Cutaneous deposition diseases encompass a variety of unrelated disorders characterized by the deposition of endogenous or exogenous substances within the skin.1 Amyloidosis, porphyria, colloid milium, and lipoid proteinosis are included in a differential of metabolic processes involved in endogenous deposition that occur as isolated entities or part of systemic diseases. In the late 1830s, German botanists Vogel and Schleiden2 first used the term amyloid to describe a substance in plants; applied to human disease, amyloidosis refers to the extracellular deposition of various host-synthesized proteins configured as β-pleated sheets, which is a tertiary protein structure that is abnormal in human tissue.2 Skin biopsy with ultrastructural immunohistochemical stains can be a tool to determine the clinical type of amyloidosis by detecting the subtype of amyloid fibril protein deposited within the skin.2-4 We describe a patient with fatal systemic deposition of amyloid light chain (AL) amyloid fibril precursor protein (a protein derived from the variable portion of monoclonal immunoglobulin light chains).5 Biopsies performed on healthy-appearing skin in patients with primary systemic amyloidosis and myeloma-associated amyloidosis were positive for amyloid in 47% of cases (16/34) in one study6 and 100% of cases (16/16) in another study.7 Although positive biopsy results that are characteristic of different types of amyloidosis can be seen, a systemic workup to characterize the presence and extent of involvement of other organs is necessary to differentiate between systemic and localized amyloidosis, which vary in prognosis and treatment.
Case Report
A 43-year-old cachectic-appearing black woman was admitted with progressive shortness of breath over 3 months. She reported that her problems started 6 months prior to admission with increasing tongue size, difficulty swallowing, and fleshy lesions on her face. Additionally, she complained of intermittent fever, history of weight loss, persistent diarrhea, fatigue, and progressive lower extremity weakness. Her past medical history was remarkable for membranoproliferative glomerulonephritis, hypertension, pulmonary hypertension, and anemia of thrombocytosis. Physical examination results revealed bitemporal wasting and numerous waxy papules around both eyes, some with underlying ecchymoses (Figure 1). Additionally, small translucent papules were noted within her nose and around her mouth, as well as on her trunk, neck, and volar wrists. The papules were nontender and nonpruritic. Examination of the oral cavity revealed macroglossia, with a substantially scalloped tongue filling the entire cavity.
A superficial shave biopsy of a typical lesion on the patient's neck revealed an atrophic epidermis and an expanded papillary dermis, with eosinophilic material distributed throughout (Figure 2A). The rete ridges were greatly elongated and encased eosinophilic deposits within the papillary dermis, sometimes forming collarettes. Congo red staining with polarization showed apple green birefringence characteristic of amyloid (Figure 2B). Results of immunohistochemistry showed diffuse staining for λ light chain throughout the dermis but were negative for κ light chain (Figure 3).
Further clinical evaluation showed widespread systemic amyloidosis. Biopsy specimens from the stomach, duodenum, and colon demonstrated amyloid deposition in the mucosa and submucosa. In addition, the results of a gastric biopsy showed evidence of focal intestinal metaplasia (Figure 4). Results of a renal biopsy were negative for Congo red, and the creatinine level was stable at 0.4 mg/dL (reference range, 0.1−0.4 mg/dL) throughout admission. The patient's history of pulmonary hypertension and low-voltage QRS complex on electrocardiogram were consistent with cardiac amyloid infiltration and resultant restrictive cardiomyopathy. Results of a chest x-ray noted bilateral pleural effusions consistent with congestive heart failure. Echocardiogram findings suggested diastolic dysfunction with a hyperdynamic ejection fraction of more than 70% and an increased E/A ratio of 15.7 (references, >70% and >1.5, respectively). A fine-needle biopsy of a mediastinal mass compressing the left atrium showed a mixed infiltrate of leukocytes and plasma cells, indicating further systemic involvement.
Urine protein electrophoresis was abnormal, with a 24-hour total urine protein level of 1.229 g/vol (reference range, 0.05−0.10 g/vol) and an M-protein spike (λ light chain) of 33.5 mg/dL (53.4% of total urine protein). The 33.5 mg/dL of urine light chain protein signified a Bence Jones proteinuria, but the amount of light chain protein in the urine fell below the World Health Organization criteria of urinary output of greater than or equal to 1 g urine light chain over 24 hours for the diagnosis of multiple myeloma.8 An osseous skeletal survey showed no evidence of punched-out lesions or other gross abnormalities. Subsequent bone marrow aspirate and biopsy results found sheets of cytologically atypical plasma cells with prominent nucleoli and occasional multinucleated forms. Quantitatively, the bone marrow showed 75% plasmacytosis, with λ light chain restriction in 75% of the plasma cells. The clinical findings, along with the M protein in the urine and bone marrow plasmacytosis of 75%, are consistent with a clinical diagnosis of multiple myeloma based on the World Health Organization criteria (Table 1).8