ARTICLE IN PRESS+ModelCLINRE-599; No. of Pages 4

Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx

Available online at

ScienceDirectwww.sciencedirect.com

MINI REVIEW

Hepatic neoplasms in children: A focus ondifferential diagnosis

Antal Dezsofia,∗, Valerie McLinb, Nedim Hadzicc

a First Department of Paediatrics, Semmelweis University, Bókay János utca 53, 1083 Budapest, Hungaryb Swiss Center for Liver Disease in Children, University Hospital of Geneva, Geneva, Switzerlandc Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, London, UK

Summary Paediatric hepatic neoplasias are rare, accounting for 1—4% of all solid childhoodtumors. Liver tumors in children can be classified into benign or malignant; some of the benignlesions can have the potential of malignant transformation. Two-thirds of liver tumors in childrenare malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children.Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, andhepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours,hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a pae-

diatric liver tumour guides the treatment and prognosis. Although benign and malignant livermasses share some clinical manifestations, treatment and prognosis differ.© 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Dezsofi A, et al. Hepatic neoRes Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/

Abbreviations: AFP, Alfa-fetoprotein; BSEP, Bile salt exportpump; CT, Computer tomography; DIC, Disseminated intravascularcoagulation; FNH, Focal nodular hyperplasia; HBL, Hepatoblastoma;HCA, Hepatocellular adenoma; HCC, Hepatocellular carcinoma;HNF1a, Hepatocyte nuclear factor 1�; IHE, Infantile haemangioen-dothelioma; LFABP, Liver fatty acid-binding protein; LTx, Livertransplantation; MRI, Magnetic resonance imaging; NRH, Nodularregenerative hyperplasia; SEER, Surveillance, Epidemiology, andEnd Results; SIOPEL, International Childhood Liver Tumours StrategyGroup; US, Ultrasonography.

∗ Corresponding author. Tel.: +36302600281.E-mail address: dezsofi.antal@med.semmelweis-univ.hu

(A. Dezsofi).

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http://dx.doi.org/10.1016/j.clinre.2014.05.0012210-7401/© 2014 Elsevier Masson SAS. All rights reserved.

ntroduction

athologic masses of the liver in children constitute about—6% of all intra-abdominal masses and 1—2% of all pae-iatric tumours. Two-thirds of such masses are malignant,mphasizing the importance of systematic approach to chil-ren with a liver mass. The differential diagnostic pathwayncludes a stepwise approach involving the age and genderf patient, clinical presentation, underlying liver disease,erum alfa-fetoprotein (�FP) level and imaging characteris-ics [1,2].

plasms in children: A focus on differential diagnosis. Clinj.clinre.2014.05.001

ymptoms

ost children with liver masses present with abdominal dis-ension and a palpable abdominal tumour. On occasion,

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he patients are asymptomatic and the mass is discoveredncidentally. Chronic fatigue due to anaemia and lack ofppetite are often reported. Occasionally, severe symptomsnd complications such as pain, biliary obstruction, inferiorena cava obstruction, dyspnea, feeding intolerance, sud-en intra-abdominal haemorrhage due to ruptured tumour,igh output heart failure, disseminated intravascular coag-lation (DIC) and sepsis can occur.

iagnostic approach

iver tumours identified in children include primary benignnd malignant neoplasms, inflammatory masses, cysts andetastatic lesions (Table 1).The most common malignant tumours are hepatoblas-

oma (HBL) and hepatocellular carcinoma (HCC). Infantileaemangioendothelioma (IHE) and focal nodular hyperpla-ia (FNH) are also seen in children [2]. Although benign andalignant liver masses share some clinical manifestations,

reatment and prognosis differ.In addition to patient age, characteristic symptoms and

erum AFP level, different imaging techniques are criticalo delineate the appearances and spread of the tumour, anduide follow-up after treatment. Standard diagnostic tech-iques are ultrasonography (US) and magnetic resonancemaging (MRI), but contrast computerised tomography (CT)s still the most informative technique at presentation. US is

Please cite this article in press as: Dezsofi A, et al. Hepatic neRes Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/

he recommended technique for follow-up. A recent studyuggests that contrast enhanced ultrasound (CEUS) is safend useful in demonstrating the benign nature of focal liver

Table 1 Benign and malignant liver masses.

BenignInfantile haemangioendothelioma (IHE)Mesenchymal hamartomaFocal nodular hyperplasia (FNH)Hepatocellular adenomaNodular regenerative hyperplasiaPrimary hepatic teratomaOthers: non-neoplastic cystic masses: including biliary,simple, parasitic, pyogenic and amebic hepatic cysts andabscess

HaematomasLymphangiomaInfarctionCystadenoma (biliary duct cell in origin)Vascular malformationsPolyarteritis nodosaGranuloma

MalignantHepatoblastomaHepatocellular carcinomaEmbryonal sarcoma (undifferentiated)Epitheloid haemangioendotheliomaAngiosarcomaEmbryonal rhabdomyosarcomaMetastatic lesions

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esions that are indeterminate on grey-scale sonography inhildren, potentially reducing the use of CT and MR imaging3].

CT and MRI are instrumental in evaluating intra- andxtra-hepatic extent of disease. Positron-emission tomo-raphy (PET) CT offers a greater sensitivity for residualnd relapsed disease and may facilitate surgery [4].1/T2-weigthted MRI can further improve diagnosis byefining features such as density, vascularity, stromal com-onent and intra-lesional necrosis and haemorrhage [5].n average, diagnosis is possible on radiological findingslone in 58% of cases, while in remainder histology isecessary [6].

nfantile haemangioendothelioma

nfantile hepatic haemangioendothelioma is the most com-on benign liver tumour in children with a peak presentationetween 3—6 months of age. Many of these lesions areiscovered antenatally. Clinical features at presentationay include abdominal distension, vomiting, hepatomegaly,

ongestive heart failure, anaemia, thrombocytopenia andonsumptive coagulopathy and occasionally skin haeman-iomata. Thyroid hormone catabolism by the tumouran cause clinical hypothyroidism [7]. Jaundice may beresent if there is biliary obstruction or due to the pres-nce of arteriovenous or portohepatic shunts inside theumour.

Histologic studies suggest that two different histologicubtypes can be distinguished. Type 1 is an orderly pro-iferation of small blood vessels lined by a single layer oflump endotheial cells. This type is histologically benign,ith a pattern identical to that of the cutaneous haeman-iomas, whereas type 2 haemangioendothelioma is moreggressive in appearance with irregular budding and branch-ng structures, larger endothelial cells, and mitotic figures,onsidered histologically equivalent to angiosarcoma withore uncertain long-term prognosis [8].Medical treatment options include corticosteroids, vin-

ristine, and propranolol (2 mg/kg/d), which has recentlyecome the first-line treatment [7]. Treatment withnterferon-alpha seems to have become obsolete due toeported development of spastic diplegia in some of thereated infants [9].

ocal nodular hyperplasia, nodularegenerative hyperplasia and hepatocellulardenomas

NH and hepatocellular adenoma (HCA) are extremely rareuring childhood. FNH is considered to be an unspecifiedyperplastic reaction to different vascular abnormalities.n histology, there is a nodular proliferation of normally dif-

erentiated hepatocytes around a central fibrovascular scar.ile ductular reaction is usually present at the interfaceetween hepatocytes and fibrous bands, which facilitates

oplasms in children: A focus on differential diagnosis. Clinj.clinre.2014.05.001

istinction from HCA.One third of children with FNH show symptoms. Two-

hirds of the patients with tumours larger than 7 cm areymptomatic. The most frequent symptom is abdominal

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Table 2 Staging of hepatoblastoma [28].

Staging Description

Stage I One section involvedThree adjoining sections are tumor free

Stage II One or two sections involvedTwo adjoining sections are tumor free

Stage III Two or three sections involvedOne adjoining section is tumor free

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ARTICLECLINRE-599; No. of Pages 4

Hepatic neoplasms in children: A focus on differential diagn

pain. Less commonly, weight loss and weakness can beobserved, mainly with large tumours [10].

The real cause of FNH is still unknown; some theories sug-gest it could be a reactive hyperplasia after hepatocellularinjury, as FNH can be associated with some predisposing fac-tors (chemotherapy, radiation therapy) in children treatedfor malignancy. In the patients without such predisposingfactors, underlying vascular anomalies are the preferredtheory, including vascularisation mismatch relative to adja-cent tissue, local venous or arterial thrombosis. In support ofthe vascular hypothesis, FNH has been described in patientswith congenital or surgical portosystemic shunts [10]. Thenatural history of these tumours is poorly understood in chil-dren, but appears to span from spontaneous involution toongoing growth.

The management of FNH ranges from expectant approachby careful monitoring to hepatic resection. In the patientswith abdominal pain, surgical resection could offer a symp-tomatic relief. Another indication for the surgery is changein radiological appearances during follow-up. The stationaryand symptom-free FNH can safely be managed conserva-tively [11,12].

Nodular regenerative hyperplasia (NRH) is a benign pro-liferative lesion characterized by diffuse involvement of theliver with nodules composed of hyperplastic hepatocytes.Clinically, NRH usually causes no symptoms and is dis-covered incidentally. Macroscopically, NRH is characterizedby multiple bulging regenerative nodules in clusters withdiameter from 0.1 to 4 cm. Histologic examination revealsregeneration of hepatocytes with multinucleated, thickenedhepatocytes with centrilobular atrophy. The pathogenesis ofNRH is poorly understood, but primary vascular process maylead to obliteration of portal vein, inducing ischemia andatrophy in the central zone, and subsequent proliferation ofhepatocytes. As imaging findings are not specific, histologicexamination is often warranted. Management depends onthe clinical symptoms; in asymptomatic patients no treat-ment is recommended [13].

It is a differential diagnostic challenge to distinguish FNH,NRH and HCAs. All three occur in otherwise normal liverparenchyma, but FNH is a polyclonal neoplasm presumablyresulting from hyperplastic response to altered blood sup-ply, while HCAs are monoclonal neoplasms [14]. Liver biopsyis sometimes necessary for diagnosis and novel immuno-histochemical techniques [15] could differentiate the HCAsubtypes such as:

• hepatocyte nuclear factor 1� (HNF1a) inactivated (H-HCA);

• inflammatory (IHCA);• B-catenin activated (B-HCA) [14]. In H-HCA complete

absence of liver fatty acid-binding protein (LFABP) stain-ing can be observed. In IHCA immunohistochemistrydemonstrates strong expression of serum amyloid-A andCRP restricted to neoplastic hepatocytes. IHCA combinedwith a beta-catenin mutation has a risk of malignanttransformation. B-HCA is often associated with glyco-gen storage disease and has a higher risk of malignant

Please cite this article in press as: Dezsofi A, et al. Hepatic neoRes Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/

transformation than H-HCA. On immunohistochemistry ofB-HCA, glutamine synthetase is usually strongly expressedin a diffuse pattern, associated with aberrant cytoplasmicand nuclear expression of beta-catenin [15].

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Stage IV Four sections involved

utcome of malignant liver tumours

he outcome of the two most common malignant hepaticumours (HBL and HCC) has improved in the past twoecades due to the multicentre collaborative trials investi-ating new diagnostic and treatment strategies. The stagingf HBL is based on resectability, size, histology and AFP levelTable 2) [16].

Patients need to be referred to a specialized centreor diagnosis and management of serious complicationsncluding pleural effusion, pulmonary atelectasis, ascites,ntraperitoneal haemorrhage, biliary leakage, and infection17].

Any chronic liver condition can increase risk for malignantransformation, possibly due to increased cellular turnover.he disturbance in metabolic role of the liver explainshe occurrence of HCCs in several metabolic (tyrosinemiaype 1, some glycogen storage diseases, mitochondrial hep-topathy) and cholestatic diseases (BSEP deficiency, Alagilleyndrome, biliary atresia, total parenteral nutrition) [9].

In most cases complete resection of the tumor can bechieved with a partial hepatectomy. There is an increas-ng role for liver transplantation (LTx) in management ofrimary malignant tumours (SIOPEL 1 study). Total hepa-ectomy with LTx is the best treatment option for HBLshat remain unresectable after chemotherapy, for multi-ocal HBLs invading all four sectors of the liver and forentral tumours with close proximity to the major hepaticlood vessels [18,19]. Although HCC is a more aggressiveumour with a higher rate of recurrence and poor responseo chemotherapy, LTx was reported potentially curative inhildren, according to the retrospective cohort study usinghe SEER registry [20]. LTx could potentially improve survivalf children with HCC and this option needs to be carefullyonsidered [21—24]. Much depends on if HCC is incidentaln situ finding or a primary diagnosis.

There is some evidence to suggest that pre-operativeiagnosis of the hepatic lesion by needle biopsy may be asso-iated with risk of dissemination. Therefore, biopsy shoulde limited to radiologically equivocal cases where histologyould change management, such as for atypical forms of HBL25].

onclusions

plasms in children: A focus on differential diagnosis. Clinj.clinre.2014.05.001

he increased use of abdominal ultrasonography may leado more frequent detection of asymptomatic liver lesions,istressing patients and their families due to a fear of

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ARTICLELINRE-599; No. of Pages 4

alignant disease [26]. The diagnosis and treatment of aiver mass is challenging and must be individualized. Inight of new advances in diagnostic radiology and moleculariology there are better chances that potential malignantvolution will be recognized and those patients who needore aggressive management identified earlier [27].

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

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