EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The development of non-Hodgkin lymphoma following liver transplant is rare. We present an unusual case of a 40-year-old female patient with morbid obesity who had undergone a deceased donor liver transplant for an unresectable neuroendocrine tumor of the liver 12 years ago. She presented with a lesion in the tail of pancreas that was suggestive of a recurrent neuroendocrine tumor. She underwent robotic-assisted distal pancre-atectomy and splenectomy, which demonstrated a final diagnosis of splenic marginal zone lymphoma. Although there is a high likelihood of recurrence of neuroen-docrine tumor after transplant, non-Hodgkin lymphoma and posttransplant lymphoproliferative disorder must be considered in the background of transplant and solid-organ malignancy.

Key words : Hepatic transplantation, Lymphoproliferative disorders, Neuroendocrine tumor, Splenic marginal zone lymphoma

Posttransplant malignancies are a common long-term complication after liver transplant, and this risk is heightened in the setting of continuous immuno-suppression. This is often a major cause of morbidity and mortality in liver transplant recipients. The incidences and outcomes of all cancer types that can occur in liver transplant recipients have not been fully determined. Therefore, greater efforts are needed to capture posttransplant cancer risk patterns so that more optimal surveillance and monitoring of immunosuppression can occur. Moreover, greater awareness is needed for rarer cancer types such as non-Hodgkin lymphoma and posttransplant lympho-proliferative disorder (PTLD). The incidence of PTLD is estimated at 1% to 2% in liver transplant recipients, with non-Hodgkin lymphoma comprising a signi-ficant subset of cases. These lymphomas vary in histology and are often driven by Epstein-Barr virus (EBV) infection, although EBV-negative cases are increasingly recognized.

A 40-year-old female patient, who received a deceased donor liver transplant 12 years prior for an unre-sectable well-differentiated neuroendocrine tumor (NET, grade 2) of the liver and was on postoperative immunosuppression therapy (tacrolimus 4 mg twice daily), presented with abdominal pain, 20-lb weight loss, fever, chills, and submandibular and periauricular lymphadenopathy. She was closely followed with hepatology to detect disease recurrence using chro-mogranin A level as a marker, the results of which were negative to date. Her comorbid conditions were morbid obesity (body mass index 62.8), hepatic steatosis, diabetes, and hypertension. She had a history of cytomegalovirus viremia, which occurred 5 months after transplant, and rejection (Banff score 7), which occurred 14 months after transplant. Computed tomography (CT) scan of the abdomen and pelvis showed a 3.2-cm rounded soft tissue 2 density at the splenic hilum distant to the splenic artery and vein, and a 2.1 × 3.1-cm lesion on the tail 4 of the pancreas (Figure 1). Gallium dotatate positron emission tomography (PET) revealed increased metabolic activity of the spleen and pancreas tail lesion suspicious of recurrent or metastatic NET. The spleen was enlarged and measured 18.9 cm. The maximum standardized uptake value was 15.3 for the liver, 15.2 for the pancreatic tail, and 34.8 for the spleen.

Chromogranin A was 39 ng/mL, and alkaline phosphatase was elevated at 152 U/L. Lipase, amylase, total bilirubin, and liver enzymes were within reference ranges. Test results were negative for EBV DNA polymerase chain reaction (PCR), EBV DNA log10 PCR, hepatitis B virus antibody and surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antigen and antibody.

Upper endoscopic ultrasonography revealed 2 hypoechoic, well-defined lesions in the pancreatic tail and splenic hilum, which were further characterized by magnetic resonance imaging. A 2.1 × 3.1-cm hypoenhancing pancreatic tail lesion and an 18.4-cm splenomegaly were observed on magnetic resonance imaging. No intrahepatic biliary ductal dilation or pancreatic ductal dilation was shown, but there was diffuse hepatic steatosis without focal lesions. Fine needle aspiration using a transgastric approach of the celiac node and pancreatic node was performed, and the test results were negative for malignant cells. This case was discussed by the multidisciplinary tumor board and given the high clinical suspicion of recurrent NET. She was scheduled for robotic-assisted distal pancreatectomy and splenectomy.

The patient was positioned in a supine, semi-right lateral orientation, with the left arm abducted at a 90-degree angle and the right arm resting alongside the body. We used a robotic surgical system with 4 arms (da Vinci Xi, Intuitive). After a quick diagnostic laparoscopy of the abdominal cavity, 4 robotic trocars were placed. Numerous omental adhesions to the abdominal wall and transplant liver were present, which we released. The gastrocolic omentum was incised, and the lesser sac was entered. The spleen was noted to be enlarged (Figure 2, A and B). A pancreatic tail lesion was noted to be present over the splenic vein. We carefully dissected the mass and excised a biopsy that measured 0.9 × 0.8 × 0.4 cm from the vein and artery, which was sent for frozen section analysis.

The frozen biopsy result favored neuroendocrine origin, although it was a difficult distinction given history of prior NET, so we proceeded with a distal pancreatectomy and splenectomy. Careful dissection was performed toward the 3 × 2-cm lesion, which was in close proximity to the splenic artery in the region of the pancreatic tail and appeared white-tan in color and hemorrhagic. The splenic artery was dissected, and a robotic stapler was fired across the splenic artery. The rest of the pancreas with the splenic vein was then divided with the stapler. The spleen was mobilized from its attachments, and the specimen was removed using a left subcostal incision. The spleen measured 28.5 × 18.5 × 11.5 cm, and the distal pancreas measured 11.5 × 9.0 × 5.0 cm. After hemostasis was achieved, a drain was placed, and all ports were closed.

The final pathology report surprisingly confirmed the lesion to be a B-cell lymphoma, most consistent with splenic marginal zone lymphoma (SMZL) with direct extension to the pancreas tail. Hematoxylin and eosin staining showed diffuse infiltration of small lymphoid cells involving the splenic white pulp, red pulp sinuses, and cords, and the pancreatic parenchyma (Figure 3A). Immunohistology staining was positive for CD19 (Figure 3B), CD45, and CD25 (dim), and CD20 kappa and lambda light chain stains showed polytypic plasma cells. The Ki67 proliferation index appeared to increase around 30% to 40%; however, this could have been because of proli-feration among the numerous interspersed T cells. Immunostaining on block B12 showed reactive follicles with germinal centers that were positive for CD10 (Figure 3C) and negative for BCL-2. The splenic mass also demonstrated positivity for immunoglobin M and immunoglobin D (Figure 3D) in mantle zones with extrafollicular B-cell staining. Results from Epstein-Barr encoded RNA in situ hybridization, EBV PCR, EBV DNA log10 PCR, and EBV DNA Quant Source were negative for the biopsy. Results from the flow cytometry of the pancreatic mass showed positivity for CD10 lambda restricted B cells on a background of CD20, CD19, and light chain, which confirmed the diagnosis of SMZL.

Postoperatively, the patient was noted to have leukocytosis and thrombocytosis. Her hospital course was unremarkable except for hyperglycemia, and she was discharged on postoperative day 4. Subsequent PET-CT demonstrated generalized lymphadenopathy above and below the diaphragm with mild to moderate intensity of the maximum standardized uptake value. The peripheral blood flow cytometry results were negative for monoclonal B cells. She was started on rituximab (weekly dose of 375 mg/m2) for 8 cycles and continued on tacrolimus (4 mg twice daily) with a goal of 4 to 6 ng/mL. Her following PET-CT 10 months after the initial PET-CT later showed no metabolic evidence of malignancy or recurrent lymphoma (Table 1).

There is an established increased risk of non-Hodgkin lymphoma following solid-organ transplant. However, a low-grade lymphoma is typically not categorized as a PTLD unless the PCR results are positive for EBV DNA. Although SMZL is not traditionally categorized under PTLD in the absence of EBV positivity, it is important to recognize that late onset, EBV-negative indolent PTLD is a well-described entity. The diffe-rentiation between de novo SMZL and indolent PTLD in the posttransplant population remains complex and may overlap clinically and histologically. The intraoperative frozen section material of the pancreatic tail lesion was highly challenging to interpret given the history of a NET. However, NET was a favored diagnosis at the time of frozen section analysis because NET has a high rate of post-transplant recurrence.

The liver is the most involved organ affected by NET.¹ Clinical-pathological staging of NET has provided indications for liver transplant to prolong survival and provide curative intent in patients with unresectable tumor bulk, expected survival ≥70%, and a 5-year recurrence-free survival rate greater than 50%.¹ Our patient’s younger age (≤45 years old) made her a candidate for liver transplant due to her likelihood of improved survival.² Nevertheless, NET relapse in cases of liver metastases has high recur-rence rate, ranging from 31.3% to 56.8% at 5 years after liver transplant.^3,4 Patients with unilobar or single metastatic spread without evidence of extrahepatic disease exhibit a 5-year tumor recurrence rate of 80%.¹ Aside from the increase likelihood of disease recurrence, little is known about posttransplant prognostic courses due to the absence of solid data.

The incidence of SMZL following liver transplant is unknown. Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma subtype among transplant recipients and individuals infected with HIV.⁵ A US registry of 175 732 solid-organ recipients between 1987 and 2008 demonstrated a bimodal onset of non-Hodgkin lymphoma and PTLD following solid-organ transplant involving patients aged 0 to 34 years or ≥50 years at transplant.⁵ The same registry revealed non-Hodgkin lymphoma had the greatest risk among lung recipients, and secondarily kidney and liver recipients.⁵ In another population-based study of 540 Finnish liver transplant recipients, 8 cases (1.4%) developed non-Hodgkin lymphoma, of which 4 cases (0.7%) were PTLD.⁶ Elevated non-Hodgkin lymphoma risk was associated with male sex, young age, and the immediate posttransplant period in this study.⁶ In another population-based study of 2005 adult liver transplant patients, 23 patients (1.1%) were identified with PTLD and 5 patients (0.2%) were identified with B-cell non-Hodgkin lymphoma.⁷ Reports of non-Hodgkin lymphoma following liver transplant for NET, in which the likelihood of NET recurrence may appear greater, are insufficient.

Given the potential role of chronic calcineurin inhibitor exposure in lymphoma pathogenesis, tacrolimus had been continued for 12 years after the liver transplant at a reduced dose with a target trough level of 4 to 6 ng/mL; this regimen was monitored closely in consultation with transplant hepatology to balance the risk of rejection and lymphoma prog-ression. Chronic immunosuppression with tacro-limus at reduced doses could have led to suppression of T-cell activation and impaired immune sur-veillance against oncogenic viruses such as EBV or malignant lymphoid clones, which could have inevitably increased the patient’s risk of lymphoma. In a large multicenter, case control study of 2495 living donor transplants, total cumulative exposure, and not just the daily dose, of tacrolimus was an independent risk factor for the development of non-Hodgkin lymphoma following living donor transplant.⁸ Thus, tacrolimus at a dose of 4 mg twice daily for 12 years after liver transplant would result in a higher cumulative exposure that could place a patient at risk for non-Hodgkin lymphoma.

After the patient’s splenectomy and pancre-atectomy, tacrolimus was restarted at the same dose with addition of rituximab monotherapy. Bone marrow biopsy was not performed because of abse-nce of cytopenias and lack of systemic symptoms. Based on the indolent histology and limited stage of disease, rituximab monotherapy was selected in alignment with National Comprehensive Cancer Network guidelines for SMZL. We used PET-CT imaging for assessment of treatment response and observed complete metabolic remission at 10 months.

The group of PTLDs encompasses a spectrum of lymphoid proliferations, and, although most cases are EBV-positive and polyclonal, late onset monomorphic PTLD may be negative for EBV and histologically indistinguishable from de novo B-cell lymphomas. Splenic marginal zone lymphoma remains a distinct entity characterized by splenic involvement and indolent behavior. In this case, despite the patient’s transplant history, the lack of EBV association and histopathological features favored SMZL, although the possibility of EBV-negative PTLD remains part of the differential diagnosis. Thus, it is important for the transplant team, oncologist, and radiologist to be alert to the possibility of non-Hodgkin lymphoma in addition to PTLD for several years after transplant.

Volume: 23 Issue: 8 August 2025

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