CUTANEOUS AMYLOIDOSIS

MD Dermatology Theory Examination Notes

I. DEFINITION & OVERVIEW

1. Protein-derived amyloid fibers (the subtype that differs between forms)
2. Amyloid P component (~15% of amyloid)
3. Ground substance

II. CLASSIFICATION

A. Primary Cutaneous Amyloidosis (Amyloid confined to skin, no systemic involvement)

1. Macular amyloidosis
2. Lichen amyloidosis (most common form)
3. Biphasic amyloidosis
4. Nodular amyloidosis
5. Familial primary cutaneous amyloidosis syndromes
6. Pharmaceutical (injection-site) amyloidosis

B. Secondary Cutaneous Amyloidosis

• Amyloid deposits within pre-existing skin lesions (seborrheic keratoses, BCC, etc.) - a histologic epiphenomenon

C. Systemic Amyloidosis with Skin Involvement

• Primary systemic (AL amyloidosis) - skin involved in ~25-40%
• Secondary systemic (AA amyloidosis)
• Dialysis-related amyloidosis
• Senile systemic amyloidosis

D. Heredofamilial Amyloidosis

III. AMYLOID: ESSENTIAL PROPERTIES

Staining Characteristics

Ultrastructure

• Straight, non-branching, non-anastomosing filaments
• 60-100 nm in diameter
• Irregularly arranged

IV. PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS (PLCA)

• Keratinocyte-derived amyloidosis
• Frictional amyloidosis
• Frictional melanosis

Pathogenesis

• Asian, Hispanic, Middle Eastern ancestry
• Use of abrasive devices during bathing (nylon brushes, towels)
• Coexistent atopic dermatitis
• Primary biliary cirrhosis
• Chronic renal failure

V. MACULAR AMYLOIDOSIS

• Moderately pruritic brown, grey-brown macules
• Characteristic rippled or "salt and pepper" appearance - best appreciated by stretching the skin
• Confluent or rippled pigmentation pattern
• Primary site: interscapular region of the back; also thighs, shins, arms, breasts, buttocks

VI. LICHEN AMYLOIDOSIS

• Persistent, pruritic plaques on the shins and other extensor surfaces (anterior thighs, forearms)
• Initial: discrete, firm, scaly, skin-colored or hyperpigmented papules
• Later: coalesce into plaques with rippled or ridged pattern
• Initially unilateral; over time bilateral symmetric distribution
• Intense pruritus is a hallmark

VII. BIPHASIC AMYLOIDOSIS

• Fine papular lesions (lichen) are superimposed upon a background of macular hyperpigmentation
• Represents the clinical overlap between macular and lichen forms
• Both forms share the same pathogenic basis (friction/rubbing)

VIII. NODULAR AMYLOIDOSIS

• Single or multiple waxy nodules or tumefactions
• Sites: acral areas, trunk, genitalia, face
• Asymptomatic; slowly enlarging
• Overlying epidermis may appear atrophic; may resemble bullae

• Sjogren syndrome (up to 25% of cases) - typically around age 60, often precedes the diagnosis
• Systemic sclerosis/CREST
• Rheumatoid arthritis

IX. VARIANT FORMS

X. FAMILIAL PRIMARY CUTANEOUS AMYLOIDOSIS SYNDROMES

1. IL-31 Receptor-Associated Amyloidosis (PLCA1 and PLCA2)

• PLCA1: Pathogenic variants in OSMR gene (oncostatin M receptor beta subunit)
• PLCA2: Pathogenic variants in IL-31RA gene (IL-31 receptor alpha subunit)
• OSMR and IL-31RA together form the IL-31 receptor
• IL-31 is important in pruritic skin conditions (atopic dermatitis, prurigo nodularis)
• Nemolizumab (anti-IL-31RA antibody) - potential therapeutic target

2. Dyschromic Amyloidosis (PLCA3)

• Guttate leukoderma superimposed on hyperpigmentation + macular/lichen amyloidosis features
• Caused by mutations in GPNMB gene (glycoprotein nonmetastatic melanoma protein b)

3. MEN Type 2A (Sipple Syndrome) - KEY ASSOCIATION

• Autosomal dominant: medullary carcinoma of thyroid + pheochromocytoma + hyperparathyroidism
• Pruritic hyperpigmentation on the upper back (macular/lichen amyloidosis)
• Unusual: early onset, often before age 10 years
• 36% incidence of lichen amyloidosis in MEN 2A
• All cases associated with pathogenic variant in codon 634 of RET proto-oncogene
• Recognition can lead to prophylactic thyroidectomy

4. X-linked Reticulate Pigmentary Disorder (Partington Amyloidosis)

• X-linked; adult women: linear streaks of hyperpigmentation; male patients: reticulated mottled brown pigmentation with dermal amyloid deposits on biopsy

XI. HISTOPATHOLOGY

Macular and Lichen Amyloidosis

• Amyloid deposits restricted to the upper (papillary) dermis
• In lichen amyloidosis: amyloid expands dermal papillae, displaces elongated rete ridges laterally
• Overlying epidermis: hyperkeratosis and acanthosis (from chronic rubbing)
• Focal necrotic keratinocytes in basal cell layer
• Melanophages present within/adjacent to amyloid deposits (explains hyperpigmentation)
• Sparse perivascular lymphohistiocytic infiltrate
• Microscopic (rarely macroscopic) bullae may be seen (analogous to lichen planus)

Nodular Amyloidosis

• Amyloid diffusely infiltrates the dermis, subcutis, and blood vessel walls
• Nearly universal perivascular infiltrate of plasma cells (usually monoclonal)
• Immunostaining for light chain deposition helps diagnosis

Histopathologic Features - Summary Table

Confirmatory Stains

• Antikeratin antibodies (MNF 116): Confirm keratin origin in macular/lichen forms
• DIF: IgM in globular pattern (passive absorption, not specific deposition) in keratin-derived forms
• Amyloid P component immunostaining: Stains all forms of amyloid

XII. SECONDARY CUTANEOUS AMYLOIDOSIS

• Most common: seborrheic keratoses and basal cell carcinomas
• Also: dermatofibromas, melanocytic nevi, pilomatricomas, trichoepitheliomas, sweat gland tumors, Bowen disease, porokeratosis
• Also after PUVA therapy
• Clinical significance: histologic epiphenomenon - no clinical implications

XIII. SYSTEMIC AMYLOIDOSIS WITH SKIN SIGNS

AL (Primary Systemic) Amyloidosis

• Skin involvement in ~25-40%
• Amyloid composed of immunoglobulin light chains, usually lambda (λ) subtype (75-80%)
• Cutaneous features:
  • Shiny, smooth, firm, flat-topped waxy papules (translucent vesicle-like appearance)
  • Periorbital purpura - "Raccoon eyes" sign / "Pinch purpura" (precipitated by coughing, Valsalva, proctoscopy, tape removal)
  • Macroglossia (enlarged, firm tongue)
  • Nail dystrophy, alopecia
  • Lesions around eyes, nose, mouth, mucocutaneous junctions
  • Petechiae, purpura, ecchymoses - especially axillae, eyelids, anogenital regions
  • Oral: rubbery swellings of mucosa, hemorrhagic papules, xerostomia

XIV. DIFFERENTIAL DIAGNOSIS

For Macular Amyloidosis

• Notalgia paresthetica (key DDx - also rippled hyperpigmentation on upper back; early lesions lack amyloid on biopsy)
• Postinflammatory hyperpigmentation
• Pityriasis versicolor
• Atrophic lichen planus
• Erythema dyschromicum perstans (ashy dermatosis)
• Drug-induced pigmentation

For Lichen Amyloidosis

• Lichen simplex chronicus - no amyloid on biopsy
• Hypertrophic lichen planus - lichenoid infiltrate, vacuolar degeneration; no amyloid
• Prurigo simplex/nodularis
• Papular mucinosis
• Pretibial myxedema
• Pemphigoid nodularis
• Epidermolysis bullosa pruriginosa
• Lichen ruber moniliformis

For Nodular Amyloidosis

• Primary systemic amyloidosis (must be excluded)
• Cutaneous lymphoid hyperplasia
• Sarcoidosis
• Colloid milium

XV. TREATMENT

General Principle

Treatment of Macular and Lichen Amyloidosis

Treatment of Nodular Amyloidosis

• Physical removal: shave excision and destruction of base
• Surgical excision, cryotherapy, electrodesiccation, CO2 laser
• Caution: local recurrences are common
• Rare recurrences may lack amyloid and show features of primary cutaneous marginal zone lymphoma
• Regular systemic follow-up for plasma cell dyscrasia

XVI. HIGH-YIELD EXAM POINTS (EXAMINER'S PERSPECTIVE)

1. Most common form of primary cutaneous amyloidosis = Lichen amyloidosis
2. Amyloid protein in macular/lichen forms = Keratin 5 (keratinocyte-derived)
3. Amyloid protein in nodular amyloidosis = AL (immunoglobulin light chains)
4. Congo red stain under polarized light = Apple-green birefringence
5. Potassium permanganate test differentiates AA from AL - AA loses birefringence; AL/cutaneous forms retain it
6. Genes in familial PLCA: OSMR (PLCA1), IL-31RA (PLCA2), GPNMB (PLCA3 - dyschromic amyloidosis)
7. MEN 2A association: Lichen amyloidosis + upper back lesions + codon 634 RET mutation
8. Nodular amyloidosis - 7% risk of systemic progression; association with Sjogren syndrome (25%)
9. Rippled pattern - best seen by stretching the skin (macular amyloidosis)
10. Dermabrasion - effective for lichen amyloidosis on limbs with effects lasting >5 years
11. Dupilumab - recent evidence for lichen amyloidosis (IL-31 pathway link)
12. "Pinch purpura" / "Raccoon eyes" = classic skin sign of AL (primary systemic) amyloidosis
13. Secondary cutaneous amyloidosis = histologic finding only, no clinical implication
14. DIF in keratin-derived amyloidosis: IgM in globular pattern (passive absorption, not specific)
15. Histology - lichen amyloidosis: Amyloid in papillary dermis + widened papillae + displaced rete ridges + melanophages + hyperkeratosis