What are the cutaneous manifestations associated with systemic amyloidosis in older adults with a history of chronic diseases?

Cutaneous Manifestations of Systemic Amyloidosis

Periorbital purpura (periorbital ecchymoses) is the most characteristic and pathognomonic cutaneous finding in systemic AL amyloidosis and should trigger immediate evaluation for underlying plasma cell dyscrasia. 1

Primary Cutaneous Manifestations in AL (Light Chain) Amyloidosis

Cutaneous lesions occur in up to 40% of patients with primary and myeloma-associated systemic amyloidosis, resulting from tissue deposition of immunoglobulin light chain material. 2 Importantly, skin involvement is specifically associated with AL amyloidosis but NOT with ATTR (transthyretin) amyloidosis, making this distinction diagnostically valuable. 1

Hemorrhagic Manifestations

• Periorbital purpura is the hallmark dermatologic finding that demands immediate cardiac amyloidosis evaluation 1
• Petechiae, purpura, and ecchymoses are the most common skin lesions, occurring due to infiltration of blood vessel walls by amyloid deposits 3
• Easy bruising can result from acquired factor X deficiency-related coagulopathy 1
• These hemorrhagic lesions typically present as waxy, purpuric mucocutaneous lesions 2

Papular and Nodular Lesions

• Waxy papules can appear on the eyelids, face, neck, and intertriginous areas 2, 4
• Nodular lesions may present as crusted nodules on the face, extremities, or acral sites 5
• Papular eruptions in the lower eyelids and chest wall have been documented, though they are relatively uncommon 3
• These lesions are indistinguishable from nodular primary localized cutaneous amyloidosis 2

Soft Tissue Infiltration

• Macroglossia (enlarged tongue) is pathognomonic when present and results from soft tissue amyloid infiltration 1, 2
• Submandibular gland enlargement from soft tissue involvement is highly characteristic 1
• The combination of carpal tunnel syndrome, macroglossia, and specific mucocutaneous lesions is highly characteristic of AL amyloidosis 2

Clinical Significance and Diagnostic Approach

The presence of cutaneous findings provides a crucial early pointer to underlying occult plasma cell dyscrasia, often preceding cardiac diagnosis. 1, 2 This is particularly critical because median survival in AL amyloidosis with heart failure is only 4 months without treatment. 1

Diagnostic Workup When Cutaneous Lesions Are Present

• Skin biopsy from affected areas demonstrating Congo red-positive amyloid deposits with characteristic apple-green birefringence under polarized light 1
• Mass spectrometry (LC-MS/MS) typing of tissue has 88% sensitivity and 96% specificity 1
• Abdominal fat pad aspiration has 84% sensitivity for AL cardiac amyloidosis 1
• Simultaneous monoclonal protein screening with serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 1
• Gingival or rectal biopsies to rule out extracutaneous amyloid deposition 5

Distinguishing AL from ATTR Amyloidosis

The presence or absence of cutaneous findings helps distinguish between amyloid types, which is crucial because treatments are completely different. 1 Skin involvement occurs in AL amyloidosis but not in ATTR amyloidosis. 1 In contrast, ATTR amyloidosis may present with biceps tendon rupture and spinal stenosis rather than cutaneous manifestations. 1

Prognosis and Treatment Implications

The prognosis of patients with plasma cell dyscrasia-related systemic amyloidosis remains poor, with little response to traditional cytotoxic agents, colchicine, or dimethylsulfoxide. 2 However, early recognition of cutaneous manifestations allows initiation of daratumumab-based chemotherapy regimens that can improve survival. 1 Patients with advanced disease are generally unable to undergo intensive therapy, making early diagnosis through recognition of cutaneous signs essential. 6

Management Challenges

• Local recurrence is common with nodular cutaneous amyloidosis, and there is no consistently effective treatment 5
• Risk of systemic progression from nodular cutaneous amyloidosis is less than 10%, but full workup including serum and urine protein electrophoresis is mandatory 5
• Macular amyloid and lichen amyloidosus generally follow a chronic course with intractable pruritus 2

Common Pitfalls

• Failing to recognize periorbital purpura as a red flag for AL amyloidosis delays critical diagnosis 1
• Assuming all purpura is benign in older adults without considering systemic amyloidosis 1
• Not performing Congo red staining on skin biopsies when amyloidosis is suspected 3
• Overlooking the diagnostic value of easily accessible skin lesions for confirming systemic disease 4