Molecular mechanisms in the development of hepatocellular carcinoma 

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Alcohol

Although the pathogenic mechanisms underlying the initiation of alcohol-induced tumorigenesis have been well defined (118,119) , the alcohol-related signaling pathways involved in tumor promotion and progression are poorly understood. Induction of cytochrome p450 2E1 (CYP2E1), by chronic alcohol consumption induces many biological effects, such as increases in alcohol metabolism, over production of ROS, as well as interactions with various drugs and carcinogens (120).

Associated mechanisms NASH, obesity and HCC

The progression of non-alcoholic steatohepatitis towards fibrosis and finally cirrhosis has been studied. Among 15-20% of NASH cases progress to cirrhosis, the latter being a recognized risk factor for the development of HCC (128).
In NASH, the main mechanisms of liver lesions are associated with endoplasmic reticulum dysfunction (ER), mitochondrial dysfunction and impaired autophagy in intrahepatic NKT and CD8+ cells and increased oxidative stress (129). During the inflammatory process in NASH, several cytokines, adipokines and lymphokines contribute to hepatic fibrogenesis through the regenerative process of hepatocytes (130). Recent studies have shown that positive regulation of the insulin-like growth factor 1 (IGF1)/insulin substrate 1 pathway caused by hyperinsulinemia (68) as well as increased levels of IL-6 and TNF- due to obesity (69) contribute to the development of hepatocarcinogenic mechanisms.
It has also been shown that obese patients experience an increase in the relative number of macrophages type 1 and 2 (131). Obesity generates a state of mild inflammation of the adipose tissue, in addition to increasing the inflammatory component mainly due to macrophages (132). Type 1 macrophages (M1), are an essential component of humoral immunity, in states of overactivation the M1 secrete large amounts of proinflammatory factors, including nitric oxide (NO) proinflammatory cytokines such as TNF-, IL-1, IL-2, IL-6 and reactive ROS (133).

Tyrosine-kinase’s receptor pathway

Approximately 50% of cases of HCC presented with an alteration of the Ras-mitogen-activated protein kinase (MAPK) and PI3K-Akt kinase pathways (160).
The activation of these pathways is linked to the binding of ligands and phosphorylation of several tyrosine kinase receptors of growth factors such as EGFR, FGFR, HGFR/c-MET, the stem cell growth factor receptor (c-kit) and VEGFR. In addition, the activation of the Ras/Raf/MEK/ERK (MAPK) pathway in turn activates the cFos protooncogene and the AP-1/c-Jun transcription factor, which induce cell proliferation, thanks to gene transcription (161).
In addition, insulin receptors or IGF receptors (such as IGFR1) cause activation of the PI3K-Akt kinase pathway, which is involved in the alteration of the mammalian rapamycin pathway (mTOR), which occurs in approximately 40% to 50% of cases of HCC (162). Likewise, the mTOR pathway is capable of deregulating PI3K, by losing the function of the PTEN gene by mutation or epigenetic silencing.

Dysplastic foci: small or large dysplasia

The term refers to small foci less than 1 mm which can only be recognized by microscopic observation. Here we find two types: small cell dysplasia and large cell dysplasia (figure5) (165). Small cell dysplasia (SCD) refers to a group of hepatocytes with reduced cytoplasmic volume, moderate nuclear plemorphism, and an increased cytoplasmic nucleus ratio (166). In addition, the SCD has histological and cytological similarities with well-differentiated HCC (167). For example, at the macro level, the involved hepatic trabeculae can reach 2 to 3 layers or form pseudo-glandular structures that resemble those often observed in the well-differentiated HCC originally described by Edmondson and Steiner (168). SCD foci also contain chromosome gains and losses that are also present in HCC but not in the underlying hepatic parenchyma (169). It has also been shown that about half of SCDs foci are composed of cells almost exclusively with the immunophenotypic profile of hepatic progenitor cells and hepatocyte-like intermediate cells, suggesting that hepatic progenitor cells may cause HCC in the human liver through the formation of SCD foci (170).
Large cell dysplasia (LCD) is defined as a group of hepatocytes with nuclear and cellular growth, a normal cytoplasmic nucleus ratio, nuclear pleomorphism, multinucleation, nuclear pseudoinclusions and a prominent nucleolus (171). LCD was initially considered a « precursor » lesion of HCC, due to the abnormal amount of DNA found. However, the DNA concentration does not correspond to histological changes, such as the low rate of proliferation (172), the low nucleus cytoplasm ratio and the strong apoptotic activity (166).

Regenerative nodules

According to the classification proposed in 1995 by Wanless et al., the regenerative nodules are lesions of a minimum size of 5 mm and do not exhibit cytological or architectural atypia (175). They can also be located mainly next to the largest portal spaces. A debate emerged though concerning the presence of the monoclonality of these lesions and their relationship with the development of HCC. It has been shown by some investigatos that a percentage of these lesions are monoclonal, but these results have not been fully replicated. Therefore, additional studies are still needed to show whether or not regenerative nodules might represent precursor lesion (176–178).

Iron-free foci

A study in patients with hemochromatosis revealed a type of lesion called iron-free foci (179), Histologically, this lesion is defined as lesions of more than 20 iron-free hepatocytes, in a parenchyma with overload (180). The mechanism by which these hepatocytes avoid overload is not known until now. However, it is known that these iron-free foci are strongly associated with the appearance of HCC (figure 6) (181).

Foci of altered hepatocytes, rich in glycogen / oncocytes

Pre-neoplastic foci of altered hepatocytes (FAH) were originally found in the liver of rats treated with hepatocarcinogenic nitrosamines. Since then, different animals have been observed, including primates in the early stages of hepatocarcinogenesis induced by genotoxic or non-genotoxic chemicals (182). Currently they are considered as precursors lesions of HCC (182). Because of their histological characteristics, 8 different varieties of these FAH have been described, the most considered are; i) foci that store glycogen (GSF) and ii) oncocytic foci (174,183).
GSFs are characterized by a relatively clear cytoplasm with only a hint of very pale eosinophilic staining and thin rows of cytoplasm that make the cytoplasmic vacuoles have an indistinct edge. The cells that make up a GSF are characterized by the central nucleus (183). There are just some reports of GSF in the human liver. GSF are present in the majority of cirrhotic livers with HCC and some of them contain SCD foci, suggesting a probable evolution path from GSF to SCD with the final development of HCC.(183–185). At present, there is insufficient evidence that the important role played by GSF in certain animal models of hepatocarcinogenesis can find itsis equivalence in the human liver (figure 7).
Oncocytic changes in hepatocytes are characterized by a granular eosinophilic cytoplasm, due to the large number of mitochondria distributed compactly in the cytoplasm (186). In the human liver affected by a chronic disease, oncocyte foci occur quite frequently, which is why they have been studied extensively (187). According the current hypothesis an environment characterized by chronic inflammation contributes to lesions and depletion of mitochondrial DNA (mtDNA), mainly due to ROS released by inflammatory infiltrate (165).

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Hepatocellular adenoma

Hepatocellular adenoma (HA), it is a rare benign tumor, accounting for 2% of all hepatic neoplasms and occurs mostly, but not exclusively, in middle-aged women with a history of oral contraceptive use for a long time (189). Clinically they are characterized by being a unique lesion, located mainly in the right lobe of the liver, with measures ranging from 1 to 30 cm (189). At clinical examination the presence of a palpable mass or hepatomegaly is the initial symptom in 30% of the cases (190). Patients with large tumors also show vague abdominal pain.
The macroscopic characteristics of the tumor include a single lesion, well delimited, not encapsulated with occasional necrosis and intratumoral hemorrhage. At the microscopic level, HA’s show hepatocytes without signs of dysplasia, arranged in plates of slightly thickened cells, with preservation of the reticulin network. The arterial vascular supply is characterized by thin walls. There is a lack of portal spaces or the elements that compose them. Other less common features include steatosis, inflammatory infiltrate, ductular reaction, hemorrhage and abnormal blood vessels (191).

Histopathology of Hepatocellular carcinoma

Just as the structure and different cell groups in the normal liver have been initially described, A careful microscopic analysis of H&E slides of the tumor tissue gives us a better understanding of their nature and the changes to which they are subjected.
The analysis of the structural pattern, that is to say the predominant or often unique histological pattern of HCC, is the first step towards a better understanding of the nature of the disease, since some of them are related to the prognosis and survival of patients.
WHO has proposed a structural classification that comprises three major histological patterns (200). There are, however, other classifications where additional classifications have been proposed(201), but for the purposes of this review, we will only consider those identified by the WHO.
We also want to emphasize that there are several cytological variants of HCC. Several studies have tried to point out the clinical relevance of these cell variants, however a clear consensus to date has not been possible. However, we must recognize that, its use brings benefits when discerning between the presence of HCC and potential mimic neoplasms.
Finally, special types of HCC have also been described, which have unique characteristics within their architecture, as well as in the population groups they affect.

Table of contents :

I) INTRODUCTION 
1) The Liver 
1.1) Celullar components
1.2) Mechanisms of liver injury
1.2.1) Apoptosis
1.2.2) Necrosis
1.2.3) Regeneration
1.2.4) Fibrosis
1.2.5) Cirrhosis
2) The Hepatocellular Carcinoma 
2.1) Epidemiology
2.2) Risk factors for hepatocellular carcinoma
2.2.1) Hepatitis B virus infection
2.2.2) Hepatitis C virus infection
2.2.3) Alcohol
2.2.4) Aflatoxin
2.2.5) Diabetes, obesity, steatosis and non-alcoholic steatohepatitis
2.2.6) Iron overload diseases
2.3) Molecular mechanisms in the development of hepatocellular carcinoma
2.3.1) Hepatitis B infection
2.3.2) Hepatitis C virus infection
2.3.3) Alcohol
2.3.4) Associated mechanisms NASH, obesity and HCC
2.3.5) Genetic and epigenetic changes in carcinogenesis of HCC
2.4) Preneoplastic lesions
2.4.1) Dysplastic foci: small or large dysplasia
2.4.2) Dysplastic nodules
2.4.3) Regenerative nodules
2.4.4) Iron-free foci
2.4.5) Foci of altered hepatocytes, rich in glycogen / oncocytes
2.4.6) Hepatocellular adenoma
2.5) Histopathology of Hepatocellular carcinoma
2.5.1) Architectural patterns
2.5.2) Cytological variants
2.5.3) Peculiar Histological subtypes
2.6) Molecular classification of hepatocellular carcinoma
2.7) Clinical manifestations
2.7.1) Paraneoplastic Syndromes
2.7.2) Serum AFP
2.8) Treatment
2.8.1) Liver resection
2.8.2) Abaltive treatments
2.8.3) Targeted Therapies
3) The non – cirrhotic hepatocellular carcinoma (NC – HCC)
3.1) Demographic characteristics
3.2) Molecular profile
4) Hepatocellular Carcinoma in Peru 
4.1) Possible causes
4.1.1) Infectious
4.1.2) Environmental pollution
II) WORK OBJECTIVES 
1) Section 1 
1.1) Description of the phenotype of the non-tumor liver of patients with NC- HCC
2) Section 2 
2.1) Description of the tumor phenotype of patients with NC-HCC
2.1.1) Material and methods
3) Section 3 
3.1) Analyze the relationship between environmental exposure to heavy metals in two cohorts and the clinical manifestations of the disease as well as in survival
III) GENERAL DISCUSSION 
IV) PERSPECTIVES 
V) REFERENCES

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