Barbital

* About two thirds of patients with multiple myeloma and M-component in serum also have light chains in urine. However, the simultaneous presence of 2 Bence Jones proteins of different immunologic types in the same patient is rare. We describe the case of a 58-year-old woman with multiple myeloma, having 2 monoclonal light chains of both types (κ and λ) and an immunoglobulin G-λ monoclonal protein in urine. The quantitative determination of light chains in urine was carried out using nephelometry, and Bence Jones proteinuria was confirmed by agarose gel immunofixation. To the best of our knowledge, this is the first reported case of double Bence Jones proteinuria after hematopoietic cell transplantation.

(Arch Pathol Lab Med. 2005;129:937-939)

Generally speaking, multiple myeloma is manifested by a malignant proliferation of plasma cells producing a specific monoclonal immunoglobulin, often referred to as M-component. About two thirds of patients with multiple myeloma and M-component in serum also have light chains in urine. However, the presence of 2 M-components in the serum or urine (biclonal gammopathy) in multiple myeloma is uncommon, and the simultaneous presence of 2 Bence Jones proteins of different immunologie types in the same patient is very rare.1,2

Normal plasma cells produce light chains in excess of heavy chains, and small amounts of these proteins escape into the plasma and hence into the urine.3 Because of their comparatively low relative molecular mass, light chains are excreted into the urine and are present in serum only in very small amounts in the absence of severe renal failure.4

REPORT OF A case

A 58-year-old woman was repeatedly treated during a 3-month period for dorsal lumbar pain radiating to the epigastrium. In June 1999, because of the persistent pain, the patient was referred to the hospital. Physical examination revealed pallor of the skin and mucous membranes. Slight pain to pressure and percussion of the lower back region was also observed. Radiographie examination showed diffuse osteopenia with compression of the lumbar vertebrae and with lytic cranial lesions. Laboratory test results revealed the following values: hemoglobin, 9.3 g/dL; hematocrit, 28.3%; platelets, 186 × 10^sup 3^/µL urea, 58 mg/dL; creatinine, 1.8 mg/dL; uric acid, 8.3 mg/dL; albumin, 2.8 g/dL; lactate dehydrogenase, 466 U/L; and sodium, 128 mEq/L (128 mmol/L). Glucose, total cholesterol, triglycerides, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, calcium, potassium, chloride, creatine kinase, amylase, and coagulation were all normal. The total serum protein level was 12.4 g/dL. Quantitative determinations of serum immunoglobulins showed the following values: immunoglobulin (Ig) G, 7360 mg/dL; IgA, 20 mg/dL; and IgM, 18 mg/dL. Serum electrophoresis revealed a large spike in the -γ-globulin region in densitometer tracing, and immunofixation showed 1 IgG-λ monoclonal protein. Nephelometric analyses of the 24-hour urine sample showed a λ (free and bound) light chain, and no κ light chain was excreted. Examination of bone marrow aspirate demonstrated hypercellularity, with many abnormal plasma cells. Histologie analysis of the biopsy sample confirmed multiple myeloma. The patient received 6 cycles of vincristine-doxorubicin with bolus of dexamethasone (VAD) intermittently for 6 months.

In February 2000, the patient underwent autologous hematopoietic cell transplantation. Examination of bone marrow aspirate showed no evidence of myeloma. The anemic syndrome and the bone pain disappeared. Histologie analysis of the biopsy sample was normal.

In August 2000, no Bence Jones protein was excreted. In February 2001, immunofixation of the 24-hour urine specimen revealed a monoclonal free λ light chain. In August 2001, no Bence Jones protein was excreted.

In December 2002, the patient came to the hospital for a routine checkup. Immunofixation of the 24-hour urine sample demonstrated Bence Jones proteins of both λ and κ type, as well as an IgG-λ. monoclonal protein. Immunonephelometric analysis of the urinary free light chains indicated a free κ light-chain concentration of 37.00 mg/24 h and a free λ light-chain concentration of 18.00 mg/24 h. Quantitative determinations of serum immunoglobulins showed the following values: IgG, 2190 mg/dL; IgA, 45 mg/dL; and IgM, 40 mg/dL. Serum and 24-hour urine specimens obtained in April 2003 were subjected to immunofixation. Immunofixation of the urine sample gave identical results (Figure 1). Nephelometric analysis of the urinary free light chains showed 118.30 mg free λ light chain/24 h and 25.13 mg free κ light chain/24 h. Serum immunofixation showed 3 M-components, indicating the presence of IgG-λ monoclonal protein, monoclonal free κ light chain, and monoclonal free λ light chain (Figure 2).

From April to June 2003, the patient was treated with 3 cycles of VAD polychemotherapy. On July 23, 2003, the patient was admitted to the hospital for a fourth cycle of VAD polychemotherapy. On August 1, 2003, the patient presented with severe hemodynamic instability and secondary septic shock from an Escherichia coli urinary infection and was taken to the intensive care unit. Two days later, the patient died as a result of multiorgan failure.

MATERIALS AND METHODS

Electrophoretic separation and immunofixation of proteins in the urine and serum samples were performed on buffered agarose gels (0.65% barbital buffer, pH 9.2) (Sebia, Barcelona, Spain) using a Sebia Hydrasys System. Densitometer scanning of stained electrophoregrams was performed on the Hyrys 2 (Sebia). The urine samples were appropriately concentrated using Millipore Minicon-B15 concentrators (Millipore Corporation, Bedford, Mass). Unlabeled antisera monospecific for IgG, IgA, IgM, and κ and λ light chains were obtained from Sebia.

The quantitative determination of urinary light chains was carried out in unconcentrated urine by nephelometry on the Immage analyzer (Beckman Coulter, Fullerton, Calif). Antisera monospecific for λ and κ free light chains were obtained from New Scientific Company (Barcelona, Spain). Antisera monospecific for λ and κ (free and bound) light chains were obtained from Beckman Coulter.

The level of IgG was determined by nephelometry on the Immage analyzer (Beckman Coulter).

PATHOLOGIC FINDINGS

Judging from the limited number of clinical cases found in the literature (10 cases),2-11 the simultaneous presence of Bence Jones proteins of both λ and κ type in the urine of the same patient seems to be rare. A summary of 11 cases of double Bence Jones proteinuria, including ours, is given in the Table. Most of the patients were men older than 60 years, diagnosed with multiple myeloma, and having 1 or more M-components in the serum.

The patient's course, determined by means of serum IgG concentration, is shown in Figure 3. In this case, a correlation between the pathologic events and changes of the IgG protein picture could be observed. The patient received 6 cycles of VAD chemotherapy and 42 days later underwent stem cell transplantation. Clinical response was supported by a notable decrease in IgG protein. Forty-one months after the initial hospital admission, the IgG protein concentration began to rise. Again, VAD chemotherapy was given, and the IgG protein level gradually decreased.

The results suggest that the absence of λ light chains was a consequence of the chemotherapy, of the autologous transplantation of hematopoietic cells, or both. Perhaps the appearance and later disappearance of Bence Jones λ proteinuria was due to the recovery of B-cell function after therapy. The following hypotheses are suggested for the onset of double Bence Jones proteinuria: changes in the production of paraprotein by the malignant clone or the presence of a second malignant clone.

Unfortunately, the patient died before immunohistologic studies could be performed, so the question of the clonal origin of the 2 Bence Jones proteins could not be investigated.

This work was supported in part by grants from the Complejo Hospitalario Universitario Juan Canalejo (Spain). We acknowledge the Department of Computer Science of Complejo Hospitalario Universitario Juan Canalejo (Spain) for their assistance in preparing the electronic formats of the figures.

References

1. Braunwald E, Fauci AS, Kasper DL, Mauser SL, Longo DL, Jameson JL, eds. Harrison Principios de Medicina Interna. Vol 1, 15th ed. Madrid, Spain: McGraw-HiII lnteramericana; 2001.

2. Kanoh T, Yago K. Double Bence Jones proteinuria. Arch Pathol Lab Mecl. 1990;114:991-994.

3. Bushell AC, Whicher JT, Yuille T. The progressive appearance of multiple urinary Bence-Jones proteins and serum paraproteins in a child with immune deficiency. CHn Exp lmmunol. 1 979;38:64-69.

4. Dalai FR, Winsten S. Double light-chain disease: a case report. CHn Chcm. 1979;25:190-192.

5. Dittmar K, Kochwa S, Zucker-Franklin D, Wasserman LR. Coexistence of polycythemia vera and biclonal gammopathy (gamma-Gκ and gamma-Aλ) with two Bence Jones proteins (BJκ and BJλ). Blood. 1968;31:81-92.

6. Engle RL Jr, Nachman RL. Two Bence Jones proteins of different immunologic types in the same patient with multiple myeloma. Blood. 1966;27:74-77.

7. Dammacco F, Trizio D, Bonomo L. A case of IgAκ-myelomatosis with two urinary Bence Jones proteins (Bjκ and BJλ) and multiple chromosomal abnormalities. Acta Hacmatol. 1969;41:309-320.

8. Riddel! S, Traczyk Z, Paraskevas F, Israels LG. The double gammopathies: clinical and immunological studies. Medicine. 1986;65:135-142.

9. Ottó S, Végh Z, Hindy I, Péter I. Multiple myeloma arising from solitary plasmacytoma of bone. Oncology. 1990:47:84-86.

10. Gibaud A, Schiff C, Gibaud H, et al. Charactérisation biochimique de deux proteines de Bence Jones isotypiquement différentes chez un mêrme malade. Lyon Med. 1976:236:141-144.

11. Nishimura S, Wakui H, Takahashi T, et al. A case of multiple myeloma with biclonal gammopathy (lgG-λ, lgA-κ) and two Bence Jones proteins (λ, κ) in the urine. Rinsho Ketsueki. 1983:24(suppl):372.

Jose-Antonio Méndez-Arredondo, MSc; Inès Rodríguez-López, AS; Isabel González-Morales, AS; Guillermo Debén-Ariznavarreta, MD; Fernando Fernández-Rodríguez, MD, PhD; Pilar Sánchez-Mozo, PhD

Accepted for publication March 4, 2005.

From the Departments of Clinical Analysis (Mr Méndez-Arredondo and Dr Fernández-Rodríguez), Immunology (Ms Rodríguez-López, Ms González-Morales, and Dr Sánchez-Mozo), and Hematology (Dr Debén-Ariznavarreta), Complejo Hospitalario Universitario Juan Canalejo, Coruña, Spain.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Pilar Sánchez-Mozo, PhD, Department of Immunology, Complejo Hospitalario Universitario Juan Canalejo, As Xubias 84, 15006 A Coruña, España (e-mail: smozo@canalejo.org).

Copyright College of American Pathologists Jul 2005
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