A Rare Case of Waldenström Macroglobulinemia Presenting as Bilateral Bloody Pleural Effusion and Pancytopenia

Introduction

Waldenström macroglobulinemia is a rare indolent B-cell lymphoma characterized by bone marrow infiltration of lymphoplasmacytic lymphoma and serum IgM monoclonal gammopathy [1]. The disease directly invades tissues with malignant cells, causing lymphadenopathy and splenomegaly. Additionally, the physicochemical and immunological properties of monoclonal IgM can cause cytopenias, hyperviscosity syndrome, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome [2]. Bilateral bloody pleural effusion occurs in less than 5% of WM patients [3], while chylothorax is even rarer, with only 7 documented cases in the literature [4]. These reports demonstrated that pleuropulmonary involvement by lymphoplasmacytic infiltrates in WM directly resulted in effusions. Lymphomas primarily induce chylothorax through either extrinsic compression of the thoracic duct or neoplastic invasion into its wall, leading to chyle leakage [4].

This case underscores the need to consider Waldenström macroglobulinemia in patients with unexplained bloody effusions and pancytopenia. It calls for integrated diagnostic strategies and timely therapeutic interventions to slow disease progression.

Case Report

A 71-year-old man developed gradually worsening symptoms over 2 months, starting with fatigue and pallor that subsequently progressed to exertional dyspnea and chest tightness. He was eventually admitted to the respiratory medicine department at an external hospital for evaluation and treatment. His medical, familial, and psychosocial histories were unremarkable, with no documented comorbidities or genetic predispositions. Physical examination revealed bilateral decreased breath sounds in the lower lung fields (left-sided predominance), significant bilateral inguinal lymphadenopathy, and pallor. Laboratory tests confirmed pancytopenia (hemoglobin 74 g/L, platelet count 32×109/L, leukocytes 3.0×109/L). The oxygen saturation was 97% on room air. CT scans demonstrated bilateral pleural effusions (Figure 1), while color Doppler ultrasound identified enlarged inguinal lymph nodes (maximum dimensions 19×7 mm). Therapeutic thoracentesis drained 1000 ml/day of bloody, turbid fluid from the left pleural space. Pleural fluid analysis showed: leukocytes 2457×106/L (mononuclear predominance), erythrocytes 52 000×106/L, protein 4.2 g/dL, glucose 97 mg/dL, and lactate dehydrogenase (LDH) 121 U/L. These findings met Light’s criteria for exudative effusion, and repeated tests of pleural fluid cytology found no malignant cells. Microbiological tests were negative. Lymph node biopsy revealed complete effacement of the nodal architecture by diffuse infiltrates of small lymphocytes accompanied by focal plasmacytoid differentiation (Figure 2A). Subsequent immunohistochemistry demonstrated strong CD20 (Figure 2B) and CD79a expression (Figure 2C) within the neoplastic cell population, confirming CD20+ B-cell lymphoproliferative malignancy.

The patient was referred to our Hematology Department. The function of his kidneys was normal. Serum immunoglobulin quantification revealed IgM: 7.6 g/l (ref: 0.3–2.2), IgG: 4.7 g/l (ref: 8.6–17.4), IgA: 0.5 g/l (ref: 1.0–4.2), κ light chain: 1.8 g/l (ref: 2.0–4.4), and λ light chain: 0.6 g/l (ref: 1.1–2.4). A serum immunofixation test revealed monoclonal bands of IgM and kappa. Bone marrow aspirate smear (Figure 3) demonstrated 2% immature and 92% mature lymphocytes, with no megakaryocytes present. Flow cytometry of bone marrow aspirate showed clonal B-cells (70% of nucleated cells) expressing HLA-DR, CD19, CD20, CD22, CD79b, CD11b, BCL-2, and cKappa. Bone marrow biopsy confirmed lymphoplasmacytic lymphoma with small lymphocytes expressing CD20+ (Figure 4A) and PAX5+, plasmacytoid cells: CD38+, CD138+ (Figure 4B), CD56−. Molecular studies identified MYD88 L252P and CXCR4 S332X mutations. The examination results indicated that the MYD88 gene mutation excluded multiple myeloma. He also had elevated serum monoclonal IgM protein. However, lymphoplasmacytic infiltration in the bone marrow and pleural effusion exclude the diagnosis of IgM MGUS. Immunophenotyping showed that CD5 was negative, which ruled out chronic lymphocytic leukemia. The final diagnosis was Waldenström macroglobulinemia, based on our patient’s anemia, thrombocytopenia, elevated IgM levels, lymphadenopathy, and pleural effusion, the immunophenotype showing CD19 was positive and CD5, CD10, CD123, and CD103 were negative, MYD88 and CXCR4 mutations, and the bone marrow biopsy results.

The patient received 4 cycles of rituximab-bendamustine (rituximab 375 mg/m2 on Day 1 and bendamustine 70 mg/m2 on Days 2–3). Concurrent therapeutic thoracentesis drained 1000 ml/day of bloody, turbid fluid from the right pleural space (Figure 5). During treatment, the left pleural effusion changed from serosanguinous to chylous (Figure 6). After the second cycle, symptomatic improvement allowed for catheter removal. After completing 4 cycles of rituximab-bendamustine, the patient underwent a 5-month follow-up, demonstrating complete resolution of pleural effusions (confirmed by thoracic ultrasound), along with hematologic normalization (hemoglobin 131 g/L, platelet count 130×109/L, leukocytes 3.6×109/L) and sustained IgM reduction (2.1 g/L, 72% decline from baseline).

Discussion

Pleural effusion is a common clinical condition caused by various factors, such as infections, malignancy affecting the pleura, and injuries to the thoracic duct [5]. Bloody pleural effusion is a rare complication of Waldenström macroglobulinemia [6], and chylothorax is even rarer [7]. Determining the cause of pleural effusion in Waldenström macroglobulinemia is challenging using standard biochemical and cytological tests. However, allele-specific polymerase chain reaction is can more sensitively detect MYD88 mutations [8]. Due to the unavailability of this testing in our hospital, the patient could not undergo flow cytometry analysis of the pleural effusion. Nonetheless, during treatment, we observed that bloody pleural effusion and chylothorax had been reported in similar cases of Waldenström macroglobulinemia [5,9], and after treatment, the pleural effusion resolved, indicating a potential link to the disease. However, the etiology of the pleural effusion remains unclear. Current hypotheses suggest 3 possible mechanisms for pleural effusion in Waldenström macroglobulinemia: direct neoplastic infiltration of pleural surfaces by lymphoplasmacytic cells, pulmonary parenchymal involvement via perivascular tumour infiltration, and IgM-mediated lymphatic obstruction [4]. Chylothorax occurs due to external pressure on the thoracic duct or cancer affecting its wall, leading to fluid leakage. Therefore, if pleural effusion develops in WM, it is crucial to start therapy immediately.

Pancytopenia is a frequent finding in Waldenström macroglobulinemia. Pancytopenia results from the infiltration of bone marrow by dense clonal lymphoplasmacytic cells [10], severely constraining normal hematopoietic stem cell proliferation and differentiation. Concurrently, the monoclonal IgM circulating in WM patients has the propensity to conjugate with surface receptors of hematopoietic cells, thereby perturbing cell growth kinetics and maturation pathways and ultimately culminating in pancytopenia [11].

After studying the disease’s pathophysiological mechanisms, we further investigated the treatment options available for our patient. According to the consensus panel report from the 11th International Workshop on Waldenström’s Macroglobulinemia, therapeutic intervention in WM is indicated when IgM monoclonal gammopathy or lymphoplasmacytic infiltration causes clinically significant manifestations, including symptomatic cytopenias (hemoglobin <100 g/L, platelets < 100×109/L), constitutional symptoms (eg, fatigue, night sweats), or IgM-mediated complications (eg, hyperviscosity syndrome, neuropathy) [12]. Current treatment modalities include monoclonal antibodies, chemotherapy, proteasome inhibitors, and Bruton’s tyrosine kinase inhibitors (BTKi) [13]. According to the NCCN guidelines, the preferred frontline regimens include combinations based on rituximab, such as bendamustine and rituximab (BR), bortezomib with dexamethasone, rituximab with dexamethasone (BDR), and a combination of dexamethasone, rituximab, and cyclophosphamide (DRC), as well as BTK inhibitors [14]. However, our patient had MYD88 and CXCR4 mutations and severe thrombocytopenia, which made him unsuitable for Bruton’s tyrosine kinase inhibitors, particularly ibrutinib [15]. Due to thrombocytopenia, the risk of bleeding with BTK inhibitors is significantly high. Thus, Zanubrutinib was also not a viable option [16].

For our patient, chemotherapy was prioritized. A retrospective comparison at the Mayo Clinic evaluated fixed-duration therapies for treatment-naïve patients. The BR regimen demonstrated superior outcomes compared to both DRC and BDR, achieving an overall response rate (ORR) of 98% and a median progression-free survival (PFS) of 5.2 years [17]. Furthermore, our patient’s high tumour burden, evidenced by pancytopenia and bilateral hemorrhagic effusions, with MYD88 L252P and CXCR4 mutations, necessitated rapid treatment. Therefore, bendamustine-rituximab (BR) appeared to be a reasonable choice [18,19]. Moreover, the BR regimen is preferred for its balanced efficacy-toxicity profile, cost-effectiveness, and defined treatment duration, with low rates of non-hematologic adverse events [11]. In contrast, BTKi therapy necessitates indefinite administration until progression or intolerance, resulting in higher cumulative costs, cardiovascular risks, and hematologic toxicity [20].

For the BR regimen, a 4-cycle course is preferred to minimize toxicity while maintaining efficacy, supported by retrospective studies indicating comparable outcomes to 6 cycles [21,22]. In patients aged >70 years, a reduced dose of bendamustine should be considered. The dose reduction of bendamustine to 70 mg/m2 was implemented based on a multicenter real-world study demonstrating equivalent PFS to the standard 90 mg/m2 over 4 years [11]. The final regimen comprised rituximab 375 mg/m2 (day 1) and bendamustine 70 mg/m2 (days 2–3). At the 5-month follow-up, hematologic normalization (hemoglobin 131g/L, platelet count 130×109/L, leukocytes 3.6×109/L), 72% IgM reduction, and complete effusion resolution were achieved, confirming the BR regimen’s rapid disease control capacity in symptomatic WM.

Conclusions

Waldenström macroglobulinemia is rarely associated with bloody pleural effusion and chylothorax. Consequently, clinicians should consider Waldenström macroglobulinemia when a patient presents with unexplained pleural effusion and pancytopenia. Comprehensive evaluations should include bone marrow biopsy, MYD88 and CXCR4 gene testing, immunophenotyping, and immunoglobulin assessments. It is advisable to perform allele-specific polymerase chain reaction testing on pleural fluid samples to detect MYD88 if feasible. Conventional chemotherapy using bendamustine (BR) is effective for patients presenting with these symptoms of Waldenström macroglobulinemia.