Liver Transplantation for Pediatric Liver Cancer

Abstract

Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.

Keywords: PRE-TEXT; chemotherapy; hepatoblastoma; hepatocellular carcinoma; histopathology; liver cancer; liver sarcoma; liver transplantation; neuroendocrine tumor; pediatric.

Figure 1

(A) HB, HCC and EMB (embryonal sarcoma) cases in the US. (B) Numbers of LT for HB, HCC and EMB in the US. (C) Estimate of HB cases treated with LT or other approaches. (D) Estimate of HCC cases treated with LT or other approaches. (SEER and SRTR 2000–2016).

Figure 2

(A) First row: Undifferentiated embryonal sarcoma: i. Contrast-enhanced CT image with a hypodense mass in segment IV. ii. Liver explant with a large yellowish necrotic tumor. iii. H&E stain shows only a peripheral zone with atypical pleomorphic cells with abundant golden brown hemosiderin pigment in this treated tumor (×400). iv: H&E stain shows a necrotic tumor with areas of coagulative necrosis, cellular debris and fibrosis (chemotherapy effect) (×40). (B) Second row: Malignant rhabdoid tumor. i. Contrast-enhanced CT image show large hypodense solid mass with small areas of necrosis in both liver lobes. ii. Liver explant with large necrotic tumor. iii. H&E. Uniform tumor cells with abundant eosinophilic cytoplasm and eccentric nuclei with dense stromal sclerosis. (×200). iv. An INI1 immunostain shows the characteristic complete loss of nuclear staining (×200) (C) Third row: Metastatic neuroendocrine carcinoma. i. CT shows multiple hypodense rim-enhancing solid liver masses (arrows). ii. Multiple yellowish nodules of varying sizes characteristic of a metastatic tumor. iii. H&E stain shows the interface between normal liver and tumor arranged in nests with some pleomorphism of nuclei, dense stromal sclerosis and lymphatic invasion at the junction with the portal area in the center (H & E × 100). (D) Fourth row: Metastatic pseudopapillary tumor: i. Contrast-enhanced CT shows multiple rim-enhancing hepatic lesions (arrows). ii. Liver explant with multiple tumor nodules favoring a metastatic tumor in a patient with a known pancreatic primary. iii. H&E stain shows the classic pseudo-papillae of the primary pancreatic tumor with cells arranged around a myxoid matrix surrounding central vessels giving the tumor a papillary configuration. (H & E × 200).

Figure 3

An example of HCN-NOS with overlapping features of HB and HCC in a 11 year old. (A) H&E showing a monotonous population of polygonal cells in a trabecular and pseudoacinar arrangement with variable sized nuclei and intranuclear vacuoles (H & E × 400). (B) beta-catenin stain shows a mainly cytoplasmic and weak to moderate nuclear stain throughout confirming a possible B-catenin mutation (B-cat × 400). (C) strong glutamine synthetase staining, thought to represent a surrogate marker of B-cat mutation (GS × 400). (D) Glypican 3 stain confirming the neoplastic nature of the lesion with fine granular staining of cytoplasm (GPC3 × 400).

Figure 4

Pre-and post-transplant chemotherapy and survival after LT for HB and HCC. All 149 patients received three cycles of pre-transplant chemotherapy. Ninety six patients also received post-LT chemotherapy.

Figure 5

(A) Patient survival after LT for HB by era. (B) Patient survival after LT for HCC by era. (SRTR 1988–2018).