Chylothorax as a result of chronic lymphocytic leukemia: case report and review of the literature.

Abstract: Chylothorax occurs when a disruption in the thoracic duct allows chyle to escape into the pleural space. The most commonly reported cause is malignancy, especially lymphoma. However, chylothorax caused by chronic lymphocytic leukemia is rarely reported in the literature. We describe a patient who developed chylothorax secondary to chronic lymphocytic leukemia. In addition, the pathogenesis, diagnosis, and treatment of chylothorax are reviewed.

Key Words: chronic lymphocytic leukemia, chylothorax, pleural effusion

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The presence of chyle in the pleural space defines a chylothorax. Chylothorax is most commonly caused by malignancies and occurs because of mechanical obstruction or damage to the thoracic duct. A number of different malignancies have been reported to cause chylothorax, most notably lymphoma and lung carcinoma. Chylothorax caused by chronic lymphocytic leukemia, as we report here, is rare, with only five cases described in the literature. (1-5)

Case Report

A 69-year-old white man was admitted to the hospital with worsening dyspnea on exertion. His medical history was significant for chronic lymphocytic leukemia (CLL), with B-cell lymphocytes expressing monotypic surface immunoglobulin M kappa, diagnosed 6 years before his acute presentation. Four years previously, he developed bleeding gums, petechial rash, and splenomegaly. He was diagnosed with immune thrombocytopenia and underwent a splenectomy. For the last 3 years, his leukocyte counts have ranged between 100,000 and 250,000/[micro]l and he has required frequent transfusions to correct anemia. Twice in the distant past, he was treated with chlorambucil, with transient improvement in his leukocytosis and anemia. Deep venous thrombosis occurred 4 months before admission, and he was anticoagulated. One month before presentation, he underwent a shortened course of fludarabine.

At presentation, the patient was able to walk only a few feet before he developed shortness of breath. In addition, he noticed three-pillow orthopnea over the previous 2 months. He denied any chest pain, pleurisy, cough, or hemoptysis. He had no fevers or chills, but did have night sweats for the previous 3 to 4 months.

On physical examination, he appeared chronically ill and was hypoxic, with room air oxygen saturations of 86%. He was afebrile, with a blood pressure of 119/61 mm Hg, a pulse of 111 beats/min, and a respiratory rate of 36 breaths/min. Breath sounds were clear on the right but absent in the lower two thirds of the left hemithorax. He lacked adventitial sounds, but did have egophony over the posterior, mid-left lung field. Heart examination was regular without murmurs, gallops, or rubs. The abdomen was scaphoid, with a well-healed left upper quadrant surgical scar and no hepatomegaly. He did not have any lymphadenopathy. He had muscle wasting in his lower extremities, but no edema and no palpable cords.

A chest radiograph revealed a small right pleural effusion and a large left pleural effusion (Fig. 1), with no mediastinal adenopathy. Laboratory values were significant for a white blood cell count of 179,000/[micro]l, a hematocrit of 40%, and a platelet count of 292,000/[micro]l. His prothrombin time was 30.8 seconds (international normalized ratio of 2.9) and his partial thromboplastin time was slightly elevated at 40.7 seconds. His blood urea nitrogen level was 37 mg/dl, but his creatinine was 1.1 mg/dl. His albumin was 2.5 g/dl, with a total protein of 4.9 g/dl. His lactate dehydrogenase was 1,108 U/L (normal range, 310-620 U/L), but his serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, alkaline phosphatase, and bilirubin were all normal.

After reversal of his anticoagulation, a thoracentesis was performed; 1,200 ml of chocolate milky fluid was obtained. The fluid had 35,445 red blood cells/[micro]l and 6,630 white blood cells/[micro]l (85% lymphocytes, 15% monocytes/macrophages). The lactate dehydrogenase of the fluid was 803 U/L, glucose was 109 mg/dl, protein was 3.1 g/L, amylase was 53 IU/L, pH was 7.51, and triglycerides were 382 mg/dl. Fluid cytology showed numerous small lymphocytes without atypical features. Flow cytometry showed mainly T lymphocytes with a minority of cells that mark as B cells expressing monotypic kappa light chain, consistent with a reactive process. This differs from previous reports of chylothorax in patients with CLL, which have found predominantly B lymphocytes in the pleural fluid. (1.3)

The patient symptomatically improved after the thoracentesis and was discharged home. Ten days later, the effusion reaccumulated and a repeat thoracentesis was performed. Total parenteral nutrition was recommended, but the patient opted for hospice care and died 5 days later.

Discussion

The accumulation of chyle in the pleural space is a chylothorax, which accounts for a small percentage of all pleural effusions. Chyle (from the Latin word chylus, or juice) consists of chylomicrons and very-low-density lipoproteins absorbed from the small intestine, secreted into intestinal lymphatics, and accumulated in the cisterna chyli. The thoracic duct arises from the cisterna chyli and carries chyle from the intestinal lymphatics and lacteals to the venous circulation in the left thoracic inlet. The duct travels cephalad through the esophageal hiatus of the diaphragm and along the anterior thoracic vertebral surfaces between the aorta and the azygous vein. Around the fifth thoracic vertebra, the thoracic duct crosses to the left side of the vertebral column, where it continues ascending behind the aortic arch, into the neck above the clavicle and terminates into the venous circulation, where the left subclavian and jugular veins combine to form the brachiocephalic vein. (6) Chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space. Chyle can accumulate in either the left or right pleural space, depending on where the thoracic duct is disrupted. If the disruption occurs below the fifth thoracic vertebra, the thoracic duct is on the right side of the vertebral column and right-sided chylothorax occurs. However, if the thoracic duct is disrupted above the fifth thoracic vertebra, the chylothorax occurs in the left pleural space.

[FIGURE 1 OMITTED]

The appearance of the pleural fluid often leads to the suspicion of chylothorax. However, less than half of all chylothoraces have a classic milky, white appearance. (7) The diagnosis must be confirmed by the measurement of triglycerides in the pleural fluid. A triglyceride level greater than 110 mg/dl is diagnostic of chylothorax. In addition, a triglyceride level between 50 and 110 mg/dl may also represent a chylothorax. In these cases, lipoprotein electrophoresis can be performed to show the presence of chylomicrons in the pleural fluid, confirming the diagnosis of chylothorax. A pleural fluid cholesterol level should also be obtained because pseudochylothorax may also have elevated triglyceride levels. Cholesterol levels greater than 200 mg/dl are suggestive but not diagnostic of pseudochylothorax. The diagnosis of pseudochylothorax can only be confirmed after the demonstration of the presence of cholesterol and/or triglycerides and the lack of chylomicrons (by lipoprotein electrophoresis) in the pleural fluid.

The most common symptoms of chylothorax include dyspnea and orthopnea. Because chyle is not irritating to the pleura, chest pain is an infrequent finding. Compression of the lung by the chyle in the pleural space leads many patients to experience dyspnea. In addition to respiratory difficulties, the main complications of chylothorax are malnutrition and depressed immune function. Chyle contains fat-soluble vitamins and a significant amount of the dietary calories from fat intake. Lymphocytes, predominantly T-lymphocytes, are also present in chyle. The loss of these vitamins, calories, and lymphocytes from the body as chyle spills into the pleural space leads to malnourished and immunodeficient states. (8,9) Fortunately, chyle is bacteriostatic, and thus chylothorax is rarely complicated by empyema. In addition, chyle is nonirritating to the pleura, and thus chylothoraces rarely develop a pleural rind or peel.

The causes of chylothorax have been divided into four main categories. (6) Malignancy, the most common cause of chylothorax, accounts for over half of all cases. Trauma is the second leading cause, accounting for 25% of cases. Idiopathic chylothorax and miscellaneous causes account for the remaining two categories. Idiopathic causes include congenital (neonatal) chylothorax (10) and cases of minor unrecognized trauma, such as coughing, yawning, and vigorous stretching. Miscellaneous causes range from cirrhosis (11) and congestive heart failure (12) to sarcoidosis (13) and lymphangioleiomyomatosis. (14-16)

Many different types of cancers have been reported to cause chylothorax, with lymphoma being the most common, and non-Hodgkin's lymphoma is more likely to cause chylothorax than Hodgkin's lymphoma. (17) Although CLL is often associated with pleural effusion, (18,19) chylothorax from CLL is rare, with only five previous cases identified in the literature. (1-5) Typically, malignancies cause chylothorax through disruption or compression of the thoracic duct from mediastinal adenopathy or mass effect. CLL causes diffuse adenopathy but rarely causes mediastinal adenopathy significant enough to obstruct the thoracic duct, (3) which probably explains the infrequent nature of it causing chylothorax.

In general, initial management of chylothorax usually is conservative, with patients being given nothing by mouth and started on total parenteral nutrition to decrease the amount of fluid traveling in the thoracic duct and to allow the duct time to heal while continuing to provide adequate nutrition through parenteral feeding. (20) If the chylothorax does not resolve with conservative treatment, more aggressive measures must be undertaken in a timely manner to ensure that the patient is adequately nourished and immunocompetent to withstand further treatments. If mediastinal adenopathy is present, either chemotherapy, radiotherapy, (21) or both can be tried as treatment. In addition, many cases often require pleurodesis of the pleural space to resolve the chylothorax. (22) In refractory cases, surgery can be performed to ligate the thoracic duct, (23) either in the thorax or in the abdomen, or to establish a pleuroperitoneal shunt. (24,25) The establishment of a pleuroperitoneal shunt allows the chyle to drain into the abdomen, where it is reabsorbed, maintaining adequate nourishment and immunocompetency.

The mechanism of how CLL causes chylothorax is not well understood and theories about its pathophysiology are lacking. We suggest three possible theories to explain how CLL may cause a chylothorax. The most common manner in which a malignancy causes chylothorax is through mediastinal adenopathy. Although CLL rarely causes significant mediastinal adenopathy, (3) it may be these rare cases that are at risk for developing a chylothorax. Our patient did not demonstrate any mediastinal adenopathy on chest radiography, but it is possible that adenopathy that was not visualized on radiography was indeed present. Another possibility involves the flow of leukemic lymphocytes through the lymphatic system. The presence of an extremely large number of abnormal lymphocytes in CLL may cause sludging in the lymphatic system. The sludging may result in a pseudo-obstruction of either the thoracic duct or lymphatics draining the pleura, resulting in a chylothorax. A third possible mechanism involves traumatic disruption of the thoracic duct. Much like patients who have just finished a high-fat meal, the large number of lymphocytes and sludging in CLL patients may distend the thoracic duct, making it more susceptible to rupture. Then, minor trauma, such as a deep cough or violent sneeze, results in microdisruptions of the thoracic duct and allows chyle to leak into the pleural space.

Unfortunately, the rarity with which CLL causes chylothorax and the lack of an adequate animal model make investigations regarding the pathophysiology difficult. In addition, little evidence exists to guide the clinician in determining which treatment option is best for these patients. Case reports suggest that mediastinal irradiation alone (even in the absence of mediastinal adenopathy), (2) mediastinal irradiation followed by talc pleurodesis, (3) and thoracic duct ligation with concomitant talc pleurodesis (1) may all be reasonable options for the treatment of CLL-induced chylothorax.

It's a recession when your neighbor loses his job; it's a depression
when you lose your own.
--Harry S. Truman

Accepted February 25, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0291

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RELATED ARTICLE: Key Points

* Lymphoma is the most common cause of chylothorax. Although chronic lymphocytic leukemia often causes pleural effusions, it rarely causes chylothorax.

* Chylothorax occurs when chyle enters the pleural space through a disruption in the thoracic duct. The diagnosis is made by demonstrating chylomicrons in pleural fluid.

* Patients with chylothorax rapidly suffer malnutrition and immunodeficiency because of the loss of fat and lymphocytes.

* Treatment of chylothorax is initially conservative, giving the patient nothing by mouth and providing total parenteral nutrition.

* If conservative treatment fails, further definitive treatment depends on the cause of the chylothorax and may include chemotherapy, radiation, pleurodesis, ligation of the thoracic duct, or development of a pleuroperitoneal shunt.

Todd W. Rice, MD, and Aaron P. Milstone, MD

From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

Supported by National Heart Lung and Blood Institute, National Institutes of Health grant HL 07123.

Reprint requests to Todd W. Rice, MD, Center for Lung Research, Vanderbilt University School of Medicine, T-1217 Medical Center North, Nashville, TN 37232-2650. Email: [e-mail]