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IMMUNOSUPPRESSION AND CANCER
672
Letters
to
the Editor
IMMUNOSUPPRESSION AND CANCER SIR,-Recent communications revealing the rare but significant occurrence of malignant tumours in patients receiving organ transplants have raised points of great interest. The theory put forward is that immune suppression designed to hold the graft also suppresses a cellular mechanism which normally clears the body of spontaneously arising defective cells and so allows them to remain and to proceed to tumour formation. This suggests that our liability to develop cancer is a measure of the inefficiency of a mechanism for abnormalcell elimination and that interference with this process further increases the risk. The evidence for this theory is insecure. The increased tumour risk in transplant patients does not seem to be the general one which depression of such a normal defence mechanism
be expected to produce. On the contrary, the which have developed in man following kidney transplants have either themselves been transplanted from donors known to be carrying these tumours at the time of death, or have been lymphomas.1-4 Since the tumours which arise in patients following foreign normal-tissue transplants and immune suppression are lymphomas, other instances of lymphoma development associated with immune disorder may be relevant. An association between homologous disease in laboratory animals and lymphoma induction has been noted in a number of different circumstances which have recently been reviewed.56 For instance, lymphomas may arise in animals which survive the injection of immunologically competent foreign cells.’-10 This work suggests that immunocytes which are foreign, or which have been altered by viruses or other means so that they react against the host, are themselves reacted against, resulting either in immune disorder or in malignant lymphoma or in both. Associations between immune disorder and lymphoma development in man were suggested some years ago.n-13 In our work on the aetiology and natural history of Hodgkin’s disease we are examining the theory that abnormal lymphoid cells in man, however produced, may also lead to a conflict between them and the normal host immunocytes, whence arise a particular multifocal tumour pattern, a mixed, remittent, tumour and reaction process, and lymphoid-cell proliferation proceeding to lymphoid-cell depletion. Death in Hodgkin’s disease may occur either as the result of tumour spread or from immunological failure, occasionally without any detectable tumour remaining. The possibility bears consideration that in normal tissue transplants the chief tumour risk is one of lymphoma development following the transfer of donor lymphoid cells aided by suppression of the host immune reaction which allows them to become established, a conflict to occur, and tumours to arise which may be either of host or of donor origin. Chromosome studies on lymphomas in patients developing such tumours after organ transplants from the opposite sex would be of great interest. Radiotherapy Department, D. W. SMITHERS Royal Marsden Hospital, E. O. FIELD. Sutton, Surrey.
might
tumours
1. 2. 3. 4. 5. 6. 7. 8. 9.
Doak, P. B., Montgomerie, J. Z., North, J. D. K., Smith, F. Br. med. J., 1968, iv, 746. Rentchnick, P. Bull. int. Un. Cancer, 1968, 6, 4. Lancet, 1968, i, 1298. Woodruff, M. F. A. Cited by Doak et al. (footnote 1). Smithers, D. W. Br. med. J. 1967, ii, 263, 337. Lancet, Jan. 25, 1969, p. 194. Bensted, J. P. M. Personal communication. Schwartz, R. S., Beldotti, L. Science, N.Y., 1965, 149, 1511. Field, E. O. Read at the Lymphoma Symposium, London, September, 1968.
10. 11. 12. 13.
Walford, R. L. Science, N.Y., 1966, 152, 78. Dameshek, W., Schwartz, R. S. Blood, 1959, 14, 1151. Kaplan, H. S., Smithers, D. W. Lancet, 1959 ,ii, 1. Smithers, D. W. J. Fac. Radiol. 1959, 10, 3.
SIR,-In your interesting leader (March 8, p. 505) you question whether organ transplantation combined with immunosuppression has any place in the treatment of cancer patients, including, in particular, patients with renal tumours. It is certainly true, as you point out, that the incidence of some tumours is increased, and even greatly increased, in immunosuppressed patients and animals, but you may perhaps have pushed the principle of logical induction too far in assuming that this will hold good for all tumours, or for that matter for renal
tumours.
Some four years ago, when faced with
a
patient whose left kidney had been removed three years previously for a hypernephroma, and who presented with a huge tumour in his right kidney, the kind of doubts you have expressed made us feel unjustified in giving him a transplant from a living donor; the patient was, however, given a cadaverkidney transplant and a few days later his own right kidney was removed. Although a recent chest X-ray had appeared clear we feared that metastases might soon develop in the lungs and elsewhere but, as my colleagues and I (Jan. 4, p. 6) have reported, the patient, to whom Professor Calne referred last week (p. 625), is still very fit and active, and shows no evidence of tumour deposits. We have another patient in whom, after renal transplantation, bilateral nephrectomy was performed on account of persisting hypertension, and who was found to have a hypernephroma in one of his own kidneys. Time will show whether or not this patient is going to develop metastases; meanwhile, however, if the occasion again presented itself, I would certainly offer a cadaver transplant to a patient with a carcinoma of a sole remaining kidney who showed no evidence of metastases. If I were the patient I would accept such an offer with alacrity. University Department of Surgical Science, Edinburgh 8.
MICHAEL WOODRUFF.
CLINICAL HÆMATOLOGY SiR,—Your leading article (March 8, p. 506) and the personal point of view contributed by Professor Prankerd (ibid. p. 519) must have come as a surprise to many who appreciate the recent developments in this specialty in this country. Professor Prankerd writes as though haematologists were responsible only for patients with disorders of the blood: yet this represents only a part of their hospital commitment. Much of the practice of modern hsematology stems from doctors whose interests, by the nature of their subject, are closely concerned with the clinical conditions of patients, but it is their laboratory training which equips them to advise their colleagues over a wider field than This is not can be covered by a training in general medicine. to deny the real interest and deep understanding of haematological disorders possessed by a cadre of physicians who have made great contributions to the subject. The members of the College of Pathologists who studied the initial draft prepared for the Royal College of Physicians by its committee on hsmatology subscribe to the view that it would be most undesirable for the laboratory haematologist and his clinical colleague to consider themselves as rivals or in competition for the bedside care of patients with blood-diseases. A department of haematology in a large general hospital should include both laboratory and clinical hxmatologists. Experience has already shown that cooperation can be richly productive and rewarding. There is room here for consultation between the Royal College and the College of Pathologists. In the report to Comitia, however, the final recommendation has been phrased differently and seems to imply that the Royal College of Physicians is now suggesting the establishment of separate departments of clinical hxmatology, apart from the central laboratories of the hospital. This is a disappointing and retrograde suggestion which in practice would be attractive only to a minority: the welfare of patients is best served by close liaison between laboratory and ward staffs and efficiency would not be enhanced by any such divisions-indeed
Letters
to
the Editor
IMMUNOSUPPRESSION AND CANCER SIR,-Recent communications revealing the rare but significant occurrence of malignant tumours in patients receiving organ transplants have raised points of great interest. The theory put forward is that immune suppression designed to hold the graft also suppresses a cellular mechanism which normally clears the body of spontaneously arising defective cells and so allows them to remain and to proceed to tumour formation. This suggests that our liability to develop cancer is a measure of the inefficiency of a mechanism for abnormalcell elimination and that interference with this process further increases the risk. The evidence for this theory is insecure. The increased tumour risk in transplant patients does not seem to be the general one which depression of such a normal defence mechanism
be expected to produce. On the contrary, the which have developed in man following kidney transplants have either themselves been transplanted from donors known to be carrying these tumours at the time of death, or have been lymphomas.1-4 Since the tumours which arise in patients following foreign normal-tissue transplants and immune suppression are lymphomas, other instances of lymphoma development associated with immune disorder may be relevant. An association between homologous disease in laboratory animals and lymphoma induction has been noted in a number of different circumstances which have recently been reviewed.56 For instance, lymphomas may arise in animals which survive the injection of immunologically competent foreign cells.’-10 This work suggests that immunocytes which are foreign, or which have been altered by viruses or other means so that they react against the host, are themselves reacted against, resulting either in immune disorder or in malignant lymphoma or in both. Associations between immune disorder and lymphoma development in man were suggested some years ago.n-13 In our work on the aetiology and natural history of Hodgkin’s disease we are examining the theory that abnormal lymphoid cells in man, however produced, may also lead to a conflict between them and the normal host immunocytes, whence arise a particular multifocal tumour pattern, a mixed, remittent, tumour and reaction process, and lymphoid-cell proliferation proceeding to lymphoid-cell depletion. Death in Hodgkin’s disease may occur either as the result of tumour spread or from immunological failure, occasionally without any detectable tumour remaining. The possibility bears consideration that in normal tissue transplants the chief tumour risk is one of lymphoma development following the transfer of donor lymphoid cells aided by suppression of the host immune reaction which allows them to become established, a conflict to occur, and tumours to arise which may be either of host or of donor origin. Chromosome studies on lymphomas in patients developing such tumours after organ transplants from the opposite sex would be of great interest. Radiotherapy Department, D. W. SMITHERS Royal Marsden Hospital, E. O. FIELD. Sutton, Surrey.
might
tumours
1. 2. 3. 4. 5. 6. 7. 8. 9.
Doak, P. B., Montgomerie, J. Z., North, J. D. K., Smith, F. Br. med. J., 1968, iv, 746. Rentchnick, P. Bull. int. Un. Cancer, 1968, 6, 4. Lancet, 1968, i, 1298. Woodruff, M. F. A. Cited by Doak et al. (footnote 1). Smithers, D. W. Br. med. J. 1967, ii, 263, 337. Lancet, Jan. 25, 1969, p. 194. Bensted, J. P. M. Personal communication. Schwartz, R. S., Beldotti, L. Science, N.Y., 1965, 149, 1511. Field, E. O. Read at the Lymphoma Symposium, London, September, 1968.
10. 11. 12. 13.
Walford, R. L. Science, N.Y., 1966, 152, 78. Dameshek, W., Schwartz, R. S. Blood, 1959, 14, 1151. Kaplan, H. S., Smithers, D. W. Lancet, 1959 ,ii, 1. Smithers, D. W. J. Fac. Radiol. 1959, 10, 3.
SIR,-In your interesting leader (March 8, p. 505) you question whether organ transplantation combined with immunosuppression has any place in the treatment of cancer patients, including, in particular, patients with renal tumours. It is certainly true, as you point out, that the incidence of some tumours is increased, and even greatly increased, in immunosuppressed patients and animals, but you may perhaps have pushed the principle of logical induction too far in assuming that this will hold good for all tumours, or for that matter for renal
tumours.
Some four years ago, when faced with
a
patient whose left kidney had been removed three years previously for a hypernephroma, and who presented with a huge tumour in his right kidney, the kind of doubts you have expressed made us feel unjustified in giving him a transplant from a living donor; the patient was, however, given a cadaverkidney transplant and a few days later his own right kidney was removed. Although a recent chest X-ray had appeared clear we feared that metastases might soon develop in the lungs and elsewhere but, as my colleagues and I (Jan. 4, p. 6) have reported, the patient, to whom Professor Calne referred last week (p. 625), is still very fit and active, and shows no evidence of tumour deposits. We have another patient in whom, after renal transplantation, bilateral nephrectomy was performed on account of persisting hypertension, and who was found to have a hypernephroma in one of his own kidneys. Time will show whether or not this patient is going to develop metastases; meanwhile, however, if the occasion again presented itself, I would certainly offer a cadaver transplant to a patient with a carcinoma of a sole remaining kidney who showed no evidence of metastases. If I were the patient I would accept such an offer with alacrity. University Department of Surgical Science, Edinburgh 8.
MICHAEL WOODRUFF.
CLINICAL HÆMATOLOGY SiR,—Your leading article (March 8, p. 506) and the personal point of view contributed by Professor Prankerd (ibid. p. 519) must have come as a surprise to many who appreciate the recent developments in this specialty in this country. Professor Prankerd writes as though haematologists were responsible only for patients with disorders of the blood: yet this represents only a part of their hospital commitment. Much of the practice of modern hsematology stems from doctors whose interests, by the nature of their subject, are closely concerned with the clinical conditions of patients, but it is their laboratory training which equips them to advise their colleagues over a wider field than This is not can be covered by a training in general medicine. to deny the real interest and deep understanding of haematological disorders possessed by a cadre of physicians who have made great contributions to the subject. The members of the College of Pathologists who studied the initial draft prepared for the Royal College of Physicians by its committee on hsmatology subscribe to the view that it would be most undesirable for the laboratory haematologist and his clinical colleague to consider themselves as rivals or in competition for the bedside care of patients with blood-diseases. A department of haematology in a large general hospital should include both laboratory and clinical hxmatologists. Experience has already shown that cooperation can be richly productive and rewarding. There is room here for consultation between the Royal College and the College of Pathologists. In the report to Comitia, however, the final recommendation has been phrased differently and seems to imply that the Royal College of Physicians is now suggesting the establishment of separate departments of clinical hxmatology, apart from the central laboratories of the hospital. This is a disappointing and retrograde suggestion which in practice would be attractive only to a minority: the welfare of patients is best served by close liaison between laboratory and ward staffs and efficiency would not be enhanced by any such divisions-indeed