the pathology of honeycomb lung · descriptions of honeycomb lung under other terms may,in the...

Thorax (1956), 11, 77.

THE PATHOLOGY OF HONEYCOMB LUNGBY

A. G. HEPPLESTONFrom the Department ofPathology, Welsh National School ofMedicine, Cardiff

(RECEIVED FOR PUBLICATION DECEMBER 17, 1955)

A form of cystic lung, characterized by numerous,widespread and usually small cavities, is a well-recognized though apparently uncommon condition,which, according to earlier accounts, occurredespecially in children (Sharkey, 1894; Tooth, 1897;Fletcher, 1901; Bernstein, 1905). Such lungs weredescribed by Fowler and Godlee (1898) as havinga worm-eaten or honeycomb appearance. Sharkeyand Fletcher both believed that the cystic changedeveloped acutely and the condition was generallyinterpreted as bronchiectasis, bronchiolectasis, orbroken-down bronchopneumonic abscesses, therebyimplying an acquired origin. To this diffuse formof cystic disease Oswald and Parkinson (1949) alsoapplied the term honeycomb lung and they attemptedto establish the nature of the disease process fromobservations on 16 instances including both childrenand adults. Having reviewed the literature, theseauthors concluded that honeycomb lung wasprobably an acquired inflammatory condition ofdiverse and often uncertain aetiology, but theywere unable to exclude a developmental origin insome instances. Nine of Oswald and Parkinson'scases came to necropsy, and lungs from five, togetherwith the case previously reported by Eernstein(1905), were selected by Cunningham and Parkinson(1950) for pathological investigation. These sixcases were chosen because they appeared to havedistinct histological features suggesting that theyrepresented stages of the same granulomatousprocess ending in extensive pulmonary fibrosis andcyst formation. Three other examples of honey-comb lung examined by Cunningham and Parkinsonwere excluded from their report, since the histo-logical characteristics, though not specified, weredifferent, again suggesting multiple causation forhoneycomb lung.

Descriptions of honeycomb lung under otherterms may, in the past, have obscured its frequency.For instance, Sandoz (1907) described foetalbronchiectasis in twin sisters, aged 18, in whomthe anatomical and histological features were

identical with those of honeycomb lung as given,below, while von Stossel (1937) and Rubenstein,Gutstein, and Lepow (1955) each reported twocases of this condition in adults as muscular cirrhosisof the lungs. Furthermore, it seems likely that thecases described by Mallory (1948) as granulomatouspneumonitis were also examples of honeycomb lurg.

I have had the opportunity to study many casesof honeycomb lung, but, in addition to the diffuseform, have repeatedly encountered cases in whichthe disease affected only parts of the lung. Further-more, the fibrocystic change was occasionallyrestricted to small circumscribed areas in thesecondary lobules of the lung. The disease process,however, appeared to be the same irrespective ofthe extent and distribution of the changes. Toelucidate further the pathogenesis of honeycomblung its pathological anatomy was investigated bymeans of serial sections and the histology examinedin detail.

CLINICAL FEATURES OF THE MATERIAL

Lung tissue was available from 66 cases, 50 beingmales and 16 females. The preponderance of malesis due to the inclusion of 32 coalworkers, butclinical information concerning them is too meagreto warrant tabulation. Thirty of the coalworkerscame from South Wales and two from the U.S.A.Their ages at death ranged from 33 to 86. Thecause of death in the coalworkers, as found atnecropsy, included pneumoconiosis (with andwithout overt pulmonary tuberculosis), carcinomaof various organs including the lung, pneumonia,chronic bronchitis and emphysema, and acute orchronic cardiovascular conditions. Hor.eycomblung was the primary cause of death in three coal-workers and their clinical associations appear inTable 1.The clinical features of the 34 cases of honeycomb

lung in non-coalworkers are presented in Table 11.As material from 12 of these cases was sent toProfessor J. Gough from diverse sources, including

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A. G. HEPPLESTON

TABLE ICOALWORKERS DYING FROM HONEYCOMB LUNGS

Age Clinical Associations Mode of Death(Years)

33 Repeated spontaneous pneumo- Pneumothoraxthoraces for 3 weeks

69 Six months dyspnoea Respiratory failure74 Ten years cough and dy.pnoea Congestive heart failure

three from the U.S.A., the total number does notreflect a local frequency of honeycomb lung.Although the ages at death ranged from 5 monthsto 77 years in 18 males and from 13 months to

TABLE I IPATIENTS OTHER THAN COALWORKERS

I f~~~~~ICase Sex Age Clinical Associations Cause of DeathNo. Sx(Years)

Cses with Non-specific FeaturesI F 41 Several years dyspnoea Congestive heart failure

due to honeycomb lungs2 M 51 Four years dyspnoea.

Onset with "in-fluenza "

3 F 52 12 years cough and dys-pnoea with pneumo-thoraces

4 F 60 Five years cough anddyspnoea. Onset with" influenza "

5 F 64 Three years cough anddyspnoea. Onset withherpes zoster

6 F 65 Five years finger club-bing, two years dys-pnoea, and one yearcough

7 XF 69 Nine years dyspnoea8 M 70 One year dyspnoea. Respiratory failure due

Onset with "in- to honescomb lungsfluenza" with pronounced ade-

nomatosis9 M 36 Three years dyspnoea Pneumothorax and sur-

gical emphysema fol-i lowing lung biopsywith

honeycomb lungs cont-tributory

10 F 63 Seven months cough Pulmonary embolismand dyspnoea whilst in congestive

heart failure due tohoneycomb lungs (con-tributory)

11 F 53 Two months cough with Carcinoma bronchushaemoptysis

12 M 53 Four months carcinoma Died under anaesthesiapalate for block dissection of

neck glands13 M 57 Six months dyspnoea Carcinoma bronchus14 M 58 Not known Coronary thrombosis15 F 60 Ten years asthma Status asthmaticus16 M 60 Six weeks ocular and Carcinoma bronchus

cerebral manifestations17 M 61 Eight months cardiac Left ventricular failure

infarction18 F 62 Three weeks vomiting, Uraemia due to sub-

abdominal pain, and acute glomeruloneph-oliguria ritis

19 M 63 Dyspnoea for years Coronary thrombosis20 M 71 22 years Addison's dis- Cardiac failure due to

ease of the adrenals Addison's disease21 M 72 Many years cough and Congestive heart failure

dyspnoea due to generalized em-physema

22 M 73 Not known Sudden cardiac failureof uncertain nature

23 M 77 None Suicide by coal-gaspoisoning

TABLE 11- contintued

Case Sex Age Clinical Associations Cause of DeathNo. (Years)

Cases with Specific Features24 F 1 4 12 Sudden unexpected Bilateral pneumothor-

death. Measles 4 12 aces due to honeycomtbpreviously lungs. Generalized

eosinophilic granulomaat necropsy

25 M 36 Sevenyearsdiabetesin- Bronchopneumoniasipidus, followed by with honeycomtib lungsorganic dementia contributory. Eosino-

philic granuloma atnecropsy

26 Ml 35 Several years dyspnoea Congestive heart fail-iredue to honec comnblungs. Histology sug-gests eosinophilic gran-uloma of the lungs

27 F Young Four and a half years Chronic berylliosis ofadult dyspnoea and cough. the lungs with honey-

Worked in fluorescent combing conttributorrlamp industry

28 M 5 12 Twenty-five days strep- Tuberculous broncho-tomycin pneumonia

29 M 9 12 Three months cough Primary pulmonary tu-and failure to gain berculosis with tuber-weight. Two months culous bronchopneu-streptomycin and moniaP.A.S.

30 M 1 3 12 Five months cough and Primary pulmonary tu-failure to gain weight. berculosis with tuber-Three months strepto- culous bronchopneu-mycin, P.A.S., and monia. HoniervconibI.N.A.H. lungs contributors

31 F 51 Ten years scleroderma Bronchopneumonia32 F 55 Ten years scleroderma. Malignant hypertension

Eight months malig-nant hypertension

33 F 1 1 12 Four weeks cough, Giant-cell pneumonia.dyspnoea, cyanosis. Honeycomb lungs con-Followed chickenpox tributory

34 F 39 Two years dyspnoea Honercomb lustgs withand pneumothoraces chylous ascites and

right pleural effusion.Pulmonary leiomyo-matosis at necropsy

69 years in 16 females, all except five cases wereadults. Only 13 out of the total 66 cases were

under the age of 50. From Table 11 it will alsobe seen that honeycomb lung was the underlyingcause of death in 11 non-coalworkers and that itwas contributory in six others.

METHODS

in the majority of cases the necropsy was performedin this or related departments, the whole lung beingfixed by intrabronchial injection of 10°% formalin con-taining 4O% sodium acetate. The lungs of most of theremaining cases were also fixed in an expanded state.Several blocks were taken from representative areas ineach case and paraffin sections were stained by haema-toxylin-eosin and in most cases for elastin, collagen, andreticulin. The periodic-acid-Schiff (P.A.S.) reactionwas observed in certain cases and sometimes frozensections were stained for fat with Sudan IV. Six cases(Nos. 9, 13, 19, 25, and 31, Table II, plus that of a coal-worker of 76) were also studied in 20 te serial sections,prepared as previously described (Heppleston, 1953), andinvolving the examination of almost 4,000 sections.

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THE PATHOLOGY OF HONEYCOMB LUNG

MACROScoPIc APPEARANCESOn section, the cysts are

rounded or irregular in shapeand vary in size not onlybetween different lung speci-mens but also in the samelung. The usual range ofdiameter is 1-10 mm., thesmaller sizes being morefrequently seen. The cystwalls consist of a coarse net- > ¢work of fibrous or granula-tion tissue. These changes i*are sometimes widespread ',throughout the lung (Fig. 1),but more often they have an ;irregular or patchy distribu-tion. Both lungs may be 9N

affected, though the honey-combing is sometimes moreextensive on one side thanthe other. Not infrequentlya peripheral band of lung2-5 cm. wide and locatedposteriorly or basally (Fig. 2)is alone involved. In other . f"cases the changes appear tobe more or less segmentallydistributed or they may in-volve only the central portionof a lobe. Sometimes the ;cysts have a roughly linear 9arrangement, lying predomi- .4'nantly along septa, vessels orbronchi. Occasionally thecystic change is circumscribedand surrounded by normallung. In such instances thecysts are related to a centralfibrous nodule from whichstrands of fibrous tissue FIG. 1.-Honeycomb lungradiate between the enlarged Note the discrete circair spaces (Fig. 3). Circum- congestion. Wholescribed lesions occur in lungsshowing typical honeycombing elsewhere (Fig. 1).Honeycomnbed areas may merge into non-cystic,fibrosed lung or show an abrupt transition to normaltissue.

PATHOLOGICAL ANATOMYBY DISSECTION.-The air passages in several fixed

specimens were exposed under a dissecting micro-scope from the hilum to the periphery of the lung.Passages traversing normal lung are not enlarged,but shortly before entering a fibrocystic area slight

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g of widespread distribution in a case (No. 25) of eosinophilic granuloma.cumscribed lesions at the base (see Fig. 6). The dark areas are due tolung xi.

or moderate dilatation is som.etimes evident andthis continues in the diseased zone. There thewalls are thickened and from them folds, with acrescentic, circular or spiral disposition, sometimesproject into the lumen of dilated airways, givingthem a convoluted appearance in longitudinalsection. Many air passages, whether dilated ornot, can be traced into the peripheral cysts througha wide or narrow orifice. Thick plugs of, mucusare frequent at the entry of the air passage into acyst. Many cysts intercommunicate. Some air

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A. G. HEPPLESTON

In fully developed honeycomb lung the differen-tiation of non-respiratory from respiratory bron-chioles is not easy owing to obliteration of alveoliand cyst formation, but, by bearing in mind thenormal mode of subdivision, it is sometimes possibleto distinguish these segments with reasonablecertainty. Many bronchioles, evidently non-res-piratory, are tortuous, sometimes dilated thoughnot narrowed, and communicate freely with thesmaller cysts, which are surrounded by fibroustissue (Fig. 4). Many of these cysts are probablyderived from respiratory bronchioles, but othersappear to originate from non-respiratory bron-chioles though not, so far as can be judged, frombronchi. Two or three bronchioles, derived froma common stem two to four segments proximally,sometimes enter the same cyst. Such anastomosisof air passages reflects the destruction of parts ofthe lung parenchyma. Some cysts, however,usually the larger ones, are not in free communica-tion with the air passages, which as they approachthe cyst are elongated and greatly compressed.Their entry into the cyst is oblique and through aslit-like aperture strongly suggesting a valvulareffect (Fig. 5). Occasionally a cyst originates fromone side of a greatly compressed bronchiole, which

FIG. 2.-Honeycombing restricted to the basal and posterior aspects ofthe lower lobe from a coalworker's lung. The fibrous tissue betweenthe cysts is deeply pigmented. Coalworkers' pneumoconiosis is alsopresent, massive fibrosis occurring towards the apex of the lobe andsimple rneumoconiosis elsewhere. x i.

passages, however, do not communicate with cystsbut end blindly.By SERIAL SEcTIoNs.-On numerous occasions in

each of the six cases studied by means of serialsections, the air passages were followed to theperiphery from the smallest bronchi or frombronchioles. Bronchioles may be distinguished bythe absence of cartilage from their walls. Normallythere are three to five orders of non-respiratorybronchioles between the smallest bronchus and thefirst order of respiratory bronchiole, as von Hayek(1953, p. 70) also found, and three orders ofrespiratory bronchiole are customary beforereaching the single order of alveolar duct (Hepple-ston, 1953).

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FIG. 3.-Two adjacent areas of the circumscribedtype of cystic change. Typical honeycombing ispresent elsewhere in this lung, together withfeatures suggesting eosinophilic granuloma (seeFig. 19). Coalworker, aged 33, who died fromhoneycomb lung. Haematoxylia-eosin. x 10.

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FIG. 4.-Honeycomb lunga bronchiole and a gro

THE PATHOLOGY OF HONEYCOMB LUNG 81

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showing free communication (X) between FIG. 5.-Same case as in Fig. 4, but showing a greatly narrowedoup of srnall cysts. Case 9. H.E. x 10. bronchiole entering (at X) a larger cyst.ILH.E. x IO.

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oF°Wk>'M~FIG. 6.-Circumscribed lesion with the termiinal bronchiole in free communication

with dilated respiratory bronchioles. The latter are grouped around a stellatenodule of fibrous tissue. Case 25. H.E. x 10.

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A. G. HEPPLESTON

continues distally as a normal-sized air passageleading freely into other cysts. One cyst oftenleads into others from which alveolar ducts oralveolar sacs may arise. In this way grape-likebunches of cysts are joined to the same stembronchiole. The apertures between cysts areusually wide but may be narrow. Judging by thereduced number of branches at various leveJs manyramifications of the bronchiolar tree are, on theother hand, completely obliterated, and in thisprocess respiratory bronchioles of all orders andtheir branches appear to suffer more severely thannon-respiratory bronchioles. Some non-respiratorybronchioles terminate blindly after a long or shortcourse in the associated fibrous tissue. A strikingfeature of some cases, even at the magnification of30 used for studying the serial sections, is theprominence of smooth muscle bundles coursingthrough the fibrous areas and surrounding certainof the cysts.

Since the circumscribed form of cystic changecould represent an early stage in the disease process,attention was also paid to its anatomy. Somerespiratory bronchioles, together with their alveolarducts and alveoli, have been obliterated and only astellate fibrous nodule, containing irregularly dis-posed smooth muscle fibres, remains. Otherrespiratory bronchioles, derived from the sameterminal (non-respiratory) bronchiole as the obli-terated ones, are dilated and form the cystic spacesaround the fibrous nodule. Proximally, the dilatedrespiratory bronchioles are in unobstructed com-munication with the terminal bronchiole (Fig. 6)and, distally, with normal alveolar ducts. It isconceivable that, as the circumscribed lesionsincrease in size and number, they become confluentand so give rise to fully developed honeycomb lung.The simple dust lesion ofcoalworkers is distinguishedfrom the circumscribed type of cystic change by thepreponderance of dust, the paucity of fibrous tissue,and the patency of all the air passages derived fromthe terminal bronchiole (Heppleston, 1953).

GENERAL HIsToLoGYTHE CYsTs.-These vary not only in size and

shape but also in their lining epithelium and contents.Some cysts without detectable epithelium are emptyas are others with a flattened or cuboidal epithelium.When present, the epithelium is usually of regularcolumnar type with or without cilia (Fig. 7). Itmay include mucus-secreting cells and sometimesrests on a basal layer of small cells. Various typesof epithelium may line different cysts of the samecase or even the same cyst. In six cases the epithe-

lial proliferation is greater than necessary simply toline the spaces and assumes a stratified (Fig. 8) orpapillary form (Fig. 9). In six instances (includingthree with stratified or papillary epithelium) squa-mous metaplasia is evident (Fig. 10). Alveolibordering fibrocystic areas occasionally show anepithelial lining. Cysts commonly contain mucuswhich is P.A.S.-positive and in which phagocytichistiocytes occur. The latter are sometimes foamy,when frozen sections reveal sudanophil fat in thecytoplasm. Giant cells, often containing dust andsometimes cholesterol crystals, may be found inthe cysts. Giant cells can also be seen on occasionin the cyst epithelium, where they probably ariseby fusion of cells, and in the interstitial tissues ofsome cases. Eosinophils may occur inside thecysts and a terminal acute inflammatory exudate isnot infrequent.

INTERSTIAL CHANGES IN CYsTIc AREAS.- rre-gularly shaped masses or strands of fibrous tissuelie between the cysts, but some alveoli may persistin the fibrocystic zones. The fibrosis is both reti-cular and collagenous and of loose or compacttexture. It is well vascularized by capillaries andvenules, and fibroblasts are present in varyingnumber. A light or dense infiltration of inflam-matory cells occurs, tending to be denser in theless fibrous areas and vice versa. Lymphocytesand plasma cells predominate, but eosinophils maybe conspicuous and a scattering of histiocytes andneutrophil polymorphs is frequently seen. Althoughthe cellular infiltration is usually diffuse, focalaccumulations are not uncommon. Phagocytesladen with carbonaceous pigment are scatteredthroughout the fibrous areas, the larger accumula-tions occurring in coalworkers (Fig. 2). Thefeatures of the pigmented, fibrous component ofhoneycomb lung in these men do not as a ruleresemble those of massive fibrosis which charac-terizes complicated pneumoconiosis (Heppleston,1951a), though sometimes only the presence ofsmooth muscle distinguishes the fibrosis of honey-comb lung. Apart from the smooth muscle oftenevident around the cysts, large and small bundlesor isolated fibres are commonly seen in varyingamount in the fibrous tissue (Fig. 11). In someareas the muscle bundles are irregularly disposed,but in other places they appear to originate fromobliterated air passages and blood vessels. Anorigin from pre- existing structures cannot accountfor all the interstitial muscle in many of the cases;hyperplasia of smooth muscle must therefore beregarded as being common in honeycomb lungs.This is emphasized by the existence in some lungs,

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FIG. 7.-Cilited epithelium, including mucin-secreting cells, liingcystic spaces. Case 19. H.E. x70.

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&} *:'ewA % ^. R * S ..;.FIG. 8.-Adenomatosis with stratified epithelium lining the spaces.

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FIG. 9.-Adenomatosis with papillary epithelium lining the cysts.Case 8. H.E. x 150.

FIG. 10.-Squamous metaplasia in epithelium which is ciliated ormucin-secreting elsewhere in the same space. Case 5. H.E.x 150.



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FIG. 11.-Bundles of smooth muscle fibres lying in the fibrous com-ponent of honeycomb lung. Coalworker. H.E. x 35.

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FIG. 13.-Fibrous area in a honeycomb lung, showing an elastinpattern resembling that of expanded parenchyma. Case 12.Verhoff. x 70.

FIG. 12.-Subpleural concentration of smooth muscle bundles.Case 19. H.E. x70.

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FIG. 14.-Another fibrous area in which the elastin pattern resemblesthat of collapsed lung. Coalworker. Verhoff. > 70.



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especially subpleurally, of concentrations of musclein which numerous bundles run in parallel (Fig. 12).Elastic tissue is always present and frequentlyprominent in the fibrous areas, either as singlestrands, small knots, or as dense, tangled massesor bands. Undoubtedly much of the elastic tissueis derived from obliterated bronchioles, alveoli, andblood vessels, but hyperplasia appears to contributein the denser areas. The pattern of the elasticfibres sometimes corresponds to that of more orless normally expanded alveoli, alveolar ducts, orrespiratory bronchioles (Fig. 13), while in otherplaces the pattern is that of collapsed alveoli (Fig.14). Arterioles and small arteries traversing thefibrous zones often show obliterative endarteritiswhich may be severe. In lung tissue so disorganizedit is impossible to say whether these vessels belongto the pulmonary or bronchial system. Broncho-pulmonary anastomotic arterioles, the " Sperrar-terien " of von Hayek (1953, p. 230), do not appearto be more prominent than usual.

INTERSTITIAL CHANGES IN NON-CYsTIC AREAS.-Where honeycombing affects only parts of the lung,the remainder may be normal or show otherhistological changes. Interstitial reticulin fibrosisof alveolar walls (Figs. 15 and 16) is present to avarying degree and extent in 15 cases. Thischange has a patchy distribution even withinsecondary lobules and is associated with a pleo-morphic cellular infiltration. In places a transitioncan be traced from normal lung through a zone ofincreasingly severe interstitial fibrosis to the denserfibrosis associated with honeycombing of the lung(Fig. 17). At the same time many alveoli are

evidently overrun by reticulin fibrosis, but some

alveoli persist and may develop an epithelial lining.Areas of interstitial fibrosis of alveolar walls alsooccur at a distance from honeycombed parts of thelung and adjacent to or between the patches offibrosis small cysts may be seen. These findingssuggest that patchy interstitial fibrosis develops intohoneycomb lung rather than that interstitial fibrosisrepresents a peripheral extension of the fibroticcomponent of honeycomb lung. To establish thisinterpretation, discontinuity between areas of inter-stitial fibrosis and fibrocystic change must bedemonstrated in three dimensions, but this was notpossible with the present material. There is no

evidence to suggest how the interstitial fibrosisoriginates.

SPECIFIC HISTOLOGICAL FEATURESThe appearances detailed above are in whole or

in part common to 53 of the cases in this series andin all of them the changes are non-specific. Thirteen

cases, however, show changes in the lungs or inother organs suggesting a more precise origin.

EosmIOPHILIc GRANULOMA.-Eosinophilic gran-uloma is known to involve extraskeletal tissues,among them the lung (Thannhauser, 1950; Lichten-stein, 1953), and to become increasingly fibrous inthe retrogressive or chronic phase (Engelbreth-Holm, Teilum, and Christensen, 1944). Honeycomblungs are sometimes associated with this granuloma(Rowland, 1928; Farber, 1942; Oswald and Par-kinson, 1949; Parkinson, 1949; MacDonald andShanks, 1954; Grant and Ginsburg, 1955). Honey-comb lungs were found by McKeown (1954) in twoinfants with Letterer-Siwe disease, which is nowgenerally regarded as an acute form of eosinophilicgranuloma (Farber, 1942; Mallory, 1942; Lichten-stein, 1953). Cunningham and Parkinson (1950)thought that their cases of diffuse cystic lungs couldfit into the eosinophilic granuloma group.

Tlwo cases of the present series are undoubtedexamples of eosinophilic granuloma with extra-pulmonary lesions and two others may well representinstances of eosinophilic granuloma confined to thelungs.

Case 24 (Table I1) was that of a child who died suddenlyand without prior illness from bilateral spontaneouspneumothoraces. At necropsy eosinophilic granulomaof the acute type involved the thymus, liver, spleen,lymph nodes, thyroid, and salivary glands as well asthe lungs. The latter show numerous focal infiltrationsof histiocytes (devoid of sudanophil fat) with someadmixture of lymphocytes, eosinophils, and fibroblasts.Fibrosis, however, is slight and mainly interstitial. Manyof these granulomatous foci, especially in the upper partsof the lungs, are related to cysts measuring up to 5 mm.across (Fig. 18). In the liver the infiltration is periportaland associated with early proliferation of bile ducts andacute cholangitis. Eosinophils are most conspicuous inthe thymus.

Case 25 (Table II and Fig. 1) was previously reportedby Spillane (1952, Case 3). Diabetes insipidus was thepresenting clinical feature, and at necropsy the hypo-thalamus contained eosinophilic granuloma. In partsof the lungs the honeycombing is associated with fibrosisand appears non-specific, but other parts are morecellular, eosinophils and histiocytes being more inevidence.

In one of the coalworkers, who died from honeycomblungs at the age of 33, the cysts are situated in relationto a granulomatous reaction in which histiocytes andeosinophils are prominent (Fig. 19) and among whichgiant cells occur. Necropsy revealed no extrapulmonarylesions.

Case 26 (Table II) resembles the preceding one, but inparts the interstitial changes are more fibrous.

SARCOIDOSIS.-The lung of one coalworker aged47 shows follicular granulomata with giant cells

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FIG. 15.-Interstitial changes in an area without cysts of a lung withhosneycombfeatures-elsewhere. Note the intra alveolar gianitcells.Case 15. H.E X70

EPPLESTON

FIG. 16.-Same case as in Fig. 15, but stained to show reticulin fibrosisof alveolar walls. Reticulin. x 70.

FIG. 17.-Transition from interstitial reticulin fibrosis of alveolar walls (left) to the moresolid fibrosis adjacent to a cyst (right). In the process alveoli are being overrun.Case 13. H.E. x70.



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~~~~~~~~~~~FIG. 19.-Granulomatous reaction, incluighsicte n oioVW: ~~~~~~phils, forming the wall of a cyst. Same case as in Fig. 3. H.E.FIG. 18.--Cyst formation in relation to foci of acute eosinophilic x 150.

granuloma of the lung. Case 24. H.E. x 4.

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FIG. 22.-Tuberculous granuloma with cyst formation after strepto-mycin therapy. Case 30. H.E. x 20.

lying in the fibrous tissue which separates the cysts(Fig. 20). Similar granulomata occur in the hilarglands, and the appearances strongly suggestpulmonary sarcoidosis.BERYLLIOSIS.-Beryllium pneumonitis is charac-

terized by a focal and diffuse histiocytic reaction inwhich giant cells and conchoidal bodies are oftennumerous (Hardy and Tabershaw, 1946; Dutra,1948). Material provided by Dr. Harriet Hardyfrom two cases of this disease occurring in theU.S.A. includes one (No. 27, Table 11) that showsfibrous-walled cysts in relation to the usual granulo-matous reaction (Fig. 21) and also considerableinterstitial fibrosis of alveolar walls.TUBERCULOUS BRONCHOPNEUMONIA.-Tuberculous

bronchopneumonia that had been treated withstreptomycin was associated with honeycomb lungin three young children (Cases 28, 29, and 30,Table II). All these cases occurred recently, andthe development of honeycombing no doubtdepends on the longer period of survival whentuberculous bronchopneumonia is treated withstreptomycin and isoniazid. In these cases a patchygranulomatous reaction, with reticulin fibrosis andoccasional tubercles, is often related to cysts

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FIG. 23.-Non-respiratory bronchiole entering, without obstruction,one of a group of cysts. These have developed in strict relation-ship to a focus of tuberculous bronchopneumonia. Case 29.H.E. x 35.

measuring 1-10 mm. across (Fig. 22). Fig. 23 fromCase 29 shows a non-respiratory bronchiole entering,without obstruction, a small cyst of a circumscribedgroup, but a valvular mechanism is probably res-ponsible for producing the larger cysts, seen espe-cially in Case 30. In places the granulomatous andfibrous elements involve the alveolar walls inter-stitially. Debre (1952) mentions three similar cases.The radiological phenomenon of " vanishing lung "in tuberculous lesions treated by streptomycin orisoniazid (Rappaport, 1955) may perhaps be con-nected with the development of honeycombing.SCLERODERMA.-Honeycomb lung is sometimes

associated with scleroderma (Evans and Parker,1954), and these lesions coexisted in two cases(Nos. 31 and 32, Table 11). In one the atypicalreaction of the pulmonary collagen to Van Gieson'sstain resembled that sometimes seen in the skin,but in other respects the histological features of thelungs are not distinctive.GIANT-CELL PNEUMONIA.-Interstitial pneumonia

of giant-cell type, as described by Hecht (1910), mayalso be combined with cystic change (Case 33,Table 11). Small cysts occur between patches of

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FIG. 24.-Giant-cell pneumonia in a child showing interstitial changes FIG. 25.-Pulmonary laiomyomatosis with cystic change. All thewith cyst formation. Case 33. H.E. x 35. darkly stained elements are smooth muscle fibres. Case 34.

Lissamine red-tartrazine. x 70.

pneumonia (Fig. 24) but not where consolidationis widespread. Reticulin fibrosis involves thealveolar walls and extends up to the cysts, butconfluent fibrosis is minimal and very few alveolarspaces are obliterated. These features lend supportto the view that patchy interstitial fibrosis mayprogress to honeycombing of the lung. Many ofthe giant cells contain inclusion bodies of differingsizes, a finding peculiar to this one case in theseries.LEIOMYOMATOSIS.-The hyperplastic muscle often

seen in honeycomb lungs is situated within fibrousareas, but Case 34 (Table Il) is peculiar in thatfibrosis is inconspicuous whereas hyperplasia ofsmooth muscle is pronounced and constitutes theessential pathological feature. So great an increasein muscle suggests a primary condition and warrantsthe term leiomyomatosis. This change, though notuniform throughout the lung, appears to be largelyconfined to the respiratory segments of the airway,especially affecting bronchioles but not sparingalveolar structures. Many of these air passagesare cystic, their greatly thickened walls consistingof smooth muscle (Fig. 25) with a supportingnetwork of fine reticulin and a few strands of elastic

tissue as the only fibrous components. Occasion-ally lymphoid foci are seen in the muscular walls.The number of branches arising at various levelsof the bronchiolar tree seems to be reduced. Anormal alveolar structure remains in parts of thelung, but some alveolar walls remote from themuscular areas show a little fibrous thickening.

LIVER LESIONSLiver and pulmonary involvement by eosinophilic

granuloma often coexist, especially in children(Rowland, 1928; Farber, 1942; Oswald and Par-kinson, 1949; Thannhauser, 1950; MacDonaldand Shanks, 1954), and the girl aged 16 months(Case 24, Table lI) provides another example ofthis combination. Biliary cirrhosis or pericholan-gitis is described as a further hepatic lesion found incases of honeycomb lung in children (Fletcher, 1901;Bernstein, 1905; Oswald and Parkinson, 1949).In the present series liver material was available forhistology in 20 of the 61 cases in adults. Fiveindividuals, four of whom were coalworkers,showed a mild or moderate degree of periportalfibrosis and chronic inflammatory cell infiltrationwith proliferation of bile ducts.

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DISCUSSIONThe cysts of honeycomb lungs have been found

only in association with other pathological changes.Occasionally these take the form of granulomatasuch as eosinophilic granuloma, sarcoid, berylliosis,or tuberculosis. Rarely interstitial giant-cell pneu-monia or myomatosis constitutes the associatedlesion. In the majority of instances, however,cysts develop in relation to fibrosis, which lacksspecific features. It is, nevertheless, possible inmany cases to suggest certain general processesleading to fibrosis.One means, as indicated above, appears to be

interstitial fibrosis of alveolar walls and respiratoryair passages. This change has a patchy distributionand cysts may therefore develop in adjacent un-involved lung tissue. Histologically, the interstitialfibrosis of alveolar walls seen in some honeycomblungs resembles the Hamman and Rich (1944) formof pulmonary interstitial fibrosis (Heppleston,1951b), but in the latter the changes are widespreadthroughout the lungs. Mild enlargement of airspaces may be seen in the Hamman and Rich con-dition, but frank cyst formation is not mentionedby Pokorny and Hellwig (1955), who referred to31 published instances and added one of their own.This is presumably because no unaffected paren-chyma remains where cysts may develop. Collapseof lung tissue may also contribute to the developmentof the fibrosis in honeycomb lungs, as is shown bythe obliteration of many respiratory and non-respiratory bronchioles as well as by the pattern ofelastic fibres in some fibrous zones (Fig 14). Inother fibrous zones, however, the disposition ofelastic fibres resembles that of normal lung (Fig. 13),which suggests that the solid fibrosis could havearisen either from interstitial fibrosis of alveolarwalls or from organization of an intra-alveolarexudate (Heppleston, 1951 b). Unresolved broncho-pneumonia, following influenza, measles, or per-tussis, could lead to patchy bronchiolar obstruc-tion and obliteration (Winternitz, Wason, andMcNamara, 1920; Opie, Blake, Small, and Rivers,1921; Blumgart and MacMahon, 1929; Engel,1947), alveolar collapse and carnification. In fourcases dying from honeycomb lung, symptoms beganimmediately after " influenza " (Cases 2, 4, and 8,Table }I) and herpes zoster (Case 5, Table II), but inno other case was an antecedent condition recog-nized. The association of recognized granulomatawith honeycomb change clearly indicates the originof the fibrosis in certain cases. The occurrence ofhoneycombing in cases of tuberculous broncho-pneumonia treated with streptomycin and in giant-zell pneumonia shows that under some circumstances

the cysts may take relatively little time to form. Inthe cases descrited above as non-specific thecharacter of the cellular infiltration in the fibroticzones does not suggest eosinophilic granuloma andno extrapulmonary granulomatous lesions of eosino-philic type are known to exist. The fibrous phaseof eosinophilic granuloma may, however, lackspecific features, as Case 25 shows, and the lungalone may be involved. It is thus impossible toassess the part played by pulmonary eosinophilicgranuloma in the production of fully developedhoneycomb lung. The circumscribed cystic lesionsmay also be explained on the basis of organizedgranulomatous or bronchopneumonic foci. Theoccurrence in five cases of a hepatic lesion bestdescribed as non-obstructive biliary cirrhosis couldsimilarly represent the healed phase of a periportalgranuloma now devoid of specific features. Almosthalf the cases of honeycomb lung in the presentseries occurred in coalworkers, but no conclusion isyet possible regarding the aetiological significanceof this particular occupation.To meet the objection that honeycomb lung repre-

sents the result of infection in congenital cysticdisease, the fibrous component must be establishedas the primary change. The preceding considera-tions leave little doubt about the acquired natureof the fibrosis, and it is also clear that cystic enlarge-ment of air passages only begins in those parts ofthe lung affected by granulomata or fibrosis. Ifthe cysts were congenital, they would sometimes beexpected to occur alone, but in the present seriesthey are always accompanied by other lung changesand these, on the other hand, may occur inde-pendently. In the light of the observations ofNorris and Tyson (1947), however, the pathologicalanatomy of honeycomb lung is decisively in favourof its acquired origin. These workers studied byserial sections two cases of cystic lung that wereundoubtedly congenital, one case being a stillbornfoetus of 6 lunar months and the other a full-terminfant dying from respiratory failure four and ahalf hours after birth. All the cysts so traced werecompletely isolated from the bronchial tree, thoughanastomoses between cysts were frequent. In onecase Norris and Tyson found many bronchioleswith blind terminations in non-cystic parts of thelung and they also noted the absence of inflam-matory exudate. These observations contrast withthe findings in honeycomb lung.Pulmonary fibroses or granulomata may there-

fore be regarded as the usual antecedents of honey-comb lung, to produce which particular segmentsof the airway must be obliterated. The anatomicalobservations show that these are some of the non-

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respiratory and respiratory bronchioles togetherwith their subdivisions. In areas overrun bvgranulomata or fibrosis the normal respiratorymovements are prevented. Bronchioles uninvolvedby fibrosis or granulomata but adjacent to immo-bilized areas then undergo compensatory dilatation,no doubt in consequence of locally exaggeratedinspiratory traction. Contraction of fibrous tissueand localized collapse of lung will augment thedilatation. Cysts are not evident in the presenceof diffuse interstitial fibrosis or where all respiratoryspaces have been obliterated. In effect the changemay be described as a bronchiolectasis, which isusually saccular and involves both respiratory andnon-respiratory bronchioles, and in the productionof which some lung parenchyrna is destroyed. Asecondary factor, however, appears to be responsiblefor the production of the larger cysts. Evidencepointing to a valvular obstruccion where bronchiolesenter certain cysts has been adduced (Fig. 5). Thefeatures strongly suggest that as the cysts increasein size under the traction of inspiration, the bron-chioles from which they originate are stretched andcompressed so that the communication betweenbronchioles and cysts is tangential or oblique. Inthis way the exit of air from such cysts is likely tobe impeded much more than its entry, with theeffect of increasing considerably the size of thecysts. These conclusions regarding the patho-genesis of honeycomb lung thus substantiate andamplify those of von St6ssel (1937), Oswald andParkinson (1949), and Cunningham and Parkinson(1950).The occurrence of hyperplasia and hypertrophy

of smooth muscle in fibrosing pulmonary diseasehas been reviewed and a series of cases describedby Leibow, Loring, and Felton (1953), who con-cluded that the fundamental factors concerned areobscure but that increased tissue tension may playa part. Hyperplasia of the muscle in honeycomblung could well represent a compensatory mechanismof the lung designed to encourage expulsion of airfrom the cysts, although the irregular dispositionof the fibres suggests that their contraction will notproduce a co-ordinated effect. A valvular obstruc-tion to the egress of air can only serve to increasethe resistance to muscular contraction and therebyprovide a further stimulus to hyperplasia. Honey-comb lungs with smooth muscle hyperplasia andwith considerable interstitial fibrosis occur intuberous sclerosis (Berg and Vejlens, 1939; Samuel-sen, 1942; Berg and Nordenskjold, 1946), thehyperplasia of muscle in the lungs being regardedas a part of the general disease process. Licht(1942) reported honeycomb lungs with fibrosis and

smooth muscle hyperplasia as an isolated findingin a woman whose daughter had tuberous sclerosisclinically, and he considered the mother was alsoan example of this condition. Dawson (1954)described a case of tuberous sclerosis in whichbiopsy showed cystic lung with a great increase inconnective tissue, many blood vessels, and somesmooth muscle. The fibrous and muscular changesin these five cases of tuberous sclerosis appearindistinguishable from those in non-specific honey-comb lungs, which, however, differ in that chronicinflammatory cell infiltration is frequent and nolesions were found in the brain, skin, kidneys, orheart to suggest tuberous sclerosis in 50 cases inwhich full details of the necropsies are available.The amount of smooth muscle in the case of

pulmonary leiomyomatosis (Case 34, Table 11,Fig. 25) far exceeds that seen in any other instanceof honeycomb lung and for this reason it must beplaced in a separate category. The only comparableexample I have found in the literature is that ofRosendal (1942), who observed cystic lungs withdiffuse myomatosis confined to the lungs and hilarglands. The pathogenesis is obscure, althoughRosendal considered tuberous sclerosis to be apossibility despite the absence of characteristiclesions in the other organs of his case. Cruickshankand Harrison (1953) found a chondromatous hamar-toma of the lung in association with honeycombingand fibro-leiomyomatous change, and they thoughtthe latter was also hamartomatous. No suchcombination occurred in the present series.

Epithelialization of the cysts, though variable intype, is common and often widespread. Con-tinuity between the epithelium of the bronchiolesand that lining cysts is usually evident and epi-thelialization probably proceeds from the bron-chioles. In most instances the epithelial prolifera-tion is limited to the formation of a simple liningto the cysts. This process may therefore bedescribed as simple epithelialization and it occursas a consequence of fibrosis and cyst formation.The degree of proliferation was, however, excessivein six cases of honeycomb lung, being greater thannecessary merely to line the cysts and resulting in athick stratified or papillary epithelium for whichthe term adenomatosis appears justified. Thedistinction between adenomatosis, with its implica-tion of neoplasia, and simple epithelialization isimportant, since Laipply, Sherrick, and Cape(1955, Figs. 2 and 7) illustrate changes indistin-guishable from simple epithelialization under thedesignation of bronchiolar adenoma, a term whichthey use synonymously with adenomatosis andmany other terms. Although admitting that the

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FIG. 26.-Primary pulmonary adenomatosis. Epithelium, in partsshowing early papillary formation, lines air spaces of approxi-mately normal size. H.E. x 70.

features in certain of their cases suggested bronchio-lectasis and chronic pneumonitis, Laipply andothers ruled out an inflammatory basis becausebronchiectasis was infrequent, carcinomatous changesometimes occurred, and small lesions lackedinflammation. This difference in interpretationmay be resolved if two points are agreed. First,simple epithelialization, whether in honeycomb lungor in non-cystic pulmonary scars, should be exclu-ded from the category of adenomatosis. In suchfibrotic or fibrocystic conditions bronchiectasis willnot be frequent, since alveolar tissues are pre-

dominantly involved. Secondly, it is suggestedthat the term pulmonary adenomatosis, even whenused in this restricted sense, covers more than onecondition. It may follow simple epithelializationof spaces in fibrotic lung, as in a few of the presentcases, or epithelium ofcolumnar or mucin-producingtype may grow over more or less normal alveolarwalls. In the latter case the epithelial changeappears to be primary, the lesions often beingnodular and multiple with little if any inflammatoryreaction (Fig. 26). Local growth of epithelium inprimary pulmonary adenomatosis could lead to

(a) extension over wider areas of alveolar andbronchiolar surfaces; (b) expansion of air spacesalready involved, with compression of surroundingstructures and almost inevitably with some degreeof parenchymal destruction; (c) papillary forma-tions or stratification of the epithelium. If condi-tion (b) predominates it is possible to visualizeepithelial proliferation as the cause of cyst formation,and fibrosis could be associated as a secondarystromal reaction. Thus, exceptional cases of honey-comb lung might develop as a consequence ofprimary epithelial changes, giving rise to appearancessuch as those observed in certain parts of Case 8(Table IT, Fig. 9). None of the examples ofadenomatosis or squamous metaplasia in this seriesof honeycomb lungs had progressed to malignancy.

SUMMARYBased on a series of 66 cases, an account is

given of the pathological anatomy and histologyof honeycomb lung, an acquired form of cysticdisease which may involve the lung focally, irre-gularly, or diffusely. In most instances honey-combing was an incidental finding of limited extent,but honeycomb lung was the basic cause of deathin 14 cases and was partially responsible for deathin six others.The essential change is regarded as being oblitera-

tion, by fibrosis or granulomata, of some of thebronchioles, non-respiratory and respiratory,together with their subdivisions. It is suggestedthat neighbouring bronchioles not so affected thenundergo compensatory dilatation to form cysticspaces in contiguity with the consolidated or fibroticareas. Secondary valvular obstruction of bron-chioles communicating with the cysts is probablyresponsible for their progressive enlargement.The fibrous component of honeycomb lung is

believed to arise in several ways. Patchy interstitialfibrosis of alveolar walls can apparently be associatedwith cystic enlargement of air passages in adjacentareas of non-fibrosed lung and the interstitial fibrosismay merge with typical honeycomb lung. Fibrosismay also develop on the basis of organized broncho-pneumonia, restricted areas of pulmonary collapse,and certain specific granulomata including eosino-philic granuloma, sarcoidosis, berylliosis, and tuber-culosis after streptomycin therapy. Giant cellpneumonia and pulmonary leiomyomatosis are rareassociations with honeycomb lung, which may alsocoexist with scleroderma.

Hyperplasia of smooth muscle is commonly seenin honeycomb lungs. Since a similar combinationmay be found in tuberous sclerosis, this condition

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must be considered in the differential diagnosis ofhoneycomb lungs.A distinction is drawn between the frequent

simple epithelialization of spaces in the lung andthe rarer adenomatosis. Adenomatosis is held to

represent an excessive degree of epithelial prolifera-tion, which may follow simple epithelialization ofcystic or non-cystic spaces in fibrotic lung or occur

as a primary epithelial change without antecedentfibrosis. Primary pulmonary adenomatosis couldconceivably give rise to honeycombing of the lung.Squamous metaplasia also occurs in honeycomblung, but in none of the cases with adenomatosis or

metaplasia had the epithelial proliferation becomemalignant.

For permission to include their cases in this seriesthanks are due to Professor C. V. Harrison and Drs.W. H. Beasley, A. C. Counsell, C. K. Davenport, L.Dunner, L. L. Friedman, L. W. Hale, Harriet L. Hardy,J. D. Heppleston, T. D. S. Holliday, R. A. Parker,Tessie Phillips, R. M. E. Seal, R. H. Smart, and G. S.Smith and the late Dr. William Susman. Mr. J. P.Napper was responsible for the photography. I am

most grateful to Professor J. Gough, who gave me thebenefit of his criticism and advice.

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Bernstein, J. M. (1905). Trans. path. Soc. Lond., 56, 330.Blumgart, H. L., and MacMahon, H. E. (1929). Med. Clin. N. Amer.,

13, 197.Cruickshank, D. B., and Harrison, G. K. (1953). Thorax, 8, 316.Cunningham, G. J., and Parkinson, T. (1950). Ibid., 5, 43.Dawson, J. (1954). Quart. J. Med., n.s., 23, 113.

Debre, R. (1952). Lancet, 2, 545.Dutra, F. R. (1948). Amer. J. Path., 24, 1137.Engel, S. (1947). The Child's Lung, p. 54. Arnold, London.Engelbreth-Holm, J., Teilum, G., and Christensen, E. (1944). Acta

med. Scand., 118, 292.Evans, M., and Parker, R. A. (1954). Thorax, 9, 154.Farber, S. (1942). New Engl. J. Med., 226, 394.Fletcher, H. M. (1901). Trans. path. Soc. Lond., 52, 193.Fowler, J. K., and Godlee, R. J. (1898). The Diseases of the Lungs,

p. 143. Longmans, Green, London.Grant, L. J., and Ginsburg, J. (1955). Lancet, 2, 529.Hamman, L., and Rich, A. R. (1944). Bull. Johns Hopk. Hosp.,74, 177.Hardy, H. L., and Tabershaw, I. R. (1946). J. industr. Hyg., 28, 197.Hayek, H. von (1953). Die menschliche Lunge. Springer, Berlin.Hecht, V. (1910). Beitr. path. Anat., 48, 263.Heppleston, A. G. (1951a). Arch. industr. Hyg., 4, 270.

(1951b). Thorax, 6, 426.-(1953). J. Path. Bact., 66, 235.Laipply, T. C., Sherrick, J. C., and Cape, W. E. (1955). A.M.A.

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(1948). Radiology, 51, 468.Norris, R. F., and Tyson, R. M. (1947). Amer. J. Path., 23, 1075.Opie, E. L., Blake, F. G., Small, J. C., and Rivers, T. M. (1921).

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Med., 42, 36.Samuelsen, E. (1942). Acta radiol. (Stockh.), 23, 373.Sandoz, E. (1907). Beitr. path. Anat., 41, 495.Sharkey, S. J. (1894). St. Thomas's Hosp. Rep., 1892-3, 22, 33.Spillane, J. D. (1952). Thorax, 7, 134.Stossel, E. von (1937). Beitr. Klin. Tuberk., W, 432.Thannhauser, S. J. (1950). Lipidoses, 2nd ed., p. 408. Oxford

University Press, New York.Tooth, H. H. (1897). Trans. path. Soc. Lond., 48, 30.Winternitz, M. C., Wason, I. M., and McNamara, F. P. (1920).

The Pathology of Influenza, p. 46. Yale University Press, NewHaven.

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