morphology and pathogenesis of desquamative interstitial

Thorax, 1977, 32, 7-18

Morphology and pathogenesis of desquamativeinterstitial pneumonitis1ENRIQUE VALDIVIA, GEORGE HENSLEY, JANE WU, ELI P. LEROY, ANDWALTER JAESCHKE

From the Departments of Preventive Medicine, Pathology, and Anesthesiology, Medical College ofWisconsin, The University of Wisconsin Health Sciences Center, Milwaukee and Madison, Wisconsinand the Abraham Lincoln School of Medicine, Chicago, Illinois

Valdivia, E., Hensley, G., Wu, Jane, Leroy, E. P., and Jaeschke, W. (1977). Thorax, 32,7-18. Morphology and pathogenesis of desquaniative interstitial pneumonitis. Thirty humanlung biopsy specimens have been diagnosed as desquamative interstitial pneumonitis. Six caseshad intraalveolar lesions, believed to be early, while 20 had advanced disease characterisedby intraalveolar cellular clumps, alveolar wall fibrosis, distortion, and loss of pulmonaryparenchyma. Electron microscopy, high resolution light microscopy, and cytologicalexamination have shown that the characteristic clumps in the alveolar air spaces are formedpredominantly by enlarged and aggregated macrophages. Lymphocytes and eosinophils are alsopresent in the intraalveolar clumps and in alveolar walls. Inflammation and immunologicalmechanisms are suggested as causes of the cellular clumping. Interstitial pneumonitis, alveolarwall fibrosis, changes in the alveolar epithelium, and loss of lung parenchyma are believed tobe secondary events.

Desquamative interstitial pneumonitis (DIP) be-longs to a poorly understood group of chronicpulmonary lesions which need lung biopsy fordiagnosis. The original series was collected mostlyfrom consultations by Liebow et al. (1965), whoestablished clinical, radiological, and morpho-logical patterns which they believed to be specificfor a human disease responsive to steroid treat-ment. Since then similar cases have been reporteddescribing light and electron microscopy featureswhich confirm the original description (Gaensleret al., 1966; Goff et al., 1967; Klocke et al., 1967;Scadding and Hinson, 1967; Leroy, 1969; Short-land et al., 1969; Farr et al., 1970; Scadding, 1970;Bates et al., 1971; Gould et al., 1971; McNaryand Gaensler, 1971; Patchefsky et al., 1971;Corrin and Price, 1972; Patchefsky et al., 1973a;Patchefsky et at., 1973b; Rhodes, 1973; McCannand Brewer, 1974). A controversial feature is theidentification and origin of the cells found inthe alveolar spaces since Liebow et al. (1965)favoured a primary exfoliation of type II granularpneumocytes, epithelial cells with late or second-ary presence of alveolar macrophages. Scadding'Supported in part by SCOR grant NHLI 15389 and NHLI grantHL 17540

and Hinson (1967), Scadding (1970), andPatchefsky et al. (1971, 1973a, b) believe thatdesquamative interstitial pneumonitis is only atemporary or microscopic variation of chronicinterstitial pneumonitis which may have muralor exfoliative types of inflammatory reaction. Thepathogenesis of the DIP lesions is obscure; aviral origin has been suggested by Liebow et al.(1965) and investigated by McNary and Gaensler(1971) while a hypersensitivity mechanism hasbeen proposed by several authors such as Liebowet al. (1965), Gaensler et al. (1966), and Leroy(1969).The present study describes the morphological

features of 30 cases which show that there maybe early, intermediate, and late stages of thedisease. Furthermore, the availability of resin-embedded material permits examination at high-resolution light microscopy and with the electronmicroscope. The presence of eosinophils in theearly and chronic phase, abundance of macro-phages, and lymphocytes suggest that the cellularreaction observed in these cases is a form of lunginjury with features characteristic of an alteredinflammatory response. The main objectives ofthis article are: (a) to describe and define the

7

on Decem

ber 1, 2021 by guest. Protected by copyright.

http://thorax.bmj.com

/T

horax: first published as 10.1136/thx.32.1.7 on 1 February 1977. D

ownloaded from

http://thorax.bmj.com/

E. Valdivia, G. Hensley, Jane W'u, E. P. Leroy, and W. Jaeschke

morphological lesions in the lung and to identifythe cellular components observed in the desquama-tive exudate; (b) to propose a differentiation be-tween early and late stages of the disease; and(c) to offer interpretations related to thepathogenesis of DIP.

Material and methods

Thirty lung specimens were obtained by biopsyin our institutions or microscopic slides werereviewed for consultation. Three necropsies, in-cluding case number 15 of Liebow's (1965) series,provided abundant pulmonary tissue since thediagnosis was made by biopsy before death. Allcases were reviewed by at least three pathologists,one of them an outside consultant, using lightmicroscopy of paraffin-embedded material withthe following stains: haematoxylin-eosin, PAS,toluidine blue, Prussian blue, osmic acid for fat,elastica, Gridley, acid fast, and trichrome (ArmedForces Institute of Pathology, 1960). The lungspecimens in 18 cases were divided for frozenstorage for immunofluorescence, bacteriology,virology, acid-fast bacilli, fungus cultures, frozensection, and formalin fixation, and small cubeswere fixed in phosphate buffered 2.75% glutar-aldehyde and Millonig's fixative (Pease, 1964). Theglutaraldehyde fixation was followed by one hour'sstaining in Millonig's fluid. Some of the speci-mens were processed including staining in blockwith uranyl acetate in the 25% ethanol dehydrat-ing agent (Pease, 1964). Embedding was in epon-araldite. The lung specimens were trimmed,preserving the pleura or small bronchi. The sur-face size of the specimens varied from 2 to16 mm2. One-micron sections were cut with thePorter Blum M3 or LKB ultramicrotomes andstained with alkaline 1% toluidine blue, and theslides were mounted in epon-araldite. Electronmicroscopy was done on a RCA EMU3G instru-ment. Cytological details were obtained by mak-ing tissue imprints, the slides being fixedimmediately after biopsy with ethanol-ether,methanol, or air dried. Stains of imprints wereH and E, PAS, methyl green pyronin, Giemsa,and Wright (Armed Forces Institute of Pathology,1960). One biopsy was obtained by the trans-bronchial technique described by Andersen andFontana (1972).

Results

GENERAL CONSIDERATIONS

All patients were adults and had a clinical diagno-

sis of idiopathic interstitial pneumonitis. Threepatients were asymptomatic but pulmonary lesionswere observed by radiographic examination; allothers had respiratory symptoms and radiographicevidence of interstitial pulmonary fibrosis. Fre-quently the disease started insidiously with cough,dyspnoea, clubbing, loss of weight, and a pro-gressive course. A few patients began theirillness more rapidly with fever and apparentpneumonic episodes. The material examined inthis study included biopsies from the left lung inthe area of the lingula or tip of lung lobes, sincefor technical reasons surgeons preferred to followa limited thoracotomy when the lung was believedto be uniformly involved. Twelve cases hadlimited clinical and operative information sinceonly microscopic slides and referral data wereavailable. Seven cases were studied serologicallyfor virus infection and the lung specimens wereinoculated in different cell strains of tissue cultureand observed for 30 days, producing negativeresults. The same number of bacteriological andfungus cultures from the lung tissue had yieldedno growth. Immunofluorescence studies includednonspecific demonstration of immunoglobulins infour cases. Two biopsies showed positive reactionsfor immunoglobulins and complement in themononuclear cells of the clump which alsoreacted with antisera to pigeon and thermophylicActinomyces antigens. Both cases also showedalveolar macrophage cells containing phagocytisedeosinophils in their cytoplasm and immuno-fluorescence evidence of fibrin fragments in thealveolar spaces.

GCROSS FEAT'URESThe gross involvement of the lung was presumedto be generalised since the sampling was limitedand permitted only restricted examination. In 16cases, lung induration was described presentingeither fine nodularity or patchy lesions. Thevisualised lung in cases 3 to 5 presented foci ofconsolidation measuring an average of 0 6 cm.The pleural vessels were conspicuous, engorged,and dilated, and the serosa was slightly thickerthan normal. The lung in cases 7 to 30 presentedpleural fibrosis; case 10 had a shell of calcifica-tion which was nodular and extensive. Two caseshad a cobblestone appearance, the protrudingnodules measuring approximately 0-8 cm in di-ameter. Case 17 had small subpleural blebs anddeveloped spontaneous pneumothorax.

LIGHT MICROSCOPYThe morphological lesions observed by light

8

on Decem



/T


ownloaded from


Morphology and pathogenesis of desquamative interstitial pneumonitis

microscopy in slides from tissues embedded inparaffin were tabulated (Table). At least two slidesper case were reviewed by a panel of threepathologists, including one outside consultant. Thelesions were identified according to the nomen-

Table Light microscopy lesions in desquamativeinterstitial pneumonitis

Early Intermediate Late(Cases 1-6) (Cases 7-10) (Cases 11-30)

Number of patients 6 4 20Age (average) 36 53 56Age range 28-48 39-62 46-67Males 4 2 10Females 2 2 10Intraalveolar cellular clumps 2+1 2 + 2+Lymphocytic infiltration

Alveolar wall 0 1 + 2 +Lymphocytic nodules 0 1 + 2 +

Eosinophils infiltrationIn clumps 2 + 2+- 2+In alveolar walls 2 + 2 + 2 +

Pulmonary fibrosisIn alveolar wall 1+ 2+ 3 +In interlobular septum 0 2+ 2 +Pleural 0 2+ 2+Honeycombing 0 0 2 +

(lung destruction)Atypical epithelium lining

air spaces 0 0 2 +Mucus in air spaces 0 0 1 +Muscle increase 0 1 + 2 +Arteries, medial thickening 0 1 + 2 +

"The values tabulated are obtained by dividing the number of + bythe number of subjects in each group.

clature depicted in the table and arbitrarilyquantitated as 0 when absent and 1+, 2+, 3+,and 4+. The 1+ positive quantitation representedthe presence of at least one lesion per slide. Sincethe size of the microscopic section varied fromcase to case, a uniform criterion was used todefine the diagnosis of DIP which was estab-lished when two lobules of Miller had a minimumof two cellular clumps in the intraalveolar airspaces. Clumps were defined as cellular aggre-gates containing 50 or more cells. The six casesexamined, presumably at an early stage (patientsI to 6 in the table), presented conspicuous fillingof alveolar spaces by clumps of aggregated cells.This lesion was distinctive for DIP (Figure 1)but was patchy in our slides while others haddescribed uniformity and extensive involvement(Liebow et al., 1965; Gaensler et al., 1966; Howattet al., 1973). Four of the six cases presentedminimal lymphocyte infiltration of the alveolarwalls, mostly in discrete groups of well-differ-entiated cells with no germinal centres. One ofthe patients had minimal hyperplasia of thelining cells with foci of prominent cuboidal cells.

The alveolar walls presented discrete changes,mostly oedema in one case, and some focalthickening in two others. The bronchioles hadadjacent tissue inflammation and also clumps ofcells in the lumina. The alveolar walls and cellularclumps had prominent eosinophils lined in rowsor forming small groups. Intermediate and latestage cases were defined because the intermediateones, patients 7, 8, 9, and 10, had focal areas ofair spaces filled with DIP clumps and evidence ofalveolar wall fibrosis while the late stage lesionswere characterised by honeycombing, secretionaccumulation, and metaplastic epithelial lining ofthe cystic spaces (Table, cases 11 to 30).The characteristic presence of clumps occurred

in all forms of the disease, the predominant cellsappearing to be alveolar macrophages. Variationswere observed in the intraalveolar clumps; theearly cases had occasional neutrophils while thelate stages showed more compact aggregation ofcells and occasional attachment to the alveolarwall. The cells forming the clumps were onaverage 20 ,u in diameter. Giant cells 40 to 60 ,uin diameter were found intermingled with eosino-phils and lymphocytes (Fig. 2). Iron stainingdemonstrated that the cells forming the clumpshad iron deposits in cytoplasmic organelles inapproximately 50% of the cases. The slides fromthe 20 cases estimated to be late stages of thedisease showed prominent fibrosis with abundantground substances replacing the structure of thethickened alveolar walls. These cases also pre-sented marked lung fibrosis with cyst formationand loss of alveolar walls which for descriptivepurposes was accepted to be honeycombing. Thecysts were lined by granular pneumocytes andwith bronchiolar epithelial cells and frequentlycontained abundant mucous material.High-resolution light microscopy This materialwas embedded in resin. The clumps observed inthe terminal air spaces had predominant largeovoidal cells with cytoplasmic granules. Theirnuclei were vesicular and had only rims oftoluidine blue stained chromatin and a smallsingle nucleolus. Because of fixation and process-ing they were slightly larger than in the slides fromthe paraffin-embedded material. Eosinophils wereobserved in the early and late stages in the clumpsand in the interstitium. Most of the early casesshowed prominent granular pneumocytes in thelittoral population but hyperplasia was absent orminimal. Few ciliated cells were observed in theair spaces. Mast cells were prominent in theinterstitium in both early and chronic stages. Thecellularity of the intraalveolar clumps was more

9

on Decem



/T


ownloaded from


E. Valdivia, G. Hensley, Jane Wu, E. P. Leroy, and W. Jaeschke

K r~~~~~~~~~~~~

Fig. 1 Case 3 (33-year-old man). Shows an early stage of DIP since there areminimal alveolar wall lesions. The intraalveolar clumps are focal (Haematoxylin andeosin XK68).

Fig. 2 Case 21. This characteristic intraalveolar clump is formed by epithelioid cells.giant cells, and eosinophils (H and E X37S).

10

on Decem



/T


ownloaded from



distinct in the 1 ,u thick sections which showeda prominent variation in cellular size and theoccasional presence of multinucleated giant cells.Slides from the early stages of the disease showedthat the periphery of the clumps had more loosecells while more intercellular contact was ob-served between the elements present in the coreof the clump. The cells lining small fibrosed ter-minal air spaces had lamellar bodies and organellescharacteristic of type II cells, the granularpneumocytes. Bronchiolar epithelium was alsofound lining the revised air spaces.Imprints Small pieces of lung biopsies, approxi-mately 0 2 cm in diameter, were used for makingcellular imprints on glass slides. The imprintswere fixed in ethanol-ether. Unfixed frozen lungmaterial was also used to make cellular imprints.The early stage cases provided abundant cellswhich were easily visualised by the phase micro-scope, regular light microscopy, and after cyto-logical staining. The cells were aggregated insheets of 200 or more but smaller groups or singlecells were also seen (Fig. 3). The predominantcells showed abundant blue cytoplasm (Wright'sstaining). With haematoxylin and eosin the cyto-

plasm stained pink, and giant cells with two ormore nuclei were prominent. The cytoplasmstained positive with pyronin, resulting in ametachromatic pink colour. Imprints from thelate stages of the disease presented sheets formedby a smaller number of cells (average 30-40 cells).The nuclei were vesicular and paracentral,usually with a prominent nucleolus and a rim ofstainable chromatin. The cytoplasm containedPAS positive granules, and in approximately one-half of the cases there was material which stainedpositive for iron. Measurements of these enlargedalveolar macrophages in imprints showed that themost abundant cells had diameters of 25 ,u, whichis a measurement 10 to 20% greater than in theparaffin-embedded tissue. The giant multinu-cleated macrophages had diameters of 50, 60, and80 ,u. Imprints from early and late stages hadfrom 3 to 5% eosinophils.Electron microscopy The ultrastructure examina-tion of this study was performed in biopsies ob-tained from four cases which were classified tobe in an early stage by light microscopy becauseof the minimal or absent alveolar wall fibrosis.Additional electron microscopy was done in 14

0.

Fig. 3 Case 6. Lung cellular imprint which presents sheets of cells, presumablyidentical with the intraalveolar clumps. There are abundant epithelioid cells, giantcells, and eosinophils (H and E X 137).

11

on Decem



/T


ownloaded from



cases which had honeycombing and extensivefibrosis. Each case had 50 resin blocks containingsmall and large lung samples from which sixspecimens were cut at 1 ,u thickness and examinedby light microscopy to obtain areas which hadalveolar structures or spaces containing cellularclumps. The early lesions were searched to obtainsections of the alveolar wall and to visualise thedifferent cells found in the intraalveolar clumps.Early lesions observed in DIP were studied in threecases which clearly showed that the clumps in theair spaces had a heterogenous population withalveolar macrophages, eosinophils (Fig. 3),lymphocytes, and occasional tangential sections ofgranular pneumocytes. The most abundantalveolar macrophages had diameters of 20 to30 ,u but larger elements and giant cells were alsopresent. The smaller alveolar macrophages hadthe ultrastructure of young or immature mono-cytes with no visible lysosomes, few mitochondria,

i 7

1W ~ ~ .~-4

and few cytoplasmic membranes (Fig. 4). Somecells presented abundant lysosomes, their cyto-plasm staining positive with the methyl greenpyronine method, suggesting active proteinsynthesis, but their rough and smooth endo-plasmic reticulum cisternae were poorly de-veloped. Frequently their cytoplasmic inclusionshad darker, smaller granules and conglomeratesof electron dense material which contained ironpositive material when stained histochemically(Figs 5 and 6). These cells had the ultrastructuredescribed for epithelioid cells by Adams (1974).Screening of the DIP aggregates from the earlyand late cases showed that in some areas themacrophages were adjacent and had an inter-digitating process while in the periphery of theclump the cells were free. Examination of thecompact cellular aggregate showed that inter-digitation was not accompanied by the formationof intercellular complexes. The cytoplasmic

". 5.5 '."' '

i-o:A<-; -'

X~~~~2 PA ,t(' _. Z; :4 tt A S2 4.+

# >Asv J 4; 2*.

.i2':

'5.

Fig. 4 Case 6. Electron micrograph presents a free alveolar macrophage with average cell diameter of 12,u.This macrophage has few lysosomes. Tissue has been fixed in Millonig's fluid (XlI 200).

12

on Decem



/T


ownloaded from



4

.4

Fig. 5 Case 6. Electron micrograph shows an alveolar macrophage (M) and an eosinophil (arrow) present inan alveolar space. This enlarged macrophage contains abundant dark-stained lysosomes in the cytoplasm andit has an average diameter of 18 A (Alillonig X5160).

organelles of the alveolar macrophages wereabundant but variable, the multinucleated giantphagocytes had numerous and prominent lyso-somes which occasionally had darker materialand may represent iron containing granules.Numerous alveolar macrophages had prominentcytoplasmic bundles of filaments (Fig. 7).A typical cases Atypical cases were defined assuch because they had morphological variationsfrom the defining features outlined in the table.Four cases were considered atypical forms ofDIP. One of the variations was seen in cases 15and 24. The variations consisted in the presenceof epithelial giant cells with giant deformed nucleicontaining eosinophilic inclusions. At higherresolution and by electron microscopy these cellshad the organelles characteristic of enlargedgranular pneumocytes, namely epithelial micro-

villi on the alveolar surface and lamellar bodies inthe cytoplasm. These giant granular pneumocyteswere always adherent to basement membranematerial. The eosinophilic nuclear inclusions wereobserved to be cytoplasmic infolds surrounded byirregular nuclear membranes and interpreted tobe outside the nucleus. Cases 1 and 2 were classi-fied to be at the early stage since the lung had noalveolar wall lesions. The imprints and tissueexamination failed to demonstrate the presenceof eosinophils which were observed in all otherspecimens.Necropsies None of the patients forming thisseries had a second lung biopsy but six died andnecropsy material was obtained in three. Patient15 of Liebow's (1965) series, also number 15 inthis group, died eight days after biopsy. Formalinfixed tissue was embedded in resin and studied by

13

.44i

on Decem



/T


ownloaded from



Fig. 6 Case 6. Electron micrograph depicts two adjacent, aggregated alveolar macrophages (MA and MB). CellMA has abundant lysosomes with dark small granules, probably containing iron. The cells have interdigitatingprolongations (Millonig X31 000).

light and electron microscopy. This 51-year-oldpatient's biopsy material had giant cells in thealveolar spaces which had microvilli, lamellarbodies, and the ultrastructure of type II granularpneumocytes. The biopsy material also showedalveolar macrophages and eosinophils in theclumps. Sections from all lobes were examined andrevealed extensive interstitial fibrosis, foci ofmetaplastic changes of the alveolar lining cellswith cylindrical and epidermoid epithelium, andoccasional accumulation of mucus. Hyaline mem-

branes and fluid were prominent exudativelesions. Purulent bronchopneumonia contributedto the patient's death. Few intraalveolar cellclumps were found focally in the sections.Necropsy permission for case 29 authorised

only examination of the lung biopsy site threeweeks after the operation. Microscopic slides

showed fibrinous exudate, honeycombing,cellular interstitial inflammation, and purulentbronchopneumonia. There was no evidence ofthe typical intraalveolar clumps. Necropsy ofcase 18 was performed four years after lungbiopsy and also showed extensive lung fibrosis,honeycombing. and prominent epithelial meta-plasia of the pulmonary cystic lesions and terminalair spaces. The postmortem examination showedno evidence of the characteristic intraalveolaraggregation of cells.

Discussion

The histological identification of DIP is outlinedby Liebow et al. (1965) and Gaensler et al. (1966)but the pathogenesis, incidence, radiology, course,aetiology, and differential diagnosis are still con-

14

41D

on Decem



/T


ownloaded from



Fig. 7 Case 6. Electron micrograph shows the cytoplasm of one alveolar macrophage belonging to anintraalveolar clump which contains abundant microfilaments (arrows) (Millonig X56 000).

troversial or unknown because of insufficientinformation, various deviant features, alternativeinterpretations of the available data, and thedifficulties encountered when attempting toseparate DIP from other forms of chronic inter-stitial pneumonitis (Scadding and Hinson, 1967;Scadding, 1970; Andersen and Fontana, 1972;Lemire et al., 1972; Howatt et al., 1973; Adams,1974; Kinjo et al., 1974; Carrington et al., 1976).Liebow et al. (1965) include 18 biopsies and

one necropsy which present the following mor-phological features: (1) group of cells in thealveolar spaces, presumably of epithelial origin;(2) absence of necrosis, hyaline membranes,and fibrin; (3) minimal or absent mural fibrosis;(4) monotonous uniformity; and (5) lymphocyteinfiltration. Both Liebow et al. (1965) andGaensler et al. (1966) believe that DIP is a

different disease entity from the usual type of inter-stitial pneumonitis (UIP) since DIP has the micro-scopic desquamative pattern, presumably a morebenign course, and it appears to have a betterresponse to corticosteroid administration.

Several reports have confirmed the morpho-logical observations but the clinical presentation,radiology, and progression showed marked varia-tions, extending from asymptomatic patients(Kinjo et al., 1974) to a short and fatal course(Howatt et al., 1973). Progression to muralfibrosis, honeycombing, and loss of pulmonaryparenchyma has been described in the seriespublished by Lemire et al. (1972), Gaensler et al.(1966), Scadding and Hinson (1967), Scadding(1970), and Patchefsky et al. (1971, 1973a, b).Carrington et al. (1976), in a recent publication,summarise their criteria which separate DIP and

15

on Decem



/T


ownloaded from



UIP into two different morphological pulmonarylesions but they believe that DIP and UIP maypresent similar radiological and clinical patterns.produce equal physiological abnormalities, andthat both may progress to honeycombing andfibrosis.Lemire et al. (1972) report eight patients whose

lungs show desquamative patterns similar toLiebow's outline of DIP in two instances whilethree patients had lesions considered intermediatebecause of fibrosis and desquamative patternsand three other cases presented only diffusefibrosis. Scadding and Hinson (1967) and Scadding(1970) present a similar series and suggest thatDIP and UIP are morphological variations ofchronic interstitial pneumonitis which may bepresent or absent at any stage of the diseasebut favour the desquamative pattern as an earlystage. Scadding and Hinson (1967) suggest thename diffuse fibrosing alveolitis to include whatthey consider to be morphological variations ofone pulmonary disease. They report cases present-ing intraalveolar mononuclear cell exudate, caseswith desquamative and alveolar wall fibrosis, andothers in which only diffuse fibrosis is observed.There is histological evidence of the persistenceof the desquamative pattern several years afterthe original diagnosis (Gaensler et al., 1966; Goffet al., 1967; Bates et al., 1971) while in othercases the intraalveolar clumps have decreased innumber (Scadding and Hinson, 1967) or are notfound in sequential biopsy or necropsy materialas observed by Patchefsky et al. (1973a) and inthis series.

This study is based on the histopathologicaldiagnosis and the tabulation of the morphologicalchanges observed in 30 lung biopsies. The localisa-tion of tissue components in resin-embedded lungspecimens allows the ultrastructural identificationof cell populations which show that the intra-alveolar desquamative patterns are formed by ac-cumulation and aggregation of alveolar macro-phages intermixed with lymphocytes, giant cells,and eosinophils. It is assumed that previous reportsof type II cell desquamation may be explainedbecause of osmiophilic concentric whorls presentin formalin fixed alveolar macrophages, tangentialsectioning of the alveolar wall, granular pneumo-cyte lining of adherent clumps, metaplastic in-crease of granular pneumocytes, lung atelectasis,reduction of size of air spaces, and frequent post-operative collapse of the lung tissue. Ourobservations suggest that the accumulation andaggregation of alveolar macrophages must be con-sidered the primary phenomenon of DIP while

the increase in number of granular pneumocytesand the alveolar wall fibrosis may be secondaryevents (see Table).The mechanism of alveolar macrophage clump-

ing offers many interesting alternative explana-tions which may depend on the biologicalproperties of the host, alveolar cells, or structuresof the pulmonary parenchyma. Damaged anddead cells agglutinate rapidly but lack of mor-phological evidence of cell death in the clumpsfails to support this simple mechanism. Thesurface of most cells is known to have anioniccharges which are mainly provided by sialic acidmolecules oriented on the outer surface of theplasma membrane. A nonspecific neutralisation ofthese negative charges may occur when proteinsor other charged molecules accumulate in thealveolar fluids. Metaplastic changes in the lining ofthe revised terminal spaces with accumulation ofplasma and mucous material may contribute tothe persistence of the lesions. Lastly, the alveolarmacrophage clumping may depend on a cellmediated hypersensitivity stage which could re-quire T lymphocytes and the production oflymphokines to induce macrophage immobilisa-tion. One attractive hypothesis is to explain thecellular inflammatory infiltration, alveolar wallfibrosis, and destruction to be secondary to pro-ducts derived from the immobilised alveolarmacrophages. This speculative view is similar tothe hypothesis of Heppleston and Styles (1967)and Kilroe-Smith et al. (1973) for the pulmonarylesions observed in silica pneumoconiosis whichproposes that silica pneumoconiosis or thealveolar macrophage exposure to silica in vitroinduces the release of fibrogenic factors.The entity described by Liebow et al. (1965) and

Gaensler et al. (1966) has characteristic but notspecific features which, to our surprise, are notfrequently observed in our series. The clinicalonset and symptoms are well described in theliterature. Our patients follow a similar pattern butDIP is not found to be the initial or preoperativediagnosis in any of the 30 records. The apparentexplanation is probably that the cases studi'ed bythe original group (Liebow et al., 1965) wereobserved at a relatively early stage of the diseasewhen an alveolar pattern is frequently found inchest radiographs. The most difficult morphologi-cal diagnosis encountered is when attempting todifferentiate idiopathic chronic eosinophilicpneumonia from early and intermediate stages ofDIP since both lesions present macrophage clump-ing in the alveolar spaces and eosinophilic in-filtrates. The presence of fibrin in eosinophilic

16

on Decem



/T


ownloaded from



pneumonia is not a distinctive feature since itmay represent an acute phase of a cellular in-flammatory exudate; furthermore, fibrin has beenshown to be present in the alveolar lesions ofour cases of DIP studied with immunofluorescencetechniques. The vasculitis described in idiopathicchronic eosinophilic pneumonia (Liebow andCarrington, 1969) is not a frequent or specificmural lesion and it may again be a secondaryfeature present at an early stage. Both entities,DIP and idiopathic chronic eosinophilic pneu-monia, are suspected to be hypersensitivitypneumonitis and develop in individuals in whichan immunological mechanism may be responsiblefor the inflammatory reaction (Leroy, 1969).Despite the presence of clinical, radiological, andmorphological differences which exist betweenDIP, UIP, Hamman Rich syndrome, diffusefibrosing alveolitis, and chronic idiopathiceosinophilic pneumonias, the similarity of thepulmonary morphology and the occurrence ofcases with mixed features support the view thatall may have common variations dependent on apresumed similar pathogenesis or the stage ofthe disease.

This report could not have been prepared withoutthe work and cooperation of the following col-leagues from the Departments of Medicine andSurgery, University of Wisconsin Chest Clinic:Helen Dickie, John Rankin, Louis Chosy, Guil-lermo Do Pico and John Pellet (Surgery), cases 1,2, 6, 8, 9, 10, 11, 12, 15, 16, 17, 18, 21, 23, 25, and29; University of Illinois Medical School, cases 4and 13; SCOR Program, Medical College ofWisconsin, cases 3, 5, 20, and 26; Donald Steven-son, Madison General Hospital, cases 14 and 19;Michael Miller and R. J. Wiarda, Kenosha, Wis-consin, case 15; Francis E. Cicarelli, Dubuque,Iowa, case 18; Rockford Memorial Hospital, De-partment of Pathology, Rockford, Illinois, case22; James Turner, Veterans AdministrationHospital, Madison, Wisconsin, case 24; CesarReyes, Marshfield Clinic, cases 7 and 27; SreedharNair, Norwalk Hospital, case 28; Averill Liebow,Department of Pathology, University of Cali-fornia, LaJolla, review of cases 4, 5, 10, 13, 15,23, 24, and 25; Armed Forces InsVitute of Path-ology, review of case 22.

References

Adams, D. 0. (1974). The structure of mononuclearphagocytes differentiating in vivo: 1. Sequential fineand histologic studies of the effect of bacillus

Calmette-Guerin (BCG). American Journal of Path-ology, 76, 17-48.

Andersen, H. A. and Fontana, R. S. (1972). Trans-bronchoscopic lung biopsy for diffuse pulmonarydiseases: technique and results in 450 cases. Chest.62, 125-128.

Armed Forces Institute of Pathology. (1960). Manualof Histologic and Special Sta.ning Technics. 2nded. Blakiston (McGraw-Hill), New York.

Bates, D. V., Macklem, P. T., and Christie, R. V.(1971). Respiratory Function in Disease, p. 294.W. B. Saunders, Philadelphia.

Carrington, C. B., Gaensler, E. A., Coutu, R. E..FitzGerald, M. X., and Gupta, R. G. (1976). Usualand desquamative interstitial pneumonia. Chest,69, 261-263 (Supplement).

Corrin, B. and Price, A. B. (1972). Electron micro-scopic studies in desquamative interstitial pneu-monia associated with asbestos. Thorax, 27, 324-331.

Farr, G. H., Harley, R. A., and Hennigar, G. R.(1970). Desquamative interstitial pneumonia: anelectron microscopic study. A inerican Journal ofPathology, 60, 347-370.

Gaensler, E. A., Goff, A. M.. and Prowse, C. M.(1 966). Desquamative interstitial pneumonia. NewEngland Journal of Medicine, 274, 113-128.

Goff, A. M., McNary, W. F.. Jr., and Gaensler, E. A.(1967). Desquamative interstitial pneumonia. Medi-cina Thoracalis. 24, 317-329.

Gould, V. E., Gleason, T. H., and Winterscheid, L. C.(1971). Desquamative interstitial pneumonia. Chest,59, 349-352.

Heppleston, A. G. and Styles, J. A. (1967). Activityof a macrophage factor in collagen formation bvsilica. Nature, 214, 521-522.

Howatt, W. F., Heidelberger, K. P., LeGlovan,D. P., and Schnitzer, B. (1973). Desquamative inter-stitial pneumonia. American Journal of Diseases ofChildren, 126, 346-348.

Kilroe-Smith, T. A., Webster, I., Van Drimmelen, M.,and Marasas, L. (1973). An insoluble fibrogenicfactor in macrophages frcm guinea pigs exposed tosilica. Environmental Research, 6, 298-305.

Kinjo, M., Watanabe, T., and Tanaka, K. (1974).Localized form of desquamative interstitial pneu-monia. Chest, 65, 458-460.

Klocke, R. A., Augerson, W. S., Berman, H. H.,Burgos, F. L., and Rivera, R. A. (1967). Desqua-mative interstitial pneumonia. A nnals of InternalMedicine, 66, 498-506.

Lemire, P., Bettez, P., Gelinas. M., and Raymond, G.(1972). Patterns of desquamative interstitial pneu-monia (DIP) and diffuse interstitial pulmonary fibro-sis (DIPF). A merican Journal of Roentgenology,Radiation Therapy and Nuclear Medicine, 115,479-487.

Leroy, E. P. (1969). The blood-air barrier in des-quamative interstitial pneumonia (DIP). VirchowsA rchiv fur pathologische A natomie und Physiolog eund fiur klinische Medizin, 348, 117-130.

Liebow, A. A. and Carrington, C. B. (1969). The

17

on Decem



/T


ownloaded from



eosinophilic pneumonias. Medicine, 48, 251-295.Liebow, A. A., Steer, A., and Billingsley, J. G. (1965).Desquamative interstitial pneumonia. A mericanJournal of Medicine, 39, 369-404.

McCann, B. G. and Brewer, D. B. (1974). A case ofdesquamative interstitial pneumonia progressing to'honeycomb lung'. Journal of Pathology, 112,199-202.

McNary, W. F.. Jr. and Gaensler, E. A. (1971).Intranuclear inclusion bodies in desquamative inter-stitial pneumonia: electron microscopic observa-tions. Annals of Internal Medicine. 74, 404-407.

Patchefsky, A. S., Banner, M., and Freundlich, I. M.(1971). Desquamative interstitial pneumonia: sig-nificance of intranuclear viral-like inclusion bodies.Annals of Internal Medic.ne, 74, 322-327.

Patchefsky, A. S.. Fraimow, W., and Hoch, W. S.(1973a). Desquamative interstitial pneumonia: path-ological findings and follow-up in 13 patients.Archives of Internal Medicine, 132, 222-225.

Patchefsky, A. S., Israel, H. L., Hoch. W. S., and

Gordon, G. (1973b). Desquamative interstitial pneu-

monia: relationship to interstitial fibrosis. Thorax,28, 680-693.

Pease, D. C. (1964). Histological Techniques forElectron Microscopy, 2nd ed. Academic Press, NewYork.

Rhodes, M. L. (1973). Desquamative interstitial pneu-

monia: new ultrastructural findings. American Re-view of Respiratory Diseases, 108, 950-954.

Scadding, J. G. (1970). Lung biopsy in the diagnosisof diffuse lung disease British Medical Journal, 2,557-564.

Scadding, J. G. and Hinson, K. F. W. (1967). Diffusefibrosing alveolitis (diffuse interstitial fibrosis of thelungs). Thorax, 22, 291-304.

Shortland, J. R., Darke, C. S., and Crane. W. A. J.(1969) Electron microscopy of desquamative inter-stitial pneumonia. Thorax, 24, 192-208.

Requests for reprints to: Dr. E. Valdivia, 1300University Avenue, Madison, Wisconsin 53706, USA.

18

on Decem



/T


ownloaded from


morphology and pathogenesis of desquamative interstitial

Documents