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Benign Hepatic Tumors: From Incidental Imaging Finding to Clinical Management

Benign hepatic tumors (BHTs) are commonly detected as incidental finding mainly due to the frequent utilization of imaging modalities, including ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). Rigorous clinical evaluation, with a particular focus on chronic liver disease (CLD) or risk factors for CLD, medication history, physical examination for signs of CLD, blood tests, and a review of past liver radiology constitute the initial steps in the evaluation of a new liver lesion. Further, contrast-enhanced imaging using US, CT and MRI, can be used depending on the clinical scenario and their availability. The contrast-enhanced MRI provides detailed tissue assessment while avoiding exposure to radiations, although it is scarcely available and expensive. While the liver tissue-specific protocols ensure precise diagnosis, a biopsy is recommended in selected or doubtful cases. Further, most BHTs, such as hemangiomas, are harmless and do not require special management or follow-up, the hepatic adenomas and large or atypical cases of focal nodular hyperplasia are clinically relevant and require management/follow-up. In such cases, it is favorable to have a multidisciplinary team approach, which includes hepatologist, radiologist, hepatobiliary surgeon, and pathologist. This review aims to elaborate the current understanding of BHTs, and provide a practical guidance for primary care and practitioners of family and internal medicine for the disease evaluation and management.


INTRODUCTION
With an extensive use of radiologic modalities, a considerable number of liver lesions are being diagnosed in routine clinical practice. Smith-Bindman et al. 1) observed a massive increase in the usage of radiologic modalities between 1996 and 2010, which has contributed to the increased rate of diagnosis of liver lesions. Most of these lesions are incidental findings in patients being evaluated for other conditions, such as kidney stones, epigastric pain, and other non-specific complaints.
Hepatic lesions may origin from all kind of liver cells including hepatocytes, mesenchymal as well as cholangiocellular line, and a reliable detection and characterization of liver lesions is critical for optimal patient management. Primary care providers are not uncommonly the first practitioners to encounter patients with imaging findings of liver lesions and thus should have a basic knowledge as well as tools to deal with these findings in order to avoid any undesirable consequences.
Fortunately, the majority of liver lesions arising in non-cirrhotic liver are benign. Cysts, hepatic hemangiomas (HH), focal nodular hyperplasias (FNH), and hepatic adenomas (HA) are among the most commonly encountered benign lesions. Despite the benign nature, HAs have been associated with a significant risk of hemorrhage and malignant transformation and thus need to be followed more closely than other benign tumors. Moreover, atypical cases of FNH or HH may have serious consequences that mandate specific management strategies.
Hepatocellular carcinomas (HCC), and to a lesser extent intrahepatic cholangiocarcinomas, represent the most common primary liver malignancies and are diagnosed primarily in the setting of cirrhosis or chronic liver disease, while the most commonly encountered malignant lesions in non-cirrhotic liver are metastases.
An outstanding development of new imaging techniques has taken place during the last decade. Contrast-enhanced imaging is the most sensitive diagnostic method, and facilitates the accurate diagnosis of majority of the lesions based on specific liver imaging protocols. 2) Still, differentiation of masses may be complex, and biopsy or resection for histological diagnosis sometimes becomes necessary.
In the current study we reviewed recent literature and society guidelines concerned with BHT evaluation and management. The current review outlines the major differential diagnosis of benign hepatic masses in adults and discusses an algorithmic approach of manage-ment for primary care practitioners.

HEPATIC HEMANGIOMAS
HHs are the most prevalent form of benign hepatic tumors (BHTs).
They are asymptomatic and discovered incidentally during imaging, 3) and the prevalence observed is up to 20% in autopsy specimens and 5% in radiological modalities. 4,5) HHs are frequent in women aged 30-40 years, with a female to male ratio of 5:1. 6) Though HHs are usually less than 4 cm in size and are solitary, giant and multiple HHs have also been reported. While HHs are hepatic vascular malformations with a poorly understood aetiology, their origin either as a congenital malformation or as an aberrant vascular growth, remains to be determined. 7) Although the use of oral contraceptives has been linked with HH, the association could not be established in the case-controlled study by Gemer et al. 8) Moreover, majority of the HHs are asymptomatic and clinically irrelevant. However, approximately 11% of the HHs, especially those of large sizes, may cause symptoms due to pressure on adjacent organs, which may be manifested as pain in the right upper quadrant, dyspepsia, nausea, and vomiting. Additionally, HHs may be complicated by bleeding or consumptive coagulopathy with thrombocytopenia and generalized bleeding, a condition known as Kasabach-Merritt syndrome. 9) HHs may be diagnosed using US, CT, or MRI (Table 1), where the HH typically appear as homogenous, hyperechoic lesions generally smaller than 3 cm in size with a well-defined rim and a few intra-nodular vessels in US. The contrast-enhanced imaging shows peripheral enhancement in the arterial phase, followed by centripetal enhancement in the delayed phases ( Figure 1). 10) According to the guidelines of the European Association for the Study of the Liver (EASL) published in 2016, US images depicting typical characteristics of a HH is sufficient for diagnosis, if the lesion has size <3 cm with no chronic liver disease. 11) Furthermore, MRI is the preferred modality as it has the highest specificity and sensitivity for identifying HHs. However, due to their benign nature, no imaging follow-up is required for typical HHs. 11,12) As per the guidelines of the EASL and American Association for the Study of Liver Diseases (AASLD), oral contraceptives and hormonal therapy are not contraindicated in these patients. However, though the

FOCAL NODULAR HYPERPLASIA
FNH is a rare BHT with 0.03% prevalence estimated by US. 13 14) FNH is formed as a result of the hyperplastic response to vascular hepatic dystrophy, along with formation of the arteriovenous shunts and the subsequent activation of hepatic stellate cells, which leads to formation of a central scar. 15) Further, the role of oral contraceptives and pregnancy in the formation or progression of FNH has not been established yet. 16) Most of the FNH cases are asymptomatic, remain stable for prolonged duration, and rarely present with complications. 17) FNH can be diagnosed using contrast-enhanced imaging modalities, such as US, CT, or MRI ( Figure   2). The combined use of MRI and hepatobiliary contrast agents, like gadobenate dimeglumine and gadoxetic acid, can help achieve the highest diagnosis accuracy rate, with a specificity and sensitivity of over 90%. 18,19) The imaging characteristics of FNH using different imaging modalities have been summarized in Table 1 The management of FNH is generally conservative, and based on the guidelines of the EASL and AASLD, oral contraceptives are not contraindicated in FNH. Moreover, if the diagnosis has been confirmed, then follow-up or surveillance using US is not required. 11,12) Additionally, a poor correlation exists between FNH and symptoms, and hence treatment administered is generally inappropriate, even in the symptomatic patients. 11) Though surgical resection or partial hepatectomy is the preferred treatment, it is recommended only in special cases, such as the exophytic or pedunculated FNH. Whereas, based on the guidelines of the EASL, non-surgical options, such as the radiofrequency ablation (RFA) and trans-arterial embolization (TAE), are administered to patients unamenable for surgery. 11)

HEPATIC ADENOMAS
HAs are rare, benign, epithelial tumors of the liver, observed predomi-A B C D  nantly in women aged 20-50 years. 20,21) Studies have shown association of use of oral contraceptives as hormonal therapy with incidence of HA in a dose and duration dependent manner. 22) Moreover, the incidence of HA is less in the Asian countries possibly due to limited usage of oral contraceptives than in the Europe and North America. 23,24) Additionally, anabolic androgens, pregnancy, and glycogen storage disease may cause HA. [25][26][27] Moreover, recent data has highlighted the emerging role of obesity and metabolic syndromes as contributing factors for the increased prevalence of HA. 28,29) HAs are usually solitary lesions located in the right lobe of the liver, vary in size from a few mil-  Table 2.
While the hepatocyte nuclear factor-1α HA or inflammatory HA can be specifically identified using MRI, identification of the β-catenin activated HA or unclassified HA and their distinction from HCC is not possible using any of the available imaging techniques. Thus, a biopsy should be considered in selected cases.
Further, the patient characteristics, such as gender, tumor size, and progression pattern influence the decisions regarding HA management. While the HA subtypes may also impact disease management, they are yet to be considered due to lack of conclusive evidences. 34) As the first therapeutic strategy, patients should be advised for discontinuation of oral contraceptives and anabolic androgens, and management of obesity. Additionally, in case of female patients, a conservative approach has been advised for management of small lesions (<5 cm) or those that would regress (to <5 cm) following cessation of oral con-traceptives. The EASL guidelines recommend contrast-enhanced MRI at regular intervals of 6-month post-discontinuation of oral contraceptives to determine regression of a large adenoma to <5 cm. Moreover, imaging using US is a cost-effective strategy, and may be preferred for the easily viewed lesions. Patients that do not show regression of HAs need to undergo treatment, and since men have a higher risk of malignant transformation, adenoma resection is advised irrespective of the size of the lesion upon diagnosis. 35) The various approaches for management of HA have been summarized in Figure 4. Furthermore, nonsurgical modalities, such as RFA and TAE, which are minimally invasive and highly successful, may serve as first-line treatments in surgically unamenable patients with spontaneous rupture and bleeding. 36) However, treatment of HA in pregnant women is challenging, due to