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Pathology of malignant liver tumors

Pathology of malignant liver tumors
Literature review current through: Jan 2024.
This topic last updated: Oct 19, 2022.

INTRODUCTION — Primary malignant liver tumors resemble and arise from the major constituent cells of the liver, namely hepatocytes (giving rise to hepatocellular carcinoma), biliary epithelial cells (cholangiocarcinoma and biliary cystadenocarcinoma), endothelial cells (angiosarcoma, epithelioid hemangioendothelioma), or combinations of these cells with various mesenchymal cells (eg, hepatoblastoma) [1]. Some (eg, combined hepatocellular-cholangiocellular carcinoma) represent collision of two different tumors or may result from malignant transformation of hepatic progenitor cells with differentiation along two different cell lineages. Secondary liver tumors (ie, metastases from a non-liver primary site) are the most frequent malignant liver tumor, outnumbering primary malignant liver tumors by a large margin (30 to 1 in one series [1]), particularly in patients without underlying liver disease. Furthermore, many now consider primary liver tumors as a continuum, with typical hepatocellular carcinoma and cholangiocarcinoma at the two ends of the spectrum and a range of tumors in between showing variable degrees of hepatocellular and cholangiocarcinoma differentiation, including those with progenitor or stem cell features [2].

Several premalignant lesions that arise in the liver have been extensively studied in order to better understand both hepatocarcinogenesis and cholangiocarcinogenesis [3,4].

Premalignant hepatocellular lesions include:

Dysplastic foci, characterized by cytologic small cell change

Dysplastic nodules, encompassing low-grade dysplastic nodules and high-grade dysplastic nodules

Premalignant biliary lesions are:

Biliary intraepithelial neoplasia

Intraductal papillary neoplasm of bile duct

Mucinous cystic neoplasm (also known as cystadenoma and its malignant counterpart cystadenocarcinoma)

This topic review will cover the pathologic appearance of malignant liver tumors, including invasive and premalignant lesions (table 1). The clinical presentation, diagnosis, and staging of these neoplasms is presented elsewhere.

HEPATOCELLULAR CARCINOMA — Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver with hepatocellular differentiation. HCC commonly develops in patients with chronic liver disease with or without cirrhosis [5]. Cirrhosis itself is the greatest single risk factor for the development of HCC. The incidence of HCC varies geographically according to the different levels of exposure to specific risk factors, such as chronic hepatitis B or C virus infection, exposure to aflatoxin (in resource-limited countries), and alcohol abuse and smoking (in developed countries). Other factors that increase the risk of HCC are nonalcoholic steatohepatitis, hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. Up to 30 percent of HCCs in non-cirrhotic liver appear to arise from hepatic adenomas [6]. Although hepatitis C remains the most common cause of HCC among United States patients for liver transplantation, nonalcoholic steatohepatitis has been increasing steadily over the past two decades as the second most common cause [7]. (See "Epidemiology and risk factors for hepatocellular carcinoma" and "Hepatocellular adenoma", section on 'Malignant transformation'.)

Classification — The 2019 World Health Organization (WHO) classification categorizes HCC not otherwise specified and several variants (fibrolamellar, scirrhous, clear cell type, steatohepatitic, macrotrabecular, chromophobe, neutrophil rich, and lymphocyte rich) as subtypes of HCC [8]. Hepatoblastoma is categorized separately, and combined hepatocellular-cholangiocarcinoma is classified under malignant biliary tumors [9]. (See 'Hepatoblastoma' below and 'Combined hepatocellular-cholangiocarcinoma' below.)

In addition to general WHO tumor type classification, other pathologic descriptions of HCC are often used as well; they are based on degree of differentiation (Edmonson-Steiner grading: well differentiated, moderately differentiated, poorly differentiated, and undifferentiated), morphologic pattern (trabecular, solid, pseudoglandular, scirrhous, inflammatory, steatohepatitic), or cell type (clear cell, small cell, spindle cell, giant cell).

Gross pathology — HCC may form a large solitary circumscribed nodule with or without adjacent smaller satellite nodules. In the presence of cirrhosis, HCC may be multinodular within one lobe, which consists of multiple nodules scattered throughout the liver, or may infiltrate the liver diffusely without forming circumscribed nodules (ie, nodular, diffuse, expansive, infiltrative, multifocal, etc) [10-12], but none has proven useful for prognostication or guiding therapy.

HCCs are usually soft, tan to yellow, often bile-stained, and show areas of necrosis and hemorrhage. Large vessel vascular invasion can be identified on gross examination, and the frequency increases with tumor size. The portal vein and hepatic veins as well as the vena cava may be involved (picture 1). Invasion of major bile ducts is an uncommon finding, but when present, it can cause biliary obstruction.

Small tumors (<5 cm if solitary, or up to three nodules, each smaller than 3 cm) have a better prognosis [13], while the presence of satellite nodules [14] and major vessel invasion are adverse features [15-17]. For patients undergoing tumor resection, the main predictor of poor outcome is incomplete resection [18]. (See "Staging and prognostic factors in hepatocellular carcinoma".)

Necrosis and fibrosis are often observed in tumors that were treated with radiofrequency or microwave ablation or transarterial chemoembolization (TACE). Although imaging studies can differentiate responders and nonresponders, the exact correlation between the extent of necrosis and disease outcome remains unclear, and imaging may overestimate the extent of necrosis [19,20]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation" and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation".)

Histology

Hepatocellular carcinoma — The cells of HCC resemble hepatocytes in function, cytologic features, and growth patterns. The degree of differentiation reflects the resemblance of tumor cells to normal hepatocytes. When the tumor is less differentiated, the neoplastic cells lose their hepatocyte trait/features or acquire changes seen in other tumors, which presents a diagnostic challenge.

Well-differentiated HCCs are often small (<2 cm) and composed of cells with mild atypia, arranged in a thin trabecular pattern with rare pseudoglandular structures (picture 2). The tumor cells are typically polygonal with granular and eosinophilic cytoplasm (picture 2). The tumor cells may secrete bile, an exclusive feature of HCC (picture 3), and contain fat (picture 4), glycogen (picture 5), Mallory-Denk hyalins (picture 6), hyalin globules, or fibrinogen (picture 7) mimicking or in exaggeration of normal hepatocyte function. A large amount of cytoplasmic fat and/or glycogen causes a clear cell appearance, which may be difficult to distinguish from metastatic clear cell renal cell carcinoma.

Most often the tumor grows in a trabecular pattern, with cords of cells separated by vascular sinusoids that are lined by endothelial cells (picture 8), mimicking the cell plates and sinusoids of normal liver (picture 2). The microtrabecular pattern consists of a thin cord of cells (picture 9), and the macrotrabecular pattern is formed by a thick cord of cells (picture 10). Expansion of the trabeculae may compress the sinusoids and form a solid or compact pattern of growth. Dilated bile canaliculi, often containing bile and producing a pseudoglandular pattern (picture 11), may be seen in the centers of trabeculae. Connective tissue stroma is sparse in typical HCCs, and reticulin fibers are significantly reduced or absent.

Moderately differentiated HCCs are usually larger tumors (>3 cm), and they are composed of polygonal tumor cells in thick trabecular pattern with frequent pseudoglandular pattern (picture 12).

Poorly differentiated HCCs are composed of pleomorphic tumor cells in a solid or compact growth pattern (picture 13).

Subtypes — There are several subtypes of HCC based on the 2019 WHO classification: steatohepatitic, clear cell, macrotrabecular massive, scirrhous, chromophobe, fibrolamellar, neutrophil rich, and lymphocyte rich.

In addition, there are also other less common histologic subtypes of HCC, such as spindle cell/sarcomatoid, giant cell, undifferentiated, and small cell subtypes. Resected HCCs often have mixed patterns/subtypes, usually trabecular with one or two other subtypes.

The tumor cells of the steatohepatitic subtype contain fat accompanied by intratumoral inflammation and fibrosis (picture 14). This subtype resembles the changes seen in fatty liver disease (steatohepatitis).

The clear cell subtype is composed of tumor cells with abundant glycogen accumulation, resulting in clear cytoplasm (picture 15).

The macrotrabecular massive subtype demonstrates trabeculae >10 cells in thickness (picture 16). The macrotrabecular massive subtype has been associated with worse prognosis, large tumor size, high alpha-fetoprotein (AFP) level, satellite nodules, and vascular invasion [21,22].

The sclerosing or scirrhous subtype [23] is morphologically composed of tumor cells in a background of dense fibrous stroma rather than the sinusoids that are typical for HCC (picture 17). This HCC subtype should be differentiated from cholangiocarcinoma, which typically shows abundant dense desmoplastic fibrous stroma. (See 'Cholangiocarcinoma' below.)

The fibrolamellar subtype differs clinically, histologically, and molecularly from other HCC subtypes and is discussed in detail below. (See 'Fibrolamellar subtype' below.)

The chromophobe subtype resembles the clear cell subtype and histologically mimics chromophobe renal cell carcinoma. The nuclei are predominantly uniform, with scattered single or clusters of anaplastic cells.

The spindle cell subtype, which has a worse prognosis than conventional HCC [24,25] mimics metastatic sarcoma (picture 18), but extensive sampling may yield polygonal hepatoid cells, which are diagnostic of HCC.

The giant cell subtype is considered to be a poorly differentiated form of HCC and is composed of large, multinucleated giant cells (picture 19). It should be differentiated from metastatic giant cell carcinoma from other organs. (See "Pathology of lung malignancies", section on 'Giant cell carcinoma'.)

The inflammatory lymphoepithelioma-like subtype (lymphocyte rich) contains pleomorphic tumor cells in a syncytial growth pattern with a lymphocyte-rich background (picture 20).

The small cell subtype often demonstrates neuroendocrine differentiation similar to other small cell neuroendocrine carcinomas arising in other organs; a metastatic small cell carcinoma (usually of lung origin in smokers, but occasionally extrapulmonary) should be in the differential diagnosis. (See "Pathobiology and staging of small cell carcinoma of the lung" and "Pathology of lung malignancies" and "Extrapulmonary small cell cancer".)

Extensive sampling of these uncommon HCC subtypes may demonstrate minor areas of typical HCC. In addition, these special HCC subtypes may lose the HCC-specific antigenicity usually seen in conventional HCC and may not stain with the usual immunohistochemical reagents. (See 'Immunohistochemistry' below.)

Dysplastic focus — Dysplastic focus is an expansile microscopic focus of hepatocytes with cytologic changes indicative of dysplasia and measuring less than 1 mm [26]. Dysplasia as a premalignant change in hepatocarcinogenesis takes the form of small cell change [27], which is cytologically recognized as hepatocytes with decreased cytoplasmic volume, cytoplasmic basophilia, mild nuclear pleomorphism and hyperchromasia, and increased nuclear cytoplasmic ratio (picture 21). According to the original definition, dysplastic focus measures <1 mm in diameter, but this arbitrary size criterion is related to the fact that the microscopic lesions are usually contained within a single cirrhotic nodule [8]. A dysplastic focus is often free of iron deposition (ie, iron-free focus) in a liver with hemochromatosis [28].

Unlike small cell change, large cell change (picture 22) is not directly related to hepatocarcinogenesis (in other words it is not a premalignant lesion), but it has been linked to cellular senescence and it is more prevalent in cirrhotic livers with HCC [29]. Large cell transformation is an important independent risk factor for the subsequent development of HCC, and its presence may be used to identify a subgroup of patients at high risk for HCC requiring more intensive screening [30,31].

Dysplastic nodules — Dysplastic nodules are considered preneoplastic lesions, supported by the accumulation of evidence that points to the existence of a sequence of events in dysplastic nodules that precedes the emergence of HCC [4,32]. The evolution of dysplastic nodules into early carcinoma includes induction of an arterial blood supply and stromal invasion [33]. They are usually (but not exclusively) detected in cirrhotic livers. On cut surface, dysplastic nodules bulge and differ from the surrounding cirrhotic liver.

Dysplastic nodules are classified into low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs) based on cytologic and architectural atypia as seen on microscopic examination:

In LGDN, the hepatocytes rarely show a clonal population, and there is minimal nuclear atypia and only a slight increase in the nuclear:cytoplasmic ratio. Large cell change is often present, but mitotic figures are absent. Without obvious clonal population, the distinction between LGDN and a large regenerative nodule is difficult and does not carry any practical consequences as long as the nodules lack the features of HGDN.

HGDN shows cytologic and/or architectural atypia but is insufficient for the diagnosis of HCC. Small cell change and architectural atypia, such as thick plates (up to three cells thick) and occasional pseudoglandular structures, are common in HGDN. In needle biopsies, the differential diagnosis between HGDN and well-differentiated HCC may be difficult or impossible. The vascular supply of dysplastic nodules is altered, particularly in HGDN, where unpaired arteries can occasionally be found with increase of sinusoidal capillarization beyond the vicinity of portal tracts as demonstrated by immunostaining for CD31 or CD34. (See 'Immunohistochemistry' below.)

A combination of glypican-3 (GPC3), heat shock protein 70 (HSP-70), and glutamine synthetase immunostaining may aid the distinction between HGDNs and HCCs. (See 'Immunohistochemistry' below.)

Small and early hepatocellular carcinoma — Small HCCs up to 2 cm in diameter are classified into distinctly nodular type and vaguely nodular type. Distinctly nodular HCCs (also known as progressed HCCs) are mostly moderately differentiated, lack portal tracts, and show evidence of microvascular invasion. Vaguely nodular HCCs (also known as early HCCs or small HCC with indistinct margins) retain the basic architecture of the background cirrhotic liver, and the neoplastic cells grow in and replace the nonneoplastic liver cords. The small neoplastic cells (reminiscent of small cell change) are arranged in irregular, thin trabeculae with pseudoglandular structures or fatty changes. They grow around preexisting portal tracts and/or invade the portal tracts (stromal invasion). A fibrous capsule is lacking, and the tumor contains "entrapped" portal tracts (picture 23).

Most vaguely nodular HCCs are well-differentiated HCCs. Most of these nodules are clinically hypovascular because of the insufficient development of unpaired tumor arteries and incomplete sinusoidal capillarization. Distinctly nodular HCC or progressed HCC is biologically more advanced and usually of higher grade, and there are typical HCC features and well-developed unpaired tumor arteries, which facilitate their detection by contrast enhanced imaging methods. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Computed tomography'.)

Small nodules with a "nodule-in-nodule" appearance are either HGDN with a subnodule of HCC, or a well-differentiated HCC with a subnodule of moderately differentiated HCC. Radiologically, these are detected as hypovascular nodules containing a hypervascular focus on contrast images, which indicates malignancy [34]. Nodule-in-nodule HCC is considered to be evidence of multistep hepatocarcinogenesis [35], where the inner, less-well-differentiated subnodule progressively overtakes the outer, better differentiated component of the tumor.

Stromal invasion, as an important criterion of a carcinoma, is easier to identify in distinctly nodular HCC but is obscured in the vaguely nodular type. The absence of cytokeratin (CK)7-positive duct staining is a feature of areas of stromal invasion in small HCC and can be helpful in distinguishing small HCCs from minimally invasive HCCs of the vaguely nodular type, and overtly invasive HCCs of the distinctly nodular type. (See 'Immunohistochemistry' below.)

Immunohistochemistry — Immunohistochemistry can aid in the diagnosis and differential diagnosis. In well-differentiated and moderately differentiated tumors, the trabeculae are lined directly by CD34 or CD31-positive endothelial cells (picture 24). The presence of bile canaliculi may be highlighted by polyclonal carcinoembryonic antigen (pCEA) or CD10 (picture 25) [36,37]. The canalicular pattern of staining for pCEA or CD10 indicates hepatocellular differentiation and is diagnostic of HCC. The tumor cells may also contain AFP or alpha-1-antitrypsin or fibrinogen that can be demonstrated by immunohistochemical staining. However, high serum levels of the tumor marker AFP do not correlate with positive AFP immunostaining. AFP immunostaining is positive in fewer than 40 percent of HCCs [36]. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Alpha-fetoprotein'.)

Immunohistochemically, most well- to moderately well-differentiated HCC's are positive for hepatocyte paraffin 1 (HepPar1) (picture 26), arginase-1, bile salt export pump transporter, cytoplasmic thyroid transcription factor-1 (TTF1) (picture 27), glutamine synthetase, GPC3, and CK8 and 18 [38-43]. Arginase-1 is the most sensitive marker for all levels of differentiations of HCC, while glypican-3 is highly sensitive for poorly differentiated tumors [43]. The combination use of arginase-1 and glypican-3 enables identification of nearly all cases of poorly differentiated HCC.

Fewer than 5 percent of HCCs may be positive for CDX2 [44]; therefore, aberrant CDX2 expression in a liver tumor does not completely exclude a diagnosis of HCC.

Immunostaining with a combination of GPC3, HSP-70, and glutamine synthetase may aid the distinction between HGDNs and HCCs [41,45]. At least two diffusely positive stains out of the three markers are seen in early or well-differentiated HCC. (See "Clinical features and diagnosis of hepatocellular carcinoma" and "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Clinical practice guidelines'.)

Stromal invasion, as an important criterion of a carcinoma, is easier to identify in distinctly nodular HCC but is obscured in the vaguely nodular type. The absence of CK7-positive ductular reaction is a feature of areas of stromal invasion in small HCC and can be helpful in distinguishing small HCCs from dysplastic nodules, minimally invasive HCCs of the vaguely nodular type, and overtly invasive HCCs of the distinctly nodular type [46]. (See "Approach to the adult patient with an incidental solid liver lesion".)

CK19 staining is a surrogate marker for progenitor cell origin, and its positivity in HCC (>5 percent) indicates activation of the epidermal growth factor signaling pathway, which correlates with aggressive behavior, microvascular invasion, fibrous stroma, less tumor-capsule formation, the presence of lymph node and extrahepatic metastasis, early relapse, and poor disease-free survival [47-50]. Other progenitor cell markers, EpCam, SALL4, and CD56, are often used in combination with CK19 in the investigation of the progenitor cell component or the so-called "stemness" feature of HCC.

In addition to necrosis and fibrosis, increased expression of CK19 and areas of biliary differentiation ("progenitor cell phenotype") often occur after chemoembolization treatment [51,52].

Endothelial cell-specific molecule 1 (ESM1) is overexpressed in many macrotrabecular massive HCCs; therefore, ESM1 immunostaining of sinusoidal stromal cells surrounding trabeculae helps to identify macrotrabecular architecture in HCC [53].

Molecular classification — Progress in HCC gene profiling over the past several years has revealed frequent mutations and chromosome alterations in multiple genes including the telomerase reverse transcriptase (TERT) promoter, beta-1 catenin (CTNNB1), TP53, axis inhibitor-1 (AXIN1), AT-rich interaction domain-containing protein 1A (ARID1A), nuclear factor erythroid 2-like 2 (NFE2L2), ARID2, tuberous sclerosis 1 (TSC1), TSC2, and ribosomal protein S6 kinase 90-kD 3 (RPS6KA3) [54-58]. CTNNB1 and TP53 mutations are mutually exclusive. Although the histologic and molecular features of HCCs are very heterogenous, there are several histologic subtypes of HCCs that are known to harbor specific genetic alterations [56] (see 'Hepatocellular carcinoma' above):

TERT promoter mutation is the most common somatic mutation in approximately 40 to 65 percent of HCCs.

Patients with TERT promotion are older and are more likely to be hepatitis C virus (HCV) positive or have a history of alcoholism.

HCCs in patients with aflatoxin B1 exposure and/or who are hepatitis B virus (HBV) positive commonly show TP53, ERFF1, and nuclear receptor corepressor (NCOR) 1 mutations. NCOR mutations function as a suppressor of beta catenin expression [57]. TERT promoter mutation is only seen in fewer than 10 percent of these HCCs due to recurrent integration of HBV into the TERT promoter [59].

HCCs in HCV-positive patients more commonly show TERT promoter mutations, CTNNB1 mutations, and cyclin-dependent kinase inhibitor 2A (CDKN2A) silencing.

Well-differentiated, often cholestatic, HCCs are associated with CTNNB1 mutation.

Poorly differentiated (picture 13), highly proliferative, and macrotrabecular-massive (picture 10) HCCs often harbor TP3 mutations and fibroblast growth factor 19 (FGF19) amplification.

Scirrhous HCC is characterized by TSC1/TSC2 mutations and an increase in transforming growth factor beta (TGFB) signaling.

Steatohepatitic HCCs show frequent IL-6/JAK/STAT activation without CTNNB1 and TP53 pathway alterations.

Tumors with the progenitor/stem cell phenotype commonly harbor RP6SKA3 and TP53 mutations.

Isocitrate dehydrogenase (IDH) 1/2 mutations are more frequent in intrahepatic cholangiocarcinomas than in HCCs. HCCs with IDH mutations are associated with poor prognosis. IDH mutations indicate a shift toward the biliary phenotype, even when tumors do not show mixed morphology or have progenitor/stem cell features.

HCCs belonging to the "immune-specific class" demonstrate molecular features resembling those of tumors most responsive to immunotherapy, such as high infiltration of immune cells, expression of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), and active interferon gamma signaling [60]. PD-L1 immunostaining, however, does not correlate well with immune-class HCC and cannot be used to predict response to immunotherapy [61]. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Checkpoint inhibitor immunotherapy'.)

Fibrolamellar subtype — Fibrolamellar carcinoma is a distinctive HCC subtype that differs clinically, histologically, and molecularly from other HCC subtypes [62-64]. It affects younger individuals 5 to 35 years of age. In contrast to conventional HCC, it does not show male predominance, involving both sexes equally, and is not associated with cirrhosis or chronic viral hepatitis. In general, fibrolamellar carcinoma has better prognosis than conventional HCC. Patients present with abdominal mass or pain. Serum AFP levels are normal in 90 percent of cases. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma".)

Grossly fibrolamellar carcinoma commonly forms a solitary, large, firm, well-circumscribed tumor, which may be encapsulated. The cut surface demonstrates gray-white fibrous bands, which subdivide the tumor into smaller nodules resembling focal nodular hyperplasia.

Histologically, fibrolamellar carcinoma consists of large polygonal tumor cells with eosinophilic granular cytoplasm, large vesicular nuclei, and prominent nucleoli (picture 28). The cytoplasmic eosinophilia and granularity are due to abundant mitochondria. The cells are separated into various-sized clusters by parallel lamellae of hyaline/hypocellular fibrous tissue. Fibrinogen-containing tumor cells with "pale inclusions" or "hyaline bodies" are often present, similar to conventional HCC. Pseudoglandular areas are occasionally present and may contain bile or mucin-like material (picture 29), which can be mistaken for combined hepatocellular-cholangiocarcinoma. (See 'Combined hepatocellular-cholangiocarcinoma' below.)

The immunohistochemical profile is similar to that of HCC, such as positive staining for HepPar1, GPC3, arginase-1, and pCEA, and CD10 positivity. However, immunostaining for CK7 and epithelial membrane antigen (EMA) is positive in fibrolamellar carcinoma only, suggesting possible dual cholangiocyte and hepatocyte differentiation of this tumor [65]. Immunostain for CD68 is also specific for fibrolamellar carcinoma; its expression is associated with the CD68 gene that encodes a transmembrane glycoprotein located within lysosomes and endosomes [66]. Although fibrolamellar carcinomas have a similar fibrogenic property to scirrhous HCC, only fewer than 40 percent of fibrolamellar carcinomas express progenitor cell markers such as CK19 and EpCam [67,68]. (See 'Immunohistochemistry' above.)

Molecular pathogenesis — The pathogenesis remains largely unknown. However, a recurrent unique fusion gene between DNAJB1 (DnaJ/HSP40 homolog, subfamily B, member 1) and PRKACA (protein kinase, cAMP-dependent, catalytic, alpha), DNAJB1-PRKACA, has been reported in fibrolamellar carcinomas but not in other HCC variants or cholangiocellular tumors [64,69,70]. Preliminary data suggest that the fusion protein plays a transformative role, although its role in pathogenesis is not conclusively established [70].

CHOLANGIOCARCINOMA — A cholangiocarcinoma (CC) is an adenocarcinoma arising from biliary epithelium. CCs may occur anywhere along the biliary tree from small bile ducts, bile ductules, and remnants of ductal plate in the liver (intrahepatic CC) to large hilar and extrahepatic bile ducts (extrahepatic CC) [71]. A Klatskin tumor is an extrahepatic CC that arises at the common hepatic duct bifurcation. (See "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma", section on 'Bismuth-Corlette classification for perihilar tumors'.)

A distinction is made between intrahepatic and extrahepatic CC not only because of differences in anatomic location, but also because they have distinct risk factors, clinical presentation, therapy, and epidemiology. Therefore, the term "cholangiocarcinoma" has been proposed exclusively for intrahepatic tumors, and the term "bile duct carcinoma" for tumors arising from large bile ducts both at the hilum and along the extrahepatic biliary tree. However, this terminology is not uniformly utilized. (See "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma".)

Intrahepatic CCs account for fewer than 20 percent of CCs. In the majority of cases, no underlying liver disease is identified, although some epidemiologic studies suggest chronic (HCV) infection as a major risk factor for intrahepatic CC. It remains unclear how HCV is involved in cholangiocarcinogenesis. (See "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma", section on 'Viral hepatitis'.)

Biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of bile duct (IPNB) are considered to be in situ lesions in the multistep progression of cholangiocarcinogenesis.

Gross pathology — There are differences in gross morphology and microscopic features of intrahepatic and extrahepatic CCs. Intrahepatic CCs are divided on the basis of morphologic appearance into mass forming, periductal infiltrating, and intraductal subtypes:

Mass forming intrahepatic CCs are multilobulated, unencapsulated, firm, white-gray tumors, owing to extensive desmoplastic stroma. The morphologic appearance is that of a sclerosing or scirrhous adenocarcinoma.

The periductal infiltrating subtype shows extensive infiltration along intrahepatic portal structures.

The intraductal subtype is confined within large bile ducts often with papillary architecture. The intraductal subtype is now referred to as IPNB and considered to be an in situ lesion. (See 'Intraductal papillary neoplasm of bile duct' below.)

In contrast, extrahepatic CCs typically form ill-defined, infiltrating, firm lesions in the hepatic hilum or along the extrahepatic bile duct.

Histology and immunohistochemistry — Intrahepatic CCs are usually well to moderately differentiated adenocarcinomas, classically consisting of small well-differentiated uniform neoplastic glands, or larger elongated or tortuous glands composed of cuboidal neoplastic cells, or nests of cribriform structures (comedocarcinoma-like) made up of small cells with scant cytoplasm and dark nuclei (picture 30). The tumors are often highly cellular at the periphery with a hypocellular densely fibrotic center. The tumor cells insinuate the sinusoids and not the trabecular cords at the border of the lesion.

Other non-classic microscopic types that can be encountered are the trabecular and hilar types and cholangiolocellular carcinoma (CCC). The trabecular type of intrahepatic CC is characterized by polygonal cells with eosinophilic cytoplasm that are arranged in anastomosing trabeculae. The hilar type shows features resembling extrahepatic CC. Cholangiolocellular type is described below. (See 'Cholangiolocellular carcinoma' below.)

Molecular analysis on intrahepatic CC has revealed two histologic subtypes (large duct type (picture 31) and small duct type (picture 32)) that are associated with distinct clinical and molecular features [72]:

Large duct type frequently harbors KRAS mutation, affects the perihilar region, and is characterized by infiltrating neoplastic ductular structures with columnar cell lining and abundant mucin production. Large duct type is also associated with perineural invasion, lymph node metastasis, high carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) levels, and poor prognosis.

Small duct type is frequently associated with isocitrate dehydrogenase (IDH) 1/2 mutation and fibroblast growth factor receptor 2 (FGFR2) translocation, is peripherally located, and is characterized by small ductular structures with a mucin-poor cuboidal cell lining.

Large duct type is positive for S100P+, and small duct type is positive for N-cadherin and natural cell adhesion molecule (NCAM, also known as CD56) immunohistochemistry.

Immunohistochemistry can be very helpful for the differential diagnosis, which includes primary hepatocellular carcinoma (HCC) and metastatic adenocarcinoma (table 2) [73]:

Immunohistochemically, almost all CCs show strong positivity for cytokeratin (CK)7 and CK19. Among common adenocarcinomas, CK7 positivity is consistent with biliary tract origin (table 3). However, metastatic cancers of the lung and breast are also CK7 positive, and the diagnosis of a CC may be a diagnosis of exclusion. Positivity for CK20 can be seen in up to 20 percent of cases of intrahepatic CC. Immunostaining for monoclonal carcinoembryonic antigen (mCEA) is diffusely positive in up to 75 percent of cases.

Immunohistochemically, most well to moderately well-differentiated HCCs are positive for hepatocyte paraffin 1 (HepPar1), arginase-1 [74], cytoplasmic thyroid transcription factor-1 (TTF1), glutamine synthetase, glypican-3 (GPC3), and CK 8 and 18. (See 'Immunohistochemistry' above.)

An antibody panel consisting of Hep Par1, arginase-1, mCEA, CK7, CK20, TTF-1 (positive cytoplasmic staining in HCC, positive nuclear staining in lung adenocarcinoma), and CDX2 (positive nuclear staining in intestinal adenocarcinoma) could be used to optimize the differential diagnosis of HCC, metastatic adenocarcinoma, and CC [75].

Cholangiolocellular carcinoma — CCC is a distinct subtype of intrahepatic CC, thought to originate from the ductules and/or canals of Hering, where hepatic progenitor cells (HPCs) reside [71,76]. HPCs can differentiate into hepatocytes and cholangiocytes and can, on their way to differentiation, give rise to tumors with a whole range of phenotypes that have varying hepatocellular and cholangiocellular differentiation characteristics. The molecular signature of stemness in combined hepatocellular-cholangiocarcinoma has supported the concept of a stem/progenitor cell origin of combined hepatocellular-cholangiocarcinoma. CCC has been reported to be associated with HCV infection [77,78].

Histologically, there are two or three different histologic areas within the tumor (CCC, HCC, and/or CC), but CCC is the predominant component (>80 percent). It is composed of mixtures of small monotonous glands in antler-like anastomosing patterns with an abundant hyalinized and/or edematous fibrous stroma with lymphocytic infiltration (picture 33) [79,80]. The tumor cells are cuboidal, smaller in size than normal hepatocytes, with scant eosinophilic cytoplasm, round or oval nuclei, and indistinct nucleoli, mimicking a benign ductular reaction (picture 34) [79]. The CCC area is CK7, CK19, NCAM (CD56), and EpCam positive. The HCC area is usually located at the interface to the nonneoplastic liver parenchyma and has a trabecular growth pattern with canalicular staining for pCEA and CD10, immunohistochemically positive for HepPar-1. The CC area is usually small with papillary and/or clear glandular formation, mucin production, and abundant fibrous stroma; it is immunohistochemically positive for CK7, CK19, and cytoplasmic pCEA immunostaining.

NCAM (CD56), a marker of progenitor cell, is useful in differentiating CCC from classical well-differentiated intrahepatic CC, which commonly does not express this marker. It should be noted, however, that NCAM is also positive in ductular reaction and bile duct adenoma.

More recently, molecular analysis revealed that CCC has a distinct biliary molecular profile with low chromosomal instability, enrichment of transforming growth factor beta (TGFB), and immune-related signaling [81].

Combined hepatocellular-cholangiocarcinoma — The 2019 World Health Organization (WHO) classification of tumors defines combined hepatocellular-cholangiocarcinoma as a primary liver carcinoma with the unequivocal presence of both hepatocytic and cholangiocytic differentiation within the same tumor that does not include collision tumors (picture 35) [9]. This tumor is distinguished from separate or multifocal HCC and CC arising in the same liver lobe (which may be separated or intermixed "collision" tumors). The combined hepatocellular-cholangiocarcinoma is thought to result from malignant transformation of a common hepatic progenitor cell with differentiation along two different cell lineages [71,82].

Combined hepatocellular-cholangiocarcinoma, also referred to as primary liver carcinoma with biphenotypic differentiation, is now acknowledged as a distinct subtype of CC [9,83,84]. They comprise <1 percent of all primary liver carcinomas and are staged and treated as intrahepatic CCs. Combined hepatocellular-cholangiocarcinomas occur in cirrhotic and noncirrhotic livers. (See "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma", section on 'Combined hepatocellular-cholangiocarcinoma'.)

The gross morphology of this tumor is not significantly different from that of HCC. Tumors with abundant fibrous stroma associated with the CC component may have firm and fibrotic cut surface. The HCC component may be well, moderately, or poorly differentiated. Confirmation of HCC differentiation is easily provided by immunohistochemical staining. Histologically, combined hepatocellular-cholangiocarcinoma must be distinguished from the pseudoglandular type of HCC (picture 11). The biliary component is usually a typical adenocarcinoma; well, moderately, or poorly differentiated; and often accompanied by abundant stroma. The cholangiocellular component is positive for CK7 and 19, epithelial membrane antigen, and mCEA. There are no published consensus guidelines for the minimum amount of HCC or CC to qualify for the diagnosis.

In 2018, an international consensus group recommended that the diagnosis of combined hepatocellular-cholangiocarcinoma be based primarily on routine histopathology with hematoxylin and eosin staining [85]. Immunostains can be used for confirmation only and are not essential for diagnosis. If stem/progenitor cell, intermediate cell, and/or CCC components are observed, they are noted in a comment as a feature rather than a formal diagnostic subtype.

Precursor (intraductal) lesions — There are three known precursors to invasive CC: IPNB, the rare intraductal tubulopapillary neoplasm of bile duct (ITPN), and the much more common BilIN. Conversion from normal to malignant bile epithelium through one of these precursor lesions probably requires a stepwise accumulation of successive genetic abnormalities [86], similar to the sequence of events that underlies colorectal carcinogenesis, although the level of understanding of molecular pathogenesis of CC is significantly less than that for other gastrointestinal cancers. (See "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma", section on 'Molecular pathogenesis'.)

Biliary intraepithelial neoplasia — The term BilIN applies to microscopic flat or low-papillary dysplastic epithelium, known previously as biliary dysplasia, atypical biliary epithelium, or carcinoma in situ [87]. Biliary intraepithelial neoplasia occurs more often in hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis [88]. BilIN is classified into three grades based on the degree of cytologic and structural atypia: BilIN-1 (low-grade dysplasia), BilIN-2 (intermediate-grade dysplasia), and BilIN-3 (high-grade dysplasia) (picture 36) [87,89,90].

BilIN can be flat, micropapillary, or pseudopapillary. Cytologic atypia ranges from mild with increased nuclear to cytoplasmic ratio in BilIN-1, to severe with marked nuclear hyperchromasia and polymorphism, diffuse loss of polarity, resembling carcinoma without invasion in BilIN-3.

Intraductal papillary neoplasm of bile duct — The IPNB is characterized by a markedly dilated and cystic biliary system and multifocal papillary epithelial lesions with or without mucin production (picture 37). This rare type of tumor resembles its counterpart: the intraductal papillary mucinous neoplasm (IPMN) of the pancreas [91-94]. (See "Pathology of exocrine pancreatic neoplasms", section on 'Intraductal papillary mucinous neoplasms' and "Classification of pancreatic cysts", section on 'Intraductal papillary mucinous neoplasms'.)

Several histologic types of IPNBs have been recognized based on their having neoplastic epithelium similar to IPMN of the pancreas (ie, pancreatobiliary, intestinal, and gastric foveolar types and the rare oncocytic type) [93,95]. More recently, two general categories of IPNBs have been proposed based on histologic similarities to their counterpart in the pancreas: type 1 IPNBs, which share many features with IPMNs of the pancreas, and type 2 IPNBs, which are variably different from IPMNs of the pancreas [94,96,97]. Type 1 IPNBs are characterized by villous architecture with thin fibrovascular cores and frequent mucin production, while type 2 IPNBs have complex papillary, polypoid, tubular, solid, or cribriform intraductal structures. Type 1 IPNBs of any subtype develop in the intrahepatic bile ducts, while type 2 IPNBs develop in the extrahepatic bile duct. These findings suggest that IPNBs arising in the intrahepatic ducts are biliary counterparts of IPMNs of the pancreas, while those arising in the extrahepatic ducts display differences from prototypical IPMNs of the pancreas. 

IPNB is associated with two types of invasive tumors: tubular carcinoma and mucinous/colloid carcinoma [91]. Tubular carcinoma is usually associated with pancreatobiliary type of IPNB, whereas mucinous/colloid carcinoma is usually associated with intestinal type of IPNB. Patients with invasive tubular carcinoma carry a worse prognosis than mucinous/colloid carcinoma or IPNB alone [95].

IPNB is classified into two grades based on the highest degree of cytologic and structural atypia: low-grade and high-grade intraepithelial neoplasia [97]. The criteria of classification are similar to those of IPMNs of the pancreas. When an invasive carcinoma is present, it should be designated as IPNB with an associated invasive carcinoma and staged similar to CC.

Intraductal tubulopapillary neoplasm of bile duct — The ITPN is a rare intraductal polypoid neoplasm composed of densely packed tubular glands with high-grade dysplasia, solid areas, or abortive papillae (picture 38) [97,98]. Necrosis in a "comedo-carcinoma"-like pattern is common. Invasive tubular carcinoma is frequently seen in ITPN (up to 90 percent of ITPN cases).

MUCINOUS CYSTIC NEOPLASMS (BILIARY CYSTADENOMA AND CYSTADENOCARCINOMA) — The term mucinous cystic neoplasm of the liver (MCN) encompasses cystic tumors previously referred to as biliary cystadenoma and cystadenocarcinoma. The 2019 World Health Organization (WHO) classification of tumors of the digestive tract categorizes MCNs based on the highest degree of cytoarchitectural atypia (ie, with low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, or an associated invasive carcinoma [99]). Imaging studies of MCN usually disclose a solitary, multiloculated, cystic structure, which on angiography is avascular and displaces the surrounding vessels [100]. MCN does not connect to the biliary tree. Thickening of internal septation and the presence of mural nodule should raise the suspicion of MCN with high-grade intraepithelial neoplasia. The term "cystadenocarcinoma" has been used to designate MCN with high-grade intraepithelial neoplasia, and it has also been used to designate MCN with an associated invasive carcinoma. The 2019 WHO classification recommends that the terms "MCN with high-grade intraepithelial neoplasia" and "MCN with an associated invasive carcinoma" be preferentially utilized [99].

Gross pathology — MCNs can measure up to 30 cm. The shape depends on the complexity of internal septation and the number of cysts. The content of the cysts varies from clear thin to thick mucoid fluid. Dark blood-tinged fluid or necrotic material may be found in either traumatized MCN or high-grade MCN, whereas purulent mucoid material is often seen in infected cyst. Mural nodules are common in high-grade MCNs.

Histology — The epithelial lining varies from a single layer of columnar, cuboidal, or flattened mucinous epithelium in low-grade MCNs, to pleomorphic malignant cells with tubulopapillary growth pattern that may invade the stroma and capsule in high-grade MCNs (picture 39). Areas of transition from benign epithelial lining to malignant cells may be found. The underlying dense fibrous, hyalinized, or cellular "ovarian-like" stroma is characteristic of these lesions, often requiring extensive sampling to demonstrate its presence. The cellular "ovarian-like" stroma is seen only in female patients and is positive for estrogen and progesterone receptors by immunostaining [101].

If there is a component of invasive adenocarcinoma, the lesions should be designated as MCN with an associated invasive carcinoma. Most associated invasive components are ductal adenocarcinomas, often requiring extensive sampling to identify the foci of invasion. (See "Diagnosis and management of cystic lesions of the liver", section on 'Mucinous cystic neoplasm with associated invasive carcinoma (cystadenocarcinoma)'.)

HEPATOBLASTOMA — Hepatoblastoma is the most common primary hepatic malignancy in early childhood. The majority of hepatoblastomas occur in the first two years of life and rarely in children older than five years. This is in contrast to hepatocellular carcinoma (HCC), which rarely occurs in children younger than five years old. The incidence of hepatoblastoma in boys is twice that in girls. Syndromes with an increased incidence of hepatoblastoma include Beckwith Wiedmann syndrome, trisomy 18, trisomy 21, Aicardi syndrome, Li-Fraumeni syndrome, Goldenhar syndrome (a type of craniofacial microsomia), type 1a glycogen storage disease (von Gierke disease), and familial adenomatous polyposis (FAP) [102,103]. (See "Beckwith-Wiedemann syndrome", section on 'Neoplasia' and "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome' and "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)' and "Syndromes with craniofacial abnormalities" and "Li-Fraumeni syndrome".)

Hepatoblastomas commonly occur as a single mass in up to 85 percent of cases and more often in the right lobe of the liver. Because of rapid growth, death can occur from rupture and hemorrhage. Serum alpha-fetoprotein (AFP) levels are markedly elevated. Sexual precocity may be present due to the synthesis of ectopic gonadotropin. (See "Epidemiology, pathophysiology, and causes of gynecomastia", section on 'Other rare causes'.)

In children, hepatoblastoma must be differentiated primarily from HCC that arises in metabolic diseases and some chronic liver diseases (eg, hereditary tyrosinemia, Alagille syndrome and other familial cholestatic syndromes, neurofibromatosis, ataxia-telangiectasia, Fanconi anemia). Cirrhosis and other risks factors are absent in patients with hepatoblastoma. (See "Disorders of tyrosine metabolism" and "Causes of cholestasis in neonates and young infants", section on 'Alagille syndrome' and "Ataxia-telangiectasia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Fanconi anemia' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Alagille syndrome".)

Hepatoblastomas arise from primitive cells that have the potential to differentiate along several lines. As such, hepatoblastoma mimics the developing fetal and embryonal liver, and is composed of a variety of cell types, giving rise to a morphologically complex tumor, which may include fetal and/or embryonal hepatocytes and heterologous tissues including cartilage, bone, striated muscle fibers, and squamous epithelium.

Gross pathology — Hepatoblastomas often present as well circumscribed, thinly encapsulated, nodular, single or multiple lesions measuring up to 20 cm in diameter. The tumor has a variegated bulging cut surface with foci of necrosis and hemorrhage. When a mesenchymal component is present, such as bone or cartilage, the cut surface of the tumor is gritty with multiple white or slightly transparent speckles.

Histology — Hepatoblastoma consists of malignant liver cells at various stages of maturation and a variable mesenchymal component. The epithelial component always predominates and consists of two types of cells: "embryonal"-type cells, which are small, basophilic, darkly stained with uniform, hyperchromatic nuclei and scanty cytoplasm, arranged in sheets, ribbons, rosettes, acini, or tubules; and "fetal"-type cells, resembling hepatocytes with central round to oval nuclei and abundant granular or clear cytoplasm depending on the amount of glycogen or fat (picture 40). The cells are larger, eosinophilic, and lighter stained than the embryonal-type cells and arranged in trabeculae or plates. They are separated by sinusoids and may form bile canaliculi. The variation of darker and lighter-stained cells is characteristic of hepatoblastoma. Extramedullary hematopoiesis is often present in the sinusoids. When the biopsy specimen is small and contains only fetal-type cells, the distinction from well-differentiated HCC may be difficult.

The presence of a mesenchymal component, most commonly osteoid tissue and rarely cartilage (picture 40), rhabdomyoblasts, or neural elements, rules out HCC. AFP is almost always demonstrable in the cytoplasm of the epithelial cell component by immunohistochemical staining.

Approximately 2 percent of hepatoblastomas are composed of small cell undifferentiated cells (small cell undifferentiated hepatoblastoma) [104], resembling a neuroblastoma or other small blue cell tumor. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma", section on 'Pathology'.)

This subtype was formerly referred as anaplastic hepatoblastoma. Small cell undifferentiated hepatoblastoma grows diffusely and is highly invasive. Rhabdoid differentiation may be encountered, resembling malignant extrarenal rhabdoid tumor. Immunostaining shows reactivity for cytokeratin (CK)8, occasionally for vimentin, and rarely for CD99. AFP immunostaining is generally negative.

Tumors composed of pure fetal cells carry a better prognosis than embryonal or mixed epithelial-mesenchymal hepatoblastomas or small cell undifferentiated hepatoblastoma [105,106].

An international consensus classification of hepatoblastoma has been proposed (table 4) [107].

MESENCHYMAL TUMORS

Epithelioid hemangioendothelioma — Epithelioid hemangioendothelioma (EHE) is a low-grade malignant vascular neoplasm that affects middle-aged patients. Women are affected more than men; there is a female predilection [108,109]. Most patients present with abdominal pain, a mass, weight loss, or malaise. Involvement of major hepatic veins may result in Budd-Chiari syndrome [110]. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Imaging studies show single or multiple masses that are avascular or calcified and may involve the entire liver [111]. Despite being a low-grade tumor, there is a high rate of regional and distant metastases (75 percent in one study [112]).

EHE is typically a firm, tan tumor. It has a zonal pattern of cellularity; the periphery or the advancing front is more cellular than the central zone, which is hypocellular, sclerotic, or calcified; and the transition zone appears myxoid or cartilaginous. The underlying lobular architecture remains preserved with remnants of portal tracts. The tumor cells assume dendritic and epithelioid appearances [113]. The dendritic cells are spindle or stellate shaped. The epithelioid cells resemble signet rings (picture 41) with vessel-like intracellular lumen, which may contain red blood cells. Immunohistochemical staining shows positivity for vascular markers, such as the ERG transcription factor, CD31, CD34, and Factor VIII antigen [114].

EHE may be misdiagnosed as cholangiocarcinoma (CC) because of the epithelioid appearance and the sclerotic pattern of growth [115]. It should be noted, however, that the lumens of CC do not contain red blood cells, and markers for endothelial cells such as the ERG transcription factor, factor VIII–related antigen, CD31, and CD34 antigens are not demonstrable in CC [108,110].

Angiosarcoma — Angiosarcoma is a high-grade malignant vascular neoplasm [116], and it is the most common sarcoma arising in the liver [117]. It occurs in older patients (>60 years old) and is more common in men. It can be caused by exposure to vinyl chloride [118], arsenic, anabolic steroids, radiation, and thorium dioxide. Patients typically present with abdominal pain, fatigue, jaundice, ascites, and weight loss. Rarely, patients present with Budd-Chiari syndrome. Hepatomegaly with or without splenomegaly and thrombocytopenia are common findings. Metastases occur frequently and rapidly to the spleen, lymph nodes, lung, bone, and adrenals [112]. Liver failure and intraabdominal bleeding due to liver rupture are common causes of death.

Angiosarcoma forms numerous poorly defined variably sized nodules that are soft, spongy, hemorrhagic, and necrotic. The entire liver is frequently involved. The tumor is composed of pleomorphic spindle or epithelioid cells, often with bizarre or multinucleated forms; mitoses are evident (picture 42). Better-differentiated areas may show large cavernous spaces that are lined by atypical endothelial cells. The tumor cells grow along and into sinusoids, peliotic areas, and branches of portal and hepatic veins. Immunostaining shows positivity for vascular markers, such as the ERG transcription factor, CD31, CD34, and Factor VIII antigen [114].

SUMMARY

Several different types of primary tumors can arise in the liver, although metastases are more common by far. (See 'Introduction' above.)

The most common primary malignant liver tumor is hepatocellular carcinoma (HCC). HCC may form a large solitary circumscribed nodule with or without adjacent smaller satellite nodules. In the presence of cirrhosis, HCC may be multinodular within one lobe, consist of multiple nodules scattered throughout the liver, or infiltrate the liver diffusely without forming circumscribed nodules. The cells of HCC resemble hepatocytes in function, cytologic features, and growth patterns. The degree of differentiation reflects the resemblance of tumor cells to normal hepatocytes. Immunohistochemically, most well- to moderately well-differentiated HCCs are positive for hepatocyte paraffin 1 (HepPar1), arginase-1, cytoplasmic thyroid transcription factor-1 (TTF-1), glutamine synthetase, glypican-3 (GPC3), and cytokeratins (CK) 8 and 18. (See 'Hepatocellular carcinoma' above.)

Fibrolamellar carcinoma differs clinically, histologically, and molecularly from conventional HCC. It affects younger individuals, is often not associated with elevated serum alpha-fetoprotein (AFP), and has a better prognosis than conventional HCC. The immunohistochemical profile is similar to that of HCC, such as positive staining for HepPar1 and GPC3. However, immunostains for CK7, epithelial membrane antigen (EMA), and cluster of differentiation (CD) 68 are positive in fibrolamellar carcinoma only. (See 'Fibrolamellar subtype' above.)

Cholangiocarcinomas (CCs) are primary cancers arising from bile duct epithelium that may occur anywhere along the biliary tree from the small bile ducts and bile ductules in the liver (intrahepatic CC) to the large hilar and extrahepatic bile ducts (extrahepatic CC). Immunohistochemistry can be very helpful for the differential diagnosis, which includes primary HCC and metastatic adenocarcinomas (table 2). (See 'Cholangiocarcinoma' above.)

Cholangiolocellular carcinoma (CCC) is a subtype of intrahepatic CC that is thought to originate from a hepatocyte progenitor cell, which can give rise to tumors with a whole range of phenotypes that have varying hepatocellular and cholangiocellular differentiation characteristics. (See 'Cholangiolocellular carcinoma' above.)

Combined hepatocellular-cholangiocarcinoma is a tumor with intimately mixed elements of both HCC and CC; it must be distinguished from separate HCC and CC arising in the same liver lobe (which may be separated or intermixed ["collision" tumors]). They are classified, staged, and treated as intrahepatic CCs. (See 'Combined hepatocellular-cholangiocarcinoma' above.)

There are three precursors to CC: intraductal papillary neoplasm of bile duct (IPNB), the rare intraductal tubulopapillary neoplasm of bile duct (ITPN), and the much more common biliary intraepithelial neoplasia (BilIN), which are divided into low- and high-grade types. When an invasive carcinoma is present, it should be separately designated and staged as CC. (See 'Precursor (intraductal) lesions' above.)

The term mucinous cystic neoplasm of the liver (MCN) encompasses cystic tumors previously referred to as biliary cystadenoma and cystadenocarcinoma. However, the term cystadenocarcinoma has been used to designate high-grade MCN and MCN with an invasive component. The terms "MCN with high-grade intraepithelial neoplasia" and "MCN with an associated invasive carcinoma" are preferred [99]. (See 'Mucinous cystic neoplasms (biliary cystadenoma and cystadenocarcinoma)' above.)

Hepatoblastoma is the most common primary hepatic malignancy in early childhood. These tumors are thought to arise from primitive cells with the potential to differentiate along several lines. Hepatoblastomas mimic the developing fetal and embryonal liver and are composed of a variety of cell types, giving rise to a morphologically complex tumor that may include fetal and/or embryonal hepatocytes and heterologous tissues, including cartilage, bone, striated muscle fibers, and squamous epithelium. (See 'Hepatoblastoma' above.)

Primary mesenchymal tumors arising in the liver include epithelioid hemangioendothelioma (EHE) and angiosarcoma. Despite being a low-grade tumor, there is a high rate of regional and distant metastases with EHE. In contrast, angiosarcoma, the most common sarcoma arising in the liver, is a high-grade malignant vascular neoplasm. In both cases, immunostaining is positive for vascular markers such as the ERG transcription factor, CD31, CD34, and Factor VIII antigen. (See 'Mesenchymal tumors' above.)

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Topic 16348 Version 20.0

References

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