Key words : Bone marrow transplant, Calcineurin, Immunosuppression, Mechanistic target of rapamycin, Solid-organ transplant

Introduction

Posttransplant lymphoproliferative diseases (PTLD) are a rare but important cause of morbidity and mortality secondary to immunosuppression after solid-organ or bone marrow transplant. The incidence of PTLD is between 1% and 20%.^1,2 Posttransplant lymphoproliferative diseases are caused by B cells in 80% to 85% of cases and caused by T cells in 10% to 15% of cases. Although PTLD is more common in the pediatric age group, the expected incidence rate is also lower in the pediatric group.³ In B-cell-derived PTLD, CD20 is positive, and 60% to 80% of the B cells are associated with Epstein-Barr virus (EBV).⁴ The EBV-associated PTLD observed immediately after transplant is the result of acute intensity of immunosuppression, whereas EBV-negative PTLD is known to occur years after transplant.⁵ Generally, PTLD develops in the first 2 years after transplant, when immunosuppressive therapy is most intense. The most important risk factors are patient age at transplant, pretransplant EBV infection status, type of transplanted organ, and the immunosuppressive regimen.^1,5 Although EBV-negative PTLD has been shown to be highly aggressive, data on this issue remain imprecise.⁶

Clinical presentation in PTLD may be nonspecific. Generally, clinically diagnosed extranodal origin non-Hodgkin lymphoma may develop in these patients. Constitutional symptoms may appear as fever, weakness, and weight loss; other possible symptoms may be specific to the type of organ. The tonsil, adenoid, gastrointestinal system, lung, and liver are the most frequently affected organs. Liver involvement presents as diffuse hepatitis or liver nodules. Specific diagnosis of PTLD versus rejection may be difficult when there is dysfunction in the transplanted organ.⁵

The treatment strategy of PTLD remains controversial, and reduction of immunosuppression is recommended as the first step for treatment. In unresponsive patients, aggressive combined chemotherapies that include rituximab are recommended.

Case Report

A 64-year-old man underwent liver transplant from a living donor in 2011 to treat hepatocellular cancer secondary to chronic hepatitis B. Tacrolimus and mycophenolate mofetil treatment was initiated for immunosuppression. Previous results of abdominal computed tomography (in response to abdominal pain during follow-up in March 2019) had shown the liver to be 178 cm and the largest lesion to be 70 mm in segment 6; multiple solid lesions showed irregular borders without arterial contrast enhancement and were observed as hypodense in the venous phase (Figure 1). The patient’s tumor markers (CA19-9, CEA, AFP) were negative. Epstein-Barr virus serology results were negative for EBV-VCA immunoglobulin M, positive for EBV-VCA immunoglobulin G, positive for EBV-EBNA immunoglobulin G, and negative for EBV DNA. Liver biopsy showed PTLD with diffuse large B-cell lymphoma, and biopsy results were negative for EBV (strong for CD45, CD20, and CD43; Ki-67 over 90%; strong BCL-6 results in about 40% of cells; strong results for vimentin). Bone marrow biopsy results confirmed normal cells. Fluorine-18 positron emission tomography/computed tomography ima­ging showed no pathology in favor of primary lymphoproliferative disease (Figure 2). Mycophenolate mofetil treatment was replaced with everolimus. In a follow-up dynamic magnetic resonance imaging examination that was performed at 3 months after treatment change, the lesion at liver segment 6 had regressed to 30 mm, and several lesions with similar features were observed in the right lobe of the liver. Additional liver biopsy results were compatible with complete remission. The patient’s clinical symptoms had fully regressed at 18 months after the diagnosis, at the time of this writing. Ongoing radiological and clinical follow-up has shown complete remission (Figure 3).

Discussion

Posttransplant lymphoproliferative diseases comprise a heterogeneous group of diseases, with a wide range of expression, from early lesions (plasmacytic hyperplasia and infectious mononucleosis-like lesions) to monoclonal monomorphic mononucleosis-like diseases (malignant lymphoma). The most common monomorphic PTLD type is diffuse big B-cell lymphoma, as in our case.^7,8

The reduction or modification of immunosup­pression regimen is significant in the treatment of PTLD.⁹ In a study by Reshef and colleagues, which consisted of 67 patients, it was shown that 45% of patients were treated by reduction of immuno­suppression alone. Although reduction of immuno­suppression is associated with a higher risk of rejection, it is more tolerable in organ transplants with high regenerative potential, such as livers and kidneys.¹⁰ In a study conducted by Tsai and colleagues, immunosuppression was reduced in 30 of 42 patients with PTLD, and remission was achieved in 19 (63%) of these patients. In these patients, the first response was obtained after an average of 3.6 weeks.¹¹ After the change in immunosuppression in our patient, by month 2 there was a 50% reduction in the mass of the lesion and complete remission as indicated by the biopsy results. The complete remission was observed in the imaging at the first year follow-up.

In a study by Duvoux and colleagues, 4 independent risk factors for PTLD after liver transplant were identified: transplant recipients older than 50 years, the use of antilymphocyte antibodies, hepatitis C virus-associated liver cirrhosis, and alcoholic cirrhosis.¹² In our patient, the only risk factor was advanced age at transplant.

In recent years, promising results have been achieved in the treatment of PTLD with the use of immune-modulatory approaches such as anti-CD20 monoclonal antibodies (rituximab), interleukin 6, and adoptive immunotherapy.¹³ In particular, rituximab has been shown to achieve complete remission in approximately 60% of patients with PTLD who were otherwise unresponsive to treatment despite reduced immunosuppression.¹⁴ Reduction of immuno-suppression alone increases the risk of rejection. Everolimus (an inhibitor of the mechanistic target of rapamycin) has been used in adult liver transplant patients in the United States and Europe since 2013 to reduce organ rejection. Studies have shown that everolimus treatment of PTLD that developed after kidney transplant reduces rejection and contributes to disease control.¹⁵ There are cases in which sirolimus treatment was applied with rituximab in PTLD that developed after liver transplant; however, data for these cases remain insufficient.

As a result, our patient who developed PTLD unrelated to EBV achieved complete remission in the week 8 with the discontinuation of tacrolimus treatment, discontinuation of mycophenolate mofetil treatment, and initiation of everolimus treatment, Ongoing follow-up has shown complete remission without rejection for 18 months.

Conclusions

The change from calcineurin treatment to treatment with an inhibitor of the mechanistic target of rapamycin may be an essential and new option in PTLD after liver transplant.

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