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Immunosuppression and Cancer
505
LEADING ARTICLES
its blood-supply is apparently favour its survival, a tumour the advantages of self-enhancing may also have mechanisms." Many experimental tumours can grow after transplantation despite wide histocompatibility barriers. It is likely, therefore, that some human tumours may grow in secondary hosts when (as between donor and recipient) only minor histocompatibility differences exist, even though such differences might not permit survival of a graft of normal tissue. Such phenomena could explain the rapid growth and fatal outcome of transplanting without immunosuppression a malignant melanoma from daughter to mother,I2 in an attempt to produce an anti-tumour serum. Thouglr conceivably many organs may have been transplanted from donors with unsuspected cancer without inducing a tumour in the recipient, most clinicians agree that, with the exception of those with localised primary cerebral tumours, cancer patients are entirely unsuitable as organ donors. To exclude the possibility of a cerebral
proliferate when inadequate); and, to can
THE LANCET LONDON
8
MARCH
Immunosuppression and
1969
Cancer
have now been the world 1 and various immunoperformed throughout suppressive regimens have been adopted. If human immunological responses are important in controlling cancer,23 long-continued and efficient immunosuppression might be expected to increase the risk of cancer. The homograft recipient whose immune responses have been suppressed is more vulnerable to bacterial and viral infection, and, according to present ideas at least, to neoplasia either in the transplanted organ or at some other unrelated site. Tumour cells transplanted from a donor with unsuspected malignant disease may flourish in the recipient. In 6 recipients of renal homografts donor-type neoplasia has developed in or around the graft. The sites of the tumours in the donors were breast,4 bronchus,5 lung,6 kidney,7 thyroid,8 and larynx.9Seven days8 to eighteen months6 elapsed before the tumour was detected in the recipient. With the exception of thyroid and renal tumours, secondary spread of these cancers to the kidney is usually a late feature of the disease. The tumour-cell emboli which produced cancer in the secondary host may have been restrained in the donor by immunological mechanisms
OVER 2000 organ
transplantations
which prevented growth into overt tumour. Human tumour cells transplanted into normal volunteers grow and spread to regional lymph-nodes before finally regressing.10 Experimental evidence suggests that tumour grafts are more readily accepted than normal tissue grafts and, once established, they are much less affected by rejection episodes. Tumour tissue has a less vital metabolic link with the host than does normal tissue (for one thing, a tumour Report of Human Kidney Transplant Registry: 2nd International Meeting of the Transplantation Society, New York, 1968. 2. See Lancet, 1966, i, 802. 3. ibid. 1968, i, 1298. 4. MacLean, L. D., Dossetor, J. B., Gault, M. H., Oliver, J. A., Inglis, F. G., Mackinnon, K. J. Archs Surg., Chicago, 1965, 91, 288. 5. Martin, D. C., Rubini, M., Rosen, V. J. J. Am. med. Ass. 1965, 192, 1. 6th
752. 6.
Wilson, R. E. Hager, E. B., Hampers, C. L., Corson, J. M., Merrill, J. P., Murray, J. E. New Engl. J. Med. 1968, 278, 479. 7. Hume, D. M. Adv. Surg. 1966, 2, 419. 8. Muiznieks, H. W., Berg, J. W., Lawrence, W., Randall, H. T. Surgery, St. Louis, 1968, 64, 871. 9. McPhaul, J. J., McIntosh, D. A. New Engl. J. Med. 1965, 272, 105. 10. Southam, C. M., Moore, A. E., Rhoads, C. P. Science, N.Y. 1957, 125, 158.
secondary deposit from a primary lesion elsewhere, biopsy is desirable. Hydrodynamic factors 13 may explain the common failure of primary cerebral tumours to metastasise, though secondary deposits in lung,14 liver,15 and bone 16 have occasionally tumour
being
a
been demonstrated. Whether immunosuppression encourages the growth of cancer arising from the recipient’s own cells is more debatable. Tumours may certainly arise from neoplastic cells present in the recipient before the homograft operation, and non-specific immunosuppression would, on present evidence, be expected to encourage their growth. It is questionable, therefore, whether immunosuppression combined with transplantation has any place in the treatment of cancer patients. Renal tumours metastasise early and are rare in solitary kidneys ’17 so that renal homotransplantation need not be considered. Primary hepatic tumours have, however, been treated by total hepatectomy and hepatic homografting.’8 The patient who survived the longest died at
twelve months from
If
a
widespread secondary tumour. has spread extensively primary hepatic throughout the liver so that total hepatectomy is necessary, it is probable that secondary foci of tumour exist outside the liver. With the present non-specific methods of immunosuppression, it seems unjustifiable to replace a cancerous organ by a homograft unless the clinician is confident the tumour has been entirely tumour
removed.
Immunosuppressive agents might facilitate infection by and proliferation of oncogenic virus. One or more immunosuppressive agents may even be carcinogenic. But is there in fact
an
increased incidence of
cancer
in
Snell, G. D. Cancer Res. 1957, 13, 2. Scanlon, E. F., Hawkins, R. A., Fox, W. W., Smith, W. S. ibid. 1965, 18, 782. 13. Shivas, A. A. J. Path. Bact. 1959, 78, 81. 14. Sherbanuik, R. W., Shoutha, T. K. Am. J. Path. 1956, 32, 53. 15. Perry, R. E. Archs Path. 1957, 64, 337. 16. Rubinstein, L. J. J. Path. Bact. 1959, 78, 187. 17. Grabstald, H., Aviero, A. Cancer, N. Y. 1968, 22, 973. 18. Starzl, T. E., Groth, C. G., Brettschneider, L., Moon, J. B., Fulginiti, V. A., Cotton, E. K., Parker, K. A. Surgery, St. Louis, 1968, 63, 549. 11. 12.
506
recipients given immunosuppressive drugs ? A simple percentage expressing the cancer-rate in homograft recipients does not mean very much. The age of the patient and the duration of immunotherapy must be taken into account. Lymphomas have developed in recipients of renal homografts on immunosuppressive regimens.3 19 20 They all received azathioprine and steroids, and 3 were also given anti(’ Imuran’) serum. Their mean age was 26 years; and lymphocytic in 6 of the 7 patients tumours developed within one year of transplantation. Usually, lymphoma, though not rare in youth or infancy, is a disease of later life.21 22 Though these data are scanty, the outstanding point is that all the reported tumours were of lymphoid origin. Moreover, they apparently appeared quite soon after the transplantation: as yet, no indication has emerged of increasing frequency in long-surviving patients. It is tempting to speculate on the link between lymphomas and virus infection and on the effect that the host’s impaired immunological state could therefore have on the progress of the tumour. Many experimental virus tumours develop only if the virus is introduced into the host during the neonatal period, before immunological competence has been achieved. In this situation a state of specific immunological tolerance to the antigens of the virus and to the virustransformed host cells may be expected. Virus infection of the adult animal may lead to multiplication within the host tissues without the induction of tumours,23 but if the immunological reactivity of the adult be depressed before injection of virus by wholebody irradiation, alone 24 or combined with thymectomy,25 or if large doses of virus are injected,26 tumours do develop. Epstein-Barr virus may be concerned in the induction of Burkitt’s lymphoma, which apparently develops only in European or African children who have been exposed to infection in early life-a situation comparable to the virus-induced tumours in mice. Burkitt’s lymphoma is thought to be particularly susceptible to the host’s control mechanisms, since spontaneous regression is not uncommon; and these tumours have been known to undergo remission after specific and non-specific immunotherapeutic measures, such as passive immunisation with sera from patients whose tumours have regressed, or smallpox vaccination.27 Tumours induced by the same virus often share common tumourspecific antigens,3 so it would be of great interest to know whether sera of convalescent Burkitt’s lymphoma patients cross-react with cells from lymphomas arising in homograft recipients. No primary tumours of other tissues have been reported in association with immunoWoodruff, M. F. A. Antibiot. Chemother. (in the press). Doak, P. B., North, J. D. K., Montgomerie, J. Z., Smith, F. Br. med. J. 1968, iv, 746. 21. Willis, R. A. Pathology of Tumours. London, 1967. 22. Gall, E. A., Mallary, T. B. Am. J. Path. 1942, 18, 381. 23. Stewart, S. E., Eddy, B. E., Stanton, M. F. in Proceedings of 3rd Canadian Cancer Conference; p. 287. New York, 1959. 24. Law, L. W., Dawe, C. J. Proc. Soc. exp. Biol. Med. 1960, 105, 414. 25. Koldovsky, P., Svoboda, J. Folia Biol. 1965, 11, 203. 26. Dmochowski, L. Br. J. exp. Path. 1945, 26, 192. 27. Br. med. J. 1966, i, 1043. 19.
20.
and the lymphomas in recipients may be virus-induced and perhaps to have immunological properties which make them more likely to arise in patients treated by immunosuppression.
suppression,
turn out to
Clinical
Hæmatology
"
HAEMATOLOGY: Time for Reappraisal?" asks Professor PRANKERD on p. 519. Is haematology to remain the preserve of the expert in laboratory medicine (old style: clinical pathologist) or is the physician once more to take the major part in the investigation and management of patients with blood diseases ? The reiteration of these questions is timely, because the Royal College of Physicians has just made known1 its proposals for a training scheme for clinical hxmatologists. The College of Pathologists approved the plan before it was published. The aim is to produce more physicians trained in the care of patients with blood diseases, so that clinical hxmatologists would have the same standing as cardiologists and neurologists now have among the clinical staff of the larger hospitals. The College’s proposed schedule of postregistration training has two parts and follows the lines agreed for other subjects. During the first three years, a minimum of one year should be spent in a routine haematological laboratory and one year in general medicine or paediatrics at registrar or equivalent level. A variety of options is proposed for the third year. A useful type of post would be a rotating appointment providing one year in the wards and one year in the laboratory; such a post " would enable the individual to decide whether he wished to devote himself to clinical or laboratory work before any irrevocable step is taken ". The second period of three or four years includes further specialist experience in general medicine and clinical and laboratory haematology. All appointments should be in hospitals recommended by the College as suitable for training; and time spent in research, general practice, a Service medical branch, or overseas may be recognised as part of the training. Diseases of the blood used to be treated by general physicians, who carried out the examination of the blood themselves; and in Scotland this arrangement persisted until recent times. The custom was for the junior staff on a medical unit to carry out blood-counts and even In marrow examinations in the ward side-rooms. England, however, clinical pathologists soon took over the laboratory side of the investigation of blood diseases; and, as the subject developed, some clinical pathologists, though receiving a general training which included morbid anatomy and bacteriology, specialised in haematology. The logical development of this specialisation was the appointment of named haematologists as members of the clinical-pathology staff, especially in teaching hospitals, and the provision of appropriate technical staff under their control. Prof. J. V. DACIE’S chair at the Royal Postgraduate Medical School and other chairs reflect the same development on the academic side. The latest College of Physicians: Committee Report, January, 1969.
1. Royal
on
Clinical Hæmatology.
LEADING ARTICLES
its blood-supply is apparently favour its survival, a tumour the advantages of self-enhancing may also have mechanisms." Many experimental tumours can grow after transplantation despite wide histocompatibility barriers. It is likely, therefore, that some human tumours may grow in secondary hosts when (as between donor and recipient) only minor histocompatibility differences exist, even though such differences might not permit survival of a graft of normal tissue. Such phenomena could explain the rapid growth and fatal outcome of transplanting without immunosuppression a malignant melanoma from daughter to mother,I2 in an attempt to produce an anti-tumour serum. Thouglr conceivably many organs may have been transplanted from donors with unsuspected cancer without inducing a tumour in the recipient, most clinicians agree that, with the exception of those with localised primary cerebral tumours, cancer patients are entirely unsuitable as organ donors. To exclude the possibility of a cerebral
proliferate when inadequate); and, to can
THE LANCET LONDON
8
MARCH
Immunosuppression and
1969
Cancer
have now been the world 1 and various immunoperformed throughout suppressive regimens have been adopted. If human immunological responses are important in controlling cancer,23 long-continued and efficient immunosuppression might be expected to increase the risk of cancer. The homograft recipient whose immune responses have been suppressed is more vulnerable to bacterial and viral infection, and, according to present ideas at least, to neoplasia either in the transplanted organ or at some other unrelated site. Tumour cells transplanted from a donor with unsuspected malignant disease may flourish in the recipient. In 6 recipients of renal homografts donor-type neoplasia has developed in or around the graft. The sites of the tumours in the donors were breast,4 bronchus,5 lung,6 kidney,7 thyroid,8 and larynx.9Seven days8 to eighteen months6 elapsed before the tumour was detected in the recipient. With the exception of thyroid and renal tumours, secondary spread of these cancers to the kidney is usually a late feature of the disease. The tumour-cell emboli which produced cancer in the secondary host may have been restrained in the donor by immunological mechanisms
OVER 2000 organ
transplantations
which prevented growth into overt tumour. Human tumour cells transplanted into normal volunteers grow and spread to regional lymph-nodes before finally regressing.10 Experimental evidence suggests that tumour grafts are more readily accepted than normal tissue grafts and, once established, they are much less affected by rejection episodes. Tumour tissue has a less vital metabolic link with the host than does normal tissue (for one thing, a tumour Report of Human Kidney Transplant Registry: 2nd International Meeting of the Transplantation Society, New York, 1968. 2. See Lancet, 1966, i, 802. 3. ibid. 1968, i, 1298. 4. MacLean, L. D., Dossetor, J. B., Gault, M. H., Oliver, J. A., Inglis, F. G., Mackinnon, K. J. Archs Surg., Chicago, 1965, 91, 288. 5. Martin, D. C., Rubini, M., Rosen, V. J. J. Am. med. Ass. 1965, 192, 1. 6th
752. 6.
Wilson, R. E. Hager, E. B., Hampers, C. L., Corson, J. M., Merrill, J. P., Murray, J. E. New Engl. J. Med. 1968, 278, 479. 7. Hume, D. M. Adv. Surg. 1966, 2, 419. 8. Muiznieks, H. W., Berg, J. W., Lawrence, W., Randall, H. T. Surgery, St. Louis, 1968, 64, 871. 9. McPhaul, J. J., McIntosh, D. A. New Engl. J. Med. 1965, 272, 105. 10. Southam, C. M., Moore, A. E., Rhoads, C. P. Science, N.Y. 1957, 125, 158.
secondary deposit from a primary lesion elsewhere, biopsy is desirable. Hydrodynamic factors 13 may explain the common failure of primary cerebral tumours to metastasise, though secondary deposits in lung,14 liver,15 and bone 16 have occasionally tumour
being
a
been demonstrated. Whether immunosuppression encourages the growth of cancer arising from the recipient’s own cells is more debatable. Tumours may certainly arise from neoplastic cells present in the recipient before the homograft operation, and non-specific immunosuppression would, on present evidence, be expected to encourage their growth. It is questionable, therefore, whether immunosuppression combined with transplantation has any place in the treatment of cancer patients. Renal tumours metastasise early and are rare in solitary kidneys ’17 so that renal homotransplantation need not be considered. Primary hepatic tumours have, however, been treated by total hepatectomy and hepatic homografting.’8 The patient who survived the longest died at
twelve months from
If
a
widespread secondary tumour. has spread extensively primary hepatic throughout the liver so that total hepatectomy is necessary, it is probable that secondary foci of tumour exist outside the liver. With the present non-specific methods of immunosuppression, it seems unjustifiable to replace a cancerous organ by a homograft unless the clinician is confident the tumour has been entirely tumour
removed.
Immunosuppressive agents might facilitate infection by and proliferation of oncogenic virus. One or more immunosuppressive agents may even be carcinogenic. But is there in fact
an
increased incidence of
cancer
in
Snell, G. D. Cancer Res. 1957, 13, 2. Scanlon, E. F., Hawkins, R. A., Fox, W. W., Smith, W. S. ibid. 1965, 18, 782. 13. Shivas, A. A. J. Path. Bact. 1959, 78, 81. 14. Sherbanuik, R. W., Shoutha, T. K. Am. J. Path. 1956, 32, 53. 15. Perry, R. E. Archs Path. 1957, 64, 337. 16. Rubinstein, L. J. J. Path. Bact. 1959, 78, 187. 17. Grabstald, H., Aviero, A. Cancer, N. Y. 1968, 22, 973. 18. Starzl, T. E., Groth, C. G., Brettschneider, L., Moon, J. B., Fulginiti, V. A., Cotton, E. K., Parker, K. A. Surgery, St. Louis, 1968, 63, 549. 11. 12.
506
recipients given immunosuppressive drugs ? A simple percentage expressing the cancer-rate in homograft recipients does not mean very much. The age of the patient and the duration of immunotherapy must be taken into account. Lymphomas have developed in recipients of renal homografts on immunosuppressive regimens.3 19 20 They all received azathioprine and steroids, and 3 were also given anti(’ Imuran’) serum. Their mean age was 26 years; and lymphocytic in 6 of the 7 patients tumours developed within one year of transplantation. Usually, lymphoma, though not rare in youth or infancy, is a disease of later life.21 22 Though these data are scanty, the outstanding point is that all the reported tumours were of lymphoid origin. Moreover, they apparently appeared quite soon after the transplantation: as yet, no indication has emerged of increasing frequency in long-surviving patients. It is tempting to speculate on the link between lymphomas and virus infection and on the effect that the host’s impaired immunological state could therefore have on the progress of the tumour. Many experimental virus tumours develop only if the virus is introduced into the host during the neonatal period, before immunological competence has been achieved. In this situation a state of specific immunological tolerance to the antigens of the virus and to the virustransformed host cells may be expected. Virus infection of the adult animal may lead to multiplication within the host tissues without the induction of tumours,23 but if the immunological reactivity of the adult be depressed before injection of virus by wholebody irradiation, alone 24 or combined with thymectomy,25 or if large doses of virus are injected,26 tumours do develop. Epstein-Barr virus may be concerned in the induction of Burkitt’s lymphoma, which apparently develops only in European or African children who have been exposed to infection in early life-a situation comparable to the virus-induced tumours in mice. Burkitt’s lymphoma is thought to be particularly susceptible to the host’s control mechanisms, since spontaneous regression is not uncommon; and these tumours have been known to undergo remission after specific and non-specific immunotherapeutic measures, such as passive immunisation with sera from patients whose tumours have regressed, or smallpox vaccination.27 Tumours induced by the same virus often share common tumourspecific antigens,3 so it would be of great interest to know whether sera of convalescent Burkitt’s lymphoma patients cross-react with cells from lymphomas arising in homograft recipients. No primary tumours of other tissues have been reported in association with immunoWoodruff, M. F. A. Antibiot. Chemother. (in the press). Doak, P. B., North, J. D. K., Montgomerie, J. Z., Smith, F. Br. med. J. 1968, iv, 746. 21. Willis, R. A. Pathology of Tumours. London, 1967. 22. Gall, E. A., Mallary, T. B. Am. J. Path. 1942, 18, 381. 23. Stewart, S. E., Eddy, B. E., Stanton, M. F. in Proceedings of 3rd Canadian Cancer Conference; p. 287. New York, 1959. 24. Law, L. W., Dawe, C. J. Proc. Soc. exp. Biol. Med. 1960, 105, 414. 25. Koldovsky, P., Svoboda, J. Folia Biol. 1965, 11, 203. 26. Dmochowski, L. Br. J. exp. Path. 1945, 26, 192. 27. Br. med. J. 1966, i, 1043. 19.
20.
and the lymphomas in recipients may be virus-induced and perhaps to have immunological properties which make them more likely to arise in patients treated by immunosuppression.
suppression,
turn out to
Clinical
Hæmatology
"
HAEMATOLOGY: Time for Reappraisal?" asks Professor PRANKERD on p. 519. Is haematology to remain the preserve of the expert in laboratory medicine (old style: clinical pathologist) or is the physician once more to take the major part in the investigation and management of patients with blood diseases ? The reiteration of these questions is timely, because the Royal College of Physicians has just made known1 its proposals for a training scheme for clinical hxmatologists. The College of Pathologists approved the plan before it was published. The aim is to produce more physicians trained in the care of patients with blood diseases, so that clinical hxmatologists would have the same standing as cardiologists and neurologists now have among the clinical staff of the larger hospitals. The College’s proposed schedule of postregistration training has two parts and follows the lines agreed for other subjects. During the first three years, a minimum of one year should be spent in a routine haematological laboratory and one year in general medicine or paediatrics at registrar or equivalent level. A variety of options is proposed for the third year. A useful type of post would be a rotating appointment providing one year in the wards and one year in the laboratory; such a post " would enable the individual to decide whether he wished to devote himself to clinical or laboratory work before any irrevocable step is taken ". The second period of three or four years includes further specialist experience in general medicine and clinical and laboratory haematology. All appointments should be in hospitals recommended by the College as suitable for training; and time spent in research, general practice, a Service medical branch, or overseas may be recognised as part of the training. Diseases of the blood used to be treated by general physicians, who carried out the examination of the blood themselves; and in Scotland this arrangement persisted until recent times. The custom was for the junior staff on a medical unit to carry out blood-counts and even In marrow examinations in the ward side-rooms. England, however, clinical pathologists soon took over the laboratory side of the investigation of blood diseases; and, as the subject developed, some clinical pathologists, though receiving a general training which included morbid anatomy and bacteriology, specialised in haematology. The logical development of this specialisation was the appointment of named haematologists as members of the clinical-pathology staff, especially in teaching hospitals, and the provision of appropriate technical staff under their control. Prof. J. V. DACIE’S chair at the Royal Postgraduate Medical School and other chairs reflect the same development on the academic side. The latest College of Physicians: Committee Report, January, 1969.
1. Royal
on
Clinical Hæmatology.