Cancer in Children: Clinical Management, 5th Edition

Chapter 24. Hepatic tumours

Hitoshi Ikeda

Tadashi Matsunaga

Yoshiaki Tsuchida

Introduction

Two-thirds of hepatic neoplasms are malignant (55–65 per cent), and 90 per cent of the malignant tumours are epithelial tumours, i.e. hepatoblastoma or hepatocellular carcinoma. Benign vascular tumours and malignant mesenchymal tumours account for the rest. The ratio of hepatoblastoma to hepatocellular carcinoma is approximately 1.8:1 in Western countries, but in Japan the incidence of hepatoblastoma is five to six times higher than that of hepatocellular carcinoma.

Hepatoblastoma

Hepatoblastoma is the most common malignant hepatic tumour in children in all parts of the world, except in areas where hepatocellular carcinoma is more common because of endemic hepatitis B infection, accounting for 1–2 per cent of all malignant tumours in children. The incidence of hepatoblastoma in children aged <15 years is <1 per 1 000 000 in North America. In Japan, the incidence appears to be higher than in Western countries, and the ratio of males to females is 1.2:1. Although hepatoblastoma can be seen at any age <15 years, more than 80 per cent of the tumours are seen in children aged 3 years and 45 per cent of the patients are diagnosed during the first year of life.

Genetics and biology

Although most cases are sporadic, hepatoblastoma may occur in association with a variety of congenital anomalies and familial conditions. Beckwith–Wiedemann syndrome and hemihypertrophy carry an increased risk of hepatoblastoma, as well as of Wilms tumour, rhabdomyosarcoma, and adrenocortical tumours. Abnormalities on the short arm of chromosome 11 have been shown in both Beckwith–Wiedemann syndrome and hepatoblastoma, and loss of heterozygosity of 11p15 has frequently been observed. A tumour suppressor gene or a growth factor gene located in the 11p15.5 region may be responsible for the development of the tumour but has not yet been identified.1 Hepatoblastoma is also a specific malignant tumour in children from families with familial adenomatous polyposis, but inactivation of the adenomatous polyposis coli (APC) gene, which is a putatively mutated tumour suppressor gene in familial adenomatous polyposis, is rare in hepatoblastoma. The relationship between hepatoblastoma and APC may be different from that in colorectal cancer, and an alternative pathogenesis involving β-catenin is apparent. APC controls the degradation of β-catenin, and mutated APCcauses the accumulation of β-catenin which acts as an oncoprotein. A high frequency of β-catenin gene mutations (48–65 per cent) has been documented in hepatoblastomas.2

Some reports suggest possible connections between environmental exposures and hepatoblastoma, including parental occupational exposure to metals, petroleum products, and paints or pigments. There also appears to be a significant association between hepatoblastoma and low birth weight.3 Epidemiologic studies have suggested that the lower the birth weight, the higher the risk of hepatoblastoma, but specific perinatal environmental factors responsible for tumour development have not been identified.

Cytogenetic studies have shown that trisomy of chromosomes 2 and 20 is frequently observed in hepatoblastoma, and there is evidence that gains of 2q24, 8q. and 20 are predictive of poor prognosis.4 DNA content analyses have shown that patients with diploid tumour have a better prognosis than those with aneuploid tumour, and a low proliferation index is another favourable prognostic factor.

Pathology

Hepatoblastoma is usually solitary, but 20 per cent of tumours extend multifocally or infiltrate diffusely into the liver. Macroscopically, the cut surface has a lobulated appearance due to fibrous septae, and multiple variegated nodules with haemorrhage and necrosis are surrounded by a pseudocapsule. The adjacent liver is not cirrhotic. Microscopically, there are two principal subtypes: pure epithelial hepatoblastoma is distinguished from mixed hepatoblastoma which contains mesenchymal tissue in addition to epithelial elements (Table 24.1).5 The epithelial components exhibit a range of differentiation represented by fetal, embryonal, and anaplastic cells. Well-differentiated ‘fetal’ cells are smaller than normal hepatocytes and have a low nucleocytoplasmic ratio, minimal nuclear pleomorphism, and small nucleoli. Mitoses are infrequent. The cells are arranged in slender cords, usually two cell layers thick, which often contain canaliculi with or without bile. Sinusoids and vessels resembling central veins are present. Foci of extramedullary haematopoiesis are common (Fig. 24.1). Poorly differentiated ‘embryonal’ cells have a higher nucleocytoplasmic ratio and mitoses are seen more frequently than in fetal areas. The embryonal cells grow in sheets, assuming a tubular configuration, or rosettes which recapitulate some features of the embryonic liver (Fig. 24.2). Anaplastic (smallcell undifferentiated) type hepatoblastoma consists of sheets of cells resembling those of neuroblastoma which have scanty cytoplasm and a high mitotic rate. The cells are small, undifferentiated, round to oval or spindle-shaped, and monotypic. The term ‘macrotrabecular’ is used to indicate foci of tumour cells which are repetitively arranged in trabeculae, 10 cells thick. The tumour cells may be fetal or embryonal in appearance, or indistinguishable from the cells of adult hepatocellular carcinoma. Immature mesenchymal components in mixed hepatoblastoma include osteoid, chondroid, or, rarely, rhabdomyoblastic tissues, in addition to blood vessels or haematopoietic tissues which are an integral part of the tumour. The epithelial differentiation occasionally yields squamous pearls or mucus-secreting glands. Neuronal differentiation is rarely seen in hepatoblastoma.

Table 24.1. Histological classification of hepatoblastoma

Pure epithelial hepatoblastoma
   Fetal
   Embryonal
   Anaplastic (small-cell undifferentiated)
   Macrotrabecular

Mixed hepatoblastoma (with mesenchymal tissue)

The nature of the epithelial components of hepatoblastoma appears to be associated with outcome. The pure fetal type is prognostically favourable when completely resected, but anaplastic (small-cell undifferentiated) histology has an unfavourable effect on outcome even in patients with complete resection.6 It is not yet conclusive that the presence of macrotrabecular foci predicts a poor prognosis. The prognostic importance of mesenchymal components has not been determined.

Fig. 24.1 Fetal hepatoblastoma. Cells are smaller than normal hepatocytes, have a low nucleocytoplasmic ratio, and are arranged in slender cords. A cluster of haematopoietic cells can be seen.

Diagnosis

Since a child with advanced disease occasionally presents with anorexia, weight loss, or anaemia, the general condition of the patient should be carefully examined and the necessary supportive care provided.

α-Fetoprotein (AFP) is a glycoprotein synthesized in the yolk sac and the liver at an early stage of fetal life. The production of AFP stops at birth and the serum AFP concentration decreases exponentially from a mean of approximately 50 000 ng/ml to <20 ng/ml at 6–8 months of age. The serum AFP concentration is raised above the upper limit of the normal range for the patient's age in >98 per cent of patients with hepatoblastoma. Although the AFP concentration is relatively higher in hepatoblastomas with embryonal histology than in tumours with fetal histology, this is not prognostically significant or diagnostically discriminatory. Fractionation of AFP by lectin-affinity immunoelectrophoresis can differentiate hepatic malignant tumours from yolk sac tumours and benign hepatic disease, such as hepatitis or cirrhosis.7 AFP derived from hepatoblastoma or hepatocellular carcinoma includes a subfraction which binds to Lens culinaris haemagglutinin (LCH), but AFP from a benign hepatic disease does not react with LCH. The presence of a greater amount (>25 per cent) of AFP fraction which is not reactive to concanavalin A (Con A) differentiates AFP derived from a yolk sac tumour from that of hepatic origin (Fig. 24.3). Since serum AFP concentrations are expected to decline exponentially after complete tumour resection and remain within normal limits unless recurrence occurs, the measurement of AFP is very useful in monitoring treatment response, as well as in making a diagnosis.

Fig. 24.2 Embryonal hepatoblastoma. Cells grow in sheets, assuming a tubular configuration or rosettes which recapitulate some features of the embryonic liver.

Isosexual precocious puberty may develop in patients with hepatoblastoma secreting human chorionic gonadotropin (β-HCG). Virilization in male children, with testicular and penile enlargement and growth of pubic hair, has been reported.

Mild normochromic normocytic anaemia is usual and thrombocytosis may be seen in some patients. Interleukin 6, which appears to be produced in stromal cells in response to local secretion of cytokines from tumour cells, has been shown to mediate thrombocytosis and other acute reactions including fever. Routine workup occasionally demonstrates hypercholesterolaemia or osteoporosis. The latter may be complicated by pathologic fracture.

Pretreatment imaging studies include plain radiography, ultrasonography, and CT or MRI. Plain films of the abdomen occasionally demonstrate the presence of calcification. On ultrasonography, the echogenicity of the tumour is minimally increased and is usually nonhomogeneous. Hypoechoic or anechoic areas, which reflect necrosis or haemorrhage within the tumour, may be seen. The unenhanced CT demonstrates the tumour with decreased attenuation with respect to the surrounding liver parenchyma, which is emphasized with intravenous contrast infusion. T1-weighted images of MRI show decreased signal intensity of the tumour, but T2-weighted images show increased signal intensity. In addition to the qualitative evaluation, the surgical resectability of the tumour should be determined from the diagnostic radiology. Tumours involving both lobes of the liver or vascular structures such as the portal veins or the inferior vena cava are usually unresectable. The presence or absence of portal and para-aortic lymphadenopathy and lung metastases are evaluated by either CT or MRI. With modern MRI techniques, adequate information can usually be obtained for surgery, although surgeons may prefer to have an angiogram performed to define the relationship of the tumour to major hepatic vessels. There is occasionally an opportunity for hepatic angiography to be combined with tumour embolization or intra-arterial infusion chemotherapy.

Fig. 24.3 AFP subfraction profiles in (a) hepatoblastoma and (b) yolk sac tumour. AFP derived from hepatoblastoma includes a subfraction which binds to LCH. The presence of a greater amount (>25%) of fraction non-reactive to ConA differentiates AFP derived from a yolk sac tumour from AFP of hepatic origin. a, reactive; b, non-reactive; A, strongly reactive; B, weakly reactive; C, non-reactive.

Bone scan should be done to investigate metastatic spread. Bone marrow examination is unnecessary as metastatic disease to this site is extremely unlikely.

Staging

There is no universally accepted system of staging in hepatoblastoma. In the staging system used by the Children's Oncology Group (previously the Children's Cancer Group and the Paediatric Oncology Group) in the USA, stage I tumour is defined as a tumour resected completely at initial laparotomy, stage II as a tumour with microscopic residue, and stage III as a tumour with gross residual tumour. Children with distant metastases have stage IV disease. The same staging system was used in the German Cooperative Paediatric Liver Tumour Study HB-89. The staging system used in the Epithelial Liver Tumour Study Group of the International Society of Paediatric Oncology (SIOPEL) is called PRETEXT (Pretreatment Extent of Disease System) and classifies the tumour by identifying the number of adjoining free section(s) of liver.

PRETEXT is a significant predictor of overall survival in patients with hepatoblastoma,8 and staging laparotomy is unnecessary as the stage can be determined from the results of imaging studies. The Japanese staging system depends on the number of liver segments involved, the extent of local invasion, the regional lymph node involvement, and the presence of distant metastases. However, the PRETEXT system has been widely used in Japan from the beginning of the Japanese Study Group for Paediatric Liver Tumour (JPLT) 2 protocol.

Surgical treatment

Complete surgical resection is ultimately necessary for cure of hepatoblastoma, but <50 per cent of tumours are resectable at the time of diagnosis. Tumours involving both lobes of the liver or invading the porta hepatis are usually unresectable, and preoperative chemotherapy is required to render them resectable at delayed surgery.9 In fact, there is evidence that the rate of incomplete resection is lower after primary chemotherapy than in patients with primary tumour resection.10 However, as there is a significant error rate in the clinical and imaging diagnosis of hepatoblastoma, histologic diagnosis prior to chemotherapy is necessary. A wedge biopsy of the tumour through a small laparotomy incision is preferred to fine-needle aspiration biopsy, and a specimen large enough to provide material not only for diagnosis but also for the investigation of biologic characteristics should be obtained.

The tumour is deemed resectable if it is localized in one or two segments of the liver. Complete resection is achieved by performing a segmentectomy or a standard lobectomy. Left or right trisegmentectomy may be done when the tumour occupies three segments of the liver. The abdomen is entered through a large transverse incision above the umbilicus. The liver is mobilized by dividing the ligaments which attach it to the abdominal wall and the diaphragm to facilitate access to the hepatic veins and the inferior vena cava. Sudden circulatory deterioration may occur if the inferior vena cava is angulated by an excess displacement of the liver. Dissection begins in the porta hepatis, and the branches of the hepatic artery, portal vein, and bile duct are isolated and divided according to the part of the liver to be excised. The hepatic vein should be carefully identified, ligated, and divided, because haemorrhage from an injured hepatic vein is difficult to control and may be fatal in some cases. After ligation of the hepatic vessels, an ischaemic colour change on the surface of the liver demarcates the lobe to be resected. An adequate margin is required, although a narrower margin between the tumour and the dissection line is acceptable in some fetal-type hepatoblastomas. The raw surface of the remaining liver is checked for bleeding and bile leakage, and covered with fibrin glue if necessary. Postoperative chemotherapy should be withheld for 1–2 weeks.

Pulmonary recurrence, which is probably the late appearance of metastatic deposits present at the time of diagnosis or initial operation, may develop within 12 months of diagnosis, rarely later. Intensive chemotherapy should be given before resection of the pulmonary metastases, but they can also be treated by an aggressive surgical approach as long as the number and location of metastatic nodules is precisely identified by radiologic evaluation (Fig. 24.4). Resection of lung metastases can be curative if there is local control of the primary tumour. Patients may survive disease free after several thoracotomies.

Liver transplantation is a promising method of treatment for unresectable hepatoblastomas (see below).11

Chemotherapy and clinical trials

The prognosis for children affected by hepatoblastoma has been significantly improved with the introduction of cisplatin (CDDP) into therapeutic trials and, as a consequence, the 3-year overall survival rate has improved from 30 per cent to 60–70 per cent. The principal chemotherapy regimens used in clinical trials for hepatoblastoma are summarized in Table 24.2.

The SIOPEL Group has been conducting studies of preoperative chemotherapy consisting of cisplatin and doxorubicin. In the SIOPEL-1 study (January 1990–February 1994), patients were treated with continuous 24-h i.v. infusion of cisplatin 80 mg/m2 followed by doxorubicin 60 mg/m2 over 48 h (PLADO) after biopsy and assessment of PRETEXT.12 Patients were reassessed after four courses of chemotherapy, at which point the primary tumour was resected where possible. Postoperatively, treatment was completed with two more courses of chemotherapy. A total of 154 patients were registered and 138 patients received preoperative chemotherapy. A partial response with tumour shrinkage and serial decrease in the serum levels of AFP was observed in 113 patients (82 per cent); 115 patients had delayed surgery and 106 patients (including six with liver transplants) had complete resection of the primary tumour. The event-free survival and the overall survival at 5 years were 66 per cent and 75 per cent, respectively. In the latest SIOPEL-3 study, an attempt is being made to avoid exposure to doxorubicin in patients with favourable disease (PRETEXT I–III tumours) who are randomized to receive either PLADO or cisplatin alone. Patients with PRETEXT IV and/or extrahepatic disease receive intensified treatment with alternating administration of cisplatin and doxorubicin–carboplatin (Super PLADO).

Fig. 24.4 Hepatoblastoma originating in the right lobe of the liver: (a) gross appearance of the tumour; (b) T1-weighted MRI images showed decreased signal intensity of the tumour; (c) MRI was useful in evaluating the number and location of metastatic nodules (arrowed) ranging from 3 to 5 mm in diameter; (d) serum AFP levels became normal after nine courses of chemotherapy with cisplatin and THP-adriamycin, and the resection of pulmonary metastases.

In the USA, the Paediatric Oncology Group (POG) ran a study in the late 1980s to evaluate the survival rate in children with grossly resected hepatoblastoma treated with cisplatin, vincristine, and fluorouracil, and to assess the response and survival rates in children with initially unresectable tumours treated with the same combination. Concurrently, the Children's Cancer Group (CCG) undertook a study to test the feasibility of administering doxorubicin (by continuous infusion) and cisplatin to patients with unresectable or incompletely resected hepatoblastoma. After these trials, the CCG and POG together conducted a randomized comparison of the two regimens: cisplatin, vincristine and fluorouracil (regimen A), and cisplatin and continuous infusion of doxorubicin (regimen B).13 A total of 182 patients were enrolled in the study (August 1989–December 1992), and 173 patients, excluding a subset of good prognosis patients (stage I pure fetal histology with minimal mitotic activity), were randomized to receive either regimen after initial surgery. Although toxicities were more frequent with regimen B, there was no statistically significant difference in the 5-year eventfree survival (57 per cent and 69 per cent for patients on regimens A and B, respectively).

Table 24.2. Chemotherapy regimens in clinical trials for hepatoblastoma

1. International Society of Paediatric Oncology, Epithelial Liver Tumour Study (SIOPEL) 3
PRETEXT I–III
   PLADO: cisplatin 80 mg/m2 over 24 h on day 1 and doxorubicin 60 mg/m2 over 48 h on days 2 and 3
   OR
   Cisplatin 80 mg/m2 alone
PRETEXT IV and/or extra-hepatic disease
   Alternating cycle of cisplatin and DOX–carboplatin (Super PLADO): cisplatin 80 mg/m2 over 24 h, doxorubicin 60 mg/m2 over 48 h, carboplatin 500 mg/m2 1 h infusion
2. CCG–POG Intergroup
Stage I (unfavourable histology) and stages II–IV
   Regimen A: cisplatin 90 mg/m2 over 6 h on day 1, and vincristine 1.5 mg/m2 and 5-fluorouracil 600 mg/m2 on day 2
   OR
   Regimen B: cisplatin 90 mg/m2 over 6 h on day 1, and doxorubicin 80 mg/m2 over 96 h on days 1–4
Stage I (favourable histology)
   Regimen C: bolus i.v. doxorubicin 20 mg/m2 /day on days 1–3
3. German Cooperative Paediatric Liver Tumour Study HB-94
First-line chemotherapy
   IFO–CDDP–DOXO: ifosfamide 0.5 g/m2 bolus on day 1 and 3.0 g/m2 over 72 h on days 1–3, cisplatin 20 mg/m2 /day on days 4–8, and doxorubicin 60 mg/m2 over 48 h on days 9 and 10
Second-line chemotherapy
   VP16–CARBO: VP16 400 mg/m2 over 96 h on days 1–4 and carboplatin 800 mg/m2 over 96 h on days 1–4)
4. Japanese Study Group for Paediatric Liver Tumour (JPLT) 2
First-line chemotherapy
   CITA: cisplatin 80 mg/m2 over 24 h on day 1 and THP–Adriamycin 30 mg/m2 /day by 1 h infusion on days 2 and 3)
   OR
   CATA-L [trans-arterial chemoembolization (TACE)]: slow transarterial injection of carboplatin 200 mg/m2 and THP–Adriamycin 30 mg/m2 + lipiodol
Second-line chemotherapy
   ITEC: ifosfamide 3.0 g/m2 /day by 2 h infusion on days 1 and 2, THP–Adriamycin 30 mg/m2 /day by 1 h infusion on days 4 and 5, etoposide 100 mg/m2 /day by 1 h infusion on days 1–5 and carboplatin 400 mg/m2 over 24 h on day 3)

The German Cooperative Paediatric Liver Tumour Study HB-89 was started in 1989.14 In this study, patients with a tumour restricted to one lobe of the liver underwent primary resection.

Larger tumours involving both lobes and those with metastases were biopsied and initially treated with a combination chemotherapy of ifosfamide, cisplatin, and doxorubicin (IFO–CDDP–DOXO) and were resected at second-look surgery. The long-term disease-free survival of all patients was 75 per cent. In the HB-94 study (January 1994–December 1998), the efficacy of chemotherapy consisting of IFO–CDDP–DOXO and/or etoposide and carboplatin (VP16–CARBO) was assessed.15 A total of 69 patients were treated, 53 of whom (77 per cent) remained alive. Primary chemotherapy with IFO–CDDP–DOXO was given to 48 patients, of whom 41 achieved partial remission. Eighteen patients with advanced or recurrent hepatoblastoma were treated with VP16–CARBO, and a response to the regimen was observed in 12 of them.

The Japanese Study Group for Paediatric Liver Tumour Protocol 1 (JPLT-1) ran from March 1991 to December 1999.16 The chemotherapeutic regimen used for tumours involving over three hepatic sections and/or with metastasis was similar to PLADO, but doxorubicin was replaced by tetrahydropyranyl–Adriamycin (THP–Adriamycin) in an attempt to reduce cardiac toxicity. Half doses were administered to patients with tumours involving one or two hepatic sections. The event-free survival rate at 6 years was 66.0 per cent, and the overall survival rates at 3 and 6 years were 77.8 per cent and 73.4 per cent, respectively. In patients with tumours involving more than three hepatic sections, intravenous chemotherapy was compared with intra-arterial chemotherapy and, although there was a trend to favour intravenous therapy, the difference in outcome was not statistically significant. In the JPLT-2 study, treatment is started with CDDP plus THP–Adriamycin (CITA) or a transarterial chemoembolization (TACE) regimen (Table 24.2). An alternative chemotherapy combination, including ifosfamide, THP–Adriamycin, etoposide, and carboplatin (ITEC) is administered for poorly responding tumours.

Experimental treatment

Despite the aggressive chemotherapeutic regimens described above, 30 per cent of unresectable tumours remain resistant to treatment and an alternative treatment has to be sought. Options including ligation of the hepatic artery or tumour embolization with materials such as Gelfoam, in combination with chemotherapy, may be effective in decreasing tumour volume and increasing surgical resectability. Immunotargeted chemotherapy with an anti-AFP monoclonal antibody conjugated with Adriamycin or cisplatin has been explored but is still no more than an experimental option.

Liver transplantation may be required as a final approach in the treatment of refractory or unresectable hepatoblastomas. Although only a limited number of patients have undergone the procedure, the results have been encouraging.11

Hepatocellular carcinoma

Hepatocellular carcinoma accounts for 10–30 per cent of primary malignant hepatic tumours in Western countries and Japan, but is more prevalent and outnumbers hepatoblastoma in areas where hepatitis B virus (HBV) infection is endemic. For example, in Taiwan, 80 per cent of primary malignant hepatic tumours in children are hepatocellular carcinoma. The tumour usually occurs in children aged >5 years. Male predominance is more prominent than in hepatoblastoma.

HBV infection is causally associated with the development of hepatocellular carcinoma. In Taiwan, nearly 100 per cent of children with hepatocellular carcinoma are seropositive for hepatitis B surface antigen. Maternal transmission is the most important route of infection, but the incidence of childhood hepatocellular carcinoma has declined since the introduction in Taiwan of HBV vaccination for neonates of mothers carrying hepatitis B e antigen.17 The extremely short incubation period from HBV infection to the genesis of hepatocellular carcinoma in children as compared with that in adults suggests that there may another, so far unrecognized, mechanism which accelerates the carcinogenesis of childhood hepatocellular carcinoma. Hepatitis C viral infection has been recognized to cause hepatocellular carcinoma in adults, but the relationship is not yet fully understood in children.

The tumour is also recognized to be associated with a number of underlying chronic liver diseases, including tyrosinaemia, biliary atresia, idiopathic neonatal hepatitis, and a1-antitrypsin deficiency. Children with the chronic form of hereditary tyrosinaemia develop cirrhosis and eventually hepatocellular carcinoma. The incidence of the tumour exceeds 35 per cent if the children survive >2 years. Patients with biliary atresia who survive >3 years after portal-jejunostomy are at high risk for the tumour. Patients with a1-antitrypsin deficiency are also at high risk, but the tumour usually develops in adult life. Glucose-6-phosphatase deficiency (type 1 glycogen storage disease), Fanconi's anaemia, and Wilson's disease are among other associated disorders. Long-term parenteral nutrition and resultant biliary cirrhosis are also underlying causes of hepatocellular carcinoma.

Pathology

The gross and microscopic features of hepatocellular carcinoma in children are similar to those seen in adults, except for the lower incidence of underlying cirrhosis. Pre-existing cirrhosis is present in 5–40 per cent of children, whereas 50–85 per cent of adult hepatocellular carcinomas occur in cirrhotic liver. The tumour occurs as multiple nodules or a diffusely infiltrating mass involving both lobes of the liver. According to the SIOPEL-1 study, 39 per cent of tumours were associated with cirrhosis and >50 per cent of patients had multifocal tumours. The disease was advanced at diagnosis in most cases; 31 per cent had metastases, and 39 per cent had extrahepatic tumour extension or vascular invasion.

The cut surface is often bile stained, and haemorrhage and necrosis within the tumour are seen more often than in hepatoblastoma. Pseudoencapsulation is less conspicuous. The tumour cells are larger than normal hepatocytes. Histologic features distinguishing hepatocellular carcinoma from hepatoblastoma include broad trabeculae, nuclear pleomorphism, nucleolar prominence, and the presence of tumour giant cells. Extramedullary haematopoiesis is not seen in hepatocellular carcinoma.

Diagnosis

Abdominal pain and a palpable mass are the most common initial manifestations, and hepatosplenomegaly is the sign most frequently observed in hepatocellular carcinoma. Fever, weight loss, and jaundice are occasionally observed. Shock due to tumour rupture and intraabdominal bleeding may be the initial manifestation. Anaemia and mild hyperbilirubinaemia are the principal laboratory abnormalities, and the serum AFP concentration is high in 50–80 per cent of patients. Serologic evaluation for the possible presence of HBV infection is essential.

The radiologic features of hepatocellular carcinoma are similar to those of hepatoblastoma (Fig. 24.5), and differentiation between the two may be difficult. Occasionally, however, the growth patterns of the tumours may be useful in differentiating between these diagnoses; tumours with smaller satellite lesions, those invading the portal vein, or those with distant metastases are more often hepatocellular carcinomas. Metastatic spread is to the lungs, regional lymph nodes, and, rarely, bone.

Treatment

Complete resection is the basis of successful treatment in hepatocellular carcinoma as in hepatoblastoma, but it is often prevented by advanced disease. Primary unresectability and the presence of metastasis are factors indicating unfavourable prognosis,18 and although intensive chemotherapy regimens of several cooperative study protocols have been used, the results so far have generally been unsatisfactory.

In the German Cooperative Paediatric Liver Tumour Study HB-89, in which unresectable or incompletely resected tumours were treated with a combination of ifosfamide, cisplatin, and Adriamycin, only three of 10 patients were free from the tumour. Data from the SIOPEL-1 study showed that only eight of 40 patients treated with cisplatin and doxorubicin were alive without disease at a median follow-up of 75 months.18 The CCG and the POG conducted a randomized comparison of treatment with cisplatin, vincristine, and fluorouracil or cisplatin, and with continuous infusion of doxorubicin.19 There was no difference between the two regimens in terms of outcome, and the 5-year event free survival rates (88 per cent, 8 per cent, and 0 per cent for patients with stage I, III, and IV disease, respectively) confirmed the importance of surgical resection.

Fig. 24.5 Unresectable hepatocellular carcinoma refractory to multiagent chemotherapy is shown. (a) MRI showed a huge heterogeneous tumour extending to both lobes of the liver. The tumour had a lower signal intensity than the surrounding liver tissue on T1-weighted MRI images. Histologically, tumour cells were growing in (b) a macrotrabecular pattern (haemotoxylin and eosin stain) and (c) were positive for β-catenin (immunostaining).

Total hepatectomy and liver transplantation may be an effective treatment for hepatocellular carcinoma. In one series, a 5-year disease-free survival of 63 per cent was obtained in 19 patients with hepatocellular carcinoma who underwent transplantation.11

Fibrolamellar carcinoma (fibrolamellar variant of hepatocellular carcinoma)

Fibrolamellar carcinoma, a distinctive variant of hepatocellular carcinoma, occurs in the noncirrhotic livers of older children and young adults without sex preference. The tumour is not associated with underlying liver disease, viral infection, or metabolic abnormality. The serum AFP is not high in the majority of patients, but a specific abnormality of the vitamin B12 binding protein has been documented and the level of unsaturated vitamin B12 binding protein is significantly high in fibrolamellar carcinoma and rises with disease progression. The imaging characteristics are generally similar to those of classical hepatocellular carcinoma. The gross appearance of the tumour generally consists of a single well-circumscribed pseudo-encapsulated mass rather than the diffusely infiltrating mass usually seen in heptocellular carcinoma. Microscopically, fibrolamellar carcinoma is characterized by large plump polygonal cells encompassed by fibrous bands (lamellar fibrosis). The cytoplasm is granular and deeply eosinophilic, and ultrastructurally shows abundant mitochondria.

Fibrolamellar carcinoma differs from the ordinary form of hepatocellular carcinoma in its clinical presentation and biologic behaviour, as well as in histologic features. It is characterized by a longer duration of symptoms prior to diagnosis and increased chance of resectability. Importantly, prolonged disease-free survival is seen compared with that usual for hepatocellular carcinoma if the tumour is completely resected, although it is suggested that the prognostic difference between the tumour types may be insignificant after adjustment for disease stage.

Undifferentiated (embryonal) sarcoma of the liver

Undifferentiated (embryonal) sarcoma of the liver is a highly aggressive tumour most often presenting in late childhood as an abdominal mass, pain, or fever. There is no sex preponderance. Serum AFP is within the normal range. Pathologically, the gross findings are relatively consistent and show cystic areas and gelatinous tissues with extensive necrosis and haemorrhage. Demarcation from the surrounding liver appears sharp, but there may be microscopic infiltration and permeation to the veins. Histologically, the tumour shows a proliferation of spindle cells, with occasional polygonal or round cells loosely or densely arranged in a myxomatous background. Bizarre and multinucleated giant cells and periodic acid–Schiff positive hyaline globules of various sizes are frequently observed. Entrapped bile ducts, together with non-neoplastic hepatocytes, are observed at the periphery of the tumour. Positive immunostaining for histiocytic markers (a1-antitrypsin, a1-antichymotrypsin), muscle markers (desmin, muscle-specific actin), and vimentin is fairly consistent. Supported by these pathologic findings, it is suggested that the tumour is of mesenchymal origin, presumably from a very primitive precursor cell.

Radiologic evaluation by ultrasonography and CT typically reveals a large intrahepatic mass with a wide range of solid and cystic components which correlate with areas of haemorrhage, necrosis, and cystic degeneration. Complete excision and adjuvant multi-agent chemotherapy appear to be essential in achieving long-term survival. There is limited information about optimal adjuvant treatment because of the lack of large-scale clinical studies.

Other liver tumours

Other primary malignant mesenchymal tumours of the liver include rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, fibrosarcoma, yolk sac tumour, and rhabdoid tumour. Embryonal rhabdomyosarcomas are rare malignant tumours of the biliary tract, and may be found anywhere from the ampulla of Vater to the liver itself. Tumours with evidence of striated muscle differentiation are diagnosed as rhabdomyosarcoma, but a histologic distinction between undifferentiated sarcoma and rhabdomyosarcoma can sometimes be difficult. Rhabdomyosarcomas are usually seen in patients <4 years of age and tend to present with obstructive jaundice. The tumour often grows as a botryoid gelatinous mass occluding the lumen of bile ducts.5 Histologically, the tumour cells lie in a loose myxoid stroma beneath the epithelium of the bile ducts and exhibit the typical features of embryonal rhabdomyosarcoma. Although surgery is critical for establishing an accurate diagnosis and determining the extent of regional disease, aggressive surgery is not usually warranted for biliary tract rhabdomyosarcoma. Primary gross total resection is rarely possible; nevertheless the outcome of treatment with chemotherapy, with or without radiation therapy, is good.20

Yolk sac tumour and choriocarcinoma, although extremely rare, may arise de novo in the liver, and a variety of paediatric solid tumours including neuroblastoma, Wilms tumour, rhabdomyosarcoma, and yolk sac tumour can metastasize to the liver (details are discussed in the chapters describing these tumours).

References

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