THE BONE MARROW OF CANCER PATIEKTS: A REPLY TO DR. FRANCIS VILLY’S FIRST PAPER. By HERBERT SXOW, M.D. (Lond.), Snrgeom to the Cancer Hospital,

Brompton, London.

I BEG to congratulate Dr. Villy on the distinction of being the first pathologist to take notice of a matter which seems, to my imperfect apprehension a t least, fraught with a far-reaching significance in many other fields than cancer.

I have also to thank hini for further proving the most important points I have previously advanced. He seems, however, quite unaware of this ; and before his promised further communication, it would perhaps be not inadvisable for him to refer again to my writings and to ascertain what I have really put forth. Should he succeed in drawing the attention of investigators to that neglected pathological field, the marrow, I can most readily condone hostile animadversions. So far as I personally am concerned, “ Strike, but hear me.”

I will first briefly recapitulate my own attitude in this matter ; secondly, point out a few of Dr. Villy’s singular misapprehensions; thirdly, discuss cursorily the cases he cites. My conclusions, based no less on years of clinical experience than on pathological research, are as follows :-

1. I n its natural course, mammary carciiioma always distally infects the marrow of bones, immediately after the enlargement of the adjoining lymph-glands.

To this rule ‘‘ atrophic ” cases constitute a doubtful exception, and there may be a few others.

2. The deposit in this tissue lies perdu therein for an indefinite period of years ; without treatment, 2 to 3 ; under opium, much longer.

3. During this term there is no palpable cancer-deposit (after operation). The peculiar chain of symptoms I have described (sternal prominence, tenderness with apparent thickening of humerus, gnawing lumbar and scapular pains) gradually appear ; but never earlier than the second year from inception.

4. Subsequently, general blood-infection ensues, with abundant deposit in’the viscera and in distant bones.

5. “ Recurrence )’ after operation, when the inarrow infection pre- exists, does not ensue for two to three years as a minimum. Hence the absurdity of the “ Volckmann’s limit ” as proving cure.

THE BONE MARROW OF CANCER PATIENTS. 353

6. I n carcinoma of the outer two-thirds of the breast, the adjoiniiig humerus first shows faint indications of the condition; aiid so is regarded by me as the first attacked in most instances, but not always.

7. I have attributed the deposit here to ,‘ regurgitation of lymph currents,” consequent on lyniph-stasis in the glands. The explanation is not final, and is subject to revision by Dr. Villy, or by any other competent investigator.

8. I n carcinoma arising near the sternum, the marrow of that bone is first implicated. That is, distally infected. Direct infiltration occurs later.

9. The infection is conveyed also by the lymphatics of the chest wall. Some penetrate the bone directly. Others communicate with the residual thymus, a lymph-organ never entirely obliterated.

10. It is believed that deposit in the thymus ordinarily precedes the “sternal symptom.” But this also is subject to revision or refutation.

11. The sternal prominence occurs, in most cases, not in all. It is hardly noticeable in spare women, is most conspicuous in stout women with broad chests. It may be simulated by natural confor- mation of the part ; it only indicates marrow infection when gradually developed under observation, and in association with cancer.

12. Infection of the marrow follows the direct growth of any form of malignant neoplasm into that structure. Thus primary sarcomata of bone, rectal cancers, melanotic cancers, have casually produced distant deposits in the skeleton.

Here, however, we always find that the malignant tumour has directly infiltrated some particular bone. This is a very different matter from the distal infection in question; and is illustrated by Professor Deldpine’s stomach case. Secondly, in these latter cases, there have nearly always been plain outward signs, fracture or tumonr.

13. On the other hand, mammary carcinoma is the only form of cancer which infects the marrow as a routine event ; which is attended by distal infection, long before there can be direct infiltration ; which displays the obscure train of physical signs I have described; and which, in all but 2.5 per cent., shows till death no palpable indication of the occurrence other than those signs.

Here the humerus may wholly escape.

These conclusions have obviously a practical bearing on the surgical and medicinal treatment of breast-carcinoma. But what seems to me still more important is, that the period of latency demonstrated by some of the cases cited in the Brit. Mcd. Joiirn. (London, March 10, 1894),’Lancct (London, January 12,189 5), and elsewhere, should surely direct the attention of pathologists and physiologists to the marrow as a passive storehouse of latent matcries morbi. I n malarious countries the hmmatophyllum occurs in that structure when absent from the

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354 HERBERT SNO lK

blood of birds. Where else can the $laria sanguinis hide itself during the remission? Such are but transitory instances, i t is true; still they trend in the same direction as the more lasting.

Dr. Villy credits me with a theory, and not with a proved fact. The only theory I have advanced concerns the mode in which the marrow-infection takes place, namely, per the lymphatics. In the particular details of this, my views are of course fully open to correction.

The eight autopsies on “ insidious ” cases detailed at Bournemouth (to say nothing of the remainder) took place without selection, as opportunity arose. I owe them largely to the pathological zeal of Mr. Cecil Beadles, then our house surgeon. Since he left us, I have been able to examine after death only two or three, very few ending their days within the hospital. Nor have I greatly cared to do so ; for I thought, however erroneously, that the autopsies aforesaid, in con- junction with the mass of clinical observations by which they were reinforced, and identification of that peculiar train of symptoms described with the infection-process, were amply suficient to establish the main point I had in view. The burden of correction or criticism in details seemed to me to lie on those who were specially concerned in pathological research, which I was not.

These observations were controlled by others on cancer in other organs, notably the uterus. No example of breast-carcinoma was exempt.

My paper showed the association of this infection with certain physical signs, and then demonstrated the very general occurrence of those signs. I hardly see what more is needed as proof, from a logical point of view, of a fact previously unknown and unsuspected, though details of its mechanism still remain to be worked out, and exceptions to the average rule indicated.

The ponderous statistics of Toriik and Wittelshofer, with which I am again here confronted, were referred to in my paper ; as were also those of Sprengel. Those eminent pathologists never thought of examining the marrow unless there was a palpable bone lesion. Hence their figures cover only the small percentage of non-insidious cases, 2.56 per cent. (12 in 467).

A valuable paper by Stephen Paget most usefully serves to display the state of scientific knowledge (or ignorance 1) before the discovery of “ insidious marrow-infection.” The bones were never examined unless there was turnour, fracture, or marked distortion. Even then the actual presence of cancer-deposit commonly escaped notice, being ascribed to other causes. The specially “ insidious ” physical signs were undescribed.

That (‘ fragilitas ossium,” or decalcification, in association with mammary carcinoma, is the result of actual cancerous infiltration, was

I n all, the marrow was implicated.

Lancet, London, March 1889.

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shown by collation of various museum specimens. In particular, by the happy accident that in one of the most typical of these pre- served in St. Thomas’s Hospital Museum, half of one femur had been preserved in spirit.

Villy repeatedly quotes from me the rather vague term, ‘( medullary infection.” I do not remember ever using it ; if it occur in any of my writings, there was probably a printer’s error. H e denounces me for ascribing ‘I cancerous cachexia ” to marrow deposits, on the ground that “ a similar cachexia occurs in cancer of other parts.” No one nowadays, I imagine, takes the word to signify more than the anzmia and emaciation due to advanced cancer in any form, though many causes combined. I merely suggested that older authors might have been induced to lay more stress on (‘ cachexia ” than they otherwise would, by the marked physical weakness and sallowness which occurs in some of these marrow cases, without palpable cancer-deposit to account for them.

I n Villy’s first case (( there was no mediastinal tumour such as he (Snow) describes as the origin of the sternal infection.” I have never seen such a tumour, much less ventured to describe it. The residual thymus appears as a mass of loose fatty tissue. At the Nottingham meeting I exhibited a specimen showing the (( sternal prominence ” developed therefrom.

I am not by any means certain whether the thymus always co-operates in the formation of the prominence between the second costo-sternal articulations. There is no reason otherwise why that part should most commonly bulge and not the remainder. But some- times the entire sternum shows the condition; and then there is probably direct transference per the lymphatics to the cancellous tissue.

All Villy’s cases were of “infiltration by contiguity.” I t is useless to examine the sternum under this condition. The adjacent humerus, also, is often liable to the same suspicion, by the time death ensues. Hence I suggested a lumbar zertebra as a test bone for the general condition. I have examined five, always with a positive result. At the same time, the test must not be regarded as absolute. When, as here, there is a blood dissemination, it does not follow that every bone simultaneously receives carcinoma-deposit, and in equal quan tities.2

Again, any one must perceive that the normal direction of the lymph-currents will be materially changed by an operation. See the remarkable instance recorded by C. H. Mo01-e.~ Hence the theory that in this way the adjoining humerus becomes infected by a cancerous breast necessarily implies exceptions.

Brit. Med. Jotkrn., London, Sept. 24, 1892. See No. 11 of the Bour~emot~th Cuses. St. Barth. Hosp. Eep., London, vol. iii. art. 5.

356 WERBERT SNO fit?

The broad general fact i s the distal infection of the marrow, i n one way or another, as a rozitilae eceizt. In his case (S), Villy found a tumour in the femur, and speaks of it as ‘I thus making this bone lesion not comparable with the ‘ insidious ’ infection described by Snow.” Comment is superfluous.

With this issue only the first five of Villy’s cases can of course be considered. The negation he has, a t I fear considerable waste of strength, laboured to prove for cancer in other organs than the niamma was already established and formulated. I n these five breast cases distal depoeits in various widely sundered bones are noted in 3 ; whether with or without a (( tuinour” makes no matter. In Case 4 no bones appear to have been examined at all, with the exception of the directly invaded sternum. I n Case 5 the sternum and ribs were directly invaded by the carcinoma ; but Villy could not detect cancer deposit under the microscope.

These scirrhous deposits in soft cancellous tissue require very careful handling, even when there are no degenerative changes ; as was doubtless the case here. I possess slides from the same specimen, prepared for me by an experienced pathological manipulator, Mr. Fearnley. One shows excellently scirrhous acini throughout ; the other displays the stroma only, almost all the cells having been washed out in the process of hardening and staining. Seeing that in Case 5 direct cancer infiltration of bone was seemingly (though the account is rather vague and meagre) not recog- nised under the microscope, where unmistakably present, it is permissible to doubt whether any satisfactory examination of the more distant bones took place. Thus in the only three cases, more fully detailed and investigated with any pretence of completeness, Villy finds the exact condition described by me.

He disputes, however, the mechanism of its production, chiefly on the ground that the marrow deposits were (( recent.” He thinks the abundant visceral metastases, which I regard as a sequence of the former, were coeval, both being but ‘( a late general metastasis from remnants of tumour left behind in the chest wall a t the time of operation.”

I n the typical examples published I have done my beet to exclude the possibility of such a. hypothesis. They were watched for years in the out-patient room, or otherwise. The gradual development of the “ insidious ” symptoms was carefully noted, and it was found that these long preceded any “ recurrence,” thoracic or visceral. The cicatrix and axilla remained in some perfectly free till the last. Fair health was long retained, with no possible doubt of marrow-infection ; a point incompatible with visceral metastasis, except as a sequel in point of time to the latter.

To assume that a marrow deposit lying concealed for years, yet throughout that period giving reliable indication t o the trained

This was the head of a humerus.

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observation of its presence, is “ recent,” because it so seems when exposed, is hardly a scientific position. I must protest most em- phatically against all such dognintising on pathological phenomena, uncontrolled by clinical observation. If Dr. Villy will study the clinical course of these chronic cases, from beginning to end, he will hardly fail to note the following sequence of events.

1. An escient operation during the first year of an average mammary carcinoma. I must lay stress on the “ efficient ” ; because a bungling one of necessity involves local recurrence within two years, often less, with direct infiltration of the parietes, and visceral deposits in abundance, No time is left for the slowly evolved development of this remarkable condition, free from perplexing complications. I n the second year both the sternal bulging and the less salient humerus condition will commonly be recognised, if looked for. Sometimes earlier, but often not for another two years, does the patient complain of gnawing lumbar and of shooting scapular pains. Yet another year elapses, and now for the first time we notice nodules in the chest wall, induration of the opposite breast, visceral phenomena. Previously there had been no such sign. After this the descent is often remark- ably rapid ; the metastases become very numerous, strength fails, and the scene closes.

I respectfully submit to any scientific judgment the question whether such a train of events is compatible with any other explana- tion than that of a consequence-not a mere sequence ?

Passing now from mammary carcinoma, the sole source of the peculiar consecntive phenomena above detailed, Dr. Villy doubts my reference of osteomalacia and osteitis deformans to a malignant tumour somewhere ia the bones. He has probably overlooked the examples cited fiom the Transactions of the Pathological Society, a t p. 303 of iny “ Cancers and the Cancer Process.” There are numerous others on record. I hope that Dr. Villy will persevere in his most useful researches, but with clinical observation, and with a fuller perception of the real points a t issue. Though based on erroneous appreciation of what is already established, the support of his three cases is valuable because so obviously involuntary and undesigned.

CHRONOLOGICAL REFERENCES.--‘~ A Neglected Symptom of Breast Cancer ” (the humerus condition, which in itself inconspicuous and unreliable, yet afforded the first clue to discovery of Inarrow infection as a routine event), Lancet, London, 1880, vol. i.; see also ibid., London, March 7 and 14, 1891, July 11, 1891, July 6, 1892, January 9, 1897 ; Brit. Ned. Journ., London, March 12 and Sept. 24, 1892, March 10, 1894, Oct. 17, 1896; Practitioner, London, August 1894.