By Prof. Shirley D’sa, University College London Hospitals, NHS Foundation Trust
Reprint from IWMF Torch January 2025
Shirley D’Sa is a Professor of Haematology at University College London Hospitals (UCLH) NHS Foundation Trust in London, United Kingdom. She leads the UCLH Centre for Waldenström’s Macroglobulinaemia (WM) and Associated Disorders and serves as the haematological lead in the Joint Neurohaematology service at the National Hospital for Neurology, Queen Square, London, where she does clinics with Prof. Michael Lunn, a specialist in inflammatory neuropathies.
In addition to her clinical work, Prof. D’Sa is actively involved in clinical research, including real world data analyses, and has served as the UK Chief Investigator on several clinical trials related to WM and cold agglutinin disease, including Phase 1, 2, and 3 trials of novel therapies. She is also an enthusiastic mentor to up-and-coming haematology and neurology trainees.
Her dedication to patient care and research has established her as a leading expert in her field, with a reputation for combining clinical excellence with compassionate patient care.
Figure 1
Lung on left side of x-ray (patient’s right side) shows fluid buildup.
A Case Study
I recently saw a lady with an IgM protein that was found during a review for her symptoms of neuropathy in 2011. Investigations at her local hospital showed that this was monoclonal gammopathy of uncertain significance (MGUS), and she was monitored periodically. Between the end of 2018 and March 2019, she lost 15 kg (33 lb) and became ill with an atypical chronic pneumonia initially resistant to antibiotics. The duration of and inability to manage the illness raised questions of underlying disease. She was then referred to haematology which confirmed a diagnosis of Waldenstrom macroglobulinaemia (WM) on her bone marrow biopsy. She received DRC chemoimmunotherapy (dexamethasone, rituximab, and cyclophosphamide) for her symptomatic WM. A very good partial response was achieved and her condition stabilised.
She continued to have recurrent/persistent chest infections and was admitted in acute distress to her local emergency department in November 2023 with bilateral pneumonia, bilateral pleural effusions, and sepsis. The respiratory specialists and radiologists questioned whether the WM could be contributing to her current infections, but haematology felt her condition more likely to be the result of immunosuppression related to previous treatment and the after-effects of sepsis following discharge.
She also continued to have recurrent pleural effusions which required drainage using a needle passed into the pleural cavity under guidance of an ultrasound probe. The pleural sample collected five weeks before I saw her showed WM cells in the fluid, confirming WM in this body compartment. The chest x-ray in Figure 1 is before drainage and shows a large collection of fluid with a concave top on the right side of the chest (to the left in the x-ray). The other lung is clear and looks dark throughout, except for the rib shadows and the triangular shadow of the heart.
Introduction
Pleural effusions, or abnormal fluid accumulation within the pleura or sac that encases the lungs, may be a complication in patients with haematologic malignancies, particularly B cell lymphomas. These effusions arise due to complex mechanisms related to both the malignancy itself and the body’s response to tumour growth. The presence of pleural effusions often correlates with advanced stages of disease. This article reviews the development, clinical presentation, diagnostic approach, and management strategies for pleural effusions associated with WM, underscoring the need for targeted therapeutic interventions.
Figure 2
Obstruction of lymphatic drainage
Causes
Pleural effusions in WM can arise from several mechanisms:
- Direct lymphomatous infiltration: WM cells can directly invade the pleura, resulting in exuda-tive (with a high level of protein) pleural effu-sions. This invasion disrupts the normal pleural fluid balance by increasing the leakiness of blood vessels, along with the loss of proteins.
- Cytokine release: Some pleural effusions occur in the absence of direct pleural invasion. This phenomenon may involve cytokine release by the tumour, triggering cascades of inflammatory chemicals that increase permeability, or the passage of fluid across blood vessel membranes, thereby contributing to fluid accumulation.
- Obstruction of lymphatic drainage: Enlarged lymph nodes, particularly in the central struc-tures of the chest (mediastinum), can compress the major drainage vessel for lymphatic fluid (the thoracic duct), reducing fluid clearance from the pleural cavity (Figure 2). Such fluid is described as chylous and usually looks milky. The milky appearance is due to the high fat content suspended in the fluid, giving it an opaque, white, or pale appearance.
- Infections: Due to the immunosuppressive effects of both lymphoma and its treatment, patients are at increased risk of infections that can contribute to pleural effusion formation. Such effusions can be inflammatory (usually exudates), or even frankly infected (known as empyema).
Clinical presentation
Patients with pleural effusions in B cell lymphomas may present with various respiratory and systemic symptoms, which often include the following:
- Dyspnea: This is shortness of breath, the most common presenting symptom, and correlates with the amount of the effusion. My patient’s experience of her pleural effusions was dominated by bouts of extreme fatigue and breathing difficulties when the fluid accumu-lated significantly. After a previous drainage procedure, there would be a re-accumulation of the fluid over a few days, which led to urgent admissions for further drainage. She was unable to lie flat during these times. However, once the fluid was drained, she rapidly felt relief and was able to breathe.
- Pleuritic chest pain: Caused by pleural irrita-tion, this symptom often intensifies during deep inhalation or cough. My patient did experience intermittent sharp pains around her rib cage.
- Cough: Typically non-productive, the cough may be persistent due to mechanical irritation. My patient had an intermittent cough which was at times more pronounced when there was an added chest infection. She needed multiple rounds of antibiotics.
- Systemic symptoms: Fever, night sweats, and weight loss could be present due to the under-lying malignancy. My patient had intermittent sweats during some nights. The sweats seemed to be more prominent when there was an active chest infection and would improve with antibiotics. I did wonder whether her relapsed WM could be contributing to the sweats (which is also possible).
- Physical examination: Findings may include decreased breath sounds and dullness when tapping on the chest.
Figure 3
Diagnostic approach
- Imaging: Several types of imaging are helpful. Chest X-rays are useful as a preliminary tool to show blunting of the costophrenic angle (formed at the junction of the chest wall—the ribs—and the diaphragm) or to show large opaque areas in cases of significant effusions. Ultrasound helps in locating the effusion and guiding drainage of the pleural fluid. CT scans are superior in assessing the size of pleural effu-sions, the compartmentalisation of fluid, and lymph node enlargement (if present) that may indicate the underlying WM disease burden in the bone marrow, lymph nodes, and so on.
- Thoracentesis: Thoracentesis is the removal of pleural fluid, a sample of which is essential for diagnostic purposes and helps differentiate exudative (high protein content) from transu-dative (low protein content) effusions. Most lymphoma-related pleural effusions are exuda-tive, characterized by high protein and lactate dehydrogenase (LDH) levels.
- Examination of removed pleural fluid can reveal malignant lymphocytes if WM is involved in the chest cavity or can indicate the presence of bacteria if there is an infective process. Such a test can be performed on the same day, as it involves placing a smear of the sample on a slide and looking with a microscope.
- Flow cytometry and immunophenotyping: For B cell lymphomas, flow cytometry of pleural fluid may demonstrate a clonal B cell population expressing specific markers (e.g., CD19, CD20) that help confirm lymphoma involvement.
- Pleural biopsy: In cases where drainage of the fluid and cytology are inconclusive, a pleural biopsy may be required to identify lymphoma infiltration.
Management
The management of pleural effusions in B cell lymphomas involves symptomatic relief and targeted treatments for the underlying malignancy. It is important for the treating haematologist/oncologist to work closely with the respiratory physicians and occasionally a thoracic surgeon. In some centres, there are pleural specialists who are expert in the interventional aspects of managing pleural effusions. If standard approaches prove to be unsuccessful, one should seek out the input of a pleural specialist.
Symptom Relief:
- Thoracentesis is frequently performed for symptom relief, although repeated thoracen-tesis procedures may be necessary in recurrent effusions. This can be done on an inpatient or outpatient basis under ultrasound guidance—a cannula-like catheter is inserted between the ribs after a local anaesthetic injection and the fluid drains into an attached bag. If there is a large collection of fluid, the drainage is usually performed in stages, using a clamping system to avoid rapid fluid shifts (Figure 3).
The presence of a chylous (milky-looking) effusion requires special dietary measures to cut out fat content in the diet. This may be required for weeks and must be carefully managed to avoid weight loss. My patient had a chylous effusion on drainage and needed to have a low-fat diet, which was a challenge due to her slender frame and poor appetite. She received input from a dietician to increase the protein content of her diet.
- Indwelling pleural catheters (IPCs) are special-ized medical devices used for the long-term management of recurrent pleural effusions, particularly in patients who are not candidates for pleurodesis (Figure 4).
Figure 4
In cases of chronic, recurrent effusions, IPCs allow for repeated fluid drainage at home, improving patient comfort and reducing hospital visits. An IPC consists of a silicone catheter, which is a flexible tube inserted into the pleural cavity, a one-way valve that prevents air or fluid backflow, and an external drainage system that can collect the extracted fluid. Complications include localised infections or rarely the development of infection of the pleural space (empyema), pain and discomfort due to the presence of the catheter, or inadvertent puncturing of the lung (pneumothorax). In some cases, chronic drainage can lead to spontaneous adherence of the pleural membranes, effectively achieving the same outcome as pleurodesis.
- Pleurodesis is a medical procedure designed to obliterate the pleural space and prevent the recurrence of pleural effusions or pneu-mothorax. It involves inducing inflamma-tion and fibrosis in the pleural layers so that they adhere together. Pleurodesis can be achieved chemically or surgically, and it can be performed through minimally invasive or open techniques. The first step is to drain any existing fluid so that the lung is capable of fully expanding. The next step is to introduce a chemical agent, such as talc or doxycycline, into the pleural space via a chest tube or under direct vision (so-called video-assisted thoracic surgery or VATS). Pleurodesis has a high success rate but is associated with short-lived pain and a low-grade fever due to the inflammation that is induced.
Owing to the potential complications of pleurodesis in my patient, I was keen to avoid pleurodesis if possible, by giving the chemotherapy a chance to work for two to three cycles. If this does not occur, then pleurodesis would be needed. This could involve a brief pause in the treatment, and certainly, close scrutiny of blood counts—if platelets are low (less than 50,000 per microlitre), invasive procedures like this need to be covered with platelet transfusions.
Systemic therapy:
- Chemoimmunotherapy regimens, often involving rituximab-based protocols, are effec-tive in managing underlying lymphoma and resolving associated pleural effusions. My patient has now started bendamustine and rituximab, and we are hoping to see an effective response to this treatment. Success would be measured by a reduction in the pleural fluid, shrinkage of enlarged lymph nodes, and a fall in her monoclonal IgM protein. Importantly, we are looking for a sustained improvement in well-being. This is a work-in-progress.
- Novel targeted therapies like BTK inhibitors (ibrutinib, zanubrutinib), BCL-2 inhibitors, and others may have an indirect benefit in resolving effusions by reducing the burden of WM in the body, including the pleural cavity. Their effec-tiveness in managing lymphomatous pleural effusions has been documented in clinical expe-riences. While these instances are promising, comprehensive clinical trials specifically evalu-ating BTK inhibitors for lymphomatous pleural effusions are limited. The current evidence is primarily based on individual case reports and small studies. Therefore, while BTK inhibitors may offer therapeutic benefits in managing pleural effusions associated with B cell malig-nancies, further research is necessary to estab-lish their efficacy in this context. There is no reason why such therapies should not work in the setting of pleural effusions.
- Radiation therapy (RT) is not a primary treat-ment for pleural effusions caused by lymphoma but can be an effective option in specific circumstances. Radiation may target areas of lymphomatous infiltration causing the effusion, particularly when bulky mediastinal or thoracic lymph nodes compress lymphatic vessels or the thoracic duct. In cases where systemic therapies fail to control the effusion or where systemic options are not indicated, RT can be used as a palliative or symptom-reducing intervention. It may be given as external beam radiotherapy (EBRT) focused on involved lymph nodes and mediastinal or pleural lesions that are contrib-uting to the effusion. Since lymphomas are systemic diseases, localized RT addresses only part of the disease and is rarely curative for pleural effusions.
- Vigilant monitoring for infection is essential, given the immunocompromised status of lymphoma patients. Presumptive administration of antibiotics based on clinical symptoms may be warranted in cases with suspected infection-asso-ciated effusions. Each time pleural fluid is taken, a sample should be sent to the lab for testing for infection. If present, testing against antibiotics in the laboratory will guide the use of appropriate antibiotics. The longer the effusion persists, the greater the chance for infection, especially when repeated procedures are performed.
Prognostic implications
>Pleural effusions in B cell lymphomas in general are typically associated with an advanced disease stage and have traditionally been associated with a worse overall prognosis. However, in WM this is not necessarily the case, as WM cells have a propensity to deposit in virtually any compartment of the body beyond the bone marrow (so-called extramedullary disease, EMD). There is a higher chance of such patients having a CXCR4 mutation as well as the more typically expected MYD88 mutation. But we know from trials that there are agents to help overcome the effect of having the CXCR4 mutation. Effectively managing EMD in WM requires combining systemic treatments that target both bone marrow and extramedullary disease, integrating novel agents and localized therapies, and adopting a patient-centred approach.
Conclusion
Pleural effusions in WM represent a challenging complication that can impact patient quality of life. The development of effusions involves several mechanisms, including direct tumour involvement, cytokine release, lymphatic obstruction, and infections. Comprehensive management encompasses both symptomatic relief and targeted lymphoma treatment and should include the relevant specialists. Emerging therapies show promise in reducing the disease burden of WM and improving patient outcomes. Further research is warranted to refine management strategies and develop novel therapeutics for improving the management of this complication.