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Urinary [[Beta].sub.2]-Microglobulin Masquerading as a Bence Jones Protein.

Bence Jones proteinuria, found in 60% or more of patients with multiple myeloma (MM) and less often in patients with other B-cell--derived malignancies, such as solitary plasmacytoma, Waldenstrom macroglobulinemia, and chronic lymphocytic leukemia,[1] is serially monitored quantitatively both for its prognostic value and as an indicator of treatment response.[1-3] Renal tubular dysfunction, most likely due to a number of factors including the nephrotoxicity of Bence Jones proteins themselves,[1,4] is a common complication of long-standing MM. As a consequence of tubular dysfunction from any cause,[5,6] urinary levels of [[Beta].sub.2]-microglobulin (B2M) become elevated, and, therefore, increased concentrations can be expected in urine samples from a substantial proportion of patients with MM. Both Bence Jones proteins and B2M share the common characteristic of being low-molecular-weight proteins that may (in the case of Bence Jones proteins) or do (B2M) migrate electrophoretically in the [Beta] region. Consequently, very high urinary B2M levels can be a potential source of interference when Bence Jones protein excretion is quantified by urine protein electrophoresis (UPEP) studies.

REPORT OF A CASE

A 47-year-old white man with a 20-year history of ptosis presented to an outside institution with complaints of progressively worsening ophthalmoplegia and difficulty swallowing. His medical history was significant for depression, subjective bouts of weakness and fatigue, hypertension, benign prostatic hypertrophy, and Gilbert syndrome. His ophthalmoplegia was suspected to be congenital in origin. During routine evaluation, a serum monoclonal gammopathy consisting of 16 g/L of immunoglobulin G [Kappa] (IgG[Kappa]) M-protein was incidentally discovered. The results of UPEP and urine immunoelectrophoresis studies were negative; urine total protein excretion levels were within normal limits. Evaluation of the bone marrow revealed a small monoclonal population of cytoplasmic [Kappa] light chain-restricted plasma cells in an otherwise normocellular marrow. Abdominal fat pad and right rectus abdominis muscle biopsy specimens were negative for amyloid, although "rare" muscle fiber degenerative changes were noted. The overall findings at that time were considered consistent with a diagnosis of a monoclonal gammopathy of unknown significance.

The patient was observed until approximately 20 months later, when he developed new complaints of a 4.5-kg weight loss, bone and joint pain, and worsening of his bilateral ptosis with ophthalmoplegia. A repeat bone marrow biopsy specimen was now consistent with a progression to multiple myeloma, showing 29% plasma cells that were morphologically atypical and cytoplasmic [Kappa] restricted. Myelomatous changes, however, were absent on radiographic studies, and serum calcium, B2M, blood urea nitrogen, and creatinine levels were all within normal limits. A normocytic anemia, however, was present (hemoglobin, 119 g/L; with a reference range of 125 to 170 g/L). Serum protein electrophoresis studies revealed an increase of the M-component to 45 g/L, although results of UPEP studies remained negative. The patient was subsequently referred to our institution for treatment options, where additional serum protein electrophoresis (Beckman Coulter PARAGON system, Brea, Calif) and serum immunofixation electrophoresis (Beckman Coulter) analyses confirmed the presence of an IgG[Kappa] M-protein that had increased to 60 g/L. A repeat UPEP (Beckman Coulter) now revealed the presence of a small (19 mg/d) Bence Jones protein peak in approximately the [Beta] to fast [Gamma] region, which was confirmed to be a monotypic-free [Kappa] light chain protein by urine immunofixation electrophoresis (UIFE) studies (Beckman Coulter, antisera against free [Kappa] and free [Lambda] light chains were purchased from The Binding Site, Birmingham, England) (Figure 1). A small amount of IgG[Kappa] M-protein was also present in the urine, and the urine total protein excretion was now elevated to 240 mg/d (range, 0.0 to 165.0 mg/d). Nephelometric quantification (Beckman Coulter Array 360) showed depressed levels of uninvolved serum immunoglobulins, with an IgA concentration of 250 mg/L (range, 740 to 3270 mg/L) and an IgM concentration of 240 mg/L (range, 290 to 2140 mg/L). Also, the serum B2M concentration had increased to 7.8 mg/L (range, 0.6 to 2.0 mg/L). Results of a fine-needle aspiration of abdominal wall adipose tissue were positive for amyloid, as confirmed by Congo red staining.

[Figure 1 ILLUSTRATION OMITTED]

Treatment was initiated with intermittent high-dose dexamethasone, which reduced the patient's serum M-protein levels to a low of 13 g/L. Progressive renal failure began, however, and eventually required long-term hemodialysis 3 times weekly. Serum M-protein levels began rising once again, whereas serum B2M concentrations, which had never returned to within normal limits, increased to 26.8 mg/L. Ultimately, the patient underwent a syngeneic stem cell transplantation that was complicated by Klebsiella pneumoniae bacteremia, intestinal graft-versus-host disease, cytomegalovirus antigenemia, and steroid myopathy. Early posttransplantation serum protein electrophoresis and serum immunofixation electrophoresis studies (at approximately 2 months) and UPEP studies (at 6 weeks) showed a small (3.0 g/L) IgG[Kappa] peak and a small Bence Jones protein peak (16 mg/d) migrating in the same regions as originally noted. Repeat analysis performed later (at nearly 6 months), however, showed the presence of 3 tiny (1.0 g/L each) bands (IgG[Kappa], IgG[Lambda], IgG[Kappa]) in the [Gamma] region of the serum, which could possibly reflect immunologic reconstitution. The UPEP, however, still displayed a prominent peak in the [Beta] region (25.5% of the total urine protein). Unexpectedly, no reactivity with antisera against IgG, bound or free [Kappa], or bound or free [Lambda] light chain proteins could be demonstrated despite repeated UIFE studies (Figure 2). A [Kappa] urinary light chain ladder pattern was also present, consisting of 4 faint, evenly spaced bands in the bound [Kappa] lane of the UIFE. All of these bands migrated within the [Gamma] region, with none corresponding to the [Beta] region location of the suspicious peak on the UPEP scan. None of these produced a visible band on the UPEP membrane, consistent with a urinary light chain ladder pattern. The urinary light chain ladder pattern, currently believed to be of little clinical significance, consists of normal polyclonal light chains that are detectable in urine because of increased production or decreased renal reabsorption combined with the high analytic sensitivity of UIFE.[7,8] Consequently, this pattern is frequently visible in UIFE studies of patients with tubular proteinuria of any cause, as a reflection of impaired tubular reabsorption.[7,8] A urinary B2M level was subsequently obtained using a 2-site immunoenzymometric assay (TOSOH, Tokyo, Japan); the value was highly elevated at 70.9 mg/L (range, 0.0 to 0.3 mg/L). Then UIFE was repeated, this time using antisera against B2M (purchased from The Binding Site), which confirmed the peak's identity (Figure 3).

[Figures 2-3 ILLUSTRATION OMITTED]

COMMENT

Normally, B2M, a [Beta]-migrating low-molecular-weight protein that is readily filtered by the glomeruli, is almost totally (99.9%) reabsorbed and degraded by the proximal tubules.[9] Consequently, under normal circumstances, urinary concentrations are small. With renal tubular dysfunction, however, independent of its origin, concentrations can become markedly elevated.[5] In individuals with MM, renal failure and tubular dysfunction are often long-term complications, the causes of which may be multifactorial.[1] Elevated levels can, therefore, be expected in a substantial proportion of these patients. The frequency with which this occurs may not be fully appreciable at the present time, because urinary levels, unlike serum concentrations, are not routinely monitored in patients with this disease.

As a gauge of patients' response to therapy, serial UPEP studies combined with densitometric scanning are commonly used to measure changes in Bence Jones protein excretion over time. Interpretation of the results, however, is not always straightforward, given that abnormally high concentrations of proteins normally found in urine can also produce visible peaks of various sizes. Some of these cases require UIFE analysis to definitively exclude the presence of a monoclonal band. The present case illustrates that on serial UPEP studies elevated B2M levels, in particular, can potentially be confused with persistent Bence Jones proteinuria because of this protein's association with renal dysfunction and electrophoretic migration pattern. This most likely occurs when the original UIFE-confirmed monoclonal protein is [Beta] migrating, since UIFE studies are often not repeated unless the peak has changed in location or number or has disappeared.[10] Consequently, the fact that high urinary B2M concentrations due to a new onset of renal failure are the cause of an abnormal peak may not be readily recognized when the peak occurs in the same location as a previously confirmed Bence Jones protein. Clinically, the implications are that actual therapeutic responses could be underappreciated. An apparent residual Bence Jones protein will be identified when it is, in fact, no longer detectable, or it may appear to be larger than it actually is, if still truly present. Serum levels, although followed as a useful prognostic marker reflecting tumor burden,[2] may not necessarily parallel urinary levels given that serum concentrations ultimately result from interactions among rates of synthesis, glomerular filtration, and proximal tubular reabsorption.[6,9] Hence, serum concentrations may not serve as reliable clues that urinary concentrations are high. In MM and other diseases that may be associated with Bence Jones proteinuria, suspicion will have to remain high if renal tubular dysfunction is also present.

Monitoring patients with these diseases using serial UPEP studies is an integral part of treatment planning because of the important prognostic and therapeutic implications of the presence and quantity of Bence Jones proteins excreted.[1-4] As an objective measure, changes in the quantity of these proteins over time must be accurately reported by the clinical laboratory to ensure optimal patient management. Therefore, factors that are potential sources of interference when interpreting these studies must be continually borne in mind by the evaluator.

The present case suggests that in patients with [Beta]-migrating Bence Jones proteins and evidence of renal tubular dysfunction, a confirmatory repeat UIFE may be warranted when serial Bence Jones protein levels measured using UPEP with densitometric scanning appear inconsistent with clinical findings (ie, do not decrease with other signs of clinical improvement) or increase unexpectedly. If the repeated UIFE shows no evidence of reactivity with antisera against immunoglobulin heavy chains, bound or free [Kappa], or bound or free [Lambda] light chains in the region of the suspicious band, obtaining a quantitative urine B2M level may be helpful. If this level is elevated, a UIFE study using antisera against B2M can then be performed. The former will confirm that the urinary levels are high, whereas the latter can provide definitive identification of the abnormal peak. Approaching these cases in this manner may help avoid underappreciation of true treatment responses and ensure that results are accurately reported.

I thank Katherine C. McClure, MT(ASCP)SC, and Dee Ann Walker, MT(ASCP), for their valuable technical assistance on the case described.

References

[1.] Solomon A. Clinical implications of monoclonal light chains. Semin Oncol. 1986;13:341-349.

[2.] Haferlach T, Loffler H. Prognostic factors in multiple myeloma: practicability for clinical practice and future perspectives. Leukemia. 1997;11(suppl 5):S5-S9.

[3.] Kyle RA. Sequence of testing for monoclonal gammopathies: serum and urine assays. Arch Pathol Lab Med. 1999;123:114-118.

[4.] Grogan T, Spier C. The B cell immunoproliferative disorders, including multiple myeloma and amyloidosis. In: Knowles D, ed. Neoplastic Hematopathology. Baltimore, Md: Williams & Wilkins; 1992:1235-1265.

[5.] Berggard I, Bearn AG. Isolation and properties of a low molecular weight beta-2 globulin occurring in human biological fluids. J Biol Chem. 1968;243: 4095-4103.

[6.] Miyata T, Jadoul M, Kurokawa K, Van Ypersele De Strihou C. Beta-2 microglobulin in renal disease. J Am Soc Nephrol. 1998;9:1723-1735.

[7.] MacNamara EM, Aguzzi F, Petrini C, et al. Restricted electrophoretic heterogeneity of immunoglobulin light chains in urine: cause for confusion with Bence Jones protein. Clin Chem. 1991;37:1570-1574.

[8.] Harrison HH. The "ladder light chain" or "psuedo-oligoclonal" pattern in urinary immunofixation electrophoresis (IFE) studies: a distinctive IFE pattern and an explanatory hypothesis relating it to free polyclonal light chains. Clin Chem. 1991;37:1559-1564.

[9.] Karlsson FA, Wibell L, Evrin PE. Beta-2 microglobulin in clinical medicine. Scand J Clin Lab Invest. 1980;40(suppl 154):27-37.

[10.] Keren DF. Procedures for the evaluation of monoclonal immunoglobulins. Arch Pathol Lab Med. 1999;123:126-132.

Accepted for publication September 19, 2000.

From the Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Tex.

Reprints: Beverly C. Handy, MD, MS, Department of Laboratory Medicine/37, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4095 (e-mail: bhandy@mdanderson.org).
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Author:Handy, Beverly C.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Apr 1, 2001
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