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Light chain proteinuria and lysozymuria in a patient with acute monocytic leukemia.

We present an unusual case of a patient presenting with both monocytic leukemia and plasma cell dyscrasia. Of interest, very high concentrations of monoclonal free light chain, Bence Jones protein (BJP) s and lysozyme were found in the urine, and identification of lysozyme by immunofixation electrophoresis (IFE) required modification of the usual methods.

An 83-year-old man entered the Veteran Administration Hospital from a nursing home with a complaint of failure to urinate. The patient was being followed for myelodysplastic syndrome. The patient was admitted to the hospital on the basis of dysuria and a low hemoglobin (reference intervals in parentheses) of 53 g/L (135-180 g/L). The white blood cell count was 8.1 x [10.sup.9]/L (5-10 x [10.sup.9]/L), with 61% monocytes. Pertinent blood chemistry results on admission were as follows: urea nitrogen, 0.9 g/L (0.07-0.22 g/L); creatinine, 0.06 g/L (0.006-0.014 g/L); potassium, 3.4 mmol/L (3.5-5.3 mmol/L); calcium, 0.076 g/L (0.092-0.107 g/L); total protein, 76 g/L (62-82 g/L); albumin, 24 g/L (35-50 g/L); IgG, 30 g/L (7.2-16.8 g/L); IgA, 2.6 g/L (0.69-3.8 g/L); IgM, 0.62 g/L (0.63-2.7 g/L); and [kappa]/[lambda] ratio, 0.49 (1.2-2.6). A monoclonal protein had not been detected previously, but results of the serum protein electrophoresis and immunonephelometric analysis performed on admission indicated a monoclonal IgG-[lambda] concentration of ~30 g/L. This profile is most consistent with myeloma. Bone marrow aspirates showed 30-40% monocytes/myeloblasts and 5-10% plasma cells. Radiologic examination, including bone radiography and computerized tomography, showed no bone lesions. Urine chemistry showed 5.8 g protein/24 h (reference values, <200 mg/24 h), with a volume of 1.5 L. The urine protein electrophoresis (UPE) screen showed a paraprotein near the origin in the gamma region. Urinary IFE identified a small monoclonal IgG-[lambda] migrating very close to a large [lambda]-BJP (Fig. 1). The amount of BJP, estimated from the densitometer tracing of the UPE screen, was ~3 g/day. The interpretation of the UPE and IFE was large BJP, most consistent with myeloma. With the UPE screen, another band was observed in the far cathodal region.

Increased lysozyme (EC 3.2.1.17) concentrations have long been known to be associated with monocytic and myelomonocytic leukemias (1), and quantification may be helpful in classification according to the French-American-British system (2). Nevertheless, it was unclear whether the cathodal band represented BJP or lysozyme. Lysozyme is a small molecule (14-15 kDa) with a high isoelectric point (pI 10.5-11.0) (1); it migrates at the cathodal end of the gel on typical agarose protein electrophoresis (3). Like BJP, it readily passes through the glomerulus where it is physiologically concentrated so that large concentrations appear in the urine (4). Furthermore, urine is mechanically concentrated before analysis so that paraproteins become more apparent. As shown in Fig. 1, lysozyme can be observed with UPE in as little as a 25-fold concentrate.

IFE was performed for definitive identification. Lysozyme was not detected by the usual IFE procedure using two different types of IFE plates (Helena Laboratories and Beckman Coulter) because it ran off the cathodal end of the gel. It could be identified (antisera obtained from Dako) by reducing the time of electrophoresis or by inoculating the gel closer to the anodal end. The advantage of maintaining the same electrophoresic time with inoculation near the anodal end is that samples for routine immunoglobulin identification can be run at the same time. The disadvantage is that the associated UPE does not show all of the banding because albumin and many globulins migrate off of the gel. In either case, these simple manipulations provide a method for definitive identification of lysozyme.

When the procedure is manipulated so that lysozyme can be identified, IFE is much more sensitive than UPE for identifying lysozyme. This increased sensitivity for identifying low protein concentrations is well established for BJP (5) and can be clearly seen for lysozyme in Fig. 1 (left side), where a 25-fold concentrate is just barely seen on UPE, but a 5-fold concentrate is clearly seen with IFE. The reason for this phenomenon is that polyclonal antibodies bound to the antigen greatly increase the mass of the stained band. This explains why, in the middle lanes in Fig. 1, the edge of the lysozyme band can be seen at the top of the gel with IFE at 20- and 10-fold concentrates, but nothing is seen in the 100-fold concentrate with UPE. In this case, most of the protein ran off the top of the gel, but a small amount, sufficient for identification by IFE but not UPE, remained.

[FIGURE 1 OMITTED]

Myelodysplastic syndrome is a syndrome characterized by refractory anemia that, in general, is preleukemic and may terminate in acute myeloid leukemia (AML). In the present case, on the basis of blood and bone marrow findings, a diagnosis of acute monocytic leukemia (M5, according to the French-American-British classification) was made. The patient also exhibited a monoclonal gammopathy. A serum monoclonal protein concentration >25 g/L and a large amount of BJP are consistent with multiple myeloma (6). However, among symptomatic patients, the percentage of plasma cells in the bone marrow usually exceeds 10%, or sheets of plasma cells are present in a lytic bone lesion (6, 7). In the present case, significant numbers of plasma cells were not seen on bone marrow examination, nor were lytic bone lesions found.

There are parallels between myeloma with BJP proteinuria and AML with lysozymuria in that, in both cases, there is an overflow proteinuria. However, there is no known causal relationship, except as a secondary event to chemotherapeutic treatment of myeloma where patients may develop myelodysplastic syndrome and AML (8, 9). Otherwise, synchronous cases are unusual (8, 9).

Among the earliest cases reported, a patient was described with overt multiple myeloma, exhibiting 55-60% plasma cells and BJP for 3 years before the development of terminal monomyelocytic leukemia (1,10). The same authors described two cases of a small IgG monoclonal protein associated with AML, but these were most likely coincidental monoclonal gammopathies of undetermined significance, which are now known to occur in as many as 3% of people over 70 years of age, often unrelated to disease (11). Recently, a review of the literature along with two cases of AML presenting concomitantly with multiple myeloma were reported (9). The present case appears to be different from these others because, although active myeloma was not apparent, the size of the serum monoclonal protein and the large urinary BJP were consistent with a plasma cell dyscrasia that will develop into overt disease over a period of time (12,13).

Received February S, 2002; accepted April 12, 2002.

References

(1.) Osserman EF, Lawlor DP. Serum and urinary lysozyme (muramidase) in monocytic and monomyelocytic leukemia. J Exp Med 1966;124:921-52.

(2.) Sexton C, Buss D, Powell B, O'Connor M, Rainer R, Woodruff R, et al. Usefulness and limitations of serum and urine lysozyme levels in the classification of acute myeloid leukemia: an analysis of 208 cases. Leuk Res 1996;20:467-72.

(3.) Strobel SL. The incidence and significance of pseudoparaproteins in a community hospital. Ann Clin Lab Sci 2000;30:289-94.

(4.) Perillie PE, Finch SC. Lysozyme in leukemia. Med Clin North Am 1973;57:395-407.

(5.) Levinson SS, Keren DF. Free light chains of immunoglobulins: clinical laboratory analysis: critical review. Clin Chem 1994;40: 1869-78.

(6.) Alexanian R, Weber D, Liu F. Differential diagnosis of monoclonal gammopathies. Arch Pathol Lab Med 1999;123:108-13.

(7.) Bataan R, Harold J-L. Multiple myeloma. N Engl J Med 1997;336: 1657-63.

(8.) Dunkley S, Gibson J, Iland H, Li C, Joshua D. Acute promyelocytic leukaemia complicating multiple myeloma: evidence of different cell lineages. Leuk Lymphoma 1999;35:623-6.

(9.) Anderson CM, Bueso-Ramos CE, Wallner SA, Albitar M, Rosenzweig TE, Koller CA. Primary myeloid leukemia presenting concomitantly with primary multiple myeloma: two cases and an update of the literature. Leuk Lymphoma 1999;32:385-90.

(10.) Osserman EF, Takatsuki K, Talal N. The pathogenesis of amyloidosis. Semin Hematol 1964;1:3-85.

(11.) Attaelmannan M, Levinson SS. Understanding and identifying monoclonal gammopathies. Clin Chem 2000;46:1230B-8B.

(12.) Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J 1980;302:1347-9.

(13.) Pascali E, Pezzoli A. The clinical spectrum of pure Bence Jones proteinuria. Cancer 1988;62:2408-15.

[5] Nonstandard abbreviafions: BJP, Bence Jones protein; IFE immunofixation electrophoresis; UPE, urine protein electrophoresis; and AML, acute myeloid leukemia.

STANLEY S. LEVINSON, [1,2] * RONALD J. ELIN, [2] and LUNG YAM [3,4]

[1] Laboratory Service and [3] Medical Service, Department of Veterans Affairs Medical Center, S00 Zorn Ave., Louisville, KY 40206.

[2] Department of Pathology and Laboratory Medicine and [4] Division of Medicine, School of Medicine, University of Louisville, Louisville, KY 40292.

* Address correspondence to this author at: Laboratory Service, Department of Veterans Affairs Medical Center, S00 Zorn Ave., Louisville, KY 40206. E-mail levinson@louisville.edu.
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Title Annotation:Case Report
Author:Levinson, Stanley S.; Elin, Ronald J.; Yam, Lung
Publication:Clinical Chemistry
Date:Jul 1, 2002
Words:1523
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