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Panniculitis: Classification, Causes, Evaluation, and Diagnosis

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1. Definition

• Firestein & Kelley's Textbook of Rheumatology, p. 842

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2. Classification

1. Whether the inflammation is primarily septal or lobular (the "center of gravity")
2. Whether vasculitis is present or absent
3. The predominant cell type in the infiltrate (neutrophilic, lymphocytic, granulomatous, histiocytic, eosinophilic)

Master Histopathologic Flowchart

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2A. The Classic Four-Category System (Rheumatology 2-Volume Set, Elsevier 2022)

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2B. Expanded Classification (Firestein & Kelley, Table 43.4)

1. Lymphocytic and mixed: Erythema nodosum and variants
2. Granulomatous: Palisaded granulomatous diseases, sarcoidosis, subcutaneous infection (tuberculosis, syphilis)
3. Sclerotic: Scleroderma, eosinophilic fasciitis, lipodermatosclerosis, toxins

1. Neutrophilic: Infection, ruptured folliculitis and cysts, pancreatic fat necrosis
2. Lymphocytic: Lupus panniculitis, post-steroid panniculitis, lymphoma/leukemia
3. Macrophagic: Cytophagic histiocytic panniculitis
4. Granulomatous: Erythema induratum/nodular vasculitis, palisaded granulomatous diseases, sarcoidosis, Crohn's disease
5. Mixed with foam cells: Alpha-1 antitrypsin deficiency, Weber-Christian disease, traumatic fat necrosis
6. Eosinophilic: Eosinophilic panniculitis, arthropod bites, parasites
7. Enzymatic fat necrosis: Pancreatic enzyme panniculitis
8. Crystal deposits: Sclerema neonatorum, subcutaneous fat necrosis of newborn, gout, oxalosis
9. Embryonic fat pattern: Lipoatrophy, lipodystrophy

• A. Neutrophilic: Leukocytoclastic vasculitis, subcutaneous PAN, thrombophlebitis, ENL (erythema nodosum leprosum)
• B. Lymphocytic: Nodular vasculitis, perniosis, angiocentric lymphomas
• C. Granulomatous: Nodular vasculitis/erythema induratum, ENL, granulomatosis with polyangiitis, Churg-Strauss

• Firestein & Kelley's Textbook of Rheumatology, p. 842-843

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2C. Clinically Oriented Classification (Bolonia Dermatology 5e, Table 100.1)

• Erythema nodosum (EN)
• Erythema nodosum migrans (subacute nodular migratory panniculitis)
• Panniculitis of morphea/systemic sclerosis
• Alpha-1 antitrypsin deficiency panniculitis* (some authors classify this as lobular)

• Erythema induratum (nodular vasculitis) - with medium vessel arteritis
• Superficial thrombophlebitis
• Cutaneous PAN
• Erythema nodosum leprosum
• Lucio phenomenon
• Perniosis (chilblain panniculitis)

• Lymphocytic: Lupus panniculitis (lupus profundus), SPTCL, post-steroid panniculitis, cold panniculitis
• Neutrophilic: Infectious panniculitis, factitial panniculitis, alpha-1 antitrypsin deficiency
• Histiocytic/granulomatous: Subcutaneous sarcoidosis, pancreatic panniculitis, cytophagic histiocytic panniculitis
• Crystal/enzymatic: Sclerema neonatorum, subcutaneous fat necrosis of the newborn, calciphylaxis, gout panniculitis, oxalosis
• Sclerotic: Lipodermatosclerosis, post-irradiation panniculitis
• Lipodystrophic/traumatic: Traumatic panniculitis, factitial panniculitis, cold panniculitis, injection-induced panniculitis, sclerosing lipogranuloma
• Malignancy-related: SPTCL, other subcutaneous lymphomas
• Bolonia Dermatology 5e, pp. 2084-2110

Note: Weber-Christian disease is no longer accepted as a primary diagnosis. Cases previously labeled as such have been reclassified as alpha-1 antitrypsin deficiency, lipodermatosclerosis, lupus panniculitis, traumatic panniculitis, or factitial panniculitis.

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3. Causes of Panniculitis

Primary (no identifiable cause)

• Idiopathic erythema nodosum (most common form of panniculitis overall)

Secondary Causes

A. Infections

• Group A Streptococcus (most common trigger of EN - upper respiratory tract infections precede EN in 20-30% of cases)
• Yersinia enterocolitica
• Mycobacterium tuberculosis (causes erythema induratum/Bazin, also EN)
• Mycobacterium leprae (erythema nodosum leprosum)
• Treponema pallidum (syphilis)
• Rickettsiae, Chlamydophila, Bartonella, Leptospira, Q fever (Coxiella)
• Mycoplasma pneumoniae

• Hepatitis B and C
• Infectious mononucleosis (EBV)
• Herpes simplex, CMV, measles, HIV

• Dermatophytes, blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, aspergillosis

• Toxoplasmosis, amebiasis, ascariasis, ancylostomiasis
• Fitzpatrick's Dermatology, p. 1286

B. Inflammatory Bowel Disease

• Ulcerative colitis and Crohn's disease (patients with EN secondary to Crohn's are more likely to have colonic involvement)
• Crohn's disease can also cause granulomatous panniculitis directly

C. Systemic Autoimmune / Connective Tissue Disease

• SLE (lupus panniculitis/profundus in 2-3% of cutaneous LE cases)
• Behcet's disease (vasculitis in fat tissue)
• Sjogren's syndrome
• Reactive arthritis
• Dermatomyositis (panniculitis recognized in DM, may precede muscle/skin disease)
• Scleroderma (septal panniculitis)
• Temporal arteritis, Takayasu arteritis

D. Sarcoidosis

• EN is the most common cutaneous manifestation of sarcoidosis
• Subcutaneous sarcoid nodules are granulomatous lobular panniculitis

E. Malignancy

• Hodgkin and non-Hodgkin lymphoma (including MALT lymphoma)
• Leukemia (acute and chronic)
• Pancreatic adenocarcinoma (pancreatic panniculitis)
• Renal carcinoma
• SPTCL (subcutaneous panniculitis-like T cell lymphoma) - classified as both a cause and mimicker

F. Drugs

• Sulfonamides, bromides, iodides
• Oral contraceptives and progesterone
• Minocycline, gold salts, penicillin, nitrofurantoin
• Phenytoin, valproate, omeprazole
• Thalidomide, isotretinoin
• Interleukin-2
• Hepatitis B vaccine, Tdap vaccine
• Vemurafenib (BRAF inhibitor), targeted therapies (dabrafenib, trametinib)
• Fitzpatrick's Dermatology, p. 1286-1287

G. Pancreatic Disease

• Acute and chronic pancreatitis
• Pancreatic adenocarcinoma, acinar cell carcinoma
• Mechanism: liberated pancreatic enzymes (lipase, amylase, trypsin) liquefy subcutaneous fat; fatty acids combine with calcium to form "calcium soap" (saponification) and ghost cells
• Often associated with arthritis and serositis (triad: panniculitis + arthritis + eosinophilia = PPP syndrome)

H. Alpha-1 Antitrypsin Deficiency

• PIZZ and PIMZ phenotypes
• Neutrophilic panniculitis with fat necrosis
• Ulcerating nodules draining oily material; lower trunk and proximal limbs
• Mechanism: unopposed neutrophil elastase destroys fat tissue

I. Physical/Traumatic Causes

• Cold panniculitis (popsicle panniculitis in infants; Equestrian panniculitis from cold)
• Traumatic/factitial panniculitis (injection of foreign substances - steroids, oils, drugs of abuse)
• Post-irradiation panniculitis
• Lipodermatosclerosis (associated with venous insufficiency)

J. Metabolic/Endocrine

• Gout (crystal-induced panniculitis)
• Calciphylaxis (calcium deposition, usually in renal failure/hyperparathyroidism)
• Lipodystrophy syndromes
• Subcutaneous fat necrosis of the newborn (associated with hypothermia, hypercalcemia)
• Sclerema neonatorum (needle-shaped crystals of lipid in adipocytes)

K. Pregnancy and Hormonal States

• Pregnancy is a recognized trigger for EN
• Estrogen/oral contraceptive use

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4. Body Map: Distribution of Major Panniculitis Types

• Erythema nodosum: bilateral anterior shins (green areas, front)
• Erythema induratum: posterior calves (yellow areas, back)
• Lupus panniculitis: proximal arms, hips, trunk, face (pink/red areas)
• Alpha-1 antitrypsin deficiency panniculitis: lower trunk and proximal lower extremities (dotted areas)
• Lipodermatosclerosis: medial lower legs bilaterally

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5. Clinical Evaluation of a Patient with Panniculitis

5A. History

1. Duration and course - acute vs. chronic/relapsing
2. Location - anterior shins (EN), posterior calves (erythema induratum), proximal extremities (lupus panniculitis)
3. Ulceration - absent in EN; present in erythema induratum, alpha-1 AT deficiency, lipodermatosclerosis
4. Systemic symptoms - fever, fatigue, arthralgias, myalgias, abdominal pain, weight loss
5. Recent infections - sore throat (streptococcus), respiratory illness, gastrointestinal symptoms
6. GI history - diarrhea, bloody stools (IBD)
7. Drug history - OCPs, antibiotics, biologics, vaccines
8. Travel history - endemic infections (TB, endemic fungi, leishmaniasis)
9. Family history - autoimmune disease, alpha-1 AT deficiency
10. Trauma - injection sites, blunt trauma
11. Prior episodes - recurrence pattern
12. Pancreatic symptoms - epigastric pain, alcohol use

• Rheumatology 2-Volume Set, p. 1558

5B. Physical Examination

• Characterize nodules: size, distribution, depth, surface changes, warmth, tenderness
• Erythema nodosum: tender, erythematous-to-violaceous, non-ulcerating nodules; bilateral anterior shins; may become confluent (erythema contusiformis); resolve without scarring
• Erythema induratum: indurated nodules/plaques on posterior calves; ulceration present
• Lupus panniculitis: indurated plaques/nodules on face, proximal extremities, hips, trunk; overlying discoid LE changes; subcutaneous atrophy; "tethering" of overlying skin; scalp involvement (especially in East Asian populations)
• Pancreatic panniculitis: nodules anywhere on the legs; ulceration with oily yellow-brown discharge; may be accompanied by arthritis and serositis
• Alpha-1 AT deficiency: ulcerating nodules draining oily material; lower trunk/proximal extremities
• Lipodermatosclerosis: firm, circumferential plaques on lower legs; pigmentation, induration; "inverted champagne bottle" appearance

• Joint involvement (arthritis vs. arthralgia)
• Lymphadenopathy
• Hepatosplenomegaly
• Parotid enlargement (sarcoidosis)
• Eye signs (uveitis - Behcet's, sarcoidosis)
• Pulmonary findings
• Signs of liver disease
• Signs of IBD (perianal disease, fistulas)
• Signs of CTD (malar rash, Raynaud's, sicca, muscle weakness)

5C. Investigations

Laboratory Tests

• Blood cultures, wound cultures
• Serology for specific organisms based on exposure
• PCR of tissue for M. tuberculosis (useful in erythema induratum; positive in 50-70% of cases)

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5D. Biopsy - The Cornerstone of Diagnosis

"An adequate skin biopsy, often involving an elliptical excision, is essential to properly diagnose the various entities that fall into the category of panniculitis." - Firestein & Kelley, p. 843

• A deep excisional or elliptical incision biopsy is required to include adequate subcutaneous fat
• A punch biopsy (>6mm) can be acceptable but may miss important features
• Shave biopsies are inadequate
• The biopsy should include the junction of the dermis and subcutaneous fat
• For calciphylaxis: biopsy at the edge of a lesion including adjacent normal skin

1. H&E staining (routine)
2. Special stains as clinically indicated:
   • PAS + GMS: fungal organisms
   • AFB (Ziehl-Neelsen): mycobacteria
   • Gram stain: bacteria
   • Congo red: amyloid
   • Von Kossa or Alizarin red: calcification (calciphylaxis)
3. Tissue polarization: for foreign material (factitial panniculitis)
4. Immunohistochemistry: for lymphoma markers (CD3, CD4, CD8, CD20, Ki-67, TCRβF1); CD56 for NK-cell lymphoma
5. T cell receptor (TCR) gene rearrangement studies: to distinguish lupus panniculitis (polyclonal) from SPTCL (monoclonal)
6. Direct immunofluorescence: for lupus panniculitis (granular IgM, IgG, C3 at the dermal-epidermal junction or fat lobule)
7. Tissue culture: if infectious panniculitis suspected
8. PCR for M. tuberculosis: in erythema induratum

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5E. Histopathologic Approach to Diagnosis

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5F. Differential Diagnosis

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6. Specific Panniculitis Entities - Key Features

Erythema Nodosum (EN)

• Prototype septal panniculitis (without vasculitis)
• Most common panniculitis overall
• Predominantly women, 2nd-4th decade; female:male ratio 5:1 (no gender difference in children)
• Clinical: tender, erythematous nodules on bilateral anterior shins; fever, malaise, arthralgias; no ulceration or scarring; self-limiting (3-6 weeks)
• Histology: widened septa with inflammatory cells (neutrophils early; histiocytes and Miescher granulomas late); thickened fibrotic septae; no vasculitis
• Miescher granuloma: pathognomonic - discrete micronodular aggregates of small histiocytes around a central stellate cleft
• Prognosis: benign; recurs in 6-34% of cases; more likely to recur with sarcoidosis, streptococcal infection, hormonal therapy
• Fitzpatrick's Dermatology, pp. 1285-1292

Erythema Induratum / Nodular Vasculitis

• Lobular panniculitis WITH vasculitis (medium vessel arteritis)
• Posterior calves; ulceration common
• Tuberculid form (Bazin's): associated with TB; PPD/IGRA always positive; PCR for M. tuberculosis positive in 50-70%
• Non-TB nodular vasculitis: Chlamydia, Crohn's, Takayasu arteritis, BCG vaccination, TNF-alpha antagonist therapy
• Differentiation: PPD/IGRA + tissue PCR for TB

Lupus Panniculitis (Lupus Profundus)

• 2-3% of cutaneous LE cases; female predominance 2:1 to 4:1
• Tender subcutaneous nodules/plaques: face, proximal extremities, hips, trunk; scalp in East Asian populations
• Associated with discoid LE in >1/3; SLE in only 10-15% - often precedes other LE manifestations
• Histology: lobular lymphoplasmacytic panniculitis; hyaline necrosis; lymphoid follicles (20-50%); clusters of CD123+ plasmacytoid dendritic cells; polyclonal TCR
• Key differential: SPTCL (see table above - monoclonal TCR, adipocyte rimming, no B cells/plasma cells)
• Results in permanent subcutaneous atrophy (disfiguring)

Pancreatic Panniculitis

• Occurs with pancreatitis or pancreatic carcinoma (especially acinar cell carcinoma)
• Any location on the legs; ulceration and drainage of oily liquid (liquefied fat)
• Triad (PPP syndrome): Panniculitis + Polyarthritis + Pancreatic disease; eosinophilia
• Histology: lobular fat necrosis with neutrophilic infiltrate; "ghost cells" (anucleate adipocytes with shadowy membranes); saponification (calcium soap deposits - basophilic homogeneous material)
• Elevated serum amylase and lipase are key diagnostic clues

Alpha-1 Antitrypsin Deficiency Panniculitis

• PIZZ and PIMZ phenotypes
• Ulcerating nodules draining oily material on the lower trunk and proximal extremities
• Histology: neutrophilic lobular panniculitis with fat necrosis
• Diagnosis: serum A1AT level + phenotyping
• Treatment: A1AT enzyme replacement therapy; dapsone; colchicine

Cytophagic Histiocytic Panniculitis

• Rare; lobular panniculitis with erythrophagocytosis
• Can evolve into hemophagocytic syndrome (life-threatening)
• Associated with SPTCL and EBV infection

SPTCL (Subcutaneous Panniculitis-Like T Cell Lymphoma)

• CD8+ cytotoxic T cell lymphoma confined to subcutis
• Multiple plaques and nodules; usually do not ulcerate
• Fever, weight loss, hemophagocytic syndrome in a subset
• Key distinguishing features from lupus panniculitis:
  • Adipocyte rimming by atypical lymphocytes
  • Monoclonal TCR gene rearrangement
  • No B cells or plasma cells
  • No MxA staining
  • Fibroid/coagulative (not hyaline) fat necrosis

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7. Summary: Evaluation Algorithm

Tender subcutaneous nodules
        ↓
History + Physical Examination
        ↓
Characterize lesions:
  - Location (anterior vs posterior leg, proximal vs distal)
  - Ulceration (present/absent)
  - Distribution pattern
  - Associated features
        ↓
Basic labs: CBC, ESR/CRP, metabolic panel, urinalysis
Chest X-ray, Throat swab, ASOT
Mantoux/IGRA (if TB risk)
        ↓
SKIN BIOPSY (deep excisional/elliptical)
  ↓                    ↓
Septal              Lobular/Mixed
  ↓                    ↓
EN spectrum       → Vasculitis?
                   Yes → Erythema induratum, PAN
                   No → Cell type?
                       Lymphocytic → Lupus panniculitis vs SPTCL
                                     (TCR rearrangement, IHC)
                       Neutrophilic → A1AT def, pancreatic, infection
                       Histiocytic → Sarcoidosis, cytophagic HPC
                       Crystal → Calciphylaxis, gout, sclerema
        ↓
Direct IF, Special stains, Culture, PCR, TCR gene rearrangement
        ↓
Targeted systemic workup based on diagnosis

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Key Takeaways (from Firestein & Kelley's Textbook of Rheumatology)

1. Many causes of panniculitis are associated with systemic conditions requiring careful history, physical, and skin biopsy
2. Biopsy should be deep enough to capture subcutaneous fat - elliptical excision preferred
3. Clinical-pathologic correlation is essential; biopsy alone rarely sufficient
4. Erythema nodosum is the most common form; frequently idiopathic but requires a search for underlying cause
5. Cases historically labeled "Weber-Christian disease" are now recognized as distinct entities
6. The overlap between lupus panniculitis and SPTCL can be diagnostically challenging; TCR gene rearrangement and immunohistochemistry are essential
7. An understanding of the heterogeneity of lymphomas involving fat is still evolving

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• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set - Chapter 43, p. 842-843 (Table 43.4)
• Rheumatology, 2-Volume Set (Elsevier 2022) - Chapter 170, pp. 1557-1558
• Bolonia Dermatology 5e - Chapter 100, pp. 2083-2110 (Classification Table 100.1, Histopathologic Approach Table, Lupus panniculitis vs SPTCL Table 100.9)
• Fitzpatrick's Dermatology - Chapter 73, pp. 1285-1295 (Erythema nodosum and panniculitis)
• Andrews' Diseases of the Skin - Chapter on nodular vasculitis/panniculitis subtypes