Simultaneous of pulmonary interstitial fibrosis and ... · an irregular, patchy, reticulonodular pattern throughout both lungs without signs of consoli-dation. ... suggestive of diffuse

Thorax, 1981, 36, 252-258

Simultaneous occurrence of pulmonary interstitialfibrosis and alveolar cell carcinoma in one family

F BEAUMONr, H M JANSEN, J D ELEMA, L P TEN KATE, AND H J SLUITER

From the Department of Pulmonary Diseases, State University Hospital, and from the

Department of Pathology, and the A nthropogenetic Institute, State University of Groningen,

the Netherlands

ABSTRACT The coexistence of interstitial pulmonary fibrosis and alveolar cell carcinoma is wellknown. The familial occurrence of a combination of these two entities, however, is very rare.

We present a family of which five members had diffuse interstitial pulmonary fibrosis. Threeof them had in addition alveolar cell carcinoma. In a sixth family member, evidence of alveolarcell carcinoma was present without proven interstitial fibrosis. An autosomal dominant trait issuggested as the mode of inheritance of both interstitial fibrosis and alveolar cell carcinoma inthis family.

In 1970, Driessen and Scherpenisse,l reported ontwo brothers with alveolar cell carcinoma (ACC)and diffuse interstitial fibrosis (DIPF). In the samefamily a female cousin had pulmonary fibrosis butwithout carcinoma. Since then we have seen othermembers of this family who have been affected byboth conditions. The only other study we couldfind reported on identical twin brothers who pre-sented with ACC, almost at the same time.2 Wewere unable to find other reports on familial oc-currence of both ACC and DIPF. This fact stimu-lated the present report as a sequel to the studyof Driessen and Scherpenisse.1

Patdents

PATIENT 1

This 37-year-old man (fig 1, case 111-1), a buildingsurveyor, was seen for the first time in 1958 be-cause of gradually increasing dyspnoea on ex-ertion. For two years he had been followed inanother hospital because of pulmonary fibrosis ofunknown origin. His mother had a chronic cough.One of his uncles had died of a "pulmonarytumour" (pedigree case 11-7).On physical examination the base of the right

lung appeared dull to percussion and breath soundswere diminished in this area. There were nocrackles or wheezes. Peripheral clubbing of the

Address for reprint requests. Dr F Beaumont, Department of Pulmon-ary Diseases, State University Hospital, Oostersingel 59, 9713 EZGroningen, the Netherlands.

digits without cyanosis was noted. The erythrocytesedimentation rate was 30 mm in the first hour.Haemoglobin was 17-6 g/dl. A chest radiograph(fig 2) showed diffuse fine reticulo-nodular shadowsand a dense mass in the right lung. The fine mark-ings had been visible in 1954.Lung function studies (table) showed a restric-

tive defect. While staying in hospital for furtheranalysis, the patient became hemiplegic becauseof a spinal tumour, which at operation appearedto be a metastasis of an alveolar cell carcinoma(ACC). Shortly thereafter he died. Necropsy re-vealed diffuse infiltration of the lungs with ACCand extensive alveolar and peribronchial fibrosis(fig 3).

PATIENT 2The brother of patient 1 (fig 1, case III-2), officeclerk, was 31 years old when he was referred toour clinic. At mass screening radiography he wasfound to have diffuse pulmonary mottling. For theprevious three years he had noticed increasingdyspnoea on exertion and recurrent bronchialinfections. On physical examination peripheralclubbing without cyanosis and basal crackles werenoted. ESR was 12 mm the first hour. Haemoglo-bin was 17-3 gr/dl. A chest radiograph showedan irregular, patchy, reticulonodular patternthroughout both lungs without signs of consoli-dation. Pulmonary function studies showed a re-

strictive defect (table 1). No diagnosis could bemade after extensive investigation, including a

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Simnultaneouis occurrence of pulmonary interstitial fibrosis and alveolar cell carcinoma

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Fig 1 Family pedigree.

In[a0t

A C CFibrosisDeceasedAge at death

transbronchial biopsy. Histological examinationof lung tissue obtained by open lung biopsy dis-closed marked fibrotic thickening of the alveolarsepta, peribronchial fibrosis, smooth muscle hyper-trophy, squamous cell metaplasia, and hyperplasiaof mucus secreting cells in the bronchial mucosa.Many areas showed a gradual change to frankmucus-producing carcinoma, lining alveolar spaces.

_ f f l ...... is

Fig 2 Chest radiograph of patient 1, pedigree case

III-.

A diagnosis of pulmonary fibrosis with ACC wasmade. Five months later the patient died.

PATIENT 3

This 48-year-old housewife (fig 1, case 111-6) wasa cousin of patients 1 and 2.

In 1962 she was investigated for upper abdomi-nal complaints and an hiatus hernia was found.At that time a chest film was normal except forincreased markings in the lower lungs. In 1968she was admitted to the pulmonary departmentbecause of dyspnoea on exertion for about oneyear and productive cough. Her father had diedof a "lung tumour" (fig 1, case 11-7). The chestradiograph showed a diffuse increase in interstitialmarkings, suggestive of diffuse interstitial fibrosis(fig 4) and pulmonary function tests showed a re-strictive defect (table 1). Extensive investigationdid not reveal a cause for the illness, nor any evi-dence of autoimmune-, systemic-, or organic dustdisease. Open lung biopsy showed peri-bronchialand interstitial fibrosis with metaplastic changesand cuboidal hyperplasia of alveolar cells (fig 5).The picture was very similar to the one found inthe lungs of her two cousins though there were nosigns of ACC. The patient was treated with oralcorticosteroids. Her pulmonary condition seemedstable for a number of years. In 1970 she under-went a hemi-colectomy for adenocarcinoma. From1973 until her death from cerebral hemorrhage in1976, she was admitted to hospital several times

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Table 1 Lung function data of affected family members

Patient VC (% pred) FEV, (% pred) FEV,/ VC R V/TLC ( pred) Lung compliance TLCO(l) {l (% (%lIkPa (% pred) mmol/tninlkPa

(% pred)1 1-6 (37) 12 (38) 74 29 (125) ND ND2 2-0(51) 1 6(55) 81 25(108) 092(41) ND3 2-2 (63) 18 (120) 83 29 (111) 0-51 (16) 3-4 (45)4 1 8 (56) 1-4 (64) 78 33 (126) 0-76 (23) 4-4 (53)5 ND ND ND ND ND ND6 August 75 4-2 (78) 3-7 (95) 88 26 (100) 1-43 (58) 7-9 (62)6 August 78 3-4 (58) 3-1 (65) 91 27 (128) 0-75 (28) 5-6 (45)VC=vital capacity; FEV,=forced expiratory volume over one second;FEV,/VC %=FEV, expressed as a percentage of the VC,; RV=residualvolume; TLC =total lung capacity; RV/TLC %=RV expressed as a percentage of the TLC; TLCO=carbon monoxide transfer factor: (°/ pred) =percentage of the predicted value in brackets; ND=not done.

Fig 4 Chest radiograph of patient 3, pedigree caseIlI-6.

'4X§' Fig 3 Lung biopsy of patient 1,lb, showing alveolar cell carcinoma.

H and E, original magnificationX140.

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because of severe respiratory insufficiency. Nonecropsy was performed but during her lifetimethere never were any radiographic or clinicalsigns of ACC.

PATIENT 4This 49-year-old housewife (fig 1, case 111-9) wasa sister of patient 3. She was always in goodhealth until early in 1978 when she developed amild, non-productive cough and malaise. A chestfilm disclosed dense infiltration in both lowerlobes. She had never smoked and did not take anydrugs. Some weeks later the radiograph showedincrease of both lobar densities. On admission tohospital she did not appear acutely ill nor dys-pnoeic. There were no signs of finger clubbing orcyanosis. Fine crackles were present, and dullnesson percussion was heard in both lower quadrants.

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Simultaneous occurrence of pulmonary interstitial fibrosis and alveolar cell carcinoma

Fig 5 Lung biopsy of patient 3showing septal fibrosis withcuboidal hyperplasia ofair spaces. H and E, originalmagnification X80.

ESR was 31 mm, haemoglobin 15-4 gr/dl, whitecell count 7800/mm3, with 440/mm3 and later1287/mm3 eosinophils. Laboratory work-up forautoimmune and systemic diseases was negativeNo rises of any anti-viral antibody titres, nor evi-dence of organic dust disease were found. Circu-lating immune complexes, determined as previouslydescribed,3 were slightly increased. A chest filmshowed dense infiltrations, predominantly on theright side. On tomography, an air-bronchogramwas visible in the consolidated right lower lobe.No diagnosis could be obtained by transbronchialand needle biopsy. At thoracotomy the right lungfelt stiff and granular. A mass was palpable in thelower lobe, from which a biopsy was taken. Micro-scopic examination showed a typical ACC, infil-trating the lung. There was scattered interstitialfibrosis (fig 6). The patient died in December 1978,after being treated unsuccesfully with various anti-tumour agents and high dose corticosteroids. Post-mortem studies of the lung showed the samepicture as in the biopsy, with patchy interstitialand peribronchial fibrosis of both lungs and mul-tiple areas of ACC. No metastases were found.

PATIENT 5This 25-year-old housewife (fig 1, case IV-4) wasthe daughter of patient 3. In 1975 she was admittedto hospital because of enlarged cervical and supra-clavicular nodes. For several months she hadcomplained of malaise, non-productive cough, andfatigue.

Seven weeks before admission, a few bloodstreaks appeared in her sputum. Three weeksbefore admission she noticed a swelling in theright upper side of the back. The patient did notsmoke and took no drugs, nor was there any knownexposure to organic dusts. Lymph nodes wereeasily palpable in the right and left side of thesternomastoid muscles and in the supraclavicularfossa. Fixed to the right ninth rib posteriorly atumour was felt. The chest radiograph showed ahomogeneous mass at the right hilum and atelec-tasis of the posterior part of the right upper lobe.ESR was 90 mm in the first hour, haemoglobin

12-9 gr/dl, haematocrit 39% white cell count12 400/mm3 with a normal differential. Histologi-cal examination of an excised supra-clavicularlymph gland disclosed malignant cells, compatiblewith a large cell carcinoma of the lung. A PASstain was negative. Transbronchial biopsy from theright upper lobe revealed atypical cells with vacu-olised cytoplasm, big nuclei, and nucleoli. Themost likely diagnosis was an ACC or large cell car-cinoma. The patient died suddenly on the tenthday in hospital. Necropsy was not permitted.

PATIENT 6This 21-year-old office clerk (fig 1, case IV-5) wasthe son of patient 3, and brother of patient 5. Heattended for the first time in 1975. For some yearshe had experienced slowly increasing dyspnoea onexertion. Until 1975 he played in the local footballteam. He had allergic rhinitis and an occasional

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productive cough. He did not take drugs, norsmoke. There was no evidence of systemic collagendisorders. Physical examination showed no dys-pnoea at rest, clubbing or cyanosis. At both lungbases some fine inspiratory crackles were heard.ESR was 3 mm in the first hour, haemoglobin15-4 gr/dl, haematocrit 43%, white cell count6800/mm3 with a normal differential. Circulatingimmune complexes were not significantly increasedand tests for autoimmune or systemic disease werenegative. His chest film showed a diffuse reticularpattern, very suggestive of interstitial fibrosis.Pulmonary function studies (table 1) showed a re-strictive ventilatory defect and a decreased trans-fer factor for carbon monoxide. Extensive clinicalinvestigation did not provide a diagnosis.

Microscopical examination of tissue obtainedby open lung biopsy revealed severe peribronchi-olar fibrosis with lymphocyte infiltration andscattered emphysematous bullae. Bronchiolarepithelium showed metaplastic changes, but therewere no signs of tumour. Immunofluorescentstudies for IgG, IgA, IgM, and complement (C3)were negative. It was decided to treat him withazathioprine (150 mg) and prednisolone (20 mg).His pulmonary condition seems stable at pres-ent apart from some intercurrent respiratoryinfections.

Discussion

The familial occurrence of ACC, with or withoutpulmonary fibrosis, has been reported only twice

Fig 6 Lung biopsy of patient 4showing alveolar cell carcinomadeveloping in fibrotic areas.H and E, original magnificationX80.

before. Driessen and Scherpenissel reported onpatients 1, 2, and 3 of the present study. Joishyet a!2 observed identical male twins having ACC,with nearly synchronous onset and with metastasisto the brain, but without pulmonary fibrosis. Thecoexistence of interstitial pulmonary fibrosis andcarcinoma of the lung, especially alveolar cellcarcinoma, is well known.4'12 Beaver and Shapiro4mentioned seven cases of ACC in which thetumour was intimately associated with areas offibrosis. They suggested that cuboidal epithelialmetaplasia of the alveoli, a histological featureoften seen in fibrotic lesions, could represent a pre-cancerous phase of cellular growth. They alsonoted that the increasing incidence went parallelwith and was probably related to the reported in-creasing incidence in pulmonary fibrosis. This viewwas supported by Spain,5 who presented 12 casesof ACC, with co-existing fibrosis, which was mostlydiffuse, sometimes of focal nodular type. AlsoMeijer and Liebow6 pointed to the fact thatatypical proliferation with marked hyperplasia andmetaplasia of bronchial alveolar cells represents apremalignant condition. This atypical proliferationmay be conceived of as a regenerative processafter damage to the lung by various agents. Thisprocess may lead ultimately to fibrosis. At present,no studies are available providing insight into theincidence of ACC in patients with fibrotic lungdisease. Other malignant pulmonary tumours arealso prone to develop in the fibrotic lung andadenocarcinoma, oat cell carcinoma, epidermoidcarcinoma, and large cell anaplastic carcinoma

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Simultaneous occurrence of pulmonary interstitial fibrosis and alveolar cell carcinoma

have been reported.6-8 In these series, however,no cases of familial origin, nor familial fibrosiswere reported.At least 13 families with familial interstitial pul-

monary fibrosis have been described in the last20 years.' 13-24 Bonanni et al'7 suggested an im-munological factor, because of eosinophilia andraised levels of gamma globulin. In this study, andthe ones by Hughes16 and Adelman,19 the auto-somal dominant trait was demonstrated as themode of inheritance. A striking fact in the re-ported cases is the great difference in the clinicalfeatures and in the age at which the pulmonaryfibrotic disease started.16 Sometimes other abnor-malities were seen in association with the familialfibrosis, such as rheumatoid arthritis, oculo-cutaneous albinism, and a platelet functiondefect.22-24

In the family at issue, five patients had con-firmed pulmonary fibrosis, and three of them hadACC as well. A fourth patient with probably alarge cell carcinoma or ACC had no radiologicalevidence of pulmonary fibrosis, though this doesnot exclude it absolutely. Epler et al showed that,in a series of 458 patients with histologicallyproven diffuse infiltrative lung diseases, the pre-biopsy chest radiograph was normal in about10%.25A specific cause for the fibrosis was not found

in any of the patients in the present study. Ourfindings suggest that the fibrosis is of a familial,hereditary origin, transmitted as an autosomaldominant trait. There may be a common aetiologi-cal background both for the tumour and for thefibrosis, possibly of genetic origin. HLA studiesof the family were not performed, and this hypo-thesis can therefore not be tested. The fact thatthe incidence of tumours other than ACC, wasfairly high in the other members of the family(table 2) suggests that an inherited gene (or genes)renders this family more susceptible to them.

We are grateful to Dr R Mulder, BeatrixoordHospital, Haren, for allowing us to study one ofhis patients.

Table 2 Other tumours in the family

Patient Age Tumour Histologicallypedigree (yr) confirmednumber

11-4 ? Intestine no11-7 47 Lung no

111-3 66 Squamous cell ca lip yes111-4 58 Pancreas yes111-6 50 Adeno-ca colon yes111-8 33 Seminoma testis yes

References

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2 Joishy SK, Cooper RA, Rowley PT. Alveolarcell carcinoma in identical twins. Ann Intern Med1977; 87:447-50.

3 Jansen HM, The TH, De Gast GC et al. Im-munoglobulin and complement inclusions inperipheral blood polymorphonuclear leucocytes ofpatients with bronchial carcinoma. Thorax 1977;32:706-10.

4 Beaver DL, Shapiro JL. A consideration ofchronic pulmonary parenchymal inflammationand alveolar cell carcinoma with regard to apossible etiologic relationship. Am J Med 1956;21:879-87.

5 Spain DM. The association of terminal bron-chiolar carcinoma with chronic interstitial inflam-mation and fibrosis of the lungs. Am Rev TubercPulm Dis 1957; 76:559-67.

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24 Hoste P, Willems J, DeVriendt J, Lamont H,Van der Straeten M. Familial diffuse interstitialpulmonary fibrosis associated with oculocutane-ous albinism. Scand J Respir Dis 1979; 60:128-34.

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Simultaneous of pulmonary interstitial fibrosis and ... · an irregular, patchy, reticulonodular pattern throughout both lungs without signs of consoli-dation. ... suggestive of diffuse