BRONCHIOLAR EMPHYSEMA (CIRRHOSIS OF THE LUNG)

BRONCHIOLAR EMPHYSEMA (CIRRHOSIS OF THE LUNG) Sheldon Oscar Burman, M.D., and Edward M. Kent, M.D., Pittsburgh, Pa. of this paper is to describe a rare and remarkable variant of T diffuse hypertrophic pulmonary emphysema in which the lung has the gross H E PURPOSE

appearance and texture of advanced Laennec's cirrhosis of the liver. Since the first description of the disease in 1879 by Rindfleisch, who called it cirrhosis cystica pulmonum," only 13 such cases have been reported, none of these in an American thoracic or surgical journal. Yet, as with most other conditions producing diffuse bilateral fibronodular lung disease and ventilatory insufficiency, the definitive diagnosis can only be made by lung biopsy. CASE REPORT

H. M. (W-5879), a 65-year-old white, unmarried, clerical worker, was admitted to the University of Pittsburgh Woman's Hospital on June 6, 1960, because of progressively increasing shortness of breath of 1 year's duration. She was unable to walk more than a few yards, to perform even light housework, or to sleep except sitting up. There hall been a mild cough of 9 months' duration productive of a little thin, stringy, white, odorless sputum. She had never complained of chest pain, hoarseness, or hemoptysis, and she had never smoked. There were no chills, fever, or sweats, and no history of exposure to tuberculosis. Since October, 1959, she has had increasing anorexia with a weight loss of 40 pounds without dyspepsia, dysphagia, vomiting, regurgitation, or melena. There were no known allergies or history of asthma. The patient had traveled extensively through the Southern United States but not elsewhere. She had kept a pet dog for some years but no birds. She had never lived on a farm and had done no gardening. She had never consumed alcoholic beverages, and had no history of seizures or syncopal attacks, nor
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Roentgenograms of the chest revealed bilateral, diffuse, fibronodular infiltration with slightly increased prominence of hilar shadows and a suggestion of mottling and honeycombing in the left upper lobe (Fig. 1). There was no free fluid. The heart appeared normal. There was calcification and slight dilatation of the thoracic aorta. An upper gastrointestinal barium study demonstrated a large esophageal hiatal hernia. Skin tests for tuberculosis, blastomycosis, coccidioidomycosis, and histoplasmosis were negative. Repeated sputum smears and cultures for anaerobic and aerobic bacteria, fungi, and tubercle bacilli produced nothing remarkable. The hematocrit was 37 per cent, the hemoglobin 12 Gm, per cent, and white blood cell count was 9,800 per cubic millimeter with 62 per cent polymorphonuclear leukocytes, 31 per cent lymphocytes, 3 per cent eosinophils, 4 per cent monocytes.

Fig. I.-Posteroanterior view of the chest which shows diffuse coarse inflltratlon with Interspersed radiolucent areas. Note honeycombed appearance of left upper lobe. Vascular markings at the hila are prominent. The blood urea nitrogen was 11 mg. per cent, serum calcium 9.2 mg. per cent, phosphorus 4.7 mg. per cent, alkaline phosphatase 1.0 Bessy-Lowry units, total protein 6.8 mg. per cent, albumin 2.9 mg. per cent, globulin 3.7 mg. per cent, prothrombin time 15 seconds, control 13 seconds. Serological tests for syphilis were negative. The electrocardiogram indicated right ventricular hypertrophy. On June 21, 1960, a limited left exploratory thoractomy was performed through a small incision in the fifth intercostal space. There was no fluid in the pleural cavity. The lung was grayish-red, dense, heavy, and nodular, and resembled the hobnail liver of advanced Laennec '8 cirrhosis. The surface was finely crepitant to palpation and, when the lingula was biopsied, the cut surface exhibited many tiny, air-containing cysts . The substance of the lung was friable and sutures tore through easily. After the operation the patient made an uneventful recovery but remained very short of breath and was severely limited in her exercise tolerance. Ten milligrams of prednisone four times daily were administered orally for one month without obvious benefit.

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Potholoqio Obaervationa.-The pleura of the gross wedge of lung was grayish-pink to tan and slightly thickened. The lung was rubbery and its external surface distinctly nodular (Fig. 2). The sectioned surface revealed discrete and confluent nodular areas of granular, firm, pale, pinkish-gray tissue containing small, cystic spaces. Microscopically, these nodular areas consisted of lobules of pulmonary parenchyma in which the alveoli were distorted and the majority were lined by prominent cuboidal cells, In addition, numerous tortuous cystic spaces were evident (Fig. 3, A). The majority were lined by low cuboidal or flattened epithelial cells, but some were partly lined by columnar bronchiolar epithelium. In the PAS preparation only a few of the cells contained droplets of mucin. The walls of these spaces frequently contained large bundles of smooth muscle. Similar muscular hypertrophy was evident about terminal bronchioles. There was a heavy infiltrate of lymphocytes and plasma cells in the loose tissue separating these cystic spaces. There was moderate interstitial fibrosis. Many of the alveoli and cystically dilated bronchioles contained desquamated lining cells in a coagulum of mucus (Fig. 3, B and C). Pulmonary arterioles showed intimal thickening and medial hypertrophy.

Fig. 2.-Photograph of tip of lingula. Note dense, airless appearance with surface nodules resembling the liver of Laennec's cirrhosis.

DISCUSSION

To emphasize by contrast the unique features of bronchiolar emphysema (cirrhosis of the lung"), a brief description of the far commoner variety of diffuse hypertrophic emphysema, the so-called vesicular type, is pertinent. This latter is defined as a diffuse disease of the lung characterized by dilatation of the respiratory units, which enlarge both by generalized elongation and segmental dilatation, and are associated with focal impairment of the elastica at the site of the dilatation. 2 o , 3 0 As the condition progresses, smooth muscle elements become increasingly prominent. These lungs grossly are pale, feathery, light, and inelastic to palpation. They are grossly overdistended and fail to collapse when the chest is opened. Generally speaking, the onset of vesicular

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hypertrophic emphysema is insidious, the course relentlessly progressive, and its duration prolonged. While its etiology is controversial and remains obscure, its pathogenesis has been clearly delineated by gross and microscopic observations of affected lungs during progressive stages of the disease. 7 More recently, physiologic determinations of pulmonary function have provided helpful objective measurements of the salient clinical features of the disease.'

The Respiratory Unit.-The term respiratory unit as used above refers to the respiratory bronchiole with its (usually) three orders'! of ramifications together with their sparse primordial alveoli and, more distally, the derived alveolar ducts with numerous single or clustered peripheral alveoli."? The ordinary form of hypertrophic emphysema is sometimes termed "vesicular" because it involves ectasia of the ductal or distal alveoli, the alveolar ducts themselves, and the more peripheral arborizations of the respiratory bronchiole. Bronchiolar emphysema, on the other hand, features marked saccular dilatation restricted chiefly to the more proximal respiratory bronchiole with prominent smooth muscle hypertrophy and hyperplasia. The cysts may be isolated or communicating and are of varying size, usually from 1 to 3 mm. in diameter. The single and clustered peripheral alveoli are moderately to markedly obliterated, while those still present may exhibit the ectasia seen so prominently in the vesicular form. The terminal bronchioles are largely uninvolved but may in part also be caught up in the destructive process. Bronchiolar emphysema, therefore, unlike vesicular emphysema, is essentially a cystic disease of the proximal respiratory unit. Confirmation of this concept is provided not only by ordinary studies of fixed surgical and autopsy material, but also by the precise and meticulous measurements by Siebert and Fisher'" of the various individual components of the respiratory units in the normal lung and in lungs having the vesicular and the bronchiolar forms of emphysema. Etiology.-The etiology of bronchiolar emphysema, like that of the vesicular variant, is obscure. Oswald and Parkinson" regarded it as an acquired inflammatory condition of multiple etiology but could not exclude a development origin. Siebert and Fisher" believe that the special factor predisposing to the development of this disease, rather than bronchiolectasis or vesicular emphysema, is a congenital structural hypoplasia of the elements of the more distal respiratory units. Gross Appearance.-The gross appearance and texture of the lung with bronchiolar emphysema is unique and diagnostic. It is dull, thick, bosselated, and grayish-red, and resembles the liver of advanced Laennec's cirrhosis. It feels dense, inelastic, heavy, and airless. The cut surface exhibits myriads of cystic spaces, usually more numerous near the margins and fissures. Differential Diagnosis.-The disease may be distinguished from vesicular hypertrophic emphysema by the criteria already enumerated. Bronchiolectasis differs from bronchiolar emphysema in that the former involves mainly the terminal and not the respiratory bronchiole." The epithelium of the terminal bronchiole, unlike that of the respiratory bronchiole, possesses mucin-containing

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I. SUMMARY OF REPORTED CASES OF BRONCHIOLAR EMPHYSEMA

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Bilateral, diffuse, with honeycombing

Bilateral, diffuse

Bilateral, more marked in lower lobes and margins j mixed with vesicular emphysema at apices Bilateral, diffuse

Bilateral, more marked in right lung; mixed with vesicular emphysema in left lung Bilateral, more marked in lower lobes and margins

Bilateral, more marked at margins; mixed with vesicular emphysema in upper lobes

Bilateral, more marked in lower lobes and at margins

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goblet cells and therefore will stain characteristically with the periodic-acid Schiff reagent." Bronchiolectasis, furthermore, often involves the preterminal bronchiole which is microscopically detectable by its cartilaginous plates. Socalled interstitial pulmonary fibrosis, when advanced, is also associated with alveolar and ductal obliteration" but is not generally accompanied by the marked and characteristic prominence of muscular elements seen in bronchiolar emphysema, nor are there found in interstitial fibrosis the myriads of air-containing cysts. While Siebert and F'isher'" firmly hold that bronchiolar emphysema constitutes a distinct nosological entity with characteristic features, Hepplestou" takes the view that it represents but one variant of a form of acquired microcystic disease of the lung called by him and others 1 3 • 2 1 honeycomb lung. Certainly honeycombing of the lung with its concomitant muscular and fibrous processes is seen as the end stage of diverse kinds of lung disease'? and represents a "final common pathway" of the lung's response to multiple inciting agents. Thus, Licht and othersv 3, 15, 29 have reported honeycomb lung in patients suffering from tuberous sclerosis. Evans and Parker" noted that the pulmonary changes in scleroderma consist of fibrosis with bronchiolar cyst formation and represent a variety of honeycomb lung. Pulmonary leiomyomatosis also can occur with cystic ehanges.P- 27 but these are not so marked and the degree of smooth muscle proliferation exceeds that seen in bronchiolar emphysema. When the specific granulomas often associated with honeycombing are excluded from consideration, such as streptomycin-treated tuberculosis.Pv " eosinophilic granuloma or histiocytosis X,t9, 21 sarcoidosis," berylliosis," giant-cell pneumonia;" and granulomatous pneumonitis," there remains a sizable, nonspecific group in which bronchiolar cyst formation, elastic tissue degeneration, and fibrous and muscular proliferation are prominent. In advanced honeycomb lung, the microscopic differentiation of respiratory from nonrespiratory bronchioles is often difficult because of sequestration of cysts from parent bronchioles, distortion by fibrosis, and epithelial metaplasia. Furthermore, microscopic fields can he found using the low-power objective where terminal bronchioles with their goblet cells appear to be involved in equal numbers with the respiratory bronchioles. However, when the process largely or totally involves the respiratory bronchioles, the diagnosis of bronchiolar emphysema would appear to be justified. Natural History.-The onset of the disease is often related by the patient to a respiratory infection in which, following the disappearance of acute symptoms, shortness of breath and exertional dyspnea persist and rather rapidly worsen. Activity is voluntarily restricted, chronic lassitude supervenes and the patient is finally impelled to have an x-ray examination of the chest. The latter reveals bilateral diffuse, fibronodular, pulmonary infiltrates, and honeycombing is often seen. Whereas vesicular hypertrophic emphysema is compatible with long, if restricted, life, bronchiolar emphysema kills relatively quickly, the average survival from the onset of symptoms being about 5 years. Although the primary respiratory bronchiole (as the name implies) and its most proximal stems

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possess rudimentary alveoli, by far the greater part of gaseous exchange occurs in those peripheral alveoli derived from the alveolar ducts where there is intimate association with the blood capillaries. With the relentless obliteration by stromal proliferation of these most functional segments of the respiratory units, the respiratory acidosis, arterial unsaturation, and hyperventilation which accompany this disease are readily explainable. As the pulmonary vasculature is progressively obliterated, pulmonary hypertension, cor pulmonale, and" cardiac failure supervene and often become the mode of demise.

Treatment.-With regard to our own case and to those reviewed in the literature (Table I), no treatment has been effective in reversing the inexorable trend of the disease. The usual ancillary measures directed toward dilating, clearing secretions from, and reducing pyogenic organisms in the tracheobronchial tree will provide a measure of comfort and symptomatic relief. In the present case, 10 mg. of prednisone orally four times daily provided no symptomatic or radiographic amelioration. SUMMARY

Bronchiolar emphysema is a rare variant of hypertrophic pulmonary emphysema in which the lung grossly resembles the liver of advanced Laennec's cirrhosis. Ante-mortem diagnosis can be made only by surgical biopsy. Microscopically, obliteration of alveoli, marked overgrowth of smooth muscle elements, fibroplasia, and saccular dilatation of the respiratory bronchioles are the salient features. The inevitable result of this massive respiratory bronchiolar ectasia is the formation of countless single and communicating air-containing cysts. The etiology of the disease is unknown, its therapy symptomatic only, its course inexorable, and its outcome relatively quickly fatal. The mode of demise comprises respiratory insufficiency, pulmonary hypertension, cor pulmonale, and right heart failure. A patient is herein described possessing the typical features of this disease, and a review of the pertinent literature is presented. The authors desire to express their gratitude to Robert S. Totten, M.D., of the Department of Pathology of the University of Pittsburgh who provided the description and photographs of the gross and microscopic specimens. REFERENCES

1. Baldwin, E. deF., Cournand, A., and Richards, D. WI;· Pulmonary Insufficiency: III. A Study of 122 Cases of Chronic Pulmonary Emphysema, Medicine 28: 201, 1949. 2. Berg, G., and Vejlens, G.: Maladie kystique du poumon et sclerose tubereuse du cerveau, Acta Paediat. 26: 16, ·1939. 3. Berg, G., and Zachrisson, C. G.: Cystic Lungs of Rare Origin-Tuberous Sclerosis, Acta radiol. 22: 425, 1941. 4. Calma, 1.: Cystic Emphysema of the Lungs With Interstitial Sclerosis, Brit.•J. 'I'uberc, 35: 40, 1941. 5. Davidsohn, C.: Doer muskulare Lungencirrhose, Berl. k liu, Wehnsehr, 44: 33, 1907. 6. Evans, M., and Parker, R. A.: Honeycomb Lung and Mitral Stenosis in Scleroderma, Thorax 9: 154, 1954. 7. Farber, S. M., and Wilson, R. H. L.: Pulmonary Emphysema. Clinical Symposia, Ciba, vol, 10, Nov.-Dec., 1958. 8. Grethman, W.: The Architecture of the Terminal Sections of the Branch of the Human Lung. The Pulmonary Acinus, Am. Rev. Tuberc. 31: 261, 1935.

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9. Hamman, L., and Rich, A. R.: Acute Diffuse Interstitial Fibrosis of Lungs, Bull. Johns Hopkins Hosp, 74: 177, 1944. 10. Hecht, V.: Die Riesenzellenpneumonie im Kindesalter, Eine Historisch-Experimentelle Studie, Beitr, path. Anat. 48: 263, 1953. 11. Heppleston, A. G.: Pathological Anatomy of Simple Pneumoconiosis in Coal Workers, J. Path. Bact. 66: 235, 1953. 12. Heppleston, A. G.: The Pathology of Honeycomb Lung, Thorax 2: 77 1956. 13. Hyde, L., Hyde, B., and Pokorny, C.: Diffuse Bilateral Fibrocystic Disease of Lungs (Honeycomb Lungs), Dis. Chest 19: 190, 1951. 14. Laurance, K. M.: Congenital Pulmonary Cystic Lymphangiectasis, J. Path. & Bact. 70: 325, 1955. 15. Licht, E. deFine: tiber Lungenzystem, Bronchioktasen und Lungenfibrosen, Insbesondeag Tuberosesklerose, Acta radiol, 23: 151, 1942. 16. Liebow, A. A., Loring, W. E., and Felton, W. L., II: The Musculature of the Lungs in Chronic Pulmonary Disease, Am. J. Path. 29: 885, 1953. 17. Loeschke, H.: Emphysema Bronchiolektaticum und praterminale Bronchiektasen als Systemerkrankungen isolierter Abschnitte des Bronchialbaumes, Verhandl. d. deutsch. path. Gesellsch. 21: 242, 1926. 18. Mallory, T. B.: Pathology of Pulmonary Fibrosis, Including Chronic Pulmonary Sarcoidosis, Radiology 61: 468, 1948. 19. McKeown, F.: Letterer-Siewe's Disease; Report of Two Cases, J. Path. & Bact. 68: 147, 1954. 20. Orsos, F.: tiber Das Elastiche Geriist der Normalen und der Emphysematosen Lunge, Beitr. z, path. Anat. u. z. allg. Path. 41: 95, 1907. 21. Oswald, N., and Parkinson, T.: Honeycomb Lungs, Quart. J. Med. 18: 1,1949, ns. 22. Pepere, A.: Della degenerazione cistica del polmone, Sperimentale, Arch. biol. 60: 171, 1906. 23. Rappaport, 1.: Chemotherapy and "Vanishing Lungs," J. A. M. A. 168: 1436, 1955. 24. Ravines, H. T.: Bronchiolar Emphysema of the Lungs, A. M. A. Arch. Path. 69: 554, 1960. 25. Rindfleisch, G. E.: Ueber Cirrhosis cystica pulmonum, VerhandI. d. Gesellsch. deutsch, Naturf. u. Aerzte, Leipzig, 22-24, 1898. . 26. Bomhanyi, G., and Maccone, V.: Zur Pathogenese der polycystischen Lungenveranderungen, Frankfurt, Ztschr. f. Path. 50: 442, 1936·1937. 27. Rosendal, T.: A Case of Diffuse Myomatosis and Cyst Formation in the Lung, Acta radioI. 23: 138, 1942. 28. Rubenstein, L., Gutstein, W. H., and Lepow, H.: Pulmonary Muscular Hyperplasia (Muscular Cirrhosis of the Lungs), Ann. Int. Med. 42: 36, 1955. 29. Samuelson, E.: Tuberous Sclerosis With Changes in Lung and Bones, Acta radioI. 23: 373,1942. 30. Siebert, F. T., and Fisher, E. R.: Bronchiolar Emphysema: So-called Muscular Cirrhosis of the Lungs, Am. J. Path. 33: 1137, 1957. 31. Von StOssel, E.: trber muskulare Cirrhose der Lunge, Beitr. Klin, Tuberk. 90: 432, 1937.