Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: Current insights and advancements

Table 1 Key differences between non cirrhotic hepatocellular carcinoma and hepatocellular carcinoma

	HCC	NCHCC
Epidemiology	Eighty percent of HCC develops with a cirrhotic background. A unimodal age distribution (peak in 7th decade) noted. Male:female ratio - 3:2	Twenty percent of tumors develop in non-cirrhotic liver. A bimodal age distribution (peak in 2nd and 7th decade) noted. Male:female ratio-2:1
Risk factors	Development of cirrhosis from any etiology can progress to HCC. Hepatotropic viruses, environmental and life-style factors (alcohol, tobacco), metabolic conditions (nonalcoholic fatty liver disease, diabetes mellitus, obesity) play a predominant role	NCHCC develops without a background of underlying cirrhosis. Viral (HBV, HCV infection) and non-viral risk factors (obesity, diabetes mellitus, toxin exposure, germline mutations and genetic disorders) noted
Clinical features	Symptoms could be related to underlying cirrhosis (from portal hypertension) or HCC (early satiety, upper abdominal pain) itself. Paraneoplastic signs such as hypercalcemia, hypoglycemia have been reported	Generalized fatigue, abdominal pain and weight loss are common symptoms. Can present at late stage with large tumor burden, extrahepatic metastasis
Diagnosis	High quality cross-sectional imaging (CT/MRI) are used with typical arterial phase hyper-enhancement and portal venous washout. LI-RADS classification is used in classification of radiological findings in HCC	Although CT and MRI are increasingly utilized for diagnosis, liver biopsy are utilized in patients when cross-sectional imaging is equivocal. LI-RADS classification cannot be utilized for NCHCC and instead tumor characteristics (size, imaging features) are utilized for staging
Treatment	Given the underlying cirrhosis, liver transplant candidacy need to be evaluated for HCC patients. Resectability of the lesion, amount of liver reserve, vascular invasion, performance status determines the treatment outcomes	Antiviral treatment recommended when etiology of NCHCC is HBV/HCV. Surgery remains the main treatment modality. Systemic and local therapy options are increasingly being utilized for NCHCC

Key differences in epidemiology, risk factors, clinical presentations, diagnosis and treatment for non-cirrhotic hepatocellular carcinoma and hepatocellular carcinoma. A multidisciplinary team evaluation is frequently utilized for diagnosis and treatment. CT: Computed tomography; MRI: Magnetic resonance; HCC: Hepatocellular carcinoma; NCHCC: Non cirrhotic hepatocellular carcinoma; LI-RADS: Liver Reporting and Data System; HBV: Hepatitis B; HCV: Hepatitis C.

Table 2 Imaging characteristics of cirrhotic and non-cirrhotic hepatocellular carcinoma

	CHCC	NCHCC
Imaging modality	Background of advance fibrosis (cirrhosis)	No background of advance fibrosis (cirrhosis)
CT	Homogenous with irregular but well defined margin	Initially hypoattenuating mass which can be come heterogenous (areas of necrosis/hemorrhage within the tumor) when tumor attains bigger size
	Multiple masses
		Large solitary mass (/dominant mass) with satellite nodules
	Extrahepatic extension less common
		Extrahepatic extension (with direct adjacent organ) is more often seen
		Metastasis frequently seen, vascular invasion less common (15%)
	Vascular invasion (encasement) more common (85%)
		Lymphadenopathy seen in 20% of cases.
MR	T1: Variable but mostly hypointense. T2: Hyperintense/isointense compared to surrounding liver	Unenhanced T1 image - Hypointense lesion (presence of hemorrhage/fat can increase the signal). T2 - Hyperintense (low grade/well differentiated can be iso/hypointense)
	DWI-high ADC when lesion is well differentiated	DWI - Used for small lesions. Shows low ADC

CHCC: Cirrhotic hepatocellular carcinoma; NCHCC: Non-cirrhotic hepatocellular carcinoma; CT: Computed tomography; MRI: Magnetic resonance; DWI: Diffuse weighted imaging; ADC: Apparent diffusion coefficient.

Table 3 Treatment options for non-cirrhotic hepatocellular carcinoma

Treatment	Comments
Antiviral therapy	If HBV or HCV are identified as potential causes of NCHCC, aggressive treatment should be pursued. Entecavir, tenofovir have been used for HBV and DAA agents are used for HCV infection
Surgery	Mainstay for the treatment of NCHCC. BCLC staging cannot be used for NCHCC patients. Tumor size, elevated bilirubin level, low platelet count, vascular invasion can predict prognosis in NCHCC individuals
Locoregional therapy	Limited data available in NCHCC patients. Isolated cases and case series showed improved prognosis with these treatment options
Systemic therapy	Multikinase inhibitors (sorafenib, regorafenib), immunotherapy (nivolumab), chemotherapeutic agents (epirubicin, cisplatin, 5-fluororuacil, capecitabine, docetaxel, GEMOX) have been used in NCHCC with various success

Potential treatment options for non-cirrhotic hepatocellular carcinoma. Antiviral therapy is indicated if hepatitis C virus or hepatitis C virus is identified as a potential cause. While surgery remains the mainstay of the treatment, locoregional and systemic therapy options have been tried. HCC: Hepatocellular carcinoma; DAA: Direct acting antiviral; NCHCC: Non cirrhotic hepatocellular carcinoma; BCLC: Barcelona-Clinic Liver Cancer; HBV: Hepatitis B virus; HCV: Hepatitis C virus; GEMOX: Gemcitabine and oxaliplatin regimen.