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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2408-2410 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.9475
Phenotypic Evolution of Waldenstrom's Macroglobulinemia to Extramedullary PlasmacytomaDivision of Medical Oncology, Department of Internal Medicine, University of Colorado Health Sciences Center
Department of Pathology, University of Colorado Health Sciences Center
Department of Surgery, University of Colorado Health Sciences Center A 61-year-old Hispanic man who had no significant past medical history presented in April 2007 with a month-long history of progressive fatigue, right flank pain, and acute renal failure. Evaluation at the Myeloma and Amyloidosis Program at the University of Colorado Health Sciences Center showed a pale skin without other physical abnormalities. Laboratory data revealed a hemoglobin of 8.0 g/dL (normal range [normal], 14.3 to 18.1 g/dL), serum creatinine of 8.9 mg/dL (normal, 0.4 to 1.2 mg/dL), blood urea nitrogen of 58 mg/dL (normal, 6 to 23 mg/dL) and normal electrolytes including calcium of 9.3 mg/dL (normal, 8.5 to 10.3 mg/dL); lactate dehydrogenase of 98 u/L (normal, 98 to 192 u/L), total protein 10.3 g/dL (normal, 6.4 to 8.3 g/dL), albumin of 3.0 g/dL (normal, 3.4 to 5.0 g/dL), immunoglobulin (Ig) G of 1,340 mg/dL (normal, 791 to 1643 mg/dL), IgA of 81 mg/dL (normal, 66 to 436 mg/dL), IgM of 4,240 mg/dL (normal, 43 to 279 mg/dL), IgM kappa monoclonal protein of 2,600 mg/dL, serum viscosity of 2.23 cP (normal, 1.1 to 1.8 cP), serum free kappa and lambda light chain of 153 mg/dL (normal, 0.33 to 1.94 mg/dL) and 3.73 mg/dL (normal, 0.57 to 2.63 mg/dL) (by nephelometry), respectively; a 24-hour urine protein of 3,598 mg (normal, 0 to 150 mg) of which 1,500 mg came from Bence-Jones proteinuria of free kappa light chain. A positron emission tomography/computed tomography (CT) scan showed a large right- sided perinephric mass of 14 cm x 16 cm with an standard unit of value (SUV) of 5.7 (Fig 1), one left upper lobe lung nodule of 1.5 cm x 1.4 cm with an SUV of 3.9 and an enlarged right perihilar lymph node with an SUV of 3.4. No lytic changes of the bone were noted. A diagnostic CT-guided needle biopsy of the perinephric mass showed a dense lymphoid infiltrate with aggregates of small mature lymphocytes, lymphoplasmacytic cells and plasma cells (Fig 2A). A bone marrow aspirate/biopsy showed several large lymphoid aggregates comprising of 20% of marrow with small round lymphocytes, lymphoplasmacytic cells, and plasma cells (Fig 2B). Immunohistochemical staining of the perinephric mass was positive for CD20 and membrane kappa light chain but negative for CD138 and CD5 (Fig 3A, CD20+; 3B, CD138–). Immunohistochemical staining of the marrow showed similar findings. Flow cytometry of both the perinephric mass and marrow showed a clonal population of B cells expressing CD19, CD38, and both membrane and cytoplasmic kappa for the mass and cytoplasmic kappa light chain for the marrow. CD138 expression was negligible. Cytogenetics on both the marrow and perinephric mass was normal with 46 XY. A needle biopsy of the left sided kidney showed numerous fractured and refractile casts in tubules admixed with an inflammatory exudates (Fig 4A). Casts within the tubules were highlighted with IgM, and kappa light chain (Fig 4B, 4C). Glomeruli, vessels, and interstitium were all negative on immunofluorescence and normal on electron microscopy studies (not shown). With the diagnosis of Waldenstrom's macroglobulinemia and acute renal failure of cast nephropathy of IgM kappa and free kappa monoclonal protein, the patient underwent two sessions of plasma exchange and daily hemodialysis, followed in a week by induction chemotherapy consisting of rituximab plus dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide (DTPACE without cisplatin).1 Renal failure rapidly improved and dialysis was discontinued within two weeks of the first cycle. A restaging study following the four cycles of therapy showed a stable disease with negligible activity of the perihilar and left upper lung lesions on the positron emission tomography/CT scan, rare lymphoid aggregates in marrow, and decreased serum kappa free light chain and creatinine levels to less than 30 mg/dL and 3 mg/dL, respectively, but showed minimal changes in the perinephric mass. Further cytoreduction was achieved by additional three cycles of the bortezomib, thalidomide, and dexamethasone plus rituximab,2 with disappearance of the perihilar and lung lesions and normalized marrow, but without changes in the perinephric mass. In preparation for autologous stem-cell transplant, the patient then underwent a debulking operation to remove the perinephric mass, adjacent enlarged lymph nodes, and the right kidney that turned out to be directly invaded by the mass. Pathology on all the resected specimens, however, showed sheets of monotonous plasma cells (Fig 5). These cells expressed CD138, both membrane and cytoplasmic IgM, and kappa light chain, but did not express CD20, CD79a, PAX-5, and CD56 (Fig 3C: CD20–; 3D: CD138+). Tissue cytogenetics was noninformative. Following the surgery, serum IgM kappa monoclonal protein disappeared and the patient condition progressively improved except for the renal dysfunction.
Waldenstrom's macroglobulinemia can be distinguished clinically from IgM myeloma by the lymphoplasmacytic versus pure plasmacytic morphology, absent versus present bone involvement, and immunophenotypic findings.3 It progresses slowly and, in rare occasions, transforms to more aggressive diffuse large cell lymphoma or immunoblastic lymphoma.4 Most of the clinical symptoms come from tumor infiltration and the consequences of abnormal IgM monoclonal protein such as hyperviscosity.5 Unlike multiple myeloma, renal dysfunction by monoclonal IgM paraprotein is known to be rare. The current case illustrates complex issues with renal failure from the cast nephropathy, a slow and discordant response to therapy, and unexpected findings of pure plasmacytic infiltrates postchemotherapy amounting to a diagnosis of extramedullary plasmacytoma. The cast nephropathy should be explained by the same pathogenesis as in multiple myeloma as both IgM and kappa light chain were seen in the tubules by immunofluorescence in the presence of Bence-Jones proteinuria.6 We chose rituximab plus dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide as induction—an effective antimyeloma regimen; and the bortezomib, thalidomide, and dexamethasone, focusing more on the control of aberrant plasma cell proliferation to expedite elimination of paraprotein. The discovery of exclusive infiltration of the resected organs by abnormal plasma cells, however, suggests that the therapy may have selected out a resistant clone with the plasmacytic phenotype, or it may represent one pathway of transformation of Waldenstrom's macroglobulinemia.7 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Lee CK, Barlogie B, Munshi N, et al: DTPACE: An effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol 21:2732-2739, 2003 2. Wang M, Giralt S, Delasalle K, et al: Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 12:235-239, 2007[CrossRef][Medline] 3. Owen RG, Treon SP, Al-Katib A, et al: Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 30:110-115, 2003[CrossRef][Medline] 4. Ling S, Joshua DE, Gibson J, et al: Transformation and progression of Waldenström's macroglobulinemia following cladribine therapy in two cases: Natural evolution or iatrogenic causation? Am J Hematol 81:110-114, 2006[CrossRef][Medline] 5. Dimopoulos MA, Kyle RA, Anagnostopoulos A, et al: Diagnosis and management of Waldenstrom's macroglobulinemia. J Clin Oncol 23:1564-1577, 2005 6. Isaac J, Herrera GA: Cast nephropathy in a case of Waldenström's macroglobulinemia. Nephron 91:512-515, 2002[CrossRef][Medline] 7. Jondeau K, Alterescu R, Franc B, et al: Unusual evolution of Waldenström's macroglobulinemia into osteolytic myeloma. Eur J Haematol 77:74-79, 2006[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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