a contribution to the pathology and clinical features of primary malignant disease of the pleura

A CONTRIBUTION TO THE PATHOLOGY AND CLIN- ICAL FEATURES OF PRIMARY MALIGNANT DISEASE OF THE PLEURA.

By THO,W HARRIS, M.D. (Lond.), F.R.C.P., Physicim to the rllnnchester Royal In$rmary ; Consulting Physician to the Manchestel. Hospital f o r Consumption and Diseases of the Throat and Chcst.

PLATE XIV.

THE pleura is one of the unusual situations where even cbpparently malignant disease has taken its origin ; in other words, where the pleura appears to be the primary seat of the growth. I have used the word apparently in this connection, because, although the pleura niay be affected with a malignant growth in such a way that it appears to have probably arisen there, it is quite possible that the appearances are misleading, and that although the pleura is the only seat where a malignant growth is found, or the chief seat of the growth, the primary seat may have been elsewhere and may, for various reasons, have escaped detection even after a careful post-mortem examination.

The two following cases I had an opportunity of seeing during life, and of examining after death. Each case I regard as one of primary malignant disease of the pleura, and after relating the history and pathological appearances of the two cases, we will consider what is the present state of our evidence in favour of and against the theory of the development of malignant growths of the carcinomatous type primarily in tissues of mesoblastic origin such as the pleura.

PRIMARY CARCINOMA OF THE PLEURA. CASE 1-M. M., a charwoman, a?t. 58 years, was admitted to the Nan-

Chester Royal Infirmary on 6th August 1891, and died two days later, on 8th August 1891.-She gave the following history :-

About 14 months before admission she began to feel weak, and too unwell to do her work. Since that time she had been gradually getting weaker. About 11 months ago she began to be troubled with shortness of breath on even slight exertion, such as going upstairs. Between 3 and 4 months ago she experienced a pain of a stitch-like character in the right side. Until 14 months ago she had always enjoyed good health.

MALIGNANT DISEASE OF THE PLEURA. 173

The family history was unimportant. The condition on admission was briefly as follows :-She was a thin, pale woman, and complained chiefly of breathlessness. The dyspnoea, however, as she lay quietly in bed was not very marked. The whole of the right side of the chest from apex to base, both back and front, was absolutely dull. All over the same side there was weak respiratory murmur and absence of vocal fremitus. The dulness extended as far as the left border of the sternum, and the heart’s apex beat was displaced downwards and towards the left. I introduced the needle of an exploring syringe into the chest just below the inferior angle of the right scapula. The pleura appeared to be very thick and very hard, and I remarked upon the fact at the time. A syringeful of perfectly clear pale yellow fluid was withdrawn.

Regarding the case as one of chronic pleurisy with much effusion, I requested the house physician to withdraw the fluid that same afternoon. On my next visit to the Infirmary, I was surprised to learn that the resident had only been able to withdraw about an ounce of fluid from the chest, and that the following day the patient had died.

I subsequently learnt that the patient had been in the Infirmary 2 months previously, under the late Dr. James Ross. A t that time the notes state that there was complete dulness all over the right side, both anteriorly and pos- teriorly, with weak respiratory murmur and diminished breath sound over the same area. On two occasions, at an interval of 6 days, a small quantity of fluid was withdrawn from the chest,-on the first occasion it being “like blood,” on the second perfectly clear. The diagnosis then made was “ pleurisy with effusion,” and the patient had left the Infirmary at her own request, after being in 3 weeks. She was discharged as being relieved.

The autopsy was made on 10th August 1891 by Mr. Warrington, who was iindertaking the pathological work in the absence of the pathological registrar.

The body was that of an adult female, considerably emaciated. Rigor mortis was marked in the lower extremities, feebly so in the upper limbs.

Tl~orax.-On attempting to open the thorax in the usual manner, the posterior aspect of the sternum and of the costal cartilages on the right side was found to be adherent to a subjacent growth, which subsequent examination showed to arise from the pleura of the right side.

Pleura-The right pleural cavity was entirely obliterated, unless a small oval cavity, 2 3 in. x 2Q in. x 14 in., which existed at the lower and posterior aspect of the chest, could be considered the remains of the pleural cavity of that side. It was evident that it was from this cavity that I had drawn the syringeful of clear fluid the day before the patient died.

The right lung was everywhere firmly adherent to the chest wall by means of the new growth which covered and everywhere concealed it. On account of the intimate connection of the right lung with the chest wall, at all parts, very great difficulty was experienced in removing the organ from the body. This was only accomplished after fully half an hour’s labour, the growth having to be cut away from the chest wall, and the diaphragm removed with the lung and the growth. It was quite impossible, by means of the hand alone, to strip the growth from the chest wall to which it was SO intimately united.

When the right lung and its complete capsule of growth had been removed from the body, an incision was made from the apex to the base of the conical inass, from the postero-lateral aspect of the lung towards the hilus of the organ (see Illustration).

It was then seen that the right lung was completely encapsuled by a mass of firm white new growth. The growth covered the whole lung from apex to base and on its costal and mediastinal aspect. The interlobular pleura was also invaded by the new growth, and everywhere thickened. The lobes of

176 THOMAS HARRIS.

the lung were bound together by a layer of new growth, which between the lobes was generally one-eighth of an inch in thickness, but in some parts attained one-fourth of an inch in thickness, especially where the thickened interlobular pleura joined the more thickened and united pulmonary and costal pleura.

Over the diaphragm the growth was the thickest. At that part the growth varied from 1 in. to 2 in. in thickness, at the apex of the lung it was 1 in. in thickness, whilst about 3 in. below the apex it reached its thinnest measurement, it being there half an inch ; but this measurement was only maintained a very short distance, as immediately below it was three-quarters of an inch thick. The growth on the inner aspect of the lung was about the same thickness as that over the apex and the outer aspect of the organ. As before stated, there existed over the lower and posterior aspect of the lung a cavity in the growth, of oval shape, and measuring 2$ in. x 22 in. x 14 in. The wall of the cavity on the costal aspect was half an inch thick, and separating it from the lung was a thinner layer of new growth which varied from one-eighth of an inch to a quarter of an inch in thickness. The inner surface of the cavity was smooth, and the cavity contained a little thin clear yellow fluid. The growth was very firm and hard throughout. It was white, and extending throughout it in all directions were white, coarser, and finer trabeculae, like bands of fibrous tissue. There were no signs of softening at any part of the new growth.

The right lung thus encased in the growth was compressed, but still contained air. It was not infiltrated by the growth, which simply formed a capsule to the organ like an enormously thickened pleura. At one or two points, however, the growth extended about a quarter of an inch into the lung substance, but even at such points the appearance was rather that the growth pushed the lung before it than that it truly infiltrated the organ. There was likewise no extension into the lung from the hilus along the course of the bronchi, such as is frequently the case in mediastinal tumours, no enlargement of the glands in the hilus of either lung, or in the mediastinum; the growth extended across the median line towards the left border of the sternum, and was, as before stated, closely adherent to the posterior aspect of that bone.

The 2eft lung was united to the chest wall by some adhesions which could be readily broken down. The lung was hyperaemic, but otherwise normal. The left pleura presented no signs of new growth.

The pericardial cavity contained a considerable quantity of blood-stained fluid. Both the visceral and the parietal layers were covered with soft lymph and various bands of similar material connected the two layers. There were no signs of new growth connected with the pericardium or the heart.

Liver.-3 lb. 14 oz. Its surface slightly granular, and on section exhibited a nutmeg appearance. No secondary deposits in the organ.

Kidneys.-&ch weighed 7 oz. Organs large. Capsule separates with difficulty, bringing with it portions of the kidney substance. Surface of the organs slightly granular. One or two small cysts, the size of peas. On section, the organs appeared to be congested. The cortex was not diminished in thickness.

Spleen.-6& oz., congested and soft. No malignant growth was found in any part of the body, excepting in

connection with the right pleura. Microscopic exan~ination.-Numerous sections were examined from various

parts of the pleural growth and also from the lung immediately adjoining the thickened pleura. The growth consisted of an alveolar structure, the stroma between the alveoli varying in amount in different parts, but everywhere consisting of fibrous tissue. In the majority of the sections examined, the stroma, relative to the area occupied by the alveoli, was small in amount ; the alveoli being closely packed together. In other parts, where the growth was

The growth over the lung varied somewhat in thickness.


firmer, the stroma was in considerable amount, and the alveoli correspondingly wider apart from one another. Generally they were large and filled with cells of irregular shape, but always contained cells, the nuclei of which stained deeply with logwood. I n many of the larger alveoli, the cells at the periphery-those lining the wall of the alveolus- were cubical, or of the short cylindrical type. In the smaller and nar- rower alveoli the cells mere all of this cubical type, so that we had alveoli simply lined by a layer of cubical epithelial cells. Some such alveoli, although narrow, were of considerable length, and appeared as narrow clefts in the stroma of fibrous tissue, lined by cubical cells, a narrow lumen intervening between the layer of cells on the opposing malls of the alveolus. Between these two types of alveolus, viz. the one full of irregular cells and the other, presenting a single layer of cubical or short cylindrical cells, was every grade ; and it seemed in the highest degree probable that those alveoli presenting a single regular layer of cubical cells represented an earlier stage of the growth, that later on as the cells in the alveoli multiplied and became numerous they lost their regular cubical type, and in part from compression one against another they became irregular in shape. As before stated in some of even the larger alveoli, whilst the majority of the cells were irregular those at the periphery still retained their cubical form.

The growth was too far advanced, and the pleura was everywhere too much thickened to allow anyone to say definitely from what structures the epithelial growth had primarily arisen. The lung tissue immediately adjoining the growth was specially carefully examined at various parts, but nowhere could any growth from any portions of the lung tissue be detected. The pulmonary alveoli appeared simply compressed. Where the growth to the naked eye did appear to extend a short distance into the lung substance, the microscope showed that this appearance was simply caused by a direct extension of the pleural growth, and that the lung tissue was rather pushed before it than infiltrated by it.

Although one could not say from what elements of the pleura the primary overgrowth had taken place, it was very evident from the uniform involvement of the pleura all over the lung of the right side, and of the pleura between the three lobes of the lung, coupled with the negative evidence of the freedom of the lung itself from any separate growth, that the primary seat was in the pleura (see Plate XIV.). One could also not help .being struck by the close resemblance of the small and the elongated narrow alveoli with their regular cubical epithelium to those cases of primary malignant disease of the pleura, where the primary source of the development has been believed to be the endothelium of the lymphatic channels.

From the naked-eye and microscopical appearances we must regard the growth as a primary cylindrical-cell endothelioma of the pleura.

CASE 2 is that of a male, set. 37 years, who was brought to me by my friend Dr. Husband, who had had him under observation for nearly 12 months previously. We persuaded the man to come into the Infirmary, but he only remained in the hospital 4 days when he insisted upon returning home to his friends. He was admitted to the Infirmary on 11th October 1890.

The alveoli varied much in size.

178 THOMAS HARRIS.

He stated that he had always enjoyed good health, with the exception of a slight cough during the winter, until between 9 and 10 months previous to his admission into the hospital. He was then seized with what was believed to be an ordinary attack of pleurisy, which confined him to bed for 3 weeks, after which he went to Southport for a fortnight. He returned home and resumed his duties as letter-carrier for a few weeks, at the end of which time he was attacked with “ inflammation of the lungs and bronchitis.” He recovered from the acute stage of the attack, but ever since has had a bad cough. About 3 months before his admission he for the first time spat a little blood with the expectoration, and a few days later a much more considerable haemorrhage ensued. Since then, up to the time of his admission, there has scarcely been a day when he has not brought up some blood, and often there has been a very considerable haemoptysis. Since his illness began he has lost much flesh, especially recently.

He had a considerable amount of dyspncea, especially on slight exertion. During his short stay in hospital there was a somewhat profuse hamoptysis, about a quarter of a pint of blood of a dark colour, mixed with a small amount of mucus, being expectorated in the course of 24 hours. The blood presented no special l)eculiarities, it was of a dark colour and clotted.

His temperature during the time he was in the Infirmary was either normal or slightly subnormal.

Above the left clavicle was a group of enlarged glands, which were hard, not very tender, and formed a mass the size of a Tangerine orange.

There was dulness all over the left side of the chest both in front and behind, from apex to base. I n front the dulness extended, not only mxoss the median line, but about half an inch to the right of the right border of the sternum, and dulness existed all over the sternum. Marked bronchial breathing existed all over the left side of the chest. As regards the kind of adventitious sounds which were present, I am unable to make any statement, as the notes are defective. We had hoped to make a subsequent and more detailed report of the case, but the patient insisted on leaving the hospital before I had an opportunity of doing so. The cardiac apex beat was in the fifth space well within the nipple line, and the heart sounds presented nothing unusual.

The diagnosis made was, “ Intra-thoracic malignant disease,” but no opinion was formed as to the primary seat of the growth.

The patient left the hospital, gradually sank, and died 7 days later, on 22nd October.

: Dr. Husband obtained permission for an autopsy, and kindly assisted at the examination.

The patient on admission was a thin, spare man, evidently emaciated.

The body was very much emaciated. A mass of enlarged glands, which were firm and hard, existed above the

left clavicle. When removed, they were about the size of a Tangerine orange, and corresponded in position to those which had been observed during life. The left lung was everywhere firmly adherent to the chest wall, and it was only with great difficulty and the free use of the knife that it could be removed from the body. The lung was especially firmly adherent to the diaphragm, which it was found necessary to remove along with the lung.

The left pleura was everywhere thickened by a fine white new <growth, which encased the left lung, and extended into that organ from the hilus, and also by delicate bands from various parts over the surface of the lung. I n addition, the interlobular pleura was thickened, and the lobes of the lung were united together. As the two surfaces of the pleura were merged into one mass of new growth it was impossible to say how much of the growth was due to an increase in the thickness of the visceral and how much to that of the parietal

The left pleural cavity was thus totally obliterated.

MALIGNANT DISEASE OP THE PLEURA. 179

layer. The greatest thickness of new growth was a t the diaphragmatic aspect of the lung, where it varied from a quarter to three-eighths of an inch in thickness, whilst over the lower part of the lung, on its outer and posterior aspects, for a distance of 4 in. from the upper surface of the diaphragm, it was a quarter of an inch thick, whilst above that, and extending over the apex of the lung, it formed a layer from an eighth to a quarter of an inch in thickness; over the inner aspect of the lung, towards the mediastinurn, it was one-eighth of an inch thick. The pleura between the lobes of the lung varied from a mere line to a quarter of an inch in thickness, where it joined the united visceral and costal layers of the pleura, and from which it had evidently extended.

From the hilus of the lung very marked thickening extended along the bronchi into the substance of the lung. This thickening extended into the substance of the lung, even to the smallest bronchi which could be recognised by the unaided eye. At the hilus of the lung the lymphatic glands were enlarged, and with the growth surrounding the bronchi compressed and nar- rowed the tubes.

The lung substance was everywhere traversed by the bands of new growth, which spread from the hilus along the course of the bronchial tubes. Between these bands the lung substance was of a greyish-black colour. The lung substance was soft, and at various parts had broken down into small cavities, which varied in size from minute points, just visible to the naked eye, to cavities about three-quarters to half an inch in diameter. The larger cavities had soft shreddy irregular walls, with no signs of any limiting or circumscribing structure.

In addition to the extension into the lung from the hilus, the growth also extended into the organ in the form of fine bands from the overlying pleura.

The right pleura and the right lung presented nothing abnormal. The lymphatic glands of the mediastinum were enlarged and firm, and

The pericardium and heart were healthy. The liver presented two small nodules of new growth, each of which was

The other organs were healthy, and elsewhere no new growth was found. The nzicroscopical examination of the thickened pleura of the right side

showed that the thickening was caused by an epithelial new growth, which presented all the features of a squainous epithelioma. The alveoli of the growth contained large epithelioid cells, which in some parts were arranged in a concentric manner, forming cell nests of an exactly similar appearance to what we find in the squainous epitheliomata of the lip for instance. In other alveoli, which were probably of more recent formation, the cells were irregularly arranged, but even in those alveoli, were of large size, and of the squamous epithelium type. In still other parts of the growth there mere very large groups of epithelial cells, situated in the midst of fibrous tissue, but which could not be described as being contained in an alveolus.

evidently infiltrated by new growth.

about the size of a pea.

Between the alveoli was well-marked and fully-formed fibrous tissue. I n this case, as in Case 1, the growth was too far advanced for any opinion

to he formed as to which elements in the pleura had been the primary source of the epithelial overgrowth.

Sections were also examined froin various parts of the infiltrated right lung. The pulmonary alveolar malls were thickened, and in the alveoli were masses of epithelial cells of the squamous type. Those cells were evidently not simply the result of any catarrhal process, but represented a new growth, and that of a similar nature, which was seen in its most advanced and perfect development in connection with the pleura. We could not state whether these cells in the alveoli had arisen from a proliferation of the epithelial lining of the pulmonary alveoli, or whether they had arisen froni the protrusiqn into the pulmonary alveoli of cells from the ontsicle of the alveoli, but the appearance was more

180 THOMAS HARRIS.

consistent with the latter being the correct interpretation. I n any case, the pulmonary alveoli in many parts of the lung had been transformed into cancer alveoli.

The microscopical examination of the nodules from the liver, and of the enlarged supraclavicular glands showed that we had to deal with a similar squamous epithelial growth to that which had caused the thickening of the pleura, but that in both cases the development was less advanced and less complete ; the typical cell nests, where the alveoli contained squamous cells arranged concentrically, not being found either in the growths in the liver or in the enlarged lymphatic glands.

I n other parts of the lung the consolidation was seen to be due to inflammation, and not to the development of a new growth. I n such parts the alveoli were filled with granular matter and catarrhal epithelial cells, the latter being often seen to be deeply charged with carbonaceous pigment. Some of the pulmonary alveoli presented the products of new growth, and also of inflammation. In some instances it was difficult to be certain that a pulmonary alveolus did contain both inflammatory products and also cells belonging to a new growth; but in many instances the contrast between the two types of cells and their arrange- ment left no room for doubt that the contents of the alveoli were partly inflammatory and partly derived from an epithelial new growth. For instance, a large number of pulmonary alveoli existed where in the centre was a closely- packed mass of flattened squamous epithelial cells, arranged more or less in a concentric manner, which were exactly similar to the cells in cancer alveoli in the thickened pleura, whilst at the periphery of these cells, between them and the wall of the pulmonary alveolus, were large cells also of an epithelial type, but frequently containing a large amount of carbonaceous pigment, and similar i n shape and appearance to the catarrhal cells seen in bronchopneumonia.

The parts of the lung which were invaded by the new growth were scattered irregularly among the parts of the lung which were consolidated by inflammatory products. The invasion of the lung by malignant growth was not confined to any one part of the organ, and the invasion appeared to have taken place in part by extension from the hilus of the organ along the course of the bronchi, and in part by direct extension from the pleura. The extension from the pleura had, however, not been a uniform one, because in many parts the alveoli situated immediately beneath the thickened cancerous pleura were filled simply with inflammatory products, with no signs of any malignant growth in their interior. This appears to be a fact of some importance, because, where a lung is so extensively affected with malignant disease as this one was, it may be open to question whether the lung was not really the primary seat of the growth, and the pleura simply affected secondarily by direct extension. The microscopical appearances, however, were more eon- sistent with the view that the pleura was the primary seat of the growth, the lung being involved afterwards partly by direct extension from the pleura, partly by extension along the course of the bronchi from the hilus.

It was unfortunate that the clinical features presented by the above two cases could not, on account of the reasons previously stated, be fully investigated and recorded. These cases, however, do illustrate how varied the physical signs may be when the plenra is the seat of primary malignant disease.


Primary malignant disease of the pleura is one of the most diflicult problems in diagnosis presented to the physician. I n the first of my two cases we thought we had to do with simple pleuritic effusion, with a very much thickened pleura. The patient was severely ill at the time the only clinical examination was made on her last admission to hospital ; and if we had had another chance of making an examination, after the failure to withdraw any large amount of fluid from the chest, we might probably have been more successful in the diagnosis. We were peculiarly unfortunate in haviug struck the small pleural space which existed. Had we introduced the needle but a very short distance from the spot where we did introduce it, we should not have withdrawn any fluid, and have noticed the solid mass into which the needle would have passed. The first case also illustrates one very important point in malignant disease of the pleura, viz. that the pleural effusion in such cases, even when the disease is advanced, may be perfectly clear, similar to many cases of simple pleuritic effusion, and free from blood. The hEmorrhagic character of the effusion in cases of malignant diseases of the pleura has been justly considered of great diagnostic value ; and although hzmorrhagic pleural effusion is not found only in malignant growths of the pleura: it is certainly a condition which in any case should make us consider the possibility of it being of such origin. The first case we recorded shows that there may be no blood, at some stages at all events, in the pleural effusion. The second case shows also that the pleural cavity may be entirely obliterated, so that there is nowhere for pleural effusion to accumulate. The two cases also show how various may be the auscultatory signs which may be present. In the first case we had extremely weak respiration and signs generally similar to those seen in cases of extensive liquid effusion into the pleura, whilst in the second case we had marked bronchial breathing and other signs pointing more especially to consolidation of the lung. The post-mortem examination in the two cases made it quite clear what was the cause of this difference in the physical signs. In the first case there was very extreme thickening of the pleura and simple compression of the lung, in the second case the pleura was much less thickened than in the first case, and the lung was not simply compressed, but extensively consolidated, by inflammation and by infiltration with new growth. Small cavities also existed in various parts of the lung.

The first case also shows that malignant disease of the pleura may exist for a very long time and be very extensive, and yet not be compli- cated by any enlarged glands either above the clavicles or elsewhere, whilst the second case shows that these may exist in a case where the pleura is much less involved. In the second case the diagnosis of intra-

1 A. Fraenkel, <‘ Ueber primiiren Endothelkrebs (Lymphangitis Prolifera) der Pleura,”

2 Wilson Fox, “ Diseases of the Lungs and Pleura ; ” see article, “ Primary Cancer of Verhandlungen dcs Congresses fiir innere Medicin, 1892, p. 374.

the Pleura,” p. 1135.

183 THOMAS HARRIS.

thoracic malignant disease, with secondary enlargement of the lynlphatic glands of the neck, was made, but it was quite impossible to say at the bedside that the pleura was the primary seat of the growth. We niay certainly get similar physical signs in some cases of primary niediastinal growths, where a bronchus is compressed and the lung consolidated by inflammatory products secondary to such bronchial compression. It may not only be dificult to distinguish a case of primary malignant disease of the pleura from one of niediastinal tumour, where compression of it

bronchus has caused secondary changes in the corresponding lung, but we may also be unable to decide between a primary rnalignant disease of the pleura and a case of mediastinal tumour which has caused a simple pleuritic eflusion.

We will now pass to the pathological considerations which thest: cases suggest.

Cases are very rare where the pleura only has been found to be the seat of malignant disease, where 110 other growth except the one affecting the pleura has been found in the body. The first of the two cases which is here recorded was one of such rare cases. Without entering into the details of the case, it may be stated that in that instance the right pleura in its visceral and parietal layers, which were bound together, was enormously thickened by a carcinomatous growth, that no involvement of the adjacent lung or of any other organ was found. It is such it case as that which affords the strongest evidence that the pleura may be the primary seat of nialignant disease. I t ninst be admitted, however, as some will maintain, that such a growth is oiily uppamiitZy primary in the pleura, that although the pleura is the only part involved, and although careful examination of the subjaceiit lung showed the absence of any discoverable malignant disease, yet it is possible that the disease took its origin at some one minute spot in the lung and extended to the pleura, and that there the growth found the conditions most suited to its further development ; hence arose the appearances which led to the belief that the pleura was the seat of primary developnient. I expect that this would be one of the strongest arguments on which a believer in the view that all carcinomata arise either from epiblastic or hypoblastic tissue would rely. The pleura is a development from the mesoblast of embryonic life, but as it lies in such close proximity to the lungs, in the development of which the hypoblast takes an important part, a believer in the above view would consider it quite within the bounds of possibility that the apparent cancer of the pleura really arose from sonie part of the subjacent lung, but that its subsequent extension took place in the pleura, where it found the conditions most favourable for its further development.

It cannot be denied that those who believe that cancers always develop primarily from tissues which have developed from either the epiblast or the hypoblast have strong arguments in support of their view, and that they are in many cases able to bring forward explanations


of the instances in which cancers are found apparently aiising primarily in tissues of mesoblastic origin. It is certainly a fact that the great majority of the cases of cancerous growths undoubtedly arise from tissues which have developed from the epiblast or the hypoblast, and that it is uncommon to find a cancer which is, even apparently, arising primarily in mesobIastic tissue. It is also true that many of the latter cases, those where the primary growth has apparently taken place in a tissue of mesoblastic origin, are situated in very close proximity to another tissue which has developed from either the epiblast or the hypoblast, and it is quite possible that although the tumour apparently arose from some constituent of the mesoblastic tissue, in reality i t developed primarily from the adjoining epiblastic or hypoblastic tissue, and only secondarily involved the mesoblastic tissue where it found the conditions most suitable for its further development. This may be very well illustrated by the cases of apparent primary cancers of the pleura; such may possibly have arisen from the subjacent lungs, which is partly a hypoblastic tissue, and then subsequently shown the chief extension in the pleura. I n the same way would, doubtless, be explained the apparent development of primary carcinomata of the peritoneum and membranes of the brain.1

This argument is undoubtedly a strong one, but the fact that no growth can be found anywhere in the lung in some of the cases, although the development in the pleura must have existed a long time and had obtained an advanced development, must be admitted as a point on the other side of the question. Also, that in the case of primary growths in the lungs we find that they do not commonly cause an infiltration of the overlying pleura in all its parts ; that the pleura may be affected by the growth immediately over the growth in the lung, but that no general infiltration of the pleura ensues a t all similar to that shown in the illustration of Case 1. Also, the manner of development and extension of the growth in the pleura is, in some instances, what we should expect in a growth of primary pleural origin, there being it

more or less uniform infiltration of all the pleura (see Case l), and not growths in isolated patches of the pleura, such as we are accustomed to recognise as undoubted secondary formations.

Another structure in which we see primary cancers appareutly clevelop is bone. Although considerable doubt has been cast upon the view that primary carcinoma occurs in bone, we can have no doubt that occasionally a bone has been found the seat of a growth of the cancer type, and that in cases where no other part of the body has presented any new growth even on careful post-mortem examination. Two such

1 Primary illalignant growths described nnder the term of endotheliomata have been found especially in connection with the pleura, peritoneum, membranes of the brain, and lymphatic glands. In some instances such growths present the features of alveolar sarcomata, whilst others are essentially of a true cancer type. It is this latter group of powths which especially concerns us when considering the possibility of growths of the cancer type having an origin in a mesoblastic tissue.

184 THOMAS HARRIS.

cases, a t least, I can recall as having occurred in the pathological department of the Manchester Infirmary during the past 15 years; and a considerable number of similar cases are on record. Those who uphold the view that cancers always take origin either from the epiblast or hypoblast would, doubtless, argue that secondary malignant growths in bone often progress very rapidly, and that a secondary growth in bone may attain very large dimensions and be quite out of proportion to the primary growth, which latter, being small, has remained undetected at the post-mortem examination, and so the large growth in the bone which they would maintain really was secondary has been wrongly regarded as a primary growth.

This argument may be met by the fact that, although it is possible that the primary growth may have been overlooked, the negative is nevertheless equally probable, considering the number of cases of primary cancers of bone which have been recorded by careful observers.

Another mesoblastic tissue in which primary cancer has been described is that of lymphatic glands. The supporters of the view we are now considering would again explain this as a fallacious argument. They would point to the fact that malignant growths of the cancer type, whether epitheliomata or true carcinomata, do occasionally retrogress, abort, in some cases undergo spontaneous cure. That it is possible that in the cases of apparent primary cancerous growths in lymphatic glands, the real primary growth, which was in a neighbouring epiblastic or hypoblastic tissue, has aborted after the adjoining lymphatic glands had become infected, and that the growth progressing in such glands then appeared to be the primary one.

This is one of the most dificult a,rguments to meet, because the fact appears to be well established that malignant growths may retrogress, and if they may disappear entirely from one part, we are conipelled to admit that any growth which we may find in an unusual position possibly owes its origin to infection from some neighbouring part. We can only say that it is a question of the balance of probabilities ; for my own part I should say that for other reasons I believe in the development of primary epithelial tumours in mesoblastic tissue, and that I consider that they very much surpass in weight the argument based on the undoubted fact that a malignant growth may in some rare instances abort.

The holders of such a view would also say that in the repair of wounds we have no evidence of the change of a mesoblastic tissue into one of an epiblastic type, that a wounded mesoblastic tissue reproduces a tissue of its own type, and that the wounded epiblast reproduces its own type,-that, for instance, in wounds of the skin the new epithelium is developed from the pre-existing and adjoining epithelium.

Although in the repair of wounds of the epiblast and mesoblast, a repair of each takes place from its own particular tissue, we must remember that the repair of wounds is an inflammatory process, and that


in inflammatory processes we may get a great modification in the type of cells of a part. Thus in the Case of the pleura, when it is inflamed we may get the thin flattened endothelial cells elongating, increasing in thickness, and becoming quite pyramidal. I n other words, a cell of mesoblastic origin under the action of an irritant alters its character, and comes to resemble a cell commonly seen on mucous surfaces of hypoblastic origin. As the repair of tissues therefore is an inflammatory process, we may cite against arguments based on it the fact that, in inflammation, cells derived from one tissue (mesoblast) alter their appearance and resemble cells derived from a diff’erent embryonic layer (hypoblast). If such happens in an inflammatory process, why may it not happen in the development of a new growth ?

Lastly, we have arguments based on a study of the development of the embryo, which may be regarded as facts in support of the view that carcinomata do not develop primarily in mesoblastic tissues. There are some recent researches especially which offer the strongest arguments which embryological studies afford on this point. I n frogs and ascidians it appears1 that each of the two first cells produced from the ovum, and which correspond to the right and left half of the future body, contain respectively the material for producing the right and left half of the body. Each of the first two cells derived from the frog ovum may after destruction of the other half develop a perfect half embryo, half a brain vesicle, one auditory vesicle, and a chorda dorsalis of half thickness. The same independence in development is shown likewise by the anterior and posterior pairs of fission masses. Thus Chaby (quoted by Roux) experimenting with ascidians could, by destruction, produce half an embryo (side half, or anterior, or posterior half), a quarter or a three quarters embryo. Roux in conclusion says that every cell derived from the ovum, at least up to the sixteen-cell stage, has a definite potentiality; it corresponds to a definite part of the animaL If we destroy one of these cells a defect ensues in the beast.

Likewise in the embryo amphioxus2 it would appear that if the blastomeres of the two-celled stage are completely separated, two quite separate and independent twins of half the natural size result. Also experiments with the four-cell stage give analogous results, a perfect but dwarf free-swimming larva one-fourth the normal size being produced. But if the blastomeres of the eight-cell stage are isolated, although they undergo a cleavage at first closely similar to that of an entire ovum, the one-eighth embryos appear to be incapable of full development. It appears probable that this inability of the one-eighth blastomeres to produce a complete embryo is not due simply to a quantitative limita-

1 W. Roux, “ Ueber das entwickelungsmechanische Yermogen jeder der beiden ersten Furchungszellen des Eies,” Veihandlungen der anatomischon Gesellschaft auf der sechsten wrsammlung in Wicn, vom 7-9 Jnin 1892, Erganzungsheft zum siabenten Jahrgang, Des Anatornischm Aweigers, 1892, s. 22.

2 Edmund B. Wilson, ‘L On Multiple and Partial Development in Amphioxus,” Annto- rniseher Anzeiger, 1892, p. 732.

186 THOMAS HARKIS.

tion of the protoplasm, but to a qualitative limitation, the protoplasm having become so far differentiated as to be incapable of regenerating the whole. These observations may be considered to be of importance when considering the question of the possibility of devclopmeiit of an epithelial tuniour of the type which usually arises in epiblastic 01’ hypoblastic tissues from a tissue of mesoblastic origin. It will probably be argued by some that if in the embryo the cells comparatively early become so differentiated, it is not probable that when that differentiation has proceeded to a much further and higher degree the cells and tissues should apparently revert and all he capable of developing the same type of growth. In other words, that the cells which have become differentiated and form a mesoblastic tissue are not likely to form the same kind of new growth as the cells which have become otherwise differentiated and form an epiblastic or mesoblastic tissue.

These enibryological studies are undoubtedly weighty arguments. We inust, however, remember that the cells of the embryo which are differentiated to form the mesoblast do not all become differentiated so as to form one type of tissue, for instance fibrous tissue ; that a mesoblastic tissue consists not only of fibrous tissue but of endothelial cells, lining the interior of lymphatic structures, and blood vessels. Such endothelial cells resemble, to a certain extent, epithelial cells of epiblastic and hypoblastic origin, and, as we have already seen, under the results of irritants, as shown in inflammation, they can alter their character and come much more closely to resemble such epithelial cells. So then I call see no reason why under some particular form of irritant, whether it be a protozoon or not I do not know, but under some kind of stimulus such endothelial structures should not alter their appearance and come to resemble the cells found in the nests of a cancer, which has developed from an epiblastic or hypoblastic tissue.

In addition, we have against the above argument from einbryological work the fact that some forms of alveolar sarcomata very closely resemble a true carcinoma. No one denies that an alveolar sarcoma may develop from mesoblastic tissue, and yet in many such growths the cells in the alveoli are most extraordinarily like true epithelial cells, and as showing that we recognise such resemblance we commonly term those cells epithelioid. Hence we have evidence that the cells of a mesoblastic tissue, both in inflammation and in the new growth termed an alveolar sarcoma, may undergo great differentiation late on in life, and come to resemble the cells found in true epithelial growths derivecl from other embryonal layers.

I have not referred to the inclusion theory of Cohnheim, which would, of course, explain the origin of the growths in the tissues under consideration, because I wished to bring forward the arguments which appeared to me worthy of consideration for and against the differentiation of mesoblastic cells late on in life into a growth resembling growths derived from the other two embryonal layers.


One of the strongest arguments, however, against the deductions of the embryologists is afforded by a consideration of the structure of the uterus, and from the fact of true carcinomata developing in that organ. The uterus and nearly the whole length of the vagina is of mesoblastic origin, according to the majority of embryologists.’ The epithelial lining of that organ resembles the epithelium derived from the other two layers of embryonic life. So that we have in the epithelial lining of the uterus conclusive evidence that the cells of the mesoblast do normally undergo very great differentiation, that whilst some of those cells form fibrous tissue others form epithelial cells, similar to those derived from the other layers of the embryo. Further- more the uterus, and especially the cervix, is not occasionally but very frequently the seat of the primary origin of true epithelial tumours of the cancer type. As the adjoining epithelial surface of the vagina is also developed from the mesoblast, it makes no difference to our present argument whether such cancers are developed from the epithelial lining of the cervix uteri or from epithelium derived from the upper end of the vagina. The undoubted fact remains that in primary carcinoma of the cervix uteri we have an instance of the development of a cancerous growth primarily in a tissue of mesoblastic origin.

From all these considerations we are forced to admit that the weight of both our pathological knowledge, and of the evidence derived from the study of the development of the embryo, is strongly in favour of the origin of epithelial tumours of the cancer type, in some instances, primarily, in tissues which have developed from the mesoblast.

That although the pleura is one of the rare structures in which primary carcinomata are met with, nevertheless the fact of the pleura having an origin from the mesoblast of embryonic life is not an extremely weighty argument against the view that the pleura may be the primary seat of origin of such growths.

BIBLIOGRAPHY. The literature bearing upon the development of malignant disease in

the pleura is copious and extremely difficult to analyse with the view of obtaining evidence as to the frequency with which the disease occurs primarily in that part. Many of the cases described as primary malignant disease of the pleura are doubtful ones. Many of those so

The portions of the embryo concerned in the development of the uterus and the Fallopian tubes are Muller’s ducts, and possibly the posterior extremity of the Wolffian ducts. The anterior and greater portion of Muller’s ducts are developments from the pleuro-peritoneal cavity, and are, therefore, of undoubted mesoblastic origin. The posterior extremity of Miiller’s duct has, according to some embryologists, an origin from the posterior extremity of the WolEan duct of the corresponding side. Although the majority of observers now believe that the Wolffian ducts are, in their whole length, of mesoblastic origin, a minority consider that the anterior extremity of those ducts is derived from the epiblast. If any portion of the Wolffian ducts is of epiblastic origin, there is of conrse a

JL. OF PATEL-VOL. 11. 13

188 THOMAS HARRIS.

described being probably of secondary and not of primary origin in the pleura.

The following references bearing upon the subject may be of some assistance to those interested in the question :-

‘‘ ktude cliniaue sur les Manifestations Canckr- 1. ARNAULT DE LA M ~ N A R - DIBRE, . . .

2. BIRCH-HIRSCHFELD,

3. BOSTROEM, . . . 4. COCKLE, JOHN,. . 5. COLLIER, W., . . 6. EPPINGER, . . . 7. EWALD, . . . .

8. FRAENKEL, A., . .

9. FRAENTZEL, OSCAR,

10. Fox, WILSON, . .

11. GOLGI, . . . . 12. GORDON,. . ’ . . 13. KUNDRAT, . . . 14. LEBERT, . . . .

15. NEELSEN, . . I

16. ORTH, . . . .

, . euse de la ‘Plevre.” Thhe pour le Doctorat

. . “Lehrbuch der ptholog. Anatornie,” zweiter

, . “Das Endothelcarcinom.” Inaug. Diss. Erlan-

. . “ Intra-Thoracic Cancer,” part ii. London, 1865.

. . “Case of Primary Malignant Disease of the Pleura.”l Lancet, 1885, p. 945. . . Prag. Vierfe$ahrsschrift, Bd. cxxvi. s. 17 ; and Prag. nzed. Woch. 1876, ss. 82 and 97.

. . Discussion on Prof. Fraenkel’s Cases (see below), Deutsche wed. Woch. 1891, No. 50, s. 1184.

. . (( Ueber primaren Endothelkrehs (Lymphan- gitis prolifera) der Pleura,” Ver7mndlungen des Congresses fur innere Medicin, 1892, s. 374; also Deutsche nzed. Wocii. 1891, Nos. 60 and 51 ; also Berlin. klin. WOC~L. 1892, s. 497. (Pathological Report on Dr. Fraenkel’s case by Dr. Troje.)

. . Cyclopsdia of the Practice of Medicine, vol. iv. p. 771, edited by Dr. H. von Zienissen, Eng. trans. London, 1876. Fraentzel there says : “ Sarcomas or cancers of the pleura are never primary.’’ . . “Treatise on Diseases of the Lungs and Pleura,” by Wilson Fox, KD., F.R.S., p. 1135.

. . ‘‘ Endothelioma.”

. . Dublin Quart. Journ. of Med. Sc. August 1863.

. . Oesterr. Jalzrbuch, 1871, Heft 2.

. Bulletin Soc. Anat. de Paris, 1850, p. 276 ; also his ‘I Traite d’Anatomie Pathologique.”

. , “ Untersuchungen ueber den Endothelkrebs.” Arch. f. klin. Med. 1882, Bd. xxxi. s. 375.

. . “ Lehrbuch der speciellen pathologischen Anatomie,” zweiter Lieferung, ss. 570 and 571 ; also the first part of the same work by the same author, s. 278.

en Mkdecin. Paris, 1874.

Adage, Bd. ii. ss. 460 and 461.

gen, 1891.

.

possibility that the offset of that portion of the Wolffian duct, which according to some authorities takes place, and assists in the formation of the uterus, etc., may contain some epiblastic elements, so that such observers do not believe in the origin of the uterus solely h m the mesoblast. As far as I can gather, however, the weight of evidence is strongly against the view of the epiblast taking part in the formation of the uterus and in favour of a simple mesoblastic origin of that organ.

Through the kindness of my friend Dr. Collier I had an opportunity of examining a number of microscopical specimens from this case. They were well-marked examples of a squamous epithelioma, very similar to my own second case recorded above.


17. PER-, . . . . . .

1s. ROBIN, . , . , . . 19. SCHOTTELIUS, . . . .

20. SCHULZ, R., . . . . . 21. SCHWENINGER, . . . .

22. WAGNER, . . . . .

23. WILKS, , . . . . . 24. WUNDERLICH, . , . .

25. ZIEQLER,. . . . . .

‘ I Lehrbuch der allgemeinen pathologischen Anatomie.” 1877, Bd. i. s. 366 ; also Virchow’s Archiv, 1872, Ed. lvi. s. 437.

“ Endothelioma.” “ E n Fall von primaren Lungenkrebs.” Inaug.

Archiv d. Heilkunde, Ed. xvii. s. 1. Annabn der Stadt. allg. Krankenhauser zu

Munchen, 1878, Bd. i. “ A Manual of General Pathology,” by Ernest

Wagner, M.D. Translation from the 6th German edition by John van Duyn, A.M., M.D., and E. C. Sequin, M.D., p. 500; also Arehiv d. HeBk. 1870, Bd. xi. s. 509.

Trans. Path. Soc. London, vol. ix. p. 31. “ Handbuch der Pathologie,” Theil. ii. Bd. iii.

s. 500. “ Lehrbuch der allgemeinen und speciellen

pathologischen Anatomie und Pathogenese. ” Zweiter Adage, zweiter Theil, s. 148.

Diss. Wiirzburg, 1874.

EXPLANATION OF PLATE XIV.

The illustration represents a section of the lung encased by the pleural new growth The section was made from the posterior and outer aspect of the lung froni Case 1.

inwards towards the mediast.inum.

a. The united visceral and parietal layers of the pleura affected by the new growth.

b. New growth extending between the upper and lower lobes, thickening the interlobular pleura and uniting the upper and lower lobes.

c. Remains of the pleural cavity from which the small amount of clear fluid was withdrawn during life.

d. Growth between the middle and upper lobes of the lung.

(For the drawing from which the illustration was executed I am indebted to Mi-. Mathwin, one of my clinical clerks.)

a contribution to the pathology and clinical features of primary malignant disease of the pleura

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