SLE in LEP patients: 10% to 41% (highest in Japanese series of 44)
• LEP in only 1%–5% of SLE patients
• Worldwide; female:male ~4:1
• Most common ages 30–60; rarely childhood or neonatal lupus
• With SLE → tends to occur in less severe SLE
• Few familial reports (LEP in >1 member, or relatives with SLE only)
• Other autoimmunity: Sjögren's syndrome, rheumatoid arthritis

• Innate immunity important in SLE; adipocytes = innate immune cells (pathogen recognition, adaptive activation, microbial reservoir)
• All TLRs expressed in AT
• Adipocytes: TLR1, 2, 3, 4, 6
• Stromovascular fraction: TLR5, 7, 8, 9, 10
• Possible causes: TLR polymorphisms → inappropriate innate activation (especially type 1 interferon); abnormal adipocyte–inflammatory cell interaction; responses to microbial/nonmicrobial antigens in AT
• Localization to specific depots may reflect adipocyte function, genetic aberration, or lymphocyte type attracted
• SLE: TLR7 (RNA) and TLR9 (DNA) recognize self-nucleic acids → adaptive activation → autoantibodies
• TLR7/TLR9 inhibitors prevent disease in mouse models; TLR9 deletion may enhance disease in some models
• Both suggested therapeutic targets
• TLR9 genetic variation predisposes to SLE (Japanese series)
• SLE regression in a patient with acquired TLR7 and TLR9 defect and antibody deficiency
• TLR7 and TLR8 encoded on X chromosome (female predominance)
• Hydroxychloroquine blocks intracellular TLRs in vitro

• Tender/painful; upper arms (lateral), shoulders, face, scalp, hips, buttocks, breasts; rarely lower extremities
• Orbital/ocular: periorbital edema
• Deep subcutaneous nodules without surface change, or with erythema and DLE features (atrophy, hyperkeratosis, hyper/hypopigmentation, telangiectasia, follicular plugging, focal ulceration/necrosis)
• Shoulder and arm sites frequently have surface DLE
• Ulceration: <7% (44 Japanese cases) to 28% (40 US cases)
• Lesions enlarge/coalesce → large atrophic areas; indurated panniculitis may coexist with DLE, atrophy, bizarre scars
• Resolves with depressed lipoatrophy (upper arms, shoulder, buttock); facial → atrophic malar areas, severe cosmetic change
• Chronic with yearly/periodic flares or long remissions
• Lesions at trauma sites (injections, surgery)
• Average duration 6 years (range <1 to 38 years)
• Serology: normal or abnormal
• Without SLE → low positive ANA; with SLE → higher titers
• C4 deficiency may be found
• Others: RF, false-positive VDRL, specific ANAs, leukopenia, anemia, thrombocytopenia

• DLE features in ~20%–30%: basal vacuolar alteration, thickened basement membrane, dermal mucin, superficial and deep perivascular lymphocytes
• BM thickening, liquefaction degeneration, pigment incontinence in significant percentages without clinical epidermal change
• AT: mostly lobular or mixed panniculitis with lymphocytes, lymphoid follicles (some germinal centers), variable hyaline fat necrosis, hyalinized sclerotic septal collagen with lymphocytes and plasma cells
• Occasional lymphocytic vasculitis of small lobular vessels; eosinophils in some; membranocystic change in some late lesions
• Calcification and/or fibrin thrombi in 10%

• AT-only cases: differentiation from subcutaneous T-cell lymphoma essential but very difficult
• Spectrum: LEP → indeterminate lymphocytic lobular panniculitis → SPTL
• Epidermal involvement in SPTL possible; two cases thought to be LEP (one with interface vacuolar change and mucin, one with vacuolar interface change) were fatal SPTL
• Multiple wedge biopsies may be needed to separate αβ TCR-SPTL (SPTL-AB) or more ominous γδ TCR (SPTL-GD) from LEP
• Hemophagocytic syndrome: reported in SLE with panniculitis, but more common in SPTL-AB and SPTL-GD

• DIF very helpful: positive in almost all SLE-associated LEP, high percentage in LEP alone; vessel Ig/complement deposition varies
• DIF may give diagnosis when histology nonspecific
• IHC: αβ T helper (CD4+) and cytotoxic (CD8+) lymphocytes mixed with CD20+ B cells and plasma cells
• TCR-γ gene: polyclonal; some LEP clonal yet respond to antimalarials/steroids without lymphoma → possible abortive lymphoid dyscrasia
• Six active LEP biopsies: high MxA (type I IFN marker) in epidermis and infiltrate; many CD123+ plasmacytoid cells; IP10/CXCL10
• 60%–90% of lobular infiltrate = cytotoxic CXCR3+ lymphocytes expressing granzyme B and TIA1 → type 1 interferon-driven response

• SPTL; panniculitis of DM or morphea; panniculitides in SLE such as pancreatic panniculitis and EN

• Challenging; response judged clinically (erythema, induration, tenderness)
• Antimalarials = first line; may be the only drug needed
• Hydroxychloroquine fails → add quinacrine
• Less effective in smokers; need at least 3 months
• Act on inflammatory cytokines and TLRs
• Smoking effect not well defined (may attenuate and enhance immune aspects; suppresses airway innate response)
• Corticosteroids: effective if active and severe; short term during antimalarial initiation; avoid long term
• Intralesional steroids NOT recommended (traumatic, induce atrophy)
• Others: dapsone, thalidomide, cyclosporine, methotrexate, IVIG, rituximab

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• Clinical: erythematous painful nodules and plaques on arms, buttocks, thighs, abdomen
• Histopathology: mostly lobular or mixed septal and lobular; lobular lymphocytic and plasma cell infiltrate, hyaline sclerosis of septal collagen, progressive lobular fibrosis; calcification in 25%; may have vacuolar DEJ alteration; membranocystic change late
• Treatment: same as for dermatomyositis

• Clinical panniculitis in DM very rare, despite focal nonspecific panniculitis in 9% (5/55) of biopsy specimens (text prints "Diabetes Mellitus (DM)" — in context means dermatomyositis)
• 2009 review: 24 cases of clinical nodular/plaque panniculitis in DM, including 6 children

• Painful indurated erythematous nodules and plaques on arms, buttocks, thighs, abdomen; may ulcerate → lipoatrophy
• Usually with characteristic DM skin findings; rarely sole manifestation
• Juvenile DM can cause lipoatrophy without preceding clinical panniculitis

• Similar to lupus panniculitis: mostly lobular or mixed; lymphocytes and plasma cells; hyaline sclerosis and fibrosis of septa; progressive fat replacement by fibrosis; calcification in 25%
• ± vacuolar DEJ alteration; late membranocystic change
• Dermis: mucin or edema with perivascular lymphocytes

• Cellulitis, infection-associated panniculitis, lupus panniculitis (clinical + lab + histology)

• May precede, accompany, or follow DM; flares and subsides with DM activity
• Infection worsens panniculitis: 3 patients — 2 S. aureus (one immunosuppressed adolescent with MRSA and Acinetobacter baumannii), 1 Mycobacterium chelonae
• Membranocystic changes → worse prognosis

• Corticosteroids alone, or corticosteroids + methotrexate, or azathioprine, cyclosporine, IVIG
• Juvenile DM panniculitis response to hydroxychloroquine variable
• Cutaneous calcification may benefit from IVIG
• Aggressively seek infection before increasing immunosuppression; may need antibiotics + reduced immunosuppression
• Panniculitis also occurs in morphea (Chapter 64) and systemic sclerosis (Chapter 157)

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• Note: only the At-a-Glance box is present in the extracted text; the narrative section is absent from the source file
• Clinical: subcutaneous erythematous to violaceous plaques and nodules on extremities, trunk (less often elsewhere); lesions ulcerate
• Fever, hepatosplenomegaly, two or more cytopenias; hemocytophagocytosis in bone marrow, lymph nodes, liver, or CNS
• Hypertriglyceridemia, ferritin >500 mg/L (as printed); ↑ soluble CD25, CD163
• Low or absent NK cell activity; low fibrinogen
• Course: rapidly fatal; intermittent remissions/exacerbations before death; or nonfatal acute or intermittent
• Histopathology: mostly lobular, no vasculitis
• Histiocytes and mature lymphocytes in lobules
• "Bean-bag" cells: macrophages containing intact or fragmented erythrocytes, leukocytes, or platelets; may be focal, hard to find
• Adipocyte necrosis
• Treatment: immunosuppression — glucocorticosteroids with cyclosporine or etoposide, combined chemotherapy, anakinra; supportive care; search for malignancy and infection

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• Clinical: circumscribed red to violaceous subcutaneous nodules/plaques; predilection for buttocks, shoulders, cheeks, thighs
• Hypercalcemia in some, even much later than acute episode; rarely hypertriglyceridemia, hypoglycemia, thrombocytopenia, anemia
• Histopathology: mostly lobular, no vasculitis; dense infiltrate of lymphocytes, histiocytes, lipophages, multinucleated giant cells; needle-shaped clefts, often radial, in histiocytes and giant cells
• Treatment: usually resolve spontaneously; monitor for hypercalcemia for 6 months after onset; treat if it develops

• Rare; first few weeks of life; full-term newborns with perinatal problems:
• Meconium aspiration, asphyxia, hypothermia (e.g., cardiac surgery, ice pack for SVT), hypoxemia, seizures, sepsis, preeclampsia, factors requiring cesarean section, forceps delivery, severe neonatal anemia, maternal cocaine use, failure to thrive
• Complications: hypercalcemia; rarely hypertriglyceridemia, hypoglycemia, thrombocytopenia, anemia

• Unknown; hypothermia or hypoxia presumed
• Biochemical defect in neonatal fat composition/metabolism → crystallization, fat necrosis, inflammation after cold stress
• Hypercalcemia: ↑ 25-hydroxyvitamin D3–1α hydroxylase in the granulomatous infiltrate
• BAT role: rapidly converts fat to heat in cold stress; widely distributed early in life; maximal relative size at birth → "thermogenic jacket" (immature thermoregulation)
• BAT leaks hydrogen ions across inner mitochondrial membrane → heat instead of ATP
• Uses uncoupling protein 1 (UCP1) (specific to BAT), cytosolic fatty acids, Ca2+

• Sharply demarcated, erythematous to violaceous, firm indurated nodules or plaques on back, shoulders, arms, buttocks, thighs, face; usually NOT anterior trunk
• One case: MRI fat necrosis in abdominal wall and fat around liver, spleen, kidney
• Size several mm to 11 cm; single or multiple; may be irregular but usually well defined
• Rarely fluctuant, draining oily or chalky white material
• Not warm; painless to pain requiring morphine

• Mostly lobular; focal lobular necrosis; dense lymphocytes, histiocytes, foreign body giant cells; few eosinophils
• Adipocytes keep outlines; contain fine eosinophilic strands/granules and needle-shaped clefts in radial array
• Frozen section: clefts contain doubly refractile crystals = triglycerides
• Similar clefts in multinucleated giant cells
• Late: fibrosis and calcification (also seen radiographically)

• Cellulitis, erysipelas, cold panniculitis (if cold-induced) — cold panniculitis lacks needle-shaped clefts
• Other childhood panniculitides with needle-shaped clefts:
• Sclerema neonatorum: diffuse skin hardening in stressed infants
• Poststeroid panniculitis: children, usually within 10 days (range 1–40 days) after rapid cessation of high-dose systemic corticosteroids
• Only one infant with both sclerema diffuse hardening and SCFN violaceous nodules

• Usually benign, excellent prognosis; lesions regress in a few weeks to 6 months, some with atrophy
• Metabolic complications during and after resolution: hypercalcemia, thrombocytopenia, hypertriglyceridemia (related to fat necrosis), anemia
• Hypercalcemia: asymptomatic or symptomatic — failure to thrive, irritability, fever, vomiting, hypotonia, seizures, polyuria, polydipsia, even death
• Soft tissue calcification may occur without hypercalcemia; calcium may deposit in kidneys and cardiovascular system
• Hypercalcemia onset may be delayed up to 6 months → serial serum calcium monitoring

• Conservative; resolve spontaneously
• Fluctuant lesions: aspiration to prevent rupture, infection, necrosis, scarring
• Serial calcium determinations
• Hypercalcemia (pediatric endocrinologist): hydration, furosemide (calcium-wasting), low calcium and vitamin D diet
• Calciuric diuretics may cause dehydration → careful monitoring
• Insufficient → systemic glucocorticoids (interfere with vitamin D metabolism; inhibit macrophage active vitamin D production); nephrocalcinosis may still develop
• Bisphosphonates (1st/2nd generation): etidronate, clodronate, pamidronate
• Nephrocalcinosis may develop despite rapid pamidronate response
• Degree and duration of hypercalcemia/hypercalciuria may drive nephrocalcinosis → early monitoring and rapid lowering of serum and urine calcium best prevents dystrophic calcification

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• Note: only the At-a-Glance box is present in the extracted text; the narrative section is absent from the source file
• Clinical: circumscribed red to violaceous subcutaneous nodules/plaques on face and thighs; rarely scrotal fat in prepubertal boys
• Follows cold weather, popsicles, ice packs, swimming in cold ocean water
• Histopathology: mostly lobular (lymphohistiocytic or mixed) without vasculitis
• Perivascular lymphohistiocytic infiltrate at dermosubcutaneous junction and overlying dermis
• Findings similar to perniosis
• Treatment: avoid direct ice on skin/mucous membranes; spontaneous resolution within 3 months

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• Clinical: erythematous nodules with disparate location or appearance in patients with personality aberrations
• Implanted materials: medications, cosmetic fillers, oils, food, human waste
• Histopathology: mostly lobular, no vasculitis
• Suppurative granuloma in lobule; cultures for various organisms needed
• Polarization may identify refractile foreign material
• Morphology (histiocyte inclusions, cystic spaces with foreign substances) varies with injected material
• Treatment: psychiatric treatment for self-inflicted; supportive care; stop injections
• Cosmetic fillers: intralesional steroids; often surgical excision of implanted material

• Reaction in AT to external factors, usually injection of foreign materials
• Iatrogenic: medications, cosmetic fillers, cupping, acupuncture; other accidental or deliberate trauma
• Self-induced injections due to psychiatric disorder
• History of therapeutic or filler injections aids diagnosis; self-inflicted cases without recognizable footprint need high index of suspicion
• Spectrum: papules, nodules, erosions, ulcers with perfectly round or angulated shapes
• Blunt trauma: ecchymotic, organized hematomas, hemosiderin
• Oily substances: foreign body reaction with foamy histiocytes and pseudocystic spaces
• Reported injected: medications, acids, milk, mustard, alkalis, infected/contaminated material, urine, feces
• Histopathology: early neutrophilic, later granulomatous
• Injected material treated as foreign (AT macrophages, lymphocytes, cytokine-producing adipocytes) → inflammation ± fat necrosis
• Self-induced → psychiatric care; iatrogenic → stop causative action; surgical excision may be needed

• Panniculitis = inflammatory disorder primarily localized in subcutaneous fat; challenging for clinicians and dermatopathologists
• All forms present clinically as subcutaneous nodules; fat is homogeneous tissue histologically, so considerable overlap among entities
• Classification: septal panniculitis (involves septa between fat lobules — prototype = erythema nodosum) vs lobular panniculitis (primarily involves fat lobules)
• Some lobular panniculitides caused by vasculitis (e.g., polyarteritis nodosa) — discussed elsewhere
• Reaction patterns (not specific entities): Weber-Christian disease, Rothmann-Makai disease, lipomembranous/membranocystic panniculitis, eosinophilic panniculitis
• Neutrophilic panniculitis may be infectious, related to α1-antitrypsin deficiency, factitial, or a variant of Sweet syndrome with panniculus involvement
• Biopsy technique critical: incisional/excisional biopsy narrow at skin surface, wider in panniculus is optimal; alternative double-punch method (6–8mm punch first, then 4–6mm punch at depth of first) is less ideal
• Dermatopathologist skill critical for clinicopathologic correlation; if biopsy doesn't match clinical picture, repeat biopsy or get second opinion
• Lupus profundus and subcutaneous lymphomas (can mimic panniculitis) discussed in other chapters

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• Most common inflammatory panniculitis; two forms — acute (common) and chronic (rare)
• Acute EN: any age/sex, but mostly young adult women (F:M 3:1–6:1)
• Bilateral symmetric deep tender nodules/plaques 1–10cm, usually ≤10 lesions (more in severe cases); initially red, smooth, slightly elevated, shiny; most common location: pretibial area/lateral shins — primarily anterior rather than posterior calf
• Also seen: upper legs, extensor arms, neck, rarely face
• Acute onset, often preceded by malaise and leg edema; arthritis/arthralgia (ankles, knees, wrists); fever, headache, episcleritis, conjunctivitis, GI complaints may occur (related to underlying associated disease, since EN is reactive)
• Evolution: flattens over days, leaves purple/blue-green bruise-like color (erythema contusiforme); no ulceration; resolves without atrophy/scarring; nodules last days-weeks, appear in crops, slowly involute
• Children: affects boys/girls equally

• Reactive process; ~half idiopathic
• Streptococcal infection (especially children); TB important in endemic areas; intestinal infection (Yersinia, Salmonella, Shigella); systemic fungal infections (coccidioidomycosis, histoplasmosis, sporotrichosis, blastomycosis); toxoplasmosis
• EN-like lesions in Helicobacter septicemia, brucellosis, psittacosis, cat-scratch fever (possibly represent septic foci rather than true reactive EN, given fastidious organisms)
• Löfgren syndrome: sarcoidosis with fever, cough, joint pains, hilar adenopathy, EN — especially Scandinavian, Irish, Puerto Rican women; linked to TNF-α polymorphism; generally responds well, self-limited
• IBD (more Crohn's than UC), linked to mutations in PTGER4, ITGAL, IKZF1; not associated with overall disease severity but strongly with female sex, eye/joint involvement, isolated colonic involvement; fecal calprotectin useful IBD screening marker
• Rarely with hematologic malignancies (Sweet syndrome/pyoderma gangrenosum more typical neutrophilic dermatoses for that association); idiopathic granulomatous mastitis (usually unilateral, mimics infection/carcinoma)
• Drugs: historically bromides/iodides; now OCs, hormone replacement, sulfonamides, penicillins; azathioprine; newer — lenalidomide, methimazole, echinacea; estrogen association suggested (young women, pregnancy occurrence); BRAF-targeted therapy (vemurafenib, dabrafenib, trametinib); infliximab used to treat Crohn's-associated EN but also reported to cause EN with ankylosing spondylitis (paradoxic, multiple challenges)
• EN-like lesions in Behçet syndrome and Sweet syndrome likely represent those processes occurring in fat (not true coexistent EN); Behçet subcutaneous lesions show lobular/mixed pattern with vasculitis (lymphocytic or leukocytoclastic, may involve arteriole) — proposed as primary event

• Much less common than acute; unilateral or asymmetric if bilateral; older women; not associated with systemic symptoms except arthralgias
• Begins as single red nodule tending to resolve but migrates centrifugally → annular plaques of subcutaneous nodules with central clearing
• Painless or less tender than acute EN; prolonged course months–years; TNF-α antagonists helpful in some cases

• Erythema induratum (TB-related, posterior calves, chronic, may ulcerate/scar); syphilitic gummas, sporotrichosis nodules (generally unilateral); pancreatitis-associated subcutaneous fat necrosis and nodular vasculitis (shins, distinguishable by associated features); Helicobacter cellulitis, primary atypical mycobacterial infection can mimic
• Classic acute symmetric tender anterior shin nodules in young woman → diagnosis without biopsy; atypical presentation → biopsy

• Septal panniculitis; inflammatory infiltrate principally in connective tissue septa; neutrophils (early) or lymphocytes/mononuclear cells (later), or mixed depending on stage; older lesions — histiocytes/multinucleate giant cells predominate
• Fat lobules only secondarily affected; foamy histiocytes possible; Miescher radial granulomas (histiocyte aggregates around stellate clefts) characteristic but NOT diagnostic
• Leukocytoclastic vasculitis is NOT a feature of EN; chronic EN shows septal fibrosis and septal granulomas of epithelioid histiocytes

• Three components: identify trigger, rest/elevation of affected extremities, antiinflammatory medications
• Workup: throat culture/perianal culture (young children) + ASO titer (especially children); pregnancy test in women; stool calprotectin for IBD; history of preceding illness (diarrhea → Yersinia stool culture); travel/exposure history for endemic fungal infections; 4% of histoplasmosis patients present with EN — exclude in endemic areas; exclude TB with exposure history
• Acute lesions: colchicine 0.6mg BID often rapidly effective; bed rest valuable (may be sufficient in mild cases, especially children); gentle support hose; curtail vigorous exercise
• Aspirin/NSAIDs (indomethacin) often helpful
• Potassium iodide (SSKI): safe/effective for acute and chronic EN — 5 drops TID increasing by 1 drop/dose/day up to 30 drops TID; or 300mg tablet TID; monitor for iodide-induced hypothyroidism; taper over 2–3 weeks once controlled
• Intralesional corticosteroids for persistent lesions; systemic corticosteroids give rapid resolution (if not contraindicated by underlying cause); refractory — antimalarials (hydroxychloroquine); TNF-α medications may help (though adalimumab paradoxically reported to cause EN)
• Prognosis: typically good, 3–6 weeks course; recurrences with persistent underlying condition or premature activity resumption; chronic/atypical lesions warrant alternative diagnosis workup + biopsy