Chylothorax in the Setting of Lung Malignancy

Abstract

Chylothorax refers to chyle within the pleural space, which frequently arises from an interruption in the thoracic duct or because of reduced lymphatic drainage. Pleural fluid that is white/milky in appearance, with a triglyceride concentration of greater than 110 mg/dL, strongly supports the diagnosis of chylothorax. Chylothorax is nearly always exudative. Transudative chylothorax is extremely rare and typically presents due to a secondary cause, such as liver cirrhosis, nephrotic syndrome, or congestive heart failure. We present a case of chylothorax that occurs in the setting of lung adenocarcinoma. A 65-year-old African American man with a past medical history of metastatic right lung adenocarcinoma presented with dyspnea and palpitations. He denied fever, orthopnea, and paroxysmal nocturnal dyspnea. Therapeutic drainage of the left pleural effusion resulted in 650 mL of milky-white fluid. Pleural fluid analysis demonstrated a triglyceride concentration of 520 mg/dL, a pleural/serum protein ratio of 0.41, a pleural/serum lactate dehydrogenase (LDH) ratio of 0.26, a total pleural LDH of 127 IU/L, and a cholesterol level of 58 mg/dL. This effusion can be classified as transudative as per Light’s criteria and exudative as per Heffner’s and pleural cholesterol criteria. A subsequent pleural fluid cytology found malignant cells consistent with lung adenocarcinoma. Malignancy is the most common cause of nontraumatic, exudative chylothorax. Light’s criteria misinterpret about 25% of transudative effusions as exudative. Therefore, to minimize this error, a combination of the 3-criterial consideration is ideal.

Background

Chylothorax is the presence of chyle inside the pleural space as a result of a thoracic duct obstruction or decreased lymphatic drainage. A triglyceride concentration of greater than 110 mg/dL in the white-colored pleural fluid is generally diagnostic for chylothorax. Typically, chylothorax is exudative when secondary to malignancy. We present a case where patient has chylothorax secondary to a right lung adenocarcinoma which has been classified as transudative with Light’s criteria but is exudative when considered Heffner’s and pleural cholesterol criteria.

Case Presentation

A 65-year-old African American man with a past medical history of metastatic right lung adenocarcinoma and recurrent left-sided pleural effusion (s/p PleurX catheter) presented with dyspnea and palpitations. He denied fever, orthopnea, and paroxysmal nocturnal dyspnea. He required weekly draining of his PleurX catheter, which was placed recently. He had previously been treated with chemotherapy and at present was on immunotherapy. The patient had previously tested positive for oncogenic PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) and KRAS G12C (Kirsten rat sarcoma virus) mutations. He was a former smoker with a 25-pack-year history, and his only other known medical condition consisted of hypertension treated with amlodipine. His family history was significant for lung cancer in his father.

In the emergency room (ER), the patient’s vitals were significant for a heart rate of 180. On physical examination, he had diminished lung sounds, worse on the right, without rales, crackles, or wheezes. His cardiac examination was unremarkable, with no appreciable jugular venous distension (JVD). Extremities were nonedematous, and the abdomen was soft and nondistended.

Initial work-up unveiled new-onset atrial flutter with 2:1 atrioventricular (AV) block. Chest X-ray revealed persistent total opacification of the right hemithorax, secondary to extensive lung malignancy and empyema, and a new 10 × 12-mm nodular infiltrate in the left midlung field (Figure 1). Noncontrast computed tomography (CT) chest reported moderate left-sided pleural effusion, total right hemithorax opacification, and no cardiomegaly (Figure 2). Liver function tests were within normal limits, except for a mildly decreased serum albumin of 3.0 L (3.4-5.4). A transthoracic echocardiogram revealed an ejection fraction (EF) of 45% (50-75). Urinalysis was negative for nephropathy. Therapeutic drainage of the left pleural effusion resulted in 650 mL of milky-white fluid (Figure 3). Pleural fluid analysis demonstrated a triglyceride concentration of 520 mg/dL, a pleural/serum protein ratio of 0.41, a total pleural LDH of 127 IU/L, a pleural/serum LDH ratio of 0.26, and a cholesterol level of 58 mg/dL. A subsequent pleural fluid cytology found malignant cells consistent with lung adenocarcinoma.

Figure 1.

Anteroposterior chest radiograph showing complete right lung collapse and a 10 × 12-mm nodular infiltrate in left midlung field (red arrow).

Figure 2.

Noncontrast CT chest showing total right lung collapse and a moderate left-sided pleural effusion (red arrow).

Figure 3.

Chylous pleural effusion with milky-white appearance.

Discussion

Chylothorax is collection of chyle within the pleural space. ¹ Chyle contains chylomicrons that transport triglycerides from the intestines to the lymphatic fluid and then eventually to the venous system by the way of the thoracic duct. ² A triglyceride concentration of greater than 110 mg/dL or the detection of chylomicrons in the pleural fluid is considered diagnostic for chylothorax. ³ In a retrospective study conducted by Maldonado et al, ⁴ almost half of the cases with chylothorax had a milky-white appearance to the pleural fluid; however, the majority were nonwhite in appearance and variations included serous, serosanguinous, or bloody effusions. Chylothorax is nearly always exudative. ⁵

An obstruction or disruption in the flow of chyle through the thoracic duct above the diaphragm may result in extravasation of chyle from the thoracic duct into the pleural space. ⁶ In patients with chylous ascites, a subdiaphragmatic lymphatic leak can cause chylous pleural effusions by way of the transdiaphragmatic flow of chyle from the peritoneal cavity. Akbar A et al ⁷ described a case where chylothorax is seen in a cirrhosis patient without having significant amount of ascites. A similar mechanism has been postulated to occur in that case. The causes of extravasation of chyle into the pleural space are due to either traumatic or nontraumatic causes. ⁸ Nontraumatic chylothorax is more common with malignancy as the most common cause.^8,9

In their review of the literature, Maldonado et al ⁴ found 86% of the chylothorax cases to be exudative. This finding intrigues us; protein concentration of chyle is usually between 2 and 3 g/dL, which should present as transudative chylous effusions. ⁶ However, majority of the reported chylothoraces have a higher protein concentration, making them exudative by Light’s criteria.^4,6 A retrospective case study suggested that under normal transcapillary hydrostatic gradients, it is likely that some reabsorption of water and small solutes occurs from the pleural to the intravascular space, leading to relatively increased protein concentrations in the chylous pleural fluid. ⁶ This has previously been described in chylous cysts, containing concentrated chyle. ⁶ However, this mechanism for exudative chylothorax does not entirely explain the events in the formation of transudative chylothorax. ¹

Transudative chylothorax is rare and, in the few available reports, has been associated with only a limited number of conditions. In a retrospective review of 7 transudative chylous effusions, Agrawal et al ⁶ noted all of the cases to be associated with both chyle leakage and a coexisting process with the potential for causing pleural effusions by itself, such as congestive heart failure, superior vena cava obstruction, pulmonary hypertension, nephrotic syndrome, amyloidosis, and ascites. ¹ This finding is consistent with our review of the literature, including a case report by Cassandra Do et al, ² in which they reported the occurrence of a transudative chylothorax secondary to recurrent chylous ascites.

Lung cancer is another condition with an established propensity for causing chylothoraces. ⁹ In our patient’s case, the left-sided chylothorax most likely has a multifactorial mechanism. At the time of diagnosis, CT chest demonstrated a total right lung collapse, secondary to extensive loculations and adenocarcinoma. Right lung collapse has previously been demonstrated to cause thoracic duct injury, or obstruction, resulting in extravasation of chyle into the contralateral pleural space. ¹⁰

In cases without an obvious injury or etiology, chylothorax should raise the suspicion for malignancy. In patients with associated trauma, it is common practice to obtain pleural fluid analysis, along with a CT scan or lymphangiography to elucidate a possible site of leakage. Treatment of chylothorax depends on the etiology, and includes both medical and surgical options. Our patient was managed with weekly therapeutic pleural fluid drainage via a PleurX catheter, alongside ongoing chemotherapy. Untreated chylothorax can lead to chyle depletion, resulting in loss of protein, fats, fat-soluble vitamins, and, therefore, malnutrition. Immunosuppression can result from the loss of antibodies and lymphocytes. Ultimately, if left untreated, chylothorax has a 50% mortality rate.^9,11

Light’s criteria, Heffner’s criteria, and pleural cholesterol levels can be used to classify pleural effusion as exudative or transudative. ¹²

As per Light’s criteria, pleural effusion is considered exudative if it meets at least 1 of the following criteria: ¹³

• - a pleural fluid protein to serum protein ratio >0.5,

• - a pleural fluid LDH to serum LDH ratio >0.6, or

• - a pleural fluid total LDH greater than two-thirds the upper limit of normal serum LDH.

If none of the criteria are met, the fluid is classified as being transudative. In our patient, thoracentesis revealed a pleural fluid protein to serum protein ratio of 0.41, pleural fluid LDH to serum LDH ratio of 0.26, and the pleural fluid LDH of 127 IU/L, which is below two-thirds the upper limit of normal serum LDH (300 IU/L). Pleural triglyceride concentration was 520 mg/dL. The pleural fluid was white in appearance. As such, he was diagnosed with transudative chylothorax according to Light’s criteria.

As per Heffner’s criteria, pleural effusions can be classified as exudative if it meets any 1 of the following criteria:

• - pleural fluid protein >2.9 g/dL,

• - pleural fluid cholesterol >45 mg/dL, or

• - pleural LDH greater than two-thirds the upper limit of normal serum LDH. ¹²

According to this criterion, this effusion can be classified as exudative. Heffner’s criteria have the advantage of using only pleural effusions investigations to classify the effusions as transudative or exudative whereas Light’s criteria also require blood investigations.

Pleural effusions can also be called as exudative if they have pleural fluid cholesterol level of greater than 45 mg/dL. ¹² Our patient has pleural fluid cholesterol level of 58 mg/dL, as such can be classified as exudative.

Light’s criteria misinterpret about 25% of transudate effusions as exudative. ¹⁴ Heffner’s criteria are considered to have a lower misidentification rate of about 10% to identify exudative effusions. ¹⁴

Light’s criteria have a higher sensitivity and Heffner’s criteria have higher specificity to identify an exudative effusion as mentioned in the Devakota et al ¹⁴ study. Hence, a combination of these criteria should be considered to minimize the misinterpretation of the pleural effusions. Our patient, considering Heffner’s criteria and pleural fluid cholesterol criteria, should be classified as an exudative chylothorax.

Conclusion

The transudative chylothorax in the setting of malignancy is rare but not uncommon. In this presentation, it is postulated that the chylothorax was due to thoracic duct injury secondary to a collapsed right lung with persistent left-sided pleural effusions due to adenocarcinoma of the lung. Even though this effusion can be classified as transudative as per Light’s criteria alone, the effusion in this case is in fact exudative effusion secondary to adenocarcinoma as per Heffner’s and pleural cholesterol criteria. Hence, combination of the 3 criteria should be taken into consideration to determine the type of effusion with minimal errors.