Fatal Central Nervous System Post-Transplant Lymphoproliferative Disease in a Patient Who Underwent Liver Transplantation for Hepatoblastoma

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Hepatoblastoma is the most common pediatric liver malignancy and is associated with low birth weight, Beckwith-Wiedemann syndrome, familial adenomatous polyposis, and hemi-hypertrophy. In North America, treatment is based on Children's Oncology Group guidelines and with the exception of pure fetal hepatoblastoma, includes cisplatin-based chemotherapy plus surgery (resection or transplantation) (1). We describe a case of fatal central nervous system (CNS) post-transplant lymphoproliferative disease (PTLD) in a patient transplanted for hepatoblastoma.
A 15-month-old (former 34 weeks) boy presented with abdominal distension and elevated alpha-fetoprotein (215,800 ng/mL). Abdominal magnetic resonance imaging showed multiple enhancing foci with low T1-weighted and high T2-weighted signal involving segments 3, 4B, 5, and 6 (PRETEXT IV). No metastasis or adenopathy was noted on chest computed tomography. Liver biopsy showed mixed epithelial and mesenchymal hepatoblastoma.
Neoadjuvant chemotherapy (cisplatin, fluorouracil, vincristine) was initiated, but after 2 cycles, the tumor remained unresectable (POSTTEXT IV). He underwent liver transplantation at 19 months of age, during the 5th cycle, with an ABO-identical, whole allograft, from a deceased donor. Explant pathology confirmed multifocal, partially viable hepatoblastoma. Conventional immunosuppression regime was used: no induction agent, methylprednisolone (initiated intraoperatively and weaned to oral prednisone, 0.3 mg · kg−1 · day−1, over the first week), and oral tacrolimus (initiated postoperative day 1 to achieve trough levels of 10–12 ng/mL). The alpha-fetoprotein decreased to 10 ng/mL after transplant and remained normal.
He received his 6th round of chemotherapy on postoperative day 22. On postoperative day 37, he developed tachypnea and chest x-ray showed a pleural effusion. He became febrile and his respiratory distress worsened, requiring endotracheal intubation. An infectious workup revealed adenoviremia (1,700,000 copies/mL in plasma) and Epstein-Barr viremia (EBV) (68,856 copies/mL in buffy coat). Cidofovir was initiated and immunosuppression was lowered, reducing the tacrolimus dose to achieve a trough of 3 to 5 ng/mL and reducing the prednisone to 0.1 mg · kg−1 · day−1. Adenovirus was undetectable by postoperative day 69, following 3 rounds of cidofovir.
The patient was naïve before transplant and his donor was EBV IgG-positive. The patient received ganciclovir prophylaxis continuously after transplant. EBV polymerase chain reaction (PCR) declined following immunosuppression reduction: 4653 copies/mL 1 week later, and 2800 copies/mL the following week. On postoperative day 54, the patient was weaned to nasal cannula after being intubated for 17 days.
On postoperative day 115, the patient developed altered mental status and asymmetric dystonic movements with oxygen desaturation. Brain magnetic resonance imaging showed diffuse cytotoxic edema in the anterior striatum with foci of restricted diffusion in the right medial parietal lobe, left cerebral peduncle, and right cerebellum (Fig. 1). These findings evoked a differential diagnosis which included acute disseminated encephalomyelitis, encephalitis, extrapontine myelinolysis, posterior reversible encephalopathy syndrome, or PTLD. Repeat EBV PCR showed 3424 copies/mL.
The patient continued to have oxygen desaturations and worsening dystonic episodes requiring endotracheal intubation. A lumbar puncture was performed on postoperative day 118 and EBV PCR of cerebral spinal fluid (CSF) showed 133,000 copies/mL, compared to 2016 copied/mL in buffy coat, suggestive of CNS PTLD. The patient was started on intravenous rituximab, deemed unstable for intrathecal treatment. The patient continued to deteriorate, with recurrent dystonic episodes and decompensated cardiovascular function. His family withdrew care on postoperative day 127.
Autopsy showed EBV-positive monomorphic PTLD in the bilateral basal ganglia (Fig. 2A), thalamus, right parietal lobe, left temporal lobe, and right dentate nucleus. PTLD foci were noted outside of the brain, with lesional cells in the liver and lymph nodes (above and below the diaphragm). Cellular constitution and antigen expression of PTLD foci within and outside the CNS were distinct. PTLD in the brain was a monomorphic large B-cell lymphoma (Fig. 2B and C) with a majority of large atypical B-cells showing diffuse reactivity for CD20 (Fig. 2E).
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