First reported post-transplant lymphoproliferative disorder after combined heart-liver transplantation

Post-transplant lymphoproliferative disorder (PTLD) is one of the most challenging complications of organ transplantation, which encompasses a heterogeneous group of lymphoid proliferations in transplant recipients ranging from benign polyclonal hyperplasia to aggressive monoclonal lymphomas (1,2). Its incidence varies dramatically based on the transplant type, with the highest cumulative incidence observed in combined organ and intestinal transplants (11–33%), followed by lung (2–9%), heart (2–6%), kidney transplants (1–3%) and liver transplants (1–2%), correlating directly with the intensity of immunosuppressive therapy (3,4). While the medical literature contains extensive documentation of PTLD occurring after single-organ transplantation, there remains a conspicuous absence of detailed reports describing this complication following combined multi-organ transplantation (5). We hereby present the first comprehensively documented case of PTLD developing after combined heart-liver transplantation (CHLT). The report may offer crucial insights for managing this life-threatening complication in the growing population of multi-organ transplant recipients. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. The study was approved by ethics committee of the Second Affiliated Hospital, Zhejiang University School of Medicine.

Our patient, a 42-year-old male with a family history of hypertrophic cardiomyopathy (his sister had died from the same condition), presented with a medical history spanning two decades. He initially developed bilateral lower extremity edema, chest tightness with exertional dyspnea, and progressively declining exercise tolerance 20 years before transplantation. Despite multiple therapeutic interventions over the years including various diuretic regimens and permanent pacemaker implantation for arrhythmia management, his cardiac function continued to deteriorate inexorably. Three years before transplantation, he developed ascites as a manifestation of congestive hepatopathy, with marked progression noted in the three months immediately preceding his transplant evaluation. Computed tomography (CT) imaging revealed congestive liver cirrhosis with multiple regenerative nodules (Hepatocellular carcinoma cannot be excluded), adding urgency to his clinical situation.

Upon admission for transplant evaluation, echocardiography demonstrated hypertrophic non-obstructive cardiomyopathy with severe tricuspid regurgitation and a preserved ejection fraction of 60%. Electrocardiography revealed multiple abnormalities, including atrial fibrillation, pathological Q waves in the anterior septal and inferior leads, complete right bundle branch block, and widespread ST-segment and T-wave abnormalities consistent with advanced hypertrophic cardiomyopathy. CT imaging manifested left-sided massive pleural effusions (occupying >90% of hemithorax volume) and right-sided moderate pleural effusions, cardiomegaly with prominent left atrial enlargement, and a small pericardial effusion. Also, massive ascites, liver cirrhosis with nodules suspicious of malignancy were found. Laboratory evaluation revealed significant hepatic dysfunction with total bilirubin of 38 µmol/L, hypoalbuminemia with albumin of 23 g/L, elevated ammonia at 49 µmol/L, and coagulopathy with prothrombin time of 16 seconds, collectively indicating Child-Pugh class C cirrhosis. Despite prior Epstein-Barr virus (EBV) exposure, baseline plasma EBV-DNA was below the limit of detection. His cardiac functional status was classified as New York Heart Association class III, and he required continuous vasopressor support and repeated thoracoabdominal drainage procedures during his pre-transplant hospitalization.

The patient was admitted for surgery following a multidisciplinary team (MDT) discussion, in which a sequential heart and liver transplant maintaining uninterrupted extracorporeal circulatory support was planned. After dissecting the recipient’s liver and isolating vasculars, the abdominal cavity was temporarily covered for the heart transplantation. Following median sternotomy, cardiopulmonary bypass (CPB) was established through cannulation of the ascending aorta, superior vena cava, and right femoral vessels. The cardiac transplant was performed using a modified bicaval anastomotic technique. After confirming satisfactory cardiac allograft function by the surgery team, we executed a critical transition from CPB to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) by removing the superior vena cava cannula while maintaining systemic perfusion. With the sternum left open and covered, we immediately proceeded with liver transplantation using a modified piggyback technique that preserved the recipient’s retrohepatic inferior vena cava. The period between re-entering abdomen and reperfusion of the liver was just an hour, with 58 minutes of anhepatic stage. Intraoperative ultrasound confirmed excellent flow in the hepatic artery, portal vein, and hepatic veins. After completing abdominal procedures and leaving drains in place, the heart transplant surgeon returned to control residual bleeding and close the chest. The combined procedure lasted 550 minutes with a CPB time of 132 minutes. The patient’s vital signs were assessed as stable and transferred to the intensive care unit postoperatively, with VA-ECMO maintained and weaned off the device after 12 hours. He was transferred to the general ward 30 days later.

His maintenance immunosuppressive regimen was with cyclosporine (100 mg twice daily), mycophenolate mofetil (0.5 g twice daily), and prednisone (5 mg once daily). Consistent monitoring demonstrated cyclosporine trough concentration at a marginal therapeutic range (50–80 ng/mL). After transferring to the general ward, the patient developed daily fever (max 39.5 ℃) with systemic myalgia and fatigue. Despite negative respiratory viral testing and unremarkable inflammatory markers, viral infection was suspected due to immunocompromised status. Blood next-generation sequencing analysis revealed low-abundance drug-resistant Pseudomonas aeruginosa along with hepatitis G virus and Torque teno virus, though the clinical significance of these findings remained uncertain. Empiric antiviral therapy with ganciclovir and intravenous immunoglobulin administration failed to improve his symptoms. EBV DNA was monitored fortnightly and remained persistently low. The diagnostic breakthrough came with a surveillance CT performed three months post-transplantation, which identified a progressively enlarging right lower lobe pulmonary nodule, with multiple enlarged mediastinal lymph nodes. EBV DNA replication was then detected above the baseline. Given the constellation of findings—severe immunosuppression, confirmed EBV seropositivity, and a rapidly growing pulmonary lesion, PTLD was suspected. Positron emission tomography (PET)-CT revealed a solitary hypermetabolic nodal lesion [maximum standardized uptake value (SUVmax) 20.7] with uptake values consistent with lymphoproliferative disease. Percutaneous image-guided biopsy with comprehensive histopathologic and immunohistochemical analysis showing EBER-ISH diffuse positive and ki67 >80%, confirmed the diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL), classified as monomorphic PTLD according to World Health Organization criteria (Figure 1).

Figure 1 Imaging and histopathology of PTLD. (A) CT showing right lower lung lobe nodule, multiple enlarged mediastinal lymph nodes, raising the possibility of lymphoma. (B) Histopathology showing atypical lymphoid hyperplasia, with immunohistochemical and molecular testing consistent with EBV-positive DLBCL (×400). (C) PET-CT showing the solid nodule with significantly abnormally increased glucose metabolism. CT, computed tomography; DLBCL, diffuse large B-cell lymphomas; EBV, Epstein-Bart virus; PET, positron emission tomography; PTLD, post-transplant lymphoproliferative disorder.

We conducted an urgent multidisciplinary consultation, in which cyclosporine and mycophenolate mofetil were recommended to be discontinued while maintaining low-dose prednisone to prevent acute rejection by transplant specialists. The PTLD pathological subtype was considered high-risk by the hematologists, thus an aggressive strategy of rituximab (anti-CD20 monoclonal antibody) with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) was recommended. Given the current left ventricular ejection fraction (LVEF) of 62%, doxorubicin was approved by the cardiologist and periodic LVEF monitoring was planned. Otherwise, high-dose intravenous immunoglobulin for passive immunity support and antiviral therapy with ganciclovir for EBV suppression were continued. This comprehensive approach led to the gradual resolution of PTLD-related symptoms over the subsequent 2 weeks. Follow-up contrast-enhanced CT 3 weeks later showed encouraging results: the previously identified node remained stable in size but demonstrated central necrosis consistent with treatment response, while an adjacent smaller satellite lymph node had decreased significantly in size. These radiographic changes, combined with resolution of symptoms, indicated a positive therapeutic response. The patient recovered well without evidence of cardiotoxicity or hepatotoxicity after 2 cycles of R-CHOP therapy and was discharged without further sequela attributable to PTLD.

This landmark case provides several critical insights, especially demonstrating the importance of multidisciplinary expertise in surgery and management of PTLD. Guided by MDT consensus, surgery strategies including sequential transplantation under uninterrupted extracorporeal support, modified piggyback technique were devised to stabilize hemodynamics and avert reperfusion injury in this fragile, dual-organ failure patient. When non-specific febrile symptoms heralded PTLD, the MDT framework, including infectious disease specialists, hematopathologists, and oncologists, enabled rapid CT/PET imaging, targeted biopsy, and EBV-positive DLBCL diagnosis within days. Also, the aggressive multimodal strategy maintaining the delicate balance between graft preservation and PTLD treatment was achieved only through continuous MDT dialogue.

PTLD in combined multi-organ transplantation remains poorly reported and has only been documented at the level of small case series (4,6,7). Though in CHLT recipients, the liver allograft has proven to be protective with comparable survival and incidence of antibody-mediated rejection compared with recipients of heart alone, the PTLD incidence of CHLT may be higher. As reported, the PTLD incidence in heart transplantation is 2–6%. Liver transplantation has the lowest PTLD incidence of 1% among solid organ transplants, while multi-organ transplantation demonstrates significantly higher incidence of 11–33% (3,4). Notably, PTLD may manifest earlier in multi-organ transplant recipients. Current consensus attributes these to elevated immunosuppressive regimens (6). Therefore, we propose enhanced monitoring protocols and tailored immunosuppression strategies in multi-organ transplant recipients to reduce PTLD incidence.

In conclusion, we report the first comprehensively documented case of PTLD following CHLT, adding crucial data to the limited literature on multi-organ transplant complications. Our institutional experience emphasizes the importance of multidisciplinary collaboration, vigilant surveillance and comprehensive treatment strategies. As combined organ transplantation becomes increasingly common for patients with multi-organ failure, establishing evidence-based protocols for PTLD prevention, surveillance, and management will be essential for optimizing outcomes in this complex patient population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at: https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-537/prf

Funding: This research was supported by National Natural Science Foundation of China (Nos. U23A20449 and 82202411), and Key Research and Development Program of Zhejiang Province (No. 2024C03143).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-537/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. The study was approved by ethics committee of the Second Affiliated Hospital, Zhejiang University School of Medicine. All patient identifiers have been removed to ensure confidentiality.

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