A Pleural Effusion with an Unusual Cause - SAGE Journals

Case Report

A Pleural Effusion with an Unusual Cause Aik Hau Tan1, MBBS, MRCP(UK), MMed(Int Med), Thun How Ong1, MBBS, MRCP(UK), Angela Takano2, Physician and Surgeon’s Degree, AM.BD., Anatomical and Clinical Pathology, AM.BD., Cytopathology

Department of Respiratory and Critical Medicine, Singapore General Hospital

1

Department of Pathology, Singapore General Hospital

2

Abstract A 35-year-old presented with an incidental finding of a small left pleural effusion on a routine chest radiograph. A diagnostic pleurocentesis revealed a chylous effusion. CT showed a small left pleural effusion, multiple small pulmonary nodules and thickened interstitial lines in the right lung. Video-assisted thoracoscopic biopsy of the right lung revealed features consistent with diffuse pulmonary lymphangiomatosis. Keywords: Chylothorax, Lung/pathology, Lung/radiography

INTRODUCTION A 35-year-old woman presented with an incidental finding of a small left pleural effusion on a routine chest radiograph. She had no symptoms except for an intermittent dry cough for two years. She was married with no children. There was no history of smoking, alcohol consumption or drug abuse. Her past history was significant for an episode of pericardial effusion at age 12, which was attributed to a mycoplasma infection. No pericardial tap was done and the effusion resolved after a course of macrolides. At age 20, she presented with recurrent episodes of chronic diarrhoea, associated with weight loss and iron deficiency anaemia. Extensive investigations were inconclusive. Of note, colonoscopy was normal except for an irregular and bulky ileocecal valve. Biopsies of the terminal ileum and ileocecal valve showed chronic inflammatory cells and eosinophils. Neither microorganisms nor lymphatic abnormalities were noted. Her symptoms resolved after empirical treatment with metronidazole and her haemoglobin levels normalised with hematinics. Her symptoms recurred one year later, but again responded

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well to another course of metronidazole. She was subsequently asymptomatic and defaulted further follow-up until the current presentation. On examination, the patient was comfortable. She had a temperature of 36.9°C, BP 110/70mmHg and pulse rate of 60 beats per minute. She had no abnormal skin pigmentations. There was a small pleural effusion detectable on the left. Physical examination was otherwise unremarkable. Chest radiograph showed a small left pleural effusion with increased interstitial infiltrates in the bilateral lower lobes (Fig. 1, see overleaf ). Screening blood tests did not show anaemia or evidence of malabsorption. A diagnostic pleurocentesis revealed a chylous effusion with a triglyceride level of 19.94 mmol/L (1695 mg/dL). Cytology studies demonstrated moderate numbers of mesothelial cells and lymphocytes. Bacterial and mycobacterial cultures were negative. Computed tomography of the thorax showed a left pleural effusion and multiple small pulmonary

Proceedings of Singapore Healthcare  Volume 20 Number 4  2011

A Pleural Effusion with an Unusual Cause

Fig 1. Chest radiograph showing a small left pleural effusion and right lower zone bronchial wall thickening.

Fig. 2 CT of the thorax showing sub-pleural nodules which are related to the septa, smooth interlobular septal thickening and a small left pleural effusion.

Proceedings of Singapore Healthcare  Volume 20  Number 4  2011

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Case Report Table 1. Comparison of Lung Function Tests 15 Years Apart Age 20

Age 35

Parameter

Absolute

Predicted

Absolute

Predicted

FEV1 (L)

2.18

69%

1.87

74%

FVC (L)

2.54

65%

2.3

74%

FEV1/FVC

86%

RV (L)

1.05

75%

1.83

143%

TLC (L)

3.59

72%

3.29

90%

DLCO (mmol/ min/kPa)

5.83

92%

5.84

80%

79%

Fig. 3. H&E stain (low power) demonstrating an increased number of interconnecting lymphatic spaces of different sizes within the interlobular septum (L). Adjacent normal alveolated lung parenchyma is seen (A).

nodules in the right middle and lower lobes with thickened interstitial lines at the peripheries (Fig. 2). There were no cysts. Pulmonary function tests (PFT) showed an FEV1 of 1.87L (74% predicted), FVC of 2.36L (74% predicted) and FEV1/FVC ratio of 79%. The residual volume was within the upper limit of normal, and the apparent increase may be due to technical issues such as incomplete exhalation. The percentage predicted PFT values were relatively unchanged compared to the previous PFT that was performed 15 years earlier (Table 1). The patient underwent a video-assisted thoracoscopic lung biopsy of the pulmonary nodules in the right lung (Fig. 3: “L” denotes lymphatics, “A” denotes alveoli). Sections of the lung showed an increased number of interconnecting and arborising lymphatic channels within the interlobular septa and pleura as well as within

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the bronchovascular bundles. In some foci, these vascular spaces were associated with small bundles of smooth muscle which were positive for smooth muscle actin (SMA) and negative for HMB45 immunohistochemical stains, in keeping with a normal smooth muscle phenotype. What Is The Diagnosis? Chylothorax secondary to diffuse pulmonary lymphangiomatosis. DISCUSSION Chylothorax is an uncommon type of pleural effusion. The usual causes can be grouped into four categories: trauma (including surgery), malignancy, miscellaneous disorders and idiopathic. Older case series reflect lymphoma being the most common cause, followed by traumatic injury to the thoracic duct. A recent retrospective study of 203 patients


A Pleural Effusion with an Unusual Cause Table 2. Causes of Chylothorax in 203 Patients at Mayo Clinic1 Cause

Number

%

Surgery or Trauma

101

49.8 16.7

Malignancy

34

Lymphoma

23

Chronic Lymphocytic Leukaemia

5

Other

6

Chylous Ascites

16

7.9

Congenital or Acquired Lymphatic Disorders

25

12.3

Pulmonary Lymphangioleiomyomatosis

6

Other

19

Miscellaneous

14

6.9

Unknown

13

6.4

with chylothorax at Mayo Clinic1 showed that surgery or trauma accounted for 49.8% of cases, while lymphoma accounted for 11.3% (Table 2, see overleaf ). In this patient, who had a non-traumatic chylothorax, differentials we considered included lymphoma, congenital or acquired lymphatic disorders (lymphangiomas, lymphangiectasis, lymphangiomatosis, lymphangioleiomyomatosis, yellow nail syndrome), other malignancies (chronic lymphocytic leukemia, lung cancer), granulomatous infection, chylous ascites, thoracic irradiation and subclavian venous thrombosis. The last three differentials were excluded by virtue of the clinical presentation, and lung biopsy helped us confirm our diagnosis to be that of pulmonary lymphangiomatosis.

Primary lymphatic disorders of the lung are rare. There are four main types seen in clinical practice:2 1. Pulmonary lymphangioma — a local lymphatic defect comprised of focal proliferations of well differentiated lymphatic tissue which are usually found in the head, neck, axilla and rarely in the mediastinum or lung parenchyma. 2. Congenital lymphangiectasia — pathologically dilated lymphatic vessels in their own normal anatomic locations. 3. Pulmonary Lymphangiomatosis — similar to lymphangiectasis but with larger numbers of lymphatic channels involved. 4. Lymphangioleiomyomatosis (LAM) — diffuse lymphatic proliferation along with the proliferation

of modified smooth muscle cells. It presents generally as discrete bilateral cystic spaces in the lung parenchyma and occurs almost exclusively in females who are of childbearing age. The incidence of pulmonary lymphangiomatosis is not known. Any tissue with lymphatics may be involved. However, it has a tendency to involve the neck and thorax. Skeletal involvement occurs up to 75% of cases.2 Faul et al described no gender preference, with late childhood as the most frequent age of presentation.2 Alvarez et al3 reviewed the published cases with pulmonary lymphangiomatosis and detailed a case series of 53 patients of which 74% were male and 70% occurred in the first two decades. Interestingly, the spleen was involved in 19% and disseminated intravascular coagulopathy was found in nine per cent of patients. Only four per cent had skin lesions. These series indicate that pulmonary lymphangiomatosis is frequently associated with other organ involvement, has a poor prognosis and frequently results in progressive respiratory failure. Symptoms described include cough, wheeze, pain and dyspnoea. Worse prognosis was observed among the younger patients and those with pleural and lung involvement. Other manifestations of lymphangiomatosis include pericardial effusion and protein losing enteropathy which our patient possibly had when she was younger. Pulmonary function tests may show either a restrictive pattern or a mixed obstructive and restrictive pattern, bearing in mind chylous pleural effusions can further diminish lung function.


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Case Report

Diffuse pulmonary lymphangiomatosis is defined as bilateral lung involvement without evidence of extrathoracic disease. In our patient, her earlier pericardial effusion and her episodes of malabsorption are suggestive of lymphatic disorders elsewhere, although these were not proven by biopsy and their apparent complete resolution is hard to explain. In addition, she has bilateral lung involvement as evidenced by a left-sided chylothorax and histologically proven lymphangiomatosis from the right lung. Most series seem to indicate that the prognosis for lymphangiomatosis is dismal. However in the case series by Alvarez et al,3 six out of 53 patients were more than 40 years old at diagnosis. This is despite the disease being thought of as a congenital developmental disorder. Our patient seems to have a more indolent form of the disease as she was relatively asymptomatic. Moreover, it is rare to find pulmonary function data 15 years apart and it has remained relatively stable. One would have expected deterioration when there is progressive growth of the anastomosing lymphatic vessels with obliteration of the lung parenchyma. Given her rather incidental presentation, it is tempting to suggest that the condition may be under-diagnosed and more common than previously reported. Multiple treatment options for pulmonary lymphangiomatosis have been attempted with varying degrees of success. Non-surgical measures include medium chain triglyceride diet,3 alphainterferon,4 thalidomide5 and radiotherapy.6,7 In patients with large symptomatic chylothorax, repeated pleurocentesis, thoracoscopic thoracic duct ligation and pleurodesis have been reported.3 Other measures include pleurodectomy,3 8 pulmonary lymphangiectomy and more recently, bilateral lung transplant.9 Unfortunately the rarity of the disease can only allow for limited case series and no definitive treatment has been found thus far. Taking into account the enormous advances made in LAM over the last 10 years, it may be worthwhile devoting similar research efforts to lymphangiomatosis to identify potential avenues of treatment. As for our patient, the management plan currently includes a medium chain triglyceride diet for control of the chylothorax. Pleurocentesis will be considered if a clinically significant chylothorax accumulates. Although pregnancy is well

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reported to cause more complications such as pneumothorax and chylothorax in LAM, pulmonary lymphangiomatosis is bereft of such literature. Nevertheless, the issue of childbearing will be discussed with the patient. RADIOLOGIC DISCUSSION Chest radiograph features typically include bilateral interstitial infiltrates, pleural and pericardial effusions. Diffuse smooth thickening of interlobular septa and bronchovascular bundles with infiltration of mediastinal fat and perihilar infiltration on CT of the thorax were found by Swensen et al10 in a case series of eight patients. Although the infiltration can be extensive, mass effect on mediastinal structures is uncommon. Thickening of both the visceral and parietal pleura as well as ground glass opacities have also been described. Our patient did have septal thickening on CT but the other striking finding on the CT was that of subpleural nodules. These are likely to correspond to conglomerations of proliferated lymphatics. In contrast, CT of patients with lymphangioleiomyomatosis will characteristically have diffuse bilateral thin-walled cysts of varying sizes which are not present in this patient. PATHOLOGIC DISCUSSION Histopathology shows prominent proliferating and anastomosing endothelial lined spaces along pulmonary lymphatic routes. These are accompanied by asymmetrically spaced bundles of spindle cells which correspond to fibroblasts and some normal smooth muscle fibres. Differentiating features from pulmonary lymphangiectasis are the increased number of complex anastomosing vessels with secondary dilatation in diffuse pulmonary lymphangiomatosis, rather than dilatation of preexisting lymphatic capillaries in lymphangiectasis. The smooth muscle cells present in the lesions of LAM, are positive for smooth muscle actin (SMA). However, they show an unusual morphology which can be spindle and epitheloid as well as delicately vacuolated and demonstrate aberrant positive reaction for HMB45 (a melanocytic marker), while the smooth muscle fibres seen in lymphangiomatosis are positive only for SMA. These markers, the typical histomorphology and the clinical-radiologic picture helped to differentiate lymphangiomatosis from LAM in our patient. Other differentials include hemangiomatosis, pulmonary involvement by Kaposi sarcoma and kaposiform hemangioendothelioma.11


A Pleural Effusion with an Unusual Cause

CONCLUSION Lymphangiomatosis can occur in adult patients and is a differential to consider in a patient presenting with chylothorax and interstitial infiltrates. REFERENCES

1. Doerr CH, Allen MS, Nichols FC 3rd, Ryu JH. Etiology of chylothorax in 203 patients. Mayo Clin Proc 2005;80(7):867-70. 2. Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD et al. Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 2000;161:1037-46. 3. Alvarez OA, Kjellin I, Zuppan CW. Thoracic lymphangiomatosis in a child. J Pediatr Hematol Oncol 2004;26(2):136-41. 4. Ozeki M, Funato M, Kanda K, Ito M, Teramoto T, Kaneko H et al. Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature. Pediatr Hematol Oncol 2007;24(7):513-24. 5. Pauznar R, Mayan H, Waizman A, Rozenman J, Farfel Z. Successful thalidomide treatment of persistent chylous pleural effusion. Ann Intern Med 2007;146(1):75-6. 6. Kandil A, Rostom AY, Mourad WA, Khafaga Y, Gershuny AR, el-Hosseiny G. Successful control of extensive thoracic lymphangiomatosis by irradiation. Clin Oncol 1997;9:40711. 7. Bermejo Casero EJ, Mongil Poce R, Arrabal Sánchez R, Fernández de Rota Avecilla A, Benítez Doménech A, Fernández Bermúdez J. Diffuse thoracic lymphangiomatosis: diagnosis and treatment. Arch Bronconeumol 2004;40(12):599-601. 8. Steinacher I, Lamprecht B, Lobendanz M, Zoller H, Dartevelle P, Fadel E et al. Successful surgical treatment of thoracic multiorgan lymphangiomatosis. Wein Klin Wochenschr 2009;121(19-20):644-7. 9. Kinnier CV, Eu JP, Davis RD, Howell DN, Sheets J, Palmer SM. Successful bilateral lung transplant for lymphangiomatosis. Am J Transplant 2008;8(9):1946-50. 10. Swensen SJ, Hartman TE, Mayo JR, Colby TV, Tazelaar HD, Muller NL. Diffuse pulmonary lymphangiomatosis. J Comput Assist Tomogr 1995;19(3):348-52. 11. Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Langston C, Colby TV. Diffuse pulmonary lymphangiomatosis. Hum Pathol 1993;24(12):1313-22.


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