Diagnosis and Follow-up of Incidental Liver Lesions in Children : Journal of Pediatric Gastroenterology and Nutrition

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Diagnosis and Follow-up of Incidental Liver Lesions in Children

Karmazyn, Boaz; Rao, Girish S.; Johnstone, Lindsey S.; Severance, Tyler S.§; Ferguson, Michael J.§; Marshalleck, Francis E.||; Molleston, Jean P.

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Journal of Pediatric Gastroenterology and Nutrition 74(3):p 320-327, March 2022. | DOI: 10.1097/MPG.0000000000003377


What Is Known/What Is New

What Is Known

  • Incidental liver lesions in children are uncommon; the main challenge is differentiating benign from malignant lesions.
  • Magnetic resonance imaging typically provides the most specific imaging characteristic of liver lesions.

What Is New

  • Contrast-enhanced ultrasound was recently approved by the Food and Drug Administration for the diagnosis of liver lesions in children and can be used to characterize incidental lesions.
  • Contrast-enhanced ultrasound has the highest specificity in lesions smaller than 3 cm.
  • Using magnetic resonance imaging, hepatobiliary contrast improves specificity in the diagnosis of focal nodular hyperplasia.
  • Magnetic resonance imaging features correlate with pathologic subtype classification of hepatocellular adenoma and can help with diagnosis and management.

Pediatric liver lesions that are incidentally discovered result in several challenges. It is important to differentiate between a variety of benign incidental liver lesions and malignant tumors. Primary malignant liver neoplasms are uncommon with an annual incidence around 1.5 per million children in the United States (1).

Although there are guidelines from the American College of Radiology on the management of incidental liver lesions in adults (2), there are no such guidelines for children. The guidelines in adults are centered around abdominal computed tomography (CT) scans (2). Ultrasound (US) studies are more commonly performed in children, to decrease the potential risk of ionizing radiation; however. CT scans in children are typically performed as a single-phase study during the portal venous phase (3), as opposed to multiphasic studies performed in adults. This significantly limits information regarding dynamic changes in enhancement pattern that can better separate lesions into benign or malignant categories (2). Several major advances in liver imaging have occurred in the last few years, including contrast-enhanced US (CEUS). CEUS is performed by administration of intravenous contrast agents consisting of microbubbles/nanobubbles of gas, which result in better characterization of liver lesions in children (4). Additionally, there has been increased use of hepatobiliary contrast (Eovist, gadoxetate disodium, Bayer HealthCare Pharmaceuticals Inc. Berlin, Germany) in magnetic resonance imaging (MRI) for improved characterization of liver lesions in children [(5)].

Given the progress in this field, we have summarized our institutional guidance on diagnosis and follow-up of incidental liver lesions in children. This guideline is based on the most contemporary clinical imaging techniques and modalities, a comprehensive review of the literature, and institutional experience. Optimally, children with incidental liver lesions should be managed in centers with multidisciplinary expertise, including pediatric hepatology, oncology, diagnostic and interventional radiology, and liver pathology.


Definition of an Incidental Liver Lesion

We defined an incidentally detected liver lesion as one unexpectedly identified on US, CT, or MRI examination, in a child without underlying liver disease or increased risk of hepatic malignancy in childhood (Table 1).

TABLE 1 - Risk factors for malignant liver tumors in children
Hepatoblastoma Hepatocellular carcinoma
Prematurity Liver cirrhosis
Low birth weight Chronic hepatitis B and C
BWS and other overgrowth syndromes Hereditary tyrosinemia
Familial adenomatous polyposis Portosystemic shunts
Trisomy 18 Bile salt export pump deficiency
Portosystemic shunts
Aicardi syndrome
Data from (6–10). BWS = Beckwith-Wiedemann syndrome.

Risk for Malignant Liver Tumors

Underlying liver disease, vascular anomalies, some metabolic disorders (especially tyrosinemia), and several genetic disorders predispose to malignant liver tumors during childhood (Table 1). The finding of a liver lesion in these patients should not be considered as incidental: this population is excluded from these guidelines (6–10).


Patient age at the discovery of an incidental liver lesion is a major consideration in their management (11–14). Tumors that present in infants and young children are very different than those presenting in older children. Congenital and infantile hemangioma typically occur in early infancy (15). At older ages, there is an increasing incidence of types of benign lesions often seen in young adults, mainly focal nodular hyperplasia (FNH), adult-type hemangioma, and focal fatty infiltration (16–18). Hepatoblastoma is the most common malignant liver tumor in children. It is usually diagnosed in the first 3 years of life and is uncommon after the age of 5 years (19,20). Hepatocellular carcinoma (HCC), the second most common malignant tumor in children, usually occurs after the age of 5 years and incidence increases with age (21).

Alpha Fetoprotein Levels

Alpha fetoprotein (AFP) is used as a marker in some primary hepatic tumors. In about 90% of children with hepatoblastoma, AFP is elevated (19). But as AFP levels are physiologically elevated in the first 6 months of life, its usefulness as a tumor marker in infants is more limited (22,23). In normal infants, the AFP level is expected to decrease with variable half-life, ranging from as low as 5.5 days in the first month of life up to 4 weeks in the second and third months (22). In 95.5% of children older than 90 days, AFP is less than 1000 ng/ml (22).

Tumor Size

The risk of malignancy directly correlates with the size of the mass, and most malignant tumors in children present with a diameter >5 cm (24). On the basis of the studies in the adult population, malignant liver tumors rarely present with a size of less than 1 cm (2).

Imaging Characteristics of Malignant Tumors

A detailed analysis and integration of lesion imaging characterization is necessary to differentiate between benign and malignant tumors. Washout (decreased enhancement compared with surrounding liver parenchyma) in the delayed phase, dynamic information that can be obtained from CEUS and MRI, is most specific for malignant tumors (4,25). Many other factors in the pharmacokinetics of contrast media affect imaging; compared with CT and MR contrast media, US contrast agent is blood pool and lacks the interstitial phase. Each type of contrast has different elimination pathways. The unique hepatocyte uptake of gadolinium-based hepatobiliary contrast is mediated by the organic anion-transporting polypeptide (26). Heterogenicity of the lesion, presence of calcium, restricted diffusion, enhancing capsule, hypoenhancement during hepatobiliary phase, invasion into hepatic vessels, bile duct obstruction, and associated lymphadenopathy are some of the complementary imaging features that increase sensitivity in the diagnosis of malignant tumor (5,14). Imaging cannot always differentiate between benign and malignant tumors, and some benign lesions, such as the rare inflammatory myofibroblastic tumor, can have imaging findings suggestive of malignant tumor (27).


Most hepatic cysts are simple and are reported during the perinatal period (28). Histologically, the cysts are lined by simple squamous, cuboidal, or columnar epithelium (28,29). Simple cysts are round or oval, have a smooth thin wall without septation, calcification, or solid component, are anechoic by US, and have simple fluid characteristics on CT and MRI (30). The role of CEUS for diagnosis of simple cyst is unknown. On the basis of the limited experience in adults, simple cysts do not enhance. There is, however, overlap with other pathology (31). Most perinatal simple cysts will remain stable in size and some regress or resolve (Supplemental Digital Content 1, https://links.lww.com/MPG/C643) (28). Uncommonly, large, growing, or exophytic cysts may require surgical intervention (28,29). Complex cyst generally requires histologic confirmation (32).

Mesenchymal hamartoma (MH) is a rare benign tumor, mainly seen in the first 2 years of life and rarely after the age of 5 years (33). It typically appears as septated cysts but may have a variable solid component (33). Less commonly, MH appears as an entirely solid mass (34). The main differential diagnosis is undifferentiated embryonal sarcoma (UES), which presents in older children and may appear predominantly cystic on CT because of its myxoid stroma. On US and MRI, UES appears as a complex cyst with a solid component (35).

In North America, echinococcus of the liver (EL) may be rarely seen as an incidental cyst. The parasitic cyst initially appears as a unilocular cyst, then develops daughter cysts and septations because of a detached inner membrane. Later, in the inactive phase, it gradually becomes smaller, solidifies, and calcifies (36).

Other rare cysts include biliary cystadenomas (37) and hepatic foregut cyst (38). They appear as complex cysts and may communicate with the bile ducts (37,38).


Congenital and infantile hemangiomas are the most common type of liver tumors in infants, with an estimated prevalence of 5% to 10% (15,39). The presence of liver hemangiomas in infants is associated with cutaneous hemangiomas, with the greatest risk of liver lesions seen in those with 5 or more cutaneous hemangiomas (40).

Congenital and infantile hemangiomas are benign solid vascular tumors that have a phase of growth followed by spontaneous involution (15). The congenital hemangioma is the hepatic form of rapidly involuting congenital hemangioma (RICH). Unlike infantile hemangioma, RICH is fully grown at birth and undergoes an accelerated involution phase (15). The true incidence of liver hemangioma in infants is not known as most are asymptomatic, and thus never evaluated (15). Hemangiomas in infants are multiple in one-third of cases, and a diffuse form may rarely occur (15).

The typical appearance of hemangioma on US is a homogeneous solid hypoechoic or hyperechoic mass less than 3 cm in diameter (41). The typical findings on MRI include a T2-hyperintense spherical lesion with centripetal enhancement (42). Larger hemangiomas may display associated cystic changes and calcifications (41). The limited experience using CEUS shows centripetal enhancement (Supplemental Digital Content 2, https://links.lww.com/MPG/C644) with variable washout on delayed phase (43).

A consensus statement based on Boston Children's Hospital's infantile hepatic hemangioma registry and a consensus guideline from several children hospitals recommends that asymptomatic patients with focal or multifocal hemangioma should be observed with follow-up US to document regression (41,42). In patients with multiple lesions, US of the adrenals should be performed to exclude metastatic neuroblastoma (14).

Hepatic hemangiomas in adults are vascular malformations composed of vascular channels with a single layer of benign endothelial cells (44), whereas congenital or infantile hemangiomas are benign endothelial cell tumors (45). These tumors are uncommon in children with the youngest patient in a large series at 18 years (16). In our experience, we occasionally identify adult type hemangiomas in adolescents. These lesions may not be well documented in the literature as in most of them, the diagnosis can be based on imaging with no need for pathologic confirmation. In adults, US findings of homogeneous hyperechoic lesions less than 3 cm, with sharp margins and posterior enhancement, are highly specific for liver hemangioma (46,47). On CT, MRI, and CEUS, dynamic enhancement has similar imaging characteristics as infantile hemangioma (48,49). The use of hepatobiliary-specific contrast can be misleading as most hemangiomas are hypointense during the hepatobiliary phase, similar to HCA and malignant tumors (50).


FNH is quite uncommon in children and accounts for 2% to 7% of all pediatric liver tumors (17). There is a female predominance (17). The pathogenesis of FNH is thought to be a result of a localized vascular anomaly leading to local hepatocyte regeneration and hyperplasia (51). FNH is associated with congenital hepatic vascular anomalies and congenital heart disease resulting in altered hepatic blood flow, and is also recognized postchemotherapy (17,52–54). On the basis of a pediatric case series of 50 patients, multiplicity can be seen in 20% of cases (17).

On US, FNH may appear as either a hypoechoic or isoechoic homogeneous nodule (55). The only specific color Doppler finding is the spoke wheel pattern (Supplemental Digital Content 3, https://links.lww.com/MPG/C645), which can be better detected with high-resolution color Doppler technique (Microflow) and CEUS (56,57). The highest accuracy of CEUS is in FNH lesions measuring less than 3 cm (58,59).

In multiphase CT, FNH has marked arterial enhancement without delayed washout and with central scarring (53). In MRI, the typical appearance of lesions less than 5 cm in size is isointense to slightly hypointense on T1-weighted images, and isointense to slightly hyperintense on T2-weighted images. They have homogeneous arterial phase enhancement, no capsule, and a T2-bright central scar with delayed enhancement (25,55,60). The central scarring is demonstrated in 75% to 80% of patients (61), and is less common in lesions less than 3 cm in size (47). The use of hepatobiliary contrast showing increased or similar intensity on the hepatobiliary phase (Supplemental Digital Content 3, https://links.lww.com/MPG/C645) improves specificity of the diagnosis of FNH (62,63). The sensitivity and specificity of hepatobiliary enhancement in differentiating FNH from HCA are 92% to 97% and 91% to 100%, respectively (47). In the past, Tc-99m sulfur colloid and Tc-99m HIDA were used to evaluate for FNH but have limited resolution and provide no advantage compared with MRI (55).

FNH should be differentiated from fibrolamellar variant HCC (fHCC). Imaging features more suggestive of fHCC than FNH are hypointense scar on both T1- and T2-weighted images, calcifications (64), and hypointensity during the hepatobiliary phase when using gadoxetic acid (65). In addition, metastatic lymphadenopathy can be seen in 50% to 60% of fHCC, most commonly at the hepatic hilum (66).

The European Association for the Study of the Liver practice guidelines on management of benign liver tumors suggest using MRI as the first-line imaging modality; however, if the diagnosis is not definite and the lesion is smaller than 3 cm, CEUS is recommended. Biopsy is suggested in lesions that do not have the typical characteristics of FNH (47).

In children, diagnostic imaging of FNH has a reported sensitivity of 83% and specificity of 97% (51). In a series of 50 patients with an imaging diagnosis of FNH, 13 underwent surgical resection, mainly because of growth or symptoms, with pathologic confirmation of FNH in all (17). In the absence of atypical imaging or symptoms, FNH does not require resection (17).


In children, hepatocellular adenomas (HCAs) represent <5% of all hepatic tumors. Most of them are in children with risk factors, such as cirrhosis, glycogen storage diseases, galactosemia, Hurler syndrome, familial adenomatous polyposis syndrome, and Fanconi anemia; incidental HCAs are rare (67).

HCA is histologically subclassified based on the presence of genetic changes (Supplemental Digital Content 4, https://links.lww.com/MPG/C646), including inactivating mutations in hepatocyte nuclear factor 1α (H-HCA; 30%–50%), activating mutations in β-catenin (bHCA; 10%–20%), or activation of inflammatory signaling pathways (IHCA; 40%–50%); some also remain unclassified (>10%) (Supplemental Digital Content 4, https://links.lww.com/MPG/C646) (68). About 15% of IHCAs have β-catenin mutation (69). bHCA is associated with the greatest risk of malignant transformation (up to 50%) (68). The main complications in adults are bleeding (15%–29%), and malignant transformation (5%) to HCC (69). A higher risk for complications is related to increased size (>5 cm), β-catenin mutation HCA, and male gender (68,69). Malignant transformation in children is extremely rare, with few case reports of malignant transformation to hepatoblastoma (70).

There are no specific characteristics of HCA on US or CT scan (71,72). On MRI, there are certain features that are associated with pathologic subtypes of HCA (Supplemental Digital Content 4, https://links.lww.com/MPG/C646) (73). The most important finding is the presence of a large proportion of fat signal with marked homogeneous signal drop on the out-of-phase images (Supplemental Digital Content 5, https://links.lww.com/MPG/C647), which is seen in about 80% of cases of hepatocyte nuclear factor 1α HCA (H-HCA) (73). It has been suggested that patients with H-HCA <5 cm identified by MRI can benefit from nonaggressive treatment and surveillance because of the rare risk of malignant transformation (69).

Inflammatory HCA (IHCA) can have MRI characteristics that overlap with FNH (74). IHCA has been described in association with obesity (75), and incidental IHCA with β-catenin mutation was described in a case report of an 11-year-old girl with obesity and nonalcoholic steatohepatitis (76). Lifestyle changes, such as discontinuation of oral contraceptives as well as appropriate weight loss, should be advised. Surgical intervention should be considered for patients with symptoms or risk factors (male patients, HCA greater than 5 cm, β-catenin activated subtype) (68). Other patients should have imaging surveillance at 6-month intervals for the first 2 years and annually thereafter (68,77). On the basis of the adults, long-term surveillance with MRI has demonstrated stability or regression in 90% of patients with solitary lesions and 71% of patients with multiple lesions (78).


On the basis of CT scans, focal fatty infiltration of the liver is common (9.2%) in children, with increasing incidence with age (18). Focal fatty sparing is less common in children, whereas in adults, it was found on US in 67% of adults with liver steatosis (79). Focal fatty lesions (infiltration or sparing) typically have a geographic or wedge shape without mass effect, and are found in characteristic locations adjacent to the falciform ligament, in the porta hepatis, or in the gallbladder fossa (80). Focal fatty infiltration is echogenic on US (Supplemental Digital Content 6, https://links.lww.com/MPG/C648), has low attenuation on CT, and has drop in signal on out-of-phase sequences on MRI (80). CEUS shows similar vascularity as compared with the surrounding parenchyma (81). Focal fatty sparing appears on US as a hypoechoic focus (Supplemental Digital Content 7, https://links.lww.com/MPG/C649) in the setting of liver steatosis (79). On CT, it appears as hyperdense areas within diffusely hypodense liver parenchyma and can mimic an enhancing lesion (82). When focal fatty sparing does not have typical characteristic on US or CT, MRI should be performed (82). MRI shows absence of mass effect on vessels, contrast enhancement similar to surrounding parenchyma, and a drop in signal in out-of-phase sequence of the surrounding liver parenchyma while the spared area maintains intensity (82) (Supplemental Digital Content 8, https://links.lww.com/MPG/C650).


All of the benign tumors and lesions described above can be multifocal and should be differentiated from multifocal primary malignant liver tumors and metastases (6). When multiple liver cysts are present, polycystic liver disease, Caroli's disease, choledochal cysts, and biliary hamartoma should be considered (30). The imaging characteristics of benign lesions should help guide whether further imaging studies are required for additional characterization, if biopsy is needed, or if the patient can simply undergo follow-up imaging. It is important, however, to know that benign lesions can appear in conjunction with malignant tumors, such as in case reports of FNH associated with malignant tumors (83). Management should, therefore, be dictated by the lesion with the most worrisome imaging characteristics.


There is no consensus on the duration of follow-up of incidental liver lesions to confirm stability or regression. For children, based on limited evidence and institutional experience, we suggest stricter follow-up compared with adult guidelines (2,77). For lesions smaller than 5 cm with distinct imaging characteristics of simple cyst, hemangioma, or FNH, we suggest surveillance of 6 to 12 months and then yearly until regression or stability for 2 to 3 years. Some lesions, such as infantile hemangioma and FNH can have a growth phase. Close surveillance every 3 to 6 months (based on lesion size and growth) is suggested for these lesions with typical benign characteristics and mild growth. Biopsy should be considered with increasing size of other lesions. For HCA and for lesions without the typical imaging characteristics of the benign lesions described above, if biopsy is not feasible, we suggest surveillance initially after 3 to 6 months, then every 6 months for 2 years, and then yearly (Fig. 1). For a single lesion, US should be used for surveillance if the lesion can be well delineated and measured reliably. To improve delineation and characterization of the lesion, CEUS can be considered. For multiple lesions, MRI is the preferred imaging.

Algorithm for the surveillance of incidental liver lesions. For a single lesion, US should be used for surveillance if the lesion can be well delineated and measured reliably. To improve delineation and characterization of the lesion, CEUS can be considered. For multiple lesions, MRI is the preferred imaging. For some lesions with typical benign characteristics, continued imaging surveillance can be considered rather than biopsy. CEUS = contrast-enhanced ultrasound; FNH- focal nodular hyperplasia; US = ultrasound.


Children often require sedation or anesthesia for liver biopsy. The primary method for liver biopsy is percutaneous with US guidance, with histopathology confirmation for the diagnosis of focal liver lesions (84,85). It is a safe procedure with high diagnostic yield and a low risk of hemorrhage (84–86). On a few occasions, CT-guided biopsy may be performed (87). In our practice, CT-guided biopsy is performed only when the liver lesion cannot be identified by US. CEUS is used successfully in adults for guiding liver biopsy (88). After our initial successful experience with CEUS liver biopsy in children, we believe it may become an alternative to CT guidance for lesions not well defined by US. Rarely, children will need to undergo surgical biopsy when percutaneous biopsy is not feasible or is not diagnostic (51,87).


Incidental liver lesions are uncommon in children and can present a challenging diagnostic dilemma. They may require multidisciplinary discussions integrating the expertise of pediatric sub-specialties, including hepatology, oncology, radiology, interventional radiology, and pathology. Management and follow-up depends on multiple factors, including the age and imaging characteristics on US (Fig. 2), CT (Fig. 3), or MRI (Fig. 4). The most important task is to differentiate benign from malignant lesions, ideally based on imaging characteristics but aided by biopsy whenever necessary. It is crucial to identify lesions, which appear benign but require long-term surveillance because of the potential for complications or malignant transformation.

Algorithm for evaluation of incidental liver lesions demonstrated by ultrasound. This algorithm represents a general guidance and imaging characteristics, clinical and laboratory findings as well as availability of expertise that should be involved in management. Follow-up depends on the size of the lesion and its stability during the surveillance; for more details refer to Fig. 1. AFP (alpha fetoprotein) is physiologically elevated in the first 6 months of life and expected to decrease. CEUS = contrast enhanced US; FNH = focal nodular hyperplasia; MRI = magnetic resonance imaging; US = ultrasound.
Algorithm for the evaluation of incidental liver lesions demonstrated by computed tomography. This is based on a single-phase CT scan during the portal venous phase. This algorithm provides general guidance; imaging characteristics, clinical and laboratory findings, and multidisciplinary expertise should be involved in management. CEUS = contrast enhanced ultrasound; CT = computed tomography; MRI = magnetic resonance imaging.
Algorithm for evaluation of incidental liver lesions demonstrated by magnetic resonance imaging. This algorithm provides general guidance; imaging characteristics, clinical and laboratory findings, and multidisciplinary expertise should be involved in management. FNH = Focal nodular hyperplasia.


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computed tomography; incidental lesions; liver; magnetic resonance imaging; ultrasound

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