EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Epstein-Barr virus, Kidney transplant, Lymphoma, Rituximab, Solid-organ transplant

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after solid-organ transplants and is thought to be one of the iatrogenic complications due to the intensive immunosup-pression administered after transplant. In adults, recipients of heart transplant have the highest risk, whereas renal transplant recipients have the lowest risk of PTLD among all solid-organ transplants.¹ The global occurrence of PTLD in renal transplant recipients has been reported to be between 1% to 3%.²

Gastrointestinal tract (in 20%-30% cases), solid allografts (10%-15%), and the central nervous system (5%-20%) are the most common sites for PTLD.³ Furthermore, early-onset PTLD, which manifests within the first year after transplant, tends to localize predominantly in the allograft.⁴ We report a case of PTLD presenting as acute airway obstruction early in the course of renal transplant; the patient’s condition was managed successfully, with complete remission and no graft dysfunction.

A 26-year-old renal allograft recipient presented to the emergency room with complaints of breathlessness. On examination, he was found to have stridor that necessitated emergency tracheostomy at admission. He had been diagnosed with type 1 diabetes mellitus at the age of 11 years. He had previously developed diabetic kidney disease at the age of 21 years that progressed to end-stage renal disease by the age of 26 years. He had received 5 units of blood transfusion while on medical management for chronic kidney disease. Dialysis vintage was 4 months before he received an ABO-compatible renal allograft from his father, with human leukocyte antigen 4/12 mismatch (high-resolution DNA typing by next-generation sequencing), at another center. The donor and recipient were seropositive for cytomegalovirus immunoglobulin G (D+/R+). Epstein-Barr virus (EBV) serologic status was not known. Induction regimen included intravenous methylprednisolone only. The patient experienced an uneventful postoperative course with a nadir serum creatinine concentration of 1.18 mg/dL. He was discharged on triple immunosuppression with prednisolone, mycophenolate mofetil, and tacrolimus.

Eight months after transplant, the patient developed recurrent episodes of runny nose, oral ulcers, and hoarseness of voice, all of which were managed as upper respiratory tract infection. Three months later, he presented to the emergency room with acute airway obstruction that required emergency tracheostomy. Oral cavity examination revealed a bulge in the left side of the soft palate that was pushing the uvula to the right side; there was also a mass in the left tonsillar fossa with superior extension. Gag reflex was absent. Endoscopy nasopharyngeal examination revealed a mass in nasopharynx that had occluded the left choana with copious secretions. Magnetic resonance imaging exhibited a left tonsillar mass of 3.8 × 4.7 × 6.8 mm extending into the nasopharynx and the retrop-haryngeal space, which had caused complete oropharyngeal airway occlusion. Biopsy from the nasopharyngeal mass revealed diffuse large B-cell lymphoma. Immunohistochemistry was positive for EBV-latent membrane protein LMP-1/CD45/CD3/-CD5/CD20/PAX-5/P-16 (EBV-LMP clone CS.^1-4; Dako). The EBV DNA was negative by real-time quantitative polymerase chain reaction. Bone marrow examination showed normal trilineage hematopoiesis, which ruled out bone marrow involvement.

Fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) imaging revealed a soft tissue density lesion in the left tonsillar fossa that had caused a partial oropharyngeal luminal obstruction with involvement of the bilateral nasopharyngeal wall and the left cervical lymph nodes (Figure 1). Immunosuppression was reduced (mycophenolate mofetil was stopped, and tacrolimus dose was reduced to half). In view of an aggressive form of disease, the patient was started on a PTLD-1 risk-stratified approach that included intravenous rituximab at 375 mg/m² on days 1, 8, 15, and 22. After 4 cycles, the 18F-FDG PET-CT scan was suggestive of complete metabolic resolution of the left tonsillar fossa lesion, the right nasop-haryngeal lesion, and the left cervical lymph nodes (Figure 2).

Our patient received the sequential rituximab doses on days 50, 72, 94, and 116; a repeat 18F-FDG PET-CT scan after the last dose showed no fluorodeoxyglucose uptake anywhere in the body, suggestive of complete remission (Figure 3). At 6-month follow-up, he remained asymptomatic, with serum creatinine concentration of 1.20 mg/dL and 24-hour urine protein at 425 mg/day. Presently, he remains on dual immunosuppression (prednisolone 5 mg once a day; tacrolimus 0.5 mg in morning and 0.75 mg in evening).

In the past, PTLD was considered to be a rare complication; however, during the past 10 years, various registries and observational studies have reported an increased incidence,³ as high as 6.34% in a study of a cohort of 63 patients done over 7 years.⁵

The 2 most recognized risk factors for PTLD are EBV infection and immunosuppression. Up to 80% of B-cell-origin PTLD has some association with EBV infection.⁶ After EBV infection, EBV DNA is integrated into the genome of B cells. This integration results in a reduced rate of apoptotic cell death and triggers vigorous proliferation of B cells, which ultimately leads to lymphoblastic transformation. In transplant recipients undergoing immunosup-pressive treatment, EBV-transformed B lymphocytes evade T-lymphocyte surveillance and give rise to various forms of PTLD.⁷ Risk of PTLD increases 5 times when the donor is positive for EBV and the recipient is negative for EBV. Presently, there is no agreement on the matching of donor and recipient EBV status in relation to the development of PTLD.⁸ In the index case, the pretransplant EBV status was unknown for both the donor and the recipient; however, biopsy showed positive stain for EBV LMP-1.

The other well-recognized risk factor of PTLD is intensive immunosuppression. The highest risks are associated with (1) muromonab-CD3 monoclonal antibody induction and (2) rabbit antithymocyte globulin (rATG) either as induction or for treatment of acute rejection episodes. Overall, the presently established view is that the level of immunosup-pression is considered crucial for the occurrence of PTLD rather than the specific use of any particular agent. Our patient did not receive rATG during induction and had no history of rejection episodes; however, a long history of diabetes had comp-romised his immune status, which may have led to ineffective clearing of EBV. Furthermore, he had received 5 units of packed red blood cells in the pretransplant period. Thus, EBV in the index case could be derived from either the donor or the blood product.

Localization of PTLD is possible in any organ. In kidney transplant recipients, gastrointestinal tract, central nervous system, allograft, skin, bone marrow, and lungs are commonly reported sites for PTLD.⁹ In our index case, the site was the left tonsil, which is less commonly reported.⁶ Furthermore, he was treated as allergic rhinitis and pharyngitis with anti-histaminics and antibiotics. Early PTLD is associated with positive status for EBV in situ hybridization, CD20-positive status, and involvement of the allograft.¹⁰ Fortunately, our patient had no graft involvement. According to the 2008 World Health Organization classification, lymphoid neoplasms are categorized into 4 groups.¹¹ Among these, the most prevalent type of monomorphic PTLD is diffuse large B-cell lymphoma, as we reported in the index case.

We followed the PTLD-1/3 trial risk-stratified sequential treatment approach.¹² In the PTLD-1/3 trial schema, patients with CD20-positive PTLD who do not achieve reduction in immunosuppression received standard-dose rituximab once each week for 4 weeks (375 mg/m² on days 1, 8, 15, and 22) followed by interim computed tomography restaging near day 50. Patients who achieved complete remission were considered low risk and received a further 4 doses of rituximab at 3-week intervals (intravenous dose of 375 mg/m² on days 50, 72, 94, and 116), followed by cessation of therapy. Our patient achieved complete remission at the point of this writing, with a normally functioning graft, and he remains in regular follow-up with us.

Conventional risk factors, such as unrelated donor, deceased donor transplant, older recipient, high-dose immunosuppression, and use of T-cell-depleting agents such as rATG as induction, were not present in index case. Our patient achieved complete remission with no graft dysfunction, which empha-sizes the points that early recognition of PTLD can increase the likelihood of complete remission and that grafts can survive on minimal immunosup-pression.

Tonsillar enlargement in a solid-organ transplant recipient should raise suspicion of PTLD. Early recognition and prompt treatment is not only lifesaving but also graft saving.

Volume: 22 Issue: 4 April 2024

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