Benign liver lesions

General

Focal nodular hyperplasia (FNH) is the second commonest benign solid liver tumour, with a prevalence of approximately 0.2%. It has a higher incidence in females, mainly between 20 and 40 years of age, but also occurs in men and even in children. It is a rare finding in children but is more commonly observed after treatment for childhood cancer, with haematopoietic stem cell transplantation as the most important risk factor. Because of the predominant occurrence in females and the young age at onset, a role for female hormones has been suggested, but a relationship with oral contraceptives has not been clearly demonstrated. In men, the lesions are often smaller and less typical.

Clinical presentation

FNH lesions are often asymptomatic and found during imaging for unrelated reasons. However, a small proportion of patients experience symptoms such as abdominal pain or a palpable mass. In up to 20%, other liver lesions are found, such as hepatic haemangiomata or adenomas. Although FNH is commonly observed, complications are very rare; there are only a few published cases of spontaneous rupture resulting in intraperitoneal haemorrhage.

Diagnosis

Ultrasound is often the initial imaging investigation when a hepatic lesion is found. There is only a subtle difference in echogenicity between FNH and the surrounding normal liver. Although the accuracy of the diagnosis increases with the use of contrast-enhanced ultrasound and colour Doppler, ultrasound is currently not the modality of choice for characterisation of an FNH.

On CT, FNH is usually homogeneous and isoattenuating to the normal liver before contrast injection. FNH lesions are hypervascular in the arterial phase and typically have a central scar (hypodense). In the portal phase, a typical FNH returns to isoattenuating compared to the normal liver. In the delayed phase, hyperattenuation of the central scar and septae are often seen.

MRI has a higher sensitivity (70%) and specificity (98%) for FNH than ultrasonography or CT. Typically, FNH is iso- or hypointense on T1-weighted images, is slightly hyper- or isointense on T2-weighted images, and has a hyperintense central scar on T2-weighted images ( Fig. 5.1 ). A typical FNH demonstrates intense homogeneous enhancement during the arterial phase of gadolinium-enhanced imaging and enhancement of the central scar during later phases.

Pathology

FNH is typically a lobulated lesion composed of nodules surrounded by fibrous septa originating from a central scar in an otherwise normal liver ( Fig. 5.1 ). On histological analysis, a classic FNH shows nodular hyperplastic parenchyma. The hepatic plates may be moderately thickened (two or three cells in thickness) with normal-appearing hepatocytes. The central scar contains fibrous connective tissue, cholangiolar proliferation with surrounding inflammatory infiltrates and malformed vessels of varying calibre, including tortuous arteries with thickened walls and capillaries, but no portal veins. Approximately 50% of lesions show some degree of fatty infiltration compared with the surrounding liver. In less than 20% of FNH lesions, the liver shows signs of steatosis.

The development of FNH is thought to be caused by an injury to the portal tract resulting in the formation and enlargement of arterial to venous shunts. This in turn causes hyperperfusion in local arteries resulting in oxidative stress that triggers a response from hepatic stellate cells to produce the typical central scar.

Management

In general, the diagnosis can be made on MRI or CT, and routine biopsy is not indicated. However, when imaging is not typical or if there is doubt about the diagnosis, e.g. with a differential diagnosis of hepatic adenoma or hepatocellular adenocarcinoma, a biopsy can be considered. FNH is currently not considered premalignant.

In asymptomatic patients with typical features of FNH on imaging, no further treatment or follow-up is required. However, further evaluation is recommended for symptomatic lesions when the diagnosis cannot be firmly established. The current American College of Gastroenterology guidelines recommend follow-up with an annual ultrasound for 2–3 years in women diagnosed with FNH who wish to continue using oral contraceptives. In individuals with a firm diagnosis of FNH who are not using oral contraceptives, follow-up imaging is not required.

General

Hepatocellular adenomas (HCAs) are rare benign hepatic neoplasms in otherwise normal livers, with a prevalence of around 0.04% on abdominal imaging. HCAs are predominantly found in women of child-bearing age (second to fourth decade) with a history of oral contraceptive use; they occur less frequently in men. ^, The association between oral contraceptive usage and HCA is strong, and the risk for HCA increases if an oral contraceptive with high hormonal potency is used, and if it is used for over 20 months. Long-term users of oral contraceptives have an estimated annual incidence of HCA of 3–4 per 100,000. More recently, an increase in incidence in men has been reported, probably related to the increase in obesity, which is reported as another risk factor for developing HCA. In addition, anabolic steroid usage by body builders and metabolic disorders such as diabetes mellitus or glycogen storage disease type I are associated with HCAs. HCAs in men are generally smaller but have a higher risk of malignant transformation.

In the majority of patients, HCAs are solitary, but in a minority of patients more than 10 lesions have been described (also referred to as liver adenomatosis).

Clinical presentation

Small HCAs are often asymptomatic and found on abdominal imaging being undertaken for other purposes, during abdominal surgery or at autopsy. Some patients present with abdominal discomfort, fullness or (right upper quadrant) pain due to an abdominal mass. It is not uncommon that the initial symptoms of an HCA are acute onset of abdominal pain and hypovolaemic shock due to intraperitoneal rupture. In a series of patients who underwent resection, bleeding was reported in up to 25%. ^, The risk of rupture is related to the size of the adenoma. Exophytic lesions (protruding from the liver) have a higher chance of bleeding than intrahepatic or subcapsular lesions (67% vs 11% and 19%, respectively, P < 0.001). Lesions in segments II and III are also at higher risk of bleeding than lesions in the right liver (35% vs 19%, respectively, P = 0.049).

Diagnosis

HCAs are often detected first by ultrasound during investigation of right upper quadrant discomfort. The high lipid content of adenomas may contribute to the hyperechoic appearance of these lesions. The ultrasound appearance is often heterogeneic due to haemorrhage, necrosis and fat content. Colour Doppler ultrasound can be used to differentiate HCA from FNH. However, the diagnosis of adenoma is not usually made definitely at ultrasonography, and subsequent CT or other imaging modalities are often required to confirm the diagnosis.

Multiphasic helical CT allows more accurate detection and characterisation of focal hepatic lesions. The degree of attenuation of the adenoma relative to the background liver depends on the composition of the tumour and liver. CT may demonstrate a hypoattenuating mass due to the presence of intratumoural fat, or the lesion may be nearly isoattenuating relative to normal liver on unenhanced, portal venous-phase and delayed-phase images (most of the adenomas; Fig. 5.2 ). Alternatively, the lesion may be hyperattenuating in all phases of both contrast enhanced and unenhanced images in fatty livers. Due to the presence of large subcapsular feeding vessels, peripheral enhancement may be seen on contrast-enhanced CT, with a centripetal pattern of enhancement. Small HCAs may enhance rapidly and are often hyperattenuating relative to the liver. The enhancement usually does not persist in adenomas due to arteriovenous shunting. Larger HCAs may be more heterogeneous than smaller lesions, and their CT appearance is less specific.

On MRI, HCAs are usually heterogeneous in appearance. They are typically bright on T1-weighted MRI, and predominantly hyperintense relative to liver on T2-weighted images ( Fig. 5.2 ). Almost one-third of adenomas have a peripheral rim corresponding to a fibrous capsule ( Fig. 5.2 ). Some groups use PET-CT scan with ¹⁸ F-fluoromethylcholine to differentiate between HCA and FNH (sensitivity 100%, specificity 97%). Alternatively, a biopsy can be considered in very selected cases when there is persistent doubt about the diagnosis.

Pathology

HCAs are typically nodular lesions with a size ranging from microscopic to lesions as large as 20 cm. They are relatively uniform, although areas of congestion, necrosis, haemorrhage or fibrosis can be observed. Often large subcapsular vessels are seen as well as intratumoural fat. On microscopic examination, HCA is defined as a tumoural monoclonal proliferation of well-differentiated, usually bland-looking hepatocytes arranged in sheets and cords that are usually one, or at most two, cells in width.

More recently, molecular classification has revealed four major subtypes of HCA (the Bordeaux classification): HNF1A (coding for hepatocyte nuclear factor 1a) inactivating mutations (30–40%), inflammatory adenomas (40–50%), β-catenin-mutated HCAs (β-HCA; 10–15%) and unclassified HCAs (10%). Inflammatory HCAs can also be β-catenin activated (10%). It is important to differentiate between these subclasses, as β-catenin mutations appear to be associated with a higher risk of malignant transformation.

Management

HCAs have a risk of spontaneous rupture and malignant transformation. The risk of rupture is related to the size of the adenoma. In a group of 124 patients, 25% of HCAs ruptured, but no rupture was observed in lesions < 5 cm. Recent hormonal treatment is also a risk factor for haemorrhage. Mortality after spontaneous rupture is approximately 5–10%.

Stoot et al. performed a systematic review and studied 1635 HCAs. They concluded that only 4.2% of patients with HCA had malignant transformation, and malignant transformation in lesions < 5 cm was a very rare finding. The risk of malignant transformation is much higher in men, and in some studies, it is reported to be as high as 47%.

There is no guideline for the treatment of HCAs, although there are general agreements. In men, all lesions should be considered for surgical resection independent of size, given the high risk of malignant transformation, while taking into account comorbidity and location of the lesion. Resection should also be considered in patients with HCAs due to a metabolic disorder. In women, lesions < 5 cm can be observed with sequential imaging after cessation of oral contraceptive treatment. In larger tumours, treatment strategies vary. Some clinicians have proposed non-surgical management if hormone therapy is stopped and patients are followed up with serial radiological examinations. The time period of waiting is still under debate; however, recent studies indicate that a waiting period of longer than 6 months could be justified. Others have advocated resection of adenomas because of the risk of haemorrhage and malignancy. Alternatively, elective transarterial embolisation could be a valid approach in women.

Hepatic arterial embolisation can be effective for controlling bleeding in patients who present with acute haemorrhage. If the lesion is atypical, resection could be considered; however, if there is no suspicion of a malignancy, it is best to wait for resorption of the haematoma before further therapy. HCAs tend to grow during pregnancy. In a prospective study of 48 women with 51 pregnancies with HCA < 5 cm, progression was seen in a quarter of pregnancies with a median increase of 14 mm. One woman with HCA that grew to > 7 cm was treated successfully with a transarterial embolisation at week 26 of pregnancy to prevent further growth. Therefore, pregnancy should not be discouraged in the presence of a small HCA; however, close sonographic surveillance is recommended. ^,

Orthotopic liver transplantation has been performed for HCAs. However, liver transplantation should be reserved for exceptional cases, such as for hepatic adenomatosis in patients with a metabolic liver disease (e.g. glycogen storage disease) or in patients with hepatic adenomatosis and (a suspicion of) malignant transformation.

More recently, the subtypes of the Bordeaux classification of HCA have been studied related to their risk of complications. Some groups report that percutaneous core needle biopsy is of limited value because the therapeutic strategy is based primarily on patient sex and tumour size. Others report a different therapeutic approach based on subtype. Thomeer et al. concluded that there was no evidence to support the use of subtype classification in the stratification and management of individual patients related to risk of bleeding. Size still remains the most important feature to predict those at risk of bleeding during follow-up. However, malignant transformation does seem to be related to differences in subtypes. β-catenin-mutated HCAs trigger a potent mitogenic signalling pathway that is prominent in HCC. Cases of inflammatory HCAs can also show activation of the β-catenin pathway with a risk of developing malignancy. Therefore, β-catenin-mutated and inflammatory HCAs are prone to malignant degeneration, and particularly if > 5 cm. In these circumstances, invasive treatment should be considered.

General

Hepatic cysts are relatively common and seen in approximately 6% of ultrasound procedures. The incidence increases with age, with more than half of patients over 60 years of age having one or more simple cysts. These non-parasitic cysts can occur as single, multiple or diffuse cysts (PLD will be discussed separately). Cysts can range from 1 mm to > 20 cm (containing several litres of fluid). Some groups report that cysts are more frequent in women with a female-to-male ratio of approximately 2:1, but others indicate a more even distribution. Symptomatic cysts are reported up to 10 times more commonly in women than in men.

Simple cysts contain clear, bile-like fluid, but have no communication with bile ducts. As bile duct epithelium covers the cyst inner lining, it is hypothesised that simple cysts arise during embryogenesis when intrahepatic ductules fail to connect with intra- or extrahepatic ducts.

Clinical presentation

In the majority of patients, the cysts are discovered incidentally. A small fraction of patients, mainly with large cysts, experience symptoms such as abdominal pain, early satiety, nausea and vomiting due to a mass effect. Physical examination may reveal a palpable abdominal mass or hepatomegaly. Complications such as haemorrhage, rupture and biliary obstruction are rare and are more likely in larger cysts.