Hakala, TR

Iwatsuki, S

Rosenthal, JT

Starzl, TE

Taylor, RJ

English

PubMed

Name not available

Histiocytic lymphoma in renal transplant patients receiving cyclosporine

D-Scholarship@Pitt

TOURAINE ET At. ve syndrome appears to be nonmal. d reversible when immunosUppres. py is withdrawn. Production of olig. develops at this phase. Whether the ;tion intervenes early or after this ~nt of restricted B-cell clones is spec. , it may be noted that the 14+ te subset is dramatically decreaSed ipheral blood of these patients duro to a degree comparable to findings patients, and that correction of this ity is slow (over 2 months) in the patients. ACKNOWLEDGMENT ( Pro P. A. Bryon and Drs. G. Lenoir, F. . Bosshard, and O. Gentilhomme for several performed. te~re also grateful to Sandol, p throughout these studies. ord DH, Thomas JA, Janossy G, et al: Lancct o . P, Gordon-Smith EC: Lancet 2:1296, 1980 z report on the first 1500 patients treated with lal communication) BA, Bieder CP, Pennock JL: In White DJG porin A. Amsterdam, Elsevier, 1982, p 317 Histiocytic Lymphoma in Renal Transplant Patients Receiving Cyclosporine J. T. Rosenthal, S. Iwatsuki, T. E. Starzl, R. J. Taylor, and T. R. Hakala THE higher incidence of cancer in immu-nosuppressed patients over. the gene.ral population has long been recogmzed. A high rcentage of these cancers have been called :;mphomas. The first clinical trial of cyclo-lporine for renal transplantation re~or~ed by CaIne et al.I included almost a 10% inCIdence of lymphoma (3/3:): Concern was ~xpressed (or the ultimate utIlity of cyclosporme based on this experience. We now have experience in over 300 cases of cadaveric renal transplanta-tion over a 3.5-year period. In this article we present the experience ~it~ f~mphomaK i~ these patients, documenting inCidence, chm-cal presentation, treatment, and outcome fol-luwing cadaveric renal transplantation. From December 1979 to September 1980, M patients underwent cadaveric renal trans-plantation in Denver in the first trials with eycJosporine and steroid combination. The re~ults of that trial have been reported in detail by Starzl et al.2.3 From March 1981 to I Q!U an additional 244 patients have under-Fone cadaveric renal transplantation in Pitts-burgh, using the same immunosuppression regimen. The results of this experience have been reported.4•5 Immunosuppression con-~i~ted of cyclosporine, 17.5 mg/kg/day, begun by mouth pretransplant and daily thereafter. Tapering occurred from 2 weeks to (, months posttransplant. The average cyclo-sporine dose at 1 year posttransplant was 6 mg/kg/day. Methylprednisolone, I g, was Itiven i.v. pretransplant. Prednisone was begun by mouth on day 1 posttransplant and tapered over 5 days to 20 mg/day. By I year, the average prednisone dose was 10 mg/day. Six patients of the 310 (1.9%) developed "lymphoma" during the course of these trial~K Two of these have been reported in detai1.2•6 Four additional cases will be discussed here in addition to these two. The clinical features of the patients are shown in Table 1. These were 5 males and 1 female; age ranged from 16 years to 57 years. Five patients developed bowel lesions, which were manifested by per-foration and peritonitis. One patient devel-oped a painless neck swelling. The time of development of the lesion was 3-6 months posttransplant. The first patient from the Denver series was receiving 16 mg/kg/ day of cyclosporine at the time of development of lymphoma at 6 months posttransplant. The other 5 patients were receiving 6-11 mg/ kg/day cyclosporine 3-5 months posttrans-plant at the time of development of lympho-ma. Only one patient had been treated for rejection; this consisted of recycling of oral steroid to 200 mg/day, with a 5-day taper again to 20 mg/day. Three patients had oral herpes within 1-2 months of transplantation, while 2 patients had elevated serum creatinine indicative of cyclosporine nephrotoxicity. The five patients with bowel lesions under-went resection of the affected segment and prompt reduction in the dose of cyclosporine .. Two of these patients received small doses of cytotoxic drugs before the lesions were ade-quately characterized. One patient received small doses of acyclovir. The others had the cyclosporine dose reduced, but received no other treatment. The patient with the neck mass received local radiation, primarily because most of the lesion was necrotic and could not adequately be characterized. No systemic therapy was undertaken in this patient, except to lower the cyclosporine dose. Dose adjustment was in the range of 1-3 mg/kg/day cyclosporine. From the Division of Urology. Department of Surgery, University of Pittsburgh, Pittsburgh. PA. Address reprint requests to Dr. J. T. Rosenthal. Divi-sion of Urology. Department of Surgery. University of Pittsburgh. Pittsburgh. PA 15261. '" 1983 by Grune & Stratton, Inc. 0041-1345/83/1505-0113$01.00/0 rrllllsplllnlBlion Proceedings, Vol. XV, No.4. Suppl. 1 (December). 1983 2805 2806 ROSENTHAl ET AL. TRANSPLANT I Table 1. Clinical Features have been fe lomonocle Whether or morphology our six case lymphoma P When polyc Iymphoproli priate, or ; described b) than acade~ enthusiasm· when the cli phoma appe was a high J fi rst group, reported by B-cell prolif suppression would be co three patie: pression on: Cyclosporine Dose Patient Age/Sex (mg/kg/Day) l.P. 25F 16 S.C. 21M 10 A.L. 49M 6 P.L. 57M 8 E.F. 30M 10 L.S. 16M 8 All 6 patients so treated are alive and well 3 months to 4 years after treatment (Table 2). Two patients suffered irreversible rejection of the graft when immunosuppression was decreased. The other 4 patients have normal renal function. Interpretation of the histopathology in each case was histiocytic lymphoma. Four lesions were subsequently characterized as polyclonal B-cell masses by immunoperoxidase staining. The neck mass tissue was mostly necrotic, precluding characterization. The tumor mass from one patient showed no immunoglobulin. Most of the tissue resected from the bowel was necrotic also, so that EBNA was identified in only one tumor. This also prevented DNA hybridization studies for Epstein-Barr virus (EBV) genome. Serology to EBV disclosed evidence of primary infection in one patient (L.P.) previously reported2 and reinfection in another (E.F.), manifested by a threefold rise Table 2. Treatment and Outcome Patient Graft Patient Treatment Survival Survival L.P. Bowel resection Yes Yes Decrease cyclosporine S.C. Bowel resection Yes Yes Decrease cyclosporine A.L local radiation Yes Yes Decrease cyclosporine P.L. Bowel resection Yes Yes Decrease cyclosporine ChemoRx E.F. Bowel resection Yes No Decrease cyclosporine ChemoRx L.S. Bowel resection Yes No Decrease cyclosporine Site Bowel Bowel Neck Bowel. prostate Bowel Bowel Time After Transplant 6 Months 5 Months 3 Months 4 Months 4 Months 3 Months in antibody titer to viral capsid antigen (Table 3). DISCUSSION Because of the high incidence of lymphoma in the early experience with cyclosporine, it was feared that the drug itself was more tumorogenic than conventional immunosup-pression regimens and that its use would be severely limited by this fact. Two issues are of concern; one is the incidence, and the other is the clinical significance of these lesions. Over-all incidence of lymphoma reported here is 1.9%, considerably less than the feared 10% and comparable to the 2.5% reported by Bird7 in cycIosporine-treated cases and comparable to the incidence reported in cadaveric renal transplantation under conventional immuno-suppression.8 Evidence that the development of these lesions is related to the general level of immunosuppression comes from the higher incidence of tumors reported from cardiac transplantation,9 where immunosuppression may be maintained at a higher level out of necessity. The role of Epstein-Barr virus in the devel-opment of these lymphomas has been well described.1O Epstein-Barr virus is implicated directly or indirectly in 3 of the 6 patients reported here. The majority of these lesions Table 3. Immunologic Studies loP. Polyclonal B cell Primary EBV infection S.C. No immunoglobulin EBNA positive A.l. P.l. Polyclonal B cell E.F. Polycional B cell Reactivation EBV infection L.S. Polyclonal B cell Pending • 12 patients. received sm the exact discerned. tions in iml immediate! all patient I. Caine I 2:1033,1979 2. Starzt . GynccolObs' 3. Starzl j plant Proc (t: 4. Hakala plant Proc l~ 5. Rosent (in press) 6. Starzl GynccolOb! ROSENTHAl ET AI.. TRANSPLANT HISTIOCYTIC LYMPHOMA 2807 Time Aftw Transplant 6 Months 5 Months 3 Months 4 Months 4 Months 3 Months viral capsid antigen (Table SCUSSION igh incidence of lymphoma ience with cyclosporine, it the drug itself was more conventional immunosup-and that its-use would be this fact. Two issues are of incidence, and the other is ance of these lesions. Over-rmphoma reported here is { less than the feared 10% the 2.5% reported by Bird' :ated cases and comparable eported in cadaveric renal tder conventional immuno-ence that the development elated to the general level of to comes from the higher ors reported from cardiac where immunosuppression ~ at a higher level out of tein-Barr virus in the devcl-lymphomas has been well in-Barr virus is implicated ctly in 3 of the 6 patients ,e majority of these lesions Immunologic Studies II Primary EBV infection butin EBNA positive • !II Reactivation EBV infection .a Pending have been found to be polyclonal, as opposed to monoclonality of killing lymphoma. Whether or not they can be distinguished by morphology is not clear. 11 All the material in our six cases was interpreted as histiocytic lymphoma prior to immunologic examination. When polyclonality is determined, the term Iymphoproliferative disorder is more appro-priate, or perhaps. fOseudo~ymp~omaI as described by IwatsukI. The Issue IS of more than academic interest, since there is great enthusiasm for the use of cytotoxic drugs when the clinical diagnosis of histiocytic lym-phoma appears on ~he chart. mrevio~slyI the~e was a high mortality, two of three 10 CaIne s first group, 1 and five of six in the cases reported by Hanto. 10 If this is a virally induced B-cell proliferation, maintenance of immuno-suppression and the use of cytotoxic drugs would be counterproductive. Iwatsuki treated three patients by reduction of immunosup-pression only, with good outcome in all three patients.12 In our six patients, only two received small doses of cytotoxic drugs before the exact nature of their lesions could be discerned. In all six cases, significant reduc-tions in immune suppression were carried out immediately. Prompt resolution occurred in all patients so treated. The effectiveness of this maneuver was vividly documented in one patient who required repeat laparotomy for persistent GI bleeding. This was found to be suture line bleeding and was corrected by repeat resection. At the time of this repeat resection, I month following his original oper-ation, large bowel lesions that had been seen at the first operation and left in place were entirely resolved. The question of transforma-tion from polyclonal to monoclonal cannot be answered from the clinical data presently available. It has been suggested that mono-clonal lesions in transplant patients are killing cancer and associated with development of chromosomal abnormalities in the B cells so transformed by virus. \3 CONCLUSION Incidence of lymphoma using cyclosporine and steroid is no different than in transplanta-tion under conventional immunosuppression. Most of these lesions are more appropriately called Iymphoproliferative disorders despite their histologic appearance. When the masses are polyclonal, prompt reduction in immuno-suppression should result in excellent survival. The role for additional antiviral agents for treatment is unclear, but played no role here. Cytotoxic drugs should be avoided. REFERENCES J. Caine RY, Rolles K, White DJG, et al: Lancet 2: I 033, 1979 2. Starzl TE, Klintmalm GBB, Wile R, et al: Surg {jynccolObstet 153:486, 1981 3. Starzl TE, Hakala TR, Rosenthal JT, et al: Trans-plant Proc (this issue) 4. Hakala TR, Starzl TE, Rosenthal JT, et al: Trans-plant Proc 15:465, 1983 5. Rosenthal JT, Hakala TR, Starzl TE, et al: J Urol (in press) 6. Starzl TE, Hakala TR, Rosenthal JT, et al: Surg Gynecol0bstet 154:819, 1982 7. Bird AG: In White DJG (ed): Cyclosporin A. Amsterdam, Elsevier Biomedical, 1982 8. Penn I: Transplant Proc 13:736, 1981 9. Lanza RP, Cooper DKC, Cassidy MJO, et al: JAMA 249:1746,1983 10. Hanto OW, Frizzera G, Purtilo OT, et al: Cancer Res 41:4253, 1981 II. Frizzera G, Hanto OW, Gajl-Peczalska KJ, et al: Cancer Res 41:4262, 1981 12. Iwatsuki S, Geis WP, Molnar Z, et al: J Surg Res 24:428, 1978 13. Klein G: Proc Natl Acad Sci USA 76:2442,1979 

Histiocytic Lymphoma in Renal Transplant Patients Receiving Cyclosporine.

http://d-scholarship.pitt.edu/3916/1/31735062114941.pdf

Histiocytic Lymphoma in Renal Transplant Patients Receiving Cyclosporine.

Abstract

Similar works

Full text

Available Versions

Name not available

D-Scholarship@Pitt

Name not available