Pleural Effusion Associated with Primary Lymphedema: A Perspective on the Yellow Nail Syndrome2 DENNIS J. BEER, WLADEMIR PEREIRA, JR., and GORDON L. SNIDER
SUMMARY A 28-year-old woman with bilateral pleural effusions and generalized, primary lymphedema beginning with facial erysipelas at 6 years of age is presented. T h e pleural effusions were exudates with 250 cells per mm3, 92 per cent of which were lymphocytes. Lymphatic stasis was demonstrated by persistence of the blue dye in the dorsa of her feet 3 months after a lymphangiogram of both lower extremities, pelvis, and abdomen. Her nails were not remarkable. Our patient represents the twentieth recorded case of pleural effusion in association with primary lymphedema. Women have been afflicted more than twice as often as men, and the age of onset has varied from birth to the eighth decade. Yellow dystrophic nails may precede or follow lymphedema or the pleural effusion and have occurred in onlv 11 of the 20 patients.
Introduction I n t h e past 15 years, p l e u r a l effusion, primary lymphedema, a n d yellow dystrophic nails have been r e p o r t e d in various combinations usually combined u n d e r t h e term "yellow nail synd r o m e " (1-10). T h i s term is u n f o r t u n a t e because, as the case r e p o r t e d h e r e a n d others collected from t h e literature illustrate, primary l y m p h e d e m a a n d p l e u r a l effusion frequently exist w i t h o u t changes in the nails ( 1 - 3 , 6, 9). I n this p a p e r we will describe the twentieth recorded case of primary l y m p h e d e m a a n d pleural effusion; we will summarize the available literature a n d place these clinical entities in p r o p e r perspective. Case Report A 28-year-old white, unmarried woman came to us in August 1977 for evaluation of bilateral pleural
(Received in original form October 25, 1977 and in revised form December 9,1977) 1 From the Department of Medicine, Boston Veterans Administration Hospital, University Hospital, and Boston University School of Medicine. 2 Supported in part by Program Project Grant No.
effusions of 8 months' duration. At the age of six and one half years, she developed recurrent episodes of erysipelas involving her face. When she was 14 years of age, these episodes subsided, and she noted swelling of her lower extremities, hands, and abdominal wall in addition to facial edema. Her hands and face were more swollen in the morning and improved as the day progressed; the leg swelling was significantly worse later in the day and during the later part of her menstrual cycles. Body edema was not constant, with her weight varying by as much as 10 kg during a period of several months. In January 1967, she underwent plastic surgery for correction of persistent upper and lower eyelid edema. Later that year, she had chest pain, dyspnea, cough productive of sputum, and fever. A diagnosis of pleurisy was made, and she was treated with isoniazid, streptomycin, and para-aminosalicylic acid for 3 months. During subsequent years, she felt well except for the persistence of generalized swelling and one episode of erysipelas involving one leg. In December 1976, she noticed dyspnea on exertion. A chest roentgenogram revealed bilateral pleural effusions, greater on the right side than on the left. At that time she had no other respiratory symptoms, fever, weight loss, gastrointestinal symptoms, rash, or arthralgia. There
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was no history of cardiac, renal, or hepatic disease. A short course of treatment with corticosteroids was of no benefit. Intermittent diuretic therapy provided modest relief of edema. When examined in August 1977, the patient appeared normal except for mild facial edema and a small ectropion of the right eye. There was mild pitting edema over her legs, sacrum, sternum, face, and iliac crest. Her fingernails and toenails were not remarkable. Blue dye stains from the previous lymphangiogram, done on May 20, 1977, remained visible on the dorsa of her feet. Her breasts were normal and of equal size. Percussion of the chest showed bilateral dullness posteriorly with decreased transmission of voice and breath sounds; these findings extended superiorly to just below the seventh rib on the right side, and to below the eighth rib on the left. Findings during the remainder of the physical examination were normal. Laboratory investigation revealed a normal urinalysis and hemogram. T h e white blood cell count was 7,000 cells per mm3 with 68 per cent polymorphonuclear cells, 3 per cent band forms, 24 per cent lymphocytes, and 1 per cent monocytes. Serum transaminases, bilirubin, lactic dehydrogenase, alkaline phosphatase, urea nitrogen, creatinine, cholesterol, triglycerides, thyroxine, triidothyronine resin uptake, and protein electrophoresis were normal. Serum complement and quantitative immunoglobulins were normal. Latex fixation, antinuclear antibody, and cryoglobulin tests were negative. Pelvic pneumoperitoneum, upper gastrointestinal series with small bowel follow-through, and a lower extremity and abdominal lymphangiogram were all within normal limits. A computerized tomographic scan of the chest was remarkable only for bilateral pleural effusions and showed normal mediastinal structures. Pulmonary function tests, with per cent of predicted values in parentheses, were as follows: vital capacity, 2.80 liters (74); total lung capacity, 3.29 liters (71); residual volume, 1.12 liters (63); forced expiratory volume in 1.0 sec, 2.17 liters (70); ratio of forced expiratory volume in 1.0 sec to forced vital capacity, 0.76; forced mid-expiratory flow, 2.10 liter per sec (45); and single breath diffusing capacity, 21 ml per mm Hg per min (89). T h e pleural fluid was clear and yellow. Chemical studies showed a protein concentration of 4.7 g per 100 ml, glucose concentration of 100 mg per 100 ml, 70 IU of lactic dehydrogenease, and 74 IU of amylase. T h e cell count was 250 cells per mm3 with 92 per cent lymphocytes. Routine bacterial smears and cultures and acid fast smears and cultures were negative. Cytologic examination of the fluid was negative for tumor cells, and lupus erythematous cells were not seen. Pleural biopsies done on 5 occasions showed only nonspecific inflammation.
Discussion Allen a n d associates (11) a n d K i n m o n t h
and
co-workers (12) divide primary l y m p h e d e m a into 3 categories on the basis of the patient's age at onset of edema. T h e r e is congenital lymphedema with onset at b i r t h (this includes Milroy's disease, a congenital familial type of lymphedema), l y m p h e d e m a praecox with onset before 35 years of age, a n d l y m p h e d e m a tarda with onset after age 35. O u r p a t i e n t fell into the category of l y m p h e d e m a praecox. Interestingly, she suffered from erysipelas before d e v e l o p m e n t of overt l y m p h e d e m a . It is well recognized that patients with a congenital a b n o r m a l i t y of the lymphatic vessels often d o n o t exhibit persistent l y m p h e d e m a u n t i l after some infection or other injury has strained the already deficient lymphatics (1). Studies of edematous fluid h a v e confirmed a large c o n t e n t of p r o t e i n (13), a n d investigations using iodine-131 a l b u m i n have shown defective removal of the labeled p r o t e i n from l y m p h e d e m a t o u s limbs (13-15). T h e latter observation is in contrast to the increased removal of subcutaneously injected iodine-131 a l b u m i n in patients with congestive h e a r t failure, h y p o p r o t e i n e m i a , or venous obstruction (14). T h e lymphatic vessels of the p l e u r a consist of 2 sets, o n e in the visceral p l e u r a a n d the o t h e r in the parietal pleura. T h o s e of the visceral p l e u r a d r a i n i n t o the superficial efferents of the lung, which t u r n a r o u n d the borders of the lungs a n d the margins of their fissures a n d converge to e n d in the nodes situated in the h i l u m . T h e lymphatic vessels of the parietal p l e u r a have 3 modes of t e r m i n a t i o n : those of the costal p o r t i o n join the intercostal lymphatics a n d so reach the sternal nodes, those of the d i a p h r a g m a t i c p a r t are d r a i n e d by the efferents of the d i a p h r a g m , a n d those of t h e mediastinal p o r t i o n t e r m i n a t e in the posterior mediastinal nodes (16). T h i s intricate network is essential for m a i n tenance of a free p l e u r a l space. Evidence accum u l a t e d thus far suggests t h a t u n d e r n o r m a l conditions fluid is filtered o u t of the parietal p l e u r a l capillaries a n d is absorbed by the visceral pleural capillaries a n d by the l y m p h a t i c vessels. P r o t e i n p a r t i c u l a t e m a t t e r a n d erythrocytes are absorbed solely by the lymphatics (17). Malfunction of the lymphatics secondary to hypoplasia will lead to a c c u m u l a t i o n of p r o t e i n a n d fluid in the pleural space. I n all of the rep o r t e d cases (1-9) of p l e u r a l effusion associated with p r i m a r y l y m p h e d e m a , the accumulated fluid h a d a p r o t e i n c o n c e n t r a t i o n greater t h a n 3 g p e r 100 ml. T h r e e separate d e t e r m i n a t i o n s in o u r p a t i e n t showed a r a n g e of p r o t e i n concen-
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tration from 3.7 to 4.7 g per 100 ml. Emerson (2) was the first to note that a lower respiratory tract or pleural infection may damage previously adequate but impaired lymphatic drainage, and so result in a persistent pleural effusion. Our patient had a lower respiratory infection with transient pleural inflammation approximately 10 years before the development of the present persistent pleural effusion. This situation is analogous to the recurrent erysipelas preceding the facial edema. There is another mechanism responsible for pleural effusion in primary lymphedema. Patients with primary lymphedema may develop some interference with the absorption and circulation of chyle from the intestine. This may show itself clinically as chylous ascites or chylothorax. Kinmonth and associates (18) describe a young man who had lymphedema of the lower extremities and genitalia since childhood with
dyspnea due to a left chylothorax at 22 years of age. At thoracotomy, there was extensive oozing of chyle from the surfaces of the lung hilum and mediastinal pleura. Decortication of the lung surface, combined with covering the oozing surfaces with flaps of pleura and pleurodesis, resulted in cure. Our patient represents the twentieth reported case of primary lymphedema and pleural effusion. A twenty-first case (19) is not included because the pleural lesion was empyemic, and insufficient detail was given to ascertain the chronicity of the pleural effusion. Sex, age at onset of symptoms, and the occurrence of lymphedema, pleural effusion, and yellow nails in the 20 collected cases are listed in table 1. The female-to-male ratio is 7:3. Age at onset of symptoms is variable, ranging from birth to the eighth decade. Lymphedema was usually the first clinical manifestation, but in at
TABLE 1 CLINICAL FEATURES OF PLEURAL EFFUSION ASSOCIATED WITH PRIMARY
Reference Hurwitz and Pinals (1)
E m e r s o n (2)
Dilley eta/. (3)
Sex and Age, (years) a t O n s e t of Symptoms
Pleural L y m p h e - effu- Yellow dema sion Nails
LYMPHEDEMA
Comment
M, birth
decreased serum g a m m a globulin, l y m p h o p e n i a , r e c u r r e n t erysipelas, cor pulmonale
F, birth
l y m p h o p e n i a , r e c u r r e n t erysipelas, H o d g k i n ' s disease, latex f i x a t i o n 1:2560
F, infancy
+
+
0
M, 4 7
+
+
+
F, 2 1
+
+
+
family h i s t o r y of Milroy's disease
M, 2 9
+
+
+
sinusitis, b r o n c h i e c t a s i s l y m p h e d e m a of face
F,43
+
+
0
F, 3 5
+
+
0
malignant melanoma
F, 1 7
+
+
0
D'Souza(4)
F, 3 8
+
+
+
macroglobulenemia
Marks and Ellis (5)
M, 5 3
+
+
+
persistent hypoalbuminemia
H i l l e r e f a / . (6)
F, 5 0
+
+
+
M, 7 1
+
+
+
M, 5 3
+
+
+
F, 3 1
+
+
0
anaplastic t u m o r
E a s t w o o d and Williams (7)
F, c h i l d h o o d
+
+
+
e f f u s i o n d e v e l o p e d in t h e 9th d e c a d e
Dwek and Green berg (8)
F, 2 3
+
+
+
sinusitis
N a k i e l n a e f al. (9)
F, 5 0
+
+
+
sinusitis, b r o n c h i e c t a s i s
Beer, Pereira, and S n i d e r
sinusitis, b r o n c h i e c t a s i s
F, 3 4
+
+
0
a b s e n c e of IgA
F, 1 4
+
+
0
r e c u r r e n t erysipelas
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BEER,
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least 3 cases (3, 6) classic nail findings consisting of cessation of nail growth, yellowish discoloration, smoothness with transverse ridging, curving from side to side, defective cuticles, a n d onycholysis, a n d a characteristic l u m p (10) app e a r e d first. T h e simple message is that w h e n any o n e manifestation of the triad is present, the others should be sought, a n d the p a t i e n t should be followed for their later development. T h i s is best exemplified by the r e p o r t of Eastwood a n d Williams (7) in which a p a t i e n t with lymphedema since childhood did not develop classic nail changes u n t i l the age of 78 years, a n d it was n o t u n t i l her n i n t h decade that p l e u r a l effusion developed. T h e pleural effusions have been bilateral or unilateral, massive or small. Once they have occurred, they t e n d to persist a n d in certain instances reaccumulate w i t h i n days after thoracocentesis. Pleurectomy or instillation of a sclerosing agent i n t o the p l e u r a l cavity has b e e n successful in controlling the p l e u r a l effusion (6). T h e lymphatic vessels in the lower extremities, pelvis, a n d a b d o m e n were n o r m a l in o u r p a t i e n t . T h i s is at variance with the r e p o r t e d experience of K i n m o n t h a n d colleages (12), in which they state that in primary lymphedema, some a b n o r m a l i t y of lymphatic vessels is always observed with r o e n t g e n o g r a p h s or p a t e n t blueviolet d e r m a l lymphangiography. T h e r e can be n o d o u b t , however, a b o u t the lymphatic stasis in o u r p a t i e n t , as d e m o n s t r a t e d by the persistent dye stains o n the dorsa of her feet 3 m o n t h s after l y m p h a n g i o g r a p h y . Only 5 of the r e p o r t e d cases of primary l y m p h e d e m a a n d p l e u r a l effusion h a d l y m p h a n g i o g r a p h y (1, 4, 7, 9). T h e y showed a spectrum of lymphatic abnormalities r a n g i n g from only o n e hypoplastic vessel to gross hypoplasia. T h e r e were n o instances of aplasia or megalymphatics. N i n e of the 20 patients h a d l y m p h e d e m a a n d pleural effusion w i t h o u t nail abnormalities. Yet most authors refer to this complex as the "yellow nail s y n d r o m e " (10). S a m m a n a n d W h i t e (10) first used the term "yellow nail s y n d r o m e " to describe 13 cases of yellow nails. T e n of their patients h a d primary l y m p h e d e m a , whereas the o t h e r 3 were a p p a r e n t l y free of clinical edema. F o u r of their patients were studied by lymphangiography, a n d all h a d lymphatic abnormalities consisting mainly of hypoplasia of the lymp h a t i c system. It is this a b n o r m a l i t y in lymphatics that is p a r a m o u n t . T h e discolored nails, if present, are merely a superficial indicator of an
u n d e r l y i n g defect. H e n c e we suggest the phrase " p l e u r a l effusion associated with p r i m a r y lymphe d e m a " as an a p p r o p r i a t e n a m e for the condition w h e n pleural effusion is manifest. Primary l y m p h e d e m a with or w i t h o u t pleural effusion has been associated with bronchiectasis a n d sinusitis (3, 6, 9, 20). T h e pathogenesis of the respiratory infection is u n k n o w n . Bronchi a n d bronchioles are richly supplied with lymp h a t i c vessels, with o n e network in the submucosa a n d a n o t h e r in the mucosa (16); it is possible that the lymphatics play a greater role in the pathogenesis of b r o n c h i a l a n d paranasal sinus infection t h a n has thus far b e e n appreciated. A n o t h e r possibility is increased susceptibility to infection from immunologic abnormalities n o t e d in association with primary l y m p h e d e m a a n d p l e u r a l effusion. N a k i e l n a a n d co-workers (9) presented a p a t i e n t with complete absence of IgA by immunoelectrophoresis. Siegelman a n d associates (21), studying 2 previously r e p o r t e d family members (1), showed l y m p h o p e n i a in b o t h a n d decreased g a m m a g l o b u l i n by p r o t e i n electrophoresis in the m a l e p a t i e n t . Interestingly, the affected w o m a n of that family h a d an elevated latex-fixation titer (1:2,560) a n d later died of H o d g k i n ' s l y m p h o m a . D'Souza's p a t i e n t (4) h a d m o n o c l o n a l macroglobulinemia, k a p p a type, with a serum IgM c o n c e n t r a t i o n of 3,320 m g per 100 ml, which was b e h a v i n g in a b e n i g n manner. W e have presented a case a n d summarized the literature w r i t t e n in English on primary l y m p h e d e m a a n d pleural effusion. T h e basic abnormality is an incompetence of the lymphatic d r a i n a g e system, a n d the clinical spectrum is q u i t e varied with interesting associations. M u c h is discussed only in descriptive terms, a n d exact pathogenesis needs to be d e t e r m i n e d . Acknowledgment T h e writers thank Dr. Warren Widrich and Dr. Thomas O'Donnell, who reviewed the lymphangiogram, and Kathy Henri and Claire Sybertz, who typed the manuscript. References 1. Hurwitz, P. A., and Pinals, D. J.: Pleural effusion in chronic lymphedema (Nonne, Milroy, Meige's disease), Radiology, 1964, 82, 246. 2. Emerson, P. A.: Yellow nails, lymphoedema, and pleural effusions, Thorax, 1966,21,247. 3. Dilley, J. J., Kierland, R. R., Randall, R. V., and Shick, R. M.: Primary lymphedema associated
PRIMARY LYMPHEDEMA AND PLEURAL EFFUSION
4.
5. 6.
7.
8.
9.
10. 11.
12.
13.
with yellow nails and pleural effusions, JAMA, 1968,204, 670. D'Souza, M. F.: Generalized lymphoedema with yellow nails, pleural effusions, and macroglobulinemia, Proc R Soc Med, 1970, 63,24. Marks, R., and Ellis, J.: Yellow nails, Arch Dermatol, 1970,102, 619. Hiller, E., Rosenow, E., and Olsen, A.: Pulmonary manifestations of the yellow nail syndrome, Chest, 1972,61, 452. Eastwood, H. D., and Williams, T. J.: Pleural effusions and yellow nails of late onset, Postgrad Med J, 1973,49, 364. Dwek, J. H., and Greenberg, G. M.: Yellow nails, lymphedema and pleural effusions, NY State J Med, 1973,73,1093. Nakielna, E. M., Wilson, J., and Ballon, H. S.: Yellow nail syndrome: Report of three cases, Can Med Assoc J, 1976,115, 46. Sammon, P. D., and White, W. F.: The/'yellow nail syndrome," Br J Dermatol, 1964, 76,153. Allen, E. V., Barker, N. W., and Hines, E. A.: Peripheral Vascular Diseases, 3rd ed., W. B. Saunders Co., Philadelphia, 1962, p. 695. Kinmonth, J. B., Taylor, G. W., Tracy, G. D., and Marsh, J. D.: Primary lymphoedema: Clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected, Br J Surg, 1957,45,1. Taylor, G. W., Kinmonth, J. B., and Dangerfield,
14.
15.
16. 17. 18.
19.
20.
21.
599
W. G.: Protein content of oedema fluid in lymphoedema, Br Med J, 1958,1, 1159. Hollander, W., Reilly, P., and Burrows, B. A.: Lymphatic flow in human subjects as indicated by the disappearance of 1131 labelled albumin from the subcutaneous tissue, J Clin Invest, 1961, 40,222. Taylor, G. W., Kinmonth, J. B., Rollinson, E., Rotblat, J., and Francis, G. E.: Lymphatic circulation studied with radioactive plasma protein, Br Med J, 1957,1,133. Goss, C. M.: Gray's Anatomy, 28th ed., Lea and Febiger, Philadelphia, 1966, p. 757. Black, L. F.: The pleural space and pleural fluid, Mayo Clinic Proc, 1972,47,493. Kinmonth, J. B., Taylor, G. W., and Jantet, G. H.: Chylous complications of primary lymphoedema, J Cardiovasc Surg (Torino), 1964,5, 324. Midana, A., Zina, G., and Mazza, C : Lymphoedeme primaire associe aux epanchements pleuraux et aux ongles jaunes (The yellow nails de Sammam et White), Soc Franc Derm Syph, 1971, 78, 225. Bowers, D.: Unequal breasts, yellow nails, bronchiectasis and lymphoedema, Can Med Assoc J, 1969,100, 437. Siegelman, S. S., Heckman, B. H., and Hasson, J.: Lymphedema, pleural effusions and yellow nails-associated immunologic deficiency, Dis Chest, 1969,56,114.
SUMMARY A 28-year-old woman with bilateral pleural effusions and generalized, primary lymphedema beginning with facial erysipelas at 6 years of age is presented. T h e pleural effusions were exudates with 250 cells per mm3, 92 per cent of which were lymphocytes. Lymphatic stasis was demonstrated by persistence of the blue dye in the dorsa of her feet 3 months after a lymphangiogram of both lower extremities, pelvis, and abdomen. Her nails were not remarkable. Our patient represents the twentieth recorded case of pleural effusion in association with primary lymphedema. Women have been afflicted more than twice as often as men, and the age of onset has varied from birth to the eighth decade. Yellow dystrophic nails may precede or follow lymphedema or the pleural effusion and have occurred in onlv 11 of the 20 patients.
Introduction I n t h e past 15 years, p l e u r a l effusion, primary lymphedema, a n d yellow dystrophic nails have been r e p o r t e d in various combinations usually combined u n d e r t h e term "yellow nail synd r o m e " (1-10). T h i s term is u n f o r t u n a t e because, as the case r e p o r t e d h e r e a n d others collected from t h e literature illustrate, primary l y m p h e d e m a a n d p l e u r a l effusion frequently exist w i t h o u t changes in the nails ( 1 - 3 , 6, 9). I n this p a p e r we will describe the twentieth recorded case of primary l y m p h e d e m a a n d pleural effusion; we will summarize the available literature a n d place these clinical entities in p r o p e r perspective. Case Report A 28-year-old white, unmarried woman came to us in August 1977 for evaluation of bilateral pleural
(Received in original form October 25, 1977 and in revised form December 9,1977) 1 From the Department of Medicine, Boston Veterans Administration Hospital, University Hospital, and Boston University School of Medicine. 2 Supported in part by Program Project Grant No.
effusions of 8 months' duration. At the age of six and one half years, she developed recurrent episodes of erysipelas involving her face. When she was 14 years of age, these episodes subsided, and she noted swelling of her lower extremities, hands, and abdominal wall in addition to facial edema. Her hands and face were more swollen in the morning and improved as the day progressed; the leg swelling was significantly worse later in the day and during the later part of her menstrual cycles. Body edema was not constant, with her weight varying by as much as 10 kg during a period of several months. In January 1967, she underwent plastic surgery for correction of persistent upper and lower eyelid edema. Later that year, she had chest pain, dyspnea, cough productive of sputum, and fever. A diagnosis of pleurisy was made, and she was treated with isoniazid, streptomycin, and para-aminosalicylic acid for 3 months. During subsequent years, she felt well except for the persistence of generalized swelling and one episode of erysipelas involving one leg. In December 1976, she noticed dyspnea on exertion. A chest roentgenogram revealed bilateral pleural effusions, greater on the right side than on the left. At that time she had no other respiratory symptoms, fever, weight loss, gastrointestinal symptoms, rash, or arthralgia. There
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was no history of cardiac, renal, or hepatic disease. A short course of treatment with corticosteroids was of no benefit. Intermittent diuretic therapy provided modest relief of edema. When examined in August 1977, the patient appeared normal except for mild facial edema and a small ectropion of the right eye. There was mild pitting edema over her legs, sacrum, sternum, face, and iliac crest. Her fingernails and toenails were not remarkable. Blue dye stains from the previous lymphangiogram, done on May 20, 1977, remained visible on the dorsa of her feet. Her breasts were normal and of equal size. Percussion of the chest showed bilateral dullness posteriorly with decreased transmission of voice and breath sounds; these findings extended superiorly to just below the seventh rib on the right side, and to below the eighth rib on the left. Findings during the remainder of the physical examination were normal. Laboratory investigation revealed a normal urinalysis and hemogram. T h e white blood cell count was 7,000 cells per mm3 with 68 per cent polymorphonuclear cells, 3 per cent band forms, 24 per cent lymphocytes, and 1 per cent monocytes. Serum transaminases, bilirubin, lactic dehydrogenase, alkaline phosphatase, urea nitrogen, creatinine, cholesterol, triglycerides, thyroxine, triidothyronine resin uptake, and protein electrophoresis were normal. Serum complement and quantitative immunoglobulins were normal. Latex fixation, antinuclear antibody, and cryoglobulin tests were negative. Pelvic pneumoperitoneum, upper gastrointestinal series with small bowel follow-through, and a lower extremity and abdominal lymphangiogram were all within normal limits. A computerized tomographic scan of the chest was remarkable only for bilateral pleural effusions and showed normal mediastinal structures. Pulmonary function tests, with per cent of predicted values in parentheses, were as follows: vital capacity, 2.80 liters (74); total lung capacity, 3.29 liters (71); residual volume, 1.12 liters (63); forced expiratory volume in 1.0 sec, 2.17 liters (70); ratio of forced expiratory volume in 1.0 sec to forced vital capacity, 0.76; forced mid-expiratory flow, 2.10 liter per sec (45); and single breath diffusing capacity, 21 ml per mm Hg per min (89). T h e pleural fluid was clear and yellow. Chemical studies showed a protein concentration of 4.7 g per 100 ml, glucose concentration of 100 mg per 100 ml, 70 IU of lactic dehydrogenease, and 74 IU of amylase. T h e cell count was 250 cells per mm3 with 92 per cent lymphocytes. Routine bacterial smears and cultures and acid fast smears and cultures were negative. Cytologic examination of the fluid was negative for tumor cells, and lupus erythematous cells were not seen. Pleural biopsies done on 5 occasions showed only nonspecific inflammation.
Discussion Allen a n d associates (11) a n d K i n m o n t h
and
co-workers (12) divide primary l y m p h e d e m a into 3 categories on the basis of the patient's age at onset of edema. T h e r e is congenital lymphedema with onset at b i r t h (this includes Milroy's disease, a congenital familial type of lymphedema), l y m p h e d e m a praecox with onset before 35 years of age, a n d l y m p h e d e m a tarda with onset after age 35. O u r p a t i e n t fell into the category of l y m p h e d e m a praecox. Interestingly, she suffered from erysipelas before d e v e l o p m e n t of overt l y m p h e d e m a . It is well recognized that patients with a congenital a b n o r m a l i t y of the lymphatic vessels often d o n o t exhibit persistent l y m p h e d e m a u n t i l after some infection or other injury has strained the already deficient lymphatics (1). Studies of edematous fluid h a v e confirmed a large c o n t e n t of p r o t e i n (13), a n d investigations using iodine-131 a l b u m i n have shown defective removal of the labeled p r o t e i n from l y m p h e d e m a t o u s limbs (13-15). T h e latter observation is in contrast to the increased removal of subcutaneously injected iodine-131 a l b u m i n in patients with congestive h e a r t failure, h y p o p r o t e i n e m i a , or venous obstruction (14). T h e lymphatic vessels of the p l e u r a consist of 2 sets, o n e in the visceral p l e u r a a n d the o t h e r in the parietal pleura. T h o s e of the visceral p l e u r a d r a i n i n t o the superficial efferents of the lung, which t u r n a r o u n d the borders of the lungs a n d the margins of their fissures a n d converge to e n d in the nodes situated in the h i l u m . T h e lymphatic vessels of the parietal p l e u r a have 3 modes of t e r m i n a t i o n : those of the costal p o r t i o n join the intercostal lymphatics a n d so reach the sternal nodes, those of the d i a p h r a g m a t i c p a r t are d r a i n e d by the efferents of the d i a p h r a g m , a n d those of t h e mediastinal p o r t i o n t e r m i n a t e in the posterior mediastinal nodes (16). T h i s intricate network is essential for m a i n tenance of a free p l e u r a l space. Evidence accum u l a t e d thus far suggests t h a t u n d e r n o r m a l conditions fluid is filtered o u t of the parietal p l e u r a l capillaries a n d is absorbed by the visceral pleural capillaries a n d by the l y m p h a t i c vessels. P r o t e i n p a r t i c u l a t e m a t t e r a n d erythrocytes are absorbed solely by the lymphatics (17). Malfunction of the lymphatics secondary to hypoplasia will lead to a c c u m u l a t i o n of p r o t e i n a n d fluid in the pleural space. I n all of the rep o r t e d cases (1-9) of p l e u r a l effusion associated with p r i m a r y l y m p h e d e m a , the accumulated fluid h a d a p r o t e i n c o n c e n t r a t i o n greater t h a n 3 g p e r 100 ml. T h r e e separate d e t e r m i n a t i o n s in o u r p a t i e n t showed a r a n g e of p r o t e i n concen-
597
PRIMARY LYMPHEDEMA AND PLEURAL EFFUSION
tration from 3.7 to 4.7 g per 100 ml. Emerson (2) was the first to note that a lower respiratory tract or pleural infection may damage previously adequate but impaired lymphatic drainage, and so result in a persistent pleural effusion. Our patient had a lower respiratory infection with transient pleural inflammation approximately 10 years before the development of the present persistent pleural effusion. This situation is analogous to the recurrent erysipelas preceding the facial edema. There is another mechanism responsible for pleural effusion in primary lymphedema. Patients with primary lymphedema may develop some interference with the absorption and circulation of chyle from the intestine. This may show itself clinically as chylous ascites or chylothorax. Kinmonth and associates (18) describe a young man who had lymphedema of the lower extremities and genitalia since childhood with
dyspnea due to a left chylothorax at 22 years of age. At thoracotomy, there was extensive oozing of chyle from the surfaces of the lung hilum and mediastinal pleura. Decortication of the lung surface, combined with covering the oozing surfaces with flaps of pleura and pleurodesis, resulted in cure. Our patient represents the twentieth reported case of primary lymphedema and pleural effusion. A twenty-first case (19) is not included because the pleural lesion was empyemic, and insufficient detail was given to ascertain the chronicity of the pleural effusion. Sex, age at onset of symptoms, and the occurrence of lymphedema, pleural effusion, and yellow nails in the 20 collected cases are listed in table 1. The female-to-male ratio is 7:3. Age at onset of symptoms is variable, ranging from birth to the eighth decade. Lymphedema was usually the first clinical manifestation, but in at
TABLE 1 CLINICAL FEATURES OF PLEURAL EFFUSION ASSOCIATED WITH PRIMARY
Reference Hurwitz and Pinals (1)
E m e r s o n (2)
Dilley eta/. (3)
Sex and Age, (years) a t O n s e t of Symptoms
Pleural L y m p h e - effu- Yellow dema sion Nails
LYMPHEDEMA
Comment
M, birth
decreased serum g a m m a globulin, l y m p h o p e n i a , r e c u r r e n t erysipelas, cor pulmonale
F, birth
l y m p h o p e n i a , r e c u r r e n t erysipelas, H o d g k i n ' s disease, latex f i x a t i o n 1:2560
F, infancy
+
+
0
M, 4 7
+
+
+
F, 2 1
+
+
+
family h i s t o r y of Milroy's disease
M, 2 9
+
+
+
sinusitis, b r o n c h i e c t a s i s l y m p h e d e m a of face
F,43
+
+
0
F, 3 5
+
+
0
malignant melanoma
F, 1 7
+
+
0
D'Souza(4)
F, 3 8
+
+
+
macroglobulenemia
Marks and Ellis (5)
M, 5 3
+
+
+
persistent hypoalbuminemia
H i l l e r e f a / . (6)
F, 5 0
+
+
+
M, 7 1
+
+
+
M, 5 3
+
+
+
F, 3 1
+
+
0
anaplastic t u m o r
E a s t w o o d and Williams (7)
F, c h i l d h o o d
+
+
+
e f f u s i o n d e v e l o p e d in t h e 9th d e c a d e
Dwek and Green berg (8)
F, 2 3
+
+
+
sinusitis
N a k i e l n a e f al. (9)
F, 5 0
+
+
+
sinusitis, b r o n c h i e c t a s i s
Beer, Pereira, and S n i d e r
sinusitis, b r o n c h i e c t a s i s
F, 3 4
+
+
0
a b s e n c e of IgA
F, 1 4
+
+
0
r e c u r r e n t erysipelas
598
BEER,
PEREIRA, AND SNIDER
least 3 cases (3, 6) classic nail findings consisting of cessation of nail growth, yellowish discoloration, smoothness with transverse ridging, curving from side to side, defective cuticles, a n d onycholysis, a n d a characteristic l u m p (10) app e a r e d first. T h e simple message is that w h e n any o n e manifestation of the triad is present, the others should be sought, a n d the p a t i e n t should be followed for their later development. T h i s is best exemplified by the r e p o r t of Eastwood a n d Williams (7) in which a p a t i e n t with lymphedema since childhood did not develop classic nail changes u n t i l the age of 78 years, a n d it was n o t u n t i l her n i n t h decade that p l e u r a l effusion developed. T h e pleural effusions have been bilateral or unilateral, massive or small. Once they have occurred, they t e n d to persist a n d in certain instances reaccumulate w i t h i n days after thoracocentesis. Pleurectomy or instillation of a sclerosing agent i n t o the p l e u r a l cavity has b e e n successful in controlling the p l e u r a l effusion (6). T h e lymphatic vessels in the lower extremities, pelvis, a n d a b d o m e n were n o r m a l in o u r p a t i e n t . T h i s is at variance with the r e p o r t e d experience of K i n m o n t h a n d colleages (12), in which they state that in primary lymphedema, some a b n o r m a l i t y of lymphatic vessels is always observed with r o e n t g e n o g r a p h s or p a t e n t blueviolet d e r m a l lymphangiography. T h e r e can be n o d o u b t , however, a b o u t the lymphatic stasis in o u r p a t i e n t , as d e m o n s t r a t e d by the persistent dye stains o n the dorsa of her feet 3 m o n t h s after l y m p h a n g i o g r a p h y . Only 5 of the r e p o r t e d cases of primary l y m p h e d e m a a n d p l e u r a l effusion h a d l y m p h a n g i o g r a p h y (1, 4, 7, 9). T h e y showed a spectrum of lymphatic abnormalities r a n g i n g from only o n e hypoplastic vessel to gross hypoplasia. T h e r e were n o instances of aplasia or megalymphatics. N i n e of the 20 patients h a d l y m p h e d e m a a n d pleural effusion w i t h o u t nail abnormalities. Yet most authors refer to this complex as the "yellow nail s y n d r o m e " (10). S a m m a n a n d W h i t e (10) first used the term "yellow nail s y n d r o m e " to describe 13 cases of yellow nails. T e n of their patients h a d primary l y m p h e d e m a , whereas the o t h e r 3 were a p p a r e n t l y free of clinical edema. F o u r of their patients were studied by lymphangiography, a n d all h a d lymphatic abnormalities consisting mainly of hypoplasia of the lymp h a t i c system. It is this a b n o r m a l i t y in lymphatics that is p a r a m o u n t . T h e discolored nails, if present, are merely a superficial indicator of an
u n d e r l y i n g defect. H e n c e we suggest the phrase " p l e u r a l effusion associated with p r i m a r y lymphe d e m a " as an a p p r o p r i a t e n a m e for the condition w h e n pleural effusion is manifest. Primary l y m p h e d e m a with or w i t h o u t pleural effusion has been associated with bronchiectasis a n d sinusitis (3, 6, 9, 20). T h e pathogenesis of the respiratory infection is u n k n o w n . Bronchi a n d bronchioles are richly supplied with lymp h a t i c vessels, with o n e network in the submucosa a n d a n o t h e r in the mucosa (16); it is possible that the lymphatics play a greater role in the pathogenesis of b r o n c h i a l a n d paranasal sinus infection t h a n has thus far b e e n appreciated. A n o t h e r possibility is increased susceptibility to infection from immunologic abnormalities n o t e d in association with primary l y m p h e d e m a a n d p l e u r a l effusion. N a k i e l n a a n d co-workers (9) presented a p a t i e n t with complete absence of IgA by immunoelectrophoresis. Siegelman a n d associates (21), studying 2 previously r e p o r t e d family members (1), showed l y m p h o p e n i a in b o t h a n d decreased g a m m a g l o b u l i n by p r o t e i n electrophoresis in the m a l e p a t i e n t . Interestingly, the affected w o m a n of that family h a d an elevated latex-fixation titer (1:2,560) a n d later died of H o d g k i n ' s l y m p h o m a . D'Souza's p a t i e n t (4) h a d m o n o c l o n a l macroglobulinemia, k a p p a type, with a serum IgM c o n c e n t r a t i o n of 3,320 m g per 100 ml, which was b e h a v i n g in a b e n i g n manner. W e have presented a case a n d summarized the literature w r i t t e n in English on primary l y m p h e d e m a a n d pleural effusion. T h e basic abnormality is an incompetence of the lymphatic d r a i n a g e system, a n d the clinical spectrum is q u i t e varied with interesting associations. M u c h is discussed only in descriptive terms, a n d exact pathogenesis needs to be d e t e r m i n e d . Acknowledgment T h e writers thank Dr. Warren Widrich and Dr. Thomas O'Donnell, who reviewed the lymphangiogram, and Kathy Henri and Claire Sybertz, who typed the manuscript. References 1. Hurwitz, P. A., and Pinals, D. J.: Pleural effusion in chronic lymphedema (Nonne, Milroy, Meige's disease), Radiology, 1964, 82, 246. 2. Emerson, P. A.: Yellow nails, lymphoedema, and pleural effusions, Thorax, 1966,21,247. 3. Dilley, J. J., Kierland, R. R., Randall, R. V., and Shick, R. M.: Primary lymphedema associated
PRIMARY LYMPHEDEMA AND PLEURAL EFFUSION
4.
5. 6.
7.
8.
9.
10. 11.
12.
13.
with yellow nails and pleural effusions, JAMA, 1968,204, 670. D'Souza, M. F.: Generalized lymphoedema with yellow nails, pleural effusions, and macroglobulinemia, Proc R Soc Med, 1970, 63,24. Marks, R., and Ellis, J.: Yellow nails, Arch Dermatol, 1970,102, 619. Hiller, E., Rosenow, E., and Olsen, A.: Pulmonary manifestations of the yellow nail syndrome, Chest, 1972,61, 452. Eastwood, H. D., and Williams, T. J.: Pleural effusions and yellow nails of late onset, Postgrad Med J, 1973,49, 364. Dwek, J. H., and Greenberg, G. M.: Yellow nails, lymphedema and pleural effusions, NY State J Med, 1973,73,1093. Nakielna, E. M., Wilson, J., and Ballon, H. S.: Yellow nail syndrome: Report of three cases, Can Med Assoc J, 1976,115, 46. Sammon, P. D., and White, W. F.: The/'yellow nail syndrome," Br J Dermatol, 1964, 76,153. Allen, E. V., Barker, N. W., and Hines, E. A.: Peripheral Vascular Diseases, 3rd ed., W. B. Saunders Co., Philadelphia, 1962, p. 695. Kinmonth, J. B., Taylor, G. W., Tracy, G. D., and Marsh, J. D.: Primary lymphoedema: Clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected, Br J Surg, 1957,45,1. Taylor, G. W., Kinmonth, J. B., and Dangerfield,
14.
15.
16. 17. 18.
19.
20.
21.
599
W. G.: Protein content of oedema fluid in lymphoedema, Br Med J, 1958,1, 1159. Hollander, W., Reilly, P., and Burrows, B. A.: Lymphatic flow in human subjects as indicated by the disappearance of 1131 labelled albumin from the subcutaneous tissue, J Clin Invest, 1961, 40,222. Taylor, G. W., Kinmonth, J. B., Rollinson, E., Rotblat, J., and Francis, G. E.: Lymphatic circulation studied with radioactive plasma protein, Br Med J, 1957,1,133. Goss, C. M.: Gray's Anatomy, 28th ed., Lea and Febiger, Philadelphia, 1966, p. 757. Black, L. F.: The pleural space and pleural fluid, Mayo Clinic Proc, 1972,47,493. Kinmonth, J. B., Taylor, G. W., and Jantet, G. H.: Chylous complications of primary lymphoedema, J Cardiovasc Surg (Torino), 1964,5, 324. Midana, A., Zina, G., and Mazza, C : Lymphoedeme primaire associe aux epanchements pleuraux et aux ongles jaunes (The yellow nails de Sammam et White), Soc Franc Derm Syph, 1971, 78, 225. Bowers, D.: Unequal breasts, yellow nails, bronchiectasis and lymphoedema, Can Med Assoc J, 1969,100, 437. Siegelman, S. S., Heckman, B. H., and Hasson, J.: Lymphedema, pleural effusions and yellow nails-associated immunologic deficiency, Dis Chest, 1969,56,114.
