Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually arises in cirrhotic livers. Increasingly, it is diagnosed in non-cirrhotic livers. A variety of risk factors and etiologies can trigger the development of HCC in non-fibrotic and non-cirrhotic backgrounds. The most important causes are metabolic syndrome and hepatitis B virus infection. Postulated pathogenetic mechanisms are direct carcinogenesis, chronic liver injury and repair cycles, and genetic/epigenetic aberrations. Histopathology has a very important role in the diagnosis of non-cirrhotic HCC. Gross features of non-cirrhotic HCC are quite different from HCC originating in a cirrhotic background. Microscopic characteristics are similar to a classical HCC. However, certain histological variants show a predilection to occur in non-cirrhotic livers. These encompass fibrolamellar, scirrhous, steatohepatitic and mixed hepato-cholangiocarcinoma subtypes. Due to the non-cirrhotic background, adenoma, metastasis and most of the other non-neoplastic and neoplastic conditions enter the differential diagnosis. Genomic studies and morpho-molecular classifications of HCC provide further understanding of the molecular pathogenesis of non-cirrhotic HCC. This group however, has rarely been exclusively studied. This review offers an update of etiology, patho-molecular characteristics and differential diagnosis of HCC arising in non-cirrhotic backgrounds.
Hepatocellular carcinoma (HCC) usually arises in a cirrhotic liver and is characterized by tremendous phenotypic and molecular heterogeneity[
HCC is the most common primary malignant liver tumor and usually arises in cirrhotic livers. The occurrence of HCC in non-cirrhotic livers varies across different geographic regions of the world with a prevalence ranging from 7% to 54%[
The existence of HCC in non-cirrhotic livers has a bimodal age distribution, with peaks in the second and seventh decades. Non-cirrhotic HCCs have a lower male to female sex ratio (1.3-2.1) in comparison to cirrhotic HCCs where the ratio is 3.2 to 8:1[
Non-cirrhotic HCCs usually display similar imaging features to cirrhotic HCCs on computed tomography (CT) and MRI, with arterial phase hyper-enhancement followed by washout on portal venous and/or delayed phase imaging[
The prognosis for non-cirrhotic HCCs is usually better than that for cirrhotic HCCs[
A variety of conditions can be a risk factor for developing non-cirrhotic HCC.
Hepatitis B virus (HBV) infection is one of the most common underlying etiologies, especially in high incidence areas. Up to 30% of HBV-related HCCs arise in non-cirrhotic livers[
Although relatively less common, chronic HCV-infection is also a risk factor for the development of HCC in non-cirrhotic livers[
Metabolic syndrome is the most frequent cause of HCCs in non-cirrhotic backgrounds[
The aforementioned cause-effect relationships for HCC development can be due to direct carcinogenic action. Nonetheless, the role of chronic liver inflammation leading to repeated cycles of cell injury and regeneration, and subsequent genetic and epigenetic alterations in hepatocytes, is equally plausible[
Hepatocyte injury resulting from microbial or sterile etiologies activates resident liver immune cells and later, facilitates the recruitment of nonresident immune cells to the liver, thereby mounting a strong inflammatory response. Persistent inflammation as a result of hepatitis virus or microbial attack resulting from breaches of the gut–liver axis lead to the production of proinflammatory cytokines such as IL-6 TNF-α, IL-1 and IL-18 through inflammasome-independent or -dependent pathways. Activated transcription factors make the hepatic milieu a fertile zone for cellular transformation[
Inherited metabolic and congenital diseases, in particular hereditary hemochromatosis, α-1-antitrypsin deficiency, Wilson disease, type I glycogen storage disease, porphyria, hypercitrullinemia, Alagille syndrome, and congenital hepatic fibrosis have predisposition to developing HCC in non-cirrhotic livers[
Other genotoxic factors such as aflatoxin B1, produced by the fungus
Other liver lesions such as hepatocellular adenoma occur in non-cirrhotic backgrounds and can undergo malignant transformation in around 15% of cases[
Gross examination of a non-cirrhotic HCC frequently displays a large solitary mass or a dominant mass with small satellite nodules. This is in contrast to HCCs in cirrhosis, which has either a single nodule or multiple small nodules[
Gross specimens: HCC in a non-cirrhotic background: massive solitary HCC in a patient with NASH (A); single HCC in HBV related liver disease (B); multinodular HCC in a patient infected with HBV (C); steatohepatitic variant of HCC in a patient with NASH (D); single large HCC in a patient infected with HCV (E); large HCC with prominent cholestasis and pseudoglandular pattern on microscopy (F); combined HCC-CC in a patient infected with HBV (G); fibrolamellar HCC (H). HCC: hepatocellular carcinoma; HBV: hepatitis B virus
Non-cirrhotic HCCs are more likely to develop intratumoral hemorrhage. It shows tumour heterogeneity with variegated appearances due to necrosis and hemorrhage[
The published literature indicate more frequent metastasis, direct invasion of adjacent organs and macroscopic portal vein or hepatic vein invasion in non-cirrhotic HCC, which is probably related to delayed diagnosis or inherent biological aggressiveness[
Fibrolamellar HCCs are a distinct variant of HCCs known to occur in non-cirrhotic livers[
The histological evaluation of HCC specimens plays a key role in tumor staging and in distinguishing HCC from its precursor lesions or other liver nodules[
The pathological characteristics are similar to those of an HCC developing in a cirrhotic background. Thickened tumor cell plates, malignant cytology, capillarization of sinusoids and evidence of invasion constitute the principal diagnostic microscopic features. The four major histological patterns in HCC are microtrabecular, compact, macrotrabecular and pseudoglandular. Of these, the trabecular form is the most common histological pattern of HCC, both in cirrhotic and non-cirrhotic livers (41%-76%)[
Histological patterns of hepatocellular carcinoma in non-cirrhotic livers: pseudoglandular (A), microtrabecular (B), macrotrabecular (C), compact (D)
There are several histological subtypes of HCC such as fibrolamellar, steatohepatitic, lymphoepithelioma-like carcinoma, combined hepatocholangiocarcinoma, clear cell HCC, sarcomatoid HCC and many others[
Microscopic sections of histological variants of hepatocellular carcinoma occuring in non-cirrhotic backgrounds: fibrolamellar (A), steatohepatitic (B), scirrhous (C), mixed hepatocellular-cholangiocarcinoma (D)
HCC is characterised by cytologic features which have prognostic importance and add heterogeneity to the tumour phenotype[
There is conflicting data on the occurrence of prognostic histological indices in non-cirrhotic HCCs. Nzeako
HCC may develop without advanced liver fibrosis or even in normal livers. The non-tumoral liver exhibits features of chronic hepatitis, varying degrees of fibrosis, steatosis, iron overload or other metabolic disorders[
HCC in a non-cirrhotic background: HCC with pseudoglandular pattern in a background with F0-F1 fibrosis (A, HE stain; B Masson Trichrome stain), HCC with microtrabecular pattern in F0 fibrosis (C, HE stain), steatohepatitic HCC with F3 fibrosis in background liver (D, MT stain). HCC: hepatocellular carcinoma
There is a plethora of inflammatory, immunologic, neoplastic and infective lesions that occur in a non-cirrhotic liver background. However, from the point of view of histopathological interpretation, the most important are preneoplastic and neoplastic conditions, HCC variants and tumor metastasis.
Dysplastic nodules are premalignant lesions, which are well-defined and circumscribed. These lesions mostly arise from a background of chronic liver disease and more often, cirrhosis[
Immunohistochemical markers helpful for confirming hepatocytic origin and in confirming well-differentiated HCC: HepPar1 (A), polyclonal CEA (B), Glypican-3 (C), HSP70 (D), CD34 (E), glutamine synthetase (F). HCC: hepatocellular carcinoma
The differential diagnosis between hepatocellular adenoma (HCA) and well-differentiated HCC arising in non-cirrhotic livers is another challenging situation, especially the HCA subtype with cytological or architectural atypia[
Focal nodular hyperplasia (FNH) is another important differential consideration for HCCs occurring in non-cirrhotic backgrounds. FNH, a benign lesion resulting from the regenerative response to vascular abnormalities, has a characteristic histomorphology. A central scar with thick-walled vessels and nodular regeneration of hepatocytes, with marked ductular reaction and inflammatory infiltrate at the junction of fibrous bands and hepatocyte nodules, distinguishes FNH from HCC. A “map-like,” geographic pattern of GS staining of FNH is especially useful in diagnostic dilemmas[
Awareness of other benign and malignant epithelial, mesenchymal and vascular tumours is crucial. Cholangiocarcinoma is the second most common primary cancer and accounts for 15% of primary liver tumors[
Certain HCC variants have a predilection to occur in non-cirrhotic livers. Fibrolamellar, scirrhous, steatohepatiic and mixed hepato-cholangiocarcinoma are the more frequent subtypes. Molecular pathways and morpho-molecular features are reviewed in the molecular pathology section.
The fibrolamellar subtype merits special mention. It was first described by Edmondson in 1980, and is a rare entity, accounting for less than 1% of all cases of primary liver cancer[
Metastasis is the most common hepatic malignancy and occurs in non-cirrhotic livers. In patients without underlying liver disease, HCC accounts for only about 2% of malignant liver neoplasms[
The etiology and etiopathogenesis for a vast number of non-cirrhotic HCCs still remain unknown. Advancements in translational research have made it possible to analyse thousands of molecular targets in HCC using microarray-based technologies as well as next-generation sequencing. However, unlike the cirrhotic HCC and HCA, molecular pathways and classifications have not been exclusively studied in non-cirrhotic HCCs. Genomic studies in this particular group would be able to elucidate the similarities and distinctness of the underlying mechanisms and biology in comparison to the cirrhotic HCC. Despite the scarcity of the literature, recent studies on the molecular pathology of HCC, regardless of the background liver, provides vital information.
The most frequent mutations affect the TERT promoter (60%), which is associated with an increased expression of telomerase. TP53 and CTNNB1 are the next most prevalent mutations. These, combined with low-frequency mutated genes (e.g., AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), represent the main deregulated pathways in HCC[
Different pathways of genetic alterations point towards different hepatocarcinogenetic mechanisms in HCC with and without cirrhosis. HCCs in non-cirrhotic livers are more often associated with higher β-catenin mutation, p21 expression, p14 inactivation, and global gene methylation, in contrast to higher p53 and Wnt/β-catenin pathway aberrations seen in cirrhotic HCCs[
Immunohistochemical markers representative of phenotypic correlates of dysregulated molecular pathways: TP53 (A), PD1 in immune cells (B), PDL1 in tumour cells (C), CK19 in tumour cells (D), β-catenin nuclear positivity (E), glutamine synthetase diffuse expression (F). PD1: Programmed death-1; PD-L1: programmed death-ligand 1
Analysis of miRNAs holds great promise for improving diagnosis and prognosis, along with the therapeutic management of HCCs originating in non-cirrhotic backgrounds. miRNA, particularly hsa-mir-149 expression, is considered an independent risk factor for the poor prognosis of non-cirrhotic HCCs but not for cirrhotic HCCs[
Few studies have pointed towards the role of altered mismatch repair genes in hepatocarcinogenesis. A study to explore the presence of microsatellite instability (MSI) in 37 non-cirrhotic HCC patients with a histologically normal liver, low alcohol intake and absence of HBV and HCV infection[
Angiogenesis related characteristics are similar between cirrhotic and non-cirrhotic HCCs[
Certain etiology specific studies have reported important molecular alterations in non-cirrhotic HCCs.
STAT signaling pathways have an important role in HCC-NASH[
HBV infection has direct oncogenic potential and the accumulation of mutations in basal core promoters and a high viral load is considered an independent predictor of HCC development. These mutational patterns have the potential to identify those at risk of HCC development. HCC development in HCV infected patients is mainly attributable to sustained necro-inflammatory processes and therefore, occurs on a background of advanced liver fibrosis or frank cirrhosis. Studies have shown that several HCV gene products (core, NS3, NS4B and NS5A) possess transformation potential in murine fibroblast culture, suggesting that HCV also has direct hepatocarcinogenic potential[
Overrepresentation of T>C at ApTpX with transcription strand bias, a pattern known to be strongly associated with genotoxic injury, was reported in HCC developing in non-cirrhotic patients with high alcohol and tobacco consumption[
Macrotrabecular massive HCC (MTM-HCC), a novel distinct subtype of HCC, is characterized by the presence of a macrotrabecular pattern of more than 6 cells thick recorded in > 50% of the tumor as described by Ziol
The steatohepatitic subtype is characterized by prominent steatotic changes in the tumor cells, namely fat accumulation, ballooning degeneration, the presence of Mallory-Denk bodies and peri-cellular fibrosis[
Lymphocyte-rich HCCs are characterized by an immune rich stroma and have been demonstrated to have cirrhosis in only 46% of cases in a recent comprehensive review[
Scirrhous HCC is another variant, which is less often associated with liver cirrhosis when compared with conventional HCC[
Fibrolamellar HCC is characterized by a chimeric transcript, found as a result of a deletion in the chromosome 19 - DNAJB1-PRKACA chimeric protein[
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) also occurs in the non-cirrhotic liver background. Genomic sequencing shows a profile similar to conventional HCCs[
Genetic aberrations in non-cirrhotic hepatocellular carcinomas (HCCs)
HCCs arising in non-cirrhotic livers are distinct from cirrhotic HCCs in many ways. The risk factors, etiologies, pathogenesis, histopathology and the differential diagnosis, along with genomic pathways, differ from the typical cirrhotic HCC. Current knowledge of phenotypic-molecular alterations are based on studies on HCC irrespective of the liver background. Studies devoted exclusively to non-cirrhotic HCCs are scarce. In the era of molecular targeted therapies, there is an urgent need to analyze the carcinogenetic mechanisms and pathology based phenotypic correlates of specific molecular aberrations in HCCs originating in non-cirrhotic livers.
Prof. (Dr.) SK Sarin, Senior Professor (Dept. of Hepatology) & Director, Institute of Liver & Biliary Sciences, Delhi, for constant guidance & support. Dr. Gayatri Ramakrishna, Additional Professor, Department of Molecular & Cellular Medicine, for creating figure of molecular pathways.
The author contributed solely to the article.
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None.
The authors declared that there are no conflicts of interest.
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© The Author(s) 2020.