Figure 18.1 Schematic diagram of malignant liver tumours.

Figure 18.2 Eighteen-month-old girl (with Beckwith–Wiedemann syndrome and hemihypertrophy) treated successfully with HB. (a) CT scan showing large tumour occupying entire left lobe, together with tumour in posterior sector of right lobe (arrowed), and (b) following adjuvant chemotherapy, marked tumour shrinkage, allowing left hepatic resection (segments 2–4).

Figure 18.3 CT scan showing the appearance of a multifocal HCC in a 6-year-old boy.

18.3  CLINICAL FEATURES

18.3.1  Presentation

Most children present with an asymptomatic abdominal mass or distension detected by caregivers or primary care physician. Some may present with an acute abdomen due to tumour rupture or haemorrhage. Jaundice is uncommon and when present, conditions causing obstruction of biliary drainage, such as biliary rhabdomyosarcoma (RMS), should be suspected. Some children with HB can present with signs of virilisation due to ectopic secretion of β-human chorionic gonadotropin (β-hCG) [10], and rarely with fractures due to paraneoplastic osteoporosis [11].

Serum α-fetoprotein (AFP) is elevated in greater than 90% of children with HB and almost 50% of the those with HCC. When elevated, the AFP level should be checked against a reference value for age, as it may be physiologically elevated in infants, and may not decrease to adult levels until after 1 year of age. A low serum AFP level (<100 ng/mL) at diagnosis may also portend a worse prognosis [12]. Other conditions, such as germ cell tumours, mesenchymal hamartoma, hereditary persistence of high AFP, haemangioendothelioma and viral hepatitis, can result in an elevated AFP, but the level is usually less than 10,000 ng/mL. Thrombocytosis is common at diagnosis. Liver function tests are usually normal. A viral hepatitis panel should be obtained in patients with HCC.

18.3.2  Imaging studies

Ultrasound is an excellent initial study for confirming liver origin, to determine the characteristics of the mass (solid vs. cystic) and for assessment of the status of the inferior vena cava and the hepatic and portal veins. In general, further evaluation of a liver mass will require contrast-enhanced abdominal computed tomography (CT) scan or magnetic resonance imaging (MRI). Both CT and MRI provide excellent delineation of the involved segments, although MRI may allow more precise assessment of the relationship between the hepatic vessels and the tumour. Although there are no distinguishing characteristic features between HB and HCC on imaging studies, imaging may help distinguish benign lesions such as infantile haemangioma, mesenchymal hamartoma of the liver and FNH without the need for a biopsy.

A CT scan of the chest should be obtained to assess the presence of metastatic disease in the lung, which is the most common site of extrahepatic disease in both HB and HCC. A nuclear medicine bone scan is also indicated in suspected HCC. The role of positron emission tomography (PET) is not well defined in HB, and MRI with newer contrast agents such as gadoxetate disodium is currently under investigation [13].

18.3.3  Staging

There are two main staging systems for HB (Table 18.1). The North American Staging System is a postsurgical staging system, and is dependent on the extent of tumour resection. In this system, the stage of the tumour is dependent on the judgement and experience of the surgeon and oncologist.

Table 18.1 Staging for HB (North America and Europe)

The European SIOPEL^* group has developed a presurgical staging system based on the pretreatment extent of disease in imaging studies (PRETEXT). The eight Couinaud^† segments in the liver are further grouped into four sections: left lateral (segments 2 and 3), left medial (segment 4), right anterior (segments 5 and 8) and right posterior (segments 6 and 7). PRETEXT staging is determined by the number of contiguous sections that are free of tumour (Table 18.1). In addition, various letters are assigned based on caudate lobe (C), multifocal (F), inferior vena cava and hepatic vein (V), portal vein (P), extrahepatic spread (E), tumour rupture (H), metastatic disease (M) and lymph node (N) involvement. PRETEXT has a tendency to overstage the patients, as it can be difficult to differentiate tumour compression and tumour ingrowth.

Both staging systems have been shown to predict outcome [14,15]. The current Children’s Oncology Group (COG) HB study AHEP0731 is studying both systems prospectively in the same group of children.

18.3.4  Diagnostic tumour biopsy

The indication for biopsy (laparoscopic, open or percutaneous) in North America has been mandatory, as tumour biopsy and histological classification are thought essential to later protocol-based management. Certainly, diagnostic tumour biopsy is essential in unresectable tumours to confirm histological diagnosis and to differentiate from HCC and benign tumours. Biopsy also provides tissue for biological studies. When needle biopsy is attempted, at least 5 and preferably 10 cores should be obtained.

18.4  PATHOLOGY

18.4.1  Hepatoblastoma

These tumours generally present as large multinodular expansile masses, well demarcated but not encapsulated. Gross appearance is usually variegated, depending on the various microscopic components present (Figure 18.4). It may present areas of necrosis, haemorrhage and even microcalcifications, if osteoid is one of the components, particularly following chemotherapy.

Histological classification schemes categorise HBs into either epithelial or mixed types, as well as a variable number of subtypes [1,16] (Table 18.2), some of which have been incorporated as risk stratification variables for HB [15,17]. Immunohistochemistry is also being increasingly used in the diagnosis and classification of HB subtypes [16]. Prognosis is excellent for resectable patients with a favourable histology (e.g. pure fetal HB with low mitotic activity) who can be cured with surgery alone, while others with histologically unfavourable tumours (i.e. small cell) have been associated with chemoresistance and poor prognosis [17,18].

Conventional cytogenetic analyses of HB generally show a limited number of numerical and structural chromosomal abnormalities, with trisomies of chromosomes 2, 8 and 20 and unbalanced translocations involving chromosome 1 (1q), some cases carrying a t(1;4) translocation or other translocations involving chromosome 1 being most frequent [19,20]. Molecular studies have started to elucidate the common underlying abnormalities in these tumours, including the almost universal activation of the canonical Wnt pathway, usually by the presence of CTNNB1 somatic mutations [21]. Expression and miRNA profiling have been attempted to identify prognostic groups of tumours and gene signatures that could be used to stratify these children further [22,23].

18.4.2  Hepatocellular carcinoma

HCC is often diagnosed at advanced stages involving both lobes of the liver, but it can also present as a solitary, non-encapsulated mass, sometimes bile stained. Vascular spread and extrahepatic metastases are frequently seen at diagnosis via the hepatic veins [24]. Microscopic features of paediatric HCC are similar to those seen in adults [25] and can be classified according to grade into well-differentiated, moderately differentiated, poorly differentiated and undifferentiated types [26], and also by nuclear features alone or in combination with microvascular invasion. Architectural patterns in well- and moderately well-differentiated HCC include the trabecular pattern as well as pseudoglandular, acinar and solid patterns [25].

The fibrolamellar variant of HCC occurs almost exclusively in adolescents and young adults [27,28] and characteristically presents in patients without cirrhosis, or other underlying chronic liver disease. They usually present as well-circumscribed tumours with characteristic radiating fibrous septa, resembling FNH. Histologically, they consist of cords and nests of large neoplastic hepatocytes with granular oncocytic cytoplasm, separated by dense hyalinised collagen bands (Figure 18.4F). A characteristic recurrent DNAJB1-PRKACA fusion gene and chimeric transcript have been recently reported in this tumour type [29]. The prognosis of children with fibrolamellar HCC is similar to that in patients with typical HCC at a similar stage [30].

The most common differential diagnosis of paediatric HCC is HB, and only rarely other metastatic lesions. Hepatic adenomas in older children may be challenging to differentiate from well-differentiated HCC, and from FNH, particularly in small biopsies. Immunohistochemical stains may be useful to differentiate HCC from other tumour types.

Figure 18.4 (a) Gross appearance of HB resection specimen, postchemotherapy. A small area of residual viable tumour is indicated by the arrow, surrounded by areas of fibrosis and a rim of uninvolved liver parenchyma. (b) HB, epithelial fetal pattern. (c) Mixed epithelial HB, embryonal and small cell patterns. (d) β-Catenin immunohistochemical staining demonstrating cytoplasmic and focal nuclear staining in the same tumour. (e) Glypican 3 cytoplasmic positivity. (f) Fibrolamellar variant of HCC.

18.4.3  Hepatocellular neoplasm NOS

There are a minority of paediatric hepatocellular tumours which are difficult to classify, sometimes sharing features of both HB and HCC [16]. Prokurat and colleagues from Warsaw, Poland, had previously reported malignant hepatocellular tumours in seven older children, which were difficult to classify and contained HB-like cells, cells resembling those of HCC and so-called ‘intermediate cell forms’, which they designated as transitional liver cell tumours [31]. The current consensus classification recommendation is to include these lesions as hepatocellular neoplasm not otherwise specified (NOS) until a precise nosological assignment is possible.

18.4.4  Undifferentiated embryonal sarcoma

UES (formerly known as malignant mesenchymoma) is an uncommon neoplasm with a primitive mesenchymal phenotype. It tends to occur in older children (6–10 years) and histologically is characterised by spindle, oval or stellate cells admixed with a myxoid stroma. There may be dot-like cytoplasmic-positive staining for cytokeratin (CK), together with membranous CD56 reactivity and negative staining for myogenin. These markers are useful in the distinction of UES from RMS [32].

Table 18.2 Classification of HB

Source: After López-Terrada D, et al., Modern Pathology 2014, 27: 472–491 [80].

Note: HB, hepatoblastoma; HPF, high power field.

There may also be a group which arise earlier in childhood from a preexisting benign mesenchymal hamartoma, the youngest one so far reported being 11 months old at presentation [33].

UES tends to appear as dark (hypodense) on CT scan with a bright fibrous pseudocapsule. Further workup includes an assessment for potential pulmonary metastases (chest CT scan), bone marrow aspiration, bone scan and usually a PET scan. Diagnosis of UES needs confirmation by biopsy.

Such tumours tend to be classified according to Intergroup Rhabdomyosarcoma Study (IRS) prognostic criteria (rather than COG or PRETEXT staging), Stages I–IV.

Children with localised UES, in North American protocols, are usually treated with vincristine, actinomycin and cyclophosphamide (VAC) chemotherapy, together with radiotherapy if there is any residual disease.

18.4.5  Angiosarcoma

These tumours can be regarded as the malignant equivalent of haemangiomas but are nowhere near as frequently seen as their benign counterparts. The largest published series of 10 cases was collated from the Armed Forces Institute of Pathology registry and published in 1992 [34]. Sometimes, they appear to be malignant transformations in preexisting angiomatous tissue [35–37], again after a period of some years, while in others they arise de novo. Age at presentation is usually from 3 to 5 years, with a rapidly growing infiltrative liver mass, typically involving both lobes of the liver. Lung metastases occur relatively early in the course of the disease. Sometimes, these tumours are difficult to diagnose from needle or core biopsies, and consideration should always be given to open-wedge biopsy for definitive tissue retrieval.

Histologically, they appear as hypercellular whorls of spindle-shaped cells interspersed with biliary ductules, blood vessels and collagen. The cells usually contain periodic acid–Schiff (PAS) eosinophilic granules and stain focally for Factor VIII antigen [35] and α-1-antitrypsin [37].

Prognosis is without doubt poor, and surgical resection is not usually possible. Total hepatectomy and transplantation has been performed [37], although many would regard this diagnosis as a contraindication to transplant because of the high rate of tumour recurrence [38].

18.4.6  Hepatic epithelioid haemangioendothelioma

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