Introduction

The rarity and diversity of liver tumors in children means that no center has adequate experience to deliver optimal care to every patient. Hence cooperative study groups have been essential in establishing diagnostic criteria, identifying prognostic factors, assembling new biologically important molecular data, and introducing and evaluating chemotherapy and other treatments.

The most significant development related to liver tumors since the fourth edition of this text was published [1] is the establishment of the Children’s Hepatic Tumor International Collaboration (CHIC) from existing national and regional registries [2]. As of July 2019, the Pediatric Hepatic malignancy International Therapeutic Trial (PHITT) has been enrolling patients with hepatoblastoma (HB) and hepatocellular carcinoma (HCC) from North America (COG; Children’s Oncology Group), Europe (SIOPEL; the Liver Strategy Group of The International Society of Pediatric Oncology), Japan (JPLT; the Japanese Study Group for Pediatric Tumors) and Germany (GPOH; German Society for Pediatric Oncology and Hematology).

The clinical presentation of the vast majority of liver tumors in children is an asymptomatic palpable mass. Hepatic functional capacity is rarely compromised by underlying cirrhosis. Most malignancies are large and may be difficult to excise without prior chemotherapy. Involvement of the perihilar segments or intrahepatic dissemination may necessitate transplantation. The vascularity of the liver and ready access of cancer cells to hepatic veins make pulmonary metastases at presentation relatively common. Therefore, knowledge of precursor conditions and screening can be life-saving.

Approximately two-thirds of all liver masses occurring in children are malignant. Twenty separate series totaling 1972 primary benign and malignant liver tumors in children from 1956 to 2001 included HB (37%), HCC (21%), benign vascular tumors (15%), mesenchymal hamartomas and sarcomas (8%), hepatocellular adenomas and focal nodular hyperplasia (7.5%), and other tumors (4%) (Table 42.1) [1].

Epidemiology

Approximately 1.1% of all childhood tumors in the USA are malignant liver tumors according to the Surveillance, Epidemiology, and End Results (SEER) program of cancer registries, with an annual incidence rate of 2.7 per 1,000,000 children younger than 15 years [3]. Of 123 children registered with malignant liver tumors in 2000, 80% had HB and they accounted for 91% of the primary hepatic malignancies in children younger than five years [4]. Primary liver tumors accounted for 6–8% of congenital tumors in 265 neoplasms discovered within 30 days of birth [1].

The mean age at diagnosis was 19 months and the median age was 16 months in the Pediatric Oncology Group (POG) series of 106 HB accrued on biologic studies, similar to findings in other studies [1]. Only 5% occurred in children older than four years. Although rare, HB has been reported in adults. It is slightly more common in males with a reported male:female ratio of 1.4–2.0:1 [1].

Data from several sources have shown an increase in the number of cases of HB since the 1970s. In the SEER data comparing the periods 1973–1977 with 1993–1997, rates per million for HB increased from 0.6 to 1.2, and for pediatric HCC they decreased (0.45 to 0.29). In the period 1979–1981, liver cancers represented 2% of all cancers in infants younger than one year, whereas a decade later, liver cancers increased to 4% of all cancers in infants [3, 5].

A higher incidence of malignant liver tumors in children has been seen in Africa and Asia, where hepatitis B virus (HBV) infection is common. It is not surprising that almost all of the tumors are HCC because this tumor has been most closely correlated with chronic viral hepatitis infection. Perinatally acquired HBV has also been demonstrated to have integrated into the genome in tumors from children with no clinical signs of present or past HBV infection. It is encouraging that aggressive immunization programs against hepatitis viruses have resulted in a significant decrease in the number of cases [1].

Hepatocellular carcinoma occurs primarily after age ten years and is the most common hepatic malignancy of adolescence. In children 15–19 years of age, HCC accounted for 87% of all malignant liver tumors, although 12.8% occurred in children under five years of age [4]. Patients with the fibrolamellar variant of HCC are more likely to be over ten years of age [6].

Etiology

The causes of most liver tumors, similar to other types of childhood cancer, are unknown. HB occurs in association with several well-described cancer genetic syndromes (Table 42.2; see “Constitutional Genetic and Metabolic Abnormalities” below). The strong association of HB with prematurity may account for part of the observed increase in HB overall, as survival rates continue to increase among very small premature infants. In Japan, HB accounts for 58% of all malignancies occurring in surviving premature infants who weighed <1,000 g at birth [1]. The Japanese Children’s Cancer Registry data revealed that 15 of 303 (5%) cases of HB between 1985 and 1995 occurred in post-premature infants weighing <1,500 g. The relative risk for infants weighing <1,000 g at birth was 15.64 compared with 2.53 for infants weighing 1,000–1,499 g and 1.21 for infants weighing 2,000–2,499 g. These data have been widely confirmed, with a relative risk of 56.9% in New York State from 1985 to 2001 [7]. They indicate the need to determine the specific factors related to prematurity that contribute to hepatic tumorigenesis, as well as the need for surveillance of the survivors of extreme prematurity. Of other pediatric cancers, only retinoblastoma and non-astrocytic gliomas had a slightly increased relative risk in a US cohort of many thousand premature infants surviving to age [8], suggesting that the exposure of immature hepatocytes to endogenous hormones and exogenous toxins while dividing rapidly makes them particularly vulnerable to acquired molecular injury. To date, no differences have been found in age of onset or histopathologic type of HB in small prematures vs. term births.

Several studies have explored relationships between perinatal and maternal factors other than congenital syndromes and low birth weight and HB. One study documented a potential link with maternal pre-eclampsia and eclampsia [1]. Environmental factors have also been implicated in HB. An association with certain occupational exposures in fathers of children with HB has been reported [1, 9]. These include excess exposures to metals such as in welding and soldering fumes (odds ratio, 8.0), petroleum products, and paints (odds ratio, 3.7). Prenatal exposure to acetaminophen in combination with petroleum products has also been noted in association with HB. Parental cigarette smoking has also been reported to be associated with an increased risk of developing HB, doubled if both parents smoked relative to neither parent smoking. A slightly increased risk was found in the New York study for mothers younger than 20 years of age, smokers, infertility treatment (in-vitro fertilization), and higher maternal body mass index [7]. Cirrhosis following parenteral nutrition in infancy has been associated with the development of HCC in childhood [1]. Understanding the role that parenteral nutrition, which is clearly life saving for many premature infants, plays in the observed increase in the subsequent development of liver cancer in premature infants awaits additional epidemiologic, pathophysiologic and molecular genetic studies.

Constitutional Genetic and Metabolic Abnormalities

Beckwith–Wiedemann syndrome (BWS) is caused by genetic abnormalities in chromosomal region 11p15 and includes the risk of diverse intra-abdominal embryonal tumors. The National Cancer Institute’s BWS Support Group data indicate a relative risk of HB as 2,280, higher than that for other embryonal tumors, including Wilms tumor [1]. The recognition of physical stigmata of BWS in an infant prompts surveillance for detection for embryonal tumors using serial abdominal sonography and serum α-fetoprotein (AFP) measurements, and this has proven very beneficial to early resection and survival [10]. It should be noted that in BWS infants, serum AFP levels normalize later, by the age of 14 months, but three-monthly monitoring should confirm its declining trend. Vascular proliferations and mesenchymal hamartoma in the liver are also observed in BWS and have been misdiagnosed as HB because of serum AFP elevation (Figure 42.1). A significantly higher risk of neoplasia was recently reported in association with certain molecular subtypes of BWS, particularly patients with uniparental disomy and imprinting control-element defects [1]. Patients with hemihypertrophy carry a higher risk of developing HB, which has also been reported in association with other overgrowth syndromes, particularly the Simpson-Golabi-Behmel syndrome, an X-linked overgrowth syndrome caused by deletions in GPC3, encoding glypican-3 [11] .

Figure 42.1 Hepatic tumors in Beckwith-Wiedemann syndrome. (A) CT at one week of age shows a large enhancing mass and prominent hepatic artery. (B) Hemangioma with cavernous channels. No hepatocellular neoplasia. (C) Embryonal hepatoblastoma with focal blastematous elements (center) in an eight-month-old infant was detected by screening and cured by surgery and adjuvant chemotherapy. (D) Multicystic mesenchymal hamartoma in the liver was biopsied at one month of age. It consists of loose myxoid stroma blending with host parenchyma and contained a few clusters of immature hepatocytes and bile ducts (see Figure 42.19). The serum α-fetoprotein at one year was 1,306 ng/mL and MR imaging showed multiple heterogeneous masses (contributed by Dr. Stacey Berry, Banner Desert Medical Center, Mesa, AZ, USA). (E) Hepatocellular carcinoma in a resection from a child aged three years reveals diverse histology. There are foci of small poorly differentiated cells with high nuclear-cytoplasmic ratio typical of embryonal hepatoblastoma, as in (C). Much larger, more pleomorphic and actively dividing cells are typical of hepatocellular carcinoma. (F) Cholangiocarcinoma. Neoplastic ductal elements representing a cholangiocarcinoma are also present. Review of the original biopsy revealed fetal hepatoblastoma.

The association of HB with familial adenomatous polyposis (FAP) was first reported in 1982. This syndrome is caused by germline mutation of the APC (adenomatous polyposis coli) gene. There is an estimated relative risk of 800 of HB in children in families with FAP compared with the general population [1]. In 50 children with apparently sporadic HB, five were found to have a constitutional mutation in APC [12]. Rare somatic mutations of APC have also been identified in HB, but much less common than CTNNB1 mutations (gene encoding β-catenin), found in a majority of sporadic HBs. The interaction of APC protein and β-catenin, and the role of the canonical WNT pathway in the pathogenesis of HB, are discussed later in this chapter. There are no definitive differences in age range, histologic type, or outcome in HB associated with FAP. FAP has also been implicated in the pathogenesis of hepatocellular adenoma, HCC, and fibrolamellar HCC, suggesting that mutated APC may confer a general low-level predisposition to tumorigenesis in the liver dependent on other environmental or developmental factors.

Children with hereditary tyrosinemia type I (fumaryl-acetoacetate hydrolase deficiency) have a very high incidence of HCC, which has been dramatically reduced by blocking the accumulation of toxic metabolites [13]. Glycogen storage diseases are also associated with the development of hepatocellular adenomas (Figure 42.2A,B) and occasionally HCC [13], while HCC and cholangiocarcinomas have been observed in patients with Alagille syndrome, Wilson disease and other familial cholestatic syndromes (Figure 42.2C–F) [14–17]. Many but not all of these are also associated with liver dysfunction and cirrhosis. The chronic cholestasis resulting from biliary atresia and choledochal cysts has preceded cholangiocarcinoma [18] as well as both HCC and HB in children [19]. A two-year-old child with HB and progressive familial intrahepatic cholestasis (PFIC) has also been documented [20], as have others [21]. We have seen three cases of HB in two-year-old children with autosomal recessive polycystic kidney disease (ARPKD).

Figure 42.2 Metabolic diseases leading to neoplasia. (A, B) Hepatocellular adenoma in autopsy liver of a 12-year-old child with glycogen storage disease type IA (GSD-IA, glucose-6-phosphatase deficiency). “Alcoholic hepatitis”-like histology with fat, Mallory bodies, and inflammation. (C, D) Alagille syndrome. Biopsy at four months of age shows bland cholestasis and paucity of the bile ducts. Cholangiocarcinoma at age eight years. (E, F) Biliary cirrhosis at age 29 months secondary to bile salt excretory protein (BSEP) deficiency (progressive familial intrahepatic cholestasis (PFIC) type 2). Hepatocellular carcinoma found in explant.

Diverse liver tumors have been reported in association with trisomy 18, precocious puberty, neurofibromatosis, tuberous sclerosis, McCune-Albright syndrome and ataxia-telangiectasia [1, 22]. Hepatic tumors occurring in patients with Fanconi anemia who are treated with anabolic steroids demonstrate how a genetic defect in DNA repair coupled with an exogenous agent may contribute to the development of neoplasia. In some cases, tumor regression has been observed with the withdrawal of steroids.

Clinical Presentation

The typical age of presentation of the various hepatic tumors, both benign and malignant, is shown in Table 42.3. Yolk sac tumors, primary endocrine neoplasms, and inflammatory myofibroblastic tumors (IMTs) are very rare and occur in adults more often than children. Most liver tumors present with an asymptomatic abdominal mass. Abdominal pain, weight loss, anorexia, nausea, and vomiting may be present, particularly in advanced disease. Jaundice is rare and usually a symptom of extensive disease or hilar growth of any neoplasm with obstruction or compression of the major bile ducts, such as IMT at the hilum or rhabdomyosarcoma, which arises in larger ducts. Hemangiomas in infants may sometimes be associated with arteriovenous malformations and may present with signs and symptoms of congestive heart failure [19]. Profound hypothyroidism may be observed with larger hemangiomas [23]. The Abernethy malformation (congenital extrahepatic portosystemic shunts) may underlie diverse hepatic masses [24]. In infants, diffuse hepatomegaly may occur secondary to transient myeloproliferative disorders or megakaryoblastic leukemia. In severe organ dysfunction, even the former may require chemotherapy. Disseminated neuroblastoma may also present as hepatic masses, as can Wilms tumor.

Clinical symptoms of precocious puberty result from secretion of human β-chorionic gonadotropin or testosterone. The prognosis for seven children with HCC producing β-chorionic gonadotropin in Japan was very poor, with only one survivor. Cushing syndrome caused by adrenocorticotropic hormone-secreting hepatic nested stromal-epithelial tumor has been seen in several children [19]. Hypertension secondary to a renin-secreting mixed HB has been reported.

Liver enzymes and bilirubin are usually normal or only mildly elevated. A mild and normochromic normocytic anemia is common. Thrombocytosis occurs in approximately 50–80% of patients with HB and is probably related to thrombopoietin production by the tumor [19]. Mild coagulation abnormalities in children with malignant liver tumors are not unusual and a picture of a consumptive coagulopathy is sometimes associated with vascular malformations or kaposiform hemangioendothelioma (Kasabach–Merritt phenomenon).

Methods of Diagnosis

Assessment of a liver tumor often begins with diagnostic imaging by plain film or ultrasound, which reveals a right upper quadrant mass. Calcifications are seen only in a minority of patients and are non-specific and plain films are of very limited value in characterizing hepatic masses. Increased echogenicity is suggestive of malignant disease, and the diagnostic yield is increased when accompanied by Doppler flow studies to assess tumor vascularity. However, ultrasound is not adequate to definitively establish resectability [25]. To define the extent of disease accurately, contrast CT is used (Figure 42.3A). Particularly in infants, none of the imaging techniques currently available has 100% specificity. Of 26 children under age three months, six were inappropriately treated in the German cooperative liver tumor study because of imaging misinterpretations. Use of MRI with enhancement may provide additional information and reduce exposure of young children to ionizing radiation (Figure 42.3B) [25]. Typical imaging features for HCC are early arterial enhancement and possibly an isodense appearance compared with the surrounding liver in the venous and delayed phases of four-phase multidetector CT (the non-contrast, arterial, venous, and delayed phases) or in dynamic contrast-enhanced MRI. These radiologic findings are related to increased vascularity of the tumor, supplied by the hepatic artery. For recurrent or metastatic HB, positron emission CT with [18^° F]-fluorodeoxyglucose has proved to be more sensitive than MRI or CT [26]. Intrahepatic vascular dissemination of HCC is more common than for HB (Figure 42.4A), but both neoplasms have this propensity and it is a poor prognostic indicator (Table 42.7, Figure 42.4B) [27]. The most common site for metastases is the lung (Figure 42.4C), whereas metastases to the brain have been reported but are extremely rare. Therefore, CT imaging of the chest, abdomen, and pelvis is essential. When bone lesions are reported, it is unclear whether these represent true metastases or areas of osteopenia, and bone marrow involvement has only very rarely been observed.

Figure 42.3 Imaging of liver tumors. (A) CT is used to demonstrate resectability of liver tumors. This patient was asymptomatic except for hepatomegaly at five days of age. Hepatoblastoma was resectable. (B) T1-weighted MRI of multifocal infantile hemangioma shows marked contrast enhancement after gadolinium (see Figure 42.16B).

Figure 42.4 Dissemination of hepatic neoplasms. (A) Multifocal hepatocellular carcinoma in an eight-year-old child with perinatally acquired hepatitis B infection. (B) Embryonal hepatoblastoma in hepatic vein. (C) Hepatoblastoma with pulmonary metastases. This is the usual reason for treatment failure, but some patients have been saved by resection.

Serum AFP is markedly elevated in more than 90% of patients with HB and in two-thirds of those with HCC [1]. It is also elevated in germ cell tumors with yolk sac components, a few of which arise in the liver. The major protein produced by the fetal liver, AFP is produced in large amounts in the newborn. In the normal term infant, serum AFP level can be as high as 100,000 ng/mL or greater. The half-life of AFP is five to seven days and it falls throughout the first several months of life (Table 42.4). By the age of one year, the serum AFP is <10 ng/mL. However, it remains elevated in two genetic diseases that could lead to HCC: hereditary tyrosinemia type I and ataxia-telangiectasia. In BWS, it serves, along with periodic abdominal ultrasound, to detect the early onset of HB. In infants younger than one year with HB, it may initially be difficult to distinguish the contribution to elevated AFP from reactive, normal liver from that of malignant tumor. However, serum AFP is a useful tumor marker to assess response to therapy as well as to monitor for disease recurrence [1]. After a complete resection, serum AFP levels should decline and approach normal ranges within several days to weeks. Failure to do so indicates residual disease.

Serum α-fetoprotein is usually normal with malignant rhabdoid tumor, fibrolamellar HCC, as well as in most benign liver tumors. However, significantly elevated AFP has been reported in patients with infantile hemangioma and mesenchymal hamartoma which has misled clinicians into treating for HB without confirmatory diagnostic biopsy [1, 28]. When serum AFP was combined with ultrasonography to screen high-risk adults in China, a five-year survival rate of 62.7% was achieved in those with HCC ≤5 cm in diameter vs. larger ones, which had a 37.1% survival rate. Des-γ-carboxyprothrombin level in the serum is a marker of advanced HCC, and higher levels before transplantation indicate a poor prognosis.

Staging

The risk-stratified staging system for HB being used by the Children’s Hepatic tumors International Collaboration (CHIC) [29] is shown in Figure 42.5. It was derived from 1,605 patients over 25 years, with pre-treatment extent of disease (PRETEXT; Figure 42.6) having the most prognostic significance, leading to four clinically relevant “backbone” groups. The PRETEXT group is defined radiologically according to extent of involved liver sections from 1 to 4 with annotation factors for: venous involvement (V=vena cava, P=portal vein), E=contiguous involvement of adjacent organs, F=multifocality within the liver, R=tumor rupture at diagnosis, and M=metastasis (Table 42.5). Serum AFP concentrations of <100 and >1,000,000 ng/mL are distinguished from those in between, and patient ages of 0<1 year, 1–2 years, 3–7 years, and >8 years determine the risk groups (Figure 42.6, [29]).

Figure 42.5 PRETEXT staging system for hepatoblastoma. For additional details and description, see Table 42.5.

Figure 42.6 Risk stratification trees for the Children’s Hepatic tumors International Collaboration – Hepatoblastoma Stratification (CHIC-HS). Used with permission from Meyers et al. 2017 [29]..

Pathology

The updated protocol for the examination of HB specimens published by the College of American Pathologists in 2019 offers guidance relevant to all pediatric liver tumors [30]. It emphasizes the need to obtain fresh frozen samples of tumor and host liver, before and after chemotherapy, to facilitate molecular investigations for new treatments (“precision medicine”). A primary hepatic neoplasm, whether benign or malignant, is typically an expansile solitary mass (Figure 42.7). Multiple lesions are found in some hemangiomas and hemangioendotheliomas, hepatocellular adenomas (HCAs), HCC, and rarely HB. Encapsulation is limited to some HCAs, although pseudocapsules secondary to compressive atrophy of the adjacent parenchyma can be deceptive with respect to an operative margin. Spontaneous focal necrosis of the rapidly growing HB is common, and many of these have large telangiectatic vessels, both of which account for highly diverse images and Doppler patterns and may lead to erroneous diagnosis, particularly in infants, whenever the serum AFP level does not reflect the expected values [31]. Metastatic spread of HB and HCC occurs via hepatic veins to the lungs and secondarily to the brain (Figure 42.4). Intravascular dissemination is frequent, but current chemotherapy can successfully eradicate tumor confined to the liver and even some that have metastasized [32].

Figure 42.7 Gross appearance of hepatoblastoma. (A) Most of this well-circumscribed tumor is tan-brown and composed of well-differentiated fetal hepatoblasts. (B) Mixed epithelial-mesenchymal HB with embryonal, fetal, and mesenchymal tissues, with hemorrhage and necrosis.

Hepatoblastomas arise from precursors of mature hepatocytes and most tumors display many histologic patterns reflecting diverse stages of differentiation (Table 42.6B, Figure 42.8). Embryonal histology is most common and resembles the histology of the liver at six to eight weeks of gestation (Figure 42.8A–C). Well-differentiated neoplastic fetal hepatocytes may be virtually indistinguishable in cytomorphology and architectural growth pattern from the normal fetal liver (Figure 42.8D). The cytoplasm is often rich in glycogen and sometimes contains neutral fats. Nuclear-to-cytoplasmic ratio is typically slightly higher than non-neoplastic host hepatocytes. Cholangioblastic, or ductular, differentiation (Figure 42.8D) has been reported, and this rare occurrence suggests origin from a precursor cell.

Figure 42.8 Histology of hepatoblastomas (HB). (A) Histology of the embryonic liver at five to six weeks postconception. Arrows indicate differentiating hepatoblasts. (B) Embryonal pattern HB. Mimicry of the stages of development is the basis for tumor designations. A continuum between tumor types is, therefore, typical of hepatoblastoma. (C) “Crowded” or mitotically active fetal pattern HB (>2 mitotic figures/10 high-power fields, circled). (D) Mitotically inactive fetal pattern HB (≤2 mitotic figures/10 high-power fields; left). The uniformity of these mature mitotically inactive cells growing in a normal cord-like manner may make them difficult to distinguish from normal hepatocytes in aspirates or small biopsies. The greater nuclear-to-cytoplasmic ratio is helpful, as is immunohistochemistry (Figure 42.12). A cholangioblastic component of HB is at right.

Hepatoblastomas may contain undifferentiated small cells that co-express cytokeratin and vimentin, reflecting neither epithelial nor stromal differentiation (Figure 42.9). Whether the small undifferentiated cell is equivalent to a “stem” cell or the “oval” cell of the rodent liver is controversial [1]. Rarely, the entire HB is composed of only one cell type; 2.0% of the 377 cases reviewed for the POG and COG from 1986 to 2005 that could be resected without chemotherapy (stages I and II) were small cell undifferentiated (SCU), whereas 3.4% were pure well-differentiated fetal with minimal mitotic activity. The remainder were mixtures of diverse epithelial cells in varying proportions and of cells intermediate among the broad categories, with either discrete nodules of a single cell type or intimate intermingling of diverse cytomorphologies (Figure 42.9). This feature makes it difficult to predict behavior on the basis of a small biopsy of an unresectable tumor, and chemotherapy affects the diverse components differently. Fetal pattern with significant mitotic activity (“mitotically active fetal” >2 mitoses in 10 high-power microscopic fields; Figure 42.8C) very rarely occurs in “pure” form except in small biopsies of stages III and IV tumor. They have been referred to as “crowded” fetal cells because glycogen content is usually less and the proportion of an image occupied by nuclei is consequently increased [1]. The cohesive nature of the poorly differentiated cells is helpful in diagnosing SCU vs. blastema (Figures 42.9 and 42.10).

Figure 42.9 Small cell undifferentiated (SCU) hepatoblastoma. (A) When the proportion of these cells is high or they are the only component, they are usually found in infants and fail to respond to standard chemotherapy. (B) Typically, small cells and fetal or embryonal hepatoblastoma are haphazardly intermingled so that small biopsies may not be representative of a large neoplasm’s constituents. (C) Intimate association of SCU (discohesive cells adjacent to bile duct) and rhabdoid tumor in an otherwise typical hepatoblastoma in a seven-month-old infant. Cells of both histotypes express cytokeratin and vimentin (see Figure 42.10), intermediate filaments reflecting mesodermal-epithelial transition (see Figure 42.10). (D) Nuclear expression of INI-1 (SMARCB1) is lost in rhabdoid tumors and the small cell hepatoblastomas of infancy. The entrapped bile ducts are positive (brown). When otherwise indistinguishable cells are part of a typically pleomorphic hepatoblastoma as in (B), they are almost always positively stained.

Figure 42.10 Blastemal pattern hepatoblastoma (HB). (A) In comparison to small cell undifferentiated (SCU) HB, blastemal HB shows greater cohesion of cells (compare to Figure 42.9). (B, C) Similar to SCU HB, blastemal HB shows simultaneous expression of vimentin and epithelial markers (CK19). (D) Blastemal HB shows retained nuclear expression of INI-1. In contrast, in SCU HB, when SCU is the predominant pattern and shows loss of INI-1 expression, the tumor has been treated as malignant rhabdoid tumor (see Figure 42.9D).

Fifteen percent of HB are classified as “mixed” because of stromal derivatives, particularly osteoid-like protein deposits, occasional rhabdomyoblasts, and, even more rarely, chondroid elements (Figure 42.11). The osteoid-like foci become more prevalent following chemotherapy when the embryonal cells are often eradicated (Figure 42.11A) [33]. The efficacy of cisplatinum-based chemotherapy often makes it difficult to determine the persistence of viable HB in resection specimens, for which immunohistochemistry for β-catenin and glypican-3 can be very helpful (Figure 42.12).

Figure 42.11 “Teratoid” hepatoblastoma (HB). (A) Bone formation in mixed HB. It is particularly abundant following chemotherapy and does not indicate a “teratoid” pattern. (B) Melanocytes (top) along with glial and other neural derivatives (primitive neuroepithelium; bottom) that invoke the designation “teratoid.” (C) When organoid differentiation occurs, as with this fetal kidney, the question of true teratoma arises. The primitive glomeruli and tubules are surrounded by fetal rhabdomyoblasts.

Figure 42.12 Helpful immunostaining. (A) Fetal hepatoblastoma has ß-catenin staining of the nuclei (right) in addition to plasma membranes (plasma membrane staining seen in normal hepatocytes on left). (B) In less mature cells, ß-catenin is abundant in the cytoplasm, and in embryonal cells it is present in nuclei (right), where it contributes to the expression of several WNT pathway genes. (C) Following chemotherapy, nuclear ß-catenin can identify persistent cancer cells (in this case, cholangioblastic pattern, on right). (D) Cytoplasmic staining for glypican-3 can be seen in fetal and embryonal patterns (fetal pattern shown, right; normal hepatocytes on left) and can also be useful in identifying tumor cells following chemotherapy.

The designation “teratoid” is used for 3% of HB where some cells reflecting neural or neural crest origin are present. These include glial cells, neurons, and melanocytes (Figure 42.11B). True teratomas arising in the liver of infants have a full range of tissues from all embryonic germ layers, including brain-like and extraembryonal derivatives such as yolk sac and trophoblastic cells. Sometimes the distinction can be difficult (Figure 42.11C).

Rarely, enteroendocrine derivatives containing chromogranin and diverse hormones, such as gastrin, serotonin, or somatostatin, are found in mixed HB and even more rarely as pure primary hepatic tumors. Small squamous pearls are frequent in mixed and teratoid tumors. Very rarely, glandular or ductal forms resembling the embryonal intestine or fetal bile ducts are found.

Primary malignant rhabdoid tumor (MRT) of the liver has deletions or mutations in the hSNF5/INI1 tumor suppressor gene, as seen in central nervous system and renal and soft tissue primaries [34, 35]. Expression of WT1, normally expressed in fetal kidney and mesoderm, has been reported in MRT, suggesting the potential role of WT1 in the process of mesodermal cells acquiring epithelial characteristics. MRT shares with SCU HB the co-expression of intermediate filaments, onset in infancy, and poor prognosis (Figure 42.9C) [33, 35]. The loss of nuclear INI1 expression observed in both SCU HB and MRT [35, 36] has led some authors to propose that SCU HB, in its pure form, likely represents MRT and should be treated similarly to MRT [37]. Loss of INI1 expression has also served to distinguish the SCU with a poor prognosis from similar poorly differentiated “blastemal” cells that may co-express cytokeratin 7 and vimentin but have no negative implications (Figure 42.10) [38, 39]. Although the name “rhabdoid” suggests a relationship to skeletal muscle, these tumors do not contain muscle proteins. However, true rhabdomyoblasts may be components of HB (Figure 42.11C) and there are full-fledged primary embryonal rhabdomyosarcomas of the liver that arise in close association to biliary epithelium, often having a polypoid growth pattern and causing obstructive jaundice.

When HB cells with either fetal or embryonal cytology grow in trabeculae of five or more cells rather than in the cords of two to four cells of the fetal liver, the pattern is called macrotrabecular. In our series, 18% of HB samples contained macrotrabecular foci, and one-third of those cases were stage IV at presentation [1]. This aggressive behavior may reflect the fact that such histology can be indistinguishable from HCC when it occurs in pure form (Figure 42.13). Malignant tumors that have features of both HB and HCC were observed in seven older children with perinatally acquired HBV in our practice. Other examples unrelated to any known precursor conditions were initially reported as “transitional cell liver tumors” by Prokurat and colleagues in 2002 (Figure 42.13A) [40]. The biology of these tumors is becoming elucidated, but the provisional category/diagnosis recommended in the 2014 consensus classification for these tumors is “malignant hepatocellular neoplasm, not otherwise specified (NOS)” [38].

Figure 42.13 Distinguishing hepatoblastoma and hepatocellular carcinoma.

Macrotrabecular growth patterns can make hepatoblastoma (A) and hepatocellular carcinoma (B) difficult to distinguish, particularly in fine needle aspirates or small biopsy samples. In some children, even as young as two years, both neoplasms are present simultaneously, or sequentially following chemotherapy. In older children and adolescents with aggressive tumors, the term “transitional liver cell tumor” has been applied [40], although it is now designated “malignant hepatocellular neoplasm, not otherwise specified” (HCN-NOS) following consensus guidelines [38]. Fluorescence in situ hybridization (FISH) analysis of macrotrabecular hepatoblastoma (C) using chromosomes 2 (aqua), 8 (green), and 20 (orange) enumeration probes, demonstrating trisomies of chromosomes 2 and 20, and of macrotrabecular hepatocellular carcinoma (D) demonstrating chromosomes 2 and 20 monosomies.

Hepatocellular carcinomas in children do not differ histologically from those in adults. The fibrolamellar variant (Figure 42.14A,C) occurs more commonly in adolescents and young adults. The presence of a central scar with radiating fibrous bands between tumor masses may suggest benign focal nodular hyperplasia (FNH) (Figure 42.14B,D), but the histology is characteristic and the large atypical neoplastic cells are readily distinguished (Figure 42.14C). Unlike most HCCs, fibrolamellar HCCs arise in otherwise normal livers and for that reason are more readily resected and in many series have a higher rate of cure. However, children with fibrolamellar HCCs do not have a more favorable prognosis and do not respond any differently to therapy from patients with typical HCC at the same stage [6].

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Chapter 5 – Cirrhosis and Chronic Liver Failure in Children Chapter 13 – Familial Hepatocellular Cholestasis Chapter 14 – Alagille Syndrome Chapter 25 – α1-Antitrypsin Deficiency Chapter 38 – Urea Cycle Disorders in Children Chapter 33 – Disorders of Bile Acid Synthesis and Metabolism in Children

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