What is the recommended diagnostic work‑up and management for cutaneous amyloidosis, including treatment options for localized skin lesions and systemic involvement?

Management of Cutaneous Amyloidosis

For primary localized cutaneous amyloidosis (PLCA), the most effective treatment is combination therapy with UVA1 phototherapy plus high-potency topical corticosteroids, which achieves complete symptom clearance in select patients. 1

Diagnostic Work-Up

Initial Confirmation

• Obtain skin biopsy with Congo red staining demonstrating apple-green birefringence under polarized light microscopy to definitively confirm amyloid deposition in the dermis 2
• Congo red staining under polarized light is the most sensitive and definitive method for diagnosis, superior to H&E staining alone 2
• Light microscopy reveals amorphous eosinophilic deposits in the papillary dermis 3

Exclude Systemic Involvement

• Perform complete monoclonal protein screening with all three tests simultaneously: serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 4, 5
• Never rely on standard protein electrophoresis (SPEP/UPEP) alone, as it misses monoclonal spikes in nearly 50% of cases 4, 5
• Obtain cardiac assessment including NT-proBNP, troponin T, and echocardiography if systemic AL amyloidosis is suspected 6
• Assess for renal involvement with 24-hour urine protein collection and serum creatinine if systemic disease is considered 6

Subtype Classification

• Lichen amyloidosis (LA) is the most common subtype (56.8-65.6% of cases), presenting as pruritic papular lesions, most frequently on the knees 1, 2
• Macular amyloidosis (MA) accounts for 15.6-28% of cases, presenting as hyperpigmented macules 1, 2
• Biphasic amyloidosis (BA) represents 16.2-18.8% of cases, showing features of both LA and MA 1, 2
• Nodular amyloidosis (NA) is the rarest form 1

Management of Primary Localized Cutaneous Amyloidosis

First-Line Treatment

• Initiate combination therapy with UVA1 phototherapy plus high-potency topical corticosteroids, which demonstrates the highest efficacy with complete clearance in 10.8% of patients 1
• This combination achieves substantial improvement in an additional 12.7% of patients 1

Alternative Treatment Options for Partial Response

• High-potency topical corticosteroids alone can achieve substantial improvement in select patients 1
• UVA1 phototherapy monotherapy shows moderate efficacy 1
• Capsaicin 0.075% cream provides substantial improvement in some cases 1
• Bath PUVA combined with high-potency topical corticosteroids is an alternative option 1

Less Effective Options to Avoid

• Low- to medium-potency topical corticosteroids show lower efficacy and should not be first-line 1
• UVBnb (311 nm) phototherapy demonstrates inferior results compared to UVA1 1

Additional Reported Treatments (Limited Evidence)

• Other options reported in case series include retinoids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, menthol, hydrocolloid dressings, surgical modalities, and laser treatment 7
• However, no definitive recommendation can be made for these therapies due to lack of randomized controlled trials 7

Management of Systemic Amyloidosis with Cutaneous Involvement

When Systemic AL Amyloidosis is Confirmed

Disease-Directed Therapy

• Initiate Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) as first-line treatment, achieving very good partial response or better in 78.5% of patients 4, 5, 6
• Consider high-dose melphalan (140-200 mg/m²) followed by autologous stem cell transplantation for highly selected patients meeting strict eligibility criteria: age <60 years, ≤2 organs involved, Mayo stage 1-2, ejection fraction >40-45%, and good performance status 4, 6

Cutaneous Manifestations

• The most common skin manifestations are intracutaneous hemorrhage presenting as petechiae, purpura, and ecchymoses due to amyloid infiltration of blood vessel walls 8
• Papular eruptions, particularly in the lower eyelids and chest wall, are relatively uncommon but pathognomonic findings 8
• Periorbital purpura (periorbital ecchymoses) is a red flag for systemic AL amyloidosis 4
• Macroglossia or submandibular gland enlargement indicates systemic involvement 4

Multidisciplinary Management

• Mandatory collaboration between hematologist (primary coordinator), cardiologist, nephrologist, and gastroenterologist is essential for effective treatment 4, 5
• Cardiac involvement drives prognosis and mortality, with approximately 30% of patients dying within the first year from diagnosis due to advanced cardiac involvement 6

Common Pitfalls and Caveats

Diagnostic Errors

• Delayed diagnosis occurs frequently due to nonspecific symptoms—maintain high clinical suspicion for pruritic papular lesions, particularly on the lower extremities 5, 1
• Missing systemic involvement is a critical error—always perform complete monoclonal protein screening in patients with cutaneous amyloidosis 4, 5
• Relying on H&E staining alone without Congo red and polarized microscopy leads to missed diagnoses 2

Treatment Considerations

• PLCA occurs most frequently in Latin Americans and Asians, but can also affect Caucasian populations in central Europe 1
• Pruritus is the most common symptom requiring aggressive management 2
• No standardized treatment exists for PLCA, and randomized controlled trials are urgently needed 7, 1
• For systemic AL amyloidosis, achieving deep hematologic responses directly correlates with improved organ function and survival 5, 6

Monitoring

• For systemic AL amyloidosis, assess treatment response at 3-6 months using difference between involved and uninvolved free light chains (dFLC) 5, 6
• Organ-specific response is generally observed 6-12 months after hematologic response 5