Tumors In The Liver - Diagnostic Problems
Case 1 -
Focal Nodular Hyperplasia (FNH)
Linda D. Ferrell, M.D.
Wendy L. Frankel, M.D.
Clinical history and operative findings:
41 year old man who was
undergoing a total proctocolectomy for rectal cancer was found at surgery to have a liver mass. The mass
measured 6 cm and was nodular. The surrounding liver was unremarkable.
Case 1 - Figure 1 - Nodular liver parenchyma with central scar (arrow), low power
Case 1 - Figure 2 - Large irregular vessel in an area of fibrosis, medium power
Case 1 - Figure 3 - Bands of fibrosis with chronic inflammation and proliferationg bile ductules (arrows), medium power
The cut surface of the lesion was nodular and tan.
The lesion was not encapsulated but was well demarcated from the surrounding liver. Sections show
nodular parenchyma with bands of fibrosis. No significant hepatocellular atypia is seen. The fibrotic
areas contain chronic inflammation and proliferating bile ductules at the interface.
Diagnosis- FOCAL NODULAR HYPERPLASIA (FNH)
Clinical features. Focal nodular hyperplasia (FNH) is a benign, nonneoplastic
lesion, which is most commonly seen in young women. A significant number of these lesions can still be
seen in men. FNHs are usually solitary lesions, but can be multifocal in a 20-30% of the cases. Classic
FNH often is noted as an incidental finding, but may also present with complications due to large size
(only rarely due to hemorrhage or with complaints of upper abdominal pain). Nodules similar to FNH have
been described adjacent to hemangiomas. Some patients with the so-called multiple FNH syndrome have at
least two FNH lesions associated with one or more lesions such as hepatic hemangioma, arterial structural
defects, vascular malformations, meningioma, and astrocytoma. A rare variant of FNH, the telangiectatic
type, is commonly associated with the multiple FNH syndrome.
Pathogenetic features. FNH is not thought to develop due to the use of oral
contraceptives, but many speculate that this lesion may increase in size with their use or regress with
their cessation. The currently favored hypothesis for the development of FNH is that it represents a
hyperplastic and altered growth response to changes in bloodflow in the parenchyma surrounding a
preexisting arterial malformation. The presence of numerous abnormal muscular vessels within the lesion
and the fact that some of these lesions or similar hyperplastic foci have been noted in association with
hemangiomas and the Budd-Chiari syndrome lend support to this theory. (The International Working Party
has recommended that FNH-like lesions associated with the Budd-Chiari syndrome and Osler-Weber-Rendu
disease not be designated as FNH, but rather referred to as regenerative nodule). FNH has no known
malignant potential and, in spite of its rare association with fibrolamellar hepatocellular carcinoma,
most feel that the lesion itself does not progress to carcinoma. Instead, it is speculated that the
association of FNH with fibrolamellar hepatocellular carcinoma may represent a hyperplastic response in
the adjacent parenchyma to the increased vascularity of the carcinoma. Some have proposed that FNH may
have clonal features to the nodules, but this is still controversial.
Gross features. FNH has a nodular appearance (which can suggest the appearance of
macronodular cirrhosis), and tends to be lighter brown than the adjacent liver. These lesions are often
located near the capsule of the liver, which can cause the surface of the liver to have a nodular
appearance mimicking cirrhosis, and occasionally, the lesions can be pedunculated. The edges of FNH
appear demarcated from the adjacent normal parenchyma because of the nodularity, but no fibrous capsule
is present. The lesions may vary considerably in size. Most of these lesions have a "central fibrous
scar," which consists of fibrovascular tissue (usually not dense scar tissue), but this central focus of
connective tissue may be absent. A rare variant of this lesion, the telangiectatic type, does not have
the central fibrous zone, but rather has a gross appearance of either the hepatic adenoma or a vascular
lesion such as hemangioma or peliosis hepatis.
Microscopic features. The classic type of FNH is composed of mostly
normal-appearing hepatocytes arranged in incomplete nodules that are partially separated by fibrous
tissue, which tends to extend from the central fibrous zone when it is present. An important feature is
the variable numbers of bile ductular structures present within the fibrous stroma and at the edge of the
nodules. The cell plate architecture with an intact reticulin framework is similar to that in normal
liver, but the cell plates are usually wider (2-3 cells thick) as in a regenerative nodule. The
hepatocytes in the lesion can demonstrate increased glycogen in the cytoplasm, as well as other findings
such as focal fatty change, bile stasis, lipofuscin, iron pigment, copper-associated protein, and Mallory
bodies. Some foci of atypical hepatocytes with larger nuclei and mild hyperchromasia, with or without
conspicuous nucleoli, can be present. Another important diagnostic feature is the presence of medium to
large, thick-walled muscular vessels, which often exhibit myointimal myxoid or fibromuscular hyperplastic
changes. These vessels are not a component of a portal tract as there is no large duct of similar
caliber or portal vein associated with them. In fact, usually no normal portal tracts are present within
the lesion, although a bile duct of intermediate or large caliber can be found in the central fibrous
zone in rare cases. Sinusoids can be somewhat dilated, and Kupffer cells can be present. Inflammatory
cell infiltrates are relatively common, and generally consist of lymphocytes, although neutrophils and
eosinophils can be noted, especially around the bile ductular structures. Rarely, granulomas may be
The telangiectatic variant contains dilated blood-filled vascular spaces instead of a
central fibrous zone, so the gross appearance may be more typical of adenoma, hemangioma or peliosis
hepatitis. The arteries in this variant are smaller and more numerous than in typical FNH, and the
fibrous septa are less prominent.
Other, relatively rare, nonclassical forms can be present, including forms that lack the
central fibrous zone, with the macroscopic and microscopic appearance mimicking adenoma and the
telangiectatic form. The thick walled vessels are present at least in part of these lesions, and bile
ductular proliferation is always present, although this latter feature may be very focal and subtle.
Special studies. FNH will stain positively for the usual hepatocellular markers
including the cytokeratin marker CAM5.2 and the canalicular marker polyclonal CEA. In addition, CD34
will often be positive on the endothelial cells lining the cell plates, so this marker cannot be used to
distinguish this lesion from adenoma or hepatocellular carcinoma (HCC). Alpha-fetoprotein is also
negative in these lesions.
Differential diagnosis. FNH resembles hepatic adenoma or normal liver on small
biopsy samples. One of the most important distinguishing feature for FNH are the bile ductular
structures (see Table 2). Due to the relative paucity of the bile ductular findings, a large sample of
core needle biopsy or a wedge biopsy is likely to be necessary to make this diagnosis. The finding of
the large vessels with abnormal hyperplastic features surrounded by connective tissue may also be very
helpful, as the larger vessels in adenoma tend to have a more normal configuration and lack significant
perivascular connective tissue stroma.
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