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Waldenstrom macroglobulinemia presenting as a pleural effusion: The utility of flow cytometry and gene rearrangement analysis in the diagnosis
From Archives of Pathology & Laboratory Medicine, 6/1/00 by Mansoor, Adnan

We describe a patient with Waldenstrom macroglobulinemia who presented with a lymphocytic pleural effusion. Pleural involvement in Waldenstrom macroglobulinemia is very rare. In addition, to our knowledge, there are no reports in the literature in which a primary diagnosis was made on the basis of pleural fluid analysis. The presence of small lymphocytes in serous cavity fluid can pose great difficulty in the differentiation between a low-grade lymphoproliferative disorder and reactive lymphocytosis. The diagnosis of malignancy in this case was established on the basis of morphologic testing, flow cytometry, and the detection of B-cell immunoglobulin gene rearrangement.

(Arch Pathol Lab Med. 2000;124:891-893)

Waldenstrom macroglobulinemia is a neoplastic clonal proliferation of B lymphocytes that secretes monoclonal immunoglobulin NI (IgM).1 This monoclonal gammopathy is associated with a neoplastic proliferation of small lymphocytes with plasmacytoid differentiation (lymphoplasmacytoid lymphoma). The clinical presentation is typically that of diffuse lymphadenopathy, splenomegaly, constitutional symptoms, and a hyperviscosity syndrome secondary to the presence of high levels of IgM. Pleural involvement in non-Hodgkin lymphoma is not uncommon and occurs in 6% to 19% of patients.2 Pleural involvement usually accompanies pulmonary neoplastic infiltrates. However, non-Hodgkin lymphoma presenting as a pleural effusion without lung involvement is unusual. Pleural effusion of this nature, when of uncertain origin, has been referred to as idiopathic lymphocytic pleural effusion. Morphologic analysis of excessive numbers of small lymphocytes in the pleural effusion in these cases remains a difficult task for the pathologist, since cytologic atypia is often absent or minimal. Flow cytometric analysis and gene rearrangement studies are 2 ancillary techniques that have proved useful in the diagnosis of lymphoproliferative disorders.3 Application of these methods results in an accurate and rapid diagnosis of the underlying disease (neoplastic versus nonneoplastic) and the timely institution of appropriate treatment.

We recently encountered a case of Waldenstrom macroglobulinemia that presented with pleural effusion of unclear origin. The diagnosis of lymphoplasmacytoid lymphoma (Waldenstrom macroglobulinemia) was established on the basis of morphologic examination of the lymphocytes in the pleural fluid and flow cytometry and gene rearrangement analysis. To our knowledge, this is the first well-documented report of a case of Waldenstrom macroglobulinemia that was diagnosed based on analysis of pleural fluid. Additional studies of the patient's serum protein and bone marrow biopsy specimen confirmed the initial diagnosis.

MATERIALS AND METHODS

DNA Extraction and Southern Blot Analysis

The cells were separated by high-speed centrifugation. Highquality genomic DNA was obtained by phenol chloroform extraction and ethanol precipitation. Ten micrograms of DNA was digested to completion with various restriction enzymes (Gibco BRL, Gaithersburg, Md), namely HindIII, BamHI/HindIII, EcoRI, and BgIII. The digests were size fractionated on 0.8% agarose gel and transferred to a nylon membrane for 3 hours at room temperature. Filters were prehybridized at 52 deg C for 3 hours in hybrisol. Probes were labeled with p32 by nick translation (Gibco BRL). Blots were hybridized with these probes overnight and washed with low stringency (0.5x SSC, 0.1% sodium dodecyl sulfate) and later with high-stringency buffer (OAX SSC, 0.5% sodium dodecyl sulfate). The filters were autoradiographed at -80 deg C (AZR Kodak, Rochester, NY) for 1 to 2 weeks.

Flow Cytometry

The cells were separated by centrifugation and resuspended in phosphate-buffered saline and 5% fetal calf serum to yield a cell count of 5000 to 10 000 cells/ (mu)L. The viability was determined by the trypan blue (Gibco BRL) exclusion method. Samples with more than 85% viability were processed for analysis. The cells were dual stained and incubated in saturating concentrations of fluorescein isothiocyanate or phycoerytherin conjugated antibodies at room temperature, protected from light. The B-cell panel was composed of antibodies to CD19, CD20, CD23, and K and X light chain antigens (Coulter, Miami, Fla), whereas the T-cell panel included antibodies to CD2, CD3, CD4, CDS, CD7, CDB, and CD43 (Coulter).

Other markers included CD10, CD25, CD30, and HLA-DR. The cells were analyzed on the EPICS XL flow cytometer (Coulter). REPORT OF A CASE

A 74-year-old man with a history of chronic obstructive pulmonary disease presented to the George Washington University Hospital with a 1-day history of severe progressive, nonexertional dyspnea, fever, and productive cough. The patient denied having chest pain. The patient stated that he had been treated for pneumonia 2 months earlier. The results of physical examination were significant for bilateral basal diffuse rhonchi and crepitation. There was moderate hepatosplenomegaly with a nodular, irregular liver border. No lymph nodes were palpable. Chest radiograph revealed a right lower lobe infiltrate with a pleural effusion. The Table summarizes the patient's laboratory test results. A complete blood cell count revealed a hematocrit of 32.9% and a leukocyte count of 9490/ mm^sup 3^, with 67% neutrophils, 24% lymphocytes, 7% monocytes, and 2% eosinophils. There were also occasional plasma cells. The patient also had a creatinine level of 1.3 mg / dL, a total serum protein level of 8.1 g / dL, and an albumin level of 3.3 g/ dL. The serum protein quantitative analysis of immunoglobulins revealed an IgG level of 193 mg/dL (reference range, 700-1700 mg/ dL), IgA level of 41 mg/ dL (reference range, 70-350 mg/dL), and IgM level of 5310 mg/dL (reference range, 50-300 mg/ dL). A serum protein electrophoresis revealed a band of restricted mobility in the gamma region. An immunofixation electrophoresis identified this band as a monoclonal IgM with K light chain expression.

A peripheral blood culture grew Streptococcus pneumonia for which the patient was treated with ceftriaxone sodium and clarithromycin. A thoracocentesis revealed an exudative fluid with a lactic dehydrogenase level of 2093 U and a total protein level of 3.9 g/dL. The pleural fluid leukocyte count was 6800/mm3, with a differential count of 19% neutrophils, 74% lymphocytes, and 7% monocytes. The pleural fluid cytologic test results were compatible with a lymphoplasmacytoid process (Figure 1). Flow cytometric analysis of the pleural fluid revealed a predominant B-cell population (CD19 and CD20 positive), which was immunoglobulin light chain (kappa) restricted (Figure 2). The B cells were negative for CDS, CD10, and CD23 but displayed moderate CD43 and K antigen expression. Of note, a small number of B cells were seen to be CD43 negative. Staining intensity was normal for all expressed antigens. This was consistent with a monoclonal B-cell population. Immunoglobulin gene analysis was performed by Southern blot hybridization on the pleural fluid lymphocytes. Southern blot analysis revealed the presence of a heavy chain gene rearrangement in 4 of the restriction enzyme digests examined (HindIII, BamHI/HindIII, EcoRI, and BgIII) (Figure 3). This confirmed the presence of a B-cell monoclonal process. A bone marrow biopsy performed for staging revealed a 50% to 80% cellular marrow with numerous paratrabecular aggregates of mature lymphocytes, with some plasmacytoid features consistent with the diagnosis of lymphoplasmacytoid lymphoma. The patient was treated with 2 cycles of chlorodeoxydenosine and achieved a complete remission. The patient is still in complete remission after 1 year of follow-up.

COMMENT

The presence of a morphologically monotonous population of small lymphocytes in an exudative pleural effusion is a diagnostic challenge for both pulmonologists and pathologists. When more than 50% of the pleural fluid cells are lymphocytes, pleural biopsy is generally indicated, since the likelihood of malignancy or tuberculosis is 95%.4 We elected to delay pleural biopsy until the completion of pleural fluid analysis. In fact, an underlying non-Hodgkin lymphoma was suspected on the basis of the lymphoplasmacytoid morphologic structure of the pleural fluid lymphocytes and the abnormal serum protein electrophoresis results. Flow cytometry and gene rearrangement studies were used to first classify and then confirm monoclonality.

In the current case, the association of CD19- and CD20positive cells, negative for CDS, CD10, and CD23, with light chain restriction and lymphoplasmacytoid morphologic structure confirmed the presence of lymphoplasmacytoid lymphoma. A DNA probe that recognizes the heavy chain joining region was used. A different array of restriction enzymes were used to visualize gene rearrangements in 4 separate DNA digests. In this manner, we obtained confirmation of a B-cell neoplasm as suggested by the previous flow cytometric analysis.

Although our patient had a pulmonary infiltrate, the origin of the pleural effusion was not clear. The etiology of idiopathic lymphocytic pleural effusion encompasses numerous conditions, which include both neoplastic and nonneoplastic diseases.5 Pleural biopsy may be helpful but can be inconclusive in a significant number of cases, either due to the pleura not being involved by the disease or sampling errors. In these situations, flow cytometry in combination with cytological morphology and gene rearrangement analysis can be helpful in determining whether an underlying lymphoproliferative disease is present. Indeed, one could argue that flow cytometric analysis alone would have been sufficient for a diagnosis in this case. However, in general, molecular analysis may detect the presence of a clonal process even in those instances where flow cytometric interpretation is problematic. This could be due to low-density antigen expression or simply too few malignant cells present in the sample. In fact, a polymerase chain reaction-based Southern blot can aid in detecting a monoclonal cell population even in very low concentrations. In this latter situation, molecular analysis should be part of a routine workup for a suspected malignant process.

In conclusion, this case report describes an unusual presentation of Waldenstrom macroglobulinemia. The diagnosis was made possible with the combination of morphologic, flow cytometry, and gene rearrangement studies. These techniques should be thought of when evaluating a suspicious lymphocytic pleural effusion, especially in the absence of underlying causes.

References

1. Feiner HD, Rizk CC, Finfer MD. IgM monoclonal gammopathy/Waldenstrom's macroglobulinemia: a morphological and immunophenotypic study of bone marrow. Mod Pathol. 1990;3:348-356.

2. Jenkins PF, Ward MJ, Davies P, Fletcher J. Non Hodgkin's lymphoma, chronic lymphocytic leukemia and the lung. Br Dis Chest. 1981;75:22-30.

3. Kavaru MS, Tubbs ML, Miller L, Wiedemann P. Immunocytometry and gene rearrangement analysis in the diagnosis of lymphoma in an idiopathic pleural effusion. Am Rev Respir Dis. 1992;145:209-211.

4. Light RW. Clinical manifestations and useful tests. In: Light RW, ed. Pleural Diseases. 3rd ed. Baltimore, Md: Williams & Wilkins; 1995:36-74.

5. Yam LT. Diagnostic significance of lymphocytes in pleural effusions. Ann Intern Med. 1967;66:972-982.

Accepted for publication December 1, 1999.

From the Departments of Pathology (Drs Mansoor and DePalma), Medicine (Dr Wagner), and Anatomy and Cell Biology (Dr DePalma), George Washington University Hospital and School of Medicine, Washington, DC.

Reprints: Louis DePalma, MD, Division of Clinical Pathology, George Washington University Medical Center, 901 23rd St NW, Washington, DC 20037 (e-mail: LDP@gwu.edu).

Copyright College of American Pathologists Jun 2000
Provided by ProQuest Information and Learning Company. All rights Reserved

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