A 62-year-old woman presenting with dyspnea on exertion was admitted to our hospital. Her medical history included type 2 diabetes and κ light chain multiple myeloma (MM) diagnosed 3 years ago.
The results of a basic biochemical examination performed 2 weeks earlier were normal. Serum protein electrophoresis revealed hypoproteinemia (65 g/L; reference interval, 68–73 g/L), associated with decreased γ globulins (4 g/L; reference interval, 9–15 g/L) but without a detectable paraprotein band. An assay for serum free light chain showed decreased κ light chains (0.5 mg/L; reference interval, 3.3–19.4 mg/L) and λ light chains (<0.3 mg/L; reference interval, 5.7–26.3 mg/L); the κ/λ ratio could not be accurately determined because of the low concentration of λ light chains. An examination of a bone marrow aspirate taken 3 months earlier showed dystrophic plasma cells accounting for 50% of the nucleated cells.
On admission, laboratory tests revealed normal values for hemoglobin (142 g/L; reference interval, 130–180 g/L), white blood cells (6.7 × 109/L; reference interval, 4–10 × 109/L), platelets (211 × 109/L; reference interval, 150–400 × 109/L), and creatinine [38 μmol/L (0.4 mg/dL); reference interval, 45–90 μmol/L (0.5–1.0 mg/dL)], but the tests also revealed mild hypocalcemia [2.14 mmol/L (8.6 mg/dL); reference interval, 2.20–2.60 mmol/L (8.8–10.4 mg/dL)].
A chest radiograph and spiral thoracic computed tomography showed a large right-sided pleural effusion.
A sample of the pleural fluid had a total protein concentration of 38 g/L and a white blood cell count of 20.5 × 109/L, with 100% lymphoid cells. The results of bacterial and mycobacterial cultures were negative. Protein electrophoresis evaluations of serum, urine, and the pleural effusion were performed in our laboratory with the Hydrasys® electrophoresis system (Sebia).
QUESTIONS TO CONSIDER
What is the differential diagnosis of a myelomatous pleural effusion in MM?
Should laboratory testing of pleural fluid in patients with myeloma include immunofixation electrophoresis?
Must measurement of pleural fluid for free light chains be considered in this patient?
The serum protein electrophoresis results confirmed the hypoproteinemia (total serum protein, 51 g/L), which was associated with a markedly decreased γ-globulin concentration (2 g/L). There was no detectable paraprotein band (Fig. 1A). The urine electrophoresis results showed proteinuria (713 mg/24 h; reference interval, <150 mg/24 h) associated with 2 bands that migrated in SDS-PAGE at the positions of free light chains (data not shown). Standard electrophoresis analysis of the unconcentrated pleural effusion showed a discrete band migrating at a position between the β and γ globulins. This band corresponded to the presence of residual fibrinogen (1), because it disappeared after reptilase treatment (Fig. 1B).
MM is a malignant proliferation of plasma cells that mainly affects bone marrow. It constitutes about 10% of all hematologic malignancies (2). Areas other than bone marrow may be invaded as well, particularly the thorax. Pleural effusion, which may be a marker of thoracic involvement, affects about 6% of patients with MM (2, 3).
A wide range of etiologic factors may cause pleural effusion in MM (Table 1) (2, 4,–,7); however, actual myelomatous pleural effusions are very uncommon, with fewer than 100 cases having been reported worldwide (8, 9). The most common causes of pleural effusion associated with MM are heart failure, renal failure, effusions related to pneumonia, and amyloidosis. The total protein concentration of the pleural fluid allowed the differential diagnosis between exudate and transudate. Exudate is defined by a fluid protein concentration >30 g/L. Consequently, in the present case, the effusion was an exudate, thus excluding heart failure, chronic renal failure, nephrotic syndrome, and hypoalbuminemia.
In 1994, three diagnostic criteria were defined to confirm a myelomatous pleural effusion (6): (a) demonstration of a monoclonal protein in pleural fluid electrophoresis, (b) detection of atypical plasma cells in the pleural fluid, and (c) histologic confirmation with a pleural biopsy sample or by autopsy. The therapy for pleural effusion is dependent on the causal disease (see Table 1). Consequently, an accurate diagnosis is essential for choosing the treatment to initiate. In the reported case, the diagnosis of myelomatous pleural effusion was not obvious.
The serum immunofixation electrophoresis result was negative for monoclonal bands (Fig. 1C). The absence of κ free light chains in the serum immunofixation electrophoresis prompted us to investigate the hypothesis of pleural synthesis of a κ free light chain linked to a pleural myelomatous involvement.
Immunofixation electrophoresis of the pleural effusion clearly identified a broad band of κ free light chains (Fig. 1D). The assay for serum free light chain showed increased κ light chains (300 mg/L) and decreased λ light chains (<0.3 mg/L). The κ/λ ratio had increased strongly (to >1000) since the last assays performed 2 weeks before. In the pleural fluid, κ free light chains were increased (to 1660 mg/L), whereas the λ light chain concentration was <0.3 mg/L and the κ/λ ratio was >5000.
The diagnosis of myelomatous pleural effusion was confirmed by cytomorphologic analysis of the lymphoid cells in the pleural effusion, which revealed a large majority of dystrophic plasma cells positive for IgG-κ, sometimes with multiple and eccentric nuclei and associated with some small lymphocytes.
Usually, the biochemical exploration of an MM-associated pleural effusion includes measurement of the total protein in the pleural fluid, serum protein electrophoresis, and pleural fluid protein electrophoresis. In this clinical case, electrophoresis of serum and pleural fluid samples showed no abnormal band, only a decrease in γ globulins. Because free light chains may be undetectable with standard electrophoresis, we decided to perform immunofixation electrophoresis of the serum and pleural fluid. Immunofixation electrophoresis of the proteins of the pleural effusion allowed the detection of a thin band revealed by the κ light chain antiserum.
Thus far, assay of serum free light chains in combination with serum protein electrophoresis and immunofixation electrophoresis has been sufficient to screen plasma cell disorders. Free light chain measurements also have a major prognostic value in MM (10). In the current case, we observed an important increase in κ free light chains in the pleural effusion (κ/λ ratio >5000). This increment was higher than that found in the serum (κ/λ ratio >1000). This finding argued for a local synthesis of κ free light chains. It might also be a reflection of different clearance mechanisms in the pleural fluid and in the blood. Such differences have never been reported previously. Moreover, the presence in the pleural effusion of a large number of dystrophic plasma cells makes the hypothesis of local synthesis more likely. Accordingly, free light chain measurement is key to confirm the diagnosis of a myelomatous pleural effusion.
In such a difficult case, immunofixation electrophoresis of the proteins of the pleural effusion associated with measurement of the free light chains in the pleural fluid allowed us to diagnose the myelomatous origin of the pleural effusion, in association with an anatomic pathology study.
POINTS TO REMEMBER
A pleural effusion is found in about 6% of MM cases, but myelomatous pleural effusion is uncommon, with <100 cases having been reported worldwide.
A basic biochemical exploration of an MM-associated pleural effusion should include protein electrophoretic analysis of the serum and pleural fluid, combined with an anatomic pathology study.
A significant decrease in the serum or pleural fluid concentration of γ globulin should be followed with a free light chain assay.
Immunofixation electrophoresis of pleural fluid must be done systematically in cases of pleural effusion associated with MM.
An assay of free light chains in the pleural fluid should be performed to diagnose a pleural myelomatous involvement.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication December 18, 2010.
- Accepted for publication February 15, 2011.
- © 2012 The American Association for Clinical Chemistry