ENTDIFFERENTIATTON I N PRIMARY CARCINOMS O F THE BEONCHI S N D LIJNGS

CARL VERNON WELLER

(Prorri tlre Urp[wtnwnt of PathfJlOgv, University of .uiclbigan, Ann Arbor, Micliigan )

The wide range of architectural and cellular varieties found in primary carcinoma of the bronchi and lnngs has tempted many observers to make use of these characteristics in found- ing an opinion as to histogenesis. Only a few years ago it was tliouglit to be justifiable to attribute the origin of the mncin-producing. columnar cell form to bronchial mucosa or bronchial glands and that of the cubical and lower cell types

This literatnre has been surveyed elsewhere (l), and need riot be repeated here. As late as 1924, Lilieiithal (2 ) wrote: “Cancer of the lung may begin in some part of the bronchial system, nsiially a t a secondary fork, or it may start in the parenchyma of the organ. The cells in the former type, derived from the bronchial rnwoLis membraiic, show cylindrical or cuboid forms ; while pavement cells are characteristic of the parenchymatous cancers.” It is significant that, during the period when it was generally accepted that the histogenesis of these neoplasms could be determined by cell type alone, pathologists were assigning a mesoblastic origin to the primary lung tumors made up of undifferentdated cells. Now it is generally accepted 1 hat these arc’ of epithelial origin, and that with the exception of lymphosarcoma cleveloping in the peribronchial lymphoid ap- paratus, primary sarcoma of the lungs is of the greatest rarity.

In 1912, EIenrici (3 ) had shown by staining the more re- sistant elastic fibers that assumption of origin from alveolar epithelium for certain lung carcinomas was nnwarrantcd, siiice it was evident that the alveolar architecture was due

- to alveolar epithelium.

218

PRIMARY CAItCINOMA O F THE BRONCHI A N D LUNGS 219

to the fact that the iicoplasm had grown through the paren- chyma of thc luiig utilizing the alveolar septa as supporting stroma.

A broad biologic concept ion of the relationship of these tumors to each other and to the possible parent cell types has been expressed by Klotz (4), whose views most nearly ap-

F I G . 1, A-1860. W~LT,-DIFFEILLNTIA'~I'ED PAPILLIFEBOUS ~ f U C I N - F O R M I X G CYS-

TADENOCARCINOMA. (Zeiss objective A A ; coiiipciisating ocular 4 ; bpllows ' Iciigth, 110 cm. The same magnification was used for a11 of the illustrations.)

proach thosc proposed in the present paper. He pointed out the difficulty eiicaouiitered in classifying carcinomas of the lungs aid bronchi upon the basis of ccll type alone since the same neoplasm may show squamous cells in one area, cuboidal in another and large masses of polyhedral cells in still an- other. He was coiiviiiccd that any portion of the bronchial or parenchymatous epithelium might through mctaplasia give rise to the squamous type and that, sjrnjlarly, broiichial epi-

220 CARL VERNON WELLER

thelium might be the source of neoplasms showing cnboidal, polyhedral or compressed and stratified cells. He concluded that the point of differentiation need not be stressed in de- t ermiiiing histogenesis for the epithelial linings of the res- piratory tubes and alveoli have a common parentage arid that it was quite impossible to differentiate by histological nnslly-

FIG. 2. A-1500. I'APILLIFEROUS ADENOCARCINOMA WITH MARKED PLEOMOR-

PHISM AND LOSS OF POLARITY I N THE LINING CELLS.

sis aloiie the carcinomas arising from the bronchial miicosa from those having their origin in the alveolar epithelium.

The material used in the present study consisted of four- teen cases of primary carcinoma of the lungs and bronchi. Thirteen of these were encountered in, a series of 3000 antop- sies aiid the fourteenth was operative material, a partial lobcctomy. Clinical descriptions of twelve of these hare ap- peared elsewhere (5). These cases will be summarized briefly, with a statement of their histopathological character

PltIMAKY CARCINOMA O F THE BRONCIlI AND LUNGS 221

and tlie extent of metastasis found in each. Carefully selected fields have been photographed at precisely the same magni- fication from each case and it will be left very largely to these illustrations to snpport the view presented.

From the standpoint of histological analysis, these fonr- teen cases of primary carcinoma of the lungs are found to be related to oiie another i n a relatively simple schematic mpn-

FIG. 3. A-1500. ADENOCARCINOM4 WIT11 MASSES OF STRINQP A'fUCIN FILLING THE ALVEOLAR SPACES, FROM THE SAME CARCINOMA A S THE PRECEDING FIGURE.

iier. If the number of cases had been much larger the transi- tions between succeeding steps would have become more gradual but it is altogether probable that a place could be found for every example of this condition without altering the general form of the scheme. This can be visualized as a Y, aloiig the left hand inclined limb of which are arranged the carcinomas of distinctly gland-celled type with the most fully differentiated columnar celled, papillomatous and mucin- forming examples at the upper extremity, the least differenti-

222 CARL VERNON WELLER

atzed medullary forms still showing traces of aclenomatous architecture at the lower eiid of this braiich aiid the inter- mediate degrees of differentiation in seqnence along its length. The right hand limb of the Y bears at its extremity the cornifying sqnamous celled form, followed by those mhich do riot produce Berato-hyalin and, finally, medullary carci- nomas which have almost entirely lost tlic sqnamous cell char- acter. At this point the coiiverging limbs of ilic diagram uiiite and tlic stem provides a place for mednllary carcinomas composed of spherical or polyhedral cells showing neithcr gland cell or sqnamous cell characteristics. On the upper portion of the stem belong those carcinomas of this general type which have somewhat larger cells and which still show some trace of alveolar arrangement. At the lower extremity is found the entirely undifferentiated diffusely infiltrating small round cell form of primary lung carcinoma which has usually been called sarcoma. The following arrangement of autopsy numbers iiidicates the placement of the cases wliich a re to be described in such a scheme.

Columnar ('lelled, Coriiif y iiig Mucin-Pr oducing, Squamous

Papilloma tous. Celled. A-1860 2494- A G

A-1500 1.1-352 A-2 9 83

A-2284 A-2140 A-2379

A-1140 A-1760 A-2776

A-2818 A-2328 A-1162

Uiidi f o r en t iat ed Celled (frequently mistaken

for sarcoma).

PRIMARY CARCINOMA OF THE BRONCI-II BND LUNGS 223

The position of each example has been dctermincd by the prevailing cell type or architectnral characteristic as the case may be. It must be boriic in mind that within certain in- dividual carcinomas of the lung there is almost as wide a

P I G . 4. A-332. ADENOCAECINOMA TVlTH A 8MALLER TYPE OF LIKING (%ELL.

Abundant forriiatioii of iriuciii.

range of degrees of antrplasia as is to be found in Ilia entire group. This point will be illustrated in certain instances.

SIJMMAIIY OF CASES

The adciio-carcinoma group will be listed first, beginning with the most, aiid passing to the least, differentiated.

A-1860. The patient was a male, sixty-five years old. At autopsy a carcinoma, apparently arising from the right main bronchus, mas found. The neoplasm estended into the bronchus and practically blocked its lumen. Microscopically

1 5

224 CARL VERNON WELLER

it was found to he a papilliferous cyst-adeno-carcinoma form- ing mncin in moderate amount. (Fig. 1.) There was a marked development of coiiiicclive tissue throughout the neo- plasm. Met astascs were found in the hroiichial, cervical and mccliastinal lympli nodes aiid in tlic left fifth rib.

A-1500. The body was that of a male, forty years old, which

sliowcd at anto1)sy a cnrc~inomn appnreiitly primary in the secoiiclarp bronchus to thc upper left lobe. There was a high degree of steiiosis of this bronchus. The prevailing histo- logical type was a papillif erons adciiocarcinoma which slio~ved, however, much less complete differentiation than did the prccwlirig example. The cells covering the papillae slio~ved a. marked pleomorphism and loss of polarity. (Fig. 2.) In some areas the papilliferous structure was lacking and masses of epithelial mncin filled the alveolar spaces.

PRIMARY CARCINOMA OF THE BRONCHI AND LUNGS 225

(Fig. 3.) I n still other portions the alveolar spaces were oc- cupied by medullary cell masses in which most of the cells contained droplets of mucin. The stroma was very heavy in areas. Metastases were found throughout the left lung and also in the bronchial, mediastinal, lower cervical, pre- vertebral and retroperitoneal lymph iiodcs, right lung and liver.

A primary carcinoma of thc luiig, believed to arise in the right msiii broiichus, of which there was complete sten- osis, WLS found in a man, forty-seven ycars old. Microscop- ically the neoplasm was a n adeiio-carcinoma with glnnd-like

A-352.

FIG. 6. A-2284. VEETEBRAL METASTASIS FROM TIIE S A M E CASE AS PRECED-

INQ FIGURE. Slight papilliferous architecture. Utilization of bone trnbeculae in formation of g l a d spaces. Coinplete lack of mucin formation.

spaces lined by from two to six rows of small spherical or polyliec2ral cells. These spaces all contained abundant mucin. There was no papilliferous structure present. (Fig. 4.) Metastases were found in the bronchial lymph nodes aiid left kidney.

226 CARL VEIlNON WELLBR

A-2284. A woman, forty years old, showed at autopsy a primary carc*iiioma of the lung, situated near the mesial siir- face of the lower left lobe. It was believed to have litid origin in one of the smaller bronchi. Microscopical examination showed the neoplasm to be a somewhat papilliferous adeno- carcinoma with a marked tendency to become scirrhous

F I G . 7. A-31 40. ADENO('ARCIN0MA WITH SPHERICAL AND I'OLYHEDRAL CELLS L O O S E L Y ArrTA(mm TO TIiE ALVEOLAR WULS. - through the development of a hyaliiie stroma. (Fig. 5.) Although somewhat more fully differentiated than thc prc- ceding in that papilliferous architcctnre and a teiideiicp for the epithelial cells to grow in a single layer had pcrsistcd, there was no evidence of muciii formation. Accordingly this neoplasm is given a lower position in the scale. In its bone metastases a similar structure was maintained, in part through the utilization of persisting bone trabeculae f o r the formation of gland-like spaces. (Fig. 6.) Metastases were found in broncliial nodes, lungs, vertebrae, pelvic bones and liver.

PRIMARY CARCINOMA OF THE BRONCXTI AND LUNGS 227

A-2140. Thc body was that of a man, aged forty-nine years. At autopsy a primary carciiioma of the upper lobe of tlic right l m g was found. It had iiivolved the anterior thoracic wall by direct extension and had perforated the sternum. Microscopically the neoplasm was a medullary ndenocarciiioma. In certain areas the adenomatous type of architecture was fairly well established with polyhedral lin-

F I G . 8. Ah-z140. MEDULLARY A411EA F R O M THE SAME NEOPLASM AS T E E P R E -

CEDIKG FIQL%E. Loose iiests of rather siixill cells with the alveolar architecture. slightly iiidieated by the coarser stromn.

iiig cells in one or two IOWS. In general, however, the growtli was medullary with an iiidcfiriite alveolar pattern of coarser stroma. (Fig. 8.)

A-1140. A man, fifty-seven years old, showed at autopsy a large snbcutaneons mass, located over, and apparently in- volving, the posterior portions of the left fifth to eighth ribs. This was fomid to be continuous with a primary neoplasm of

(Fig. 7.)

228 CARL VERNON WELLEB

the lung centering about a bronchus of the third order in the lower left lobe. &licroscopical examiiiatioii showed it to he in part an adciiocarciiioma forming small acini lined by a single row of low cubical or polyhedral cells. Albuminous material which did riot give staining reactions for mncin was present in these spaces. (Fig. 9.) Elsewhere, aiid in the greater part of the mass, the neoplasm ~ 7 a s entirely medul- lary iii type a r i d could scarcely have been differentiated from

FIG. 9. A-1140. ADENOPAR('INOXA WITH SMALL CUBICAL AND POLYHEDRAL CELLS. Muciii forniation lacking.

a iioii-coriiifyiiig squamous cell carcinoma. (Fig. 10.) The medullary type prevailed in the metastases. Intermediate transition stages were readily found so that there was no doubt that but oiie neoplasm was present. Metastases 'were fouiicl in both luiigs, bronchial, mediastinal, rctroperitoncal aiid left cervical lymph nodes and liver.

A t nacropsy of the body of a man fifty-six years old, a large iieoplustic mass centering about the main bronchus

A-1760.

PRIMARY CARCINOMA OF THE B R O N C H I S N D LUNGS 229

to the right lung was found. This was part of an extensive mediastiiial irivolrement. I n the upper part of this lung was a second rouiided neoplastic mass which on microscopical ex- aminatioii proved to be an area of chronic fibroid pneumonia infiltrated with carciiioma. While the right main bronchus seemed to be the area of origin, the possibility that the neo- plasm might have arisen at the site of the fibroid pneumonia could not be excluded. Only in this area was a distinct adeno- ctwciiiomat ous structure present. (Fig. 11.) However, the peribroiichial mass showed the greater devclopmeiit of stroma. Here and elsewhere the neoplasm was of sciri.hous

FIQ. 10. A-1140. MEDULLARY ~ A R C l N 0 3 I A FROM THE SAME CASE AS TEE PRECEDING FIGURE. This was the prevailing type in both primary and metastases.

iypc with slender columiis and cords of cells running through a very dense Eiyaline stroma. (Fig. 12.) Metastases were found in the bronchial, mediastinal, prevertcbral, retroperi- toneal and mesenteric lymph nodes and in the choroid plexus, spleen, liver, kidneys, adrenals, pancreas aiid prostate.

230 CARL VERNON WELLER

The cases of frankly squamous cell type were as follows : 249P.AG. This case could be studied only from operative

material. Partial pulmoiiary lobectomy was doiie upon a mail, f orty-nine years old, for a neoplasm which was invading the lowcr tlioraeic wall. &Clicroscopically i t mas a typicla1

3’10. 11. A-I 760. LOOSE MESHED MEDULI~AI~Y ADESOCARCINOMA WITH SEMI-

GLBNDPLAR ~’OlllLrATlONS StJQQESTINQ ‘rERMINAL ~KONC!IIIOI~ES OR REQENERATION

B’IQIIRES I N h &’II3NOID 1’NEUMONlA.

eoriiifyiiig medullary squamous cell carcinoma with rathcr large cells. In some areas it formed abundant kcrato-hyalin whicli rapidly liquefied. In other areas tliere were small epithelial pearls with little horny substance. (Fig. 13.) There TWS 110 clinical evidences of metastases. Autopsy wax riot obtained.

A-2983. A farmer, aged fifty years, s l io~~ccl at autopsy a partially steiiosiiig primary neoplasm, apparently having origin in the left maiii broriclius at its first bifurcation. Mi- croscopically a coriiifying medullary squamous cell carcinoma

PItIMAIlY CARCINOMA O F T H E B R O N C H I A N D L U N G S 231

of practically the same type as in the preceding case was found. (This and the succeeding case are not illiistrated.) The only metastases were in the lung, pleura and bronchial nodes of the involved side although the primary neoplasm was of large size and had infiltrated extensively in a radial maiiner along the bronchial tree.

A-24T9. At autopsy the left lnng of a laborer, fortp-nine years old, showed an active chronic tuberculosis with cavita- tion. There were numerous broiichiectatic cavities through- out this Imig and reas as of chronic fibroid rmeiirnonia. The

&G. 12. A-1760. RCIRRIIOUS CARCINOMA WHICH WAS THE PREVAILING TYPE IN THE <‘ASE FROM TVHICII TIIE PRECEDING ILLUSTRATIOX WAS TAKEN.

secondary division of the left main bronchus leading to the lower lobe was infiltrated and practically occluded by a neo- plasm which extensively invaded the neighboring lung tissue. Microscopically it proved to be a medullary squamous cell carcinoma sliowing somewhat less cornification, but otherwise resembling the two preceding cases. Netastases were found in the right lung and the bronchial nodes.

232 CAKL VERNON WELLER

A-2776. This patient was ail automobile factory mechanic, fifty-one years old. At autopsy the riglit main bronclms was found to be surrounded by a neoplastic mass beginning two centimeters helow the tracheal bifurcation and extending par- ticularly into the lower lobe. Five centimetcrs below tlie bi-

Fro. 13. 2494-AG. MEDULIAKY SQUAMOUS CELL CARCINOMA WITII FORMA- TION 02’ & ~ I T N E ~ I I A L 1’EARLS AND EARI,Y CORNIFICATION. ( 1 II Other UWaS there mds licavy comification.)

ftircatioii the main bronchus sliomcd complete stcnosis. Bl i - croscopically this was a non-cornifying mediillary squamous cell carcinoma, growing in rather large nests. (Fig. 14.) Many of the cells were of small size with scant cytoplasm. The general resemblaiice of this microscopical picture to that of Fig. 10, a t a nearly corresponding position in the adeno- carcinoma line of descent, is striking. Metastasis had taken place to the right lung, bronchial and retroperitoneal lymph nodes.

PRIMARY CllItCINOMA O F THE BRONCHI A N D LUNGS 233

Examples with insufficient differentiation to shorn whether llie parent type was gland celled or squamous celled, placed upon the stem of the Y, are next described. It will be noted that this condition has been approached from either side by thc convergence of the two lines of descent.

At autopsy the body of a sheet metal worker, fifty p a r s old, showed a firm neoplastic mass about three

A-2818.

FIG. 14. 11-2776. MEDTJLLARY HQIJAMOVS CELL c lRCINOIl.4 WITHOUT CORNI-

FIPA\TIOli AND APPROACHING THE ~TNI>IFFEKEKTIATED c E I , L GROTJP.

centimeters in diameter at the root of the left lung and in relatioilship to the left main bronchns. A t a point 2.5 cen- timeters below the tracheal bifurcatioii the neoplasm ap- peared within the wall of thc bronchus, infiltrating the mu- cosa. A fan-shaped radiation of the neoplasm occurrcd within the substance of the lung reaching practically to the apex. Microscopical cxamination showed a medullary carci- noma made up chiefly of small rouiid cells. There was no trace of cornification or prickle cells 011 thc one hand, or of'

234 CARL VERNON WELLER

glanciular nrcliitcctnrc on tlic other save an evident alveolar arrangement of tlic stroma. In a few areas the cells liad become spindlc-shaped, apparently from prcssurc. Rletastuscs \\-ere found iii the left lung a d b1.011~hiill nodes, liver, paiicreas, prcrcrtchral lymph nodes, lumbar vcrtel)rae, ilium, pubis and right femur.

A iicgro liibor~1r, aged thirty-eight years, showccl a t aiitopsy, in addition to a n aneurism of the lower tlioracic

(Fig. 15.)

A-2328.

aorta, thc right maiii bronchus completely surrounded by a ncoplust ic mass beginning about two centimeters below the bifnrcatioii. The wall was infiltrated and the new growth appeared on tlie mucosal side as a soft irregular clevatcd mass. Microscopically this proved t o he a medullary carci- noma made up of small to medium sized spherical cells, with- out evidence of either scpamons cell origin or glandular ar-

PRIMARY CARCINOMA OF THE BRONCHI AND LUNGS 235

chitectnre. Ti1 a few areas a coarser stroma pro- duced an alveolar meshwork. The cells of the neoplasm had spherical nuclei with coarsely reticulated chromatin and very little cytoplasm. Metastases were found in the bronchial, mediastinal, pcripaiicreatic and retroperitoneal lymph nodes, liver mid slrull cap.

The hilum of the right luiig of a coal miner, sisty-

(Fig. 16.)

A-1162.

seven years old, was clenscly iiifiltrated by a neoplasm which exteiided particularly along the bronchus of the lower lobe. For a considerable distance this bronchus showed complete stenosis. The pleura was extensively involved. Microscop- ical examiiiation showed a medullary carcinoma composed of small round cells with very little cytoplasm. In a few areas there was a very slight alveolar arrangement (Fig. 17), but usually even this was lacking. The resemblance to a

236 CARL VERNON WELLER

emall round cell sarcoma was especially marked in the latter case. I n the liver metastases, many of the cells werc comprcssed to a spindle shape both as to cytoplasm and nnclci.

(Fig. 18.)

nISCUSSION

Notwithstanding the fact that all of the described histo- logical varieties of carciiiomtL of the liing are iiicludecl amoiig

F I G . 17. A-1162. MFDTJLL4HY ~JNDIFFFKENTI \TED HOUND CPLL CARCINOMA

WITH HLIGIIT A~,vEoI..\R ARRANGEMENT.

the fourteen cases here summarized there is no iiistaiice in wliicli more than presumptive evidence of origin from the alveolar epithelium existed. Oiily association of tlie appar- ent area of origin with chronic fibroid pneiimonia snpportcd that possibility. Since examples of tlie most fully diffc.~eiiti- ated and of tlic lcast differentiated forms were found in re- lationship to chief broiiclii and all intermediate forms call be arrtiiiged in a logical series, it seems clear that all types

PRIMARY CAlLCINOMA O F THE BRONCHI AND LUNGS 237

of carcinoma of the lung can take origin from bronchial struc- tures.

Series of carcinomas of the lung of columnar cell origin and of squamous cell origin, as they become progressively less differentiated, converge to pass into the undifferentiated type. The same variation in degree of differentiation may exist in ditfcrciit portioiis of one neoplasm as between dif-

FIG. 18. A-1162. THE PREVAILIKG TYPE IN THE S A M E G A S E AS T H A T FROM

WHICH THE PRECEDING ILLUSTRAT~ON WAS TAKEN. Very small spherical cells with scant cytoplasiii. This type has commonly been diagnosed a small round cell sarcoma or lyniphosarcoma. Medullary uiidiff crentiated small round cell car- cinoma.

ferent members of the same series. It is evident that the histopathological picture of a particular neoplasm, or of a particular portion of a neoplasm, of this group is evidence only of the degree of entdifferentiation and should not be used to cletcrmiiie histogenesis. Apparently, qnestions of precise histogenesis in regard to primary carcinoma of the

238 CARL PEFtNON WELLER

lung caii be settled only by the fortuitous discovery of early examples in thc course of routine autopsies. This is exactly what should be anticipated from the fact that all of the epi- tlielial structures of the pulmonary tract bave a common ein- bryological parent age.

Judging by this relativcly small series of cases, the imdif- fereiitiated ccll carcinomas of the 1mig.s and hroilclii arc c:t- pable of giving rise to widely dissemiiiatccl metastases, as miglil bc expected. The more fully diffcrentiatcd columnar celled types, liowever, fall but little bcliiiid in this respcvt and usually show bone metastases by tlic time death occiws. I n the squarnons cell series those mlii(~l1 w e cnpnhlc of ex- teiisive coriiificatioii spread chiefly by locd extension aiid show oiily rcyyioiitil lymphogciious metastases until l a t ~ jii

the discme. Tliis appears l o be true, also, of the iioii-co~+iii- fyiiig mcdul1ar.y scyuamous ccll carcinomas, h i t to a less dc- grce. h hroail biologic coiicc:ptioii of the rclatioiiship of llic va-

I’ious forms of caraiiioma of tlic lung to each other as A series, in which the asccndiiig line of differentiation of par.cnt wlls itiid the descciiding h e of varying degrees of eiitdi Rerciitin- tioii rail be appreciated, seems to lie justified. Rncli a coii- ocptioii is equally useful, altho~igh not al\vays so evidently demoiistrtiblci, in coiiiicct ion with other forms of malignancy.

REFERENCES

1. WELLER, C. V.: Grncral Krvirw: The pathology of primary r:irriiioiiia of

2, LILIESWAL, H. : M:iligiiant tunlois of tlir lungs; iicccssity for eiirly o p c ~ n -

3. HENRICT, A. T.: l’riiiiary c:iiic.er of tlie lung. J. Mcd. Res., 1912, xxvi, 395. 4. KLOTZ, 0.: Cniierr of tlie lung; with B report upon twenty four rases. Cmad.

5. WELLER, C. V.: Tho pathology of certaiii s i p s and syniptoiiis i n primiry Annnls Int . Bled., 1929, ii, 725.

thc lung.

tion.

Arcli. Path., 1929, vii, 478.

Arch. Surg.., 1924, viii, 308.

M. A. Journiil, 1927, xvii, 989.

carcinoma of the lung: illuvtrativr cases.