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Hepatology Research 2015; 45: 356–362
doi: 10.1111/hepr.12345
Case Report
Severe post-transplant lymphoproliferative disorder after living donor liver transplantation Kaori Kuramitsu,1 Takumi Fukumoto,1 Kenji Fukushima,1 Takeshi Iwasaki,1 Masahiro Tominaga,1 Toshimitsu Matsui,2 Fumi Kawakami,3 Tomoo Itoh3 and Yonson Ku1 1
Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, 2Department of Medicine, and Department of Pathology, Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, Hyogo, Japan 3
Post-transplant lymphoproliferative disorder (PTLD) is a wellknown complication after transplantation. A living donor liver transplantation was performed on a 31-year-old man for fulminant hepatitis. He again developed liver dysfunction after 7 months. He was diagnosed as having acute cellular rejection and the steroid pulse therapy introduced resulted in little improvement. He gradually developed a high fever and right axillary lymphadenopathy appeared. Chest computed tomography (CT) was performed revealing small lung nodules and axillary lymphadenopathy. Because his serological status for Epstein–Barr virus was positive, PTLD was highly suspected and immunosuppression treatment was withdrawn with little improvement. One week later, he developed tachycardia. Chest CT was re-performed revealing an infiltration to the left
cardiac chamber. For diagnosis, axillary lymph node biopsy was performed and during the procedure, he developed ventricular tachycardia (VT). Immunohistological staining revealed PTLD of T lymphocytes, and chemotherapy was introduced on the same day he developed VT. After two cycles of tetrahydropyranyl, adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide treatment, he completely recovered. This is a first case report of severe PTLD with VT, and our case implies the feasibility of chemotherapy after the appearance of dissemination symptoms.
INTRODUCTION
incidence of PTLD in EBV seronegative transplant recipients is 24-fold higher compared to the EBV seropositive recipients.7 For the development of PTLD, immunosuppression is a major determinant.8 Therefore, PTLD usually occurs within the first year after transplantation, during the peak of the immunosuppression regimen. Clinical symptoms range from fever, tiredness and weight loss to those of lymphoma such as cervical, abdominal or thoracic lymphadenopathy. In addition, most patients develop extranodal solid tumors leading to pain, bleeding and neurological disorders. The diagnosis of PTLD can be made based on either laboratory tests or histopathology; when suspected from clinical symptoms, real-time quantitative polymerase chain reaction is effective for the detection of EBV DNA load in blood,9 and lymphadenopathy detected by imaging can be followed by tissue biopsy and histopathological analysis for staging. The categorization of PTLD is important for prognostic and therapeutic purposes. The World Health Organization’s classification of hematopoietic and lymphoid tumors includes a separate classification for PTLD.10 Based on this classification, most
P
OST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) is one of the most serious and potentially fatal complications after solid organ transplantation. The incidence of PTLD in liver transplant recipients ranges 2–3% in adults,1,2 with a higher incidence of 10% associated with pediatric transplantation.3 The increased incidence of PTLD among the pediatric transplantation is related to a higher incidence of posttransplant primary Epstein–Barr virus (EBV) infection in children compared to adult recipients,4,5 because the occurrence of PTLD is mostly associated with the activation of EBV.6 This is also confirmed by the fact that the Correspondence: Associate Professor Takumi Fukumoto, Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, Hyogo 650-0017, Japan. Email: fukumoto @med.kobe-u.ac.jp Conflict of interest: None to declare. Received 1 October 2013; revision 7 April 2014; accepted 16 April 2014.
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Key words: chemotherapy, Epstein–Barr virus, liver transplantation, post-transplant lymphoproliferative disorder
© 2014 The Japan Society of Hepatology
Severe PTLD after liver transplantation 357
Hepatology Research 2015; 45: 356+–362
CASE REPORT
A
31-YEAR-OLD MAN caught a common cold. He was treated with a cold medicine, and recovered within a few days. He developed high fever, general fatigue and vomiting 2 weeks later, and consulted a nearby clinic. There was no previous history of tobacco, alcohol or illicit drug use. Although antibiotics were administrated, his symptoms did not recover, and accordingly he consulted the same clinic again 5 days later. Laboratory tests were performed that revealed an elevated aspartate aminotransferase (AST) level of 3940 IU/L and alanine aminotransferase (ALT) of 5115 IU/L. Under a diagnosis of hepatitis A virus-related liver disease, he was transferred to a larger hospital. As he rapidly developed impaired consciousness, he was diagnosed as having fulminant hepatitis and referred to our hospital on the same day. Vital signs on admission were stable with a blood pressure of 140/106 mmHg and a heart rate of 97 b.p.m. He had flapping tremor, disorientation of time and place, somnolent tendency, and was sleeping most of the time. The severity of hepatic encephalopathy was graded between 2 and 3 based on the proposal by the Inuyama Symposium in
197218 or grade 3 based on the proposal by the World Organization of Gastroenterology, which was developed at the 11th World Congress of Gastroenterology in 1998.19 Laboratory test results for hepatitis B, C, cytomegalovirus (CMV) serology and HIV were negative. hepatitis A immunoglobulin (Ig)M antibody was negative, whereas EBV serology was positive (Epstein–Barr virus nuclear antigen [EBNA] negative, viral capsid antigen [VCA] IgG antibody positive, VCA IgM antibody positive). Under a diagnosis of fulminant hepatic failure caused either by the cold medicine or by EBV infection, plasma exchange, continuous hemodiafiltration and steroid pulse therapy were administrated. For steroid pulse therapy, he received 1000 mg (20 mg/kg) of methylprednisolone on day 1, which was reduced to 500 mg on day 2 and 250 mg on day 3. After 4 days of intensive care, as his consciousness did not recover, his 64-yearold father offered to be a living donor. Laboratory test results of the donor for hepatitis B, C and HIV were negative, whereas EBV serology was positive (EBNA positive, IgG positive, IgM negative). Blood type was identical to the recipient, and LDLT was performed using a right lobe graft. Operation time was 14 h and 40 min, bleeding volume was 2595 mL, cold ischemia time was 30 min and warm ischemia time was 52 min. Native liver volume was 1070 g and graft volume was 730 g. The original liver was histologically diagnosed as massively necrotic. Subsequent immunosuppressive therapy consisted of tacrolimus and low-dose prednisone. Figure 1 shows the kinetics of tacrolimus trough levels after transplantation. Tacrolimus trough levels ranged 15–20 ng/mL for the first 2 weeks and between 10–15 ng/mL thereafter for the first 3 months; these levels were slightly higher compared with the target trough level at each of the corresponding time (10–
25 Tacrolimus trough level (ng/ml)
PTLD are of B-cell origin (85%) and are commonly associated with EBV infection.11–13 Rarely, PTLD originates from T cells or natural killer (NK) cells with an infrequent association with EBV.14–16 Treatment of PTLD varies according to the types of lymphoproliferative disease, and basically it consists of reduction of immunosuppression and chemotherapy.17 Although numerous studies have clearly proved the association of PTLD and EBV, incidence, pathophysiology, risk factors, clinical presentation, diagnosis and treatment of PTLD varies widely among each of the recipients and accordingly still remains as a major cause of morbidity and mortality after transplantation.4–8 Herein, we experienced a severe case of T/NK-cell PTLD after living donor liver transplantation (LDLT). To date, there have been no clinical case reports of PTLD infiltrating to the left cardiac chamber and presenting the symptom of ventricular tachycardia (VT), which was also successfully treated by the induction of chemotherapy within 24 h. Although the finding is skewed because of its rarity, we emphasize the importance of aggressive investigations of cardiac involvement with PTLD cases to improve therapeutic and prognostic factors, and also the administration of chemotherapy treatment even after the appearance of dissemination symptoms.
20 15 10 5 0 0
20
40
60
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Time (days)
Figure 1 Kinetics of tacrolimus trough level after liver transplantation.
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358 K. Kuramitsu et al.
15 ng/mL for the first month and 5–10 ng/mL thereafter for the first year) because he experienced an episode of acute cellular rejection (ACR), which was successfully treated with steroid pulse therapy. He was also suffering from CMV, which was treated with antiviral therapy. He was discharged from the hospital 2 months after LDLT. After discharge, he was followed up as an outpatient every 2–4 weeks and laboratory tests were performed at each visit. Seven months later, he was admitted to the hospital for elevated levels of AST (587 IU/L), ALT (666 IU/L) and total bilirubin (1.8 mg/dL). His leukocyte count was 4500/μL (38.8% neutrophils, 5.3% eosinophils and 9.9% monocytes) on admission. The following day, liver biopsy was performed and ACR was diagnosed. High-dose corticosteroids were administrated i.v.; he received 500 mg (10 mg/kg) of methylprednisolone on day 1, which was reduced to 250 mg on day 2 and 125 mg on day 3, but he showed little improvement. His leukocyte count increased up to 10 200/μL (78.4% neutrophils, 0% eosinophils and 3.6% monocytes) on day 3 after the induction of steroid pulse therapy. Because CMV was also serologically positive, antiviral therapy was started. One week after the induction of antiviral therapy, his leukocyte count decreased to 4400/μL (51.8% neutrophils, 2.9% eosinophils, 3.4% monocytes and 41.9% lymphocytes), and after 2 weeks to 2200/μL (43.4% neutrophils, 0.9% eosinophils, 2.7% monocytes and 53.0% lymphocytes). Despite the recovery of liver function, he gradually developed unexplainable high fever once a day 1 month after admission. As progressive axillary lymphadenopathy and pain appeared, a chest computed tomography
a
b
(CT) was performed that revealed small lung nodules (Fig. 2a) and multiple axillary lymphadenopathy (Fig. 2b). At this time, there was no infiltration to the cardiac chamber (Fig. 2c). Because PTLD was highly suspected, his serological status for EBV was checked, which was revealed to be positive. As a treatment, immunosuppression treatment was withdrawn at first. He suddenly developed tachycardia 1 week later. As echocardiography examination showed less motion of the left cardiac chamber, chest CT was re-performed. Bilateral pleural effusion appeared at this time point, and an increase in the size and number of the small lung nodules (Fig. 3a), multiple axillary lymphadenopathy (Fig. 3b) and infiltration to the left cardiac chamber were revealed (Fig. 3c). For diagnosis, an axillary lymph node biopsy was performed, and during the procedure, he developed VT. Echocardiography, which was performed after the development of VT, revealed a hypoechoic lesion in the left ventricular wall, suggesting infiltration to the left cardiac chamber (Fig. 3d). Histologically, diffuse proliferation of large atypical lymphoid cells with nuclear hyperchromasia and prominent nucleoli were confirmed (Fig. 4a). In the background, a variety of inflammatory cells, including small reactive lymphocytes and eosinophils were observed. Immunohistochemically, the large cells were positive for CD3 (Fig. 4b), T-cell-restricted intracellular antigen I (Fig. 4c) and granzyme B (Fig. 4d). CD20 was positive for reactive B cells, but negative for atypical cells (Fig. 4e). A large number of atypical cells were positive for EBV by in situ hybridization (Fig. 4f). Histological examination revealed EBV-related neoplastic proliferation of cytotoxic T cells, and finally he was diagnosed as
c
Figure 2 Chest computed tomography of the patient which was performed 1 month after re-admission. The patient developed unexplainable high fever once a day, progressive axillary lymphadenopathy and pain at this time point. White arrow indicates (a) small lung nodules and (b) multiple axillary lymphadenopathy. (c) There was no infiltration to the cardiac chamber.
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 356+–362
a
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Severe PTLD after liver transplantation 359
c
d
Figure 3 The patient suddenly developed tachycardia and chest computed tomography (CT) was performed 1 week later since the first chest CT (Fig. 2). Bilateral pleural effusion appeared at this time point. White arrow indicates an increase in the size and number of (a) small lung nodules and (b) axillary lymphadenopathy. (c) White arrow indicates infiltration to the left cardiac chamber. (d) Echocardiography, which was performed after the development of ventricular tachycardia. White arrow indicates hypoechoic lesion in the left ventricular wall, suggesting infiltration to the left cardiac chamber.
having monomorphic T/NK-cell PTLD. Chemotherapy was introduced on the same day. After two cycles of tetrahydropyranyl, adriamycin (pirarubicin), cyclophosphamide, vincristine, prednisolone and etoposide (THP-COPE) treatment, he recovered and was discharged from the hospital. Ten years after LDLT, he is still free of recurrence and treated at an outpatient clinic every 2 months.
DISCUSSION
W
E DESCRIBED A case of severe T/NK-cell PTLD, which infiltrated into the left cardiac chamber and the patient developed VT. The recipient was successfully treated by the introduction of chemotherapy on the same day he developed VT, and he is still free of recurrence 10 years later. Our study is unique because there are no other reported cases of PTLD that infiltrated
into the left cardiac chamber and presented the symptom of VT. Cardiac infiltration by hematological neoplasms leading to clinically detectable cardiovascular disease is extremely rare. In the clinicopathological study of 25 autopsy cases that revealed cardiac involvement of malignant lymphoma, cardiac manifestation was evident in eight (32%) cases and no case was diagnosed before death.20 In their report, the authors also stated that T-cell lymphomas invaded the heart more frequently with a greater variety of cardiac manifestations compared with B-cell lymphomas. Chemotherapy and/or radiotherapy have been already reported as a successful treatment for cardiac lymphoma.21–24 These previous data also suggest the importance of our study; aggressive investigations of cardiac involvement are strongly recommended for cases of PTLD, and chemotherapy should be administrated even after cardiac manifestation because severe clinical symptoms
© 2014 The Japan Society of Hepatology
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a
b
c
d
e
f
Figure 4 For diagnosis, an axillary lymph node biopsy was performed. (a) Diffuse proliferation of atypical lymphoid cells (hematoxylin–eosin, original magnification ×400). (b) Atypical cells were positive for CD3 (×400). (c) T-cell-restricted intracellular antigen I (×400). (d) Granzyme B (×400). (e) Epstein–Barr virus-encoded small RNA (×400). (f) Although reactive B-cells were scattered, neoplastic cells were negative for CD20 (×400).
resulting from cardiac dysfunction are amenable to aggressive treatment. The clinical symptoms of PTLD are highly variable and sometimes delay the diagnosis. Although PTLD may occur at any time after transplantation, the risk is at its highest level within the first year after liver transplantation.8 Several factors have been described to contribute to the development of PTLD. Suppression of recipient T-cell function by calcineurin inhibitors and antilymphocyte antibodies facilitates clonal expansion of EBVinfected B cells, thereby increasing the risk of PTLD.25 Moreover, the use of tacrolimus has also been reported to be associated with a higher incidence of PTLD compared with cyclosporin.26 Other previously reported factors were the presence of viral infections,27 use of OKT3,28 EBV-IgG negative status in recipient pretransplant sera,27 lower age,29 race,30 allograft type31 and host genetic variations.32 In our case, tacrolimus trough
© 2014 The Japan Society of Hepatology
levels were slightly higher compared with the target trough level, which might have resulted in the subsequent PTLD. Aside from the degree of immunosuppression, the possible risk factors in our case were EBV and CMV infections. Again, our recipient experienced CMV infection at an earlier phase after LDLT and this infection repeated several times, although we had performed universal CMV prophylaxis. The higher rate of CMV re-infection for the recipient can be mainly explained from the mismatch of serological pretransplant status between the donor and the recipient. Retrospectively, with the background of CMV serological mismatch and also from previous reports that CMV donor positive/ recipient negative solid organ transplantations are at high risk of developing PTLD,27 PTLD should have been listed as a differential diagnosis at an earlier stage following the second admission. The diagnosis of PTLD was finally validated from the laboratory data of an
Hepatology Research 2015; 45: 356+–362
increased number of lymphocytes and histology of the lymphadenopathy. Pathologically, he was diagnosed as having monomorphic T/NK-cell PTLD. PTLD of T-cell origin is extremely rare; approximately 4–14% of adult cases of PTLD are reported to be of T-cell origin with an infrequent association with EBV.33 George et al. reported a review of EBV-associated T-cell PTLD in 2005.34 In this published work review, there were 21 case reports of EBV-associated T-cell PTLD; among them, three cases were associated with transplantations and only one case was an adult liver transplantation. Compared with the common B-cell origin EBV-related PTLD, there are three characteristics of the T-cell PTLD: (i) longer interval between transplantation and occurrence; (ii) lower response rate; and (iii) poorer prognosis. In the previous review, the mean interval for occurrence was reported as 4.9 years, which was longer than that for B-cell PTLD (within 2 years).34 In our case, the recipient developed PTLD 7 months after LDLT, which was a comparatively shorter onset compared with that reported in the previous report. Standard treatment for B-cell PTLD consists of a reduction of the immunosuppression,35 and chemotherapy. However, compared with B-cell PTLD, T-cell PTLD is less likely to respond to treatment. The overall response rate is reported to be 65%,36 and prognosis is lower than that of the B-cell counterparts. In the previous review, among the 18 recipients with outcomes, 10 recipients (55.6%) died of PTLD or its complications.34 Of note, among the 10 dead recipients, eight (80.0%) were adults. Poorer prognosis of T-cell PTLD is similarly caused by dissemination, as in our case.37,38 Involvement of the central nervous system, bone marrow and pulmonary system has been reported to have an adverse effect on prognosis for PTLD.6 Among the dead recipients mentioned in the previous review, dissemination appeared in the stomach, small intestine, spleen, lymph node, allograft, peripheral blood and skin.34 However, there was no case of dissemination to the left cardiac chamber as in our case. Initially, for our patient, we reduced the immunosuppression regimen with little improvement. Chemotherapy was introduced after the diagnosis of T-cell PTLD, to which the recipient responded dramatically without recurrence. In summary, we experienced an unusual case of EBV positive T-cell PTLD with dissemination to the left cardiac chamber occurring in an LDLT patient. Of additional note, the patient recovered after the development of VT despite the poorer prognostic factors of cell type, dissemination and involvement of the pulmonary system. The case illustrates the importance of listing
Severe PTLD after liver transplantation 361
PTLD as a differential diagnosis, particularly for cases of serological CMV mismatch between donor and recipient. In general, as T-cell PTLD has poorer prognosis, pathological diagnosis should be performed once the occurrence of PTLD is suspected, and chemotherapy should be aggressively administrated as a first-line therapy even after the exhibition of severe dissemination symptoms.
REFERENCES 1 Duvoux C, Pageaux GP, Valemmens C et al. Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients. Transplantation 2002; 74: 1103–9. 2 Jain A, Nalesnik M, Reyes J et al. Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience. Ann Surg 2002; 236: 429–36. 3 Guthery SL, Heubi JE, Bucuvalas JC et al. Determination of risk factors for Epstein-Bar virus associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment. Transplantation 2003; 75: 1603–10. 4 Collins MH, Montone KT, Lehey AM et al. Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 2001; 107: E89. 5 Dror Y, Greenberg M, Taylor G et al. Lymphoproliferative disorders after organ transplantation in children. Transplantation 1999; 67: 990–8. 6 Yang J, Tao Q, Flinn IW et al. Characterization of EpsteinBarr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood 2000; 96: 4055–63. 7 Nathanson S, Debray D, Delarue A et al. Long-term survival after posttransplant lymphoproliferative disease in children. Pediatr Nephrol 2002; 17: 668–72. 8 Dotti G, Fiocchi R, Motta T et al. Lymphomas occurring late after solid-organ transplantation. Transplantation 2002; 74: 1095–102. 9 Jabs WJ, Hennig H, Kittel M et al. Normalized quantification by real-time PCR of Epstein-Barr virus load in patients at risk for posttransplant lymphoproliferative disorders. J Clin Microbiol 2001; 39: 564–9. 10 Harris NL, Swerdlow SH, Frizzera G et al. Post-transplant lympholroliferative disorders. In: Jaffe ES, Harris NL, Stein H et al., eds. Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumors. Lyon, France: IARC Press, 2001; 264–9. 11 Collins MH, Montone KT, Leahey AM et al. Post-trasnplant lymphoproliferative disease in children. Pediatr Transplant 2001; 5: 250–7. 12 d’Amore ES, Manivel JC, Gajl-Peczalska KJ et al. B-cell lymphoproliferative disorders after bone marrow
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transplant: an analysis of ten cases with emphasis on Epstein-Barr virus detection by in situ hybridization. Cancer 1991; 68: 1285–95. Domingo-Domenech E, de Sanjose S, Gonzalez-Barca E et al. Pots-transplant lymphomas: a 20-year epidemiologic, clinical and pathologic study in a single center. Haematologica 2001; 86: 715–21. Leblond V, Davi F, Charlotte F et al. Posttransplant lymphoproliferative disorders not associated with EpsteinBarr virus: a distinct entity? J Clin Oncol 1998; 16: 2052–9. Nelson BP, Nalesnik MA, Bahler DW et al. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Sur Pathol 2000; 24: 375–85. Penn I. The changing pattern of posttransplant malignancies. Transplant Proc 1991; 23: 1101–3. Swerdlow SH. T-cell and NK-cell Posttransplantation lymphoproliferative disorders. Am J Clin Pathol 2007; 127: 887–95. Mochida S, Takikawa Y, Nakayama N et al. Diagnostic criteria of acute liver failure: a report by the Intractable Hepato-Biliary Disease Study Group of Japan. Hepatol Res 2011; 41: 805–12. Ferenci P, Lockwood A, Mullen K et al. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 2002; 35: 716–21. Chinen K, Izumo T. Cardiac involvement by malignant lymphoma: a clinicopathologic study of 25 autopsy cases based on the WHO classification. Ann Hematol 2005; 84: 498–505. Ceresoli GL, Ferreri AJM, Bucci E et al. Primary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic management. Cancer 1997; 80: 1497–506. Liedtke AJ, Adams DF, Weber ET et al. Remission of cardiac lymphoma with supervoltage radiation. Am J Med 1971; 50: 816–22. Petersen CD, Robinson WA, Kurnick JE. Involvement of the heart and pericardium in the malignant lymphomas. Am J Med Sci 1976; 272: 161–5. Terry LN, Kligerman MM. Pericardial and myocardial involvement by lymphomas and leukemias: the role of radiotherapy. Cancer 1970; 25: 1003–8. Lim WH, Russ GR, Coates PTH. Review of Epstein-Barr virus and post-transplant lymphoproliferative disorder post-solid organ transplantation. Nephrology 2006; 11: 355–66.
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26 Cao S, Cox KL, Berquist W et al. Long-term outcomes in pediatric liver recipients: comparison between cyclosporine A and tacrolimus. Pediatr Transplant 1999; 3: 22–6. 27 Walker RC, Marshall WF, Strickler JG et al. Pretransplantation assessment of the risk of lymphoproliferative disorders. Clin Infec Dis 1995; 20: 1346–53. 28 Kremers WK, Devarbhavi HC, Wiesner RH et al. Posttransplant lymphoproliferative disorders following liver transplantation: incidence, risk factors and survival. Am J Transplant 2006; 6: 1017–24. 29 Chinnock R, Webber SA, Dipchand AI et al. A 16-year multi-institutional study of the role of age and EBV status on PTLD incidence among pediatric heart transplant recipients. Am J Transplant 2012; 12: 3061–8. 30 Nee R, Hurst FP, Dharnidharka VR et al. Racial variation in the development of posttransplant lymphoproliferative disorders after renal transplantation. Transplantation 2011; 92: 190–5. 31 Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4: 222–30. 32 VanBuskirk AM, Malik V, Xia D et al. A gene polymorphism associated with posttransplant lymphoproliferative disorder. Transplant Proc 2001; 33: 1834. 33 Nelson BP, Nalesnik MA, Bahler DW et al. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000; 24: 375–85. 34 George TI, Jeng M, Berquist W et al. Epstein-Barr virus associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature. Pediatr Blood Cancer 2005; 44: 270–6. 35 Rees L, Thomas A, Amlot PL et al. Disappearance of an Epstein-Barr virus-positive post-transplant plasmocytoma with reduction of immunosuppression. Lancet 1998; 352: 789. 36 Choquet S, Trappe R, Leblond V et al. CHOP-21 for the treatment of post-transplant lymphoproliferative disorders (PTLD) following solid organ transplantation. Haematologica 2007; 92: 273–4. 37 Van Gorp J, Doornewaard H, Verdonck LF et al. Posttransplant T-cell lymphoma: report of three cases and a review of the literature. Cancer 1994; 73: 3064–72. 38 Wang LC, Lu MY, Yu J et al. T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 2000; 26: 893–7.
Hepatology Research 2015; 45: 356–362
doi: 10.1111/hepr.12345
Case Report
Severe post-transplant lymphoproliferative disorder after living donor liver transplantation Kaori Kuramitsu,1 Takumi Fukumoto,1 Kenji Fukushima,1 Takeshi Iwasaki,1 Masahiro Tominaga,1 Toshimitsu Matsui,2 Fumi Kawakami,3 Tomoo Itoh3 and Yonson Ku1 1
Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, 2Department of Medicine, and Department of Pathology, Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, Hyogo, Japan 3
Post-transplant lymphoproliferative disorder (PTLD) is a wellknown complication after transplantation. A living donor liver transplantation was performed on a 31-year-old man for fulminant hepatitis. He again developed liver dysfunction after 7 months. He was diagnosed as having acute cellular rejection and the steroid pulse therapy introduced resulted in little improvement. He gradually developed a high fever and right axillary lymphadenopathy appeared. Chest computed tomography (CT) was performed revealing small lung nodules and axillary lymphadenopathy. Because his serological status for Epstein–Barr virus was positive, PTLD was highly suspected and immunosuppression treatment was withdrawn with little improvement. One week later, he developed tachycardia. Chest CT was re-performed revealing an infiltration to the left
cardiac chamber. For diagnosis, axillary lymph node biopsy was performed and during the procedure, he developed ventricular tachycardia (VT). Immunohistological staining revealed PTLD of T lymphocytes, and chemotherapy was introduced on the same day he developed VT. After two cycles of tetrahydropyranyl, adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide treatment, he completely recovered. This is a first case report of severe PTLD with VT, and our case implies the feasibility of chemotherapy after the appearance of dissemination symptoms.
INTRODUCTION
incidence of PTLD in EBV seronegative transplant recipients is 24-fold higher compared to the EBV seropositive recipients.7 For the development of PTLD, immunosuppression is a major determinant.8 Therefore, PTLD usually occurs within the first year after transplantation, during the peak of the immunosuppression regimen. Clinical symptoms range from fever, tiredness and weight loss to those of lymphoma such as cervical, abdominal or thoracic lymphadenopathy. In addition, most patients develop extranodal solid tumors leading to pain, bleeding and neurological disorders. The diagnosis of PTLD can be made based on either laboratory tests or histopathology; when suspected from clinical symptoms, real-time quantitative polymerase chain reaction is effective for the detection of EBV DNA load in blood,9 and lymphadenopathy detected by imaging can be followed by tissue biopsy and histopathological analysis for staging. The categorization of PTLD is important for prognostic and therapeutic purposes. The World Health Organization’s classification of hematopoietic and lymphoid tumors includes a separate classification for PTLD.10 Based on this classification, most
P
OST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) is one of the most serious and potentially fatal complications after solid organ transplantation. The incidence of PTLD in liver transplant recipients ranges 2–3% in adults,1,2 with a higher incidence of 10% associated with pediatric transplantation.3 The increased incidence of PTLD among the pediatric transplantation is related to a higher incidence of posttransplant primary Epstein–Barr virus (EBV) infection in children compared to adult recipients,4,5 because the occurrence of PTLD is mostly associated with the activation of EBV.6 This is also confirmed by the fact that the Correspondence: Associate Professor Takumi Fukumoto, Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, Hyogo 650-0017, Japan. Email: fukumoto @med.kobe-u.ac.jp Conflict of interest: None to declare. Received 1 October 2013; revision 7 April 2014; accepted 16 April 2014.
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Key words: chemotherapy, Epstein–Barr virus, liver transplantation, post-transplant lymphoproliferative disorder
© 2014 The Japan Society of Hepatology
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Hepatology Research 2015; 45: 356+–362
CASE REPORT
A
31-YEAR-OLD MAN caught a common cold. He was treated with a cold medicine, and recovered within a few days. He developed high fever, general fatigue and vomiting 2 weeks later, and consulted a nearby clinic. There was no previous history of tobacco, alcohol or illicit drug use. Although antibiotics were administrated, his symptoms did not recover, and accordingly he consulted the same clinic again 5 days later. Laboratory tests were performed that revealed an elevated aspartate aminotransferase (AST) level of 3940 IU/L and alanine aminotransferase (ALT) of 5115 IU/L. Under a diagnosis of hepatitis A virus-related liver disease, he was transferred to a larger hospital. As he rapidly developed impaired consciousness, he was diagnosed as having fulminant hepatitis and referred to our hospital on the same day. Vital signs on admission were stable with a blood pressure of 140/106 mmHg and a heart rate of 97 b.p.m. He had flapping tremor, disorientation of time and place, somnolent tendency, and was sleeping most of the time. The severity of hepatic encephalopathy was graded between 2 and 3 based on the proposal by the Inuyama Symposium in
197218 or grade 3 based on the proposal by the World Organization of Gastroenterology, which was developed at the 11th World Congress of Gastroenterology in 1998.19 Laboratory test results for hepatitis B, C, cytomegalovirus (CMV) serology and HIV were negative. hepatitis A immunoglobulin (Ig)M antibody was negative, whereas EBV serology was positive (Epstein–Barr virus nuclear antigen [EBNA] negative, viral capsid antigen [VCA] IgG antibody positive, VCA IgM antibody positive). Under a diagnosis of fulminant hepatic failure caused either by the cold medicine or by EBV infection, plasma exchange, continuous hemodiafiltration and steroid pulse therapy were administrated. For steroid pulse therapy, he received 1000 mg (20 mg/kg) of methylprednisolone on day 1, which was reduced to 500 mg on day 2 and 250 mg on day 3. After 4 days of intensive care, as his consciousness did not recover, his 64-yearold father offered to be a living donor. Laboratory test results of the donor for hepatitis B, C and HIV were negative, whereas EBV serology was positive (EBNA positive, IgG positive, IgM negative). Blood type was identical to the recipient, and LDLT was performed using a right lobe graft. Operation time was 14 h and 40 min, bleeding volume was 2595 mL, cold ischemia time was 30 min and warm ischemia time was 52 min. Native liver volume was 1070 g and graft volume was 730 g. The original liver was histologically diagnosed as massively necrotic. Subsequent immunosuppressive therapy consisted of tacrolimus and low-dose prednisone. Figure 1 shows the kinetics of tacrolimus trough levels after transplantation. Tacrolimus trough levels ranged 15–20 ng/mL for the first 2 weeks and between 10–15 ng/mL thereafter for the first 3 months; these levels were slightly higher compared with the target trough level at each of the corresponding time (10–
25 Tacrolimus trough level (ng/ml)
PTLD are of B-cell origin (85%) and are commonly associated with EBV infection.11–13 Rarely, PTLD originates from T cells or natural killer (NK) cells with an infrequent association with EBV.14–16 Treatment of PTLD varies according to the types of lymphoproliferative disease, and basically it consists of reduction of immunosuppression and chemotherapy.17 Although numerous studies have clearly proved the association of PTLD and EBV, incidence, pathophysiology, risk factors, clinical presentation, diagnosis and treatment of PTLD varies widely among each of the recipients and accordingly still remains as a major cause of morbidity and mortality after transplantation.4–8 Herein, we experienced a severe case of T/NK-cell PTLD after living donor liver transplantation (LDLT). To date, there have been no clinical case reports of PTLD infiltrating to the left cardiac chamber and presenting the symptom of ventricular tachycardia (VT), which was also successfully treated by the induction of chemotherapy within 24 h. Although the finding is skewed because of its rarity, we emphasize the importance of aggressive investigations of cardiac involvement with PTLD cases to improve therapeutic and prognostic factors, and also the administration of chemotherapy treatment even after the appearance of dissemination symptoms.
20 15 10 5 0 0
20
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Time (days)
Figure 1 Kinetics of tacrolimus trough level after liver transplantation.
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15 ng/mL for the first month and 5–10 ng/mL thereafter for the first year) because he experienced an episode of acute cellular rejection (ACR), which was successfully treated with steroid pulse therapy. He was also suffering from CMV, which was treated with antiviral therapy. He was discharged from the hospital 2 months after LDLT. After discharge, he was followed up as an outpatient every 2–4 weeks and laboratory tests were performed at each visit. Seven months later, he was admitted to the hospital for elevated levels of AST (587 IU/L), ALT (666 IU/L) and total bilirubin (1.8 mg/dL). His leukocyte count was 4500/μL (38.8% neutrophils, 5.3% eosinophils and 9.9% monocytes) on admission. The following day, liver biopsy was performed and ACR was diagnosed. High-dose corticosteroids were administrated i.v.; he received 500 mg (10 mg/kg) of methylprednisolone on day 1, which was reduced to 250 mg on day 2 and 125 mg on day 3, but he showed little improvement. His leukocyte count increased up to 10 200/μL (78.4% neutrophils, 0% eosinophils and 3.6% monocytes) on day 3 after the induction of steroid pulse therapy. Because CMV was also serologically positive, antiviral therapy was started. One week after the induction of antiviral therapy, his leukocyte count decreased to 4400/μL (51.8% neutrophils, 2.9% eosinophils, 3.4% monocytes and 41.9% lymphocytes), and after 2 weeks to 2200/μL (43.4% neutrophils, 0.9% eosinophils, 2.7% monocytes and 53.0% lymphocytes). Despite the recovery of liver function, he gradually developed unexplainable high fever once a day 1 month after admission. As progressive axillary lymphadenopathy and pain appeared, a chest computed tomography
a
b
(CT) was performed that revealed small lung nodules (Fig. 2a) and multiple axillary lymphadenopathy (Fig. 2b). At this time, there was no infiltration to the cardiac chamber (Fig. 2c). Because PTLD was highly suspected, his serological status for EBV was checked, which was revealed to be positive. As a treatment, immunosuppression treatment was withdrawn at first. He suddenly developed tachycardia 1 week later. As echocardiography examination showed less motion of the left cardiac chamber, chest CT was re-performed. Bilateral pleural effusion appeared at this time point, and an increase in the size and number of the small lung nodules (Fig. 3a), multiple axillary lymphadenopathy (Fig. 3b) and infiltration to the left cardiac chamber were revealed (Fig. 3c). For diagnosis, an axillary lymph node biopsy was performed, and during the procedure, he developed VT. Echocardiography, which was performed after the development of VT, revealed a hypoechoic lesion in the left ventricular wall, suggesting infiltration to the left cardiac chamber (Fig. 3d). Histologically, diffuse proliferation of large atypical lymphoid cells with nuclear hyperchromasia and prominent nucleoli were confirmed (Fig. 4a). In the background, a variety of inflammatory cells, including small reactive lymphocytes and eosinophils were observed. Immunohistochemically, the large cells were positive for CD3 (Fig. 4b), T-cell-restricted intracellular antigen I (Fig. 4c) and granzyme B (Fig. 4d). CD20 was positive for reactive B cells, but negative for atypical cells (Fig. 4e). A large number of atypical cells were positive for EBV by in situ hybridization (Fig. 4f). Histological examination revealed EBV-related neoplastic proliferation of cytotoxic T cells, and finally he was diagnosed as
c
Figure 2 Chest computed tomography of the patient which was performed 1 month after re-admission. The patient developed unexplainable high fever once a day, progressive axillary lymphadenopathy and pain at this time point. White arrow indicates (a) small lung nodules and (b) multiple axillary lymphadenopathy. (c) There was no infiltration to the cardiac chamber.
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a
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Figure 3 The patient suddenly developed tachycardia and chest computed tomography (CT) was performed 1 week later since the first chest CT (Fig. 2). Bilateral pleural effusion appeared at this time point. White arrow indicates an increase in the size and number of (a) small lung nodules and (b) axillary lymphadenopathy. (c) White arrow indicates infiltration to the left cardiac chamber. (d) Echocardiography, which was performed after the development of ventricular tachycardia. White arrow indicates hypoechoic lesion in the left ventricular wall, suggesting infiltration to the left cardiac chamber.
having monomorphic T/NK-cell PTLD. Chemotherapy was introduced on the same day. After two cycles of tetrahydropyranyl, adriamycin (pirarubicin), cyclophosphamide, vincristine, prednisolone and etoposide (THP-COPE) treatment, he recovered and was discharged from the hospital. Ten years after LDLT, he is still free of recurrence and treated at an outpatient clinic every 2 months.
DISCUSSION
W
E DESCRIBED A case of severe T/NK-cell PTLD, which infiltrated into the left cardiac chamber and the patient developed VT. The recipient was successfully treated by the introduction of chemotherapy on the same day he developed VT, and he is still free of recurrence 10 years later. Our study is unique because there are no other reported cases of PTLD that infiltrated
into the left cardiac chamber and presented the symptom of VT. Cardiac infiltration by hematological neoplasms leading to clinically detectable cardiovascular disease is extremely rare. In the clinicopathological study of 25 autopsy cases that revealed cardiac involvement of malignant lymphoma, cardiac manifestation was evident in eight (32%) cases and no case was diagnosed before death.20 In their report, the authors also stated that T-cell lymphomas invaded the heart more frequently with a greater variety of cardiac manifestations compared with B-cell lymphomas. Chemotherapy and/or radiotherapy have been already reported as a successful treatment for cardiac lymphoma.21–24 These previous data also suggest the importance of our study; aggressive investigations of cardiac involvement are strongly recommended for cases of PTLD, and chemotherapy should be administrated even after cardiac manifestation because severe clinical symptoms
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a
b
c
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f
Figure 4 For diagnosis, an axillary lymph node biopsy was performed. (a) Diffuse proliferation of atypical lymphoid cells (hematoxylin–eosin, original magnification ×400). (b) Atypical cells were positive for CD3 (×400). (c) T-cell-restricted intracellular antigen I (×400). (d) Granzyme B (×400). (e) Epstein–Barr virus-encoded small RNA (×400). (f) Although reactive B-cells were scattered, neoplastic cells were negative for CD20 (×400).
resulting from cardiac dysfunction are amenable to aggressive treatment. The clinical symptoms of PTLD are highly variable and sometimes delay the diagnosis. Although PTLD may occur at any time after transplantation, the risk is at its highest level within the first year after liver transplantation.8 Several factors have been described to contribute to the development of PTLD. Suppression of recipient T-cell function by calcineurin inhibitors and antilymphocyte antibodies facilitates clonal expansion of EBVinfected B cells, thereby increasing the risk of PTLD.25 Moreover, the use of tacrolimus has also been reported to be associated with a higher incidence of PTLD compared with cyclosporin.26 Other previously reported factors were the presence of viral infections,27 use of OKT3,28 EBV-IgG negative status in recipient pretransplant sera,27 lower age,29 race,30 allograft type31 and host genetic variations.32 In our case, tacrolimus trough
© 2014 The Japan Society of Hepatology
levels were slightly higher compared with the target trough level, which might have resulted in the subsequent PTLD. Aside from the degree of immunosuppression, the possible risk factors in our case were EBV and CMV infections. Again, our recipient experienced CMV infection at an earlier phase after LDLT and this infection repeated several times, although we had performed universal CMV prophylaxis. The higher rate of CMV re-infection for the recipient can be mainly explained from the mismatch of serological pretransplant status between the donor and the recipient. Retrospectively, with the background of CMV serological mismatch and also from previous reports that CMV donor positive/ recipient negative solid organ transplantations are at high risk of developing PTLD,27 PTLD should have been listed as a differential diagnosis at an earlier stage following the second admission. The diagnosis of PTLD was finally validated from the laboratory data of an
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increased number of lymphocytes and histology of the lymphadenopathy. Pathologically, he was diagnosed as having monomorphic T/NK-cell PTLD. PTLD of T-cell origin is extremely rare; approximately 4–14% of adult cases of PTLD are reported to be of T-cell origin with an infrequent association with EBV.33 George et al. reported a review of EBV-associated T-cell PTLD in 2005.34 In this published work review, there were 21 case reports of EBV-associated T-cell PTLD; among them, three cases were associated with transplantations and only one case was an adult liver transplantation. Compared with the common B-cell origin EBV-related PTLD, there are three characteristics of the T-cell PTLD: (i) longer interval between transplantation and occurrence; (ii) lower response rate; and (iii) poorer prognosis. In the previous review, the mean interval for occurrence was reported as 4.9 years, which was longer than that for B-cell PTLD (within 2 years).34 In our case, the recipient developed PTLD 7 months after LDLT, which was a comparatively shorter onset compared with that reported in the previous report. Standard treatment for B-cell PTLD consists of a reduction of the immunosuppression,35 and chemotherapy. However, compared with B-cell PTLD, T-cell PTLD is less likely to respond to treatment. The overall response rate is reported to be 65%,36 and prognosis is lower than that of the B-cell counterparts. In the previous review, among the 18 recipients with outcomes, 10 recipients (55.6%) died of PTLD or its complications.34 Of note, among the 10 dead recipients, eight (80.0%) were adults. Poorer prognosis of T-cell PTLD is similarly caused by dissemination, as in our case.37,38 Involvement of the central nervous system, bone marrow and pulmonary system has been reported to have an adverse effect on prognosis for PTLD.6 Among the dead recipients mentioned in the previous review, dissemination appeared in the stomach, small intestine, spleen, lymph node, allograft, peripheral blood and skin.34 However, there was no case of dissemination to the left cardiac chamber as in our case. Initially, for our patient, we reduced the immunosuppression regimen with little improvement. Chemotherapy was introduced after the diagnosis of T-cell PTLD, to which the recipient responded dramatically without recurrence. In summary, we experienced an unusual case of EBV positive T-cell PTLD with dissemination to the left cardiac chamber occurring in an LDLT patient. Of additional note, the patient recovered after the development of VT despite the poorer prognostic factors of cell type, dissemination and involvement of the pulmonary system. The case illustrates the importance of listing
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PTLD as a differential diagnosis, particularly for cases of serological CMV mismatch between donor and recipient. In general, as T-cell PTLD has poorer prognosis, pathological diagnosis should be performed once the occurrence of PTLD is suspected, and chemotherapy should be aggressively administrated as a first-line therapy even after the exhibition of severe dissemination symptoms.
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