Enhancement in the arterial phase and washout in the portal venous phase is essential for the diagnosis of a liver lesion > 2 cm in a cirrhotic liver. More than 80% of masses > 2 cm in a cirrhotic liver are HCC[3334]. An elevated AFP confirms the diagnosis. If AFP is normal, further imaging will be diagnostic (triphasic CT, MRI)[13]. If there is still doubt, FNCB might be indicated (Figure 1).

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Figure 1 Algorithm for the investigation of a liver mass in a cirrhotic liver. Some hepatologists consider biopsy to be unnecessary for a mass in a cirrhotic liver even if the α-fetoprotein (AFP) < 10; FNCB: Fine needle core biopsy; MRI: Magnetic resonance imaging.

Seventy-five percent of masses < 2 cm in a cirrhotic liver are HCCs[35]. AFP levels and imaging might secure the diagnosis. If still in doubt, repeated imaging that detects enlargement of the lesion, or FNAB/FNCB might be indicated. Due to the risk of tumor seeding, biopsy should be avoided if surgical resection is possible[36]. A small nodule can be preneoplastic or benign. The American Association for the Study of Liver Diseases (AASLD) distinguishes lesions < 1 cm from those > 1 cm but < 2 cm. They suggest performing two imaging techniques from among US, CT, and MRI with IV contrast injection. If two techniques display typical imaging criteria, it is possible to diagnose HCC. Larger nodules should be diagnosed and small lesions should be surveyed every three months[37]. Caturelli showed that 69% of new nodules in a cirrhotic liver are malignant. Moreover, liver cell dysplasia is found in 60% of cirrhotic livers containing HCC and in only 10% of non-cirrhotic livers[38].

In this case, repeated dynamic CT or MRI every three months is the rule[39]. An elevated AFP does not necessarily diagnose HCC, especially in patients with HCV who commonly have modest elevation of AFP without HCC. A marked AFP is helpful, but modest elevations would certainly not be an indication for OLT in the absence of a liver mass.

HCC: HCC is a common malignancy with an incidence of 1%-6% among cirrhotic patients[1340–42]. Risk factors include cirrhosis, alcohol, HBV, HCV, metabolic liver diseases, environmental carcinogens, hormonal treatments and smoking[4344]. Ninety to ninety five percent of HCCs arise in cirrhotic livers. Autopsy studies indicate that 20%-40% of patients with cirrhosis have HCC. Tumor size and severity of liver disease influence the survival rate. Patients with tumors < 5 cm have a survival of 80% at one year and 20% at three years. New abdominal pain, recent hepatomegaly, hemoperitoneum, persistent fever or weight loss in a cirrhotic patient should raise suspicion of HCC. Laboratory results that characterize HCC include a sudden increase in alkaline phosphatases, an increased ratio AST/ALT, an erythrocytosis, persistent leukocytosis, recurrent hypoglycemia, hypercholesterolemia and hypercalcemia. The last four findings are paraneoplastic manifestations[45] together with ectopic hormonal syndrome, hypertrophic osteoarthropathy and porphyria cutana tarda[46]. Complications of HCC include obstructive jaundice[47], and rupture of HCC (60%-90% mortality).

Screening for HCC includes US + AFP levels every six months. The AASLD guidelines recommend US only. AFP is of little additional value. Lesions > 2 cm need just one imaging technique showing typical findings (arterial hypervascularization) or one imaging technique and AFP levels > 400 in order to make a non-invasive diagnosis of HCC[13]. Lesions < 2 cm are divided into larger and smaller than 1 cm. Nodules > 1 cm but < 2 cm (1-2 cm) need diagnostic workup with two coincident or serial imaging techniques, rather than just proceeding with a biopsy. Nodules < 1 cm need screening follow up every three months. Nine to thirty seven percent of HCC are resectable at diagnosis[48]. Contraindications to resection include decompensated cirrhosis, extra-hepatic metastases, involvement of hepatic nodes or inferior vena cava (IVC), or bilobar extension[45]. The histological variants in cirrhotic livers include trabecular (65%), mixed (15%), compact (12%), pseudo glandular (5%) fibro lamellar (1.5%), and scirrhous 0.5%[49].

Regenerative nodules: Dysplatic nodules often occur within regenerative cirrhotic nodules. They can show low- or high-grade dysplasia. A progression from regenerative nodule with low-grade dysplasia to high-grade dysplasia, in well differentiated and poorly differentiated HCC, is possible[5051]. MRI best differentiates this iso-or hypo- intense lesion from hyper intense HCC. In difficult cases, histology is required after liver resection or liver transplant. If HCC cannot be confirmed, the investigation must be repeated later. Over time, high-grade dysplastic nodules can become malignant, suggesting preventive ablation by ethanol[7].

Hemangiomas: Hemangiomas are found in 20% of the general population, more commonly in women[5657]. The majority are asymptomatic. Giant hemangiomas (> 4 cm) are symptomatic in 40% of cases. Symptoms are rare and can include abdominal pain, early satiety, anorexia, and nausea[58]. Tc-99m labelled RBC Spect is the best and least expensive modality (specificity 100%) for lesions > 2.5 cm and MRI for lesions < 2 cm[5960]. University centers rarely require RBC Spect for diagnosis of hemangiomas due to the use of cross sectional imaging. Histology of liver hemangiomas is blood-filled vascular sinusoids separated by connective tissue septa (peliosis lacks endothelial layer and fibrous trabeculae)[61]. The risk of rupture is minimal and does not justify resection. Other complications include thrombosis, sclerosis, and calcification. Liver hemangiomas can grow during pregnancy or oral contraception. Kasabach-Merritt syndrome (consumption coagulopathy) and Bornman-Terblanche-Blumgart syndrome (fever and abdominal pain) constitute uncommon complications[61].

FNH: Focal nodular hyperplasia is found more often in women 20-50 years of age (80%). The pathogenesis is unknown, but includes vascular injury. The lesion is usually < 3 cm, asymptomatic and discovered accidentally. The main difficulty for the physician is differentiating FNH from adenoma or fibrolamellar carcinoma by imaging techniques. However, fibrolamellar carcinomas enhance heterogeneously, wash out, and have central calcifications and enlarged lymph nodes. These features are very rarely found in FNH. Lack of symptoms, normal liver enzymes and no use of oral contraceptives argue in favour of FNH. Recent literature suggests that MRI has 70% sensitivity and 98% specificity for FNH (homogeneous hypervascular lesion with central scar)[6263]. If radiology is unequivocal, most hepatologists advocate a “wait and see” attitude. Otherwise, image guided percutaneous biopsies are performed, one in the tumoral tissue and the other in the normal liver tissue. The histology resembles inactive cirrhosis with proliferating hepatocytes around a normal prominent central artery with a central fibrous scar[62]. The natural history of FNH is variable (stable, regressive or progressive over time), but resection is not necessary because it does not progress to malignancy. Complications are rare and include hepatic vein thrombosis or Kasabach-Merritt syndrome[6364].

HA: Adenoma occurs in women with oral contraception use > 5 years[65] or in diabetic patients. Multiple adenomas are associated with glycogen storage disease type I and type III[66]. Adenomatosis (> 10 adenomas) is observed with anabolic or androgenic steroids consumption[67]. Abdominal discomfort is common[68]. The lesion is hypo- to hyper- echoic on US and hypo- to hyper- dense on CT. MRI is not specific[6970]. The lesions are often < 8 cm but can be > 15 cm microscopically; they appear as monotonous sheets of normal or small hepatocytes with no bile duct, portal tract or central vein. Five percent of hepatic adenomas transform to HCC[71]. β-catenin immunostaining might be useful for diagnosis. Spontaneous rupture and hemoperitoneum occur in 10% of cases, especially during menstruation, pregnancy or post partum. Most hepatologists advocate resection and discontinuation of oral contraception[7273].

NRH and partial nodular transformation (PNT): NRH (large regenerative nodule) is associated with Behcet’s disease, rheumatic diseases, myeloproliferative disorders, chronic venous congestion, metastatic neuroendocrine tumors, Budd-Chiari syndrome, and various drugs (steroids, contraceptives, antineoplastics, anticonvulsives, and immunosuppressives)[74]. Some lesions present with portal hypertension and cholestasis. A diagnostic open liver biopsy is rarely required[75]. NRH shows diffuse hyperplastic nodules with thickened liver cell plates without fibrosis. Reticulin changes are characteristic. Portal vein thrombosis could lead to NRH by parenchymal atrophy and compensatory hyperplasia. Portal vein thrombosis has also been invoked in the pathogenesis of PNT[76].

Focal fatty infiltration of the liver: In 10% of patients with fatty liver, fat accumulates focally or shows focal sparing, usually in the anteromedial segment of the left lobe. These patients usually have diabetes, hyperlipidemia, obesity, drink alcohol or take steroids[77]. On US, fat is hyper echoic. On CT, it has low attenuation. Focal fatty liver does not displace intrahepatic vessels. The gold standard imaging technique is MRI with increased signal on T1 sequence[78]. Fat suppression techniques are also very promising.

Hepatobiliary cyst adenoma: This lesion is rare, occurs predominantly in middle-aged women and causes abdominal pain. It differs from benign cyst by having thick septated wall. Up to 25% become malignant (cystadenocarcinoma), therefore surgical excision is indicated[79].

Bile duct adenoma (cholangioma): Bile duct adenomas are solitary sub capsular nodules measuring 1-20 mm described in patients with α-1-antitrypsin deficiency. The bile ducts are smaller and do not contain bile.

Biliary papillomatosis: Only 50 cases have been described worldwide[80]. It is a tumor of middle age, leading to biliary obstruction by tumor shedding, mucus and lithiasis, cholangitis and hemobilia. Diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP), which shows typical mucinous discharge from a dilated ampulla, multiple filling defects and stenosis. Hepatectomy can effect a cure.

Mesenchymal and neural tumors: This category includes lipomas, myolipomas, angiomyolipomas, schwannomas, neurofibromas and chondromas.

Inflammatory pseudotumor: This is a rare, benign inflammatory condition of middle-aged men. Patients might present fever, weight loss, leukocytosis and elevated ESR. If the diagnosis can be made on biopsy, there should be no need for resection; rather the primary source should be treated[81].

Pseudo-lesions: A pseudo-lesion is a non-diseased area of different signal intensity, attributable to focal alteration in hemodynamics or parenchymal metabolism[82]. Pseudo-lesions seen in cirrhotic and non-cirrhotic livers include arterio-portal shunts, regenerating nodules, confluent fibrosis, and abnormal blood inflow.

Liver metastasis: The liver is the most common site of metastasis from the gastrointestinal tract, pancreas, breast, and lung[41]. Multiple defects in the liver imaging suggest a metastatic process. Only 20% of liver metastases present as solitary lesions. Generally, both hepatic lobes are involved. On CT-scan, colorectal metastases appear as low attenuation lesions, often with irregular margins and necrotic centres[14]. During the early vascular phase of dynamic CT, metastasis appears with increased enhancement. The sensitivity of CT (85%) can be augmented by CT arterial portography[83]. Intraoperative US has excellent sensitivity and specificity for colorectal adenocarcinoma metastasis[84]. The most promising imaging modality is PET CT with FDG that accumulates in cells with hypermetabolism. Colon, lung and breast cancers can be staged with PET CT with sensitivity of 92%-100% and specificity of 85%-100%[85]. The hypervascularity of neuroendocrine tumors is often evident on dynamic CT[86]. Somatostatin receptor scintigraphy can localize 90% of neuroendocrine tumors (gastrinoma)[87].

In metastatic colorectal carcinoma, the prognosis is improved following surgical resection. Contraindications to resection include: N > 4 liver metastases, extrahepatic spread and involvement of hepatic lymph nodes. Metastatic liver tumors that might calcify include colon, leiomyosarcoma, osteogenic sarcoma, rhabdomyosarcoma, chondrosarcoma, ovarian cystadenocarcinoma, melanoma, pleural mesothelioma, neuroblastoma, and testis tumors. Calcified metastases from stomach, pancreas, lung and breast to the liver are extremely rare. Guided FNA will help identify the primary lesion[88].

HCC (see previous section on HCC): Almost all patients with HCV related HCC have cirrhosis, whereas patients with HCC related to HBV are less likely to have cirrhosis. The absence of cirrhosis makes this tumor more amenable to surgical resection[34].

Fibrolamellar carcinoma: The fibrolamellar variant is a distinctive subtype of HCC but is not associated with classic risk factors for HCC. It occurs at a mean age of 26 years, presenting as a large, solitary painful mass usually located in the left lobe. The AFP level is normal[89]. The term “fibrolamellar” characterizes the microscopic appearance of the lesion: thin layers of fibrosis separate the neoplastic hepatocytes[90]. A fibrous central scar may be seen on imaging studies[91]. 50% of lesions are resectable at the time of diagnosis[90].

Intrahepatic cholangiocarcinoma: Cholangiocarcinoma accounts for 20% of primary liver tumors and arises as adenocarcinoma or papillary or mucinous carcinomas[92]. Risk factors include cirrhosis, primary sclerosing cholangitis (PSC, 10%), bile duct adenoma, choledochal cysts, biliary papillomatosis, Caroli’s disease, and liver fluke[93–95]. Jaundice is the most common clinical presentation[96], and rapidly increasing bilirubin associated with weight loss predicts cholangiocarcinoma. Tumor markers CEA, CA-19-9 or AFP might be elevated. CA 19-9 level > 100 has 89% sensitivity and 86% specificity[97]. There are three anatomic subtypes: Peripheral intrahepatic 15%, perihilar central (Klatskin tumor) 60%, and distal common bile duct 25%. Peripheral cholangiocarcinoma resembles HCC without cirrhosis. The central hilar and distal types are associated to sclerosing cholangitis, inflammatory bowel disease, or other chronic biliary disease. US and CT show marked intrahepatic duct dilatation[98]. An abrupt change in the calibre of the bile duct suggests malignancy[99]. Digital image analysis and fluorescent in situ hybridization are more sensitive than routine standard brush cytology in the diagnosis of cholangiocarcinoma. ERCP, percutaneous transhepatic cholangiography (PTC) and magnetic resonance cholangiopancreatography (MRCP) assess the resectability of the tumor.

PET CT stages these tumors with a sensitivity of 93%. The suggested screening includes US, CEA and CA 19-9 every six months, ERCP and brush cytology if there is biliary stenosis. Combined HCC-cholangiocarcinoma shows features of both hepatocellular and biliary epithelial differentiation[100].

Epithelioid hemangioendothelioma: This low-grade malignancy affects individuals between 20-80 years of age. It is associated with oral contraception and exposure to polyvinyl[101]. Epithelioid hemangioendothelioma presents with abdominal pain, hepatomegaly, low fever and normal liver enzymes. Endothelial cells stain for CD34, CD31 and factor VIII. The prognosis is good with surgical resection or liver transplantation[102103].

Cystadenocarcinoma: Usually in the right lobe, cystadenocarcinoma is multicystic and contains bile-stained material. It presents as abdominal pain with weight loss[104] and prognosis is good[105].

Lymphomas and leukemia: Liver involvement is common in Hodgkin’s disease including lymphoma infiltration (diffuse small nodules or large masses), drugs, viral hepatitis, and sepsis. Cholestasis is uncommon and vanishing bile duct syndrome has been described[106]. The differential diagnosis includes reactive infiltrate and T-cell lymphomas.

Primary hepatic lymphoma is rare and can present as solitary or multiple masses, as a diffuse hepatic involvement with hepatomegaly, or as hepatic failure with elevated LDH[107]. Peripheral gamma delta T cell lymphomas with massive hepatic sinusoidal infiltration and splenic involvement have also been described[108]. The liver might be diffusely or locally infiltrated by multiple myelomas or leukemia (chronic lymphoid leukemia, hairy cell leukemia)[109–113].

Neuroendocrine tumors: Neuroendocrine tumors originating in the gastrointestinal tract frequently metastasize to the liver[114]. Liver metastases can be resected[115]. Traditional chemotherapy is not effective. α-interferon has been associated with tumor response. The use of somatostatin analogs in the carcinoid syndrome improves symptoms. Liver transplant remains an option[116].

Angiosarcoma: Angiosarcoma is associated with exposure to vinyl chloride[117]. Most patients are not amenable to surgery. Usually both hepatic lobes are involved and rapid tumor growth and tendency to metastasize contribute to its dismal prognosis. Chemotherapy and radiotherapy have no role, and ligation of the hepatic artery might permit palliation.

Undifferentiated sarcoma of the liver: This rare tumor mainly affects children. The clinical features are fever and a liver mass with recurrent hypoglycemia. The median survival is two months. Imaging shows a solid and cystic lesion with multiple loculi[118].

Other mesenchymal cell malignancies: Rhabdomyosarcoma is the most common tumor of the biliary tree in young children. The tumor can mimic a choledocal cyst[119].

Fibrosarcoma presents as a hepatic mass with recurrent hypoglycemia that will resolve after resection. Serum IGF-2 is elevated[120] and Leiomyosarcoma presents with general deterioration and right upper quadrant pain. Angiograms or CT-angiography show a hypervascular tumor. Liver transplantation is possible[121].