Allograft-localized post-transplant lymphoproliferative disorder in a pediatric kidney transplant recipient: a case report and focused review

Abstract

Background

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of pediatric kidney transplantation. PTLD confined to the kidney allograft is uncommon, and optimal management in this setting remains uncertain.

Case presentation

An eight-year-old boy with chronic kidney disease stage G5D due to posterior urethral valves developed monomorphic PTLD limited to the kidney allograft one year after deceased-donor kidney transplantation. Histopathology demonstrated high-grade B-cell lymphoma of the activated B-cell phenotype, with negative Epstein–Barr virus DNA and low-level cytomegalovirus DNA without evidence of end-organ disease. In the absence of systemic disease, a multidisciplinary team pursued a graft-preserving strategy rather than upfront nephrectomy, consisting of reduction of immunosuppression and rituximab-based chemoimmunotherapy with cyclophosphamide, prednisolone, and rituximab (CPR). Despite treatment-related cytopenias and transient hemodialysis, the patient achieved complete metabolic remission on PET-CT and remains disease-free with preserved graft function at five years of follow-up.

Conclusion

This case demonstrates that graft-preserving, risk-adapted chemoimmunotherapy can achieve durable remission in selected pediatric patients with allograft-localized PTLD while maintaining long-term kidney allograft function.

Introduction

Solid organ transplantation has transformed the prognosis of children with end-stage organ failure, offering improved survival and quality of life [1]. However, this life-saving intervention carries the risk of long-term complications, most notably infections, malignancies, and metabolic derangements due to sustained immunosuppression [2, 3]. Among post-transplant malignancies, post-transplant lymphoproliferative disorder (PTLD) occupies a unique position as both one of the most common and one of the most challenging to manage [4, 5].

PTLD encompasses a heterogeneous group of lymphoid proliferations that range from benign polyclonal hyperplasia to aggressive monoclonal lymphomas. Its incidence is influenced by multiple factors, including the type of organ transplanted, intensity and duration of immunosuppressive therapy, and the recipient’s serostatus for Epstein–Barr virus (EBV). Children are particularly vulnerable, as they are often EBV seronegative at the time of transplantation and thus more susceptible to primary EBV infection in the setting of immunosuppression [6–8].

The clinical spectrum of PTLD is notoriously variable, with presentations involving fever, lymphadenopathy, organ dysfunction, or nonspecific systemic symptoms [9]. This heterogeneity, combined with overlapping features of infection, rejection, and drug toxicity, frequently delays diagnosis. Advances in diagnostic modalities ranging from molecular detection of EBV viremia to histopathological classification have enhanced our ability to recognize PTLD early [10]. Nonetheless, timely clinical suspicion remains essential.

Data from the United States reports cumulative incidence of adult PTLD of about 1–2% and 3% in the pediatric kidney transplant recipients (PKTR) [11]. In PKTR, the disease usually develops during the first two years after transplantation [8].

Management strategies for PTLD continue to evolve and often require a delicate balance between reducing immunosuppression, employing targeted therapies such as rituximab, and considering chemotherapy in particular cases [12]. Despite improved outcomes with current approaches, morbidity and mortality remain significant, particularly in pediatric recipients with complex post-transplant courses.

Herein, we report the case of an 8-year-old boy who developed PTLD following a deceased-donor kidney transplant for posterior urethral valve–related end-stage kidney disease.

Case presentation

An 8-year-old boy with chronic kidney disease stage G5D secondary to posterior urethral valves underwent deceased donor kidney transplantation in early 2020 from a 21-year-old EBV-seronegative donor. His immediate post-transplant course was uncomplicated, and he was maintained on standard triple immunosuppression consisting of tacrolimus (2 mg twice daily, target trough 5–10 ng/mL), mycophenolate mofetil (500 mg twice daily), and prednisolone (5 mg every other day). Kidney allograft function remained stable during routine outpatient follow-up for several months.

Approximately one year after transplantation, routine surveillance laboratory testing demonstrated a progressive rise in serum creatinine and blood urea nitrogen (BUN), raising concern for significant graft dysfunction. The child remained clinically well, without fever, constitutional symptoms, graft tenderness, urinary complaints, or features suggestive of acute rejection or infection. Physical examination was unremarkable. Laboratory evaluation demonstrated marked pancytopenia, including severe leukopenia (white blood cell count 0.95 × 10⁹/L), anemia (hemoglobin 8.4 g/dL; hematocrit 24.8%; mean corpuscular volume 66.85 fL), and thrombocytopenia (platelet count 80 × 10⁹/L). Kidney function indices showed substantial deterioration, with a blood urea nitrogen level of 75 mg/dL and an increase in serum creatinine from a baseline of 2.1 mg/dL to 5.3 mg/dL. Serum electrolytes at initial presentation were within normal limits (sodium 140 mmol/L, potassium 3.7 mmol/L). Screening for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus was negative.

Given the combination of graft dysfunction and severe cytopenias, imaging was pursued. Ultrasonography of the abdomen and pelvis demonstrated a markedly enlarged kidney allograft measuring 132 × 68 mm, containing multiple well-circumscribed heterogeneous intraparenchymal masses, the largest measuring 48 × 38 mm, without evidence of extrarenal disease. These findings raised strong suspicion for a post-transplant lymphoproliferative process of the allograft. An ultrasound-guided core needle biopsy of the transplant kidney was therefore performed.

Histopathological examination revealed dense nodular aggregates of atypical lymphoid cells with effacement of normal kidney architecture, suggestive of high-grade lymphoproliferative neoplasm (Fig. 1). Immunohistochemical analysis confirmed monomorphic post-transplant lymphoproliferative disorder, high-grade B-cell lymphoma. Tumor cells were diffusely positive for CD20, CD30, MUM1, and PAX5, and negative for CD10, CD5, and BCL6, consistent with an activated B-cell phenotype. The Ki-67 proliferation index was approximately 50%. C4d staining was negative (0%), p53 was negative, and there was no histologic evidence of concomitant acute rejection or viral inclusion bodies.

Fig. 1.

a & b: Kidney allograft biopsy showing diffuse lymphoid infiltration with effacement of normal parenchymal architecture (H&E stain)

Comprehensive virological testing demonstrated absence of Epstein–Barr virus DNA in peripheral blood, while cytomegalovirus DNA was detectable at a low level (200 copies /ml), with no clinical features of CMV end-organ disease. The patient received intravenous ganciclovir for two weeks followed by oral valganciclovir, with serial CMV PCR monitoring demonstrating complete resolution of viremia.

Following confirmation of PTLD on kidney biopsy, whole-body FDG PET–CT imaging was performed for disease staging. PET imaging demonstrated FDG-avid lesions confined to the kidney allograft, with no evidence of metabolically active nodal or extranodal disease elsewhere. The accompanying low-dose, non-contrast CT acquired for attenuation correction and anatomical localization showed no gross extrarenal abnormalities. In the view of accompanying cytopenias, bone marrow aspirate and biopsy were obtained which demonstrated a hypocellular marrow with preserved trilineage hematopoiesis and normal megakaryocyte number and morphology, without abnormal clustering. Immunophenotyping showed polyclonal B cells expressing CD19 and CD20 with κ and λ light chains, and T cells comprising approximately 60% of lymphoid cells expressing CD5. Flow cytometry and immunohistochemistry revealed no evidence of lymphomatous involvement. Peripheral blood smear demonstrated microcytic hypochromic erythrocytes with relative lymphocytosis (48%). Collectively, these findings supported a diagnosis of monomorphic post-transplant lymphoproliferative disorder confined anatomically to the kidney allograft, without evidence of bone marrow or systemic involvement at presentation.

Given the graft-localized yet high-grade nature of the disease, the presence of substantial intragraft tumor burden, and the absence of systemic dissemination, a multidisciplinary tumor board involving pediatric nephrology, transplant surgery, infectious diseases, and pediatric oncology specialists was convened. Therapeutic options including immediate graft nephrectomy, reduction of immunosuppression with rituximab monotherapy, and systemic chemoimmunotherapy were carefully considered. In view of the child’s age, curative intent, and the potential to preserve long-term graft function, a graft-preserving strategy was favored over upfront nephrectomy.

Immunosuppression was judiciously reduced by discontinuation of mycophenolate mofetil and replacement of tacrolimus with sirolimus, while prednisolone was continued at a maintenance dose of 5 mg every other day. Systemic therapy was initiated using a rituximab-based immunochemotherapy regimen consisting of cyclophosphamide, prednisolone, and rituximab (CPR), with rituximab administered in two doses eight days apart.

Liver function tests were normal at the time of CMV viremia, with a mild transient elevation in transaminases during chemotherapy that resolved with supportive care. The treatment course was complicated by febrile neutropenia requiring hospitalization and supportive care. During this period, the patient developed acute kidney injury necessitating temporary hemodialysis. He also experienced a mild SARS-CoV-2 infection, which was managed conservatively without respiratory compromise or interruption of oncologic therapy. With appropriate supportive management, hematologic parameters recovered, kidney function improved, dialysis was discontinued, and the planned chemotherapy course was completed.

Post-treatment assessment with FDG PET-CT demonstrated a small residual lesion at the lateral margin of the kidney allograft that was metabolically inactive, with no evidence of disease elsewhere, consistent with complete metabolic remission.

At the most recent follow-up, nearly five years after diagnosis, the patient remains in sustained complete remission with preserved kidney allograft function and no clinical, radiologic, or laboratory evidence of PTLD recurrence. Having been monitored through regular clinical assessments, serial kidney function tests, and complete blood counts, with imaging performed selectively based on clinical or laboratory indications. The clinical timeline and key therapeutic milestones are summarized in Fig. 2.

Fig. 2.

Timeline illustrating the course from kidney transplantation, immunosuppressive therapy, onset of symptoms, diagnostic workup including biopsy and PET-CT, to initiation of treatment for PTLD

Discussion

Post-transplant lymphoproliferative disorder represents a biologically and clinically heterogeneous spectrum of disease, encompassing a wide range of histopathologic subtypes, patterns of organ involvement, and clinical behavior. In pediatric kidney transplant recipients, diagnosis is frequently challenging because presentations may be subtle, extranodal, or limited to the allograft, and there remains no universally accepted approach to surveillance, staging, or risk stratification. Current clinical practice therefore relies on a high index of suspicion, histologic confirmation, and individualized staging to guide management with therapeutic decisions balancing disease extent, immunologic risk, and the need to preserve allograft function [13]. As demonstrated by this case, clinically significant PTLD may present despite close post-transplant surveillance and in the absence of systemic symptoms, underscoring the need for ongoing vigilance even in apparently stable pediatric recipients.

Several recent single-center and registry analyses have sought to define predictors of outcome in pediatric PTLD. In a 23-year single-institution series of 54 children, the authors reported a 5-year overall survival of 87.6% and identified type of transplanted organ (notably heart), poor response to first-line therapy, prior allograft rejection, and low Karnofsky score as univariate predictors of worse survival; on multivariable analysis, progression after initial treatment and prior rejection remained independent adverse factors. Notably, EBV serostatus did not significantly affect survival in that cohort [14]. As illustrated in Fig. 3, the interaction between disease biology, disease extent, and patient-specific clinical factors rather than virologic status alone often shapes therapeutic decision-making in pediatric PTLD. Notably, these considerations were central to treatment selection in the present case.

Fig. 3.

Case-specific disease characteristics, disease extent, and clinical considerations that informed selection of a graft-preserving, rituximab-based chemoimmunotherapy strategy in this pediatric patient with PTLD

Our patient developed PTLD within the first year post-transplantation, consistent with the typical timing of pediatric cases, which most often arise early and are frequently associated with Epstein–Barr virus (EBV) [13, 15]. However, unlike the more typical EBV-driven early PTLD, the disease in this case was EBV-negative and biologically aggressive, emphasizing the heterogeneity of early-onset presentations in children.

EBV remains a central driver of PTLD due to its ability to transform B cells in the absence of adequate cytotoxic T-cell surveillance [16]. However, as many as one-third to nearly one-half of cases are EBV-negative, and these tend to occur later post-transplantation, often with more aggressive features [13, 15]. EBV-negative monomorphic PTLD in children has been increasingly recognized, comprising around 10% of cases, and carries outcomes similar to EBV-positive disease but inferior to immunocompetent pediatric lymphoma counterparts [17]. In our case, the patient was EBV-negative but CMV-positive, emphasizing the growing recognition that PTLD may arise through mechanisms independent of EBV infection. The EBV-negative status in this patient further supported consideration of treatment escalation beyond reduction of immunosuppression alone, given the reduced likelihood of spontaneous disease control.

Clinical presentation varies widely by site. Registry data demonstrate that tonsillar and adenoidal PTLD is associated with superior survival compared with gastrointestinal, kidney, or multisite involvement [16]. Pediatric kidney recipients often present with extranodal disease, including direct allograft infiltration in up to a quarter of cases, typically manifesting as graft dysfunction, as seen in our patient [13]. Histologically, the majority of pediatric cases are monomorphic and frequently of the activated B-cell phenotype, paralleling the findings in this case [18, 19]. The current World Health Organization classification of post-transplant lymphoproliferative disorder (PTLD) is outlined in Table 1. As observed here, graft-localized disease may present primarily with declining allograft function rather than overt systemic manifestations, which may delay diagnosis if PTLD is not actively considered.

Table 1.

Classification of post-transplant lymphoproliferative disorder (PTLD) according to the world health organization framework [12]

Category	PTLD Subtype	Histopathological Features	EBV Association
Non-destructive PTLD	Plasmacytic hyperplasia	Preserved tissue architecture with polyclonal plasma cell proliferation, resembling reactive hyperplasia.	Usually EBV-positive
	Infectious mononucleosis-like PTLD	Preserved architecture with polymorphic lymphoid infiltrate mimicking acute EBV infection.	EBV-positive
	Florid follicular hyperplasia	Expanded reactive follicles with preserved nodal architecture; EBV-positive B cells may be present.	EBV-positive B cells may be present
Polymorphic PTLD	B cell hyperplasia, Polymorphic B cell lymphoma included	Destructive lymphoid proliferation with architectural effacement and a mixture of small and large lymphoid cells that does not meet criteria for a defined lymphoma.	Usually EBV-positive
Monomorphic PTLD (B-cell neoplasms)	Diffuse large B-cell lymphoma (DLBCL)	Monoclonal B-cell proliferation fulfilling diagnostic criteria for DLBCL.	Often EBV-positive
	Burkitt lymphoma	Monoclonal high-grade B-cell lymphoma characterized by MYC rearrangement.	EBV-positive or EBV-negative
	Plasma cell neoplasm	Monoclonal plasma cell proliferation fulfilling criteria for plasma cell myeloma or plasmacytoma.	EBV-positive or EBV-negative
Monomorphic PTLD (T-/NK-cell neoplasms)	Peripheral T-cell lymphoma, NOS	Monoclonal T-cell lymphoma with aggressive clinical behavior.	Usually EBV-negative
	EBV-positive T-/NK-cell lymphoma	Monoclonal EBV-associated T- or NK-cell proliferation with aggressive features.	EBV-positive
Classic Hodgkin lymphoma-type PTLD	Classic Hodgkin lymphoma-like PTLD	Fulfills diagnostic criteria for classic Hodgkin lymphoma with Reed–Sternberg–like cells.	Typically EBV-positive

Case reports of monomorphic PTLD after kidney transplant in the allograft are exceedingly rare in the literature. A retrospective analysis from a pediatric nephrology unit in India where 95 kidney allograft recipients were analyzed, PTLD developed in < 5% of the patients (4 cases) and all cases were successfully managed with RIS, rituximab and one patient with excision. In the four cases of PTLD, one patient with monomorphic diffuse large B-cell lymphoma presented with an enlarged right tonsil. The patient was adequately handled with RIS, and rituximab was not utilized because of its unavailability [20]. Another study from an Irish pediatric centre of hematopoietic stem cell transplantation (HSCT) and SOT reported an overall survival of 90% over an 11 year period with the use of rituximab ± low dose chemotherapy [21].

Therapeutic approaches must balance oncologic control with preservation of graft function. Reduction of immunosuppression (RIS) is universally recommended as the initial step [15], though it is often insufficient in monomorphic or high-grade disease. Current therapeutic approaches to PTLD are guided by histologic subtype, disease extent, and clinical context; a concise overview of contemporary management strategies is provided in Table 2.

Table 2.

Commonly used treatment strategies for post-transplant lymphoproliferative disorder (PTLD), stratified by histologic subtype and disease characteristics [12, 13]

Step	Clinical / Pathological Context	Management Strategy	Key Notes / Conditions
1	Suspected or confirmed PTLD (all subtypes)	Reduction of immunosuppression (RIS)	Immunosuppression reduction, typically involving discontinuation of antimetabolites and/or modification of calcineurin inhibitor therapy.
2	Early lesions / non-destructive PTLD (plasmacytic hyperplasia, infectious mononucleosis-like PTLD, florid follicular hyperplasia)	RIS alone	Early lesions may resolve with RIS alone; close monitoring is required due to the risk of disease progression and allograft rejection.
3	Polymorphic PTLD (CD20-positive)	RIS + rituximab	Rituximab is added when disease persists or is clinically significant. Chemotherapy or surgical intervention is reserved for selected cases.
4	Monomorphic PTLD – CD20-positive (e.g., diffuse large B-cell lymphoma, Burkitt lymphoma)	RIS + rituximab ± chemotherapy (R-CHOP)	Chemotherapy is typically added in cases of incomplete response to rituximab alone or in patients with aggressive disease.
5	Monomorphic PTLD – CD20-negative or patients not eligible for rituximab	RIS + combination chemotherapy (CHOP-based)	Rituximab is not effective in CD20-negative disease; combination chemotherapy is required.
6	Classic Hodgkin lymphoma-like PTLD	Chemotherapy ± radiation therapy	Managed according to standard Hodgkin lymphoma treatment protocols rather than B-cell PTLD-specific algorithms.
7	Refractory or relapsed EBV-positive PTLD	EBV-specific cytotoxic T-cell therapy (EBV-CTLs)	Increasingly used in rituximab- or chemotherapy-refractory disease; third-party EBV-CTLs reduce delays related to cell production.
8	Localized complications	Surgery and/or radiation therapy (adjunctive)	Reserved for selected cases; not considered primary therapy for disseminated PTLD.

Rituximab has become a cornerstone for CD20-positive PTLD, and its incorporation into treatment algorithms has significantly improved survival, particularly when used sequentially with chemotherapy [15]. The Children’s Oncology Group and several European pediatric registries have demonstrated that rituximab, either as monotherapy or in combination with low-intensity chemotherapy, can induce remission while sparing the graft in many children [17, 18]. Similarly, case-based experiences confirm that rituximab alone may occasionally suffice, leading to durable remission in select patients [22]. In a phase 2 trial involving the addition of rituximab to a combination of cyclophosphamide and prednisolone (CPR regimen) in 55 pediatric patients with EBV+ CD20 + PTLD, a complete remission rate of 69% and an overall survival rate of 83% were reported [23].

Outcomes in pediatric PTLD have improved substantially over recent decades. In the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, patient survival now exceeds 85% at five years, with graft survival above 65%, particularly in those diagnosed more recently [24]. The German Ped-PTLD registry also demonstrated that rituximab with or without low-dose chemotherapy, alongside modification of immunosuppression, preserved kidney function in the majority of affected children, with stable allograft function documented in 85% over five years [18]. These results parallel the excellent outcome in our case, where systemic immunochemotherapy achieved complete metabolic remission and preserved graft function over a five-year follow-up. The durable remission and long-term graft preservation observed in this patient reinforce the feasibility of graft-sparing strategies when treatment intensity is carefully matched to disease biology.

Molecular studies further highlight differences between pediatric PTLD subtypes. Integrated genomic analyses have shown that PTLD-associated Burkitt lymphomas resemble their immunocompetent counterparts, whereas PTLD-associated diffuse large B-cell lymphomas (DLBCL) display lower mutational complexity yet respond well to low-intensity treatment [19]. Such findings reinforce the rationale for adapting therapy intensity to histological subtype and underline the favorable outcomes possible with carefully tailored treatment strategies. This case provides a clinical correlation to these observations, demonstrating that individualized biology-informed therapy can achieve sustained remission while preserving organ function in selected pediatric patients.

Conclusion

This case illustrates that high-grade, EBV-negative PTLD confined to the kidney allograft can be successfully managed with a graft-preserving, rituximab-based chemoimmunotherapy approach. Early recognition, multidisciplinary decision-making, and risk-adapted treatment were key to achieving sustained remission with long-term preservation of allograft function.

Clinical implications and future directions

Graft-preserving rituximab based immunochemotherapy may represent a viable therapeutic option in carefully selected pediatric patients with PTLD, even in the setting of high-grade monomorphic disease. However, as this is a single-case report, the findings are inherently limited in generalizability and caution is warranted in extrapolating the success of graft-sparing strategies to all cases of monomorphic PTLD. In clinical practice, consideration of graft preservation may be most appropriate in patients with disease confined to the allograft, absence of systemic or bone marrow involvement, and the capacity for close multidisciplinary surveillance. In contrast, disseminated disease, central nervous system involvement, suboptimal response to initial therapy, or rapidly progressive clinical courses are more likely to require intensified or graft-sacrificing treatment approaches.

Although reduction of immunosuppression remains a cornerstone of PTLD management, rituximab monotherapy may be insufficient in the presence of substantial tumor burden or aggressive disease biology. In such contexts, intermediate-intensity regimens, such as cyclophosphamide–prednisolone–rituximab (CPR), may offer effective disease control while potentially avoiding the morbidity associated with graft nephrectomy or full-intensity lymphoma chemotherapy.

Future studies are needed to better define patient- and disease-specific factors that predict benefit from graft-sparing chemoimmunotherapy in pediatric PTLD, with particular emphasis on long-term graft survival, relapse risk, and treatment-related toxicity, to further individualize therapy in this high-risk population.

Abbreviations

BUN

Blood urea nitrogen

CMV

Cytomegalovirus

EBV

Epstein–Barr virus

FDG PET

CT–Fluorodeoxyglucose positron emission tomography–computed tomography

HBsAg

Hepatitis B surface antigen

HCV

Hepatitis C virus

HIV

Human immunodeficiency virus

PTLD

Post–transplant lymphoproliferative disorder

RIS

Reduction of immunosuppression

Authors’ contributions

D.D and A.D contributed to patient care, supervision, conceptualization, data collection and initial drafting. F.B drafted and edited the final manuscript, performed critical revisions and conducted the literature review. All authors critically revised the manuscript for important intellectual content and approved the final version.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All relevant data supporting the findings of this report are included within the article. Further details are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

All procedures performed were in accordance with the ethical standards of the institutional research committee (Ethics approval No. IR.SUMS.MED.REC.1404.497) (approved on 7 December 2025) and with the Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. All necessary steps were taken to ensure patient confidentiality at all stages.

Competing interests

The authors declare no competing interests.