THE INCIDENCE A ND PATHOLOGY OF TUMOURS OF DOMES TICA TED
ANIMALS IN SOUTH AFRICA.
A Study of t he Onderstepoort Collection of Neoplasms
with Special Reference to their Histo•
pathology
By
CECIL JACKSON, B.Sc., B.V.Sc.
FORE\VORD.
The present number of the Onderstepoort Journal d'iffers from its predecessors inasmuch as it contains one cirticle only. This departure froni precedent was considered justified in view of the exceptional scope rind importrince of the subject dealt with in this worlc.
Mr. Jackson imposed upon himself an arduous task. He undertook to study, classify, and describe the tumows in the extensive collection of pathological specimens at Onderstepoort. But he achieved more than that.
He has presented a cornprehensive, closely-reasoned, and critical study of neoplastic conditions in general in OW' domesticated animals.
It is considered that his striking contribution to our knowledge of new growths will prove to be of lasting value, not only to veterinary science, but also to hionan pathology. And so the hope may be expressed that this stiidy may aid in the ultimate solu,tion of that greatest unsolved problem in medicine, cancer.
5
P. J. nu Ton, Editor.
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PREFACE.
SINCE the inception of a routine pathological (l inµ:nostic service at Onclerstepoort o\·er 18,000 pathological specime11s haYe heen :rnhmitte(l for histological diagnosis over a peri(Hl of so1np fiftePn yean;. Much of this material hacl been earmnr];ecl as of interest for furt~her examina- tion or for museum purposes anil mnong it ocnirs n wealth o{
examples of 11eoplasti(' (lisease in thP rlornesticate(l nnimab.
The present wmk is the i·esult of a prognunrne 1-<1 makP this material conYPni.ently aYailablP for refPrPnce nrnl further stud>·, whereby it is proposed to estahlic;h a complete (·ollediou of micrn- scopie pre1)aratio11s representatiYe of thP i1atholog;.· of llonwst.icate(l animals in this countr,,- serving at once ns a cht>l'k 011 the a('Clll«H·>·
of the diagnosis of the macroscopic spef'imens in the Pxte11si ve rn trneum of patholog~- 11hich has been huilt up at this lnshtutt> aurl .~uIJplP menting the st nd.v of this material from the histologi('al stanrlpoinL In the preparation and arrangement of a microsr·opic collt>dion of this type it is oln·ious that accuracy i11 (liap:nosis ancl uniformity of d assificatirrn are the first essentials. In ibP,.;e hrn re,,;ped s tht> !'Olll- pilation of that portion of the collPction oomprising the neoplastic diReases offered the most difficnltv, and it: was thereforp (le('irled io attack this part of the \rnrk
fo<s t.
\Vith the eompletion of thi,;chapter of the pnthology there has been e~tabli,;hrrl an aunotatPrl aiHl classified collection of histological preparation,; of the neoplasms whid1 haYe been encotrntere!l amoug clollwsii(' animals i11 Sonth Africa whi('h not onl,,- has a statisticnl Yalue(') but whi('h g·i\·ps instant access to preparntions of thP Yinions kill(ls of tnrnours whost>
pathological-anatomical an cl histio logical rl escr i ption s all(l \\-hose position in the cb ssifieatory scheme arP maclP aYailahle h>· flip JH'PSP11t
>York.
'l'he collectiou is housed in steel cabinets (each of which is
<lesigned to accommodate 2,400 sli(les) containing- sloti:erl \rnodP11 tray;; in which the slicles are vertically placed. A system of col01ue(l ranls is used to facilitate access to the (lifterent classt>s of tumours, ancl each slide is affixed to a cnrdho:ml label of ihe snme sizP (with a window to a!lmit light to the section) and on which (through thP glass) ma)" he read the species of animal, the site affecterl, the
«liagnosis and (where necessan·) a summnr>· of the histologir·al features. At present apprnximately :),000 slides of the neoplash(' diseases are so stored, but it is intended that the collection shou lcl be a mobile one, allowing of constant expansion as morP mat-Prial is :_icriuired and of reYision anrl re-dassitication ns 0111' lmO\derlge nuproves.
(1) A small proportion of the earlier specimens have unfortunatcl:v been destroyed and a fe11· have heen used up in the preparation of sections for teaching purposes.
rrrnFACE.
E\·en in the coun;e of its compilation, this collection proYe<l of the greatest U8e in fac-ilitahng accurate diagnosis in <lifficult cases by proYi <l in~, a rea<ly means of colllparison. Hef erence to it shmrn also at a glance \\·hether the tumour one is dealing with is a lesion rare or unknO\YH iu this country or elsewhere. The value which the ('Ollediou has acquired at ()n<li>rstepoort has led me to feel that a prese11tatio11 of ifa salient features woul<l bf' of asc;i;;tance to patho- logists \1·ho lrnYe not access to these specimens ancl \1·ho may have to
\1·rp:-;t.]t; ,,-it h the of trn ex CJ ni,;i tel:r difficult pro hlems en countered in the tliaguosi,; of neoplasm:-;. vVe all kno"· how common it is in such l'a;;e:-; to <'Onsnlt textbook,, 01· other li teratme "·ithou t obtaining the
<lefinite information ,,-e seek. It is in the hope that a more detailed study of the hist,Jlop;ical aml espeeially the cytological aspects of oncology may in·o\·e of use in thi,; connection that my comments 011
thesr a.-;ped:-; of t ht! celled ion are here ernbod i ed as a text· to "·hi<' h the sy,;tpmati<' <'atalogue of the specimens J.HO\-illeR a11 appendix (C).
f
Originally it was plaunell to incorporate in thi8 appendix the desnip- hve prot·o('ols of all those tumours \1·hieh hacl not heen dealt with in the text. This project hall to lie :1lrnuc1011ecl on account of the length to "·hi<'h the Litter gre\\·.] The nim of this \\·ork has, ho"·ever, in no c;e1rne been the provic1ing· of a trxtbook. Kot· only is the Onderste- poort collection, large as it is, drficiPnt in certain kinds of tumours, but gooll general texts on neoplasms of animals ahead~- exist, both Feldman's (HJ;~2) textbook antl Joest's Szrnzie71c I'a!liologie providing a wealth of information regarding veterinary oneology and it..;bibliography. Hat her has it bern my aim to <liscusii those problems and <lescribe tho"e appearances which, for the ner~- reason that they are so rneagrrl.Y to11d1etl upon in the liternture, caused me great
<lifficnltie,; \\·hen first T em harked on this \rnrl;.
It is inevitable that in a ta;;k of this kind I han had to lean
heaYil~- on the <'o-operation aud encouragement of many scientific friends. To Dr. P .. J. du Toit, lhredor, arnl Dr. G. de Kock, Deputy Director of Veterinary Services, I am grateful for their approval and encouragement of this shul>·· To m.y colleague Dr. ,\. D. Thomas I am clerpl>r intlebterl. It is owing to his energy ancl enthusiasm for the shuly of tumom·~ that a great man>' of the spe<'imens have been obtained, and from his profound kno"'leclge of minosrnpic natholog.v·
he ha,; ernr willing!>' advised me. I have also matle use of the rec·onls left h:\' present colleagues in awl past memlwrn of the Department of Pathology. The surgical staff and poultr.Y pathologists at this Institute have contributed man.\· interesting specimens and much Yaluable information. 'l'o tho:-;e who haYe bPP·n goocl enough -to g·o out of their "·a)· to suppl_v· :>pec·imens \\·hirh might othen1·ise Jtever ha1·e receiYecl notice this I11~titute also 01n:-; a rlebt. )fr. R. Paine, M.ll.C.V.S. (both as Government Vete1·inary Officer, GrahamstmYn, and as Officer in Charg·e, Allerton Laboratol')·) an<l Dr. G. Kind han been especially helpful in this re~pect, \\·hi le many other Yeterinarians in Government ServiC"e, Mnnicipal Service, aml private prartice have, in re;iponse to anpeals, been Yer» willing· to ('()lled specimens awl to forwanl partirulars thereof. V\There po~sible acknowledgement:-; of such c·o-oµeration am nrncle i11 the text. I eanuot sufficiently praise the excellence of the tec-hnirnl assista1wp wh i l'h I have reC'ei ved from Miss Dorothy Armstrong, who has been responsible for the cutting·
7
PREFACE.
ancl staining of the sections, among which many beautiful prepara- tions are to be found. Mr. F. D. Horwell, who has been in charge of the records associated "·ith the \YOrk, has prepaTed the two text figures. Mr. Th. Meyer has expended his usual care in the photo- graphy, whid1 could not have been in better hands. I haYe also to thank several friends "·hose discussion of those problems in which our inYestigatory paths have crossed has been a constant source of inspiration to me, and would especially mention Dr. H. H. Curson, Professor of Anatomy, U niYersity of Pretoria, Dr. Joseph Gillman of
the . University of the Witwatersrand and Mr. A. i->. ~falan,
Statistician at· Onderstepoort. Lastly, I wish eordially to aclmmY- lerlge the hrnlness of thf' State Librarian, Pretoria, ancl the Librarian of the National Central Library, London, through whose co-operation it was possible to borrow from British universities (Linrpool, Sheffield, and Aberdeen) copies of nian.'' important com- munications on tumours whirh are not aYailable in our 0\\'11 libraries.
0NDERSTEPOORT, November, 1935 . C .. J.
CONTENTS.
l'AGE
CHAPTEH T...... . . Is:rRovucTION....... . . . . . . . . . . . . . • . . . . . . • . . . . . • . . . . . . . . 11
CHAPTJ-:lt Ir. ....... . P.l'ITHEl.IAL Ti-MOCHS: Tumours deri•·cd from Squamous Epithelium ...................... . 37
CHAPTER III........ J<:1·rr11ET.IAl. Ti·MoUHS (cc>ntinuNl): Adcnorn11 and Carcinoma 85· CHAPTER IV..... l·:1T1'HELIAI. T1·l\10Uns (conclude:!): The special probl0ms of Epithdinl Tumours of the Liver and the Thyroi:I... B5 CHAPTER V......... THn 10MA (primal',\' tumoms of the thymic parcnd1yn1n) 199 CHAPTER VI. ..... :l[E.';OTllELIO)IA ........•............................ 219
C1·fAT'TER \rII........ CO:'.'\TNEC'!'IVE·TI.-ss1;E TUMOURS: Benign conne<:ti,·e.tissue tumours nnd Sarcomata...... . . '.241
CHAl"l'El{ \Tff ..... . TurorRs O'F KKDO'l'HELIUM ...•..................... CHAl'TER IX........ Sno1n No'l'Es ox U1.I03'1A: A"D ON Tc3IOl'Rs or M~:LANI"· l'It:ME~T1•;n CELL:-;, OF i\{Psc1.1<:, CH' TllE AnttE:XAI., AXD 01' 'l'HE PRECl'RSUHS 01•' 'l'HE Bl.OOD·CEl.l.S. . . . ....... . .. :123
ClfAl"l'l::l! X......... TnE l\frxED ~E01'1.AS3IS............................. 343
CHAPTER XI....... . THE CoNTAGrocs (Y1·:NEREAr.) Tc3IOl'R AN" THE l-l 1-:AR'l'·llASE TUMOURS or Tll l·: Doo ......... " " .... "... 387
S U ::'111\'CAlt Y . . . . . . . . • • . • . . . . • . . . . . . . . . . . . . . . . . • . . • . . . . . .•. 4lii HErER"EKCEs TO LITERA'lTlrn . .. . . .... . . . • ....•.....•..... • . . . ..... . ...• . . .... 419
A1·1·EXDIX A: Species J nciclencc of Neoplasms.............................. 492
APPESJHX B: Organ Inei<lence of Primary Neoplasms..................... 430
APrE~DIX C: Catalogue of the Onclcrstepoort Collection of Xcoplasms . . . 434
INDEX............ . . .......... . . . . 444
9
CHAPTER 1.
Introduction.
THE ueces~ity of prefacing any strnly in compa1·atiYe oncology with an apologia in 1Yhich is pointed out the value of such iurnsiiga- tion is, happily, becoming a thing of lhe past. In the purely morphological sphere, the iuvestigations of pioneers srn·h as Bash- ford an<l :Murray, Cramer. all<1 J oest have pro1·e<1 01·er a 1J d over again their 11·orth, while from the biological aspect the epod1-rnah11µ:
disuJ\·eries of Peytou Rous and of Fuiinarni in reµ:an1 to trnnsrni,~ihle
tumours of domestic 1Ji1·ds, an<l of Yamagi,va :1rn1 Itchika11·a in <·011- nection w itli the experimental ca us a ti on of mali gnauc:-· in nurnu11~1 b are nm1·a<la:n; familiar even i.o laymen. But much remains io he clone. 'fhe pathology of tumours iu animals i,~ virtually a ue1·er- ending stud:v to which everyone 11·l10 encounter::; any < onsi<lt>rahl<e number of animals affede(l b~- neoplastic <lisease i" bon11tl to hav<i something to contribute.
'L'bt> ( lrnlerstepomt Colle<.:tion of JLeoplasms of <101ne:;ticai.Pd animals is one of the most complete in the 11orlcl, and ceitainl:v the largest in an)· tropical or "uhtropical country. By its establislnneut is pro1·i<1ecl ready access to the <lirect study of the grns:; au(l miern- seopic pathology of almost en~r.)· known kirnl of tumour cf animals and of many little known or 1u11ecognised ones. A11yrn1p who c:nes to eonsuH it will be re\varclecl b.\· an a(hance in the k1w11·le<lge, the fouurlaho11s of 11·hi«h haYe been laid hy those palholog·isb- .Toest, Kitt, Joest and Ernesti, Sticker, Casper, and Felclman-\\·hose general ll'orks ·On neoplasms of clornestic manuna l,.; ·OJ binls have become elassical, and by the many others 1Yho have coutriliutecl to the stucly of neopln,.;ms of certain kinds or of certain mgans.
The solll'ces of the spe(:imens have been: " distrid " specimens suhmittr<1 by firld veterinarians, pri1·ate practitioners, an<l la)·rnen for rliagnosis, 01· submitted by abattoir ,officials as contributions to the museum: " local " specimens accruing from the i·outine autopsiPs both on hospital patients and experimental aninrnls at 0ll<1end.ep-oort;
while Jtot a fe1y hrn10ur specimPns have been obtained li)· collt>agues in the Department of Patholog-~- 1Yho have often gone out of their way to collPct matei·ial. Yian_r of 1 he older specimens ha Ye sufferetl changes through long preservatil)n, and in those case" 11·here it wa"
possihle to gain assistance from the llescriptions made nt the time or from autops>· J'f'cords such information has het>n m::ule use of. In very many C<lses one could have "·ishecl £01· more complete inforrnatio11 from the senders of specimens, especially regarding ihe site of occur- reuct>, the presence of 111etast:-1se~. and the history of the subject. .\s a result of propaganda, the resvorn;e of members of the profession to appeals for a fuller (1escription of spef'irnens lrns been very gratif)·iug.
It is heµ:in11ing to he more widely recognised, not onl:-· that the
INTRODUCTION.
accurate diagnosis of neoplasms does not depend entirely on mino- scopic examination of an often haphazardly selecterl fragment of the
tissue, and that a full history of the subject and careful descriptioa of the fresh specimen in sitit are of the greatest assistance to the pathologist; but also that the records at Onder::itepoort are often in validated by incomplete information. ln a fe\\· instances in the past, even the species of the subject has not been stated, rendering such material almost worthless from the statistical point of Yiew.
As might be expected, the iutensiYe study of the neoplastic cliseases at Ornlerstepoort has resulted in an apparent increase of their incidence. This senes to shmY of what limited Yalue the actual figures are. These can be given only in terms of pathological speci- mens received, but the:-· do at least serYe to sho11· how frequently the pathologist encounters tumours of rlomestic animals all(l what an impmtant part these lesions play in routine diagnosis. Some 4 per cent. of all routine sperirnens are neoplastic diseases ancl in Ye1·y many othe1· cases a thorough knowledge of oncolog:-· is esRential for
\:Orrect interpretations; it is therefore olivious that any weakness i11 the diagnosis of such specimens must Yery seriously re:Aert ou thP efficieucy of the routine diagnostic senice. It has consequently been an important a.irn in this work to attempt to place on a surer and mm·e unifonn hflsis the cliagnosis and nomenclature of animal tumourt>
encountered in this cou11tr~·. To do this it is fouucl necessary to pay dose attention to the minute histological anc1 more especially tlw cytological morphology of the tumours, with a Yie"· to making avail- able more detailecl tlescriptions than are usually to be fomHl in the literature. I believe that more exhaustive descriptions in reports of tumours woulrl lead to much greater clarity and \Yould form a more satisfador:v basis for romparison, apart from the Yalue they haYe from the general biological standpoint. In the last analysi~, however, the diagnosis of tumonrn still remains almost as mtu:h an " art " as a science, ancl iio one ran tell another ho,1· to diagnose lleoplasurn, but only ho"· to learn to do so. l<'acility in diagnosis is to be obtainerl only by calling all available emhryologiral and r;dologirnl knowledge to the assista11C'e of one'R mental equipment in pathology.
It is this ramification of neoplaRtic patholog_v into sewral other spheres which renders it impossible to undertake its stucly without contributing in some measure to other phases of pathology ancl to our know ledge of normal morphology anrl of tissue and cell biology.
As William James has saicl: "We lem·n most about a thing' "·hen we vie\Y it in its most cxaggernted form "; and this generalisation is neYer more true than when appliecl to the ohsenation ·of cells and tissues in their 1ieoplastic rnanifestahons.
PROBLE:'IIS OF CLASSU'ICATIOK.
The effective classi fi ca ti on of neoplasms an<l closely rel a tecl lesions presents one of the subtlest problems in pathology. Impatient as some people may be of the apparently barren nosological cliscus- sions in which our pathological literature abounrls, nornendature is yet the measure of the orderliness of the state to which a given biological subject has advanced. Arni one should <h~tinguish between two dilemmas of nomenclature which may confront the pathologist, the one more elementary, the other more arlvancerl: those difficulties
12
PIWDLEMS O:F CL~SSU'ICATIOX.
of nomenclature which depend, not upon an insuffil'iency of fadual knowledge, but rather upon the circumstance that thorough observa- tion of the facts has brought us to a eonsicleration of fundamentals.
belono' to the latter cateuory · such classificatorv diRc.;ussions under- taken '\Yhen no long-er do~bt. e~ists as to the adu~l nature of the facb observed, are to be respertecl as indicative of the depths to "·hich observation has led the pathologist; not as confessions of ignorance but, on the other hand, as declarations of the iHterest "·hich a challenging problem and an appreciation of its intricacies has aroused.
vV e are to-clay «Ollllll i ttecl to a classificatory system \Yhi ch rests upon a dual basis of histology and histogenesis (vd1ile in certain cases also aetiological fTiteria are u~ecl, e.g. especially in assessing trans- missible tumours and tumour-like diseases). But our clefinitions of the
cell types and of their histological products and the patterns in \Yhich these are arrangecl are often vague, as are alw tlw u·iteria which are usecl as evidence of histogenesis. Regarding the latter, the difficult question of the significance of the phenomenon of tissue-continuity, so often tacitly assumed as a proof of histogenesis, "·ill ieceiYe atten- tion later iii this work. It \\·ill be seen that, in some cases at least, one may fall into graYe error through assuming that eoJJtinuity of a neoplastic tissue \Yith pre-existing tissue c1enotes an origin of the former from the latter, because pictures of most intimate continuity may arise bet\\·een a neo1Jlastic.; tissue and the structures that it is invading. Yet one \rnnld not, on the basis of this ohserYation in the ca:;e of certain tmHom·s, wish entirely to S\Yeep away the phenomenon of continuity as eYidenl·e of histogenesis in other cases, where indeed we often haYe little else to depend upou in our determination of the origin of a tumour. Judgment must be used in each indi,-ic1ual f·a"e,
uru1 I have not hesitated in allowing myself to be influenced by the appearance of continuit.'· as evidence of histo1rnnesis in mai1.'· C'ases.
While admitting that \\e are often working \Yitl1 poor or double- edged tools in can·ing out our classification, we rnu~t neYertheless striYe to make them render the most effedi.Ye and safest sen·ice possible.
There is always the tendency for thP enthusiastic histopatho- logist to multiply nomenclatural terms on the b>isis of Y>iriation in those morphological appeara nres which characteri;.:e 1 h(' histological rnrieties of tumours or \vhich provide evi f1enC'e of hi~togenesis; anrl this tendency has to he kept in check for two reasons: firstly, apparen tl:v genuine morphological distinctions, not correspon cling 11·ith clinical, prognostic, or aetological differences, may be of little interest to any one exC'ept the histopathologists themsehes;
sec.;onrlly, non-essential rn orphologi cal vari atiou s may be mis ta ken for essential ones and may then he erroneousl:v assesserl as being of sufficient importance to "·anant the establishment of distinct classi- ficatory v>irieties. In a sense, almost eYery tumour has its patho- logical-anatomical individuality, and we should bear in mind that although " no two leaves are alike ", yet " there is nothing new under the sun ". Enthusiasm for morphology, if carried to its extremes, could don btless succeed in devising a new name for almost every tumour encountered. The morphological variations that have been mentioned as non-essential from the classificator.'' standpoint include two main types :-(1) Further stages of development ,,·hich
INTRODUCTION.
are undergone by the tumour tissue: the difticulty here arises that
"·e usually examine a tumour at a ::;ingle stage of its clevelopmellt, and try to understand \Yhat is temporally a contiuucnu; prol'.ess b.-- means of studying a single "c:ross-;oedion in time ". The ch nger may be illustrated by the simile of cutting up a cinematograph film
into its constituent units, and arrauging them as a gallery of different- ly labelled photographs: one and the same entity may be dassifiecl by different names if isolatecl in clifte1·ent stages of it,; unfolding. 'l'his may espel'.i ally he the case ill neopla:-;tic: and pre-neoplastic;
processes oc;cu1Ting i11 organs "·hosp cell~ a re ('ha raderisecl by n certain vigour of proliferatiYe ability and a Yarialile growth-mode, such as the liYer ancl the thyroid. In the former, for example, it is probable that a proliferatiYe 1n·ocess may be Yariousl.-- classed as nodular hyperplasia, adeuoma, or earci nom<.t clependi ng on \\·hat stnge it has reachecl "·hen the ;;pecimeu i,,; examined. \Vhile "·e rnn11ot, a;;
histopathologists, clo :rn·ay "·ith these distinct io111i, it should be remembered that the1· are. to sornp extent at 1Past, artifil·ial: and ihe oecu1Tence of i11te1·ii1erliate gracles hetwet>n the~e three i.'·pes of proliferation 'rnrrn; us again ~t en11.~i cle1· i ng· the~<-' ('I a,;,.;ifiC'a tm.'· ('Olll- partme11 ts 1rn.tertight in all rnses. Rimilar considerations apply i11 c·onnedion 11·ith eertain '' rnetapb,;1.ic· " tra11,.;format ions of tumour
ti~sues wbich are nothing lrnt retledion,,; of tlw votentialltles of their uonual ho1notypes: it is, for example, a 1·er.1· 11ormal prncess for houe to replace cai·iilagP, so that i11 lll<lll,\. cases we should hesitate to make any radical <lis1.ind io11 lehn~Pll chonclrogenic sarcoma
\<·houclro-Hareorna) and o,.;teochonchog·r>nic sarcoma (osteochondro-
~arcoma). On the oiher hand, su('h ohjedio11s neecl not apply to the tlistiuction bet\\·pen, for ex;unple, lymphoc.-·toma arnl lll,\·elocytoma or Prythroleu<·osis: although the ('ells of the one urn.\· rt>1n·.,~e11t the 1·etlect-ion of a norm:il lliffPrent-iation-poteJ1liality of the other, the 11·hole nature or pathology of the 11l'Ol'esses ma.\· he Yery different.
(2) Seconclar.\· cha11ges occuTring in neoplas111s rnay sometimes he difficult to clistinguish from primm·y or esseutial cha1aclPrs: thus we atteiupt to clistinguish het\Yeeu a fihroma affP<'ied h_,. oeclernatous or m11coi<l chai1ges and myxoma; heh1·een .. verithelioma '' an<l h1mo111·s in which 11ecrosi.s, affecting all the ('ells t>s:cept iluhe i11 the ueiµ;h- hourhoocl of Hoocl-Yes,;els. has protl UC' eel a fa be iwrit hel iornatons appearance. In such cases 1Ye may haYe to be gniclPcl less 11)' the grosser histological f Pa hires t hau b,,. a de ta i le cl st uc1,,- of the ce 11 t.ypes.
Similarl5-, c·hanp:es O<·c·urring in the sfrorna of tuniom·,; (e.p:. ostPo- plasia) al'e to be clic;tiugnishecl from an es,;ential o;;teogeuetic tPnclern·»
of the tumour cells. Su!'l1 examples conlcl easil)· hP nrn1tiplie1l a1Hl are finite familiar to patl10log'i,;b.
It t11us become,; ahunclanth- clear that enthusiasm for rlPtailecl morphological analysis as a 1rns1s for nomenclature rn ust be kept 011 a tight rein. l'athologi C'a l nomenclature hac; a n:1hll'al h istor.v of its
mn1: firstl.--, a stage of chilrlhoocl, "·herP mriel.\' on account o±
ignorance one term ma» serve to coYer 11·hat are in rt>ality a uumbe1· of distinct processes; seconclly, an age of aclolesceuce, where names must perforce he multipliPd in onler to pigeon-hclP the Yario11s appearances for future comparison and revision mdil, with time, gre;1ter experience shall have heen gained; and fin:illy, the ;;iage of maturity, "·hen comparison has succeede<l in cleterminiug "·hat are but natural cleYelo1miental changes, in 1Yeecliug out the secon<lar.-·
14
PROBLEMS OF DIAGNOSIS.
from the essell ti al morphological distinctions, and in correlating morphological appearances "·ith clinical and above all with aetio- logical considerations; with a resulting re-simplification of the terminology. ~ omenclature is thus, far from static or pennanent, nothing more than a summary of the knowledge at any given moment. It starts b>· being indiscriminatingly snuple and ends by being discriminatingly simple. The stage of adolescent nomen- clature has always to face discouragement ancl scientific ridicule by
tho~e who are oYer-anxious for progress or by those \Yho do not appreciate the natural growth of classification. But multiplication of terms during that stage is unavoidable and is, incleerl, essential to progrnss. The re-sin1plification of n{nnenclature may, it is true,
;;ometimes be ovenlue, pathologists not seldom being reluctant to
" put away chilrlish things ". vVe see to-clay, for example, a move- ment to abolish the term " hypernephr.oma " and to bring the adrellal tumours back into line "·ith previousl_,. established types (adeuoma, carcinoma, neuroblastom.a). 'rhe smne applies t'J
" thymoma " ; \\·bile some more rut.bless (but equally logical) i·eformists are urging more rarlical changes in nomenclature beC'ause they consider that the older terms haYe lost. thei1· significan!'t' in the light of ne>1·el' aetiological .lmowlerlge or of more fundamental embryological considerations. Oer!el (lfrH) contends that llie time- honoured rlistincti on of <'a rcinorna from sarcoma has to-<lav lost its
;;ignificance. But the majority of pathologists hesitate to a·g1·ee that the time i,; ripe for nulit·al rnform, although all look forwanl to the clay "·hen, on the seC'ure foundation of aetiological enlightenment, \Ye shall be able to put a'rn.\· the classification ''"hich has servecl us so long but 80 in<lifferen tl~· well. The experimental production of mesohlastic tumours (sarcoma, myelocytoma) hy the :1gent (tnr)
\\·hith is alread.\· well known as a cau,;e of epitJ1elioma ma.'· "·ell he the \\Titing on the wall foreshadowing the advent of such reforms: from the experimental starnlpoint it \\"Oulrl seem that all are
"' cam·en; ", whether of epithelium, <·onllt'diYe tissue, 01· luwmo- poietic tissue. Yet one must he cautious not to C'oufuse a cau.-;e \\·ith
:1 di8ease: to the clinician adiuomycosis of a lymph-node remains a lympliaclenitis aHcl actinomycosis ·Of the lung a pneumonia, nlthough
thG aetological iclentity is established; and the clinieian will, how- eYer the pathologist ma.\· classif,'I·, rightly continue to concern himself iirimarily with the disease ancl secondarily "·ith causes of disease.
It is intenderl in this work to follo1\· the general outline of accepted histological-histogenetic classification of neoplasms, so far as possible and in accordanC'e ''"ith the neecl of presenting intelligibly the material containe<l in the Onderstepoo1·t collectiou, although the sub-classification of the main groups "·ill he rlisc·u,,secl in detail "·hen dealing \\·ith the turn.oms in queiitio11. The arrangement of the tumours in chapters has 110 special classificatory significanr·e. hut is macle mainl>· for <·onvenienc·e of presentation.
PROIILEMS Ol•' DIAGNOSIS.
The completion of this \rnrk necessitaterl a re-examination of many cases that hacl already been examined in the routine. A small percentage of such cases harl been erroneously assessed, in relatively fe"· cases no diagnosis at all had been venturerl, ancl in a large
IXTlWDUCTIOX.
number of cases i·e1·isiom; ·of the nomenclature employed had to be underta keu in order to con fonn to a nn i form :-; n;tern. :Jiost of the more recent specimens in the colledion "ere s11b1;1ittell to me <hrel'tly, and the research i tlYet>tigation wa·,, 'theu combined ".it h the examina- tion for purvoses of routine cliaguosis. Iu thii; work, it \\·as i11eYiiahle that wme i1rnight was ohtaiuecl into the lliffirulties >l°l1il'h haYe he8et my l:Olleagues and pre<lecesson; ai this Institute regarding the cliagnosi.s of neoplasms. It is impo:Siiihle to mention ;111 of these, but some of the mosi important and th r rno:-;t fruitful s011 n·es of error appeared to he as follo1Y: -
Differentiation of Neoplastic from. tlic .\'on-11ro11lmti1· T,esions.
This, as is 1Yell kno11·n, ofte11 i m·olYe:; exiremely pu:.-::.-: ling problems. J<:spet· ially are here conceu1ed those hyperpla:-d i<' prol'esses which app1·oa('h iwoplashc gn1<le, of whi1·h l'Ommon PXHllljilPs an':-
(1) Fibtolilostic 1nolifuolio11s of tlie s/,/11 of eq11i11cs.- It \\·as found that rn:rny lt'sio11s of the ski11 of equi.11e,; 11·hit·l1 had been Yariously <liag·uosecl as :;ai·cornas or gn111 ulo1nas "·ere i 11 reali.t)· the
"san:oids" clescrihed lntcr i11 this work. Then• >Yas, 011 dose histo- logical analysis, sPen to e.\is1 no unil.orrnit.1 i11 th<' as,il'ssrnen1 of su('li lesio11s, all<l p\·e11 tumours 11·li it·li I t·onsiderP<1 us s~u·t·ornas lw<l hPe11 diagnosed a:; (cellnlar) tibronw,;. There appeai·s io lie little doubt, hu1n'l'Pl" lea1·i11g asille the rnm·e olwious enm·s urising frorn insu.ffi-
<·iPntl.1· dose st\l(ly of suC'h lesions, ll1;1t grnde,; of prnliferntion adually intenne<liate hell,-een surcoma antl grannlorna e:-.:ist. To these the term "sarcoi<l " has been avplied. ( )ne can easily pi('J;
out from the collectiou a dosely graded series of spP('irnens sho11·i11g e1-ery transition iu histological :;1nt('hne f1 om granuloma to
" spirnlle-eelled .. s;1rl:o11ia. ])ifferent ial <liagnosis <lepends, as pointed out in Chapter VII, on the dPmnnstr;1tio11 of aiwpListi.c changes in ilie lJI'Olifernting fibrobln,;h, especiall)· llllt·lear inPg'll- Lirities an<l a <listind i11cre;1se of the nul·lPohir-mHJear rntio.
(:!) fl!}}Jl'r/ilostic prn1·cssrs of llrr1 awl l/iyro/1/ CJJ/t/1eli111i1.-
These are de:1lt 11ilh in Chapter IY. It is tliffirnlt in ihe ('<1Sl' of liwr- l'dl i um ours ·to tli sti 11 gui sh hehYPe11 a (len om ;1 a 11 II ('arci 11 om a. 'L'he ot·(;Ul'J'ence of inte1·gnides has resnltP1l in thl' introduci.ion into ihe literature of the non-conunittal ien11 " hepato111a ". It iR also possible t·o ohsene hansitiolls from 110rluL1r h:qwrpla.~ia.s to b'11ig·11
t umom·s a 1ul
.i
u dgme ii t <l epen cl s on an <l ssessmen t of the degree of in<lependencP a11<l ai.1tonon10us gnrn·th (((11s sicl1 hcr1111s) whil'h the tissue has atiaine<l, e:-ipe('i;1lly as shrJ\1"11 1.1 e11f'apsulntion, l»·prei;sure against the .smTou11di11g iwrmal ti . ..;:;ue, arnl h.Y ihP att.1iJ1- rnent or posRihility of aih1i11rn<'11t of l'Onsi(lernlile 1lirnc-1isi(ii1,,'h>· the proliferating area. ThP "a111e npIJlies io the <listin('(ion· heh1·een no<lular hyperplasia antl th,vrni<l a<lenoma. 11 ere, also one feels thnt one ma)- be ilea.ling "·ith a hiologil'ally ('()lliinuous Jll'Ot·P..-s, aml that our classificatory tlis1inci ions are to smne exient· artificial.
(3) Many 71(){folrs romposrd of o.rfi.e11fll cortirnl tissue anll diagnosed as a<lenomas inoYe to he nothing· lrni a<·<·essm·;.- ('Ol'til'al nmlu.les' comp'osed of normal rHlrenal cells whicli haYe <luring em br)·onic deYelopmen t ('Ollle to occ n P.\' an a hnor111~1 l posi ti.on an cl arrangement with reference to the rest of the glan<l.
16
PROBLEMS OF DIAG:NOSIS.
(4) C.l)stic conditions may be.mi·stakeu for lumoms. Among sud1 were cy::;tic degeneration of the pituitary (mistaken for adenoma), c01rgenital bile-duct cysls ( enon eously diagnosed as bile-cl uct-cell arleu'oma of ihe liver), cystic Brnnner's glan<ls in the sheep (<liagnosed
. as adenoma of the duodenum), an<l rystic lyrnphangiect:rnia of the
serous membranes of binls (likely to he confuse.cl with lymphangioma).
(5) In fo1cls, man~' lesions had been diagnose<l a::; neoplasms, and called enclotheliomas, peritheliomas, round-celled sa1·coma::;, which on critical re-examination pl'ovecl to be nothing but gr an uloma,,;
in which proliferating capillaries or round cell infiltration arnl multi- plication were prominent. The subcutis of the bird appears to han remarkable po1Yers of proliferation in respom;e to various stimuli and its haemopoietic pot en tiali ties ai-e well knmn1 io a \·iau haem a lo- logists. One should in any case be cautious before diagnosing endo- thelioma of fo\ds. I have never enf'ountered such a tumour nor appareutly haYe Felrlman (19'.W) or J oest ::md Ernesli (191G) in the exami.nati on of. their exte11'i Ye collectio11::;; and although both Hegg (1927) arnl Furth (19'.-l4) ba,,e reported transmissible " endotheliorna "
of fmds, the
.i
u;:;tification of the term from the hic;tolog-i.cal and histo- geneti c ;:;ta,rHlpoints cannot be regarded as satisfactory. In granula- tion tis:rne of the bird, the prolifernting ernlothelium ma>· be nry prominent, actually dominating the picture. The rliffereutiatiou of gnmulomas characterised by prorni11e11t proliferation of 1;.-mphoi(l elements from lymphocytomas also req ui rec; (·a utiou and one shoulrl he at pains, by examining a number of sections, to exclude an inflam- matory origin for the lesion, especially by the employment of bacterial stains. Chrci11ie infiammatorv lPRions ·of the abdominal serosae of fowb, \\·hi.ch ·m·ise ec;peciali~· ·from the irritation causPll hy frep egg- yolk in . the peiitoneal caYity ui·e not i11frel1uently mistaken for implantation-carci11osis or Harcoinatosis. The nodules ou the sernsae;1re usnally rather uniformly small in size, and their diagnosis depen<ls on the finding of iufiltrnting ancl proliferating macrophages, e8pecial1y associated with cleposits of yolk. 'l'he distinction horn imtilantatio·ns of histocytic sarrnma, in \1·hich lipophagoc»tosis i,;
often also a promi.neut feature, de pen <11' finally on the llemonstra ti on of the presence or absence of anaplastic changes in the cells and of invasive growth. The lesions urnlPr rli,,;nission often occm· togt>tlier with implantation-metastases, for the rea::;on that the primary tumour responsible for the latter is in most case,; situated in the onn·y, invasion of which organ favom·s the setting free of egg-yolk in the peritoneum; and it must consequently be remembered that not all of the miliarv no<lules found on the serosae in cases of abdominal malig1iancy 'of fowls nee<l necesRarih· he yonug secoudar~- neoplasms.
In fmds <litfin1lties mav also arise iu tht> clistinction hehYeen leueotic disease:-; and lymphatic proliferntiYe nroeesses: hyperplasia of l_vmp ho i <1 celb i u the li. ,-er iR sometimes rl i :fficult to <li;;tiugnish from lymphoicl leucosis: the distinctiou iR t-o he based 011 the degree of rlifferentiahon which the cells tend to undergo, the extent of the process (difficult>· of lesions of lymphoid leucosis iu the earliest stages!), and the presence or absence of actual inYnsive gr·O\Yth; the latter feature iR most important, and in all cases rliagnoserl as lymphoid leucosis, one should be able to demonstrate actual aggreHiYe gTO\Yth, e.g. in the hepatic parencbym a. Similarly, rnyeloi d cells often appear to participate in i.nflarnmatory hyperplasias in fowl::;
IXTRODUCTION.
arnl in a<lclitiou to grnnuloc,vtes "·hich haYe infiltrated the <lamage<l
ti~s ues from the bloodstream one ma)· encounter local pro lifer a ti on an<l <lifferentiation of granular cells from their precursors. Such lesions ma)" often be seen in the ovary, whose strorna appears to liaYe wi<le potentialities of proliferative response in infectionR or irritation ca11se<l by ruptured ova. Such lesions ham to be clistinµ:uished from lll)·elor·ytmua (often also foun<l in the ovary) or myeloi<l leu('osis.
Again, judgment rlepen<ls largely on the demonstration of a ca1rne for inflammation or on the finding of actual inYasive "'rmdh. It may be saicl that surh problems enl'.ountere<l iu aYian path~Jog)" are es1Je('Lll.\·
1 i kely to embarrass t hn~e ".hose experience is largely confinecl to mammalian patholog)". The same funrlamental criteria apply, but a slightly different set of value;; is ne-cessar)" in a,;sessing many of these proliferative processes in birds, some of whose tissues appear to possess a readier an<l more elastic responsiveness to stimuli than is the t'ase in mammals.
Dif/icidties 1:n the Assessment of Malignancy.
The establi:-;hiug of the nature of the ti,,ime and the cells involved in a neoplasti(' proliferative process having been accomplished, rlifficulty often occm·,.; in decidiug whether one is dealing "·ith a heuign or n malignant tumour. Further, the interpretation of malignancy, of (e.g.) carcinoma ais opposecl to arlenorna, yaries some- what. In this \\·ork we have based our conception of rnalignaney on the criterion of inYasive grO\d h, whether or not actual metastases are or even are likely to he estahlishecl. As is well known, however, the decision may present extreme <lifficulties an<l in some cases it may be necessary to rely lai·gely on feature;; of the cytology, especially the demorn;tration of anaplastic changes in the cells. Yet even anaplastic changes may be absent in tumours capable ·of invasirn growth. 'l'he cli ffi cul ties of the <lifferen ti al diagnosis of acleuorna arnl carcinoma of the liver ham been i·eferred to anrl "·ill be returne<l to in detail in Chapter IY. TlH',"\- may he n ry embanassing, if not. impossible of solution, in cases whf're <me is re[[uirecl to make a <liagnosis from a small fragment of lite tnmonr, espe•·iall,"\· if it doPs uol inrlude the boundary behYeen the neoµlaslic and the normal tissue. '11here "-erP aho eucounterecl lesions rliagnosed as fibroma, of whirh, had su tfi cieu t attenti 011 been paicl to an a pla she cellular changes, espeeially nuclear abnormalities and nudeolar enlargement, the sar- l'.omatous natm·e •Yould haYe been apparent. :;\Iany lesions in fo\\·ls.
especiall.v of the 0Ya1·y, commonly reftrred to aR adenornata, an>
reall.\· <'arcinomas. 1'he t.umonn; rnay lack anaplastie cellular l'hanµ;e:;, haYe a slm\· growth rate, and fail to produce trut>
meta;;(ases('), but their ability to penetrate the ser-osa under which they rlevelop ancl to give rise lo hansrnelomic implantations sta1nps tht>tll as malignant tumours which sh-oulcl therefore be termed
<'an·inomas. In thiK rnnnection it ma.v hf'1·e he pointer] out that in thi,; •York the term malignant ac1e11oma has not been admitted; the tmno1u:-; <le,;crilierl as sucl1 are carcinomas, the criteria of a
(1
) This is no unusual character of avian carcinomas, which having no or little tendency to invade blood-vPssels fail to produce metastases rpadily hecanse the anatomy of the hird does not favonr lylllphogeno11s metastasis. Allowance should be made for this in assessing the nature of epithelial neoplasms in a Yin ns.
18
PlWBLE~iS OF DIAGNOSIS.
can:inoma being its q>ithelial natuie uml it,.; capal"it·y for inrnsirn growth; in the last u1ialysis, its adtwl structure tloeH not count, the invaHi ve capacity oveui <ling a 11 other niteria, ho"·eYe1· n:-;pful thP::>e may oftf'n lw in the ,;hHl.Y of a tumour.
Other Difficulties.
Sornp, thymoma,.; had been 1liag·11osed as lymphosan·o111as. the situation of the turnou1· not haYing been taken into a««ount allll
<letailetl hi:-;tologil·al ,;huly ha1·iug been la«ki11g. A srnall thyroi<l adenoma hacl been tliagno;;ecl as spindle-celletl sa1To11ta because a s11perfil'ial resernhlarn·f> cf the spi11tlle-Hhape1l cell,; to fibrnbbsts ha<l bPen «onsidered, 1·atlwr than thP 1lPterminatio11 of 1Yht>thp1· these ct>lls actualll· 11·ere fihrohla,;t,;;: the criterion of lhe latt?r i;; of «our,;e their fi.hroph~.stic l'apacity.
rn
human imtholog_\' the striking 11·a:v i11 11·h i«h proliferating cells arising from thyroid epithPlium 1n:t\ re,;PrnH1' fihrn-hlusts is 11ell knmn1, an1l the actual es.isteure of san·oma of tlrn thyroid is Rtill a nxetl (jUPstion. 'l'he diagnosis of ernbr.rnnal nephro111a, both in fowls anrl <lomeoitic rnammals 11·as often fournl to giYe rise to rlitficulty. The'' :rnrcomatou:-;" moiet.\· of tlwse tumcnns rn ;1 ;.- oftpn be o rnrloo ked, the 11eo J>lasti« spirn1l0 <"ell,; 1Jeiu g rn isl :1 keu for a «ellnlar stroma. lnrleecl, it is not certain 11·bethe1· lesions which st.ill are das:-;ifiecl in the r·ollPdion <1s !'limple adenoma or «an·i11oma of the kid11ey m·e 11ot ;ilso ernbr)·m1nl iurnonr,;, in origi11 i1lt>ntil'al 1Yith the t>mb1·:\'lmal nephromas, tho only <liffer<'nce lieing that i1J ihe simple tumours full re;ilisation of the Ppithelioiil polPutialities of the cell~ lrns been attained. ln snc-h cases, howeYer, one has 110 means of proof; but it is interesting in this connection to re«a 11 tlrn them·:;
that rnost, if 11ot all acle11ornata, are to lie asnihe<l to a11ornnlies iu P111bryonie lleYelopment.
As .is mentioned in more rletail irntle1· the hea<lings of li;1sal-«ell t>pithelioma an<l of the co11tagiou:i (1·p11ereal) tumours of the clog·, i he basal-cell 1.mnours were oHPn mistaken for acle110mab. Us11alh the tissue frou1 whid1they 1Ye1·e suppooie<l to nrise 1n1s not· statPcl, l;ut .in some «asps a s11·eat glarnl 01·ig·in, rn· iu others (lhesp le:-;ions occur on the he::ul) an origin horn n salirnry gland 1,·as thought of. 'l'he transmissible «aninP tumour,;, on the oth<~r hand, wen' .-;ometiiue,.;
mistaken for bnsal-C'ell tum1rnrn. 'L'hern .is of r·onrse little similnrit>-, but in both rnses ~1 histoµ-enesi,.; «i1JlllOt lw cleterrnined.
Letls serious differe11ces of 01>i11io11 11·hich arose on l'P-exa1uination of the 11taterial after routi1w cliag11osis coucPnierl Pmhn·onal tun101ns of the 11iam11u11·:v g-laml of hitches. whiC'h ha<l oft.en hef>n cli:ignosetl a,;
simple carcinoma 01· simple (spiuclle-cellc~rl) sarcoma rlue to failure to take accmrnt of an.\· hut. the preclomi1wting t_vpe of proliferation or failure to c11t a s11ffi1·ient numlwr of sections from difterent parts.
Gonfnsion ha rl al so ~1l'i8en in the <listi nction hehnen liYer-cell anrl bile-c1uct tumours of the liYP-r arnl also of primary from secondary liYer tumours: in rnan.v of these cases nn opinion (\\·hir·h is esseni ial to a complete cliagnosis) had not been wnturecl.(")
(2) H 1nnst not be thought that the foregoing rernnrks nrc intended as nny reflection on tbe excellent patholngicnl routine sen·ice l':t'rriecl ont b.v rn~·
colleagut>s at Ontlcrstepoort. From them the a uthm· has recei 1·ecl every possi blo help in the cm-rt>ction of mistakes and he himself is one of the routine 11·orkers 11·ho in the past has been guilty of rnnny errors in tu111our diagnosis.
I:NTROJlUCTIO~.
Enough examples have been given to sho1Y that the accurate h i:stological diagnosis of neoplasms of anirn als (1 ike those of man) often presents great difficulties. The remelly appears to lie largely in acquiring that experience which is gamed by familiarity not only with all kinds of true neoplastic pro('esses, hut also with pro{·es,;es resembling or likely to be confused ''i!h the neoplusti<:. In this country, such experience is readily to he obtained by commliing the annotated histological colledion of neoplasms at Onderstepoort.
TnE NucLEoLus JN Tu11.ouu CELLS.
Scarcely any attention has been paid to the lllOJ'l>hology of the nudeolus iu neoplasms of clorne~ticated animab. Occasionally one finds it mentioned in descriptious of tumours that the nucleolus is
" easily visible " or " nol easil:v <1istinguished ", or that it is
"prominent". Such terms clo not con1·e~· with accuracy the adual state of the nucleolus. Regarding human tumours, in Ewing's Neoplastic JJ·isertses we reacl that "in epi.theliomas great excess and multiplicity of paranuclein bodies is some"-hat chamderistic, while in endotheliomas the nudeoli are relatiYely small ". 'rhis tStatemeut leaves one with but a Yague impression of the state of the nucleohrn in tumoul's of man: \Yhether it is intended to apply to all of the seYerul kincls of epitheliomas, "-hether tbe featul'e is ('onflnetl to epitheliomas, whether in endot he liomus the Tela ( i Ye smallness of the nucleoli is judged by comparison "-ith the large nucleoli of epitheliomas Ol' by comparison ,,-ith the non-neoplastic endothelial cell, and what the position is in the cells of the other ],incls of tumours is left doubtful. Further, we haYe no information regarding nucleolar changes other ( han those "-hi ch coucern nmnber and size.
More re<'enll.v J'liacCarty (19:28) and JHacCarty an(l Hamrne(le1·
(1934) haYe inYestigated the question of the size of nucleoli in humau tumour cells "·i th more precision, an cl ha Ye con cl udecl that an enlargement of the nucleoli is constant in all malignant tumours, while in heuign tumours and 11011-neoplastic proliferations stH'h enlargement does not occur. The absolute size of the nucleolus is not measured, bui. the size is stated in te1 ms of the " nucleolar- nudear ratio ", by which is meani. thf' areal ratio exi,;ting bebn•en a nucleus in section aucl its nucleolus. They clo not make clistindions behYeen the various classes of malignant tumours, c01wluding· with the general statement that the aYerap:e nudeolar-nuclear rai io(') is 1:5 to 1:17 for malignant C'ells arnl 1:1'.i to l:M> for non-malignant ('ells. I believe that these authors have performed a Yaluable sen-i('e by dra"·ing attention to the prevalence of nudeolar e11lm·gement in rnalignant tumours; hut in making the generalisation just mentioned, they omit to define what they mean by a malignant cell or a malignant tumour, conceptions which are hy no means free from ambiguity. Further, it appears to me that in co11si(lering- nucleolar enlargement in any tumour cell, it is essential to take into account the size of the nucleolus of the corresponding normal l'ell: for it is obvious that any given n:N ratio may represent Yery different degrees of nuceolar enlargement in different kirnls of cells: ill normal hod>- cells, great variations in the n:N ratio occur, and it is well known
(3) Subsequently in this work this term is abbreviated to n:N.
20
TIJE ~TCLEOl.TS IK Tt;CllOCH CELLS.
that iu so.me (e.g. nene celb, cells of the acli·enal cortex, e]Jilhelial rells in general) the rntio is large or l'Onsi<leraLle. '"hile i11 otl1er,;
(e.g. filiroc.des aJl(l en,1othelinl celb) it is ,m1:dl, anc1 in still ollters (e.g. le11('0l·y(es) 11udeoli are not onlimnily Yisible ::it all. Thus a 11: X ratio of, s:1~ ] : 10 lllay retied liUle euLng·ement of the nucleolus of . ..:orne evithelial (·Plls, 11·hile it rna.\ represent consi,leralile enlarge-
JHP11t of ilH' nueleol n,-; of e.g. an e11dot11dial (:ell. ,-\ dingr:1rn of ( lw 1a11ge of ii:>: ratios \1·hich 11ill be rdened to iu this \Y<Jrk is slw1Y11 in fig. l.
DI AG RAMA TIC SCALE OF n: N RATIOS
~ @ @®
1:1 5 1:2 1:3 1:5
08
1 :9 1: 1680
1: 25 1: 50Fm. l.- Diagram of thC' various n11e!C'olar-nuckar ratio" referred to in th(• tt•xt.
Uf l·hange.-; in .-d1:1pe and t<'x(n1·c· ailll st:iiuing real'!ion of iliP nuc·lPolns I fi1Hl i10 llH'nhon in 1etPrinar,v pa(holog',\" a111l haYP bPell nuable to fill cl cle:n stahernPnts in lrnlllilll pat holog'.\". 11i:11H',iP (I'd.
K11·ing') as earl.\· as 18DG desnibed l'ertain 1Jol1ie-; "·ithin the n11elP11s, oc-cun·i11g· espcwially in thP 1nmonrs of tl1P liYPJ', as "psernlo-aclipcse and l',\·stic (]egC'll<'J'atiou of m1dC'us ". ]t seems almost l'Pdain tliai he "·as al'hiall>- (lP:iling \Yith ;dterC'cl Jluc·lc>oli, a111l similar 11oclieH whi('h I had !he oppodnuity of o1isen·iug· i11 luuuau li1·er turnonrs(') :ire undouh!edl.1· of 1111c!Pob r origi11 :i.nd sirnilai· to those ''"hil'li 11·e shall clesnilw in :i11irnal t.muours. Tl woul<l apvear prohalilC', lw11·- PYer, tha( !lw biter pro1·i<1t· more suitahle rn:derial fo1· study, in (hat the c·hang'C'S iil lJUPlitlon are more often C'lll'Ollltt?recl, C'SlJPf'iall,,· i11 the ex(rp111e forrn 11·hi('h Pi:mP:-;e <leserilwcl as a. hyaliuoc;is of p:il'( 01· the
\Yhole of !lie m1deopla:-:rn.
l. (}!11111/)Cs i11 sizc.-In t.urnour~ of clorne,;tic anirnaL, iw·n•:isP of the n::.'f ra( io (.-;ep e.g. figs. '2, !), 4) is 1·e1',\' often fournl in malign:rn( tnmonrs, and ne1·e1· i11 benign hnuours, in m,,- c>xperie11l'e. B,v malignant t11rnom·s T hc>re mean those that :ire l'harndel'ised hy in1·[1,;i,-e groll'th arn1 in ''"hich, therefore, rnetasta.-;i:-; cccun; m· a possibility of metnsia,;is e'.\:ists, anrl I inrhH1e hel'e the tumours sornc·- times spoken of a,; maliµ:1iant arlenorna~;. e.g. of the ]iYel'. The larg·e,.;t n:N ndios an• to bt' founr1 iu acantliorna, i11 hepatoma, in thP ha11,;- missihle (YC'nerPal) titrnom·s of the r1og ;rncl those head-base tm11ours (Chapter XI) whi"11 ha\e a silllib r 111oq1holog,\· to them, au,] ill ,;an:omas. lnnease of n :X ratio nHn· also he e11co1rnten-'tl in othc'l' malignant 1.m11011rn e.g. l~11,\otl1eliorn:i, rne,.;othelioma. It 11·as ll01
(') Exnt11inecl thrnugli tlie <·ottrlesy .of J)r. J. Gtll111a11 and Dr. C. Hc1·111a11.
IKTIWDUCTION.
enc;ouutered in thyrnomas. A ltliough the thymomas a1·e not usually associated "-ith metastasis, they gro\Y invasively and rnust he reckoned as malignant tumuurs; arul in some endotheliornus it "·a,;
also absent. )£embers of both these groups of tnrnonrs woul<l appear to r:onstitute exceptions to the i·ule of 2\IacCarty and Harnmeder that an increased n:N ratio is ahsolutel:v co11stant in malignant tumourR. The largest n:K ratio rnentione1l by the::le author::> \Yao> 1:0. In the tumours of domesticated animals, ratios of l ::2 l1aYe uot infreguentl~
bePn encountered. The largest ratio I have ·obsen·erl, Yiz. l : l ·5 ''as encountered in a cell of n " rnixerl-celled " ~arcoma of the fowl (fil28).
l"rc. 2.-.A distorted and enlarged nucleolus in" rnixc:l-cellcd "sarcoma of the fowl (8487 ; 750 X ).
FIG. 3.- An enlarged, twisted, and elongated nucleolus in a neoplastic macrophage occurring in mixccl-cellccl sarcoma of the fowl (8487; 750 X ).
