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Giant Cell Interstitial Pneumonia (GIP)
•
CLINICAL INVESTIGATIONS
Giant Cell Interstitial Pneumonia (GIP)
Prathapchandra A. Reddy, M.D., F.C.C.P.,· David F. Gorelick, M.D.,·· and Charles S. Christianson, M.D., F.C.C.P.t
Three cases of an unusual interstitial pneumonia, designated by Liebow as giant cell interstitial pneumonia, were encountered by us. Dyspnea, weight loss, cough, chest pain, rales in the lungs and clubbing of the fingers were the frequently observed clinical features. RoentgenograpbicaDy, there were bilateral, patchy, nodular Infiltrates of varying density, more prominent in the mldlung fields. Histologic features are quite striking, characterized by predominant lymphocytic interstitial Infiltrate along with numerous, bizane, multinucleated giant cells In the alveoli as well as varying numbers of alveolar pneumocytes. The Intraalveolar cells showed a positive reaction with PAS and Iron stains. Extensive etiologic studies undertaken In one case were negative. The cUBical, radiologic and functional improvement seen In our first case Indicates that c0rticosteroids may Induce a rewarding remission. The alteration of histologic features after steroid therapy, suggests a possible relationship between giant ceUinterstitial pneumonia and desquamative interstitial pneumonia.
Giant cell pneumonia, often referred to as Hecht's giant cell pneumonia, was originally observed in children. Hecht ! in 1910 described the process as an interstitial infiltration of giant cells and mononuclear cells. In 194.5, Pinkerton 2 demonstrated inclusion bodies in the giant cells and suggested a relationship to distemper and measles virus. Investigators wen' ahle to isolate measles virus from the lung tissue of children who had a defective immunologic system and presented similar histologic changes in the lungs.~-'· These features, occurring in children, had not been reported in adults until Liebow" described two autopsied cases and gave the designation, giant cell interstitial pneumonia (GIP). We have encountered three cases of this unusual condition at the .\Iissouri State Sanatorium, a center for chest diseases.
This communication is a report of these cases with their clinical, functional, radiologic features; and comments on the electron photomicrographic findings, etiology, prognosis and treatment. CASE REPORTS
I A 44-y ear-old plumber entered th .. \li."ouri State Sanatorium in February, 1968 because of extreme shortness of breath, progressive over the pas t six years. He had also experienced episodes of intermittent chest puin which was sharp, stabbing and nonradiatlng. Other symptoms included a productive cough, malaise, fatigahility and weight loss. He had been a heavy cigarette smoker for 25 years. The patient had consulted his physictan in HIl1.5 and 1966 for shortness of br eath and cough. Chest x-ray films taken in June, 1965, and August, 1966, rev eal ed bilateral, nodular densities in both mid lung field", more pronounced in the riJ,tht lung. He had received several courses of antiluotics without appreciable improvement. His symptoms gradually increased until the time of his present admission. On physical examination there was dullness to percussion over the rij(ht lower lunj( field posteriorly, and in the ri~ht axilla, diminished breath sounds and moist rales in both low e r lung fields. The extremitres showed advanced clubbing of all his fingernatls and toes. There was no cyanosis or peripheral edema, CASE
·Staff Physician, Missouri State Sanatorium, ~tt. Vernon. MissOllri. ··Consultant Pathologist and Acting Director of Lahoratones, ~tissollri State Sanatorium, ~1t. Vernon, ~fissouri. tChief of ~1E'(licine, ~Ii."ouri State Sanatorium, ~It. Vernon. \tissouri. Presented in part at the First Fall Scientific Assembly (3.5th Annual \I"t'linj() American Collej(e nf Ch est Physicians, Chicago. Illinois, October 29-loOovemlX'r 2, 1969.
319
320
REDDY, GORELICK AND CHRISTIANSON
Fl<:l-RE l. ROt'nt~l'nO!!rams of the che-t in case 1. A. left: (prior to therapy) showinu dense nodular infiltrates in the right mid and lower lunu fields. abo. patchy infiltrates in the left hilum and along the cardiae border. B. nnht: (.3 months after corticosteroid therapvI showina mark..-cl cle-arinu of the- infiltration in both 11Inl.{ fields.
In \lay. 196k. dllrin\.! an open wedc;t;' hiopsy of the riJl:ht middle lohe, it was noh'd that the entire lung was cnnsolidakcl and of firm consiste-ncy. Histolo~k sections (Fig :2 A. B) showed the alveolar span's to lx- fille..d with some de-squamate..d alveolar pnr-umocvtcs. as well as many large. lnzarre. multinucleated giant cells. sunu- of which contained phagoc-yttzed cells, The ju-rihronc-hia! intervtitium was thida'ned and pn-se-nt,..d a predominant IYlllphocytit.' infiltrate. Differen(,l'lIs and pneruuocvtes to Hal stain ShOWl..d many of the ~iant c-ontain P:\S-positi\'t' llliltl'rial (Fi~ 2C). Potassium Ierrocyanide- as we-ll as prnxxiun blue stains n-veuled homogeneous stainable iron in both giant cells and tllt" pneumocytex l Fig 2D i. These finduurs e-stablished a diaunovis of giant cell mterstitial pneumonia l (;IP). In view of the patient.... poor clinical condition. therapy with corticosteroids was instituted on June II, 1968. with initial dosage.' of -to me; of pn-duisone daily. and this resulted in marked improvement. On JlIly 10. HJnS. prednisone dosalle
:\dlliissioll chest roentm-nnarams (Fig 1:\) Tt'H'aled some
patchy nodular infiltrutiun in the left Illidlllllt.: nt·ltl dost> to tht' hilar areas and alollg the cardiac borders. There were dense nodular infiltr.m-s in the entire nuht mid and lower (tllle: fit·lds with SOIll(' ('\"idt'll(.'(' of emphysema. The costophrenic anules were fret'. Pulmonary function determinations art' sllllllllarizf·d in 'I"<,hlt' I. On admission, 1lt'lIloglohin was In.I/iOn IIlI; Hct .51 IX'rc-e-nt, ami whitt' blood ce-ll count (\\'Be) 11.504 per 111m:'. with normal diffen·ntial. Sedimentation rate was 5 nun/hr. Purifie-d prote-in de-rivative ( PPD) and histoplasmin skin tests Wt"T(' positiq·, Result, of complement fixation tests for histoplasmosis, hlastomycosis, and l'Ol'cidioidomyl'osis were negativt-. SputUlI1, bronchial washings and ,LI;a~tri<: cultures ~iln' Ill'gativl' n-sults for fungi and AFB. Eleetrnphoresis and uumunoeh-ctrophoresi-, IIf St'T\111\ proteins showed no abnormal Hndinas. Diffusion stlldit·..; re-ve-aled 10 ml CO/minute-'mlll JIg l normal runue :2,'5 to :3() l. Attempts at viral cultures from the hiopsy tissue were unsuccessful.
TablE' I-Pulmonary Function S'udiel in Cale 1 \'('ntilat(lr~'
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FE\'
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CHEST, VOL. 58, NO.4, OCTOBER 1970
321
GIANT CELL INTERSTITIAL PNEUMO IA
zc.
Show, abundant PAS- po,;iti\'t' m at eri al in both th e.' uian t ('("lis and alveolar pneu mocytes ( PAS stain, X :!SOI.
FIC ;t"H E
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" n-duc...-d to 10 m~ d ;) iI ~ li t· (.'untinw"C'l to ..how hmcal, ratl inllll:i<' ( I' il: I n I a",1 In n('tinn.,1 (T••hl ,' I ) im prnv ..m nt , .\ r«'pt "Olt w(-
hea rd i ll lilt" right lung posteriorl y, The re W:.L'i reduction in duh hin$! com pa red to that of th e previous ad missio n. He.'I'H.'at pu lmonary [un ct ion stu d it's ( T able I l sh owed no l'hangc.'. He was reh osp ital ized in ~I a y . 196 H, for repa ir of a ri~ht IUllc ln-eniation de n ·lullinJ! in th t' previou« surc it'al sca r. It was ou r op inion th at hern iatio n prob ahl y (K:c.'urrt'(l a.. a n-vult of poor fih rolls tisSIIl: f onn ~.t i on an d lu-alimr, ht.'<.·.msc,· of cortico..teroid th e rap y a t th e tim e of the pre vious th or acotomy and lung biopsy. During su rJ;:t'Ty. tilt.' ("tUlsist t'nl'y o f ti lt' hlll~ wns Ielt to he similar to previous observa tion an d ano ther wedge biopsy was ob ta ined . .\ t th i.. tim e. th e histologic.' ft ·ahm .'~ ha d unde rgon e stri king cha ng e. S("(,tions t Fi g ,'3) vhowed 1I1;,11IY desq uamate d pue u mncyt es RllinJ.: tll t' alveoli and snme- con tai ned bro wn ish pig men t. T he re was a lmos t com plet e absence of mu ltinu cleat ed ghlOt ce lls, Oth er histo, loc it.· fi ndin~s W e n' t"'isen tiall y tlu- ~alllt' us ht· fo rt>. TI lt' histulog ie fe atures see n on th e thin) biopsy wc' rt' simila r tn th at 't't"'ll in d t>S(lu.u natin> inters fitia l pneu m on ia ( D IP ). e-vce p t for the increased amount uF sta iuabh- i ron wi thi n ti lt" des quu ma ted a lveol ar pllt·ulluK·yh's. Th e pa tien t wa .. d i'ich ar gl"t.1 on lIlt' l -tth postopt' ratin' day n n iI n-duced mai nn-nunce- dose Hfpredni..o ne-, ,'30 m g t"\"t'r y othe-r da y. :2. :\ 3 1-yea r-o ld jail supervisor ent ered the \Iis..our! State Sanato rium in April, 1960, because progressive ..hortnes.. of breath o f si.\ months' duration. He t-nmplu ine-el of cough. CA~E
or
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of p fl't;llIi~UIlt" ~,e rr u tJU'r da)'. On no ,l ",r I ~, 100 ', th.. put.. 'n t w,,-, n """ Uro a .tn ("fIlt·~en("~ _ O n thdt tidY_ fuUnw m · a hou t o f C'Ous;:hinl.:. h... n\t:" th '~ l)(X'l ' d his f.u "mt n L: ~an to "'Wt'll. E ,t n i ' .... ' ul..·u t a tlt"U lI :!I t*lIlph)' 'lIIa III thc' fao-. tlf><'L: C'~ t Ut't:t: :'o llatc-tl Imlnt-dia l f r. ,hc.......... to m ) Uti n ) 'Ct"u the r.1 , ' . 11 ,r ('.\a ct ~i h ' of thto ft'ftl- nJIIld nll t ht:· d de n nint"{L " 'ithin a W (,'(·k. th t' pa tiptlt im pro n 'd and wa.. di 'i(·hanwd to (·onti nllt· P ft't; llli ~ I Hlt · :30 mc ('\"l'ry o th er d ay . m~
lo
.mo
T ilt· IMtic'flt t'n h 'ft "t! t ht · hll ... p ital Oil \I a rch 2 . UJfi9. for follow -up . Phy, i(.'al t".\a mi na tion rt·\·c·a led dim inu tio n of Im 'at lt "0 1111( 1.. in ti lt: riJ.!h t h",,' , ,-\ few sl'a t tt-n 'c1 r al t · ~ ""t>Tt>
CHEST, VOL. 58, NO.4, OCTOBER 1970
F IC,l'HE :2. D . Silows th t' p rt'''i(' IK 't ' of h o m o ~ t'n t"l Jtl s i ron-lik e mat erial in ho th ~i
322
REDDY, GORELICK AND CHRISTIANSON
FJ(;CR£ 4. Chest roentgenograms in case 2. Miliary calcific infiltrations are seen in both lung fields and also soft, patchy, nodular infiltrations in both midlung fields with prominence in right lung.
FH'l'HE :3. Case 1. Third lung biopsy, ~Iay, 1009. A (upper). Shows predominance of desquamated alveolar pneumocytes within the alveoli, some of them in mitosis. There is absence of the bizarre, multinucleated !(iant cells (hematoxylin and eosin. X 40n). B (lower). Same section as A. Showtng marked increase in stainable iron within the alveolar pneumocytes ( acid Icrrocynnide stain, X 4(0).
chest pain, malaise, easy fati!(ability and weight loss of 30 pounds in one year. He had had no hemoptysis. fever. or chills. In 1955, a routine chest x-ray film revealed bilateral, healed, calcified lesions interpreted as healed histoplasmosis. On physical examination. fine crepitations were audible in the left lung posteriorly. The extrermties revealed first degree clubbing of tilt' finzemuils. The results of lahoratorv shldies wen' within normal limits. Skin te-sts with PPD and' histoplasmin results were posttlve. Complement fixation titers for histoplasmosis, blastomycosis, and cocc-idioidomyc-osis were negative. Several sputum cuitun's for Histoplasma and add-fast nrganisms were negative. Chest roe-ntge-noarams (Fig ...) revealed bilateral miharv calcificution and soft, patchy, nodular infiltration in rnidhmc fields with prominence in the right lung. Pulmonary function studies showed restrictive ventilatory impairment (Table 21.
both
The patient underwent right thoracotomy with wedge biopsy of tilt' right lower lobe on Mav 6, 1000. Sections revealed thickening of the alveolar septa. Within the alveoli there we-re' present numerous. bizarre, multinucleated giant cells and varviru; numbers of desquamated pneumocytes. Some of the !(iaot cells were actively phagocytic (Fil( 5) with clumpe-d nuclei and numerous engulfed cells within abundant cytoplasm. These eeUs Were positive to PAS stain. Spe-cial stains for iron showed some homogeneous, bluish material within the ~iant cells. The patient's postoperative course was uneventful and he was discharged to his home without any therupy in June, 1960. TIl(> patient was seen by one of us (P.R.) in September. 1968, and April. 100\J, at which time he stated that he was asymptomatic. His dyspnea had improved one to two years after disehar!(e and he had rezained his weight. Although the patient had no symptoms, pulmonary function studies (Table 2.) still showed restrictive ventilatory impairment. The paticnt did not wish til undergo additional studies. C."E 3
A 72-year-old housewife entered St. John's Hospital, Springfield, \Iissouri, in May, 1967, with a five-month history of fever, productive cough, chest pain, dyspnea, malaise, diarrhea, headache and weight loss. On admission, she appeared acutely ill. Temperature was 99.4 F, respiratory rate 0
Table 2--Pulmonar:r Func,ion S,udipil ill
FEV
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,H{)l'r'i 2.2~1·1
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.=)Sf·;
'I
CaliP
2
peo,
FEV
~I\'\'
2,2\)8 ml
lI.i L
pH
I SeC'. ~I
i~H'('~
2.\8.i rnl
146
L~I
:16
'95'('
CHEST, VOL 58, NO.4, OCTOBER 1970
323
GIANT CELL INTERSTITIAL PNEUMONIA DISCl'SSIO~
FIGeHE .5. Lung hiopxy hom case :2, showina "cannibalistic" giant ce-ll within the alveoli. The nuclei an' pushed to the pertpherv. also within the alumclant cytoplasm are numerous
pha.l.!ocytizt'd cells (1H'lllatoxylin ,lml eosin, X :JO{J).
48/min, pulse IOf). and hlood pressure 104/.50. Crepitant rules WPTe multblc in hoth lung fields. Clubbing of the finuers, cyanosis and mild pitting edcma of the ankles wert> present. The chest roentzenouram (Fig (j) showed dense-, nodular opacities in hoth June: fit'hls. more pronounce-d in tilt' left lung with ('OOf1I1('II<..:t' in the nudlunu field gi vin.!!; a ground-glass appe-arance. The-n- was no evideucc of honcvcominz. The patient's condition rapidly deteriorated and she died on \lay :JI. 1967. At nocrup..y. there was cxtcnstvo consolidation of all the lobes bilaterully. \Iicros<:opie examination of sections revealed thickeninu of the interstitium and of the alveolar septa. The cells lining the alveoli were prominent and in-nerally cuhoidul in shape. There was marked interstitial lymphocytic infiltration. mon- prominent in the pe-npherv. The alveoli contained many. varvinu sized. multinucleuted uiant c('I1...-; and also some desquamated alveolar pne-umm-ytes. PAS stain revealed abundant positive man-rial in the uiant c('lIs. Stains for iron showed a homogeneous hill ish material within the intra-alveolar cells.
Interstitial pneumonia has been an inconclusive term used 1)\· pathologists for several decades to describe the tissue response in the lung which takes place predominantly in the supporting structures rather than within the alveoli. Clinical and radiologic features are not pathognomonic and may be seen with all disorders producing alveolar capillary block, The etiology of several of these disorders is unclear and no satisfactory classification exists. Liebow" in 1968. proposed a classification of the interstitial pneumonias into fin' groups according to their histologic Features. This workable classification offers a better understanding of the complete disease spectrum of interstitial pneurnonias and pt'rmits the clinician not only an understanding of the disease process. but also relates to the management of the patient. Scadding and Hinson," however, criticized such a classification based on cytologic features and suggested the term "diffuse fibrosing alveolitis' as a broad term for the entire group. L'sual interstitial pneumonia (l'IPl. bronchiolitis obliterans (BIP), desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP I have been well recognized and are of special interest to clinicians and pathologists. ,- I " Extending Liebows classification, Moran and Totten 1" recently described plasma cell interstitial pneumonia (PIP) which we have included in our Table :3. Histologic Features of GlP: Although the histologic picture varies somewhat from case to cast', there arc features in each which affords recognition and permits definitive diagnosis of giant cell interstitial pneumonia. Generally, the interstitium is thickened and presents a lymphocytic infiltration which in some areas appears aggregated and even shows folIide formations. The alveolar septa are somewhat thickened and show an infiltrate made up of lymphocytes. plasma cells, small numbers of oosinophils and a few neutrophils as well as proliferating fibroblasts. The cells lining the alveoli are prominent and cuboidal. \Yithin the alveoli arc varying numbers of rather large. bizarre-shaped, multinucleated giant cells. These cells measure from 40 to 60 microns. While some present a definite cell wall, Tab!e
3---Cla~B;ficat;o"
of l merstitiat Pneumonia.
1-:"lIal (If ('Ia,.. . . ir-nl intcrstit iul pm-umoniu 1("11), 2 Bronr-hiolit is obliterans and diffll:O:t' alveolar d:lIna~f' Desquamntive interst it inl pnr-umonin DIPI I
FH;nu: fi. Cln-vt roentucnozram in cast' :3 sh(}\n dense. nodu-
lar opacitit's in hoth lunu fjplds. mort- pronounc-e-d in the left lung 1!i"in1! a "ground-glass" appearance.
CHEST, VOL. 58, NO.4, OCTOBER 1970
Lvmphoid intcrstit iul pneumonia I LIP]
.=j tj
Giaut r-oll interst ir inl pneumonia l(;IPI
Plasmoevr ic intorst it ial pneumonia (PIP,
\ Hl Pi
324 many show a "splashed" appearance with peripheral pseudopod-like projections. The nuclei are usually uniform in size with reticulated chromatin and tend to be pushed to one side, or at times are congregated near the center. 1':0 definite asteroid or inclusion bodies are present, although some giant cells contain varying numbers of engulfed alveolar cells, and thus present a cannibalistic feature. Also present within the alveoli are small to moderate numbers of desquamated alveolar pneumocytes. These show a fairly uniform appearance and an occasional mitosis is secn denoting active proliferation of some of these cells. Generally, the cells show a uniform, salmon-pink cytoplasm, although one may also see fine brownish pigment in both the pneumoeytes and the giant cells. There are minimal numbers of Inflammatory cells. :\'0 necrosis is present. With periodic acid-Schiff stain, both the giant cells and the alveolar pneumocytes contain abundant homogeneous PAS positive material. When stained with acid ferrocyanide, both the giant cells and the desquamated alveolar pneumocytes contain a homogeneous bluish stained iron material. The stained iron is not granular and shows no features characteristic of either hemosiderin or hemofuscin. The nature of this material is still problematic. It may be ferritin or an iron metabolite bound to an intracytoplasmic enzyme system. It is of interest that in case 1, the stained iron material had increased at the time of the second biopsy and was markedly increased in the third biopsy specimen. Whether there is a relationship between the increase in iron and the disappearance of the giant cells is conjectural. Electron photomicrographs were obtained on the biopsied tissue from case 1. The findings were interpreted by Dr. Matthew Divertie as showing "Severe damage to alveolar lining epithelium. Cells are being cast off into alveolar spaces and breaking up. The organelles are intact. Septa show distinct capillary changes and those present are nearly obliterated by swollen endothelial cytoplasm." The predominant clinical features of GIP were progressive dyspnea, clubbing and rales in the lungs. Cough, chest pain. malaise, fatigue and weight loss were seen in all the cases. Chest roentgenograms were consistently abnormal, although the degree of infiltration varied. Xlidlung fields were involved in all three cases. The costophrenic angles and the lung apices were spared. In two. the infiltrations were more pronounced and the densities were confluent, giving a ground-glass appearance. The disease was bilateral in all three cases. Cavitation and honeycomhing did not occur. The x-ray appearance is often misleading. At sur-
REDDY, GORELICK AND CHRISTIANSON gery or necropsy, all portions of the lungs were involved in a similar manner. Ventilatory studies revealed restrictive impairment. In case 1. there was marked improvement three months after therapy with corticosteroids was begun. Case 2, although experiencing subjective improvement without any therapy, showed persistence of restrictive ventilatory impairment when tested nine years later. Arterial blood gas studies revealed hypoxia and impaired diffusion. Extensive laboratory determinations provide no clue to the etiology. Autoimmune studies were negative. Antilung antibodies were looked for and found to be absent in our first case. \\'e were unable to demonstrate the presence of infections in our patients. Histologic, bacteriologic and viral studies of the lung tissue failed to reveal an infectious agent. Although it somewhat resembles measles virus pneumonia, the giant cells do not contain inclusion bodies and attempts to culture the virus from the lung tissue were unsuccessful. Based on these studies, etiology of this entity is obscure. Relationship to DIP: The clinical syndrome of progressive dyspnea, clubbing, rail'S in the lungs accompanied by abnormal chest x-ray appearance is consistent with all diseases producing alveolar-capillary block resulting in impaired diffusion of gases. GIP has great similarities to DIP in clinical features although certain differences can be recognized. Radiologically, DIP is said to exhibit triangular densities radiating from the hilum to the bases obscuring cardiac margins. In GIP we have seen a different pattern where there is more frequent involvement of midlung fields. Histologic features of DIP and GIP are strikingly diffl'rent. The third biopsy from case 1 showed almost complete absence of giant cells, but there were numerous desquamated pneumocytes within the alveoli which are PAS-positive. These cells contained material that was positive to iron stain in contrast to the intra-alveolar cells in DIP. The striking alteration of histologic picture from GIP to DIP suggests a possible transition from GIP to DIP. Similar to Liebow's" observation of the relationship between the granular pneumocytes and alveolar proteinosis, there may exist a relationship between desquamated alveolar pneumocytes and the giant cells. We believe that the initial phase in giant cell interstitial pneumonia is a desquamation of granular pneumocytes which give rise to giant cell forms. Whether this represents a foreign body type of reaction or autoimmune phenomenon, or an event initiated by infection is not clear. Our observations indicate that with favorable response to corticosteroids, the giant cells disappear and the granuCHEST, VOL. 58, NO.4, OCTOBER 1970
325
GIANT CELL INTERSTITIAL PNEUMONIA lar pneurnocytes predominate. It remains to be seen whether continued corticosteroid therapy will produce ablation of the granular pneumocvtes. From the variable courses seen in this group of three patients, it is not possible to generalize about the prognosis of the disease, Case 2, in whom the diagnosis was established nine years ago, was symptomatic for six months prior to diagnosis. Without any therapy, he improved subjectively. Case 2 and the two patients described by Liebow had died within a year. The clinical, radiologic and functional improvement seen in our first case indicates that corticosteroids may induce a rewarding remission. ACKNOWLEDC\IENTS:
w~ gratefully acknowledge the assistance of Dr. Averill A. Liebow for \'erifyin~ the diagnosis and useful personal discussions; Dr. Mathew Divertie fnr interpreting the electron photomicrographs; Dr. Guido Podrecca and Dr. Thomas L. Tomhridge for diagnosing case 3 and case 1; Dr. Leo Cawley for several immunologic studies; and also Drs. Leon Galinsky, Howard Larsh, and Charles A. Brasher who offen-d invaluable help in the several studies.
REFERE!'\CES
Hecht V: Die Riesenzellenpneumonie irn kindesalter eine historicheexperimentelle studie. Beitr Path Anat 48:263, 1910 2 Pinkerton H, Smiley WL, Anderson WAD: Giant cell pneumonia with inclusions. Lesion common to Hecht's disease. distemper, and measles. Amer J Path 21:1, 1945 3 Enders JF: Present status of etiologic discovery in viral diseases. Ann Intern Med 45:331, 1956 4 \IcCarthy K, \lihlS A, Cheatham W, et al: Isolation of virus of measles from three fatal cases of giant cell pneumonia. Amer J Dis Child 96:.500, 1958
5 Enders JF, \IcCarthy K, Mitus A, ct al: Isolation of measles virus at autopsy in cases of giant cell pneumonia without rash. Xew Eng J \led 261 :87.5, 19.59 6 Liebow AA: Xew concepts and entities in pulmonary disease, in The Lung. Liebow, AA, and Smith, DD, od., Balfimore, Williams and Wilkins, 1968, p 332 i Scudding JG, Hinson KF\\': Diffuse fihrosing alveolitis (dtfluse interstitial fibrosis of the lungs). Thorax 22:291, 1967 8 Hamman L, Rich AR: Acute diffuse interstitial fihrosis of the lungs. Bull Hopkins Hosp74:177,1944 9 Grant IWB, Hills BR, Davidson J: Diffuse interstitial fihrosis of the lungs (Hamman-Rich syndrome}. Amer Rev Tuberc 74;48.5, 1956 10 Livingstone JL, Lewis JG, Heid L, et al: Diffuse interxtitial pulmonary fibrosis, a clinical. radiological and pathological study based on 45 patients. Quart J Med 33:71. 1964 11 Stack, BHR, Grant IWB. Irvine WJ. e-t al: Idiopathic diffuse interstitial lung disease: A review of 42 cases. Amer Rev Hesp Dis 92:939, 1965 12 Hosen SH, Castleman B, Liebow Ai\.: Pulmonary alveolar proteinnsis. New Eng J Med 258; 1123, 1958 13 Liebow AA, Steer A, Billingsley JG: Desquamative interstitial pneumonia. Amer J \Ied 39:369, 1965 14 Caensler EA, Goff AM, Prowse C\l: Desquamative interstitial pneumonia. New Eng J Med 274: 113, 1966 15 Gray FB, Field AS: Muscular hyperplasia of the lung: a physiopathologic analysis. Ann Intern Med 53:683, 1960 16 Saltzstein SL: Pulmonary rnaliguant lymphomas ami pseudolyrnphomas , classification, therapy and prognosis. Cancer 16:928, 1963 17 Moran TJ, Totten RS: Plasmocytic interstitial pneumonia with hypergamrnaglobulinenua. Bull Path, 10:66, 1969 Reprint request... : Dr. David F. Gorelick, torium, ~lt. Vernon, Missouri 65712
~1issouri
State Sana-
National Tuberculosis and Respiratory Disease Association Fellowships Fellowships in the field of respiratory disease are being offered by the Xational Tuberculosis and Respiratory Disease Association. Training fellowships directed toward a career in that specialty are offered to physicians entering their second or third year of residency in internal medicine, pediatrics, thoracic surgery, or other specialty: to candidates holding the degree of \1.0., Ph.D. or Sc.D. for further training as scientific investigators ill this field; and to graduate students with a bachelor's or master's degree to work on a research project for an
CHEST, VOL. 58, NO, 4, OCTOBER 1970
advanced degree (limited to V.S. citizens or those with permanent visas). Physicians who have completed their formal training in pulmonary disease and who have been assured a teaching or research faculty appointment may apply for an Edward Livingston Trudeau Fellowship. Limited to C.S. citizens. Applications must be submitted by November I. Address inquiries to: National Tuberculosis and Respiratory Disease Association, Director of Medical Education, li40 Broadway, Xew York, :\.Y.
10019.
CLINICAL INVESTIGATIONS
Giant Cell Interstitial Pneumonia (GIP)
Prathapchandra A. Reddy, M.D., F.C.C.P.,· David F. Gorelick, M.D.,·· and Charles S. Christianson, M.D., F.C.C.P.t
Three cases of an unusual interstitial pneumonia, designated by Liebow as giant cell interstitial pneumonia, were encountered by us. Dyspnea, weight loss, cough, chest pain, rales in the lungs and clubbing of the fingers were the frequently observed clinical features. RoentgenograpbicaDy, there were bilateral, patchy, nodular Infiltrates of varying density, more prominent in the mldlung fields. Histologic features are quite striking, characterized by predominant lymphocytic interstitial Infiltrate along with numerous, bizane, multinucleated giant cells In the alveoli as well as varying numbers of alveolar pneumocytes. The Intraalveolar cells showed a positive reaction with PAS and Iron stains. Extensive etiologic studies undertaken In one case were negative. The cUBical, radiologic and functional improvement seen In our first case Indicates that c0rticosteroids may Induce a rewarding remission. The alteration of histologic features after steroid therapy, suggests a possible relationship between giant ceUinterstitial pneumonia and desquamative interstitial pneumonia.
Giant cell pneumonia, often referred to as Hecht's giant cell pneumonia, was originally observed in children. Hecht ! in 1910 described the process as an interstitial infiltration of giant cells and mononuclear cells. In 194.5, Pinkerton 2 demonstrated inclusion bodies in the giant cells and suggested a relationship to distemper and measles virus. Investigators wen' ahle to isolate measles virus from the lung tissue of children who had a defective immunologic system and presented similar histologic changes in the lungs.~-'· These features, occurring in children, had not been reported in adults until Liebow" described two autopsied cases and gave the designation, giant cell interstitial pneumonia (GIP). We have encountered three cases of this unusual condition at the .\Iissouri State Sanatorium, a center for chest diseases.
This communication is a report of these cases with their clinical, functional, radiologic features; and comments on the electron photomicrographic findings, etiology, prognosis and treatment. CASE REPORTS
I A 44-y ear-old plumber entered th .. \li."ouri State Sanatorium in February, 1968 because of extreme shortness of breath, progressive over the pas t six years. He had also experienced episodes of intermittent chest puin which was sharp, stabbing and nonradiatlng. Other symptoms included a productive cough, malaise, fatigahility and weight loss. He had been a heavy cigarette smoker for 25 years. The patient had consulted his physictan in HIl1.5 and 1966 for shortness of br eath and cough. Chest x-ray films taken in June, 1965, and August, 1966, rev eal ed bilateral, nodular densities in both mid lung field", more pronounced in the riJ,tht lung. He had received several courses of antiluotics without appreciable improvement. His symptoms gradually increased until the time of his present admission. On physical examination there was dullness to percussion over the rij(ht lower lunj( field posteriorly, and in the ri~ht axilla, diminished breath sounds and moist rales in both low e r lung fields. The extremitres showed advanced clubbing of all his fingernatls and toes. There was no cyanosis or peripheral edema, CASE
·Staff Physician, Missouri State Sanatorium, ~tt. Vernon. MissOllri. ··Consultant Pathologist and Acting Director of Lahoratones, ~tissollri State Sanatorium, ~1t. Vernon, ~fissouri. tChief of ~1E'(licine, ~Ii."ouri State Sanatorium, ~It. Vernon. \tissouri. Presented in part at the First Fall Scientific Assembly (3.5th Annual \I"t'linj() American Collej(e nf Ch est Physicians, Chicago. Illinois, October 29-loOovemlX'r 2, 1969.
319
320
REDDY, GORELICK AND CHRISTIANSON
Fl<:l-RE l. ROt'nt~l'nO!!rams of the che-t in case 1. A. left: (prior to therapy) showinu dense nodular infiltrates in the right mid and lower lunu fields. abo. patchy infiltrates in the left hilum and along the cardiae border. B. nnht: (.3 months after corticosteroid therapvI showina mark..-cl cle-arinu of the- infiltration in both 11Inl.{ fields.
In \lay. 196k. dllrin\.! an open wedc;t;' hiopsy of the riJl:ht middle lohe, it was noh'd that the entire lung was cnnsolidakcl and of firm consiste-ncy. Histolo~k sections (Fig :2 A. B) showed the alveolar span's to lx- fille..d with some de-squamate..d alveolar pnr-umocvtcs. as well as many large. lnzarre. multinucleated giant cells. sunu- of which contained phagoc-yttzed cells, The ju-rihronc-hia! intervtitium was thida'ned and pn-se-nt,..d a predominant IYlllphocytit.' infiltrate. Differen(,l'lIs and pneruuocvtes to Hal stain ShOWl..d many of the ~iant c-ontain P:\S-positi\'t' llliltl'rial (Fi~ 2C). Potassium Ierrocyanide- as we-ll as prnxxiun blue stains n-veuled homogeneous stainable iron in both giant cells and tllt" pneumocytex l Fig 2D i. These finduurs e-stablished a diaunovis of giant cell mterstitial pneumonia l (;IP). In view of the patient.... poor clinical condition. therapy with corticosteroids was instituted on June II, 1968. with initial dosage.' of -to me; of pn-duisone daily. and this resulted in marked improvement. On JlIly 10. HJnS. prednisone dosalle
:\dlliissioll chest roentm-nnarams (Fig 1:\) Tt'H'aled some
patchy nodular infiltrutiun in the left Illidlllllt.: nt·ltl dost> to tht' hilar areas and alollg the cardiac borders. There were dense nodular infiltr.m-s in the entire nuht mid and lower (tllle: fit·lds with SOIll(' ('\"idt'll(.'(' of emphysema. The costophrenic anules were fret'. Pulmonary function determinations art' sllllllllarizf·d in 'I"<,hlt' I. On admission, 1lt'lIloglohin was In.I/iOn IIlI; Hct .51 IX'rc-e-nt, ami whitt' blood ce-ll count (\\'Be) 11.504 per 111m:'. with normal diffen·ntial. Sedimentation rate was 5 nun/hr. Purifie-d prote-in de-rivative ( PPD) and histoplasmin skin tests Wt"T(' positiq·, Result, of complement fixation tests for histoplasmosis, hlastomycosis, and l'Ol'cidioidomyl'osis were negativt-. SputUlI1, bronchial washings and ,LI;a~tri<: cultures ~iln' Ill'gativl' n-sults for fungi and AFB. Eleetrnphoresis and uumunoeh-ctrophoresi-, IIf St'T\111\ proteins showed no abnormal Hndinas. Diffusion stlldit·..; re-ve-aled 10 ml CO/minute-'mlll JIg l normal runue :2,'5 to :3() l. Attempts at viral cultures from the hiopsy tissue were unsuccessful.
TablE' I-Pulmonary Function S'udiel in Cale 1 \'('ntilat(lr~'
Datt·
,\l'1t'rial Blood
:-\tudi('~
FE\'
FE\'
2.S0·1 ml IfiW';1
1,20,1 ml
I,O!I:l m] ,IlHV; I
2,OliS rnl 1.:;4(~ I
~I
vv
I~H)S
H,'fon' ,hl'rap,\~'I)tt'lIItlt·,.
iii. 1!lliS
mil, afrl'r tflt'r:lpy :{I!,
:\Iar(,h 2:;. I!HW !I mo. ufn-r ttlt'r:q).\'
----- -
I,lN;~ i
ml
10(ll;!
(·t:l(';1
I.n.~~. (-tW'~
ml i
II;
I..~1.
:-:tudips 1'( '02
PO:!
~IEF
lOW; 0,
H,·,t
J.
~I
.it)
52
:\·10
12
III
~"
7.~1
IO~
L
~I
is
ml
~SO
III
10
~:l
7~1
lIN)
J.
~I
72
Ih·,t
I :'f'('.
2n.
~I:t~.
(;a~
SI
EXf'Tf'i:-,,'
EXt'Tf,j:-'f'
0, I'll
IOO'~
I:lSC; I
77 I
L.~1.
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72.;,
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7.~O
(fjar-; •
CHEST, VOL. 58, NO.4, OCTOBER 1970
321
GIANT CELL INTERSTITIAL PNEUMO IA
zc.
Show, abundant PAS- po,;iti\'t' m at eri al in both th e.' uian t ('("lis and alveolar pneu mocytes ( PAS stain, X :!SOI.
FIC ;t"H E
F IG l "' U ' 2. . I. Fir~ t lunu hiup,,-y. \1 .1) .. 1 . A. uppe r : h" \\in.: t1", ulv... ,Ii 611..<1 w ith hiza rr , nml tinucl a ted •.... It cel l...mll OI1H ah eolar pOl"'UI1IClC)o If • ~'pbl " II" an " th ick . ened md contain Ullmernu I~mphcx :)o tc . ( IKoma tu, :"lm and f'(J"'jn, 9.10 ), 8 , [o w er-: vam ~ hon ... in .-\. to "ho" th
6t1t..!
WIll) 1111fll('nHl\ m ul n uucl a tf-rl ·ia n t lIumllt°" of Ul q uam at cd lveolu r pneun t K1 ·h .~ ( h~ rn ,J, t ( )\ }" li n and eo-in. . IU ..
~ h ' ( '( )l a r
'pi
lct~
C't"11... And \ oAr) ill~
" n-duc...-d to 10 m~ d ;) iI ~ li t· (.'untinw"C'l to ..how hmcal, ratl inllll:i<' ( I' il: I n I a",1 In n('tinn.,1 (T••hl ,' I ) im prnv ..m nt , .\ r«'pt "Olt w(-
hea rd i ll lilt" right lung posteriorl y, The re W:.L'i reduction in duh hin$! com pa red to that of th e previous ad missio n. He.'I'H.'at pu lmonary [un ct ion stu d it's ( T able I l sh owed no l'hangc.'. He was reh osp ital ized in ~I a y . 196 H, for repa ir of a ri~ht IUllc ln-eniation de n ·lullinJ! in th t' previou« surc it'al sca r. It was ou r op inion th at hern iatio n prob ahl y (K:c.'urrt'(l a.. a n-vult of poor fih rolls tisSIIl: f onn ~.t i on an d lu-alimr, ht.'<.·.msc,· of cortico..teroid th e rap y a t th e tim e of the pre vious th or acotomy and lung biopsy. During su rJ;:t'Ty. tilt.' ("tUlsist t'nl'y o f ti lt' hlll~ wns Ielt to he similar to previous observa tion an d ano ther wedge biopsy was ob ta ined . .\ t th i.. tim e. th e histologic.' ft ·ahm .'~ ha d unde rgon e stri king cha ng e. S("(,tions t Fi g ,'3) vhowed 1I1;,11IY desq uamate d pue u mncyt es RllinJ.: tll t' alveoli and snme- con tai ned bro wn ish pig men t. T he re was a lmos t com plet e absence of mu ltinu cleat ed ghlOt ce lls, Oth er histo, loc it.· fi ndin~s W e n' t"'isen tiall y tlu- ~alllt' us ht· fo rt>. TI lt' histulog ie fe atures see n on th e thin) biopsy wc' rt' simila r tn th at 't't"'ll in d t>S(lu.u natin> inters fitia l pneu m on ia ( D IP ). e-vce p t for the increased amount uF sta iuabh- i ron wi thi n ti lt" des quu ma ted a lveol ar pllt·ulluK·yh's. Th e pa tien t wa .. d i'ich ar gl"t.1 on lIlt' l -tth postopt' ratin' day n n iI n-duced mai nn-nunce- dose Hfpredni..o ne-, ,'30 m g t"\"t'r y othe-r da y. :2. :\ 3 1-yea r-o ld jail supervisor ent ered the \Iis..our! State Sanato rium in April, 1960, because progressive ..hortnes.. of breath o f si.\ months' duration. He t-nmplu ine-el of cough. CA~E
or
!(Jditio nal tfl ' ~lhl wn t. ) S.OCt10fL
4
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IH~)l:lr
pnt"llIlkx·}'t
•
'l1u..' il1tt.. ·otiti I
Itt-nod . At th..... t i lllt' I) { tll ...,h.lr
t o.
dlam~t:' .. \",' rr thc' 5'
of p fl't;llIi~UIlt" ~,e rr u tJU'r da)'. On no ,l ",r I ~, 100 ', th.. put.. 'n t w,,-, n """ Uro a .tn ("fIlt·~en("~ _ O n thdt tidY_ fuUnw m · a hou t o f C'Ous;:hinl.:. h... n\t:" th '~ l)(X'l ' d his f.u "mt n L: ~an to "'Wt'll. E ,t n i ' .... ' ul..·u t a tlt"U lI :!I t*lIlph)' 'lIIa III thc' fao-. tlf><'L: C'~ t Ut't:t: :'o llatc-tl Imlnt-dia l f r. ,hc.......... to m ) Uti n ) 'Ct"u the r.1 , ' . 11 ,r ('.\a ct ~i h ' of thto ft'ftl- nJIIld nll t ht:· d de n nint"{L " 'ithin a W (,'(·k. th t' pa tiptlt im pro n 'd and wa.. di 'i(·hanwd to (·onti nllt· P ft't; llli ~ I Hlt · :30 mc ('\"l'ry o th er d ay . m~
lo
.mo
T ilt· IMtic'flt t'n h 'ft "t! t ht · hll ... p ital Oil \I a rch 2 . UJfi9. for follow -up . Phy, i(.'al t".\a mi na tion rt·\·c·a led dim inu tio n of Im 'at lt "0 1111( 1.. in ti lt: riJ.!h t h",,' , ,-\ few sl'a t tt-n 'c1 r al t · ~ ""t>Tt>
CHEST, VOL. 58, NO.4, OCTOBER 1970
F IC,l'HE :2. D . Silows th t' p rt'''i(' IK 't ' of h o m o ~ t'n t"l Jtl s i ron-lik e mat erial in ho th ~i
322
REDDY, GORELICK AND CHRISTIANSON
FJ(;CR£ 4. Chest roentgenograms in case 2. Miliary calcific infiltrations are seen in both lung fields and also soft, patchy, nodular infiltrations in both midlung fields with prominence in right lung.
FH'l'HE :3. Case 1. Third lung biopsy, ~Iay, 1009. A (upper). Shows predominance of desquamated alveolar pneumocytes within the alveoli, some of them in mitosis. There is absence of the bizarre, multinucleated !(iant cells (hematoxylin and eosin. X 40n). B (lower). Same section as A. Showtng marked increase in stainable iron within the alveolar pneumocytes ( acid Icrrocynnide stain, X 4(0).
chest pain, malaise, easy fati!(ability and weight loss of 30 pounds in one year. He had had no hemoptysis. fever. or chills. In 1955, a routine chest x-ray film revealed bilateral, healed, calcified lesions interpreted as healed histoplasmosis. On physical examination. fine crepitations were audible in the left lung posteriorly. The extrermties revealed first degree clubbing of tilt' finzemuils. The results of lahoratorv shldies wen' within normal limits. Skin te-sts with PPD and' histoplasmin results were posttlve. Complement fixation titers for histoplasmosis, blastomycosis, and cocc-idioidomyc-osis were negative. Several sputum cuitun's for Histoplasma and add-fast nrganisms were negative. Chest roe-ntge-noarams (Fig ...) revealed bilateral miharv calcificution and soft, patchy, nodular infiltration in rnidhmc fields with prominence in the right lung. Pulmonary function studies showed restrictive ventilatory impairment (Table 21.
both
The patient underwent right thoracotomy with wedge biopsy of tilt' right lower lobe on Mav 6, 1000. Sections revealed thickening of the alveolar septa. Within the alveoli there we-re' present numerous. bizarre, multinucleated giant cells and varviru; numbers of desquamated pneumocytes. Some of the !(iaot cells were actively phagocytic (Fil( 5) with clumpe-d nuclei and numerous engulfed cells within abundant cytoplasm. These eeUs Were positive to PAS stain. Spe-cial stains for iron showed some homogeneous, bluish material within the ~iant cells. The patient's postoperative course was uneventful and he was discharged to his home without any therupy in June, 1960. TIl(> patient was seen by one of us (P.R.) in September. 1968, and April. 100\J, at which time he stated that he was asymptomatic. His dyspnea had improved one to two years after disehar!(e and he had rezained his weight. Although the patient had no symptoms, pulmonary function studies (Table 2.) still showed restrictive ventilatory impairment. The paticnt did not wish til undergo additional studies. C."E 3
A 72-year-old housewife entered St. John's Hospital, Springfield, \Iissouri, in May, 1967, with a five-month history of fever, productive cough, chest pain, dyspnea, malaise, diarrhea, headache and weight loss. On admission, she appeared acutely ill. Temperature was 99.4 F, respiratory rate 0
Table 2--Pulmonar:r Func,ion S,udipil ill
FEV
nah' ~I:t~'
s. UII~)
t-eptember In. 1!It;X
2.~"2
ml
,H{)l'r'i 2.2~1·1
m\
.=)Sf·;
'I
CaliP
2
peo,
FEV
~I\'\'
2,2\)8 ml
lI.i L
pH
I SeC'. ~I
i~H'('~
2.\8.i rnl
146
L~I
:16
'95'('
CHEST, VOL 58, NO.4, OCTOBER 1970
323
GIANT CELL INTERSTITIAL PNEUMONIA DISCl'SSIO~
FIGeHE .5. Lung hiopxy hom case :2, showina "cannibalistic" giant ce-ll within the alveoli. The nuclei an' pushed to the pertpherv. also within the alumclant cytoplasm are numerous
pha.l.!ocytizt'd cells (1H'lllatoxylin ,lml eosin, X :JO{J).
48/min, pulse IOf). and hlood pressure 104/.50. Crepitant rules WPTe multblc in hoth lung fields. Clubbing of the finuers, cyanosis and mild pitting edcma of the ankles wert> present. The chest roentzenouram (Fig (j) showed dense-, nodular opacities in hoth June: fit'hls. more pronounce-d in tilt' left lung with ('OOf1I1('II<..:t' in the nudlunu field gi vin.!!; a ground-glass appe-arance. The-n- was no evideucc of honcvcominz. The patient's condition rapidly deteriorated and she died on \lay :JI. 1967. At nocrup..y. there was cxtcnstvo consolidation of all the lobes bilaterully. \Iicros<:opie examination of sections revealed thickeninu of the interstitium and of the alveolar septa. The cells lining the alveoli were prominent and in-nerally cuhoidul in shape. There was marked interstitial lymphocytic infiltration. mon- prominent in the pe-npherv. The alveoli contained many. varvinu sized. multinucleuted uiant c('I1...-; and also some desquamated alveolar pne-umm-ytes. PAS stain revealed abundant positive man-rial in the uiant c('lIs. Stains for iron showed a homogeneous hill ish material within the intra-alveolar cells.
Interstitial pneumonia has been an inconclusive term used 1)\· pathologists for several decades to describe the tissue response in the lung which takes place predominantly in the supporting structures rather than within the alveoli. Clinical and radiologic features are not pathognomonic and may be seen with all disorders producing alveolar capillary block, The etiology of several of these disorders is unclear and no satisfactory classification exists. Liebow" in 1968. proposed a classification of the interstitial pneumonias into fin' groups according to their histologic Features. This workable classification offers a better understanding of the complete disease spectrum of interstitial pneurnonias and pt'rmits the clinician not only an understanding of the disease process. but also relates to the management of the patient. Scadding and Hinson," however, criticized such a classification based on cytologic features and suggested the term "diffuse fibrosing alveolitis' as a broad term for the entire group. L'sual interstitial pneumonia (l'IPl. bronchiolitis obliterans (BIP), desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP I have been well recognized and are of special interest to clinicians and pathologists. ,- I " Extending Liebows classification, Moran and Totten 1" recently described plasma cell interstitial pneumonia (PIP) which we have included in our Table :3. Histologic Features of GlP: Although the histologic picture varies somewhat from case to cast', there arc features in each which affords recognition and permits definitive diagnosis of giant cell interstitial pneumonia. Generally, the interstitium is thickened and presents a lymphocytic infiltration which in some areas appears aggregated and even shows folIide formations. The alveolar septa are somewhat thickened and show an infiltrate made up of lymphocytes. plasma cells, small numbers of oosinophils and a few neutrophils as well as proliferating fibroblasts. The cells lining the alveoli are prominent and cuboidal. \Yithin the alveoli arc varying numbers of rather large. bizarre-shaped, multinucleated giant cells. These cells measure from 40 to 60 microns. While some present a definite cell wall, Tab!e
3---Cla~B;ficat;o"
of l merstitiat Pneumonia.
1-:"lIal (If ('Ia,.. . . ir-nl intcrstit iul pm-umoniu 1("11), 2 Bronr-hiolit is obliterans and diffll:O:t' alveolar d:lIna~f' Desquamntive interst it inl pnr-umonin DIPI I
FH;nu: fi. Cln-vt roentucnozram in cast' :3 sh(}\n dense. nodu-
lar opacitit's in hoth lunu fjplds. mort- pronounc-e-d in the left lung 1!i"in1! a "ground-glass" appearance.
CHEST, VOL. 58, NO.4, OCTOBER 1970
Lvmphoid intcrstit iul pneumonia I LIP]
.=j tj
Giaut r-oll interst ir inl pneumonia l(;IPI
Plasmoevr ic intorst it ial pneumonia (PIP,
\ Hl Pi
324 many show a "splashed" appearance with peripheral pseudopod-like projections. The nuclei are usually uniform in size with reticulated chromatin and tend to be pushed to one side, or at times are congregated near the center. 1':0 definite asteroid or inclusion bodies are present, although some giant cells contain varying numbers of engulfed alveolar cells, and thus present a cannibalistic feature. Also present within the alveoli are small to moderate numbers of desquamated alveolar pneumocytes. These show a fairly uniform appearance and an occasional mitosis is secn denoting active proliferation of some of these cells. Generally, the cells show a uniform, salmon-pink cytoplasm, although one may also see fine brownish pigment in both the pneumoeytes and the giant cells. There are minimal numbers of Inflammatory cells. :\'0 necrosis is present. With periodic acid-Schiff stain, both the giant cells and the alveolar pneumocytes contain abundant homogeneous PAS positive material. When stained with acid ferrocyanide, both the giant cells and the desquamated alveolar pneumocytes contain a homogeneous bluish stained iron material. The stained iron is not granular and shows no features characteristic of either hemosiderin or hemofuscin. The nature of this material is still problematic. It may be ferritin or an iron metabolite bound to an intracytoplasmic enzyme system. It is of interest that in case 1, the stained iron material had increased at the time of the second biopsy and was markedly increased in the third biopsy specimen. Whether there is a relationship between the increase in iron and the disappearance of the giant cells is conjectural. Electron photomicrographs were obtained on the biopsied tissue from case 1. The findings were interpreted by Dr. Matthew Divertie as showing "Severe damage to alveolar lining epithelium. Cells are being cast off into alveolar spaces and breaking up. The organelles are intact. Septa show distinct capillary changes and those present are nearly obliterated by swollen endothelial cytoplasm." The predominant clinical features of GIP were progressive dyspnea, clubbing and rales in the lungs. Cough, chest pain. malaise, fatigue and weight loss were seen in all the cases. Chest roentgenograms were consistently abnormal, although the degree of infiltration varied. Xlidlung fields were involved in all three cases. The costophrenic angles and the lung apices were spared. In two. the infiltrations were more pronounced and the densities were confluent, giving a ground-glass appearance. The disease was bilateral in all three cases. Cavitation and honeycomhing did not occur. The x-ray appearance is often misleading. At sur-
REDDY, GORELICK AND CHRISTIANSON gery or necropsy, all portions of the lungs were involved in a similar manner. Ventilatory studies revealed restrictive impairment. In case 1. there was marked improvement three months after therapy with corticosteroids was begun. Case 2, although experiencing subjective improvement without any therapy, showed persistence of restrictive ventilatory impairment when tested nine years later. Arterial blood gas studies revealed hypoxia and impaired diffusion. Extensive laboratory determinations provide no clue to the etiology. Autoimmune studies were negative. Antilung antibodies were looked for and found to be absent in our first case. \\'e were unable to demonstrate the presence of infections in our patients. Histologic, bacteriologic and viral studies of the lung tissue failed to reveal an infectious agent. Although it somewhat resembles measles virus pneumonia, the giant cells do not contain inclusion bodies and attempts to culture the virus from the lung tissue were unsuccessful. Based on these studies, etiology of this entity is obscure. Relationship to DIP: The clinical syndrome of progressive dyspnea, clubbing, rail'S in the lungs accompanied by abnormal chest x-ray appearance is consistent with all diseases producing alveolar-capillary block resulting in impaired diffusion of gases. GIP has great similarities to DIP in clinical features although certain differences can be recognized. Radiologically, DIP is said to exhibit triangular densities radiating from the hilum to the bases obscuring cardiac margins. In GIP we have seen a different pattern where there is more frequent involvement of midlung fields. Histologic features of DIP and GIP are strikingly diffl'rent. The third biopsy from case 1 showed almost complete absence of giant cells, but there were numerous desquamated pneumocytes within the alveoli which are PAS-positive. These cells contained material that was positive to iron stain in contrast to the intra-alveolar cells in DIP. The striking alteration of histologic picture from GIP to DIP suggests a possible transition from GIP to DIP. Similar to Liebow's" observation of the relationship between the granular pneumocytes and alveolar proteinosis, there may exist a relationship between desquamated alveolar pneumocytes and the giant cells. We believe that the initial phase in giant cell interstitial pneumonia is a desquamation of granular pneumocytes which give rise to giant cell forms. Whether this represents a foreign body type of reaction or autoimmune phenomenon, or an event initiated by infection is not clear. Our observations indicate that with favorable response to corticosteroids, the giant cells disappear and the granuCHEST, VOL. 58, NO.4, OCTOBER 1970
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GIANT CELL INTERSTITIAL PNEUMONIA lar pneurnocytes predominate. It remains to be seen whether continued corticosteroid therapy will produce ablation of the granular pneumocvtes. From the variable courses seen in this group of three patients, it is not possible to generalize about the prognosis of the disease, Case 2, in whom the diagnosis was established nine years ago, was symptomatic for six months prior to diagnosis. Without any therapy, he improved subjectively. Case 2 and the two patients described by Liebow had died within a year. The clinical, radiologic and functional improvement seen in our first case indicates that corticosteroids may induce a rewarding remission. ACKNOWLEDC\IENTS:
w~ gratefully acknowledge the assistance of Dr. Averill A. Liebow for \'erifyin~ the diagnosis and useful personal discussions; Dr. Mathew Divertie fnr interpreting the electron photomicrographs; Dr. Guido Podrecca and Dr. Thomas L. Tomhridge for diagnosing case 3 and case 1; Dr. Leo Cawley for several immunologic studies; and also Drs. Leon Galinsky, Howard Larsh, and Charles A. Brasher who offen-d invaluable help in the several studies.
REFERE!'\CES
Hecht V: Die Riesenzellenpneumonie irn kindesalter eine historicheexperimentelle studie. Beitr Path Anat 48:263, 1910 2 Pinkerton H, Smiley WL, Anderson WAD: Giant cell pneumonia with inclusions. Lesion common to Hecht's disease. distemper, and measles. Amer J Path 21:1, 1945 3 Enders JF: Present status of etiologic discovery in viral diseases. Ann Intern Med 45:331, 1956 4 \IcCarthy K, \lihlS A, Cheatham W, et al: Isolation of virus of measles from three fatal cases of giant cell pneumonia. Amer J Dis Child 96:.500, 1958
5 Enders JF, \IcCarthy K, Mitus A, ct al: Isolation of measles virus at autopsy in cases of giant cell pneumonia without rash. Xew Eng J \led 261 :87.5, 19.59 6 Liebow AA: Xew concepts and entities in pulmonary disease, in The Lung. Liebow, AA, and Smith, DD, od., Balfimore, Williams and Wilkins, 1968, p 332 i Scudding JG, Hinson KF\\': Diffuse fihrosing alveolitis (dtfluse interstitial fibrosis of the lungs). Thorax 22:291, 1967 8 Hamman L, Rich AR: Acute diffuse interstitial fihrosis of the lungs. Bull Hopkins Hosp74:177,1944 9 Grant IWB, Hills BR, Davidson J: Diffuse interstitial fihrosis of the lungs (Hamman-Rich syndrome}. Amer Rev Tuberc 74;48.5, 1956 10 Livingstone JL, Lewis JG, Heid L, et al: Diffuse interxtitial pulmonary fibrosis, a clinical. radiological and pathological study based on 45 patients. Quart J Med 33:71. 1964 11 Stack, BHR, Grant IWB. Irvine WJ. e-t al: Idiopathic diffuse interstitial lung disease: A review of 42 cases. Amer Rev Hesp Dis 92:939, 1965 12 Hosen SH, Castleman B, Liebow Ai\.: Pulmonary alveolar proteinnsis. New Eng J Med 258; 1123, 1958 13 Liebow AA, Steer A, Billingsley JG: Desquamative interstitial pneumonia. Amer J \Ied 39:369, 1965 14 Caensler EA, Goff AM, Prowse C\l: Desquamative interstitial pneumonia. New Eng J Med 274: 113, 1966 15 Gray FB, Field AS: Muscular hyperplasia of the lung: a physiopathologic analysis. Ann Intern Med 53:683, 1960 16 Saltzstein SL: Pulmonary rnaliguant lymphomas ami pseudolyrnphomas , classification, therapy and prognosis. Cancer 16:928, 1963 17 Moran TJ, Totten RS: Plasmocytic interstitial pneumonia with hypergamrnaglobulinenua. Bull Path, 10:66, 1969 Reprint request... : Dr. David F. Gorelick, torium, ~lt. Vernon, Missouri 65712
~1issouri
State Sana-
National Tuberculosis and Respiratory Disease Association Fellowships Fellowships in the field of respiratory disease are being offered by the Xational Tuberculosis and Respiratory Disease Association. Training fellowships directed toward a career in that specialty are offered to physicians entering their second or third year of residency in internal medicine, pediatrics, thoracic surgery, or other specialty: to candidates holding the degree of \1.0., Ph.D. or Sc.D. for further training as scientific investigators ill this field; and to graduate students with a bachelor's or master's degree to work on a research project for an
CHEST, VOL. 58, NO, 4, OCTOBER 1970
advanced degree (limited to V.S. citizens or those with permanent visas). Physicians who have completed their formal training in pulmonary disease and who have been assured a teaching or research faculty appointment may apply for an Edward Livingston Trudeau Fellowship. Limited to C.S. citizens. Applications must be submitted by November I. Address inquiries to: National Tuberculosis and Respiratory Disease Association, Director of Medical Education, li40 Broadway, Xew York, :\.Y.
10019.