Focal nodular hyperplasia

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

Epidemiology

Focal nodular hyperplasia is most frequently found in young to middle-aged adults, with a strong female predilection ^3,4. Around 15% (range 10-20%) of cases occur in men ⁷. Exogenous oestrogens do not cause focal nodular hyperplasia, nor do they cause an increase in size of these masses. Isolated occurrence is the most common but up to 20% of cases may be multiple and can occur with other lesions such as haemangiomas, etc. 

Recent studies have shown that focal nodular hyperplasia can occur de novo after chemotherapy treatment with oxaliplatin (chemotherapy agent used for bowel and other types of cancer) ²². 

Associations

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

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

Clinical presentation

Focal nodular hyperplasias are either found incidentally on imaging or present due to mass effect, with right upper quadrant pain in 20% ⁵. Unlike hepatic adenomas, complication by spontaneous rupture and haemorrhage is rare ^1,4.

Pathology

The origin of focal nodular hyperplasia is thought to be due to a hyperplastic growth of normal hepatocytes with a malformed biliary drainage 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. Focal nodular hyperplasia does not have a portal venous supply ⁹.

Focal nodular hyperplasia is divided into two types ⁴:

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

Typical focal nodular hyperplasia

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. Portal veins are absent.

Microscopically, the lesion is composed of abnormal nodular architecture, malformed vessels, and cholangiolar proliferation. Nearly normal hepatocytes are arranged in one to two 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 focal nodular hyperplasia

An atypical focal nodular hyperplasia refers to a lesion which lacks the central scar and central artery (making it harder to distinguish from other lesions on gross inspection and imaging), or which demonstrates abnormal nodular architecture and abnormal cholangiolar proliferation ⁴. 

Atypical features also include a 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 focal nodular hyperplasia into several variants which include ⁸:

• telangiectatic variant (also known as an inflammatory hepatic adenoma): most common
• mixed hyperplastic and adenomatous variant
• lesions with large cell hepatocellular atypia

Radiographic features

As focal nodular hyperplasia is usually treated conservatively, accurate imaging is essential in preventing unnecessary intervention. Moreover, in women of childbearing 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 a focal nodular hyperplasia will have multiple lesions ⁴ and a further 23% will have haemangiomas ⁴. 

Ultrasound

The echogenicity of both focal nodular hyperplasia 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 demonstrate a central scar with 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
  • focal nodular hyperplasia will enhance relative to background liver
  • typical focal nodular hyperplasia shows early arterial centrifugal filling (from the centre outwards)
  • prominent feeding vessel may be seen
• late arterial phase
  • 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 multiphase 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.

Focal nodular hyperplasia 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. Focal nodular hyperplasia 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%).

• T1
  • iso to moderately hypointense
  • hypointense central scar
• T2
  • iso to somewhat hyperintense
  • hyperintense central scar
• T1 C+ (Gd)
  • central fibrotic scar retains contrast on delayed scans ¹³
  • isointense to liver on portal venous phase ^10-12
  • intense early arterial phase enhancement, similar to CT
• 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)
  • central fibrotic scar typically does not enhance on hepatobiliary phase
• T2* C+ (SPIO) 
  • hypointense mass as a result of susceptibility signal loss due to uptake by Kupffer cells (cf. adenomas, which show a lower signal loss because of uptake by fewer Kupffer cells) ²⁴

Nuclear medicine

Two radiopharmaceuticals can be used to image focal nodular hyperplasia: Tc-99m sulfur colloid and Tc-99m HIDA.

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

Classically, uptake pattern of Tc-99m sulfur colloid can be used to distinguish focal nodular hyperplasia from other liver lesions which do not contain normal liver cellularity, such as hepatic adenomas, hepatocellular carcinoma, and hepatic metastases. Focal nodular hyperplasia 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 focal nodular hyperplasia ¹⁹.

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

HIDA radiopharmaceuticals are taken up and excreted by hepatocytes in a similar way to bilirubin and bile. Since focal nodular hyperplasia contains all hepatic cell types (including hepatocytes and bile canaliculi) HIDA can be used to image focal nodular hyperplasia. Limited evidence suggests that HIDA scans might be more accurate than the more traditionally used sulfur colloid scan.

The usual HIDA scan findings consistent with focal nodular hyperplasia are increased blood flow, prompt hepatic uptake and delayed tracer clearance from the lesion. This pattern is reportedly seen in more than 90% of patients ²³.

Treatment and prognosis

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

History and etymology

The term focal nodular hyperplasia was used initially by the American pathologist Hugh A Edmondson, in 1958 ¹³.

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) hepatocellular carcinoma
  • both focal nodular hyperplasia and fibrolamellar hepatocellular carcinoma commonly have a hypointense "central scar" representing fibrosis, so this feature is less useful for differentiation
  • fibrolamellar hepatocellular carcinoma tends to appear more distinct from adjacent liver parenchyma on pre-contrast T1 / T2-weighted imaging
  • often larger (>12 cm)
  • calcification (uncommon in focal nodular hyperplasia), 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 tumour
• hepatic haemangioma: peripheral and centripetal enhancement; blood vessels isodense; no central scar; only small ones with rapid enhancement simulate focal nodular hyperplasia
• 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 a focal nodular hyperplasia unless you have definitely excluded hepatocellular carcinoma
• focal nodular hyperplasia typically has no capsule; if a hypervascular liver mass has a capsule, put hepatocellular carcinoma above focal nodular hyperplasia on the differential diagnosis
• there is likely overlap in appearance between focal nodular hyperplasia and inflammatory hepatic adenoma when using gadoxetate sodium (Eovist/Primovist); if the patient has risk factors (e.g. metabolic syndrome), consider both in the differential diagnosis ¹⁵