Further observations on Paget's disease of the nipple

618. 191-006. 468

FURTHER OBSERVATIONS ON PAGET'S DISEASE O F THE NIPPLE.

ROBERT MUIR. From the Pathology Depcwtment q j G'lnsgow University

and Glnsyow Western Infirmary.

(PLATES LV. -LVIII. )

SIKCE my first paper on this subject (1927) I have been able to examine a large number of cases of the disease. I do not intend, however, to describe these individually, though naturally they have presented a great variety of features of interest. They have all been critically examined and considered, especially in relation t o the views which I have previously expressed, and I shall deal mainly with matters which bear on the chief questions concerned. What follows thus represents a general survey of the subject in the light of these additional observations. I desire to thank the numerous friends and colleagues who supplied me with specimens, thus enabling me to see the disease in so many aspects.

The questions at issue. In connection with the pathology of Paget's disease it is essential

to recognise that there are two main questions. (1) The first is as to the nature of the histological changes seen in the epidermis of the nipple-how are we to interpret them ? ( 2 ) The second is the relation of the nipple lesion to the development of the infiltrating cancer of the breast which is so often associated with it. These questions are independent, at least in the sense that there may be agreement on the first and not on the second, and they are best considered separately.

With regard to the first question, the view expressed in my first paper (1927) was that the nipple lesion represents a spread of cancer cells to the epidermis from malignant disease in the upper parts of a, duct or ducts-intruduct carcinoma-with subsequent intra-epidermal growth and extension. In the related cutis there follow reactive changes which give rise to the main clinical signs of the disease. This is the view expressed originally, so far as I know, by Jacobzus (1904) and it is supported by the observations

299

300 R. MUIIZ

of others as well as my own. I need not inention these in detail as the matter is not to be settled by the weight of authority, but excellent histological accounts are given by Simard (1930) and Keith Inglis (1936). This view is supported by the whole series of cases which I have since examined and I do not propose to discuss it further in the present paper. The great diversity of opinion with regard to Paget’s disease is notorious. This is due in part to the fact that, in a particular case, when the Paget cells are in a degenerate state it is not possible to pronounce an opinion on their nature, and in part to the fact that opinions have often been formed without regard to the changes in the mamma itself.

As to the second question, the relation of Paget’s disease to the associated mammary carcinoma, there are t’hree possibilities, naniely (a) that the Paget lesion causes the cancer ; (b) that the cancer causes the Paget lesion; and (c) that both are the result of some other condition. The first view has been upheld by various writers, e .g . Schanibacher (1905), Kilgore (1921) and notably Keith Inglis (1936) in his recently published book on Paget’s disease. According to it the first occurrence is a malignant change at the junction of a duct or ducts with the epidermis and from this there is a spread downwards within a duct to the breast substance, where the malignant process breaks through and gives rise to an infiltrating growth. There is thus believed to be a continuity between the nipple lesion and the resulting breast cancer. The second possibility need not be discussed as it is quite contrary to the main facts. The only exception is that an infiltrating cancer of the nipple may sometimes invade the epidermis and spread in it in a manner analogous to what is seen in Paget’s disease. This, however, is a very rare occurrence and has nothing t o do with the disease as ordinarily niet with ; it is referred to again below.

The third possibility is the one which I have adopted in putting forward the view that the underlying and causative condition of both Paget’s disease and the accompanying cancer is intraduct, carcinoma, that is, a condition in which nialignancy is present within ducts but has not broken through their walls. Such a disease is of common occurrence, indeed in my experience, the commonest detectable precursor of ordinary carcinoma. It may occur in any part of the duct system and it may arise in multiple independent foci. If it occurs in the ducts of the nipple it may spread to its epidermis, Paget’s disease resulting ; this is a rare occurrence. The conimon event is a breali-through in some part of the breast with carcinoma as the result. According to this view such infiltrating cancer has the same history or =etiology whether Paget’s disease is present or not, the latter being in fact a rare complication of quite a common condition. On the other hand, according t o the view of direct downward spread from the nipple the cancer is

PAGET’S DISEASE OF NIPPLE 301

produced in a different way from that ordinarily occurring. The usual sequence of events is of importance in relation to our conception of mammary changes in general and will form the main consideration in this paper.

Some characters of intraduct carcinoma. As intraduct carcinoma is of primary importance it will be well

to summarise some of its chief features. It is a condition in which malignant anaplastic cells have arisen and are proliferating within the ducts, the cells being as a rule arranged either in several layers lining the duct or filling it completely (figs. 1 and 2). The condition is called by Schultz-Brauns (1933) in his review of tuniours of the niamma “ Milchgangskarcinom.” It is described by Cheatle and Cutler (1931) as “ masses of malignant-looking cells filling the ducts ” and is regarded by them as malignant epithelial neoplasia ; the cells are “ not precancerous or potentially carcinomatous ” but “ actually in a state of carcinoma.” It is abundantly illustrated in their book on tuinours of the breast as well as in Keith Inglis’s work and in my own papers. Schultz-Brauns says that it is often difficult to decide whether such a condition has developed primarily within the duct or is due to invasion from outside. In some cases where cancer within a duct is surrounded by infiltrating cancer the condition within the ducts may be secondary and, as a matter of fact, invasion from outside can sometimes be seen. But that does not affect an interpretation of intraduct carcinoma in general as being a primary condition. One must recognise that often it niay be extensive in a given case without any trace of infiltration in the surrounding tissues ; or it may be present alone in one part of the breast while in another infiltrating cancer has been superadded. Further, earlier stages in the development of malignancy may be found in other parts of ducts-different stages of evolution niay be seen. Another point is that one can frequently find reactive changes in the affected ducts leading to’all degrees of obliteration, the ultimate result being a hyaline and almost acellular centre, often surrounded by greatly hyperplastic elastic tissue (figs. 3 and 4). Such changes when present are, of course, a valuable indication of the duration of the disease. Since Dr Aitkenhead and I (Muir and Aitkenhead, 1934) described this condition I have frequently found it in cases of intraduct carcinoma with or without infiltration around, though never again on so extensive a scale. In the present series of cases I have had no difficulty in interpreting the intraduct carcinoma as the primary condition except in a very fern instances. I may add that the age incidence of intraduct carcinoma is earlier than that of infiltrating cancer and there is abundant evidence that it may exist for a long time before infiltration of the surrounding tissues occurs.

302 R. X U I R

As already stated, intraduct carcinoma may have independent foci of origin. This is important in connection with Paget’s disease and has been insisted on by Cheatle and Cutler ; it is well illustrated in their book. I have been much impressed by this fact since adopting the method of making horizontal sections immediately below the nipple. I have repeatedly found several main ducts affected a t a particular level whilst the disease diminished above and disappeared in several of the ducts. The multiplicity of foci of origin obtains not only between different ducts but also between different parts of the same duct.

Another important point is the intra-epithelial spread of intraduct carcinoma, that is, invasion of normal epithelium by the malignant cells, the epithelial layer being still intact. This intra- epithelial spread is the essential feature in Paget’s disease, but it is also seen in the ducts of the nipple and breast and occasionally also in the acini. In these last-mentioned positions it has been found less frequently in my later cases. I have gained the impression that the higher the level in the duct the more frequently is intra- epithelial spread seen. It seems to depend in part on the resistance of the epithelium. When a duct in the nipple is the seat of squamous inetaplasia as not infrequently happens and intraduct carcinoma supervenes, the intra-epithelial growth of the cancer cells is often beautifully seen. As I have stated elsewhere, a Paget cell may be defined as a malignant epithelial cell growing in normal or, at least, noii-neoplastic epithelium in ducts as well as in epidermis.

Intraduct carcinoma is sometimes very extensive ; for instance, I have recently seen a case, for which I am indebted to Dr Heggie, where the condition was practically universal throughout both mamma and nipple. There was no infiltrating carcinoma and no clinical evidence of Paget’s disease, but unfortunately the epidermis of the nipple could not be properly examined as it had become hardened by drying. Cheatle and Cutler also describe two cases of similar general involvement of the ducts. These raise the question whether multiple foci of origin with intra-epithelial spread, aided by direct spread by continuity within the duct, are sufficient to account for such conditions, or whether we must recognise a more or less general action of the carcinogenic agent (whatever it may be) on the duct epithelium. One cannot speak definitely, but the question is one of importance in connection with the modes of early development of cancer. When the intraduct carcinoma is restricted to the ducts for a long time, degeneration and necrotic changes may occur in the cancer cells, and ducts so affected are enlarged and filled with yellowish material. In this way the so-called “ comedo carcinoma ” is produced. Calcification in the duct contents may follow.

On re-reading what I have written on the subject years ago

JOURNAL O F PATHOLOGY-VOL. XLIX.

INTRADUCT CARCINOMA

PLATE LV

FIG. 1.-Active intraduct carcinoma in mamma FIG. 2. -Longitudinal section of duct with in case of Paget’s disease, showing masses of A very early anaplastic cancer cells within ducts. x 125. Paget lesion was present at the orifice.

intraduct carcinoma in nipple.

x 250.

FIG. 3.-Process of obliteration of duct with intraduct carcinoma. Small group of cancer cells in centre : zone of newly formed connective tissue surrounded by hyperplastic x 55. elastic tissue. x 75.

FIG. 4.-Obliteration of duct following intraduct carcinoma, showing hyaline connective tissue core surrounded by hyperplastic elastic tissue.


there is practically nothing I should wish to alter with the exception of one statement. I have stated that intraduct carcinoma is a “ relatively mild form of cancer” and others have used similar expressions. This, however, is in a sense incorrect and misleading. There are, of course, stages in the development of the disease, but when the anaplastic stage within the ducts has been reached the cells must be considered to possess full malignant properties and are only prevented from exerting them by the restraining influence of the duct wall. In fact, both in intraduct carcinoma and in Paget’s disease we have striking examples of the restraining powers of normal tissue. When the cells escape from the ducts into the tissue spaces an ordinary anaplastic carcinoma results ; it is usually of the scirrhous type but varieties are met with. As I have already said, quite apart from the occurrence of Paget’s disease intraduct carcinoma is the commonest discoverable ante- cedent of infiltrating carcinoma. After the malignant cells have escaped into the tissue spaces the time elapsing till metastasis occurs in lymph glands varies greatly. Sometimes it is short, and I have actually met with two cases of intraduct carcinoma in which glandular metastasis had occurred whilst no infiltrating carcinoma could be found in the existing breast. This, of course, siniply means that the focus present was very small and had escaped observation.

As a rule the malignant cells in the ducts are quite anaplastic and have lost their polarity but occasionally there is a suggestion of gland-like arrangement and sometimes they form small circles in the cell mass-the so-called cribriform carcinoma. The latter condition is, however, rare in the Paget cases. When break through ~

occurs the cribriform type may be retained in the infiltrating growth or i t may be lost and the carcinoma be of the usual type. I have dealt a t some length with these features of intraduct carcinoma as they are essential to an understanding of the relation of Paget’s disease to carcinoma of the breast. With this account as a basis I may summarise the facts with regard to the present series of cases.

Xuminary of cases.

The number of cases examined is forty-two including the five in niy original series. In a few examination was restricted, as sections only had been sent to me, but this does not affect the positive findings. In all of them intraduct Carcinoma was present and all the changes support the view that the Paget cells are malignant cells of duct origin which are growing intra-epidermally. I have not yet met with a case in which the disease had arisen from epidermal cells, though, as I have previously said, I do not deny the possibility of such an occurrence, just as intra-epidermal

carcinoma occurs in other parts of the surface of the body. In three of the forty-two cases I am unable to speak as to the condition of the breast. This leaves thirty-nine cases in which a full statement is possible. In five of these the disease was confined to the nipple ; there was no intraduct carcinoma nor infiltrating carcinoma in the breast. These cases will be referred to separately. In the remaining thirty-four, intraduct carcinoma was present also in the breast, and in twenty-nine of these infiltrating carcinoma also was present. This is a higher proportion than I expected from my earlier cases and from the accounts of others, but it corresponds pretty closely with the cases of Paget’s disease fully recorded in Cheatle and Cutler’s book. They speak of the duct disease as “ malignant- looking epithelial neoplasia within the ducts,)) but there is no doubt from the excellent illustrations that it corresponds with intraduct carcinoma. I have gone through their cases carefully and I give the results of the two series in tabular form.

Crises of Paget’s disease.

I Total

___- ____ Cheatle and Cutler . 1 1 7 ! 3 14 11

I ‘ 34 1 30

* 111 t ime arlditioiial ~ ~ t 3 . c ~ the brcast was not examined.

8. I~itrailuct carcinonia only in nipple. B. Intraduct carcinoma in nipple and also in breast. C. Infiltrating carcinoma along with intraduct carcinoma present in breast.

All the cases have been carefully examined but it would serve no good purpose to give details. There are great diversities in the histological picture but they are merely variants of the fundamental change. With the variation of the sites and the multiplicity of origin in view, all the facts become readily intelligible. Spread from a focus in the nipple gives rise to Paget’s disease and a break through from a focus in the breast results in infiltrating carcinoma. The fact that in a sinall proportion of cases the disease is confined to the nipple might suggest that the duct disease always starts there and spreads downwards to the breast but, on the other hand, we must keep in view the fact that without the presence of Paget’s disease, which is rare, intraduct carcinoma in the breast is very common and usually ends in infiltrating carcinoma. Keith Inglis considers that the intraduct disease, which he believes to spread downwards from the upper extremities of the ducts, is of a special nature in Paget’s disease and differs from the lesions present in the ducts apart from it. I can, however, find no evidence of this. Varieties in intraduct carcinoma are 110 doubt met with, but they

PAGET’S DISEASE OB NIPPLE 305

occur at any level of the duct system, the only peculiarity being that the type of intre-epithelial spread, like that in the epidermis, is more commonly seen at higher than at lower levels.

C‘uses with intraduct carcinoma in nipple only. In only five of the cases of Paget’s disease was the substance

of the breast free from intraduct carcinoma and infiltrating carcinoma. In all of these several ducts in the nipple were affected, especially in their upper parts. One case, for which I am indebted to Professor Learinonth with the note that it was the earliest that he had seen, is of interest as the Paget cells in the epidermis are so scanty. Severtheless there is multiple involvement of the ducts towards their orifices and there is direct continuity between the lesion in one of these and that in the epidermis. The question naturally arises as t o whether the ducts were independently affected or whether the disease had started in one and spread to the other orifices and then downwards. A definite answer is impossible but certainly the appearances are in favour of multiple foci of origin at the orifices. In three other cases, for two of which I am indebted to Professor Stewart and for one to Professor Cappell, the epidermal lesions were more, extensive and downward spread from the epidermal lesion might have occurred in some of the ducts. The question, however, is not of much importance as there is abundant evidence that intraduct carcinoma can affect several ducts independently. I have, for example, seen it present in several ducts in the lower part of the nipple and absent above. In the fifth case the lesion in the epidermis is advanced and several ducts in the nipple are extensively involved down to the lower part of the section. Unfortunately I had not an opportunity of examining the ducts immediately below. The substance of the breast is free froin any important change. In all these five cases intraduct carcinoina mas confined to the nipple and in four of thein had apparently started in one or more ducts close to the epidermis. This, however, is a sniall number in relation to the number where intraduct carcinonia was present also in the breast, and in viewing the whole subject we have to bear in mind that there are numerous cases of intraduct carcinoina where the nipple is free from the disease.

The relation of Paget’s disease to carcinoma of the breast. In the first place, discontinuity between intraduct disease at a

higher level and that at a lower can frequently be traced. The disease in the nipple may, in fact, be completely cut off from that in the breast, as may often be shown by the ducts below the nipple being completely free from the disease. This discontinuity is noted also by Cheatle and Cutler. In nine of their seventeen cases

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306 R. M U I R

it is stated that the disease in the breast is separated by healthy ducts from that at a higher level. There is thus no question that carcinoma is often not the result of a downward spread. I put aside for the present the question as to what is the usual occurrence.

Apart from the relation of Paget’s disease to carcinoma of the breast, the site of origin in the nipple and the direction of spread are of subsidiary importance. Various writers consider that the carcinoma usually starts at the upper extremities of the ducts and what I have described in the cases where the disease was confined to the nipple supplies examples of this. There are two points of importance in connection with this question of direction of spread. The first is that when Paget’s disease is established the malignant cells niay spread in any direction in the epidermis, around sebaceous glands, etc., and also downwards in unaffected ducts. For example. in a particular case a duct may be affected in its whole length with evidence that the disease is of older standing in its lower part whilst in another duct or ducts the disease is spreading downwards. Downward spread in some ducts may thus be secondary to the disease in the epidermis.

The second point in the histological examination is that an indication of the relative duration may be got from the degree of reactive change in the duct wall. When intraduct carcinoma has existed for some time these are of common occurrence. The sub- epithelial connective tissue becomes thickened, often to a great extent, and this is associated with degenerative change in the cancer cells, followed often by their atrophy and ultimate dis- appearance. Thus one may find a duct in the nipple affected in its whole extent and in it these reactive changes present in the lower part whilst absent in the upper. It is safe in such a case to conclude that the disease below has been of longer standing. Appearances of this kind have, however, been taken merely as confirm:ttory of other observations.

The relative times of appearance of the Paget’s disease and the infiltrating carcinoma of the breast are often referred to. These can, however, be judged of only approximately, as the earliest stage of each cannot be recognised clinically. One not infrequently finds a minute focus of cancer in a breast on niicroscopic examination when the breast was supposed to be free from it. And, on the other hand, I have now had a number of cases of cancer of the breast where only a microscopic Paget lesion was present. It is generally considered that in most cases the Paget lesion comes first and I should judge this to be so in the present series, but there are cases where, from the clinical point of view, the Paget lesion is clearly n late occurrence and we have to consider how this fact can be explained on the view that the cancer is due to a downward spread from the nipple. It has been supposed, for example by Keith Iqlis,

T O I 'l7 NA 1, 0 F l'.kTHOJ.OG Y-VOL. S LIS. PLATE LVI

ASCENI) ING INTRAUUCT CARCINOMA IN NIPPLE

Ftc. 5.-Tlic. large ilrict in centre of f i c k l FIG. li.--Tntm(lnct carcinoma in duct of nipple, of older standing in lower part and just, reaching the orifice. Case 2. i\ IS.

shows in1 rvxtliii,t, cm-chmm in lowor half. At lerel markctl X intra-epit,helial growth

on highcr magnification. No Paget lesion of epitlorrnis. Cancer of inamma was present. (I'asc 3. ?: 1s.

of cancer cells spreading upu-ads is seen

PIC. 7.-(h'ifice of tlnt-t shown in fig. 0. A Paget cell is present in the epirlerrriis on elthcr sitlc. No other lesion in epiclorinis found. Case 2. XI".

FIG. 8.-Another example of ascending intraduct carcinoma in duct of nipple. A inicroscopic Paget lesion was present at orifice. Case 4. ~ 2 0 .

PAGET'S DISEASE OF NIPPLE 307

tha't in such cases t,he intraduct disease starts as usual a t the juiict,ion of a duct and the epidermis, spreading downwards to t'he breast and causing carcinonia, and that only at a late period do the malignant cells invade the epidermis. I have found no evidence that this is the correct explanation. In quite a number of cases clear evidence exists t,hat the Paget lesion may be the result of an upwa'rd spread of intraduct carcinoma, infiltrating carcinoma in the breast' having previously arisen. I n saying this I wish to make it clear that Paget's disease is not ordinarily produced in this way.

Cases illustrating the ascent of intraduct carcinoma. These were six in number and in none of them was there any

lesion of the nipple visible to the naked eye. On microscopic examination, however, early Paget's disease was found in five, whilst in the sixth intra-epithelial spread of carcinoma in a duct was just approaching t'he epidermis of the nipple. I should have thought it difficult to find cases just a t this stage, and meeting with so many examples may be accidental ; but in view of the fact that intraduct carcinoma is commoner in the breast than in the nipple, it is likely that if the ducts as a whole were systematically examined, such an occurrence would be found to be not infrequent.

The case was one of carcinoma of the mammit with much intraduct carcinoma present in various phases. A single duct in the nipple was t,he seat of int'raduct carcinoma. It was affected in its whole ext,ent but rea.ctive changes were more marked a,round i t in its lower part. A few clumps of Paget cells, active and well defined, were present in the t~pidcmiis around the orifice of the duct. The appearances are illustrated in a. previous paper (Muir, 1934-35). The condition had not been recognised clinically as, of course, there was no Paget lesion visible to the naked eye but therc had been some hinorrhagic discharge from the nipple a short timr pre\-iously. Here we have a clear example of extensive disease in the breast with upward extension along a duct a,nd early secondary implication of the epidermis of the nipple.

J. W., aged 49. Extensive intraduct carcinoma was present in the nipple and breast,, also infiltrating cancer in the breast and in the lower part of the nipple. One duct in the nipple was completely filled with Paget cells right iip to the orifice but only one or two Paget cells were present in the epidermis (figs. 6 and 7 ) . The disease was thus in its very t%arlicst stage.

This is an interesting case for which I am indcbtect to Professor Cappell. There was no Paget lesion but the changes found alrowed that, this would have soon supervened. Intraduct carcinoma and extensive infiltrating carcinoma were present in the mamma. A large wction t.lirougli the whole breast showed a large cluct and its lactiferous sinus t.he seat of intraduct carcinoma (fig. 5 ) . The disease diminished in iLn upward direction and tlis upper part of the duct was free, but i t is noteworthy that,, just above the margin of the malignant change, isolated cancer t:ells were present in the duct epithelium-a beitutiful examplc: of intra- t~pithelial growth extending upwards.

C a s e 1. 31. C. , aged 46.

C a s e 2.

C a s e 3. J. H., aged 42.

305 R. M U I R

Case 4. K., aged 26. I am indebted to Professor Shaw Dunn for this casie. I n the breast there were localised intraduct carcinoma and infiltrating carcinoma, with metastases in the lymph glands. The examination was restricted in this case but in a section through the nipple a single duct’ was the seat of intraduct carcinoma (fig. 8). Tho cut towards its upper end was somewhat oblique and the appearance was as if the disease had not quite reached the epidermis. There were, however, a few Paget cells in the deep part of the epidermis a t the orifice. Some might question whether they are really Paget cells, but the important point is that, again with cancer in the breast, intraduct carcinoma had ascended to a point close t,o the epidermis. I should add that the reactive changes were more marked around the lower part of the duct and the disease wa,s clearly of older standing there. The age of this patient is noteworthy.

Case 5. G. McL., aged 50. This was another case of intraduct carcinoma and infiltrating carcinoma in the breast with metastases in lymph glands. There was also a good deal of intra-acinous carcinoma. A horizontal section a short distance below the nipple showed that seven main ducts were the seat of intraduct carcinoma, the disease here being apparently of varying duration (three ducts arc shown in fig. 9). At a higher level the disease disappeared from all the ducts except one, and this single duct was found to be affected up to the epidermis, where it opened in a rather eccentric position. Around the orifice of t#he duct there was an early Paget lesion, quite localised; the cells were growing in small masses (fig. 10). I am unable to speak as to the condition of t’he ducts below the 1<vel first mentioned but we have here another clear example of the intraduct disease just reaching the epidermis by upward cxtension.

There was in this case carcinoma of the breast apparently arising from intraduct Carcinoma. Carcinoma of the nipple was also present. Below the nipple three ducts were found to be the seat of intraduct carcinoma, a t a higher level only one. Paget’s disease at an early stage was present in relation to t.he origin of the latter and was apparently progressing slowly, most of the cells being degenerat>e.

Case 6. J. McK., a.ged 67.

In all these six cases infiltrating carcinoma was present in tJhe breast and ascending intraduct carcinoma in the nipple had just produced or was about to produce Paget’s disease. In all, the intraduct disease had spread from a level below the nipple. I do not consider that this represents the way in which the nipple lesion usually develops. All of them, however, are clear examples of nianimary carcinoma associated with, but not due to, Paget’s disease. They are quite against the view that, the carcinoma of the mamma in Paget’s disease is ordinarily due to a downward spread of intraduct carcinoma in the nipple.

General considerations. I have endeavoured to give a general picture of this type of

mammary disease. It is a picture of malignancy arising in the duct system and often in independent foci-in different ducts and in different parts of the same duct, in the breast or in the nipple or in both. The disease in the ducts of the nipple may extend to the epidermis, resulting in Paget’s disease ; the disease in the

J O 1 1ISAI. O P PATHOI~O(:\’ -Vor,. XLIX.

INTI?ADITC~T CARCINOMA AND PAGET’S DISEASE

PLATE LVII

FIG. g.---Horizctntal st&on just holow l e d of FIG. 10.-Early Paget lesion around orifice of nipple, showing iiit;atlu(.t carcin~~ina in three &lasses of cancer ducts (srren were affect rtl). At higher levels c d s preisent in epiderrnis. l‘his was the the clirrasc. tiis:rppt!iircd in all hu t cine (sco fig. 10). Case 3 . A 65.

duct referred to in fig. :).

oiily Paget lesion present. Case 5 . x 65.

Fro. 11.-Paget lesion in which the cancer Fro. l‘.-Paget lcsion in which many of‘ the cells arc disscroinat.cd throughout the cancer cells are columnar and tend to form epiclormis and are uniisually well preserved. dnct-like structures. x 1%. x 150.


breast-much the commoner occurrence-frequently gives rise to carcinoma. These are the fundamental facts but, in addition, extension of the disease along the ducts may also play a part in producing the results. It is possible that the intraduct carcinoma starting at the nipple may sometimes spread downwards and give rihe t o cancer in the breast; on the other hand I have given examples of upward spread of the disease to the nipple from a lower level. Nevertheless, either of these occurrences must be regarded as in a sense accidental and in no way affecting the general conception of the relation of Paget’s disease to carcinoma of the breast. It is certainly clear that the time of appearance or the stage of the nipple lesion gives no indication whatever as to the condition of the breast in Paget’s disease. The Paget lesion may mean that the first seat of malignancy is in a duct in the nipple or it may be a terminal phenomenon when there is already extensive malignant disease in the breast. The cases recorded show that whatever the stage of the nipple lesion, in the great majority of cases intraduct carcinoma is present in the breast and that in a large proportion of these ordinary carcinoma has developed. Anything in the nature of local treatment of the disease of the nipple is accordingly quite unjustifiable.

Some fucts regarding the nipple. The histology of Paget’s disease is well known but one or two

points may be referred to. The appearances vary greatly iii different cases, the variations depending chiefly on the rapidity of growth of the invading cells. At one extreme in the epidermis there may be masses of large cells with many mitoses just like a rapidly growing carcinoma (figs. 13 and 14). At the other the cells are sparsely arranged and may be so degenerate as to be uiirecognisable as cancer cells. It is common to find the Paget cells in an active state in the deeper parts of the rete Malpighii, while a t higher levels they become more and more degenerate. Rarely, they are disseminated and well preserved throughout the different layers of the epidermis ; fig. 11 shows an example of this. Different appearances may be found in different parts of the same nipple. One interesting variation from what is usually seen is that occasionally the Paget cells have a columnar form; such an occurrelice is not surprising in view of their origin. Traces of this appearance have been not uncommon in my series and in one or two cases it has been a striking feature. Fig. 12 is from a case for which I am indebted to Dr Heggie and illustrates the eoiiditioii better than any written description could do. Figs. 513 and 514 in a previous paper (Muir, 1934-35) are other examples. Such appearances are simply those of an adenocarcinoma which has reached the epidermis by the intra-epithelial route. Again, some-

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310 R. M U I R

times the Paget cells instead of being rounded or oval are of small size and somewhat angular or even spindle shaped. This has been a noteworthy feature in five cases. Cells of this character may grow in compact masses more like an epidermoid growth, but there are others in which a considerable amount of fluid is present between the cells (figs. 15 and 16). When the ducts in the breast are extensively involved in this way, considerable enlargement of the affected part may result. It is an interesting fact that when there are unusual cell features in a given case these are found in different situations, that is, not only in the epidermis but in the affected ducts and even in the infiltrating carcinoma which has occurred as a secondary result. This is another illustration of the fact that the Paget cells in the epidermis are of direct origin. The only exception to what I have stated was found in a case for which I am indebted to Professor J. S. Young. In the breast a mucoid (“ colloid ”) carcinoma was present, whereas the cells in the intraduct carcinoma in the nipple and in the Paget lesion were of the ordinary type-not mucin-forming. Thus apparently two types of malignant growth were present.

The naked-eye appearances of the Paget lesion also varied considera,bly, but in the great majority of cases it was confined to the nipple and corresponded in character with that usually described. In only one case was the area of epidermis affected very large ; it was circular and measured 4 in. in diameter, with the nipple in the centre. It is not possible to say why the disease sometimes spreads widely ; this certainly does not depend on its duration. In the case mentioned the lesion was of one-and-a-half years’ standing, whereas in another case of nine years’ standing the lesion had not passed beyond the nipple. It is noteworthy that when the disease has been of long duration there may occur obliteration of ducts with much fibrosis around and this may result in retraction of the nipple, sometimes to a marked degree, without the presence of infiltrating carcinoma. Sometimes the affected epidermis shows considerable thickening with little or no redness. This occurs when the growth of malignant cells in the epidermis is abundant and has led to a relatively thick layer which obscures the redness of the vascular tissue underneath. In such cases the ordinary red oozing surface may not be present.

Ordinary carcinoma of the nipple has been present in five of the cases of Paget’s disease. It occurs either as an upward spread from carcinoiiia in the breast substance or as a primary growth in the substance of the nipple. In the latter case I consider that it must frequently arise from intra-acinous carcinoma in the nipple which lias occurred as a result of spread from intraduct carcinoma. The ducts in the nipple have relatively thick and resistant walls and direct spread through them does not readily occur. Occasionally

JOURNAL O F PATHOLOGY-VOL. XLIX.

PAGET'S DISEASE

PLATE LVIII

FIG. 13.-Example of thc somewhat rare '' encephaloid " type of Paget lesion. of Paget cells in epidermis. x 140. Two masses of' cancer cells are seen sharply marked off from the cells of the epidermis ; also some scattered Paget cells. ~ 1 2 6 .

PIG. 14.-Another example of massive growth

FIG. 15.-Type of Paget lesion in which the F ~ G . 16.-Intraduct carcinoma from same cells are somewhat small and angular and case as fig. 15, showing correspondence in are surrounded by fluid. x 200. type of cells to those in epidermis. x 200.


an infiltrating carcinoma underlying the epidermis invades it and then spreads widely in it, as in Paget’s disease. This has been described especially by German writers but in my experience it is of very rare occurrence. I have seen it in only three cases, none of them in the present series. In the cases in which cancer of the nipple has accompanied Paget’s disease there has also been intraduct Carcinoma and from it Paget’s disease has occurred in the usual way, i . e . by the intra-epithelial route from the upper extremity of a duct. I have accordingly formed the opinion that the histological features of Paget’s disease occur only quite exceptionally as the result of direct spread to the epidermis of an infiltrating carcinoma underlying it.

The invaded epidermis is not infrequently shed in places and ulcerated areas of cellular granulation tissue are present. Attempts at healing are little in evidence but in one case a growth of new epithelium of considerable extent had occurred. The newly formed epithelium, which was of fair thickness, presented almost a straight line at its junction with the cutis and there was no new formation of papillae.

The question as to whether carcinoma in general arises very frequently from duct or from acinus epithelium is not one of importance and in most cases cannot be definitely answered. So far as my observations go, the position simply seems to be that malignant change arises more frequently in ducts than in acini but that a break through into the tissue spaces will take place more readily when the malignant cells are in the acini. The characters of the malignant cells give no clue as to the exact site of origin. They are of similar nature in intraduct and in intra- acinous carcinoma.

The presence of extensive growth of malignant cells in the epidermis without infiltration of the subjacent tissues is a striking phenomenon and has often been commented upon. It is an example of balance between the invasive properties of the neoplastic cells and the resisting power of the tissues. Other examples are seen in the duct system throughout the breast. I have only once seen what I consider infiltration of the cutis in Paget’s disease. It was relatively superficial but the appearances certainly showed that the cells were in the tissue spaces. In another case the changes present were probably of the same nature. In no case, however, have I seen deep invasion of the substance of the nipple and one can say that spread of malignant disease from the Paget lesion plays no important part in infiltrating cancer of the nipple.

Summary.

1. The examination of 42 cases of Paget’s disease of the nipple fully supports the view that the nipple lesion is due to intra-epithelial

312 R. MUIR

growth of cancer cells which have spread from malignant disease in the upper extremity of a lactiferous duct-intraduct carcinoma. It also supports the view formerly expressed as to the association of Paget’s disease with carcinoma of the mamma.

2 . In all the cases, intraduct carcinoma was present in the nipple. Of 39 cases fully examined it was present in both breast and nipple in 34 ; in 30 it was accompanied by infiltrating carcinoma of the breast.

3. The carcinoma of the breast which is so often associated with Paget’s disease is ordinady due to extension from an independent focus of intraduct carcinoma in the breast. In view, however, of the mode of spread of intraduct carcinoma, the possibility of carcinoma of the breast resulting from a downward direct extension of intraduct carcinoma in the nipple must be admitted, but no undoubted example of this has been met with in this series of cases. On the other hand, in six cases of carcinoma of the breast there was found an upward spread of intraduct carcinoma from a level below the nipple, and this had just reached or was just reaching the epidermis, before the appearance of the clinical signs of Paget’s disease.

4. The time of appearance or the stage of Paget’s disease gives no information as to the presence or absence of carcinoma in the breast. The cases here recorded show a high frequency of carcinoma of the breast and emphasise the grave significance of the Paget lesion.

5. Observations are given regarding intraduct carcinoma and lesions of the nipple.

In addition to those mentioned, I wish to thank Dr J. F. Heggie, Dr Janet Niven and Dr A. C. Lendrum for their services in supplying me with specimens from the routine material of the Glasgow Western Infirmary, and also Mr John Kirkpatrick of the University Department of Pathology for making the photomicrographs.

REFERENCES.

CHEATLE, G. LENTHAL, AXD

INGLIS, KEITH . . . . . CUTLER, 31.

JACOBBUS, H. C. . . . . KILGORE, A. R. . . . . . MUIR, R. . . . . . . .

. . . . . . . >,

MUIR, R.,AXDAITKENHE.4D,A.C. SCHAMBACHER, A. . . . . SCHULTZ-RRAUNS, 0. . . .

s l ~ ! l A R D , c. . . . . . .

1931. Tnmours of the breast, London.

1936. Paget’s disease of the nipple, London.

1904. 1921. Arch. Sccrg., iii. 324. 1927. This Jourwal, xxx. 451. 1934-35. Brit. J. Surg., xxii. 728. 1934. This Journal, xxxviii. 117. 1905. Dtsch. 2. Chir., lxxx. 332. 1933. Dir Geschwulste der Brustdruse, in-

Henke and Lubarsch’s Handbuch der speziellrn pathologischcn Anatomit? und Histologic, Berlin, vol. vii. pt. ii. p. 300.

Arch. path. Antat., clxxviii. 124.

1930. Bull. Assoc. fmng. cancer, xix. 50.

Documents

Further observations on Paget's disease of the nipple