Light chain amyloidosis: a case presentation and review

In 1977, an asymptomatic 68-year-old woman underwent biopsy of a supraclavicular node that had been detected at the time she presented for breast biopsy. While the breast biopsy was benign, pathology from the lymph node revealed amyloid. For unclear reasons, no further evaluation or treatment was undertaken then. Two years later, a paratracheal node was noted during screening chest x-ray. Biopsy again showed amyloid. At that time, the patient's spleen and liver were enlarged. Howell-Jolly bodies were identified on peripheral blood smear, suggesting hyposplenism. This was confirmed by a radionuclide liver-spleen scan, which showed decreased splenic uptake (1). Initial 24-hour urine specimen collected 5.1 g of protein, 64.4% of which was albumin by urine protein electrophoresis (Figure 1). Despite significant albuminuria, her serum albumin was 3.9 g/dL. Quantitative immunoglobulins were depressed, with IgG of 385 mg/dL, IgA of 72 mg/dL, and IgM of 140 mg/dL. While serum immunofixation electrophoresis (IFE) was negative for monoclonal light chain (“Bence Jones”) protein, urine IFE did detect a monoclonal lambda protein (Figure 2). Skeletal x-rays showed no lytic lesions. Bone marrow aspirate (Figure 3) and biopsy revealed plasmacytosis of 10% to 15% and light chain amyloid, with a kappa:lambda ratio of 1:50. Subsequent renal biopsy also showed lambda light chain amyloid.

Figure 1.

Urine protein electrophoresis of our patient, showing heavy albuminuria but no clear-cut monoclonal protein. Anode is on the right. Urine concentrated 50x.

Figure 2.

Urine immunofixation electrophoresis from our patient. The dense, broad anodal band against anti–whole human serum (AWHS) in the upper left column indicates albumin. Antisera to kappa and lambda light chains showed a homogeneous band against the lambda reagent, indicating a monoclonal protein. There was no reaction with the kappa antiserum. Anode is at the top. Urine was concentrated 25×.

Figure 3.

Bone marrow aspirate of our patient. Congo red staining revealed amorphous eosinophilic material lying free in the marrow space. These areas displayed apple-green birefringence under polarized light, confirming amyloid.

After initiation of low-dose prednisone and colchicine, the patient's hepatomegaly, functional hyposplenism, albuminuria, and Bence Jones proteinuria resolved. She was maintained on this therapy for more than a decade. Despite eventual discontinuation of these medications, she remained in clinical complete remission through her last follow-up, 21 years after presentation. She died the following year of an unknown cause.

DISCUSSION

Amyloidosis describes the extracellular deposition of insoluble fibrils in the walls of small blood vessels and various organs. At least 24 different lower-molecular-weight proteins are capable of forming these fibrillar deposits which, when extensive, can interfere with normal physiological function (2). Our patient had primary systemic (AL) amyloidosis, which occurs when a monoclonal population of plasma cells generates excess amyloidogenic immunoglobulin light chains. In 75% of cases, the fibrillar deposits of AL amyloidosis are composed of monoclonal lambda light chain proteins or fragments from their variable regions (3, 4). In the remaining cases, these protein deposits are products of kappa-restricted plasma cell clones. AL amyloidosis is rare, with an incidence of 4.5 per 100,000, approximately one tenth the incidence of multiple myeloma (3).

Tissue deposits from AL amyloidosis can occur in many organs, including the kidney, liver, heart, spleen, tongue, skin, ligaments, peripheral nerves, adrenal glands, bladder, small bowel, and bone marrow. The location of the deposits determines the clinical manifestations. Cardiac infiltration can cause arrhythmias and/or restrictive cardiomyopathy. Gastrointestinal deposition can induce diarrhea, bleeding, protein loss, and/or malabsorption. Peripheral nerve amyloidosis may generate a variety of neuropathies. Accumulation of fibrils in the liver can cause hepatomegaly and liver dysfunction (5). Infiltration of the tongue musculature may generate macroglossia. Periorbital vascular infiltration can manifest as purpura, which may result after Valsalva, a classic finding in amyloidosis (Figure 4) (3).

Figure 4.

Prototypical physical findings in primary systemic (AL) amyloidosis. (a) A patient with macroglossia and purpura, Macroglossia is observed in 12% of patients with AL. (b) Periorbital purpura exacerbated by the Valsalva maneuver is seen in 6% of patients. Reprinted with permission from Merlini and Stone, Blood 2006 (3). Copyright © American Society of Hematology.

As with our patient, at least 75% of patients with AL amyloid have clinical evidence of renal deposition. While glomerular deposition is most common, fibrils may also accumulate in Bowman's capsule, renal tubules, and various renal vessels. Clinical signs of renal amyloidosis may include albuminuria, hypoalbuminemia, and Bence Jones proteinuria. Up to 20% of individuals ≥50 years with nephrotic-range proteinuria (>3.5 g/day) have AL amyloidosis (6). Although most patients have evidence of multisystem deposition, they typically present with complaints related to involvement of a particular organ system.

While both multiple myeloma and AL amyloid are clonal plasma cell disorders, amyloidogenic light chains do not typically cause lytic bone lesions or hypercalcemia, findings associated with multiple myeloma. In the 10% of cases when myeloma and amyloid overlap, patients almost always present with signs of myeloma first. In a Mayo Clinic series of 1596 patients with AL amyloidosis, only 6 (0.4%) showed delayed progression (at 10 to 81 months) to overt myeloma (7).

Light chain deposition disease (LCDD), a pathogenetic variant of AL amyloidosis, occurs when a monoclonal population of plasma cells generates granule-forming light chains (8). Light chain granular deposits do not bind Congo red stain and are almost always kappa restricted (8, 9). In LCDD, granules form in the kidneys about 90% of the time but can also occur in most organ systems. Renal deposits most frequently appear in the glomeruli, often resulting in heavy albuminuria. Although LCDD also frequently results in Bence Jones proteinuria, it is generally less prominent than in AL amyloidosis (8, 9). Overall survival (OS) rates for LCDD are approximately 90% at 1 year and 70% at 5 years. Patients with significant renal involvement have reported survival rates of approximately 67% at 1 year and only 37% by 5 years (10).

Diagnosis

Patients with suspected AL amyloid or LCDD should undergo serum and urine protein electrophoresis with immunofixation, 24-hour urine protein measurement, skeletal survey, serum-free light chain analysis, and bone marrow biopsy. Unless a patient has preexisting renal disease, the presence of significant albuminuria (>600 mg/day) in combination with Bence Jones proteinuria strongly suggests either AL amyloidosis or LCDD (11). While serum and urine studies may be suggestive, the diagnosis of amyloidosis is established through biopsy of an affected organ. Although most patients with AL amyloid have evidence of renal or hepatic deposition, less invasive biopsies will often establish the diagnosis. Abdominal fat pad aspiration is at least 60% sensitive, while skin or rectal biopsy will detect amyloid more than 50% of the time. In one series, 95% of the pathology specimens from patients with AL amyloidosis who underwent carpal tunnel decompression contained amyloid (12). Biopsies should be approached cautiously, as amyloid infiltration of small blood vessels may predispose patients to bleeding. Moreover, patients may be factor X deficient due to amyloid binding of this coagulation factor (13).

Amyloid can be identified by its characteristic fibrillar appearance on electron microscopy or by its ability to bind Congo red stain, leading to apple-green birefringence under polarized light (14). The differential diagnosis for microscopically confirmed amyloid includes primary systemic, secondary, hereditary, senile, dialysis-related, and various forms of localized amyloidosis. Of these, only AL amyloid is treated with cytotoxic chemotherapy. Therefore, identification of light chain clones, which will be present only in this type of amyloidosis, is critical. Light chain monoclonality is established with immunofluorescence microscopy or immunohistochemical staining of affected tissue (3). Identification of a serum M-protein is not sufficient, as some patients with other forms of amyloid may have a monoclonal gammopathy of undetermined significance. Stains for transthyretin, serum amyloid A (SAA), and other protein precursors can also be used to distinguish among the various forms of amyloid.

Prognosis and treatment

In older series, median OS for patients with untreated AL amyloidosis was approximately 5 months (15). With treatment, median OS improves to at least 18 months. In a Mayo Clinic series of 220 patients, only 34 survived 5 years (16). Patients with predominant peripheral nerve involvement generally survive longer, with median OS of 34 months, while patients with cardiac disease have median OS of 5 months. Patients who present with renal amyloidosis have an intermediate prognosis (Figure 5) (16). Besides cardiac involvement, poor prognostic signs include a peripheral blood plasma cell count >500,000/L, circulating plasma cells >1%, serum beta-2-microglobulin ≥2.7 μg/mL, and bone marrow plasmacytosis >10% (17).

Figure 5.

Overall survival from the date of randomization among patients with primary systemic amyloidosis, according to the chief clinical manifestation. PN indicates peripheral neuropathy; Nephr, nephrotic syndrome or renal insufficiency; CHF congestive heart failure. Reprinted with permission from Kyle et al, 1997 (16).

The goal of treatment is to reduce the production of Bence Jones protein, leading to decreased amyloid deposition. Standard cytotoxic chemotherapy consists of melphalan and high-dose prednisone. This was established by the foregoing Mayo series, where patients treated with this regimen had median OS of 18 months as compared to single-agent colchicine (8.5 months) or a three-drug regimen including melphalan, prednisone, and colchicine (17 months) (Figure 6) (16).

Figure 6.

Survival from the date of randomization among patients with primary systemic amyloidosis, according to treatment group. MP indicates melphalan and prednisone; MPC, melphalan, prednisone, and colchicine; and C, colchicine. Reprinted with permission from Kyle et al, 1997 (16).

In two small series, melphalan in combination with high dose oral dexamethasone has also shown benefit. In a recent Italian series of 46 patients treated with this approach, 15 patients had a complete response, defined as disappearance of any detectable clone, with 10 of these patients remaining in complete remission at 3-year follow up. Another 16 patients had a partial response, defined as a 50% reduction in demonstrable Bence Jones protein. Of the 31 responding patients, 22 achieved significant functional improvement of involved organs. None of the 15 nonresponders saw any such improvement. At a median follow up of 5 years, median progression-free survival among the entire group was 3.8 years, with OS of 5.1 years (18). Conventional-dose treatment options for AL amyloid also include thalidomide (19), lenalidomide (20), and bortezomib (21), with or without dexamethasone. While these novel agents have shown early promise in several small series, larger studies are needed.

A more aggressive but as yet unproven treatment option for patients with AL amyloid is high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). A number of nonrandomized, single-institution series have suggested that this approach might benefit some patients. In the largest of these studies, a Boston group treated 312 of 701 evaluated patients with high-dose melphalan followed by ASCT. Patients were excluded if they were over age 80 or had uncompensated heart failure, left ventricular ejection fraction <40%, persisting pleural effusion, systolic pressure <90 mm Hg, oxygen saturation <95%, or a performance status ≥3. In this select population, median survival was 4.6 years. Complete response was seen in 40% of the patients, with the median survival of this group likely exceeding 8 years. Improved organ function was seen in 66% of complete responders and in 30% of the remaining patients. The 100-day treatment-related mortality was 13% (22).

While nonrandomized studies are encouraging, only one trial has directly compared ASCT with conventional-dose chemotherapy. A French group randomized 100 patients aged 18 to 70 between the foregoing melphalan-dexamethasone regimen and high-dose melphalan with ASCT. After a median follow-up of 3 years, median OS was 56.9 months in the melphalan-dexamethasone group vs 22.2 months in transplanted patients (P = 0.04) (Figure 7). Treatment-related mortality in the transplant group was 24%, higher than in the Boston series or in other single-arm studies, which accounts for at least some of the difference in outcome (23).

Figure 7.

Overall survival according to treatment group. The crude estimated hazard ratio for death in the group assigned to receive melphalan plus dexamethasone was 0.57 (95% confidence interval, 0.32 to 0.99; P = 0.05). Reprinted with permission from Jaccard et al, 2007 (23).

Despite evidence of multiorgan disease, our patient experienced a complete and durable clinical remission on long-term low-dose prednisone and colchicine. Her extended survival of over 21 years on a regimen that is no longer the standard of care reinforces how much we have yet to learn about the best way to manage patients with AL amyloidosis.

Acknowledgments

Many thanks to Dr. Marvin Stone, who guided me with so much wisdom and encouragement throughout my residency and fellowship. I am also grateful for the expert assistance of Ms. Cynthia Orticio in preparing this manuscript for publication.