**2.5 Fibrolamellar hepatocellular carcinoma (FL-HCC)**

Rare variant of HCC accounting for only 1% cases. In contrast to conventional HCC, FL-HCC is common in young patients aged <40 years, occurs in normal liver and has normal AFP levels [53]. FL-HCC is chromosomally stable tumor and displays genomic homogeneity in contrast to conventional HCC. Mutations in AFP, TP53 beta-catenin and surviving are not seen in FL-HCC, however increased expression of anterior gradient-2, CD133, CD44 and nuclear factor-kB pathway are seen in FL-HCC. Chromosomal imbalances involving chromosomes 1, 7 and 8 are noted in aggressive FL-HCC [54–56]. FL-HCC is typically large tan colored well-circumscribed firm mass without underlying chronic liver disease or cirrhosis. Central stellate scar is seen in 75% cases. Microscopically it is composed of cluster or sheets of large polygonal or spindle shaped cells with eosinophilic cytoplasm and prominent nuclei. Fibrous stroma is seen around the tumor cells. It has capsule and central scar [57, 58]. On immunohistochemistry it shows hepatocyte paraffin 1, CK7, CD133, CD44, α-1 antitrypsin, fibrinogen, C-reactive protein, carcinoembryonic antigen and copper [55, 59]. Patient presents with abdominal pain, malaise, weight loss and abdominal lump [57]. On ultrasound FL-HCC has no specific features [60]. On computed tomography scan tumors are well defined with lobulated outline. It has hypodense large >2 cm central scar and radiating fibrotic bands are more common. Central scar may show calcification. On contrast enhancement in arterial phase it shows heterogenous hyperattenuation. On the portal venous phase and delayed phase, approximately 50% of fibrolamellar HCCs become isoattenuating to liver. However, they may also be hyperattenuating (36%) or hypoattenuating (16%). Central scar may show delayed enhancement in 25–65% cases. Venous and biliary obstruction is rare [60]. On MRI, FL-HCC is hypointense on T1 imaging and hyperintense on T2 images. Central scar is hypointense on T1 and T2 weighted images. On contrast injection, it shows heterogenous enhancement which becomes iso or hypointense in delayed phase [60]. Nodal metastasis occur in 50–65% of FL-HCC and commonly occur in hepatoduodenal ligament and hepatic hilum. Cornerstone for treatment is surgical resection with


#### **Table 5.**

*Summary of new tumor markers in HCC.*

adequate lymph node dissection. The 5 year overall survival rate after partial hepatectomy was 70%. Radioembolization using 90Y is helpful in unresectable FL-HCC. Liver transplantation is therapeutic option in selected patients [60, 61].

#### **2.6 Diagnosis of HCC in noncirrhotic liver**

About 10% HCC can occur in noncirrhotic liver. Risk factors include alcohol (21%), chronic hepatitis B(30.60%), chronic hepatitis C infection (14.36%), diabetes (40%), family history (13.85%) and cryptogenic (39%). Other risk factors include aflatoxin B, metabolic liver diseases, chemical and industrial carcinogens like vinyl chloride. HCC in noncirrhotic liver present as advanced disease, larger in size [62]. Male to female ratio is 2:1. Hepatomegaly, abdominal pain, malaise, weight loss and anorexia are common presenting features [62, 63]. On ultrasound, lesion can be hypoechoic, hyperechoic due to intralesional fat or mixed echogenicity due to necrosis. On unenhanced CT, lesions appear as hypodense circumscribed masses. Few of them show calcifications, hemorrhagic areas and necrosis. On contrast injection, it does show arterial phase hyperenhancement and washout in delayed phase but specificity is lower as other lesions like hepatocellular adenoma and hypervascular metastasis. On MRI these tumors have variable T1 and T2 weighted images depending on degree of fat, necrosis and fibrosis. On contrast injection, features are similar to CT scan. Liver biopsy is often required for diagnosis [62, 63].
