The pathologic features of hepatocellular carcinoma (HCC) of the adult type (ordinary HCC) are well established (Figs. 18.9). Adult-type HCC also develops in children, adolescents, and young adults. Similar to cancers occurring in the older age group, HCCs in younger individuals display distinct macroscopic growth patterns, including expanding, invasive, pedunculated, multinodular, and diffuse lesions. The main clinical and biological features have been reviewed [15–17]. To date, no differences have been recognized among children, adolescents, and adults in the biology and pathology of typical, ordinary HCC. A systematic analysis of the significance of histopathologic risk factors identified in patients with adult-type HCC [18] has yet to be performed in adolescents and young adults.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer characterized by a single expanding mass with typical histologic features consisting of large eosinophilic cells embedded in an abundant collagen-rich stroma, the latter forming “fibrolamellae” between the cancer cells (Fig. 18.10). This tumor occurs most often in young individuals. It accounts for about 30 % of HCC in patients younger than 20 years of age. Typically, FL-HCC develops in the absence of underlying cirrhosis, hepatitis viral infection, or metabolic disorders, and serum AFP is not elevated. FL-HCC may be associated with high serum vitamin B12-binding capacity, express a neuroendocrine signature [20], and exhibit aromatase activity causing gynecomastia [21]. A clear cell variant of FL-HCC exists [22]. The neoplasm has distinct immunohistochemical features [23], including reactivity for cytokeratin 7 [24]. FL-HCC markedly differs from ordinary HCC with respect to karyotypic and genomic abnormalities. Recently, a recurrent and highly characteristic chimeric transcript located to chromosome 19 has been identified in FL-HCC. The transcript encodes a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A (DNAJB1-PRKACA fusion) [25]. The fusion results in increased cAMP-dependent protein kinase A activity, and the fusion protein is oncogenic in HCC cells. Later studies confirmed the association of this chimeric transcript with FL-HCC, suggesting that this alteration is a highly characteristic molecular signature for FL-HCC [26–29]. A second gene fusion event found in FL-HCC is a translocation between CLPTM1 and GLIS3 genes, generating a transcript that promotes malignant transformation in cell lines [29].

Hepatoblastoma (HB) is rare in adolescence and adulthood [30]. In fact, the large majority of HB is diagnosed in infants and children less than 5 years old. There is evidence that HB is the most prominent member of a HB family of tumors, which share distinct molecular features, including abnormalities of the Wnt/beta-catenin signaling pathway (see below). Conventionally, HBs were divided into epithelial HB and mixed epithelial-mesenchymal HB, the latter subclassified into those with or without teratoid features [31–33] (Figs. 18.11). A novel classification was worked out in the frame of an International Pathology Symposium in March 2011 in Los Angeles. Twenty-two expert pathologists of COG, SIOPEL, GPOH, and JPLT as well as pediatric oncologists and surgeons formulated a consensus classification published in 2014 [34] (Table 18.2).

HB can develop in young adults and older patients [35]. The pathology of HB is the same in young and older subjects, and the criteria for histological diagnosis have been reviewed recently [32, 36]. However, molecular signatures will be required to test whether adult HBs are the same or different entities in comparison with HB of young age. There are intriguing situations whereby HCC occurs in combination with HB [37] or HCC recurring as HB [38], suggesting a possible filiation of these neoplasms. Part of hepatic tumors in older children and adolescents contain HCC-like components and exhibit signs of cholangiocyte differentiation. Such highly aggressive lesions have been termed “transitional liver cell tumor” [39] and may be related to pleomorphic or anaplastic variants of HB. Similar to infants and children, adolescents and young adults may also develop unusual HB family tumors that have recently been identified, including small cell HB with “rhabdoid features” (tumors that do not immunohistochemically express the chromatin-remodeling protein INI1/hSNF5/SMARCB1) [40], and cholangioblastic HB.

The oncogenic pathways of HCC and HB differ in many respects. HCCs show multiple chromosomal aberrations (mainly losses), whereas HBs exhibit a lower number of chromosomal changes [30, 41]. In contrast to HCC, p53 gene (and related genes) mutations are almost lacking in HB, and p53 protein overexpression is seen infrequently [15, 42–44]. HB can develop in the setting of imprinting disorders, including Beckwith-Wiedemann syndrome (BWS) involving the loss of imprinting of IGF2 [45]. In BWS, HB was only detected in patients with chromosome 11p15 paternal uniparental disomy (UPD) [46]. HB can also complicate paternal uniparental disomy 14 and epimutations and microdeletions that affect the maternally derived 14q32.2 imprinted region, a constellation found in Kagami-Ogata syndrome [47].

In cancerogenic pathways leading to HB, abnormalities of the Wnt/beta-catenin signaling pathway play a central role [41, 48]. This signaling cascade is critically involved in cancer stemness and malignant behavior [49]. Beta-catenin gene mutations in HB involve the degradation targeting box [50], and the activation of beta-catenin involves both epithelial and mesenchymal HBs [51]. Mutations of beta-catenin gene in HB are associated with overexpression of proliferation factors, including cyclin D1 [52]. Based on its role on priming and expansion of stem and progenitor cells, beta-catenin activation may affect hepatic stem cells, including DLK1-positive oval cells present in HB [53]. Beta-catenin activation in a distinct progenitor cell type is sufficient to cause HB and HCC [54]. Beta-catenin can activate different transcriptional programs in subsets of HB, associated with distinct expression of hepatic stem-cell markers in immature tumors [55]. Alterations of other components of the Wnt signaling pathway have been found in HB, including mutations of the adenomatous polyposis coli (APC) and AXIN genes.

A further hepatic tumor showing abnormal Wnt/beta-catenin signaling is nested stromal-epithelial tumor (NSET; ossifying stromal-epithelial tumor) [56, 57]. This neoplasm occurs in both the pediatric age group and in adolescents and rarely in adults and is characterized by multiple clustered nests of immature epithelial cells embedded in a spindle-cell stroma with osteoid foci, surrounded by a sheath of myofibroblasts. NSET may be associated with Cushing’s syndrome due to ectopic ACTH production [58] and usually shows a benign course, although recurrent and metastatic disease occurs. Marked nuclear reactivity of nested cells for beta-catenin is a consistent finding [31]. A later study uncovered mutations of the beta-catenin gene in NSET, characterized by large deletions in exon 3, suggesting that this neoplasm is related to HB with defective mesenchymal-epithelial transition [59]. This relation is supported by the association of NSET with Beckwith-Wiedemann syndrome [60]. Beta-catenin mutations occur in a subset of hepatocellular adenoma. Beta-catenin-activated hepatocellular adenoma can give rise to malignant hepatic tumors, including well-differentiated atypical HCC [61].

Recently, gene mutations affecting cellular functions other than those linked to Wnt signaling were detected in HB, including the ubiquitin ligase complex [62] and the transcriptional coactivator, Yap1 [63]. A subset of HB exhibits mutations of the transcription factor NFE2L2, involving residues that are recognized by the KEAP/CUL3 complex for proteasomal degradation [64]. Aggressive subsets of HB with HCC-like properties showed loss of genomic stability and promoter mutations of telomerase reverse transcriptase (TERT) [64].

Some other liver tumors (non-HB and non-HCC) which can occur in this age group should be considered in the differential diagnosis are discussed below.