Brettschneider, L

Hammond, W

Penn, I

Starzl, TE

PubMed

Name not available

Malignant lymphomas in transplantation patients

D-Scholarship@Pitt

Malignant Lymphomas in Transplantation Patients By I. PENN, W. HAMMOND, L. BRETISCHNEIDER, AND T. E. STARZL IT IS KNOWN from animal studies 1 that malignant tumors may develop in certain conditions characterized by disturbances of the host's immune defenses. The same is apparently true in man. For example, pa-tients suffering from agammaglobulinemia, hypogammaglobulinemia and deficiencies of cell mediated immunity have a high incidence of malignancy involving either lymphoid or other tissues.2,4 An increased frequency of neoplasms has also been ob-served in a variety of "autoimmune" dis-orders.3 A prerequisite for success in clinical or-gan transplantation is the iatrogenic alter-ation of the host immune apparatus. A co-incidental effect might be predicted to be an increased incidence of neoplasia. This possibility is supported in the present com-munication, which describes the develop-ment of malignant lymphoid tumors in 5 recipients of renal homo grafts, treated with differing immunosuppressive regimens at 3 widely separated transplantation centers (Table 1). A brief summary of the cases has already been reported.5 The occurrence of these tumors indicates that malignant disease may be a significant hazard of organ transplantation and long continued immu-nosuppressive therapy. CLINICAL MATERIAL Case 1 (Denver)-Prior to transplantation in May 1967, the patient complained of headaches, dizziness, blurred vision, nausea and vomiting. He From the Departments of Surgery and Pathol-ogy, University of Colorado School of Medicine and the Veterans Administration Hospital, Denver, Colorado. Supported by United States Public Health Ser-vice grants AM-06344, HE-07735, AM-07772, AI-04152, FR-00051, FR-00069, AM-12148 and AI-AM-08898. also suffered 2 generalized epileptiform seizures. Neurologic examination was negative and his symp-toms were attributed to severe hypertension. Renal homotransplantation was performed in May 1967. Immunosuppression was with azathio-prine, prednisone, and horse antilymphocyte globu-lin (ALG). Two months after operation, he had a generalized seizure and remained confused and in-coherent for several days. At that time he was being treated for threatened rejection of the homograft, was hypertensive, and was observed to be exceed-ing his restricted fluid allowance. Serum chemis-tries showed evidence of marked hemodilution. He was considered to be suffering from water intoxi-cation. His condition promptly improved on a regimen of fluid restriction and administration of sodium chloride and potassium supplements. There were no further neurologic symptoms until 9 days before the diagnosis of reticulum cell sarcoma was made by craniotomy. The very extensive tumor of the brain (Figure 1) was the cause of the patient's death. Renal function was normal in the last months of life. In this case, the possibility could not be ex-cluded that the tumor was present at the time of transplantation and was the cause of his earlier neurologic symptoms. Case 2 (Denver)-The patient was treated with continuous azathioprine and prednisone, and with actinomycin C and local homograft irradiation for threatened rejection. He had persistent hyper-calcemia following his renal transplant operation. A parathyroidectomy performed on March 29, 1966. The thyroid gland was found to be normal at this operation, but at autopsy on December 6, 1967 was found to be enlarged and almost com-pletely replaced by tumor. Renal function was subnormal, but adequate, throughout life. Death occurred 6 days after emergency vagot. omy and gastrectomy performed to control massive upper gastrointestinal bleeding. The resected por-tion of stomach contained several ulcers, in the bases of which were small collections of tumor cells that were strikingly similar to those found in the brain of the first patient. At autopsy wide-spread tumor was found (Figure 2). Case 3 (Denver)-Immunosuppression was with azathioprine, prednisone and a 7 week course of heterologous ALG. Seven months after renal homo-transplantation the patient developed a rapidly 106 TRANSPLANTATION PROCEEDINGS, VOL. I, No.1 (MARCH), 1969. Table 1.-Clinical Features of Lymphomas in Renal Transplant Recipients Transplant Date of Date Malignancy Organs Splenec-Thymec-Predni-Type of Number Patient Center Age Sex Transplant Donor Diagnosed Involved tomy tomy Imuran sone ALG Tumor Outcome 1 ToC. Denver 14 M 5/29/67 Mother 11/16/67 Brain Yes No Yes Yes Yes Reticulum Cell Died Sarcoma 12/4/67 2 S.D. Denver 23 M 6/15/65 Father 12/6/67 Thyroid Yes Yes Yes Yes No Reticulum Died Liver Cell 12/6/67 Lung Sarcoma Stomach Prostate Pituitary Skin Psoas Muscle 3 E.C. Denver 20 F 9/15/67 Father 4/11/68 Brain Yes No Yes Yes Yes Possible Alive Plasma-8/20/68 cytoma 4 WoAo Minneapolis 27 M Sept 1964 Brother June 1965 Liver Yes No Yes Yes No Lympho-Died 0 Brain sarcoma 11/6/65 Bone Marrow 5 MoM. Edinburgh 26 F 1/17/66 Mother 2/1/68 Mediastinal No No Yes Yes Yes Reticulum Died Scotland Lymph nodes Cell 2/16/68 00 Pleura Sarcoma o Co R. Hitchcock-Personal communication 00 Mo Fo Ao Woodruff-Personal communication f-' ~ 108 Fig. I.-Case 1. Tumor nodules (arrows) in the left occipital lobe and cerebellum. The flattened gyri reflect increased intracranial pressure caused by the tumor. Tnsert- The large, uniform cells with indistinct cytoplasm and round to oval nuclei are characteristic of reticulum cell sarcoma (X350). progressing left hemiparesis. A lesion in the right anterior and mid-thalamic areas was identified with pneumoencephalography and biopsied with a stere-otaxic technique. The histologic findings were con-sistent with a tumor of lymphoid origin, possibly a plasmacytoma. Extensive special diagnostic studies revealed no evidence of multiple myeloma or any other site of tumor. Radiotherapy to the brain (5650 rads) combined' with reduction in the dosage of prednisone and azathioprine (Figure 3) resulted in striking im-provement in the patient's neurologic condition. She is well with moderate but stable residual hemiparesis at the present time. Case 4 (Minneapolis, Dr. Claude Hitchcock)-Renal homotransplantation was performed under treatment with azathioprine and prednisone. Ten months later, the liver became enlarged and was proved by biopsy to contain a lymphosarcoma. Two courses of radioactive cobalt therapy, each of 2,500 rads, were given to the liver area. Thirteen months after transplantation the patient became jaundiced and developed ascites. Death in hepatic coma occurred one month later. Autopsy examina-tion revealed tumor nodules in the liver, varying from 2 to 10 em in diameter. Similar tumor in-volvement was found in the left cerebellar cortex. The bone marrow was Riled with lymphosarcoma. Case 5 (Edinburgh, Mr. M.F.A. Woodruff)-A patient being treated with azathioprine and pred-nisone developed right-sided pleurisy 518 days after renal homotransplantation. About fg~ months earlier, a 10 day course of horse ALG had been given for the indication of late rejection. A locu-lated effusion between the right upper lobe and mediastinum was seen in the chest x-ray. This slowly diminished in size when antibiotics were given and could no longer be easily seen OF~ months later. A chest x-ray 725 days post-trans-plantation showed a recurrence and extension of the aforementioned radiographic abnormalities. Operation revealed a reticulum cell sarcoma affect-ing th e mediastinal lymph nodes and ulcerating through the pleura. The patient died 760 days after Fig OK-C:Kls~ 2. A.-This 5 cm nodule was one of several found in the liver. B.-Malig-nant reticulum cclls have massively in6ltrated the thyroid, separating the follicles widely (X80). WBC Ccr (ml / min.l BUN (mg per 100 mil AZATHIOPRINE (mg) PREDNISONE (mg) ALG 35.000 YJ,OOO 25,000 200 LD 152 TUMOR IRRADIATION ~109 o 10 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 . RENAL TRANSPLANTAT:ON TIME IN DAYS Fig, 3.-The course of a patient (Case 3) who developed a plasmacytoma in the di-encephalon more than 7 months after renal homotransplantation from her father. The tumor w as inaciiated and the doses of both azathioprine and prednisone were drastically reduced. The neurologic deficit was partially reversed and has not progressed subsequently. Renal function has remainecl good. llO transplantation. The kidney functioned throughout life. OTHER PATHOLOGIC STUDIES The lymphoid tissues from autopsy ex-amination were reviewed in 24 recipients of kidney or liver homo grafts who died without previous evidence of malignancy. In 13 of these cases, immunosuppressive therapy had been with azathioprine and prednisone and in the other ll, ALG had also been administered. In no case was there any abnormal proliferation of lym-phoid tissue. In fact, the lymphoid tissues were grossly depleted, more so in the thy-mus and gastrointestinal tract than in the lymph nodes. In the lymph nodes, lym-phoid follicles were small and poorly formed and germinal centers were ex-tremely rare. There was a proportionately greater reduction in small lymphocytes than in plasma cells. DISCUSSION In these patients, the probability is strong that the neoplasms began de novo at some time after the transplantation. Only in Case 1 was there any suggestion that the tumor might have antedated the original operation. Moreover, there was no evidence that the tumors were trans-planted from the donors. All 5 kidneys were obtained from living related volun-teers who have remained in good health from one to 4 years after their nephrec-tomies. A number of the conditions present in the human recipients of renal homo grafts herein reported have been shown in ex-perimental animals to be capable of induc-ing or influencing oncogenesis under the appropriate circumstances. These include the depression of immunologic reactivity by thymectomy,6.8 antilymphocyte serum,7.8 and azathioprine 9 or by the provision of chronic antigenic stimulation.1.1o.1l In the clinical situation, the relative con-tribution of any single factor is impossible to assess. All 5 of the patients received immunosuppressive therapy with azathio-prine and prednisone, 4 underwent sple-nectomy, one had a thymectomy and 3 re-ceived heterologous ALG. Beside therapy with azathioprine and prednisone, the common feature in all cases was the con-tinuous presence of antigen in the form of a homograft. Four of the 5 patients had severe problems with rejection and re-ceived large doses of immunosuppressive agents to control this reaction. It has been suggested that the increased incidence of malignancy which follows im-munologic depression is due to a loss of the surveillance mechanism by which mu-tant cells are repudiated as "non-self." 3.12 This point of view has been strongly sup-ported by the ease with which neoplasms have been accidentally transplanted from cadaveric renal donors who died of can-cer,13 and by the subsequent disappearance of a transplanted malignant growth in at least one case after immunosuppression had been discontinued.14 While probably germane to the pres-ently reported cases, the foregoing se-quence of events does not explain the pe-culiar predisposition to the development of lympho-reticular tumors. It is conceivable that chronic antigenic stimulation was an added pathogenetic determinant, even though the lymphoid tissues in our 3 pa-tients (Cases 1-3), as well as in 24 others who died without neoplasia, had variable involution. It remains to be determined to what ex-tent the appearance of neoplastic growth will be a complication of clinical organ transplantation. At the moment, it appears that the incidence will be low enough so that the usefulness of such procedures will not be vitiated. In the meanwhile, it is im-portant to be alert to this diagnostic pos-sibility since only in this way can effective therapy be instituted as was accomplished in Case 3. So far the predominant risk after trans-plantation has seemed to be the appear-ance of mesenchymal tumors, although there have also been 2 reported epithelial malignancies which developed anew in re-cipients of renal homografts. One was a fatal dysgerminoma of the ovary in Good's patient.3 The other was a squamous cell carcinoma of the ear in one of our patients who was included in Hume's inter-institu-tional compilation.13 In the latter case the lesion of the ear appeared 2 years after renal homotransplantation and was cured by a radical excision. The patient died of a perforated sigmoid diverticulitis 2 years later. Further knowledge about the general ef-fect of transplantation and immunosup-pression on tumor growth will have an im-portant bearing on the advisability of or-gan replacement for the treatment of pri-mary malignancies of vital structures such III as the kidney, liver, and lung. In Hume's report 13 there were several examples of renal homotransplantation in patients with Wilm's tumor or hypernephroma. There was only one example of a recurrence. In our series of orthotopic liver transplantations for hepatoma, there have been 3 recipients with survival of 5 months or longer. One of these patients died of widespread metas-tases after fP~~ months, another has radio-graphic evidence of early pulmonary metas-tases at 5 months, and the third is free of detectable tumor after 6 months.15 SUMMARY Malignant lymphomas developed in 5 renal homograft recipients treated at 3 widely separated transplantation centers. The development of these tumors appears to be an indirect complication of organ transplantation and/ or the meamres taken to prevent rejection. REFERENCES 1. Schwartz, R, Andre-Schwartz, J., Armstrong, M. Y. K. and Beldotti, L.: Neoplastic sequelae of allogenic disease. I. Theoretical considerations and experimental design. Ann. N.Y. Acad. Sci., 1966, 129:804. 2. Fialkow, P. J.: "Immunologic" oncogenesis. Blood, 1967, 30:388. 3. Good, F. A.: Experimental and clinical ex-periences with chemical suppression of immunity. A personal review. In Immunopathology Fifth In-ternational Symposium (Eds. Miescher, P. A. and Graher, P.). Grune and Stratton, Inc., New York, 1967, p. 366, p. 416. 4. Schwartz, R: Immunologic disorders in ma-lignant lymphomas. In Proceedings of the Fifth National Cancer Conference. J. B. Lippincott Com-pany, Philadelphia, 1964, p. 645. 5. Starzl, T. E., Groth, C. G., Brettschneider, L., Smith, G. V., Penn, I. and Kashiwagi, N.: Perspec-tives in organ transplantation. (Proceedings of the Swiss Society of Immunology). Excerpta Medica, in press. 6. Martinez, C., Dalmasso, A. P. and Good, R. A.: Homotransplantation of normal and neo-plastic tissue in thymectomized mice. In The Thy-mus in Immunobiology (Eds. Good, R. A. and Gabrielsen, A. E. ). Hoeber Medical Division, Harper and Row, New York, 1964, p. 465. 7. Allison, A. C. and Law, L. W.: Effects of antilymphocyte serum on virus oncogenesis. Proc. Soc. Exp. BioI. Med., 1968, 127:207. 8. Davis, R C. and Lewis, J., Jr.: Effect of thymectomy on an antilymphocyte serum treated human tumor xenograft. Surg. Forum, 1967, 18: 229. 9. Casey, T. P.: Azathioprine (Imuran) admin-istration and the development of malignant lympho-mas in NZB mice. Clin. Exp. Immunol., 1968, 3: 305. 10. Walford, R L.: Increased incidence of lymphoma after injections of mice with cells dif-fering at weak histocompatibility loci. Science, 1966, 152:78. 11. Armstrong, M. Y. K., Schwartz, R. S. and Beldotti, L.: Neoplastic sequelae of allogeneic dis-ease. III. Histological events following transplanta-tion of allogeneic spleen cells. Transplantation, 1967, 6: 1380. 12. Prehn, R T.: Tumor antigens. In Immunity, Cancer and Chemotherapy (Ed. Michich, E.). Academic Press, New York, 1967, p. 265. 13. Hume, D. M.: Progress in clinical renal homotransplantation. In Advances in Surgery (Ed. Welch, C. E.). Year Book Medical Publishers, Inc., Chicago, 1966, 2:419. 112 14. Wilson, R. E., Hager, E. B., Hampers, C. L., Corson, J. M., Merrill, J. P. and Murray, J. E.: Immunologic rejection of human cancer trans-planted with a renal allograft. New Eng. J. Med., 1968, 278:479. 15. Starzl, T. E.,. Brettschneider, L., Groth, C. G., Penn, I. and Blanchard, H.: Orthotopic liver transplantation in man. Proceedings of the Second International Congress of the Transplanta-tion Society, New York, 1968, in press. 

Malignant lymphomas in transplantation patients.

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Malignant lymphomas in transplantation patients.

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