epstein-barr virus-related localized hepatic lymphoproliferative disorders after liver...

1344

Epstein-Barr Virus-Related Localized Hepatic Lymphoproliferative Disorders after Liver Transplantation Eric Raymond, M.D.,* Vivianne Tricottet, Ph.D.,t Didier Samuel, M.D.,$ Michel Reynis, M.D.,t Henri Bismuth, M.D.,$ and Jean-Louis Misset, M.D.*

Background. Localized hepatic post-transplant lymphoproliferative disease is uncommon. In such cases, lymphocyte Epstein-Barr virus (EBV) infection may pro- mote an intrahepatic B-lymphocyte monoclonal expan- sion.

Methods. From 1990 to 1991,149 patients underwent liver transplantation for various liver failures. Immuno- suppressive therapy was azathioprine, cyclosporine-A, and methylprednisolone. Rejection episodes were treated by methylprednisolone bolus injection with or without OKT3 therapy. Three patients (2%), aged 38, 50, and 47 years, developed lymphoproliferative disease localized in the transplanted livers within 5 months of liver transplantation (a patient had been immunusuppressed for 3 years before the lymphoproliferative disease occurred within the third allografted liver). Diagnoses were obtained by fine needle aspiration. In situ hybridizations were performed with the kappa/lambda mRNA-kit FITC DAKO (DAKO Corporation, Carpenteria, CA) and the early mRNA-EBER oligonucleotide FITC DAKO.

Results. Lymphoproliferative diseases were all classified as diffuse polymorphic large cell lymphomas in the working formulation and considered as lymphoproliferative disorders with polymorphic large cells in the Friz- zera classification. All large cells were CD2O-positive, CD45-positive and CD45RO-negative. In situ mRNA light chain hybridization demonstrated monoclonality in two cases. In all three cases, EBV mRNA was detected in large cells by early mRNA-EBV (EBER) in situ hybridization.

Presented in part at the 1995 Annual American Association for Cancer Research meeting, Toronto, Canada, March 18-22, 1995.

From the *Department of Medical Oncology and Hematology, "Service des Maladies Sanguines Immunitaires et Tumorales"; the TDepartment of Pathology; and SHepatobiliary Surgery and Liver Transplant Research Unit, Hospital Paul Brousse, Villejuif Cedex, France.

The authors thank E. Cvitkovic for critical reading of this article. Address for reprints: Eric Raymond, M.D., Service des Maladies

Sanguines Immunitaires et Tumorales (SMSIT), H6pital Paul Brousse, 14 Avenue, Paul Vaillant Couturier, BP 200, 94804 Villejuif Cedex, France.

Received March 3, 1995; revision received May 30, 1995; accepted June 26, 1995.

Patients were treated with doxorubicin, cyclophosphamide, vincristine, and VM26. Two patients maintained a complete remission 3 years after six cycles of chemotherapy, whereas one died of an early opportunistic infection.

Conclusion. Epstein-Barr virus may play a special role in the pathogenesis of lymphoproliferative disorders that develop in patients who have undergone liver transplantation. Cancer 1995; 76:1344-51.

Key words: liver transplantation, lymphoma, lymphoproliferative disorders, immunosuppression.

Posttransplantation lymphoproliferative disorders (PTLDs) are well recognized complications of organ transplantation and therapeutic immunosuppression. These disorders more often have high grade and extra- nodal localizations than lymphomas occurring in non- immunocompromised patients. A recent collaborative study quantified the risk of PTLDs after kidney and heart transplantation to be 20 and 120 times higher, respectively, than the rate in the general population.' In liver allograft recipients, the overall incidence of lymphoproliferative disorders has been retrospectively assessed to range from 3.6 to 7.3%.2-4 However, the risk of developing neoplastic disease is known to vary with the kind of graft transplanted and is related to the ag- gressiveness of the immunosuppressive drugs used. Be- sides, a wealth of evidence suggests that Epstein-Barr virus (EBV) carrying lymphoid cells may have a special role in the pathogenesis of PTLD.5

Until recently, only four cases of localized lymphoma involving the transplanted liver (LLTL) have been reported, to the best of our Diagno- sis of LLTL was difficult, because clinical, biologic, and radiologic manifestations could be related to opportunistic infections and other liver allograft complications. Pathologic and immunohistochemical analyses have revealed malignant B large cell PTLDs, and some have suggested that lymphoproliferations may be either of recipient or donor origin.

Graft-Liver Lymphoprolilerative Disorders/Raymond et af. 1345

We present three new cases of LLTLs, all EBV positive. These cases and a review of the literature show that LLTLs differ in many way from usual diffuse PTLDs involving the liver and suggest similarities between LLTL and primary hepatic lymphoma. We suggest than LLTL be regrouped as a common nosologic entity. Our therapeutic option-chemotherapy-is dis- cussed.

Patients and Methods

Case Material

From February 1990 through July 1991, 149 patients underwent liver transplantation for various liver disorders in the liver transplant unit of Paul Brousse Hospital. The standard immunosuppressive regimen was azathioprine (2 mg/kg/ day), methylprednisolone (10 mg/kg on day 1, decreased to 0.3 mg/kg/day on day 7) and cyclosporin A (venous continuous infusion 1 mg/kg on day 1, increased to reach 5 mg/kg/ day, followed by oral maintenance dose from day 15). Rejec- tion episodes were assessed with liver biopsies and treated by methylprednisolone bolus injection (1 g). Refractory rejection episodes were treated by additional OKT3 treatment. During this period, three cases (2%)~ of localized posttransplantation lymphoproliferative disorders were observed, as described below.

Patient 1. In February 1987, a 35-year old man underwent orthotopic liver transplantation for acute liver failure related to piroxicam toxicity. The patient’s posttransplantation course included renal failure and acute rejection begin- ning 5 days after transplantation. At day 25 after transplantation, cholangiography revealed sclerosing cholangitis, and liver biopsy showed cytomegalovirus hepatitis infection. The deterioration of liver function lead to a second orthotopic liver transplantation in June 1987. In September 1989, physical examination revealed mild ictems. Evaluations revealed cholangitis and subacute liver rejection associated with thrombosis of the hepatic artery. A third orthotopic liver transplantation was performed in January 1990. Epstein-Barr virus serology (EBV nuclear antigen and v:iral capsid antigen) results were positive at the time of transplantation. The major early posttransplantation complications were an intrahepatic fungal abscess (Candida albicans) needing drainage and acute bleeding from esophageal varices. During the first month after liver transplantation, a monoclonal rise of immunoglobulin lambda light chains was observed. In May 1990 (4 months after the third liver transplantation), ultrasonography revealed three solid nodules bracketed in the right hepatic lobe. A fungal abscess was suspected. A first ultrasonographically guided puncture was unrevealing, and blood cultures were negative for fungi and bacteria. A second percutaneous ultrasonographically guided liver biopsy revealed a malignant PTLD. Further standard staging procedures, including clinical examination, computed tomography (CT) scans of the chest and abdomen, and bone marrow examination, failed to dis- close other sites of disease. lHuman immunodeficiency virus (HIV) types 1 and 2 serology results remained negative.

Patient 2. A 50-year-old man with a 7-year history of hepatitis C virus cirrhosis developed an acute hepatic failure in January 1990. He underwent orthotopic liver transplantation in February 1990. Epstein-Barr virus serology results (EBV nuclear antigen and VCA) were positive at the time of transplantation. Histopathologic examination of the liver revealed a 1.5-cm hepatocellular carcinoma in the right lobe. The patient’s postoperative course included systemic sepsis due to Staphyiococcus aureus, pneumonitis, and peritonitis, thus a second laparotomy was performed. Five months after transplantation, in July 1990, the CT scan revealed a focal 7- cm solid intrahepatic lesion expanding in the left lobe or the liver. Concurrently, a fever and clinical and radiologic pneumonitis developed. Blood counts revealed leukopenia and thrombocytopenia. Cytomegalovirus infection was diagnosed in the bronchial washings, and the patient was treated with ganciclovir. Serology results for HIV remained negative. ACT scan-guided hepatic biopsy revealed a PTLD. No increased level of immunoglobulins was observed. Further staging, including clinical examination, chest and abdominal CT scans, and bone marrow biopsy, failed to reveal other sites of disease.

Patient 3. A 47-year-old man with a 5-year history of hemochromatosis underwent orthotopic liver transplantation in December 1990. Serology results for EBV were negative at the time of transplantation. A few days before transplantation, the patient had acute bleeding from esophageal varices. Three months after the operation, a systemic infection with cholangitis caused by Escherichia coli was diagnosed and treated with antibiotics. Laboratory studies reveal an increased level of bilirubin, aspartate transaminase, alanine transaminase, and lactic dehydrogenase levels. A CT scan revealed disseminated multilocular nodules within the liver. An ultrasonographically guided biopsy was performed. Histo- pathologic findings revealed a multilocular PTLD. Serology results for HIV were negative. An increased level of IgG kappa chains was observed. Extensive workup, including clinical examination, chest and abdomen CT scans, and a bone marrow biopsy, failed to reveal any extrahepatic lymphoma.

Treatment

Initial therapeutic intervention based on a reduction of the immunosuppression level was coupled with chemotherapy. The chemotherapeutic regimen consisted of doxorubicin 45 rng/m2 day 1, cyclophosphamide 300 mg/m2 days 2-5, vincristine 2 mg day 2, and teniposide 100 mg/m2 day 6. Six of these treatment cycles were given at 4-week intervals. Toxicity and response to chemotherapy were assessed with use of the World Health Organization criteria.

Pa thologic Studies

Tissue specimens were obtained by liver biopsy; fixed in a solution of ethanol, formaldehyde, and acetic acid; and embedded in paraffin. Fine-micron sections were

1346 CANCER October 25,1995, Volume 76, No. 8

stained with hematoxylin-eosin. The lymphoid in- filtrations were classified in accordance with the Na- tional Cancer Institute's working formulation of non- Hodgkin's lymphomas and with the posttransplantation lymphoproliferative disorders classification estab- lished by Frizzera et a1.I'

Immunohistochemical cell typing was performed to detect the following antigenes: CD20, CD45 (LCA), and CD45RO. A multilinked secondary antibody labeled with peroxydase was used and detected using diamino- benzydine and H202.

In situ hybridization was used to detect the presence of EBV and immunoglobulin light chain mRNAs. The probes used were, respectively, an EBV-specific early-mRNA EBER oligonucleotide fluorescein isothio- cyanate (FITC) (DAKO) and a kappa/lambda mRNA kit FITC (DAKO). The FITC probes were detected by anti-FITC antibodies with alkaline phosphatan and alkaline phosphatase system detection. Clonality of tumors was assessed by Kappa/lambda ratios as described by Nalesnik et al."

Results

Pat ho logic Findings

The LLTLs were classified as polymorphic diffuse large cell lymphomas in the working formulation. The immunohistochemical study showed a strong positivity for CD20 and CD45 and a negativity of the large cells for the CD45RO. For Patients 1 and 3, the mRNA kappa light chain was highly expressed, with a superior kappa/lambda ratio of 5:l (Fig. 1). Unfortunately, this study was not performed for Patient 2 because the sam- ple was to small.

Based on these results, the three cases can be classified as lymphoproliferative disorders with polymorphic large cells in the Frizzera classification. The monoclonality was demonstrated for Patients 1 and 3.

In all three cases, the specific EBV-mRNA-EBER was strongly detected in numerous large lymphoid cells (figure 2).

Responses to Therapy, Patient Survival, and Graft Functions

Patients 1 and 2 received full doses of chemotherapy. Patient 3's condition was not evaluable for toxicity and response. Maximal Grade 2 neutropenia was observed in Patients 1 and 2, who had Grade 1 and Grade 3 thrombopenia, respectively.

Patient 1. A CT scan of the liver, performed at the completion of chemotherapy, revealed the persistence of a hypodense mass. Serologic lambda light chains had

Figure 1. Light chain mRNA in situ hybridization (original magnification X400). (Top) Kappa chain. Numerous cells are expressed strongly in the cytoplasm in the presence of the Kappa chain. (Bottom) Lambda chain. In the same area, very rare lymphoid cells are positive. The ratio is superior, at 5:1, for the kappa chains.

disappeared after six cycles of chemotherapy. Histo- pathologic examination of the mass specimen obtained by ultrasonographically guided liver biopsy showed that the lesion consisted of a necrotic area without residual lymphatic tumor. No further treatment was given. One year after chemotherapy, a calcification ap- peared at the original site of the liver lymphoid lesion. The patient's disease is in complete remission 6 years after the first transplantation and 38 months after the diagnosis of LLTL. The hepatic function parameters have been normal while this patient has been receiving maintenance dosages of cyclosporine and prednisolone.

Patient 2. After the sixth course of chemotherapy, the liver CT scan showed a residual 1.6-cm nodule. This nodule disappeared progressively during the next months. No rejection of the transplanted liver was observed. The patient's disease is in complete remission 38 months after the diagnosis of hepatic lymphoma, and hepatic function is preserved.

Patient 3. Azathioprine was stopped, and biologic

Graft-Liver Lymphoproliferative Disorders/Raymond e t al. 1347

Figure 2. EBV-mRNA EBER in situ hybridization. Numerous nuclei are strongly positive (original magnification X400).

examinations showed decreased aspartate transaminase, alanine transaminase, and lactic dehydrogenase levels, but multilocular intrahepatic nodules remained unchanged. A first course of combined chemotherapy, which involved doxorubicin, vincristine, teniposide, and cyclophosphamide, was given. Two weeks after the start of this treatment, an acute pneumonitis was diagnosed during a Grade 3 neutropenic episode. Cytomeg- alovirus and Pneurnocystis carinii were observed in bronchial aspiration samples. The patient was treated with ganciclovir, trimethoprim, and sulfamethoxazole but died of acute respiratory distress syndrome. Craft function remained norm,al until death.

Discussion

Because liver transplantation is an accepted therapy for irreversible liver failure of different causes, there is great interest in posttransplantation lymphoproliferative malignancies. The cause of PTLD is multifactorial and has included the respective roles of dosage and agents used for immunosuppression, EBV infection, and probably unknown oncogenic graft-versus-host immunologc conflicts induced by liver transplantation."

The importance of combinations and doses of immunosuppressive drugs in the development of PTLD has been emphasized b y several a~thors.", '~- '~ It ap- pears that patients receiving immunosuppressive drugs are unable to mobilize the cytotoxic T-cell response nec- essary to control the proliferation of B cells infected by EBV.I7-l9

Latent EBV infection has been detected in the lym- phocytes of the majority of PTLDs observed in immunocompromised patients.20-22 A high expression of early mRNA transcribed by the EBER-1 gene is observed in EBV-induced PTLD lymphoid cells.23 A

multistep process is suspected. A generally accepted model implies EBV-induced benign polyclonal B-cell proliferation, with secondary events that result in malignant monoclonal B-cell lymphoma. A third potential mechanism suggests antigenic stimulation promoted by human lymphocyte antigen mismatching graft, which might result in uncontrolled proliferation, as suggested by Egan et al.24 Prolonged experimental antigenic stimulation is known to induce lymphatic neoplasia in mice. Continuous antigenic stimulation associated with nonspecific infectious diseases (e.g., cytomegalovirus, fungal infection) in transplant recipients may trigger the proliferation of a lymphocyte clone, eventually result- ing in malignant lymphoproliferative disorder. Thus, lymphomas are a well recognized complication after heart, lung, or kidney transplantation. 1f24-26

Since 1990, three cases of PTLD involving liver transplantation exclusively have demonstrated several characteristics that differentiate this form of the condition from others. Three men, age range 38-50 or 38, 47, 50 years, who had undergone liver transplantation developed diffuse large cell LLTLs within 5 months of the procedure. The only exception was Patient 1, for whom the interval between the first transplantation and diagnosis was 37 months, but in this case the time from the last (third) transplantation was only 5 months. Post- transplantation liver disorders have occurred within 17 months in all published cases.3 Early-onset PTLD pref- erentially occur!j in patients with aggressive early rejection who received high doses of immunosuppressive drugs, and late PTLD seems to develop in patients with low grade rejection, who have been receiving low doses of immunosuppressive drugs. The short interval to diagnosis observed in our patients could be due to closer imaging follow-up, or to a more potent immunosuppression.

Since 1991, only two cases of diffuse Stage IV PTLDs have been observed in our institution. Most of the patients treated since then have received FK506 as substitute for cyclosporine therapy, and OKT3 therapy for refractory rejection episodes has been abandoned progressively. 'These modifications may partially ex- plain the absence of further PTLD observations.

Previous reports have described an increased incidence of monoclonal immunoglobulins in posttransplant imrriunocompromised patients, suggesting the presence 01' deregulated B-lymphocyte clones.27r2s In the current report, we observed an increased level of immunoglobulins in two patients. Patient 1 developed a serologic monoclonal lambda low chain during the first months after the third transplantation, which disappeared at the time of complete remission.

So far, only four other cases (occurring in five men and seven women, current study included) of localized

1348 CANCER October 25, 2995, Volume 76, No. 8

Table 1. Clinical Features and Pathologic Findings in

Interval: allograft to Age

Patient (yrs) Immunosuppressive diagnosis Contemporaneous (re0 at Tx Sex Original disease therapy Rej (mod Clinical presentation infection

1 38 M Fulminant hepatitis Prednisone, CyA Yes 37 3 abscess images in Fungal abscess in caused by piroxicam liver on CT liver toxicity

2 50 hl Cirrhosis due to chronic Methylprednisolone, No 5 hepatitis C infection Aza, OKT3 with hepatocarcinoma

3 47 M Hemachromatosis with Methylprednisolone; No 3 cirrhosis Aza, CyA

49 25 F Wilson's disease with acute hepatic failure after anesthesia

Prednisone, Aza, Yes 4 CyA, OKT3

7-cm mass in segment CMV pneumonitis IV

Fever and multilocular nodes in liver on the CT (abscess ?)

Fever, malfunctioning liver, fungal abscess suspected in liver on CT

E. coli cholangitis, systemic infection bacteroides fragilis , CMV and Pneumocystis carinii pneumonitis

No

57 42 M Decompensated cirrhosis Prednisone, Aza, No 2 Malfunctioning liver No due to chronic CYA several nodules hepatitis B infection within liver on MRI

6' 54 M Liver failure due to Methylprednisolone, Yes 5 Icterus, 3-cm mass CMV infection on chronic hepatitis C Aza, CyA, OKT3 posterior to left lobe liver biopsy infection of liver on CT

76 49 F Primary biliary cirrhosis Prednisone, Aza Yes 5 Icterus P. carinii pneumonia

ref reference no.; Tx: transplantation; CyA: cyclosporine; Aza: azathioprine; Rej: rejection; CT: computed tomography scan; MRI: magnetic resonance imaging; CMV: cytomegalovirus; PCR: polymerase chain reaction; EBV: Epstein-Barr virus; DOXO: doxorubicin; VCR: vincristine; CTX: cyclophosphamide; VM26: tenoposide; EPI: eoirubicin: CR: comdete resmnse.

hepatic PTLD (Table 1) have been de~cr ibed .~-~ Median age was 43 years.

The diagnosis was suspected by means of ultra- sound or a CT scan of the liver. Contrast-enhanced CT examinations revealed a nodular solid intrahepatic lesion sometimes with a low density central area (autopsy- or biopsy-revealed necrosis) at times. The multifocal characteristic of those nodules could be an important variable for prognosis, because the three patients with multifocal nodular disease died rapidly. The differential dlagnosis entails the elimination of opportunistic infections (including bacterial, fungal, parasitic, and mycobacterial infection) also occurring within 6 months after transplantation. In some cases, the fever

caused by systemic bacterial (Patient 3 ) or cytomegalovirus concomitant infection (Patients 2 and 3 ) can be attributed to abscess f o r m a t i ~ n . ~ ~ , ~ '

We therefore recommend a CT scan or ultrasonographically guided biopsy for histopathologic diagnosis. This type of testing reveals a diffuse infiltrate of large lymphoid cells with basophilic cytoplasm and prominent nucleoli. For all patients, the LLTL was classified as polymorphic diffuse large cell lymphomas (working formulation). The pathologic features of LLTL differ from the immunoblastic HIV-related lymphomas. In all cases, immunophenotypic analyses revealed a monoclonal B-cell lineage.

The cellular origin of LLTL can be determined by

Graft-Liver Lymphoproliferative DisorderslRaymond et al . 1349

Clinical Features and Pathologic Findings in Isolated Hepatic Lymphomas After Liver Transplantation

Immunohistochemistry/ EBV _ . Diagnosis (Frizzera) Multifocal immunophenotype hybridization Treatment Outcome

Diffuse large-cell lymphoma (lymphoproliferative disorders with polymorphic large cells)

Diffuse large-cell lymphoma (lymphoprolifera tive disordels tih polymorphic large cells)

Diffuse large cell lymphoma (lymphoproliferative disorders with polymorphic large cells)

3 nodes iin same paraffin only: CD45 (LCA)+, mRNA EBV CD45RO (UCHL1)-, CD2O+, detected monoclonal mRNA kappa

area

No

Yes

mRNA EBV paraffin only: CD45 (LCA)+, CD45RO (UCHL1)-, CD20+, detected mRNA Kappa/lambda nonsignificant

paraffin only: CD45 (LCA)+, CD45RO (UCHL1)-, CD20+ detected monoclonal mRNA kappa

mRNA EBV

Malignant lymphoma, diffuse large cells

No paraffin only: monoclonal cytoplasmic immunoglobulins and f i types, HLA-DR (LN3)+, CD45RO (UCHL1)-, MAC-, PKKI-, Vimentin-desmin-, 5100-. Recipient origin (cytogenetic)

Malignant lymphoma, Yes paraffin: "B-cell markers" I diffuse large cells

Malignant lymphoma, No diffuse large cells

DOXO, VCR, CTX, CR, alive in CR 44 VM26 (X6 mos) months+, graft

function retained to date

DOXO. VCR,. CTX, CR, alive in CR 44 VM26 (X6 mos) months+, graft

function retained to date

DOXO, VCR, CTX, VM26 X 1 cycle

Died of pneumonia (CMV, pneumocystis) 3 wks, graft functioned until death

nuclear antigen Acyclovir and 6-drug EBNA + in combination tumor cells chemotherapy with

EPI and VP16 X 1 mo followed by surgical extirpation of lesion

EBV DNA + in Withdrawal CyA, tumor cells reduction of

prednisone dose, acyclovir

CR (no lymphatic tumor remaining on histopathologic exam), alive in CR 36 months +, graft function retained to date

Died rapidly of malignant lymphoma (autopsy +)

Frozen sections: IgC-k +, CD20 Not done Surgery and radiation Not done +, CD5 -, CDlO -, CD3 +/ -. Donor origin (PCR) mass

therapy at region of

Reticulum cell sarcoma Nodules 1- to 2- No immunophenotype Not done No treatment Died rapidly of cm diameter performed, histologic sexing (diagnosis made malignant lymphoma in right lobe techniques reveal malignant after necropsy) (autopsy t)

cells of host origin

histologic and cytogenetic sex-identification techniques or through the polymerase chain reaction. In one case the origin of LLTL was the donor8 and in two cases the h ~ s t . ~ , ~ In our cases, two patients were transplanted with sex-mismatched grafts, but discriminant techniques were not performed.

Epstein-Barr virus encoded small RNA transcribed by EBER-1 gene during latent EBV infection was detected in lymphoproliferative cells in most cases of PTLD. Other researchers have detected a strong corre- lation between RNA-EBER expression and PTLD. They have suggested the possibility of identifying patients at risk for PTLD through in situ hybridization in liver specimens.23 This technique showed a high expression of mRNA-EBV (EBER) in all our cases.

Our observations as well as the literature suggest

some similarities between LLTL and primary hepatic lymphoma. Occurrence of the latter in a nonimmuno- compromised population is extremely rare. Fewer than 100 case reports of this occurrence have been pub- l i ~ h e d . ~ ' A search of the autopsy files of Washington University School of Medicine, including over 32,000 autopsies, revealled a single case involving primary hepatic Most of the patients were male and had nonspecific symptoms, such as fever or weight loss. Most patients had palpable hepatomegaly and biologic liver dysfunctions. Hepatic lymphoma was com- posed of large cells with abundant, deeply eosinophilic cytoplasm and central nucleoli. Mitotic rate was high and normal mitoses were rare. Immunohistochemical studies revealed a B-cell lineage in 80% of cases. Pri- mary hepatic lymphoma seems to have a better progno-

1350 CANCER October 25,1995, Volume 76, No. 8

sis than advanced lymphomas with gastrointestinal tract involvement. Some have argued that primary hepatic lymphoma confined to one site probably involves a smaller tumor burden and therefore a better prognosis. Recent reports have suggested that chemotherapy is highly effective against primary hepatic lympho- m a ~ . ~ ~ - ~ ~

Therapy for posttransplantation-related malignancy remains controversial. Cherqui et al. described partial remission for prolonged periods after reduction of immunosuppressive therapy in posttransplantation lymphoma.35 Others have found that high doses of acyclovir are effective against tumors. Studies have shown that localized lesions occurring within the allografted liver have been amenable to surgical resection in two cases. For one of these patients, surgery was followed by radiotherapy, but the follow-up has not been published.* The other patient was the only one treated with combined chemotherapy involving six different drugs.’ In this case, the pathologic examination of the remaining liver lesions after surgery showed complete response. When the amount of immunosuppressive drugs was reduced, patients died rapidly of evolutive malignant lymphoma. 36

Our patients’ initial clinical presentations were sim- ilar to those of patients without transplantations who had primary hepatic lymphoma. Histopathologically, lymphoproliferative disorders contained polymorphic large B cells, and monoclonality could be demonstrated in two cases. It seems that these monovisceral lesions differ from usual diffuse oligoclonal lymphoid prolifer- ations observed in PTLD. We therefore chose to treat them with curative-intent chemotherapy. Simulta- neously, the immunosuppression was reduced. Two patients tolerated 6 months of chemotherapy with sub- sequent long term complete remission without graft rejection or opportunistic infection. The third patient died of early infection, which may have been facilitated by Grade 3 neutropenia. Even if chemotherapy is a valid therapeutic option for treatment of LLTL, we must con- sider the increased risk of infectious complications due to immunosuppression and neutropenia in this particu- lar form of lymphoma.

References

1, Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993;342:1514-6.

2. Renard TH, Andrews WS, Foster ME. Relationship between OKT3 administration, EBV seroconversion and the lymphoproliferative syndrome in pedlatric liver transplant recipient. Transplant Proc 1991;23:1473-6. Stieber AC, Boillot 0, Scotti Foglieni C, Nalesnik MA, Gordon RD, Starzl TE. The surgical implications of the post transplant lymphoproliferative disorders. Transplant Proc 1991; 23: 1477-9.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

16.

17.

18.

19.

20.

21.

22.

Levy M, Backman L, Husberg B, Goldstein R, Mcmillan R, Klint- malm G. De novo malignancy following liver transplantation: a single-center study. Transplant Proc 1993;25:1397-9. Hanto DW, Frizzera G, Purtilo DT, Sakamoto K, Sullivan JL, Najarian JS. Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of Ep- stein-Barr virus. Cancer Res 1981;41:4253-61. Portmann B, Schindler AM, Murray Lyon JM, Williams R. His- tologcal sexing of a reticulum cell sarcoma arising after liver transplantation. Gastroenterology 1976; 70:82-4. Palazzo JP, Lundquist K, Mitchell D, Mittal KR, Hann HWL, Martin P. Rapid development of lymphoma following liver transplantation in a recipient with hepatitis B and primary hemochromatosis. A m J of Gastroenterology 1993;88:102-4. Spiro IJ, Yandell DW, Chuan Li SD, Saini S, Ferry J, Cosimi AB. Lymphoma of donor origin occurring in the porta hepatis of a transplanted liver. N Engl lMed 1993;329:27-9. Barkholt L, Billing H, Juliusson G, Porwit A, Ericzon B, Groth C. 8-cell lymphoma in transplanted liver: clinical, histological and radiological manifestations. Transplant lnt 1991;4:8-11. Frizzera G, Hanto DC, Gajl Peczalska KJ, Rosai J, Mckenna RW, Lindquist LL. Polymorphic diffuse B cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 1981;41:4262- 79. Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Locker J. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pafhol 1988; 133:173- 92. Frizzera G. Immunosuppression, autoimmunity, and lymphoproliferative disorders. Hum Pathol 1994; 25:627-9. Penn I. Tumor incidence in human allograft recipients. Transplant Proc 1979; 11:1047-52. Ferry JA, Jacobson JO, Conti D, Delmonico F, Harris N. Lym- phoproliferative disorders and hematologic malignancies following organ transplantation. Modern Pathol 1989; 2:583-92. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Bahnson HT. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; 17:

Mc Alister V, Grant D, Roy A, Yilmaz 2, Ghent C , Wall W. Post- transplant lymphoproliferative disorders in liver recipients treated with OKT3 or ALG induction immunosuppression. Transplant Proc 1993; 25:1400-1. Klein G, Purtilo D. Summary: symposium on Epstein-Barr virus- induced lymphoproliferative diseases in immunodeficient patients. Cancer Res 1981;41:4302-4. Hanto DW, Gajl Peczalska KJ, Frizzera G, Arthur DC, Balfour HH, Najarian JS. Epstein-Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative dseases occurring after renal transplantation. Ann Surg 1983; 198:356-69. Kame1 OW, Van De Rijn M, Lebrun DP, Weiss LM, Wamke RA, Dorfman F. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum

Ho M, Miller G, Atchison RW, Breining MK, Dummer IS, Rosen- thal JT. Epstein-Barr virus infections and DNA hybridization studies in posttransplantation lymphoma and lymphoproliferative lesions: the role of primary infection. Infect Dis 1985; 152: 876-86. Llyas M, Trendell Smith N, Snead D. Expression of Epstein-Ban virus in liver-transplant recipients with lymphoproliferative disease. N Engl J M e d 1993;329:208-9. Hardarson S, Anderson ME, Lutz CT. Presence of Epstein-Ban

583-7.

Patho1 1994;25:638-43.

Graft-Liver Lymphoproliferative Disorders/Xaymond et al. 1351

23.

24.

25.

26.

27.

28.

29.

virus in many types of benign and malignant lymphoid lesions: detection by polymerase chain reaction and in situ hybridization. Diagn Mol Pathof 1994;3:22-31. Randhawa PS, Jaffe R, Demetris AJ, Nalesnik M, Starzl TE, Weiss LM. Expression of Epstein-Ban virus-encoded RNA (by EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med

Egan J, Stewart J, Yonan N, Amand J, Woodcock A. Non-Hodg- kin lymphoma in heart/'lung transplant recipients. Lancet 1994;343:481. Lombard0 L, Rota Scalabrini D, Vineis P, De La Pierre M. Malig- nant lymphoproliferative disorders in liver cirrhosis. Ann Oncof

Filipovich AH, Mathur A, Kamat D, Shapiro RS. Immunoregu- latory abnormalities in immunodeficient hosts with EBV-associated B cell Iymphoproliferative disorders. Blood 1990; 76(1):349. Peest D, Deicher H. Non-Hodgkin lymphoma in heart/lung transplant recipients. Lancet 1994;343:481-2. Pham H, Lemoine A, Sol 0, Azoulay D, Royer P, Samuel D, et al. Monoclonal and oligoclonal gammapathies in liver transplant recipients. Transplantation 1994; 58(2):253-7. Tubman DE, Frick P, Hanio DW. Lymphoma after organ trans-

1992;327:1710-4.

1993;4:245-50.

plantation: radiology manifestations in the central nervous system, thorax, and abdomen. Radiology 1983; 149:625-31.

30. Harris KM, Schwartz ML, Slasky BS, Nalesnik M, Makowka L. Posttransplanta'tion Cyclosporine-induced lymphoproliferative disorders: clinical and radiologic manifestations. Radiology

31. Zafrani ES, Gaulard P. Primary lymphoma of the liver. Liver

32. Strayer DS, Reppun TS, Levin M, Deschryver K. Primary lymphoma of the liver. Gastroenterology 1994; 78:1571-6.

33. Aozasa K, Misliima K, Ohsawa M. Primary malignant lymphoma of the liver. Leuk Lymphoma 1993; 10:353-7.

34. Leahy MF, Ibralrlim EM, Worth AJ. Primary hepatic lymphoma: two case reports and a review of the literature. Med and Pediatr Oncof 1982; IO:!i75-81,

35. Cherqui D, Duvoux C, Plassa F, Gaulard P, Julien M, Farcet JP. Lymphoproliferative disorder of donor origin in a liver transplant recipient: complete remission after drastic reduction of immunosuppression without graft loss. Transplantation 1993;56:1023-6,

36. Holmberg SB, Levy MF, Mulligan DC, Husberg BS, Goldstein RM, Gonwa TA, et al. Lymphoma after liver transplantation [ab- stract]. Proc Am Assoc Cancer Res 1995;36:3794.

1987; 162:697-700.

1993; 13:57-61.

epstein-barr virus-related localized hepatic lymphoproliferative disorders after liver...

Documents