Assessment of extrahepatic abdominal extension in primary malignant liver tumours of childhood

In the SIOPEL 3 study, 17 (4.1%) of 417 patients with hepatoblastoma registered before the end of 2004 were classified as E+ (M. Childs, personal communication). The original PRETEXT system, which was used in this study, included patients with lymph node metastases in this group. This indicates that direct extension of tumour, as detected by imaging findings at diagnosis, is clearly very uncommon in hepatoblastoma. Isolated extrahepatic spread is even less common: only 6 of the 17 patients (1.4% of those with hepatoblastoma) were classified as high risk on this basis alone. As a consequence, until the 2005 revision of the PRETEXT system, all SIOPEL protocols required that extrahepatic abdominal spread of tumour (E+), including lymph node metastases, be proved by biopsy. It was unfortunate that this rule failed to distinguish between different tumour types. A second problem was that some types of direct tumour spread (through the diaphragm, for example) are difficult to biopsy safely. In addition, the requirement for biopsy proof prevented the full use of the emerging capabilities of modern imaging techniques.

In the revised system, two stages of intra-abdominal spread are recognized. In the first, E1, there is direct growth of tumour into adjacent structures. This must be distinguished from an exophytic tumour growth pattern. In fact, hepatoblastoma often grows in a pedunculated manner, and when there is no unequivocal evidence of invasion of adjacent structures, tumours of this type are regarded as being confined to the liver [3].

In principle, the tumour may grow into any of the structures that are anatomically related to the liver. Although it is uncommon in hepatoblastoma, about 10% of adults with hepatocellular carcinoma have diaphragmatic adhesion or invasion by tumour [7]. At the time the original PRETEXT system was devised, there was no good preoperative method for assessing involvement of the diaphragm [7]. Diaphragmatic penetration by tumour may now be shown convincingly by MRI or CT (Fig. 1). Coronal or sagittal images may be more helpful than transverse images in this context. Subtle diaphragmatic invasion and tumour adhesion to the diaphragm without tumour invasion will be missed at cross-sectional imaging.

Invasion of the duodenum or colon (Fig. 2) appears to be quite rare in both hepatoblastoma and hepatocellular carcinoma, although there is little published information on this subject. There may also be direct extension of tumour into the retroperitoneum, with involvement of the pancreas (Fig. 3). When this occurs, the alternative diagnosis of pancreatoblastoma (another tumour that may secrete alpha-fetoprotein) with liver involvement should be considered.

Peritoneal spread of tumour is also unusual in children, but may be shown by cross-sectional imaging (Figs. 4 and 5). Ultrasonography is particularly sensitive in the detection of small peritoneal implants in the presence of ascites. It seems intuitively likely that this form of spread is prognostically worse than direct extension, and for this reason the 2005 revision defines peritoneal implants as E2. Biopsy proof is not required if the imaging findings are diagnostic.

In current SIOPEL protocols, children with hepatoblastoma and either E1 or E2 are assigned to the high-risk treatment group. This allocation is arbitrary, because there is so far no evidence from any large study that extrahepatic abdominal spread is an independent risk factor. All patients without evidence of E1 or E2 are coded as E0. Abdominal lymph node metastases are considered separately in the 2005 revision [3].

It is not known whether ascites, which is seen at presentation in a minority of children with primary liver tumours, is a marker of poor prognosis. The suffix “a” is added to the E number of patients with ascites (i.e. E0a, E1a or E2a as appropriate) in order to facilitate prospective analysis of its significance [3].

Tumour rupture (Fig. 6) is a well-recognized presentation of both hepatoblastoma and hepatocellular carcinoma in childhood [8‐10]. Its prognostic significance is not certain, but since the opening of the SIOPEL 4 study in September 2004, tumour rupture (H1) has become a defining feature of high-risk hepatoblastoma in SIOPEL studies. It should be noted that characteristic imaging and clinical findings (such as hypotension and low haematocrit or haemoglobin level) are regarded as sufficient to make this diagnosis. Paracentesis is not recommended unless there is any clinical doubt. Embolization may be appropriate if there is continuing haemorrhage [11‐13]. Localized or subcapsular haemorrhage (Fig. 7) is a fairly common finding and is specifically excluded from H1, as is biopsy-related intraperitoneal bleeding. Patients with no evidence of tumour rupture or haemorrhage are coded as H0 [3].