Diagnosis and Management of Benign Liver Tumors

Common Benign Liver Tumors

Solid Lesions

Hemangioma Cavernous hemangiomas (Fig. 1) are the most common BLT, with an incidence of up to 20% in the general population, depending on the ultrasound studies^[1] or autopsy series.^[2] This usually small lesion is a congenital hamartomatous proliferation of vascular endothelial cells and may be multiple in 10% of cases.^[3] The term "giant hemangioma" is used for any lesion over 5 cm, although this does not have any particular significance.

Hemangiomas are rarely symptomatic (pain due to necrosis, infarction, or thrombosis), except in cases involving large tumors (> 10 cm). Hemangiomas may increase in size during pregnancy^[4] and shrink after menopause. Although estrogen receptors have been identified in certain tumors,^[5] oral contraceptive (OC) intake is not a risk factor associated with the growth of hemangiomas.^[6] Complications consist of spontaneous or posttraumatic rupture causing acute hemorrhagic shock in very rare circumstances; Kassabach-Meritt syndrome, including bleeding, thrombocytopenia, and coagulopathy; and Blumgart-Bornman-Terblanche syndrome, including fever and abdominal pain. Sclerosing hemangioma represents an involutive change in a cavernous hemangioma; its diagnosis by imaging can be difficult, requiring confirmatory pathological examination.^[7] Angiomatosis is an extremely rare condition with multiple hemangiomas, which is commonly asymptomatic and associated with hemangiomas in the skin or other organs.

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is the second most common solid BLT, occurring in up to 3% of the population.^[8] FNH is considered to be a nonneoplastic lesion that is caused by a hyperplastic response to a congenital vascular malformation or a disruption in blood supply.^[9] On pathology, FNH usually forms a firm, lobulated, and well-circumscribed lesion.^[10] Macroscopically, the main feature is the presence of a central stellate scar from which fibrous septa emanate and divide the lesion into many nodules or pseudonodules (Fig. 2).

Focal nodular hyperplasia has a higher prevalence in women from their second to fourth decades.^[9,11] In 10 to 20% of cases, the lesions are multifocal, and up to 20% of FNH coexist with hemangiomas.^[12] Oral contraceptive use is not involved in FNH formation, but its effects on FNH progression still remain controversial. According to World Health Organization (WHO) guidelines, OC intake should not be interrupted in women with FNH.^[13] A history of treatment of pediatric cancers with chemotherapy or hematopoietic stem cell transplantation has also been reported as a risk factor for the development of FNH in children, among whom one third of the cases exhibit multifocal FNH.^[14,15]

Focal nodular hyperplasia has no malignant potential and usually remains stable or decreases in size over time. Less than 20% of patients with FNH develop symptoms. Spontaneous rupture and hemorrhage most likely do not exist, and most of the reports concerning bleeding are old case reports that involve misdiagnoses of telangiectatic FNH, which has been recently reclassified as inflammatory hepatic adenoma.^[16]

Focal nodular hyperplasia occur mainly in normal liver and should be distinguished from FNH-like lesions, which occur in livers affected by alcoholic cirrhosis or vascular diseases, such as portal venous thrombosis, Budd-Chiari syndrome, and Rendu-Osler disease, in which FNH-like lesions are often multiple. In these cases, the major issue is to distinguish FNH-like nodules from hepatocellular carcinoma (HCC).

Nodular regenerative hyperplasia (NRH) corresponds to a diffuse transformation of normal hepatic parenchyma into small regenerative nodules, which are distinct from the nodules of cirrhosis or FNH.^[17] One of the pathogenic hypotheses is that obliteration of the portal vein causes ischemia followed by hyperplasia of hepatic acini in response to the atrophy of hepatocytes in the central area.^[18,19] Numerous diseases and drugs have been reported to be associated with NRH, such as myeloproliferative or lymphoproliferative disorders, chronic vascular disorders, rheumatologic disorders, and use of steroids or chemotherapeutic agents.^[20] Usually, NRH is discovered incidentally. However, patients may experience hepatomegaly, cholestatic symptoms, and symptoms of portal hypertension, such as ascites, splenomegaly, or esophageal varices.^[20,21,22]

Hepatocellular Adenoma Hepatocellular adenoma (HCA) is a very rare, benign hepatic neoplasia (incidence: 1/10⁶) that is usually identified as a well-defined, solitary lesion (Fig. 3). Hepatocellular adenoma occurs predominantly in childbearing women (M:F 1:8-15)^[23,24] and is related to endogenous or exogenous estrogen levels. High doses and long duration of OC, as well as pregnancy, are associated with a higher incidence of HCA,^[25] whereas discontinuation of OC is associated with regression of HCA.^[26–29] The use of anabolic androgen steroids,^[30] glycogen storage diseases (type I and III), and galactosemia also promote HCA, with a male preponderance.^[31] Furthermore, HCAs associated with type I and type III glycogen storage diseases are more likely to be multifocal and to become malignant.^[32]

The two main complications are spontaneous rupture with subsequent subcapsular or intraperitoneal bleeding and malignant transformation into HCC.^[33,34] Growth (~20%) and rupture have been reported in pregnant women for a tumor size > 6.5 cm, occurring even during the postpartum course, although not all adenomas are hormone sensitive.^[35,36] The incidence of malignant transformation is estimated to be 5% (varies from 4-10%).^{[24,37,38,39,40]} Several risk factors for this transformation have been identified: size > 5 cm, male gender, glycogen storage disease, androgen or steroid use, and β-catenin mutations.^[33–41]

Based on recent molecular^[42] and immunohistochemical studies^[43] and international guidelines,^[44] HCA are now categorized into four subtypes based on genetic and pathological criteria: hepatocyte nuclear factor-1 α (HNF1-α) inactivated HCA (35-40%), β-catenin mutated HCA (10-15%), inflammatory HCA (> 50%) of which ~ 10% have a β-catenin mutation, and unclassified HCAs (< 10%) lacking specific phenotypical markers. HNF1-α mutated adenomas are mostly found in women and are often histologically associated with intratumoral steatosis. Beta-catenin mutated adenomas are more often found in male patients, and are more frequently associated with the development of hepatocellular carcinoma.^[45] Inflammatory HCAs are more often found in patients with a body mass index > 25 kg/m^[2,46] and with chronic alcohol consumption.^[43] These tumors present a higher risk of hemorrhage and a slight risk of malignant transformation.^[37,46]

Hepatocellular carcinoma can be solitary or multiple, including vast numbers called adenomatosis (> 10 nodules of various sizes). Liver adenomatosis is a rare entity that was first described in 1985.^[47] It is more frequently encountered in the HNF1-α-inactivated subgroup, but also presents in the inflammatory HCA subgroup, has a higher incidence in women (including 52% with a history of OC), and is associated with hepatic steatosis in 80% of the cases.^[48] The complications are similar to those resulting from solitary adenomas and are not influenced by the number of lesions (Fig. 4).^[37,49]

Less Common Solid Benign Liver Tumors An angiomyolipoma is a very rare hepatic tumor consisting of fat, epithelioid, and smooth muscle cells with thick-walled blood vessels. An association with tuberous sclerosis and renal angiolipomas are found in 10% of cases with a female preponderance.^[50] The complications of this rare tumor include compressive effects due to its growth potential, and malignant transformation though this is much rarer than in the kidney.^[51]

Hepatic lipoma is a homogeneous and well-defined lesion that is less common than angiomyolipoma. Background hepatic steatosis may be associated with hepatic lipoma in 50% of the cases.^[52] These rare lesions must be distinguished from more frequent nontumor lesions, which are focal fatty lesions resulting from heterogeneous distribution of fat often located adjacent to the falciform ligament or in subcapsular areas.^[53] The lesions may be associated with obesity, diabetes, alcoholism, steroids, total parental nutrition, chemotherapy, and antiretroviral therapy.

A mesenchymal hamartoma is another uncommon benign lesion, which is composed of bile ducts, immature mesenchymal cells, and hepatocytes and is usually diagnosed during childhood.^[54] Benign biliary hamartomas, such as bile duct adenomas (also called peribiliary gland hamartoma), biliary adenofibromas and Von Meyenburg complexes are small, often subcapsular nodules. If the hamartomas are fortuitously discovered by surgeons, then pathologists must distinguish these tumors from adenocarcinoma metastases.

Cystic Lesions

Hepatic Cyst Simple hepatic cysts (SHCs) are congenital biliary hepatic lesions that are thought to result from progressive dilatation of biliary microhamartomas. They do not communicate with the biliary tree. Based on recent data from imaging studies, the prevalence of these lesions is between 1.6 and 18%.^[55–57] They are mostly found in women between 50 and 60 years of age.^[58,59] Rare complications, usually in very large cysts, include intracystic hemorrhage, compression of the biliary tree, vascular compression, visceral compression, rupture, secondary infection, and rarely cholangiocarcinoma.^[60–64]

Multiple cysts are quite common, typically less than five small or medium cysts. This is distinct from polycystic liver disease (PCLD), which is an autosomal dominant genetic disease with a prevalence of less than 0.1%^[65] characterized by the development of multiple macroscopic and microscopic cysts throughout the hepatic parenchyma (Fig. 5). These cysts are histopathologically similar to SHC, so PCLD is defined by the gross number of cysts. The most common form of PCLD is associated with autosomal-dominant polycystic kidney disease due to mutations of at least one of the following genes: PKD1 or PKD2.^[66] The prevalence of combined disease ranges from 1 in 400 to 1 in 1,000 and represents ~10% of all cases of end-stage renal failure.^[67] Several factors are correlated with more extensive liver involvement: increasing age, female gender, and the severity of renal disease and renal dysfunction.^[68] The second form is much rarer and occurs with liver-only involvement; in one third of cases, the disease is caused by mutations occurring in two other genes (PRKCSH and SEC63).^[69] Repeat pregnancies and OC intake are associated with faster development of hepatic cysts,^[68,70] which could explain why massive hepatomegaly rarely occurs before the fourth decade^[71] and why the prevalence and size of cysts are greater in women compared with men.^[69] Approximately 80% of patients with PCLD are asymptomatic.^[72]

Based on the number and size of the remnant liver parenchyma, Gigot et al described a classification of three types of PCLD, which is useful to guide the therapeutic approach: type I, large cysts; type II, localized disease; and type III, diffuse disease with small- and medium- size cysts.^[73] A more recent classification added the symptoms that are related to PCLD.^[74]

Hepatobiliary Cystadenoma Hepatobiliary cystadenomas are uncommon, benign cystic neoplasms of the biliary system, and comprise less than 5% of all hepatobiliary cystic masses.^[75] These arise more often within the liver (80%), but can affect the extrahepatic bile duct, and rarely, the gallbladder.^[76,77,78] They can be serious, or more commonly, mucinous (called mucinous cystic neoplasms as of the last WHO classification), characterized by the presence of an ovarian-like stroma under the mucin-secreting epithelium.^[79] These tumors are premalignant, and transformations into cystadenocarcinomas are not uncommon.^[79,80,81]

Mucinous cystic neoplasms occur predominantly in women of middle age (40-60 years) and are usually discovered based on symptoms at a large size (> 10 cm).^[79] Complications may occur due to mass effect and include obstructive jaundice, chronic cholecystitis, and cholelithiasis.^[80] The serum CEA and CA19-9 concentrations are usually normal, but elevated levels should alert the physician to possible malignant transformation.

Semin Liver Dis. 2013;33(3):236-247. © 2013  Thieme Medical Publishers