Introduction
Background
Focal nodular hyperplasia (FNH) is the second most common tumor of the liver, surpassed in prevalence only by hepatic hemangioma.1 FNH is believed to occur as a result of a localized hepatocyte response to an underlying congenital arteriovenous malformation. FNH is a hyperplastic process in which all the normal constituents of the liver are present but in an abnormally organized pattern. Results of liver function tests in these patients usually are within the reference range.
Dynamic MRIs in a 36-year-old woman referred for a gallbladder sonography, during which the patient was found to have a vague ill-defined hypoechoic mass in the right lobe of the liver (not shown). (Top left) Gadolinium-enhanced T1-weighted MRI demonstrates an ill-defined low-signal-intensity mass. (Top right) The mass enhances intensely in the arterial phase after the administration of contrast medium. (Bottom left) Minor enhancement persists in the portal venous phase. (Bottom right) The lesion becomes isointense relative to the liver on delayed images.
Although the use of contraceptive agents has not been implicated in the pathogenesis of FNH, their use is associated with an increase in the risk of complications for patients with FNH, and they may be a factor in the development of FNH. In symptomatic females, hemorrhagic foci or infarctions may occur within the FNH; these are aggravated by administration of contraceptive agents. The rare complication of a spontaneous rupture into the peritoneum has also been associated with contraceptive use.
In most patients, the clinical course is silent, and FNH is incidentally discovered during cross-sectional imaging, angiography, radionuclide liver scanning, or surgery. In most cases, FNH occurs as a solitary lesion (80-95%), but multiple lesions may occur.2 Although FNH usually has no clinical significance, recognition of the radiologic characteristics of FNH is important to avoid unnecessary surgery, biopsy, and follow-up imaging.
Malignant transformation of FNH has not been reported. FNH must be differentiated from a fibrolamellar variant of hepatocellular carcinoma, with which it shares imaging and gross features.
Related eMedicine topics:
Liver Tumors
Liver, Metastases
Liver Transplantation, Complications
Pathophysiology
Focal nodular hyperplasia (FNH) is not a true neoplasm, but it probably represents a local hyperplastic response of hepatocytes to a congenital vascular anomaly.2,3 It is a proliferation of normal, nonneoplastic hepatocytes that are abnormally arranged. Supporting this hypothesis is the fact that FNH is found in association with cavernous hemangiomas, as well as other vascular malformations of other organs and neoplasms of the brain.4,5,6 Intermediate lesions (ie, lesions with characteristics of both cavernous hemangiomas and FNH) have been reported.5 A rare transitional lesion that has been reported as a mixed hamartoma and found most often in infants and children has similarities to both FNH and hemangioma.1,7
It is hypothesized that a congenital vascular malformation (either an arteriovenous shunt or localized hyperperfusion) triggers focal hepatocellular hyperplasia. On pathologic examination, anomalous arterial branches, unaccompanied by portal venous branches, have been seen feeding the numerous small lobules that constitute the FNH lesion.3 As with hyperplasia and hypertrophy seen around vascular malformations in the extremities, hepatic hyperplasia is seen in the liver.
Focal nodular hyperplasia is a localized, well-delineated focal lesion (not a diffuse mass) within an otherwise normal liver. It is composed of multiple, spherical aggregates of hepatocytes held together in a fibrous meshwork with a dominant scar or scars. In 80-90% of patients, the FNH lesion is solitary, and the macroscopic appearance is a highly characteristic finding. Although FNH has no capsule, it tends to be a fairly well marginated, lobulated, subcapsular mass.
On naked-eye examination of a gross pathologic specimen, the lesion is often lighter in coloration than the surrounding liver tissue. In some patients, FNH blends in with normal liver tissue, making it difficult to distinguish surrounding normal liver tissue from FNH in a gross pathologic specimen. The hallmark feature of the lesion is found on a cut specimen; the lesion appears as a central stellate scar with radiating fibrous septa dividing the tumor into lobules. The central scar contains an arterial malformation in which spiderlike branches supply the component nodules. On microscopic examination, the central stellate scar is found to be associated with radiating fibrous septa that divide the hyperplastic nodules into smaller units.
The tumor is composed of multiple spherical aggregates of hepatocytes, which often contain increased amounts of fat (triglycerides) and glycogen. Proliferation of the biliary structures is marked; these structures are surrounded by inflammatory cells, primarily at the periphery of the fibrous septa. Bile duct structures show no connection to the biliary tree. Arteries in the fibrous septa have thick walls; this change is associated with intimal and medial fibromuscular hyperplasia of the larger arteries. Sinusoidal dilatation and, occasionally, hemorrhagic foci and areas of infarction are seen. Hemorrhage and infarction occur more frequently in women using contraceptive medications. Kupffer cells are usually present in the lesion; in fact, the concentration of Kupffer cells may be higher in the lesions than in normal liver tissue.
In a study correlating MRI results with pathologic findings, a central scar was seen in 30 of 38 lesions. In a large series of 130 patients with FNH, 84% were found to have a single nodule smaller than 5 cm in diameter; in 13% of patients, FNH nodules measuring 5-10 cm were found; in only 3% of patients was the lesion greater than 10 cm in diameter. Calcification is rare in patients with FNH, but it has been described.8
Frequency
United States
Focal nodular hyperplasia is the second most common benign hepatic tumor (after hemangioma); in an autopsy series, about 8% of primary hepatic tumors were found to be FPH.1
Mortality/Morbidity
- For patients with focal nodular hyperplasia, mortality and morbidity are related to hepatic surgery; surgery is occasionally performed in patients who are symptomatic or in patients for whom imaging findings are equivocal.
- The natural morbidity resulting from the lesions is low; to our knowledge, no deaths caused by FNH have been reported.
Sex
Focal nodular hyperplasia is found most commonly in women (80-95% of cases) who are in their third or fourth decade of life.7,9,10,11,12,13,14,15
Age
Focal nodular hyperplasia occurs most commonly in patients in the third or fourth decade of life.7,9,10,11,12,13,14,15 However, FNH may occur in childhood or late adulthood.
Presentation
In 50-80% of cases, focal nodular hyperplasia is detected as an incidental finding at autopsy, by laparotomy, or during radiologic investigation.7,9,13 The most common mode of discovery of FNH is as an incidental finding during ultrasonography (US) or computed tomography (CT). In symptomatic cases, patients most often complain of an abdominal mass (10-15% of all patients) or abdominal pain.7,9,13 The pain is usually caused by larger lesions, which stretch the liver capsule or have a mass effect on adjacent organs. Results of liver function tests are usually normal.
Patients using oral contraceptives are more likely to present with symptoms, because contraceptive use is often linked to tumor hemorrhage or infarction. The relationship between focal nodular hyperplasia (FNH) and the use of oral contraceptives, however, is often misunderstood; FNH itself is not caused by or even associated with the use of oral contraceptives.13,16,17 We believe that this misconception most likely arose because hepatocellular adenoma, a neoplasm that has been definitively related to the use of oral contraceptives, was mistakenly included in early series of FNH. On the other hand, however, oral contraceptives may promote the growth of FNH.1,16
Classification
Focal nodular hyperplasia is subdivided into 2 types: classic (80%) and nonclassic (20%).18 Nonclassic FNH is further divided into 3 subtypes: telangiectatic FNH, FNH with cytologic atypia, and mixed hyperplastic and adenomatous FNH. In classic FNH, all 3 characteristic features are present: abnormal nodular architecture, malformed vessels, and cholangiolar proliferation. In nonclassic FNH, 2 of the 3 characteristic features are present; bile duct proliferation is always present.18
Telangiectatic FNH shares several morphologic patterns with hepatocellular adenomas. Paradis et al conducted a study in which they attempted to reclassify telangiectatic FNH on the basis of molecular analysis.19 Their results showed that the molecular pattern seen in cses of telangiectatic FNH closely resembles that of hepatocellular adenomas. They suggested that telangiectatic FNH be referred to as telangiectatic hepatocellular adenoma.
Preferred Examination
Increasingly, focal nodular hyperplasia (FNH) is being recognized as an incidental finding, owing to the widespread use of diagnostic imaging for unrelated conditions. For imaging of the right upper quadrant, US is more widely used than other modalities; usually, US findings raise the possibility of FNH. US, particularly when combined with duplex Doppler US, may be the only type of imaging required. However, further confirmation may be required, particularly in patients in whom cancer is suspected at other sites. In this setting, CT, MRI, angiography, and radionuclide imaging may be used to increase diagnostic confidence.
Limitations of Techniques
The diagnosis of focal nodular hyperplasia (FNH) is made on the basis of the demonstration of a central scar; however, a typical central scar is not demonstrated in every patient. In as many as 20% of patients, a scar may not be visible. Moreover, a central scar may be found in some patients with fibrolamellar hepatocellular carcinoma, hepatic adenoma, or intrahepatic cholangiocarcinoma. This limitation applies to all cross-sectional imaging techniques, including US, CT, and MRI.
The detection of lesions by use of radionuclide scans with technetium-99m sulfur colloid depends on the concentration of Kupffer cells in the FNH. If the concentration of Kupffer cells is low, FNH may appear as a photon-deficient mass that is indistinguishable from other liver mass lesions. On angiograms, the characteristic spokelike appearance is demonstrated in only 33% patients; moreover, FNH may be avascular in 10% of patients.
The diagnosis of FNH is achieved by use of several complementary imaging techniques. In patients for whom the diagnosis is not clearly determined with imaging findings, open biopsy or surgical resection may be needed; findings on needle biopsy may substantially overlap with those of well-differentiated hepatocellular carcinoma.13,20,21,22,23
Differential Diagnoses
Cavernous Hemangioma, Liver
Cholangiocarcinoma
Hepatic Adenoma
Hepatocellular Carcinoma
Hepatocellular Carcinoma, Fibrolamellar
Liver, Metastases
Other Problems to Be Considered
Well-differentiated hepatocellular carcinoma
Giant cavernous hemangioma
Hypervascular liver metastases
Intrahepatic cholangiocarcinoma
More on Focal Nodular Hyperplasia |
 Overview: Focal Nodular Hyperplasia |
| Imaging: Focal Nodular Hyperplasia |
| Follow-up: Focal Nodular Hyperplasia |
| Multimedia: Focal Nodular Hyperplasia |
| References |
| Further Reading |
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References
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Further Reading
Guidelines and clinical studies:
Procedure guideline for hepatic and splenic imaging 3.0. Society of Nuclear Medicine, Inc. 1999 Feb (revised 2003 Jul 20). 5 pages. NGC:003579
ACR Appropriateness Criteria® liver lesion characterization. American College of Radiology. 1998 (revised 2006). 7 pages. NGC:005115
A Comparison of Contrast Enhanced Ultrasound (CEUS) and Contrast Enhanced Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) for Characterization of Focal Liver Masses
Keywords
focal nodular hyperplasia, FNH, liver tumors, hepatic tumors, Kupffer cells, Kupffer's hepatic central stellate scar
