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Adult hepatoblastoma: Learning from children

Open AccessPublished:February 13, 2012DOI:https://doi.org/10.1016/j.jhep.2011.10.028

      Summary

      Hepatoblastoma is the most common malignant liver tumour in infants and young children. Its occurrence in the adult population is debated and has been questioned. The aim of this paper is to review the histological and clinical features of adult hepatoblastoma as described in the adult literature, and to compare the findings with those of paediatric hepatoblastoma. The developmental and molecular aspects of hepatoblastoma are reviewed and their potential contribution to diagnosis of adult hepatoblastoma discussed.
      Case reports of adult hepatoblastoma identified by a PubMed search of the English, French, German, Italian, and Spanish literature through March 2011 were reviewed.
      Forty-five cases of hepatoblastoma were collected. Age at presentation was variable. Survival was uniformly poor, except for the rare patients who presented with the relatively differentiated, foetal type. The common denominator between adult and paediatric cases is the occurrence of embryonal or immature aspect of the tumours. Whether the adult cases of hepatoblastoma represent blastemal tumours, stem cell tumours, or unusual differentiation patterns in otherwise more frequent adult liver tumours remains to be established. Adult tumours labelled as hepatoblastoma are characterised by malignant appearing mesenchymal components. Surgical management is the cornerstone of therapy in children and also appears to confer an improved prognosis in adults.
      Whether adult hepatoblastoma exists, remains controversial. Indeed, several features described in adult cases are markedly different from hepatoblastoma as it is understood in children, and other differential diagnoses should also be entertained. Nonetheless, hepatoblastoma should be considered in adults presenting with primary liver tumours in the absence of pre-existing liver disease. Adult and paediatric patients with immature hepatoblastoma appear to have worse outcomes, and adults presenting with presumed hepatoblastoma have an overall poorer prognosis than children with hepatoblastoma. In all patients, surgery should be the treatment of choice, neoadjuvant chemotherapy is advisable.

      Abbreviations:

      HB (hepatoblastoma), AFIP (Armed Forces Institute of Pathology), HCC (hepatocellular carcinoma), AFP (alpha-fetoprotein), SIOP (International Society of Paediatric Oncology), PRETEXT (pre-treatment tumour extension), HPF (high power field)

      Keywords

      Introduction

      Hepatoblastoma (HB) accounts for approximately 1% of all paediatric malignancies. Although rare, HB is the most common primary malignant hepatic tumour in children, with an annual incidence of 0.5–1.5 per million in the paediatric population. A majority of cases occur between the ages of 6 months and 3 years [
      • Schnater J.M.
      • Kohler S.E.
      • Lamers W.H.
      • von Schweinitz D.
      • Aronson D.C.
      Where do we stand with hepatoblastoma? A review.
      ,
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. Although HB has been reported in adults, its occurrence in the adult population remains controversial. In the 2001 edition of the Armed Forces Institute of Pathology (AFIP) on Tumours of the Liver and Intrahepatic Bile Ducts, the authors declare that not one adult HB case had been recorded at the AFIP [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. They postulate that the majority or all adult HB cases reported in the literature (approximately 40 at that time) were actually misdiagnosed hepatocellular carcinomas (HCC), combined HCC–cholangiocarcinomas, or carcinosarcomas. Even in paediatric malignant liver cell tumours, clear-cut distinction between HB and HCC may prove difficult, since molecular, histological, and clinical findings often overlap. These features are even more confusing in adults. We discuss the similarities and differences between paediatric and reported adult cases with respect to clinical presentation, treatment, outcome, and pathological findings.
      In addition, we review what is known about the developmental aspects, the molecular characteristics and regulation of the different types of HB, how these relate to progenitor cells, and how these tools might be of use in identifying adult HB. Finally, we review surgical and medical management in children and offer recommendations as to how these should be considered in adults with HB features.

      Materials and methods

      This paper by no means intends to be an exhaustive review of paediatric HB. Instead, we review all 45 adult HB cases identified by a systematic PubMed search of the English, French, German, Italian, and Spanish literature through March 2011. The data were compared and contrasted to internationally recognised HB criteria. Finally, in order to better characterise the outcome of adult HB, survival was assessed according to the Kaplan Meier method and group comparisons were performed using the log-rank test. Standard alpha level of 0.05 indicated statistical significance. Analyses were conducted using SPSS 15.0 (SPSS, Chicago, IL).

      Clinical findings

      Paediatric HB

      Most HB affect children below the age of 3 years, and the median age at diagnosis is 1 year [
      • von Schweinitz D.
      Identification of risk groups in hepatoblastoma – another step in optimising therapy.
      ]. It classically arises within a healthy liver, unaffected by underlying disease. Children typically present with an asymptomatic abdominal mass, and diagnosis is thus often made late, when disease is already metastatic [
      • Fabre M.
      • Yilmaz F.
      • Buendia M.A.
      Hepatic tumors in childhood: experience on 245 tumors and review of literature.
      ]. These tumours most commonly present within the right lobe of the liver [
      • Exelby P.R.
      • Filler R.M.
      • Grosfeld J.L.
      Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey – 1974.
      ]. The lung is the most frequent site for metastasis. Lymph node involvement is rare [
      • Fabre M.
      • Yilmaz F.
      • Buendia M.A.
      Hepatic tumors in childhood: experience on 245 tumors and review of literature.
      ]. On occasion, HB presents with intra-abdominal bleeding secondary to a ruptured liver mass. Approximately 90% of patients have highly elevated serum alpha-fetoprotein (AFP) levels, which is both a sensitive diagnostic marker and a tool to monitor response to therapy [
      • De Ioris M.
      • Brugieres L.
      • Zimmermann A.
      • Keeling J.
      • Brock P.
      • Maibach R.
      • et al.
      Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience.
      ,
      • Sayar D.
      • Yaniv I.
      • Goshen Y.
      • Cohen I.J.
      Treatment of alpha-fetoprotein secreting hepatoblastoma by response of serum alpha-fetoprotein levels: a new concept.
      ]. However, the most poorly differentiated HBs (small cell undifferentiated for instance) often have normal AFP levels and are associated with poorer outcomes [
      • De Ioris M.
      • Brugieres L.
      • Zimmermann A.
      • Keeling J.
      • Brock P.
      • Maibach R.
      • et al.
      Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience.
      ].

      Adult HB

      HB is rare in older children and exceedingly so in adults. The age span of adult patients presenting with presumed HB was 17–78 years (Fig. 1). Since 1958, 45 adult HB cases have been reported in the literature [
      • Bartok I.
      Metastasizing hepatoblastoma in an adult.
      ,
      • Carter R.
      Hepatoblastoma in the adult.
      ,
      • Meyer P.
      • LiVolsi V.
      • Cornog J.L.
      Letter: hepatoblastoma associated with an oral contraceptive.
      ,
      • Baird P.J.
      • McGovern V.J.
      Test and teach Number 7 diagnosis: embryonal hepatoblastoma with malignant epithelial and mesenchymal tissue components occurring in an adult.
      ,
      • Jameson C.P.
      • Chatkadakis C.B.
      Hepatoblastoma in a middle-aged white South African woman. A case report.
      ,
      • Yoshida T.
      • Okazaki N.
      • Yoshino M.
      • Shimamura Y.
      • Miyazawa N.
      • Miyamoto K.
      • et al.
      A case of hepatoblastoma in adult.
      ,
      • Popper H.
      Bidermal hepatoblastoma in an adult (author’s transl).
      ,
      • Honan R.P.
      • Haqqani M.T.
      Mixed hepatoblastoma in the adult: case report and review of the literature.
      ,
      • Babaryka I.
      • von Bouquoy F.
      Hepatoblastoma in adults (author’s transl).
      ,
      • Genova G.
      • Rimi C.
      Hepatoblastoma in adults. Description of a case.
      ,
      • Baroni C.
      • Tognoli S.
      • Spadon S.
      • Astuni M.
      • Lora P.A.
      • Lazzarini G.
      • et al.
      Hemoperitoneum caused by spontaneous rupture of a hepatoblastoma in an adult, with arrest of the hemorrhage by peroperative cryoapplication.
      ,
      • Bhatnagar A.
      • Pathania O.P.
      • Champakam N.S.
      Hepatoblastoma in an adult female.
      ,
      • Diaz-Faes M.
      • Lamamie de Clairac E.
      • Pozo F.
      • Urdiales G.
      • Valverde D.
      • Sampedro A.
      Mixed hepatoblastoma in an adult.
      ,
      • Sugino K.
      • Dohi K.
      • Matsuyama T.
      • Asahara T.
      • Yamamoto M.
      A case of hepatoblastoma occurring in an adult.
      ,
      • Seabrook G.R.
      • Collin J.R.
      • Britton B.J.
      Hepatoblastoma: successful resection in an adult.
      ,
      • Green L.K.
      • Silva E.G.
      Hepatoblastoma in an adult with metastasis to the ovaries.
      ,
      • Slugen I.
      • Fiala P.
      • Pauer M.
      • Majercik M.
      • Ondrias F.
      • Cernak P.
      Mixed hepatoblastoma in the adult: morphological and immunohistochemical findings.
      ,
      • Oda H.
      • Honda K.
      • Hara M.
      • Arase Y.
      • Ikeda K.
      • Kumada H.
      Hepatoblastoma in an 82-year-old man. An autopsy case report.
      ,
      • Altmann H.W.
      Epithelial and mixed hepatoblastoma in the adult. Histological observations and general considerations.
      ,
      • Mondragon Sanchez R.
      • Bernal Maldonado R.
      • Sada Navarro L.A.
      • Hernandez A.I.
      • Hurtado Andrade H.
      • Cortes Espinoza T.
      • et al.
      Epithelial hepatoblastomas in the adult.
      ,
      • Harada T.
      • Matsuo K.
      • Kodama S.
      • Higashihara H.
      • Nakayama Y.
      • Ikeda S.
      Adult hepatoblastoma: case report and review of the literature.
      ,
      • Kacker L.K.
      • Khan E.M.
      • Gupta R.
      • Kapoor V.K.
      • Pandey R.
      • Gupta R.K.
      • et al.
      Hepatoblastoma in an adult with biliary obstruction and associated portal venous thrombosis.
      ,
      • Inoue S.
      • Nagao T.
      • Ishida Y.
      • Wada C.
      • Beck Y.
      • Uchida H.
      • et al.
      Successful resection of a large hepatoblastoma in a young adult: report of a case.
      ,
      • Bortolasi L.
      • Marchiori L.
      • Dal Dosso I.
      • Colombari R.
      • Nicoli N.
      Hepatoblastoma in adult age: a report of two cases.
      ,
      • Kuniyasu H.
      • Yasui W.
      • Shimamoto F.
      • Fujii K.
      • Nakahara M.
      • Asahara T.
      • et al.
      Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance.
      ,
      • Parada L.A.
      • Bardi G.
      • Hallen M.
      • Hagerstrand I.
      • Tranberg K.G.
      • Mitelman F.
      • et al.
      Cytogenetic abnormalities and clonal evolution in an adult hepatoblastoma.
      ,
      • Ahn H.J.
      • Kwon K.W.
      • Choi Y.J.
      • Kim H.J.
      • Hong S.P.
      • Oh D.
      • et al.
      Mixed hepatoblastoma in an adult–a case report and literature review.
      ,
      • Reddy K.S.
      • Karak P.K.
      • Sharma S.
      • Rao R.C.
      • Vijayaraghavan M.
      • Sahni P.
      Epithelial hepatoblastoma in a middle aged woman.
      ,
      • Diotallevi P.
      • Cristofaro M.
      • Broglia L.
      • Carletta C.
      Hepatoblastoma in an HCV-positive adult. Report of a case.
      ,
      • Dumortier J.
      • Bizollon T.
      • Chevallier M.
      • Ducerf C.
      • Baulieux J.
      • Scoazec J.Y.
      • et al.
      Recurrence of hepatocellular carcinoma as a mixed hepatoblastoma after liver transplantation.
      ,
      • Vicente D.
      • Bernabe R.
      • Mazo J.
      • Moreno Nogueira J.A.
      Hepatoblastoma in an adult.
      ,
      • Inagaki M.
      • Yagi T.
      • Urushihara N.
      • Shima Y.
      • Sadamori H.
      • Takakura N.
      • et al.
      Successfully resected hepatoblastoma in a young adult with chronic hepatitis B: report of a case.
      ,
      • Yamazaki M.
      • Ryu M.
      • Okazumi S.
      • Kondo F.
      • Cho A.
      • Okada T.
      • et al.
      Hepatoblastoma in an adult A case report and clinical review of literatures.
      ,
      • Kasper H.U.
      • Longerich T.
      • Stippel D.L.
      • Kern M.A.
      • Drebber U.
      • Schirmacher P.
      Mixed hepatoblastoma in an adult.
      ,
      • Ke H.Y.
      • Chen J.H.
      • Jen Y.M.
      • Yu J.C.
      • Hsieh C.B.
      • Chen C.J.
      • et al.
      Ruptured hepatoblastoma with massive internal bleeding in an adult.
      ,
      • Remes-Troche J.M.
      • Montano-Loza A.
      • Meza-Junco J.
      • Garcia-Leiva J.
      • Torre-Delgadillo A.
      Hepatoblastoma in adult age. A case report and literature review.
      ,
      • Zhang J.
      • Cheng C.
      • He C.L.
      • Zhou Y.J.
      • Cao Y.
      The expression of Bcl-XL, Bcl-XS and p27Kip1 in topotecan-induced apoptosis in hepatoblastoma HepG2 cell line.
      ,
      • Mukhopadhyay P.
      • Kundu S.S.
      • Banerjee A.
      • Mukherjee A.
      Adult hepatoblastoma in a female Down’s.
      ,
      • Masuda T.
      • Beppu T.
      • Horino K.
      • Komori H.
      • Hayashi H.
      • Okabe H.
      • et al.
      Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.
      ,
      • Nakamura S.
      • Sho M.
      • Kanehiro H.
      • Tanaka T.
      • Kichikawa K.
      • Nakajima Y.
      Adult hepatoblastoma successfully treated with multimodal treatment.
      ,
      • Fiaschetti V.
      • Fiori R.
      • Gaspari E.
      • Crusco S.
      • Simonetti G.
      Mixed hepatoblastoma in a young male adult: a case report and literature review.
      ,
      • Di Benedetto F.
      • Di Sandro S.
      • D’Amico G.
      • De Santis M.
      • Gerunda G.E.
      Role of Chemoembolization as a Rescue Treatment for Recurrence of Resected Hepatoblastoma in Adult Patients.
      ]. An epidemiological survey of fatal primary liver tumours in US residents less than 20 years of age, between 1979 and 1996, disclosed four histologically proven HB cases in the 15–19 year-old group [
      • Darbari A.
      • Sabin K.M.
      • Shapiro C.N.
      • Schwarz K.B.
      Epidemiology of primary hepatic malignancies in U.S. children.
      ]. These cases were not included in Table 1 since the authors considered their survey as paediatric.
      Figure thumbnail gr1
      Fig. 1Age distribution of adult hepatoblastoma. No rule can be found regarding age at manifestation.
      Table 1Overview of the clinical findings of all published reports of cases recognised by the authors as adult hepatoblastoma (English, French, German, Italian, and Spanish literature).
      HB, hepatoblastoma; AFP, alpha-fetoprotein; no, normal; ↑, moderately elevated; ↑↑, highly elevated; LN, lymph nodes; n.a., not available, R, right; L, left; wk, weeks; mo; months; yr, years; LS, liver side; LD, liver disease; Ø, diameter.
      Figure thumbnail fx4

      Pathological findings in HB

      Gross findings

      Histology is central to the diagnosis of HB, but first we will briefly review the gross characteristics.

      Paediatric HB

      The gross findings in the 35 HB case series reported by Ishak and Glunz vary according to the subtype [
      • Ishak K.G.
      • Glunz P.R.
      Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases.
      ]. Half of the tumours considered were encapsulated. A large majority showed a bulging nodular or lobulated cut surface. In the mixed epithelial and mesenchymal HBs, a lobulated appearance is described, with intervening white collagen bands, and areas of necrosis or haemorrhage. The tumour nodules were variegated, tan to yellow to greyish white, and a minority of cases showed bile-stained, green nodules. Six of the 19 reported mixed HBs had prominent vascular channels on the capsular or cut surface, and calcifications were noted in some of them. Most of the 16 epithelial HBs were nodular, uniform and solid. They appeared greyish to yellow or tan, with a minority displaying areas of haemorrhage or necrosis.
      According to the AFIP fascicle, pure foetal HB is characterised by lobulated nodules whose colour often resembles normal liver parenchyma. Mixed epithelial and mesenchymal HB shows a more variegated appearance, with white and dense mesenchymal areas alternating with brown or green epithelial nodules [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. Osteoid may be grossly apparent. Areas of necrosis and haemorrhage may be seen in both cases.

      Adult HB

      The gross findings in the described adult HBs are not different from those described in children. Some tumours are described as encapsulated or surrounded by a pseudocapsule, whereas others may display indistinct margins. The lesions are either single or multiple, and are frequently described as variegated, with areas of haemorrhage or necrosis. In mixed epithelial and mesenchymal HBs, osteoid, bone, and cartilage may be grossly identified.

      Histological criteria

      Histological criteria of paediatric HB

      The diagnosis of HB is mainly based on histology. In 1967, Ishak and Glunz proposed two HB subtypes: (1) epithelial, (2) mixed epithelial and mesenchymal. Prior to this description, HB may have been unrecognised or labelled differently [
      • Ishak K.G.
      • Glunz P.R.
      Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases.
      ]. A more aggressive macrotrabecular pattern, and the small cell undifferentiated subtype were recognised later [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ,
      • Kasai M.
      • Watanabe I.
      Histologic classification of liver-cell carcinoma in infancy and childhood and its clinical evaluation. A study of 70 cases collected in Japan.
      ]. Not all of these conventionally accepted characteristics are found in adult lesions. In paediatrics, histology is commonly accepted to be of prognostic value, and as such plays a central role in determining therapeutic regimen.

      Foetal and embryonal epithelial HB

      The histological features of epithelial HB consist of irregular lobules delineated by collagen septa of varying thickness [
      • Ishak K.G.
      • Glunz P.R.
      Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases.
      ]. The septa contain vessels, some with a thick collagenous wall, and occasional lymphatics. The epithelial cells are subdivided in “foetal-type and embryonal-type cells” [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ].
      Foetal cells closely resemble the developing foetal liver, and are arranged in irregular 2-cell thick plates (Fig. 2A ). They are smaller and more irregular than normal hepatocytes, with a moderately abundant acidophilic cytoplasm, and a round to oval, slightly irregular and basophilic nucleus. Pale cells, rich in glycogen, alternate in a typical pattern with darker cells. Steatosis, and intracytoplasmic or intracanalicular bile plugs may also be present. Extramedullary haematopoiesis is frequent.
      Figure thumbnail gr2
      Fig. 2Histological features of different types of paediatric hepatoblastoma (HB). (A) Foetal HB. Foetal cells resemble the developing foetal liver, and are arranged in irregular 2-cell thick plates. A characteristic light and dark pattern is imparted by variable cytoplasmic amounts of glycogen (haematoxylin & eosin stain (H&E); original magnification 100×). (B) Embryonal HB. Embryonal cells appear less differentiated, small, elongated and poorly cohesive, forming pseudorosettes (H&E, 200×). (C) Mixed (epithelial and mesenchymal) HB. In addition to the epithelial elements (arrowheads), primitive mesenchyme consists of spindle–shaped cells with plump elongated nuclei, in a parallel orientation (arrow) (H&E, 200×).
      Embryonal cells appear far less differentiated: they are small, elongated and poorly cohesive (Fig. 2B). They are arranged in sheets or ribbons, focally organising into acinar or papillary structures, or pseudorosettes. Embryonal cells are dark cells, with poorly defined contours. Cytoplasm is scant and amphophilic. The round to oval nucleus is hyperchromatic and contains a large nucleolus. Mitoses are much more frequent in the embryonal areas than in the foetal-type areas. Unlike in the foetal type, the embryonal type is characterised by the absence of glycogen, bile pigment, or steatosis.

      Mixed epithelial and mesenchymal HB and teratoid features

      The presence of mesodermal derivatives is characteristic of mixed, epithelial and mesenchymal HB. (Fig. 2C) [
      • Ishak K.G.
      • Glunz P.R.
      Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases.
      ]. These mesenchymal elements consist of a proliferation of primitive-appearing mesenchymal spindle-shaped cells, intimately admixed with the epithelial elements in a highly cellular pattern. Cytoplasm is more abundant than that of mature fibroblasts, and the nucleus is elongated, and plump. These cells blend progressively with areas of less intense cellular mesenchymal proliferation, and with the relatively acellular, fibrous septa. Osteoid is present in a majority of cases, either within the primitive mesenchyme, near the fibrous septa or pseudocapsule, or admixed within the epithelial elements. Osteoid foci contain cells morphologically identical to osteoblasts. Occasionally, squamous foci and a variety of mesenchymal and epidermal derived tissues are visible, which are considered teratoid elements [
      • Manivel C.
      • Wick M.R.
      • Abenoza P.
      • Dehner L.P.
      Teratoid hepatoblastoma. The nosologic dilemma of solid embryonic neoplasms of childhood.
      ,
      • Ruck P.
      • Kaiserling E.
      Melanin-containing hepatoblastoma with endocrine differentiation. An immunohistochemical and ultrastructural study.
      ]. Of note, neither cartilage nor rhabdomyoblasts were appreciated in the original description by Ishak and Glunz [
      • Manivel C.
      • Wick M.R.
      • Abenoza P.
      • Dehner L.P.
      Teratoid hepatoblastoma. The nosologic dilemma of solid embryonic neoplasms of childhood.
      ].

      Macrotrabecular pattern

      Gonzalez-Crussi et al. further described the more aggressive macrotrabecular pattern in HB, stressing the difficulties of classifying such tumours as HB or HCC [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ]. They argued however that other areas in such tumours displayed a typical foetal pattern, thus lending support to a diagnosis of HB. The five patients described all died with progressive disease, some with unusual, skeletal metastases. The tumours displayed 10–20 or more cell thick trabeculae composed of foetal- or embryonal-appearing cells admixed with occasional cells larger than the normal uninvolved hepatocytes and anaplastic cells. In addition, there was marked vascular invasion within the tumours [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ].

      Small cell undifferentiated HB

      The final HB subtype described in children is the small-cell undifferentiated pattern (SCU) previously called “anaplastic” [
      • Kasai M.
      • Watanabe I.
      Histologic classification of liver-cell carcinoma in infancy and childhood and its clinical evaluation. A study of 70 cases collected in Japan.
      ]. This pattern is characterised by small, undifferentiated and poorly cohesive cells, with scant cytoplasm and hyperchromatic nuclei, initially described as “resembling neuroblastoma cells” [
      • Yoshida T.
      • Okazaki N.
      • Yoshino M.
      • Shimamura Y.
      • Miyazawa N.
      • Miyamoto K.
      • et al.
      A case of hepatoblastoma in adult.
      ]. Since 1989, small cell undifferentiated HB is the term used to describe tumours presenting with more than 50% of small-cell undifferentiated areas [
      • Haas J.E.
      • Muczynski K.A.
      • Krailo M.
      • Ablin A.
      • Land V.
      • Vietti T.J.
      • et al.
      Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma.
      ]. High mitotic rates and a possible primitive spindle cell component were reported in these tumours [
      • Haas J.E.
      • Muczynski K.A.
      • Krailo M.
      • Ablin A.
      • Land V.
      • Vietti T.J.
      • et al.
      Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma.
      ]. Some cases were associated with a foetal or an embryonal pattern [
      • Haas J.E.
      • Feusner J.H.
      • Finegold M.J.
      Small cell undifferentiated histology in hepatoblastoma may be unfavorable.
      ].

      Correlation between histology and outcome

      Only HBs displaying a pure foetal histology and a low mitotic rate (<2 mitoses/10 high power fields, 400×) are defined as favourable histology, and have better survival [
      • Haas J.E.
      • Muczynski K.A.
      • Krailo M.
      • Ablin A.
      • Land V.
      • Vietti T.J.
      • et al.
      Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma.
      ]. All other subtypes are defined as unfavourable histology; in particular, SCU histology is associated with an adverse outcome [
      • Haas J.E.
      • Feusner J.H.
      • Finegold M.J.
      Small cell undifferentiated histology in hepatoblastoma may be unfavorable.
      ].
      In children with incompletely resected HB or with metastasis at initial diagnosis, identification of osteoid or chondroid foci, or of squamous differentiation has been associated with increased survival [
      • Haas J.E.
      • Muczynski K.A.
      • Krailo M.
      • Ablin A.
      • Land V.
      • Vietti T.J.
      • et al.
      Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma.
      ]. However, these elements had no influence on prognosis in completely resected HB. Since paediatric HBs with mesenchymal components have not been shown to behave more aggressively than other subtypes, they are not mistaken for sarcomas, unlike what might be a challenge in adult cases [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ].

      Histological criteria of adult HB

      Whether HB exists in adults is controversial. As previously mentioned, most or all adult cases published were deemed misdiagnosed by the authors of the 2001 edition of the AFIP on Tumours of the Liver and Intrahepatic Bile Ducts [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. We have not personally been confronted to adult cases of HB. This section will thus mostly be dedicated to a summary of the main findings in published adult HB cases, and to a discussion of the potential differential diagnoses in adults.
      Underlying fibrosis or cirrhosis was identified in 11 of the 45 published HB adult cases [
      • Popper H.
      Bidermal hepatoblastoma in an adult (author’s transl).
      ,
      • Babaryka I.
      • von Bouquoy F.
      Hepatoblastoma in adults (author’s transl).
      ,
      • Slugen I.
      • Fiala P.
      • Pauer M.
      • Majercik M.
      • Ondrias F.
      • Cernak P.
      Mixed hepatoblastoma in the adult: morphological and immunohistochemical findings.
      ,
      • Oda H.
      • Honda K.
      • Hara M.
      • Arase Y.
      • Ikeda K.
      • Kumada H.
      Hepatoblastoma in an 82-year-old man. An autopsy case report.
      ,
      • Altmann H.W.
      Epithelial and mixed hepatoblastoma in the adult. Histological observations and general considerations.
      ,
      • Ahn H.J.
      • Kwon K.W.
      • Choi Y.J.
      • Kim H.J.
      • Hong S.P.
      • Oh D.
      • et al.
      Mixed hepatoblastoma in an adult–a case report and literature review.
      ,
      • Dumortier J.
      • Bizollon T.
      • Chevallier M.
      • Ducerf C.
      • Baulieux J.
      • Scoazec J.Y.
      • et al.
      Recurrence of hepatocellular carcinoma as a mixed hepatoblastoma after liver transplantation.
      ,
      • Kasper H.U.
      • Longerich T.
      • Stippel D.L.
      • Kern M.A.
      • Drebber U.
      • Schirmacher P.
      Mixed hepatoblastoma in an adult.
      ,
      • Masuda T.
      • Beppu T.
      • Horino K.
      • Komori H.
      • Hayashi H.
      • Okabe H.
      • et al.
      Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.
      ,
      • Zhang S.H.
      • Xu A.M.
      • Lin W.H.
      • Zhang X.Y.
      Mixed hepatoblastoma with teratoid features in an adult.
      ]. An additional five patients had a history of viral hepatitis (A, B or C), but no reported fibrosis [
      • Yoshida T.
      • Okazaki N.
      • Yoshino M.
      • Shimamura Y.
      • Miyazawa N.
      • Miyamoto K.
      • et al.
      A case of hepatoblastoma in adult.
      ,
      • Bortolasi L.
      • Marchiori L.
      • Dal Dosso I.
      • Colombari R.
      • Nicoli N.
      Hepatoblastoma in adult age: a report of two cases.
      ,
      • Diotallevi P.
      • Cristofaro M.
      • Broglia L.
      • Carletta C.
      Hepatoblastoma in an HCV-positive adult. Report of a case.
      ,
      • Inagaki M.
      • Yagi T.
      • Urushihara N.
      • Shima Y.
      • Sadamori H.
      • Takakura N.
      • et al.
      Successfully resected hepatoblastoma in a young adult with chronic hepatitis B: report of a case.
      ,
      • Ke H.Y.
      • Chen J.H.
      • Jen Y.M.
      • Yu J.C.
      • Hsieh C.B.
      • Chen C.J.
      • et al.
      Ruptured hepatoblastoma with massive internal bleeding in an adult.
      ]. In contrast, childhood HB occurs almost always in patients with no underlying liver disease [
      • Richter A.
      • Grabhorn E.
      • Schulz A.
      • Schaefer H.J.
      • Burdelski M.
      • Ganschow R.
      Hepatoblastoma in a child with progressive familial intrahepatic cholestasis.
      ].
      In adult HB, authors often underscore the malignant appearance of mesenchymal elements. Such areas are described as reminiscent of fibrosarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, or rhabdomyosarcoma [
      • Carter R.
      Hepatoblastoma in the adult.
      ,
      • Yoshida T.
      • Okazaki N.
      • Yoshino M.
      • Shimamura Y.
      • Miyazawa N.
      • Miyamoto K.
      • et al.
      A case of hepatoblastoma in adult.
      ,
      • Popper H.
      Bidermal hepatoblastoma in an adult (author’s transl).
      ,
      • Honan R.P.
      • Haqqani M.T.
      Mixed hepatoblastoma in the adult: case report and review of the literature.
      ,
      • Genova G.
      • Rimi C.
      Hepatoblastoma in adults. Description of a case.
      ,
      • Slugen I.
      • Fiala P.
      • Pauer M.
      • Majercik M.
      • Ondrias F.
      • Cernak P.
      Mixed hepatoblastoma in the adult: morphological and immunohistochemical findings.
      ,
      • Altmann H.W.
      Epithelial and mixed hepatoblastoma in the adult. Histological observations and general considerations.
      ,
      • Kuniyasu H.
      • Yasui W.
      • Shimamoto F.
      • Fujii K.
      • Nakahara M.
      • Asahara T.
      • et al.
      Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance.
      ,
      • Ahn H.J.
      • Kwon K.W.
      • Choi Y.J.
      • Kim H.J.
      • Hong S.P.
      • Oh D.
      • et al.
      Mixed hepatoblastoma in an adult–a case report and literature review.
      ,
      • Kasper H.U.
      • Longerich T.
      • Stippel D.L.
      • Kern M.A.
      • Drebber U.
      • Schirmacher P.
      Mixed hepatoblastoma in an adult.
      ,
      • Di Benedetto F.
      • Di Sandro S.
      • D’Amico G.
      • De Santis M.
      • Gerunda G.E.
      Role of Chemoembolization as a Rescue Treatment for Recurrence of Resected Hepatoblastoma in Adult Patients.
      ]. The latter deserves particular mention, since rhabdomyoblasts were not observed in the two large paediatric series [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ,
      • Kasai M.
      • Watanabe I.
      Histologic classification of liver-cell carcinoma in infancy and childhood and its clinical evaluation. A study of 70 cases collected in Japan.
      ], although they were described sporadically in another series [
      • Keeling J.W.
      Liver tumours in infancy and childhood.
      ]. Identification of rhabdomyoblastic differentiation should therefore prompt careful evaluation of all tumour features, and consideration of differential diagnoses, such as teratoma [
      • Gonzalez-Crussi F.
      • Upton M.P.
      • Maurer H.S.
      Hepatoblastoma. Attempt at characterization of histologic subtypes.
      ]. Conversely, small undifferentiated cells are not pathognomonic of HB. For example, scattered clusters of highly undifferentiated oval or round cells, with scant cytoplasm in the epithelial component of a rhabdomyosarcoma-like liver tumour, were not considered diagnostic of HB in a 70-year old patient [
      • Kubosawa H.
      • Ishige H.
      • Kondo Y.
      • Konno A.
      • Yamamoto T.
      • Nagao K.
      Hepatocellular carcinoma with rhabdomyoblastic differentiation.
      ].

      Differential diagnosis of adult HB

      Hepatocellular carcinoma, and combined hepatocellular–cholangiocarcinoma with stem cell features

      The main differential diagnosis of HB is HCC. The challenge is to distinguish HB from HCC which often show significant gross and histological overlap. Both tumours can present with a macrotrabecular pattern or poorly differentiated characteristics. Moreover, immunohistochemistry is of limited value in distinguishing between HCC and HB. To further complicate matters, both mixed HB and HCC features can exist within a same tumour [
      • Lopez-Terrada D.
      • Finegold M.J.
      Tumors of the Liver.
      ]. Furthermore, the sequential development of HB and HCC in the same patient has been reported [
      • Masuda T.
      • Beppu T.
      • Horino K.
      • Komori H.
      • Hayashi H.
      • Okabe H.
      • et al.
      Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.
      ,
      • Basile J.
      • Caldwell S.
      • Nolan N.
      • Hammerle C.
      Clear cell hepatocellular carcinoma arising 25 years after the successful treatment of an infantile hepatoblastoma.
      ]. Finally, chemotherapy may result in cytologic and architectural modifications that mimic HCC, with resulting increases in both tumour cell size and nuclear anaplasia [
      • Wang L.L.
      • Filippi R.Z.
      • Zurakowski D.
      • Archibald T.
      • Vargas S.O.
      • Voss S.D.
      • et al.
      Effects of neoadjuvant chemotherapy on hepatoblastoma: a morphologic and immunohistochemical study.
      ]. When present, mesenchymal elements are a key feature of paediatric HB. In contrast, in adult liver tumours, the presence of spindle-cells is not conclusive, since they can also be seen in HCC and in sarcomatous liver tumours. Table 2 summarises the main histological criteria to distinguish HB from HCC. Extramedullary haematopoiesis is a useful criterion in the diagnosis of HB, but may also be observed in a small subset (5%) of HCC cases. Bile production is more rarely seen in HB than in HCC [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. Paediatric HB rarely occurs in the setting of underlying liver disease while 25% (11/45) of published HB adult cases showed underlying fibrosis or cirrhosis [
      • Yoshida T.
      • Okazaki N.
      • Yoshino M.
      • Shimamura Y.
      • Miyazawa N.
      • Miyamoto K.
      • et al.
      A case of hepatoblastoma in adult.
      ,
      • Popper H.
      Bidermal hepatoblastoma in an adult (author’s transl).
      ,
      • Babaryka I.
      • von Bouquoy F.
      Hepatoblastoma in adults (author’s transl).
      ,
      • Slugen I.
      • Fiala P.
      • Pauer M.
      • Majercik M.
      • Ondrias F.
      • Cernak P.
      Mixed hepatoblastoma in the adult: morphological and immunohistochemical findings.
      ,
      • Oda H.
      • Honda K.
      • Hara M.
      • Arase Y.
      • Ikeda K.
      • Kumada H.
      Hepatoblastoma in an 82-year-old man. An autopsy case report.
      ,
      • Altmann H.W.
      Epithelial and mixed hepatoblastoma in the adult. Histological observations and general considerations.
      ,
      • Ahn H.J.
      • Kwon K.W.
      • Choi Y.J.
      • Kim H.J.
      • Hong S.P.
      • Oh D.
      • et al.
      Mixed hepatoblastoma in an adult–a case report and literature review.
      ,
      • Dumortier J.
      • Bizollon T.
      • Chevallier M.
      • Ducerf C.
      • Baulieux J.
      • Scoazec J.Y.
      • et al.
      Recurrence of hepatocellular carcinoma as a mixed hepatoblastoma after liver transplantation.
      ,
      • Kasper H.U.
      • Longerich T.
      • Stippel D.L.
      • Kern M.A.
      • Drebber U.
      • Schirmacher P.
      Mixed hepatoblastoma in an adult.
      ,
      • Masuda T.
      • Beppu T.
      • Horino K.
      • Komori H.
      • Hayashi H.
      • Okabe H.
      • et al.
      Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.
      ].
      Table 2Histological clues and criteria distinguishing hepatoblastoma (HB) from classical hepatocellular carcinoma (HCC). HB and HCC may show significant architectural and morphological overlap; unambiguous distinction may prove difficult, especially in particular HB variants. Histological clues to diagnosis are provided and variants with major overlapping features described. Histologic HCC variants (fibrolamellar HCC, clear cell carcinoma, sarcomatoid HCC, sclerosing HCC) are not considered. N/C ratio, nuclear/cytoplasmic ratio; HPF, high power field.
      Patients with combined hepatocellular–cholangiocarcinoma are thought to have worse clinical outcome than patients with pure HCC [
      • Kassahun W.T.
      • Hauss J.
      Management of combined hepatocellular and cholangiocarcinoma.
      ]. Some tumours further display stem cell features, with clusters of small cells with high nucleocytoplasmic ratio, and hyperchromatic nuclei. The immunophenotype recapitulates that of stem or progenitor cells, with reactivity to the progenitor cell/ductular markers cytokeratins 7 and 19, neural cell adhesion molecule (NCAM1/CD56), KIT (CD117), epithelial cell adhesion molecule (EpCAM), and the hepatic progenitor cell marker OV–6 [
      • Zhang J.
      • Cheng C.
      • He C.L.
      • Zhou Y.J.
      • Cao Y.
      The expression of Bcl-XL, Bcl-XS and p27Kip1 in topotecan-induced apoptosis in hepatoblastoma HepG2 cell line.
      ,
      • Ding S.J.
      • Li Y.
      • Tan Y.X.
      • Jiang M.R.
      • Tian B.
      • Liu Y.K.
      • et al.
      From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis.
      ,
      • Kim H.
      • Park C.
      • Han K.H.
      • Choi J.
      • Kim Y.B.
      • Kim J.K.
      • et al.
      Primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype.
      ,
      • Komuta M.
      • Spee B.
      • Vander Borght S.
      • De Vos R.
      • Verslype C.
      • Aerts R.
      • et al.
      Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.
      ]. It remains to be determined to what extent these features observed in patients with conflicting clinical outcome relate to the poorly or undifferentiated aspects described in some of the adult HBs.

      Ossifying stromal–epithelial tumour/(calcifying) nested stromal epithelial tumour of the liver

      Another important differential diagnosis is the rare, ossifying stromal–epithelial tumour. The three initial cases reported as ossifying stromal–epithelial tumours in the AFIP fascicle had been present since childhood, as a calcified liver mass [
      • Ishak K.G.
      • Goodman Z.D.
      • Stocker J.T.
      Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts. Hepatoblastoma.
      ]. Nomenclature is confusing: these rare tumours have also been called ossifying malignant mixed epithelial and stromal tumours of the liver [
      • Heywood G.
      • Burgart L.J.
      • Nagorney D.M.
      Ossifying malignant mixed epithelial and stromal tumor of the liver: a case report of a previously undescribed tumor.
      ], nested stromal epithelial tumours of the liver [
      • Heerema-McKenney A.
      • Leuschner I.
      • Smith N.
      • Sennesh J.
      • Finegold M.J.
      Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with cushing syndrome.
      ], desmoplastic nested spindle cell tumours of the liver [
      • Hill D.A.
      • Swanson P.E.
      • Anderson K.
      • Covinsky M.H.
      • Finn L.S.
      • Ruchelli E.D.
      • et al.
      Desmoplastic nested spindle cell tumor of liver: report of four cases of a proposed new entity.
      ], and calcifying nested stromal epithelial tumours of the liver [
      • Makhlouf H.R.
      • Abdul-Al H.M.
      • Wang G.
      • Goodman Z.D.
      Calcifying nested stromal-epithelial tumors of the liver: a clinicopathologic, immunohistochemical, and molecular genetic study of 9 cases with a long-term follow-up.
      ]. Age range at presentation varies from 2 to 14 years [
      • Heerema-McKenney A.
      • Leuschner I.
      • Smith N.
      • Sennesh J.
      • Finegold M.J.
      Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with cushing syndrome.
      ], while age at the time of diagnosis is 2–33 years [
      • Makhlouf H.R.
      • Abdul-Al H.M.
      • Wang G.
      • Goodman Z.D.
      Calcifying nested stromal-epithelial tumors of the liver: a clinicopathologic, immunohistochemical, and molecular genetic study of 9 cases with a long-term follow-up.
      ]. Tumours consist of mixed epithelial and stromal elements arranged in spindle and epithelioid cellular nests, surrounded by a concentric myofibroblastic proliferation. The stroma contains variable amounts of calcifications, osteoid, and bone [
      • Heerema-McKenney A.
      • Leuschner I.
      • Smith N.
      • Sennesh J.
      • Finegold M.J.
      Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with cushing syndrome.
      ,
      • Makhlouf H.R.
      • Abdul-Al H.M.
      • Wang G.
      • Goodman Z.D.
      Calcifying nested stromal-epithelial tumors of the liver: a clinicopathologic, immunohistochemical, and molecular genetic study of 9 cases with a long-term follow-up.
      ]. The main difference with HB is immunohistochemistry: this rare tumour does not stain for HepPar1, AFP, and cytokeratin 7, whereas WT–1 reactivity is observed [
      • Heerema-McKenney A.
      • Leuschner I.
      • Smith N.
      • Sennesh J.
      • Finegold M.J.
      Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with cushing syndrome.
      ,
      • Makhlouf H.R.
      • Abdul-Al H.M.
      • Wang G.
      • Goodman Z.D.
      Calcifying nested stromal-epithelial tumors of the liver: a clinicopathologic, immunohistochemical, and molecular genetic study of 9 cases with a long-term follow-up.
      ].

      Transitional liver cell tumours

      There is one report of aggressive malignant liver cell tumours displaying morphological aspects intermediate between HB and HCC which were labelled as transitional liver cell tumours (TLCT) [
      • Prokurat A.
      • Kluge P.
      • Kosciesza A.
      • Perek D.
      • Kappeler A.
      • Zimmermann A.
      Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin.
      ]. This is a clinically relevant paediatric series because some of these tumours were identified as HB on pre-treatment diagnostic biopsy, whereas the post-treatment liver specimen displayed features more in keeping with HCC. Recently, as previously stressed, phenotypic modifications have been reported in post-treatment HB [
      • Wang L.L.
      • Filippi R.Z.
      • Zurakowski D.
      • Archibald T.
      • Vargas S.O.
      • Voss S.D.
      • et al.
      Effects of neoadjuvant chemotherapy on hepatoblastoma: a morphologic and immunohistochemical study.
      ], with cellular maturation or modification to a HCC-like phenotype. Together, these reports highlight the difficulties in distinguishing between the two entities and should be considered in clinical management.
      Figure thumbnail fx5

      Developmental and molecular aspects of HB

      Early descriptions of HB highlighted its histological resemblance to the hepatoblast, commonly accepted as the bipotential precursor of both the hepatocyte and cholangiocyte lineages [
      • Ishak K.G.
      • Glunz P.R.
      Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases.
      ]. AFP expression by the tumour attests the expression of a ‘foetal’ programme. With the advent of molecular methods, a progenitor-cell origin has been convincingly demonstrated for HCC, joining the vast body of literature in support of a cancer stem cell hypothesis [
      • Lee J.S.
      • Heo J.
      • Libbrecht L.
      • Chu I.S.
      • Kaposi-Novak P.
      • Calvisi D.F.
      • et al.
      A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.
      ,
      • Mishra L.
      • Banker T.
      • Murray J.
      • Byers S.
      • Thenappan A.
      • He A.R.
      • et al.
      Liver stem cells and hepatocellular carcinoma.
      ,
      • Yao Z.
      • Mishra L.
      Cancer stem cells and hepatocellular carcinoma.
      ]. Several elements support a similar origin for HB: onset in infancy and childhood, association with genetic syndromes favouring overgrowth and tumour development [
      • Hoyme H.E.
      • Seaver L.H.
      • Jones K.L.
      • Procopio F.
      • Crooks W.
      • Feingold M.
      Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review.
      ,
      • Perilongo G.
      Link confirmed between FAP and hepatoblastoma.
      ,
      • Steenman M.
      • Westerveld A.
      • Mannens M.
      Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways.
      ], and frequent absence of underlying liver disease. In addition, histological subtypes appear to recapitulate foetal development to some extent and may include teratoid elements [
      • Moll A.
      • Krenauer A.
      • Bierbach U.
      • Till H.
      • Hirsch W.
      • Leuschner I.
      • et al.
      Mixed hepatoblastoma and teratoma of the liver in a 3-year-old child: a unique combination and clinical challenge.
      ], suggesting a pluripotency of the tumour, or at the very least, the creation of a permissive environment for diverse cellular differentiation within the tumour itself. Finally, and perhaps most convincing, is the finding that the bipotential oval cell marker DLK1 has been shown to be upregulated in HB [
      • Lopez-Terrada D.
      • Gunaratne P.H.
      • Adesina A.M.
      • Pulliam J.
      • Hoang D.M.
      • Nguyen Y.
      • et al.
      Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.
      ].
      Several investigators have indeed used gene expression analysis to identify molecular signatures between subtypes. The different histological subtypes described above (foetal vs. embryonal, epithelial vs. mesenchymal, and small cell undifferentiated) offer an attractive avenue to explore genotype–phenotype correlations and possible embryonic origins. The common denominator of most of these studies has been the use of the foetal liver (usually murine) as a reference for liver development [
      • Cairo S.
      • Armengol C.
      • De Reynies A.
      • Wei Y.
      • Thomas E.
      • Renard C.A.
      • et al.
      Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.
      ,
      • Adesina A.M.
      • Lopez-Terrada D.
      • Wong K.K.
      • Gunaratne P.
      • Nguyen Y.
      • Pulliam J.
      • et al.
      Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways.
      ]. Most recently, Buendia and colleagues used a combination of gene expression profiles and array comparative genomic hybridization (CGH) analysis to show that foetal and embryonal subtypes mirror the molecular signature of early or late liver development [
      • Cairo S.
      • Armengol C.
      • De Reynies A.
      • Wei Y.
      • Thomas E.
      • Renard C.A.
      • et al.
      Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.
      ]. This important study confirms a genetic and molecular origin to the long standing assumption that the more immature, embryonal phenotype leads to a more aggressive disease than the foetal type, commonly accepted as a sign of favourable outcomes [
      • Cairo S.
      • Armengol C.
      • De Reynies A.
      • Wei Y.
      • Thomas E.
      • Renard C.A.
      • et al.
      Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.
      ].
      Furthermore and most relevant to this review, a recent analysis using gene profiling of different adult HCCs showed that a subset of tumours clustered with mouse hepatoblasts around embryonic day 13–16 [
      • Lee J.S.
      • Heo J.
      • Libbrecht L.
      • Chu I.S.
      • Kaposi-Novak P.
      • Calvisi D.F.
      • et al.
      A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.
      ]. The subset of patients having this type had worse outcomes than non hepatoblast-like HCCs [
      • Lee J.S.
      • Heo J.
      • Libbrecht L.
      • Chu I.S.
      • Kaposi-Novak P.
      • Calvisi D.F.
      • et al.
      A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.
      ]. Taken together, these last two observations beg the question whether these tumours with molecular, foetal characteristics were not in fact adult HBs which might have warranted a different management than conventional HCC therapy.
      The possibility of molecular overlap between HCC and HB is important when approaching an atypical adult hepatic epithelial tumour. Mixed HB and HCC phenotypes have been described within the same tumour [
      • Lopez-Terrada D.
      • Finegold M.J.
      Tumors of the Liver.
      ], and the presence of both tumour types has been described in patients either in a synchronous or sequential fashion [
      • Masuda T.
      • Beppu T.
      • Horino K.
      • Komori H.
      • Hayashi H.
      • Okabe H.
      • et al.
      Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.
      ,
      • Basile J.
      • Caldwell S.
      • Nolan N.
      • Hammerle C.
      Clear cell hepatocellular carcinoma arising 25 years after the successful treatment of an infantile hepatoblastoma.
      ]. There can be significant histological resemblance between HB and HCC. Furthermore, as many as 28% of HCCs in one series stained positively for CK7 and/or CK19, compatible with a progenitor-cell origin. Interestingly, these CK19 positive tumours had a worse prognosis [
      • Durnez A.
      • Verslype C.
      • Nevens F.
      • Fevery J.
      • Aerts R.
      • Pirenne J.
      • et al.
      The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin.
      ]. Additionally, developmental signalling pathways such as Wnt, Hh, and Notch which have all been shown to be important in HB pathogenesis [
      • Zhang J.
      • Cheng C.
      • He C.L.
      • Zhou Y.J.
      • Cao Y.
      The expression of Bcl-XL, Bcl-XS and p27Kip1 in topotecan-induced apoptosis in hepatoblastoma HepG2 cell line.
      ,
      • Lopez-Terrada D.
      • Finegold M.J.
      Tumors of the Liver.
      ,
      • Gramantieri L.
      • Giovannini C.
      • Lanzi A.
      • Chieco P.
      • Ravaioli M.
      • Venturi A.
      • et al.
      Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma.
      ,
      • Koch A.
      • Denkhaus D.
      • Albrecht S.
      • Leuschner I.
      • von Schweinitz D.
      • Pietsch T.
      Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.
      ,
      • Roskams T.A.
      • Libbrecht L.
      • Desmet V.J.
      Progenitor cells in diseased human liver.
      ], also play a more or less important role in the development and maintenance of HCC, which suggests that there is at least some overlap in oncogenic programmes in these two tumours [
      • Gramantieri L.
      • Giovannini C.
      • Lanzi A.
      • Chieco P.
      • Ravaioli M.
      • Venturi A.
      • et al.
      Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma.
      ,
      • Tada M.
      • Kanai F.
      • Tanaka Y.
      • Tateishi K.
      • Ohta M.
      • Asaoka Y.
      • et al.
      Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma.
      ,
      • Eichenmuller M.
      • Gruner I.
      • Hagl B.
      • Haberle B.
      • Muller-Hocker J.
      • von Schweinitz D.
      • et al.
      Blocking the hedgehog pathway inhibits hepatoblastoma growth.
      ,
      • Gao J.
      • Song Z.
      • Chen Y.
      • Xia L.
      • Wang J.
      • Fan R.
      • et al.
      Deregulated expression of Notch receptors in human hepatocellular carcinoma.
      ].
      Figure thumbnail fx6

      Therapeutic protocols and outcome

      Therapy and outcome in paediatric HB

      Overview

      The International Childhood Liver Tumour Strategy Group (SIOPEL), a committee of medical specialists founded in 1988 under the umbrella of the International Society of Paediatric Oncology (SIOP), promotes basic and comprehensive clinical research on childhood malignant neoplasms of the liver, mainly HB and HCC. The ultimate goal of this study group is to ameliorate the prognosis and the quality of life of children affected by these rare neoplasms and to promote international cooperation (www.siopel.org).
      Worldwide, there are two different strategies regarding the treatment of paediatric HB. The North American groups support immediate surgery for localised tumours [
      • Finegold M.J.
      Chemotherapy for suspected hepatoblastoma without efforts at surgical resection is a bad practice.
      ,
      • Litten J.B.
      • Tomlinson G.E.
      Liver tumors in children.
      ], whereas Europe favours pre-operative chemotherapy in all cases, followed by surgery. In most cases and depending on risk factors and staging, post-operative chemotherapy is also recommended. In the following paragraphs, we summarise the current European strategy of risk-adapted therapy, as outlined by SIOPEL following European-wide research.
      The prognosis for HB has dramatically improved since the introduction of effective, cisplatin-based chemotherapy in the 1980’s. Five-year overall survival has improved from 25% to around 70% [
      • Otte J.B.
      • Pritchard J.
      • Aronson D.C.
      • Brown J.
      • Czauderna P.
      • Maibach R.
      • et al.
      Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.
      ]. Alternating cycles of cisplatin, doxorubicin and even carboplatin are administered based on the risk-groups of HB patients (histological type, tumour extension, AFP secretion, etc.). The SIOPEL group is currently investigating the efficacy of a high-dose cisplatin regimen in high-risk patients and the efficacy of irinotecan in patients with recurrent disease [
      • Zsiros J.
      • Maibach R.
      • Shafford E.
      • Brugieres L.
      • Brock P.
      • Czauderna P.
      • et al.
      Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.
      ]. These approaches might be part of future therapeutic strategies against advanced HB (www.siopel.org).
      The SIOPEL established the PRETEXT (pre-treatment tumour extension) staging system, reflecting the number of liver sections with or without tumour (Fig. 3). The aim of the PRETEXT classification is to assess the feasibility of complete tumour resection prior to any treatment. This approach has shown reliable inter-observer reproducibility and an excellent prognostic value [
      • Perilongo G.
      • Shafford E.
      • Plaschkes J.
      SIOPEL trials using preoperative chemotherapy in hepatoblastoma.
      ,
      • Roebuck D.J.
      • Aronson D.
      • Clapuyt P.
      • Czauderna P.
      • de Ville de Goyet J.
      • Gauthier F.
      PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group.
      ]. Its main limitation is the difficulty to distinguish between actual invasion of a liver segment or displacement of an anatomical border. This may lead to over-staging [
      • Aronson D.C.
      • Schnater J.M.
      • Staalman C.R.
      • Weverling G.J.
      • Plaschkes J.
      • Perilongo G.
      • et al.
      Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study.
      ]. The SIOPEL studies have identified factors associated with lower survival in patients with HB: (1) tumour involving all four hepatic sections (Fig. 3), (2) presence of distant metastasis, (3) tumour extension into the vena cava, all three hepatic veins or the main and/or both branches of the portal vein, (4) biopsy-proven extrahepatic intra-abdominal disease, (5) low serum AFP (<100 ng/ml), (6) tumour rupture at presentation [
      • De Ioris M.
      • Brugieres L.
      • Zimmermann A.
      • Keeling J.
      • Brock P.
      • Maibach R.
      • et al.
      Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience.
      ,
      • Zsiros J.
      • Maibach R.
      • Shafford E.
      • Brugieres L.
      • Brock P.
      • Czauderna P.
      • et al.
      Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.
      ]. Meyers et al. further exposed a histological factor to be prognostic: small undifferentiated histology showed to have worse prognosis [
      • Meyers R.L.
      • Rowland J.R.
      • Krailo M.
      • Chen Z.
      • Katzenstein H.M.
      • Malogolowkin M.H.
      Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group.
      ].
      Figure thumbnail gr3
      Fig. 3PRETEXT (pre–treatment tumour extension) staging system (www.siopel.org). PRETEXT reflects the number of liver sections, which are free – or involved – of tumour: PRETEXT I: three adjoining liver sections free, one section involved; PRETEXT II: two adjoining sections free, two sections involved; PRETEXT III: two non-adjoining sections free or just one section free, in the latter case three sections involved; PRETEXT IV: no free section, all four sections involved.

      Surgical strategies for paediatric HB

      In Europe, surgery is usually performed after pre-operative chemotherapy. Complete tumour resection is the crucial step in curing HB [
      • Czauderna P.
      • Otte J.B.
      • Roebuck D.J.
      • von Schweinitz D.
      • Plaschkes J.
      Surgical treatment of hepatoblastoma in children.
      ]. Radical tumour resection can be achieved either by conventional hepatic surgery or orthotopic liver transplantation. As a general rule, PRETEXT I–III tumours are treated with partial hepatectomy, and PRETEXT IV or unifocal, centrally-located tumours with total hepatectomy, i.e. liver transplantation [
      • Czauderna P.
      • Otte J.B.
      • Roebuck D.J.
      • von Schweinitz D.
      • Plaschkes J.
      Surgical treatment of hepatoblastoma in children.
      ].
      Large solitary PRETEXT IV HBs can be an exception to this principle as a local resection can become feasible after successful downstaging with pre-operative chemotherapy (thus avoiding liver transplantation). This may be the case when the anatomical border of a liver sector is compressed without true malignant invasion. On the other hand, unifocal, centrally-located HBs are more likely to be treated by liver transplantation when they involve the main hilar structures or main hepatic veins, as these structures would presumably not become tumour-free even after a good response to chemotherapy. Indeed, initial invasion of the portal or hepatic veins is not a definite contraindication to liver transplantation [
      • Czauderna P.
      • Otte J.B.
      • Aronson D.C.
      • Gauthier F.
      • Mackinlay G.
      • Roebuck D.
      • et al.
      Guidelines for surgical treatment of hepatoblastoma in the modern era – recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL).
      ,
      • Reyes J.D.
      • Carr B.
      • Dvorchik I.
      • Kocoshis S.
      • Jaffe R.
      • Gerber D.
      Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence.
      ]. Yet, a review including the worldwide experience with HB has shown that such venous invasions are associated with significantly lower survival after liver transplantation: long-term survival was 54% if macroscopic venous invasion was present vs. 78% if there was no invasion [
      • Otte J.B.
      • Pritchard J.
      • Aronson D.C.
      • Brown J.
      • Czauderna P.
      • Maibach R.
      • et al.
      Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.
      ].
      Of note, children with multifocal PRETEXT IV tumours in whom tumour nodules respond to pre-operative chemotherapy should also benefit from primary liver transplantation (provided that all lesions cannot be removed by partial liver resections). This principle is guided by the high risk of recurrence from small non-detected viable HB cell remnant after chemotherapy. The sites of all currently and previously visible HB lesions should be excised [
      • Dall’Igna P.
      • Cecchetto G.
      • Toffolutti T.
      • Cillo U.
      • Cecchetto A.
      • Guglielmi M.
      • et al.
      Multifocal hepatoblastoma: is there a place for partial hepatectomy?.
      ].
      Lung metastases are not an absolute contraindication to liver resection or even liver transplantation. All pulmonary metastases should be removed first (wedge resection with wide margins) and the primary tumour subsequently resected – either by partial hepatectomy or by liver transplantation [
      • Otte J.B.
      • De Ville de Goyet J.
      • Reding R.
      Liver transplantation for hepatoblastoma: indications and contraindications in the modern era.
      ]. Some data even support that liver transplantation is a reasonable option if lung metastases have been eradicated by chemotherapy [
      • Otte J.B.
      • Pritchard J.
      • Aronson D.C.
      • Brown J.
      • Czauderna P.
      • Maibach R.
      • et al.
      Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.
      ].
      The rare absolute contraindications to liver transplantation are (1) the persistence of one or more viable extrahepatic tumour deposits not amenable to surgical excision; and (2) non-response to pre-operative chemotherapy, because of the high likelihood of systemic dissemination of the tumour [
      • Otte J.B.
      • Pritchard J.
      • Aronson D.C.
      • Brown J.
      • Czauderna P.
      • Maibach R.
      • et al.
      Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.
      ].
      In selected patients with HB, special hepatic resection techniques may be used by experienced liver surgeons [
      • Otte J.B.
      Progress in the surgical treatment of malignant liver tumors in children.
      ]. Exceptionally, if the tumour is adjacent to major vessels, they may be resected and reconstructed. Similarly, pre-operative hepatic artery chemoembolization may be considered [
      • Li J.P.
      • Chu J.P.
      • Yang J.Y.
      • Chen W.
      • Wang Y.
      • Huang Y.H.
      Preoperative transcatheter selective arterial chemoembolization in treatment of unresectable hepatoblastoma in infants and children.
      ]. Even tumour encasement or ingrowth into the retrohepatic vena cava may not preclude a radical excision, since the vein can be resected en bloc and replaced under total vascular exclusion of the liver (which usually is very well tolerated by children) [
      • Evans P.M.
      • Vogt D.P.
      • Mayes 3rd, J.T.
      • Henderson J.M.
      • Walsh R.M.
      Liver resection using total vascular exclusion.
      ,
      • Zografos G.N.
      • Kakaviatos N.D.
      • Skiathitis S.
      • Habib N.
      Total vascular exclusion for liver resections: pros and cons.
      ]. Yet, difficult resections should be avoided. They carry a high probability of leaving residual tumour, especially with tumours adherent to major hepatic vessels. The significantly better survival rates obtained in patients who received a primary transplant after a good response to chemotherapy support the strategy of avoiding partial hepatectomies when radical resections seem difficult and unlikely. Excellent results have been reported with primary liver transplantation compared to those obtained by rescue transplantation: 6-year survival after primary transplantation has been shown to be 82% vs. 30% for patients with rescue transplantation after primary partial liver resection [
      • Otte J.B.
      • Pritchard J.
      • Aronson D.C.
      • Brown J.
      • Czauderna P.
      • Maibach R.
      • et al.
      Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.
      ]. Consequently, when intra-hepatic recurrence is observed after a previous partial hepatectomy, the indication for rescue liver transplant remains controversial.

      Therapy and outcome in adult HB

      Figure thumbnail fx7
      Outcome of adult HB is poor. Overall median survival in the reviewed adult population was 2 months (95% CI 0.09–3.91), 1-year survival being 24% (Fig. 4A). Similar to children, adult patients with foetal HB may have better survivals. However, only two such cases have been reported (only one including outcome data) and no meaningful statistical analysis could be conducted with this subgroup of HB. Younger patients demonstrated significantly better survivals (1-year survival: 42 ± 13% if age ⩽45 and 0% if age >45, p = 0.004, Fig. 4B). Patients undergoing liver resection demonstrated improved survivals compared to those with biopsy and/or palliative treatment. One-year survival was 41 ± 12% in patients with resection and 0% in those with palliative management (p ⩽0.001, Fig. 4C). Chemotherapy had no impact on outcome. Patients reported since 1995 demonstrated better survivals than those reported prior to 1995, suggesting an improvement in the management of HB in adults (p = 0.018, Fig. 4D). Upon analysis of risk factors of the reported adult HB cases, the following variables did not impact on outcome: AFP-secretion (p = 0.34), size of largest tumour (p = 0.81) (univariate Cox analysis), as well as presence of metastasis (p = 0.51) (Kaplan Meier analysis).
      Figure thumbnail gr4
      Fig. 4Survival of adult hepatoblastoma patients. (A) Overall survival of adult hepatoblastoma patients (n = 34). Median survival: 2 months (95% CI 0.09–3.91). One-year survival: 24%. (B) Survival of hepatoblastoma patients younger than and older than 45 years. One-year survival: 42 ± 13% if age ⩽45 (n = 17), 0% if age >45 (p ⩽0.004, n = 17). (C) Survival of surgically treated patients with adult hepatoblastoma. One-year survival: 41 ± 12% in patients with resection (n = 17), 0% in those with palliative management (p ⩽0.001, n = 16). (D) Survival of adult patients with reported hepatoblastoma before and after 1995. Patients treated after 1995 show a better survival curve (p = 0.018, n = 17 in both groups).

      Conclusions

      Whether adult hepatoblastoma exists, remains controversial since many features of published cases are not found in paediatric HB and vice versa, and differential diagnoses were felt to be possible. However, the diagnosis of HB should be considered in adults presenting with primary liver tumours in the absence of pre-existing liver disease. Patients with immature tumour characteristics have a poor prognosis. In all patients, surgery should be the treatment of choice, neoadjuvant chemotherapy is advisable. Collaborative efforts are necessary to confirm the existence of adult HB and further characterise these rare tumours. Molecular tools may soon help in making this diagnosis. Multicentre efforts will help in designing standardised protocols.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Financial support

      A.L.R. was supported by a Fondation pour la Recherche Nuovo–Soldati Fund. C.T. was supported by the Swiss National Science Foundation (SCORE Grant 3232230–126233 ).

      Acknowledgements

      We thank Piotr Czaudzerna for sharing SIOPEL data and O James Garden for his suggestion to review adult HB.

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