Chylothorax as a complication of Waldenström macroglobulinaemia with a patient’s perspective

Abstract

Chylothorax has rarely been reported as a pleuropulmonary complication of Waldenström macroglobulinaemia (WM). In general, when a unilateral effusion is discovered particularly in patients with a history of cancer or active malignancy, a broad differential including chylothorax needs to be considered. We present the case of a 50-year-old woman found to have chylothorax secondary to progression of WM as confirmed by cytology and presence of MYD88 L265P mutation in the pleural fluid specimen and subsequent resolution with chemotherapy. This review centres particularly on non-traumatic causes of chylothorax with a focus on WM and includes a unique patient perspective.

Background

Chylothorax is a rare cause of pleural effusion. While gross appearance is not a particularly sensitive indicator of chylothorax, a milky or turbid pleural fluid is associated with either chylothorax or cholesterol effusion which is also known as pseudochylothorax.^1–5 Distinguishing between these two processes is important as management varies. Trauma and malignancies, particularly lymphomas, are two main causes of chylothorax. Malignancy primarily causes chylothorax either through extrinsic compression or invasion of the thoracic duct resulting in chyle leak.3 4 6–8 Trauma, either from surgical or non-surgical causes, is the next most common cause followed by idiopathic and various less common causes of direct lymphatic invasion, obliteration, fibrosis or congestion.

Case presentation

We present the case of a 50-year-old woman non-smoker with a history of asthma and long-standing, asymptomatic Waldenström macroglobulinaemia (WM) with known MYD88 L265P mutation (present in over 90% of patients with WM) who initially presented with fever, wheezing and cough productive of green sputum. Chest radiography revealed a hazy infiltrate in the right middle lobe. She was treated with 7 days of levofloxacin and a short course of prednisone for presumed community-acquired pneumonia and noted initial improvement in her symptoms.

She returned 4 days after discharge with fatigue, persistent fevers and dyspnoea. Physical examination demonstrated decreased breath sounds in lower lung fields bilaterally worse on the left, with dullness to percussion and no palpable lymphadenopathy.

Investigations

CT of the chest without contrast revealed airspace consolidation in the lower lobes bilaterally, left greater than right with moderate left pleural effusion and trace right effusion. Also noted were splenomegaly and pericardial adenopathy. She received broad spectrum antibiotics and underwent left-sided thoracentesis which yielded milky fluid.

Pleural fluid analysis revealed pH 7.94, protein 4.8 g/dL, glucose 97 mg/dL, lactate dehydrogenase (LDH) 109 U/L (serum protein 7.8 g/dL, serum LDH 89 U/L) consistent with an exudative effusion by Light’s criteria. Cell count and differential revealed white blood cell (WBC) 7.62×10⁹/L, red blood cell (RBC) 11×10¹²/L, 75% lymphocytes. Pleural fluid triglyceride level was 883 mg/dL consistent with chylothorax. An infectious workup including evaluation for acid-fast bacilli and fungus returned negative. Flow cytometry of pleural fluid confirmed B cell lymphoma and further analysis showed positivity for CD19, CD20, MYD88 L265P mutation and negativity for CD5 and CD10. Further cytopathology was consistent with diffuse large B cell lymphoma. These findings were consistent with WM.

Outcome and follow-up

After pleural fluid drainage, the patient noted improvement in her exertional dyspnoea and required no additional procedures. During hospitalisation, she was managed with a low-fat diet and antibiotics were discontinued when workup returned no evidence of infection. She was discharged with a plan to follow-up closely with her primary oncologist. When flow cytometry and biomarker results were available, they were communicated to her oncologist who initiated R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) therapy with subsequent resolution of her chylous effusion. She continues to be disease-free over 5 years later.

Discussion

WM is a low-grade non-Hodgkin’s lymphoma typically associated with lymphoplasmacytic bone marrow infiltration accompanied by serum monoclonal IgM.⁹ WM typically presents as anaemia, thrombocytopaenia as well as lymphadenopathy, hyperviscosity and hepatosplenomegaly but it may be asymptomatic.^{10 11} Bulky lymph node involvement is common but the degree to which this correlates with the development of chylothorax is uncertain. Some studies have demonstrated that pulmonary involvement in WM ranges from about 3% to 5%. However, these reports demonstrated pleural or parenchymal involvement with pulmonary neoplastic infiltrates due to WM that subsequently resulted in effusions.¹² Other studies suggest that pleural effusion without lung involvement is unusual and chylothorax complicating WM is rarely reported with only seven cases described.¹³ WM as a whole is considered incurable but treatment may be indicated when symptoms arise or conversion occurs.

Pleural effusions are a known complication of non-Hodgkin’s lymphomas with around 12% being chylous and is thought to result from thoracic duct obstruction in most of these cases.¹⁴ Chylothorax typically presents unilaterally on either side depending on the level at which the thoracic duct leak occurs and individual patient anatomy.3 4 15 16 The most common route of thoracic duct trajectory after originating in the cisterna chyli around L1–L3 involves ascension on both the left side of the azygous vein and the right side of the descending thoracic aorta with a traverse around T5 or T6 ultimately terminating in the left jugular vein.^{15 17} Wide anatomical variability is reported, however.

Symptoms of chylothorax are those of pleural effusion including shortness of breath and non-productive cough. Gross appearance of the pleural fluid is insufficient for diagnosis given that only around 40% of chylous effusions have a characteristic milky appearance. Pleural fluid studies, including triglyceride levels and lipoprotein electrophoresis are indicated but require a clinical suspicion of the diagnosis.^{1 2} Chylous effusions are usually exudative by biochemical parameters but can be transudative as well.² Pleural triglyceride levels <50 mg/dL can be considered non-chylous. A commonly accepted pleural triglyceride cut-off for diagnosing chylothorax is >110 mg/dL.^{4 5} If triglyceride levels do not exceed 110 mg/dL, however, or diagnostic uncertainty arises, lipoprotein electrophoresis should be performed with the presence of chylomicrons being consistent with chylous effusion.¹ Of note, a potentially falsely low pleural triglyceride level may be present in malnourished or fasting patients.² Pseudochylothorax is defined as a pleural triglyceride level below 110 mg/dL, pleural cholesterol level >200 mg/dL and a pleural cholesterol/triglyceride ratio >1.0, often with concomitant cholesterol crystals.1 4 5 18

Among lymphatic anomalies and other related pathologies associated with chylothorax are lymphangiectasia, lymphangiomas, lymphangioleiomyomatosis, sarcoidosis, amyloidosis, fibrosing mediastinitis, radiation-induced fibrosis, Yellow nail syndrome, Noonan syndrome and Gotham-Stout syndrome. Infectious diseases such as tuberculosis, parasitic infections and hepatitis A have also been reported as causal. Cirrhosis, nephrotic syndrome and congestive heart failure have been shown to cause chylothorax, with a tendency to present bilaterally.^{3 9 14}

Management of chylothorax is essentially threefold; conservative management with or without drainage, definitive surgical management only if indicated and treatment of the underlying condition.

Modifying nutrition to minimise chyle formation and replace fat-soluble vitamins, proteins and electrolytes which may be lost in chyle is a key consideration especially if repeat or ongoing drainage occurs.^{1 16 19} For the purposes of this discussion, in non-traumatic chylothorax, efforts should focus on diagnosis of the underlying cause including CT imaging focused on lymph node visualisation. Further imaging depending on clinical context could include magnetic resonance lymphangiography or direct lymphangiography.¹⁵ Conservative medical management with octreotide, somatostatin or etilefrine have been shown to be efficacious in limited studies.¹⁹ Only if recurrent effusions with symptoms occur should a discussion regarding in-dwelling catheter, talc pleurodesis, thoracic duct ligation or other interventional radiographic intervention be considered.6 16 17 19 If there is concern for malignancy, that is, lymphoma, less invasive diagnostic modalities should be considered in order to minimise the need for mediastinal exploration or lymph node biopsy including peripheral and pleural flow cytometry, advanced cytogenetic testing, bone marrow biopsy and surgical lymph node biopsy.

The presence of non-traumatic chylothorax warrants suspicion and further workup for the presence of lymph node involvement due to various neoplasms, inflammatory processes and infectious processes.

Chylothorax due to WM is quite rare with very few cases reported.^{20 21} In a patient with known WM and known MYD88 L265P mutation, the presence of MYD88+ cells in an effusion suggests pleural involvement. In the age of genomics, the MYD88 L265P mutation has been identified to be present in greater than 90% of patients with WM and may well arise as a target for WM-specific therapies.^{11 22} It is still unclear the exact aetiology of chylothorax in WM and pleural or pulmonary parenchymal biopsy has not been performed in reported cases. Therefore, the consideration that chylothorax may have developed due to direct pleural invasion, pulmonary invasion or lymphatic obstruction warrants treatment of the underlying WM regardless. Recent studies evaluating targeted therapies such as anti-CD20 antibodies, Bruton-tyrosine kinase inhibitors, proteasome inhibitors and novel CXCR-4 inhibitors either as monotherapy or combined with traditional chemotherapy bring further treatment options. However, guidelines remain uncertain as of the completion of this review.^{23 24}

In our patient’s case, we feel, in consultation with her primary oncologist, that her WM had progressed to a more aggressive form more consistent with diffuse large B cell lymphoma. Given the minimal degree of adenopathy on CT imaging, it seems more likely that chylothorax developed either from pulmonary invasion or direct pleural involvement, however, the left-sided laterality is indeed consistent with an aetiology related to thoracic duct obstruction.

This case report emphasises the importance of maintaining a broad differential when approaching a pleural effusion in a patient with a history of malignancy and presumed recent infection. It further reveals various areas of ongoing diagnostic and therapeutic uncertainty in pleural disease specifically as it relates to WM. We also offer a unique look at the patient’s perspective over the course of her diagnosis in her own words. Our hope is that this case will reveal the difficulties of living with a rare disease, suffering through its potential complications and the ultimate benefit of patient-centred care and effective communication.

Patient’s perspective.

My compromised immune system dictates that every minor cold has the potential to blossom into a weeklong event. But as the fevers continued and the mystery grew, it became clear that my watery lungs were not merely my body’s response to the pneumonia. It was the cancer itself wreaking unanticipated havoc. The nagging concern ‘it’s my cancer’ perpetually looms at the back of my mind, but I didn’t imagine this to be more than a mere bug until the team introduced me to the term chylothorax.

The quality of this communication system—among the members of my medical team and with me—created a powerful ‘circle of care’ that was essential to my understanding, trust and acceptance of what was unfolding. I credit the strength of our ongoing partnership—and the team’s commitment to honest, in-depth patient education—with successfully preparing me to face the treatment decisions and important challenges that lay ahead.

Learning points.

• Patients with pleural effusion and signs of infection warrant thoracentesis.

• Novel biomarkers can aid internists, hospitalists and subspecialists alike as long there is an appropriate index of suspicion and plan for follow-up.

• Non-traumatic chylothorax should be included when considering a differential diagnosis for pleural effusion especially in patients with a history of lymphoma or other lymphoplasmacytic neoplasms.

• Eliciting the patient’s insight into his or her condition may not only broaden one’s differential diagnosis but also opens a line of communication that can be key to subsequent treatment and follow-up.