Classification of amyloidosis from standard dermatology textbooks
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Classification of Amyloidosis in Dermatology
Amyloid is an eosinophilic, homogeneous, hyaline material representing beta-pleated sheet conformations of various host-synthesized proteins. The deposited protein differs between forms, but all share the same histologic appearance (Congo red positivity with apple-green birefringence under polarized light, thioflavin T fluorescence, PAS-positive, and ultrastructurally non-branching fibrils of 60-100 nm diameter).
Standard Classification (Andrews' Diseases of the Skin)
I. SYSTEMIC AMYLOIDOSIS
| Type | Protein | Notes |
|---|---|---|
| A. Primary (myeloma-associated) systemic amyloidosis | AL (immunoglobulin light chain, usually lambda) | Most common systemic form; involves skin in ~40% of cases |
| B. Secondary systemic amyloidosis | AA (serum amyloid A protein) | Complicates chronic inflammatory/infectious diseases |
| C. Dialysis-related amyloidosis | Beta-2 microglobulin (AB2M) | Cutaneous amyloidomas rarely described |
| D. Senile systemic amyloidosis | Wild-type transthyretin (ATTR) | Age-related; mainly cardiac |
II. CUTANEOUS AMYLOIDOSIS
| Type | Notes |
|---|---|
| A. Macular amyloidosis | ~35% of cutaneous cases |
| B. Lichen amyloidosis | ~35% of cutaneous cases; most common subtype |
| C. Nodular amyloidosis | AL type; risk of associated plasma cell dyscrasia |
| D. Secondary (tumor-associated) cutaneous amyloidosis | Adjacent to BCCs, SCCs, Bowen disease, seborrheic keratoses |
| E. Familial primary cutaneous amyloidosis | Mutations in OSMR, IL31RA, RET genes |
| F. Pharmaceutical amyloidosis | E.g., subcutaneous insulin, enfuvirtide injection sites |
III. HEREDOFAMILIAL AMYLOIDOSIS
Caused by genetic defects in transthyretin, apolipoprotein A-I or A-II, gelsolin (Meretoja syndrome), fibrinogen A-alpha, cystatin C, or lysozyme. Autosomal dominant in most cases; only 50% have a positive family history.
- Andrews' Diseases of the Skin, pp. 598-604
Cutaneous Amyloidosis in Detail
Primary Localized Cutaneous Amyloidosis (PLCA)
Andrews' divides PLCA into four forms: macular, lichen, nodular, and familial. The macular and lichen forms are also called "keratinocyte-derived" amyloidosis or frictional amyloidosis, because chronic rubbing/friction by keratinocytes leads to deposition of keratin (primarily keratin 5) as the amyloid protein.
1. Macular Amyloidosis
- Clinical: Moderately pruritic, brown, rippled macules in the interscapular region; "salt-and-pepper" appearance with alternating hyper- and hypopigmentation. Women outnumber men 5:1.
- Sites: Interscapular back, extensor surfaces of arms, thighs, shins.
- Histology: Small amyloid "corpuscles" in the papillary dermis; melanin-containing histiocytes encircle the deposits; mild epidermal hyperkeratosis.
- Associations: Often linked to notalgia paresthetica; also atopic dermatitis and chronic pruritic states (primary biliary cirrhosis, chronic renal failure).
- Fitzpatrick's Dermatology, p. 2292
2. Lichen Amyloidosis
- Clinical: Linear rows of firm, hyperpigmented, grouped, hyperkeratotic papules that can evolve into plaques. Intensely pruritic.
- Sites: Shins and forearms most commonly; occasionally upper back.
- Epidemiology: Men in their fifth-sixth decades; ~35% of cutaneous cases.
- Histology: Acanthotic and papillomatous epidermis; elongated rete ridges; basal layer hyperpigmentation; small amphophilic amyloid deposits in papillary dermis surrounded by melanophages.
- Fitzpatrick's Dermatology, p. 2292 (Table 125-3)
3. Biphasic (Mixed) Cutaneous Amyloidosis
- Accounts for ~15% of primary cutaneous amyloidosis cases.
- Overlapping features of both macular and lichen types.
- Fitzpatrick's Dermatology, p. 2291
4. Nodular Amyloidosis
- Clinical: Deep-seated, waxy, single or multiple papules, nodules, or plaques; common on feet and trunk. Can grow large if untreated.
- Protein: AL type in the large majority; produced by contiguous monoclonal plasma cells (local synthesis).
- Important associations: Up to 25% associated with primary Sjogren syndrome. Systemic plasma cell dyscrasia or lymphoproliferative disease develops in some - long-term follow-up is mandatory.
- Fitzpatrick's Dermatology, p. 2293-2294
5. Amyloidosis Cutis Dyschromica
A rare variant with progressive diffuse hyperpigmentation and hypopigmentation with atrophy. Amyloid is localized to the papillary dermis and stains with antikeratin antibodies. Occasionally associated with neurologic changes or connective tissue disease signs.
- Fitzpatrick's Dermatology, p. 2294
Systemic Amyloidosis: Skin Manifestations
Primary Systemic (AL) Amyloidosis
- Cutaneous involvement in ~40% of patients.
- Skin findings: Shiny, smooth, waxy flat-topped papules around the eyes, nose, mouth, and mucocutaneous junctions; coalescence into nodules/plaques.
- Pinch purpura: Periorbital ecchymoses after minor trauma - pathognomonic. Mechanism: amyloid infiltrates vessel walls making them fragile; AL amyloid binds factor X impairing coagulation; hepatic infiltration reduces fibrinogen.
- Macroglossia: In at least 20% of patients; tongue enlargement with lateral dental indentations, papules/nodules with hemorrhage.
- Bullous amyloidosis: Rare; tense hemorrhagic or clear bullae at trauma sites, healing with scarring and milia.
- Associated with multiple myeloma in ~20% of AL cases; also non-Hodgkin lymphoma and lymphoplasmacytic lymphoma.
- Andrews' Diseases of the Skin, pp. 599-603
Secondary Systemic (AA) Amyloidosis
- Complicates chronic inflammatory/infectious diseases: tuberculosis, leprosy (lepromatous), rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, dystrophic epidermolysis bullosa, generalized psoriasis, systemic sclerosis, dermatomyositis, familial Mediterranean fever, Muckle-Wells syndrome, and SLE.
- Deposited protein: AA (amyloid A - an acute phase reactant synthesized by the liver).
- Cutaneous deposits are rare in AA amyloidosis; amyloid can be detected in fat aspirates.
- Main organs affected: kidneys, liver, spleen, adrenals, heart.
- Distinction: AA amyloid loses Congo red birefringence after KMnO4 treatment; AL and keratinocyte-derived forms do not.
- Dermatology 5e, p. 930
Heredofamilial Syndromes with Dermatologic Relevance
| Syndrome | Defective Protein | Cutaneous Features |
|---|---|---|
| Meretoja syndrome (Finnish type) | Gelsolin (mutant) | Cutis laxa starting on face (5th decade), premature aging, xerosis, easy bruising, occasional lichen amyloidosis |
| Transthyretin (ATTR) familial | Transthyretin (mutant or wild-type) | Waxy papules, peripheral neuropathy |
| MEN 2A-associated | RET protooncogene mutation (codon 634) | Lichen amyloidosis on the upper back; may precede medullary thyroid carcinoma; 30% likelihood with codon 634 mutation |
| PLCA with OSMR/IL31RA mutations | Oncostatin M receptor-beta (OSMR), IL-31 receptor A | Macular or lichen amyloidosis; familial; linked to pruritus signaling pathways |
- Fitzpatrick's Dermatology, p. 2294-2295
Key Histologic and Staining Summary
| Property | Result |
|---|---|
| Congo red | Positive (apple-green birefringence under polarized light) |
| Thioflavin T | Fluorescent positive |
| PAS | Weakly positive, diastase resistant |
| Crystal violet | Purple (metachromasia) |
| Cotton dyes (Pagoda Red, Dylon) | Intense bright orange |
| KMnO4 pretreatment | AA amyloid loses birefringence; AL and keratinocyte-derived forms do NOT |
| Anti-keratin immunoperoxidase | Confirms primary cutaneous (keratinocyte-derived) amyloidosis |
| Anti-SAP immunoperoxidase | Stains all forms (SAP present in all amyloid) |
| Electron microscopy | Straight, non-branching, non-anastomosing fibrils, 60-100 nm diameter |
- Andrews' Diseases of the Skin, p. 598
Sources:
- [Andrews' Diseases of the Skin](clinical dermatology, Ch. 26), pp. 598-604
- [Fitzpatrick's Dermatology](9th ed.), Ch. 125, pp. 2291-2295
- Dermatology 5e (Callen/Griffiths/Lebwohl), Ch. 47 & 72, pp. 929-930
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