Hepatoblastoma HB

HB is the most common primary hepatic malignancy in children and represents approximately 45% of all pediatric liver neoplasms. It is generally detected in children younger than five years of age; in roughly 66% of cases the mean age for detection is one year. From an etiological point of view, a correlation has been observed with prematurity, with a gestational age of <37 weeks, and with a birth weight of <1000 g. Other risk factors are trisomy 18, hemi-hypertrophy, Beckwith-Wiede-mann syndrome, familial adenomatous polyposis, fetal alcoholic syndrome, maternal use of go-nadotropin, and maternal exposure to metals or petroleum products [47, 74, 89]. Liver cirrhosis is not considered a risk factor.

HB can be considered the infantile form of HCC. Histological classification divides HB into two main types: a pure epithelial form and a mixed epithelial-mesenchymal form. The pure epithelial form includes fetal, embryonal, macrotrabecular and undifferentiated small cell variants. Fetal epithelial HB is composed of cells that are smaller than normal hepatocytes and which have an eosinophilic cytoplasm. They have a relatively low nucleus to cytoplasm ratio and although some nu-cleoli are present, mitoses are rare and growth occurs with a compact trabecular pattern. The embryonal variant has a high nucleus to cytoplasm ratio, a basophilic cytoplasm and ductal elements with cells that can form acini, tubules and pseudorosettes. Mitoses are frequent in this form of HB. The macrotrabecular form is a variant comprising a recurrent combination of both the fetal and the embryonal cell types in cords or plaques. The cell dimensions of this form frequently exceed those of normal hepatocytes. The anaplastic small cell type of HB is composed of typically round or oval cells that may be fusiform but which always have a high mitotic index. Infiltration of the adjacent hepato-cytes is normally observed, with vascular invasion and necrosis.

The mixed epithelial-mesenchymal form contains an epithelial component identical to that of epithelial HB, plus a mesenchymal component with osteoid, chondroid and rhabdomyoblastic elements. It is often associated with areas of calcification, hemorrhage and necrosis [34,90].

The histological classification of HB carries marked prognostic implications; the survival rate for patients with the pure fetal variant is 90%, compared with 54% for the mixed form and 33% for the embryonal variant. Unfortunately the survival rate for patients with the anaplastic variant is 0% [13].

HB frequently presents as a single, large, bulky mass, most often in the right lobe of the liver. Macroscopically, its appearance varies according to the histological type: epithelial HB has a typically homogeneous appearance whereas the mixed form possesses calcifications, fibrotic bands and osteoid and cartilaginous material, and is consequently more heterogeneous in appearance [83].

The nodules may sometimes be multiple, in which case they may affect both lobes of the liver. A diffuse variant involving the whole organ has been reported but is less common. The presence of multifocal nodules, diffuse involvement, and vascular invasion is encountered in approximately 50% of cases overall and is indicative of unre-sectability and a worse prognosis. In 30% of cases, remote metastases are detected; the organs most often involved are the lung, kidney, brain and abdominal lymph nodes [46].

The variable presentation of HB means that the lesion can be defined as belonging to one of two categories according to the potential risk: (1) standard risk hepatoblastoma for patients with single or apparently multifocal neoplasms involving no more than three hepatic segments in the absence of metastases and extrahepatic abdominal involvement, (2) high risk hepatoblastoma with neoplastic disease extending to four or more liver segments and evidence of extrahepatic spread [90]. HB can be seen, albeit infrequently, in older children, in which case it tends to have clinical and anatomo-pathological characteristics in common with HCC and the prognosis is worse than in children of younger age. In older children HB may acquire macrotrabecular features similar to the trabecular characteristics of HCC, with vascular invasion and recurrence, as well as cholangiocellular differentiation [90].

Approximately 50% of children with HB are symptom-free; the diagnosis is often made during a medical check-up due to the incidental finding of a palpable mass or an increase in abdominal circumference. Abdominal pain, fever, loss of appetite and weight loss are reported in 25% of patients, whereas jaundice occurs in fewer than 10% of cases [89,90].

In addition to histological type, factors that suggest the likely evolution of the disease include the number of lesions, the presence of metastases, and - of considerable relevance - the level of a-fe-toprotein (AFP).

AFP is a protein produced exclusively in the fetal liver that disappears from the serum in the first few weeks of life. Its values rise in the presence of certain tumors, such as HB, HCC and endodermal breast tumors, and it is occasionally found in the serum of patients with pancreatic and gastric carcinoma. AFP positivity in pediatric HB and HCC is much higher than in adult HCC, with high values being detected in 96% of cases. The values of this tumor marker are indicative of a worse prognosis when they are higher than 1,000,000 ng/mL or lower than 100 ng/mL. The reason for such low values in the latter case, which corresponds to undifferen-tiated neoplasm, is that the cells are too immature and malignant to produce the protein [98]. High values of human chorionic gonadotropin (HCG) are sometimes observed and in these cases HB is associated with signs of early puberty. Thrombo-cytosis is also present in 93% of cases [34].

Prognosis and long-term survival depend on the feasibility of completely resecting the tumor, hence the fundamental role of imaging diagnostics in accurately assessing the extent of the neoplasm and its relationship with the intra- and extra-hepatic vascular structures.

The correct diagnosis and staging of HB, and its assignation to the correct risk category, can be achieved using most imaging modalities. A straightforward standard abdominal x-ray, however, reveals alterations that are generally non-specific. This approach merely shows a solid mass or calcifications (in 50% of cases) and therefore contributes little towards the distinction between benign and malignant lesions. The areas of calcification probably represent dystrophic calcifications in necrotic portions of the lesion [62].

US findings vary according to the histological type. Masses are normally well-defined, multilobu-lated and septate. The epithelial variant of the tumor is normally homogeneously hypo- or hypere-chogenic while the mixed form invariably presents as a heterogeneous mass with hyper- and hypoe-chogenic areas that reflect calcification and tumor necrosis, respectively. Color Doppler assessment is very sensitive to the rich neo-vascularization of the tumor (Fig. 8) [5,90].

Fig. 8. Hepatoblastoma. Color Doppler US reveals a slightly hy-perechoic and hypervascular mass (asterisk). An impression of the portal vein (PV) and of the right branch of the portal vein (RPV) can be seen

CT is of fundamental importance for the staging of HB, not only to assess the intrahepatic extension of the neoplasm correctly and thus decide on its resectability or non-resectability, but also to determine the presence or absence of metastases to the abdomen and chest. In the latter case, a further problem is posed by the frequent presence of atelectasis in the lower thoracic portions that may confound or mask lung nodes. For this reason it is often necessary to repeat the scans in the prone position. This method is also necessary during follow-up [90].

During the staging procedure, the SIOPEL protocol of June 1998 [90] recommends performing the examination before and after the administration of intravenous contrast medium. Prior to the administration of contrast medium the epithelial variant of HB is typically homogeneously hypo-dense and any calcifications that are present are usually small and punctiform (Fig. 9). Conversely, the mixed form of HB tends to be more heterogeneous (Fig. 10), often with larger and coarser calcifications. After injection of contrast medium, HB typically demonstrates enhancement during the arterial phase, which subsequently fades in the portal venous phase. Enhancement may be patchy and is usually inferior to that of the healthy parenchyma. A peripheral ring or hyperdense septa may be apparent in the late phase. This is due to the stromal component [34,89,90].

On MR imaging the SI of the tumor varies in relation to the histological type. Epithelial HB is seen as hypointense on T1-weighted images (Fig. 11) and as hyperintense on T2-weighted images. As in CT, the mixed form is much more heterogeneous due to the variable presence and extent of necrosis, hemorrhage and fibrosis. In this variant, hypointense bands and high signal areas are often y ^ ** >

Fig. 9a-d. Hepatoblastoma (epithelial variant). The unenhanced CT scan (a) reveals a homogeneously hypodense lesion with a small and punctiform calcification (arroW). The lesion shows enhancement in the arterial phase after contrast medium administration (b) and washout of the contrast medium in the portal-venous (c) and equilibrium (d) phases. Note the retraction of the liver capsule (arrowheadin c)

Punctiform Intracranial Calcifications

Fig. 10a-d. Mixed hepatoblastoma. On the unenhanced CT scan (a) the neoplasm (arrows) is heterogeneously iso- and hypodense. During the arterial phase after contrast material administration (b), the cellular component of the lesion (asterisk) enhances. However, this becomes hypodense in the portal-venous (c) and delayed (d) phases. Conversely, the stromal component (asterisk in d) enhances markedly in the delayed phase

Fig. 10a-d. Mixed hepatoblastoma. On the unenhanced CT scan (a) the neoplasm (arrows) is heterogeneously iso- and hypodense. During the arterial phase after contrast material administration (b), the cellular component of the lesion (asterisk) enhances. However, this becomes hypodense in the portal-venous (c) and delayed (d) phases. Conversely, the stromal component (asterisk in d) enhances markedly in the delayed phase

Fig. 11a, b. Hepatoblastoma. The unenhanced Tl-weighted image (a) reveals a large, well-defined, lobulated hypointense mass with a small central area of lower SI (arrowhead) that corresponds to calcification. After contrast agent administration (b), the neoplasm demonstrates early, inhomogeneous enhancement

Hepatoblastoma

Fig. 11a, b. Hepatoblastoma. The unenhanced Tl-weighted image (a) reveals a large, well-defined, lobulated hypointense mass with a small central area of lower SI (arrowhead) that corresponds to calcification. After contrast agent administration (b), the neoplasm demonstrates early, inhomogeneous enhancement observed on both T1- and T2-weighted images, the latter being due to areas of hemorrhage. Unfortunately, calcifications cannot be diagnosed reliably using this technique. Unenhanced GRE T1-weight-ed sequences permit evaluation of the vascular components of both the tumor and the healthy parenchyma [34, 75].

Early enhancement and rapid wash-out are typical features of HB on post-contrast dynamic phase imaging (Fig. 12) [89]. In the arterial phase most lesions appear as heterogeneously hyperin-tense due to the presence of fibrotic and necrotic areas. Thereafter, in the portal-venous and equilibrium phases, the neoplasm is isointense and hy-pointense, respectively, with hyperintense areas corresponding to the stromal component. In the delayed hepatobiliary phase after the injection of Gd-BOPTA, the lesion is usually heterogeneously hypo- or isointense (Fig. 13).

Catheter angiography can reveal malignant tumoral neo-vascularization, vascular distortion and stretching, and invasion or encompassing of the portal vein or hepatic artery; occasionally it can also visualize a characteristic spoke wheel pattern due to the presence of multiple septa and fibrous bands [34]. Unfortunately, catheter angiography requires the use of ionizing radiation which is not ideal in young children. The availability of 3D CE-MRA has recently been shown to permit accurate preoperative evaluation of the liver vasculature in children with HB [33,71].

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