HCC in patients without cirrhosis: A review

Abstract

INTRODUCTION Liver cancer makes up the fifth most common cause of cancer worldwide, with HCC being the most common type of primary liver cancer (80%). HCC is most frequently seen in patients suffering from cirrhosis; however, up to 10%–20% of cases are seen in patients without cirrhosis.1,2 Consensus is lacking with regard to screening for HCC in patients without cirrhosis. In this review, we discuss the risk factors and clinical features of noncirrhotic HCC. Epidemiology and clinical features Noncirrhotic HCC is typically diagnosed at a more advanced stage when compared to patients with cirrhosis, given underlying intact liver function, lack of symptoms, and lack of surveillance, with up to 25% being metastatic.3 Noncirrhotic HCC has a bimodal age distribution (second and seventh decade), with the median age of diagnosis being 69 years old. Noncirrhotic HCC has been shown to be more prevalent in females and those of Asian descent when compared to cirrhotic HCC.1,4 Risk factors There are a number of risk factors for the development of HCC in patients without cirrhosis. Risk factors include hepatotropic viral infections, metabolic dysfunction–associated steatotic liver disease (MASLD), obesity, metabolic syndrome, inherited conditions, toxin exposure, and alcohol-associated liver disease. (Table 1) Among the previously listed, MASLD and hepatotropic viral infections are the most common causes.2,5 TABLE 1 - Risk factors for HCC in patients without cirrhosis Metabolic dysfunction–associated steatotic liver disease HBV HCV Alcohol-associated liver disease Alpha-1 antitrypsin Hemochromatosis Glycogen storage disorders Wilson’s disease Toxins Sex hormones Viral HBV is the leading cause of hepatotropic viral-related noncirrhotic HCC. A member of the Hepadnaviridae family, HBV is a double-stranded DNA virus that, upon entering hepatocytes, incorporates its DNA into that of the host genome. This results in chromosomal instability, insertional mutagenesis, and the production of mutant HBV proteins; these mutant HBV proteins lead to decreased apoptosis of the infected hepatocyte and increased transformation and proliferation of the hepatocyte. HBV’s ability to transform and proliferate hepatocytes without accompanied fibrosis and inflammation may explain the relatively high number of HBV-related HCC in patients without cirrhosis, which is estimated to be around 30% of all HBV-related HCC.2 High viral loads and particular HBV genotypes (such as the T1762/A1764 mutation) are associated with a higher risk of the development of HCC in patients without cirrhosis.2 In patients without cirrhosis with chronic HBV, routine surveillance is indicated in patients with the following risk factors: family history of HCC, patients of African descent > 20 years of age, Asian men > 40 years of age, and Asian women > 50 years of age. Surveillance typically consists of abdominal ultrasound±serum alpha-fetoprotein level every 6 months.6 These indicated screening protocols may allow for HCC in patients without cirrhosis to be diagnosed at an earlier stage. HCV is another cause of hepatotropic viral-related noncirrhotic HCC. A member of the Flaviviridae family, HCV is a single-stranded RNA virus that, upon infection of hepatocytes, leads to the expression and production of HCV-related oncogenic proteins. HCV’s core protein is deleterious to cell regulation, and its nonstructural proteins (including NS3, NS4B, and NS5A) have the potential to induce HCC through their interactions between cellular proteins and promoters.2 Chronic HCV infection is shown to lead to hepatic inflammation and fibrosis, which explains why HCC related to HCV infection is most commonly seen in the setting of cirrhosis. However, given HCV’s oncogenic potential, it still occurs in the absence of cirrhosis; the estimated annual incidence of noncirrhotic HCC is estimated to be anywhere from 4.4% to 10.6%.7 There remains a risk of developing HCC even after successful HCV treatment/achieving sustained viral response. Given the continued risk of HCC after achieving sustained viral response, other potential risk factors for the development of HCC have been investigated (MASLD, toxins, co-viral infection). However, the consensus on how to approach these patients is not clear in the guidelines.2 Furthermore, there is a lack of consensus between the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the European Organization for Research and Treatment of Cancer (EORTC) in how to approach screening for HCC in patients infected with chronic HCV. The current AASLD guidelines only recommend screening for HCC in these patients if they have concomitant cirrhosis. This is in contrast to both the EASL and European Organisation for Research and Treatment of Cancer practice guidelines, which currently recommend HCC surveillance in patients with cirrhosis as well as in patients with advanced liver fibrosis (stage 3 fibrosis).8,9 Metabolic dysfunction–associated steatotic liver disease (MASLD) With the rise of the obesity epidemic and metabolic syndrome, MASLD has become the most common cause of liver damage in the United States. MASLD encompasses a spectrum ranging from simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The comorbidities associated with MASLD (type 2 diabetes mellitus and obesity) are known to lead to the release of pro-inflammatory cytokines (TNF-alpha, IL-6), which cause hepatic steatosis and inflammation. This process and overall chronic level of inflammation is a risk factor for the development of HCC. Other proposed mechanisms of oncogenesis include lipid peroxidation (resulting in oxidative stress and free radical formation), and elevated levels of insulin + IGF-1 resulting in cellular proliferation.10,11 Patients with MASLD and metabolic syndrome have been shown to possess a higher risk for HCC development in patients without cirrhosis than when compared to patients without cirrhosis with hepatotropic viral infection or alcohol use disorder. In fact, a 2014 study demonstrated that the leading etiology of noncirrhotic HCC was related to metabolic syndrome.3,11 In addition, a study from 2018 revealed that the annual incidence of HCC in patients with MASLD without cirrhosis was about 0.08 per 1000 patients. Among MASLD-related HCC, the percentage of cases without underlying cirrhosis has ranged from 10% to 75%.12 Hereditary A number of hereditary conditions have been shown to increase one’s risk of developing HCC, even in the absence of cirrhosis. Examples of these conditions include, but are not limited to, alpha-1 antitrypsin deficiency (A1AT), Wilson’s disease, glycogen storage disorders, hereditary hemochromatosis, and acute hepatic porphyrias.4,5,13,14 A1AT is an autosomal codominant disease in which the mutation of the A1AT gene results in an alteration of the A1AT protein structure, leading to intra-hepatocyte trapping of the faulty molecule. The accumulation of this protein precipitates a cascade of hepatocyte apoptosis, death, and regeneration; overtime this places a patient at higher risk of the development of HCC, regardless of the presence/formation of concomitant cirrhosis.13 Wilson’s disease, an autosomal recessive disorder, is a rare cause of HCC in patients without cirrhosis. The mechanism of disease involves a faulty copper transporting protein, leading to copper accumulation inside the hepatocyte. Copper impairs the hepatocyte’s function and promotes oncogenesis through copper-induced oxidative stress.15 glycogen storage disorders encompass a group of inherited disorders related to glycogen metabolism; they are characterized by the accumulation of atypical glycogen in the liver and/or muscle. It is common in glycogen storage disorders type 1 for HCC to occur in the absence of cirrhosis.8 Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism that is characterized by an increase in iron accumulation in various organs. Hepatocytes store a large proportion of the excess iron in this disorder, which puts the patient at high risk of developing HCC. Iron itself is thought to be oncogenic through its role in the production of reactive oxygen species, leading to DNA damage, inactivation of tumor suppressor genes, fibrosis, and eventual malignant hepatocyte transformation.14 Acute hepatic porphyrias encompass 3 autosomal dominant disorders—acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria—and all have been associated with the development of HCC in patients without cirrhosis.10 Alcohol-associated Alcohol is considered a serious risk factor for the development of HCC largely due to its mechanism of injury to the hepatocytes (oxidative stress, free radical production, and toxic DNA effect). Alcohol’s association with HCC is mainly seen in patients whose cirrhosis is secondary to alcohol abuse or in combination with other significant risk factors for the development of cirrhosis (chronic HBV/HCV infection, MASLD). Despite its association with HCC in patients with cirrhosis, heavy alcohol intake in itself has not been shown to be a major cause of HCC in patients without cirrhosis. Current data has shown that alcohol’s association with HCC occurs almost only in the setting of a cirrhotic liver.5,10 Toxins and hormones Various toxins have been associated with the development of HCC in patients without cirrhosis.5 Aflatoxin B1 (produced by the fungi Aspergillus flavus and Aspergillus parasiticus) is an exceedingly potent hepatotoxin which, after metabolism by the cytochrome P450 enzymes, binds to hepatocyte DNA and instigates mutation of the p53 tumor suppressor gene yielding increased risk of HCC development.4 Other toxins associated with the development of noncirrhotic HCC include vinyl chloride, arsenic, nitrosamines, azo dyes, organic solvents, and pesticides.4 These toxins are hard to come by outside of an industrial work environment. Hepatocellular adenomas Hepatocellular adenomas (HCAs) are rare, solid, benign tumors of hepatocellular origin that are often asymptomatic and found incidentally. The exact pathogenesis and mechanism of the development of HCAs remain unknown; however, clinicians have become familiar with them, given HCA’s association with oral contraceptives (OCPs) and/or androgen-containing steroids. A leading concern and complication of HCAs is malignant transformation into HCC, though it is not a common complication. In fact, a systematic review focusing on the risk of malignant transformation of HCAs into HCC found that the overall frequency of malignant transformation was only 4.2%.16 Risk factors for malignant transformation include, but are not limited to, an HCA size > 5 cm, male gender, and beta-catenin-activated HCAs.16,17 Conservative, nonsurgical management is the initial treatment strategy for HCAs < 5 cm and/or associated with OCP use. If associated with OCP use, cessation of the OCP is recommended and usually leads to regression of the HCA. Surgical resection of the HCA is recommended in all male patients—regardless of HCA size—and for women with HCAs greater than 5 cm.18 Diagnosis and management Similar to cirrhotic HCC, noncirrhotic HCC is typically diagnosed with imaging studies including multiphasic CT scan and MRI. In cases where imaging modalities are nondiagnostic, histopathologic assessment can be utilized. Compared to those with cirrhosis, patients without cirrhosis more frequently undergo surgical resection as primary management for their HCC. Patients without cirrhosis with HCC were less likely to receive locoregional therapies (chemoembolization or radioembolization), liver transplantation, or referral for palliative therapies than patients with cirrhosis.1 Although surgical resection is often employed with curative intent, tumor recurrence in patients without cirrhosis is noted to be high, with a 5-year recurrence reported to be as high as 65%.19 High-risk features for recurrence include up to 3 tumors with the largest being > 5 cm, ≥ 4 tumors with the largest being ≤ 5 cm, and up to 3 tumors with the largest being ≤5 cm with associated vascular invasion. Given the high recurrence risk, adjuvant chemotherapy has been utilized, and a regimen of atezolizumab plus bevacizumab has been shown to improve recurrence-free survival.20 Despite often more advanced disease with a larger tumor burden on initial diagnosis, patients without cirrhosis with HCC have been shown to have improved overall survival (Table 2).1 TABLE 2 - Features of HCC in patients with cirrhosis versus patients without cirrhosis HCC in patients with cirrhosis HCC in patients without cirrhosis Median age at diagnosis 62 y old 69 y old Gender Male > female Female > male % cases ∼80% of HCC cases ∼20% of HCC cases Stage at diagnosis More likely to be diagnosed at an early stage (likely due to HCC surveillance guidelines) More likely to be diagnosed at a more advanced stage; up to 25% of cases being metastatic Leading etiology HCV Metabolic syndrome/MASLD Typical presentation Variable; can range from abdominal pain, lethargy, newly decompensated cirrhotic featuresa, and laboratory abnormalities More likely to be clinically silent in early stages, likely due to higher hepatic reserve Five-year survival ∼20% ∼50% aAscites, variceal bleeding, and HE.Abbreviations: MASLD, metabolic dysfunction–associated steatotic liver disease. CONCLUSION HCC remains one of the leading global malignancies, with its prevalence less common in those without cirrhosis. Various risk factors have been noted to be associated with HCC in patients without cirrhosis, most notably MASLD, HCV, and HBV. Further research is needed to help maneuver screening guidelines for patients who may be at increased risk.

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