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 Pathologic findings: 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) Comment 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 seen. 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. References Ferrell L: Hepatocellular carcinoma arising in a focus of multilobular adenoma. American Journal of Surgical Pathology 17:525-529, 1993. Hytiroglou P, Theise N: Differential diagnosis of hepatocellular nodular lesions. Sem Diag Pathol 15:285-299, 1998. Ishak K, Rabin L: Benign tumors of the liver. Medical Clinics of North America 59:995-1013, 1975. Kong C, Appenzeller M, Ferrell L: Utility of CD34 reactivity in evaluating focal nodular hepatocellular lesions sampled by fine needle aspiration biopsy. Acta Cytologica 44:218-222, 2000. Nguyen B, Flejou J, Terris B, et al: Focal nodular hyperplasia of the liver: A comprehensive pathologic study of 305 lesions and recognition of new histologic forms. 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