Figure 17.1 Causes of benign liver tumour in childhood.
Figure 17.2 King’s College Hospital experience: liver haemangiomas (1979–2011) (n = 71). Mode of presentation (symptomatic [n = 49] vs. antenatal detection or incidental [n = 22]). (With thanks to Alexander MacDonald.)
1. Focal – solitary, well demarcated, mostly asymptomatic, with rapid involution (Figure 17.3)
2. Multifocal – multiple foci in the liver, again predominantly asymptomatic, but some may present with high-output cardiac failure (Figure 17.4a,b).
3. Diffuse – numerous bilobar hepatic lesions causing hepatomegaly with subsequent increased abdominal pressure and respiratory problems [5]
Figure 17.3 Solitary haemangioma of liver. Antenatal detection of large left lobe tumour, palpable postnatally with falling platelet count and failure to thrive. Marked parasitisation of blood supply from retroperitoneum, spleen and adjacent diaphragm noted during resection.
IHs have been described in association with Kasabach–Merritt* syndrome [6], and other cutaneous or visceral haemangiomas [4,7]. Increasing volume of abnormal liver parenchyma may cause anaemia and thrombocytopenia due to sequestration and consumptive coagulopathy within the dilated abnormal sinusoidal channels [4]. Obstructive jaundice is possible but unusual [7]. Both hyper- and hypothyroidism are possible with IH (typically multifocal and diffuse), probably due to abnormal production of a thyroid-stimulating hormone (TSH)–like molecule [8]. If here is rapid transit through lesions with increased overall arterial input, then high-output congestive heart failure may lead to a clinical presentation characterised by respiratory distress, poor or prolonged feeding and failure to thrive. Laboratory tests may show anaemia and occasionally jaundice, with moderately elevated serum AFP (albeit much lower than a typical hepatoblastoma) [9,10].
Figure 17.4 Multifocal liver haemangiomas within left and right lobes. Infant presented at 4 weeks with high-output cardiac failure requiring ventilation. HAL reduced cardiac output and hepatomegaly, allowing extubation. MRI with coronal T1-weighted (a) and T2-weighted (b) images showing almost complete replacement of normal liver tissue.
BOX 17.1 King’s College Hospital experience: Hepatic arterial ligation for haemangiomas (1969–present)
Haemangiomas are preferentially supplied by the hepatic artery, and its ligation was recognised as one of the first effective treatments for the often life-threatening cardiac failure seen in these infants. Alfred De Lorimier from San Francisco published the first successful application of this in 1967 [85], and Martin Rake from King’s published the second in 1970 [86]. This then became our standard treatment, despite the increasing availability of interventional radiological techniques during the 1980s and 1990s [7]. In the period 1979–2011, 71 infants were diagnosed with haemangiomas. of these, 49 (69%) were symptomatic in some way and 26 came to HAL. All but one survived.
A combination of clinical symptoms and US and CT scan imaging usually provides the diagnosis. An area of lower density is enhanced from the periphery towards the centre on contrast CT, and after intravenous administration of contrast material, a complete isodense appearance of the liver and lesion is noticed after a short delay. In particular cases with refractory symptoms, angiography may be performed, when embolisation or hepatic arterial ligation (HAL) are considered as treatment options [7] (Box 17.1).
17.2.2 Pathology
Macroscopically, just more than half appear as reddish-brown or tan solitary tumours, located in any of the liver lobes and measuring up to 15 cm in their largest diameter. These lesions often show haemorrhagic or fibrotic centres, sometimes with focal calcifications. Multiple lesions usually measure <1 cm in size but may involve a much larger volume of the liver, with a red-brown, spongy appearance on cut section [5].
Histologically, these lesions have numerous capillary-like vascular channels lined by a single-layered plump endothelium with a fibrous stroma seen, particularly in the peripheral areas of the tumour. The centre of the lesion is usually characterised by involutional changes, where cavernous vascular spaces lined by a single layer of flattened endothelial cells can be seen, some of them showing thrombosis, leading up to areas of infarction, fibrosis or calcification. Foci of extramedullary haematopoiesis and entrapped bile ducts and normal hepatocytes can be seen at the edges of the lesion. Immunohistochemically, the endothelial cells express vascular markers (VIII-related antigen, CD31 and CD34) and GLUT1. The latter has been proposed as a particularly useful marker to distinguish IM from a congenital vascular malformation associated with vascular proliferation [11].
Figure 17.5 King’s College Hospital experience (1979–2011): liver haemangiomas (1979–2011) (n = 71), treatment and outcome.
17.2.3 Treatment and prognosis
Lesions may undergo spontaneous regression, and therefore intervention, be it medical or surgical, should be reserved for symptomatic lesions only. This may involve corticosteroids [12] and interferon-α [13,14] or HAL/embolisation [7], hepatic resection (Figure 17.3) and perhaps liver transplantation as a last resort [5]. The use of radiation therapy for reducing arteriovenous shunting, plus symptomatic management of congestive heart failure [15], has also been reported.
The most recent addition to the treatment of symptomatic haemangiomata has been the β-adrenergic receptor blocking agent, propranolol (2 mg/kg/day). It is highly lipophilic, and the oral drug undergoes considerable first-pass metabolism and appears to be highly effective in controlling cardiac symptoms and stimulating involution. This was first reported in 2008 [16] and has become the first-line treatment since, with a multiplicity of small series and a consensus paper [17].
Figure 17.5 illustrates our experience in the period 1979–2011 with 71 infants, of whom 49 were symptomatic. Medical therapy alone was sufficient in 22 (45%), with propranolol being used in 8 with excellent results. HAL (n = 26) was the main mode of treatment prior to this, but liver resection was also used for solitary lesions in eight infants. Two liver transplants were also performed. The overall survival for symptomatic IH of the liver in this series was 92%.
Other therapies have been reported, again typically in isolated case reports, using chemoembolisation and anti-angiogenic metronomic therapy (cyclophosphamide and tamoxifen) [18].
17.3 PELIOSIS* HEPATIS
This is a rare condition of the liver characterised by the formation of blood-filled spaces, often throughout the whole liver [19]. It is not a tumour as such, but shares enough features in common with vascular tumours to be considered here.
Figure 17.6 Peliosis. Three-year-old girl with acute onset hepatomegaly and haemoperitoneum. MR images show disruption of liver architecture and multiple vascular spaces. Full recovery after supportive care.
17.3.1 Classification
It is considered to be due to primary rupture of reticulin fibres (phlebectatic variant) or secondary to hepatocellular necrosis (parenchymal variant), as the blood-filled cavities do not have an endothelial lining. It is usually described in association with a number of underlying diseases, such as infections (e.g. Bartonella spp. – the causative organism of cat scratch fever or staphylococcal septicaemia), underlying genetic conditions (e.g. X-linked myotubular myopathy [19]), chronic disease (e.g. chronic renal failure, Fanconi’s anaemia or an underlying malignancy) and exposure to drugs or toxins such as anabolic steroids.
17.3.2 Clinical features
Presenting features vary but include an expanding liver mass, acute bleeding and haemoperitoneum from rupture [19,20] and obstruction of the cava [21] or biliary tree (Figure 17.6). The diagnosis is difficult and imaging can be confusing. Contrast CT scan (or even angiography) shows persisting accumulation of contrast in the arterial phase through to the venous phase. Biopsy may be warranted if it can be haemostatic (i.e. open or perhaps transjugular) and should be definitive.
The treatment varies according to the nature of the presentation. In the first instance, supportive measures may be needed to correct coagulopathy or thrombocytopenia. Angiographic embolisation should be considered, or a laparotomy if there is acute bleeding from rupture. Localised involvement, if discrete, can be resected.
MH of the liver is the second most common benign liver tumour in the paediatric population. However, its biology and pathogenesis remain poorly understood [22], although the cell of origin has been suggested as the hepatic stellate cell (of Ito*) [23].
Ten (six female) children presenting at a median age of 13 (2–65) months. Normal antenatal scans were documented in all. Eight had symptoms of an abdominal mass. The tumour was right-sided in nine, with a median diameter of 12 (range 2–21) cm, and the median FP was 50 (range 2–120,900) IU/L. On review, the classical solid or cystic appearance was present in most (>90%), although the correct diagnosis was only made in four initially.
Two children had attempted resections elsewhere, but with complications. Definitive treatment was surgical and included extended right or left hepatectomies (n = 4) and was curative in all cases.
Note: With thanks to Charlotte Holbrook FRCS (Paeds) for the data.
17.4.1 Clinical features
Typically, MHs present before 2 years of age, as an incidental typically asymptomatic mass. Examination may show painless abdominal enlargement, nontender right upper quadrant mass and sometimes abdominal wall vein engorgement (Figure 17.7). A prenatal diagnosis of MH, also associated with hydrops, has also been reported [24,25] (Box 17.2).
MH on imaging appears as heterogeneous, with hypoattenuating stromal components and water attenuation cystic elements on CT scan. The mesenchymal components show enhancement on contrast CT scan. The MRI also shows a variable appearance due to the cystic/stromal ratio of the lesion and also the protein content of the cystic fluid [26], solid areas appearing hypointense on T1- and T2-weighted images an cystic areas showing variable signal intensity on T1-weighted images, but coming closer to water signal intensity on T2-weighted images. Enhancement of the lesion after administration of iodinated intravenous contrast material is low and limited to the septa and stromal components [27].
There exists no specific laboratory test for MH, although an elevation of serum AFP sometimes occurs [28].
17.4.2 Pathology
MH is located in the right lobe in about 75% of cases and is typically a large, well-demarcated, nonencapsulated lesion [29]. The mass may vary in appearance from mostly cystic to a predominantly stromal lesion, although 85% of lesions are said to contain cysts [29]. Younger patients tend to have lesions with fewer cystic structures, with fluid content of different consistency which can range from amber to gelatinous.
Figure 17.7 Mesenchymal hamartoma. Two-year-old boy presenting with gross abdominal distension. (a) Initial MR scan shows multiple cystic areas occupying abdominal cavity – misdiagnosed as lymphatic malformation and subjected to aspiration and sclerotherapy. (b) CT scan shows remnants actually arising from right lobe of liver.
On histological examination, there is a combination of mesenchymal elements, hepatocytes, biliary epithelium and cystic structures lined by cuboidal or flattened epithelium. Foci of extramedullary haematopoiesis are usually noted [22].
17.4.3 Treatment and prognosis
A nonoperative approach of MH, with US and CT scan surveillance, has been tried in the past, based on the spontaneous involution and regression of the tumour [30]. Due to a possible transformation to undifferentiated embryonal sarcoma (UES) and the potential of rapid growth, this approach is not advisable [31,32], and we consider complete excision by an anatomical or nonanatomical hepatic resection as the best treatment for MH, with an excellent prognosis for children in good clinical condition. Antenatal presentation may occur, but unless there are significant obstetric indications, it is advisable to leave until term. If this is causing fetal distress and so forth, then serial aspiration of the cystic component has been reported, together with definitive resection postnatally [33]. Laparoscopic resection for pedunculated lesions has also been reported [33].
17.5 FOCAL NODULAR HYPERPLASIA
FNH is a rare lesion that occurs in up to 0.02% of the general hospitalised paediatric population and in 0.45% of the children previously treated for malignancy [34–36] or following haematopoietic stem cell transplantation [37,38]. We have also identified a marked association with congenital portosystemic (Abernethy*) shunts (unpublished observation) (Figure 17.8a and b).
Most present later in childhood, with a modal age in one study of 7 years [39]. However, presentation during the prenatal period or infancy is also possible.
The aetiology of the disease is still unknown, although disturbance in the normal vascular supply to the liver has been hypothesised due to its reported association with conditions such as Budd–Chiari syndrome, portosystemic shunts, haemangioma, vascular dysplasia and hereditary haemorrhagic telangiectasia [40,41]. Paradis et al. also reported that angiopoietin-1/2 (Ang-1/2) genes are involved in the regulation of vasculogenesis in FNH. The Ang-1/Ang-2 ratio was increased in this lesion compared with benign or malignant hepatocellular neoplasms and to normal liver [42].
17.5.2 Clinical features
Most of the lesions are discovered incidentally and are asymptomatic, although larger lesions can compress adjacent organs and present with abdominal pain.
The US appearance of FNH is as a mass with different degrees of echogenicity, but with a characteristic hyperechogenic central scar. Doppler shows that about half are hypervascularised, with an arterial-type flow which radiates from the centre towards the periphery [43]. Unenhanced CT scan shows FNH to be hypodense or isodense compared with liver parenchyma [44]. During the arterial phase, lesions become hyper-dense, only to become isodense in the later phases. MR scans appear to have the highest sensitivity and specificity (70% and 98%, respectively) for the diagnosis [44
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