7.2 Granulomatous & Deposition Disorders and Panniculitis
Key Takeaways
- Löfgren syndrome combines erythema nodosum, bilateral hilar lymphadenopathy, and ankle arthritis or periarthritis, and it has a good prognosis in most patients.
- Necrobiotic xanthogranuloma causes yellow periorbital plaques and is strongly associated with a monoclonal gammopathy, usually IgG, so serum and urine protein electrophoresis are required.
- Amyloid stains with Congo red and shows apple-green birefringence under polarised light; pinch purpura, periorbital purpura, and macroglossia suggest systemic AL amyloidosis.
- Erythema nodosum is a septal panniculitis without vasculitis that heals without ulceration or scarring, whereas erythema induratum is a lobular panniculitis with vasculitis linked to tuberculosis.
- Subcutaneous fat necrosis of the newborn can cause hypercalcaemia for up to about 6 months, so serum calcium should be monitored.
7.2 Granulomatous & Deposition Disorders and Panniculitis
Granulomatous Disorders
A granuloma is an organised collection of macrophages (epithelioid histiocytes), often with multinucleated giant cells. The dermatopathology section covers granuloma types. This section focuses on the clinical diseases. Always exclude infection (mycobacteria, fungi, leishmaniasis) with special stains and culture before diagnosing a non-infectious granulomatous disease.
Cutaneous Sarcoidosis
Sarcoidosis is a multisystem disease of non-caseating ("naked") epithelioid granulomas. The skin is involved in about a quarter of patients.
| Type | Examples |
|---|---|
| Specific lesions (granulomas on biopsy) | Red-brown papules around the nose, eyes, and lips; plaques; annular lesions; lupus pernio (violaceous swelling of the nose, cheeks, and ears; chronic, linked to upper airway and lung fibrosis); scar sarcoidosis (old scars and tattoos become infiltrated); subcutaneous nodules |
| Non-specific lesions | Erythema nodosum, a sign of acute sarcoidosis |
- Löfgren syndrome: erythema nodosum + bilateral hilar lymphadenopathy + ankle arthritis or periarthritis, often with fever. It is common in Scandinavia, is linked to HLA-DRB1*03, and usually resolves within 2 years.
- Heerfordt syndrome: uveitis, parotid swelling, facial nerve palsy, and fever.
- Work-up: biopsy; chest radiograph or CT; lung function; serum calcium and urinary calcium; renal and liver tests; ECG (cardiac sarcoidosis); eye examination. Serum ACE is supportive but neither sensitive nor specific.
- Treatment: potent topical or intralesional steroids for limited disease; hydroxychloroquine, methotrexate, or tetracyclines for widespread skin disease; systemic corticosteroids and TNF-alpha inhibitors (infliximab, adalimumab) for severe or disfiguring disease such as lupus pernio.
Granuloma Annulare (GA)
- Skin-coloured or pink papules in rings on the backs of the hands and feet in children and young adults. Forms include localised, generalised, subcutaneous (children, scalp and shins), perforating, and patch forms.
- Histology: a palisading granuloma around degenerated collagen with abundant mucin (Alcian blue positive), or an interstitial pattern.
- Localised GA often clears within 2 years. Treatments include potent or intralesional steroids, cryotherapy, and phototherapy for generalised disease.
Necrobiosis Lipoidica (NL)
- Yellow-brown atrophic plaques with a red-violet border and telangiectasia, usually on the shins, mainly in women.
- Associated with diabetes mellitus in a large share of patients; test glucose and HbA1c.
- Histology: layered ("tiered") palisading granulomas through the whole dermis, with sclerosis and plasma cells.
- Ulceration after minor trauma is common. Squamous cell carcinoma in long-standing lesions is rare.
- Treatment: potent topical or intralesional steroids at the active edge, topical calcineurin inhibitors, photodynamic therapy, pentoxifylline, and TNF inhibitors in refractory ulcerating disease.
Necrobiotic Xanthogranuloma (NXG)
Yellow-orange indurated plaques, typically periorbital, which may ulcerate. NXG is strongly associated with a monoclonal gammopathy (usually IgG), and sometimes with myeloma or lymphoma. Request serum and urine protein electrophoresis with immunofixation and free light chains.
Other Granulomatous Conditions
- Orofacial granulomatosis and cheilitis granulomatosa: persistent lip swelling. Melkersson-Rosenthal syndrome adds facial palsy and a fissured tongue. Exclude Crohn disease and sarcoidosis.
- Foreign-body granulomas: tattoo pigments (especially red), silica, zirconium, and cosmetic fillers.
- Metastatic Crohn disease: granulomatous skin lesions distant from the bowel.
Deposition Disorders
Amyloidosis
Amyloid is misfolded protein in beta-pleated sheets. It stains pink with Congo red and shows apple-green birefringence under polarised light.
| Type | Protein | Features |
|---|---|---|
| Macular amyloidosis | Keratin-derived | Itchy, rippled grey-brown pigmentation between the shoulder blades; linked to friction (nylon brushes) |
| Lichen amyloidosis | Keratin-derived | Very itchy hyperkeratotic papules on the shins |
| Nodular amyloidosis | AL (light chain) from local plasma cells | Waxy nodules; a minority later develop systemic disease, so follow-up is needed |
| Systemic AL amyloidosis | Immunoglobulin light chain (plasma cell dyscrasia) | Pinch purpura, periorbital purpura ("raccoon eyes"), waxy papules, macroglossia, nail dystrophy; heart and kidney failure |
| Systemic AA amyloidosis | Serum amyloid A | Chronic inflammation (hidradenitis suppurativa, rheumatoid arthritis, familial Mediterranean fever); skin signs uncommon |
Mucinoses
- Pretibial myxoedema: firm pink-brown plaques on the shins in Graves disease, often with eye disease and thyroid acropachy.
- Generalised myxoedema: dry, puffy, waxy skin in hypothyroidism.
- Scleromyxoedema: widespread waxy papules and skin thickening with a monoclonal gammopathy (usually IgG lambda). It can cause the "dermato-neuro syndrome". IVIG is used as treatment.
- Scleroedema (of Buschke): woody thickening of the upper back and neck, associated with poorly controlled diabetes, streptococcal infection, or a paraprotein.
- Reticular erythematous mucinosis (REM): a red reticulated patch on the midline chest or back that responds to antimalarials.
Calcinosis Cutis and Calciphylaxis
| Type | Mechanism | Examples |
|---|---|---|
| Dystrophic | Normal calcium and phosphate; damaged tissue | Dermatomyositis (especially juvenile), systemic sclerosis (limited cutaneous), lupus, trauma |
| Metastatic | Raised calcium-phosphate product | Chronic kidney disease, hyperparathyroidism, vitamin D excess |
| Idiopathic | No cause | Scrotal calcinosis, subepidermal calcified nodule |
| Iatrogenic | Extravasation | Calcium gluconate infusions, EEG paste |
Calciphylaxis (calcific uraemic arteriolopathy): calcification and thrombosis of small skin vessels, usually in dialysis patients. Risk factors include warfarin, obesity, hyperphosphataemia, and hyperparathyroidism. It starts as very painful livedo or indurated plaques, then black necrotic ulcers on the thighs and abdomen. Mortality is high, often from sepsis. Management includes pain control, wound care, stopping warfarin and calcium-based binders, optimising dialysis and minerals, and sodium thiosulfate.
Xanthomas
| Type | Clinical | Associated Lipid Disorder |
|---|---|---|
| Eruptive | Crops of yellow papules with red halos on buttocks and extensors | Severe hypertriglyceridaemia (risk of pancreatitis), poorly controlled diabetes |
| Tuberous and tendinous | Nodules over elbows and knees; thickened Achilles and finger tendons | Familial hypercholesterolaemia |
| Palmar crease (striate) | Yellow palmar creases | Dysbetalipoproteinaemia (type III) |
| Xanthelasma | Yellow plaques on the eyelids | About half have normal lipids; check lipids anyway |
| Plane (diffuse normolipaemic) | Yellow patches in flexures or on the trunk | Monoclonal gammopathy or myeloma |
Panniculitis
Panniculitis is inflammation of the subcutaneous fat. The key histological questions are: septal or lobular? and with or without vasculitis? An adequate deep biopsy (incisional or deep punch) is needed.
| Pattern | Disease | Key Features |
|---|---|---|
| Septal, no vasculitis | Erythema nodosum (the most common panniculitis) | Tender red nodules on the shins; heals in 3–6 weeks like a bruise, without ulceration or scarring; Miescher radial granulomas. Causes: streptococcal infection, sarcoidosis, inflammatory bowel disease, pregnancy and oestrogen, drugs, tuberculosis, Yersinia, many idiopathic |
| Lobular, with vasculitis | Erythema induratum (Bazin) / nodular vasculitis | Tender nodules on the calves of women that may ulcerate; linked to tuberculosis (positive IGRA); treat the TB |
| Lobular, no vasculitis | Lupus panniculitis (profundus) | Nodules on the face, upper arms, and buttocks leaving lipoatrophy; lymphoid follicles; overlaps with subcutaneous panniculitis-like T-cell lymphoma, so review carefully |
| Pancreatic panniculitis | Nodules around the ankles that may discharge; ghost adipocytes with calcium soaps; raised lipase; pancreatitis or pancreatic cancer | |
| Alpha-1 antitrypsin deficiency | Ulcerating nodules with oily discharge on the trunk and thighs; PiZZ phenotype | |
| Cold panniculitis | Infants' cheeks (popsicle panniculitis) or women's thighs after horse riding | |
| Subcutaneous fat necrosis of the newborn | Firm purple nodules in the first weeks after a difficult delivery or hypothermia; risk of hypercalcaemia for up to about 6 months | |
| Lipodermatosclerosis | Woody induration of the lower legs ("inverted champagne bottle") in chronic venous disease | |
| Infective, factitial, traumatic | Consider in atypical cases |
A 30-year-old Swedish woman has fever, painful red nodules on both shins, and swollen, painful ankles. A chest radiograph shows bilateral hilar lymphadenopathy. What is the most likely diagnosis?
A 65-year-old man has indurated yellow-orange plaques around both eyes, some with ulceration. Biopsy shows palisading granulomas with necrobiosis, cholesterol clefts, and bizarre giant cells. Which investigation is most important?
A 3-week-old infant born after a difficult delivery with hypothermia develops firm, purple nodules on the back and shoulders. What complication must be monitored for over the following months?
A 68-year-old woman on haemodialysis who takes warfarin develops extremely painful violaceous livedo on her thighs, which progresses to black necrotic ulcers. What is the most likely diagnosis?