Pitfalls in the Diagnosis of Primary Amyloidosis

Cheng E. Chee; Martha Q. Lacy; Ahmet Dogan; Steven R. Zeldenrust; Morie A. Gertz


Clin Lymphoma Myeloma. 2010;10(3):177-180. 

In This Article

Case 2

Patient B is a 36-year-old white man who presented with a one-and-a-half-year history of progressive bilateral foot pain and bilateral sensorineural hearing loss. He also had an unintentional 40-pound weight loss, constipation, and lower extremity edema. Evaluation for his foot pain resulted in a sural nerve biopsy, which showed amyloid deposition in the endoneurial vessels and endoneurium. He was referred to our institution for further evaluation.


Laboratory studies were performed and showed the following: hemoglobin, 14.3 g/dL (normal, 13.5–17.5 g/dL); normal kidney and liver function, carotene, factor X activity, troponin T, and NT-proBNP; albumin, 2.1 g/dL (normal, 3.5–5.0 g/dL); monoclonal IgG κ on serum and urine immunofixation with a serum M-spike of 0.4 g/dL; no urine M-spike was detected; normal IgG, IgA and IgM levels; κ FLC, 1.72 mg/dL (normal, 0.33–1.94 mg/dL); λ FLC, 0.37 mg/dL (normal, 0.57–2.63 mg/dL); κ/λ FLC ratio, 4.64 (normal, 0.26–1.65); β2-microglobulin, 2.76 μg/mL (normal, 0.7–1.8 μg/mL); nephrotic syndrome with 24-hour urine protein: 12,741 mg per 24 hours (normal, < 102 mg per 24 hours), which was predominantly albumin (77%). Transthoracic echocardiogram was normal. Amyloid was focally positive in a few blood vessels in the bone marrow, which was positive on Congo red staining, but no amyloid was found on fat aspirate. Bone marrow biopsy and aspirate showed < 5% plasma cells that were monoclonal κ by flow cytometry studies. The plasma cell labeling index was 0%. LC MS/MS was attempted on peptides extracted from Congo red– positive, microdissected areas of paraffin-embedded bone marrow tissue, but it was inconclusive. A renal biopsy was then pursued, which confirmed amyloidosis on electron microscopy; however, no immune complex or light chain deposition was identified. Mass spectrophotometry of nerve and kidney tissues suggested unusual heavy chain amyloidosis (AH). He had bilateral cochlear implants placed, with recovery of his hearing, and then underwent an autologous peripheral blood stem cell transplantation.


The challenge in this case was the determination of primary amyloidosis. Virtually all patients with AL amyloidosis have elevations of the responsible FLC. In this patient, the initial concern was that this was nonimmunoglobulin light chain amyloidosis with an incidental IgG κ monoclonal gammopathy of unknown significance (MGUS). At the age of 36, this patient was 30 years younger than the median for immunoglobulin-derived amyloidosis and well within the range for patients with inherited forms of amyloid. In fact, this was not AL amyloidosis but the much rarer AH, in which immunoglobulin heavy chains without light chains are deposited. This rare and likely under-recognized form of amyloidosis can lead to serious diagnostic confusion because an FLC abnormality might not be detected, as in this instance.[7–9]

The unusual presentation of hearing loss and amyloidosis is seen in Muckle-Wells syndrome, in which AA is the type of amyloidosis, and chemotherapy is not indicated. However, the presence of a monoclonal protein in serum and urine made the case suspicious for AL amyloidosis. Initially, FLCs could not be measured because of the lipemic sample (the patient had nephrotic syndrome–associated hyperlipidemia). The renal biopsy did not provide evidence for AL amyloidosis because, although the glomeruli showed mesangial and segmental capillary wall amyloid deposition, it did not show light chain restriction by immunofluorescent histology or by immunohistochemical staining. Ultimately, mass spectrophotometry on the kidney and nerve tissues identified heavy chain amyloidosis, which is a rare disorder.

This case also highlights the limitations of immunohistochemistry in detecting amyloid deposits. Immunohistochemistry has been shown to be a fast, reliable, and inexpensive technique, provided that appropriate antibodies are being applied together with sufficient controls.[10] Interpretation can be challenging in formalinfixed, paraffin-embedded tissues because of higher background staining compared with unfixed samples (frozen tissue, air-dried fat aspirates, bone marrow smears) that give better results.[8] This detection technique can also miss early, minute amyloid deposits, possibly from the inaccessibility of the tissue for antibodies.[11] This effect is especially observed in hereditary amyloidosis when the patients are aware of the ensuing amyloidosis and insist on an early biopsy. Another limitation of immunohistochemistry is the heterogeneity of AL amyloid fibril proteins, which are derived from the amino-terminal end of the light chain containing a variable region; the outcome of the immunohistochemical stain largely depends on the extent to which the C-region is present.[8] Furthermore, when the immunoglobulin light chain transforms from its native α-helical conformation to the amyloid β-pleated sheet, previously exposed epitopes may no longer be available after the completion of the abnormal protein folding.[5] Therefore, it may be anticipated that not all AL amyloid deposits will be reactive to commercial antibodies for κ or λ light chains.[8] Mass spectrometry has the ability to precisely identify the protein nature of the pathologic amyloid deposits. It is performed using material extracted from formalin-fixed, amyloid-containing tissue biopsy specimens or subcutaneous fat aspirates.


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