Boillot, O

Gordon, RD

Marino, I

Mazzaferro, V

Nalesnik, MA

Scotti-Foglieni, C

Starzl, TE

Stieber, AO

English

PubMed

D-Scholarship@Pitt

r i 1/1 :J The Surgical Implications of the Posttransplant Lymphoproliferative Disorders A.C. Stieber, O. Boillot, C. Scotti-Foglieni, M.A. Nalesnik, R.D. Gordon, I. Marino, V. Mazzaferro, and T.E. Starzl THE posttransplant Iymphoproliferative disorders IPTLDs) represent a category of neoplastic·like con· ditions that occur in approximately 2<if to 2jCii of the transplant population. I PTLDs have been described in transplant patients receiving all types of solid organ grafts. 1·7 Several complications result from the presence of PTLDs and their treatment. Although primarily of medical interest. Iymphoproliferative disorders have important sur· gical implications both of a diagnostic and a therapeutic nature. Here we report our experience with the surgical implications of PTLDs in a large series of liver transplant patients. MATERIALS AND METHODS Forty·six patients of a total population of I ~TS tJ.67c' with orthotopic liver transplants IOLT) who received transplants be· tween January I. 19n and December 31. 1988 allhe University of Colorado at Denver and the University of millsbu~h developed PTLDs. This percentage represents less than one·halfthe cases of PTLD in patients with transplants of various solid organs at our center. However. the decision was made to analyze only those PTLD arising in OL T patients up to the end of 1988. in order to have a relatively homogenous population and a follow-up of at least 18 months. The immunosuppression consisted of azathio-prine ([muran) in combination with sterOids and antilymphocyte globulin (ATGl until 1980. cyclosporine A CCyAI and steroids after 1980. with the addition of aZathioprine and monoclonal ATG lOKT3; Onhoclone. Raritan. NJI as needed for the treatment of acute rejecllon episodes. Thiny-six of these patients (78.3'( I had some form of surgery related to PTLDs t Fig lal. The Epstein-Barr virus (EBV) and herpes simplu virus (HSVI statu~ were checked in almost all the patients. In well studied patients. the a~sociation of EBV and PTLD was almost universal. I.' RESULTS The condition was diagnosed an average of 17 months after the transplant (range. 0.75-153 months. median 4 monthsl. The organ or organ-systems involved were lymph nodes (including tonsils. in 30 patients (65.2%). gastrointestinal tract in 15 patients (32.6CiiI. homograft liver in 9 (19.6CiiI. other solid organs in 11 (23.9Iii I. and other sites in 418. 7<if) (Fig 2al. In 18 patients (39.1%) the tumors had a nonclonal character. in 14 patients (30.4Cii) clonal. while in 14 pa-lients (30.4Cii) the character of the PTLD was mixed or could not be determined with accuracy (Fig 2bl. The EBV status was positive for primary infection or reactivation of old disease at the time of the PTLD in 40 patients (87%). negative in 2 patients (4.3%1. and unknown in 4 (8.7%) <Fig 2c). a Patients with surgical interventions * '0 "." b Frequency of various surgical procedures • I . t . .. ..-, ........ --Fig 1. Thirty-six patients 178.3%) had some surgical procedure related to PTLDs: 19 patients (41J<if) had a superficial lymph node biopsy. 5 patients II 9. 2 <if I had exploratory laparotomy. 9 patients (19.6t;f) had some gastrointestinal tract resection. 3 patients (6.5<if. had resection of a solid tumor (including one patient who had a native nephrecto· my). and 7 patients (15.2%) had punch or needle biopsy From the Transplantallon Division. Department 01 Surgery, University of Pittsburgh School 01 Medicine, Pittsburgh. Pennsyl-vat1l3. Supported by research grants from the Veterans Administration and projec1 grant no. AM 29961 from the National Institutes 01 Health. Bethesda, Maryland. Address reprint requests to Thomas E. Starzl. MO. PhD, Falk cnc 5 C. 3601 5th Ave. Pittsburgh. PA 15213. , 1991 by Appleton & Lange 0041-1345·91,'$3.001+0 Transplantation PrOCtJ«jngs. YoI23. No 1 (February), 1991: 1477-1419 1477 1478 a -I : J : b c ... o. Frequency of organ involvement ------a.-Clonafrty of tumors EBV status Fig 2. --(Fig I b). Some of these patients had more than one procedure. Although there was a total of ~P deaths /SO'I() in this group. only 6 patients (131)t) died as a direct result of the PTLD. and none of the deaths could be attributed to the surgical intervention itself. Nine patients ( 19.6t;1) died of sepsis. and 8 patients ( 17.4t;1) died of various other causes (for ego cardiorespiratory arres\. multiple organ failure. hemorrhage. and drowning in one patient) (Fig 3a). None of these 17 patients had evidence of PTlD at the time of their death. All survivors are apparently free of disease at the present time. Eleven patients (23.9lft) were treated by decreasing their immunosuppressive drug dosages (one also received al-pha-interferon (a-IFNI> and 5 (45.St;1, are still alive. Twel\e patients (26.1'k1 had their immunosuppressive drugs decreased. as well as high dose acyclovir or a-IFN therapy: 6 (SO'k) are still alive. Five patients (IO.7t;1) were treated with a decrease of their immunosuppression com-bined with resection of at least one tumoral mass and all (\ooq I survived. Five patients (10.7%) were treated with immunosuppression reduction. high dose acyclovir. and resection: they are all alive (100C7c). One patient (2.21)t) had immunosuppression reduced and conventional chemother-apy without survival. One patienl (2.211) was treated with immunosuppression reduction. conventional chemother-apy. and resection: she survived tumor-free for S years. STIEBER. BOILLOT, SCOTII-FOOLENI ET Ai... a PTlD and mortality b SurvlYal by SptSClflC treatment regimen • _ '."'GD 1/1) .. • • • ....... ... ...,.,.... D O.CT .... ~ ",.,.." - .u.o' ~~~::KKKI . ..,-. D_: C Survival of resection VS. non-resection groups ~ • ~ • --.. -, • .GOt Fig 3. but died of sepsis 6 years after OLT. Finally one r"tient (2.21)t I was onh' treated with resectional therap~ and survived (Fig 3bl. Ten patients C!1.7t;1) were diagno~d as having PTLD only at the postmortem examination. DISCUSSION It is now quite clear that PTlDs are the end result of the modification~ caused by the antirejection therapy on the host immune system. All major immunosuppressive d~gs (CyA. azathioprine. antilymphocytic globulin prerara-tions. and monoclonal antibodies) have been m:pli-cated. ~Ia The mechanisms known or presumed t(\ be implicated in the de\'eIopment of PTLDs have been n:en-sively studied. U.Y Two factors complicate the management: (I) since PTLDs are a result of overimmunosuppression. treatmtnt with conventional antineoplastic chemotherapy could ac-celerate the process: and (2) the reduction or discontinua-tion of the immunosuppression. with the purpose of ree<;-tablishing the host defenses ma}' result in graft rejection. The essence of mana@lement is to allow enough immune reconstitution to permit oncologic surveillance to be esLlb-lished. while maintaining graft function. The balance may be favorably altered by treatment with acyclovir. since the tumors have a viral etiology. 10.11 Surgical intel'\'ention in transplant patients who develop L YMPHOPROLIFERATlVE DISORDERS PTLDs is done either for diagnostic or therapeutic pur-poses. Diagnostic biopsie~ were performed in 21 patients. In addition. clinical criteria (high index of suspicion. lymph-adenopathy by CT s.:an. elevated uric acid levels l ) were also taken into consideration. Biopsies allow both accurate diagnosis and classification I. 7 of the lesions. with the polyclonal disorders having a better prognosis. 1.1.7 In nine patients. the surgical intervention had a thera-peutic purpose. This was either intended as a primary resection of involved tissue with the goal of eradicating residual tumor or as a means of dealing with PTLD complications. Small bowel perforation was characteristic in patients with gastrointestinal involvement. The perfora-tions commonly occurred during the early remission phase. presumably \I, hen transmural lesions were under-going necrosis. The accepted treatment of PTLDs is a reduction or temporary suspension of the immunosuppressive regimen. coupled with adjunctive chemotherapy with acyclovir. The early attempts at treatment with conventional antineo-plastic chemotherapy lead to worsening of the patients' condition and death. < This is easily e\plainable on basis of the theory that the posttransplant Iymphoproliferative dis-orders are the result of immunosuppression. Conventional chemotherapy adds its immunosuppressive effect to that of the antirejection therapy. thus preventing the body's de-fenses from successfully fighting the EBV-triggered neo-plastic process. The underlying theme in patients with PTLD is thus an overimmunosuppressed status. This not only results in the I} mphoproliferative disorder itself. but also leads to frequently lethal septic complications. In fact. sepsis was the most frequent cause of immediate or delayed death in our group. Isolated visceral tumors can behave like ordinary gas-trointestinal lymphomas. in the sense that an adequate local resection can be curative in many patients. even if the tumor has not regressed \I, ith reduction of the immunosup-pression and acyclo\ir. Patients with these tumors hal .. e benefited from aggressive surgical resection: 12 of 24 patients treated only medkally (S<YC) survived as com-pared with II of 12 (91. 7C;( I treated \10 ith a combination of medical manipUlation and surgical resection (p < .(01) (Fig 3c). Thus surgery emerges as a very pO\loerfultool in the treatment of PTLDs. 1479 If operation is not perf()fl11ed in such cases. high index of suspicion and careful m\."\nitoring are necessary in order to diagnose early the occurrence of perforation. The patient is probably not "safe" until the complete disappearance of the mass has been documented by CT scan or endoscopy. Tonsillar involvement has been frequent in the pediatric age group: consequentl~ . tonsillectomy often has been the means for diagnosing PTLD in children. However. the danger of postoperati, e edema with acute respiratory distress dictates that onl~ a unilateral tonsillectomy should be performed if the pnxedure is primarily for diagnostic purposes. Now that the disease can be treated so well by medical means. tonsille-.=tomy is not often indicated any longer. The mortality of liver transplant recipients with PTLDs has been higher than that for kidney transplant recip-ientsl.<·': higher immunosuppressive drug doses. more generalized organ invo" ement. and above all. deteriora-tion of a vital graft without artificial organ support account for this difference. REFERENCES I. Nalesnik MA. Mako ... ka L. Starzl TE: In Ravitch M (ed): Current Problems in SUfl:Cry. Year Book Medical Publishers. ChicaLZo. IL. 1988. p 367 2. Nalesnik MA. iock~r J. Jaffe R. et al: Transplant Proc 20 (Suppl II: 280. 1988 3. Penn I. Hammond". Brettschneider L. et al: Transplant Proc I: 106. 1969 4. Penn I. HalLZrimson CG. Starzl TE: Transplant Proc 3:773. 1971 ~K Starzl TE. ~alesnik ~fK~K Porter KA. et at: Lancet 8377:583. 19114 fl. StarLI TE. Penn 1. Pvnam CWo et al: Transplant Rev 7: 112. 1971 7. Makowka L. :-.Ialesr.:1.. ~tK Stieber :\c. et al: In Good RA fed): The Nature. Cellular and Biochemical BaSIS and Manage-ment of fmmunodefkienK:~sK FK Schattauer Verlag. Stutt(Zart. Germany. 1987. p ~ST 8. Thiru S. Caine RY. :"\agington J: Transplant Proc 1P:P~9K 1981 9. Hanto OW. dajl-meK:zK;Kf~ka KJ. Frizzcra G. ct al: Ann Surg 19U:P~SK 1983 10. Purtilo DT: Adv Ca."l.:er oe~ 34:279. 1981 II. Hanto DW. Frizzer.. G. Gajl-Peczalska KJ. et al: Trans-plantation 39:461. 19U~ 

The surgical implications of the posttransplant lymphoproliferative disorders.

Stieber, AC

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The surgical implications of the post-transplant lymphoproliferative disorders

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The surgical implications of the posttransplant lymphoproliferative disorders.

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