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SECONDARY neoplastic bone disease arises eitherby invasion from contiguous primary or secondarytumours, or as true metastatic deposits.’ Direct
spread is not common, the periosteum apparentlyforming an effective barrier. True bone metastasesare hxmatogenous in origin and develop almostexclusively from within the sinusoids of red bone-marrow. Once established, tumour cells spread intomarrow spaces and the canal system of compactbone, surrounding the trabeculæ and subsequentlyinvading the cortex. Direct extension into cartilageor periosteum is unusual. Discrete blood-bornemetastases in the periosteum, without underlyingcortical and medullary deposits, are rare. This
sequence of events is well established and is basi-
cally similar to that propounded by VorrRECKLINGHAUSEN in 1891. The main source of dis-
agreement now seems to centre on the importanceof the paravertebral venous plexuses in the initiallocalisation of spinal metastases. 1 2 Lymphaticpathways are not involved. I 3
Early morphological studies suggested thatmetastatic tumour cells acted directly on the bonematrix, independently of physiological mechanismsof bone resorption;4 5 contrary views have emergedfrom more recent investigations. Using the Brown-Pearce squamous-cell carcinoma, implanted intothe femora of rabbits, FACCINI6 observed osteoclas-tic resorption of bone near the developing tumourand at some distance from it. As resorption cavitiesdeveloped in the cortex, tumour extended intothem. Once tumour cells came to lie close to bone,osteoclasts were no longer seen; resorption, how-ever, continued. The implication is that bothtumour cells and osteoclasts resorb bone. This dualmechanism has now been clarified by GALASKO.7VX2 squamous-carcinoma cells, implanted into thetibia or ilium of rabbits, evoked an early and in-tense osteoclastic reaction and local bone destruc-tion in advance of the developing tumour. (Thereaction is likely to involve accumulation of osteo-clasts rather than the proliferation described byGALASKO ; whether osteoclasts have any capacity todivide is doubtful.8) The stimulus for osteoclasticaccumulation seems to emanate from the tumour.VX2 cells, implanted in a Millipore filter diffusion
1 Willis, R. A. The Spread of Tumours in the Human Body. London, 1973.2. Drury, R. A. B., Palmer, P. H., Highman, W. J. J. clin. Path. 1964, 17, 448.3. Yoffey, J. M., Courtice, F. C. Lymphatics, Lymph and the Lymphomyeloid
Complex. New York, 1970.4. Milch, R. A., Changus, G. W. Cancer, Philad. 1956, 9, 340.5. Shivas, A. A., Black, W. J., Finlayson, N. D. Br. J. Cancer, 1963, 17, 711.6. Faccini, J. Virchow’s Arch. path. Anat. Histol. 1974, 364, 249.7. Galasko, C. S. B. Nature, 1976, 263, 507.8. Owen, M. Int. Rev. Cytol. 1970, 28, 213.
chamber near the ilium, elicited a local osteoclasticresponse beneath the adjacent periosteum and
superficial cortex. Once, however, the intraosseoustumour implants were large enough to envelop re-sidual bone trabeculae, osteoclasts disappeared- even though resorption again continued. Giventhe earlier situation of tumour-induced activationof osteoclasts, this change is difficult to understand.Perhaps mechanical factors such as pressure atro-phy5 may be relevant at these late stages of growth.GALASKO’S investigations support a two-phase pro-cess of osteolysis-a conclusion which is strength-ened by his parallel review of histological mater-ial from the spines of 68 patients who died withbone metastases, most of them from carcinomas ofthe breast, prostate, and bronchus.The chemical and pharmacological aspects of
tumour-associated osteolysis have been extensivelystudied.9- 14 Certain transplantable tumours in themouse, 9 11 rat,1O and rabbit 12 14 induce bone
resorption in vitro, measured most commonly byrelease of 45Ca from isotopically labelled neonatal-mouse calvaria. The osteolysis-inducing agent hasbeen extracted from biologically active tumoursand shown by bioassay, paper chromatography,and radioimmunoassay to be prostaglandin (P.G.).By different extraction procedures it is possible toestimate baseline P.G. levels and also de-novoP.G.
biosynthesis. The notion that the tumour-asso-
ciated osteolytic factor is a prostaglandin gainsstrength from the blocking effects of compoundssuch as aspirin and indomethacin which inhibitP.G. synthetase.15 16 Most studies implicate p.G.E2,a known osteolytic agent," as the principal P.G. in-volved. P.G.F has also been detected in some of the
experimental systems, but the frequency of P.G.Fformation, the amount present, and its biologicalsignificance are disputed: some workers believe thatit has little or no osteolytic activity.9 11 17 p.G.-pro-ducing tumours in the intact animal are associatedwith hypercalcaemia and raised P.G.E2 levels in theserum; high levels of P.G.E2 have also been des-cribed in the venous effluent draining the tumourtransplants. The raised concentrations of calciumand p.G.E2 in the serum are reduced by inhibitorsof P.G. synthetase. The local effects on bone ofcharacterised tumour-associated osteolytic pro-ducts are difficult to assess in vivo since there areno experimental tumours that regularly metastasiseto the skeleton. PowLES et al.10 compromised by in-
9. Tashjian, A. H. Jr., Voelkel, E. F. Levine, L., Goldhaber, P. J. exp. Med.1972, 136, 1328.
10. Powles, T. J., Clark, S. A., Easty, D. M. Easty, G. C., Neville, A. M. Br.J. Cancer, 1973, 28, 316.
11. Tash)ian, A. H. Jr., Voelkel, E. F., Goldhaber, P., Levine, L. Fédn Proc.
1974, 33, 81.12. Voelkel, E. F., Tashjian, A. H. Jr., Franklin, R., Wasserman, E., Levine, L.
Metabolism, 1975, 24, 973.13. Tashjian, A. H. Jr. New Engl. J. Med. 1975, 293, 1317.14. Galasko, C. S. B., Bennett, A. Nature, 1976, 263, 510.15. Vane, J. R. Nature New Biol. 1971, 231, 232.16. Flower, R. J. Pharmac. Rev. 1974, 26, 33.17. Klein, D. C., Raisz, L. G. Endocrinology, 1970, 86, 1436.
jecting Walker carcinosarcoma cells into the ab-dominal aorta of rats and produced osteolytic de-posits and hypercalcsemia, together with soft-tissuetumours. Indomethacin and aspirin, given threedays before or seven days after the injection oftumour cells, prevented detectable bone depositsand hypercalcxmia. GALASKO and BENNETT,14 con-tinuing the previous work with bone implants ofthe VX2 tumour in rabbits, found that indometha-cin reduced (but did not prevent) osteolysis. In bothinvestigations the development of soft tissue de-
posits was not hampered by indomethacin.The potential clinical implications of this work
are considerable, especially for carcinomas of
breast, prostate, and bronchus. In parallel withtheir experimental studies, PowLES et al.10
reported that some, but not all, of an unstatednumber of human breast cancers showed in-vitro
osteolytic activity which could be suppressed byaspirin. More recently, breast cancers from 38
patients have been tested for in-vitro osteolysis. ISOf 15 patients whose tumours showed no osteolyticactivity, none had bone metastases when tested andnone was detected in the ensuing three years,though 2 patients developed soft-tissue deposits. Of23 patients whose tumours showed in-vitro osteo-lysis, 4 had bone metastases when first tested and3 more have since developed skeletal deposits; 2further patients have soft-tissue deposits. 8 of 9active tumours showed reduced in-vitro osteolysiswhen incubated with aspirin, suggesting that P.G.Swere implicated. The number of patients is smalland the three-year follow-up is short; but these in-terim results are of considerable interest. Morecases must, however, be studied because alreadythere are discrepant reports. Using a different
experimental system, some workers19 have found amuch lower incidence of in-vitro osteolysisby breast cancers. Others20 have shown thathuman breast cancers contain and synthesisep.G.-like material in larger amounts than does un-involved breast tissue from the same patient; butthe presence of bone metastases in a very small
group of patients seemed to correlate with p.G.F,the osteolytic capacity of which is disputed, ratherthan with p.G.E. Full characterisation of the P.G.Sinvolved, and close correlation between in-vitroand in-vivo osteolysis, is obviously essential infuture studies on breast-cancer patients. Estima-tions of P.G. metabolites in the urine may be a use-ful additional investigation. 21 Another disputecentres on whether benign breast lesions elaboratep.G.S.19 20 22 If they do, they presumably act locally,
18. Powles, T. J., Dowsett, M., Easty, D. M., Easty, G. C., Neville, A. M.Lancet, 1976, i, 608.
19. Jenkins, M. V., Polanska, N., Wills, M. R. ibid. p. 1186.20. Bennett, A., McDonald, A. M., Simpson, J. S., Stamford, I. F. ibid. 1975,
i, 1218.21. Seyberth, H. W., Segre, G. V., Morgan, J. L., Sweetman, N. J., Potts, J. T.
Jr., Oates, J. A. New Engl. J. Med. 1975, 293, 1278.22. Dowsett, M., Gazet, J.-C., Powles, T. J., Easty, G. C., Neville, A. M. Lancet,
1976, i, 970.
since no systemic manifestations of hypercalcæmlahave been described in such patients.The topic of non-neoplastic lesions raises the im-
portant question as to the source of P.G.s and thepossible contribution made by host cells. Tissuescultured from dental cysts, for example, resorbbone in vitro and release indomethacin-sensitiBe
P.G.E2 in much the same way as many tumoursdo.23 ’Inflamed dental cysts are a particularly activesource of P.G., and P.G.s are known to be present inacute and chronic inflammatory infiltrates wherethey mediate some aspects of the inflammatory res-ponseÚ24 25 There is, however, another element toconsider since cultured lymphocytes have beenshown to release an in vitro osteolysin which is
entirely separate from P.G.S.26 27 Positive resultshave been reported with normal unstimulated lym-phocytes and with lymphocytes exposed to pb-tohaemagglutinin or to antigenic material from den-tal-plaque deposits.To return finally to osteolysis and malignant
tumours: many tumours are infiltrated with var-ious leucocytes28 29 which may augment the localproduction of p.G.s and generate additional osteoly-tic factors. The tumour cells themselves may alsosynthesise osteolytic agents other than or in ad-dition to P.G.s, thus explaining some of the reporteddiscrepancies in P.G. production and the responseto P.G. inhibitors. Possible candidates include ec-
topic parathyroid hormone, osteolytic activatingfactor, and active vitamin-D metabolites or relatedsterols-.3O Both tumour cells and infiltrating host
leucocytes may release lysosomal hydrolases whichwill destroy bone matrix. Lastly, the role played byprostaglandins is becoming increasingly complex,with experimental evidence or interaction with
complement3l (particularly C6) and with colla-
Diagnosis of Brain DeathSOME patients who are rescued from impending
death after cardiorespiratory arrest are left with adead brain, artificial ventilation, and a beatingheart. Even when mechanical ventilation is main-
tained, progressive dissolution of the brain, andthen of other organs, continues; and the heart will
23. Harris, M., Jenkins, M. V., Bennett, A., Wills, M. R. Nature, 1973, 245,213.
24. Eakins, K. E., Whitelocke, R. A. F., Perkins, E. S., Bennett, A, Unger,W. G. Nature New Biol. 1972, 239, 248.
25. Robinson, D. R., Tashjian, A. H., Jr., Levine, L. J. clin. Invest. 1975, 56,1181.
26. Horton, J. E., Raisz, L. G., Simmons, H. A., Oppenheim, J. J., Mergen-hagen, S. E. Science, 1972, 177, 793.
27. Harris, M., Jenkins, M. V., Bennett, A., Hird, V. M., Wills, M, R Lancet,
1974, i, 265.28. Kerbel, R. S., Pross, H. F., Elliott, E. V. Int. J. Cancer, 1975, 15, 918.29. Wood, G W., Gillespie, G. Y. Int. J. Cancer, 1975, 16, 1022.30. Mundy, G. R., Luben, R. A., Raisz, L. G., Oppenheim, J. J., Buell, D. N.
New Engl. J. Med. 1974, 290, 867.31. Raisz, L. G., Sandberg, A. L., Goodson, J. M., Simmons, H. A. Mergen-
hagen, S. E. Science, 1974, 185, 789.32. Dowsett, M., Eastman, A. R., Easty, D. M., Easty, G. C., Powles, T. J.,
Neville, A. M. Nature, 1976, 263, 72.