<i>APC</i> germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

Abstract

Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to <i>APC</i> (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline <i>APC</i> mutations, with no events in the main hotspot of classical <i>APC</i> mutations at codon 1309 (<i>P</i> < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/β-catenin pathway without <i>CTNNB1</i> mutation, confirming that germline <i>APC</i> and somatic <i>CTNNB1</i> mutations are mutually exclusive (<i>P</i> < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy (<i>P</i> < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that <i>AP</i>C inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.