MEDICINE

Dasatinib as a Probable Cause of Bilateral Chylothorax in a Patientwith Chronic Myeloid Leukemia: Case Report

Sze Shyang Kho1& Larry Ellee Nyanti1 & Chan Sin Chai1 & Siew Teck Tie1

Accepted: 7 April 2020# Springer Nature Switzerland AG 2020

AbstractDasatinib-induced chylothorax has been sporadically reported, and its pathophysiology has yet to be fully elucidated. We report a53-year-old man with underlying chronic myeloid leukemia in remission on regular dasatinib who was referred to pulmonologyteam with an incidental finding of a right upper lobe lung nodule with bilateral pleural effusion on chest radiograph. Computedtomography confirmed a solid spiculated solitary pulmonary nodule (SPN) with bilateral pleural effusions with no mediastinal orintra-abdominal lymphadenopathy. Initial diagnostic thoracentesis of the left pleural effusion revealed serous fluid, which wasexudative with negative cytology and medical thoracoscopic pleural biopsy yielded only chronic inflammatory changes. Post-procedurally, as appetite further improved, intercostal tube drainage turn chylous, centrifugation and triglyceride levels confirmedchylothorax. Diagnostic thoracentesis was then done over the right pleural effusion, which revealed serous appearance, bio-chemically exudative with triglyceride of 1.7 mmol/l. Bilateral chylothorax probably due to dasatinib was suspected, and the drugwas withheld. Chest tube was removed after 10 days. PET/CT scan showed only hypermetabolism in the SPN and hilar lymphnode with no mediastinal involvement. Tuberculosis workup was negative. The SPN was biopsied under fluoroscopy-guidedbronchoscopy, which confirmed limited stage neuroendocrine carcinoma of the lung. Patient remained well at 1 month follow-upwith no recurrence of bilateral chylothorax.We discuss the implications of concurrent bilateral exudative chylothorax in SPN andthe diagnostic challenges of chylothorax.

Keywords Dasatinib . Chylothorax . Tyrosine kinase inhibitor . Pleural effusion . Lung cancer

AbbreviationsCML Chronic myeloid leukemiaCT Computed tomography

LDH Lactate dehydrogenasePET/CT Positron emission tomography

/computed tomographyPf Pleural fluidR-EBUS Radial endobronchial ultrasoundSPN Solitary pulmonary noduleTKI Tyrosine kinase inhibitor

Introduction

Dasatinib is a potent second-generation tyrosine kinase inhib-itor (TKI) frequently used in treatment of chronic myeloidleukemia (CML). Pleural effusion is commonly encounteredin patients treated with dasatinib with an incidence of 7–39%[1]. However, chylothorax related to dasatinib is still a rareencounter. Chylothorax is defined by the presence of chyle inpleural effusion, which is commonly due to thoracic duct dis-ruption [2]. Majority of chylothorax is unilateral, with around22% of cases present bilaterally [3]. Trauma and malignancy

This article is part of the Topical Collection on Medicine

* Sze Shyang Khobzk99@hotmail.com

Larry Ellee Nyantilarryen90@yahoo.com

Chan Sin Chaichansinchaics@gmail.com

Siew Teck Tiebryantie75@gmail.com

1 Division of RespiratoryMedicine, Department ofMedicine, SarawakGeneral Hospital, Ministry of Health, Jalan Hospital,93586 Kuching, Sarawak, Malaysia

SN Comprehensive Clinical Medicinehttps://doi.org/10.1007/s42399-020-00280-6

/Published online: 15 May 2020

(2020) 2:817–821

remain the commonest cause of chylothorax with lymphomabeing the commonest malignancy [2]. We hereby report a caseof bilateral chylothorax probably due to dasatinib in a middle-aged gentleman. In this report, we also highlight the chal-lenges in chylothorax diagnosis as well as the good clinicalacumen required to determine the most probable cause ofchylothorax in a patient with high malignancy risk.

Case Presentation

A 53-year-old man was referred to our unit for incidentalfinding of bilateral pleural effusion and solitary pulmonarynodule (SPN) on chest radiograph. He had underlying CMLdiagnosed in 2013 but had been in remission since 2016 asevidenced by complete suppression of BCR/ABL and was onoral dasatinib 100 mg once daily since then.

He had been admitted for lower limb cellulitis this admis-sion, having presented with acute onset of fever and chills for3 days with anorexia, associated with swollen right lower limband a tender right inguinal lymph node. He denied any cough,shortness of breath, hemoptysis, or chest pain; his saturationwas 100% under room air. Blood investigations revealed leu-kocytosis with mild renal impairment (serum urea 5.1 mmol/land creatinine 129 μmol/l). Liver enzymes and lactate dehydro-genase (LDH) levels were within normal limits. An ultrasoundof the right lower limb showed subcutaneous edema consistentwith right lower limb cellulitis, and Doppler ultrasonographyruled out deep vein thrombosis. Blood culture was negative,and he responded well to intravenous ampicillin/sulbactamand hydration, as evidenced by resolving cellulitis changes,improving appetite and normalized renal function.

A routine chest radiograph performed on admissionshowed an incidental finding of a SPN in the right lung withbilateral pleural effusion, predominantly over the left (Fig. 1).Physical examination revealed reduced air entry and dull per-cussion notes at bilateral bases of the lungs. No lymph nodeswere palpable, and there was no hepatosplenomegaly. A re-view of previous chest radiograph done a year ago revealed noSPN. Urgent computed tomography (CT) confirmed a solidenhancing spiculated right upper lobe SPN measuring 2.6 cmwith a 1.2 cm right hilar lymph node, associated with bilateralpleural effusions (Fig. 2). There was no central vein thrombo-sis and mediastinal or intra-abdominal lymphadenopathy.Using the validated risk assessment calculator for SPN, themalignancy probability was estimated at 92.5% [4]. Sputumsmear for acid-fast bacilli and Xpert MTB/RIF was negative.

Ultrasound-guided thoracentesis was performed over leftpleural effusion upon suspicion of metastatic disease. Thepleural fluid was serous in appearance, with pleural fluid(Pf) pH of 7.423 and glucose 4.99 mmol/l. Light’s criteriaconfirmed an exudative effusion, with protein of 46 g/l (ratio0.64) and LDH of 399 mmol/l (ratio 0.68). Pleural fluid

cytology revealed a predominant lymphocytic pleural effusionwith no malignant cells seen. As pleural fluid cytology wasnegative for malignancy, the patient underwent diagnosticmedical thoracoscopy, revealing slight pleural thickening atthe inferior-posterior aspect of the left pleural cavity andhemidiaphragm, with no other abnormalities (Fig. 3).Residual serous pleural fluid was drained, and a 24Fr inter-costal chest tube was inserted. The procedure was uncompli-cated, and no attempt was made to explore the mediastinalpleural. Parietal pleural biopsy yielded only chronic inflam-matory changes with lymphocytes and plasma cells infiltra-tion (Fig. 4). There were no epithelioid granuloma or evidenceof malignancy. Twenty-four hours after the thoracoscopic pro-cedure, the drain output from the left pleural cavity increasedand turned milky in appearance. Pleural fluid centrifugationyielded a milky supernatant consistent with chylothorax; Pftriglyceride was 1.14 mmol/l, and Pf cholesterol was1.7 mmol/l. This was in line with improving appetite of ourpatient after treatment of cellulitis and drainage of pleuraleffusion. In view of this new clinical finding, we proceededwith ultrasound guided thoracentesis over the right pleuraleffusion, which yielded serous, exudative pleural effusionwith Pf pH 7.67, glucose 5.40 mmol/l, protein of 46 g/l (ratio0.65), and LDH of 445mmol/l (ratio 0.76). Pf triglyceride wasraised at 1.78 mmol/l, and Pf cholesterol was 1.57 mmol/l.The pleural fluid analysis from both pleural cavities confirmedbilateral chylothorax.

For the right upper lobe SPN, whole-body PET/CT scanshowed avid uptake with SUVmax of 4.2 with right hilar avidnode of SUVmax 3.2; otherwise, mediastinal and intra-abdominal lymph nodes were clear. Following discussionand detailed review by the multidisciplinary lung tumor board,

Fig. 1 Initial chest radiograph demonstrated a right upper lobe nodulewith bilateral pleural effusion

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local causes of chyle leak secondary to mediastinal metastasisfrom SPN were deemed unlikely in view of no mediastinallymphadenopathy involvement on PET/CT. Tuberculosis wasalso ruled out, with negative sputum and pleural fluid acid fastbacilli coupled with normal lung parenchyma on CT. A pre-emptive diagnosis of probable dasatinib-induced chylothoraxwas made, and after consulting the hematology team,dasatinib was withheld [5]. Upon withdrawal of dasatiniband imposing a strict fat-free diet, the drain output progres-sively reduced and intercostal chest tube was removed after10 days successfully. Patient remained well during a 1-monthpost-discharge follow-up review with no recurrence of bilat-eral chylothorax (Fig. 4) during the interim period of dasatinibwithdrawal. He was subsequently commenced on nilotinibtherapy by the hematology team.

Having ruled out potential pleural metastasis, weproceeded for biopsy of the right upper lobe SPN. Flexiblebronchoscopy revealed no intraluminal lesion; hence, atransbronchial lung biopsy of the right upper lobe SPN wasperformed with radial endobronchial ultrasound guided

bronchoscopy (R-EBUS) under fluoroscopy (Fig. 5).Histopathological examination confirmed combined smalla n d l a r g e c e l l n e u r o e n d o c r i n e c a r c i n om a .Immunohistochemistry tests were positive for CKAE1/AE3,CD56, and synaptophysin. Proliferative index marker (Ki67)is 50%. A staging CT brain did not demonstrate any evidenceof brain metastasis. A consensual decision for concurrent che-moradiation therapy was made in the multidisciplinary lungtumor board meeting after considering the risks and benefit ofsurgical resection. Our final diagnosis was an early limitedstage neuroendocrine carcinoma of the lung with bilateralchylothorax most probable secondary to dasatinib.

Discussion

Dasatinib is a potent second-generation TKI frequently used intreatment of CML, which may cause pleural effusion and, rarely,chylothorax. Dasatinib is among the TKI with the highest likeli-hood of developing pleural and pericardial effusions [6].

Fig. 3 Normal pleural cavity onmedical thoracoscopicsexamination (a) with focalpleural thickening (b)

Fig. 2 CT Thorax demonstrated asolid enhancing right upper lobespiculated solitary pulmonarynodule (a) with pleural effusion(b)

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Dasatinib-induced chylothorax remains a diagnosis of exclusionafter ruling out other conditions, such as trauma, mediastinal pa-thology, or lymphoma. Although the exact mechanism ofdasatinib-related pleural effusion is unknown, it is postulated thatits pathophysiology may be due to microvasculopathy from overinhibition of platelet-derived growth receptor beta (PDGFR-β)and vascular permeability and pleural epithelium stability interfer-ence from Src kinase inhibition [7, 8]. A temporal relationshipbetween resolution of chylothorax and withdrawal of dasatinib inour case supports the causal relationship. Moreover, in view of the

high-risk SPN, extensive workups were performed to ensure nomediastinal and pleural metastasis, which maybe also leads tobilateral chylothorax. Although pleural effusion usually developwithin 6–12 months of dasatinib initiation, report of chylothoraxoccurrence can happen even after 4 years of initiation, as in ourcase, whichmay be related to the total accumulative dosage [7, 8].

Traditionally, Pf triglyceride level of more than 1.24 mmol/l(110 mg/dl) or detection of chylomicrons in pleural fluid is re-quired to confirm the diagnosis of chylothorax [2]. However, thediagnosis of chylothorax can be challenging in acutely ill andmalnourished patients, as portrayed in our case as both pleuralfluid appearance and triglyceride levels are dependent on pa-tient’s nutritional status [2, 3]. The classically described “milky”appearance is not sensitive for chylothorax; in a review of 74chylomicron-defined chylothorax patients, only 44%had amilkyappearance [3]. Moreover, the Pf triglyceride cut-off level wasalso not without limitations; Agarwal et al also demonstrated thatin 12 patients where chylomicrons were present in the pleuralfluid, only 50% demonstrated Pf triglyceride level of more than1.24 mmol/l [9]. Another cohort also demonstrated that only14% of the chylothorax were associated with the traditional cutoff value of 1.24 mmol/l [3]. Hence, it is imperative that pleuralfluid appearance and triglyceride levels are interpreted with thenutritional status of the patient in mind. Our patient had a rightchylothorax that was serous in appearance but had a raised Pftriglyceride level, while his left chylothorax was confirmed bythe milky chylous appearance as well as a milky super-natant post-centrifugation, despite that the Pf triglyceridelevel did not achieve the cut-off value of 1.24 mmol/l.We postulate that our patient’s Pf triglyceride level andappearance would have fulfilled the traditionally accept-ed chylothorax diagnostic criteria if sampled during im-proved nutritional status. In the fasting or malnourishedpatient, pleural fluid chylomicron levels are superior inconfirming the diagnosis of chylothorax [2]. However,this test was not available in our clinical setup.

Fig. 4 Chest radiograph during 1 month follow-up with no recurrence ofpleural effusion

Fig. 5 Normal sub-segmentalairway at apical segment of rightupper lobe during flexible bron-choscopic examination (a).Transbronchial biopsy of solitarypulmonary nodule was performedunder fluoroscopic guidance afterlocalization by radialendobronchial ultrasound

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To our knowledge, the relationship between TKItreatment and development of secondary malignancy re-mains uncertain. In CML patients treated with TKI,neuroendocrine carcinoma as a secondary malignancyis rare, with only a handful of case reports [10].Neuroendocrine carcinoma of the lung is an aggressivedisease, and the majority present as centrally locatedlesions, such as mediastinal masses or hilar lymphade-nopathy. Only a minority comprising less than 5% pres-ent with SPN, most of which have been described aswell-defined homogeneous nodules with lobular marginsand spiculation [11]. The presence of exudative pleuraleffusion on the background of suspected malignancy isa cause for alarm for the clinician, which warrants fur-ther workup. Although a negative medical thoracoscopicpleural biopsy may raise the dilemma of a false-negativeresult, as in our case, Vakil et al demonstrated thatmedical thoracoscopy has a high negative predictivevalue for malignancy of 97% even in patients with con-firmed advanced malignancy [12]. This is of utmostimportance in the management of our patient as inap-propriate clinical assumption may lead to over-stagingof underlying early stage malignant disease. However,a cautious follow-up remain utmost important especiallyin high-risk patients of such.

In conclusion, bilateral chylothorax secondary todasatinib is rare and can occur even years after initia-tion of therapy as a result of total accumulative dose.Diagnostic aspects of chylothorax such as gross appear-ance and Pf triglyceride levels need to be assessedalongside the nutritional status of the patient. Causesof bilateral chylothorax need to be assessed cautiouslyin patients with underlying early stage malignancy asinappropriate clinical assumptions may lead to over-staging of underlying malignant disease.

Acknowledgments We would like to thank our colleagues fromHematology Unit, Sarawak General Hospital for co-managing this pa-tient. We would also like to express our deepest gratitude to theSarawak Lung Cancer Special Interest Group (SLCSIG) in providingvaluable insights in the management of this case.

Authors’ Contributions SSK initiated the idea for case reporting. SSKand LEN prepared the final copy of the manuscript. SSK and CSC wereinvolved in the overall management of the patient under the supervisionof STT. All authors have read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of Interests The authors declare that they have no conflict ofinterest.

Ethics Approval and Consent to Participate Not applicable.

Consent for Publication Written informed consent was obtained fromthe patient for publication of this case report and accompanying images.A copy of the written consent is attached and available for review by theEditor-in-Chief of this journal.

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