Skin as a Window to Systemic Disease: A Case of Systemic Amyloidosis Unmasked through Dermatologic Findings

INTRODUCTION

Monoclonal gammopathies represent a diverse group of disorders which result in the excess production of monoclonal proteins due to clonal proliferation of plasma cells.^[1] This clonal proliferation of plasma cells aberrantly produces monoclonal kappa or lambda light chains; these proteins can serve as the basis for amyloid fibril formation, contributing to the pathogenesis of immunoglobulin light chain (AL) amyloidosis.^[2] The clinical presentation of AL amyloidosis is largely influenced by the specific sites of amyloid deposition. In primary systemic amyloidosis, cutaneous and mesenchymal tissue involvement occurs in around 30–40% of patients.^[3] This report emphasises the importance of recognising cutaneous findings in reaching a critical diagnosis of primary systemic amyloidosis.

CASE REPORT

A 61-year-old man presented to the cardiac outpatient clinic with progressive shortness of breath, generalised weakness, skin lesions and weight loss over 2 months. His shortness of breath was insidious in onset and worsened to dyspnoea at rest, prompting hospital admission. The patient had underlying renal dysfunction (serum urea: 100 mg/dL; creatinine: 3.1 mg/dL), and echocardiography revealed left ventricular dysfunction with an ejection fraction of 25%. The cutaneous examination revealed multiple, discrete to coalescent, skin-coloured, waxy, dome-shaped papules measuring approximately 2–5 mm in diameter, predominantly distributed over the dorsum of both hands [Figure 1a]. The lesions were smooth-surfaced, firm in consistency, non-tender and non-compressible. Extensive non-blanchable ecchymotic patches and purpura were present over the bilateral forearms, neck, anterior chest and periorbital regions [Figure 1b]. Examination revealed no macroglossia, mucosal papules, nail dystrophy or subungual haemorrhage, alopecia or sclerodermoid changes over the body. A skin biopsy was performed from the dorsum of the right hand with the suspicion of cutaneous amyloidosis or mucinosis. The histopathological examination showed the deposition of amorphous, eosinophilic, acellular extracellular material predominantly in the superficial papillary and upper reticular dermis, with perivascular accentuation and compression of adjacent collagen bundles [Figure 2a]. Focal erythrocyte extravasation was present, correlating with the clinical purpura. Congo red staining demonstrated salmon-pink amorphous deposits in the epidermis and papillary dermis, as well as in perivascular and peri-appendageal locations, exhibiting apple-green birefringence under polarised microscopy, consistent with amyloid deposition [Figure 2b and c]. Mucicarmine stain did not highlight any mucin deposition. There was no evidence of leucocytoclastic vasculitis, fibrinoid necrosis, granulomatous inflammation or dermal sclerosis. Subsequent bone marrow biopsy showed a hypercellular marrow with plasma cell prominence (>10%) and markedly elevated free lambda light chains (27620 mg/L; normal: 5.71– 26.3 mg/L). Urine electrophoresis showed a monoclonal spike (0.11 g/24 h) seen in the gamma region. Serum electrophoresis showed hypoalbuminaemia (2.79 g/dL), increased alpha-1 and alpha-2 fractions and a low albumin: globulin ratio. Based on the presence of >10% clonal plasma cells in the bone marrow, markedly elevated free lambda light chains, monoclonal protein on electrophoresis and associated renal impairment, the patient was diagnosed with multiple myeloma with AL (light-chain) systemic amyloidosis.

Close

Figure 1: (a) Skin coloured, waxy papules (black arrows) distributed over the dorsal surface of the hands. (b) Extensive purpuric lesions on the forearms.

Export to PPT

Close

Figure 2: (a) Histopathology (H&E×10) revealing acellular, eosinophilic, amorphous deposits within the dermis (green arrows) (b) Histopathologic sections (10×) demonstrating congophilic deposits within the stratum corneum and dermis in Congo red staining (black arrows). (c) Histopathology examination (4×) of skin biopsy showing dermal amyloid deposition with Congo red stain viewed under polarised light, demonstrating characteristic apple-green birefringence (white arrows). (H&E: Hematoxylin and eosin).

Export to PPT

The patient was initiated on combination chemotherapy comprising bortezomib, cyclophosphamide and dexamethasone. In view of cardiac involvement, he received concurrent supportive management including diuretics for volume overload, amiodarone for arrhythmia control and appropriate antibiotics for intercurrent infection.

DISCUSSION

Plasma cell dyscrasias, also known as monoclonal gammopathies, paraproteinemias or dysproteinemias, encompass a continuum of disorders which are defined by the proliferation of monoclonal plasma cells. The major plasma cell dyscrasias include multiple myeloma, monoclonal gammopathy of undetermined significance, solitary plasmacytoma of bone, extramedullary plasmacytoma and heavy chain diseases.^[1] These conditions can present with a variety of cutaneous manifestations, which have been categorised into four distinct groups based on the underlying patho-mechanism of cutaneous involvement: Group I conditions result from the direct infiltration, proliferation and extension of malignant plasma cell in skin; Group II, conditions arising secondary to autoantibodies or cytokine-mediated effects, are non-malignant monoclonal gammopathies and strongly correlate with dermatologic diseases, Group III includes miscellaneous cutaneous manifestations that have been anecdotally linked to monoclonal gammopathy, with support from small case series or individual reports; Group IV consists of cutaneous symptoms, and complications occurring due to M proteins but not specific to monoclonal gammopathy, including adverse reactions to therapies used for plasma cell disorders [Table 1].^[4]

Amyloidosis belongs to Group I disorder characterised by the deposition of insoluble protein fibrils in the extracellular matrix of various tissues and organs.^[2] Systemic amyloidosis is classified into primary (AL), from plasma cell dyscrasia; secondary (AA), from chronic inflammation (rheumatoid arthritis, infections, inflammatory bowel disease, periodic fevers) and familial/hereditary forms. Cutaneous involvement in amyloidosis may be either primary and localised or part of systemic disease. In primary (AL) systemic amyloidosis, skin lesions occur in about 30–40% of patients and can be an early diagnostic clue. In secondary (AA) systemic amyloidosis, however, specific cutaneous manifestations are uncommon, with reported frequencies generally well below 10%. The dermatological manifestations of AL amyloidosis are diverse, with classic features including periorbital and facial purpura. Other skin findings may include petechiae, spontaneous ecchymoses (due to infiltration of amyloid into superficial blood vessels), dome-shaped, waxy, translucent papules, nodular lesions, alopecia, scleroderma-like changes, cutis laxa, oral involvement (macroglossia, induration of the tongue, gum bleeding) and nail dystrophy (onychorrhexis, onychoschizia and nail splitting).^[5] These lesions result from the deposition of immunoglobulin light chains in the dermis and blood vessel walls in AL amyloidosis. Therefore, the presence of such characteristic skin findings should prompt evaluation for an underlying plasma cell dyscrasia. Of the amyloid diseases, those that affect the heart lead to the greatest morbidity and mortality through restrictive cardiomyopathy, arrhythmia and sudden death.

Cutaneous presentations of primary systemic amyloidosis may be misdiagnosed or even missed during diagnosis, and definitive diagnosis is established through histopathological examination, revealing faintly eosinophilic, amorphous amyloid deposits within the dermis and subcutaneous tissues.^[5] Confirmation is achieved with Congo red staining showing apple-green birefringence under polarised light, while mass spectrometry remains the gold standard for determining the amyloid protein subtype and distinguishing AL amyloidosis from other variants. A comprehensive systemic evaluation is essential, as prognosis depends largely on the extent and pattern of organ involvement rather than the initial site of presentation. Serum and urine immunofixation combined with free light-chain assay are preferred over serum protein electrophoresis alone because they provide greater sensitivity for detecting an underlying clonal plasma cell disorder. Organ-directed investigations – including renal, cardiac, hepatic, gastrointestinal and neurologic assessments – are necessary to determine the extent of systemic involvement.

Management of systemic amyloidosis focuses on suppressing the underlying clonal plasma cell disorder to reduce further amyloid deposition. Primary systemic amyloidosis without treatment has a median survival of approximately 12 months. In patients with multiple myeloma-associated AL amyloidosis, bortezomib-based regimens combined with dexamethasone, with or without cyclophosphamide, are commonly used as first-line therapy due to their rapid light-chain reduction. Selected patients may be candidates for autologous stem cell transplantation. Supportive care, particularly for cardiac and renal involvement, is crucial and includes diuretics, careful fluid balance and management of heart failure.

CONCLUSION

This case highlights the importance of a multidisciplinary approach, particularly integrating a thorough dermatologic evaluation. Although the patient initially received only symptomatic treatment, maintaining a high clinical suspicion due to cutaneous lesions for systemic amyloidosis and promptly investigating for plasma cell dyscrasia enabled timely diagnosis and intervention, ultimately enhancing the potential for a better prognosis.