PAGET’S DISEASE OF THE NIPPLE WITH SPECIAL REFERENCE TO ITS RELATION TO DERMAL

GLAND CARCINOMATA

By Kai S e t & l o .

(Ilecchi\ctl fo i - l)ul)lic*atioii .Iuly 16th, 1948.)

Approxim:ilely 75 years ago Sir Juiiies Paget described a lesion in the skin of the nipple, >>a disease of the mammary gland<<. It has sincc I)ecn known as Paget’s disease. Although much has been written on this disease the genesis and character of the affection are still obscurc, and using Weiner’s expression >>the history of the disease, as recorded in a voluminous literature, is n history o f prolonged controwrsycc.

The idea used in the present work of connecting Paget’s disease with certain dermal appendagc carcinomata is by no means a new oiic. However, altogether satisfactory evidence that Paget’s disease on thc one hand and derriial gland carcinomata on the other hand ha \e coiiiiiion features has not heretofore been presented, although several :illusions to it havc appeared in the literature. In some of the earlier papers hy the author, especially in that on >>Cutaneous C:rncer Arising fro111 the Sehaceous and the Sweat Glandscc, sonic facts were disclosed which indicated that the >)true<< Paget’s disease may have some con- nection with carcinomata arising simultaneously froin the sebaccous anti thc sudoriferous elements. In this connection the working hypo- thesis is offered a valuable addition on the one hand by the existence of so-c:illcd extr:iin~iiiiin~~ry Paget’s disease and on the other hand 1)y the I‘act that ))there is no longer any douht that the maiiiiiiary acini anti ducts havc been modified from sweat glands: a itiamiiia represenla :I

group o f sweat glands developed from a circuiiiscribcd area o f the skin lying under the primitive mammary ridgecc (Sir Rrthrrr lieit11 j .

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Various theories concerning the nature of Paget’s disease.

Suffice it to refer to only some exhaustive papers of earlier authors, especially to the excellent work of‘ Weiner (other papers: Patitrier, Darrier, Rang and Giildberg, Lubschi fz , etc.) . The following opinions of the pathogenesis of the lesion havc received most support:

( 2 ) Paget’s disease is a purely epidermal lesion. - It is supposed to be cancer, a non-malignant ))dyskeratotic<( lesion (Darrier) , or n precancerous affection.

Paget’s disease is a cutaneous metastasis either of carcinoiii:~ of the mammary gland or of the ducts thereof. Thus e. g . , Znglis di- stinguished ordinary duct cancer in which the growth arises as a rc- sult of the proliferation of the lining epithelial cells i n si tn from the special duct cancer of Paget’s disease in which the cancer cells havc infiltrated from a distance as part of a centrifugal spread by the intraepithelial route from the primary duct cancer which has arisen in a duct near its outlet.

( 3 ) Paget’s disease is caused by some agents which may simul- taneously induce the epidermal changes above and the cancer helolv, (e .g . , Sir Lenthal Cheatle). - Parsons and Lohlein also say that the theory of two independent types of cancer - - that of the epidermis with Paget’s cells, and that occurring in the glandular epithelium beneath it - is attractive on the basis of the possibility that some carcinogenic influence was simultaneously exerted on both the epi- dermis and the underlying glands ( c f . Fig. 2, p. 426 in their paper) .

( 4 ) Paget’s disease is cancer having two forms, namely a nieta- static one in which coexisting cancer of the breast is present and a primary, epidermal form (e. g., Bang and Guldberg).

( 5 ) it has also been said that Paget’s cells are anaplastic melano- blasts with the lipoid function retained, hut the pigment-making func- tion lost (Kreibich, in 191 1 ) . Darrier expressed the opinion that naevo- carcinomata, Paget’s disease and Bowen’s disease are all analogous, and that all of them are due to dysembryoplasia. Stout reported n c:isc of tumour believed to be a pigment-free malignant inelanonla tlic primary manifestation of which was indistinguishable froni Pagc t’5 disease ( c f , Fig. 2, p. 200 in his paper).

(2)

These different theories of the character and genesis of the Pugct’s cells leave the question of what is the origin of Paget’s cells open. If additional light can be thrown on the problem, the following question may be put : are these Paget’s cells malignant or not? -- Owing to the nature of the matter these question cannot be handled altogether separately.

All the earlier papers which discuss the relations between Paget’s disease and the dermal appendage cancer are of interest.

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Jacobaeris (1904) was perhaps the first author to maintain that Paget’s cells were intraepidermal metastases from underlying glandular carcinoma, and Rousset (1931) was perhaps the first to point to the fact that Paget’s cells were skin metastases of sebaceous cancer; he laid special strcss on the neck cells of these glands. He also supposed that the cxtramarnrnary Paget’s disease has a similar etiology, especial- ly in view of its genital occurrence.

However, the suggestion that the associated carcinoma ariscs in the sudoriferous elements has been made more often than the one that the scbaceous elements a re the origin of Paget’s disease (as far back as Crocker, in 1888, as quoted by W e i n e r ) . The apocrine sweat glands especially come into question, but definite proof is lacking (e . g . , Hual, W e i n e r ) . -- Lubschitz, for instance, states that it is evident that Paget’s disease must in some way have something to do with milk ducts o r acini. On presenting his own case, a carcinoma of the apocrine sweat glands with proliferating cells resembling Paget’s cells, Liibschitz stated that the probability exists that Paget’s cells are cells in the orifices of the milk ducts of the sudoriferous glands, which become cancerized and invade the epidermis. According to Weiner, Paget’s disease is due to intraepidermal metastases of carcinoma of the npo- crinc swcat glands with secretory activity and this may offer a reason- able explanation for the loosely arranged Paget’s cells, which look as if they are bathed in fluid, frequently and classically found in the full- blown epidcrmal lesion and forined also in Weiner’s case in ‘the distant metastases ; vacnolization of the cells was observed in the epidermis and in the distant rib metastases ( c f . Fig, 1 , p. 375, Fig. 5, p. 378, and Fig. 11, p. 383 in his paper).

Material and technique.

Thc material used in the present work was partly obtained from the Department of Pathology, Central Institute for Radiation Therapy, IIclsiiiki, Finland (CTIlaT) and partly from the Department of Radio- Pathology, Radiumhemmet, Stockholm, Sweden (RaH) as follows : 7 cases of Paget’s disease from the former institute, 3 cases of Paget’s disease and two cases of Bowen’s disease from the latter one. 10 cases of sebaceous and of simultaneous sebaceous and sudoriferous c:ir- cinornata are from the author’s earlier paper.

The fixation of the biopsy specimens was performed in solutions generally used for this purpose. The common staining techniques such as iron-haematoxylin-van Gicson, eosin, azocarmin (Heidenhain 1, Mas- son, etc., were used. The biopsy specimens were not fixed with any special technique, but they were embedded in paraffin. For this reason no fat-stainings were performed. Meirowsky and Kegs when describing the structure, occurrence and significance of Paget’s cells say, for instance, that an outstanding feature is the affinity of the dots ( i . e.,

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the vacuolated cytoplasm) to osmic acid compounds. And, further , 1ha1 it is possible that the vacuoles of the cytoplasm consist o f liimid- protein, but confirmation is still lacking. See also Setiilii ( 3 ) .

T h e hisfo-pathologg of Paget’s disease.

In typical Paget’s disease large, pale-stained cells are scattered throughout the epidermis (Fig. 1 ) . The cells have large, light-coloured vesicular nuclei and the cytoplasm is much lighter in color than the adjacent prickle cells. Paget’s cells show no intercellular bridges 01’

tonofihrils. ‘rhr cytoplasm shows considerable vacuolizntion, dissolu- tion of continuity and loss of prickles. Vacant spaces or holes arc aI\o to he noted. - More detailed descriptions of thc subject are to I)c l’ouncl in histo-pathological manuals.

Although the microscopical appearance of Pagel’s disease is often clear, it is not always easy to make a correct diagnosis. It niay often he impossible to differentiate betn-een the cxtrainainni:irg Paget’s disease and atypical Bowen’s disease. The Paget’s cells arc t t i r h

distinguishing feature, but they inay be simulated by swollen, de- generated epithelial cells found in Bowen’s disease (Fig. 2 ) . According to Hval , for instance, true Paget’s disease can be spoken of only in the cases in which deep cancer is present; in the cases without d c q ) tumour Paget’s cells are found only in the middle layer of the epidcrnii4 wherefore they must be considered cases of Rowen’s disease or C : I S C ~

related to it. In ))Diseases of the Skin<(, Ormshy and ~ ~ ~ ~ I Z ~ ~ O I I I P J Y ~

mentioned that :i niarked yacuolation occurs in some of the cell4 t o such aii extent that they simulate Paget’s cells in Paget’s diseaw. Frcrzer stated that >)there is strong evidence that the so-callecl cstra- ninin~nary Paget’s disease is Howen’s disease(<.

Similarities between Paget’s disease crntl certuiri tiernid glnntl carcinomata.

A s the author indicated in an earlier paper, the inicroscol)ical : 1 1 ) - pearaucc of certain dermal appendage carcinomata -- particu1:irly the presence of ))intraepidermal phenomena<< - niay be approximately the saine a s in the i;dysl<eratoticcr pagetoid andJor howenoid types of lesion ( c f . Figs. 1, 2, 3, and 1 1 ) . This, in addition to other facts such as n similar clinical appearance (Figs. 9 and l a ) , and since, :I(*-

cording to the present point of view, the mamniary glands havc brcn modified from the sweat glands, may support the opinion that Paget’.; disease could be sebaceous cancer or - more often -- cancer origiii;it- ing simultaneously from the sebaceous and the sudoriferous eliwi(~rit\.

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The facts which defend the above-mentioned genesis are: (1) a number of cutaneous carcinomata arising from the dermal

glands contained simultaneously both sebaceous and sudoriferous compounds (Figs. 5 , 6, 7 and 8). Either the one or the other of thesc elements was predominant.

This is also histogenetically comprehensible in particular as regards the sudoriferous elements. Thus, for instance, when speaking of naevus syringo-cystadenomatosus papilliferus Arzf and Kumer assert that it may be traced to >>Epithelkeimecc, which have the potentiality to be de- differentiate and to form pilous, sudoriferous and/or sebaceous tissue. Dorffel, when describing the tumours mentioned above, rcported to have found sebaceous cells in them (the cells in his microphotographs resembled the so-called a-type cells described in an earlier paper of Sefula) . Diirffel had in his case observed the occurrence of sudoriferous elements in the primary tumour and of sebaceous elements in the recurrent one. Reuterwall also noted cells resembling sebaceous coni- pounds in this type of tuniour. Parreira reported six cases of seba- ceous adenomata, three of which had simultaneously sudoriferous elements also. Gates, Warren and Warvi showed a microphotograph (Fig. 4, p. 629 in their paper) of a hydradenoma papilliferum with cells resembling sebaceous cells. Loos mentioned that cells containing vacuolated cytoplasm could be found in the sudoriferous cancer re- ported by him, and he presented a microphotograph thereof (Fig. 6, p. 487 in his paper). Consequently, it is possible that also the case

F i g . 4 . Same section as in Fig. 3. Intraepidermally ))clear cellscc, saccule-ihromb

formations subepideymally. (Masson.)

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Fig. 5. Sudoriferous cancer with elements resembling sebaceous cells. The nuclei arc also secreted at the same time (i. e., no true apocrine secretion) (RaH-B.

1036/31). Biopsy specimen (lip) of female, aged 45. (Masson.)

Fig. 6. Same section as in Fig. 5. Higher magn. The development of vscuolated,

sebaceous cell-like elements (i. e., holocrine secretion).

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of Loos belongs to the dermal gland carcinomata containing both glandular compounds.

( 2 ) i t was also apparent that the differentiation might 11:1\c startccl in two directions from elements with seemingly the same nlorpllologic,;il appearance, i. e. , by forming compounds resembling on the one h:i11(1

sudoriferous and on the other hand sebaceous elements (Figs. 5, 6, 7 and 8 ) . I t was also possible ( in these simultaneous sehaceous :inti sudoriferous carcinomata) to follow the development of the seeininglj.

pure sudoriferous compounds into the vacuolated sebaceous cell-lihc elements. Fig. 6, for instance, represents such n differentiation. This microphotograph shows sudoriferous cells in the surroundings. :ind one can clearly distinguish the development of vacuolated, s e . 1 ~ - ceous-cell-like elements. I t w a s very important that a11 the w l l szrh- stance, not a part of it, was separated out (i. e., the nuclei \vcrc> c t l so secreted). Thus, it seemed to be a true holocrine activity (not :I :il)oc.rinc. activity) in these cases. The patient in question was n female, :igctl -13, with :I little tumour on the lip. She died later of general c:ircino\i\.

- Fig. 7 presents cysto-papillary sebaceous and sudoriferoub canccr, the lining epithelium of which contained vacuolated sehaccous clc- inents. The tuniour, reddish, lobulated, and measuring 6 j< 3 cni, of the patient, a female, aged 59, was located in the parietal region.

Accortlin g to the 111 aterial contain in g dermal gland c'a rrin oin:~ \a, tumours of this type in:ty arise either directly from glantl~ilui. rut:intLoii\

21 6

F i g . !O. Clinically cn cuirasse-mode of growth. Microscopically highly differentiatctl sebaceous cancer. Male, aged 67, died of generalized carcinosis. Sebaceous cells also in pulmonary lymph node metastases. (Cf . Figs. 3, 4, 12, 13 and 14.)

elements or from cutaneous elements, in general, which still retain the tendency (or they later develop this quality) to differentiate into the compounds in question. - Often these >>sebaceous<< cells deviated to some extent from the ordinary sebaceous gland cells. Many of thc cells had shorter or longer cytoplasmic >>processes<< ( e . g . , Fig. 6 ) . In this connection it is interesting to note that anatomic peculiarities of this kind had led several authors ( e . g., Pautrier, Muir, Sintard) to postulate ameboid activity for the true Paget’s cells. Weiner also states that he has found similar formations in Paget’s disease.

( 3 ) the malignant tissue, which arose from the derinal gland elements, tended to retain certain characteristics of its tissue of origin. These types of dermal gland carcinomata were often comparatively highly differentiated (particularly the >>pure<< sebaceous carcinomata, and carcinomata arising simultaneously from sebaceous and sudor- iferous elements). This also effected the mode of growth especially on the part of the sebaceous carcinomata.

Two different types of sebaceous carcinomata were microscopically distinguishable: firstly, a highly differentiated type, the so-called glandular sebaceous carcinoma (Fig. 3 and 13) . The malignant cells

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F i g . id. Squamous-celled cancer with sebaceous structures ())clear cells(() (RaH--H

1373/40). Sebaceous cells of a-type. (Haematoxylin-van Gieson.)

Fig. 42. Same section as in Fig. 3. Higher magn. (Masson.)

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o f Llicse tuinours wcrc usually like >>true(< scbaccous cells, a s in Fig. 13 ( the author has in an earlier paper termed these compounds >>scha- ccous cclls of p-typecc). Owing to the specific function o f the tissiic. of‘ origin (holocrine secretion), the carcinomata arising from this clc- ment, when more highly differentiated, a t least partly tended to cari- cature this activity, i. e. , a part of the cells appeared to >>secrctc~( therri- sc l res (Fig. 3, and Fig. 13) . The carcinomatous tissue tended to forni atypical sebaceous saccules or glands. On passing into subpapillary blood capillaries or lymphatics, for instance, the sebaceous cleincnt\ may grow along them in a saccule-thromb-like manner (Figs. 3, 4 ant1 13) . Thus a mode of growth arises, which may be diagnosed hoth microscopically (Figs. 3 arid 4 ) , and clinically (Figs. 9 :rnd l o ) , ant1 which resembled the en cuirasse-mode of growth of hreast cancer (i. ( I . ,

specialized sweat gland cancer) to an astonishing degree. Microscopic- ally both the sebaceous, and the simultancous sebaceous and sudor- iferous carcinomata had in these cases an intraepideriiial occurrciiw like actual Paget’s disease (c f . Figs. 1 and 3 ) . ’II’htn ol)ser\iris the matter from this >>secretory<< point of view a great similarly hit- twccn the microphotographs of some authors and those of our OM n can be seen. In Frazer’s Paget’s disease case, for instance, holoerinc activity is found (Fig. 6, p. 820 in his paper). Further, the micro- scopical appearance of Weiner’s case (Fig. 2 , p. 376, and Fig. 5 , 1,. 378 in his paper) resembles the microphotographs in the prescnt n o r l c ( P . {I., Fig. 3 ) . The same occurrence can perhaps be noted in Stouf’s photograph (Fig. 3, p. 200 in his paper) although hc treats the suhjccl f rom the viewpoint of the relationship of nielanoniata to Paget’s tiis- ease. It is, therefore, possible that the cases presented by the authors mentioned belong to dermal gland carcinomata (i. e. , to dcrm:il car- cinomata containing sebaceous elements) .

A s (;ruenzoald pointed out, the liability of determination and thc presence of latent potencies of cells a rc more common thnn I\ :is originally hclieved. Recently Hartz presented n beautiful exainplc of thc fact that, first, the sebaceous elements, when occurring in placc4 whcre they do not appear normally, are able to retain holocrinc activity to soine extent and that, secondly, the cells (in the parotid glnntl in his case) may have a >>prospective potencycc.

Secondly, the other type of sebaceous carcinoma is characterized by less highly differentiated tissue, so-called epidermal sehaceous cancer. The cells in this type oftcn rcsembled the >>clear cells<( of the skin (Figs. 11 and 14) . A clumping of the nuclei was also ohscrved. Thc hyaloplasm was not stained by ordinary staining techniquc. The cc~lls, the contours of which were stained a dark shade, wew in t-losci~ contact with each other than the more highly differentia tetl sebaceous cells of the foregoing group. In parts these elements resembled the ncanthotic cells of the prickle cell layer and one could often distinguish iiiterccllular hritlges ( thc author ha \ i n : in earlier paper termed thew elements >>sch:iceous cells of n-typec ) .

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In certain cases one could construct whole series of these cells l o the most highly differentiated 1-type cells (i. e., to true sebaceous elcments, >>pagetoid<<-like cells). In addition, these different types wew found side by side in the distant metastases (for instance in pulmonary lymph node metastases) of highly differentiated sebaceous carcino- mata. These circumstances particularly support the opinion that also the less highly differentiated ))clear cells<( ( i . e . )>bowenoid<c-like elc- ments) are of sebaceous origin ( c f . Figs. 2, 11 and 14) .

( 4 ) some sebaceous carcinomata as well as some simultaneous sebaceous and sudoriferous carcinomata were found - as mentioned earlier - to have a clinical appearance similar to that of certain m:m- mary cancer (Figs. 9 and 10) . On the contrary, as mentionrd in an earlier paper by the author, the pure sudoriferous carcinomata did not even once either clinically or microscopically prove to h a w :I inotlc of growth of this type.

General conclusions.

Taking into consideration the facts mentioned in both an earlier work of the author and in the present paper, the author is of the opinion that the intraepidermal changes found in >)true(< Paget’s disease a re somewhat similar to those occuring in certain dermal appendage carciomata, particularly in simultaneous sebaceous and sudoriferous cancer ( c f . Figs. 1 and 3 ) . Especially the concept that thc mammary gland is a t present believed to have developed from the sweat glands and the opinion - presented in this paper - that certain dermal cle- ments (both epidermal and underlying glandular) could differenliatc into both of the glandular compounds may be of significance (cf. Fig. 6 ) . I t was a t rue holocrine activity, not an apocrine activity, i n these cases ( the nuclei were also secreted),

Therefore, it is not impossible that the ordinary mammary glands also possess components which have retained a capability for differcnt- iating into sebaceous elements, i . e., into >>pagetoid<( cells.

On the contrary, the less highly differentiated sebaceous cancer ap- peared, in general, to form more primitive cell types ()>clear cells<(, acanthotic cells) which in certain cases resembled the bowcnoid coin- pounds a great deal.

No definite answer, however, can be given to the question arc these intraepidermal pagetoid elements malignant or not. - The author is, however, of the opinion that these elements are >)cancerous+ in cases having, a t the same time underlying dermal gland cancer. Although tlic intraepidermal pagetoid cells morphologically resemble the cells of the actual underlying sebaceous or sebaceous and sudoriferous cancer, they are not always quite similar to these latter ( c f . Figs. 3 , 12 and 13) . The intraepidermal formations and thr unclcrlying carcino-

iiiatous tissue seemed to have no direct connection between each other (Figs. 3 and 13). One can often follow the formation of intraepidermal elements in situ (Figs. 12 and 1 4 ) . The pagetoid elements haye pro- bably not infiltrated from an underlying dermal gland cancer, but the essential phenomenon may be the intraepidermal holocriiie activity, clearly indicated in the microphotographs ( c f . particu1:irly Figs. 5, ti, i and 8 ) .

Summary.

The paper presents 10 cases of sebaceous, and simultaneous seba- ceous and sudoriferous carcinomata as well as 10 cases of Paget’s disease and 2 cases of Bowen’s disease.

By referring to his earlier work the author tends to prove that similar intraepidermal (both microscopical and clinical) phenomena could appear in both Paget’s disease and in certain dermal gland carcinomata. Illustrative microphotographs are presented.

The author sets forth the concept that Paget’s cells may be of sebaceous origin.

REFERENCES

Arz t , L., and Kurnri., L.: Arch f . Dermat. und Sphil., 1925, .148, 323. Bang, F., and Guldberg , G.: Ugeskrift f . Laeger, 1935, 97, 51. Cheatle, Sir G. L m t h a l : Lancet, 1936, 2, 1462. - Surgery, etc., 1938, 66, 525. Darrier, J.: Bull. -4ssoc. franC. p. 1’6tude du cancrr, 1920, 9, 169. - Bull. Soc. franq. de drrmat. et syphil., 1925, 32, 1.

DoTffeZ, J.: Dermat. Wschr., 1934, 99, 1318. - Ibid., 1935, !OO, 229. - - Ibid., 1935, .101, 855. - hled. Klin., 1935, 31, 1436.

Frazer , J . P.: Arch. of Dermat. aiid Syphil., 1928, f8, 809. Gates, O., Warren S., and Warvi , W . N.: Am. J. of Path., 19i3, 19, 629. Gruentuald, P.: Arch. of Path., 1943, 36, 190. Har t z , P. 11.: Ibid. , 1946, 4.1, 651. Hual , E: Norsk. Mag. f . Laegc\idensk., 1936, 176, 124. Inglis, I<.: AJn. J. of Path., 1946, 22, 1. Jacobaeus, A. C.: Virchows Arch. f. path. Anat., 1904, i78, 124. K c i t h , Sir Arthur: Human Embryology and Morphology, London, 1933. Kreibicli, C.: Berl. klin. Wschr., 1911, 48, 2193. Loos, H . 0.: Arch. f . Dermat. u. Syphil., 1936, 478, 465. Liibschitz, I<.: Acta rndiol., Stockh., 1944, 25, 127. Meirowsky, E., and Keys, S.: Proc. Roy. SOC. Med., 1945, 36, 495. Muir, R.: J. of Path. a. Bact., 1927, 30, 451. Ormsby , 0. S., and Montgomery, €I.: Diseases of the Skin, London, 19U. Paget, Sir l a m e s : St. Barth. Hosp. Rep., 1874, .10, 87. Parreira, H.: Arq. path., 1935, 7 , 244. Parsons , L., and Lohlein, II . E.: Arch. of Path., 1943, 36, 424. Pautrier, 1,. M . : Arch. of Dcrmnt. a. Sypliil., 1928, 17, ’767.

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Heute?'wuZZ, 0.: Acta Path. et Microbiol. Scand., C:opeiiliageii, suppl. 16. 376 Housset, b.: Les dyskcratiiiisations Bpitheliomateuses, Paris, 1931. Setulu, K.: (1) Duodecim, Helsinki, 1966, 63, 1088.

-- -- (3) Ibid. , (in press).

t2) Ann. Cliir. et Gynaec. Fcnn., Helsinki, 1948, 37, suppl. 3.

Sirnard, C.: Bull. Assoc. franc. p. l'etuilc du caiicer, 1930, l9, 30. S t o u t , A. P.: Ani. ,J. of Cxiicei., 1938, 33, 196. Il'cir/vr, H . A.: Zbid., 1937, 31, 373.