Lymphangioleiomyomatosis

Study objective: Pulmonary lymphangioleiomyomatosis (LAM) is a rare, serious disorder characterized by proliferation of abnormal smooth-muscle cells and affects almost exclusively women of childbearing age. Optimal management of chylothorax, a well-recognized complication of LAM, in these patients has not been defined. This study was performed to characterize the clinical course and identify appropriate management options for chylothorax occurring in patients with LAM.

Design: Identification and retrospective review of available medical records on patients with LAM and chylothorax.

Setting: Tertiary-referral medical center.

Patients: All patients with LAM seen at Mayo Clinic, Rochester, MN, from January 1, 1976, to December 31, 2000.

Intervention: None.

Measurement and results: Eight of 79 patients (10.1%) with LAM had chylothorax. All were women aged 33 to 51 years, and four patients had underlying tuberous sclerosis complex. These eight women represented 3.5% of the 229 patients with chylothorax seen over this 25-year period at Mayo Clinic Rochester. Six patients had unilateral pleural effusion and two patients had bilateral effusions at initial presentation. The size of the chylothorax varied and was not necessarily progressive. Management of chylothorax ranged from thoracentesis only to thoracotomy with thoracic duct ligation and parietal pleurectomy. When needed, pleurodesis by instillation of sclerosing agents or parietal pleurectomy appeared to be effective in controlling chylothorax.

Conclusions: Chylothorax occurring in patients with LAM has a variable clinical course. Although pleurodesis with or without thoracic duct ligation appears to be effective in controlling intractable chylothorax, less invasive treatments such as thoracentesis or observation may suffice in some cases. Management of chylothorax in patients with LAM should be individualized depending on the size and clinical effects of the chylous pleural effusion, as well as comorbid factors and local expertise.

Key words: chylothorax; lymphangioleiomyomatosis; pleural effusion; tuberous sclerosis complex

Abbreviations: HRCT = high-resolution CT; LAM = lymphangioleiomyomatosis; TSC = tuberous sclerosis complex

Pulmonary lymphangioleiomyomatosis (LAM) is a disorder characterized by proliferation of abnormal smooth-muscle cells throughout the peribronchial, perivascular, and perilymphatic regions of the lung. LAM may occur sporadically (noninheritable) or be associated with tuberous sclerosis complex (TSC), an inheritable multiorgan hamartomatosis. (1-3) Studies suggest that approximately one third of women with TSC have LAM. (3-5) In either situation, LAM occurs almost exclusively in women of reproductive age. (1-3,6)

The myoproliferative process of LAM is associated with diffuse, cystic changes in the lung parenchyma. (1,2) Clinical features of LAM include exertional dyspnea, recurrent pneumothoraces, hemoptysis, cough, chest pain, chyloptysis, and chylothorax. (7-11) Chylothorax usually results from obstruction or disruption of the thoracic duet or its tributaries. (12,13) Although chylothorax is a well-recognized complication of LAM, optimal management of this problem has not been defined. Herein, we report eight women with LAM and chylothorax, emphasizing their variable clinical course and management.

MATERIALS AND METHODS

Patients with LAM seen at Mayo Clinic, Rochester, MN, from January 1, 1976, to December 31, 2000, were identified by a computer-assisted search of medical records. In addition, all patients with TSC were identified, and available medical records along with imaging studies were reviewed to identify additional patients with LAM. (3) The diagnosis of LAM required the following: (1) diagnostic histopathologic findings on surgical or bronchoscopic lung biopsy, (2) characteristic high-resolution CT (HRCT) findings of LAM (Fig 1) in patients with known renal angiomyolipomas or extrapulmonary lymphangioleiomyoma, or (3) characteristic HRCT findings of LAM in patients with known TSC. (2)

[FIGURE 1 OMITTED]

A pleural fluid triglyceride level of > 110 mg/dL or the presence of chylomicrons in the pleural fluid defined the presence of chylothorax. (13) The following data were abstracted from available medical records: age at presentation, sex, symptoms, physical signs, presence or absence of TSC, comorbid medical conditions, chest radiography and CT results, pleural fluid findings, lung biopsy results, treatment, complications, and outcomes. Additional follow-up data were obtained by a telephone interview when needed. This study was approved by the institutional review board of Mayo Clinic Rochester.

RESULTS

Seventy-nine patients with LAM were seen at Mayo Clinic Rochester over the 25-year period from January 1, 1976, to December 31, 2000; 25 of these patients had TSC. All were women > 18 years old at the time of the LAM diagnosis, except for one 17-year-old patient. The presence of a pleural effusion had been documented in eight of these patients (10.1%); all of these pleural effusions were chylous. Clinical characteristics and course of these patients are described in Table 1. These patients with chylothorax were 30 to 51 years old (mean age, 40.8 years) when pulmonary LAM was diagnosed and 33 to 51 years old (mean age, 41.1 years) when chylothorax was diagnosed. All were nonsmokers. Four of these eight women with chylothorax had underlying TSC that had been diagnosed up to 26 years before the diagnosis of chylothorax. These eight patients represented 3.5% of the 229 patients with chylothoraces seen over this 25-year period at Mayo Rochester Medical Center.

All eight patients were symptomatic with varying degrees of dyspnea. In addition, one patient described a sudden-onset chest pain accompanying her dyspnea. Chylothorax was bilateral in two patients and unilateral in six patients at presentation. By gross appearance, all pleural fluids were described as milky. Two were blood tinged as well.

None of these eight patients had chyloptysis or chylous ascites during their clinical course, with the exception of one patient who had chylous ascites diagnosed 12 years before the onset of her chylothorax. Four patients had one to three pregnancies, including one patient with TSC-associated LAM. None of these patients were pregnant at the time the chylothorax developed. Pulmonary function data were available in seven of eight patients and revealed normal (two patients) to severe obstruction (one patient). Three patients had a mild restrictive defect; two of these patients had a pleural effusion at the time of testing, and one patient had a prior thoracotomy. One patient had an isolated reduction in diffusing capacity.

CT of the chest, abdomen, and pelvis had been performed in seven of eight patients, and none demonstrated significant lymphadenopathy. However, extensive involvement of kidneys with angiomyolipomas was noted in all four patients with TSC-associated LAM, two of whom had already undergone unilateral nephrectomies for this problem. In one of three patients with sporadic LAM (CT not available in one patient), several tiny low-density lesions consistent with renal angiomyolipomas were seen, but the remaining two patients had normal-appearing kidneys.

Thoracentesis or tube thoracostomy alone was employed in three patients with sufficient control of chylothorax. In three other patients, chemical pleurodesis via chest tube was performed using bleomycin or talc, with no further recurrence of chylothorax in two of these patients. One patient with recurrence of chylothorax after bleomycin pleurodesis (performed elsewhere) underwent thoracotomy with thoracic duct ligation and parietal pleurectomy with no further recurrence. Two remaining patients underwent thoracoscopic surgery or thoracotomy with mechanical or talc pleurodesis, parietal pleurectomy, or thoracic duct ligation (Table 1). Neither of these patients had recurrence of chylothorax thereafter.

Progestin therapy in the form of IM medroxyprogesterone acetate injections (usually administered at a dosage of 400 mg once per month) was included in the initial treatment regimen for five patients with LAM and chylothorax. In three of these patients, chyle continued to reaccumulate despite progestin therapy of 8 to 12 months in duration (Table 1). A low-fat diet was tried in two patients, but its therapeutic effects were difficult to assess.

DISCUSSION

Chylothorax and pneumothorax are two major complications of LAM. Pneumothorax is more common and is noted in 39 to 53% of patients at presentation and in 60 to 81% of patients during the course of disease. (1,2,7-11) The occurrence of chylothorax has been described in patients with sporadic LAM, as well as in patients with TSC-associated LAM. (1,2,14,15) Pleural effusions occurring in patients with LAM are nearly always chylous. (1,2,9,14,16) Previous reports have suggested that LAM-associated chylous effusion is more often unilateral than bilateral as seen in the current case series. (14,16)

Chylothorax has been described in 0 to 14% of patients with LAM at presentation (7-10,17,18) and in 22% to 39% during the course of the disease. (7,9-11,12) In our series, the frequency of chylothorax in patients with LAM was 10%. Less commonly, patients with LAM may manifest chylous ascites and chyluria. (12,14,19) The mean age of our patients with LAM and chylothorax was 41.1 years, similar to that reported by Urban and colleagues. (10) This is several years later than the mean age at symptom onset for women with LAM (ie, 34 years). (1,2) The occurrence of chylothorax in our patients did not appear to correlate with the severity of lung involvement, history of pregnancies, degree of renal involvement with angiomyolipomas, or the presence of lymph node involvement detectable by CT.

Three main mechanisms of chylothorax formation in LAM include the following: (1) chyle leak (secondary to proximal lymphatic obstruction or direct involvement) from the thoracic duct or its tributaries, (2) general oozing from pleural lymphatics or collateral vessels, and (3) transdiaphragmatic flow of chylous ascites. (12,16,20) Lymphangiography and thoracotomy in patients with LAM and chylothorax have demonstrated obstruction to lymphatic flow at various levels that is associated with dilated lymphatic channels and chyle leaking from the thoracic duct, the mediastinal pleura, lung surface, and diaphragmatic surface. (12,16,21,22) Lymphangiomyomatous process often directly involves the thoracic duct. (12,14,20,23) In the lungs, there may be proliferation of atypical smooth muscle cells in the perilymphatic areas.

Although earlier reports emphasized a progressive course with repeated episodes of chylous effusion and/or chylous ascites, (14) more recent series have demonstrated a variable course including some patients who required no therapeutic intervention for their chylothorax. (9,11) Spontaneous improvement in chylothorax was seen in one patient with LAM. (22)

Management of chylothorax, in general, is tailored to the underlying cause and individual patient's circumstances. (13) Those patients with chylothorax associated with tumors, such as lymphoma, or infections should have their underlying cause treated. In contrast, chylothorax associated with esophagectomy and persistently high chest tube drainage should be managed by early surgical intervention. (13)

The optimal method of managing chylothorax in LAM has been problematic. A low-fat diet alone with or without supplementation with medium-chain triglycerides has generally been unsuccessful in controlling chylothorax. (11,16,24,25) Hyperalimentation may decrease the rate of chylous leak. Repeated thoracenteses have been used to control reaccumulation of chylothorax in some patients with LAM, although most of these patients eventually require chemical pleurodesis or surgical procedures. (16,23-26) Diuretic therapy was used in the 1970s and provided variable benefit in controlling the amount of chylothorax. (16,23,27) Irradiation of the thoracic duct or the mediastinum was performed in a few cases with no consistent effect. (16,20,23,28-30)

Chemical (17,20,23,27,31,32) or mechanical pleurodesis (24,32-34) has been largely successful in preventing recurrent pleural effusion. Sclerosing agents used for pleurodesis have included nitrogen mustard, tetracycline, and talc. (2,26,27) Similarly, parietal pleurectomy has also been usually effective. (16,23,33) In our series, pleurodesis or pleurectomy was effective in controlling chylothorax in four of five patients. Although pleural adhesions may make future lung transplant procedures more complicated, previous bilateral pleurodesis does not represent an absolute contraindication to subsequent lung transplantation. Bleeding is the most serious complication in transplantation following pleurodesis. (35) In cases of unilateral pleurodesis, single-lung transplantation can be performed on the contralateral side. (35) Pleurodesis or pleurectomy should be considered for symptomatic chylothorax that continues to reaccumulate after therapeutic thoracentesis. (2,9)

Thoracic duct ligation has been used for the past 40 years in the treatment of chylothorax in LAM. (13,20,23,26,29,31) Ligation of the thoracic duct is performed close to the diaphragm and has generally been used in conjunction with pleural abrasion and/or parietal pleurectomy. (16) Although thoracic duct ligation is usually successful in controlling chylothorax, there are reports of recurrence following the procedure. (23) In addition, a few patients have died after thoracic duct ligation. (31) Excision of the thoracic duct or the mediastinal lymph node masses has uncertain therapeutic value in the control of chylous effusions in patients with LAM. (12,16,23)

Johnson and Tattersfield (11) reported 11 patients in their case series of 50 patients with LAM who acquired chylous pleural effusions during the course of their disease. Two patients with small effusions required no intervention. The remaining nine patients were treated initially by thoracentesis or chest tube. Seven of these patients needed further procedures including pleurodesis via chest tube or thoracoscopy (three patients), pleurectomy (two patients), and pleurodesis, pleurectomy, and thoracic duct ligation (two patients).

In our case series and others, progesterone treatment was used as an adjunct to other treatments in these patients with LAM and chylothorax. It is difficult to determine whether this medical intervention was of benefit due to the relatively small number of patients, inconsistent results, and other concomitant therapeutic procedures used in these patients.

We conclude that chylothorax occurring in patients with LAM is more often unilateral than bilateral at initial presentation and has a variable clinical course. Thus, the management of chylothorax should be tailored to the size and clinical effects of the chylous pleural effusion, as well as comorbid factors and the availability of physicians with expertise in managing chylothorax. Thoracentesis or observation alone may suffice in managing some cases of chylothorax. When needed, pleurodesis by instillation of sclerosing agents or parietal pleurectomy, with or without thoracic duct ligation, appears to be effective in controlling intractable chylothorax.

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Jay H. Ryu, MD FCCP; Clint H. Doerr, MD; Susan D. Fisher, RN; Eric J. Olson, MD, FCCP; and Steven A. Sahn, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Ryu, Doerr, and Olson, and Ms. Fisher), Mayo Clinic, Rochester, MN; and Pulmonary and Critical Care Medicine Division (Dr. Sahn), Medical University of South Carolina, Charleston, SC.

Funding was provided by Mayo Institutional funds and Robert N. Brewer Family Foundation.

Manuscript received January 29, 2002; revision accepted June 5, 2002.

Correspondence to: Jay H. Ryu, MD, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St, SW, Rochester, MN 55905

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