Introduction

Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or tumor-like lesions with cell structures and morphologies that resemble those of normal hepatocytes. These lesions commonly include focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), macroregenerative nodule (MRN), dysplastic nodule (DN), and well-differentiated hepatocellular carcinoma (HCC). The diagnosis of well-differentiated hepatocellular tumors and nonneoplastic lesions is challenging, particularly with small sample sizes (such as core needle biopsies) [1]. This review focuses on the histopathological characteristics and diagnostic approaches for WDHLs. It comprises two major sections: the first discusses the histopathological characteristics of common WDHLs and the second addresses the diagnostic approaches for these mass lesions.

Benign hepatocellular tumor-like lesions and tumors

1. Focal nodular hyperplasia

1) Clinical features

FNH is a benign, nonneoplastic lesion caused by the hyperplastic reaction of hepatocytes in response to changes in blood flow [2]. These lesions are the second most frequently occurring benign liver nodules after hemangiomas and are observed in 0.8% of adults [3]. FNH is most frequently identified in young women, accounting for 80% to 90% of cases, and is rarely found in men or children [4]. Most patients are asymptomatic and are identified incidentally. FNH is associated with vascular disorders (such as hereditary hemorrhagic telangiectasia, Budd–Chiari syndrome, portal vein thrombosis, and atresia) and chemotherapy [5-7]. It may coexist with HCA and occur with liver hemangioma in 20% of the cases [8]. The surrounding liver tissue is usually normal. Genetic analyses of FNH have revealed changes in the expression of angiopoietin genes (ANGPT1 and ANGPT2) that play a role in blood vessel maturation [9]. FNH also contains a unique type of sclerostin-expressing endothelial cell that may promote fibrosis [10]. A significant increase in angiopoietin-1 levels has been observed in patients with FNH [11]. Activation of the β-catenin pathway is elevated only in enlarged perivenous regions [12]. To the best of our knowledge, no malignant transformation of FNH has been reported to date. However, a recent study suggested a clonal relationship between FNH and HCC, and in very rare cases, FNH can progress to malignant transformation [13].

2) Pathological features

FNH is usually well-circumscribed; however, it is not encapsulated. Most FNHs are <5 cm in diameter, although large FNHs can occur. They are characterized by a central stellate scar with radiating fibrous septa (Fig. 1), and the background liver is noncirrhotic. Histologically, the lesion displays nodular architecture composed of benign-appearing hepatocytes arranged in one to two cell-thick plates (Fig. 2A). Dystrophic thick-walled arteries are present in the central scar. The ductular reaction can be highlighted by immunostaining for cytokeratin 7 (CK7) and cytokeratin 19 (CK19) at the interface between fibrous areas and nodules. Although the central fibrous area has radiating branches resembling portal tracts, true portal tracts are absent. Lymphocytic or mixed inflammatory cell infiltrates. Steatohepatitic changes, such as ballooned hepatocytes, steatosis, and large cell change may occur [14-16]. Immunohistochemistry (IHC) for glutamine synthetase (GS) reveals wide interconnected bands of lesional hepatocytes creating a highly distinctive geographic or map-like pattern (Fig. 2B) [15,17]. CD34 usually exhibits patchy sinusoidal staining; however, it can show diffuse staining in a subset of cases.

The term “FNH-like” lesions has been used to describe lesions that are morphologically similar to FNH; however, they occur in the context of liver disease (e.g., cirrhosis) and vascular disorders (e.g., Budd–Chiari syndrome) [18-20]. These FNH-like lesions mimic FNH, but they lack the characteristic map-like GS staining pattern observed in FNH.

3) Differential diagnosis

Differential diagnoses include regenerative hepatic pseudotumor (RHP), cirrhotic nodules, HCA, HCC, and fibrolamellar carcinoma (fibrolamellar subtype of HCC). RHP is a newly described hepatic pseudotumor that results from localized changes in vascular flow [21]. It is characterized by portal vein and hepatic artery anomalies, portal and central vein thrombi, sinusoidal dilatation, and the associated regenerative parenchymal changes. The presence of true portal tracts excludes cases of FNH. FNH is similar to cirrhotic nodules, particularly in needle biopsy specimens. The clinical history of underlying liver disease and the absence of thick-walled arteries favor cirrhotic nodules over FNH [22]. The central stellate scar, nodular hepatocytic regeneration, ductular reaction, and map-like GS pattern distinguish FNH from HCA [23]. In contrast, unpaired arteries, relatively monomorphic hepatocytic proliferation, and the absence of map-like GS staining suggest HCA rather than FNH. HCCs are differentiated from FNH by cytological atypia, thick cell plates (>two cells thick), and reticulin loss [2]. Additionally, the diffuse GS staining observed in β-catenin–activated HCA (B-HCA) or HCC should not be misinterpreted as a map-like pattern, particularly in core needle biopsies. Fibrolamellar carcinomas have large polygonal cells with eosinophilic cytoplasm, prominent macronucleoli, and dense lamellar fibrosis and are characterized by the DnaJ homolog subfamily B member 1 (DNAJB1)::cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) fusion gene [24].

2. Hepatocellular adenoma

1) Clinical features

HCA is an uncommon benign hepatocellular tumor consisting of cells that show hepatocellular differentiation [25]. The annual HCA incidence is 3 to 4 cases per 100,000 individuals in North America and Europe [26], with a lower incidence in Asia [27]. Approximately 85% of HCAs occur in women of reproductive age and oral contraceptive use is a considerable risk factor. Other risk factors include drugs (such as anabolic steroids and androgens), glycogen storage disease types I and III, galactosemia, tyrosinemia, familial adenomatous polyposis, β-thalassemia, and congenital hepatic fibrosis [28,29]. Recently, there has been a significant increase in the HCA incidence associated with obesity and metabolic syndrome [30-32]. HCAs may manifest as abdominal pain, palpable masses, intratumoral hemorrhage, or rupture. With the advent of modern imaging technology, most tumors are found incidentally during imaging [26]. Hepatic adenomatosis is defined as the presence of ≥10 tumors [33,34]. This condition can be familial, caused by a germline mutation in TCF1, which encodes hepatocyte nuclear factor 1α (HNF1A) [35,36]. The background liver is usually noncirrhotic. Inflammatory HCAs (I-HCAs) are often associated with alcohol abuse and metabolic syndrome, and cirrhosis may occur in nonneoplastic liver tissues [37,38]. Malignant transformation of HCA to HCC occurs in 4% to 8% of cases, primarily affecting men [39-41]. Catenin beta-1 (CTNNB1) gene and telomerase reverse transcriptase (TERT) gene promoter mutations have been identified as early and late genomic events involved in the adenoma-carcinoma transition [42]. Changes in body weight and duration of estrogen exposure influence HCA evolution after discontinuation of estrogen-based contraception [43]. The natural history of HCAs in unresected patients requires further investigation.

2) Pathological features

Grossly, HCAs are well-demarcated or poorly defined, yellow or brown-tan in color, and soft (Fig. 3) [44]. Areas of hemorrhage or necrosis may also occur. The size of HCAs usually ranges from 5 to 15 cm; however, wide variations exist. Numerous small microscopic tumors may be present in adenomatosis. Histologically, HCAs are composed of well-differentiated hepatocytes arranged in plates one or two cells thick. However, the reticulin framework remains intact. The tumor cells are typically uniform in size and shape. Mild nuclear atypia may also be associated with ischemic changes in tumors. The cytoplasm may contain fat, lipofuscin granules, or bile [45]. Mitoses are uncommon. A pseudoglandular pattern is occasionally observed.

In the 5th edition of World Health Organization (WHO) Classification of Tumours (2019), HCAs are classified into four subtypes, namely HNF1A-inactivated HCA (H-HCA), I-HCA, B-HCA, and β-catenin–activated inflammatory HCA (BI-HCA) (Table 1) [25]. Additional subtypes such as sonic hedgehog HCA (SH-HCA) and unclassified HCA (U-HCA) have been described. Each HCA subtype presents distinct genetic alterations and clinical and histopathological features and has important implications for patient management [25,46-48]. Different HCA subtypes can occur in the same liver [41]. Mutation testing is recommended in all cases with inconclusive histopathological and immunohistochemical features [49].

3) Hepatocellular adenoma subtypes

(1) Hepatocyte nuclear factor 1α-inactivated hepatocellular adenoma

H-HCA accounts for 30% to 35% of all HCA cases. Biallelic inactivating mutations of HNF1A have been identified; 90% are somatic mutations, whereas 10% are germline mutations. Histologically, H-HCAs typically exhibit prominent steatosis (Fig. 4A). A mixture of eosinophilic and swollen cells with a clear, glycogen-rich cytoplasm is present in the nonfatty areas. A pseudoglandular pattern is observed. In rare cases, prominent sinusoidal dilatation and myxoid changes can be focally observed [50]. Atypical cases may exhibit minimal or no steatosis. HNF1A positively regulates FABP1, which codes for liver fatty-acid binding protein (LFABP). IHC reveals that LFABP expression is either low or absent in H-HCAs, making it a valuable diagnostic marker (Fig. 4B). The risk of HCC transformation is <2% [51].

(2) Inflammatory hepatocellular adenoma

I-HCA accounts for 35% to 40% of HCA cases and is commonly associated with obesity and metabolic syndrome. I-HCA occurs more often in women than in men; however, it can also occur in men if appropriate risk factors are present. Mutations in IL6ST, encoding glycoprotein 130 (gp130; 60% of cases), Fyn-related Src family tyrosine kinase (FRK; 10%), signal transducer and activator of transcription 3 (STAT3; 5%), guanine nucleotide-binding protein alpha-stimulating (GNAS; 5%), and Janus kinase 1 (JAK1; 3%) have been implicated in I-HCA [25,42]. These recurrent mutations activate the interleukin-6/JAK/STAT3 signaling pathway. Histologically, I-HCAs show prominent sinusoidal dilatation (telangiectasia), inflammation, thick-walled arteries, arterioles, and ductular reactions mimicking the portal tracts (Fig. 5A). Steatosis and steatohepatitis are common in nonneoplastic livers. Acute-phase reactants, such as C-reactive protein (CRP) and serum amyloid A (SAA), are overexpressed in I-HCAs (Fig. 5B). Therefore, IHC for SAA and CRP aids in confirming the diagnosis of I-HCA. However, careful correlation with morphology is required because SAA and CRP levels may also be positively correlated in the adjacent nonneoplastic liver.

(3) β-Catenin–activated hepatocellular adenoma

B-HCA accounts for 5% to 20% of HCA cases. This subtype is characterized by mutations or deletions of CTNNB1, which encodes β-catenin and activates the WNT signaling pathway [25]. Mutations or deletions in exon 3 of CTNNB1 result in high levels of β-catenin activation, leading to a high risk of HCC. In contrast, mutations specifically in exon 3 S45 and in exon 7 or 8 of CTNNB1 result in moderate and weak β-catenin activation, respectively, leading to different GS staining patterns and a low HCC risk [52]. Histologically, B-HCAs often exhibit cytoarchitectural atypia, with large nuclei and prominent nucleoli. Small cell change and pseudoglandular pattern can be observed. Lipofuscins and bile pigments may also be present in tumor cells. Immunohistochemically, GS expression patterns are associated with β-catenin alterations [53,54]. B-HCAs with exon 3 non-S45 mutations show diffuse homogeneous (>90% of tumor cells) GS staining and frequent nuclear β-catenin staining. B-HCAs with exon 3 S45 mutations show diffuse heterogeneous (>50% but ≤90% of tumor cells) GS staining, referred to as a starry-sky pattern, and minimal to absent nuclear β-catenin staining. B-HCAs with exon 7 or 8 mutations show faint GS staining with or without perivascular staining and no nuclear β-catenin staining. GS is an excellent surrogate marker for identifying different mutation types of CTNNB1. However, molecular tests can be conducted in cases with inconclusive GS patterns to assess the risk of malignancy [25].

The term “borderline HCA” is applied to B-HCAs that exhibit focal cytoarchitectural atypia and reticulin abnormalities that are insufficient for the diagnosis of HCC [42]. The term “atypical hepatocellular neoplasm” has been proposed for all β-catenin–activated tumors, excluding those with exon 7/8 mutations, irrespective of cytological and architectural atypia because of the high risk of HCC development [55]. The term “well-differentiated hepatocellular neoplasm of uncertain malignant potential (HUMP)” was proposed because “atypical hepatocellular neoplasm” may not adequately reflect the need for close follow-up [56].

(4) β-Catenin–activated inflammatory hepatocellular adenoma

BI-HCA is a distinct subtype of HCA that exhibits mixed features of both B-HCA and I-HCA [25]. It accounts for 10% to 15% of HCA cases and has a malignant transformation risk similar to that of B-HCAs with exon 3 mutations.

(5) Sonic hedgehog-activated hepatocellular adenoma

SH-HCA is a recently identified subtype of HCA. It constitutes 4% to 5% of HCA cases and arises from activation of the sonic hedgehog pathway by deletions of inhibin subunit beta E (INHBE), resulting in INHBE and glioma-associated oncogene homolog 1 (GLI1) fusion. This genetic fusion leads to the overexpression of several genes such as prostaglandin-H2 D-isomerase (PTGDS), also known as prostaglandin D₂ synthetase. This subtype is associated with a high risk of bleeding. Immunohistochemically, tumor cells show increased PTGDS expression [50]. Argininosuccinate synthase 1 (ASS1), which is involved in arginine synthesis, is overexpressed in SH-HCA [57].

(6) Unclassified hepatocellular adenoma

U-HCA accounts for 5% to 10% of HCA cases. This subtype lacks distinct pathological or genetic characteristics and cannot be classified further into any existing subtype. Immunohistochemically, ASS1 is expressed in all U-HCA cases, with 64.7% of cases presenting with bleeding [57]. Further studies are needed to characterize the U-HCA.

(7) Newly described subtypes of hepatocellular adenoma

Three newly described HCA subtypes do not fit well into the traditional classification schema: androgen HCA [58], pigmented HCA [59], and myxoid hepatic adenoma [60]. These three adenoma subtypes are rare, but clinically substantial because they have an increased risk of malignancy [61]. ASS1-positive HCA has also been recently described [57]. Further studies of these rare subtypes are required.

4) Differential diagnosis

Differential diagnosis includes focal fatty changes, FNH, well-differentiated HCC, and epithelioid angiomyolipoma [1]. Focal fatty changes can mimic neoplasms in imaging studies [23]. Histologically, focal fatty changes contain well-demarcated nodules composed of hepatocytes with diffuse macrovesicular steatosis and no cytologic atypia [23,62,63]. Portal tracts and central veins are present in these lesions. Features typical of FNH, such as fibrous septa, nodularity, and ductular reactions, are observed in I-HCAs. In addition, IHC is used to aid in differential diagnosis. FNHs show map-like GS staining, whereas I-HCAs stain positively for SAA and CRP. The presence of cytological atypia, prominent pseudoglandular pattern, thick cell plates, and reticulin network loss favor well-differentiated HCC over HCA. Positive staining for glypican-3 (GPC3), GS, and heat shock protein 70 (HSP70) supports HCC diagnosis [64]. Epithelioid angiomyolipomas may mimic HCA, and GS staining may be positive [65]. Positivity for smooth muscle and melanocytic markers such as smooth muscle actin (SMA) and human melanoma black (HMB45), respectively, is helpful in the diagnosis of angiomyolipomas.

Macroregenerative and dysplastic nodules

1. Macroregenerative nodule

1) Clinical features

MRN, also known as a large regenerative nodule, is a nodular lesion with a diameter ≥10 mm [66]. Most MRNs range between 10 and 20 mm, with an average size of 12 mm [67,68]. MRNs are most commonly present in cirrhotic livers, usually in patients with a history of hepatitis B, hepatitis C, or alcoholic liver disease. Approximately 15% to 30% of cirrhotic livers have MRNs. Although MRNs are typically observed in cirrhosis, they can develop during regeneration after extensive parenchymal necrosis, as observed in fulminant autoimmune or viral hepatitis. Additionally, MRNs can occur in vascular diseases, such as Budd–Chiari syndrome or portal vein thrombosis. MRNs generally lack a premalignant potential. However, one study indicated a low risk of MRNs developing into premalignant lesions [69]. MRNs can be regarded as premalignant lesions in patients with chronic hepatitis and cirrhosis [70].

2) Pathological features

MRNs may be solitary or multiple, and generally measure ≥1.0 cm. However, they rarely exceed 5 cm in size (Fig. 6A). MRNs usually have a color and texture similar to those of adjacent cirrhotic nodules; however, they sometimes appear pale or bile-stained. Histologically, the cytological and architectural features of hepatocytes in the MRNs resemble those of hepatocytes in the surrounding liver (Fig. 6B). Little or no cytological atypia is observed, and the reticulin framework remains intact. MRNs contain portal tracts that may exhibit mild chronic inflammation and ductular reactions [71]. The liver cell plates are one or two cells thick. Fatty changes can occur if the surrounding liver undergoes steatosis. MRNs that develop during regeneration following massive necrosis display residual necroinflammatory activity and occasional mitotic figures. MRNs do not contain dysplastic foci or exhibit clonality.

3) Differential diagnosis

The differential diagnoses of MRNs include low-grade DN (LGDN). Distinguishing between MRNs and LGDNs is challenging because there are no reliable criteria. The morphology of hepatocytes in MRNs is cytologically identical to that in the surrounding liver. In MRNs, hepatocytes may exhibit patchy and large cell change. However, cytological atypia or small cell changes should not be observed. LGDNs may exhibit minimal cytological atypia, are characterized by clonal hepatocellular proliferation, and exhibit cytoplasmic or nuclear variations that cluster topographically to form distinct cell subpopulations. Clonal proliferation is not observed in MRNs [71].

2. Dysplastic nodule

1) Clinical features

Dysplastic foci and DNs are precancerous HCC lesions typically observed in cirrhotic livers [72,73]. Dysplastic foci have a diameter of <1 mm and are usually incidentally found during histological examination of cirrhotic livers [74]. DNs typically have a diameter of 5 to 15 mm and can be identified macroscopically or radiologically as solitary or as multiple lesions in cirrhotic livers. The prevalence of DNs in cirrhotic liver ranges from 11% to 40% [75,76]. Depending on the severity of cytological and architectural atypia, DNs are categorized as low- or high-grade. Livers with DNs are at increased risk of developing HCC. One study found that 9% of LGDNs and 32% of high-grade DNs (HGDNs) transformed into HCC during a median follow-up period of 36 months [77]. In another study, 45.5% of DNs disappeared, and 12% progressed to HCC when imaging studies were followed up for a median of approximately 2 years [78]. HGDNs exhibit molecular features that are more similar to those of HCC than to those of LGDNs, such as telomere shortening, TERT activation, and inactivation of cell cycle checkpoint regulators [79]. Accumulation of genetic alterations occurs from the progression of DN to early HCC and then to progressed HCC [80], with TERT promoter mutations representing an early molecular event found in approximately 15% of HGDNs [81].

2) Large cell changes and small cell changes

The two distinct hepatocellular changes associated with carcinogenesis in chronic liver diseases and DNs are large and small cell changes (previously known as large and small cell dysplasia, respectively). Large cell changes are characterized by nuclear and cellular enlargement, resulting in a preserved nuclear-to-cytoplasmic (N:C) ratio. These cells exhibit pleomorphic nuclei, nuclear hyperchromasia, abundant cytoplasm, and occasional multinucleation (Fig. 7A). Large cell changes may serve as risk markers for HCC in patients with chronic hepatitis B infection [82]; however, they can also be attributed to cellular senescence [83]. Large cell changes are heterogeneous lesions, and the evidence of their premalignant potential remains inconclusive [82]. Small cell changes are characterized by the presence of small hepatocytes exhibiting nuclear hyperchromasia, cytoplasmic basophilia, an increased N:C ratio, and increased cell density (Fig. 7B). Small cell changes include increased proliferative activity compared to adjacent hepatocytes, chromosomal instability, telomere shortening, and p21 checkpoint inactivation. Collectively, these characteristics suggest that hepatocytes undergoing small cell changes are premalignant [84,85].

3) Pathological features

DNs are macroscopically identified as nodular lesions that differ from adjacent cirrhotic nodules in size, color, texture, and extent of protrusion from the cut surface [86]. Histologically, LGDNs show more cytological atypia than the surrounding liver tissue (Fig. 8). The nuclei may exhibit mild atypia. The hepatic plate architecture remains two cells thick, with a mild increase in cell density. Mitoses are rare and pseudoglandular patterns are generally absent. Portal tracts are usually present within the LGDNs and often contain a small number of unpaired arteries. Nodule-in-nodule growth is not observed. In contrast, the HGDNs exhibit an overall increase in cell density and nuclear hyperchromasia (Fig. 9). They often show loss of many or nearly all portal tracts, frequently show an increased number of unpaired arteries, and tend to display small cell changes. Pseudoglandular pattern and nodule-in-nodule growth are observed in some cases.

4) Differential diagnosis

The differential diagnoses of DN include MRN and well-differentiated HCC. Histologically distinguishing between LGDNs and MRNs is challenging [1]. MRNs contain hepatocytes that are cytologically identical to those of the surrounding liver and exhibit no cytological atypia or reticulin loss. Unpaired arteries and cytologic atypia greater than that of the adjacent liver favor the diagnosis of DN. Features such as a pseudoglandular pattern, thickened hepatocyte plates (>two cells thick), and loss of reticulin framework support the diagnosis of HCC [23]. Unlike HCC, DNs show no reticulin loss and have few or no mitotic figures. A panel of three IHC markers (GPC3, GS, and HSP70) is useful for detecting well-differentiated HCC in biopsies [87].

Malignant hepatocellular neoplasms

1. Well-differentiated hepatocellular carcinoma

1) Clinical features

HCC is a primary liver malignancy characterized by the presence of epithelial cells that exhibit hepatocellular differentiation [72]. HCC accounts for –75% to 85% of all cases of primary liver cancer. In ≥90% of cases, HCC is associated with a specific cause [88], typically chronic liver diseases [89], including hepatitis B [90], hepatitis C [91,92], alcoholic steatohepatitis, and nonalcoholic steatohepatitis (NASH) because of metabolic syndrome [93,94]. The etiology and epidemiology of HCCs are rapidly evolving globally [95], and the proportion of patients with NASH-associated HCCs has also increased. Small HCCs, defined as lesions with diameters ≤2 cm, are classified as early HCC or small progressed HCC. In most cases, progression to HCC begins with chronic liver disease, leading to premalignant lesions (dysplastic foci and DNs), which evolve into well-differentiated early HCC and eventually progress to less-differentiated HCC [72]. Table 2 summarizes the clinical and histopathological features of the WDHLs.

2) Pathological features

Early HCC presents as a vague nodule with ill-defined margins that lacks a tumor capsule (Fig. 10). In contrast, small progressed HCCs exhibit distinct margins and frequently contain tumor capsules [96]. Histologically, the WHO grading system for HCC is based on a three-tier classification: well-differentiated, moderately differentiated, and poorly differentiated [72]. Well-differentiated HCCs contain tumor cells that closely resemble mature hepatocytes and exhibit minimal to mild nuclear atypia (Fig. 11A). Early HCCs are well-differentiated. Tumor cells display increased proliferation and are characterized by loss of the normal reticulin framework. HCCs commonly exhibit unpaired arterioles and diffuse sinusoidal capillarization. Immunohistochemically, well-differentiated HCCs often exhibit aberrant GPC3 expression (Fig. 11B). Early HCCs frequently exhibit stromal invasion [11], which is defined as the infiltration of malignant hepatocytes into the fibrous stroma surrounding the tumor. The stroma includes portal tracts and fibrous bands that separate nodules of the liver tissue. Identifying stromal invasion can be challenging and may require confirmation using CK7 or CK19 IHC [97-99]. In CK7 and CK19 immunostaining, the lack of a ductular reaction at the interface of the HCC nodules supports the presence of stromal invasion (Fig. 12).

3) Differential diagnosis

Differential diagnoses for well-differentiated HCC include FNH, HCA, MRN, DN, neuroendocrine tumors, epithelioid angiomyolipoma [66], and adrenal lesions. The differential diagnosis of HCC is based on the degree of differentiation and the presence of cirrhosis in the surrounding liver. FNH and HCA arise in noncirrhotic livers and usually exhibit no or minimal cytological atypia and pseudoglandular pattern. In cirrhotic livers, MRNs and DNs are included in the differential diagnosis. Both types typically contain portal tracts. Cytological atypia is absent or mild, and focal in MRNs and LGDNs, whereas HGDNs exhibit small cell changes and more pronounced atypia. Distinguishing HGDNs from well-differentiated HCCs is challenging, particularly when biopsy material is used. The presence of a nodule-in-nodule growth pattern suggests HCC. Stromal invasion is an objective and significant indicator of HCC. Neuroendocrine tumors and epithelioid angiomyolipomas mimic well-differentiated HCCs. IHC facilitates hepatocellular differentiation in well-differentiated neoplasms. Well-differentiated HCCs are positive for hepatocyte paraffin-1 (Hep Par-1) and arginase-1. Neuroendocrine tumors are positive for synaptophysin, chromogranin, and insulinoma-associated protein 1 (INSM1). Epithelioid angiomyolipomas are positive for SMA and HMB45. Heterotopic adrenal cortical hyperplasia or adenoma, and the direct extension of adrenal cortical carcinoma into the liver may be mistaken for HCA. Adrenal cortical adenomas comprise lipid-rich cells arranged in the nests or cords.

Pathological diagnostic approach

1. Clinical features

Clinical history of any underlying chronic liver disease, alcoholic liver disease, metabolic disorder, or oral contraceptive use should be carefully investigated [100-102]. Patients may exhibit clinical signs and symptoms because of the tumor itself or an underlying chronic liver disease. Alpha-fetoprotein (AFP) is a well-established serum marker for HCC [73]. However, serum AFP levels are normal or mildly elevated in patients with MRNs and DNs. HCC is diagnosed in patients with chronic viral hepatitis, liver cirrhosis, liver mass, and serum AFP levels of >400 ng/mL. Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) levels determine the serum glycosylated AFP levels. The proportion of AFP-L3 relative to the total AFP concentration (AFP-L3%) has been used as a marker for early HCC diagnosis [103]. An AFP-L3% greater than 35% is highly specific for HCC [104]. Des-gamma-carboxy-prothrombin (DCP), also known as a protein induced by vitamin K absence or antagonist II (PIVKA-II), is an abnormal form of prothrombin. DCP levels are elevated in approximately 75% of patients with HCC [105].

2. Radiological features

WDHLs can be detected using imaging during HCC screening. Common imaging modalities include contrast-enhanced ultrasonography, contrast-enhanced computed tomography, and magnetic resonance imaging (MRI). On MRI, FNHs appear isointense or slightly hypointense on T1-weighted images (T1WI) and slightly hyperintense or isointense on T2-weighted images (T2WI) [106-108]. The central scar typically appears hypointense on T1WI and hyperintense on T2WI. Different HCA subtypes exhibit distinct imaging features [109-111]. H-HCAs show diffuse and homogeneous signal dropout on T1WI and moderate arterial enhancement, which does not persist during the delayed phase. I-HCAs are hyperintense, diffuse, or predominantly located at the periphery (atoll sign) on T2WI [25]. Typically, they exhibit strong arterial enhancement that persists during the delayed phase. Early HCCs usually appear isovascular or hypovascular, whereas small progressed HCCs typically show hypervascularity (wash-in) during the arterial phase and hypovascularity (wash-out) during the venous phase. Owing to their overlapping features, imaging cannot reliably distinguish early HCCs from DNs, particularly HGDNs. Accurate identification of small HCCs with diameters <2 cm is challenging [112].

3. Special stains

Hematoxylin and eosin (H&E) staining, widely regarded as the gold standard in liver pathology, facilitates accurate histological assessment of benign and malignant liver diseases [113]. In addition to H&E staining, special stains are often required to verify the abnormal structures or findings observed on H&E-stained slides. Trichrome staining is used to assess the degree of fibrosis and highlight the portal areas and fibrous septa. Reticulin staining is used to evaluate hepatocyte plate thickness and changes in lobular architecture. In the normal liver, reticulin staining shows hepatic trabeculae composed of single- or double-cell layers, a pattern that is also observed in FNHs and HCAs (Fig. 13). Reticulin loss and thickened cell plates (>two cells thick) support HCC diagnosis [114]. However, benign conditions, such as fatty liver disease [115], areas adjacent to necrosis, and congestive hepatopathy, may also demonstrate reticulin loss. Therefore, the results of reticulin staining should be evaluated together with morphological findings and other immunostaining results.

4. Immunohistochemistry

IHC can be helpful in confirming hepatocellular differentiation and in distinguishing benign from malignant WDHLs. The immunohistochemical markers of hepatocellular differentiation include Hep Par-1, arginase-1, polyclonal carcinoembryonic antigen (pCEA), cluster of differentiation 10 (CD10), and AFP. The three primary IHC markers used to distinguish benign from malignant WDHLs are GPC3, , and HSP70 [116,117]. A crucial aspect when using IHC is its interpretation in conjunction with H&E staining.

1) Immunohistochemical markers and albumin messenger RNA in situ hybridization for hepatocellular differentiation

(1) Hepatocyte paraffin-1

Hep Par-1 is a monoclonal antibody derived initially from formalin-fixed failed allograft liver tissue [118] and is an antigen reflecting hepatocytic differentiation. It stains normal and neoplastic hepatocytes, and usually shows a diffuse granular cytoplasmic pattern. Hep Par-1 positivity is observed in 75% to 90% of HCC cases [119-121]. It performs best in well-differentiated and moderately differentiated HCCs and has a lower sensitivity in poorly differentiated HCCs. Other tumors, such as gastric, esophageal, colorectal, pancreatic, pulmonary, urothelial, adrenocortical, and uterine cervical carcinomas, can also be positive for Hep Par-1 [122,123]. However, in these cases, Hep Par-1 expression is usually focal and weak.

(2) Arginase-1

Arginase-1 is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of arginine to ornithine and urea. Nuclear and cytoplasmic staining are observed in both normal and neoplastic hepatocytes. Arginase-1 is a highly sensitive and specific marker of hepatocellular differentiation [86,124]. However, some well-differentiated HCCs are negative for arginase-1; therefore, a panel of markers is recommended [125]. Rare cases of focally positive arginase-1 staining have been reported in intrahepatic cholangiocarcinoma (CCA) and metastatic carcinomas of the colon and prostate [124,126].

(3) Polyclonal carcinoembryonic antigen and cluster of differentiation 10

pCEA is a glycoprotein involved in cell adhesion that cross-reacts with biliary glycoprotein I in the bile canaliculus. CD10 is a zinc-dependent metalloendopeptidase located on the cell surface, which plays a central role in immune regulation, peptide degradation, and cellular interactions. Both pCEA and CD10 reveal hepatocellular differentiation by their characteristic canalicular staining patterns [86,127,128]. The sensitivities of CD10 and pCEA for HCC are approximately 50% to 75% and 45% to 80%, respectively [86]. Canalicular staining for pCEA and CD10 is most likely to be observed in well-differentiated HCCs; however, their sensitivities are low in poorly differentiated HCCs.

(4) Alpha-fetoprotein

AFP is an oncofetal glycoprotein that is expressed in approximately 30% of HCCs cases. However, it has limitations in terms of sensitivity and specificity for HCC. Nonetheless, AFP can help diagnose poorly differentiated HCCs that are negative or equivocal for other markers of hepatocellular differentiation. Metastatic hepatoid carcinomas of the ovary, stomach, lungs, pancreas, and gallbladder are also positive for AFP [129,130].

(5) Albumin messenger RNA in situ hybridization

In situ hybridization of albumin messenger RNA (mRNA) effectively detects hepatocellular differentiation [131]. The staining is strongly granular within the cytoplasm. Intrahepatic CCAs are frequently positive for albumin mRNA in situ hybridization [132]. Moreover, hepatoid adenocarcinomas can be positive for albumin mRNA using in situ hybridization [133]. Therefore, correlation with morphological features is essential for an accurate differential diagnosis. Table 3 presents the IHC markers and albumin mRNA in situ hybridization of WDHLs.

2) Immunohistochemical markers for distinguishing benign from malignant well-differentiated lesions

(1) CD34

CD34 is a transmembrane phosphoglycoprotein that plays a role in cell-cell adhesion and is expressed in endothelial cells. In a normal liver, CD34 highlights the sinusoids in zone 1; however, it does not extend further into the lobules (Fig. 14). HCCs typically show a strong diffuse sinusoidal staining pattern for CD34 [134]. CD34 staining is typically patchy in FNHs and HCAs [135-137]. However, diffuse CD34 staining has been observed in 27% of HCA cases, particularly in B-HCAs and U-HCAs [138].

(2) Glypican-3

GPC3 is a heparan sulfate proteoglycan expressed in the fetal liver and placenta, but not in the adult liver. Wang et al. [139] reported GPC3 immunostaining in 8% of LGDNs, 22% of HGDNs, and 60% of early HCCs. GPC3 shows positive granular cytoplasmic staining. HCAs and FNHs are negative for GPC3. However, in rare cases, I-HCAs may exhibit focal and weak GPC3 staining. GPC3 can also stain benign hepatocytes in severely inflamed livers [140]. The lipofuscin material of pigmented HCAs shows strong positivity, indicating a potential diagnostic pitfall [45].

(3) Glutamine synthetase

GS catalyzes the hepatic conversion of ammonia and glutamate to glutamine for nitrogen metabolism [141]. In a normal liver, GS is expressed in hepatocytes around the central veins [142]. GS is a target gene of β-catenin and strong diffuse GS staining indicates β-catenin activation [143-145]. FNHs show a characteristic map-like staining pattern. B-HCAs without exon 3 S45 mutations show diffuse homogeneous staining, whereas B-HCAs with exon 7 or 8 mutations show faint staining, with or without perivascular staining [20]. GS immunostaining gradually increases from precancerous lesions to early and advanced HCCs. GS is expressed in approximately 13% of early HCC cases and 39% of advanced HCC cases [145].

(4) Heat shock protein 70

HSP70 is a member of the heat shock protein family that regulates the cell cycle, apoptosis, and tumorigenesis [146-148]. HSP70 is expressed in most HCCs, but not in nonmalignant nodules [87], indicating its potential as a malignancy marker. Among the 12,600 genes in early HCC components, HSP70 is the most abundantly upregulated [149]. Immunohistochemical analysis reveals that HSP70 expression is notably higher in early HCCs than in precancerous lesions.

Using a panel of three markers (GPC3, GS, and HSP70), the sensitivity and specificity for detecting well-differentiated HCCs with at least two positive results were 72% and 100%, respectively [87]. Therefore, combining more than one putative malignancy marker may improve diagnostic accuracy [73].

(5) Cytokeratins 7 and 19

The bile ducts are positive for CK7 or CK19. Stromal invasion is a crucial diagnostic indicator for early HCC. Immunohistochemical staining using CK7 and CK19 is helpful in distinguishing true stromal invasion from pseudoinvasion [150]. If a ductular reaction highlighted by CK7 or CK19 is observed, it is regarded as a pseudoinvasion, which does not support the diagnosis of HCC.

⑥ Antigen Kiel 67

Antigen Kiel 67 (Ki-67) is a nuclear protein expressed during the active phases of the cell cycle (G1, S, G2, and mitosis), and is commonly used as a proliferation index marker. Benign hepatocellular lesions typically have a low Ki-67 proliferation index (>1%–2%) [151-153]. Conversely, HCCs usually exhibit a higher Ki-67 proliferation index than benign hepatocellular lesions. Ki-67 is a potentially valuable supplementary marker for the evaluation of well-differentiated hepatocellular neoplasms. “Hot spot” proliferative rates, measured by digital analysis, are consistently very low in HCAs, but vary substantially in well-differentiated HCCs [153]. Consequently, increased Ki-67 staining can help distinguish benign hepatocellular lesions from well-differentiated HCCs. Ki-67 staining is particularly helpful when comparing results between tumor and non-tumor tissues [1]. Table 4 shows the IHC markers used to differentiate benign and malignant hepatocellular lesions.

5. Diagnostic approach to well-differentiated hepatocellular lesions

A systematic approach is essential for the diagnosis of WDHLs [154]. The initial step involves careful histological examination of H&E-stained sections at a low magnification. This examination is beneficial for recognizing architectural and cytological changes. Pathologists should assess the presence of lesional and non-tumoral liver tissue, morphology of lesional cells, and architectural patterns [23]. Special staining, IHC, and molecular analyses are useful in challenging cases [64,155]. An immunohistochemical panel, including LFABP, CRP, SAA, β-catenin, and GS, is helpful for subclassifying HCAs. A thorough review of patients’ clinical information (such as sex, age, and race), medical history (such as cirrhosis), radiological findings (such as number, size, and location of liver lesions), serum tumor markers (such as AFP), and histological features of the lesion and background liver are essential for developing a differential diagnosis and ultimately achieving a definitive diagnosis [23]. Pathologists must review any previous biopsies relevant to the case. The differential diagnosis of WDHLs is determined based on the background liver condition. In noncirrhotic livers, the differential diagnosis includes FNH, HCA, and HCC, whereas in cirrhotic livers, the differential diagnosis primarily includes MRN, DN, and HCC. Fig. 15 shows the diagnostic algorithm for WDHLs.

Future perspective

The frequencies of TERT promoter mutations in HGDNs and HCCs are 19% and 60%, respectively [81]. TERT promoter mutations have been found in approximately half of HCA cases with malignant transformation and are associated with CTNNB1 mutations [156]. Chromosomal alterations, such as copy number variations, have also been observed in premalignant hepatic lesions, with the most common broad copy number aberrations occurring on chromosomes 1 and 8 [157]. Shen et al. [158] suggested that barrier-to-autointegration factor 1 (BANF1); procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3); and splicing factor 3b subunit 4 (SF3B4) serve as diagnostic markers for early-stage HCC and have potential therapeutic value in HCC treatment. Methylome profiling has revealed a gradient of DNA methylation changes across the different histological stages of hepatocarcinogenesis [159]. Therefore, molecular profiling may be useful in challenging cases [160]. The advent of molecular diagnostics using tissue or liquid biopsies marks a promising new era in HCC diagnosis and management, providing sensitive and effective tools applicable to all disease stages [161]. However, the role of multidisciplinary teams in early screening and disease prevention requires further research [162].

Stromal invasion is a valuable criterion for diagnosing malignancies in HGDNs and well-differentiated HCCs [97,163]. However, markers that can differentiate benign and malignant hepatocellular lesions must be identified. Diagnosing and treating borderline HCAs is challenging because their biological behavior, particularly their malignant potential, remains controversial [164]. Therefore, additional studies are warranted to refine the criteria for borderline HCAs. New immunohistochemical and molecular markers for HGDNs and well-differentiated HCCs are still under investigation and show promise for future diagnostic applications [148,165]. Artificial intelligence (AI) integrated with digital pathology is considered a valuable tool for diagnosis, classification, risk assessment, treatment planning, and treatment outcome prediction in HCCs [166,167]. Further research is necessary to standardize and rigorously evaluate AI algorithms through prospective studies in order to enhance their interpretability, generalizability, and transparency.

Conclusion

WDHLs, including FNH, HCA, MRN, DN, and well-differentiated HCC, are characterized by distinct histopathological features and differential diagnosis. A systematic approach to diagnosing these lesions requires a comprehensive assessment of cytological findings, architectural changes, immunohistochemical results, and molecular testing. These elements should be interpreted in conjunction with clinical and radiological findings. Further investigation of biological markers for differentiating between benign and malignant hepatocellular lesions is required.

Article information

Conflicts of interest

Joon Hyuk Choi has been editorial board member of Journal of Yeungnam Medical Science since 2002. He was not involved in the review process of this manuscript. There are no other conflicts of interest to declare.

Funding

None.

Author contributions

Conceptualization, Data curation, Investigation, Resources, Formal analysis, Methodology, Project administration, Visualization, Supervision: JHC, SNT; Writing-original draft: JHC; Writing-review & editing: JHC, SNT.

Fig. 1.

Focal nodular hyperplasia. A round, well-circumscribed, and lobulated mass with a central whitish scar and fibrous septa extending from the center toward the periphery is present. The background liver is noncirrhotic.

Fig. 2.

Focal nodular hyperplasia. (A) The central scar area shows thick-walled arteries, ductular reaction, inflammatory cell infiltration, and nodular architecture (hematoxylin and eosin stain, ×40). (B) Immunohistochemical staining for glutamine synthetase reveals an anastomosing map-like pattern (immunohistochemical stain, ×40).

Fig. 3.

Hepatocellular adenoma. The cut surface shows an ill-defined, soft, yellow-brown tumor without a fibrous capsule.

Fig. 4.

Hepatocyte nuclear factor 1α-inactivated hepatocellular adenoma. (A) The tumor shows diffuse steatosis compared to the surrounding liver parenchyma (hematoxylin and eosin stain, ×100). (B) Immunohistochemical staining for liver fatty-acid binding protein shows staining loss in the tumor (left side of the image) but positive staining in the adjacent liver (right side of the image; immunohistochemical stain, ×100).

Fig. 5.

Inflammatory hepatocellular adenoma. (A) Tumor cells are uniform with minimal cytological atypia. Focal telangiectasia and mild inflammatory cell infiltration are observed (hematoxylin and eosin stain, ×100). (B) Immunohistochemical staining for serum amyloid A shows positivity in tumor cells (immunohistochemical stain, ×100).

Fig. 6.

Macroregenerative nodule. (A) The macroregenerative nodule (arrow) has a slightly different color and is larger than 1 cm. (B) Hepatocytes show no cytological atypia. Portal tracts (arrow) are seen in the nodule (hematoxylin and eosin stain, ×20).

Fig. 7.

Large and small cell changes. (A) Large cell change. The hepatocytes show large cell change, with large atypical nuclei, but a preserved nuclear-to-cytoplasmic ratio. (B) Small cell change. The hepatocytes show small cell change, with an increased nuclear-to-cytoplasmic ratio and mild nuclear hyperchromasia (hematoxylin and eosin stain, ×100 [A, B]).

Fig. 8.

Low-grade dysplastic nodule. (A) A low-grade dysplastic nodule (arrow) is present in the background of the cirrhotic nodules. (B) Hepatocytes show minimal nuclear atypia. (C) Portal tract is present in the nodule. (D) Hepatocytes show a clone-like appearance. Fatty change is present (hematoxylin and eosin stain, ×100 [B, C] and ×200 [D]).

Fig. 9.

High-grade dysplastic nodule. (A) A hepatocellular carcinoma (asterisk) and high-grade dysplastic nodule (arrow) coexist. The background liver is cirrhotic. (B) Low magnification shows a high-grade dysplastic nodule (arrow). (C) Hepatocytes show small cell change. (D) Increased cell density is observed. Focal fatty change is observed (hematoxylin and eosin stain; ×1 [B], ×200 [C], and ×100 [D]).

Fig. 10.

Early hepatocellular carcinoma. A vaguely nodular tumor is observed. The background liver is cirrhotic.

Fig. 11.

Well-differentiated hepatocellular carcinoma. (A) Neoplastic hepatocytes show mild nuclear atypia. A slight increase in the nuclear-to-cytoplasmic ratio is observed. The tumor grows in a thickened trabecular pattern (hematoxylin and eosin stain, ×100). (B) Immunohistochemical staining for glypican-3 shows positivity in tumor cells (immunohistochemical stain, ×100).

Fig. 12.

Stromal invasion. (A) The hepatocellular carcinoma has invaded along the fibrous septa (arrow), extending from the main tumor mass (hematoxylin and eosin stain, ×100). (B) The hepatocellular carcinoma shows no ductular reaction at the epithelial-stromal interface, indicating an invasive phenotype. Cytokeratin 7-positive immunoreactive structures are preexisting bile ducts (arrow) entrapped within the lesion (immunohistochemical stain, ×100).

Fig. 13.

Reticulin stain. (A) Normal liver shows an intact reticulin framework. (B) Focal nodular hyperplasia shows no reticulin loss. (C) Hepatocellular adenoma shows focal reticulin loss. (D) Well-differentiated hepatocellular carcinoma shows reticulin loss (reticulin stain, ×100 [A–D]).

Fig. 14.

Immunohistochemical stain for CD34. (A) Normal liver shows no sinusoidal staining. (B) Focal nodular hyperplasia shows a patchy sinusoidal staining. (C) Hepatocellular adenoma shows a patchy sinusoidal staining. (D) Well-differentiated hepatocellular carcinoma shows a diffuse sinusoidal staining (immunohistochemical stain, ×100 [A–D]).

Fig. 15.

Pathological diagnostic algorithm for well-differentiated hepatocellular lesions. The diagnostic approach is based on clinical findings (such as cirrhosis), morphology, and immunohistochemical results. ^a)Stromal invasion is highly valuable when available; however, most biopsies are often missing. ^b) Nuclear β-catenin expression and GS expression depend on mutation type: exon 3 (non-S45) mutations often show nuclear β-catenin and diffuse homogeneous GS expression; exon 3 S45 mutations show little or no nuclear β-catenin and diffuse heterogeneous GS expression, with a starry-sky pattern; exon 7 or 8 mutations show no nuclear β-catenin expression and focal/patchy and peripheral rim GS expression. GS, glutamine synthetase; FNH, focal nodular hyperplasia; HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; WD-HCC, well-differentiated HCC; LFABP, liver fatty-acid binding protein; CRP, C-reactive protein; SAA, serum amyloid A; B-HCA, β-catenin–activated HCA; I-HCA, inflammatory HCA; PTDGS, prostaglandin-H2 D-isomerase; ASS1, argininosuccinate synthase 1; H-HCA, hepatocyte nuclear factor 1α-inactivated HCA; BI-HCA, β-catenin–activated inflammatory HCA; SH-HCA, sonic hedgehog-activated HCA; MRN, macroregenerative nodule; LGDN, low-grade dysplastic nodule; HGDN, high-grade dysplastic nodule.

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