Papillary neoplasms of the bronchus of low-grade malignancy

Thorax (1963), 18, 340

Papillary neoplasms of the bronchus oflow-grade malignancy

J. F. SMITH AND D. DEXTER

From the Department of Morbid Anatomy, University College Hospital Medical School,London, W.C.I, and the Department of Pathology, St. George's

Hospital Medical School, London, S.W.1

In this paper we describe eight examples ofpapillary neoplasms of the bronchus in whichatypical cytological features were present. In seventhe lesion was localized and invasion was not pre-sent, in one extensive spread within the bronchialtree of a lobe had occurred but invasion into thelung parenchyma was doubtful. Lesions of thistype receive little comment in the literaturealthough they can be perplexing in diagnosis andmanagement. Typical benign papillomas of thebronchus are also rare, and one is briefly describedfor comparison.

CASE REPORTS

CASE I This man was a physician, aged 50. a non-smoker except for occasional cigars. Although a milddiabetic, he had been in good health until June, 1959,when a febrile illness occurred. At this time a radio-graph of the chest showed a shadow in the right lowerlobe which was thought to be a collapse in theposterior basal segment.At bronchoscopy on 4 July 1959 the larynx. trachea.

carina. and right main bronchus appeared normal butblood, pus, and a soft tumour were seen in the basalstem below the medial basal branch. A biopsy wastaken which was not very satisfactory because ofbleeding. Histological examination showed two smallpieces of hyperplastic squamous epithelium withnumerous vessels but no fibrous stroma and nonormal bronchial wall (Fig. 1). Variation in nuclearsize was considerable with occasional binucleate cells(Fig. 2) and a few mitotic figures present. A diagnosisof squamous-celled carcinoma was made and on 13July 1959 a lobectomy was done.

In the specimen a segment of collapse and shottyinduration was identified in the posterior basal area.The bronchi and all visible ramifications were slit upbefore fixation, and no residual tumour could befound. There was slight bronchiectasis in the posteriorbasal segment. Histological examination yielded noevidence of residual tumour or even of the site ofremoval. No squamous metaplasia was present in thebronchiectatic segment. He has remained well since.

CASE II A woman aged 55 had had bronchitis in thefour winters preceding 1960 when she was admittedto the Whittington Hospital because of a further acuteattack. A bronchoscopy showed some reddenedmucosa in the right main bronchus. She was dis-charged on tetracycline therapy and had a broncho-gram in November, a few weeks later. This showed afilling defect in the right main bronchus below themiddle lobe orifice. On readmission to the Whitting-ton Hospital a friable piece of tissue on the medialwall of the intermediate bronchus, just above the levelof the middle lobe orifice, was seen and biopsied.

She was referred to University College Hospital forfurther treatment. The biopsy had been reported assquamous-celled carcinoma. but on reviewing it wewere struck by the histological similarity to the biopsyof case I. Hyperplastic squamous epithelium waspresent with a papillary and trabecular pattern, andin some places there was an inflamed stroma of youngfibrous tissue (Fig. 3). Variation in nuclear and cellsize was less marked than in case 1. but mitoses weremore numerous (Fig. 4). Bronchial wall was notidentified. A further bronchoscopy on 8 December1960 showed a group of small white spots 1 to 2 mm.in diameter on the medial wall of the lower lobebronchus around which the mucosa was red. Themedial basal orifice was blowing bubbles throughclear mucus. There was a little projection of apparentgranulation tissue at the edge of the orifice. A biopsytaken from the upper edge of the medial basal orificeshowed patches of rather flat squamous epitheliumlining a slightly inflamed bronchial wall.Although invasive squamous-celled carcinoma had

not been identified the atypical cytology of th_ firstbiopsy suggested that it might well be present.Thoracotomy was performed on 14 December 1960.The lower bronchus was freed and incised posteriorly.A diffuse, red, swollen area in the bronchus extendedfrom close to the middle lobe orifice; no definitetumour was seen but, on the assumption that thismight be submucous infiltration by carcinoma, it wasdecided to resect both middle and lower lobes.The thickening and irregularity of the mucosa at

the junction of the main bronchus to the lower andmiddle lobes was confirmed in the resected specimenwhich showed no other lesion. Histological examina-

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Papillary neoplasms of the bronchus of low-grade malignancy

FIG. 1. Neoplastic squamous epithelium from biopsy ofcase I. H. and E., x 55.

FIG. 2. High-power view of Fig. 1 showing variation in nuclear size and occasionalbinucleate cells. H. and E., x 670.

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J. F. Smith and D. Dexter

FIG. 3. Neoplastic squamous epithelium from biopsy ofcase IL H. and E., x 55.

FIG. 4. High-power view ofFig. 3 showing mitoses. H. and E., x 550.

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FIG. 5. Residual neoplasm at biopsy site in resected specimen from case I. Notegrowth extending into necks ofmucous glands. H. and E., x 55.

FIG. 6. Serial section from same b.ock as Fig. 5, showing continuity of growth inneck ofmucous gland and surface, i.e., there is no true invasion. H. and E., x 58.

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J. F. Smith and D. Dexter

tion of this area shows fibrin and inflammatory cellsat the biopsy site and residual localized squamous-celled papillary neoplasm. The cytology is similar tothat of the initial biopsy, and the growth extends intothe necks of the mucous glands (Fig. 5). However,serial sections demonstrate continuity of the surfaceand deeper foci of the neoplasm so there is no trueinvasion (Fig 6). There was no evidence of squamousmetaplasia in sections from other bronchi. She hasremained well since.

CASE III A 61-year-old market porter had attendedthe London Hospital in March 1949 with a sixmonths' history of blood-stained sputum in the earlymorning, following an initial small haemoptysis; aslightly larger one had made him seek medical advice.In the three months preceding the hospital visit hiscigarette consumption was 10 to 20 a day; before thatit had been 40 a day. On examination he was anobese, cheerful man without physical signs. A radio-graph of the chest showed some shadowing in the leftmid-zone, and on examination of the sputumsquamous carcinoma cells were identified on severaloccasions. Bronchoscopic examination was negative.At thoracotomy on 4 April 1949 there was some diffi-culty in locating the growth. and it was finally decidedto do a left upper lobectomy. After section of thebronchus growth was seen in the lumen, so a resectionof a further 2 in. (12 7 mm.) of bronchus was per-formed. the stump being covered with an intercostalmuscle graft. The patient made an uneventfulrecovery and he has remained well since.The resected specimen showed a neoplastic mass,

2 5x 1 5 cm., in the main bronchus which wasobstructed, the lumen being reduced to 0 3 cm. Fromit papilliferous growth extended into all the chiefbranches, some of which were dilated and containedthin pus in the periphery of the central part of thelung. Microscopical examination confirmed thisbronchiectasis and showed the neoplasm to be asquamous papillary lesion situated at the junction ofand involving the main branches to the upper lobe.In one place it appeared to be originating from a

fairly wide area of bronchial epithelium; elsewhere itwas extending into the lumina of bronchi. At the timethis section was first examined (in 1949) it was thoughtthat superficial invasion of the inflamed bronchialwall had occurred at one place. Re-examination nowsuggests that this might well be tangential section ofpapillary non-invasive extensions. However, there isconspicuous mitotic activity, nuclear variation, super-ficial keratinization, and necrosis in the growth.Comment This was a rather extensive papillary

neoplasm with cytological evidence of malignancybut no convincing invasion.

CASE IV This man, aged 66 years, was admitted to St.George's Hospital in April 1949 with a six months'history of a productive cough. the sputum beingblood-stained on admission as it had been several

times in the previous months. Night sweats hadoccurred, and he had lost two stones in weight.Details of the smoking habits were not available.There was patchy collapse and bronchiectasis in the

left lower lobe. Purulent sputum, 6 to 10 oz.. wascoughed up daily, and in this malignant squamousepithelial cells were identified. Death occurred sud-denly on 16 April 1949 following an attack of cough-ing with bronchospasm.At necropsy a large, polypoid tumour situated at

the bifurcation of the trachea was causing completeobstruction of the left and partial obstruction of theright main bronchus. Consequent to this there wasbronchiectasis and collapse in the left lower lobe andpatchy collapse of the right lower lobe. The tumourappeared to be confined to the lumen of the trachea,and no local or distant metastases were present.Histological examination showed a papillarysquamous-celled neoplasm similar to that of case 111.The epithelium of the papillae was thick with irregu-lar and incomplete differentiation. There was con-siderable nuclear variation and mitotic activity andisolated trabeculae of cells within the tumour stroma.Invasion of the wall of the trachea was not present.In some areas near the tumour there was squamousmetaplasia of bronchial mucosa.

CASE v A man aged 63 years, a heavy cigarettesmoker for many years, developed pneumonia affect-ing the lingula in May 1954. He was given antibioticsbut resolution was slow. In the next few months hehad blood-stained sputum on several occasions. InJuly 1954 a chest radiograph showed an area of seg-mental collapse. He was bronchoscoped on 10 August1954 and a mulberry-like tumour was seen on thecarina between the left upper and lower lobe bronchi.A biopsy showed a papillary tumour covered bysquamous epithelium in which gross cellular irregu-larity with atypism was present. Numerous mitoticfigures were seen. No invasion was present. A diagno-sis of squamous cell carcinoma was made.The patient had a poor respiratory reserve. It was

decided to treat him by radon seed implants. Atthoracotomy no tumour could be seen outside thebronchus, but the radon seeds were inserted into theperibronchial tissues. Bronchoscopy was carried outand several fragments of tumour were seen lying freein the bronchial lumen. These were removed by suc-tion. After this the bronchial lumen appeared normal.It was impossible to identify the point of origin orattachment of the tumour. The tumour fragmentsshowed an identical structure with the biopsy material.Again no invasion was present. The patient attendedfollow-up clinics regularly and had no recurrence ofchest symptoms.He was re-admitted on 2 August 1956 with acute

intestinal obstruction due to a carcinoma of thesigmoid colon. Resection was carried out. A broncho-scopy was performed at the end of the operation andshowed no abnormality. He developed post-operativeileus and died on 15 August 1956.

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At necropsy no metastases from the bronchial carci-noma were present. A block of tissue including thecarina between the left upper and lower lobe bronchiwas taken and serial sections were prepared. Theseshowed no residual neoplasm. The bronchial mucosaat the site of the tumour and from other bronchishowed a few areas of pseudostratification but noother abnormality.

CASE VI A labourer aged 60 had smoked 20 cigarettesa day for many years. He was admitted to St. George'sHospital in February 1960 with a productive cough.Radiological examination showed areas of abnormalshadow in the left upper lobe. Repeated sputum ex-aminations for tubercle bacilli and malignant cellswere negative. The patient refused to be broncho-scoped. During the next 18 months a slow increase inthe size of the left upper lobe shadow occurred. On22 August 1961 bronchoscopy showed a tumour aris-ing from the origin of the left upper lobe bronchus.Lobectomy was carried out; it was necessary to removepart of the lower lobe bronchus. The patient appearedto be making satisfactory progress but had a massivehaemorrhage and died on 21 September 1961.The specimen consisted of the left upper lobe.

There was a polypoid tumour, 1 cm. in diameter,loosely attached to the wall of the left bronchus nearits cut end. The bronchi peripheral to the tumour weredilated and filled with pus. There was patchy con-solidation of the lung parenchyma.

Histologically there is a papillary tumour occupy-ing the bronchial lumen (Fig. 7). The tumour is coveredby abnormal squamous epithelium showing irregularand incomplete differentiation. Numerous mitoticfigures are present (Fig. 8). There is no invasion of thestroma or of the bronchial wall. Semi-serial sectionsfailed to reveal a point of attachment to the bronchialwall. The lymph nodes present are free from growth.There is bronchiectasis and organizing pneumoniaperipheral to the tumour.

At necropsy there was no residual tumour and nometastases were present.

CASE VII A labourer, aged 48 years, who had smoked20 to 25 cigarettes daily for many years, was admittedon 7 December 1960 complaining of a productivecough for the past five weeks. During this period hehad been breathless on exertion. There was no historyof haemoptysis. On examination there was partialcollapse of the right upper lobe. A radiograph showedcollapse of the anterior segment of the right upperlobe. A bronchogram showed complete blockage ofthe anterior segmental bronchus. Bronchoscopy con-firmed this finding, the appearances suggesting abronchial carcinoma. A biopsy was taken but did notinclude tumour tissue. Three specimens of sputumwere examined but no tumour cells were seen. On 16December 1960 a right upper lobectomy was carriedout. The patient made a satisfactory post-operativerecovery and remains well.The resected specimen showed a friable papillary

tumour, approximately 1 cm. in diameter, filling theanterior segmental bronchus at its origin. The tumourwas loosely attached to the bronchial wall and did notappear to be infiltrating the bronchus or the lung.The bronchi peripheral to the tumour were dilatedand filled with pus. There was organizing pneumoniain the anterior segment.

Microscopical examination shows the tumour to bea papillary mass covered by abnormal squamousepithelium. There is irregular and incomplete differen-tiation of the epithelium and a moderate number ofmitotic figures. Isolated trabeculae of tumour cells arepresent in its stroma. Semi-serial sections failed toreveal a point of origin from the bronchial wall. Thereis, however, an area of the bronchus near the tumourwhere the bronchial surface consists of epitheliumshowing similar histological features to those presentin the tumour. There is no invasion of the bronchialwall. The lymph nodes are free from tumour.

CASE VIII A 52-year-old hotel valet, who smoked 10cigarettes a day, was admitted to University CollegeHospital in June 1962 with a two years' history of anunproductive cough which had been worse in recentmonths. He had been short of breath on exertion forsix months during which time swelling of the anklesand feet as well as stiffness of the wrists had also beenmajor symptoms. For two months the left knee hadbeen swollen and uncomfortable. On examination hewas a thin man with gross clubbing of the fingers, inaddition to swollen ankles and wrists and a moderateeffusion into the left knee. Radiographs showed alarge opacity in the apical segment of the upper lobeof the right lung and gross changes of pulmonaryosteoarthropathy in the ankles and wrists. Onbronchoscopy there was slight reddening of themucosa of the right upper lobe bronchus but theapical segment branch was not seen. The sputum con-tained cells highly suggestive of squamous-celled car-cinoma. A right upper lobectomy was performed andafter an initial post-operative infection he made asatisfactory recovery. The joints were more comfort-able the day after operation, and five days later painhad disappeared.The resected specimen consisted of the right upper

lobe together with the lateral segment of themiddle lobe. On opening the bronchi a white cauli-flower-like mass, about 5 cm. in diameter, was seenarising from the apical segment bronchus and fillinga dilated part of it (Fig. 9). Distal to this growth therewas some dilatation of bronchi and immediately be-neath the pleura an indurated area of chronic pneu-monia. No growth was seen in seven hilar glands or ina gland sent as a separate specimen.On microscopical examination the tumour was a

papillary squamous-celled neoplasm arising from thewall of the bronchus, extending along its lumen andthat of some of its branches. A few islands of growthwere isolated in the fibrous stroma, but convincinginvasion of the adjacent parenchyma was not seen.There was conspicuous nuclear variation, mitotic

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FIG. 7. Case VI. Tumour projectintg intolumen of bronchus. H. and E., x 5.

FIG. 8. High-power view of tumourin Fig. 7 showing mitotic activity.

H. and E., x 700.

FIG. 9. Cut surface of resected upper lobe from case VIIIshowing cauliflower-like mass filling a dilated apical

segment bronchus.

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....--465¢5 4 5 t5 7 a 9~~~~~~~~~~~Ol

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Papillary neoplasms of the bronchus of low-grade malignancy 347

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FIG. 10. Squtmous-celled papilloma resected from case IX. Note vascularfibrous core. H. and E., x 30.

FIG. II. High-power view of basal layer of epithelium of papilloma in Fig. 10.Crowding ofnuclei and mitotic activity. H. and E., x 800.

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3. F. Smith and D. Dexter

activity, and incomplete maturation of epithelium.The adjacent lung showed collapse and chronic pneu-monia. There was no secondary growth in the glands.

CASE IX This middle-aged man was a non-smoker.He had a haemoptysis in 1958 and was referred to SirClement Price Thomas. On bronchoscopy a smallpolyp in the right upper lobe bronchus was seen and asleeve containing this growth was resected at subse-quent thoracotomy. The resected bronchus was about3 x 1 cm. and showed at its centre a small papillarylesion about 3 mm. in diameter (Fig. 10). Microscopicexamination showed this to be a small squamous-celled papilloma with nuclear crowding and mitoticactivity in the basal layer but no suggestion ofinvasion (Fig. 11).The man has remained well except that in the latter

part of 1960 he had streaking of the sputum. Hisradiograph remained normal and he refused broncho-scopy.

DISCUSSION

Pathologists differ in their interpretation of the dis-tinction between benign and malignant tumours.Willis (1960) stresses that the terms are relative,that the distinction between the two is not funda-mental or clear-cut, and that the intelligent ques-tion to ask is, 'How innocent or malignant is thistumour?' On the other hand, Payling Wright (1958)stresses the distinction with the forthright phrase,'To confuse these two valuable antonyms is puretranscendentalism and does disservice to clearthought on a difficult problem'. Until recently thisquestion has not excited much interest in con-nexion with squamous epithelial neoplasms of thebronchus. Willis (1960) and Liebow (1952) men-tion the occurrence of papillomas but give fewdescriptive details. Liebow (1952) illustrates an ex-ample of widespread extension of papillomatosisof the larynx to the trachea and bronchi. We haveexamined specimens from a somewhat similar casein which so far the extension has reached the lowertrachea. In the numerous biopsy specimens there isno evidence of atypical features except for an occa-sional mitosis. We think the histology of case IXis similar and that it should be regarded as apapilloma. This is the only solitary papilloma inthe bronchial tree that we have encountered; thehistory of further slight haemoptysis in this case isdisquieting. It is possible that case IX representsthe earliest stage of the neoplasms seen in cases Ito VIII, and that its natural evolution would be tosuch a lesion.We consider that cases I to VIII are examples of

low-grade papillary carcinomas. In none of them isthere convincing evidence of invasion. All pro-truded into the bronchial lumen and in one, case

III, extensive spread along the lumina of thebronchi of an upper lobe had occurred. All showedevidence of nuclear variation and mitotic activity.In those where enough tissue was available for thepoint to be assessed, the maturation of theepithelium was variable or incomplete. These arethe cytological features of intra-epithelialcarcinoma or carcinoma in situ. However, thosepathologists who use these terms appear to beloath to employ them in connexion with papillarylesions. We have therefore used the term 'papillaryneoplasms of the bronchus of low-grademalignancy'. Hinson (1958) makes the point thata carcinoma may initially be polypoid within thelumen of the bronchus, but he does not discussthe presence or absence of local microscopicalinvasion in such neoplasms.

It is probable that the presence or absence ofsuch invasion can only be determined in the re-sected lobe or at necropsy. It may be possible,however, to recognize that the lesion is one of thistype if the bronchoscopic and histological findingsare considered together. Thus in case V the tumourwas described as mulberry-like on bronchoscopicexamination, and in case VIII as cauliflower-like inthe resected lobe (this tumour was not accessible tothe bronchoscope). In the latter example thetumour tissue was friable, easily coming away inpieces. Cases I and II were so friable that most orall of the tumour came away with the biopsy; theword friable was also used in describing case VII.

If a friable polypoid tumour on bronchoscopyshows a histological and cytological picture com-parable with that illustrated in Figs. 1 to 6, itwould be worth considering if it belongs to thegroup delineated here. A similar group has beendescribed recently by Sherwin, Laforet, andStrieder (1962) under the name 'exophytic endo-bronchial carcinoma'. They give an account ofnine lung carcinomas that were characterized by apredominantly endobronchial growth of a papillo-matous, polypoid, or verrucous nature. (One of us,J. F. S., had given a preliminary account of threeof the cases reported in this paper to the Patho-logical Society of Great Britain and Ireland in 1961under the title Warts of the Bronchus.) However,of the nine cases described by these authors,several had microscopical evidence of invasionof the bronchial wall although none had metasta-sized. In our group we found no such invasion,although it was only excluded in several cases bycareful semi-serial sections.

It is not within our province to discuss theclinical management of these cases, but it is worthwhile to consider briefly the responsibility of the

348


pathologist confronted with such tissue as that pro-vided by cases I to VIII when reporting onbronchial biopsies. Before encountering these ithad been our policy to regard hyperplasticsquamous epithelium from this site, in whichatypical cytological features were present, as indi-cative of carcinoma, whether or not invasion wasdemonstrated. Investigations of carcinoma in situreported by Auerbach, Gere, Forman, Petrick,Smolin, Muehsam, Kassouny, and Stout (1957) andby Valentine (1957) had indicated its associationwith invasive carcinoma. Black and Ackerman(1952), in discussing the problem, stated that ifsuch a lesion were found in biopsy material itcould be assumed that invasive carcinoma waspresent also. This is no longer so. One should com-ment in a report on the presence-or absence ofinvasion in the tissue available for examination.Woolner, Andersen, and Bernatz (1960) have re-cently reported a series of 15 cases of in situ orearly invasive carcinoma. While the histologicalappearances of their cases were similar to those inthe present series, the tumours they report weresituated in the bronchial wall and none showed thewell-defined papillary structure occupying thebronchial lumen.We do not propose to discuss the clinical

features of the group. So far as it can be ascer-tained the prognosis is good, reflecting the absenceof invasion rather than the atypical cytology.Seven of our group of eight were in men. The inci-dence is as yet difficult to determine. The fourcases from St. George's Hospital occurred in a 12-year period in which 660 specimens of bronchialcarcinoma were encountered as surgical or post-mortem specimens. The three cases from Univer-sity College Hospital were seen over a three-yearperiod in which 54 resections of lung for car-cinoma were possible. The nine cases of Sherwinet al. were encountered in a study of 85 patientswith lung cancer suitable for definitive resection byone thoracic group at one hospital over a 16-yearperiod.

SUMMARY

The pathological features of a group of low-gradesquamous-celled carcinomas of the bronchus areoutlined; one papilloma is included for compari-son.The essential features are a warty or mulberry-

like projection into the lumen of the bronchus andan absence of invasion into the bronchial wall onhistological examination. Atypical cytological fea-tures similar to those of typical invasive carcinomamay be present, but a papillary architecture is con-stant. Extensive spread within the lumen of thebronchus sometimes occurs.

We thank the following clinicians for permission touse their case notes: Dr. Howard Nicholson, Profes-sor R. S. Pilcher, Sir Clement Price Thomas, Mr. V. C.Thompson, Mr. A. H. M. Siddons, and Miss DoreenNightingale.

Dr. Sybil Robinson kindly provided the initialbiopsy sections from case II. We thank Mr. A. Blighfor the photomicrographs.

REFERENCES

Auerbach, O., Gere, J. B., Forman, J. B., Petrick, T. G., Smolin,H. J., Muehsam, G. E., Kassouny, D. Y., and Stout, A. P. (1957).Changes in the bronchial epithelium in relation to smoking andcancer of the lung; a report of progress. New Engi. J. Med.,256, 97.

Black, H. and Ackerman, L. V. (1952). The importance of epider-moid carcinoma in situ in the histogenesis of carcinoma of thelung. Ann. Surg., 166, 44.

Hinson, K. F. (1958). In Carcinoma of the Lung. Ed. J. R. Bignall.Livingstone, Edinburgh and London.

Liebow, A. A. (1952). Atlas of Tumor Pathology, Sect. V, Fasc. 17Tumours of the lower respiratory tract. Armed Forces Instituteof Pathology, Washington.

Sherwin, R. P., Laforet, E. G. and Strieder J. W. (1962). Exophyticendobronchial carcinoma. J. thorac. cardiovasc. Surg., 43, 716,

Valentine, E. H. (1957). Squamous metaplasia of the bronchus;a study of metaplastic changes occurring in the epitheliumof the major bronchi in cancerous and noncancerous cases.Cancer, 10, 272.

Willis, R. A. (1960). Pathology of Tumours, 3rd ed. ButterworthLondon.

Woolner, L. B., Andersen, H. A., and Bernatz, P. E. (1960). "Occult"carcinoma of the bronchus: A study of 15 cases of in situ orearly invasive bronchogenic carcinoma. Dis. Chest, 37, 278.

Wright, G. Payling (1958). An Introduction to Pathology, 3rd ed.Longmans Green, London.

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Papillary neoplasms of the bronchus of low-grade malignancy