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Home , Epiphysis

TUMOURS OF *

By JOHN FRASER, Ch.M., M.D., F.R.C.S. {From the Departvient of Clinical Surgery, University of Edinburgh.)

Thought it might be of interest to discuss to-night the Problem of the tumours which are met with in connection vvith bone. The subject is one which has lately attracted Mention because of the difficulties which arise in connection )Vlth the appreciation of much of the pathology; and the way ln which many of these difficulties have been lessened, if not completely solved, is an object-lesson of the value of con- Centrated effort and team-work in the elucidation of disease Problems. We have had an opportunity during the past five ^ears of dealing with a certain number of these cases, and it |S Principally our records and results which I propose to put efore you to-night. The Origin of Bone.?We may remind ourselves that bone ?ne of the connective tissues of the and that its ^ body, nsity and apparent hardness are but an adaptation of S^cture designed to render the connective tissue sufficiently distant and strong to bear the body weight. This may seem an Unduly obvious statement, and yet it is one which is funda- mental in the appreciation of much of the pathology of bone ^our. If we remove the mineral content by such an agent s * Penny's fluid, we are left with the connective tissue basis, it is from this that the primary tumour of bone takes s origin. Let us trace certain of the more interesting and significant f^ages in the life-history of bone. The original bone outline condensed mesoblastic tissue containing a variable amount in its constitution. As growth proceeds, the propor- ?n of cartilage increases until what is virtually a cartilaginous ?del of the later bone comes to exist. Into this cartilaginous virtually avascular tissue, blood vessels penetrate; they ter thg centre Qf the shaft through an aperture which ^ er becomes the nutrient foramen, and they penetrate the emities smaller , of the bone through openings?the epi- yseal canals. This is the stage of vascularisation, and a omark of great significance. The process has a remarkable * Read 7th May 1930. John Fraser influence, for, as the vessels penetrate and come into contact with the cartilage cell, the cytoplasm of the latter disintegrates, the nucleus is liberated and on liberation assumes new and specific functions, for it now acquires the power of assimilating calcium and of depositing it in the surrounding tissue. What was formerly the nucleus of a cartilage cell becomes an active . It is the extension of this process from the centre of the shaft centrifugally and independently at each which results in the ultimate of the bone. The demonstration of the effect of vascularisation upon the process of ossification is not confined to embryonic and foetal tissues, it is evidenced upon a smaller scale as long as growth persists in the diaphyseal surfaces of the epiphyseal cartilage, but to this I shall refer later. I need not go into further detail regarding the development of bone?the essential point is the appreciation of the influence of vascular tissue in initiating and maintaining the cellulaf changes which result in ossification. The Growing Bone.?Let us now consider for a few minute5 the general structural arrangements of growing bone. The descriptive terms of the different regions are familiar to you ; speak of the epiphysis, of the or shaft, of that porti?11 at of the diaphysis which comes into contact with the epiphysis the epiphyseal cartilage?the , and of the - not These are terms in general and everyday use, and I need elaborate them; but where tumour formation is concerned) t0 there are certain peculiarities of structure in relation individual tissues to which reference must be made. The Periosteum.?The periosteum is the limiting fibr?U5 membrane which covers the bone; between it and the under lying bone there is a potential space of some significant or Ihe) This space contains bone-forming cells . vaO are constantly present, though their numbers and activity al1 from time to time. For example, in the early stages of acute inflammatory infection of the bone medulla (oste0^.0 myelitis), they stream in great numbers from the region the marrow into the subperiosteal area; on the other hand,1)1 the early stages of periosteal infection or injury, they leave the space and enter the bone interior. In all likelihood ^lCrJ is a ceaseless ebb and flow of osteoblastic cells into the) from the subperiosteal space, and the routes by which pass are the minute bone canaliculi and the more specials 154 * sf

** * >

PippTp ? . . 1>?-Section*??Section of metaphysis illustrating Fig. 2.?Chondro-sarcoma2.? of left . Phases of transition from cartilage cell to (A. S., 64 years.) One quadrant of micro- Psteoblast. of of bone field shows commencement of ls Deposit palisades scopical shown.shovvn. (X140.)(x 140.) sarcomatous change. (XI40.)

P PjQIq ' ^ of 3-?Parosteal of femur.femur, Fig. 4.?Myeloma of bone. Section C., 42 years.) Shows structure of a of child (H. D.) aged 2 years. jp.1 years.) myeloma 'bro-sarcoma,r?~sarcoma, originated from outer layer Characteristic giant-cell formation shown. Periosteum. ( x 60.) (XI40.)( x 140.) Tumours of Bone

aversian and Volkmann's canals. Apart from this relation- JP vve cannot regard the periosteum as other than a limiting brous membrane. The Epiphyseal Cartilage and Metaphysis.?Where the eP'physis joins the shaft of the bone there exists the disc-like of the epiphyseal cartilage, and the actual area ^lucture. surface contact between epiphyseal cartilage and diaphysis !S *-he area of the metaphysis. This latter is of peculiar lnterest: it is the area in which activity is manifest as long as growth continues; it is also, as we might anticipate, the r_ea in which much of the pathology of bone arises?such )Vldely differing diseases as rickets, scurvy, syphilis, acute infections, tuberculosis, and certain of the tumour ^mmatory_r'nations demonstrating their activities in this area. Structur- y is a vascular space lined by a single layer of endothelium an

L John Fraser

The Marrow.?This structure concerns us in only ?,ie particular?with its blood-forming cells, leucocyte series and hsemoglobin-holding series we are not concerned?but it may be that we are concerned with its giant cells, mono-nucleated, multi-nucleated, with the connective tissue cells of its reticulum and with the endothelial cells of its vascular and lymph spaces. 0 Such is a brief survey of the origin and the structure the composite tissue called bone, and if I am asked to indicate lieS its most outstanding general feature, I would say that it in the remarkable co-ordination of coincident tissue growth and absorption?an adjustment which implies a constant sub' periosteal and endosteal growth balanced by a regular proce^5 the of absorption in the medulla in order to retain intact sufficiency of marrow space, an adjustment which involve5 the most accurate balance of anabolic and katabolic activity' suC so that we are not surprised that certain influences as trauma upset the balance and lead to an erratism vvhi we recognise as tumour formation. ? ? has Classification.?The classification of bone tumours IJ the until recently been unsatisfactory, and I cannot say that position is yet completely stabilised. It has been impi"?ve ha5 and the problem greatly elucidated by the efforts of what come to be known as the American Registry of Bone Tum?urS inaugurated by Codman and sponsored by the American Colle?e of Surgeons. The American classification, modified in certai11 minor particulars, is the one upon which we have worked. way* If we regard the problem of classification in a logical we shall ask ourselves the question: What are the individ tissues existent in bone from which tumours may arise? ^ answer will be: the fibrous and connective tissues of periosteum and medulla, the cartilage of the epiphyseal af the osteoblastic cells wherever they occur, the mono-nucleate and multi-nucleated cells of the marrow, and the endotne j( tissues of the blood and lymph vessels. Using this "s?urC^11 principle as the basis and accepting the universal distinc of simple and malignant types, we find ourselves confr?n* with a classification which I may state as follows :?

Simple Tumours. Arising from osteoblasts?Exostoses, Osteomata. Arising from cartilage cells?Chondromata. Arising from marrow cells?Giant-cell tumours. i56 Tumours of Bone

Border-line Tumours. Arising from marrow cells?Myelomata.

Malignant Tumours. Arising from fibrous tissue?Fibro-sarcomata. Arising from osteoblasts?Osteogenic sarcomata. Arising from blood vessels?Malignant angiomata. Of doubtful origin but probably vascular?Ewing's sarcoma.

Secondary or Metastatic Tumours of Bone. I am aware that this classification is open to certain ^riticisms, as, for example, the inclusion of myelomata in the order line group, but at present we accept it as a working asis, being prepared to alter it and adapt it as necessity may lndicate. The Individual Tumours.?I now propose to take up the of individual tumours. Certain of these may ??nsideratione dismissed in a few words, others call for more detailed ^?nsideration; and I shall as far as is possible illustrate what have to say by the records of cases which have come under ?Ur care. Simple Tumours?The exostoses and the osteomata.?Bland- tton has urged that we should clearly distinguish between the ex?stosis and the in so far as the former is an out- growth of normal bone while the osteoma is a true innocent The exostosis is the result of the liberation of osteo- j-^our.asts from the subperiosteal space; the fibrous limiting mem- rane of the periosteum splits or tears, and the bone-forming s escape into the overlying tissue where they deposit bone. ^ ls thus that exostoses occur in relation to the attachment ^ Muscle and tendon and in such a condition as "calcanean P r. -phe error js noj- a tumour formation?it is a ? en?menon which is traumatic in its origin and reactionary lri character. ^he osteoma, on the other hand, is a true tumour, and ?Wes its origin to the activity of the osteoblast. The ivory Pe of , met with on the skull is a subperiosteal deposit dense ^suiting from an eruption of osteoblasts at a single point j^ne. response to some obscure irritation. The cancellous osteoma is Comm?n and most tumour. It is in fact a bone in interesting miniature, for it is provided with its own epiphyseal cartilage c?iR. 157 l 2 John Fraser and metaphysis, and, as long as body growth in length continues, it too will continue to grow. It is the pedunculated and elongated outgrowth of bone provided with a cap of cartilage which grows from the epiphyseal ends of growing long , and its origin is without doubt a segment of epiphyseal cartilage which has passed out of alignment from the natural plane, possibly as the result of an error in the attachment as of the limiting periosteum. The cap of cartilage behaves an epiphysis should, and growth in length is the natural sequel. A simple osteogenic osteoma has been described. We have not met with an example of the tumour, which is described " as a tumour which arises independently of normal bone growth from an aberrant activity of bone-forming cells." Chondromata have certain points of interest. We have experience of two types of this tumour, one is multiple, the other is single. The multiple type is met with in children and especially in the early years of childhood; it affects the short bones of the hands and feet, and its locale is in the centre of the shaft. The pathology is a collection of cartilage grow- ing in the centre of the bone, and gradually expanding the surrounding cortex. The origin is of interest. It has been pointed out that when these tumours arise the nutrient vessel al1 is deficient, and it seems reasonable to believe that imperfection in the early vascularisation of the cartilaginouS protoplast has left within the centre of the shaft isolated island5 of cartilage which have later assumed activity. The tumoui"s are simple, they are deforming and ugly, but otherwise harn1' less, and if left alone may disappear when growth in leng^1 ceases. The single arises in connection with cartilage occupying a superficial and extra-articular position. Its site5 of choice are the , the pelvis and the lesser trochanter of the femur; it arises when growth in length has ceased; al1 it may attain a large size. The chondroma is at first a simp^jan tumour of fibro-cartilage, but, as it grows, myxomatous ^ cystic changes develop, and, if disturbed by injury or incomplete removal, it undergoes tissue changes which conveft it into a rapidly growing tumour of a chondro-sarcomatous tyPe (Fig. 2). d Three tumours of the single chondroma type are include ?ne in the present series; two originated from the scapula and from the lesser trochanter of the femur. Both of the scapu ?58 Tumours of Bone

tumours were treated by excision of the bone, leaving the SuPra-spinous fossa and glenoid fossa intact; one has recurred *s a fibro-sarcomatous tumour of slow growth, but its activity as been definitely checked by heavy surface applications of radium. The chondroma which originated from the lesser of the femur was the size of a large orange when ^?chantercarne under observation. It was removed and ^ by operation monstrated at that time as a simple chondroma undergoing Myxomatous degeneration. A year later there was a ^Urrence which grew with great rapidity; it showed the aracters of a chondro-sarcoma. I ought to say that at the me of the original operation the capsule of the tumour Ruptured, and there may have been an implantation infection tumour cells in the wound walls. I have sometimes thought the growth of the secondary tumour in the vascular soft sues may have explained the relatively rapid progress of the the will make me cautious in Urrence>an<^ experience particularly the preservation of the chondroma in the future. yy- e capsule believe that single chondromata are serious tumours with S1derable potential tendencies towards malignancy. The giant-cell tumour (Fig. 5).?Eighteen months ago a n came under our care from a tumour which was ^ suffering ?-row*n? fr?m the left half of the frontal region of thearentIye ^11. It was an example of a giant-cell tumour. The n?psis of the history is as follows :? J' kj 42 years old, a ship's engineer. He sustained a severe ?n ^e^t side Th of the forehead in the middle of August 1928. Was a bruise at the site of the blow, but this appeared to Slli^e ? Six jn- weeks later swelling reappeared at the site of the ^ ^rGW suc'1 rapidity that by the end of October 1928 there^'Was a tumour development in the left frontal region equal in sj2e t0 a sma^ at this tirn cocoanut. The man was in Johannesburg anC* treatment was This to arres by deep X-ray adopted. appeared t^S 8rowth of the but the was tem swelling, improvement only presPOrary' an<^ wben he came under our care in January 1929 it the appearance shown in 5. *^uted Fig. ^>art ^rom was 7^ the swelling the clinical history relatively negative. Was cra6re virtually no pain and there was no evidence of any intra- lnvasion. X-ray examination showed absorption of the left half the ^ frontal bone with peripheral invasion of the diploic space. remova^ was successfully carried out. The tumour was gro\v'^era^Vein lng relation to the left half of the frontal bone, it was soft in

*59 John Fraser consistency, purplish-brown in colour, and showed numerous cysts containing a brownish liquid composed of broken-down blood pign1611* and lipoid material. The tumour had destroyed a great portion the left half of the bone, but strands of thickened bone passeda throughout its substance. Towards the periphery of the area periosteal reaction had led to the deposit of subperiosteal bone> waS and, though this was invaded in places, the fibrous periosteum

FlG. 5 (D. M.).?Benign giant-cell tumour of left frontal bone.

complete and imperforated. On the other hand, the membr^ covering the deep surface of the cranium was destroyed, and tumour filled that portion of the extradural space which lay immedia beneath. The dura, though in contact with the tumour, was to ^ invaded, and its fibrous texture presented an effective barrier further spread of the disease.

The intimate structure of the tumour, as revealed by scopical examination, was composed of stroma, giant-cells ^ blood spaces. The stroma consisted of a network of spin 160

< \ Tumours of Bone

shaped cells with large nuclei; the blood vessels were spaces ned by endothelium ; the giant-cells (the distinctive feature ?f the tumour) were scattered throughout the stroma, but the ^ajority appears to gather at the periphery. In structure ey resembled , the nuclei being of equal size and Central in position. It was evident that they were exercising a. destructive influence upon the surrounding bone. The Sltuation was unusual for this type of tumour. In our series there were two other examples of a similar rn?Ur> and I am indebted to Mr Mercer for permission to refer to ern- Both occurred in the neighbourhood of the knee- in the lower end of the femur, the other in the upper end the . This localisation is the usual one; an analysis ^ incidence of these tumours shows that 47 per cent, of ajj tumours in the of the j S^ant-celled appear neighbourhood Ce-Joint. Why this should be so has been the subject of conjecture?the localising influences are probably the ^Uche ... surface of metaphysis existing in the upper end of the ]a and the lower end of the femur and the liability to trauma, C eXact ce^ OI"igin the tumour is a matter of doubt, but th e Prominence of the giant multi-nuclear cell both in numbers in activity has been accepted as indicating that it is derived the Q?m multi-nuclear giant-cell of the marrow, a phagocyte bone. If this is correct, the stroma is but secondary and Pporting in type and derived from the connective tissue of the marrow. Tumours of this class used to be included in the malignant but the absence of metastasis (and no instance of CornP^'cation has ever been recorded) has justified its re^egation to the simple class. Though the tumour is an entially simple one, under certain conditions such as Perative trauma and soft tissue implantation?the rapidity ?r?wth may be so stimulated that its local effects resemble ^ Se of a malignant tumour. It is of interest to recall that a . lory regards the tumour as being closely akin to an ammatory condition. order-line Tumours?The myelomata.?In September 1928, tW? was referred to us because of a the years limp affecting Ieg" Examination indicated that the hip might be at fault, but n? definite clinical signs could be elicited. X-ray examination ^ revealed the existence of a central lesion in the iliac bone of 1 e affected side. The appearances were those of a deposit in 161 John Fraser the cancellous tissue of the bone, a deposit which had led to rare- faction and the disappearance of the cancellous tissue. We were frankly at a loss to explain the finding; it in no way resembled tuberculosis, and the Wassermann reaction was negative. A somewhat moth-eaten appearance of the bone suggested a secondary carcinoma- On ioth November 1928, an exploratory incision was made int0 the bone, a segment of the deposit was removed, and the appearances which the microscope revealed I show to you now. The cytology resembles marrow tissue, but there are certain distinctions. There

Fig. 6.?Multiple myelomata of bone. (X-ray of H. D., aged 2 years). There an tumour deposits in upper ends of both femora, in right half of ilium spinal column.

0 are no hsemoglobin-content cells; there is an undue proportion small multi-nuclear cells; and the stroma is composed of an abundance of connective tissue in spindle-shaped cells, evidently type (Fig. 4)- .? The further progress of the case is typical. The original dep? deeP in the left ilium was treated by heavy doses of radium and X-ray therapy. It responded and appeared to undergo a ^^r0.fS which we regarded as curative, but, to our distress, further depos have appeared?in the ilium of the opposite side, in the head shaft of the and in the skull. The latest to right femur, appear ^ been in the body of the tenth thoracic , and this develop111 has been followed by collapse of the body and secondary kyphosis. 162 Tumours of Bone

The origin of the tumour has been the subject of much 1Scussion, but no decision has been arrived at. It has been ^ggested that it originates from the myelocyte, others hold at it originates from lymphoid cells. It is our view that e Myelocyte is the cell from which it arises. ^ has been stated that the Bruce-Jones protein is recognisable in the urine in cases of this nature, but it was so in this instance. The ultimate sequel of these cases k?tas . hitherto been fatal, death occurring from asthenia. The Improvement which has resulted in this case from radium and "^~ray h?lds out the hope that the prognosis may not as hopeless as we believed. Malignant Tumours?Periostealfibro-sarcoma (Fig. 3).?The Periosteal or parosteal fibro-sarcoma should not be regarded a true bone tumour because specific bone-forming tissue es not enter into its primary formation. It may be said Its relation to bone is fortuitous, for it arises from the fibrous of the and in its structure jj. 5r layers periosteum, similar to the fibro-sarcoma which arises from fascia- the tumour springs from the fibro-periosteum, it is true t^encertain in the k secondary changes may appear underlying vv,?ne> but they are the result of pressure and contact, and thus n<^ saucer"shaPed erosions where the tumour is in contact ^th the cortex, and areas of periosteal bone overgrow at the ery* The intimate structure of the tumour is that of the j?e fibro-sarcoma. The cells are spindle-shaped, and there _ undant intra-cellular substance. The degree of vascularity according to the cellularity of the tumour. These j.^es?urs to be but the is more a appear encapsulated, property SuParent than real. They do not readily infiltrate the rounding tissues, and it is the condensation of the surround- which the of a re ?arts gives appearance capsule. They Ultiain ^oca^sed for a considerable period of time; but they become more cellular and more vascular, and, ^ly1S their increases. When this c^anSe proceeds, malignancy stage is reached a secondary metastasis in the lungs is the fatal issue. G^ause sarcoma is ? 0steogenic sarcoma (Fig. 7).?The osteogenic ?Ur the most and the most formidable of fu exPerience frequent e rnalignant bone tumours. Its incidence in this country sHSKbeen estimated at 1 in 75,000 of the population. It is v more frequent in males (4 to 3); and, while no age 163 John Fraser can be considered strictly immune, the great majority of cases occurs in the second and third decades of life. In hospital and private practice we have encountered fifteen examples of the disease. Three cases occurred in children under ten years a of age ; one, an of the , appeared in

Fig. 7.?X-ray of osteogenic sarcoma of upper end of femur. Co right (M. 0 15 years.) The reactive triangle of Codman is seen at the upper extremity tumour area.

a)1 woman of fifty ; and the remaining eleven cases were in age period extending from the fourteenth to the thirtieth yeaI"' The localisation of the disease has been worked out 1 ?vVef various observers: 72 per cent, of cases occurs in the v limb, and of these 82 per cent, occurs around the knee, ce1 59 per cent, of all cases. The femur is attacked in 52 per ti of cases, and four times out of five at its lower end : the < in 20 per cent, of cases, and in nine times out of ten upper end. This localisation around the knee is remarks 164 Tumours of Bone

it has been explained by the greater liability to trauma ln ^is region. In 9 per cent, of cases the is attacked, and the site of occurrence is usually in the centre of the ?ne close to the insertion of the deltoid muscle. It is yernarkable that the American investigation recorded no ^stance of an osteogenic tumour affecting the bones of the rearm?we have encountered one instance of an osteogenic of the radius. In another instance a tumour affecting ^rc?mae upper end of the right radius was at first regarded as an ?s^eogenic tumour, but we are a little doubtful about the 0steogenic properties of the cells. It is probable that the osteogenic sarcoma arises from cells ich may be termed ancestral to the later and more specialised ?artilaSe an<^ k?ne?in other words, from incompletely diffSeren^a^ed tissue. It is to recall for a moment th important c?nception which we have of the morphology of the k ?ne cell. I have already alluded to this question in sum- riSlng the process of bone development. The original cell js 3- large spindle-shaped mesoblastic one equipped with a y active and cells of this c hyperchromatic nucleus, type ProtoP^as^ or original model of bone. The second SC Pha^1^6ln 's a in the life"history signalised by striking change . aPPearance of the cell; the nucleus shrinks, mitosis is in eyance, while the cell acquires a relatively large amount of r 1^ is a natural that cells of thi C^?Plasm- physical sequel Pac^e(^ closely together within a relatively small bulk > acquire a somewhat outline. These in ^ square changes ?e^ are an while the la indication of lessened tissue activity, amount of cytoplasm, together with the method of cell ^r?e which j ngernent, affords that increased degree of stability at this further stage of the life-history of the bone, -p^essentialCells now cells, ?j, justify the description of primitive cartilage ^ird and last of the evolution is the conversion of \ stage cell into an osteoblast. The mutation is aCCo cartilage mPlished, we believe, through the medium of vascularisa- tj0^ an^ c^anSe is evidenced by a lessening of the cytoplasm bulk' an *ncrease in size and of the nucleus. The cell "an<^ activity n?W an fulfilment of its function lie ^ oste?t?last, and the further the power of assimilating calcium, probably in collosol f0r^ln' of tissue from the calcium and the Procluction conversion of this tissue into bone. We believe thaj.U^^matethere are certain additional features to be borne in mind *65 John Fraser where tumour formation is concerned, and they are these?atl " t? early" osteoblast is at first an unstable cell, called upon assume a specialised biochemical function ; if for any reason this function is not assumed, the cell may remain inactive, it may disintegrate, or it may return to one or other of its origina types, the spindle-shaped mesoblastic cell of the primitive cartilage cell. When an osteogenic sarcoma arises, we believ'e ?nC that it originates from "early" osteoblast cells or from or other of its more primitive types. Certain etiological facts support this view. The comm011 site of occurrence around the knee-joint represents the largest metaphyseal area of the body, a locale in which the evoluti?n lS of the osteoblast continues as long as growth in length maintained. Subsidiary etiological features are the influeflce the of injury in arresting the natural evolutionary process, and Th? relation of the age period to the incidence of the disease. pathology may be quoted as supporting the view expi"esse above, because it is often possible to demonstrate the vari?uS cell types within the purview of a single tumour. Pathology.?I propose to trace briefly the more import'1 phases of the pathology. The early stages of the tumour f?rrri^j tion arise within the bone medulla, and in the central or endoste f?r type of the disease it may be confined to this situation certain length of time. Recalling, however, the physiological1 of the constant circulation of osteoblasts from the medulla 11 the space, the of tumour tissue wh subperiosteal development ^ the latter is a relatively early feature. While the turn ^ occupies the cancellous area, its extension is characterised the coincident absorption and deposit of bone, the tis c& of the original shaft being absorbed, while the tumour themselves in down an and imper busy laying irregular ^ deposit of osteoid and osseous tissue. This coincident Pr?C is ultimately apparent within the tumour itself, where 1 ^ deposit of tumour bone exists at the periphery, but has undergone absorption at the centre. s ^ With the advent of the tumour tissue into the periosteal space, further characteristic changes appear. ^urn?jjt bone is here deposited in an arrangement which is at angles to the line of the shaft of the bone. The meth? j deposit is controlled by the arrangement of the Perl0S to . blood vessels ; these enter the bone cortex at right angles axis of the shaft, and, as the periosteum is gradually ele 166 Tumours of Bone

y the accumulation of tumour tissue, the vessels are increasing drawn outwards in a series of parallel vertical lines and rrn a scaffolding against which the tumour deposit is laid, so at the arrangements of the tumour bone deposit is necessarily at right angles to the shaft. The maximum subperiosteal ePosit is in the immediate neighbourhood of the region ?CcuPied by the metaphysis. It is therefore close to the articular end of the bone, and from this point it extends along the outline of the bone shaft. It is evident ^ntrallyat an arrangement of this sort results in the characteristic ^die-shaped outline of the osteogenic tumour. At the Periphery of the subperiosteal extension the periosteum may ^-trate reactive congestion changes, so that there is a P?sit of a of bone which, in contrast ? segment subperiosteal the tumour deposit, is laid in plates parallel to the bone t. The of between the reactive ^ point junction parallel Posit and the vertical arrangement of the tumour tissue is feature, and Codman has given it the name of th e 1(^tlnctive reaction triangle." ^rous forms a resistant barrier to the out- w periosteum sPread of the but a is reached Mi disease, point ultimately ^arr^er gives way and the tumour extends into the sur^ tissue. When this is reached the of the ?Unding stage rapidity <"Urnour bone and the growth increases, deposit largely ceases, is that of a mesoblastic CeU otology presented spindle-shaped division. In this the of ^ndergoing frequent stage vascularity is intense, the vessels of the sPac e.tumour being primitive ^"like type lined by a single layer of endothelium. in a . finical history cannot be discussed in detail paper 1S but I be to recall certain of the ^escription, may permitted outstanding points. There is a history of trauma in Sllc,rnorea cases has been ascribed g, large percentage of that injury the but it is difficult to decide Mi T arnonS etiological factors, er the lesion or (jr trauma influences the origin of only .attention to it. It is a most unusual event to find the casWS occurrence of a fr 6'history introduced by the pathological Ure> and in tumour differs from ^ this respect the osteogenic anc* the giant-cell tumour. The general health a oVermetastaticPeriod the onset of the disease is often Un preceding thatSUally ^??d' an^ this fact has led some observers to believe -lt- ^ an over-activity of the bone production mechanism ^a JOle de vivre, as I might express it?which leads to the 167 i John Fraser erratic growth resulting in tumour formation. Pain is the the introductory feature of the symptomatology ; it precedes an development of an appreciable tumour, and it arises from increase of the endosteal and subperiosteal tension. When swelling is detected it assumes the characteristic outline I have described, and its progress is one of slow but tragically Pr0' the gressive increase. With rupture of the fibrous periosteum rapidity of growth is noticeably increased. Ewing's tumour (Fig. 9).?The recognition of this tum?ur as a clinical and pathological entity is a comparatively recent event. It was originally described by Ewing as a diffuS_e endothelioma. We have met with a single instance of th1^0 tumour, and, as certain points in the case-history are interest, I shall briefly recite the story. A boy of t\velve struck his left shin against the sharp edge of a boat in August 1924, and a bruise of some severity resulted. In October al1 ^ same year boring pain was complained of in the limb, swelling at the site of the injury was detected. The swells affected the lower end of the left tibia, it was bony in character so and a recurrent type of pyrexia had been in existence for of a weeks. An X-ray examination showed signs suggestive in chronic osteomyelitis ; there was an area of rarefaction ^ while the surface showed the deposit of new medulla, periosteal1 bone in the laminated form which one associates with inflammatory condition. The diagnosis of a chronic ?ste?cj was made, and an exploratory operation was cafrie myelitis ^ out. On exposing the medulla of the bone a cavity revealed containing a soft, greyish-white deposit rather j1 inspissated pus. The focus was treated by local eradicate11' and I confess I had no of the true nature of suspicion ^ condition until microscopical examination revealed that I h case was one of Ewing's tumour. After a delay, which was carried but twelve ra0il. always regretted, amputation out, ^ a11 later a secondary focus appeared in the spinal column fatal results. paraplegia developed with e consti It is said that examples of Ewing's tumour ^ cases as . I 7 per cent, of all diagnosed but it be thatvv0^e say that this figure is unduly high, may true character of many cases of this type is unrecognised, the , sex occurrence is three males to one female, and incidence is from the fifth to the fifteenth year?the age Pe j5 outHlie of osteomyelitis. The tumour tissue is soft, the 168 1G. Fig. 8?' p. Usteogenic sarcoma of femur. Fig. 9.?Ewing's tumour of bone. (D. M., (?g ? S., aged 17 years.) (x 80.) aged 12 years.) From tumour centre of shaft of right tibia showing character of cells, their distribution around blood channels and occasional syncytial group- ing. ( x 120.)

-?* ICWr i e sarcoma of mandible. io?Telangiectaticang]ectaticgiectatic sarcoma of bone.bone, Fig. ii.?Telangiectatic rUttlou of mandiblelandible in child D., aged 10 years.) Illustrates infiltra- a?ed^umourSed io10r (K?(K. D.) (K. and masseter years,years. (x(XI40.) 140.) tion by tumour of periosteum muscle, (xioo.) Tumours of Bone

0 ulated by an arrangement of strands of coarse connective thSUe' co^our resemt)les that of granulation tissue, but in existence of haemorrhage it may assume a dark maroon ^Ppearance. The tumour infiltrates throughout the cancellous .Ue ?f the bone interior, and, as it spreads, the bone with ^ COmes *n contact is removed, while the more superficial tis ucs of the cortex are expanded. Activation of the periosteum ts in the deposit of plates of new subperiosteal bone in a the?S success^ve and superimposed lamellae. Ultimately tumour makes its way into the extra-osseous tissues. It ? i.ears be provided with an imperfect capsule, but it readily rates the related muscles and fasciae. The most common oite of occurrence is in the centre of the shaft of the long bones l?wer but of the tumour have been r limb, examples ed in the ilium, 0g humerus, clavicle, , scapula, vertebrae, ischium, radius, mandible, metatarsals, and ribs. c^lcis,11 examination, the tumour is found to be CQ]^ microscopical of small cells, rounded, polyhedral, or fusiform in ?Ut,P?Sedne. The nucleus is large, the cytoplasm is scanty. There no intercellular so that the cells lie cj Vlrtually substance, Pac^e<^- certain instances the cohesion is so marked Sroups of cells appear to be merged into syncytial-like ^lere considerable variation in the of arrangement e Ce^s: be around a bj0o they may grouped concentrically 1 be in e channel, they may arranged columns, they may reticular. *S a summary ?f the clinical pathology of this highly inte^UCk tumour. Its remains a matter of but rCs^nS origin dispute, ^ose best to believe that it originates ejt^ qualified judge ^r?ni the endothelium of the vascular tissue of the bone ^ ,?r la or from the reticular endothelium of the bone-marrow. atignant io and the series of oUr angiomata (Figs, ii).?In Cases there is one which we include under this heading. K r> a of io demonstrated a fusiform enlargement of lhe y Sirl years, cause be in .J? t^ie mandible. No obvious could assigned XP'anation of the examination showed ari(j swelling. X-ray expansion central some 0f rarefaction of the bone with reactionary deposit 0 SubPeri?steal bone. No symptom accompanied the swelling. a 1Ve revealed the fact that the interior of the bone \Vas exploration a in resembled a ^ vascular tissue, which appearance m highly fir?CCU^e^ of this tissue sh Sranulation tissue. Microscopical examination to be composed of vascular channels lined by endothelium CHIR- 169 John Fraser and supported by a stroma of dense connective tissue. The rrucr?' scopical appearances closely resembled those of the hsemangiom3 group of the endothelioblastomata. Examination of the soft tissue overlying the jaw revealed the fact that the tumour was involving and infiltrating the masseter muscle and the fascial planes. We regard tl>e a was one of histological appearances as indicating that the case ^ie telangiectatic sarcoma arising from the vascular endothelium of bone medulla.

It is a pleasure to record that in this instance the application of a radium plaque to the surface of the jaw (720 mgm. hours) has resulted in apparent disappearance of the tumour. Treatment.?I am afraid I have been so much interests in matters of pathology that I have left until too late tbe discussion of the all-important question of treatment. Wi^1 your permission, I would like, however, to say one or two thin?s on this point. The simple tumour rarely presents any difficulty, but would utter a warning about the risk of incomplete operate6 interference in this class of case, and the risk of implanti^ relatively simple cells into new and more vascular tissue. TblS warning is particularly important where the chondromata tumours are concerned. ^ When the tumour is of a localised type and is unassociate with metastasis, when, in fact, its clinical grouping is eitbc^tfl definitely simple or is of such a low degree of malignancy it may be said to be on the border-line (and in this class tnvV^ put the giant-cell tumour and the myeloma), we believe the operation of ex-section, keeping well beyond the boun _ ^llS of the tumour, offers good results, and, where it is possible, is the procedure which we practise. If ex-section has bccl1 >s complete, no ancillary treatment is practised; but if there suspicion that the operation has been in any way incomple^' radium is implanted in the surrounding areas and deep X-ra^ therapy is advised. In the Ewing's tumour, if confined within the bone medu and in the periosteal sarcoma, if localised, we advise a sin11 procedure. 0 The treatment of the osteogenic sarcoma is one of a most difficult and anxious problems. My own views beginning to crystallise on certain points. I have said fifteen examples of this disease have been under our ca[C - a tfl Eleven were treated by amputation, and all are dead, 170

A Tumours of Bone

duration of life after the operation being i| years; j.0l|gestUr were treated by the ex-section method (the wide removal - of 1"Vluie #? anected segment of bone), and of these, one, an osteogenic Sarcoma of the lower end of the femur, died 3^ years after Operation, while the other cases are alive at periods of 3 years, 2 years, and 9 months after the operation?in the last- 1Tlentioned instance an insufficiency of time has elapsed to ^ake the consideration important. over these events, I have the that where th linking feeling tumour is reasonably early, amputation is not the best ?Urse to pursue. Experience seems to indicate that dis- tillation takes place as soon as if not sooner than local Vldences appear. May it not be that the severity of a major Putation so lowers the vitality that "secondaries" which ?ht otherwise be destroyed are in the critical post-operative ri?d permitted to acquire a dangerous activity? It is my Pression that ex-section is the for an e ar preferable operation y osteogenic sarcoma. ^ ex-section is practised, however, I am convinced that it s be combined with other ^ therapeutic measures?radium, eP and fluid. k X-ray Coley's My experience of radium, where (j?ne humours are concerned, is so limited that I can express no sa^rna^C ?P'n^on- I am satisfied of its value in the angio- types of tumour, but I cannot say that I have seen matousf?H?w its use in the sarcomata. It has thee osteogenic further disadvantage that, if used in heavy dosage in a?t with ] bone, it produces a slow necrosis which ultimately fracture. We have had Q|- s.to Pathological personal experience ls complication on one occasion. am a ^rm ^e^'ever in the value ?f and it is our X-ray therapy, as soon as after the ex-section (or ^rac^ce> possible operation has been completed, to expose the entire ^1 6imputation) In 0ut^ne> and such obviously vulnerable parts as the an<^ mediastinum, to intensive treatment concentrated re Whe^ possible into a of ^ period twenty-four hours, 250,000 a 7?"Per cent, (sarcoma) dose. I am fully satisfied that^0111 two ex-section cases this procedure has been responsible r the prolongation of life. a^so ^at fluid is of value in or del Foley's preventing the I ^ aying growth of secondaries. fully appreciate the which accompanies its use, and to be of real value it musresss be in a dosage which ultimately becomes heroic. We 171 John Fraser begin with a dose of \ to 1 minim, repeated every third day> and gradually increased to the limit of tolerability, whatever fevV that may be. We have found that the addition of a minims (5) of adrenalin to the Coley's fluid diminishes the 0 intensity of the reaction, possibly by lessening the degree immediate absorption. I intended to say something regarding the value of the_ 0 collosol metals, but this is all that I shall add : in one case the parosteal sarcoma of the skull, a local disappearance of tumour followed the use of collosol selenium ; six months late1" there was recurrence with metastasis, but the disappearancC of the original tumour was a definite and impressive event.

Discussion.

Mr Wade said?In listening to Professor Fraser's paper, my mi'1^ went back to a Surgical Congress which we both attended in Londo'1 when the question of the treatment of sarcoma of bone was discussed- The conclusions that were come to there were extremely pessimist'0' so much so that it was generally accepted that when a malignant f?r sarcoma of bone was treated by amputation and the patient lived I one and a half years, the original diagnosis had been wrong. ^v) inclined to believe that those of us who practise general surgery m?re confirm this opinion. It is in the treatment of this condition m? than any other that one finds dramatic surgery carried out. The ever) drastic and is carried and in mutilating surgery through virtually ' case the patient lives and has a satisfactory immediate convalescent comes In the course of nine months or a year, however, the patient ^ of the of blood, you again complaining recurring expectoration 11 examination reveals the presence of secondary metastatic deposits which he succumbs. the lung from ultimately ^ I was interested to hear Professor Fraser refer to the use of see fluid in the treatment of these cases. Undoubtedly when you in carried out under Coley's direction in the Memorial Hospital have 1 York, some remarkable results are observed. In my hands I obtained similar success, and I cannot determine its true value. I have seen in Bristol a remarkable demonstration Recently ^ as Dr Todd of the results that have followed what he described fllll have r medical treatment of malignant disease. No man could ^ forward a more honest statement than he did. He frankly stated that the cases he demonstrated showed his best results, but some n successes. He before us one showed were remarkable brought ^ under with a large tumour of bone that had entirely disappeared treatment carried out by him. 172 Tumours of Bone

^le treatment of malignant disease is always a difficult matter and e astonishing thing about it is that, although so far we have not S?t any single line of treatment that will produce a cure, and a wide Variety of methods are employed, with all of them occasionally a Marvellous success is obtained in a manner that is very difficult to account for.

Professor Wilkie said?There are two points to which I would like re^er- First, as regards the malignancy of these tumours. I confess j? a j^Was little surprised, towards the end of Professor Fraser's paper, to him mention myeloma as one of the less malignant tumours, ^earcause in my very limited experience of two cases, a fatal issue the^6^ relatively short periods in spite of all that was done for ti.m" ^he other point is the question of treatment. There is, I ' n? ^ou^)t those who have the of this dis amongst largest experience ^at by amputating the affected limb sarcoma of the bone is cured, and we continue to in these cases. ^ yet amputate Why? are sure that this will not cure the not resort to ^ patient, why 6 0t^er f?rrn treatment. Reference has been made to Coley's flu" ' country few reports of good results have been presented before the profession, and the reason is, I think, because surgeons and entS ^lave not been can show a lar sufficiently persevering. Coley Ser^es results which he has over to fift 8?od had, long periods, up ^0ars" That the results are good is proved by the fact that so ^ SurSeons refer their cases to for treatment. He has seen the Coley good results and he is able to inspire the patients with sufficient nce to on treatment which is no means but g? by pleasant, *n his has to be curative. We have at our dis hands, proved Posal X-rays and radium which have also been shown, in a certain oer of cases, to be curative. Should we therefore any longer those limbs where there is sarcoma of bone, or should we ^ot rather depend on those other methods which have given a certain er of good results without any mutilation?

Cochfwie said The question of diagnosis is often very cult are diffi^. without actual of the tumour. of v exploration X-rays great Ue in diagnosis, but the X-ray film must be a good one. I know of ^lan one case of mistaken diagnosis due to a poor X-ray film : OnJ6 Was a case of ossificans in the e traumatic myositis quadriceps ens?r cruris who was advised to have the limb amputated 0n muscle, was sent to ev*dence of a poor X-ray film. The patient another sur^6geon, who ordered fresh and the condition was at once seen t0 X-rays be benign. ^rofessor Fraser has out how commonly these tumours of bo Ue pointed affect the region of the knee. I have been impressed by two chir. 173 M 2 John Fraser cases of tumours of the lower end of the femur, whose first physical sign was a painless effusion into the knee. The condition was regarded of by the patient and the doctor as one of simple sprain. Palpation bone the lower end of the femur revealed very slight thickening of the t'ie and X-rays showed, in both cases, an early osteogenic sarcoma of lower end of the femur. Where simple tumours of bone have reached a considerable size, a great deal can be done by reconstructive, surgery to preserve the function of the limb. Mr Struthers also spoke. a Mr J. J. M. Shcwo considered that justification existed for measured degree of hopefulness in regard to methods of treatment which did not rely chiefly on mechanical extirpation. Professor Fraser had indicated a considerable range of method, and the work of Todd of Bristol had met with sufficient success to warrant careful considera- tion of every possibility of affecting the nutrition of the cell through the blood stream.

Professor John Fraser in reply, said?In replying to the various questions asked, I may take together those of Mr Wade, Mr Struthers> and Professor Wilkie all have been relative to the problem ?r treatment, and more especially to the question of amputation ex-section. I am convinced that in early cases of osteogenic sarcoid' those ex-section offers possibilities as good as or even better than afforded by amputation. One of the specimens before you to-nigh1 of a? is that of a young man of eighteen years. It is an example osteo-sarcoma of the lower end of the femur. When the case came under our observation a mid-thigh amputation was recommended, for certain social reasons the advice was refused. We then advise ^vaS an ex-section of the lower two-thirds of the femur, and this accepted. The operation was carried out and an ox bone gra inserted. Treatment by Coley's fluid was immediately begun. Eig^ months later erysipelas developed in the scar of the ex-section, thig ultimately the site of the graft became infected. A high amputation was then recommended and carried out. The young lived for two and a half years longer, and during that time he receive regular injections of Coley's fluid. Ultimately he grew restive unde^ the treatment and he abandoned it. Three months later secondary disease appeared in the right lung. This case impressed me, and I have read it as indicating ^at ex-section, in conjunction with Coley's fluid, has a field of possibilit,eS as great if not greater than those of amputation. ear; Mr Cochrane has spoken of the value of X-rays in the diagnosis of malignant bone tumour, and I am in cordial agreeme with what he has said. *74 A