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De novo malignancies after organ transplantation
De Novo Malignancies After Organ Transplantation F. Catena, B. Nardo, G. Liviano d’Arcangelo, S. Stefoni, G. Arpesella, A. Faenza, and A. Cavallari
A
N INCREASED incidence of malignancies (DNM) in organ transplant patients was first predicted by Thomas E. Starzl in 19681 and confirmed shortly thereafter.2 Since then, the incidence of postransplantation DNM shows some discrepancy among different reports: it has been estimated to range from 4.1% to 16% with an average of 6%.3 Prevalent among these tumors are posttransplants lymphoproliferative disorder (PTLD), squamous cell carcinoma of skin, and Kaposi’s sarcoma (KS).4 A variety of carcinogenic influences have been identified, such as ultraviolet light exposure and skin cancer, analgesic nephropathy and urinary tract cancer, acquired cystic disease of the kidney and renal cancer. Virus infections also play an important role in the development of many of these neoplasms in immunosuppressed hosts including Epstein-Barr virus in most cases of PTLD, human papilloma virus in cervix cancer, human herpes 8 in KS, and hepatitis B and C virus in hepatomas.4 The aim of this study was to review our experience in DNM complicating KT (kidney transplantation), OLT (orthotopic liver transplantation), and HT (heart transplantation) performed in a single center. MATERIALS AND METHODS The incidence and characteristics of DNM in KT, OLT, and HT recipients who underwent transplantation until 1997 at the Department of Surgery and Transplantation of University of Bologna were analyzed. Eight hundred sixty-nine KT, 353 OLT, and 124 HT were carefully followed for an average respectively of 15.3, 6.1, and 4.2 years after primary transplantation. All charts were analyzed retrospectively: patients with DNM were reviewed according to their age, sex, type of immunosuppression, histology, interval between transplantation and the diagnosis of cancer, method of treatment, and survival.
RESULTS
Of 1346 solid organ transplant recipients, we detected 49 DNM (3.6%). A total of 32 cancers were diagnosed in 30 renal transplant recipients (3.6%). Twenty-one patients were males and 9 were females, and the mean age was 48 years (range 28 to 61). Skin cancer and KS were the most encountered tumors (11 patients). Three recipients had cervix cancer, 4 developed PTLD, and in 4 patients, 2 bladder cancers and 2 colon cancers were diagnosed respectively. Six subjects respectively had 1 breast cancer, 1 duodenum cancer, 1 testis cancer, 1 gastric cancer, 1 kidney cancer, and 1 hepatocellular cancer. Two patients devel0041-1345/01/$–see front matter PII S0041-1345(00)02724-X
oped both de novo prostate cancer and de novo skin cancer. Tumors presented at a mean time of 69 months (range 4 to 210 months) after transplantation. IT was with azathioprine and steroids in 13 patients, cyclosporine and steroids in 8 patients and a triple therapy in 9 patients. Seventeen patients showed rejection episodes and were treated with bolus dose steroids and/or antilymphocyte globulin. Five recipients had a disseminated cancer, and they were not submitted to surgery. Radical surgery was performed in 18 patients (60%), radiotherapy was used in 4 patients, and chemotherapy in 3. In 20 patients, IT was reduced. 28 patients maintained a normal graft function while 2 patients returned to dialysis treatment. Eight recipients died of tumor related causes, 2 died of other causes, and 20 are alive with a follow-up of 138.8 months with no evidence of recurrent disease. Among OLT recipients, 13 DNM occur (3.6%): 9 patients were males and 4 females with a mean age of 45.7 years (range 23 to 55 years). IT was based on cyclosporine and steroids in 8 patients while 5 recipients received triple therapy. Eight patients had episodes of rejection and treatment consisted of steroids and/or OKT3. The following cancer types were found: skin cancer occurred in 2 patients, bladder cancer in 2 patients, breast cancer in 2 patients and in 2 patients colorectal cancer was identified. The other 5 recipients had respectively: 1 pancreas cancer, 1 lung cancer, 1 larinx cancer, 1 tongue cancer, and 1 PTLD. The diagnosis of cancer was made at an average time of 44.3 months after transplantation (range 6 to 90 months). Surgical treatment was performed in 12 recipients: 10 patients (77%) were amenable of radical resections while 2 were submitted to palliative procedures; 1 patient with pancreas cancer and diffuse hepatic metastasis was referred to medical treatment. Of 3 deaths occurred during the follow-up, 2 were tumor related. The remaining 10 patients are alive after a mean follow-up of 56.3 months with no evidence of recurrence. Four heart recipients developed DNM (3.2%). All were males with a mean age of 55 years (range 44 to 62 years). All patients received triple IT, and all showed rejection episodes. When cancer diagnosis was made, all patients had already meta-
From the Department of Surgery and Transplantation and Nephrology, University of Bologna, Bologna, Italy. Address reprint requests to Dr Fausto Catena, Via P. da Palestrina 24, 40141 Bologna, Italy. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1858
Transplantation Proceedings, 33, 1858–1859 (2001)
DE NOVO MALAGNANCIES
static disease caused by 2 skin melanoma, 1 pancreas cancer and 1 kidney cancer. Symptoms of neoplasms occurred within 24 months after transplants, and all patients died of progressive malignant disease within 30 months. Chemoradiotherapy, surgery, and reduction of immunosuppression did not change the outcome of malignancy. DISCUSSION AND CONCLUSIONS
Although a high percentage of DNM after transplantation are low grade neoplasms that are readily amenable to treatment, cancer has become a major cause of death in patients otherwise successfully treated by transplantation.4 The incidence of DNM in our studied groups was similar or even lower than in other reports.5 Moreover, the frequency in all transplant groups of PTLD was lower than that reported previously in literature. This could be explained by the already known regional difference in cancer incidence in transplant populations.4 DNM in transplant recipients occur in relatively young population whose average at the time of transplantation is 41 years, and the mean time to the diagnosis of DNM is 61 months.6 Our findings were comparable to these data even if HT recipients were a little older (55 years). We also noted a marked disparity in the interval to DNM between KT and HT recipients (69 versus 24 months); this is probably related to the higher level of IT in the last ones even if in the literature the incidence appears to be related to the duration of immunosuppression exposure.7 This phenomenon may be a result of decreased immune surveillance, which allows activation and/or proliferation of oncogenic viruses or to direct mutagenic effects of the immunosuppressive agents them-
1859
selves.8 However, among KT, OLT, and HT, DNM incidence was comparable (3.6% vs 4.6% vs 3.2%). In all patients, we opted for an appropriate treatment without cessation of IT with the intention to prolong the patients’ life with a functional graft. According to literature data, only two virus-related neoplasms, PTLD and KS, have a well-established benefit from reduction or cessation of immunosuppressive therapy.4 We also noted an aggressive biology of DNM after HT (100% mortality); whereas, 60% and 77% of patients with DNM after HT and OLT respectively were submitted to radical surgical procedures. We may conclude that the occurrence of DNM in transplant patients demands careful long-term screening protocols which will help to facilitate the diagnosis at an early stage of the disease. Nevertheless, the organization of preventive measures and surveillance may allow for early institution of therapy therefore improving the survival. The findings of our study emphasize the need for lifetime follow-up and DNM screening of transplant recipients. REFERENCES 1. Strazl TE: Ann Surg 168:416, 1968 2. Penn I, Hammond W, Brettschneider L, et al: Transplant Proc 1:106, 1969 3. Flattery MPL: J Transplant Coord 8:105, 1998 4. Penn I: Transplant Proc 31:1260, 1999 5. Mihalov ML, Gattuso P, Holmes EW, et al: Clin Transplant 10:248, 1996 6. First MR, Peddi VR: Transplant Proc 30:2768, 1998 7. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 8. Gruber S, Matas AG: Transplant Sci 4:87, 1994
A
N INCREASED incidence of malignancies (DNM) in organ transplant patients was first predicted by Thomas E. Starzl in 19681 and confirmed shortly thereafter.2 Since then, the incidence of postransplantation DNM shows some discrepancy among different reports: it has been estimated to range from 4.1% to 16% with an average of 6%.3 Prevalent among these tumors are posttransplants lymphoproliferative disorder (PTLD), squamous cell carcinoma of skin, and Kaposi’s sarcoma (KS).4 A variety of carcinogenic influences have been identified, such as ultraviolet light exposure and skin cancer, analgesic nephropathy and urinary tract cancer, acquired cystic disease of the kidney and renal cancer. Virus infections also play an important role in the development of many of these neoplasms in immunosuppressed hosts including Epstein-Barr virus in most cases of PTLD, human papilloma virus in cervix cancer, human herpes 8 in KS, and hepatitis B and C virus in hepatomas.4 The aim of this study was to review our experience in DNM complicating KT (kidney transplantation), OLT (orthotopic liver transplantation), and HT (heart transplantation) performed in a single center. MATERIALS AND METHODS The incidence and characteristics of DNM in KT, OLT, and HT recipients who underwent transplantation until 1997 at the Department of Surgery and Transplantation of University of Bologna were analyzed. Eight hundred sixty-nine KT, 353 OLT, and 124 HT were carefully followed for an average respectively of 15.3, 6.1, and 4.2 years after primary transplantation. All charts were analyzed retrospectively: patients with DNM were reviewed according to their age, sex, type of immunosuppression, histology, interval between transplantation and the diagnosis of cancer, method of treatment, and survival.
RESULTS
Of 1346 solid organ transplant recipients, we detected 49 DNM (3.6%). A total of 32 cancers were diagnosed in 30 renal transplant recipients (3.6%). Twenty-one patients were males and 9 were females, and the mean age was 48 years (range 28 to 61). Skin cancer and KS were the most encountered tumors (11 patients). Three recipients had cervix cancer, 4 developed PTLD, and in 4 patients, 2 bladder cancers and 2 colon cancers were diagnosed respectively. Six subjects respectively had 1 breast cancer, 1 duodenum cancer, 1 testis cancer, 1 gastric cancer, 1 kidney cancer, and 1 hepatocellular cancer. Two patients devel0041-1345/01/$–see front matter PII S0041-1345(00)02724-X
oped both de novo prostate cancer and de novo skin cancer. Tumors presented at a mean time of 69 months (range 4 to 210 months) after transplantation. IT was with azathioprine and steroids in 13 patients, cyclosporine and steroids in 8 patients and a triple therapy in 9 patients. Seventeen patients showed rejection episodes and were treated with bolus dose steroids and/or antilymphocyte globulin. Five recipients had a disseminated cancer, and they were not submitted to surgery. Radical surgery was performed in 18 patients (60%), radiotherapy was used in 4 patients, and chemotherapy in 3. In 20 patients, IT was reduced. 28 patients maintained a normal graft function while 2 patients returned to dialysis treatment. Eight recipients died of tumor related causes, 2 died of other causes, and 20 are alive with a follow-up of 138.8 months with no evidence of recurrent disease. Among OLT recipients, 13 DNM occur (3.6%): 9 patients were males and 4 females with a mean age of 45.7 years (range 23 to 55 years). IT was based on cyclosporine and steroids in 8 patients while 5 recipients received triple therapy. Eight patients had episodes of rejection and treatment consisted of steroids and/or OKT3. The following cancer types were found: skin cancer occurred in 2 patients, bladder cancer in 2 patients, breast cancer in 2 patients and in 2 patients colorectal cancer was identified. The other 5 recipients had respectively: 1 pancreas cancer, 1 lung cancer, 1 larinx cancer, 1 tongue cancer, and 1 PTLD. The diagnosis of cancer was made at an average time of 44.3 months after transplantation (range 6 to 90 months). Surgical treatment was performed in 12 recipients: 10 patients (77%) were amenable of radical resections while 2 were submitted to palliative procedures; 1 patient with pancreas cancer and diffuse hepatic metastasis was referred to medical treatment. Of 3 deaths occurred during the follow-up, 2 were tumor related. The remaining 10 patients are alive after a mean follow-up of 56.3 months with no evidence of recurrence. Four heart recipients developed DNM (3.2%). All were males with a mean age of 55 years (range 44 to 62 years). All patients received triple IT, and all showed rejection episodes. When cancer diagnosis was made, all patients had already meta-
From the Department of Surgery and Transplantation and Nephrology, University of Bologna, Bologna, Italy. Address reprint requests to Dr Fausto Catena, Via P. da Palestrina 24, 40141 Bologna, Italy. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1858
Transplantation Proceedings, 33, 1858–1859 (2001)
DE NOVO MALAGNANCIES
static disease caused by 2 skin melanoma, 1 pancreas cancer and 1 kidney cancer. Symptoms of neoplasms occurred within 24 months after transplants, and all patients died of progressive malignant disease within 30 months. Chemoradiotherapy, surgery, and reduction of immunosuppression did not change the outcome of malignancy. DISCUSSION AND CONCLUSIONS
Although a high percentage of DNM after transplantation are low grade neoplasms that are readily amenable to treatment, cancer has become a major cause of death in patients otherwise successfully treated by transplantation.4 The incidence of DNM in our studied groups was similar or even lower than in other reports.5 Moreover, the frequency in all transplant groups of PTLD was lower than that reported previously in literature. This could be explained by the already known regional difference in cancer incidence in transplant populations.4 DNM in transplant recipients occur in relatively young population whose average at the time of transplantation is 41 years, and the mean time to the diagnosis of DNM is 61 months.6 Our findings were comparable to these data even if HT recipients were a little older (55 years). We also noted a marked disparity in the interval to DNM between KT and HT recipients (69 versus 24 months); this is probably related to the higher level of IT in the last ones even if in the literature the incidence appears to be related to the duration of immunosuppression exposure.7 This phenomenon may be a result of decreased immune surveillance, which allows activation and/or proliferation of oncogenic viruses or to direct mutagenic effects of the immunosuppressive agents them-
1859
selves.8 However, among KT, OLT, and HT, DNM incidence was comparable (3.6% vs 4.6% vs 3.2%). In all patients, we opted for an appropriate treatment without cessation of IT with the intention to prolong the patients’ life with a functional graft. According to literature data, only two virus-related neoplasms, PTLD and KS, have a well-established benefit from reduction or cessation of immunosuppressive therapy.4 We also noted an aggressive biology of DNM after HT (100% mortality); whereas, 60% and 77% of patients with DNM after HT and OLT respectively were submitted to radical surgical procedures. We may conclude that the occurrence of DNM in transplant patients demands careful long-term screening protocols which will help to facilitate the diagnosis at an early stage of the disease. Nevertheless, the organization of preventive measures and surveillance may allow for early institution of therapy therefore improving the survival. The findings of our study emphasize the need for lifetime follow-up and DNM screening of transplant recipients. REFERENCES 1. Strazl TE: Ann Surg 168:416, 1968 2. Penn I, Hammond W, Brettschneider L, et al: Transplant Proc 1:106, 1969 3. Flattery MPL: J Transplant Coord 8:105, 1998 4. Penn I: Transplant Proc 31:1260, 1999 5. Mihalov ML, Gattuso P, Holmes EW, et al: Clin Transplant 10:248, 1996 6. First MR, Peddi VR: Transplant Proc 30:2768, 1998 7. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 8. Gruber S, Matas AG: Transplant Sci 4:87, 1994