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β2-Microglobulin accumulation with resultant tumor formation is a known albeit rare complication of long-term hemodialysis. Although these tumors may occur in various locations, subcutaneous shoulder nodules are very infrequent. We report a patient with end-stage kidney failure who had been on hemodialysis for 16 years and noted left shoulder nodules after initiation of hemodialysis; these nodules had slowly grown larger. Biopsy of one of these nodules revealed β2-microglobulin amyloidosis by histopathology, Congo red stain, electron microscopy, and immunohistochemistry.
A 75-year-old woman with end-stage kidney disease secondary to membranous glomerulonephritis on hemodialysis for 16 years was noted to have several small subcutaneous nodules on the superior surface of her left shoulder. Her past medical history included end-stage kidney disease, congestive heart failure, coronary artery disease, aortic stenosis, hypertension, chronic anemia, cerebral vascular accident, hyperlipidemia, bilateral lower extremity deep vein thrombosis, and bullous pemphigoid.
These shoulder nodules were asymptomatic and had been slowly enlarging since she had started hemodialysis (Figures (Figures11 and and22). Biopsy of one of the nodules revealed areas of acellular glassy pink amorphous material, typically seen in amyloidosis, on routine histopathology (Figure (Figure33a). A Congo red stain showed apple-green birefringence confirming the glassy pink amorphous material as amyloid (Figure (Figure33b). Electron microscopy showed typical nonbranching amyloid fibrils (Figure (Figure33c). Immunohistochemistry showed that a major amyloid component was β2-microgloblin (rabbit, polyclonal; DAKO, Carpinteria, CA) (Figure (Figure33d). These morphologic features were diagnostic of nodular amyloidosis due to β2-microglobulin deposition. Soon after this diagnosis was made, the patient elected to discontinue hemodialysis and was transferred to hospice care.
β2-Microglobulin, an 11.8-kDa low-molecular-weight protein (1) containing two antiparallel beta-pleated sheets (2), accumulates in patients undergoing long-term hemodialysis, and elevated levels are associated with amyloidosis (3).
In general, amyloidosis is a manifestation of a heterogeneous group of disorders caused by the extracellular insoluble deposition of various generally soluble proteins. Systemic amyloid deposition causes organ dysfunction and death, unless the underlying disease is successfully treated or the process is halted by therapy. Amyloidosis can be classified on the basis of the various proteins that can form amyloid. There is a growing list of amyloid diseases, with over 25 different amyloid proteins identified (4).
Serum amyloid A protein associated with chronic infection or inflammation, monoclonal immunoglobulin light chains due to plasma cell disorders, and mutated transthyretin are the most common amyloid proteins. β2-Microglobulin deposition is a less common form of amyloidosis. It typically occurs in patients with a history of chronic kidney failure undergoing long-term dialysis therapy, as in the case presented here.
The deposition of β2-microglobulin may occur as systemic amyloidosis and produce organ dysfunction and/or tumor formation. β2-Microglobulin tumors have been reported in numerous anatomic locations, including bone (2), genitalia (5), axilla (6), buttocks (7–10), bladder (11), dermis (12), heart, gastrointestinal tract, lungs, liver, kidneys (13), tongue (10), gastric mucosa (14), and carpal and femoral synovium (15). However, tumoral deposition of β2-microglobulin is very rare and usually occurs in patients with other manifestations of amyloidosis, mostly around the buttock region. In our case, subcutaneous shoulder nodules were a clear manifestation of amyloidosis.
β2-microglobulin, a subunit of the HL-A antigen, is found on the surface of most nucleated cells. It is released into the circulation and then removed by the kidney. Megalin, an endocytic receptor on the luminal surface of proximal tubules, binds β2-microglobulin, and it is then metabolized in kidney lysosomes (16). The synthesis rate of β2-microglobulin is similar in hemodialysis patients and normal controls. This suggests that β2-microglobulin accumulation in dialysis patients is due to decreased clearance and not increased production (1). β2-Microglobulin levels rise linearly over the first 10 years of hemodialysis and then plateau (17). Elevated serum β2-microglobulin levels in hemodialysis patients are associated with higher mortality rates (18). High-flux dialysis membranes reduce β2-microglobulin levels and are associated with decreased risk of carpal tunnel syndrome and improved survival (19, 20).
Nodular β2-microglobulin amyloid deposition should be considered in the differential diagnosis of masses or nodules in patients on long-term dialysis therapy. Diagnosis requires histological examination to show fibrillar protein deposition, which is characteristically stained with Congo red, revealing apple-green birefringence under polarization.