Unusual Cancer of the Lung

Unusual Cancer of the Lung 11. Bronchiolar Carcinoma of the Lung* RONLDJ. KNVDSON. M.D.,HCRSTB. HATCH,Y D.. \\'ILLIA)I T MITCHELL, JR., M.D hao A L T ~ OCHSSER, N KD., F.C.C.P. Neu, Orleans, Louisiana

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RONCHIOLAR CARCINOMA OP THE LUNG has been called the mmt controversial, most interesting, and least common primary malignant lesion of the lung.' The name, origin, etiolog), prognosis, characteristics, and definition of this disease have been sources of confusion. It was our hope that by reviewing the experience at the Ochsner Clinic and the observations of others concerning this entity, a clearer understanding of it might evolve. .\NALYS~S OF CASES In re\.iewing 45 cases originally diagnosed a 5 primary adenocarcinoma of the lung, we now consider two to be bronchiolar carcinomas and two others had features that would be considered suggestive of bronchiolar carcinoma. Of 11 cases originally considered bronchiolar carcinoma, one was found to be primary adenocarcinoma and two had some features of adenocarcinoma. Therefore, 12 proved cases of Bronchiolar carcinoma have been found among the 1,057 patients with primary malignant dhease of the lung seen at the Ochsner Clinic since 1942, an incidence of 1.14 per cent. Seven of the 12 patients were men and five women, ran$ng in age from 41 to 66 years, with an average age of 55 years. T h e pulmonary lesion was first seen on survey or routine roentgenography of the chest in three patients. Cough was the most common s)mptom, but only two patients had excessive production of sputum. Three patients noted hcmoptysis. C>zologic examination of the sputum was performed in ten cases. rZtypical cells were noted in four cases and malignant cells in three. Scalene lvmph node biomv was

'From the Dcpanrnenrs of Surgery, Chest Dire m s . and Pathology, Orhrner Clinic

performed in four cases, results of which were negative for malignant tumors in even. instance. Bronchwopy, performed on five patients, yielded no abnormal obsenration. Two patients had bilateral pulmonary invol\,ernent when first seen. Seven patients had right-sided disease, the middle lobe being involved in four cases, the upper lobe in two, and the lower lobe in one. The remaining three had involvement of the left lung, one with bilobar disease and two with left upper lobe disease. We were impressed with the variability of the roentgenographic obsemations which these patients presented. There appeared to be no specific diagnostic feature demonstrated on roentgenography of the chest which distinguished this disease from any other. Indeed, this disease can, and does, mimic almost any other neoplasm of the lung. Figures 1-6 demonstrate this wide diversity of roentgenographic observations seen in patients with bronchiolar carcinoma. Nine patients had lesions that were considered resectable. One wedge resection, one lingulectomy, three lobectomies, and four pneumonectomies were performed. Two who underwent pneumonectomy and two patients who had lobectomies are living at this writinq. Less than one year has elapsed since three of the patients were operated on, but one already has evidence of recurrence. The remaining two patients sunrived three and one-half and four and one-half years, respectively. DISCUSSION Bronchiolar carcinoma ha5 many controversial. often confusing aspects which have been subjects for discussion in recent reports. The confusion has been compounded

BRONCHIOLAR CARCINOMA OF THE LUNG

by the fact that more than 30 different terms have been used to describe this dii ease." The literature contains such terms as primary multiple carcinoma, multiple nodular carcinoma, diffuse lung carcinoma, alveolar or ahrolar cell carcinoma, carcinosis. carcinomatoides alveogenica multicentrica, alveolar cell tumor of lung, primary multiple alveolar cell tumor, primary alveolar epithelial carcinoma. diffuse primary alveolar carcinoma. cancer of alveolar epithelium, alveolar cell cancer, adenoma-like tunlor of the lung, pulmonary mucous epithelial hyperplasia, diffuse epithelial hyperplasia, pulmonary alveolar adenomatosis. multicentric alveolar cell carcinoma, papillan gelatinous adeno-carcinoma. mucocellular papillary adenocarcinoma, general pulmonary carcinosis, alvtolite cancGreuse, diffuse primary alveolar epithelial carcinoma. mucin secreting carcinoma, diffuse. solitary, or multiple bronchiolar carcinoma, and. more recently, bronchiolo-alveolar carcinoma. .An attempt to define beni
Flocrr 1 : Rocntgmognm of the chrrt shoring a multilocular cavitary lesion in the right lower

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mor of lung, malignant adenomatosis, cancerous or malignant pulmonary adenomatosis, and multiple pulmonary adenomatosis. The definition of bronchiolar carcinoma as a separate entity has been difficult. Before 1935 "hiiar" and "peripheral" lung cancer were discussed, but themafter peripheral tumors were considered, for the most part, to be adenocarcinorna. It has been suggested that many cases of bronchiolar carcinoma were reported as adenocarcinoma in the past.'" Inarmuch as this tumor is slow to metastasize, many authors have doubted its rnalignant nature, and the term "pulmonar). adenomatosis" a m . Swan4 suggested that this term was appropriate and the adjective "cancerous" he added if metastases occur. He pointed out, however, that this disease may kill by extension or metastases while remaining histologically benign. Some authors' noted the similarities between bronchiolar carcinoma and the s u p pmcdly benign pulmonar?. adenomatosis though some noted malignant changes in

FIGCRE 2 : A mlitary "coin" lesion is right lower lahe of the lung.

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in the

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KSUDSON, HATCH, MITCHELL AND OCHSNER areas of adenomatosis. Mears and co-workcrs' called attention to the largc areas of benign-appearing cells in their spccimem, while careful xarch revealed foci of malignant change in which the pulmonar). architecture was not preserved. Storey' concluded, therefore, that pulmonary adenomatosis and bronchiolar carcinoma, as well a9 the lesions described under the previously mentioned titles, represent a single entity which may v a n in malignant potential in different patients or portions of the same lesion. Contmvers). over the cell of origin of this tumor introduced the terms relating to the alveolar cells. Many authors believed thii tumor arose from the alveolar septa1 or lining cells,'"'" whereas others suggested origin from terminal bronchiolar cells."" The existence of, or cell of origin of, the pulmonar). alveolar epithelium itself has been a source of controvers).. However, the awociation of neoplastic nodules with bronchiola. continuih between neoplastic cells lining alveoli and bmnchides, formation of mucin by the tumor, and demonstration of ciliated neoplastic cells favor the terminal bronchiolar cells a$ the cells of origin of this tumor.' Herbut's" evidence that regenerated alveolar epithelium arises from basal cells of the bmnihides c o m b rates this. Bmnchiolar carcinoma, once de-

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Ftcunr 1. ally.

I.argc nodular masses am wen bilatcr-

fined, was assigned a separate catego? apart from other pulmonary neoplasms of bronchiogenic origin.' It is, neverthelcs, poorly defined. In his excellent revim of the subject, Liebow" suggated that thii is a well-differentiated form of adenocarcinoma, of bronchiolar origin, but often not differentiable from bronchiogenic adenocarcinoma, of bmnchidar origin, but often not differentiable from bmnchiogenic adenocarcinoma. Kreyberg" concurred, but placed this tumor in a separate category. Hukill and Stern" pointed out that, unlcs distinction from other tumors can he made, the entire concept of bronchiolar carcinoma is uselcss, and believed it is a histologically reco~gnizabletumor of unique hiitogenesis but of variable natural history. Their criteria for dia.gnosis include "( 1 ) good differentiation; ( 2 ) regular size and pattern of acini: ( 3 ) at leaqt a tendency to papill a y formation; and ( 4 ) marked use of lung stmma at margins of tumor." Pmnounced formation of papillary structures and the finding of satellite lesions within air spaces at a distance from the original lesion arc considered diagnostic. Further discussion of the histology would add noth-

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F i c r ~ r4: Roentgenogram of thr chert showing partial collapse of the left u p p r lobe.

BRONCHIOLAR CAR( ZINOMA OF THE LUNG

ing to the many excellent descriptions in the literature. \Ve have attempted to diierentiate our cases of bronchiolar carcinoma by reviewing the c a m reported as primary adenocarcinoma as well as those of bronchiolar carcinoma. Our series of adenocarcinoma of the lung will be reported elsewhere. Bronchidar carcinoma often appears as a multifocal lesion. Thought to be a tumor of multicentric origin by some"'" it is now considered to originate in a single focus'"' and may then spread by way of the Iymphatics or air payges to other portions of the same or oppusite lung. Two types were described, the nodular or miliary form and the diffuse or pneumonic type. It has been pointed out that there is no clear division between the two forms' and that it is an artificial classification' describing different stages of the same process. Bilateral involvement is a late manifestation, but has been reported to occur in 20 per cent of patients when first Fecn with this disease.' Several authorsM"*have noted an a p parent incrca-ed incidence of bronchiolar carcinoma. .is ha< been pointed out" before 1943 only 25 cases had been reported.

It is possible that this type of pulmonary tumor had been classified with bronche genic tumors in the past.' On the other hand, some authors? taking note of the increasing incidence of pulmonary fibrosis secondary to pneumonia, s u m t e d that chronic inflammation of the pulmonary parenchyma may play an etiologic role in bronchiolar carcinoma. If there is an ctiologic relationship, the increasing incidence of bronchiolar carcinoma since the advent of the antibiotic era'' may be more real than apparent. Epithelization of alveoli has been seen to occur in association with various pathologic conditions, and bronchiolar carcinoma has been found to arise in peripheral scars." The finding of small, subpleural, adenomatous malformations and similarly appearing bronchiolar neoplafms' has suggested another possible cause. Many authors have noted a resemblance between bronchiolar carcinoma and jaa~qiekte,' a viral disease of sheep. No concrete evidence has been offered to support a viral etiology for the human disease, and it is mentioned only for the sake of completeness. Bronchiolar carcinoma constitutes 0.4 to 5 per cent',' of primary pulmonary neoplasms. There appean to be no sex predominance in this disease. The average age

F r c r a ~5 :

FIGURE6 : A distinct right hilar mau u seen in this mntgcnograrn of the chert.

Bilateral. ditTuw. fine. nodular disease

is demunsrraced in this roentgenogram of the chert

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KNUDSON, HATCH,

M l l'CHELL AND

of patients with bronchiolar carcinoma is 54 yean.' Opinion has varied concerning prognosis, some authors reporting an extremely poor survival rate"""' Overholt and coworkers,'' among others: believe bronchiolar carcinoma should offer a good prognosis with early treatment. Nevertheless, Fitzpatrick and coworken" found only ten patients recorded in the literature up to 1961, as living five years after surgical treatment. The silent phase of pulmonary cancer has long been strgscd, and this is particularly characteristic of bronchiolar carcinoma. This type of tumor seems slow to spread, and cases are recorded of tumors being observed roentgenographically for as long as eight" and 12 years without causing symptoms. Yokoo and Suckow" suggested, however, that the shadow seen roentgenographically may be a peripheral scar in which cancer later arises. Nevertheless, it would seem that cancer detection by regular or mass roentgenographic surveys of the chest would assume great importance in this type of pulrnonay cancer. Hiist* noted a higher resectabilih rate for bronchiolar carcinoma detected by survey roentgenograms than those diagnosed by s)mptoms. At the end of three years, 75 per cent of thme whose disease was detected by surve)s in this Norwegian series were alive, whereas only 33 per cent of those whose tumors were diagnosed after s ) m p toms occumd were alive. Unfortunately, the radiographic picture is not characteristic and may mimic many other pulmonary diirden.' The common slmptoms are cough, usually productive of sputum, dyspnea, thoracic pain, hemophsis, loss of weight, anorexia, weakness, and fever. Production of large amounts of clear, watery sputum is considered characteristic of this disease and patients have been reported to produce 3 or 4 quarts in 24 houn. However, cough and sputum may be variable, many patients producing little, if any, sputum. .4s this is a slowly pmgrrsi\~e malignant disease, qmptoms often occur late in its

OCHSNER

Dluof the Chnt

course, and death may occur by the sheer extent of pulmonary involvement. Apart from histologic examination of the m c t e d specimen, ck~ologic examination of the sputum has proved the mmt valuable aid in diagnosis. This examination has demonstrated or k e n suggestive of malignant d k a s e in 63.6 per cent of patients examined b! Slean and coworken' and 80 per cent of those of Watson and Smith." Bronchial washings similarly are helpful, but bronchoscopy itself has been of little diagnostic value. Conservative surgical excision is considered the treatment of choice. Roentgentherapy and cytotoxic agenu have been found ineffective modes of therapy."' Our experience has confirmed this. SUMMARY Historically, bronchiolar carcinoma of the lung has been a difficult disease to define. It is a pulmonan mali~gnant disease. probably of unicentric bronchiolar origin, which resembles adenocarcinoma in many respects, may spread by way of Ikmphatics or air pasages to other parts of the same or opposite lung, and may kill by sheer extent of pulrnonan. involvement. Cytologic examination of the sputum has proved a valuable aid in diagnosis, but early roentgenographic detection is of paramount importance. Conservative surgical excision is the treatment of choice and, coupled with early diagnmis, should offer a favorable prognosis. Twelve cases, encountered among 1,057 patients with primary malignant disease seen at the Ochsner Clinic since 1942, have been reviewed. RESUMEN

Historicamente el carcinoma bronquiolar ha sido una entidad nosol6gica de dificil definiribn. Er una cnfennedad pulmonar maligna. de prohable origcn unicCntrico hronquiolar, que re as.meja al adenocarrinoma en muchor arpecror. que puede dircminarse por via linfitica a ranalicular a o t n parte del pulmirn afectado o al rontralatenl y que puede llegar a ser letal simplemente por la extenriirn del territorio pulmonar afcctado. El examen citol6gico del erputo rs un mCtodo de investigaciirn valiow, pem el diag nirnico ndiolirgico precor es de capital importanria. La rewcri6n quiri~rgira ronservadora es

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BRONCHIOLAR CARCINOMA OF THE LUNG

el tratamiento de elecci6n. Si se practica a tiempo, gracias a un diagnostico precoz, puede ofrecer un pronosrico fa\.orable. Doce casos de erte t i p , entre 1.057 pacientes con tumores malignos primitivos del pulm6n obsewados en la Clinica Ochmer, son devisados por el autor. Zcs*rrrr~s~~sstisc Historisch gerehen war das bronchiolare Lungencarzinom eme rchwierlg zu definierende Erkrankung. Es handelt sich um einen pulmonalen bij~artigen Prozcrr, wahrschelnlich von unuentrischen bronchiolarem Ursprung, der in vleler Hinrirht dem Adenocarzinom Phnlich sleht; die Aussaat kann erfolgen auf lymphogener oder aerogener Baslr in andere Teile der gleichen oder der Lunge der Gegenseite und kann zum Tode fiihren durrh p u P r h u s d ~ h n u n g der pulmonalen Befalls. Die cytalogische Sputumuntersuchung hat sich all aertvolle diagnort~scheHilfe erwirrm. jrdorh 17r cinp friihr rontgenologisrhp Erkennong \.on allrrenter \Tichtigkeit. Chirurgirche Excision i,t die Behandlung der Wahl und s t ~ l l tin \'~rI,indung ,nit der Frhhdiapose doch tcohl cine elnrtige Propose. Bericht uber 12 Falle unter lO5i Patienten mit primiren, k s a r tigen Krankheitd,biIdern aus der Othsner Klinik au? dem Jahre 1942 werden heschrieben. Resraescas I Sroaar. C F . K h r o r s o x . K. P. Are LAWar\cr. B J.: "Bronchtolar ('Alveoli cell') Carcinoma of the Lung," ] Thor. Surg., 26. ??I 1951 . ... . ... ? LNPPLI., T. C., S H E ~ R I C J. K , C AND CAP:; W. E . "Bronchiolar (Alveolar Cell) Tumors, A M . A . Arch Poth., 59:35, 1955 3 LIEBOW, .4. A,: "Tumon of the Lower Reriratory Tract," Fascicle 17. Atlar o/ Tumor Pofholocv. Armed Forces Institute of Patholow. ~Ghihington, 195?. 4 S w ~ s ,L L.: "Pulmonary Adenomatoris of Man Re\iew of the Literature and Report of 9 Carer." Arch P a t h . 4 i : S l i . 1949. 5 IKED*, K.: "Alveolar Cell Carcinoma of the Lung," A m . 1 . CBn. Path.. 15:50. 1945. 6 S ~ o a r u .C. F.: "Bronchiolar Carcinoma (Alveolar Cell Tumor-Pulmonary Adcnomatosir)," A m . 1 . Surg., 89:515, 1955.

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7 M e m s , T . W., KIRKLIN,J. W. A N D WOOLSER, L. B.: "Fate of Pafienu with Alveolar-cell Tumor of the Lungr, J. Thor. Surg., 27:420, 1954. 8 D e ~ A a u r ,N. C. Aao GRAHAM,E. A.: "Alveolar Cell Carcinoma of the Lung (Pulmonarv Adenomatais. l a a n i e h e ? ) . A Multiceniric Tumor of ~ ~ i i h on&," c h I . Thor. Surp., 18:237, 1949. 9 N ~ u s u s n o ~ aK., T. AND Geevea, E. F.: "Al veolar Cell Tumor of the Human Lung," Arch. Path., 33:551, 1942. 10 H E ~ B V TP., A.: "Alveolar Cell Tumor of the Lung. Further Evidence of Its Bronchiolar Origin," Arch. Pofh., 41 : 175, 1946. I I LIEBOW, A. A.: "Bmnchiolo-Alveolar Carcinoma" Adr,oncr Int. M e d . , 10:329, 1960. H i ~ t o l o g i ~ o lLung Cancer 12 K R E Y B E ~ OL.: , T y p e s , Norwegian Universities Pres, Oslo. 1962. 13 HPKILL,P. B. * s o STEBS, H . . "Adenocarcinoma of the Lung, Histological Factors Aff e c t i n- ~Promoris." Cansrr. 15:505. 196?. 14 FtrzpArrucK, H. F., MILLEX,R. E.. E m u , M. S., Ja. *so BEOD.C. F.: "Bronchiolar Carcinoma of the Luna. A Review of 33 Paticnu." I . Thor. Cnrdioi. bur^., 42: 310, 1961 . L. A N D SMITH, R. R . : "Terminal 15 W ~ r s o s W. Bronchiolar or Alveolar Cell Cancer of the Lung. Report of 33 Caaer." J A M A , 147:7, lqil 16 BEAVEE, D. L. *so SHAPIRO, J L.: "A Consideration of Chronic Pulmonary Parenchymal Inflammation and Alveolar Cell Carcinoma uith Regard to a Pouible Etiologic Relationrhio." A m . I. M e d . .. 21:879. 1956. 17 SPAIN,D. M.: "The Asmiation of Terminal Bmnchiolnr Carcinoma with Chronic Intentitial Inflammation and Fibrosis of the Lungs," A m . Rco. Tubrrc.. 76:559. 1957. 18 Yoaoo, H. *so Sucuow, E. E.: "Peripheral Lung Canren Arising in Scan," Cancer, 14: 1205. 1961. 19 O v r a e o r r . R. H., M ~ r s s s ~ W. a . A. AND DELn a s ~ c o ,J. E.. Ja.: "Favorable Bronchiolar Carcinoma." Du. Chert. 27:403. 1955. 20 H 8 r r . H.: "The Value of Periodic Mass Chest Roentgenographic Sun.eyr in the Detection of Priman Bronchial Carcinoma in Norwav."

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