Role of Immune Dysfunction and EBV in ALK‐Positive Inflammatory Myofibroblastic Tumor: Observations in a Pediatric Kidney Transplant Recipient

To the Editor, Most cases of post-transplant lymphoproliferative disorders (PTLD) are associated with Epstein–Barr virus (EBV) as a consequence of viral reactivation due to immunosuppression [1, 2]. EBV-associated lymphoproliferative disorders can be seen in other immunocompromised states as well. Inflammatory myofibroblastic tumor (IMT), historically known as inflammatory pseudotumor, which are now thought to be a distinct entity [3]. Certain genetic abnormalities are associated with IMT, including anaplastic large cell lymphoma kinase (ALK) gene rearrangements. PTLD has an incidence of less than 1% [4]. The occurrence of IMT with renal transplantation is uncommon; the incidence of pulmonary IMT is between 0.04% and 1.2% of all tumors of the lung [5-7]. The synchronous occurrence of PTLD and IMT in transplant recipients is exceptionally rare. Here, we present a case of a kidney transplant recipient who concurrently developed pulmonary ALK-positive IMT and EBV-positive PTLD and discuss potential contributing factors and provide a focused review of the relevant literature. A Caucasian boy with history of end-stage renal disease secondary to posterior urethral valves received a kidney transplant from his father at the age of 11 years. Both the recipient and donor were EBV-negative at the time of transplant. He was maintained on cyclosporine A and prednisolone. Two months after transplantation, the patient was found to have EBV viremia. A chest X-ray revealed right-sided focal opacity, and computerized tomography showed a 2.3 cm multilocular mass without significant surrounding inflammatory changes 15 months after the transplantation. Enlarged left axillary lymph nodes were also observed. Thoracoscopic wedge resection of the lung mass confirmed IMT. A subsequent positron emission tomography (PET) study revealed increased FDG uptake within enlarged left axillary lymph nodes. An excisional biopsy of the enlarged axillary lymph nodes was consistent with EBV-positive PTLD on histology with architectural effacement and occasional pleomorphic appearing nuclei, prominent nucleoli in neoplastic cells, and a background of necrosis. Immunohistochemical stains showed strong and diffuse positivity for CD20, CD79, PAX5, and OCT2; CD15, CD30, EMA, and ALK-1 were negative. EBV in situ hybridization for EBV-encoded small RNA (EBER) was positive, consistent with monomorphic PTLD, diffuse large B-cell lymphoma type. Immunosuppressive therapy was decreased by 50%. He was also treated with four weekly doses of rituximab with the eventual resolution of axillary lymph nodes on PET study, followed by transfer to our center. Six months later, a follow-up PET study demonstrated recurrence of FDG-positive intrathoracic mass. The resected mass consisted of myofibroblasts and mixed inflammatory cells with plasma cells, lymphocytes, and eosinophils in fibrotic background, confirming IMT (Figure 1A–C). These cells had a Ki-67 index of 10%–15%. Immunohistochemical stains demonstrated ALK-1 and smooth muscle actin positivity in myofibroblasts and EBV focal positivity in leukocytes (Figure 1D–F). The serum EBV VCA-IgG and EBV early antigen antibodies were positive, while EBV VCA-IgM and EBNA antibodies were negative without EBV viremia at the time. Following initial treatment of PTLD and resection of recurrent pulmonary IMT mass, he remained free of both diseases without any additional interventions for 5 years until the last follow-up at our institution. Although considered reactive lesions, accumulating evidence suggests that IMT can exhibit neoplastic behavior, particularly in cases harboring gene rearrangements or fusions; ALK rearrangements are seen in 50% of IMT cases [8, 9]. Some ALK-negative IMT may be associated with alternative oncogenic pathways, such as ROS1, NTRK, or RET fusions [9, 10]. One study reviewing 21 cases of IMT found that 15 were ALK-positive and six cases were ALK-negative. Regardless of ALK expression, all 21 IMTs were negative for EBV, suggesting that EBV may play a minor role in the pathogenesis of ALK-positive IMT [11]. A single case of concurrent EBV-positive PTLD and IMT was described in a 2-year-old liver transplant recipient in which EBER was also shown in myofibroblastic tumor cells [12]. Inflammatory pseudotumor cases with EBV-positive lesional cells are reported outside transplant recipients as well [13, 14]. Nevertheless, the hypothesis that EBV may play a direct role in the development of myofibroblastic tumors is reminiscent of the role of EBV in smooth muscle tumors [15, 16]. However, in our case, only the leukocytes were positive for EBV in the IMT tissue; therefore, the underlying potential mechanism of EBV contribution to IMT development remains to be explained and could be coincidental. An argument can be made that immunosuppression predisposes to the development of IMT. Development of ALK-positive IMT in a hematopoietic stem cell transplantation further supports this view [17]. A pulmonary IMT case has been reported in common variable immunodeficiency; IMT could be associated with various autoimmune diseases, viral infections, and exposure to immunosuppressive agents [18-20]. Our case is the first reported patient presenting with concurrent EBV-positive PTLD alongside ALK-positive IMT in a renal transplant patient. This case highlights the potential link between immune dysregulation, EBV infection, and the development of IMT, particularly in the presence of ALK rearrangement; though, without direct EBV role due to lack of positive EBER staining in neoplastic cells (Figure 2). Studying such rare cases may help unravel novel interplay between different variables in the pathogenesis of neoplastic processes in immunocompromised patients and to optimize treatment strategies for transplant recipients. M.M. drafted the manuscript and prepared one of the figures, C.Y. prepared IRB application, and contributed to the preparation of the draft, J.P. provided the one of the figures and edited the manuscript, A.J. contributed to the case history and edited the manuscript, S.S. planned the study, and contributed to preparing the manuscript. The case summarized in the manuscript was partially presented at Central Michigan University College of Medicine Medical Education Partners 2025 Research Symposium in April 2025, Saginaw, Michigan, USA. This study proposal is reviewed by CMU IRB and determined as “not human subject research.” The authors declare no conflicts of interest.