Intrathoracìc Lymphangiomatosis Mimicking Lymphangioleiomyomatosis in a Young Woman

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1 «'...' I>' -Vi f i / ί*> * »\ **, t» <» ""' ί -i Intrathoracìc Lymphangiomatosis Mimicking Lymphangioleiomyomatosis in a Young Woman DARRELL W. SWANK, Ph.D., M.D., Department of Laboratory Medicine and Pathology; NORMAN G. G. HEPPER, M.D.,* Division of Thoracic Diseases and Internal Medicine; KEITH E. FOLKERT, M.D., University of North Dakota, Minot, North Dakota; THOMAS V. COLBY, M.D., Division of Pathology In this report, we describe a case of lymphangiomatosis that mimicked lymphangioleiomyomatosis in a 20-year-old woman. Lung biopsy specimens showed proliferation of anastomosing lymphatic channels in the visceral pleura and dilated peribronchiolar and septal lymphatic channels. During 8 years of follow-up, this process behaved like lymphangioleiomyomatosis with reticulonodular infiltrates and worsening obstructive and restrictive changes evident on pulmonary function tests. Chylous pleural effusion in a young woman may have various causes. The leading cause is trauma. Other potential etiologic factors are tumors, granulomatous disease, and iatrogenic intervention. Less likely causes include parasitic infections, anatomic anomalies of the lymphatic system, and lymphangioleiomyomatosis. In this report, we describe an unusual and possibly unique case of pleural and pulmonary lymphangiomatosis that simulated lymphangioleiomyomatosis clinically. REPORT OF CASE In October 1980, a 20-year-old woman had sought medical attention because of a 3-month history of easy fatigability, a feeling of heaviness in the chest, nonproductive cough, and mild dyspnea on exertion. A review of her history showed that *Emeritus staff. Address reprint requests to Dr. T. V. Colby, Division of Pathology, Mayo Clinic, Rochester, MN Mayo Clin Proc 64: , she had never smoked, had had chickenpox in 1978, and was taking oral contraceptives. Prior chest roentgenograms were not available. The patient had bibasilar lung infiltrates and a chylous pleural effusion on the right, and thoracentesis yielded 200 ml of chylous fluid. A lymphangiogram showed normal abdominal lymph nodes but lymphatic obstruction at the upper thoracic level and filling of irregular, subpleural spaces. Mediastinoscopy disclosed grossly dilated lymphatic channels in the right side of the mediastinum, which oozed 50 to 60 ml of chyle when traumatized. The left side of the mediastinum appeared normal. The thymus was histologically normal on biopsy. The patient was referred to our institution for further diagnostic studies. On initial examination, she weighed 63.6 kg and her vital signs were normal. The base of the right lung was dull to percussion, but her lungs were normal to auscultation. A prominent S 2 was heard at the base of the heart (aortic more than pulmonary) in conjunction with inspiratory splitting. The results of urinalysis, routine

2 Mayo Clin Proc, October 1989, Vol 64 INTRATHORACIC LYMPHANGIOMATOSIS 1265 blood and serum lipid studies, serum protein electrophoresis, and serum thyroxine studies were normal. Chest roentgenography revealed reticulonodular infiltrates in the lower lung fields and a small right pleural effusion. The heart was normal, and no masses or pneumothorax was present (Fig. 1). Results of pulmonary function tests at the time of initial examination are shown in Table 1. No significant changes in flows or volumes were noted after bronchodilation. Thoracentesis yielded 60 ml of fluid that was chylous on biochemical analysis and did not show malignant cells. Cultures were negative for mycobacteria, fungi, yeast, and bacteria. Bronchoscopy revealed milky-appearing secretions throughout both sides of the tracheobronchial tree, particularly in the lower lobes. No endobronchial lesions were seen. A right-sided thoracotomy demonstrated approximately 300 ml of a chylous-appearing fluid. On biopsy of the lung, chylous fluid exuded. The mediastinum was boggy with fluid. The thoracic duct was not identified, and no abnormal nodes were palpated. The diaphragmatic surface of the lower lobe, mediastinal pleura, pleura of the basilar part of the lung, and pericardium were granular and dark. The pleural surfaces were abraded to produce adhesions. A wedge resection of the right lower lobe and a biopsy of the pericardium were performed. The sections showed an abnormal proliferation of nonectatic, anastomosing lymphatic channels in the visceral pleura (Fig. 2). The walls between the lymphatic channels were composed of mature collagen and variable amounts of elastic tissue but no smooth muscle. The peribronchial and septal lymphatic channels were dilated but not increased in number. The cells lining the lymphatic spaces stained positively for factor VIII and negatively for epithelial membrane antigen, and they were interpreted as endothelial cells. The pleura was also infiltrated by moderate numbers of lymphocytes and plasma cells. The pericardial biopsy specimen revealed lymph stasis and pooling of lymphatic fluid within dilated lymphatic channels. Fig. 1. Chest roentgenogram, showing bilateral basilar reticulonodular infiltrates and right pleural effusion. The patient was dismissed from the hospital, and a low-fat diet emphasizing medium-chain triglycérides was recommended in an effort to control the chylous effusion. Her cough persisted, she lost weight, and the pleural fluid reaccumulated and necessitated aspiration of about 1,000 ml by her personal physician in February Roentgenograms of the chest in April and May disclosed a large, right-sided pleural effusion. In June 1981, therapy with medroxyprogesterone acetate (400 mg administered intramuscularly monthly) was initiated. Roentgenograms obtained in September and December showed progressive diminution of the pleural effusion. Her cough subsided, she regained weight, and she felt well. The patient has been examined annually. She neither smoked nor resumed use of oral contraceptives. The administration of progesterone was discontinued after 4 years. During this time, she had only minimal dyspnea, but she did have lower abdominal discomfort, presumably from pelvic congestion. The chest roentgenographic findings did not change noticeably, ex-

3 1266 INTRATHORACIC LYMPHANGIOMATOSIS Mayo Clin Proc, October 1989, Vol 64 Table 1. Results of Pulmonary Function Tests Before and After Operative Intervention in a Young Woman With Intrathoracic Lymphangiomatosis Test Predicted 1981* Total lung capacity (L)t Forced vital capacity (L) Forced expiratory volume in 1 second (L) Forced expiratory flow, 25-75% (L/s) Maximal voluntary ventilation (L/min) Diffusing capacity for CO (ml/min per mm Hg) *Preoperative values. tnitrogen washout method cept that only thickened pleura remained in the base of the right lung. In 1985, a computed tomographic scan of the lungs revealed relatively diffuse reticulonodular infiltrates throughout both lungs but greater in the bases (Fig. 3). The mediastinum and retroperitoneal space showed a diffuse infiltrative process that substantially changed the density of the normal fat and had the appearance of lymphangiomatous adenopathy combined with chylous engorgement of perinodal fat. She was last examined in January 1988, 2V2 years after the use of progesterone had been discontinued. Although she complained only of mild dyspnea, the degree of measurable airway obstruction had worsened and the diffusing capacity of the lungs for carbon monoxide had decreased (Table 1). DISCUSSION Once an abnormality of the lymphatic system was recognized grossly and biopsy of the lung excluded other causes, the differential diagnosis of the chylous pleural effusions in this case included lymphangiectasis, lymphangioleiomyomatosis, and lymphangiomatosis (Table 2). Fig. 2. Proliferation of nonectatic, anastomosing lymphatic channels (arrows) in visceral pleura. (Hematoxylin and eosin.) A, At low magnification. B, At high magnification.

4 Mayo Clin Proc, October 1989, Vol 64 INTRATHORACIC LYMPHANGIOMATOSIS 1267 Pig. 3. Computed tomographic scan of lungs, showing bilateral basilar reticulonodular infiltrates and diffuse infiltrative process of mediastinum and retroperitoneal space. According to Noonan and associates, 1 pulmonary lymphangiectasis may manifest as a primary developmental defect of the lung, as a generalized lymphangiectasis associated with visceral lymphangiomas and hemangiomas, or as a result of chronic pulmonary venous obstruction. Both generalized and primary types of pulmonary lymphangiectasis occur almost exclusively in infants and young children 26 and are uniformly fatal. In a report by Wagenaar and colleagues, 7 however, the primary type was described in three young adults, one of whom Table 2. Definitions of Various Abnormalities of Pulmonary Lymphatic Structures Term Lymphangiectasis Lymphangioleiomyomatosis Lymphangioma or lymphangiomatosis Definition Nonproliferative, dilated, normal lymphatic structures Disorderly proliferation of smooth muscle cells, often arising from walls of lymphatic structures Proliferation of lymphatic channels; no smooth muscle cell proliferation was 19 years old. Histologically, dilated lymphatic channels were identified along bronchovascular bundles and in interlobular septa and the pleura. Pulmonary lymphangioleiomyomatosis occurs only in women and almost exclusively during the reproductive years. Oral contraceptive agents have been implicated as a possible etiologic or exacerbating factor. Clinically, progressive dyspnea, chylous pleural effusions, or recurrent pneumothoraces develop. Histologically, a disorderly fascicular proliferation of immature smooth muscle cells, some arising from the walls of the lymphatic system, leads to a progressive obstruction of the airways, emphysema, and airspace enlargement. In our patient, the absence of smooth muscle proliferation distinguished the disorder from lymphangioleiomyomatosis. Lymphangiomatosis (including lymphangiomas) occurs primarily in newborns, infants, and young children. The head and neck regions are usually involved, but lymphangiomatosis also may occur in the mediastinum or retroperitoneum. The lesions usually are cavernous or cystic. Histologically, a proliferation of anastomosing lymphatic channels lined by flattened endothelial cells and a variable infiltrate of lymphocytes are seen. 8,9 We believe that our case is an example of primary pulmonary lymphangiomatosis and concomitant involvement of the mediastinum and pericardium, together with secondary lymphangiectasis of intrapulmonary lymphatic structures. The case is unusual because of the age of the patient at the time of initial examination and the sparing of the head and neck regions. Wagenaar reviewed our case and thought it to be an example of pulmonary lymphangiectasis (personal communication), similar to his cases. 7 Nevertheless, we think that the pleural and subpleural anastomosing channels in our case are indicative of a lymphangiomatous proliferation rather than simply being dilated, normal lymphatic structures (that is, lymphangiectasis). Deeper in the biopsy specimen, however, ectasia of normal lymphatic channels in septa and along bronchovascular bundles was

5 1268 INTRATHORACIC LYMPHANGIOMATOSIS Mayo Clin Proc, October 1989, Vol 64 present. The distinction may, in part, be semantic and only of academic interest. Because of the age of the patient, the history of use of oral contraceptive agents, the chylous pleural effusions, and her clinical course, pulmonary lymphangioleiomyomatosis was a leading diagnostic consideration. The computed tomographic scan, however, revealed a nodular process rather than the characteristic cystic changes seen with lymphangioleiomyomatosis. Neither cystic lesions nor smooth muscle proliferation was seen histologically. Nevertheless, treatment for lymphangioleiomyomatosis was tried, including administration of progesterone for 4 years. Coincidental with or causally related to the administration of progesterone, the chylous effusions ceased to be a problem. During 8 years of follow-up, however, the patient continued to have deterioration in pulmonary function. REFERENCES 1. Noonan JA, Walters LR, Reeves JT: Congenital pulmonary lymphangiectasis. Am J Dis Child 120: , 1970 Hernandez RJ, Stern AM, Rosenthal A: Pulmonary lymphangiectasis in Noonan syndrome. AJR 134:75-80, 1980 France NE, Brown RJK: Congenital pulmonary lymphangiectasis: report of 11 examples with special reference to cardiovascular findings. Arch Dis Child 46: , 1971 Brown MD, Reidbord HE : Congenital pulmonary lymphangiectasis. Am J Dis Child 114: ,1967 Li Y-W, Snow J, Smith WL, Franken EA Jr: Localized pulmonary lymphangiectasia. AJR 145: ,1985 Lloyd ES, Press HC Jr: Congenital pulmonary lymphangiectasis. South MedJ 72: ,1979 Wagenaar SS, Swierenga J, Wagenvoort CA: Late presentation of primary pulmonary lymphangiectasis. Thorax 33: , Balbaa A, Chesterman JT: Neoplasms of vascular origin in the mediastinum. Br J Surg 44: , Goetsch E: Hygroma colli cysticum and hygroma axillare. Arch Surg 36: , 1938