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JUNE 28TH, 1930.

Hunterian LectureON THE

PAPILLOMA AND ITS MENACE.

Delivered before the Royal College of Surgeons ofEngland on Jan. 31st, 1930,

BY W. SAMPSON HANDLEY, M.S. LOND.,FELLOW AND COUNCILLOR OF THE COLLEGE; SENIOR SURGEON

TO THE MIDDLESEX HOSPITAL.

THOUGH the subject of this lecture has never

been entirely divorced from surgery it has beenin the main handed over to the special atten-tion of dermatologists. My reasons for choosingit are several. In the first place, I believe thatthe accepted theories of the pathogenesis of wartsare superficial and unsatisfactory, owing to theirneglect of certain basic facts in the minute anatomy ofthe skin and mucous membranes. In the secondplace, warts are not confined to the skin. Essentiallysimilar neoplasms, described as adenomata or papillaryadenomata or papillomata, are found not only uponthe mucous membranes but also in the mucous liningof the narrow excretory ducts, even in channels sonarrow that the full morphological development of apapilloma is impossible. These internal warts are ofmuch greater frequency and importance than thewarts of cutaneous origin. The subject, then, is awide one, and concerns the pathology of many of theinternal organs. Its main interest, however, liesin this : that recent work by many investigators hasshown with continually increasing emphasis thecloseness of the relationship between papilloma andcarcinoma. The papilloma, though it may remaininnocent for many years, would appear on the evidenceto be a precancerous phenomenon. The connexionmay be obscured by the slow adagio of the processeswhich intervene. The first part of my lecture will beoccupied in establishing the relationship betweenpapilloma (or adenoma) and malignancy in particularvarieties of cancer. In so doing I will give only abrief outline, with special attention to the more recentwork.

A REGIONAL SURVEY.

Tongue.-Leukoplakia, which is a state of papillo-matous hyperplasia, precedes cancer of the tongue inthree cases out of ten. At the margin of a tongue cancerpapillary hypertrophy can generally be recognised.

Larynae.-It is the rule for laryngeal cancer to

begin as a papilloma, as in the classical case of theEmperor Frederick.

OMMC.—An association between polypi of thestomach and carcinoma has long been suspected.Cruveilhier (1835-42), quoted by M. J. Stewart,figured an example of multiple gastric polypi in hisatlas, and thought that cancers of the pylorus notinfrequently originated in such polypi. P. Menetrier andClunet emphasised this view. H. Brunn and F. Pearl(1926) collected 84 cases of diffuse polyposis of thestomach, of which ten (12 per cent.) were malignant.G. A. Mills (1922-23) found malignancy in four out oftwenty cases of diffuse gastric polyposis. Prof. Stewart,of Leeds, from whose paper 1 I have abstracted theearly history of the subject, has recently placed theprecancerous quality of gastric polypi beyond cavil orquestion. Among 11,000 necropsies performed at theLeeds Infirmary between 1910 and 1928 he found47 cases in which gastric polypi were present; single in27 cases, numerous in 10 cases, and few in number in10 cases. In six of the cases where a single polyp waspresent, and in seven of the cases of multiple polypi,a carcinoma was also present. In three cases it couldbe said with certainty that the carcinoma had originatedin a polyp. and in no case could such an origin beexcluded. Thus in 28 per cent. of cases of polypus

1 The Relation of Malignant Disease to Benign Tumours of theIntestinal Tract, Brit. Med. Jour., 1929, ii., 567.

of the stomach a carcinoma is also present. Prof.Stewart says the association of these conditions in thestomach is much less intimate than in the largeintestine, but it appears to me not less decisive andunmistakable.As Prof. Stewart insists, these ostensibly harmless

growths have a sinister significance. Do most gastriccancers originate in adenomata ? In the 11,000 casesreviewed by Prof Stewart there were 263 cases ofcancer of the stomach, but only 47 of gastric polypi.This fact might appear to relegate polypus to a

minor r6le in the production of cancer, as comparedwith chronic ulcer. But it must be remembered thatin the bowel, and possibly also in the stomach,carcinoma tends as it grows to destroy the evidence ofits origin. The margin of a chronic ulcer of thestomach, as of the leg, is exactly the site in which alocal septic lymphangitis must frequently producepapillomatous hypertrophy. It must also be remem-bered that in the bowel, at any rate, as J. P. Lockhart-Mummery and C. E. Dukes have shown, the evolutionof a carcinoma is accompanied by the disappearanceof papillomata in adjoining parts of the mucosa.In the breast, as I shall show, a papilloma only justvisible to the naked eye may have already become acarcinoma. Until a practical gastroscope is evolved itis unlikely that such evidence will be obtainable instomach cancer. But the assumption that all gastriccancers originate in adenomata contradicts no factat present known. Hauser in 29 cases of stomachcancer, found one which was associated with polypoidovergrowth and five which had arisen from chroniculcer. Polypoid overgrowths were thus found inonly 3’5 per cent. of stomach cancers, while theywere present in 20’8 per cent. of cancers in the largebowel. But Hauser finds that all forms of cylindricalcancer arise from adenomatous gland proliferation,which is at first simple in character, and presents itselfas a small rounded thickening of the mucosa not muchraised above the level of the surrounding mucosa andwith a slightly uneven or warty surface. The adenomais at first not ulcerated. Hauser describes theseadenomatous changes as sometimes found in ahigh degree at the margin of chronic ulcers. Thereis evidently no essential difference between these flatareas of adenomatous proliferation and the stalkedadenomata of similar structure, though the formermay escape the observation of the naked eye. Theedge and not the floor of a chronic ulcer is the part inwhich cancer arises, and the ulcer leads to cancerbecause it favours the production at its edge ofadenomatous proliferation of the mucosa. I shalllater suggest how gastric ulceration produces theseprecancerous adenomatous changes at its margin.When it is remembered how small an adenoma

may give rise to cancer and how rare are the oppor-tunities of examining early gastrb cancer, and whenHauser’s observations on the adenomatous changesround chronic gastric ulcers are taken into account,there seens no difficulty in accepting the view thatgastric cancer always begins as an adenoma strictly =comparable with the warty growths seen on the skinin lupus or around a chronic ulcer of the leg.Konjetzny states that chronic polypoid gastritisprecedes most cases of gastric cancer. P. Menetrier,after prolonged researches on the origin of stomachcancer, states that the sequence : chronic gastritis-adenoma--cancer is a constant one, and firmly believesthat " cancer is a transformed adenoma; it succeedsto the adenoma and takes its place." I think we mustaccept this conclusion. He goes on :’ " What we have said about the formation of cancer inthe gastric mucosa, we could repeat for the liver, the kidneys,the uterus, the skin and its glands, the breast, and for allepithelial organs and tissues.....but we have gone moreinto detail concerning gastric neoplasia because it was thesubject of our particular study, and because the stomachlends itself better than any other organ to this kind ofdemonstration. "

Small Intest i)ze. -This part of the intestine, by itshigh absorptive power, is subject in a maximal degree

2 Das chronische magengeschwür, Leipzig, 1883.CC

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to irritations arising from food products, yet isalmost immune to carcinoma except at its lower end.I want to associate this fact with the unique activity oflymphatic absorption in this part of the intestine,a physiological fact which surgeons can frequentlyverify during laparotomies when they see the whitelines of the lacteals. It can hardly be an accidentthat where the lymph circulation is at its maximumthe incidence of carcinoma is minimal. The converseof this proposition is my theme to-night.

Large Intestine.-It has long been known thatintestinal polyposis, in which multiple-stalked adeno-mata are found along the large bowel, is a familialdisease the tendency to which is strongly hereditary.Lockhart-Mummery, Jungling, and others have pub-lished striking family histories, covering severalgenerations. Its connexion with malignant diseaseof the bowel is so close that Lockhart-Mummerystates that he has never known a case which did notdevelop malignant disease. In one family, he records,seven out of nine children of a father who had cancer ofthe bowel also died of cancer of the bowel betweenthe ages of 30 and 54. A grand-daughter at the age iof 31 submitted to complete colostomy for multiplepolypi. Intestinal polyposis appears to be a raredisease, while cancer of the rectum is a relativelycommon one. Nevertheless Lockhart-Mummerysuggests it as possible that all cancers of the bowelarise in a polypus. " A careful examination ofspecimens of cancer of the rectum shows that inquite a number part of the tumour is a simple non-malignant adenoma, though the remainder may betypical adenocarcin-oma.’ 1 3

It must not be forgotten that a single very smallpolypus or flat adenoma may form the basis of a carci-noma of the bowel. On two occasions I have seen atiny polypus appear at the margin of a colostomyopening. In the first case I left the polypus alone, andwhen I saw the patient again, some months later, car-cinomatous stricture of the colostomy had developed.In the second case I excised the polyp a few weeksafter it first appeared. It was already becomingbroad-based and indurated, and on section, thoughonly t in. in diameter, it was an early carcinoma.Dukes has investigated the frequency of coincident

papillomata in a series of 75 specimens of cancer of therectum, dividing the cases into three classes : (a) sub-mucosa only infiltrated ; (b) muscular coat infiltrated ;(c) the perirectal tissues infiltrated. Class Acontained one case, which was associated withpapillomata, Class B contained 18 cases, nine ofwhich were associated with papillomata. Class Ccontained 56 cases, of which 17 were associated withpapillomata. For the early, intermediate, and latecases the respective percentages were 100, 50, and 30.Thus papillomata are commoner in the early than inthe late stage of rectal cancer, and are not a secondaryproduct of the irritant discharges of the growth.Furthermore, according to Dukes, these facts indicatethat soon after a carcinoma originates, papillomata inits neighbourhood tend to atrophy and disappear undersome obscure process of immunisation.4 Dukes hasfurthermore clearly shown that carcinomatousdegeneration may occur in very small polypi. Thechange appears to begin at the free end of the polyp.W. Susman, of Manchester, among 883 necropsies,found 38 cases (4-3 per cent.) of polypi of the colon.Polypi were associated with gastro-intestinal cancerin 14 of these cases, with cancer elsewhere in threecases. Carcinoma of polypi of the colon was observedin four instances of multiple polyposis. InDr. Susman’s opinion there is a common cause forgastro-intestinal cancer and polypi, 5

Breast.-Sir Lenthal Cheatle, by patient andaccurate work with a giant microtome for cuttingsections of the whole breast, has placed our knowledgeof precancerous conditions of the breast epitheliumupon a secure footing. He shows that these changes

3 THE LANCET, 1925, i., 427.4 Brit. Med. Jour., 1929, ii., 196.

5 Ibid., 1929, ii., 196.

are often confined to one particular lobe of the breast,a fact suggesting the intrusion of some extrinsic agentsuch as a parasite or bacterium, and furthermore thatthey affect mainly the small ducts just before theyopen into the acini. He divides epithelial hyperplasiaas seen in the breast into two varieties, desquamativeand dysgenetic, and he appears to regard the firstvariety as the precursor of the second. In desquama-tive hyperplasia the cells are cast off into the interiorof the ducts and the process does not appear to meritthe term hyperplasia, but is rather a catarrh withretained products-probably, I suggest, due tobacterial infections along the ducts, and comparableto catarrh of the uterine cervix or of the nose. The" dysgenetic " hyperplasia of Cheatle may be lessequivocally described as a papillomatous hyperplasia.In it three stages are seen :-

1. The individual cells remain normal but papillomata.are produced within the acini and terminal ducts. Theacini are never thus affected alone.

2. The individual cells show the signs of incipientmalignancy (hyperchromatosis, variation in size, mitosis).

3. Infiltration of the tissue around the ducts and aciniby the altered epithelium is beginning.

Clinical carcinoma and precancerous papillomatoushyperplasia were frequently found in the same breast.Cheatle points out the exact analogy of these processeswith the changes seen in experimental tar carcinoma.In a case of tar carcinoma with papilloma formation but >without infiltration, Dr. J. A. Murray inoculated theepithelium of the papilloma at a fresh site and produceda growth which metastasifed. Cheatle infers byanalogy, and rightly I think, that in the second stageof the hyperplasia in the breast the epithelium of thepapilloma is essentially malignant, though it has notfound an opportunity to infiltrate.

’, It is possible, I find, to distinguish the simple fromthe malignant papilloma of the breast, not only by thecharacter of the individual cells but by the picturepresented by the papilloma itself. In the simplepapilloma the pattern is regular and the vascular core,though branched and complicated, is easily traceablein continuity, and is covered by a regular and usuallyone-layered epithelium. In the following two cases Iwas able to demonstrate the occurrence of carcino-matous degeneration in a duct papilloma which hadapparently only existed for a very short time. In thefirst case at the time of the operation the papillomawas affected by carcinoma, but the disease had not yetattacked the tissues of the patient herself.CASE I.-A married woman, aged 70, noticed a serous

discharge from the left nipple a week before she was firstseen on June 12th, 1928. The breast was normal on pal-pation except that, vertically half an inch below the leftnipple, a tiny very superficial shot-like swelling could be felt.Pressure at this point made fluid exude from the nipple.No other nipple changes were found. There were no glandsin the axilla. On June 15th, 1928, this lump was cut downupon, two dilated ducts were exposed, divided close to thenipple surface, and then again divided where they began toramify in the breast substance. On section of the excisedportion across the ducts a small papilloma, just visible to thenaked eye and perhaps one-fiftieth of an inch in diameter,was found within the duct, attached to it by a slenderpedicle. A section across the tissue showed that thisminute and early morphological papilloma had alreadybecome a carcinoma within its own substance. The fibroustissue of its core was infiltrated with carcinoma cells, thoughthere was no evidence that the physiological tissues of thepatient had been attacked by the disease. The pedicle ofthe papilloma, fortunately included in the section, wascomposed of fibrous tissue only, and showed no infiltration. 6An indication of the pathogenesis of the papilloma was,however, given upon examination of the pedicle. Itshowed several cylindrical groups of round-celled infiltra-tion, some cut as circles, others as ovals. In company withone of the groups was a small artery. These are exactlythe appearances given by blocked lymphatics which havelost their lumen by proliferation of their endothelium, asI know from my experience of lupus and elephantiasis.In other words, the patient had suffered from a chroniclymphangitis of the tissues of the breast, and it appears

6 Illustrations of this growth will be found in my article onLymph Stasis the Precursor of Cancer, Brit. Med. Jour., Oct. 5th,1929.

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highly probable that the resulting lymph stasis was thecause of the papilloma which so rapidly developed into apotential carcinoma.CASE 2.-Aged only 38, a married woman with two

children, the younger aged 4, and neither of them breast-fed, noticed a tiny lump just to the inner side of the rightnipple ; she remembered having felt a pain in this situationa year previously. Two months after its appearance thelump was excised by Dr. H. Simmons, of Bournemouth. Itwas as large as a small pea, and felt hard. Its wall wasrather thick, and it contained two drops of fluid. A sectionshowed a tiny group of papillomata springing from the walland projecting into the cyst, which had the characters of adilated duct. The papilloma group had an irregular andconfused structure, and was composed mainly of epithelium.The fusion of two or more papillomata to form it was indicatedby the presence of several distinct pedicles (Fig. 1). The Ierosive power of the papilloma is seen at C, where it has Ipartly penetrated the epithelial lining of the duct, and atD, where the same process is complete. The point C isrepresented under a high power in Fig. 2, and at A in thatfigure the epithelium of the papilloma has begun to fusewith the epithelium lining the duct. At E in Fig. 1,incipient papillomata are seen, and at B in the same figurethe epithelial lining of the duct is infiltrating the underlyingconnective tissue. B is represented under a high power inFig, 3, where F marks the limit of the epithelial infiltration.

This early carcinoma, for as such it must be classified, wasabout two months old. Infiltration was present outsidethe wall of the duct at one point. The papilloma groupshowed its essential malignancy by (1) interfusion ofadjoining papillomata ; (2) infiltration of the vascular coreof the papilloma by epithelium ; (3) erosive action of theepithelium of the papilloma on the epithelium of the wallof the duct; (4) a simultaneous process of fusion of the twoepithelia, and (5) hyperchromatosis and irregularity in sizeof the epithelial cells.These two carcinomas are probably among the

earliest ever removed at operation. Each wascharacterised clinically by a tiny mobile lump,unaccompanied by any other sign of cancer. The

FIG. 1.

Case 2.-Incipient malignancy in a group of papillomatalying within a duct of the breast.

first patient, however, had haemorrhage from thenipple. In the first case the carcinoma affected thepapilloma only and had not attacked the tissues ofthe patient. The second case is a slightly later phase.The only rarity in these two cases consists in their veryearly detection and removal. They illustrate well thedifficulty of early diagnosis in cancer of the breast, andthe origin of the disease in duct papilloma of the largeducts. As Cheatle has shown, it is more common forpapilloma to start in the small ducts near the glandularacini. I may add that the first patient remains welltwo years after operation. I

Lupus Carcinoma.-Lupus carcinoma was firstrecorded by Devergie in 1857, long before the discoveryof X rays, and I have seen at least three cases whichhad never been subjected to radiation. The diseaseis not very rare, for K. Asihara was able to collect 122

FiG. 2.

Penetration of the wall of the duct by the papilloma seen atC in Fig. 1. (x440.)

cases. Persistent X ray treatment may no doubtaccelerate its onset. In a case recently under my carea lupus carcinoma of the left cheek was associatedwith an innocent wart on the right cheek. Thenon-ulcerative forms of lupus usually show papillaryhypertrophy, and when this is marked the namelupus verrucosus becomes appropriate. It seemsprobable that all lupus carcinomas originate in areasof papillary hypertrophy.

Carcinoma of Chronic Ulcers.-Carcinoma may ariseupon the margin of an old chronic ulcer of the leg.The neoplasm is preceded by chronic thickening andwarty hypertrophy of the surrounding skin. Thepapillomatosis may reach an extreme degree, as in acase recently published by W. Donald Bedford. 7 Inthis case the ulcer had been present for 25 years,and the papillomata presented no definite sign ofmalignancy.

Thyroid.-During the last few years brilliant workupon the thyroid gland and its relations to thelymphatic system has been done in this college, on theside of comparative anatomy by the physiologicalcurator Mr. R. H. Burne, and on the side of pathology byDr. G. Scott Williamson and Miss 1. H. Pearse, whosestudies have illustrated once more the unexhaustedpossibilities of morbid histology. They have shownthat multiple adenomata of the thyroid, a conditionwhich they prefer to call simple hyperplastic goitre,occur as the result of a process of focal perilobular

fibrosis. I believe this term to be an alias for chroniclymphangitis. These adenomata present theappearances of a simple local hypertrophy of thegland tissue, and are a reaction against the loweringof the thyroid function which the fibrosis produces.This form of thyroid enlargement is the one par-ticularly liable to lead to malignant disease. Infour out of 20 such cases in Williamson’s experienceremoval of part of the goitre was followed by cancer

7 Brit. Med. Jour., 1929, ii., 1108.

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of the adenopapilliferous type. " In three other

cases the central lobules ..... showed changes quiteindistinguishable from adenopapillomata." 8 Theauthor goes on to state that in the thyroid the adeno-papilloma and papilliferous carcinoma resultingtherefrom are analogous to the similar growths seen

FIG. 3.

Represents the region AB in Fig. 1 under a high power, andshows infiltration beginning at the base of the papilloma.( x 440.)

in the breast, prostate, ovary, and other organs. Thescirrhous form of cancer is relatively rare.The evidence for the onset of thyroid carcinoma

from papilloma thus appears to be convincing. Eventhe scirrhous forms may have such an origin. I mayremark in passing that the cramped conditions underwhich the thyroid adenomata grow are ideal for theaggravation of local lymphatic obstruction.

Occupational Cancer.-Percival Pott, who describedsweep’s cancer of the scrotum 150 years ago and thuslaid the foundation of our knowledge that cancer isat first a local disease, pointed out that the malignantgrowth originates in a simple wart. Leitch, who hasspecially studied occupational cancer and whodetected the action of the sebaceous secretion of thescrotum in dissolving an active agent from the sootparticles, points out that the kangri cancer of Kashmir,the cancer of the cheek and gums which results fromthe habit of chewing betel-nut, arsenic cancer, andaniline cancer of the bladder, are all associated withpreceding papillomatous formations. e

PAPILLOMA AND EXPERIMENTAL CANCER.Fibiger, in 1913, showed that a squamous carcinoma

of the stomach could be produced by feeding rats withcockroaches infected by a certain nematode worm.This form of cancer is called spiroptera cancer. Hesays: " The disease consists in its initial stage ofepithelial hyperplasia and inflammation. In moreadvanced cases papilloma formation supervenes ; itmay reach a colossal development, and may fill upthe whole cavity of the stomach. This may be theprecursor of a malignant epithelioma with invasiveheterotopic growth of epithelium. Metastases mayoccur, in which no parasites or eggs were found."The thread-like worms are found burrowing in theepithelial layer, and Fibiger lays no stress on thechanges found in the submucosa. Nevertheless, he

8 Jour. Path. and Bact., 1925, xxviii.9 Cancer Control: Report of Lake Mohonk Symposium, 1927,

p. 208.

says : " everywhere in the submucosa inflammatoryappearances were seen in a greater or less degree."Examination of his photographs shows, below theepithelium in the superficial part of the submucosa,a band of round-celled inflammation which in myopinion indicates a lymphangitis, and this opinion isconfirmed by the gigantic papillary hypertrophy, aclear indication of lymphatic obstruction. The r6leof the spiroptera, burrowing about in the epithelium,is exactly comparable to that of the infected needle,which may set up an acute or chronic lymphangitis.But neither in the spiroptera nor in the bacterialparasites it carries is there any specific carcinogenicagent. The specific factor, as I shall endeavour toshow, is the resultant lymphatic obstruction.The evidence that a papilloma or an adenoma is a

very frequent precursor of cancer could be multiplied,if time allowed, by the consideration of other formsof cancer. There is, however, an earlier stage in thecancer process which we must now consider briefly.

Pre-Cancerous Inflammatory Changcs in the Sub-Epithelial Tissues.-There is abundant evidence thatthe epithelial proliferation characteristic of carcinomais preceded by chronic inflammatory changes ofancient date in the underlying connective tissue. Suchis the testimony of Waldeyer, Ribbert, Borrmann,Menetrier and, in this country, of my colleague,Victor Bonney,lo who made a close study of theconnective tissues in carcinoma. As Bonney says,the hypertrophy of the epithelium only developsafter the sub-epithelial changes are established, andthese changes are invariably characterised by increasedcellularity. Billroth said : " Without previous chronicinflammation, cancer does not exist." These changes,it should be noted, precede papillomatosis. Theymust be significant. Their occurrence has remaineda basic but isolated fact not related intelligibly to therest of the story. Some observers, especially LenthalCheatle, have minimised their importance. I wantto suggest that they are the result of long-standinglocal chronic lymphangitis, a process which inelephantiasis produces extreme hypertrophic changesin the connective tissues, associated with papilloma-tosis.

PATHOLOGY OF THE PAPILLOMA.If a papilloma is a very frequent forerunner of

cancer a study of the pathology of the papillomamay be one line of approach to the most importantand baffling problem of pathology, the origin of cancer,a problem which has hitherto defied all attacks. Thegenesis of a papilloma cannot be understood withouta knowledge of the lymphatic arrangements of theskin. Some years ago, in the course of a lecture onlupus, I showed in this theatre a scheme of thearrangement of the lymph vessels of the skin, whichI had inferred partly from my own direct lymphaticinjections but mainly from a study of the skinlymphatics as mapped out by lupus or malignantdisease. The main facts demonstrated were that theaxis of each papilla of the skin is occupied by a centrallymphatic vessel terminating blindly towards theapex of the papilla, but joining below its base withfour or five more similar lymphatics from adjacentpapillae as the fingers join the hand to form a singlevessel. By the union of a group of these vessels inthe superficial third of the thickness of the dermis,horizontally running lymphatics are formed which,uniting by groups and changing their direction,pierce the deeper layers of the dermis, again uniteby groups in the subcutaneous fat, and run verticallythrough the fat to join the fascial lymphatic plexus(Fig. 4).

It is a satisfaction to me this evening that I canplace before you independent evidence of the broadtruth of this description of the skin lymphatics.Prof. D. T. Harris, of University College, drew myattention to a specimen of skin, showing the lymphaticsinjected, presented many years ago to the Museum .

by Prof. Hyrtl, of Vienna. The specimen attracted

10 Arch. of the Middlesex Hosp., 1908, xiii.

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no particular attention, though it is a beautifulexample of the " lost " art of lymphatic injection, andso far as I know Hyrtl never published a descriptionof the minute lymphatics of the skin. It confirmsin all important particulars the description of theskin lymphatics which I gave in 1921, and places theminute lymphatic anatomy of the skin upon an

unassailable basis. The entire path-ology of diseases of the skin willrequire reconsideration in the light ofthis specimen (Fig. 5).

-

Each papilla of the skin is providedwith a separate drainage system, andthe lymphatic vessel lies in theaxis of the papilla but is alwaysseparated from the overlying epithe-lium by a thin layer of connectivetissue. Furthermore, if the fibrouslayer of the skin is considered,nearly all the lymphatic vessels arefound .in its superficial third. Inthe deeper two-thirds of the dermisthe lymphatic vessels are compara-tively scanty, and run vertically, incompany with the blood-vessels.With these anatomical facts I want to correlate

certain pathological facts. In elephantiasis a bandof round-celled infiltration is often seen in the super-ficial third of the dermis. Lupus affects, at firstexclusively, the superficial third of the dermis. InPaget’s disease of the nipple a band of round-celledinfiltration is often found in the superficial third ofthe dermis. In moles the characteristic cells, calledby the Germans" neevus cells," affect the superficialthird of the dermis without ever quite reaching the

epithelium. I ask you to infer that all these conditionsare genetically related to the lymphatic system. Inthe case of elephantiasis no proof is needed. Infavourable cases of lupus and Paget’s disease I havegiven direct visual proof in earlier lectures in thistheatre. Lupus is a tuberculous lymphangitis.Paget’s disease depends initially upon cancerous

To show the lymphatic arrangements of the skin. A schematic vertical section ofthe skin and subcutaneous fat, with a small horizontal shelf of deep fascia pro-jecting forward from it. Below this is muscle in vertical section. AB and BCare two of the primary lymphatic areas of the skin. These areas measure one-third to half an inch in diameter, and the only lymph-vascular communicationbetween them appears to be by way of the subjacent fascial lymphatic plexusDDDD which is seen on the flat. The lymphatic end-sacs of the skin papillaeunite by groups of five or six to form small lymphatic vessels, which again unitein the superficial third of the dermis (plane of primary confluence EEE) to formother lymphatic vessels which pierce the dermis vertically and unite just beneathit (plane of secondary confluence FFF) into a smaller number of vessels whichrun down through the subcutaneous fat to discharge into the fascial lymphaticplexus DDD. (Handley: "Lupus in its Surgical Aspects," Annals of SurgeryJan., 1922.)

permeation of the lymphatic vessels of the skin, and Ilater shows fibrotic destruction of these vessels withthe typical band of round-celled infiltration. Nowall these conditions are associated with papillaryhypertrophy or with the appearance of papillomata.This can hardly be an accident. There is evidentlysome very close relation between lymphatic obstruction

Iand the genesis of a papilloma. Here we may turnaside for a moment to consider the accepted views Iupon the pathogenesis of a papilloma.

Accepted Views on its Pathology.To obtain these views we must turn to the volumes of

dermatological pathology dominated by the oracularUnna, who decides questions of cutaneous pathologyby an intuitional process.Unna objects entirely to the term papilloma, and

FIG. 5.

A section of skin under a low magnification in which the papillary lymphatics, com-pletely injected, are seen above. This specimen was presented to the Museumof University College many years ago by Prof. Hyrtl, of Vienna.

,

i wishes to substitute the word acanthoma, because heconsiders that the primary factor in a papilloma is aproliferation of the prickle epithelium.l1 In my opinionthis sterile conception must be replaced by one basedon anatomy and physiology. As I said in an addressgiven last year in New Zealand, " the papilla is a

little physiological engine. From its blood capillariesthere exudes into its connective tissue a constantnutritive stream of dilute blood plasma at a certainpressure. The excess of fluid is removed and theequilibrium maintained by the drainage action of thecentral lymphatic. Block this lymphatic and whatwill happen ? The first effect will be a rise in thepressure in the intercellular spaces of the papilla, andon ordinary hydraulic principles the papilla willincrease in size until the intercellular pressure iseaual to the pressure in the capillary blood-vessels.

A second effect will be overnutri-tion and consequent proliferation ofthe papilla itself, and of the overlyingepithelium."

This view is based upon certainobservations made in cases of wartyor non-ulcerated lupus which I mustbriefly summarise. They are simpleand, I think, convincing. In suchan area of lupus, if the length ofthe papillae is measured they arefound to be slightly hypertrophiedat the edge of the patch, but as

its centre is approached they showa gradual increase in length up toten times the normal. If now theskin is examined immediately beyondthe edge of the patch of lupusthere is no definite papillary hyper-trophy, but the central lymphaticof each papilla, though still anato-mically recognisable, is seen tobe blocked by proliferative tuber-culous lymphangitis (Fig. 6). Thereis no other abnormality to bedetected in the tissues. The infer-

ence I draw, and it seems an

inevitable one, is that the blockingof the papillary lymphatic hasestablished the necessary conditions

I for papillary hypertrophy and wart formation-changes which in the centre of the patch of lupushave had time to reach their full development. It.is true that I have not blocked a papillary lymphaticand seen a papilloma arise but, short of experimentaldemonstration, the proof of origin could hardly bemore conclusive. The elongation of the papillae in

a papilloma is not due to the downgrowth of the

11 Histopathology of the Skin, trans. N. Walker, 1896, p. 671.

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interpapillary cell columns for, as has been noted byother observers, the relation of the deepest part ofthese columns to the hair follicles deeper downremains unaltered. Moreover, in conditions ofpapillomatosis the interpapillary epithelial cellcolumns tend to atrophy and disappear, a clearproof that their r6le is a passive one. They are thevictims, not the agents, of pressure.

If the tubercle bacillus, by setting up a local area

FIG. 6.

A section ( x 95) taken from near the edge of an area of non-ulcerative lupus, lying beyond the visible edge of the diseasein apparently normal skin. The lymphatics of the skinnevertheless show advanced proliferative lymphangitis. Agroup of the lymphatic end-sacs, which lie in the skin papillae,is seen uniting in the plane of the section to form one of thevertically running lymphatics which pierce the dermis. Tothe left is seen another Y-shaped lymphatic junction, whichalso is converted into a solid cord of cells by proliferationof its endothelium. (Handley: "Lupus in its SurgicalAspects," Annals of Surgery, Jan., 1922.)

of chronic obstructive lymphangitis, can producepapillomatosis and finally carcinoma, is it not likelythat other bacteria which are known to produce asubepithelial chronic inflammation, followed bypapilloma and cancer, also act by producing a locallymph block ?

Malignant Tumours Arising From Congenital SkinMalformations.

The local congenital malformations of the skincalled naevi in France and Germany, and in thiscountry described as nsevi only if vascular but other-wise as moles or warty moles, are known to be seatsof election for malignant tumours, especially if theyare subjected to irritation.But malignant tumours may arise in nsevi without

any precedent process of chronic inflammation, suchas is usually seen in other cancers. There wouldappear, therefore, to be a factor at work in neevi whichacts as a substitute for chronic irritation and inflam-mation. What is it ? A study of the minute anatomyof the pigmented naevus shows that the characteristicnsevus cells, closely aggregated pigmented or unpig-mented connective tissue cells, occur chiefly in thesuperficial third of the dermis, the layer which wehave already recognised as the lymphatic zone. This

fact suggests that the naevus is an area in which thecells which should produce the lymph vessels haveproliferated irregularly and have failed to form thenormal lymphatic network. This conclusion isconfirmed by the frequency of papillary hypertrophy,which in the typical warty naevus reaches a highdegree of development. The excess of pigment inneevi also indicates some defect in metabolism, andcan also be interpreted as due to a defective circulationof tissue fluid, such as would result from lymph stasis.You may look upon these arguments as special

pleading. Let me therefore say that a number ofdistinguished pathologists have independently cometo similar conclusions. Von Recklinghausen, Bauer,and Borst 12 all hold that the peculiar naevus cellgroups found in moles are produced by proliferationof the endothelium of the lymph vessels and spaces.Von Recklinghausen gave to moles the name lymph-angiofibromata. Borst found in moles lymphaticvessels still recognisable but partly filled up withnsevus cells, pigmented and unpigmented. He. couldalso recognise thickening and proliferation of theendothelium of the lymph vessels. On the other hand,he found no such changes in the blood-vessels. Wartyor papillomatous moles are liable to give rise tosquamous-celled carcinoma. Renoul,13 among 121examples of tumours arising from naevus, found 34carcinomas. Melanotic sarcomas arise from them evenmore frequently, and mixed carcino-sarcomas havebeen recorded.

There is very good reason for considering that theliability of moles to malignant change is due to alocal lymph block of congenital origin.

RECENT CANCER THEORIES.The two most recent general theories of the origin

of cancer are those of L. Kreyberg, of Oslo, andA. Lumiere, of Paris. Kreyberg has shown by veryneat methods that areas irritated by tar exhibit, inthe precancerous stage, a dilatation of the cutaneousvessels associated with increased transudation ofserum into the tissues. This hypersemia comes

immediately after the tar application and after thefirst application disappears within 48 hours, but afterlater applications is more and more persistent. It isnot of reflex origin but is ascribed hypothetically tolocal injury of the contractile apparatus of the smallvessels. Capillary ectases appear at the end of amonth and precede the development of warts. Theaffected vessels are capillaries and venules, andthrombi are frequently seen within them, without anyevidence of proliferation of the vascular endothelium.Polymorphic leucocytes,later replaced by lymphocytes,wander into the tissue of the corium and subcutaneousfat within two days of the first tar application, andthe fibrous bundles increase, so that the coriumbecomes fibrous and rich in cells. A diffuse hyper-plasia of the epidermis develops within a few days,but is later than the connective fibre changes.Painting with spirit of mustard or with hot water at60° C. led, on the contrary, to a transient hypersemia,with later degeneration of the epidermis and theproduction of scarred corium, poor in cells.14

Kreyberg finds in the power of tar to cause lastinghyperaemia the secret of its power to cause cancer,and ascribes to hyperaemia a predominant r6le in theproduction of malignancy. He finds in the persistent" irreversible " dilatation of the vessels the factorwhich may cause cancer even though the applicationof tar be stopped. He remarks that human cancersoriginate at the time of life when vascular degenerationis frequent and in organs which are intermittentlyfunctional and subject to great circulatory alterations,such as the uterus. His work takes no account of thelymphatic vessels, and it cannot be right to omitfrom consideration such an important anatomicalelement in the skin. Chronic hypereamia seems toowide and general an agency to be invoked as the

12 Die Lehre von den Geschwulsten, 1902, i., 117 and 453.13Thèse de Paris, 1892.

14 Virchows Arch., 1929, cclxxiii., 367.

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cause of cancer. This is not to belittle the importanceof Kreyberg’s observations, but they may be anisolated chapter of the story of which I believe Ihave given a more complete and documented account.

It is evident that inflammatory hyperaemia mustaccompany the earlier stages of a chronic lymphangitis.As to the later persistent hyperaemia, it so happensthat in my study of lupus I have already describedthe vascular dilatations, followed by vascular restric-tion, which Kreyberg has described in the laterstages of tar-painting. I ascribed them in lupus tothe comitance of lymphatics and blood-vessels.From this anatomical circumstance it inevitablyarises that the fibrous changes of a chronic lymphang-itis and perilymphangitis produce pressure at firstupon the comitant vein with vascular congestion andincreased transudation, and later upon the arterieswith vascular constriction, followed by necrosis. Itwill not escape notice that the early changes in thecorium described by Kreyberg precede the epithelialand vascular changes, and that they are preciselythose which are already known to occur in a lymphang-itis of tuberculous origin. Kreyberg’s observationsare thus an independent confirmation of my own,and are especially important as showing that the veryfirst effect of tar-painting is seen in the lymphaticregion of the corium, and that the earliest epithelialchanges come later. Kreyberg’s theory offers noexplanation of the close association between papillomaand cancer, which on my view receives an easy andnatural explanation.According to Lumiere 15 the essential preliminary

for the production of cancer is a scar. This is untrueif the word ‘‘ scar " is used in its clinical and ordinarysense. It is probably true, except in the case of moles,that microscopic processes of subepithelial chronicinflammation which lead to the formation of scar tissueinvariably precede a carcinoma. That mere scar-

formation is not the cause of cancer is, however, shownby the extreme rarity of malignant growths in thescars of " clean " surgical operations, where the con-ditions for the infection and subsequent obliterationof lymphatic vessels have been excluded by thesurgeon’s precautions. The hypothesis of Lumierefails by its vagueness and its limited applicability,though it contains an element of truth.

It is to be noted that not one of the theories of theorigin of cancer hitherto current applies equally tocases originating in chronic infections, in chemicalirritations such as those of tar, and in malformed areasof skin. Parasitic theories fail to explain tar cancer.Cohnheim’s theory fails to explain the origin of cancerin such conditions as chronic gastritis. Chronicirritation and parasitic theories fail to explain thespecial liability of moles to become malignant.The occurrence of papillomatosis preceding every

variety of carcinoma suggests for all three classes ofgrowth a similar pathogenesis, and points to chroniclymph stasis as the x of the problem. Congenitalmalformation of lymph vessels and pathologicalobstruction of them have, as might be expected, thesame effect.

A. Leitch has stated that cancer is due not to onecause but to many. I believe this is a superficialview and that these multiple and alternative chainsof causation will be found to converge to a single lineof links which leads through local lymphatic obstruc-tion-often manifested by papillomatous hypertrophy-and certain consequent metabolic changes to theonset of a carcinoma, and that not otherwise can acancer be produced. The language and thought ofmankind upon the subject of causation is in a

singularly muddled condition. Any given consequencesuch as cancer springs from a chain of previousevents stretching back to infinity, and not from asingle cause. But if among those events one can bedetected which for a given consequence is veryfrequently present, and has never been provedabsent, the clue to the problem of causation has been

15 A. Lumière: Le Cancer, Maladie des Cicatrices, Paris,Masson et Cie.

obtained, and this event may be provisionally andloosely spoken of as the cause. In this sense I ambold enough to claim that lymphatic obstruction isthe cause of cancer, though the labours of generationsmay be required to trace the intermediate steps. Theevidence for this view is so substantial that it mayclaim to rank not as a hypothesis but as an establishedtheory-that is to say, as the solvent and unifier ofall the relevant facts hitherto observed and the guideto future research upon the subject. My part in thistheory has been to explain the real pathology of thepapilloma and to demonstrate the lymphangitis-papilloma-carcinoma sequence in lupus carcinoma.Had this been all, the theory would have remaineda plausible hypothesis proved only for lupus cancer.It has been raised to the rank of a theory by successivewaves of evidence, coming in like a tide from indepen-dent observers and referring to distinct varieties ofcarcinoma, but all bearing testimony to the geneticrelationship of papilloma or adenoma and carcinoma.Some of these observers have been surgeons, somepathologists, but I am glad to observe, as showingthat the originality of our nation is not exhausted,that most of them have been English. I mentionthe names of Hurry Fenwick, Lenthal Cheatle,Cuthbert Dukes, Lockhart-Mummery, M. J. Stewart,G. Scott Williamson, and I. H. Pearse.

I rejoice in these facts for another reason, because*they show the continued vitality of morbid histology.The phase of dangerous neglect through which thissubject has passed is giving place to renewed interest,though academic recognition of its importance anddignity is still to seek. I continue to hope for thetime when this building will contain a histologicalmuseum equal in importance and authority to itscollection of naked-eye specimens. As Prof. C. Regaudsaid of morbid histology, " Not only does it lie at thebottom of all classifications that we make, and playa preponderant r6le in diagnosis, but it has alsobecome the indispensable guide of all who devotethemselves to the difficult problem of the biologicalaction of radiations "-a subject of very immediateimportance now that radium is coming into itskingdom.

DOES LYMPH STASIS PRECEDE SARCOMA? toThe peculiar relations of epithelium to the under-

lying connective tissue provide, in the precancerouspapilloma or adenoma, an early criterion of theexistence of lymph stasis. No such criterion isavailable in the case of the sarcomas, which arise notupon surfaces but in the depths of the connectivetissue. The problem of presarcomatous conditionshas hardly been approached. Nevertheless there areindications that forces of the same order as thosewhich produce carcinoma may also produce sarcoma.Warty moles may become the seat either of a

carcinoma or of a sarcoma, or of a carcino-sarcoma.Some experimenters, while trying to producecarcinoma by injecting tar, have produced instead asarcoma. It may at any rate be said that theapplication of the lymph-stasis theory to sarcomapresents no difficulty, except that in the sarcomas ofyoung children the normal snail’s pace of the geneticprocess of cancer must have been much accelerated.

CONCLUSION.To sum up, the genesis of cancer has been linked

up firstly with a predominant extrinsic factor-chronic irritation either of bacterial, viral, parasitic,or physical origin; secondly, with a predominantmorbid anatomical factor-papillomatosis or adenoma-tosis ; and, thirdly, if you accept my conclusions,with a predominant physiological factor-locallymphatic obstruction. Finally, if the work ofWarburg holds good, the genesis of cancer is intimatelylinked with a biochemical factor, a change-over on thepart of the precancerous cell from nutrition byoxidation to nutrition by hydrolysis. It is easy toimagine how this change may be imposed upon thecell by conditions of lymph stasis. Is it too much,

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then, to say that the main outlines of a solution of thesetiological problem of cancer are visible through themist ? Concordant facts have an unmistakable musicof their own, which even Beethoven cannot excel.

Menetrier has divided theories of the origin ofcancer into two classes : (a.) the parasitic theories,which seek the cause of cancer in a specific livingagent reaching the body from without ; (b) the cellularor cytophysiological theories, which lay stress uponthe intrinsic modifications of organs and tissues.It will be seen that the apparently conflicting factsupon which the opposing views are based can beharmonised if it is admitted that various non-specificinfections and chemical and physical irritations mayset up a chronic local obstructive lymphangitis whichin the course of years profoundly modifies the vitalprocesses of the surrounding cells. The circulationof tissue fluid is impaired, and in the obstructeddistrict the cells no longer receive their due share ofthe products of the other cells of the body. Theyare deprived of the hormones by which the cellsociety exercises its influence upon the cell individual,and particularly of the hormone which limits celldivision. Under these conditions it is not surprisingthat they may ultimately revert to the condition ofthe primitive unicellular organisms from which theyare all descended.You all remember the story of Mowgli as related

by Mr. Kipling. Cut off from the influence of hiskind and from the apparatus of civilisation, Mowglimade shift in the jungle by reverting to the habitsof the primitive man, his ancestor. The story ofMowgli is a parable of the origin of the cancer cell.The analogy is incomplete. The cancer cell hasreverted to the very beginnings of life, when allliving beings were single cells, to a time when egotism,modified by an urge to voluntary bisection, was theonly virtue. Such was the moral code required topreserve life through the cataclysms of the prime, andsuch to-day is the code of conduct of the cancer cell.

It has been said, for I said it myself, that man isomnipotent till he is 30, omniscient till he is 40, andimmortal till he is 50. In the 25 years which haveelapsed since I first held my present office-and Ihave held it eight times-I have lost the support ofthese delusions. But the younger generation ofsurgeons, the future holders of this chair, will find,as I have found, that attempts to advance knowledgein the service of this College and to present theresults in a form fit for this critical audience are asource of abiding satisfaction, a satisfaction whichsurvives the delusions of youth, and perhaps evenoutlives the fire of personal ambition and the thrillof professional success.

CLINICAL EXPERIMENTS WITH

ŒSTRIN.

BY E. C. DODDS, M.V.O., M.D. LOND., PH.D.,COURTAULD PROFESSOR OF BIOCHEMISTRY IN THE UNIVERSITY

OF LONDON;

AND

J. D. ROBERTSON, M.B. ST. AND., D.P.H.,ASSISTANT CHEMICAL PATHOLOGIST TO THE MIDDLESEX

HOSPITAL.

(From the Courtauld Institute of Biochemistry,Middlesex Hospital.)

SINCE many monographs and reviews 2 3 dealingwith the literature on the discovery, preparation, andphysiological and chemical properties of this sub3tancehave app?"’ed within the last year, it will only benecessity to refer very briefly to the outstandingpoints in this discussion. The fact that the ovariesplay an essential part in the sexual cycle of animalshas been known for generations in consequence of the

obvious effects of castration in animals. During thelast 30 years a continuous series of attempts has beenmade at substitution therapy, and, as in the case ofother hormones, the outstanding landmark was

found at that particular time when a definite methodof testing the potency of the extract was discovered.The earlier workers employed such phenomena asenlargement of the uterus and growth of the genitalsas a sign of the activity of their products, but it caneasily be seen that this type of observation can rarely,if ever, be developed into a quantitative study. Themost important observation was made by Allenand Doisy,4 who were the first to apply Stockard andPapanicolaou’sá vaginal smear method to the study ofthe activity of ovarian extracts. This reaction is theone by which the material at present under discussionis standardised.

It was shown by these workers that if daily vaginal smearswere made from small rodents, such as the rat and the mouse,a series of cyclical changes occupying about three days wasfound. This phenomenon is known as oestrus and can bedivided into three stages-pro-oestrus, oestrus, and meta-oestrus. The cellular changes occurring in the smear arecharacteristic for each stage ; in the resting stage can beseen leucocytes and degenerating cells ; in pro-cestrus theleucocytes begin to disappear and epithelial cells in variousstages of cornification take their place ; at the height ofoestrus the leucocytes have vanished and the smear consistsof eosin-staining cornified cells which have lost their nuclei;in meta-cestrus retrogression appears, heralded by the appear-ance of leucocytes, and the reaction thus returns to the restingstage. If the ovaries are removed from the animal thesechanges cease, and the vaginal smear takes on the appearanceof the resting stage, which is known as dieestrus. Allen andDoisy showed that the injection of extracts made with the useof volatile solvents would cause the cyclical changes toreappear,and this has been developed as a method of standard-isation. The important point to realise is that there is a

definite quantitative relationship between the amount ofhormone injected and the changes in the vaginal smear, andthat in this technique we have a certain method of assayingthe hormone.A great deal of controversy centred around the actual

definition of the unit. The earlier workers employed thetechnique known as the " descending dose " method. Thisconsisted of giving small quantities of the hormone to a seriesof rats and noticing the minimum quantity capable of produc-ing cestrus in one or more animals. This type of method wasvigorously attacked by Coward and Burn," who showed thatthe possibility of error was in the region of many hundredper cent. on account of the great individual variability in theresponse of the rats to the substance. They proposed that astatistical technique should be adopted in which a series ofrats, say, 20 to 50, were given approximately the amountrequired to produce oestrus, the unit to be defined as thatquantity of hormone capable of producing oestrus in 50 percent. of th3 animals so tested. By this means the highlysensitive rats in the group were balanced by the relativelyinsensitive ones, and thereby an accurate method was pro-duced. Although the importance of this work has not beenfully realised, it is safe to say that the time is not far distantwhen the principles of the method will form an essential part

I of any standardisation of this type of product. The material1 described in this paper has been standardised on this principleand the results of Coward and Burn were very.rapidly con-firmed in these laboratories.

The importance of this work can readily be seen, forit provided the biochemist with a method of estimatingthe strength of his preparations in a quantitativemanner and enabled him to proceed with the purifica-tion of the hormone. For example, the preparationssome years ago were in the form of a stiff oil, insolublein water, with a rat unit of some 10-15 mg. Thissubstance was administered to animals dissolved inolive oil or else in the form of an emulsion, and variouslocal and general disturbances resulted from itsirritating characteristics and slow absorption. Ananimal that had been injected for a considerableperiod lost weight and developed ulcerating soresat the site of injection. The very properties of thissubstance forbade its use in clinical medicine, andthe few isolated attempts that were made to injectit were all followed by severe local and general’reac-tions which quite masked any possible therapeuticaction. The purification of the material, however,has proceeded rapidlv, with the result that to-dayit is possible to obtain material containing several