Abstract
Focal nodular hyperplasia (FNH) is the second most common benign hepatic mass. The primary purpose of this article is to provide a relevant case study and offer a review of the recent literature related to FNH with a discussion of both the clinical and imaging findings of this classically benign hepatic lesion. Although magnetic resonance imaging is considered the gold standard of FNH imaging, the sonographic and computed tomography appearance also is offered in this article. Furthermore, contrast-enhanced ultrasound, which boasts a 96% success rate at differentiating FNH from other hepatic tumors, is analyzed. The historical treatment options, including medical and possible surgical intervention, are provided as well. Last, this article offers an analysis of the prognosis for the patient diagnosed with FNH.
Keywords
The case study provided in this article confirms the need for both clinical and imaging follow-up of pathology discovered during either a routine sonographic examination or, in this case, during educational training. Although the sonographic appearances of benign hepatic lesions often overlap, it is imperative for the sonographer to understand the etiology of these benign lesions. Sonographers should also have a comprehensive understanding of valuable clinical history information that can assist an interpreting physician to make a proper diagnosis.
Case Presentation
A young white woman in her early 20s entered the sonography program and was offered an educational assignment that included the sonographic evaluation of her liver. Incidentally, during a practice scanning laboratory session, a liver mass was recognized using an ATL HDI 5000 (Philips/ATL, Philips Healthcare, Andover, Massachusetts) C5-2 transducer. The lesion was well marginated, hyperechoic, and positioned adjacent to the inferior vena cava within the right lobe of the liver (Figures 1 and 2). The mass did appear to distort the hepatic architecture in a manner that was inconsistent with a cavernous hemangioma. Color Doppler revealed blood flow around and within the mass, thus providing another sonographic feature that was thought to be less likely indicative of a cavernous hemangioma (Figure 3). The student denied the use of oral contraceptives, and she was nulliparious and asymptomatic. She also denied having weight loss or any history of abdominal pain or surgery. She was referred to her primary care physician for clinical evaluation.
Longitudinal sonographic image of the liver showing a hyperechoic mass (between calipers) adjacent to the inferior vena cava.
Transverse sonographic image of the liver demonstrating the location of the incidentally discovered tumor (between calipers).
Color Doppler analysis of the lesion revealed flow both within and around the mass.
Her physician performed a physical examination of the abdomen and stated that the liver did not feel enlarged upon palpation. The physician ordered a right upper quadrant sonogram and blood work, including an analysis of liver function. The blood work revealed a slightly elevated bilirubin level, with all other laboratory values unremarkable. An elevation in bilirubin levels could indicate a biliary obstruction, anemia, cirrhosis, or one of several other clinically noticeable abnormalities.
A complete sonographic examination of the right upper quadrant was performed using a GE-Logiq 7 (General Electric Medical Systems, Milwaukee, Wisconsin) curvilinear 3.5-MHz abdominal transducer. A well-defined hyperechoic lesion was visualized in the right posterior lobe of the liver measuring 4.4 × 3.8 × 3.6 cm (Figure 4). Color Doppler demonstrated blood flow both around and within the central portion of the mass (Figure 5). Pulsed-wave Doppler of the portal vein confirmed hepatopedal flow, and the main portal vein measured 14 mm in the anteroposterior dimension. No biliary ductal dilatation was noted. The right kidney, inferior vena cava, pancreas, and gallbladder all appeared unremarkable. The patient was referred for magnetic resonance imaging (MRI) of the abdomen.
The mass (between calipers) was again demonstrated on this longitudinal image taken during the follow-up sonogram.
Color Doppler imaging showed the presence of vasculature within the central portion of the mass (white arrow), suggesting the presence of a central scar that contained a prominent vessel.
MRI was performed with and without contrast. After routine noncontrast abdominal images were obtained, the patient was injected with 20 mL of gadolinium. The liver was reported to be normal in morphology, volume, and signal characteristics. No inflammation, fatty infiltration, or cirrhosis was visualized. The liver lesion was seen as a solitary mass that initially had the same appearance as the surrounding parenchyma on precontrast images (Figure 6). The mass was best demonstrated on the arterial phase postcontrast. On these images, the mass transiently enhanced brighter than the liver but, shortly after, faded back to its original isointensity (Figure 7). The delayed-phase images demonstrated enhancement of a central scar within the lesion (Figure 8). This finding was consistent with the diagnosis of focal nodular hyperplasia (FNH). The mass measured 3.2 × 3.8 × 3.5 cm on MRI, with a volume of 28 mL. It was noted to be located subjacent to the confluence of the hepatic veins and was in contact with the intrahepatic inferior vena cava, without effacement. The middle hepatic vein was located over the anterior border of the FNH, and it was effaced, with no indication of outflow obstruction or limitations. The spleen, pancreas, kidneys, adrenal glands, gallbladder, biliary system, retroperitoneum, and mesentery were all normal. The patient was given the definitive diagnosis of focal nodular hyperplasia. No follow-up care has been suggested or required.
Magnetic resonance image of focal nodular hyperplasia (between white arrows) without contrast. The liver lesion was seen as a solitary mass that initially had the same appearance as the surrounding parenchyma on precontrast images.
Magnetic resonance image of focal nodular hyperplasia (between black arrows) with contrast. On this image, the mass appears brighter than the liver.
Magnetic resonance image showing the presence of the central scar (black arrow) within the tumor, providing a definitive diagnosis of focal nodular hyperplasia.
Discussion
FNH is one of the most common benign hepatic masses. Its incidence is second only to the frequently encountered cavernous hemangioma of the liver.1,2 FNH was originally mentioned in the literature by Edmundson in 1958 and officially recognized as a distinct hepatic lesion by the World Health Organization in 1975.3,4 Prior to this acknowledgment, FNH may have been misdiagnosed as a hepatic adenoma, also termed
Composition of FNH
Differing studies have mentioned FNH as either a lesion that is neoplastic in nature, consisting of polyclonal cells, or nonneoplastic, consisting of monoclonal cells. Lesions that are polyclonal consist of different types of cells, whereas monoclonal lesions are composed of similar cells. The determination as to whether FNH is a true neoplasm is significant, however, specifically because a differentiation usually needs to be made between FNH and other hepatic masses, as prognosis and follow-up can vary considerably. A recent study by Gong et al 4 in 2009 established that FNH is indeed more likely a mass consisting of proliferated polyclonal cells and that it is nonneoplastic in nature, thus confirming that FNH is a hyperplastic rather than a neoplastic process. 6
Histologically, FNH consists of hyperplastic units of hepatocytes fixed together in an abnormal arrangement with dense fibrous tissue.2,7 The mass also contains proliferating bile ducts, Kupffer cells, connective tissue, and a central stellate (an arrangement resembling that of a radiating pattern, like that of a star) scar.7,8 The stellate scar contains a large artery that courses within it, causing hyperperfusion and arterializations of sinusoids. 5 Radiating out from the scar are often dense fibrous septa, often in a spoke-wheel pattern toward the periphery.6,9,10 Surrounding the FNH is a pseudo-capsule, although with imaging, the pseudo-capsule often appears as a genuine capsule surrounding the FNH because of the compression of adjacent liver parenchyma. 10
The average size of an FNH at the time of discovery is approximately 6 cm. 11 Three criteria typically have to be recognized to differentiate FNH from other hepatic masses microscopically: (1) the existence of a central stellate scar within the mass, (2) the presence of multiple bile ducts in fibrous intervals, and (3) a mass that lacks small cell changes. 12 The appreciation of this latter characteristic is crucial, for small cell change is a fundamental step in hepatocarcinogenesis. Moreover, it is significant to note that the central scar can be absent in anywhere between 20% and 50% of FNH cases.4,11
Etiology of FNH
The etiology of FNH has been an area of concentrated research. FNH has a low occurrence rate in males but is often discovered incidentally in females of childbearing age, which correlates with the case study discussed in this article.12,13 These findings support a theory that proposes that the mass is the outcome of an estrogen-stimulating vascular alteration combined with hepatocyte hyperplasia. 4 The role that estrogen, and specifically the use of oral contraceptives (OCs), plays in the development of FNH has not been clearly established. It should be noted that FNH has been found in children, males, and females who are not taking OCs. 14 One small study revealed no change in the character of tumors on follow-up imaging in patients who continued to take OCs. 12 It has been suggested that patients on OCs may have a risk of tumor enlargement, however, therefore signifying that FNH may be responsive to estrogen, but that estrogen is not a causative factor in its development.15,16 Younger women tend to have larger lesions than do postmenopausal women and men, and although not predictive, one study demonstrated that a pregnant patient with FNH did have an increase in the size of her tumor.11,17 Some research has revealed that a decrease in size or regression of FNH is seen after abandonment of oral contraceptives. 17 Furthermore, most investigators agree that OCs are not responsible for FNH, but they discourage the further use of OCs in patients with FNH secondary to the risk of complications such as enlargement of the tumor, hemorrhage, rupture, or necrosis. 5
Irregular blood flow patterns, vascular abnormalities, and preexisting arterial malformations have been proposed as the origin of FNH. 5 Altered blood flow patterns in association with an elevated angiopoietin 1/angiopoietin 2 mRNA ratio can result in FNH. 7 The angiopoietins are protein growth factors that encourage angiogenesis from preexisting blood vessels. One study has suggested that FNH is a result of the development of hyperplastic nodules in an area of the liver secondary to blood flow in an irregular hepatic artery branch. 6 Another source states that the origin of FNH results from a vascular anomaly that occurs before birth, which leads to a hyperplastic response within the hepatocytes. 6 This theory is supported by the consistently confirmed link between FNH and hereditary hemorrhagic telangiectasia (HHT), an inherited disease linked with numerous vascular anomalies.17,18
Finally, an additional hypothesis that strengthens the vascular association is that FNH may be the result of the development of an abnormal, spider-like, arterial malformation that produces an excessive amount of cells in a localized area, thus resulting in a change in the sinusoidal pressure and the development of a focal area of hyperplasia. 11 The theory that FNH is the result of a vascular malformation of the liver is supported by the fact that FNH is often accompanied by other vascular lesions of the liver, such as cavernous hemangioma. 13 The coexistence of FNH and hepatic hemangioma is 23%. 17 Although not as common, FNH also has been discovered in patients with hepatic adenomas and hepatocellular carcinoma.
In the past, it was once assumed that abnormalities of the portal vein were not associated with FNH, but recent studies have shown that mild abnormalities of the portal vein were present in a significant number of cases. One such case of FNH was reported in a patient with portal hypertension, which was thought to be associated with the anomalous portal tract syndrome, in which abnormal portal veins and arteries cause hyperplastic nodules to develop such as those seen in the presence of FNH. 19
There appears to be no risk for FNH to undergo malignant degeneration, although FNH was discovered adjacent to an area of hepatocellular carcinoma (HCC) in one case study mentioned in the literature. 20 However, FNH in association with HCC is rare, with an incidence of only 2%.11,21 One study examined 77 patients with FNH who underwent surgical resection, and of those patients, only 2 had evidence of HCC, with one of the patients ultimately having a recurrence of HCC shortly after the removal of the tumor. 22 Although this rate is extremely low, there has been speculation by some that FNH has the potential to lead to HCC, although this has not been definitively demonstrated. 4
Risk Factors and Clinical Presentation of FNH
FNH is more often seen in females in reproductive years, although it can be discovered in both sexes and at any age. Patients who smoke, have undergone chemotherapy, or have experienced blunt abdominal trauma are also at risk for developing FNH. 6 Patients with a history of cirrhosis and those who have been exposed to azathioprine, a drug that may be used to treat rheumatoid arthritis, have an increased risk for developing FNH as well. 7
Patients with FNH typically lack any clinical signs or symptoms. Acute abdominal pain can be a presenting symptom, although this has occurred in very few documented cases.11,16 The abdominal pain caused by FNH is thought to be the result of a large FNH that impinges upon adjacent hepatic structures, leading to a feeling of bloatedness for some individuals. 12 Patients with FNH may begin to experience symptoms and pain if the lesion suddenly begins to increase in size and certainly if the mass undergoes hemorrhage or rupture. 12 Five cases of intraperitoneal hemorrhage from FNH have been recorded since 1975, with four of the five cases being reported between 2000 and 2006. 5
Imaging Findings of FNH
FNH is most often incidentally discovered during an imaging study such as sonography, accounting for an estimated 3% to 8% of all primary hepatic tumors.12,13 Sonography is often the initial imaging modality for the identification of FNH, especially in asymptomatic patients. The sonographic appearance of FNH is variable, with a mixture of lesions that may be isoechoic, hypoechoic, or hyperechoic. 8 The isoechoic lesions can be overlooked without careful sonographic investigation. This attribute leads to the tumor’s descriptive nickname as the “stealth lesion” of the liver because of the possibility that the mass can be practically invisible on sonography. 1 For these instances, the use of B-color to highlight the borders of the mass can be beneficial, and a vigilant analysis of contour changes within the liver will help identify these masses.
Within the tumor, sonography may demonstrate the presence of the aforementioned central scar. This scar may appear hyperechoic or hypoechoic and contain prominent vasculature. Color Doppler may demonstrate evidence of vascularity surrounding the mass. 23 Although not yet approved by the US Food and Drug Administration (FDA) for this application, contrast-enhanced ultrasound (CEUS) is a dependable modality for the evaluation of focal liver lesions, with a 96% success rate at differentiating FNH from the hepatic adenoma.11,24 An FNH under CEUS interrogation will yield hypervascularity on the arterial phase and demonstrate the presence of stellate lesional vessels and a tortoise feeding artery. 1 Germany and France have both participated in well-known multicenter studies involving focal liver lesions and CEUS. The German study consisted of 1349 patients with focal liver lesions, and although the CEUS study was compared primarily with biopsy, some cases were compared with computed tomography (CT) or MRI. The study presented an accuracy rate of 90.3%, a sensitivity rate of 95.8%, and a specificity rate of 83.1%. 24 In this particular study, CEUS correctly diagnosed 87.1% of FNHs. 24 The French study consisted of 1034 focal liver lesions, and CEUS provided an accuracy rate of 86.1% compared with standard ultrasound, which had an accuracy of only 62.4%.
CT and MRI are especially useful in differentiating FNH from other hepatic tumors and are typically used subsequent to the incidental identification of FNH during a sonographic study. On an unenhanced CT, FNH will appear as a hypoattenuating or isoattenuating mass, with about one-third of the cases presenting with a prominent hypoattenuating central scar.9,16 Contrast-enhanced CT findings typically show a mass that is homogeneous, with some enhancement of the scar noted during the arterial phase and possibly on delayed images as well. 9
MRI has become the gold standard in diagnosing liver lesions, as it is considered to have a higher sensitivity and specificity compared with CT.5,12 On T1-weighted MRI images, FNH will appear either isointense or slightly hypointense compared with the normal hepatic parenchyma, whereas T2-weighted images may show a relatively hyperintense mass. 9 The central scar, when present, is readily identified with MRI. Specific contrast media used in MRI can also be used to identify the presence of Kupffer cells. 10 This is beneficial in the differential diagnosis between FNH and hepatic adenoma because adenomas do not typically contain Kupffer cells. 13
Prognosis and Treatment
Since there is a low risk for malignancy, current medical treatment remains conservative for the patient with an asymptomatic FNH with no need for medical intervention. The termination of oral contraception may be indicated secondary to a possible increase in the growth of the lesion, although as mentioned earlier, the link has not been clearly established. Close monitoring of a known FNH during pregnancy could be easily managed with routine sonographic examinations, possibly at the time of scheduled antenatal sonograms.
Surgical intervention may be necessary in a small number of individuals. The surgery can be performed by open surgery or laparoscopic resection. 11 However, this is typically only considered for patients who are symptomatic and have a previous history of bleeding episodes, hepatomegaly, elevated hepatic enzyme levels, or jaundice from compression on the biliary system.7,22 A sudden increase in the size of the lesion may warrant surgical intervention, however, even in the asymptomatic patient.6,17 In one study of 120 patients with hepatic lesions, 27 of whom had FNH, only one had an increase in the size of FNH located on her caudate lobe, which occurred during pregnancy. She had surgical intervention and did not survive the surgery. 17 Liver masses that measure over 5 cm have shown some increased risk for rupture, hemorrhage, or abnormal growth and may need to be managed and monitored more closely. 5 When masses cannot be definitively diagnosed with imaging, biopsy may be necessary.
Conclusion
FNH is a benign hepatic mass that may appear as a well-defined lesion of varying sonographic echogenicity. The role of the sonographer in the diagnosis of FNH is apparent. Sonographers are obligated to identify the lesion, measure it, and describe the sonographic appearance and location relative to other hepatic anatomy. Sonographers should also use critical thinking while obtaining clinical history information and employ every technical tool to examine a hepatic mass when discovered, including the use of image optimization and color Doppler. The identification of a central scar may be difficult with sonography. Although MRI may play a larger role in obtaining a more definitive diagnosis of FNH, it is the obligation of the sonographer to understand any diagnostic differentiations and attempt to show these sonographic variations when a hepatic mass is identified. By obtaining an accurate, thorough clinical history from our patients, we can collect valuable information that can be used both during and after the sonographic examination of a hepatic mass, thus ultimately contributing to a definitive diagnosis of FNH.