muscular hyperplasia lung as diffuse fibrosing alveolitis · d. davies, a. macfarlane, c. s. darke,...

Thorax (1966), 21, 272.

Muscular hyperplasia ('cirrhosis') of the lungand bronchial dilatations as features of chronic

diffuse fibrosing alveolitisD. DAVIES, A. MACFARLANE, C. S. DARKE, AND

0. G. DODGE

From Ransom Hospital, Mansfield, and the Royal Infirmarv, Sheffield

Muscular 'cirrhosis' of the lung was first describedby von Buhl in 1872. An occasional case wasdescribed afterwards, but the number has increasedin recent years. We have found 25 cases publishedbetween 1940 and 1964 that have conformedreasonably well to the accepted concept of thecondition. Sixteen of these have come from theUnited States of America, four from Mexico, two

from France, and one each from Scandinavia,Canada, and Britain. These cases are summarizedin Table I, together with the five cases nowreported. They have been published under varioustitles, the commonest being muscular cirrhosis ofthe lung, pulmonary muscular hyperplasia, andbronchiolar emphysema. Some cases publishedunder these titles have not been included because

TABLE I

Author

CalmaRosendalRubenstein et al.

Siebert & Fisher

SchaffnerDelarue et al.RavinesMcAdamsBurman & KentGonzalez-AnguloFraimow & Cathcart

Hirshfield et al.Brun et al...Gonzales-Licea et al.

Bowerman & TowbinJerry & Ritchie

Present series:Case I ..Case 2 ..

Case 3 ..

Case 4 ..

Case 5.S .

Dura-Age tion of

Year at Sex Dys-Death pnoea

(years)

1941 36 M -1942 51 F 71955 63 F 3 12

65 M 1 121957 61 M 5 +

65 M 41959 64 M 151960 58 F 71960 78 F 41961 75 F _1962 65* F 1*1962 46* M 4*1962 53 M 1±1 63 lM 1+

54 M 727* F 14 *

54* F 14*1962 40 F 21963 50 M 31963 70 F S

48 F I47 M S59* F 10*

1964 56 M 31964 65 F 7

6857

M 15M 7

Lengthof x-rayAbnor-mality(years)

62,121 125137

5 days8

<I*3*SI

4

1*4

l l

A

5

7

227

64 M 6 4

65 F 7 1262 M 4 1

Club- Crepita-bing tions

0

0

0+

000

0+

++++0+

+

H-

RightVen-

ItricularHyper-trophy

0

40

0

+ Slight4+ + 0

0 + +

ISlight

IntrapulmonaryCysts

0_

0

- 20 mm.pea1-5 mm.

1-2 mm.1-3 mm.small1-5 mm.< 5 mm.small4 mm.

0+ 1- 4mm.

_ +-- 3-30 mm.

+ + 3- 5mm.- 1- 5mm.

0+

+ 5-20 mm.

+ <30mm.+ <10mm.

+ <15mm.

<15 mm.+ 5mm.

Remarks

Lymph nodes involved

NegroCoal-miner

Died carcinoma lungNegro. No benefit

prednisolone

Negress. No benefitcorticosteroids

Negress

Spontaneous pneumo-thorax

Coal-miner; aorticstenosis

Coal-miner; aorticstenosis

Coal-miner

+ = Present; * still alive; - not recorded; O = nil.

272

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Chronic diffuse fibrosing alveolitis

the information available is insufficient to makeit reasonably certain that they fitted into thepattern.Most of the patients have certain features in

common. They were middle-aged or elderly menor women with a fairly long history of graduallyincreasing shortness of breath. With the exceptionof the cases of Rubenstein, Gutstein, and Lepow(1955), shortness of breath had been present forat least a year, four to seven years being thecommonest range. In one of our patients dyspnoeawas present for 15 years. Cough is a commonsymptom but is seldom distressing. Sputum maybe present, but it is often absent or scanty. Wheez-ing is not a feature. Clubbing of the fingers andcrepitations at the lung bases are frequent find-ings. Where respiratory function tests have beendone there is a common pattern of reduced vitalcapacity without airways obstruction togetherwith impairment of diffusion. Radiologically thelungs show diffuse bilateral mottling and fibrosis,occasionally with some shift of the mediastinumto one side. Honeycombing or small cysts may bevisible. These features may show progression overa number of years. Spontaneous pneumothoraxhas only once been reported (Jerry and Ritchie,1964). Five patients were still alive when reported,but death usually resulted from respiratoryinsufficiency or sometimes from right ventricularfailure.At necropsy the pleural spaces were usually free

and the lungs small or fairly normal in volume.Their surface was often knobbly like a cirrhoticliver (Fig. 1). The cut surface usually, but notinvariably, showed honeycombing affecting manyparts, most of the cysts measuring 3 to 15 mm.in diameter. Histologically the lungs showed littlenormal structure. In the honeycombed areas therewas extensive loss of alveolar tissue and itsreplacement by fibrous tissue and muscle withlittle or no evidence of active inflammation. Thesurviving air spaces were dilated to form cystswhich were often lined by cubical or columnarepithelium. There was a marked excess of smoothmuscle, usually surrounding the air spaces andblood vessels but also lying scattered in haphazardfashion in the fibrous tissue and often in thickbundles under the pleura. The cases did not showclinical or necropsy evidence of such conditionsas tuberose sclerosis, xanthomatosis, scleroderma,or rheumatoid arthritis. In one of our cases, how-ever, the Rose-Waaler test was positive, as wasthe rheumatoid latex fixation test in another.The clinical, radiological, and physiological

pattern is indistinguishable from chronic diffuse

FIG. 1. Case 3. Nodular lung surface simulating a cirrhoticliver.

fibrosing alveolitis, and this diagnosis was madein all our cases. Lung biopsy or necropsy, how-ever, revealed the muscular hyperplasia describedin muscular 'cirrhosis' of the lung.

CASE HISTORIES

CASE 1 H. H., born in 1895. worked for sevenyears as a barrel maker, spent five years in the Army,cleaned railway engines for 17 years, and was a rail-way clerk for 20 years. About 1945 he began to noticeshortness of breath, which slowly became worse andby 1957 was troublesome. He had to give up workin 1958 and was first seen by us in December of thatyear. He also gave a history of cough with scantypurulent sputum for eight years, but no previouschest radiograph had been taken.On examination his general condition was good.

He was cyanosed and dyspnoeic at rest. There wereextensive crepitations over both lungs, and he hadmarked finger-clubbing. He said that his fingers had

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D. Davies, A. Macfarlane, C. S. Darke, and 0. G. Dodge

Necropsy The body was that of a thin elderly man.The pleural sacs showed dense adhesions in the left.with a few over the right apex. The trachea andbronchi contained pus. Pleural adhesions obscuredthe surface of the left lung, but the surface of theright was nodular due to the presence of subpleuralcysts. The left lung, sectioned post mortem, showedsevere honeycombing in the upper lobe, includingPthe lingula, a few of the cysts measuring 3 cm. indiameter. The cysts had a smooth inner lining andsome intercommunicated. Confluent broncho-pneumonia was present in the lower lobe, and therewas also some honeycombing subpleurally. The rightlung was distended with 10 formalin, and whole-lung paper-mounted sections were prepared by theGough-Wentworth technique. Honeycombing was

....l~~~~'- ..

J ~*. . .S. ' 9'y.

IG. 2. Case 1. Radiograph of right lung showinghoneycombing and diffuse shadowing.been the same shape for many years. The haemo-globin level was normal, and the blood sedimentationrate was 62 mm. in one hour (Westergren). His serumy-globulin was 2-7 g. /100 ml. The electrocardiogramshowed tall P waves but no other abnormality. Hischest radiograph showed diffuse shadowing through-out both lungs with honeycombing. most marked inthe right upper lobe (Fig. 2). Three specimens of .-~sputum were negative for tubercle bacilli on directs. T hm xexamination and culture.He managed to get back to a light job inter-

mittently but had to retire in October 1959. Hethen had tachycardia at rest and a vital capacity of1c65 1. and an FsEh.V of 1s2 1. He was treated -,with prednisolone, 15 mg. daily. Sputum cultureseventually produced a growth of acid- and alcohol-fast bacilli. Two further specimens in January 1960 ; -showed atypical acid-fast rods. The organism grew *-r-. X j _on culture and was identified as a photochromogenicmycobacterium in Runyon's group I.He did not improve after starting treatment with

prednisolone. It was continued, and P.A.S. andisoniazid were added in January 1960. Mycobacteria * $were not found in the sputum thereafter. He becamemore short of breath, and the left upper lobe becameconsiderably more cystic. He died at home in Sep-tember 1960, 15 years after the onset of dyspnoea.

During life it was considered that the myco-bacterial infection was not the cause of his diseasebut that it was a secondary infection in damaged FIG. 3. Case I. Right lung, coronal section showing severelungs. honeycombing in all lobes.

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Chronic diffuse fibrosing alveolitis 275

4......

V s.-

Case 1. Wall of subpleural cyst containing a thick band of plaini muscle.E., x 50.

1 4~~~4

1.4wVvgdR4Axi

.~- I ..::

..:

'4. * ....

1.. ..

.A

Z4

FIG. 5. Case 1. Subpleural overgrowth of plain muscle with diffuse muscular hyperplasiaon left. Pleural surface, top right. Black areas are deposits of carbon. All the supportingframe-work is muscle. H. and E., x 50.

FIG. 4.H. and i

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severe in the upper and middle lobes and in the basalhalf of the lower lobe (Fig. 3).The heart showed generalized dilatation and

slight right ventricular hypertrophy.

Histology of the lungs The most striking featurewas the presence of abundant plain muscle aroundand between the cysts and under the pleura. Themuscle often formed a distinct coat around the cysts,particularly subpleurally (Fig. 4). but it was alsopresent in some areas as thick subpleural slabs un-related to the honeycombing (Fig. 5). The collagenousstroma was variable in amount, but in most placesit was overshadowed by the plain muscle. There wasmuch cellular desquamation due to post-mortemautolysis, but in some areas a cubical or columnarepithelium lined the cysts. Chronic inflammatory cellswere scanty. Towards the centres of the upper andlower lobes of both lungs the structure was essen-tially normal, apart from patchy areas of interstitialfibrosis. There was an acute bronchopneumonia, bestdeveloped in the lower lobes.

In two sections from the left lung a few smallcysts were lined by chronic granulation tissue con-taining an occasional Langhan's giant cell. This wasconsidered to be a tuberculoid type of reaction tothe mycobacterium isolated from the sputum duringlife.The pulmonary arteries showed marked medial

hypertrophy and intimal fibrosis.

CASE 2 J. V. S. was born in 1905. In his early lifehe worked for seven years as a coal-miner and forseven years in an ironworks where there was amoderate amount of dust. He was not exposed to anyimportant degree of dust or fumes thereafter. He firstcomplained of dyspnoea and a slight dry cough in1955. He was found to have a moderate degree ofaortic stenosis. There was no previous history ofrheumatic fever. The chest radiograph showed wide-spread nodulation in both lung fields. Dyspnoeabecame progressively worse. A tentative diagnosis ofsarcoidosis was made in 1958, and treatment withcorticosteroids was begun and continued until hisdeath. This did not halt his steady downward course.When admitted to hospital in August 1962 he had

lost 41 stones (28-6 kg.) in weight. He had tachypnoeaat rest and mild finger-clubbing. There were coarsecrackling sounds over both lungs. His blood pressurewas 140/80 mm. Hg. A rough aortic systolic murmurwas audible. There was no evidence of heart failure.Serial chest radiographs since 1955 had shown in-creased shadowing (Fig. 6). Radiographic evidenceof calcification of the aortic valve was also found.The erythrocyte sedimentation rate was normal.Electrophoresis showed an increase in serum y-globulin. The electrocardiogram showed left ventri-cular hypertrophy. His vital capacity was 1-2 l., andhe expired all this in one second. The total lungcapacity was reduced to 2-6 litres. Gas mixing(helium) was complete in 14 minutes. His arterial

Case 2. Chest radiograph showing widespread dijiuse shadowing.

b

.s

:a

:N.4

.s!

276

FIG. 6.



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Chronic diJffuse fibrosing alveolitis

oxygen saturation was 970O at rest and 86% onexercise. The arterial pH was 7-24 and the Pco2 53mm. Hg. The carbon monoxide diffusing capacity was6-5 ml./min./mm. Hg (steady-state method).

After thoracotomy biopsies of the right upper andlower lobes were taken. The pleura was free. Thelung contracted considerably on opening the pleuralcavity, and it felt fibrotic. Its surface was coveredwith small cysts.

His post-operative course was very stormy, dueto a recurrent right pneumothorax. A remarkabledegree of negative intrapleural pressure was noted,amounting to 60 to 75 cm. of water. He died fourweeks after operation.

Biopsy of lung The normal lung architecture wascompletely destroyed. The tissue consisted of smallbronchi and cysts lined by bronchiolar epithelium,surrounded by thick sheaths of smooth muscle (Fig.7). There was little fibrosis and no evidence of activeinflammation.

Necropsy The body was that of a thin, middle-aged man with clubbed fingers and a thoracotomyscar. There was an advanced calcific aortic stenosiswith left ventricular hypertrophy and a recentfibrinous pericarditis with early organization. Thelungs felt firm throughout. and subpleural cysts wereprominent over the surfaces of the lower lobes.After perfusion with formalin, the lungs were slicedand showed honeycomb changes throughout thelower lobes, with smaller areas of honeycombing inthe other lobes (Fig. 8).

Histology of lungs The honeycomb cysts were 'Linedby bronchiolar epithelium and were often embeddedin sheaths of hypertrophied smooth muscle. Thepulmonary vessels showed marked medial hyper-trophy, and areas of smooth muscle in zones of inter-stitial fibrosis often appeared to arise from vesselwalls. The bronchi showed focal squamous meta-plasia. and there were many spicules of ectopic bonein the interstitial fibrous tissue.

CASE 3 J. D., born in 1900, started work as a coal-miner in 1914 and continued with undergroundwork until he had to give up because of breathless-ness in September 1963. A 35-mm. chest film inOctober 1957 was passed as normal then and onrescrutiny later. When first seen in October 1959 hegave a history of a slight cough and scanty sputumin winter for three or four years, and shortness ofbreath for a year. He could keep up with otherpeople of his age wh:n walking on the flat but noton hills. His general condition was good. He hadspade-like fingers but no clubbing, and there weremultiple fine crepitations over the lower half of bothlungs. Other systems were normal. The chest radio-graph showed fine pinhead nodulation throughoutboth lung fields, more marked at the bases (Fig. 9).The electrocardiogram was normal. A diagnosis ofchronic diffuse fibrosing alveolitis was made.He was kept under observation. A year later he

was rather more short of breath, but there was nochange in his chest radiograph. Breathing tests showeda restrictive impairment of ventilation.He slowly deteriorated, having to take lighter jobs

44'FIG. 7. Case 2. Lung biopsy. Irregular thick bands of plain muscle with epithelial-lined air spacesamong them. H. and E., x 125.

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TABLE IICASE 3

Diffusing02 Satura- Capacity

V.C. F.E V .0P.F.R. Pco, tion ((ml. mg.0.) (I-" (m ~~Mm. Hg)

mmn.) Hgm)RestExer- RetExer-_Rest ciseRest scie

Sept. 1960, 2-85 2-45 97 95May 1962 3-15 2-25 440 33-5 95 90Oct. 1963 2 31 2-16 380 44 92 87 12 27

and white cell count were normal. The blood sedi-mentation rate was 20 mm. in one hour (Westergren>and the serum y-globulin 1-7 g./100 ml. Liver functiontests were normal. The rheumatoid latex fixation teston the serum was negative, but the Rose-Waaler testwas positive. The electrocardiogram showed that rightventricular hypertrophy had developed since 1960.At thoracotomy the left lung had a rather knobbly

surface and felt firm throughout. There were somesmall subpleural cysts at the tip of the lingula. Abiopsy included this area. together with deeper firmtissue.

FIG. 8. Case 2. Left lung. Honeycombing in lower half,nodular basal surface.

and losing more time from work. There was a gradualincrease in lung shadowing and a deterioration inlung function tests (Table II). He eventually agreedto undergo investigation in hospital.When ad Tnitted in October 1963 his general condi-

tion was still good. His breathing was rapid at restwithout any wheezing or prolongation of expiration.He was slightly cyanosed. There were still extensivefine crepitations over the lower half of both lungsbut no other clinical abnormality. His haemoglobin

FIG. 9. Case 3. Radiograph of right lung showing finenodulation.

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elderly man. There was a healed thoracotomy scarover the left side. The right pleural sac was healthy;

1f' d the left contained fibrous adhesions around the siten;;,/.zxi of biopsy. The trachea and bronchi were filled with

pus. Both lungs were distended with formalin andsectioned after fixation. The surface of each was

A nodular, and there were subpleural bullae in the right% middle lobe (Fig. 1). Whole-lung paper-mounted sec-_ _ _ _s i a_¢tionsshowed extensive honeycombing in each lungro w Finvolving almost the whole of each lower lobe and

the right middle lobe and the anterior portion of the< upper lobe (Fig. 11). The cysts varied from a few

;0,,p*b_ millimetres to 15 cam. in diameter, the majority beingabout 5 mm. In the lower lobe many of the cystscontained pus.The heart weighed 390 g. and showed generalized

dilatation and moderate right ventricular hyper-< +.4 ~~~~~~~trophy.

.A. V ...wHistology of the lungs In the areas of honey-combing there was a considerable excess of plainmuscle around and between the cysts, many of whichwere lined by a single layer of epithelial cells. Wherethe cysts were small the bands of muscle usually

AL

FIG. 10. Case 3. Lung biopsy. Marked excess of plainmuscle among partially collapsed epithelial-lined cysts.H. and E., x125.

Lung biopsy The cysts were lined by cubical orcolumnar epithelium, and their walls were composed A

of a mixture of collagen and plain muscle. Moredeeply the same epithelial-lined air spaces were pre- i s 3 $ *o4tsent, but they were collapsed. Around and between 'them were thick bands of plain muscle with very little .connective tissue among them and only minimalevidence of inflammation (Fig. 10).There were no post-operative complications, but he pA

was too short of breath to return to work, and by i3December 1963 he could walk for 100 yards only. Hewas given prednisolone, 20 mg. daily. There was no *improvement, and he was readmitted to hospital on8 February 1964 with acute breathlessness, a trouble- Vsome cough, and mucoid sputum. His temperaturewas raised. Radiography revealed a moderately exten- rsive right mid-zone consolidation. His sputum con-tained only normal flora. He was treated with oxygen, ' t:'-intravenous aminophylline, and oxytetracycline, andthe dose of prednisolone was increased. After 36hours he improved a little but died suddenly on14 February, six years after the onset of shortness A

of breath.FIG. 11. Case 3. Right lung. Severe honeycombing in all

Necropsv The body was that of a normally nourished areas.

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t 41~~~~~~~~~~.

;KA X :

A~~~Ar~ P -

9f . ,'e..FIG.12. Case 3. Diffuse over-r\~vXR growth of plain muscle among

cYstic spaces of varying size. H.- ~~~~~~~~andE., x 50.

M/-,>

I

A.

formed a lattice work among them (Fig. 12). Therewere, however, many areas in both lungs where thecysts were enclosed by fibrous tissue and musclewas sparse. In areas free from honeycombing thehistological features were those of chronic diffusefibrosing alveolitis (Fig. 13). Acute broncho-pneumonia was present in both lower lobes. The pul-monary arteries showed widespread muscular hyper-plasia and sclerosis.

,v, ' KY-

4

FIG 13. Case 3. Diffuse > Afibrosing alveolitis.Muscle inconspicuous.Terminal pneumonia.H. and E., x 50.

CASE 4 C. T., born in 1900, was admitted to hospitalin March 1964 because of pain in the chest and backand shortness of breath.She gave a history of dysphagia in 1954, but no

cause was found, and her symptoms soon improved.A chest radiograph at that time was reported to benormal. She had been twice in hospital in 1958. com-

plaining of pain in the back and the front of thechest with breathlessness. The back pain dated from

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a fall some weeks earlier. Radiographs of the spinewere normal, and that of the chest was reported toshow some fibrosis or bronchiectasis. No firm diag-nosis was made. Her symptoms continued, but shehad little cough or sputum. She became worse in theautumn of 1963 and was admitted to hospital inMarch 1964.She was well nourished. She had clubbing of the

fingers, which had appeared about five years earlier.There were fine crepitations over the lower halvesof both lungs, and she was dyspnoeic on slight exer-tion. She was tender over the lower thoracic spine,but there was no other clinical abnormality. Thehaemoglobin and white blood count were normal,and the erythrocyte sedimentation rate was 45 mm.in one hour (Westergren).

She was found to have marked spinal osteoporosiswith collapse of several thoracic vertebrae. The serumcalcium was 10-3 mg./100 ml., inorganic phosphate3-6 mg./100 ml., alkaline phosphatase 20 K.A. units/100 ml. The serum proteins were normal, and noBence-Jones proteose was detected in the urine. On alow calcium diet the daily urinary calcium outputover three days averaged 125 mg. She was consideredto have post-menopausal osteoporosis and was puton a high calcium diet. The back pain improvedand was not troublesome thereafter.Her vital capacity was 1.1 1., F.E.V.1.o 0.99 1.,

oxygen saturation 89% (ear oximeter), and carbonmonoxide diffusing capacity 9-8 ml./min./mm. Hg(steady-state method). The electrocardiogram showedno abnormality. The rheumatoid latex fixation test

was negative. The chest radiograph showed smalllungs with high diaphragms. There was diffusenodulation and some honeycombing (Fig. 14). Herprevious radiographs were traced. Those taken in1953 and 1954 showed nodulation in the left mid-zone and possibly some fine mottling in theremainder. The films taken in 1958 showed coarsernodulation throughout both lungs, more marked onthe left side. The 1964 films showed further progresswith shrinkage in lung volume and elevation of thediaphragms.A diagnosis of chronic diffuse fibrosing alveolitis

was made, but because of her age and the longduration of the disease it was anticipated that thelungs would show the changes of 'muscular cirrhosis'.It was considered that treatment with corticosteroidswould not be of value, and she went home.There was little change in her condition over the

next few months, but by the end of 1964 she wasmore short of breath and hyperventilating at rest.She had also developed mild ankle oedema. She diedfairly suddenly at home on 11 January 1965, nearlyseven years after the onset of dyspnoea and 12 yearsafter the first radiographic evidence of disease.

Necropsy The body was that of a normally nourishedelderly woman with slight peripheral oedema. Therewere a few fibrous adhesions in both pleural sacs.Small amounts of mucopus were present in thetrachea and bronchi. Both lungs were perfused withformalin. The posterior surfaces of both lower lobes

FG. 14. Case 4. Chest radiographshowing diffuse nodulation andhoneycombing.

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were nodular due to honeycombing, most marked inthe posterior part of the left lower lobe (Fig. 15). Thecysts measured up to 1-5 cm. in diameter. Theremainder of both lungs felt firm and fibrotic.The heart showed slight right ventricular hyper-

trophy.

Histology of the lungs In the honeycombed areas iX

the cysts were usually lined partly or wholly by epi-thelium, and their walls consisted of a mixture of . .. ;.fibrous tissue and plain muscle (Fig. 16). Elsewhere win both lungs the histological appearances were thoseof diffuse fibrosing alveolitis. Acute bronchopneu- -monia was present in both lower lobes, someof the cysts containing pus. The pulmonaryarteries showed marked muscular hypertrophy andintimal fibrosis.

CASE 5 A. N., born in 1901, started work as a coal-miner at the age of 14 years. He began to noticeshortness of breath in 1960 and changed to a lighterjob underground. He had little cough or sputum. Hisfirst chest radiograph was taken in May 1963. andhe was investigated as a result.

His general condition was quite good. Apart fromclubbing of the fingers there was no clinical abnor-mality. The chest radiograph showed some shift ofthe mediastinum to the right with apparent broaden-ing of its upper part. There was diffuse mottlingthroughout both lungs, more marked on the right andat the left base (Fig. 17). The erythrocyte sedimenta-tion rate was 94 mm. in one hour (Westergren) and FIG. 15. Case 4. Left luIng. HoneYcomzbing restricted tothe serum y-globulin 2-8 g. I 00 ml. On various occa- posterior aspect of lower lobe.

Filft;

44t~~ '-0A

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t~~~~~ =_<- }; t ~~~~~~~~~~~~E., x 50.



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FIG. 17. Case 5. Chest radiograp ' showing diffuse shadowing at both bases.

FIG. 18. Case 5. Lung biopsy. Collapsed air spaces embedded in fibrous tissueand plain muscle with chronic inflammatory cell infiltration. Masson, x 50.

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stons the rheumatoid latex fixation test was positiveonce. weakly positive once, and negative once. TheRose-Waaler test was negative. Bronchoscopy showedno abnormality. The scalene lymph nodes containedonly an excess of carbon. A right bronchogramshowed that the sub-segmental bronchi reached outftirther to the periphery than usual, with narrowingof the unfilled peripheral zone. Ventilatory functiontests showed a restrictive pattern, and the diffusingcapacity was low.He was too short of breath to go back to work,

and in September 1963 a biopsy of the right middlelobe was done. The pleura was free. The lung wasgranular on palpation and difficult to inflate.

Lunig biopsy A wedge of lung, 2-5 by 2 by I cm..was taken with subpleural thin-walled cysts andfirmer tissue more deeply. Histologically the cystswere lined by cubical epithelium. and their walls werecomposed of collagen fibres. The firmer tissuebeneath the cysts was collapsed and contained air

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TABLE IIICASE 5

Diffusing0° Satura- Capacity

V.C. F.E.V. P.F.R. tion (°/) (ml. min.'(..I) n(1.mm. Hg)min.); Breath- Exer-Rest in ~ Rest cs

31 May 1963 2-49 2 19 465 -8 July 1963 2 28 2-04 - 14 46-6

23 Dec. 1963 1192 1-65 440 8 5 20 46April1964 - - 77 87

spaces often lined by epithelium and embedded in aframework of connective tissue and plain muscleinfiltrated by chronic inflammatory cells. The musclewas distributed haphazardly and rarely appeared tobe forming part of the walls of the air spaces (Fig.18).Treatment with prednisolone was begun. but he

continLued to get more short of breath. Soon he was

~FIG. 19. Caise 5. Rig/it lunig.Sligit honev'eombing int upper- anidlower lobes.

:j'

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dyspnoeic after walking 20 yards but was still com-fortable at rest. Respiratory function tests showedfairly rapid deterioration (Table III). By Novembercrepitations had developed at both lung bases. Treat-ment with prednisolone was tailed off in January. InApril 1964 he was too short of breath to get out ofbed and he died from respiratory insufficiency soonafter, four years after the onset of shortness ofbreath.

Necropsy The body was that of a normallynourished elderly man. The pleural sacs were free,apart from adhesions around the site of lung biopsy.The trachea and bronchi contained mucopus. Bothlungs felt firm, but the surfaces were not knobbly.They were distended with formalin and sectioned afterfixation. They showed very early honeycombing inthe posterior parts of both lower lobes and in theanterior part of the right upper lobe (Fig. 19). Noneof the cysts measured more than 5 mm. in diameter.Elsewhere the lungs felt fibrotic.The heart weighed 430 g. and showed generalized

dilatation with right and left ventricular hypertrophy.The aortic valve was bicuspid with early calcificstenosis.

Histology of the lung In all lobes the histologicalfeatures were those of chronic diffuse fibrosing alveo-litis. There was still considerable lymphocytic and

histiocytic infiltration along with the increase inreticulum and collagen fibres in the wall of the airspaces (Fig. 20). In most areas plain muscle was notconspicuous, but it could be seen as small bundles orbands irregularly distributed throughout the fibrosedpulmonary framework. Occasionally were found largeirregular sheaths of plain muscle (Fig. 21). Wherehoneycombing was present muscle became moreprominent (Fig. 22), though nowhere reaching theproportions seen in cases 1 to 4. Acute broncho-pneumonia was present in the lower lobes. The pul-monary arteries showed muscular hyperplasia andsclerosis.

DISCUSSION

TERMINOLOGY The two most commonly usednames for this condition are 'muscular cirrhosisof the lungs' and 'bronchiolar emphysema'. Thzformer is a descriptive title for the condition andgives a fairly clear picture of firm, knobbly lungswith fibrosis and an excess of muscle, withdestruction and distortion of normal tissue andarchitecture. It is, of course, only a descriptivetitle.The authors choosing the title 'bronchiolar

emphysema' or 'idiopathic diffuse bronchiolectasis'

FIG. 20. Case 5. Diffuse fibrosing alveolitis with patchy muscular hyperplasia.Note long band of muscle running transversely above centre. H. and E., x 50.

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s:;,.Sw * ,.& *.Y^

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x.$.. ,X f.e <..# 5t..t &

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FIG. 21. Case 5. Marked overgrowth of muscle in fibrotic area. Masson, x 50.

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FIG. 22. Case 5. Patchy muscular hyperplasia in area of honeycombing. Masson, x 50.

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(Gonzalez-Licea and Perez-Tamayo, 1963) havespeculated on the origin of the cystic spaces inthe lungs. In our opinion it is impossible to saywhether these are terminal bronchioles, respiratorybronchioles, alveolar ducts, or epithelializedalveoli, or a mixture of all these. We considerthat the most important change in the lungs isthe obliteration and destruction of respiratorytissue at alveolar level and that the cystic changesare secondary to this. As this is only in a veryminor way a 'condition of the lung characterizedby increase beyond the normal in the size of airspaces distal to the terminal bronchiole, eitherfrom dilatation or destruction of their walls' (CibaSymposium definition of emphysema, 1959), it isincorrect to classify it as a form of emphysema.We do not agree with Siebert and Fisher (1957)that these cases show essentially the same physicaland laboratory findings as do those with vesicularemphysema.

Because multiple small cysts are almostinvariably a feature of this condition, it is one ofthe varieties of honeycomb lung. Oswald andParkinson (1949) divided their cases of honey-comb lung into those with specific features andthose without. Those with specific features wereall young and had such diseases as xanthomatosis,biliary cirrhosis, tuberose sclerosis, or pituitarydisorders. Their other cases were of uncertainaetiology, but spontaneous pneumothorax wascommon, whereas it has only once been reportedin muscular cirrhosis of the lung. Heppleston(1956), in discussing the pathology of honeycomblung, likewise divided the cases into those withand without specific features. To the specificfeatures he added such conditions as berylliosis,giant-cell pneumonia, disseminated tuberculosistreated with drugs, and scleroderma. In the caseswithout specific features he noted that the lungsoften contained an excess of smooth muscle ingreater or lesser degree. 'Muscular cirrhosis' ofthe lungs is therefore a non-specific form ofhoneycomb lung in which hyperplasia of smoothmuscle is so marked as to be very prominent andto excite comment.

Heppleston in his series also classified one caseas primary leiomyomatosis. We have not seen sucha condition and cannot say whether it exists asan entity independent of tuberose sclerosis.Heppleston's patient had chylous ascites andpleural effusion, and this condition may be relatedto that described by Fraimow and Cathcart (1962)as 'intrathoracic angiomyomatous hyperplasiawith chronic chylothorax and retrop?ritonealpseudocystic- angiomyomatous hyperplasia'.

Rosendal's (1942) patient included in Table I mayhave been an example of primary leiomyomatosisbecause the lymph nodes were involved.

PATHOGENESIS A variety of theories have beenput forward to explain the development of thiscondition. Early authors suggested an inflamma-tory cause. Siebert and Fisher (1957) put forwardan ingenious theory that it is a form of hyper-trophic emphysema, but that hypoplasia of thedistal respiratory unit caused the emphysema tobe bronchiolar in location rather than 'vesicular'.Gonzalez-Licea and Perez-Tamayo (1963) con-sider the condition to be primarily a selectivedilatation of the terminal bronchioles, a sort ofno-man's-land between bronchiectasis andemphysema. They suggested idiopathic diffusebronchiolectasis as the most appropriate name.Fraimow and Cathcart (1962), however, specu-lated that the earliest change might be that ofinterstitial pulmonary fibrosis (diffuse fibrosingalveolitis) and pneumonitis.We have already indicated that our cases and

those described in the literature are indistinguish-able on clinical, radiological, and physiologicalgrounds from diffuse interstitial pulmonaryfibrosis or chronic diffuse fibrosing alveolitis(Scadding, 1964; Gough, 1964). Our cases 1 to 4showed histological evidence in parts of bothlungs, generally away from the honeycombedareas, of diffuse interstitial pulmonary fibrosis.Case 5, of shorter duration, was considered duringlife to be a further example of muscular cirrhosisof the lungs on the basis of the lung biopsy whichcontained a considerable amount of muscle.Necropsy, however, showed it to be an exampleof chronic diffuse fibrosing alveolitis with patchymuscular overgrowth. We have reviewed necropsylung sections from other cases of chronic diffusefibrosing alveolitis and have found evidence ofmuscular hyperplasia in several, particularlywhere honeycombing has occurred. From the sheeramount of muscle present in the cases of muscularcirrhosis we cannot accept that this is merely acondensation of existing muscle (Livingstone,Lewis, Reid, and Jefferson, 1964) due to thehoneycombing, but consider it must be due to areal increase from hyperplasia.The normal lung does contain a considerable

amount of muscle in the walls of its blood vessels,bronchi, and bronchioles, including the respiratorybronchioles. Fine interweaving bands are alsopresent in the alveolar ducts but not in the wallsof the alveoli themselves. A few muscle fibres mayalso be present in the walls of the large subpleural

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lymphatics (Heppleston, 1963). Liebow, Loring,and Felton (1953) stressed the difficulty of identify-ing the source of the increased muscle which issometimes a feature of various chronic pulmonarydiseases, and serial sections are often needed. Wehave occasionally identified abnormal bands ofmuscle arising from pre-existing bronchiolarmuscle or hypertrophied blood vessels, but inmost instances it is impossible to define the source.Th-e origin of the cysts in the honeycombedarea also gives rise to doubt. Some are almostcertainly distended bronchioles, but others maywell be greatly enlarged alveolar ducts or evenalveoli, particularly when the muscle forms alattice-work among the cysts rather than a definitewall around each (Fig. 12).Some degree of muscular hyperplasia appears

to us to be a common accompaniment of chronicdiffuse fibrosing alveolitis. A study of a rapidlyfatal case of three months' duration has showntiny sheaths of proliferating muscle cells in thethickened and oedematous walls of the air spaces.Much of this proliferating muscle appears to bearising from respiratory bronchioles and alveolarducts, and it is possible that at least some of theexcess muscle in cases of muscular cirrhosis hasoriginated from these sites.The average age at the onset of dyspnoea is

about the same in muscular cirrhosis as in chronicdiffuse fibrosing alveolitis. The range for cases inTable I is 25 to 78 years with, as far as can bedetermined, a mean of 52 years and a medianof 52 5 years. In the 45 cases of 'diffuse interstitialpulmonary fibrosis' reported by Livingstone et al.(1964) the range was 20 to 78 years, with a meanof 50 5 years and a median of 55 years. Theduration of the disease tends to be longer in'muscular cirrhosis'. Based on symptoms, it wasfive years or more in 15 out of 30 (50%), com-pared with 15 out of 45 (33%) in Livingstone'sseries. In contrast to Scadding's (1960) findings,Livingstone and his colleagues found that longsurvival was associated with an early onset anda short life with a later onset. Of the 26 whodeveloped symptoms at the age of 50 or over,16 (62%) were dead in less than three years andonly five (19%) survived four years. This com-pares with three out of 18 (17%) dead in lessthan three years among those with muscularcirrhosis who developed symptoms at the age of50 or more. Twelve (67°,) of these survived forover four years. It seems that if a person developschronic diffuse fibrosing alveolitis at the age of50 or more and survives longer than three yearshe tends to end up with muscular cirrhosis.

Cases of chronic diffuse fibrosing alveolitiswhich run a short course do not as a rule showhoneycombing. Many of the more chronic cases,however, do show this as the main feature atnecropsy, though the relationship between dura-tion of disease and honeycombing is not clear-cut.The cysts occupy in the main the peripheral basaland lateral areas, the central and apical areasbeing spared (Gough, 1965). Except in case 1,this is also the distribution in our patients, theposterior parts of the lower lobes being mostheavily involved. It is almost certainly true thatchronic diffuse fibrosing alveolitis is the common-est cause of honeycomb lung, and many paperson the pathology of the former mention fibro-muscular hyperplasia as a common feature, e.g.,Herbert, Nahmias, Gaensler, and MacMahon(1962).

In our opinion, 'muscular cirrhosis of the lung'and 'bronchiolar emphysema' are descriptiveterms for variants of chronic diffuse fibrosingalveolitis. A long duration, when the conditionappears in the elderly, seems to provide a greateropportunity for honeycombing and muscularhyperplasia to develop. A satisfactory descriptivetitle for this condition would be a 'chronic diffusefibrosing alveolitis with muscular hyperplasia andhoneycombing".

It seems doubtful if exposure to coal and otherdust plays a part in determining this variation ofdiffuse fibrosing alveolitis. Though three ofour patients were coal-miners this mayeasily have occurred by chance because a con-siderable proportion of our patients are soemployed. One of Siebert and Fisher's (1957)patients was a coal-miner and the one describedby Brun, Perrin-Fayolle, Cassan, and Tommasi(1963) also had some dust exposure. Bowermanand Towbin's (1964) patient was a welder. Four-teen out of the 30 patients in Table I, however.are women, so it is unlikely that exposure to dustis very important. Even so, Chatgidakis (1960)found that nodular muscular hyperplasia was acommon finding in the lungs of South Africangold- and coal-miners.

In two of our three patients in whom the testswere done, the rheumatoid latex fixation test orthe Rose-Waaler reaction were positive. Suchfindings are becoming increasingly recognized asfeatures in patients with chronic diffuse fibrosingalveolitis who never develop rheumatoid arthritis(Turner-Warwick and Doniach, 1965; MacKayand Ritchie, 1965). Two of our patients also hadaortic stenosis, but this was only of clinical signi-ficance in one: it does not seem to have been

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Chronic difluse fibrosing alveolitis

recorded in other published cases and may bea coincidence.

TREATMENT Four of our patients were treatedwith corticosteroids without benefit. The resultwas the same in two other cases recorded in theliterature (cases 2 and 4 of Fraimow and Cathcart,1962). With such well established and irreversiblechanges, this is only to be expected.

SUMMARY

The literature on 'muscular cirrhosis of the lungs'and 'bronchiolar emphysema' has been reviewed.The patients are, in the main, middle-aged orelderly people with slowly progressive dyspnoea.The chest radiographs show diffuse fibrosis andat necropsy the lungs are honeycombed. Hyper-plasia of smooth muscle is conspicuous. Theyshow no evidence of such conditions as eosino-philic granuloma, tuberose sclerosis, scleroderma,or other specific conditions associated with honey-combing.

Five new cases are described. Clinically, radio-graphically, and physiologically they displayedthe features of chronic diffuse fibrosing alveolitis.They deteriorated slowly and died from four to15 years after the onset of dyspnoea. Pathologi-cally they had honeycombing of the lungs withexcess muscle in the cystic areas and the histologi-cal features of diffuse fibrosing alveolitiselsewhere. Four were classical examples of'muscular cirrhosis' of the lungs. In the fifth,that diagnosis was made on the lung biopsy,but post-mortem examination showed thatthe muscular overgrowth was patchy and notnearly as well developed as in the others, theoverall picture being that of chronic diffusefibrosing alveolitis.The increase in plain muscle in these cases is

real and not due merely to condensation of lungtissue.'Muscular cirrhosis of the lungs' and 'bron-

chiolar emphysema' are not separate entities butdescriptive terms, the latter being a particularlyunfortunate one. They are variants of chronicdiffuse fibrosing alveolitis, related to a late onsetand long duration of the disease.

We acknowledge the help of many colleagues whohave assisted and given information. For most of the

photographs our thanks are due to Mr. A. G.Sylvester and the staff of the Photographic Unit ofthe Sheffield Regional Hospital Board. We aregrateful to Miss B. Buck for secretarial work.

REFERENCESBowerman, D. L., and Towbin, M. N. (1964). Bronchiolar emphy-

sema: its significance in industrial medicine. Dis. Chest, 46, 349.Brun, J., Perrin-Fayolle, M., Cassan, G., and Tommasi, M. (1963).

La cirrhose musculaire lisse (l6iomyomatose) des poumonsempoussieres. J. franc. Mid. Chir. thor., 17, 325.

Burman, S. O., and Kent, E. M. (1962). Bronchiolar emphysema(cirrhosis of the lung). J. thorac. cardiovasc. Surg., 43, 253.

Calma, I. (1941). Cystic emphysema of the lungs with interstitialsclerosis. Brit. J. Tuberc., 35, 40.

Chatgidakis, C. B. (1960). Nodular muscular hyperplasia in the lungsof South African miners. Arch. industr. Hlth, 21, 160.

Ciba Guest Symposium (1959). Terminology, definitions, and classi-fication of chronic pulmonary emphysema and related conditions.Thorax, 14, 286.

Delarue, J., Paillas, J., Paley, P., Daumet, P., and Daussy, M. (1960).Insuffisance respiratoire progressive, emphysime bulleux etleiomyomatose pulmonaire diffuse. J. franc. Med. Chir. thor.,14, 761.

Fraimow, W., and Cathcart, R. T. (1962). Clinical and physiologicalconsiderations in pulmonary muscular hyperplasia. Ann. intern.Med., 56, 752.

Gonzalez-Angulo, A. (1962). Diffuse bilateral peribronchiolar andinterstitial muscular hyperplasia associated with bronchiolardilatation (bronchiolar emphysema). Amer. Rev. resp. Dis., 86,256.

Gonzales-Licea, A., and Perez-Tamayo, R. (1963). Idiopathic diffusebronchiolectasis-so-called bronchiolar emphysema. Amer. J.clin. Path., 40, 157.

Gough, J. (1964). Fibrosing alveolitis. Brit. med. J., 2, 818.-(1965). Pathological changes in the lungs associated with cor

pulmonale. Bull. N. Y. Acad. Med., 41, 927.Heppleston, A. G. (1956). The pathology ofhoneycomb lung. Thorax,

11, 77.(1963). Lung muscle. Lancet, 1, 1107.

Herbert, F. A., Nahmias, B. B., Gaensler, E. A., and MacMahon,H. E. (1962). Pathophysiology of interstitial pulmonary fibrosis.Arch. intern. Med., 110, 628.

Hirshfield, H. J., Krainer, L., and Coe, G. C. (1962). Cystic pulmonarycirrhosis (bronchiolar emphysema). Dis. Chest, 42, 107.

Jerry, L. M., and Ritchie, A. C. (1964). Bronchiolar empbysema.Canad. med. Ass. J., 90, 964.

Liebow, A. A., Loring, W. E., and Felton, W. L. (1953). The muscula-ture of the lungs in chronic pulmonary disease. Amer. J. Path.,29, 885.

Livingstone, J. L., Lewis, J. G., Reid, L., and Jefferson, K. E. (1964).Diffuse interstitial pulmonary fibrosis. Quart. J. Med., 33, 71.

McAdams, G. B. (1961). Bronchiolar emphysema. Arch. intern. Med.,108. 279.

MacKay, I. R., and Ritchie, B. (1965). Diffuse fibrosing alveolitis(diffuse interstitial fibrosis of the lungs): two cases with auto-immune features. Thorax, 20, 200.

Oswald, N., and Parkinson, T. (1949). Honeycomb lungs. Quart. J.Med., 18, 1.

Ravines, H. T. (1960). Bronchiolar emphysema of the lungs. Arch.Path., 69, 554.

Rosendal, T. (1942). A case of diffuse myomatosis and cyst formationin the lung. Acta radiol. (Stockh.), 23, 138.

Rubenstein, L., Gutstein, W. H., and Lepow, H. (1955). Pulmonarymuscular hyperplasia (muscular cirrhosis of the lungs). Ann.intern. Med., 42, 36.

Scadding, J. G. (1960). Chronic diffuse interstitial fibrosis of the lungs.Brit. med. J., 1, 443.- (1964). Fibrosing alveolitis. Ibid., 2, 686.Schaffner, F. (1959). Clinico-pathological conference. J. Mt Sinai

Hosp., 26, 324.Siebert, F. T., and Fisher, E. R. (1957). Bronchiolar emphysema,

so-called muscular cirrhosis of the lungs. Amer. J. Path., 33, 1137.Turner-Warwick, M., and Doniach, D. (1965). Auto-antibody studies

in interstitial pulmonary fibrosis. Brit. med. J., 1, 886.

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muscular hyperplasia lung as diffuse fibrosing alveolitis · d. davies, a. macfarlane, c. s. darke,...

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