T h e Journal of Pathology and Bacteriology

Vol. XXXIII., No. 2

616.27-006.4

PRIMARY MALIGNANT INTRATHORACIC TUMOURS.

JAMES MAXWELL. I+om St Bartholomew’s Hospital, and The Royal Chest IIos;l,ital, Loadom.

(PLATES XIX.-XXI.)

ALTHOUGH the subject of primary malignant intrathoracic new growth is accorded extremely scanty mention in the majority of standard text-books on pathology, it is really a matter of increasing importance to the clinician and the pathologist alike. It is now generally acknow- ledged that these growths are becoming increasingly frequent in this country, and this increase has recently been discussed by Guguid from Manchester, Simpson from the London Hospital, Nicholson and myself from St Bartholomew’s Hospital, and by Dunn and Powell White from six british hospitals.

It is surprising to note how common these tumours are becoming at St Bartholomew’s Hospital, no less than 14’15 per cent. of all malignant growths discovered in the post-mortem room during the past five years taking their origin within the thoracic cavity. From 1867 to 1928 inclusive, 25,227 post- mortem examinations were surveyed ; malignant tumour was found in 2981, and of these 204 arose primarily within the thorax. In the same series the stomach was primarily involved in malignant disease in 530 cases, the colon in 323, the esophagus in 313, and the rectum in 226, so that thoracic new growths were fifth in order of commonness of all the primary malignant tumours of the body, It must be remembered, however, that these figures are relative rather than absolute, for many cases of surgical malignant disease will survive operation for a time and so may never appear within the post-mortem room of a general hospital, whereas from their medical interest special efforts will frequently be made t o obtain post-mortem examinations in cases of intrathoracic tumour. It is a curious fact that during the last twenty-five years at St Bartholomew’s Hospital the absolute number of malignant growths found at autopsy has

288 Q JOURN. OF PATH.-VOL. XXXIIL

934 /. MAXWELL

remained practically stationary, partly no doubt because fewer post-mortem examinations are now being made and partly on account of the great improve- ment in the surgical treatment of malignant disease.

The series of cases dealt with in this paper is composed of 204 cases previously recorded (Maxwell and Nicholson) with the addition of those which have occurred a t St Bartholomew’s Hospital up to September 1929, and a post-war series from the Royal Chest Hospital, making a total of 239 cases in all. A paper recently published by Schuster includes some of the cases from the Royal Chest Hospital. The method of investigation employed was to read through and consider each case which was described as a primary malignant intrathoracic tnmour. Not all the cases so described were accepted as such. I n some the description was so vague that some other focus of origin could not be excluded, in others one could not rule out the possibility of a non-malignant condition such as lymphogranuloma or Hodgkin’s disease. The cases in which it was certain that the disease had originated within the thoracic cavity were then classified according to their probable site of origin; guided in the first instance by the morbid anatomical changes described, they were grouped under the following headings :-

(1) Primary bronchial carcinomata (184 cases). The standard accepted in these cases was gross involvement of a

bronchus. Either the tumour was described as originating in a bronchus or the bronchus itself was described as ‘(infiltrated ” ‘( ulcerated” or “ destroyed.” The reason for this arbitrary selection was purely empirical, yet on coming to examine sections of these cases subse- quently it was found that in each one the histological appearances were consistent with the diagnosis of primary bronchial carcinoma.

(2) Tuntours arising primarily within the mdiastinunt (37 cases). Some of these cases selected themselves, as, for instance, malignant

changes occurring within dermoid cysts. The remainder were composed of tumours which were alleged to be situated within the mediastinurn and only slightly involving the hilum or one or both lungs. On subsequent histological examination this group wa6 found to be exceedingly unsatisfactory.

(3) Primary pleural growths ( 5 cases).

These were selected entirely on morbid anatomical grounds, but subsequent histological investigation appears to confirm their nature in the three cases in which sections were available for esamina tion.

(4) The remaining 13 cases could not be classified, either because the description was couipletely inadequate or sometimes because the

MEDIAS TINA L T UMO URS 235

growth was so extensive that it was impossible t o conjecture exactly where it had originated. They will not be further considered in this paper.

Primary bronchial carcinomata (184 cases).

The average age was 464 years, the youngest being 16 and the oldest 78. The sex incidence was 140 males and 44 females, a ratio of 3.2 males to each female. These figures are substantially in agree- ment with those previously recorded by most observers. The greatest concentration of cases was found between the ages of 40 and 55, although it should be noted that the condition was found with increasing frequency after the age of 20.

Simpson found that the two sides were equally liable to be affected, and this is borne out in the present series, 93 cases commencing on the right side, 90 on the left and the remaining one a t the lower end of the trachea. The tumours usually arose near the bifurcation of the trachea and further analysis showed the following distribution :-

Riglit. Lrtft.

main bronchus . . 54 main bronchus . . 59 upper ,, . . . 21 upper ,, . . . 15 middle ,, . . . 2 lower ,, . . . 16 lower ,, . . . 16

There is thus a remarkably symmetrical distribution of the sites of primary origin on the two sides of the chest, by far the greater number of the cases commencing in the main bronchi or in their primary divisions. Only 2 cases began in the middle bronchus on the right side. I n only 2 cases was there any doubt as to the bronchial origin of a growth, it being possible that in these a tumour had originated in the lung substance, probably in a bronchiole (see below).

1. Infiltration.

On reading through the individual details of a large series of cases the first impression is apt to be one of confusion. On further consideration, however, it became clear that the cases could be classified in an extremely simple manner on an anatomical basis, for it is plain that the primary tumour may remain localised a t its site of origin, it may infiltrate the lung, it may infiltrate the mediastinum, or, lastly, it may involve both of these adjacent structures.

There may be a local tumour surrounding a main bronchus without obvious infiltration of either lung or mediastinum. This type of growth would naturally be expected to be comparatively rare, and of the 184 cases only 15 were of this type, a percentage of 8.2 The consistency was “firmy’ or “hard” in 12 of these cases and “soft”

Type I.

236 J. MAXWELL

in the remaining 3, and, by definition, infiltration of surrounding structures was minimal.

Type IT. The tumour, having arisen in the bronchus, proceeds directly to infiltrate the corresponding portion of the lung. As would be expected this proved a relatively common type, occurring in 49 cases, or 26.6 per cent. The infiltrative process was of two distinct varieties. I n the first, and commoner, the growth extended from the primary focus along the main divisions of the bronchi as a firm surrounding sheath, from to 4 inch in thickness, appearing under the mucous membrane but leaving it intact and not destroying the lung substance. Under the niicroscope this process could be seen to consist of a direct spread of malignant cells along the course of the peribronchial lymphatics, encircling the bronchi themselves in a continuous sheath of neoplastic tissue. I n the second group of cases, usually as an extension of the process just described, the lung tissue itself was infiltrated and destroyed, and under the microscope the malignant tissue could be seen replacing the alveoli themselves. I n consistency these tumours varied considerably, 7 being described as

hard,” 25 as ‘I firm,” 2 as (( soft,” and 12 as ((necrotic,” the remaining 3 cases varying in consistency in different parts of the tumour. In the necrotic tuniours and those associated with gangrene of the lung it was frequently noted that the main vascular supply to the affected part had been infiltrated or otherwise destroyed by the malignant process.

Type 111. The tumour, having arisen from a main bronchus, instead of infiltrating the lung, extends directly outwards into the mediastinal tissues. This is a difficult group of cases to sort out, for many of them had been accepted on pathological grounds as examples of primary mediastinal tuniour. It is, however, one of the objects of this paper to show that in cases where a main bronchus is grossly involved in malignant growth the tumour is of the nature of a bronchial carcinoma and this hypothesis is borne out by the results of the microscopical sections examined. Thirty-six cases of this type were discovered, a percentage of 19.6, although subsequent investigation showed that some of the tumours accepted as arising primarily in the mediastinurn should probably have been included in this group. In all of the cases of this type there was infiltration, usually of a main bronchus, with‘attachment to a mass in the mediastinum, frequently described a3 being in the situation occupied by the remnants of the thymus. A t other times the mass was found to lie in the middle part of the mediastinurn, infiltrating the pericardium, the heart and occasionally the esophagus and spine. The masses produced by this process of infiltration were carefully distinguished from glandular enlargements, the result of metastasis, which will be considered in a later section. It was a most striking feature in all of these cases,

MEDZASTZNAL TUMOURS 237

some apparently arising primarily in the mediastinum, that the description expressly mentioned infiltration of the hilum and main bronchus orb one side only, the opposite hilum being stated not to be involved in growth: it is difficult to understand why, if these growths had really originated in the mediastinum, this curious selective type of infiltration should have occurred. As would be expected from experience in the post-mortem room these tumours were found to be firm rather than soft; 12 were classed as “hard,” and 15 as “firm,” whereas only 5 were classed as “soft” and one as “necrotic,” the remaining 3 being of variable consistency.

Type IV. I n tumours of this group infiltration, starting in the main bronchus, spread into the surrounding lung tissue and also into the mediastinum. As would be expected, this was the largest group, containing 84 cases or 45.6 per cent. Infiltration of the lung and mediastinum was found to correspond exactly to that already described in the separate cases of types I1 and 111, showing that this type of tumour is merely a combination of the preceding two varieties. Similarly the consistency is a combination of the characters of the other types. I n 20 the entire tumour was described as “hard,” in 3’7 as “firm,” in 11 as “soft,” in 6 as “necrotic,” in the remaining 10 cases the tumour varied in consistency but in the majority of these cases it was found that the portion of tumour invading the lung was the portion which wfis soft, whereas that part in the mediastinum was of firmer consistency.

The effects of infiltration of mediastinal structures have been analysed in detail. Gross vascular disturbance occurred in 37 out of the 120 cases of types I11 and IV. I n these, the face and arms were cedematous in 5, both arms in 2, thearm on the affected side in 6 and the opposite arm in one. The lower half of the body was cedematous in 13 cases. The causation of this cedema was usually obstruction to the great veins by permeation of their walls by neoplastic tissue, although in 6 cases ante-mortem thrombosis had occurred. The euperior vena cava was grossly infiltrated in 25 cases, the left innominate vein in 4 cases. With regard to the remaining mediastinal structures the heart and pericardium were most frequently involved, infiltration being noted on 40 occasions, the cesophagus was involved in 25 cases, and the aorta in 20, while the pulmonary artery was obstructed in 14. The remaining structures were less frequently involved but the chest wall was infiltrated by direct spread of growth 15 times and on 3 occasions the growth had completely perforated the intercostal spaces, appearing as a mass on the outer aspect of the chest,. Nervous involvement was probelily iiot noticed as frequeiitly as i t occurretl, although thc recurrent laryiigeal nerve was recorded as being iiifiltrated 14 tiiiies, tho left vagus once and the right phrenic twice.

Q 2 JOURN OF rt.m.-voL. XXXIIX.

238 J MAXWELL

2. Metastases. Secondary deposits were found in the great majority of the cases,

the spread usually occurring by means of the lymphatic channels. The cases were divided up approximately according to the extent of metastases and the result were as follows :-

1. No deposits . . 14 cases 2. Few deposits * 95 ,?

3. Multiple deposits . . 75 ))

The dividing line between the groups classed as having few and multiple deposits was difficult to draw, but cases in which the mediastinal glands were involved together with perhaps a few small deposits in one other organ were classed in the former group, whereas any cases showing more deposits than this were classed in the group of multiple deposits. In 164 cases there were deposits within the chest distributed as follows :-

mediastinal glands . lung on the affected side lung on the opposite side bothlunge . pleura on the affected side pleura on the opposite side pleura on both sides . heart and pericardium thoracic wall . diaphragm . spinal cord . mophagus .

. .

In all of these cases the deposits were in direct lymphatic connection with the site of primary growth and the connection was ObviOUs, and this same connection could also be shown to exist in the cervical and abdominal deposits in the majority of cases. The cervical glands were affected altogether in 45 cases, those on the same side as the primary tumour being involved in 24 cases, those on the opposite side in 6, and those on both sides in 15 cases. Nodules were found in the thyroid gland in 4 cases. Abdominal deposits were found in altogether 112 cases, and in the majority i t was noted that the lymphatic glands in the upper part of the abdomen were occupied by deposits, a s were also those glands situated in more direct relation to the affected organs; it is reasonable to assume froin this that the metastases in these organs had occurred as a result of lymphatic spread from the chest to the upper abdominal glands and thence to the final site of deposit. The chief sites of abdominal metastases were as follows:-

MEDIASTZNAL TUMOURS

abdominal glands liver . right kidney . left kidney . both kidneys . right suprarenal left suprarenal . both suprarenals pancreas peritoneum . spleen . ileum . ovary . uterus . stomach.

239

With regard to other sites in which the dissemination occurred, presumably as the result of lymphatic spread, the axillary glands were found involved on the same side in 5 cases and on both sides in 3, while nodules were found in the chest wall in one case and in the lumbar muscles in another. I n organs and structures distant from the side of priniary growth it is clear that a blood stream dissemination must have occurred and these organs were found to be affected as follows :-

brain : right side . left side . both sides

bones : right femur ilium . clavicle . skull , sternum .

4 cases 3 19

9 99

3 1 1

1 99

1 case

J1

2 cases

Complete examinations were not made in all cases so that these figures are certainly an underestimate. Diffuse nodules were found in the skin and subcutaneous tissues usually of the trunk and abdomen in 6 cases and the inguinal glands were twice found to be involved.

A further analysis was carried out to discover whether the site of origin had any relation to the site of secondary 'deposit. The cervical glands were involved usually when the growth originated in the main bronchus, and not more frequently in association with growths arising from an upper rather than from a lower division of a bronchus. The abdominal deposits were found to occur with every variety of primary growth, being just as frequent when the primary was in the upper as in the lower division of the bronchus. Cerebral deposits almost invariably occurred when the primary growth arose in the main bronchus and it was found that they arose equally commonly on whichever side of the chest the priniary focus was situated.

240 1. MAX WELL

3. Associuled lung conditions. Pneumonia. Consolidation of the lung waR found ill 57 cases,

pneunionic in type in 18, broiicho-pne~iiiionic in 39. Lung abscesses occwrecl 38 tinies and gangrene 15 times ; there was no demonstrable preponderance in the side affected. With regard to the morc chronic complications, bronchiectasis was found in 65 cases, 34 on the right and 31 on the left. Fibrosis was noted 13 tinies and did not appear to be of significance in the aetiology of the condition.

Ewing and some of the german writers have stated that tuberculosis is the commonest cause of pulmonary cancer. This statement is not borne out by Schuster nor does it find any support in the present series of cases : evidence of old and healed tuberculosis or tuberculous scarring was noted only in 15 cases and active tuberculous lesions were demonstrated in a further 10 cases. Syphilitic lesions were noted only in 5 cases and it cannot be held that this disease has anything to do with the Etiology of bronchial carcinoma.

4. Associated pleural conditions.

Clear effusion wa.s not noted so frequently as would have been expected, being found on the same side as the growth in 18 cases and on the opposite side in ’7 cases. Blood-stained %uid was found on the same side as the growth in 17 cases only. Enipyema was recorded 23 times and pyopneumothorax twice. A curious and possibly significant feature in pleural involvement was however noticed. The records frequently stated that (‘dense old” adhesions were present on the same side as the malignant growth, and on investigating this matter further it was found that such adhesions were present in 105 out of 184 cases. From specimens personally observed it would appear that in the majority of cases these adhesions are older than could possibly be accounted for by the apparent age of the growth unless there were also extensive infiltration of the pleural surface. Yet it was found that in only 25 of these 105 cases was there obvious macroscopical evidence of neoplastic infiltration. This observation leads to an interesting speculation. I n view of the attempt made by some authors to associate bronchial cancer with preceding inflammatory chest disease it is a t least possible that such inflammatory disease, by causing pleiiral adhesions, tends to limit the movement of the lung on the affected side. If now it be correct that some inhaled irritant is a definite exciting cause of bronchial cancer then it would seem a t least possible that some limitation of movement would predispose to a concentration of such irritant on one side and thus determine the starting-point of a malignant change.

JOURNAL OF PATHOLOGY.-Vor.. X X X I I I .

TlJMOUltY OF LUNG

PLAT12

PIG. I.--Normal large broiiclius : secreting glandular tissue underneath mucosa.

FIG. 2.-SS:iine section : norinal mucos:i : twn layers of transitioid c*oIumniLr epitheliurri.

PIG. 3.-Sanie section : place where coluriinar epitheliuni has been accidentally detached.

JOURNAL OF PATHOLOGY.-VOL. XXXIII.

r . ~UBIOURS OF LUNG

PLATE XX

FIG. 4.-Typicd columnar-celled bronchial carcinoma : variation in shape and size of cells.

FIG. 5. --Squamous-celled carcinoma : other parts of this growth were columnsr-celfed.

FIG. 6. -Columnar-celled carcinoma showing alveolar arrangement and mucoid secretion.

JOURNAL OF PATHOLOGY.--VOL. XXXIII.

ir..rJlolrlls o1 l . ~ ' s G

PLATE XXI

FIG. 8.--Saiiie tiinioiir : col~rr~~n:tr-looki~ig cclls on oiiter edge of iiiiiss.

PIG. 9. --Srnnll-celled carcinoma of looser texture with less fibrous tissue.

MEDZASTZNAL TUMOURS 24 1

5. General changes. lV(&ing is not a siarkecl feature. According to the notes, in

’1’7 cases there was no wwiting, in 39 the patient was noted to have heen thin, in 56 the patient was described as wasted, and in only 12 was the wasting sufficiently extreme to be described as emaciation. There were few other general changes recorded, although clubbing of the fingers was noted in 5 cases and hypertrophic pulmonary osteo- arthropathy once. I n one case also a pathological fracture of the femur occurred. Terminal jaundice of an obstructive type was present in 9 cases, the glands in the portal region being involved in 5, while in the remaining 4 the liver itself was almost replaced by enormous masses of secondary growth.

With regard to the actual cause of death, analysis showed that this was extremely variable, lobar pneumonia occurring in 18 cases, pleurisy and broncho-pneumonia in 39, abscess in 38 and gangrene in 15. In 18 cases toxic absorption from an empyema appeared to be the final cause of death and two of these were associated with lung abscess. Two cases died as a result of hemorrhage from a large branch of the pulmonary artery which had been perforated by an extension of the growth. I n the remaining cases the cause of death wa8 either obscure or not directly connected with the chest lesion, being partly the result of cerebral compression in ’7 cases and of heart failure with pericarditis in 4. Occasionally it was found that the cause of death had nothing to do with the malignant disease in the chest, e.9. a perforated non-malignant gastric ulcer and a ruptured abdominal cyst of uncertain nature.

6. Microscopical appearances. The chief divergence of opinion on the subject of primary intra-

thoracic growths is centred around the histological appearances of what is known as the “oval-celled” or “oat-celled” tumour, and it is only recently that the true nature of this group of tumours has been determined.

It is interesting to note the complete reversal of opinion which h a occurred within the last forty years. In the histological reports of the older cases from the earliest time at which such reports were added to the notes, these growths were described as carcinomatous. Such cases were recorded by Percy Kidd in 1883, while R. F. Jowers, writing in 1887, discusses the. nature of bronchial growths and states that of the cases recorded in the medical journals of the time only one is classed as a sarcoma, the remainder being described as encephaloid cancer. In the earlier years of the present century it became customary to divide intrathoracic new growths into two varieties : obvious carcinomata, composed of columnar or syuamous cells, and a large group of tumours composed of smaller cells which were variously described as “ alveolar ” “ spindle-celled ’’ or “oval-celled ” sarcomata. Thenceforward, until the year 1926, all the tumours of this type were commonly recorded as sarcomata. In 1926, however, Barnard published a classical paper in which he brought forward convincing evidence in support of the view that all the tumours which spring from the bronchi are

242 /. MAXWELL

essentially of similar nnturc, being in reality varieties of carcinoma. He found that the small-celled tumours (which hc termed “ oat-celled ”) consisted mainly of cells arranged in an acinar manner. Cells other than small oat cells could be found and in the majority of them the other cells were numerous. The commonest additional cells were large, oat-shaped, spindle and polygonal cells with occasional multinuclear giant cells. Large polygonal cells indistinguishable from cells of epithelial origin, were seen in the nujority of tumours. I n some cases large oat cells were clumped together, each clunip surrounding R central spacc as though attempts were being made to form tubulcs. Barnard concluded that tho small- celled tumours were in reality true carcinomata. I n his survey of the Aberdeen cases Shennan agrees with this interpretation. Simpson summarised the evidence in favour of this same conclusion without giving exact statistical details. On the whole he found that the intermediate forms were more various, yet tending in places to convey a more typical appearance of carcinoma. He stated that their classification as carcinomata depends partly upon the absence of formation of intercellular fibrils, or any other matrix, but chiedy upon the fact that careful examination of many sections will reveal small areas in which the cells have definite epithelial characters or in which the cells tend to take on a definite epithelial arrangement. H e also makes the significant statements that ‘(the arrangement of the cells may even resemble that of the deeper layers of the bronchial epithelium,” that the typical oat cells are frequently present in sections of an obvious and accepted bronchial carcinoma, and that a secondary deposit from a large celled tubular or squamous primary growth may consist entirely of small oat cells. Schuster accepts these arguments as being adequate and discusses the various types of tumour which may be found.

I n the present series 102 sections were discovered from the cases belonging to this group. In addition, reports of columnar or squamous- celled carcinoma were found in 9 cases although the actual sections could not be examined: these have been included in the series as there seems no reason to doubt the accuracy of the diagnosis. In 18 other cases the reports stated that the growth was an “alveolar” celled, I‘ spindle ” celled or (I oval ” celled sarcoma, and although it would seem justifiable to assume that these cases were really examples of the oat-celled tumour, yet as the sections could not be fonnd they have been excluded. The total number of cases for description under the heading of histology is therefore 111: 47 showed the characters of obvious carcinoma and 64 the characters of the small oval-celled tumour.

Among the obvioiu carcinontata the characteristic tumour is a columnar - celled carcinoma (fig. 4) : this clearly arises from the bronchial mucous inernbrane. Search among several sections from the same turnour or from its metastases frequently shows irregular and atypical forms of cell which may be polygonal, spherical or even characteristic of B squamons-celled carcinoma (fig. 5). In a few instances (’7 out of the 47 under discussion) the tumour appeared to be mainly composed of squamous cells, yet in all of these search showed some region where the coluxrinar structure was evident. I n 4 cases the growth appeared to consist chiefly of spheroidal cells; the presumable site of primary origin in this case is the glandular

MEDIASTINAL TUMOURS 243

tissue composed of similar cells to be found beneath the mucous membrane in all the larger bronchi and illustrated in fig. 1. In all cases it was found that considerable variation in the tumour cells occurred in various places and the findings of Barnard were confirmed, cubical, spindle and small oval cells being repeatedly seen in sections of the primary growth or of its metastases.

Both were examples of type I1 and macroscopically presented a curious gelatinous appearance. The microscopical appearances are illustrated in fig. 6. The structure of the growth is roughly that of the lung itself, in other words, there are well-marked alveoli lined by tall columnar epithelium and filled with a mucinous material. The findings in one of these cases, a man under my care at the Royal Chest Hospital, have been previously described in detail by Schuster. From their general structure it might be suggested that these tumours had arisen from the alveolar epithelium, though it is difficult to believe that the unusually tall and columnar epithelium has arisen from the normally flat cells which line the alveoli. I n two other cases of the series a similar attempt at alveolus formation with secretion of mucin was found; in one a portion of the primary growth had undergone this change, in the other a metastasis in a mediastinal gland. It would appear, therefore, more likely that the primary site of origin in these cases was the columnar epithelium lining a bronchus or more probably a bronchiole, and that they are of essentially the same pathological origin as the other tumours in this series.

Two cases represent a type of tumour found rarely in the lung.

The remaining 64 cases can all be included in the group of small- called tumour. These could be roughly divided into two classes, one in which the cells were closely packed with fairly well-marked fibrous stroma, the other in which the cells were much more loosely arranged and the fibrous tissue was less evident. The first group was the commoner, being the predominant arrangement in 37 of the cases (figs. 7 and 8). The cells were oval, with, in places, a rectangular outline strongly suggestive of small columnar cells but in point of size quite distinct from the latter. Although closely packed in masses each mass was distinct and the cells a t the margin were sharply defined as if lying on a basement membrane. Thc whole appearance was very Suggestive of a basal-celled carcinoma. The blood vessels were always well formed and quite unlike those commonly found in sarcoma. A t the same time it was frequently noted that in other portions of the tumour, sometimes even in the same section, the masses were less distinct and the cells were widely separated, while in yet other places there were longer spindle-shaped cells and quite frequently isolated cell formations which could not be distinguished from those origiiiatiiig in an epithelial rncmbrane. It is curious to note that although these tuiiiours werc for so long regarded as sarcomata yet every now and then in the reports we find references to the appearance of epithelial cells, and on one occasion in the Royal Chest Hospital series a tumour of this type was recorded as a “carcino-sarcoma.” 111 27 caserJ the predoininaiit structures of the tumour wcre much

244 J. MAXWELL

looser (fig. 9) corresponding roughly with the macroscopical structure found. The cells in these were small and rounded or oval and the basement nieinbrane not so well defined. The blood vessels were still well formed and in places the appearances described in the commoner group of tumours could be discerned. In all tumours of this type where there were masses of elongated cells it was only to be expected that other masses of partly round cells would also be found: this appearance is clearly due to the fact that in some cases the masses are cut longitudinally, whereas in others they are cut transversely.

Although the evidence already quoted that these tumours are really carcinomatous should really be sufficient, two other points may be brought forward. The exponents of the sarcomatous theory of origin are bound to conclude that in the majority of cases the primary focus is in the mediastinurn, yet beyond this very vague site of origin no more definite view can be expressed. An analysis was therefore carried out on these 111 cases to see whether the general behaviour of the tuniours, from the point of view of morbid anatomy, differed in the two groups. Firstly, with regard to type, should these oat-celled tumours arise primarily in the mediastinum it must be regarded as a strange coincidence that they exhibit such a tendency to infiltrate the hilum of the lung, and this tendency is still more astonishing when we consider that in all of these cases only one hilum was affected. It would seem probable that if these turnours arose in the mediastinum and infiltrated the liilum secondarily, then we should find that the oat-celled tumours preponderated in types 111 and IV in which alone mediastinal infiltration was marked, whereas obvious carcinomata would be found chiefly in type I1 where the lung only was involved. In fact, the oat-celled tumours preponderated in all types :-

L' Obt ious,, Oat-cnllal corciiiomi. turnour. Tumourb of

Type I . . . . , 3 7

,> 111 . . . . . 8 12 ,, 11 . . . . . 18 19

Iv . . . . . 18 26

47 64 - -

The other characteristic feature in which carcinoma in general tends to differ from sarcoma is the consistency, the latter being usually softer, especially when it takes its origin in a loose connective tissue. Investigation of the cases from this point of view yields the following result :-

"Obvrrn1n Slllrlll-Ll.lllYl ~ ~ i c i i l u n ~ ~ . " ~ I I I J I O I I I .

coll~l\terley.

Firm or l i ~ r d . . . . 31 44 Soft or iiecrotic . . . 16 20

There is no approciable cliflcroncc iii the uonsisloncy of the two It would appear, therofore, that in all cases there is types of turnour.

MEDIASTINAL TUMOURS 24 5

a similarity of character between all the tuiiiours in this group, and the assumption which appears justifiable in the circumstances is that all these tumours arise in the same situation and that that site of primary origin is the bronchial mucous membrane. Further comparisons were carried out concerning the other characterislics of the various types of tumour and it was found that there was no macroscopic character by which the tumours could be differentiated, in other words, it is impossible to say a t a post-mortem examination to which type the predominant cell will belong.

Although, however, the evidence for the carcinomatous nature of the oat-celled tumour may be regarded as convincing, yet the very striking differences in general histological appearance between the two main types is such as to make it impossible to believe that they arise from precisely the same cells. It is obvious that the ordinary carcinomata arise from the columnar lining of the bronchial mucous membrane. If we consider the normal histological appearance of the bronchial mucous membrane (figs. 2 and 3) it can be seen that beneath the superficial layer of ciliated columnar epithelium there lies a layer of cells smaller in size which appear rounded or oval according to the manner in which the section is cut. This layer of cells can be well seen in the trachea and the larger bronchi, and it can also be traced into the smaller bronehioles, even those of less than a millimetre in diameter showing a complete layer of basal cells. The exact point a t which this layer is lost is not certain although it is definitely not present in most of the bronchioles of microscopic dimensions. These cells are remarkably similar to those found in the oat-celled tumour and fig. 3 shows well their main characteristics. This section was taken from the same block of tissue as was that illustrated in fig. 2 but the layer of columnar epithelium has become accidentally detached and the outlines of the basal cells can be seen in a manner impossible when they are closely overlaid by the superficial layers. Occasionally in sections from the main bronchi larger cells can be seen growing up from this basal layer between the true columnar cells. These are usually spindle in shape and their apparent Taison d’ettre is to replace the columnar lining cells when these become detached in the normal processes of nature. It is thus seen that the normal bronchial mucosa contains in itself cells of all the shapes and sizes which are found in the different varieties of tumour, and the conclusion becomes almost inevitable that these different types of cell give rise to the different main types of primary growth. At the same time this also explains the reason why intermediate forms are found in nearly every section : it may be noted in passing that it is far more common to find the oat- celled tumour attempting to form columnar cells than.it is for the columnar-celled tumour to revert to the oat-celled type. It may also be noted that in many of the small-cellcd tumours no actual ulceration of the bronchial epithelium could be found : thickening of the tissues,

246 J. MAX WELL

raised, flattened patches and occasionally even papillomatous outgrowths could be demonstrated and these appearances of themselves are very suggestive of the similar cutaneous manifestatione commonly met with in some stages of rodent ulcer formation.

It may be asked why such a distinctive tumour as the oat-celled carcinoma should arise only in connection with bronchial epithelium and not in any other mucous membrane also lined by columnar epithelium. The answer to this lies in the anatomical structure already described : in the intestinal tract, the other extensive mucous surface lined by columnar epithelium, the cells lie directly upon a basement membrane with no interposition of a deeper layer of smaller parent cells. The explanation of this stratification and of the appearance of stratified squamous epithelium from the bronchial mucosa would appear to be one of embryology. In the developing embryo the primitive lung bud can be found in the fourth week springing from the groove in the floor of the primitive pharynx and esophagus, from the hypoblastic layer behind the ventral end of the sixth arch. The mucous membrane of the respiratory system is therefore originally derived from stratified squamous epithelium and its transition to a membrane lined by columnar epithelium has taken place at a slightly later stage of development. It would seem, however, that some of the primitive characters of the original epithelium have been retained. This helps to explain why it is that there is such a tendency for squamous metaplasia to occur either as a sequence to inflammation or in a primary columnar-celled tumour, and abolishes the necessity for the assumption of the existence of squamous cell rests.

Mediastinal tumours.

This group was composed of 37 cases in which there was a mass lying in the mediastinum and not obviously connected with the main bronchus. The majority of these cases dated back to the earlier years and with the advances of pathological technique fewer cases are being recorded each year. The site of primary origin was determined according to the anatomical structure of the parts affected and could be classified as follows :-

Anterior superior mediastinum . . 16cases ,, mediastinum . - 12 ,,

Middle and posterior mediastinum - 5 ,I

Pericardium . . 2 9,

Dermoid cysts . 2 I ,

The tumours in the anterior superior mediastinum were usually stated to have arisen in the thymus gland and those in the anterior and posterior mediastinum were thought to have originated in lymphatic glands. The evidence that two cases had arisen in the pericardium was entirely unconvincing ; both occurred before the period of accurate histological diagnosis, the sections cannot now be traced and they will not be considered further in this paper. The main anatomical features of the remaining tumours were those of obstruction to the more important thoracic contents. The mode of death was by pressure and asphyxia in at least 16 of the cases, and was doubtful, but possibly of similar nature, in 11 of the remainder.

MEDTASTINAL TVMOVRS 247

Five died as the result of malignant cachexia, 2 with heart failure and pericardial effusion, and only 2 with lobar pneumonia. I n one case death resulted independently from perforation of a gastric ulcer. There is thus a considerable difference in the mode of death in this type of malignant disease as compared with that occurring in primary bronchial carcinoma. The superior vena cava was obstructed in 15 cases, the aorta in 12, cedema of the face and arms was noted in 10 cases, and of both arms only in 2. Infiltration was a fairly well marked feature, the heart and pericardium being involved in 19 cases, the chest wall in 12, with perforation to the extrathoracic parietes in 4. Of the other structures the trachea was infiltrated in 5 cases, the czsophagus in 4, ths right lung was stated to be infiltrated in G and the anterior margins of both lungs in 5, although subsequent investigations rather tended to the conclusion that those cases in which the hilum of the lung was stated to be slightly involved were more probably primary bronchial tumours. Secondary deposits were noted in the same way as in the series of bronchial carcinomata. It was found that there were no deposits in 5 cases, few deposits in 21 and numerous deposits in 16 : the majority occurred in mediastinal glands (15 cases), cervical glands (20 cases) and abdominal glands (13 cases). The remaining structures which were noted to be involved in secondary deposits in bronchial carcinoma were found to be involved in similar proportion in this series; the brain was found to be affected in only one case.

Unfortunately it was only possible to discover sections in 21 of these 37 cases and on examining them it was found that 12 cases were carcinomata-5 obvious columnar-celled carcinomata and 6 oat- celled tumours. This proportion, so similar to that recorded in the bronchial carcinoma group, leads strongly to the suspicion that these 11 cases were really primary bronchial carcinoma and that the mediastinal tuniour was either an infiltration outwards from a small primary focus in a main bronchus (in other words a carcinoma of type 111) or that with a small unnoticed primary focus in a bronchus there had been extensive metastases in the mediastinal glands. The remaining carcinoma occurred in a dermoid cyst. I n 8 cases the section showed a definite sarcoma and it is noteworthy that these were all cases in which the anterior or posterior mediastinal glands were stated to be those primarily involved. Srriall round-celled sarcoma was found in 3 cases, large round-celled sarcoma once, lymphosarcoma twice, and a iiiixed-celled sarcoincz twice. In none of these cases was there the least degrec of resemblance to tho tuniour described under the heading of bronchial carcinoma ; in all the appearances were typical of those described under the heading of sarcoma in general. Two sections remain: in each the malignant change originated in a ciermoid cyst of the niediastinum. In both the liistological picture was coiiiposite Lnt in one the changes of carcinoma predomiiiated ;

248 /. MAXWELL

the other showed much more evidence of sarcoma. It will be seen that there was no evidence which would suggest an important group of tumours arising primarily in the anterior and superior mediastinum in the region of the thymus, and in none of these cases was it possible to be sure that any malignant new growth had arisen in remains of this gland. It follows, therefore, from this histological analysis, that until the microscopical appearances of a tumour have been examined it is not safe to predict either the site of origin or the probable histological nature of the growth ; it is only on microscopical examination* that any case of tumour arising apparently within the mediastinum can be regarded as proved, and it is because this group has proved on this examination to be so heterogeneous that a fuller description of the various pathological findings has not been recorded.

Tumoure originating in the pleura.

Thesc are rare growths and only 5 examples were found in the whole series of 239 cases. I n each of the 5 there was good morbid anatomical reason for classification under this heading. I n each the growth involved the pleural cavity on one side only, arising three times from the right side and twice from the left. The lung was definitely stated not to be involved in growth although infiltration of the diaphragm occurred in 3 cases, in one of which actual perforation with direct spread into the liver was noted. The ages were very variable, the youngest being 12 and the oldest 79 years of age. Secondary deposits were not a prominent feature, the left suprarenal being involved in one case, the pericardium in one, the mediastinal glands in 2 and the liver in 2 cases. On the whole these turnours did not appear to be very malignant and death occurred from compression of the lung and pleural effusion in most iof the cases. Sections were found in 3 of these 5 cases, in 2 of which the growth had the microscopical characters of an endotheliome, in the other of a mixed-celled sarcoma.

Summary. A series of 239 cases of primary malignant intrathoracic tumours

is discussed and the histological appearances are recorded in 135 of these cases.

Primary bronchial carcinoma was found to occur lin 184 cases. The chief morbid anatomical findings are described and the micro- scopical findings in 111 cases are discussed; reasons are given for accepting all of these cases as carcinomata in two main groups, an obvious columnar-celled group wi tli a tendency to squaiiious metaplasia a i d a small oval-celled group which is slightly commoner.

The oval-celled carcinomata are discussed in detail and reasons * Duguid and Kennedy (this Journal, vol. xxxiii. p. 93), record one, possibly two,

c_ - - - - - -- __ - - .- - -

oat-celled tuinours arising from mediastinal tissues.

MEDlASTINAL TUMO URS 249

are given for the conclusion that they spring from the basal layer of the bronchial epithelium. It has not been shown that any of the tumours in this series arose directly in the epithelial lining of the pulmonary alveoli.

The mediastinal tumours are shown to be a heterogeneous group, some being the result of infiltration or metastasis from a small primary bronchial focus, others being accepted as sarcomata arising in the mediastinal glands. No conclusive evidence could be found to show that any arose within the thymic remnants.

Primary pleural tumours are shown to be a rare but well-defined group and are briefly discussed.

In conclusion, I wish to express my thanks to Prof. E. H. Kettle, of St Bartholomew’s Hospital, and to my colleagues on the staff of the Royal Chest Hospital, particularly Dr N. H. Schuster, the pathologist, for affording me access to the records and sections of the cases, as well as for advice and assistance in many other ways.

REFERENCES.

BARNARD, W. G. . . . . . this Journal, 1926, xxix. 241. DUGUID, J. B. , . . . . . Lancet, 1927, ii. 111. DUGUID, J. B., AND KENNEDY, this J o u r d , 1930, xxxiii. 93.

Du”, J. S., AND WHITE, C. P. Report of International Conference on Cuncer,

JOWERS, R. F. . . . . . . St Bart.’s Hosp. Repts., 1887, sxiii. 231. KIDD, P. . . , . . . . . Ibid., 1883, six. 227. MAXWELL, J., AND NICBOLSON, Ibid., 1929, lxii. 204.

SCHUSTER, N. H. . . . . . this J o u r d , 1929, xxxii. 199; J . State hfed.,

SHENNAN, T . . . . . . . . this Joiwnal, 1928, xxxi. p. 365. SIMPSON, 8. L. . . . . . . Quart. Journ. Meed., 1929, xxii. 413.

A. M.

London, 1928, p. 400.

W. A.

1929, xxvii. 270.

Faulds (J. Hygiene, 1930, xxk. 362) finds no definite increase of cancer of the lung in recent years at the Claagow Royal Infirmary.

JOURN. OF PATfL-VOL XXXIII. R