Focal nodular hyperplasia

Focal nodular hyperplasia (FNH) is a regenerative mass lesion of the liver and the second most common benign liver lesion (most common is a haemangioma). Many FNHs have characteristic radiographic features on multimodality imaging, but some lesions may be atypical in appearance. FNHs are typically asymptomatic lesions, usually requiring no treatment. 

Epidemiology

FNH is most frequently found in young to middle-aged adults, with a strong female predilection ^3,4; ~15% (range 10-20%) occur in men ⁷. Although exogenous oestrogens do not cause FNH, they have been shown to increase the size of these masses ⁴. The isolated occurrence is the commonest but in up to 20% may be multiple and could occur with other lesions such as haemangiomas, etc. 

Clinical presentation

These masses are either found incidentally on imaging or present due to mass effect, with right upper quadrant pain in 20% ⁵. Unlike hepatic adenomas, FNHs are only rarely complicated by spontaneous rupture and haemorrhage ^1,4.

Associations

Association with other benign lesions is commonly seen (~25%) ⁸:

• hepatic haemangiomas (most common) ⁶
• hereditary haemorrhagic telangiectasia
• arteriovenous malformations (AVM)
• anomalous venous drainage
• hepatic adenoma (possible but not proven) ¹⁶
• congenital absence of portal vein/portal vein atresia
• Budd-Chiari syndrome
• portal shunts
• idiopathic portal hypertension
• portal or pulmonary hypertension ⁷

Pathology

The origin of FNH is thought to be due to a hyperplastic growth of normal hepatocytes with a malformed biliary draining system, possibly in response to a pre-existent arteriovenous malformation ^1,4. The arterial supply is derived from the hepatic artery whereas the venous drainage is into the hepatic veins. FNH does not have a portal venous supply ⁹.

FNH is divided into two types ⁴:

1. typical: 80%
2. atypical: 20%

Typical FNH

Macroscopically, typical lesions demonstrate a mass which is often quite large with well-circumscribed margins but poorly encapsulated. A characteristic feature is a prominent central scar with radiating fibrous septa, but this is present in less than 50% of cases ⁷. A large central artery is usually present with spoke-wheel like centrifugal flow ^3,4 (no portal veins).

Histologically the lesion is composed of abnormal nodular architecture, malformed vessels, and cholangiolar proliferation. Nearly normal hepatocytes are arranged in 1-2 cell-thick plates.  Bile ductules are usually found at the interface between hepatocytes and fibrous regions ^1,2. Kupffer cells are present ^4,7.

There is no malignant potential ¹.

Atypical FNH

An atypical FNH refers to a lesion which lacks the central scar and central artery, thus harder to distinguish from other lesions on gross inspection and imaging, or abnormal nodular architecture but with abnormal cholangiolar proliferation ⁴. 

Atypical features also include pseudocapsule, lesion heterogeneity (more commonly seen in adenoma), non-enhancement of the central scar and intralesional fat ⁶.

Nodules can grow and disappear, and new nodules can appear even after resection ⁷.

Variants

Some authors also describe division of atypical FNH into several variants which include ⁸:

• telangiectatic variant: most common
• mixed hyperplastic and adenomatous variant
• lesions with large cell hepatocellular atypia

Radiographic features

As FNH is usually treated conservatively, accurate imaging is essential in preventing unnecessary intervention. Moreover, in women of child-bearing age, hepatic adenoma is the chief differential diagnosis and biopsy of the latter can result in haemorrhage ^1,17.

It should be noted that up to 20% of patients with an FNH will have multiple lesions ⁴ and a further 23% will have haemangiomas ⁴. 

Ultrasound

The echogenicity of both FNH and its scar is variable, and it may be difficult to detect on ultrasound. Some lesions are well marginated and easily seen whereas others are isoechoic with surrounding liver. Detectable lesions characteristically will demonstrate a central scar with the displacement of peripheral vasculature on colour Doppler examination. However, these findings are seen in only 20% of cases ⁴. 

Contrast-enhanced ultrasound

• early arterial phase ¹⁴
  • FNH will enhance relative to background liver
  • typical FNA shows early arterial centrifugal filling
  • prominent feeding vessel may be seen
• portal venouslate arterial phase¹⁴
  • centrifugal filling (opposite to haemangioma and adenoma)
• portal venous phase ¹⁴
  • sustained enhancement in the portal venous phase (as opposed to adenoma)
  • unenhanced scar may be present

CT

A multi-phase liver CT is ideal ⁴. On the non-contrast series, the lesion is usually hypo- or isoattenuating but may appear hyperattenuating if the rest of the liver is fatty. A hypoattenuating central scar can be seen in up to 60% of lesions >3 cm in size ⁴.

FNH demonstrates bright homogeneous arterial contrast enhancement except for the central scar which remains hypoattenuating ⁴. Enlarged central arteries may be seen. 

In the portal venous phase, the lesion becomes hypo/isoattenuating to liver and poorly visualised in many studies. FNH is generally not associated with fat, calcification or haemorrhage. 

The fibrotic scar demonstrates enhancement on delayed scans in up to 80% of cases ⁴.

MRI

Liver MRI is both sensitive (70%) and specific (98%).

Signal characteristics

• T1
  • iso to moderately hypointense
  • hypointense central scar
• T2
  • iso to somewhat hyperintense
  • hyperintense central scar
• contrast studies
  • T1 C+ (Gd)
    • intense early arterial phase enhancement, similar to CT
    • isointense to liver on portal venous phase ^10-12
    • central fibrotic scar retains contrast on delayed scans ¹³
  • T1 C+ (Eovist/Primovist) 
    • early arterial enhancement
    • enhancement persists into delayed phases ¹¹ to a greater degree than the background liver due to the presence of normal hepatocytes and abnormal bile ductules
    • fades toward background liver intensity on the delayed hepatobiliary phase, with a small amount of enhancement remaining (cf. adenomas, which are classically hypointense relative to liver on hepatobiliary phase)
  • T2* C+ (reticuloendothelial agent: SPIO) 
    • hypointense mass as a result of susceptibility signal loss due to uptake by Kupffer cells

Nuclear medicine

Sulfur colloid is taken up by the reticuloendothelial system, specifically the Kupffer cells which line the hepatic sinusoids ¹⁸. Because FNH is essentially focally malformed hepatic tissue, these lesions contain functioning Kupffer cells and take up technetium (Tc) 99m sulfur colloid on nuclear imaging.

Classically, uptake pattern of Tc-99m sulfur colloid can be used to distinguish FNH from other liver lesions which do not contain normal liver cellularity, such as hepatic adenomas, HCC, and hepatic metastases. FNH is associated with normal or increased radiotracer uptake, whereas the others are associated with focal decreased uptake ⁴. Intense focal uptake is thought to be quite specific for FNH ¹⁹.

That being said, up to 30% of FNH lesions present with photopenia ¹⁹. Hepatic adenomas may rarely contain Kupffer cells and may be associated with normal uptake ¹⁹.

Treatment and prognosis

FNH is benign, with no malignant potential and a minuscule risk of complication (rupture, haemorrhage) and thus are usually treated conservatively ¹.

Differential diagnosis

General imaging differential considerations include:

• hepatic adenoma: usually more heterogeneous CT portal and delayed phases contrast washout; no gadoxetate retention on delayed phase MR and associated with fat, calcification or haemorrhage
• hepatocellular carcinoma (HCC): usually in cirrhosis; vascular invasion 
• fibrolamellar (FL) HCC
  • both FNH & FL-HCC commonly have a hypointense "central scar" representing fibrosis, so this feature is less useful for differentiation
  • FL-HCC tends to appear more distinct from adjacent liver parenchyma on pre-contrast T1 / T2 weighted imaging
  • often larger (>12 cm)
  • calcification (uncommon in FNH), corresponding to necrosis and foreign body type reaction histopathologically ²⁰
  • 70% present with metastases, or evidence of biliary, vascular, and nodal invasion
  • decreased activity on Tc-99m / sulfur colloid scan
• hypervascular hepatic metastases: usually multiple; CT portal and delayed phases hypodense (washout); older patients with known primary tumor
• hepatic haemangioma: peripheral and centripetal enhancement; blood vessels isodense; no central scar; only small ones with rapid enhancement simulate focal nodular hyperplasia (FNH)
• intrahepatic cholangiocarcinoma (hypoenhancing in earlier arterial/venous phases with delayed enhancement, dominant large central scar) ²¹

Practical points

• in the setting of cirrhotic liver, be wary of diagnosing a hypervascular lesion as an FNH unless you have definitely excluded HCC
• FNH typically has no capsule; if a hypervascular liver mass has a capsule, put HCC above FNH on the differential diagnosis
• there is likely overlap in appearance between FNH and inflammatory hepatic adenoma when using gadoxetic acid (Eovist/Primovist); if the patient has risk factors (e.g. metabolic syndrome), consider both in the differential diagnosis¹⁵