+Model CLINRE-599; No. of Pages 4
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Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
Hepatic neoplasms in children: A focus on differential diagnosis Antal Dezs˝ ofi a,∗, Valerie McLin b, Nedim Hadzic c a
First Department of Paediatrics, Semmelweis University, Bókay János utca 53, 1083 Budapest, Hungary Swiss Center for Liver Disease in Children, University Hospital of Geneva, Geneva, Switzerland c Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, London, UK b
Summary Paediatric hepatic neoplasias are rare, accounting for 1—4% of all solid childhood tumors. Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation. Two-thirds of liver tumors in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, and hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a paediatric liver tumour guides the treatment and prognosis. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction
Abbreviations: AFP, Alfa-fetoprotein; BSEP, Bile salt export pump; CT, Computer tomography; DIC, Disseminated intravascular coagulation; FNH, Focal nodular hyperplasia; HBL, Hepatoblastoma; HCA, Hepatocellular adenoma; HCC, Hepatocellular carcinoma; HNF1a, Hepatocyte nuclear factor 1␣; IHE, Infantile haemangioendothelioma; LFABP, Liver fatty acid-binding protein; LTx, Liver transplantation; MRI, Magnetic resonance imaging; NRH, Nodular regenerative hyperplasia; SEER, Surveillance, Epidemiology, and End Results; SIOPEL, International Childhood Liver Tumours Strategy Group; US, Ultrasonography. ∗ Corresponding author. Tel.: +36302600281. E-mail address: dezsofi[email protected] (A. Dezs˝ ofi).
Pathologic masses of the liver in children constitute about 5—6% of all intra-abdominal masses and 1—2% of all paediatric tumours. Two-thirds of such masses are malignant, emphasizing the importance of systematic approach to children with a liver mass. The differential diagnostic pathway includes a stepwise approach involving the age and gender of patient, clinical presentation, underlying liver disease, serum alfa-fetoprotein (␣FP) level and imaging characteristics [1,2].
Symptoms Most children with liver masses present with abdominal distension and a palpable abdominal tumour. On occasion,
http://dx.doi.org/10.1016/j.clinre.2014.05.001 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
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the patients are asymptomatic and the mass is discovered incidentally. Chronic fatigue due to anaemia and lack of appetite are often reported. Occasionally, severe symptoms and complications such as pain, biliary obstruction, inferior vena cava obstruction, dyspnea, feeding intolerance, sudden intra-abdominal haemorrhage due to ruptured tumour, high output heart failure, disseminated intravascular coagulation (DIC) and sepsis can occur.
Diagnostic approach Liver tumours identified in children include primary benign and malignant neoplasms, inflammatory masses, cysts and metastatic lesions (Table 1). The most common malignant tumours are hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Infantile haemangioendothelioma (IHE) and focal nodular hyperplasia (FNH) are also seen in children [2]. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ. In addition to patient age, characteristic symptoms and serum AFP level, different imaging techniques are critical to delineate the appearances and spread of the tumour, and guide follow-up after treatment. Standard diagnostic techniques are ultrasonography (US) and magnetic resonance imaging (MRI), but contrast computerised tomography (CT) is still the most informative technique at presentation. US is the recommended technique for follow-up. A recent study suggests that contrast enhanced ultrasound (CEUS) is safe and useful in demonstrating the benign nature of focal liver
Table 1
Benign and malignant liver masses.
Benign Infantile haemangioendothelioma (IHE) Mesenchymal hamartoma Focal nodular hyperplasia (FNH) Hepatocellular adenoma Nodular regenerative hyperplasia Primary hepatic teratoma Others: non-neoplastic cystic masses: including biliary, simple, parasitic, pyogenic and amebic hepatic cysts and abscess Haematomas Lymphangioma Infarction Cystadenoma (biliary duct cell in origin) Vascular malformations Polyarteritis nodosa Granuloma Malignant Hepatoblastoma Hepatocellular carcinoma Embryonal sarcoma (undifferentiated) Epitheloid haemangioendothelioma Angiosarcoma Embryonal rhabdomyosarcoma Metastatic lesions
lesions that are indeterminate on grey-scale sonography in children, potentially reducing the use of CT and MR imaging [3]. CT and MRI are instrumental in evaluating intra- and extra-hepatic extent of disease. Positron-emission tomography (PET) CT offers a greater sensitivity for residual and relapsed disease and may facilitate surgery [4]. T1/T2-weigthted MRI can further improve diagnosis by defining features such as density, vascularity, stromal component and intra-lesional necrosis and haemorrhage [5]. On average, diagnosis is possible on radiological findings alone in 58% of cases, while in remainder histology is necessary [6].
Infantile haemangioendothelioma Infantile hepatic haemangioendothelioma is the most common benign liver tumour in children with a peak presentation between 3—6 months of age. Many of these lesions are discovered antenatally. Clinical features at presentation may include abdominal distension, vomiting, hepatomegaly, congestive heart failure, anaemia, thrombocytopenia and consumptive coagulopathy and occasionally skin haemangiomata. Thyroid hormone catabolism by the tumour can cause clinical hypothyroidism [7]. Jaundice may be present if there is biliary obstruction or due to the presence of arteriovenous or portohepatic shunts inside the tumour. Histologic studies suggest that two different histologic subtypes can be distinguished. Type 1 is an orderly proliferation of small blood vessels lined by a single layer of plump endotheial cells. This type is histologically benign, with a pattern identical to that of the cutaneous haemangiomas, whereas type 2 haemangioendothelioma is more aggressive in appearance with irregular budding and branching structures, larger endothelial cells, and mitotic figures, considered histologically equivalent to angiosarcoma with more uncertain long-term prognosis [8]. Medical treatment options include corticosteroids, vincristine, and propranolol (2 mg/kg/d), which has recently become the first-line treatment [7]. Treatment with interferon-alpha seems to have become obsolete due to reported development of spastic diplegia in some of the treated infants [9].
Focal nodular hyperplasia, nodular regenerative hyperplasia and hepatocellular adenomas FNH and hepatocellular adenoma (HCA) are extremely rare during childhood. FNH is considered to be an unspecified hyperplastic reaction to different vascular abnormalities. On histology, there is a nodular proliferation of normally differentiated hepatocytes around a central fibrovascular scar. Bile ductular reaction is usually present at the interface between hepatocytes and fibrous bands, which facilitates distinction from HCA. One third of children with FNH show symptoms. Twothirds of the patients with tumours larger than 7 cm are symptomatic. The most frequent symptom is abdominal
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
+Model CLINRE-599; No. of Pages 4
ARTICLE IN PRESS
Hepatic neoplasms in children: A focus on differential diagnosis pain. Less commonly, weight loss and weakness can be observed, mainly with large tumours [10]. The real cause of FNH is still unknown; some theories suggest it could be a reactive hyperplasia after hepatocellular injury, as FNH can be associated with some predisposing factors (chemotherapy, radiation therapy) in children treated for malignancy. In the patients without such predisposing factors, underlying vascular anomalies are the preferred theory, including vascularisation mismatch relative to adjacent tissue, local venous or arterial thrombosis. In support of the vascular hypothesis, FNH has been described in patients with congenital or surgical portosystemic shunts [10]. The natural history of these tumours is poorly understood in children, but appears to span from spontaneous involution to ongoing growth. The management of FNH ranges from expectant approach by careful monitoring to hepatic resection. In the patients with abdominal pain, surgical resection could offer a symptomatic relief. Another indication for the surgery is change in radiological appearances during follow-up. The stationary and symptom-free FNH can safely be managed conservatively [11,12]. Nodular regenerative hyperplasia (NRH) is a benign proliferative lesion characterized by diffuse involvement of the liver with nodules composed of hyperplastic hepatocytes. Clinically, NRH usually causes no symptoms and is discovered incidentally. Macroscopically, NRH is characterized by multiple bulging regenerative nodules in clusters with diameter from 0.1 to 4 cm. Histologic examination reveals regeneration of hepatocytes with multinucleated, thickened hepatocytes with centrilobular atrophy. The pathogenesis of NRH is poorly understood, but primary vascular process may lead to obliteration of portal vein, inducing ischemia and atrophy in the central zone, and subsequent proliferation of hepatocytes. As imaging findings are not specific, histologic examination is often warranted. Management depends on the clinical symptoms; in asymptomatic patients no treatment is recommended [13]. It is a differential diagnostic challenge to distinguish FNH, NRH and HCAs. All three occur in otherwise normal liver parenchyma, but FNH is a polyclonal neoplasm presumably resulting from hyperplastic response to altered blood supply, while HCAs are monoclonal neoplasms [14]. Liver biopsy is sometimes necessary for diagnosis and novel immunohistochemical techniques [15] could differentiate the HCA subtypes such as: • hepatocyte nuclear factor 1␣ (HNF1a) inactivated (HHCA); • inflammatory (IHCA); • B-catenin activated (B-HCA) [14]. In H-HCA complete absence of liver fatty acid-binding protein (LFABP) staining can be observed. In IHCA immunohistochemistry demonstrates strong expression of serum amyloid-A and CRP restricted to neoplastic hepatocytes. IHCA combined with a beta-catenin mutation has a risk of malignant transformation. B-HCA is often associated with glycogen storage disease and has a higher risk of malignant transformation than H-HCA. On immunohistochemistry of B-HCA, glutamine synthetase is usually strongly expressed in a diffuse pattern, associated with aberrant cytoplasmic and nuclear expression of beta-catenin [15].
3 Table 2
Staging of hepatoblastoma [28].
Staging
Description
Stage I
One section involved Three adjoining sections are tumor free One or two sections involved Two adjoining sections are tumor free Two or three sections involved One adjoining section is tumor free Four sections involved
Stage II Stage III Stage IV
Outcome of malignant liver tumours The outcome of the two most common malignant hepatic tumours (HBL and HCC) has improved in the past two decades due to the multicentre collaborative trials investigating new diagnostic and treatment strategies. The staging of HBL is based on resectability, size, histology and AFP level (Table 2) [16]. Patients need to be referred to a specialized centre for diagnosis and management of serious complications including pleural effusion, pulmonary atelectasis, ascites, intraperitoneal haemorrhage, biliary leakage, and infection [17]. Any chronic liver condition can increase risk for malignant transformation, possibly due to increased cellular turnover. The disturbance in metabolic role of the liver explains the occurrence of HCCs in several metabolic (tyrosinemia type 1, some glycogen storage diseases, mitochondrial hepatopathy) and cholestatic diseases (BSEP deficiency, Alagille syndrome, biliary atresia, total parenteral nutrition) [9]. In most cases complete resection of the tumor can be achieved with a partial hepatectomy. There is an increasing role for liver transplantation (LTx) in management of primary malignant tumours (SIOPEL 1 study). Total hepatectomy with LTx is the best treatment option for HBLs that remain unresectable after chemotherapy, for multifocal HBLs invading all four sectors of the liver and for central tumours with close proximity to the major hepatic blood vessels [18,19]. Although HCC is a more aggressive tumour with a higher rate of recurrence and poor response to chemotherapy, LTx was reported potentially curative in children, according to the retrospective cohort study using the SEER registry [20]. LTx could potentially improve survival of children with HCC and this option needs to be carefully considered [21—24]. Much depends on if HCC is incidental in situ finding or a primary diagnosis. There is some evidence to suggest that pre-operative diagnosis of the hepatic lesion by needle biopsy may be associated with risk of dissemination. Therefore, biopsy should be limited to radiologically equivocal cases where histology could change management, such as for atypical forms of HBL [25].
Conclusions The increased use of abdominal ultrasonography may lead to more frequent detection of asymptomatic liver lesions, distressing patients and their families due to a fear of
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
+Model CLINRE-599; No. of Pages 4
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malignant disease [26]. The diagnosis and treatment of a liver mass is challenging and must be individualized. In light of new advances in diagnostic radiology and molecular biology there are better chances that potential malignant evolution will be recognized and those patients who need more aggressive management identified earlier [27].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Jha P, Chawla SC, Tavri S, Patel C, Gooding C, Daldrup-Link H. Pediatric liver tumors — a pictorial review. Eur Radiol 2009;19:209—19. [2] Meyers RL. Tumors of the liver in children. Surg Oncol 2007;16:195—203. [3] Jacob J, Deganello A, Sellars ME, Hadzic N, Sidhu PS. Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice. Ultraschall Med 2013;34:529—40. [4] Das CJ, Dhingra S, Gupta AK, Iyer V, Agarwala S. Imaging of paediatric liver tumours with pathological correlation. Clin Radiol 2009;64:1015—25. [5] Bartolozzi C, Cioni D, Donati F, Lencioni R. Focal liver lesions: MR imaging-pathologic correlation. Eur Radiol 2001;11:1374—88. [6] Kochin IN, Miloh TA, Arnon R, Iyer KR, Suchy FJ, Kerkar N. Benign liver masses and lesions in children: 53 cases over 12 years. Isr Med Assoc J 2011;13:542—7. [7] Avagyan S, Klein M, Kerkar N, Demattia A, Blei F, Lee S, et al. Propranolol as a first-line treatment for diffuse infantile hepatic hemangioendothelioma. J Pediatr Gastroenterol Nutr 2013;56:e17—20. [8] Ackermann O, Fabre M, Franchi S, Pariente D, Debray D, Jacquemin E, Gauthier F, et al. Widening spectrum of liver angiosarcoma in children. J Pediatr Gastroenterol Nutr 2011;53:615—9. [9] Hadzic N, Finegold MJ. Liver neoplasia in children. Clin Liver Dis 2011;15:443—62. [10] Franchi-Abella S, Branchereau S. Benign hepatocellular tumors in children: focal nodular hyperplasia and hepatocellular adenoma. Int J Hepatol 2013:215064. [11] Navarro AP, Gomez D, Lamb CM, Brooks A, Cameron IC. Focal nodular hyperplasia: a review of current indications for and outcomes of hepatic resection. HPB (Oxford) 2013, http://dx.doi.org/10.1111/hpb.12169.
[12] Bonney GK, Gomez D, Al-Mukhtar A, Toogood GJ, Lodge JP, Prasad R. Indication for treatment and long-term outcome of focal nodular hyperplasia. HPB (Oxford) 2007;9:368—72. [13] Choi BY, Nguyen MH. The diagnosis and management of benign hepatic tumors. J Clin Gastroenterol 2005;39:401—12. [14] van Aalten SM, de Man RA, Jn IJ, Terkivatan T. Systematic review of haemorrhage and rupture of hepatocellular adenomas. Br J Surg 2012;99:911—6. [15] Balabaud C, Al-Rabih WR, Chen PJ, Evason K, Ferrell L, Hernandez-Prera JC, Huang SF, et al. Focal nodular hyperplasia and hepatocellular adenoma around the world viewed through the scope of the immunopathological classification. Int J Hepatol 2013:268625, http://dx.doi.org/10.1155/2013/268625. [16] Hiyama E. Current therapeutic strategies for childhood hepatic malignant tumors. Int J Clin Oncol 2013;18:943—5. [17] Jin S, Fu Q, Wuyun G, Wuyun T. Management of postcomplications. World J Gastroenterol hepatectomy 2013;19:7983—91. [18] Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant 2005;9:557—65. [19] Otte JB, Meyers RL, de Ville de Goyet J. Transplantation for liver tumors in children: time to (re)set the guidelines? Pediatr Transplant 2013;17:710—2. [20] McAteer JP, Goldin AB, Healey PJ, Gow KW. Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 2013;17:744—50. [21] Czauderna P, Mackinlay G, Perilongo G, Brown J, Shafford E, Aronson D, et al. Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 2002;20:2798—804. [22] Yu SB, Kim HY, Eo H, Won JK, Jung SE, Park KW, et al. Clinical characteristics and prognosis of pediatric hepatocellular carcinoma. World J Surg 2006;30:43—50. [23] Pham TH, Iqbal CW, Grams JM, Zarroug AE, Wall JC, Ishitani MB, et al. Outcomes of primary liver cancer in children: an appraisal of experience. J Pediatr Surg 2007;42:834—9. [24] Ismail H, Broniszczak D, Kalicinski P, Markiewicz-Kijewska M, Teisseyre J, Stefanowicz M, et al. Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients? Pediatr Transplant 2009;13:682—92. [25] Cho SW, Marsh JW, Steel J, Holloway SE, Heckman JT, Ochoa ER, et al. Surgical management of hepatocellular adenoma: take it or leave it? Ann Surg Oncol 2008;15:2795—803. [26] Graziadei I. Overview: liver tumors. Wien Med Wochenschr 2013;163:109—12. [27] Szor DJ, Ursoline M, Herman P. Hepatic adenoma. Arq Bras Cir Dig 2013;26:219—22. [28] Emre S, Umman V, Rodriguez-Davalos M. Current concepts in pediatric liver tumors. Pediatr Transplant 2012;16:549—63.
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
Hepatic neoplasms in children: A focus on differential diagnosis Antal Dezs˝ ofi a,∗, Valerie McLin b, Nedim Hadzic c a
First Department of Paediatrics, Semmelweis University, Bókay János utca 53, 1083 Budapest, Hungary Swiss Center for Liver Disease in Children, University Hospital of Geneva, Geneva, Switzerland c Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, London, UK b
Summary Paediatric hepatic neoplasias are rare, accounting for 1—4% of all solid childhood tumors. Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation. Two-thirds of liver tumors in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, and hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a paediatric liver tumour guides the treatment and prognosis. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction
Abbreviations: AFP, Alfa-fetoprotein; BSEP, Bile salt export pump; CT, Computer tomography; DIC, Disseminated intravascular coagulation; FNH, Focal nodular hyperplasia; HBL, Hepatoblastoma; HCA, Hepatocellular adenoma; HCC, Hepatocellular carcinoma; HNF1a, Hepatocyte nuclear factor 1␣; IHE, Infantile haemangioendothelioma; LFABP, Liver fatty acid-binding protein; LTx, Liver transplantation; MRI, Magnetic resonance imaging; NRH, Nodular regenerative hyperplasia; SEER, Surveillance, Epidemiology, and End Results; SIOPEL, International Childhood Liver Tumours Strategy Group; US, Ultrasonography. ∗ Corresponding author. Tel.: +36302600281. E-mail address: dezsofi[email protected] (A. Dezs˝ ofi).
Pathologic masses of the liver in children constitute about 5—6% of all intra-abdominal masses and 1—2% of all paediatric tumours. Two-thirds of such masses are malignant, emphasizing the importance of systematic approach to children with a liver mass. The differential diagnostic pathway includes a stepwise approach involving the age and gender of patient, clinical presentation, underlying liver disease, serum alfa-fetoprotein (␣FP) level and imaging characteristics [1,2].
Symptoms Most children with liver masses present with abdominal distension and a palpable abdominal tumour. On occasion,
http://dx.doi.org/10.1016/j.clinre.2014.05.001 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
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the patients are asymptomatic and the mass is discovered incidentally. Chronic fatigue due to anaemia and lack of appetite are often reported. Occasionally, severe symptoms and complications such as pain, biliary obstruction, inferior vena cava obstruction, dyspnea, feeding intolerance, sudden intra-abdominal haemorrhage due to ruptured tumour, high output heart failure, disseminated intravascular coagulation (DIC) and sepsis can occur.
Diagnostic approach Liver tumours identified in children include primary benign and malignant neoplasms, inflammatory masses, cysts and metastatic lesions (Table 1). The most common malignant tumours are hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Infantile haemangioendothelioma (IHE) and focal nodular hyperplasia (FNH) are also seen in children [2]. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ. In addition to patient age, characteristic symptoms and serum AFP level, different imaging techniques are critical to delineate the appearances and spread of the tumour, and guide follow-up after treatment. Standard diagnostic techniques are ultrasonography (US) and magnetic resonance imaging (MRI), but contrast computerised tomography (CT) is still the most informative technique at presentation. US is the recommended technique for follow-up. A recent study suggests that contrast enhanced ultrasound (CEUS) is safe and useful in demonstrating the benign nature of focal liver
Table 1
Benign and malignant liver masses.
Benign Infantile haemangioendothelioma (IHE) Mesenchymal hamartoma Focal nodular hyperplasia (FNH) Hepatocellular adenoma Nodular regenerative hyperplasia Primary hepatic teratoma Others: non-neoplastic cystic masses: including biliary, simple, parasitic, pyogenic and amebic hepatic cysts and abscess Haematomas Lymphangioma Infarction Cystadenoma (biliary duct cell in origin) Vascular malformations Polyarteritis nodosa Granuloma Malignant Hepatoblastoma Hepatocellular carcinoma Embryonal sarcoma (undifferentiated) Epitheloid haemangioendothelioma Angiosarcoma Embryonal rhabdomyosarcoma Metastatic lesions
lesions that are indeterminate on grey-scale sonography in children, potentially reducing the use of CT and MR imaging [3]. CT and MRI are instrumental in evaluating intra- and extra-hepatic extent of disease. Positron-emission tomography (PET) CT offers a greater sensitivity for residual and relapsed disease and may facilitate surgery [4]. T1/T2-weigthted MRI can further improve diagnosis by defining features such as density, vascularity, stromal component and intra-lesional necrosis and haemorrhage [5]. On average, diagnosis is possible on radiological findings alone in 58% of cases, while in remainder histology is necessary [6].
Infantile haemangioendothelioma Infantile hepatic haemangioendothelioma is the most common benign liver tumour in children with a peak presentation between 3—6 months of age. Many of these lesions are discovered antenatally. Clinical features at presentation may include abdominal distension, vomiting, hepatomegaly, congestive heart failure, anaemia, thrombocytopenia and consumptive coagulopathy and occasionally skin haemangiomata. Thyroid hormone catabolism by the tumour can cause clinical hypothyroidism [7]. Jaundice may be present if there is biliary obstruction or due to the presence of arteriovenous or portohepatic shunts inside the tumour. Histologic studies suggest that two different histologic subtypes can be distinguished. Type 1 is an orderly proliferation of small blood vessels lined by a single layer of plump endotheial cells. This type is histologically benign, with a pattern identical to that of the cutaneous haemangiomas, whereas type 2 haemangioendothelioma is more aggressive in appearance with irregular budding and branching structures, larger endothelial cells, and mitotic figures, considered histologically equivalent to angiosarcoma with more uncertain long-term prognosis [8]. Medical treatment options include corticosteroids, vincristine, and propranolol (2 mg/kg/d), which has recently become the first-line treatment [7]. Treatment with interferon-alpha seems to have become obsolete due to reported development of spastic diplegia in some of the treated infants [9].
Focal nodular hyperplasia, nodular regenerative hyperplasia and hepatocellular adenomas FNH and hepatocellular adenoma (HCA) are extremely rare during childhood. FNH is considered to be an unspecified hyperplastic reaction to different vascular abnormalities. On histology, there is a nodular proliferation of normally differentiated hepatocytes around a central fibrovascular scar. Bile ductular reaction is usually present at the interface between hepatocytes and fibrous bands, which facilitates distinction from HCA. One third of children with FNH show symptoms. Twothirds of the patients with tumours larger than 7 cm are symptomatic. The most frequent symptom is abdominal
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
+Model CLINRE-599; No. of Pages 4
ARTICLE IN PRESS
Hepatic neoplasms in children: A focus on differential diagnosis pain. Less commonly, weight loss and weakness can be observed, mainly with large tumours [10]. The real cause of FNH is still unknown; some theories suggest it could be a reactive hyperplasia after hepatocellular injury, as FNH can be associated with some predisposing factors (chemotherapy, radiation therapy) in children treated for malignancy. In the patients without such predisposing factors, underlying vascular anomalies are the preferred theory, including vascularisation mismatch relative to adjacent tissue, local venous or arterial thrombosis. In support of the vascular hypothesis, FNH has been described in patients with congenital or surgical portosystemic shunts [10]. The natural history of these tumours is poorly understood in children, but appears to span from spontaneous involution to ongoing growth. The management of FNH ranges from expectant approach by careful monitoring to hepatic resection. In the patients with abdominal pain, surgical resection could offer a symptomatic relief. Another indication for the surgery is change in radiological appearances during follow-up. The stationary and symptom-free FNH can safely be managed conservatively [11,12]. Nodular regenerative hyperplasia (NRH) is a benign proliferative lesion characterized by diffuse involvement of the liver with nodules composed of hyperplastic hepatocytes. Clinically, NRH usually causes no symptoms and is discovered incidentally. Macroscopically, NRH is characterized by multiple bulging regenerative nodules in clusters with diameter from 0.1 to 4 cm. Histologic examination reveals regeneration of hepatocytes with multinucleated, thickened hepatocytes with centrilobular atrophy. The pathogenesis of NRH is poorly understood, but primary vascular process may lead to obliteration of portal vein, inducing ischemia and atrophy in the central zone, and subsequent proliferation of hepatocytes. As imaging findings are not specific, histologic examination is often warranted. Management depends on the clinical symptoms; in asymptomatic patients no treatment is recommended [13]. It is a differential diagnostic challenge to distinguish FNH, NRH and HCAs. All three occur in otherwise normal liver parenchyma, but FNH is a polyclonal neoplasm presumably resulting from hyperplastic response to altered blood supply, while HCAs are monoclonal neoplasms [14]. Liver biopsy is sometimes necessary for diagnosis and novel immunohistochemical techniques [15] could differentiate the HCA subtypes such as: • hepatocyte nuclear factor 1␣ (HNF1a) inactivated (HHCA); • inflammatory (IHCA); • B-catenin activated (B-HCA) [14]. In H-HCA complete absence of liver fatty acid-binding protein (LFABP) staining can be observed. In IHCA immunohistochemistry demonstrates strong expression of serum amyloid-A and CRP restricted to neoplastic hepatocytes. IHCA combined with a beta-catenin mutation has a risk of malignant transformation. B-HCA is often associated with glycogen storage disease and has a higher risk of malignant transformation than H-HCA. On immunohistochemistry of B-HCA, glutamine synthetase is usually strongly expressed in a diffuse pattern, associated with aberrant cytoplasmic and nuclear expression of beta-catenin [15].
3 Table 2
Staging of hepatoblastoma [28].
Staging
Description
Stage I
One section involved Three adjoining sections are tumor free One or two sections involved Two adjoining sections are tumor free Two or three sections involved One adjoining section is tumor free Four sections involved
Stage II Stage III Stage IV
Outcome of malignant liver tumours The outcome of the two most common malignant hepatic tumours (HBL and HCC) has improved in the past two decades due to the multicentre collaborative trials investigating new diagnostic and treatment strategies. The staging of HBL is based on resectability, size, histology and AFP level (Table 2) [16]. Patients need to be referred to a specialized centre for diagnosis and management of serious complications including pleural effusion, pulmonary atelectasis, ascites, intraperitoneal haemorrhage, biliary leakage, and infection [17]. Any chronic liver condition can increase risk for malignant transformation, possibly due to increased cellular turnover. The disturbance in metabolic role of the liver explains the occurrence of HCCs in several metabolic (tyrosinemia type 1, some glycogen storage diseases, mitochondrial hepatopathy) and cholestatic diseases (BSEP deficiency, Alagille syndrome, biliary atresia, total parenteral nutrition) [9]. In most cases complete resection of the tumor can be achieved with a partial hepatectomy. There is an increasing role for liver transplantation (LTx) in management of primary malignant tumours (SIOPEL 1 study). Total hepatectomy with LTx is the best treatment option for HBLs that remain unresectable after chemotherapy, for multifocal HBLs invading all four sectors of the liver and for central tumours with close proximity to the major hepatic blood vessels [18,19]. Although HCC is a more aggressive tumour with a higher rate of recurrence and poor response to chemotherapy, LTx was reported potentially curative in children, according to the retrospective cohort study using the SEER registry [20]. LTx could potentially improve survival of children with HCC and this option needs to be carefully considered [21—24]. Much depends on if HCC is incidental in situ finding or a primary diagnosis. There is some evidence to suggest that pre-operative diagnosis of the hepatic lesion by needle biopsy may be associated with risk of dissemination. Therefore, biopsy should be limited to radiologically equivocal cases where histology could change management, such as for atypical forms of HBL [25].
Conclusions The increased use of abdominal ultrasonography may lead to more frequent detection of asymptomatic liver lesions, distressing patients and their families due to a fear of
Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
+Model CLINRE-599; No. of Pages 4
ARTICLE IN PRESS
4
A. Dezs˝ ofi et al.
malignant disease [26]. The diagnosis and treatment of a liver mass is challenging and must be individualized. In light of new advances in diagnostic radiology and molecular biology there are better chances that potential malignant evolution will be recognized and those patients who need more aggressive management identified earlier [27].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Dezs˝ ofi A, et al. Hepatic neoplasms in children: A focus on differential diagnosis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.05.001
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