EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Posttransplant lymphoproliferative disorder (Burkitt lymphoma) may occur after liver transplant. A 3.5-year-old boy who was 17 months after liver transplant developed multiple millimeter-sized nodular lesions in the liver. Before transplant, the patient tested seronegative for Epstein-Barr virus; within 1 month after transplant, he tested seropositive for Epstein-Barr virus (1000 copies). Biopsy of the liver nodules showed posttransplant lymphoproliferative disorder (Burkitt lymphoma). Tacrolimus was stopped, sirolimus was started, and the patient was treated with chemotherapy (etoposide, doxorubicin, cyclophosphamide, corticosteroids and intrathecal methotrexate). Remission was achieved, and follow-up at 76 months after transplant showed no recurrence of the posttransplant lymphoproliferative disorder. In conclusion, posttransplant lymphoproliferative disorder (Burkitt lymphoma) may occur after liver transplant, and monitoring Epstein-Barr virus level may helpful after transplant because of the association between Epstein-Barr virus and Burkitt lymphoma.

Key words : Cancer, Epstein-Barr virus, Liver transplant, Pediatrics

Non-Hodgkin lymphoma is the most common malignancy diagnosed in solid-organ transplant recipients.^1-3 The risk of developing non-Hodgkin lymphoma is increased 6-fold after transplant.^3,4 Burkitt lymphoma is an aggressive B-cell non-Hodgkin lymphoma that is endemic in parts of Africa and New Guinea and occurs sporadically in Europe and North America.^1,5 Although endemic and sporadic Burkitt lymphoma are recognized by the World Health Organization as distinct entities, they are indistinguishable on histology. In addition, they have a common translocation of the c-Myc proto-oncogene on chromosome 8 (8q24) near the sequences that regulate heavy or light chain immunoglobulin genes on chromosomes 14q32, 2p12, and 22q11. Endemic Burkitt lymphoma is linked to Epstein-Barr virus and Plasmodium falciparum malaria infections, but the cause of sporadic Burkitt lymphoma is unknown.⁵

Transplant recipients may have an increased risk of developing Burkitt lymphoma, but limited information is available about the incidence of Burkitt lymphoma and risk factors after transplant. There is an increased risk of developing diffuse large B-cell lymphoma and Burkitt lymphoma, the most common subtypes of lymphoma that occur after transplant, in patients aged < 20 years and patients who received liver or thoracic organ transplant.³ In patients having liver transplant, the risk of developing Burkitt lymphoma may be lower in patients who have noncholestatic cirrhosis and higher in patients who have cholestatic liver disease as the indication for liver transplant.⁵ Although most posttransplant lymphoproliferative disorders originate from postgerminal center cells, Burkitt lymphoma has a germinal center molecular profile and has more aggressive behavior than other posttransplant lymphoproliferative disorders.⁶ Therefore, it is important to understand the clinicopathologic features of Burkitt lymphoma in transplant recipients.

We treated a child who developed Burkitt lymphoma after liver transplant.

A 2-year-old boy had a liver transplant (left lateral segment) from his uncle because of progressive familial intrahepatic cholestasis. He received tacrolimus-based immunosuppression (tacrolimus blood levels after surgery: < 1 mo, 10 to 15 ng/mL; > 1 mo, 5 to 10 ng/mL). Methylprednisolone was given at surgery (10 mg/kg), continued after surgery (10 mg/kg, daily, for 1 mo; then tapered to 0.1 mL/kg, daily), and stopped after 3 months. The patient received prophylaxis against fungal, viral, and pneumocystis organisms for 6 months after surgery. After liver transplant, he was followed every 3 months with lung radiographs, abdominal ultrasonography, and liver function tests.

Before transplant, the patient tested seronegative for Epstein-Barr virus; within 1 month after transplant, he tested seropositive for Epstein-Barr virus (1000 copies). He developed acute cellular rejection on postoperative day 9 and 32 and was treated with high-dose corticosteroids. On postoperative day 50, he was treated with ganciclovir for cytomegalovirus hepatitis.

At 17 months after transplant (age, 3.5 y), multiple millimeter-sized nodular lesions were noted in the liver allograft by abdominal computed tomography. Biopsy of the liver nodules showed posttransplant lymphoproliferative disorder (Burkitt lymphoma). Medium-sized, unindented lymphoid tumor cells with a high proliferation rate (95%) were noted infiltrating the allograft. Between the tumor cells, scattered tingible body macrophages with a “starry-sky” appearance were noted throughout the biopsy specimen (Figure 1). Immunohistochemical analysis of the tumor cells showed diffuse positive staining with CD20 (Figure 2) and CD10 and no staining for Bcl-2 protein. The Ki-67 proliferation index was > 97% (Figure 3). Tumor cells tested positive with the Epstein-Barr encoding region in situ hybridization method. Bone marrow biopsy showed lymphoid infiltration similar to that noted on the liver allograft biopsy.

After the diagnosis of posttransplant lympho-proliferative disorder was made, tacrolimus was stopped and sirolimus was started. The patient was treated with chemotherapy (etoposide, doxorubicin, cyclophosphamide, corticosteroid and intrathecal methotrexate), and remission was achieved. Follow-up at 76 months after transplant showed no recurrence of the posttransplant lymphoproliferative disorder.

Burkitt lymphoma is a rare monomorphic posttra-nsplant lymphoproliferative disorder that has distinct clinical and pathologic features. The interval between liver transplant and development of posttransplant lymphoproliferative disorder (Burkitt lymphoma) in the present patient was consistent with other published pediatric cases (range, 6 to 107 mo after transplant).^{4, 6-8}

In 70% Burkitt lymphomas that occur after organ transplant, genes or gene products related to Epstein-Barr virus may be demonstrated within the tumor cells.⁴ Burkitt lymphomas in transplant recipients may include tumors that stain positive or negative for Epstein-Barr virus, and the different types of Burkitt lymphoma may have different causes.⁵ The presence or absence of Epstein-Barr virus with the tumor is important for prognosis; Epstein-Barr virus-positive Burkitt lymphoma after transplant, which developed in the present patient, may respond well to reduction or cessation of immunosuppressive therapy or may have permanent complete remission without chemotherapy, but Epstein-Barr virus-negative Burkitt lymphoma has a very poor prognosis and may not respond to aggressive chemotherapy protocols.⁴

There is a positive correlation between Epstein-Barr virus DNA level in the bloodstream after transplant and the development of posttransplant lymphoproliferative disorder, which suggests that monitoring viral load may be important after transplant.^{4, 6-10}

Subtyping also is important in patients diagnosed with posttransplant lymphoproliferative disorder. Burkitt lymphoma may have a high tumor growth rate and aggressive behavior, and early diagnosis is very important for effective treatment. In addition, monitoring Epstein-Barr virus is advised for pediatric patients because of the close relation between Epstein-Barr virus and posttransplant lymphoproliferative disorder.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

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