PAGET’S DISEASE OF THE NIPPLE AND ITS RELATIONSHIPS.

ROBERT MUIR, M.D., F.R.S. From the Pathological Department of Glasgow University and

Glasgow Vestern In$rrnarq.

(PLATES XL.-XLIII.)

I N this paper I propose to give an account of the pathological changes in Paget’s disease of the nipple and t o state my opinion as to their nature and significance. The account concerns chiefly my own observations, though reference is made also to the chief views which have been put forward. It is a remarkable fact that although fully fifty years have elapsed since Paget’s description of the disease appeared (1874) opinion as to the interpretation of the lesions still varies greatly. It is not necessary to refer in detail to this diversity of opinion-one has only t o refer to recently-published books in this country and America in order to see how great it is. Paget’s original account was, of course, a clinical one, but before long it came t o be seen that the essential and characteristic feature in Paget’s disease is the presence of peculiar cells in the epidermis of the nipple-cells which are now generally spoken of as “Paget cells,” and it is with regard to their nature and origin that so many different views are expressed. It is sometimes said that the difference of opinion referred to is due to the fact that really different affections may lead to appearances such as those originally described by Paget. This is true only to a limited extent, and if one takes his full description of the local lesion along with his statement that cancer not infrequently develops at some other part of the breast, it will be found that Paget’s disease is a special affection whose clinical features are intimately related to the histological changes. And further, if one compares the illustrations given by different writers whose interpretations disagree, one sees that they are dealing with the same lesion; the divergence of opinion is thus a real one.

It would serve no good purpose to review in detail the many opinions which have been put forward by individual workers. It will however be of advantage to classify them briefly. If we omit the now discarded view of Darier and Wickham that the Paget cells are invading parasites (psorosperms), we may say that the various opinions are modifications of two main views. (1) One view is that the peculiar

451

452 R. M u m

appearances seen in the surface epithelium are the result of degenerative changes, alone or in combination with non-neoplastic proliferation. Such changes have been ascribed t o various causes-to irritating discharge from the nipple (Thin) ; to inflammatory change in the cutis with formation of granulation tissue, this in its turn being the result of slowly-growing carcinoma (Hannemuller and Landois) ; to cedema resulting from lymphatic blockage below (Handley). Unna, whose opinion naturally carried much weight, in his work on the histo- pathology of the skin described the most important change as a degeneration of the prickle cells, which might be regarded as a peculiar forin of cellular cedema; the cells become swollen, lose their fibrillary system and compress the adjacent epithelial cells into deeply-staining cellular rafters. He pointed out that the change had no resemblance to that met with in eczema or other affections of the skin but expressed no opinion as to its causation. I t may be noted that his description is confined to the epidermis of the nipple and no reference is made to the condition of the underlying ducts. (2) The other view is that they are the result of neoplastic change-the Paget cells are tumour cells. According to this view there are two possibilities-(a) either the cells are formed in sit% from the epidermis by a process of anaplasia or de-differentiation, or ( b ) they have spread to and invaded the epidermis from elsewhere. I n the latter case there are again two possibilities- either they have spread into the epidermis from the ducts a t their orifices or directly from the alveoli of an underlying carcinoma. That occasionally such a carcinoma may invade the epidermis and give rise to changes in i t resembling those seen in Paget’s disease must be admitted, as will be described below; but when lhis occurs the case is recognisa>ble as one of cancerous infiltration of the nipple. The real pathological problem is as to the source of the Paget cells i n the epithelium of the nipple when there is no cancerous infiltration of the lymphatsics and tissue spaces of the underlying cutis; and this condition conforms wilh that in Paget’s original description. I may mention here that in none of the cases on which this account is based was there infiltration of the tissues of the nipple by ordinary cay cinorna.

With regard to the cases which I have examined, I may make the preliminary statement that I have never found any evidence that the Paget cells are the result of degenerative changes. I consider that they are really tuniour cells and that (at least as a rule) they are produced by a neoplastic proliferation of the epithelium of the upper parts of the ducts of the nipple and thence they pass into the epidermis, within which they extend-the mode of extension is thus intra-epithelial. I formed this opinion a good many years ago, but have recently had occasion t o re-examine the matter in view of the opinions put forward by other writers and the result has been to confirm my earlier conclusions. The account which follows is

PAGET’S DlSEASE O F NZPPLE 4 53

based mainly on five cases which I have examined within the last few years; I have sections from other cases, but as I have no clinical notes I have not referred to them though the changes are of the same kind. The view as to the Paget cells being of neoplastic nature is adopted by the majority of recent investigators but the view that these cells spread from the ducts to the epidermis has been put forward by only a few. Reference is made to this below.

Changes in the ducts. In view of the opinion expressed with regard to the nature of

Paget’s disease the related changes in the ducts of the mamma come to be of special importance and may with advantage be first discussed. These changes were described in the first account of the histology of the disease given by Butlin in 1876 and have since attracted the attention of many writers on the subject. As is well recognised, the ducts may be the seat of a great variety of morbid changes and in the lesions all stages of transition are met with, from simple papillomatous growths with thick and well-formed stroma to the formation of masses of large de-differentiated epithelial cells. It is the latter condition which is of importance in relation to Paget’s disease; it is often spoken of as “duct carcinoma” but it is advisable to consider the significance of the term. The cells within the ducts are often relatively large and of rounded form and are usually massed together irregularly, though sometimes there are traces of acinus-like arrangement in the cell masses and sometimes when the cells form a lining to the duct there may be small papilla-like projections. But in the extreme type of change there is no stroma between the cells. The nuclei of the cells are large and of the vesicular type with distinct and often large nucleoli. Some nuclei are hyperchromatic and there is a tendency to aberrant types; mitotic figures are not uncommon. In fact, the general appearance as regards both characters of cells and their arrangement is that of an encephaloid cancer; but of course the cells are still contained within the normal boundaries (figs. 1, 2). I believe that in such cells the change of malignant neoplasia has already occurred and that they t e ~ ~ d t o break through tho walls of the ducts and invade the tissue spaces. One meets with cases of cancer in which the cells within the ducts and those in the tissue spaces have precisely the same character and one may sometimes see the cells within the ducts in process of breaking through, as has been figured by Cheatle. The changes referred to represent the extreme stage of what he has called “dysgenetic hyperplasia,” and my views as to its nature and significance correspond with his. Nevertheless, the term duct carcinoma has certain disadvantages especially from the clinical point of view. If, as is the ordinary custom, carcinoma is used as implying an actual invasion of the tissue spaces and lymphatics-a progressive infiltration and one which

454 R. MUZR

ordinarily leads to the death of the patient-then the term duct carcinoma becomes misleading. We cannot even say that a duct carcinoma will always break through the confines of the ducts and become a carcinoma with the ordinary properties. I t s cells may be regarded from the pathological point of view as having undergone the change of malignant neoplasia, yet they are only potentially malignant in relation to the subsequent events, that is from the clinical standpoint. The term should be used with this significance, though " intra-duct carcinoma '' would be more correct. After this discussion as to the nature of the lesion we may next consider some of its characteristics.

A striking feature of the disease is the extensive involvement of the ducts which is often found without the presence of any break- through into the tissue spaces ; sometimes there is also a spread of the neoplastic cells to the acini, occasionally with extensive involvement of them. Clearly the growth must either be of a low order of malignancy or the walls of the ducts and acini have a markedly restraining effect on it. The facts known with regard to the invasive behaviour of cancer generally speak in favour of the former explana- tion and there are also some other facts yhich go to support it. One of these is the mode in which the proliferating cells extend in the ducts, that is, the manner in which epithelium previously healthy becomes affected by the change. This is a point on which I have failed to find reference by other writers. The earliest changes may sometimes be seen in the larger ducts and especially in the lactiferous sinuses or ampullae of the nipple. A t one part the epithelium may be normal while in an adjacent part there may be masses of the altered and proliferating cells. Now just where the change is commencing the epithelial lining, usually composed of a double layer of cells, is seen to be in process of invasion by the tumour cells which appear to push their way under the superficial layer and then actively proliferate. The result is that the proliferating cells are covered by a layer of cells which have not undergone the change, these cells being small with deeply-staining nuclei (fig. 3). It is remarkable how long the snper- ficial layer may persist; even when the neoplastic cells have formed a lining several cells in thickness it may be still present as a sort of internal limiting membrane (figs. 4 and 5). Sometimes a line of basal epithelial cells can be seen under the proliferating cells; they are of small size and of somewhat pyramidal form but they rarely form a continuous layer of any extent. So far as I can judge, the epithelial cells of the duct or ampulla which is being affected act in a passive manner and, usually a t least, do not join in the neoplastic prolifera- tion; though of course this is a point on which it is impossible to be quite certain. The fact that a t the extending margin of the disease we see a gradual tapering-off of the proliferating cells is also in favour of this view. And further, when a portion of a mamillary duct lined

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PAGET’S DISEASE OF THE NIWLE. PLATE XL.

FIG. 1.-Intra-mammary duct showing the char- acteristic appearance of intra-duct carcinoma. x 70. showing characters of the cells. x 200.

FIG. 2.-Higher power view of portion of the same

FIG. 3.-Section of portion of lactiferous sinus showing the mode of early affection of its epi- thelium. At the right the pale tumour cells are growing in the epithelium ; the superficial cells, seen as a darkly-stained atrophied layer, still survive. ‘1 his is analogous to what is seen in of the growth. x 35. the epidermis. x 160.

FIG. 4.-Duct in nipple (case 1) lined by several layers of tumour cells separated from the lumen by a thin layer of flattened and deeply-staining cells which represent survivals of the original layer. This illustrates the intra-epithelial feature

FIG. 5.-Nipple (case 2) showing two adjacent lactiferous sinuses. In the lower part of the right, intra-duct carcinoma at an early stage is seen as masses of cells which have grown in the substance of the normal epithelium. Extensive intra-duct carcinoma was present in the mamma while the Paget’s disease of the nipple was at a very early stage. x 30.

FIG. 6 -Two fairly large intra-mammary ducts, the seat of intra-duct carcinoma. The lower, seen just a t its division, contains degenerated material in addition to the tumour cells. In the upper duct the greatly thickened wall is con- tracted on the tumour cells which are undergoing degeneration and atrophy. Note cellular infiltra- tion around the ducts. (Case 1.) x 60.

PAGET’S DISEASE OF NIPPLE 465

by stratified squamous epithelium is being affected the appearance is certainly that of an infiltration of the deeper layers rather than a tranformation of the cells in situ into the neoplastic type (fig. 18).

There may thus be said to be an invasion of the epithelium by the proliferating tuniour cells or, in other words, the growth of the latter is intra-epithelial in position. This seems to me to be a feature of great importance in connection with the changes in the surface epithelium in Paget’s disease which have been regarded by certain writers (with whom I agree) as the result of an intra-epidermal growth of glandular epithelial cells. The mode of extension within the ducts can be traced only where healthy epithelium is beginning to be affected, but a t this stage I have repeatedly observed the appearances just described. The proliferating cells thus present another feature not related to what is seen ordinarily in malignant disease, since they may respect the pre-existing arrangement of the epithelium as a layer for a considerable time. A t a later period any definite arrangement of the cells may disappear and the ducts are then simply filled by masses of anaplastic epithelial cells.

While the cells filling the ducts may have a healthy and active appearance degenerative and necrotic changes are common, especially in the larger and medium-sized ducts. Thus accumulations of partly degenerated cells and debris are formed and calcification in these masses is sometimes seen. Another change which may be met with is reactive thickening of the connective tissue around a duct (fig. 6). This may reach a high degree and may be associated with retrograde changes in the cells within them. Masses of compressed and atrophied cells niay be seen to be surrounded by a zone of condensed tissue, and evidence of complete disappearance of the contained cells is occasionally present. I n other words, a process of local involution of the growth with healing has occurred. Such a process is quite comparable with the healing-in which was described by M. E. Schmidt as occurring within the sniall branches of the pulmonary arteries when they are the seat of embolism by cancer cells, and which I also have observed.

Although the neoplastic proliferation within the ducts spreads widely by direct continuity and whole duct systems may thus become affected, this does not exclude the possibility that the disease may start a t several different places. I n fact this must be so, as the main ducts are independent and several may be the seat of the disease. If the cause of the condition is some form of irritation acting over a long time it is quite in accordance with experimental results that neoplasia may be set up in different foci. So far as the results of the disease are concerned, a distinction may be drawn between the ducts above the lactiferous sinuses or ampulke and those below with their branches. The former are related to the epidermal changes of Paget’s disease and the latter t o the outbreak of cancer in the substance of the breast. In two cases I have seen the disease extending downwards in a sinus

456 R. MUIR

from the duct above it, the lower part of the sinus being unaffected. This shows that either there must have been an independent affection of the duct above or that the duct had become secondarily affected from the disease in the epidermis.

Extension to the acini. There seems t o me to be no doubt that the proliferative process

extends widely along the walls of the ducts, as has been said, and one of the most striking occurrences is the involvement of the related acini. These come to be somewhat enlarged and contain large, rounded or polyhedral cells, similar in character to those in the ducts. The cells may be in masses filling the acini or may form a sort of lining to them. An interesting point is that in some of the acini thus affected it may be seen that Ihe invading cells have not completely destroyed the pre-existing epithelium but have invaded i t in a manner similar t o what has been described in the case of the ducts. This is well shown in fig. 10 where the neoplastic cells are seen separated from the lumen by a layer of the pre-existing cells with deeply- staining nuclei and little protoplasm. The, surviving basal cells may be occasionally seen, though less frequently than in the ducts, and sometimes the pre-existing cells in an atrophied state can still be distinguished between the tumour cells. Here again an intra-epithelial growth of the invading cells can be observed. Evidence of this mode of growth naturally becomes lost a t a later period and the pre-existing acini are filled with masses of large cancer-like cells. I t seeins that, a t least as a rule, this change represents a direct extension from the terminal ducts to the acini; wherever the acini have undergone the neoplastic change the small ducts related to them are filled with cancer cells (fig. 9). A remarkable fact is that over considerable areas the acini have undergone this change without there being any evidence of break-through into the tissues around. The affected areas thus come t o have the appearance of having undergone a sort of cancerous transforniation and present a marked contrast to those where the acini are still not involved. This feature is illustrated in figs. '7 and 8, and it will be noted that whilst the acini are stuffed with cells like cancer cells their arrangement is not disturbed. It may be added that similar changes may occur in the acini of the nipple itself; there may be localised duct carcinoma and the related acini may be siinilarly invaded, whilst there ist no evidence of any infiltration of the tissue spaces around. The invasion of the acini in the mamma may be seen only a t some places but occasionally may be very extensive. I n one case (number 1) two fairly large parts were taken from different parts of the breast and in both of these the neoplastic transformation of the acini had occurred over considerable areas. A very abundant infiltration of plasma cells and lymphocytes was present and this was definitely around the affected acini, the interstitial tissue

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PAGET’S DISEASE OF THE NIPPI,*:.

PLATE XLI.

FIG. 7.-Mamma in a case of Paget’s disease FIG. 8.-Another part of the same breast showing two adjacent groups of acini. more highly magnified in which the Those above are the seat of intra-acinous normal epithelium has been almost com- carcinoma, while those below are un- pletely replaced by tumour cells. x 85. affected. Note the marked cellular infil- tration. x 70.

FIG. 9.-Breast showing a duct with its FIG. lO:-Acini the scat of intra-acinous related acini affected by intra-duct car- carcinoma. Lining epithelium infiltrated cinoma and intra-acinous carcinoma by large ale turnour cells, which are respectively. The normal epithelium separated from the lumen by a surviving has been almost completely replaced by layer of the original cells darkly stained. tumour cells. x 55. The growth, of intra-epithelial type, is

still contained within the normal confines. (Case 4.) x 180.

PAGET'S DISEASE O F NlPPLE 467

of the normal acini being unaffected (vida imfra). It may be that a change similar to that in the ducts may start independently in the acini, but the evidence appears to me to be chiefly in favour of the view that the proliferating cells extend from the terminal ducts. Certainly the characters of the cells in the two positions correspond closely.

Changes in the epidermis.

For the satisfactory study of the lesions in the epithelium of the nipple i t is essential that the disease should be in a fairly active state. In some cases nearly all the Paget cells are undergoing retrogressive changes, their nuclei are irregular and pyknotic whilst the protoplasm is reticulated or has a somewhat shrivelled appearance. In fact, all structural details may have gone and the individual cells occupy a sort of space enclosed by a capsule-like structure resulting from condensation of the substance of the surrounding epithelium. Were cells in this state to be studied alone-and sometimes nearly all are thus altered-it would be impossible to pronounce definitely as to their nature. In many cases however such retrogressive forms may be present along with actively growing cells and i t may be readily seen that there are all stages of transition between the two types.

If we examine sections of the nipple when the disease is fairly extensive and active, we find in some parts that there are comparatively large masses of cells which have replaced the deeper parts of the surface epithelium and which may have also led to a considerable increase of its total thickness (figs. 11-13). In other parts there are smaller groups and scattered individual cells. These may be seen in anypart of the epidermis but are inore numerous in the deeper layers. When the epidermis is extensively invaded its lower part forms blunt projections into the cutis underneath. The papill% between the projections may be reduced to mere lines, whilst thin strands of connective tissue with small blood vessels may sometimes be seen extending high up into the epidermis. Although the downward growth resulting from the epithelial invasion may be considerable I have never found any actual invasion of the tissue spaces by the cells. Such changes in the epidermis vary greatly in their degree in different cases and are very irregular in their distribution. Portions of normal epithelium may intervene between the affected areas and the appearances suggest that the groups of invading cells are often separated from one another : this question will be referred to below. In places the Paget cells may occur singly or may form an interrupted layer of single cells in the deepest part of the epidermis. Extension to the sebaceous glands may also be met with.

The Paget cells appear first and are most numerous and of largest size in the rete Malpighii. Their characters are well shown in the illustrations (figs. 16,19, 20). Where they are actively growing they

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458 R. iMUZR

are coniparatively large, rounded or oval with abundant and faintly staining protoplasm, and of somewhat undifferentiated character. Their nuclei are vesicular, often hyperchromatic with large nucleoli, m c l aberraot forms may be present. Mitotic figures are not infrequent in the Paget cells, especially in those lying in the deeper part of the rete Malpighii, but I have never seen any in the cells of the rete itself. As the invading cells grow, the cells of the rete become compressed, often flattened or drawn out (fig. 19), though the cell bridges persist for a long time and can be recoguised in the compressed and often distorted cells. As has been stated, a t no place is there any true infiltration of the cutis, and a point of interest is that, when the rete is largely replaced by the turnour cells, somewhat flattened cells with darkly stained nuclei can often be seen between them and the connective tissue beneath. These flattened cells may form almost a distinct limiting layer and they can be readily traced to be simply the deepest cells of the rete which have heen compressed and flattened by the invading cells. The latter are, as a rule, undifferentiated and irregularly arranged, but in one case those next to the tissue of the cutis had a somewhat columnar character: this appearance in shown in fig. 1 6 where the limiting layer of flattened basal cells is also well seen. Occasionally spaces may be seen in the masses of the invading cells, apparently filled with serous fluid in which are leucocytes and cellular debris. Where the tumour cells are less active they are of small size and are sharply separated from the surrounding cells of the epidermis by capsule-like structures, as mentioned above. Their nuclei gradually lose their structure, become irregular in forin and shrunken and stain more deeply. It is cells in this condition which give rise t o appearances which formerly led to tiheir being regarded as psorosperms. All stages of degeneration can be seen in such cells and the degeneration is specially apt to occur in the more resistant superficial layers. The cells appear to flourish well only in the deeper parts of the rete and apparently many are carried upwards in the normal growth of the epidermis, becoming atrophied and encapsulated as they grow. Occilsionally there can i)e seen high up in the squanious layers degenerated cells of small size and even in process of being cast off with the superficial squames. The invading cells sometimes reach nlniost to the surface and still retain their healthy appearance, but this occurs only when the cells form fairly large masses and grow actively, the superficial layers then being thinned before them. It may be noted that everywhere the Paget cells appear t o me to be quite distinct from those of tlie epidermis and I have found no indication of intermediate fornis between them. At a late stage of the disease, the superficial epithelium may become destroyed and the epidermis is represented by the deeper blunt processes composed of Paget cells, nimy of which are often in a degenerated condition.

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PAGET’S DISEASE OB TIIY: NIrI>m.

PLATE XLII.

FIG. 13. Epidermis of nipple showing invasion of FIG. 14.-Direct infiltration of epidermis of iiipple the deeper layers with masses of Paget cells Masses of cancer which are somewhat angular and compressed. cells are seen in the deeper parts of the The cells in the ducts beneath had the same epithelium ; in the superficial parts isolated characters, as shown in fig. 15. (Case 5 . ) x 110. degenerated cancer cells are surrounded by

capsules ; the appearances resemble those seen in Paget’s disease. x 165.

by underlying carcinoma.

PAGET’S DISEASE O F NIPPLE 469

I have stated above that in the ducts and acini the proliferating cells tend in the first instance to grow for a time within the lining epithelium without destroying its arrangement as a layer. I n the epidermis we see a corresponding invasion with the same cells, and the difference in this situation is due to the greater resistance offered to the invading cells by the cells of the epidermis. Growth is thus most marked in the softer and less resistant layers of the rete and even there it is of patchycharacter, the appearance being as if the balance between growth and no growth was often very little in favour of the former. An interesting example of a type of growth intermediate between that in the ducts and that in the epidermis was observed in one case. This was in the wall of a duct above the lactiferous sinus or ampulla and the layers next the lumen had been changed into a fairly thick lining of flattened and almost cornified cells while the deeper layers were almost uniformly infiltrated and replaced by tumour cells which formed a sort of sheathing to the superficial layers of flattened cells (fig. 18). In this duct, probably as a result of some form of irritation, the superficial cells had undergone metaplasia to a more resistant type, whilst the deeper cells retained the characters of duct-epithelium and thus were readily permeated by the growing tumour cells. It may be added that in other cases when the upper parts of the ducts are filled by the neoplastic cells, separate masses of surviving squamous epithelium may be seen to be surrounded by them.

Origin of the Paget cells.

I have already mentioned that I consider that the Paget cells are clearly tumour cells and not the result of any degenerative change in the cells of the epidermis. When, as in the present series of cases, there is no cancerous infiltration of the substance of the nipple, the cells in question must either be derivatives of the cells of the epidermis by a process of anaplasia or spread in the substance of the epitheliuni from the cells within the ducts a t their orifices. The cells invading the epidermis are, as a rule, like those of a glandular carcinoma; the occasional tendency to assume a columnar form, as shown in fig. 16, is also noteworthy. I have not been able to find cell bridges in them, and Unna and others have obtained the same result; there is no evidence of the formation of cell-nests etc. In short, so far as I can judge, they are unlike the cells of any growth originating from the epidermis. In all the cases examined intra-duct carcinoma was present and the characters of the cells in the epidermis and of those in the ducts of the nipple beneath correspond in their characters, although the cells in the epidermis vary more in size owing no doubt to the varying resistance offered to their growth. It is noteworthy that in one case where the cells in the epidermis were somewhat angular and

460 R. MUIR

compressed, being less distinct from those of the epidermis than is usual (fig. 13), the cells in the ducts immediately below had the same features (fig. 15), as had also the cells of an ordinary carcinoma which had broken out deep in the substance of the mamma. Further, in three cases (one of these not being in the present series of five), direct continuity was found between the cells filling the upper parts of the ducts and those infiltrating the epidermis (fig. 17). The conclusion thus seems to me to be inevitable that the proliferating cells within the ducts when they reach the junction with the epidermis grow into and spread in its deeper and softer layers. The intra-epithelial growth of the neoplastic cells is seen not only in the epidermis but also, as has been described above, within the ducts a t an early stage and also within the acini when extension occurs t o them.

The distribution of the invading cells in the epidermis is peculiar, as their growth seems to be discontinuous and they often occur in apparently isolated groups. This however may be in part only apparent, and in connection with the question it is interesting to note that in one case Schambacher found by serial sections that all the cells in the epidermis were in continuity and that, the appearance of isolated groups was due to sections of narrow strands of cells. Kyrle obtained a similar result by means of serial sections, ahhough in his case the epidermis had been invaded directly from an underlying carcinoma. I n spite of these results, however, i t is difficult to believe that all the appearances are produced in this way-that the cells are always in continuity. One occasionally sees in Yaget’s disease a single layer of the invading cells in the deepest part of the rete Malpighii, some of which are undergoing atrophy and disappearance. Such a layer is manifestly in process of interruption and one can imagine that in some parts the cells may take on more active growth and thus the appearances of isolated foci may be produced. It is to be kept in view that the disease is an extremely chronic one, the invading cells are growing in a dense and resistant tissue and the degree of resistance no doubt varies in different parts. It is accordingly not difficult to imagine that a peculiar distribution of the cells may result in course of time. The possibility that the cells may actually wander in the epidermis cannot be excluded, and a t first I thought that such a process of wandering was necessary in order to explain the appearances; but in view of the chronicity of the process it seems possible that these may be the result of the cells growing in some parts and dying out in others. We have also the all-important fact that a similar distribution, with the occurrence of scattered cells, may be met with when a carcinoma invades the epidermis from the cutis. The distribution of the Paget cells does not appear to me to be a real objection to the view which I have expressed. And any difficulty of explaining the distribution exists equally on the supposition that the Paget cells are derived from the cells of the epidermis.

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PAOET’S DISEASE OF THE NIPPLE.

PLATE XLIII.

FIG. 15.-Part of duct of nipple underlying the Paget lesion, from the same case as fig. 13. The cells of the inha-duct carcinoma are more angular and of smaller size than is usual. x 85.

FIG. 16.-Skin of nipple from the same case as fig. 11. The invading cells have in places a columnar form and tend to a duct-like arrange- ment ; the surviving flattened basal layer of the epidermiq is well seen. x 145.

PIG. l?.-Upper part and orifice of lactiferous Horny epithehm in duct showing direct continuity of the cells of the centre, surrounded by a sheath of tumour cells duct-carcinoma with those in the epidermis which were continuous above with the cells infil- where the cells have the characteristic scattered trating the epidermis, and below with the masses arrangement. Extreme cellular infiltration of of tumour cells within the lactiferous sinus. the cutis. x 45. x 45.

FIG. 18.-Duct of nippIe.

FIG. 19.-High - power view of inter-papillary FIO. 20.-Another section of surface of nipple showing Paget cells in the deeper parts of the e ithelium ; some of the cells show degenerative cganges, pyknotic nuclei, etc.

process of epidermis of nipple, showing the characters of the infiltrating Paget cells ; the prickle-cells of the rete are seen to be becoming compressed and atrophied between the invading cells. x 325.

x 145.

PAGET’S DISEASE O F NZPPLE 461

Reactive phenomena. The growth of the Paget cells in the epidermis is attended by

secondary changes in the connective tissue beneath. These consist in vascular reaction attended by an extensive cellular infiltration. The cells which accumulate are chiefly ,plasma cells and lymphocytes in varying proportion, a large number of the former being often a striking feature ; occasionally a few eosinophile leucocytes are inter- spersed. The elastic fibres of the cutis are opened out and pushed down by the cellular accumulation, and immediately under the epidermis may have practically disappeared. The amount of cellular infiltration appears to vary roughly in proportion t o the degree of the disease in the epidermis and when the latter is marked the cellular layer may be of considerable thickness (fig. 11). The Paget cells in the lowest layers of the epidermis appear t,o exert a chernotactic influence on the cells: as soon as they appear small accumulations of plasma cells and lymphocytes appear in the tissue underneath. This is sometimes strikingly seen when the Paget cells Occur in small isolated clumps, the cellular reaction in the connective tissue being definitely related to them. This cellular infiltration has been noted by nearly all writers on the subject. Unna, for example, describes it in detail and calls it a “plasmorna.” AIong with the cellular reaction the superficial blood vessels become dilated and the formation of new capillaries follows. Thus a cellular vascular layer results, and it is this layer seen through the epidermis which gives the characterist,ic red appearance to the surface of the nipple, whilst a certain amount of serous exudate gives the watery discharge from the surface. The presence of the Paget cells in the epidermis thus seems to exert a slightly irritating action on the connective tissue below along with a distinct chemotactic effect.

As the inter-papillary processes of the epidermis become widened by the invading Paget cells the papillae of the cutis become narrowed and may be reduced to thin strands, which also appear to grow upwards. Thus the thickened layer of epidermis may come to be intersected by vertical lines of connective tissue with blood vessels and some of these strands may extend t o a short distance from the surface. This apparent ingrowth of connective tissue into the epidermis was noted a t an early stage, e.y. by Thin in 1881. I may mention that the cellular reaction referred t o has been present in all the cases which I have examined, and seems to increase with the duration of the skin lesion. I n one case (no. 2, p. 468), where the disease was a t a very early stage, although the invasion by the tumour cells was active, there was comparatively little infiltration of round cells.

Around the affected ducts and acini similar infiltration of plasma cells and lymphocytes may be seen, but here its occurrence is less frequent than under the epidermis of the nipple, I n some examples there is little or no cellular accumulation around the affected ducts

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whilst in others i t is abundant. In these latter I have observed that i t is definitely related to the proliferation of epithelial cells within the ducts. For example, where the lining of a large duct is partially affected the accumulation of lymphocytes etc. is seen outside the masses of proliferating cells, whilst it is absent in relation to the parts of the ducts still normal. A similar statement applies to the acini when these have become the seat of the neoplastic proliferation (fig. 7). I n one example (case 1) the epithelial proliferation was very widespread ; it was present in the epidermis and in some of the large tluct,s of the nipple, in the ducts and their branches within the niamma and in groups of acini, and in all these situations the small-cell infiltration was abundant in relation to each affected part. There was thus presented the striking picture of tumour growth strictly contained within the normal confines of epithelial structures and surrounded by the zone of cellular reaction. Whether the latter exertiany restraining influence on the growth or whether it only represents a cheniotactic phenomenon which has been enabled t o become specially marked in the absence of epithelial infiltration of the tissues around, i t is inipossible to say.

The direct spread of cancer to epidermis. The cases on which the above account is based are typical examples

of the classical Pnget’s disease, inasmuch as along with the character- istic changes present in the skin of the nipple there was no intiltrating carcinoma of the substance, the spread of the tumour cells being from the clucts by the intra-epithelial route. Reference may however be made t o the direct spread of cancer cells to the epidermis from the connective tissue spaces of the cutis when these are invaded. I have examined a large number of infiltrating growths of the nipple in relation to this question. As a rule, when cancerous infiltration of the cutis is present with subsequent implication of the epidermis, the latter siniply becomes thinned and destroyed. a cancerous ulcer resulting. The cancer cells usually do not invade the epidermis and spread in its substance in such a way as to produce the appearances described above. I have however occasionally seen actual growth of the cancer cells within the epidermal layers and their behaviour then corresponds with that seen in Paget’s disease. Fig. 14 is a section from a case where the connective tissue spaces and lymphatics of the papillz were extensively infiltrated by carcinoma. It will be seen that the invading cells have penetrated and have become incorporatecl with the epidermis, and have formed groups in its substance. Isolated cancer cells also are seen in the epidermis and it is interesting to note that as the cells pass into the more superficial layers they become atrophied and appear t o be encapsulated just as occurs in Paget’s disease. Similar changes in the epidermis have been figured and described by others. For example, a micro-photograph by Dunn of the

PAGET'S DISEASE OF NZPPLE 463

same condition is published in a paper by Beatson, and figures illns- trating this type of spread are given by Jacobaeus, Ribbert, Kyrle and others. It is interesting further to note that in some such cases not only has there been the characteristic appearance of the cells but also the peculiar distribution, especially a lateral spread in the deeper layers over a wide area from the actual site of invasion. But whilst such an occurrence may be occasionally met with, it is somewhat exceptional ; from the accounts it would appear to occur chiefly in the case of slowly growing tumours. The epidermis is usually destroyed before it is actually invaded, and when it is invaded the growth of the cancer cells within it is somewhat restrained. The epidermis thus invaded is, as a rule, soon destroyed by the cancer from below so that the actual infiltration of the epidermis is seen over a limited area; accordingly the typical appearances and distribution in the epidermis are rarely met; with. In cases of such a kind though the nipple may externally present some of the appearances seen in Paget's disease, the actual invasion by cancer can generally be recognised by the degree of induration and contraction present.

The intra-epidermal spread of cancer cells, which is a matter of much pathological interest, has chiefly been observed in glandular carcinoma involving the nipple. Borst however describes a case in which a similar mode of extension occurred in connection with an ordinary epithelioma of the lip. I n the deeper layers of the epithelium, for some distance around the actual growth, groups of somewhat undifferentiated tumour cells were present and these showed no tendency to grow downwards and invade. Continuity of such cells with the cells of the epithelioma was traced a t the margin of the latter, and Borst came to the conclusion that the cells in question were the result of an intra-epidermal spread from the epithelioma and did not represent independent foci of growth. I n all such cases it would appear that the growth in the epidermis is less active, evidently more restrained, than in the tissue spaces. The cells apparently grow with difficulty, indeed they are unable to flourish in the horny layers, a d they show little tendency to grow down again into the subjacent tissue. These features are fully illustrated also in the account of Paget's disease given above. The isolated cells and groups of cells in the epidermis which may be seen in the neighbourhood of a melanoma are probably to be regarded as evidence oE the same type of growth, as held by Jacoljaeus and others ; but I am not a t present prepared to express a definite opinion on this.

The occurrence of Paget's disease on other parts than the nipple, e.g. genitals, skin of body, etc., has been described but the cases are extremely few. A number of these have been brought together in a paper by Hartzell. I have not met with a case niyself but I am indebted to Sir Lenthal Cheatle for a section from an illustrative example of the condition. It shows an intra-epidermal growth spreading in the deeper part of the skin epithelium, with practically

464 R. MUZR

no tendency to pass downwards and infiltrate the corium. The cells which are of somewhat indeterminate character, rather like those of some rodent ulcers, are arranged in clusters and singly, and the mode of growth corresponds with that seen in Paget’s disease of the nipple. In cases of this kind, so far as I can judge, we have apparently to do with a neoplasin originating from cells of the epidermis or its appendages and spreading laterally in the epidermis, instead of growing downwards into the tissues beneath. The remarkable fact is that such an occurrence may take place and that a t the same time i t is so rare. Theoretically of course there is the possibility that such a growth might occur in the epidermis of the nipple, but this does not affect my main conclusion that ordinarily in Paget’s disease the cells which spread in a similar way in the epidermis reach it from an intra- duct carcinoma. The intra-epithelial type of growth of the latter within the ducts is manifestly of importance and has been emphasised in the account given above.

Discussion.

Without giving a detailed account of the literature of the subject reference may be made to some of the opinions of others in relation to what has been described.

When the view as to the neoplastic nature of the Paget cells was first put forward by writers, it was generally believed by them that they originated from the cells of the epidermis by a process of anaplasia. Stiles in his account of the disease describes it as originating near the orifices of the ducts and then extending downwards within them, alveolar carcinoma occasionally occurring in the substance of the breast as a subsequent phenomenon ; he speaks of the Paget cells as altered epidermal cells. The most detailed account of the disease in recent years in this country is that of Cheatle (a), who considers that some irritant or other agent may set up malignant proliferation in the epidermis, in the ducts and in the acini, the growth in each of these being independent though produced by the same or a similar canse. He thus regards the infiltrating cells in the epidermis as of epidermal origin. Rosenberg takes a similar view.

So far as I can find it is little more than twenty years since the opinion was first definitely expressed that the Paget cells are the cells of a glandular carcinoma which have invaded the epidermis. Jacobaeus (1905) arrived a t this conclusion from observations on three cases of Paget’s disease, in all of which carcinoma was present in the nipple. In two of these he traceddirect continuity between the underlying cancer and the Paget cells in the epidermis ; in the third he failed to do so, but considered that there had been continuity at one time and that it had been interrupted by the contraction of the fibrous tissue. He formed the opinion that the carcinoma originated from the ducts of the nipple, was of a low order of malignancy and did not really pass into the substance of the breast. He ,did not however consider the possibility of a spread from the orifices of the ducts into the adjacent epidermis. Ribbert in the following year, from the examination of two cases, states a similar view as to the origin of the Paget cells. He notes that the lesions in the epidermis may be more extensive than the area of continuity between i t and the underlying growth ; in other words, the cells extend laterally in the epidermis while they do not show any tendency to grow downwards and invade the underlying tissue. He describes in one case the presence of strands of cancer cells which

PAGET’S DISEASE OF NlPPLE 465

probably represent infiltrated ducts and supposes that the cancer has broken into the ducts and then spread to the skin. But he makes no reference to the existence of primary disease in the ducts themselves. Ribbert somewhat later describes a third case where underlying cancer was present and others of like nature are recorded by Hirschel and by Kyrle.

It is to be noted that these observers ascribe the Paget’s disease in the epidermis of the nipple to invasion by the cells of a glandular carcinoma present in the connective tissue of the nipple. Schambacher however records a case in which he traced the origin of the cells to an intra-duct carcinoma of the nipple, extension having occurred by what I have called the intra-epithelial route. The ducts of the nipple were filled with cancer cells, the area around their openings was partly ulcerated and showed the remains of the infiltrated epidermis, while around this part again extension of the cancer cells was takiug place in the deeper parts of the still intact epidermis. He considered that the malignant growth within the ducts hitd extended downwards from the nipple into the substance of the mamma and had then broken through and given rise to an ordinary carcinoma. His account of the changes observed both in the nipple and in the substance of the mamma accords generally with that given above. Reuter in a thesis on the subject expresses a similar view.

The origin of the Paget cells from glandular epithelium has been accepted by the majority of recent German writers. Kaufmann for example in his text-book on pathological anatomy adopts this view and states that they originate either from the ducts of the nipple in the manner described above or spread directly from a cancer in the substance of the nipple. And Aschoff describes the disease as the result of an intra-epithelial growth of cylindrical or polymorphous cancer cells which originate from the orifices of the lactiferous ducts and then extend over the nipple and areola. Heilmann in a recent paper comes to the conclusions that intra-epidermal cancer may develop on any part of the body though it is rare, and that Paget’s disease, though occasionally a primary growth of epidermis, is usually due to a secondary intra-epidermal growth of cancer which has invaded the skin from outside.

On the whole in German literature there are more accounts of direct spread from actual carcinoma in the nipple than of extension from the orifices of the ducts. The view as to the glandular origin of the Paget cells has received little acceptance by writers in this country and in America, and some still deny that these cells are really tnmour cells. For example, Jopson and Speese consider that Paget’s disease is a primary affection commencing in the rete Malpighii and characterised by cedema and vacuolisation of the prickle cells, active mitosis and thickening of the rete: it is poteritially malignant or pre- cancerous in the sense that it induces epithelial changes in the superficial ducts and acini which are followed by cancer. Deaver McFarland and Herman in their book on the diseases of the breast also regard the disease as starting in the epidermis and state that the Paget cells have no resemblance to cancer cells: a similar proliferation may occur in the ducts adjacent to the affected surface but this they regard as being more of a catarrhal condition of mild type than as a malignant process : this primary change may be followed afterwards by squamous epithelioma or by glandular cancer. In a recent paper Arnd expresses the view that Paget’s disease is a pre-cancerous change and that the characteristic cells, which owe their appearance to infiltration with glycogen, originate in independent and multicentric foci in the epidermis, appendages of the skin or milk ducts : cancer may develop secondarily in connection with any of these structures.

These examples will serve to illustrate the many types of opinions which have been put forward.

466 R. MUIR

Relations to clinical facts.

It will be seen from the above that intra-duct carcinoma varies much in its distribution; though not a generalised affection of the manimary ducts, it is often extensive. From the characters and behaviour of the cells within the ducts it seems evident,, as has been stated, that they have acquired neoplastic properties. On the other hand from the clinical point of view the growth is only potentially malignant, as the change may remain for an indefinite time confined to the duct system, and carcinoma in the ordinary sense occurs only when the cells have broken through the normal confines and have invaded the tissue spaces. The view which has been expressed as to the relations of intra-duct carcinoma to Paget’s disease and to ordinary mammary carcinoma is based on what I consider can be observed, and it is also in accordance with and explains the clinical facts. If the disease is in the ducts of the nipple above the lactiferous sinuses, the proliferating cells may spread by the intra-epithelial route to the epidermis and produce the lesion of Paget’s disease. On the other hand, actual break-through of the cells usually occurs from duets deep in the breast substance and thus, as Paget first stated, the actual cancer is often a t some distance from the nipple. Theoretically, such a break- through might occur also in the nipple itself, the result being an ordinary carcinoma of its substance, but I have not with certainty seen this occurrence, though it has been described by others. Possibly the walls of the ducts in the nipple, owing to their greater thickness, may have a more restraining influence than those in the substance of the mamma. And from what I have seen I am convinced that ordinary carcinoma in the breast substance is more frequently preceded by the disease in the ducts than is generally supposed; the latter may be readily overlooked, especially when the cancer is extensive.

Paget’s disease and true carcinoma in the breast may thus be sequels to intra-duct carcinoma and are clinically the most easily recognised results of the pre-existing disease. Paget described how the disease in the nipple might exist for years before the actual out- break of cancer and this has been fully confirmed by others: it appears indeed to be the common experience. I have however hacl an opportunity of examining two very early cases of Paget‘s disease in which ordinary invasive carcinoma had preceded the Paget’s disease. One was a case (number 4) of duct carcinoma with localised early carcinoma of ordinary type. No Paget’s disease was observed clinically but on making sections of the nipple a small and quite localised patell of the Paget lesion was found; in the nipple intra-duct carcinoma was present but there was no infiltration of its connective tissue. 111 another case (number 5) along with duct carcinoma there was exten- sive cancerous invasion of the breast with involvement of the lymphatic glands, and the lesion of the nipple in the form of a crust had appeared

PAGET’S DISEASE O F NZPPLE 467

orily six weeks before thc operation for excision, though a year previously there had been some serous discharge which had lasted a month and then dried up. On microscopic examination, the Paget’s disease was a t an early stage and direct spread along the ducts to the nipple could be traced; there was no cancerous invasion of the substance of the nipple. I n this instance it seemed clear from the extent of the cancer in the mamma that it had existed before the signs of Paget’s disease; there had been first a break-through of the cancer cells from the ducts into the substance of the mamma and only a t a later period had the spread from the ducts in the nipple to the epidermis taken place. I formed this opinion from the histological changes found, and the surgeon, Mr Roy Young, had definitely come to the same conclusion from the clinical facts.

I n two other cases in which no infiltrating cancer was present, it was manifest that the disease in the ducts had preceded the Paget’s disease. I n one of these (case 2) the diagnosis of duct carcinoma was made from examination of a portion removed. The breast was excised about a month later and just before the operation a slight serous dis- charge from the nipple had been noted. On microscopic examination of the nipple the early lesions of Paget’s disease were found. The invasion of the deeper parts of the epidermis was however very active, there being clumps of neoplastic cells which were compressing the surrounding cells of the rete Malpighii so that the latter appeared to form a stroma-like arrangement around the invading cells (fig. 12). The lesion was quite localised and immediately underneath it the ducts showed the usual neoplastic change; the ducts in the other parts of the nipple were free. The clisease in the ducts in the sub- stance of the breast was pretty extensive but a t no part was there any cancerous infiltration of the tissue spaces ; probably this would have occurred a t a later stage. The interesting fact is that while the duct carcinoma was clearly of considerable duration, the invasion of the epidermis by the proliferating cells was quite recent; in fact, it had not yet given rise to the ordinary appearance of the Paget nipple.

My experience as to the possible sequence of events, as illustrated by the above cases, is no doubt an exceptional one in view of the published accounts of others. It is shown that occasionally infiltrating cancer in the breast niay precede the Paget’s disease, though the converse is the usual sequence. The fact also that the lesion in the nipple may be distinct on microscopic examination before there are manifest naked-eye appearances (case 2) is of importance. Thus both the Paget’s disease of the nipple and the outbreak of ordinary invasive carcinoma are etiologically on the same footing, inasmuch as they may be sequels of intra-duct carcinoma. One often finds the latter alone in the substance of the manima and possibly it may remain within the ducts indefinitely ; on the other hand it may break through their walls and infiltrate. The growth may occur above the sinuses

466 R. MUJR

in the nipple either by direct spread from below or as a separate lesion, and then the neoplastic cells may extend from the orifices of the ducts and invade the epidermis. So far as I can see, all the clinical facts with regard to Paget’s disease are readily intelligible on the basis of the view put forward and follow in a natural way.

Cases.

I add a short account of the cases on which the above account is based, and I desire to thank the surgeons in charge of them, Prof. A. Young, Mr Farquhar Macrae, Mr Roy Young and Mr Matthew Whyte, for the clinical notes. It will be seen that in the first two cases there was no infiltrating carcinoma, while it was present in the other three.

Case I.-Eztensive intra-duct carcinoma in nipple and breast, intra-acinous carcinoma, and fa i r ly advanced Paget’s disease ; no cancerous infiltration of connective tissue-Mrs M. G. aet. %.-This was a case of typical Paget’s disease involving practically the whole of the surface of the right nipple. The affection had begun about a year before, the first syrnptom being itching, and this was followed by an “ eczematous ” condition, increasing redness etc. The breast and axillary glands were excised on 1/9/22, and on examining them after removal I found, in addition to the lesion of the nipple, only a certain amount of diffuse induration of the breast a t places. Microscopic examination of the nipple showed the typical changes of Paget’s disease a t a somewhat advanced stage (figs. 11 and 19) and a t places a tendency of the cells to assume a columnar form was noted (fig. 16). Some of the ducts in the nipple were the seat of intra-duct carcinoma, others were free; and direct spread from a duct to the epidermis could be traced (fig. 17). Within the breast there was extensive intra-duct carcinoma in many of the ducts and their finest branches, and there was also spread to groups of related acini, the latter having undergone a sort of cancerous transformation (figs. 7 and 8). I n fact in this case there was present the most extensive neoplastic proliferation within the ducts and acini which I have yet met with. At no place was there any clear evidence of a break- through from the ducts with subsequent infiltration of the tissue spaces. Examination of the axillary glands also gave a negative result.

Case 8.--lnt?-a-duct carcinoma of nipple and breast, followed by Paget’s disease ; no carcinoma in connective tissue-Mrs G. aet. &-This was a case of very early Paget’s disease undoubtedly following on intra-duct carcinoma. A portion of the breast had been removed for diagnosis and extensive intra-duct carcinoma with extension to the acini was found. A month later the whole breast was excised. Shortly before this there had been some serous discharge from the nipple but there was no alteration i n appearance and the existence of Paget’s disease was not suspected. On microscopic examination, however, the epidermis a t one side of the nipple was found to be the seat of an active Paget lesion. The cells, which were unusually well preserved, were stretching out and causing atrophy of the prickle cells, especially in the deeper parts of the epidermis (fig. 12). Single Paget cells also were present but they were relatively scanty. There was little cellular infiltration or congestion and there was practically no new formation of blood vessels. Some of the ducts and acini underneath were inarkedly affected with the neoplastic change and these were definitely related in position to the lesion in the epidermis. Only a slice of the nipple had been taken and in this actual continuity between the cells in the ducts and those in the epidermis could not be traced. This is the earliest example of Paget’s disease which I have met with and, as already stated, there was clear evidence that it had appeared subsequently to the intra-duct carcinoma.

PAGET’S DISEASE OF NIPPLE 4 69

Case s.-Intra-duct carcinoma of nipple and breast with early Paget’s disease; localised carcinoma-Mrs C. aet. 48.-This was another early case, as according to the patient’s account the “eczema” had existed for only four weeks. A portion of the breast supposed to be the seat of chronic mastitis was excised ; intra-duct carcinoma and localised infiltrating carcinoma were found. Complete excision was then performed. On microscopic exam- ination, the Paget lesion though a t an early stage was seen to be fairly extensive, the Paget cells occurring singly, in small clumps or sometimes as a thin line in the deepest part of the epidermis; many showed signs of atrophy and were in process of disappearance. The lesion was clearly of somewhat longer duration than was indicated by the history. Intra-duct carcinoma was present with extension to acini at places, both in the nipple and in the breast. I n some ducts the cells were large and there was a tendency to acinus-like arrangement, whilst in others they were more of the rounded form. I n one lactiferous sinus an interesting and important condition was found, I t s upper part was occupied by a mass of tumour cells, the lower part of the duct above it was similarly filled, and then came a part where the duct was lined by a layer of cornified epithelium which was ensheathed by tumour cells (fig. 18). The duct was traced up to the epidermis and the cells in question were found to be continuous with those in the rete Malpighii. The origin and spread of the Paget cells in this case were accordingly clearly shown. There was no infiltrating carcinoma found in any part of the breast with the exception of the portion first excised.

Case e.-Localised intra-duct carcinoma and ordinary carcinoma ; early Paget’s disease-Mrs A. T. aet. 43.-A tumour of the breast was excised and found to be due to intra-duct carcinoma with infiltrating carcinoma around ; it appeared to be quite localised. Thereafter the breast was excised and no lesion was noted in the nipple at that time. On examining microscopic sections however a localised patch of early Paget lesion was found (this was seen in the paraffin block as a small brown patch owing to the vascularity). The Paget cells were of large size and pretty active appearance with a tendency a t places to assume a coluninar form. They were growing chiefly in masses, in which were small spaces containing fluid. The lesion was clearly an active one, though at an early stage. Only one duct in the nipple was the seat of intra-duct carcinoma, but as the slice of tissue was thin continuity with the surface lesion could not be traced. No cancer was found in the original wound after the whole breast was removed; examination of other parts of the breast likewise showed no lesion. From what was found it seemed quite clear that the duct carcinoma, and in all probability also the infiltrating cancer, had preceded the Paget lesion.

Case s.--Carcinoma of breast and axillar?y glands, intra-duct carcinoma of nGp1e and breast; early Paget’s disease-Mrs L. aet. 44.-About one-and-a-half years before operation there was some oozing of blood from the nipple; the latter was examined and found healthy in appearance. Six months later there was some clear discharge, which went on for a month and then stopped. Three months before operation there was noticed a lump in the breast which increased in size, and six weeks later a crust was noticed to be forming on the nipple. Excision of the whole breast and axillary glands was performed. A considerable amount of cancerous infiltration was present in the substance of the breast, and the axillary glands were markedly affected (confirmed by microscopic examination). At one side of the nipple there was a small area slightly reddened with a yellowish crust over it. On microscopic examination of this, Paget’s disease was found but it was localised to the area mentioned and was apparently a t an early stage. There was a considerable amount of intra-duct carcinoma in the ducts underlying the lesion of the nipple, with extension to

470 x. MUIR

some of the acini. The cells in the epidermis and in the ducts presented the same characters being somewhat angular in form with denser nuclei than is usually the case (figs. 13 and 15). No infiltrating cancer was present in the nipple. Although from the history there was evidence that some lesion was probably present within the nipple at a fairly early period, it seemed quite evident from the changes found that the cancer in the breast had preceded the Paget’s disease. hfr Roy Young, under whose charge the patient was, was distinctly of the same opinion.

Cunclusioizs. In stating the following conclusions I wish to make it clear that I

exclude the cases where the epidermis of the nipple is implicated by direct spread of the cells of an ordinary carcinoma infiltrating the underlying cutis, these cells then spreading intra-epidermally. Such cases do not conform to Paget’s original description, although, as described above, the histological features of Paget’s disease may occasionally be produced. Further, as a primary neoplasm spreading intra-epidermally has occasionally, though seldom, been observed in the skin of other parts of the body, the possibility that such a growth may originate in the epidermis of the nipple cannot be absolutely excluded, though I have never seen such a case. The typical Paget’s disease, however, is ordinarily caused in quite another way. With these explanations my conclusions are the following :-

(1) Paget’s disease, as usually met with, is the result of the invasion of the epidermis of the nipple by tumour cells of glandular type which reach i t from the upper extremities of the lactiferous ducts affected by neoplastic disease. These tumour cells constitute the “ Paget cells ” ; their growth is intm-epidermal.

( 2 ) The invasion of the epidermis leads to reactive changes in the underlying connective tissue--infiltration of plasma cells etc., new formation of capillaries, congestion with serous exudate. In this way the characteristic appearance of the nipple results ; later, the superficial layers of epithelium may become destroyed and this process may spread.

(3) The disease of the ducts which may be spoken of as “intra- duct carcinoma,” may be said to have a low degree of malignancy, inasmuch as it may affect systems of ducts and even spread to the acini without breaking through the normal confines.

(4) The growth of the tumour cells is in the first instance i iztm- epithelial, and in the larger ducts and sinuses much proliferation may occur before the internal lining is actually broken. This mode of growth is comparable with that seen when the cells reach and infiltrate the epidermis.

(5) The growth within the ducts or acini may ultimately break through and then an ordinary infiltrating cancer results. Both Paget’s disease and ordinary carcinoma are thus possible sequels of the same disease-intra-duct carcinoma.

The photo-micrographs are by Mr John Kirkpatrick of the Pathological Department of the University of Glasgow.

PAGET’S DISEASE OF NIPPLE 47 1

REFERENCES. ARND . . . . . . . . . Virchow’s Arch., 1926, cclxi. 500 : literahre. ASCHOFF . . . . . . . . Pathologische Anatomie, 1923, 6th edit. ii. 626. BEATSON . . . . . . . . Glasg. Med. J., 1911, lxxvi. 161. BORST . . . . . . . . . Veerhand. d. Deulsch. path. Gesellsch., 1904,

BUTLIN . . . . . . . . . iMed.-Chir. Trans., 1876, lix. 107. CHEATLE , . . . . . . . a Paget’s disease ; Brit. J. Xurg. 1923, xi. 295 ;

Tag. vii. 118.

1924, xii. 284. ,, . . . . . . . . b dysgenetic hyperplasia : ibid. 1926, xiii. 609.

DEAVEX, MCFARLAND AND The breast: its anomalies, its diseases and

DUHRING AND WILE . . . . dmer. Journ. &led. Xc., 1884, lxxxviii. 141. HANDLEY . . . . . . . . Brit. J. Surg., 1919, vii. 183; Cancer of the

breast, 2nd. edit., London, 1922. HANNEMULLER AND LANDOIS . Beitr. 8. klin. Chir., 1908, 1s. 296. HARTZELL . . . . . . . . J, Gut. Dis., 1910, xxviii. 379. HEILMANN . . . . . . . . Ztsclir. f . Krebsforschung, 1926, xxiii. 446. HIRSCHEL . . . . . . . . Ziegler’s Beitr. z. path. Anat. u. ally. Path.,

1905, supplement, vii. 573. JACOEAEUS . . . . . . . . Virchow’s Arch., 1904, clxxviii. 124. JOPSON AND SPEESE . . . . Ann. of Surg., 1915, Ixii. 212. KAUFMANN . . . . . . . Specielle Pathologische Anatomie, 1922, 7th

edit., 1387. KYRLE . . . . . . . . . Arch. f . Derm. u. X:qph., 1907, lxxxiii. 187. PAGET . . . . . . . . . St. Barth. Hosp. Rep., 1874, x. 87. REUTER . . . . . . . . . Ueber Pagetkrebs der Mamma, Inaug.-Dis.,

Leipzig, 1912. RIBBEKT . . . . . . . ‘. Dtsch. med. Woch., 1905, 1218; Beitrage zur

Entstehung der Geschwiilste. Erganzung zur Geschwulstlehre fur Arzte und Studierende, Bonn, 1906, 87.

HERMAN their treatment, London, 1918.

ROSENBERG . . . . . . . Afonatsh. f . prakt. Derm., 1909, xlix. 235. SCHAMBACHER . . . . . . Dtsch. %eit.fiir Chir., 1905, lxxx. 333. SCHMIDT . . . . . . . . Die Verbreitungsweye der Karzinome, JeNa,

STILES . . . . . . . . . Art. IWumma in Encyclopsdia Medica,

THIN. . . . . . . . . . Brit. Med. Journ., 1881, i. 760, 798. UNNA . . . . . , . . . The histopathology of the diseasesof the skin

1903.

Edinburgh, 1901.

(Eng. transl.), Edinburgh, 1896, i37.