Contributed by Douglas R. Johnson, MDFINAL DIAGNOSIS:
Waldenstrom's macroglobulinemia, representing approximately 2% of hematologic malignancies (2), is less common than multiple myeloma, and must be differentiated on predominantly clinical grounds from other entities presenting with monoclonal spikes of IgM. These conditions include the monoclonal gammopathy of undetermined significance (MGUS), various B-cell lymphomas, chronic lymphocytic leukemia, IgM myeloma, essential macroglobulinemia, and plasmacytoma (1). The condition is diagnosed in approximately 1,500 individuals annually in the U.S., and is usually not detected until either the paraprotein level exceeds 3.0 g/dL (1,2), or until the blood viscosity is at least four times that of normal serum (2). As demonstrated by this case, the common presentation occurs in elderly males showing signs of organ involvement and bone marrow infiltration. The most common finding in patients (not appreciated in this current case) is the hyperviscosity syndrome, seen in approximately 15% of cases (2). The clinical presentation includes fatigue, dizziness, blurred vision, and easy bleeding of mucous membranes (2). In addition, cryoglobulinemia, peripheral neuropathy, hemorrhagic diatheses, and diffuse systemic amyloidosis have also been described (1), and usually occur in patients without lymphoma (2). The current case demonstrated acute renal involvement with the infiltrating lymphoma and glomerular-based changes which is of significance since severe proteinuria in the nephrotic range, and renal insufficiency are usually an infrequent finding in Waldenstrom's as compared to multiple myeloma (1). The difference in clinical presentation is felt to be secondary to the lower frequency of both Bence-Jones proteinuria and hypercalcemia in Waldenstrom's macroglobulinemia (1,2).
The pathologic renal findings in Waldenstrom's macroglobulinemia by light microscopy and other methods are described as four potential patterns of involvement, with simultaneous overlap of each pattern possible in any given patient. The first is apparent widespread capillary loop "thrombosis" by acellular hyaline material that is PAS positive (as seen in this case). Of significance is the near total lack of a cellular response to the amorphous material giving the appearance of "pseudothrombi," and which is also seen to expand the mesangium. These deposits directly correspond to the amyloidotic IgM material, with a glomerular and vascular distribution (as illustrated in this patient's renal biopsy). Interestingly, the "pseudothrombi" result from the amyloid / IgM deposits displacing the endothelial cells from a subendothelial / mesangial location to occlude the capillary lumen. True thrombi can be ruled out on light microscopy and immunofluorescence, as fibrin stains will be negative in the glomerular capillary loops (1). The second presentation on renal biopsy consists of a proliferative glomerulonephritis consistent with cryoglobulinemia and hypocomplementemia (1). This condition can also lead to massive true capillary loop thrombosis with a cellular proliferative glomerulonephritis and complement activation (not seen in the current case). Amyloidosis, the third possible presentation, is seen in less than 5% of Waldenstrom's patients, and represents the most frequent cause of nephrotic range proteinuria in affected patients (1). This finding is illustrated to a degree by this patient as shown by the immunostaining results and electron microscopic findings of organized fibrils. These changes overlap with the light microscopic features presenting as "pseudothrombi." The fourth, and considered the most common presentation, is that of diffuse renal parenchymal infiltration by the actual lymphoproliferative cells causing the Waldenstrom's macroglobulinemia (illustrated in the current case) (1). The atypical lymphocytes are morphologically and phenotypically identical to the cells usually detected in the bone marrow, in 90% of cases (2), or elsewhere including lymph nodes, the lungs, the gastrointestinal tract, or the skin (2). Of importance for the renal biopsy, these infiltrates have been described in all anatomic locations of the kidney, including the cortex, medulla, and hilar / peripelvic fat. The infiltrates may also surround and involve the ureter (1). Within the kidney, the lymphoid infiltrates usually circumscribe and compress the tubules with or without tubular damage. In cases with significant tubular damage, the infiltrates are thought to contribute directly to the acute renal insufficiency (1).
To illustrate the variability of clinico-pathologic presentations, the reader is referred to a case report of a 53 year-old man with Waldenstrom's macroglobulinemia and acute renal failure (3). The authors describe a monoclonal IgM kappa-restricted paraprotein spike detected in the gamma range on electrophoresis, normal serum viscosity, and a less severe degree of renal failure showing a creatinine clearance of 78 mL/minute. A bone marrow biopsy also revealed an immunocytoma, but the renal biopsy showed only a minimal lymphocytic infiltrate without atypia. Similar glomerular changes were noted as in the current case with a mild degree of tubular atrophy; however, Congo Red stains were negative for amyloid. The patient underwent an extensive chemotherapy regimen including cyclophosphamide, vincristine, and prednisone with improvement in renal function and clearing of the kappa light chains by urine immunoelectrophoresis. The serum IgM paraprotein, although decreased, was still present after 21 months of chemotherapy; and the patient still had residual hematuria suggestive of persistent glomerular damage. These results, however, are consistent with the impression that depending on the severity of the proteinuria, the renal insufficiency can be mild and reversible with treatment (2).
Another case report describes a 66 year-old female with very similar clinical findings as described in the current case, with mild persistent edema of the feet and lower extremities for four months duration as the only significant finding on exam (4). As in our case, this patient showed a monoclonal IgM lambda-restricted paraprotein, and proteinuria also in the nephrotic range. The renal biopsy showed subepithelial and subendothelial deposits of Congo Red positive fibrillary material consistent with glomerular amyloidosis, and IgM deposition in both the mesangium and along the glomerular capillary membrane. The reader is referred to the excellent discussion of the clinical differential diagnoses provided in this case report (4). Information on prognostic factors is limited due most likely to the relatively infrequency of Waldenstrom's; however, age greater than 60 years, male gender, hemoglobin less than 10 g/dL, and neutropenia, are associated with a shorter survival (1,2).
Current treatment options include those discussed above (3), the use of chlorambucil on daily low-dose and intermittent high-dose schedules (1,2,4), interferon-alpha (2), and plasmapheresis to decrease the level of circulating IgM paraprotein since 80% of the IgM exists in a circulating form (1,2). In cases with hyperviscosity syndrome, chemotherapy is recommended to aid in rapidly decreasing the paraprotein level, and to target and control the underlying lymphoproliferative disorder. The therapeutic regimens were adapted from those used for chronic lymphocytic leukemia, and have shown a median survival of 5 years, with 20% of patients dying of unrelated causes (2). A reported 10% of patients will achieve complete clinical remission with clearance of the IgM paraprotein on studied by electrophoresis and immunofixation, with median survival regarded as 11 years (2). Alternative chemotherapeutic agents including fludarabine and 2-chlorodeoxyadenosine have also shown some promise in the treatment of this disease.
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Contributed by Douglas R. Johnson, MD
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