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SKIN CANCER AND IMMUNOSUPPRESSION
1282
SKIN CANCER AND IMMUNOSUPPRESSION BRIEN K. WALDER MALCOLM R. ROBERTSON DAVID JEREMY
of squamous-cell carcinoma to forty-five months:
was
in the range of four
Divisions of Dermatology and Renal Diseases, Department of Medicine, Prince Henry Hospital, Little Bay, New South Wales, Australia
(14%) Summary 7recipients
of 51
kidney-allograft developed a total of 19 malignant skin tumours four to forty-five months after transplantation. Immunosuppressive treatment, out
be associated with an increased risk of development of tumours of lymphoreticular type, also enhances the occurrence of squamous-cell carcinoma. Under the influence of immunosuppression cutaneous hyperkeratoses more rapidly evolve into squamous-cell carcinoma, multiple skin cancers occur in some patients, and keratoacanthoma is not only more frequent but also prone to early recurrence. known
to
development of malignant neoplasms has been reported in patients undergoing treatment with immunosuppressant drugs,1-3 but only for neoplasms of lymphoreticular type has the association been common enough not to be due to chance alone.4 In our experience immunosuppression can also lead to an increased risk of development of epithelial THE
carcinoma of the skin. 51 patients under treatment with immunosuppressive drugs for up to six years after kidney transplantation were examined for skin lesions. 2 patients had been given a kidney from a related living donor, and the rest had had cadaver kidneys. All patients were being treated with prednisone and azathioprine, but antilymphocyte serum (or globulin) was not used. Prednisone was given initially in high dosage (approximately 3 mg. per kg. per day) and subsequently reduced to a maintenance dose of 10-20 mg. per day after six months. Azathioprine therapy was started at time of transplantation in a dose of 3 mg. per kg. per day and generally maintained at that level throughAcute rejection episodes were treated with out. increased doses of corticosteroids in all patients, and many received actinomycin C and graft irradiation in the early weeks after transplantation. Skin lesions regarded as suspect on clinical examination were biopsied and examined histologically. 7 patients (14%) had malignant skin cancers. All were recipients of cadaver kidney allografts. The lesions were often multiple, so that in the 7 patients there were 16 instances of squamous-cell carcinoma, 1 basal-cell carcinoma, and 3 keratoacanthomas. The lesions were mostly found on the exposed areas of the hands, arms, and neck. The age of the 51 patients examined was in the range nine to fifty-six years
(mean thirty-six)
at
the time of
In 2 patients numerous hyperkeratoses had been present, and in these patients multiple squamous-cell After the initial carcinomas developed (fig. 1). observation in patient 7 of a squamous-cell carcinoma of the ear which was resistant to local irradiation therapy all lesions were treated by excision. No metastatic tumour has developed in these patients. Keratoacanthoma developed in 3 patients (2 of whom also had one or more squamous-cell carcinomas excised) and tended to recur. In patient 1 a keratoacanthoma was treated by diathermy excision, but subsequently recurred twice and was finally treated
transplanta-
tion : the 7 patients with skin cancer were 3 females and 4 males aged thirty to fifty-six (mean forty-four) at the time of transplantation. None of these patients had previously been treated for skin cancer and the interval from the start of immunosuppressive treatment (time of transplantation) and initial diagnosis
Fig. 1-Patient 2: multiple hyperkeratoses and warts on dorsum of hand, and recurrent squamous-cell carcinoma on proximal middle finger.
1283
characteristic of this lesion depends upon immuno-. logical mechanisms; when these -are suppressed the lesion persists and recurs. In our skin clinics basal-cell carcinoma is diagnosed about eleven times more often than squamouscell carcinoma, but in this series of patients the ratio of basal-cell carcinoma to squamous-cell carcinoma was 1/16. It seems likely that this reflects the conmore siderably rapid development of squamous-cell carcinoma from hyperkeratoses in these patients under
Fig. 2-Patient 1: 1
cm.
diameter keratoacanthoma of neck
presenting with typical appearance on second recurrence site of original removal three months previously.
at
by wide surgical excision.
These lesions recurred within one or two months and the second recurrence was still a typical keratoacanthoma (fig. 2). The keratoacanthoma in patient 3 recurred two months after cautery excision. Patients 3 and 7 died twenty-two and twenty-three months after transplantation from systemic cryptococcosis. Patient 5 died eighteen months after transplantation from metastatic spread of an ureteric transitional-cell carcinoma that had been excised by nephroureterectomy two weeks before transplantation. The other four patients are alive and well with excellent function of the grafted kidney. Schneck and Penn2 reported 18 superficial epithelial tumours (including skin) in " some 5000 kidney and 170 heart recipients throughout the world " —a frequency of about 0-4%. In their own experience 11 patients had developed neoplasms of any type in a group of 184 renal homograft recipients, giving a frequency of 6% which Schneck and Penn thought unlikely to be due to chance. The development 01 19 skin cancers in 7 (14%) of our patients suggests that immunosuppressive therapy may facilitate the development of skin cancer as well as tumours of lymphoid tissue. It seems likely that the high level of solar exposure to which our patients are liable is an important initiating factor, and we have noted that hyperkeratoses are very prevalent on exposed areas in our patients. These premalignant skin lesions seem to undergo malignant transformation more readily in the patient under immunosuppressive treatment, and in some patients multiple squamous-cell carcinomas arise from pre-existing hyperkeratoses. Our experience with patient 7 suggests that squamous-cell carcinoma which develops in a patient on immunosuppression is especially resistant to radiotherapy. Keratoacanthoma may present the typical appearance (fig. 2) but behave in a most atypical manner in these patients. These lesions may persist much longer than usual and may recur after local excision. It seems likely, therefore, that the self-limiting course
immunosuppression. Proposed reasons for the increased incidence of malignant neoplasms in patients under immunosuppressive treatment include the facilitation of infection by oncogenic viruses, the direct effect of the immunosuppressive drug inducing neoplastic transformation, or the suppression of an immunosurveillance mechanism normally responsible for the destruction of mutant cells with malignant potential.’ Persistent antigenic stimulation (e.g., donor antigen of transplanted organ) may provide the basis for cell transformation in the development of lymphoid tumours under the influence of immunosuppressive drugs.5 The very high frequency of skin cancer in our patients supports the view that, under appropriate stimulation, malignant transformation of tissue occurs and that malignant cells have an increased chance of unhindered development due to suppression of an immunosurveillance mechanism. We thank Dr. A. Tait Smith and Dr. C. M. reviewed the histology of the skin tumours.
Atkins, who
Requests for reprints should be addressed to D. J., Departof Medicine, Prince Henry Hospital, Little Bay, New
ment
South Wales 2036, Australia. REFERENCES 1. 2. 3. 4. 5.
Schneck, S. A., Penn, I. Archs Neurol., Chicago, 1970, 22, 226. Schneck, S. A., Penn, I. Lancet, 1971, i, 983. Fahey, J. L. Ann. intern. Med. 1971, 75, 310. Doll, R., Kinlen, L. Br. med. J. 1970, iv, 420. Krueger, G. R. F., Malmgren, R. A., Berard, C. W. Transplantation, 1971, 11, 138.
EFFECTS OF SODIUM INTAKE ON INHERITED HYPERTENSION IN THE RAT WILLIAM J. LOUIS RYO TABEI
University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg 3084, Victoria, Australia SIDNEY SPECTOR Roche Institute of Molecular Biology, Nutley, New Jersey 07110, U.S.A. The effect of sodium chloride intake on systolic blood-pressure was studied in genetic hypertensive Wistar rats. In these animals hypertension can develop on a sodium-" free " diet, but the height to which the blood-pressure rises is related to the sodium intake; increasing the amount of potassium in the diet promotes sodium excretion and ameliorates the hypertension. It is suggested that this form of inherited hypertension may be determined by two different sets of autosomal alleles only one of which is sodium-dependent.
Summary
SKIN CANCER AND IMMUNOSUPPRESSION BRIEN K. WALDER MALCOLM R. ROBERTSON DAVID JEREMY
of squamous-cell carcinoma to forty-five months:
was
in the range of four
Divisions of Dermatology and Renal Diseases, Department of Medicine, Prince Henry Hospital, Little Bay, New South Wales, Australia
(14%) Summary 7recipients
of 51
kidney-allograft developed a total of 19 malignant skin tumours four to forty-five months after transplantation. Immunosuppressive treatment, out
be associated with an increased risk of development of tumours of lymphoreticular type, also enhances the occurrence of squamous-cell carcinoma. Under the influence of immunosuppression cutaneous hyperkeratoses more rapidly evolve into squamous-cell carcinoma, multiple skin cancers occur in some patients, and keratoacanthoma is not only more frequent but also prone to early recurrence. known
to
development of malignant neoplasms has been reported in patients undergoing treatment with immunosuppressant drugs,1-3 but only for neoplasms of lymphoreticular type has the association been common enough not to be due to chance alone.4 In our experience immunosuppression can also lead to an increased risk of development of epithelial THE
carcinoma of the skin. 51 patients under treatment with immunosuppressive drugs for up to six years after kidney transplantation were examined for skin lesions. 2 patients had been given a kidney from a related living donor, and the rest had had cadaver kidneys. All patients were being treated with prednisone and azathioprine, but antilymphocyte serum (or globulin) was not used. Prednisone was given initially in high dosage (approximately 3 mg. per kg. per day) and subsequently reduced to a maintenance dose of 10-20 mg. per day after six months. Azathioprine therapy was started at time of transplantation in a dose of 3 mg. per kg. per day and generally maintained at that level throughAcute rejection episodes were treated with out. increased doses of corticosteroids in all patients, and many received actinomycin C and graft irradiation in the early weeks after transplantation. Skin lesions regarded as suspect on clinical examination were biopsied and examined histologically. 7 patients (14%) had malignant skin cancers. All were recipients of cadaver kidney allografts. The lesions were often multiple, so that in the 7 patients there were 16 instances of squamous-cell carcinoma, 1 basal-cell carcinoma, and 3 keratoacanthomas. The lesions were mostly found on the exposed areas of the hands, arms, and neck. The age of the 51 patients examined was in the range nine to fifty-six years
(mean thirty-six)
at
the time of
In 2 patients numerous hyperkeratoses had been present, and in these patients multiple squamous-cell After the initial carcinomas developed (fig. 1). observation in patient 7 of a squamous-cell carcinoma of the ear which was resistant to local irradiation therapy all lesions were treated by excision. No metastatic tumour has developed in these patients. Keratoacanthoma developed in 3 patients (2 of whom also had one or more squamous-cell carcinomas excised) and tended to recur. In patient 1 a keratoacanthoma was treated by diathermy excision, but subsequently recurred twice and was finally treated
transplanta-
tion : the 7 patients with skin cancer were 3 females and 4 males aged thirty to fifty-six (mean forty-four) at the time of transplantation. None of these patients had previously been treated for skin cancer and the interval from the start of immunosuppressive treatment (time of transplantation) and initial diagnosis
Fig. 1-Patient 2: multiple hyperkeratoses and warts on dorsum of hand, and recurrent squamous-cell carcinoma on proximal middle finger.
1283
characteristic of this lesion depends upon immuno-. logical mechanisms; when these -are suppressed the lesion persists and recurs. In our skin clinics basal-cell carcinoma is diagnosed about eleven times more often than squamouscell carcinoma, but in this series of patients the ratio of basal-cell carcinoma to squamous-cell carcinoma was 1/16. It seems likely that this reflects the conmore siderably rapid development of squamous-cell carcinoma from hyperkeratoses in these patients under
Fig. 2-Patient 1: 1
cm.
diameter keratoacanthoma of neck
presenting with typical appearance on second recurrence site of original removal three months previously.
at
by wide surgical excision.
These lesions recurred within one or two months and the second recurrence was still a typical keratoacanthoma (fig. 2). The keratoacanthoma in patient 3 recurred two months after cautery excision. Patients 3 and 7 died twenty-two and twenty-three months after transplantation from systemic cryptococcosis. Patient 5 died eighteen months after transplantation from metastatic spread of an ureteric transitional-cell carcinoma that had been excised by nephroureterectomy two weeks before transplantation. The other four patients are alive and well with excellent function of the grafted kidney. Schneck and Penn2 reported 18 superficial epithelial tumours (including skin) in " some 5000 kidney and 170 heart recipients throughout the world " —a frequency of about 0-4%. In their own experience 11 patients had developed neoplasms of any type in a group of 184 renal homograft recipients, giving a frequency of 6% which Schneck and Penn thought unlikely to be due to chance. The development 01 19 skin cancers in 7 (14%) of our patients suggests that immunosuppressive therapy may facilitate the development of skin cancer as well as tumours of lymphoid tissue. It seems likely that the high level of solar exposure to which our patients are liable is an important initiating factor, and we have noted that hyperkeratoses are very prevalent on exposed areas in our patients. These premalignant skin lesions seem to undergo malignant transformation more readily in the patient under immunosuppressive treatment, and in some patients multiple squamous-cell carcinomas arise from pre-existing hyperkeratoses. Our experience with patient 7 suggests that squamous-cell carcinoma which develops in a patient on immunosuppression is especially resistant to radiotherapy. Keratoacanthoma may present the typical appearance (fig. 2) but behave in a most atypical manner in these patients. These lesions may persist much longer than usual and may recur after local excision. It seems likely, therefore, that the self-limiting course
immunosuppression. Proposed reasons for the increased incidence of malignant neoplasms in patients under immunosuppressive treatment include the facilitation of infection by oncogenic viruses, the direct effect of the immunosuppressive drug inducing neoplastic transformation, or the suppression of an immunosurveillance mechanism normally responsible for the destruction of mutant cells with malignant potential.’ Persistent antigenic stimulation (e.g., donor antigen of transplanted organ) may provide the basis for cell transformation in the development of lymphoid tumours under the influence of immunosuppressive drugs.5 The very high frequency of skin cancer in our patients supports the view that, under appropriate stimulation, malignant transformation of tissue occurs and that malignant cells have an increased chance of unhindered development due to suppression of an immunosurveillance mechanism. We thank Dr. A. Tait Smith and Dr. C. M. reviewed the histology of the skin tumours.
Atkins, who
Requests for reprints should be addressed to D. J., Departof Medicine, Prince Henry Hospital, Little Bay, New
ment
South Wales 2036, Australia. REFERENCES 1. 2. 3. 4. 5.
Schneck, S. A., Penn, I. Archs Neurol., Chicago, 1970, 22, 226. Schneck, S. A., Penn, I. Lancet, 1971, i, 983. Fahey, J. L. Ann. intern. Med. 1971, 75, 310. Doll, R., Kinlen, L. Br. med. J. 1970, iv, 420. Krueger, G. R. F., Malmgren, R. A., Berard, C. W. Transplantation, 1971, 11, 138.
EFFECTS OF SODIUM INTAKE ON INHERITED HYPERTENSION IN THE RAT WILLIAM J. LOUIS RYO TABEI
University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg 3084, Victoria, Australia SIDNEY SPECTOR Roche Institute of Molecular Biology, Nutley, New Jersey 07110, U.S.A. The effect of sodium chloride intake on systolic blood-pressure was studied in genetic hypertensive Wistar rats. In these animals hypertension can develop on a sodium-" free " diet, but the height to which the blood-pressure rises is related to the sodium intake; increasing the amount of potassium in the diet promotes sodium excretion and ameliorates the hypertension. It is suggested that this form of inherited hypertension may be determined by two different sets of autosomal alleles only one of which is sodium-dependent.
Summary