Liver lesions are commonly encountered in our current practice of medicine. Focal liver lesions
encompass the cystic and solid lesions that providers may encounter. Lesions vary greatly.
Most encountered lesions are benign. These include common lesions like the hemangioma,
simple cyst, and focal nodular hyperplasia, or the rarer hepatic adenoma. If uncomplicated,
these lesions rarely need intervention. Malignant lesions are also encountered. These nefarious
lesions include hepatocellular carcinoma and cholangiocarcinoma. Though less common than
benign lesions, these malignant lesions are still frequently identified in clinical practice. Given
the plethora of liver lesions and the various methods for evaluation, it is prudent for primary
care providers and specialists alike to be familiar with this topic. This review aims to highlight
salient information regarding characteristics focal liver lesions and modalities for evaluation.
INTRODUCTION
Our modern practice of medicine is rich with information. The widespread use of abdominal imaging for diagnostic and screening purposes has led to an increase in the detection of liver lesions, many of which are discovered incidentally. Furthermore, advances in radiologic techniques and equipment have greatly improved the accuracy when characterizing liver lesions into benign versus malignant, fluid versus solid, or simple versus complex. It is even possible to subclassify liver lesions based on imaging features alone.
The common use of abdominal imaging, the frequency at which liver lesions are identified, and the prevalence of chronic liver disease worldwide make it essential for all healthcare providers to have familiarity with focal liver lesions and the imaging modalities that assist with further evaluation. In this article, we begin by reviewing various imaging studies available for the detection and evaluation of focal liver lesions. We then highlight clinically relevant benign and malignant liver lesions, their epidemiology, the evaluation of the lesion, and recommendations for management.
Diagnostic Imaging for Focal Liver Lesions
The abundance of information collected in radiologic imaging has transformed the field of hepatology. Abdominal imaging is the cornerstone for the evaluation and management of focal liver lesions, so it is important for providers to understand key features of each modality.
Ultrasound
Ultrasonography is a non-invasive, readily available, and inexpensive form of abdominal imaging. Because of the high number of ultrasounds (US) performed in everyday practice, many liver lesions are first identified with this modality. These studies can provide insight into the characteristics of the lesion – including echogenicity, shape of the margins, or the presence of vascularity.1 US is particularly helpful for the differentiation between cystic lesions and solid lesions.
The convenience, safety, and low cost of US make it a good option for screening and surveillance exams. Society guidelines recommend screening patients with cirrhosis every six months for the development of hepatocellular carcinoma (HCC) using a right upper quadrant US with an alpha-fetoprotein (AFP) level. It is important to note that these twice-yearly HCC screening guidelines extend to those infected with hepatitis B virus (HBV) with or without evidence of cirrhosis, as about 20% of patients with HBV who develop HCC will not have cirrhosis.2,3
When a lesion is identified on traditional non-contrasted US, follow up imaging with another modality may be prudent. For example, simple asymptomatic hepatic cysts can be observed with expectant management, but complicated cysts and solid liver lesions should undergo further workup with contrast enhanced imaging.
Contrast-Enhanced Ultrasound
The addition of contrast to the abdominal US has improved the diagnostic capabilities when evaluating liver lesions. Contrast-enhanced US (CEUS) utilizes a gas-filled microbubble contrast agent which allows for visualization of the microcirculation of a liver lesion. The contrast allows for greater assessment for hypervascularity, which can be seen in lesions such as HCC. Similar to other imaging modalities, the pattern
of enhancement with contrast during arterial phase followed by subsequent contrast washout is an important feature of HCC on CEUS.2
CEUS is not as widely available in the United States as it is in European countries, largely due to the need for approval of contrast agents from the Food and Drug Administration (FDA). The FDA has currently approved the use of the contrast agent Lumason, however utilization has not yet been adopted into common clinical practice. European studies have shown that CEUS has high sensitivity (97-100%) for diagnosing HCC when lesions are >2.0 cm, which rivals that of computed tomography (CT) and magnetic resonance imaging (MRI).4 However, similar to CT and MRI, the sensitivity and accuracy decrease when lesions are <2.0 cm.4 It is worth noting that the American Association for the Study of Liver Diseases (AASLD) initially included CEUS as an acceptable imaging modality for the diagnosis of HCC, however this recommendation was removed in 2010 after data had shown false positive HCC diagnoses in patients actually affected with cholangiocarcinoma.5
Computed Tomography
The “triple-phase” or “triphasic” CT is one of the most helpful imaging modalities when evaluating focal liver lesions. “Triple-phase” refers to three points in time where images are captured after injection of a contrast agent. The first phase refers to the arterial phase which captures images about 30 seconds post-injection. This is followed by a portal venous phase, where images are captured after a 75 second delay from the contrast administration. The final image set captured is the delayed venous phase which occurs about 3 minutes post-contrast bolus. Studies have found that HCC can be diagnosed with >90% accuracy when a lesion is >2cm.6 This means that this technique allows many liver lesions to be diagnosed without the need for invasive biopsy.
The AASLD and the American College of Radiology (ACR) both support the use of a standardized system for the terminology, technique, interpretation, and reporting of liver lesions suspected to be HCC. This is called the Liver Imaging Reporting and Data System (LI-RADS).7 LI-RADS categories range from LI-RADS 1, representing a lesion that is “definitely benign,”
to LI-RADS 5 which is “definitely HCC.” It also includes categories such as “not categorizable,” “probably or definitely malignant, not necessarily HCC” and “tumor-in-vein.” Finally, there are categories that reflect treatment response after a lesion has undergone therapy, such as a lesion having “viable” tissue present, a lesion being “non-viable,” or “equivocal.”7
Magnetic Resonance Imaging
MRI provides detailed, non-invasive images to assist with the characterization of solid liver lesions. Similar to CT, the specific filling pattern of a lesion can often lead to a diagnosis without the need for a tissue biopsy. The LI-RADS system for the classification of HCC tumors can be applied to images obtained via MRI.
Gadolinium-based contrast agents (GBCA) are used to enhance MR imaging. There are two hepatospecific contrast agents which have improved the sensitivity and specificity for detection of focal liver lesions: gadoxetic acid (Gd-EOB-DTPA, Eovist) and gadobutrol (Gd-BT-DO3A, Gadavist).8 These agents act to enhance functionally intact hepatocytes along with the extracellular spaces. To this end, these agents enable evaluation of the hepatic tissue perfusion and the hepatobiliary excretion.8
Gadoxetic acid is a linear chelating GBCA that was approved for clinical use in the United States in 2008. About 50% of the contrast dose is taken up by hepatocytes and then eliminated by biliary excretion. This is in comparison to only about 3-5% of uptake seen in other non-hepatospecific contrast agents.9 Hepatobiliary phase images (i.e., images in which parenchyma is hyperintense compared to vasculature and there is excretion of contrast into the biliary system) can be acquired about 20-40 minutes after the injection of contrast, as opposed to over 1.5 hours after injection of other contrast agents.9 The unique properties of gadoxetic acid create both advantages and disadvantages to using this agent. The advantages include improved distinction between the appearance of lesions such as hepatocellular adenoma and focal nodular hyperplasia. Pitfalls include the “pseudowashout” appearance with benign lesions. This is when the brisk uptake of contrast into hepatocytes can make some hypervascular lesions (such as hemangiomas)
seem like they are experiencing a “washout,” which would be more suggestive of a malignant lesion.9,10
Gadobutrol is a GBCA that was approved in the United States in 2011. This agent chelates gadolinium in a macrocyclic, clam-shell-like arrangement. Gadobutrol is useful for the evaluation of possible metastatic lesions or cholangiocarcinoma. There is robust enhancement of lesions during the arterial and portal venous phases. It can also help with evaluation of the arterial and venous anatomy of the liver. Response to local therapies such as transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) can also be assessed with gadobutrol.
Nuclear Medicine Scans
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) detects metabolically active malignant cells. When evaluating solid liver lesions, this study can be useful for identifying metastatic disease or primary malignancy such as cholangiocarcinoma. Of note, the sensitivity of FDG-PET in diagnosis HCC is limited and has been reported to be between 50%-70%1, and is therefore not a preferred study for HCC evaluation.
An additional nuclear study is the technetium- 99m sulfur colloid scan. This is a study that utilizes radioactive technetium attached to a colloid particle. These particles are extracted by cells of the reticuloendothelial system, including Kupffer cells of the liver. Focal nodular hyperplasia appears as a hot area on this uptake scan, while other lesions appear cold.11
Benign Liver Lesions
Each of the various lesions that occur within the liver has its own unique fingerprint of risk factors, characteristic features, and techniques for diagnosis and management. An intuitive way to categorize lesions is by globally identifying them as benign or malignant. Below, we review some of the most notable examples of benign focal lesions that providers encounter in practice.
Cystic Lesions
Hepatic cysts are a heterogeneous group of fluid filled lesions lined by a thin layer of fibrous tissue. These are usually asymptomatic, but if symptoms are present, they are likely the result of mass effect.
Symptoms include abdominal pain, distension, nausea, vomiting, early satiety, or biliary obstruction. Hemorrhage of the cyst, rupture, and infection are other potential complications. Uncomplicated cysts are usually managed conservatively, though if complications or symptoms are present, or if there is concern that a lesion has potential for malignant transformation, then treatments such as aspiration, alcoholic sclerotherapy, surgical deroofing, or partial hepatectomy can be considered.
Simple hepatic cysts are fluid-filled lesions lined with an outer layer of fibrous tissue comprised of cuboidal columnar epithelium.12 Simple cysts have an estimated prevalence of 1%12, occur four times more frequently in women than in men, and usually occur after the age of 40. Studies have not demonstrated an increased risk of cysts with the use of oral contraceptives, which is a notable difference from other focal liver lesions. They are typically asymptomatic, though patients may experience abdominal pains, early satiety, or complications such as rupture or hemorrhage of the cyst.13,14 Uncomplicated, simple cysts can be managed expectantly.
Mucinous cystic neoplasm of the liver (MCN-L), previously known as biliary cystadenoma, is a lesion characterized by a smooth, thin-walled fibrous stroma lined by biliary-type mucus-secreting cuboidal or columnar epithelium.15 It has been reported that 1-5% of all hepatic cysts are MCN-L. The prevalence increases to 10% if only considering lesions >4 cm.16 MCN-L can be categorized into non-invasive or invasive (previously called biliary cystadenocarcinoma). Imaging can help with raising the suspicion of diagnosis of MCN-L, though ultimately the final diagnosis is made histologically. Needle biopsy is not recommended, as it has limited sensitivity and introduces the risk of seeding the tract with malignant cells if the lesion was in fact an MCN-L with invasive carcinoma.17 Surgical resection is recommended, as this provides tissue for the definitive diagnosis and serves as treatment of the lesion3,18.
Polycystic liver disease (PCLD) is the development of multiple benign cysts within the liver. It is hypothesized that the cysts arise from aberrant formation of fetal bile ducts that lack connection to the main biliary system. This can occur through two distinct pathologic processes. The first is by inheriting an autosomal dominant genetic mutation of either PKD1 or PKD2 genes, leading to the development of autosomal dominant polycystic kidney disease (ADPKD). Another process is isolated polycystic liver disease (IPCLD), which results from mutations in the protein kinase C substrate 80K-H (PRKCSH) or SEC63 genes.19 In rare cases, significantly symptomatic PCLD or hepatic failure due to the cysts can warrant consideration for orthotopic liver transplantation (OLT).
Hepatic Hemangioma
Also referred to as cavernous hemangiomas, these vascular lesions are the most common benign hepatic tumor and have a prevalence of 0.7-1.5%.20,21 Prior studies suggest that they occur three to five times more often in woman than in men,22,23 however other recent data suggests that the distribution between men and women may be rather equal.24 They are most commonly diagnosed between the ages of 40-60 but can occur at any age.24 These lesions are largely asymptomatic and are typically discovered incidentally. If symptoms occur, patients may present with abdominal pains, nausea, vomiting, and earlier satiety, which is likely related to mass effect.22 A rare condition known as Kasabach-Merritt syndrome can occur in those with large hemangiomas >4cm. This syndrome is characterized by bleeding due to consumptive coagulopathy, thrombocytopenia, or disseminated intravascular coagulation.25 It has previously been postulated that hemangiomas are related to female sex hormones and oral contraceptive (OCP) use. However, case-control studies have not shown a direct correlation. Tumor growth has been shown in men, post-menopausal woman, and woman who
do not take OCPs.26,27
These lesions can be identified on contrast-enhanced abdominal imaging with US, CT, or MRI. Typical features include a discontinuous peripheral nodular enhancement in the early phase along with a progressive centripetal fill-in during the late phase.3,19 If the imaging is equivocal, a Technetium- 99m-labeled red blood cell scan (Tc99-m RBC scan) can be completed. These are relatively inexpensive exams, and specificity has been described as 100%.1 Given the high vascularity, biopsy is not recommended if imaging is consistent with hemangioma. Hemangiomas rarely need treatment or intervention. If a hemangioma is very large (>10 cm) or is symptomatic, then intervention can be considered. Procedures such as enucleation, RFA, cryoablation, and resection have been reported approaches to treatment.19
Hepatocellular Adenoma
Hepatocellular adenoma, also called hepatic adenoma, is a rare benign solid liver lesion. The prevalence is estimated to be between 0.007- 0.012% of the population.3 When the lesions occur, they are typically found in women who use OCPs. This is due to elevated estrogen levels acting as a risk factor for the development of hepatocellular adenoma. Men and women with high endogenous androgen levels, women who are on OCPs or other hormonal therapy, and those who are on anabolic androgen steroids are at increased risk.28 If a patient is diagnosed with an adenoma and is taking hormonal medications, then it is recommended that those medications be discontinued.19 Furthermore, obesity has been identified as a risk factor for the development and progression of hepatocellular adenomas.29 The exact mechanism is not clear, but it has been proposed that it may be related to increased oxidative stress from fatty liver deposition, hepatic inflammation, or from higher amount of estrogen due to adipose tissue.29
These lesions are often discovered incidentally, though they have a greater tendency to be symptomatic than other lesions. Symptomatic patients describe epigastric or right upper quadrant abdominal pains. One of the more common complications of hepatocellular adenoma is spontaneous hemorrhage, which can occur in 11- 29% of patients.30
Hepatocellular adenomas can be subclassified based on histology and genetics into 4 different subtypes: hepatocyte nuclear factor-1 alpha, inflammatory hepatocellular adenoma, inflammatory beta-catenin, and non-inflammatory beta-catenin. Each subtype has been associated with varying risk factors, patient population affected, and risk of complication such as rupture or malignant transformation.31
The evaluation of a possible hepatocellular adenoma starts with obtaining multiphasic cross-sectional imaging. The use of MRI with a GBCA such as gadoxetic acid can help with differentiating hepatocellular adenomas from other benign lesions, such as focal nodular hyperplasia.3,19 MRI can often elucidate the subclass of adenoma based on imaging features. Imaging characteristics include a homogenous, well demarcated lesion with peripheral enhancement. MRI can suggest the presence of steatosis or hemorrhage depending on the density of the contrast present within the lesion.19 CT can be used though is not as informative as MRI and cannot be used to subclassify adenomas.
Notable complications of adenomas include malignant transformation and rupture. It is estimated that up to 5% of hepatic adenomas progress to HCC.32 Spontaneous rupture of the lesion can occur in 10% of people1, however this rate may be higher in patients with symptomatic lesions. Because of the risk of complications, the management of hepatic adenomas is more aggressive than other benign liver lesions. Surgical resection of a suspected adenoma is recommended if the lesion is >5 cm. Alternatively, if the patient is a woman currently on OCPs, then OCPs can be held and repeat imaging can be obtained to look for interval decrease in size of the adenoma. Lesions <5 cm can be managed with a conservative approach, as small adenomas have rarely been complicated by rupture or transformation to HCC.19 Some experts recommend that lesions of any size be resected in men due to the risk of transformation to HCC.33
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is the second most common benign liver tumor with a prevalence of 0.3-3%.3 They are usually discovered incidentally, but about 20-40% of patients may present with vague symptoms such as abdominal pains,
palpable mass, hepatomegaly or weight loss.19 FNH typically occurs in women around age 30- 40, though lesions can develop in men and women of all ages.19 It was once suspected that estrogen and other female sex hormones may play a role in the development of FNH. There has been a slight correlation drawn between OCP use and FNH from prior observational studies, but modern OCPs seem to contribute very little to the development or progression of these lesions.34 There have been associations observed between FNH and other vascular anomalies such as hepatic hemangiomas and the vascular hepatic adenomas. Up to 23% of cases of FNH have concurrent hemangioma or adenoma present in the liver.35
The exact pathogenesis of FNH is not known. It is hypothesized that the lesion starts after an injury to the portal tract. This results in the formation of arterial to venous shunts which in turn causes oxidative stress. This stress triggers hepatic stellate cells to form a characteristic central scar that is typically seen in these lesions.36,37
It is necessary to differentiate FNH from hepatic adenoma as the management of these two lesions differ. FNH can be well-characterized by abdominal imaging. A classic feature is the “spoke wheel” central scar which can be seen on triphasic CT and GBCA enhanced MRI.38,39 Biopsy is rarely required during the workup of FNH but can be considered if the diagnosis is in question.
The management of FNH is largely conservative. Most tumors are asymptomatic, the size remains stable or can regress, and rarely is complicated by rupture.19,40 If tumors are severely symptomatic, or if the definitive diagnosis cannot be established, then surgical resection can be considered. Pregnancy, the use of OCPs, and the use of anabolic steroids are not contraindicated when a patient has a known FNH.3 However, it is recommended that the lesion be monitored with abdominal imaging (such as US) every 2-3 years for women who wish to remain on OCPs.19
Malignant Liver Lesions
The liver is one of the most common sites of metastatic cancer deposits due in part to its rich blood supply. However, providers should bear in mind that primary liver malignancies are unfortunately commonly encountered in our modern practice of medicine. We now shift our discussion to two nefarious primary liver malignancies.
Hepatocellular Carcinoma
HCC is one of the more common cancers worldwide. It is the fourth leading cause of cancer death worldwide,41 accounting for 75% of primary malignant tumors of the liver.42 The largest risk factor for the development of HCC is the presence of cirrhosis; about 1-6% of patients with cirrhosis develop HCC each year.1 Additional risk factors for the development of HCC include those with a history of chronic HBV or HCV (hepatitis C virus), alcohol use, hormonal treatments, metabolic liver disease, those who smoke, and those exposed to environmental or occupational carcinogens.1
Current guidelines suggest that patients with cirrhosis or chronic HBV with or without cirrhosis undergo HCC screening every 6 months with an abdominal ultrasound with AFP serology.43 Patients with cirrhosis who are found to have a liver lesion of >1 cm on screening US should undergo further diagnostic imaging. This similarly applies to those who have lesions found incidentally on other abdominal imaging, those with a rising AFP in the absence of an identified liver lesion on ultrasound, and in those for whom there is strong clinical suspicion for HCC.44 Triphasic CT or MRI should be performed; the preferred study should depend on a center’s availability of radiologic expertise. Characteristic findings of HCC include enhancement during the arterial phase, followed by washout in the portal venous phase. An enhancing capsule may also be seen on the portal venous or delayed phases.45,46 When present, these findings are highly sensitive and specific for HCC. When these typical features of HCC are not present, and the diagnosis is still in question, then an image-guided biopsy of the lesions can be considered. This decision should be made cautiously, as there is potential risk of seeding tumor through the biopsy tract.1
Several therapeutic options exist after diagnosis of HCC. TACE is a procedure that directs chemotherapy directly to a lesion with the intent of shrinking tumor size. Radioembolization and systemic chemotherapy can similarly be utilized to reduce tumor burden. Curative treatments include RFA, hepatic resection, or OLT. These can be
curative and have a 5-year survival rate >50%.3 It is important to carefully choose candidates for OLT. The Milan criteria establish guidelines to help with selection of those who may benefit from treatment of their HCC by OLT. A patient is considered to be within the criteria if they have the following: one lesion ≥2 cm but ≤5 cm; or up to three lesions, each ≥1 cm but ≤3 cm.47
Cholangiocarcinoma
Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. It accounts for approximately 25% of primary liver tumors.48 Most cases of CCA are sporadic, though risk factors for development include a medical history of primary sclerosing cholangitis (PSC), choledochal cysts, Caroli’s diseases, biliary papillomatosis, or infection with liver flukes such as Opisthorchis viverrini and Clonorchis sinensis.1,48,49 CCA lesions are subclassified by anatomic location: intrahepatic CCA (ICCA), perihilar CCA (PCCA), or distal CCA (DCCA).48
The diagnosis of CCA can be challenging, as clinical symptoms and lab testing can be nonspecific. Patients may present with abdominal pains and loss of appetite, along with characteristic “B symptoms” such as fatigue, weight loss, and night sweats. Tumor markers can be helpful if elevated, as a carbohydrate antigen (CA19-9) level greater than 100 U/mL has been shown to have sensitivity and specificity of >80% in patients with concomitant PSC.50 Significantly elevated levels of CA 19-9 (≥ 1000 U/mL) have been associated with metastatic ICCA.48 In most scenarios, however, markers such as CA19-9, AFP, and cancer embryonic antigen (CEA) lack sensitivity and specificity. Imaging with CT or MRI can be very helpful with diagnosing CCA. Imaging may reveal hepatic capsular retractions, encasement of vasculature that may lead to lobar atrophy, and biliary ductal dilation due to obstruction. If a lesion is identified, biopsy should be obtained for definitive diagnosis, as it can be difficult to differentiate CCA from metastatic disease.51
Prognosis for patients diagnosed with CCA is poor. Treatment options include resection if possible. However, it is important to note that recurrence can occur in up to 62% of patients after 26 months of follow up, and median survival time is 36 months.52 For patients with inoperable tumors, the current recommended chemotherapy includes gemcitabine plus cisplatin.53
CONCLUSION
Focal liver lesions are commonly encountered in the clinical practice of both the general internist and the subspecialist. The relatively high prevalence combined with the widespread use of abdominal imaging has led to increasing detection of lesions. The lesions range greatly in significance, from benign “incidentalomas” to advanced malignancies. It is therefore prudent for a practitioner to have a sturdy knowledge base so that one can appropriately evaluate, manage, or refer when a lesion in found.
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