Liver Tumors of Childhood

Incidence and Demographics

Although HB is a rare tumor (1 case per 1 to 1.5 million population), it is the most common primary malignant hepatic tumor in infancy and childhood, making up 55% of all malignant liver tumors in this age group. The peak incidence is in the first 2 years of life, and the vast majority (80% to 90%) of patients present before 5 years of age. Prenatal presentation is well documented and in rare cases has been associated with placental metastasis. There is a slight preference for boys. Infants with low or very low birth weight have a significantly increased risk of developing hepatoblastoma; improved survival of these infants probably contributes to the increased incidence of HB that has been observed in recent decades. Although the underlying etiopathogenesis is not clear, the therapeutic agents used to maintain low-birth-weight infants have been suspected to play a role. HB is also associated with the Beckwith-Wiedemann syndrome and familial adenomatosis polyposis.

Clinical Manifestations

HB commonly presents as an enlarging abdominal mass that may be associated with nonspecific symptoms and signs such as anorexia and weight loss. In up to 90% of patients, marked elevation of serum alpha fetoprotein (AFP) is noted. However, a subgroup of primary pediatric liver tumors shows low or normal levels of serum AFP; this group is associated with an aggressive clinical course and with special high-risk subtypes such as small cell undifferentiated HB. At diagnosis, extrahepatic disease may be present in up to 20% of cases. HB may be associated with paraneoplastic syndromes, including thrombocytosis and gonadotropin-induced precocious puberty.

Current Classification

Traditionally, HB has been classified into two main groups: epithelial hepatoblastoma (E-HB) and mixed epithelial and mesenchymal HB (MEM-HB). The most widely used classification, which is used in International SIOPEL trials, is shown in Box 35.1 . Although this classification is sufficient in most cases, the identification of novel phenotypes and availability of molecular and genetic data necessitated a revised and extended classification to integrate this new information ( Table 35.1 ). This classification separates members of the HB tumor family (in part novel or recently described phenotypes) from the clinically and therapeutically distinct hepatocellular carcinoma (HCC) family of tumors, and from hepatocellular adenoma. The working formulation shown in Table 35.1 also includes neoplasms that are in some respects similar to “classical” HB members, such as nested stromal-epithelial tumor and neoplasms that are characterized by epithelial-mesenchymal transition (EMT; tumors with features of EMT, or “EMT tumors”). These related lesions or lesions thought to be related to HB family members are still incompletely characterized in regard to potential ontogenetic and molecular relationships, mostly because of the rarity of cases and therefore a lack of collective experience.

An updated but simplified classification was however again necessary to assimilate accumulating knowledge about the more common subtypes such as those of fetal HB. An International Pathology Symposium held in March 2011 in Los Angeles arrived at such a classification by consensus between 22 expert pathologists of COG, SIOPEL, GPOH and JPLT as well as pediatric oncologists and surgeons ( Table 35.2 ). A novel group of lesions in this classification are neoplasms with pleomorphic or anaplastic, undifferentiated phenotypes. Some of these lesions may represent tumors intermediate between HBs and HCCs, and have previously been classified as transitional liver cell tumor (discussed in a later paragraph).

It is almost certain that classifications shown in Table 35.1 as well as entities listed in Table 35.2 will undergo further refinement as additional information is gained on molecular genetics, pathologic patterns, ontogenetic pathways, and therapeutic responses. It is also conceivable that information on shared pathogenic pathways may lead to regrouping of tumors; for example, nested stromal-epithelial tumor, mesenchymal hamartoma, and undifferentiated embryonal sarcoma (UES), currently considered to be disparate tumors, share features of epithelial-mesenchymal transition (EMT) (the concept of “EMT tumors”). In the meantime, these classifications will assist in the design of future therapies based on individual tumor molecular signatures, potentially leading to personalized treatments.

Radiologic Features and Gross Pathology

On ultrasound, HB are hyperechoic, solid masses. Computed tomography (CT) demonstrates delineated hypoattenuated masses in HB compared with normal adjacent tissue ( Fig. 35.1 ). Approximately 55% to 60% of HBs occur in the right lobe of the liver. Most lesions are solitary; only about 15% are multifocal at presentation. The interface of the tumors with adjacent liver is usually distinct. The cut surface is rather variegated, depending on the amount and distribution of hemorrhage and necrosis ( Fig. 35.2 ). Because the histopathologic sampling of resection specimens, both in those who have received presurgical chemotherapy and those who have not, markedly affects final tumor classification and therefore risk stratification, standardized work-up of these specimens is essential. A detailed protocol for examination of resection specimens of HB has been published, and it is recommended that these guidelines be followed.

Microscopic Pathology

Epithelial HB is further classified into fetal, embryonal, macrotrabecular (MT), or undifferentiated subtypes. Fetal-type HB cells are well-differentiated and indistinguishable from the cells in the normal fetal liver. Individual cells are medium-sized, with a cytoplasm that is either clear or eosinophilic, resulting in a characteristic “clear-and-dark-cell” pattern ( Fig. 35.3A–B ) ( eSlide 35.1 ). These cells are arranged in cords or slender plates with intervening sinusoids. In typical fetal HB, the number of mitotic figures is low, usually less than 2 per 10 high-power field (40×) (fetal, well-differentiated, with minimal mitotic rate). A characteristic feature is the presence of extramedullary hematopoiesis (see Fig. 35.3C ). Fetal-type HB may contain vascular areas that superficially resemble portal tracts; however, these areas lack bile ducts. In thin biopsies, this feature may be confused with normal liver (see Fig. 35.3D ). Although more common in tumors that have received presurgical chemotherapy, epithelial islands surrounded by stromal lamella may be observed in untreated fetal HB (see Fig. 35.3E ). A subset of fetal HB shows significant mitotic activity (>2 per 10 high-power field) (mitotically active fetal HB). These tumors should be differentiated from mitotically inactive HB; some protocols do not advocate presurgical chemotherapy for well-differentiated fetal HB that is mitotically inactive.

The embryonal phenotype is the most commonly encountered pattern and is usually found intimately admixed with fetal-type tissue, the mixed embryonal/fetal subtype. Embryonal histology resembles the morphology of the liver at 6 to 8 weeks of gestation; the cells are arranged in sheets interrupted by immature tubule-like profiles or rosettes. Embryonal HB cells exhibit less abundant cytoplasm and contain larger, more hyperchromatic nuclei. Numerous mitotic figures are seen in embryonal HB (see Fig. 35.3F–H ).

Macrotrabecular HB (MT-HB; Fig. 35.4 ) grows in the form of trabecula, which are 10 to 20 or more cells thick. Pure MT-HB is rare, but focal areas of MT subtype have been observed in almost 20% of cases. There is evidence that a subgroup of tumors with this morphology displays more aggressive behavior; these tumors are composed of cells that resemble adult HCC, “hepatocyte-like,” or “HCC-like” cells. To accurately characterize these phenotypes further, we have proposed to split MT-HB into two groups: MT1, which consists exclusively of hepatocyte-like cells, and MT2, which consists of large trabecula composed of fetal/embryonal cells. I expect the latter subgroup to be of standard risk and the former to exhibit the more aggressive behavior that has been associated with this subtype. It may be difficult to distinguish MT1 from transitional liver cell tumors (TLCTs; see later discussion) or even HCC.

Fetal, embryonal and macrotrabecular HB share distinct immunohistochemical features, whereas the small cell undifferentiated subtype has a different immunophenotype (see later). Differentiated forms of HB variably express cytokeratins 8, 18, and sometimes 19. Fetal-type cells with a “dark” cytoplasm are more strongly stained for cytokeratin 8 than clear cells. Osteoblast-like cells in tumor osteoid can express cytokeratins. HB are variably reactive for AFP and alpha-1 antitrypsin. Important diagnostic markers for HB are glypican-3 and glutamine synthetase, a key target of β-catenin. Cytoplasmic glypican-3 staining is found in almost all HB showing some degree of differentiation. Depending on cell differentiation and the mutational status, HB cell often express β-catenin in various patterns. Fetal cells usually show membranous staining, whereas less differentiated HB cells demonstrate cytoplasmic and/or nuclear staining. Nuclear staining is typical for cells with a mutated β-catenin gene. HB can express various markers associated with hepatic progenitor/stem cells.

Undifferentiated subtypes of HB may consist of small cells or intermediate cells and may demonstrate rhabdoid features. Hepatoblastoma composed of small, anaplastic-looking cells is termed small cell undifferentiated HB (SCUD; previously designated “anaplastic HB”). Clinically, these tumors show low or normal serum AFP levels. The cells of SCUD grow in a diffuse pattern ( Fig. 35.5A ) and are highly invasive, infiltrating adjacent liver parenchyma (see Fig. 35.5B ). SCUD-HB in its pure form is very rare, composing approximately 2% of all HB, but focal areas of SCUD admixed with other subtypes of HB are not infrequent. The SCUD phenotype is a high-risk lesion, and even focal expression of this phenotype (see Fig. 35.5C ) confers an adverse effect on outcome. However, the term SCUD-HB is best restricted to pure forms of this tumor. When the phenotype occurs focally, this feature should be mentioned in descriptive terms (eg, epithelial HB, fetal/embryonal, with focal SCUD). Immunohistochemically, SCUD cells coexpress epithelial and mesenchymal markers, being positive for both cytokeratin 8 and vimentin. Some cells are reactive for CD99, a phenotype termed primitive neuroectodermal tumor (PNET)-like small cell HB. The proliferation fraction in SCUD usually exceeds 80% (see Fig. 35.5 D ). SCUD-HB may occur in intimate association with rhabdoid tumor (RT). Whether or not this reflects a pathogenic connection between these two lesions is unknown, but it is pertinent that some cases of SCUD-HB, similar to RT, are INI1-negative, suggesting that at least this subset of SCUD cases may in fact represent small cell variants of RT. Both RT and INI1-negative SCUD are AFP-negative, high-risk lesions with poor response to chemotherapy. Exceptionally, undifferentiated HB is not characterized by small cells but by cells of intermediate or even large size, similar to what has been described in subsets of neuroblastoma and medulloblastoma. These tumors are called intermediate cell undifferentiated and large cell undifferentiated HB, or ICUD and LCUD, respectively.

Mixed epithelial and mesenchymal hepatoblastoma (MEM-HB) is characterized by an epithelial component of any subtype but most commonly fetal/embryonal and a mesenchymal component that is usually osteoid ( Fig. 35.6A ) ( eSlide 35.2 ). MEM-HB is encountered frequently in postchemotherapy resection specimens. It may or may not demonstrate teratoid components and is accordingly classified as MEM-HB with or without teratoid features; the latter being more common. Approximately 3% of MEM-HBs are termed teratoid (MEM-HB with teratoid features), an entity that must not be confused with teratomas that are germ cell tumors. Teratoid mixed HB show a varying number of cell lineages that deviate from the usual hepatoblast lineage, including neuroectodermal differentiation (melanocytes, glial cells, and neuronal cells) and endodermal differentiation resembling embryonal gut (see Fig. 35.6B–C ). Osteoid, immature-looking mesenchyme, smooth muscle cells/myofibroblasts, and squamous epithelium do not qualify for the diagnosis of teratoid HB.

Pathology of Treated Hepatoblastoma

Resection or transplantation of HB is often preceded by chemotherapy, and characteristic changes are seen in these postchemotherapy resection specimens. Macroscopically, response to chemotherapy causes shrinkage of tumors. The cut surfaces show a nodular pattern with large areas of necrosis and old hemorrhage ( Fig. 35.7A ). Histologically, the spectrum ranges from absence of viable tumor to various manifestations of residual HB. Residual fetal HB commonly presents as small nests or nodules of clear and/or dark cells embedded in fibrous tissue (see Fig. 35.7B ). When nests are very small, it may be difficult to identify them as viable tumor (see Fig. 35.7C ). In some cases, the presence of hematopoiesis indicates the site of previous fetal HB (see Fig. 35.7D ). Chemotherapy may induce changes in tumor cells, which may appear variably enlarged and sometimes multinucleated (see Fig. 35.7E ). Some treated HBs exclusively contain osteoid in the absence of viable epithelial tumor tissue; such lesions are best classified as mixed HB without teratoid features, epithelial component not otherwise specified (NOS). Extensive regressive changes, characterized by necrosis and fibrosis/scarring are seen (see Fig. 35.7F ) ( eSlide 35.3 ). Fibrous or sclerosed nodules, called “regression spheres,” may be seen embedded in a more diffuse fibrous area. These nodules, which often contain old blood and iron deposits in the center, probably represent altered large tumor blood vessels (see Fig. 35.7G ). Foci of squamous epithelium are most commonly seen in HBs that have received prior chemotherapy (see Fig. 35.7H ).

Staging of Pediatric Liver Tumors

The tumor, node, metastasis (TNM) system for liver tumors was mainly designed for use in adults with liver cancer and is not widely used for HB. Currently, two main staging systems for primary malignant liver tumors of childhood are in use. The system used by the American-based COG is based mainly on tumor resectability and findings at surgery; it is therefore most appropriate for use in treatment protocols that favor surgery immediately after diagnosis. Decreasing grades of resectability equate to higher tumor stage ( Table 35.3 ).

The pretreatment extent of disease (PRETEXT) system designed by SIOPEL is widely used to stage tumor before initiation of any treatment, including surgery. Although the PRETEXT system has been devised to stage all primary childhood liver tumors, it is most commonly used for staging of HB. PRETEXT staging is based on Couinaud’s liver segments; the eight segments are grouped into four sections (formerly called sectors): segments 2 and 3 comprise the left lateral section, segments 4a and 4b comprise the left medial section, segments 5 and 8 comprise the right anterior section, and segments 6 and 7 comprise the right posterior section. PRETEXT stages I to IV are based on the number of contiguous liver sections that are not involved by tumor ( Fig. 35.8 ). When applying a stage, it is important to distinguish actual involvement of the respective section from mere compression by the adjacent tumor. The PRETEXT system was revised in 2005 to improve original definitions, clarify criteria for extrahepatic disease, and add new criteria ( Table 35.4 ). This refinement of criteria allows identification of patients who would benefit from a high-risk treatment protocol.

Variants of Hepatoblastoma and Tumors Probably Related to Hepatoblastoma

Cholangioblastic hepatoblastoma represents a variant of HB characterized by the presence of cholangiocellular elements with or without detectable bile duct–like profiles. The prognostic significance of this phenotype is not yet known but is suspected to be unfavorable. Cholangioblastic features present in the form of bile duct–like structures embedded in HB or as cholangiocellular nodules at the periphery of the tumor ( Fig. 35.9A ). Immunohistochemically, the cholangiocellular components are reactive for cytokeratins 7 and 19.

Ductal plate tumors of the liver are a recently proposed entity and are defined as liver cell neoplasms in the form of cholangiocellular structures that morphologically mimic the embryonal ductal plate. These rare tumors occur in children, adolescents, and young adults, and they most likely represent a high-risk lesion (see Fig. 35.9B–C ).

Other novel variants of HB include a group of pediatric liver neoplasms characterized by a marked predominance of stromal elements with differentiation along several types of lineages. Epithelial components may be detectable but, unlike MEM-HB, form a very minor component of the tumor. These rare lesions have been termed pediatric hepatic stromal tumors (PHSTs). The stromal component consists of a spindle cell population of variable cellularity ( Fig. 35.10A ), sometimes with prominent myxoid change (see Fig. 35.10B ). Some PHST demonstrate predominant leiomyoid or rhabdomyoid differentiation (see Fig. 35.10C–D ), with marked reactivity for α–smooth muscle actin (see Fig. 35.10E ). Complex organoid patterns may also occur (see Fig. 35.10F ).

A distinctive tumor belonging to the stromal-epithelial group is the nested stromal epithelial tumor of the liver . It is an unusual hepatic tumor in children ranging from 2 to 14 years of age. Histologically, the lesions are characterized by organoid cohesive nests of epithelioid cells surrounded by a mantle zone of spindle cells, with variable cellularity and sometimes marked desmoplasia ( Fig. 35.11A ). Calcification and ossification are frequently seen (see Fig. 35.11B–C ). Immunohistochemically, the epithelioid nests are positive for cytokeratin 8, epithelial membrane antigen, CD56, and sometimes S100 protein, but they are negative for hepatocyte markers (see Fig. 35.11D ). The epithelioid cells show strong nuclear and focally, cytoplasmic reactivity for β-catenin (see Fig. 35.11E ). This finding has previously been reported. The spindle cells surrounding the nests are reactive for vimentin and smooth muscle actin, suggesting myofibroblastic features (see Fig. 35.11F ). Recent molecular and mutational analysis revealed large deletions in exon 3 of the β-catenin gene, and the tumor exhibits increased expression of EMT-associated factors such as SNAIL, SLUG, TWIST, c-met, and vimentin. These findings suggest that nested stromal epithelial tumor is related to HB and displays deranged EMT.

A further group of rare pediatric hepatic tumors, termed multilineage tumors , are wholly epithelial neoplasms with a highly diverse pattern of cell differentiation. Multilineage tumors is a term proposed to denote HB composed of cells apparently developing along several lines of differentiation, ranging from immature/undifferentiated cells to more mature-looking cells, including embryonal-type, fetal-type, and hepatocyte-like cells ( Fig. 35.12A ). Such lesions seem to cover the entire spectrum of liver cell ontogenesis and cannot be neatly allocated to standard subtypes of HB. The papillary-type HB is one variant of multilineage HB (see Fig. 35.12B ). Some HBs, including the SCUD subtype, may produce large amounts of intercellular substance and are called myxoid variants (see Fig. 35.12C–D ).

Genetics and Molecular Pathology

Hepatoblastomas exhibit complex patterns of chromosomal aberrations characterized by either gains or losses involving several chromosomes (eg, 1q, 2q, 4q, 8, 11q, 17q, and 20). Detailed analyses of the respective loci are not yet available, but molecular studies have uncovered several genetic changes involved in cell fate, growth, apoptosis, signaling pathways, and differentiation. Several gene products involved in cell cycle regulation and cycle checkpoint control may be altered in HB, including polo-like kinase-1 (the PLK1 oncogene), p16 protein (epigenetically hypermethylated in some HB), p27/KIP1 (preserved in well-differentiated fetal HB and lost in most SCUD-HB), and p53. Among growth factors, deregulation of the insulin-like growth factor II (IGF-II) mitogenic signaling pathway seems to play a role in HB. PLAG1 , encoding a sumoylated and phosphorylated zinc finger transcription factor, is overexpressed in HB and acts via IGF-II signaling. Patients with Beckwith-Wiedemann syndrome have an increased risk for HB. The molecular basis of Beckwith-Wiedemann syndrome is complex and involves deregulation of imprinted genes found in two domains within the 11p15 region. One telomeric domain is of specific interest because it involves loss of imprinting at IGF-II, in association with H19 silencing.

HBs are characterized by complex alterations in important cellular signaling pathways, the most prominent being those of Wnt/β-catenin signaling. Mutations of the β-catenin gene are the most frequent molecular alterations in sporadic HB, occurring in at least 50% of HBs, both in epithelial and mixed types. Mutations in the degradation box of the β-catenin gene cause proteasome bypassing of β-catenin and its accumulation in the nucleus, where it can then be detected by immunohistochemistry. Nuclear localization of β-catenin is more frequently found in less differentiated variants of HB, while it is present, together with E-cadherin, in a membranous staining pattern in the differentiated fetal subtype. HB cells showing changes in β-catenin expression are arranged in a distinctive pattern within tumors. We have observed that HB, particularly the fetal/embryonal subtype, exhibits numerous small spherical cell nests ( Fig. 35.13A ). The cells in these nests show marked nuclear positivity for β-catenin (see Fig. 35.13B–C ), whereas the surrounding tumor cells have membranous staining. The small cells are much less proliferatively active than the neighboring cells (see Fig. 35.13D ) and have scant cytoplasm poor in mitochondria in contrast to surrounding cells (see Fig. 35.13E ). In larger tumor nodules, nuclear β-catenin staining may be found exclusively in cells at the invasion front (see Fig. 35.13F ). These findings suggest a distinct tumor microarchitecture driven by heterogeneous expression of genetic events, especially in the β-catenin signaling pathway. In addition to β-catenin, other protein components of this signaling pathway have been shown to be mutated in HB, including axins 1 and 2 and APC . Mutations in APC , the underlying genetic abnormality in familial adenomatous polyposis, explain the association of HB with this entity.

Novel genomic features additionally identified in HB include the oncogene CAPRIN2 , the tumor suppressors SPOP , OR5l1 and CDC20B , upregulated genes at 2q24, changes in Hippo/YAP signaling, and alterations of the IGF2 regulator PLAG1 . There is increasing evidence that altered expression patterns of several microRNAs and long noncoding RNA (lncRNA) play a pathogenic role in HB.

Treatment and Prognosis

The three known factors of prognostic importance in HB are clinical stage, AFP levels, and some histologic subtypes. Before the introduction of current therapeutic strategies, only about 30% of patients with HB had resectable disease, which remains the mainstay of curative therapy. Introduction of effective cisplatin-based chemotherapeutic regimens in the mid-1980s and the efforts of large international cooperative trials have led to current cure rates of at least 70%. By inducing necrosis and shrinkage of the tumor, preoperative chemotherapy downstages tumors and renders them resectable. These markedly improved results were obtained in all major large studies that aim at treating HB with modern strategies (ie, SIOPEL, the North American groups, GPOH, JPLT). The second SIOPEL trial (SIOPEL-2) stratified patients into standard- and high-risk groups: patients with standard risk received presurgery cisplatin, whereas those at high risk received presurgery cisplatin alternating with carboplatin, plus doxorubicin. Both groups subsequently underwent surgery and postsurgery chemotherapy. The 3-year overall and progression-free survival was 91% and 89% for the standard-risk group, and 53% and 48% for the high-risk group, respectively. In current SIOPEL treatment protocols, patients with HBs are stratified for distinct therapy protocols into high-risk and standard-risk groups ( Table 35.5 ).

The role of histology in prognosis and risk assessment is certain only for a few subtypes of HB. Pure fetal histology has excellent prognosis. Some centers in the United States do not recommend adjuvant chemotherapy in completely resected stage I, mitotically inactive pure fetal HB. This is in contrast to SIOPEL treatment protocol that treats all children with preoperative chemotherapy. Small cell undifferentiated HB (SCUD-HB) and its variants are regarded as high-risk lesions, even when present focally. This phenotype has recently been shown to be overrepresented in a high-risk subgroup of HB with low serum AFP levels at diagnosis. In addition, there is increasing evidence that a subset of HB with an apparent small cell undifferentiated phenotype either belongs to the RT group, or at least contains RT components (INI1 negative); these neoplasms are high-risk lesions. Of pediatric liver cell tumors composed of cells that resemble mature hepatocytes rather than hepatoblasts, TLCTs and HB-MT1 are considered to be high-risk lesions. The latter is a subgroup of MT-HB that is made up of hepatocyte-like or HCC-like cells, in contrast with MT2, which is made of macrotrabecular consisting of embryonal or fetal type cells. Definite evidence of enhanced risk in HB-MT1 is awaited from current large prospective trials.

Clinical Manifestations

The chief manifestations include detection of a liver tumor in individuals, usually older than 5 years of age; large and initially solitary tumors, commonly in the right liver lobe, sometimes with satellite nodules; and high or very high serum AFP levels.

Radiologic Features and Gross Pathology

CT scans show large, more or less spherical, hypodense, nonhomogeneous tumors. The lesions are of the expanding type with pushing borders, and they sometimes exhibit large central necrosis.

Microscopic Pathology

The pertinent histologic features of TLCT include the following:

• 1.

  A growth pattern that is more commonly diffuse than trabecular or MT ( Fig. 35.14A )

• 2.

  Relatively poor stromal development

• 3.

  Lack of a typical sinusoidal architectural pattern

• 4.

  Predominance of a cell type resembling hepatocytes or HCC cells but somewhat smaller

• 5.

  Presence of HB-like cells, chiefly fetal-type cells, intermingled with the former cell type (see Fig. 35.14B )

• 6.

  Multinuclear syncytial giant cells

• 7.

  Acinar-like profiles, mainly at the periphery of the tumor

Immunohistochemically, marked reactivity for AFP is present, sometimes more in the center of tumor nodules. Focal expression of biliary markers (cytokeratins 7 and 19) is seen in part of the tumors (see Fig. 35.14C ). The lesions markedly express β-catenin, typically in a mixed nuclear and cytoplasmic pattern (see Fig. 35.14D ).

Differential Diagnosis

The main differential diagnoses include MT-HB and HCC. In small samples, the diagnosis may be difficult, and some TLCTs have probably been labelled HB in the past. In such situations, the clinical presentation, including patient age, radiologic features, and AFP status, are important factors in arriving at the correct diagnosis.

Treatment and Prognosis

TLCTs are highly aggressive lesions that are resistant to the chemotherapy regimens currently used for the treatment of HB. The biology of TLCT therefore seems to be closer to that of HCC than to HB.

Incidence and Demographics

FLC accounts for less than 10% of all HCCs but represents about 30% of all HCCs found in patients younger than 20 years of age. In contrast with adult-type HCC, FLC develops in the absence of underlying chronic liver disease, specifically in the absence of cirrhosis. Based on a retrospective study using data from the registries of the SEER program, FLC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases in individuals younger than 40 years of age.

Clinical Manifestations

Patients with FLC present with an abdominal mass in the presence or absence of abdominal discomfort or pain, with infrequent jaundice and usually normal serum AFP. Unsaturated vitamin B ₁₂ –binding protein may be elevated in serum. FLC may be associated with gynecomastia, and aromatase has been detected in some male patients.

Radiologic Features and Gross Pathology

CT shows well-defined margins in close to 80% of cases and a central scar in 70% of lesions. Macroscopically, FLC usually presents as a solitary, well-circumscribed tumor. In contrast with most liver tumors, approximately two thirds arise in the left lobe. The cut surface usually has a firm, tan to brown appearance with radiating septa ( Fig. 35.15A ). In a study of 41 patients, median tumor size was 9 cm (range, 3 to 17 cm); of these patients, 36% of cases had vascular invasion and 50% had lymph node metastasis.

Microscopic Pathology

Bands or columns of large, polygonal, and strongly eosinophilic epithelial cells are embedded in a rich and partly sclerosed stroma, forming the parallel fibrous lamellae that give the lesion its name (see Fig. 35.15B ) ( eSlide 35.4 ). The fibrous stroma may be more pronounced in the center, with formation of a stellate scar-like structure, similar to focal nodular hyperplasia (FNH). About 30% to 50% of tumor cells exhibit large and lightly eosinophilic, ground glass–like cytoplasmic inclusions, so-called pale bodies (see Fig. 35.15C ). Periodic acid–Schiff (PAS)-positive inclusions may also be found. A clear cell variant of FLC has been described. Immunohistochemically, a distinct feature of FLC is marked reactivity for cytokeratin 7 (see Fig. 35.15D ). The tumor cells are variably positive for fibrinogen, which in many cases stains the pale bodies previously described, as well as ferritin and alpha-1 antitrypsin. The latter correspond to PAS-positive inclusions.

Differential Diagnosis

Differential diagnosis mainly includes well-differentiated adult-type (ordinary/classical) HCC, particularly variants with marked stromal reaction.

Genetics and Molecular Pathology

FLC is clearly different from ordinary HCC with respect to genetic and molecular features. A characteristic molecular signature comprising a recurrent and specific chimeric transcript assigned to chromosome 19 has been found in FLC. This transcript encodes a fused protein that contains the amino-terminal domain of DNAJB1, a chaperone DNAJ homolog, fused in frame with the catalytic domain of protein kinase A, PRKACA (the DNAJB1-PRKACA fusion). The fusion protein is oncogenic and is associated with increased cAMP-dependent protein kinase A signaling. The targets of the fusion protein are not yet elucidated but may include interactions with fibroblast growth factor receptor (FGFR) functions. FLC exhibit polysomy of chromosome 8 and the FGFR1 locus, suggesting an altered FGFR1-mediated signaling pathway. A further fusion observed in FLC is a translocation between CLPTM1 and GLIS3 genes, resulting in a transcript that induces malignant transformation in cell lines.

Treatment and Prognosis

Anecdotally, FLC has been reported to have higher resection rates and better survival when compared with adult-type HCC. This has however not been confirmed in more rigorous studies, which have shown that when compared stage for stage, response to therapy and outcomes of FLC are not different from those of HCC.

Incidence and Demographics

HCC is rare in children and young adults; only 0.5% to 1% of all cases of HCCs occur in individuals younger than 20 years of age. More than two thirds of cases occur in children older than 10 years of age, and very few cases occur in children younger than 5 years of age. The incidence of pediatric HCC is 0.5 to 1.0 case per million in Western countries and 2.1 cases per million in Southeast Asia, an area endemic for hepatitis B virus infection.