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Case Report

Ann Liver Transplant 2021; 1(1): 95-99

Published online May 31, 2021 https://doi.org/10.52604/alt.21.0014

Copyright © The Korean Liver Transplantation Society.

Successful treatment of the Epstein-Barr virus-negative post-transplant lymphoproliferative disorder, Ann Anbor stage IVB, using R-CHOP: a case report

Mi-Rin Lee1,2 , Jae-Do Yang1,2 , Hee-Chul Yu1,2

1Division of Hepatopancreaticobiliary Vessel Transplantation, Department of Surgery, Jeonbuk National University Hospital
2Research Institute of Clinical Medicine of Jeonbulk National University, Jeonju, Korea

Correspondence to:Hee-Chul Yu
Department of Surgery, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea
E-mail: hcyu@jbnu.ac.kr
https://orcid.org/0000-0003-2766-1354

Received: May 10, 2021; Revised: May 15, 2021; Accepted: May 17, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Post-transplant lymphoproliferative disorder (PTLD) is recognized as one of the most fatal complication of solid organ transplantation and allogenic hematopoietic stem cell transplantation. Standard treatment of PTLD is reduction in immunosuppression (RIS) and “R-CHOP” (rituximab-cyclophophamide, doxorubin, vincristine, prednisolone) regimen. We report successful chemotherapy treatment using R-CHOP without RIS in a patient with Ann Arbor stage IV PTLD and the high risk group based on the international prognostic index score. The patient was 69-year-old man who had been receiving immunosuppressive therapy with tacrolimus since undergoing a living liver transplant 7 years prior. He presented that he had experienced chronic dry cough for 3 months and uncontrolled hiccup 1 week prior to the current admission. Abdominal pelvic computed tomography (CT) and Positron emission tomography (PET)-CT revealed liver, small bowel, bone (C7 and T1) and extra-nodal (both diaphragm). Ultrasonography-guided biopsy was performed, and he was histologically diagnosed with EBV-negative diffuse large B-cell lymphoma (DLBCL). Six-cycles of chemotherapy with a R-CHOP regimen without RIS were administered, and 6 months later, CT and PET-CT performed thereafter indicated complete remission. In this case, even if therapeutic efficacy is predicted to be low because of an Ann Arbor stage IVB and the high risk group based on the International prognostic index score, the patient with an EBV-negative PTLD achieved complete remission using 6-cycles R-CHOP regimen without RIS.

Keywords: Post-transplant lymphoproliferative disorder, Liver transplantation, Rituximab

Post-transplant lymphoproliferative disorder (PTLD) is recognized as one of the most disastrous complications of solid organ and allogeneic hematopoietic stem cell transplantation [1] Moreover, PTLD incidence is dependent on the type of organ transplanted, and its incidence following liver transplantation is approximately 1.5%–5.5% [2,3]. According to the 2008 World Health Organization classification, PTLD is typically classified into four histological types: early lesion, polymorphic, monomorphic, and Hodgkin-like, which can all be categorized as either having an early (<2 years) or late onset (≥2 years). Risk factors for PTLD after liver transplant include Epstein-Barr virus (EBV)-seronegativity in the recipient, age ≥18 years, degree of immunosuppression, and first year transplant. To date, no cases of PTLD, such as Ann Arbor Stage IVB involving the bone marrow, liver, and small bowel, have been reported.

Herein, we describe the case of a patient with diffuse large B-cell lymphoma (DLBCL) constituting late-onset EBV-negative monomorphic PTLD, which developed 7 years after a liver transplant, achieving complete remission via chemotherapy.

A 69-year-old male patient was admitted due to a history of dry cough for 3 months and severe hiccups for one week.

The patient had been followed up regularly since undergoing a living liver transplant 7 years ago due to a history of HBV and HCC. He had been taking 1 mg entecavir for the past 12 years due to HBV infection, along with 0.5 mg tacrolimus taken regularly since liver transplantation. He then developed dry cough 3 months prior to the current admission, and one week before admission, he also developed severe hiccups to the point that he could no longer eat properly. A month before hospitalization, HRCT scans were performed showing a solitary nodule, which could be attributed to his chronic dry cough. A short outpatient follow-up was then recommended for the patient’s benign nodule. There were no findings of tenderness distention upon abdominal palpation.

Complete blood count results with their respective normal ranges are as follows: white blood cells, 7.15×103/μL (4.8–10.8×103/μL); hemoglobin, 13.7 g/dL (13–16.5 g/dL); and platelets, 188×103/μL (130–150 103/μL). Blood biochemistry results with their respective normal ranges include: total bilirubin, 0.88 mg/dL (0.2–1.2 mg/dL); aspartate aminotransferase, 24 U/L (12–33 U/L); alanine aminotransferase, 8 U/L (5–35 U/L); albumin, 3.2 g/dL (3.5–5.3 g/dL); blood urea nitrogen, 17 mg/dL (8–23 mg/dL); and creatinine, 0.81 mg/dL (0.7–1.7 mg/dL). Among the tested tumor markers, α-fetoprotein (0.3 ng/mL; normal range: 0–8.1 ng/mL), prothrombin in vitamin K absence-II (6 mAU/mL; normal range: 0.0–40 mAU/mL), and carcinoembryonic antigen (0.88 ng/mL; normal range: 0.0–5.0 ng/mL) were all normal, whereas carbohydrate antigen (CA) 19-9 (383.03 U/mL; normal range: 0.0–37.0 U/mL) and lactate dehydrogenase (727 IU/L; normal range: 218–472 IU/L) were elevated.

Abdominal computed tomography (CT) scan showed diffuse irregular terminal ileum wall thickening with mass-like lesions, solid masses in the liver, and multiple enlarged lymph nodes (Fig. 1), making lymphoma as the primary suspect. Positron emission tomography (PET-CT) further revealed abnormal hypermetabolism in the liver, lymph nodes, ileum, and bones (C7 and T1) (Fig. 2).

Figure 1.Abdominopelvic computed tomography. Computed tomography (CT) depicting four liver solid masses, irregular terminal ileum wall thickening with mass-like lesions and multiple enlarged lymph nodes.

Figure 2.Positron emission tomography-computed tomography. Positron emission tomography (PET)-computed tomography (CT) depicting abnormal hypermetabolism in multiple LNs (both side of diaphragm), liver, small bowel, bone (C7 and T1).

Histological examination was performed on the liver and small bowel mass using percutaneous ultrasonography-guided core needle biopsy, definitively diagnosing the mass as DLBCL (CD20+, B-cell lymphoma 6+, CD3—, CK—). Other tissue markers were negative for Epstein-Barr virus-encoded small RNAs (EBER) and human herpesvirus 8 (HHV-8). Likewise, serum EBV RT-PCR and serum EBV viral capsid IgM testing were also negative, indicating that EBV infection was not present. Additionally, hepatitis B antigen and hepatitis C antibody testing were negative, whereas hepatitis B antibody testing was found to be positive. Based on these results, the patient was diagnosed with DLBCL as an EBV-negative monomorphic PTLD that had developed 7 years following liver transplant. The condition was further classified as Ann Arbor Stage IVB with bone marrow, liver, and small bowel involvements. Moreover, his international prognostic index score was in the high-risk group (5-year survival: 26%), which is indicated for patients at 69 years of age with elevated lactate dehydrogenase levels.

Ideally, the dosage of tacrolimus, an immunosuppressor, should be reduced in PTLD patients; however, the patient did not want to reduce his tacrolimus dose, and instead, his tacrolimus level was maintained at 5 ng/mL. In addition, six cycles of an “R-CHOP” (rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen, the standard treatment for DLBCL, were administered without dosage reduction.

After six R-CHOP regimen cycles, PET-CT suggested a partial response. CT performed 3 months later suggested complete remission. The patient currently remains under observation, with no evidence of recurrence (Fig. 3).

Figure 3.Abdominopelvic computed tomography. Post-chemotherapy CT depicting no signs of mass lesion at liver, terminal ileum and lymph nodes.

PTLDs are a heterogeneous group of diseases that range from benign polyclonal lymphoproliferation, polymorphic PTLD, and monomorphic PTLD, to even presentations of classic Hodgkin lymphoma-like PTLD. Notably, the EBV genome is found in the majority (>90%) of early-onset B-cell PTLD, occurring within the first year after solid organ transplantation. On the other hand, late-onset PTLD in adult populations is increasingly attributed to EBV negative findings [4]. Moreover, PTLD may be nodal or extra-nodal, localized, often in the allograft, or widely disseminated, encompassing a wide spectrum of clinical conditions characterized by lymphoproliferation after transplantation, which may or may not be symptomatic. These syndromes range from uncomplicated infectious mononucleosis to true malignancies [5,6].

As previously mentioned, EBV is known to play a major role in the development of EBV-positive PTLD [7]. However, in EBV-negative lymphomas, the role of EBV in the pathogenesis remains uncertain, with a distinct gene expression analysis as compared to EBV-positive PTLD. Interestingly, chronic antigenic stimulation by allograft, including antibody-mediated rejection, has been hypothesized but not proven to play a role in the development of EBV-negative PTLD [8].

Given all these, PTLD treatment remains challenging. Although reduction in immunosuppression (RIS) has been a common initial approach to PTLD management, it is difficult to perform in practice due to concerns of rejection. Despite its weak evidence, suggestions for reducing immunosuppression based on expert opinion are outlined in the British Transplantation Society PTLD management guidelines [9]. Complete or partial surgical resection, as well as local radiotherapy, have also been used as adjunctive therapy along with RIS. Among these, the R-CHOP regimen is considered the standard therapy, showing a better response compared to rituximab monotherapy followed by chemotherapy at relapse. Recently, in a larger prospective phase II trial involving 74 adult patients with ECOG >2 who received rituximab and CHOP, an overall response rate of 90%, complete remission rate of 68% and a median survival of 6.6 years were observed [10].

Although the outcomes for PTLD patients have improved as evidenced by recent adult [10,11] and pediatric phase II clinical trials [12,13], PTLD has a poorer prognosis than malignant lymphoma, with a 5-year survival rate of approximately 40%–60% [2,14]. In a French registry containing the largest post-rituximab era study with 500 enrolled PTLD cases in kidney transplant recipients, the suggested prognostic score included age, creatinine, lactate dehydrogenase level, disease localization, and histologic features [15]. On the other hand, the International Prognostic Index (IPI) used in immunocompetent lymphoma patients includes variables of age, performance status, stage, lactate dehydrogenase level, and number of extra-nodal sites, showing superior results as compared to the earlier prognostic score [16].

In this case, therapeutic efficacy is predicted to be low due to his diagnosis of Ann Arbor Stage IVB and his classification in the high-risk group (5-year survival: 26%) based on the IPI score. Despite this, he achieved complete remission after undergoing six R-CHOP regimen cycles without RIS.


This paper was supported by Research Institute of Clinical Medicine, Jeonbuk National University Hospital.


All authors have no conflicts of interest to declare.


Conceptualization: All. Data curation: All. Formal analysis: All. Funding acquisition: None. Investigation: MRL, HCY. Methodology: None. Project administration: HCY. Resources: All. Software: HCY. Supervision: All. Validation: HCY. Visualization: All. Writing - original draft: All. Writing - review & editing: JDY, HCY.

  1. Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative disorder. Am J Transplant 2013;13:41-54.
    Pubmed CrossRef
  2. Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma 2013;54:2433-2440.
    Pubmed CrossRef
  3. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019-5032.
    Pubmed KoreaMed CrossRef
  4. Peters AC, Akinwumi MS, Cervera C, Mabilangan C, Ghosh S, Lai R, et al. The changing epidemiology of posttransplant lymphoproliferative disorder in adult solid organ transplant recipients over 30 years: a single-center experience. Transplantation 2018;102:1553-1562.
    Pubmed CrossRef
  5. Natkunam Y, Goodlad JR, Chadburn A, de Jong D, Gratzinger D, Chan JK, et al. EBV-positive B-cell proliferations of varied malignant potential: 2015 SH/EAHP workshop report-part 1. Am J Clin Pathol 2017;147:129-152.
    Pubmed KoreaMed CrossRef
  6. de Jong D, Roemer MG, Chan JK, Goodlad J, Gratzinger D, Chadburn A, et al. B-cell and classical hodgkin lymphomas associated with immunodeficiency: 2015 SH/EAHP workshop report-part 2. Am J Clin Pathol 2017;147:153-170.
    Pubmed KoreaMed CrossRef
  7. Chadburn A, Said J, Gratzinger D, Chan JK, de Jong D, Jaffe ES, et al. HHV8/KSHV-positive lymphoproliferative disorders and the spectrum of plasmablastic and plasma cell neoplasms: 2015 SH/EAHP workshop report-part 3. Am J Clin Pathol 2017;147:171-187.
    Pubmed KoreaMed CrossRef
  8. Weisenburger DD, Gross TG. Post-transplant lymphoproliferative disorder: a heterogeneous conundrum. Br J Haematol 2017;179:854-856.
    Pubmed CrossRef
  9. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al.; Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS guidelines. Br J Haematol 2010;149:675-692.
    Pubmed CrossRef
  10. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al.; German PTLD Study Group; European PTLD Network. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 2012;13:196-206.
    CrossRef
  11. Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol 2017;35:536-543.
    Pubmed CrossRef
  12. Gross TG, Bucuvalas JC, Park JR, Greiner TC, Hinrich SH, Kaufman SS, et al. Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 2005;23:6481-6488.
    Pubmed CrossRef
  13. Gross TG, Orjuela MA, Perkins SL, Park JR, Lynch JC, Cairo MS, et al. Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group report. Am J Transplant 2012;12:3069-3075.
    Pubmed KoreaMed CrossRef
  14. Kinch A, Baecklund E, Backlin C, Ekman T, Molin D, Tufveson G, et al. A population-based study of 135 lymphomas after solid organ transplantation: the role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival. Acta Oncol 2014;53:669-679.
    Pubmed CrossRef
  15. Caillard S, Porcher R, Provot F, Dantal J, Choquet S, Durrbach A, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol 2013;31:1302-1309.
    Pubmed CrossRef
  16. Dierickx D, Tousseyn T, Morscio J, Fieuws S, Verhoef G. Validation of prognostic scores in post-transplantation lymphoproliferative disorders. J Clin Oncol 2013;31:3443-444.
    Pubmed CrossRef

Article

Case Report

Ann Liver Transplant 2021; 1(1): 95-99

Published online May 31, 2021 https://doi.org/10.52604/alt.21.0014

Copyright © The Korean Liver Transplantation Society.

Successful treatment of the Epstein-Barr virus-negative post-transplant lymphoproliferative disorder, Ann Anbor stage IVB, using R-CHOP: a case report

Mi-Rin Lee1,2 , Jae-Do Yang1,2 , Hee-Chul Yu1,2

1Division of Hepatopancreaticobiliary Vessel Transplantation, Department of Surgery, Jeonbuk National University Hospital
2Research Institute of Clinical Medicine of Jeonbulk National University, Jeonju, Korea

Correspondence to:Hee-Chul Yu
Department of Surgery, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea
E-mail: hcyu@jbnu.ac.kr
https://orcid.org/0000-0003-2766-1354

Received: May 10, 2021; Revised: May 15, 2021; Accepted: May 17, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Post-transplant lymphoproliferative disorder (PTLD) is recognized as one of the most fatal complication of solid organ transplantation and allogenic hematopoietic stem cell transplantation. Standard treatment of PTLD is reduction in immunosuppression (RIS) and “R-CHOP” (rituximab-cyclophophamide, doxorubin, vincristine, prednisolone) regimen. We report successful chemotherapy treatment using R-CHOP without RIS in a patient with Ann Arbor stage IV PTLD and the high risk group based on the international prognostic index score. The patient was 69-year-old man who had been receiving immunosuppressive therapy with tacrolimus since undergoing a living liver transplant 7 years prior. He presented that he had experienced chronic dry cough for 3 months and uncontrolled hiccup 1 week prior to the current admission. Abdominal pelvic computed tomography (CT) and Positron emission tomography (PET)-CT revealed liver, small bowel, bone (C7 and T1) and extra-nodal (both diaphragm). Ultrasonography-guided biopsy was performed, and he was histologically diagnosed with EBV-negative diffuse large B-cell lymphoma (DLBCL). Six-cycles of chemotherapy with a R-CHOP regimen without RIS were administered, and 6 months later, CT and PET-CT performed thereafter indicated complete remission. In this case, even if therapeutic efficacy is predicted to be low because of an Ann Arbor stage IVB and the high risk group based on the International prognostic index score, the patient with an EBV-negative PTLD achieved complete remission using 6-cycles R-CHOP regimen without RIS.

Keywords: Post-transplant lymphoproliferative disorder, Liver transplantation, Rituximab

INTRODUCTION

Post-transplant lymphoproliferative disorder (PTLD) is recognized as one of the most disastrous complications of solid organ and allogeneic hematopoietic stem cell transplantation [1] Moreover, PTLD incidence is dependent on the type of organ transplanted, and its incidence following liver transplantation is approximately 1.5%–5.5% [2,3]. According to the 2008 World Health Organization classification, PTLD is typically classified into four histological types: early lesion, polymorphic, monomorphic, and Hodgkin-like, which can all be categorized as either having an early (<2 years) or late onset (≥2 years). Risk factors for PTLD after liver transplant include Epstein-Barr virus (EBV)-seronegativity in the recipient, age ≥18 years, degree of immunosuppression, and first year transplant. To date, no cases of PTLD, such as Ann Arbor Stage IVB involving the bone marrow, liver, and small bowel, have been reported.

Herein, we describe the case of a patient with diffuse large B-cell lymphoma (DLBCL) constituting late-onset EBV-negative monomorphic PTLD, which developed 7 years after a liver transplant, achieving complete remission via chemotherapy.

CASE PRESENTATION

A 69-year-old male patient was admitted due to a history of dry cough for 3 months and severe hiccups for one week.

The patient had been followed up regularly since undergoing a living liver transplant 7 years ago due to a history of HBV and HCC. He had been taking 1 mg entecavir for the past 12 years due to HBV infection, along with 0.5 mg tacrolimus taken regularly since liver transplantation. He then developed dry cough 3 months prior to the current admission, and one week before admission, he also developed severe hiccups to the point that he could no longer eat properly. A month before hospitalization, HRCT scans were performed showing a solitary nodule, which could be attributed to his chronic dry cough. A short outpatient follow-up was then recommended for the patient’s benign nodule. There were no findings of tenderness distention upon abdominal palpation.

Complete blood count results with their respective normal ranges are as follows: white blood cells, 7.15×103/μL (4.8–10.8×103/μL); hemoglobin, 13.7 g/dL (13–16.5 g/dL); and platelets, 188×103/μL (130–150 103/μL). Blood biochemistry results with their respective normal ranges include: total bilirubin, 0.88 mg/dL (0.2–1.2 mg/dL); aspartate aminotransferase, 24 U/L (12–33 U/L); alanine aminotransferase, 8 U/L (5–35 U/L); albumin, 3.2 g/dL (3.5–5.3 g/dL); blood urea nitrogen, 17 mg/dL (8–23 mg/dL); and creatinine, 0.81 mg/dL (0.7–1.7 mg/dL). Among the tested tumor markers, α-fetoprotein (0.3 ng/mL; normal range: 0–8.1 ng/mL), prothrombin in vitamin K absence-II (6 mAU/mL; normal range: 0.0–40 mAU/mL), and carcinoembryonic antigen (0.88 ng/mL; normal range: 0.0–5.0 ng/mL) were all normal, whereas carbohydrate antigen (CA) 19-9 (383.03 U/mL; normal range: 0.0–37.0 U/mL) and lactate dehydrogenase (727 IU/L; normal range: 218–472 IU/L) were elevated.

Abdominal computed tomography (CT) scan showed diffuse irregular terminal ileum wall thickening with mass-like lesions, solid masses in the liver, and multiple enlarged lymph nodes (Fig. 1), making lymphoma as the primary suspect. Positron emission tomography (PET-CT) further revealed abnormal hypermetabolism in the liver, lymph nodes, ileum, and bones (C7 and T1) (Fig. 2).

Figure 1. Abdominopelvic computed tomography. Computed tomography (CT) depicting four liver solid masses, irregular terminal ileum wall thickening with mass-like lesions and multiple enlarged lymph nodes.

Figure 2. Positron emission tomography-computed tomography. Positron emission tomography (PET)-computed tomography (CT) depicting abnormal hypermetabolism in multiple LNs (both side of diaphragm), liver, small bowel, bone (C7 and T1).

Histological examination was performed on the liver and small bowel mass using percutaneous ultrasonography-guided core needle biopsy, definitively diagnosing the mass as DLBCL (CD20+, B-cell lymphoma 6+, CD3—, CK—). Other tissue markers were negative for Epstein-Barr virus-encoded small RNAs (EBER) and human herpesvirus 8 (HHV-8). Likewise, serum EBV RT-PCR and serum EBV viral capsid IgM testing were also negative, indicating that EBV infection was not present. Additionally, hepatitis B antigen and hepatitis C antibody testing were negative, whereas hepatitis B antibody testing was found to be positive. Based on these results, the patient was diagnosed with DLBCL as an EBV-negative monomorphic PTLD that had developed 7 years following liver transplant. The condition was further classified as Ann Arbor Stage IVB with bone marrow, liver, and small bowel involvements. Moreover, his international prognostic index score was in the high-risk group (5-year survival: 26%), which is indicated for patients at 69 years of age with elevated lactate dehydrogenase levels.

Ideally, the dosage of tacrolimus, an immunosuppressor, should be reduced in PTLD patients; however, the patient did not want to reduce his tacrolimus dose, and instead, his tacrolimus level was maintained at 5 ng/mL. In addition, six cycles of an “R-CHOP” (rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen, the standard treatment for DLBCL, were administered without dosage reduction.

After six R-CHOP regimen cycles, PET-CT suggested a partial response. CT performed 3 months later suggested complete remission. The patient currently remains under observation, with no evidence of recurrence (Fig. 3).

Figure 3. Abdominopelvic computed tomography. Post-chemotherapy CT depicting no signs of mass lesion at liver, terminal ileum and lymph nodes.

DISCUSSION

PTLDs are a heterogeneous group of diseases that range from benign polyclonal lymphoproliferation, polymorphic PTLD, and monomorphic PTLD, to even presentations of classic Hodgkin lymphoma-like PTLD. Notably, the EBV genome is found in the majority (>90%) of early-onset B-cell PTLD, occurring within the first year after solid organ transplantation. On the other hand, late-onset PTLD in adult populations is increasingly attributed to EBV negative findings [4]. Moreover, PTLD may be nodal or extra-nodal, localized, often in the allograft, or widely disseminated, encompassing a wide spectrum of clinical conditions characterized by lymphoproliferation after transplantation, which may or may not be symptomatic. These syndromes range from uncomplicated infectious mononucleosis to true malignancies [5,6].

As previously mentioned, EBV is known to play a major role in the development of EBV-positive PTLD [7]. However, in EBV-negative lymphomas, the role of EBV in the pathogenesis remains uncertain, with a distinct gene expression analysis as compared to EBV-positive PTLD. Interestingly, chronic antigenic stimulation by allograft, including antibody-mediated rejection, has been hypothesized but not proven to play a role in the development of EBV-negative PTLD [8].

Given all these, PTLD treatment remains challenging. Although reduction in immunosuppression (RIS) has been a common initial approach to PTLD management, it is difficult to perform in practice due to concerns of rejection. Despite its weak evidence, suggestions for reducing immunosuppression based on expert opinion are outlined in the British Transplantation Society PTLD management guidelines [9]. Complete or partial surgical resection, as well as local radiotherapy, have also been used as adjunctive therapy along with RIS. Among these, the R-CHOP regimen is considered the standard therapy, showing a better response compared to rituximab monotherapy followed by chemotherapy at relapse. Recently, in a larger prospective phase II trial involving 74 adult patients with ECOG >2 who received rituximab and CHOP, an overall response rate of 90%, complete remission rate of 68% and a median survival of 6.6 years were observed [10].

Although the outcomes for PTLD patients have improved as evidenced by recent adult [10,11] and pediatric phase II clinical trials [12,13], PTLD has a poorer prognosis than malignant lymphoma, with a 5-year survival rate of approximately 40%–60% [2,14]. In a French registry containing the largest post-rituximab era study with 500 enrolled PTLD cases in kidney transplant recipients, the suggested prognostic score included age, creatinine, lactate dehydrogenase level, disease localization, and histologic features [15]. On the other hand, the International Prognostic Index (IPI) used in immunocompetent lymphoma patients includes variables of age, performance status, stage, lactate dehydrogenase level, and number of extra-nodal sites, showing superior results as compared to the earlier prognostic score [16].

In this case, therapeutic efficacy is predicted to be low due to his diagnosis of Ann Arbor Stage IVB and his classification in the high-risk group (5-year survival: 26%) based on the IPI score. Despite this, he achieved complete remission after undergoing six R-CHOP regimen cycles without RIS.

FUNDING


This paper was supported by Research Institute of Clinical Medicine, Jeonbuk National University Hospital.

CONFLICT OF INTEREST


All authors have no conflicts of interest to declare.

AUTHORS’ CONTRIBUTIONS


Conceptualization: All. Data curation: All. Formal analysis: All. Funding acquisition: None. Investigation: MRL, HCY. Methodology: None. Project administration: HCY. Resources: All. Software: HCY. Supervision: All. Validation: HCY. Visualization: All. Writing - original draft: All. Writing - review & editing: JDY, HCY.

Fig 1.

Figure 1.Abdominopelvic computed tomography. Computed tomography (CT) depicting four liver solid masses, irregular terminal ileum wall thickening with mass-like lesions and multiple enlarged lymph nodes.
Annals of Liver Transplantation 2021; 1: 95-99https://doi.org/10.52604/alt.21.0014

Fig 2.

Figure 2.Positron emission tomography-computed tomography. Positron emission tomography (PET)-computed tomography (CT) depicting abnormal hypermetabolism in multiple LNs (both side of diaphragm), liver, small bowel, bone (C7 and T1).
Annals of Liver Transplantation 2021; 1: 95-99https://doi.org/10.52604/alt.21.0014

Fig 3.

Figure 3.Abdominopelvic computed tomography. Post-chemotherapy CT depicting no signs of mass lesion at liver, terminal ileum and lymph nodes.
Annals of Liver Transplantation 2021; 1: 95-99https://doi.org/10.52604/alt.21.0014

References

  1. Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative disorder. Am J Transplant 2013;13:41-54.
    Pubmed CrossRef
  2. Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma 2013;54:2433-2440.
    Pubmed CrossRef
  3. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019-5032.
    Pubmed KoreaMed CrossRef
  4. Peters AC, Akinwumi MS, Cervera C, Mabilangan C, Ghosh S, Lai R, et al. The changing epidemiology of posttransplant lymphoproliferative disorder in adult solid organ transplant recipients over 30 years: a single-center experience. Transplantation 2018;102:1553-1562.
    Pubmed CrossRef
  5. Natkunam Y, Goodlad JR, Chadburn A, de Jong D, Gratzinger D, Chan JK, et al. EBV-positive B-cell proliferations of varied malignant potential: 2015 SH/EAHP workshop report-part 1. Am J Clin Pathol 2017;147:129-152.
    Pubmed KoreaMed CrossRef
  6. de Jong D, Roemer MG, Chan JK, Goodlad J, Gratzinger D, Chadburn A, et al. B-cell and classical hodgkin lymphomas associated with immunodeficiency: 2015 SH/EAHP workshop report-part 2. Am J Clin Pathol 2017;147:153-170.
    Pubmed KoreaMed CrossRef
  7. Chadburn A, Said J, Gratzinger D, Chan JK, de Jong D, Jaffe ES, et al. HHV8/KSHV-positive lymphoproliferative disorders and the spectrum of plasmablastic and plasma cell neoplasms: 2015 SH/EAHP workshop report-part 3. Am J Clin Pathol 2017;147:171-187.
    Pubmed KoreaMed CrossRef
  8. Weisenburger DD, Gross TG. Post-transplant lymphoproliferative disorder: a heterogeneous conundrum. Br J Haematol 2017;179:854-856.
    Pubmed CrossRef
  9. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al.; Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS guidelines. Br J Haematol 2010;149:675-692.
    Pubmed CrossRef
  10. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al.; German PTLD Study Group; European PTLD Network. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 2012;13:196-206.
    CrossRef
  11. Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol 2017;35:536-543.
    Pubmed CrossRef
  12. Gross TG, Bucuvalas JC, Park JR, Greiner TC, Hinrich SH, Kaufman SS, et al. Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 2005;23:6481-6488.
    Pubmed CrossRef
  13. Gross TG, Orjuela MA, Perkins SL, Park JR, Lynch JC, Cairo MS, et al. Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group report. Am J Transplant 2012;12:3069-3075.
    Pubmed KoreaMed CrossRef
  14. Kinch A, Baecklund E, Backlin C, Ekman T, Molin D, Tufveson G, et al. A population-based study of 135 lymphomas after solid organ transplantation: the role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival. Acta Oncol 2014;53:669-679.
    Pubmed CrossRef
  15. Caillard S, Porcher R, Provot F, Dantal J, Choquet S, Durrbach A, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol 2013;31:1302-1309.
    Pubmed CrossRef
  16. Dierickx D, Tousseyn T, Morscio J, Fieuws S, Verhoef G. Validation of prognostic scores in post-transplantation lymphoproliferative disorders. J Clin Oncol 2013;31:3443-444.
    Pubmed CrossRef
The Korean Liver Transplantation Society

Vol.1 No.1
May, 2021

pISSN 2765-5121
eISSN 2765-6098

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