Focal Nodular Hyperplasia and Hepatic Adenoma: Epidemiology and Pathology

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Focal nodular hyperplasia (FNH) and hepatic adenoma (HA) represent the most frequent non-vascular benign liver tumors. They are often asymptomatic. The widespread use of high-resolution imaging modalities leads to an increase of incidental detection of FNH and HA. Physicians are thus increasingly confronted with these formerly rarely recognized conditions, stressing the need for concise but adequate information on the optimal clinical strategies for these patients. FNH is the most common non-vascular benign tumor of the liver. It probably arises as a polyclonal, hyperplastic response to a locally disturbed blood flow. It is typically found in asymptomatic women. Histologically, FNH can be described as a focal form of cirrhosis. Complications of FNH are extremely rare and surgical resection is generally not advised. HA is a rare monoclonal, but benign liver tumor primarily found in young females using estrogen-containing contraceptives. Although its exact etiology is unknown, a direct link between sex steroid exposure and the uncontrolled hepatocellular growth is suspected. Complications of HA are spontaneous bleeding and malignant transformation. Withdrawal of estrogen treatment and excision of large tumors Published online: April 1, 2010 Prof. Dr. Ulrich Beuers Department of Gastroenterology and Hepatology, G4-213 Academic Medical Center, University of Amsterdam PO Box 22700, NL–1100 DE Amsterdam (The Netherlands) Tel. +31 20 56 62 422, Fax +31 20 69 17 033, E-Mail u.h.beuers @ amc.uva.nl © 2010 S. Karger AG, Basel 0253–4886/10/0271–0024$26.00/0 Accessible online at: www.karger.com/dsu D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 12 :4 8: 05 A M Focal Nodular Hyperplasia and Hepatic Adenoma Dig Surg 2010;27:24–31 25 nosed by pathological evaluation. On rare occasions even then a diagnosis cannot be made with certainty. This paper focuses on the differences and shared properties of focal nodular hyperplasia (FNH) and hepatic adenoma (HA) ( table 1 ). Focal Nodular Hyperplasia The exact etiology of FNH is still incompletely understood. FNH generally does not cause complaints or require treatment, but an adequate evaluation of the lesion is indicated to discriminate it from other focal abnormalities in the liver. Pathophysiology FNH most probably arises as a reaction to local hemodynamic instability in the liver. The generally accepted theory on the genesis of FNH lesions is that arterial malformations disturb the local blood flow, thus causing a hyperplastic response of normal liver cells to either hyperperfusion or hypoxia [1] . As a hyperplastic adaptation is still responsive to growth control mechanisms, FNH is considered to be a truly benign condition and not expected to cause spontaneous bleeding complications or to undergo malignant transformation [2] . The notion that FNH lesions develop secondary to vascular abnormalities is supported by several observations. In some adults, the liver contains both hemangiomas and FNH. A study among 247 patients with hepatic masses identified 148 patients with FNH, of which 20% had concomitant hemangiomas of the liver, while in only 9% of patients with non-FNH lesions additional hemangiomas were identified [3] . Another indication is the differential prevalence of FNH in families with hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant genetic disorder characterized by vascular malformations. In a study of 275 family members, FNH was found in 5 persons, all affected with HHT, bringing the prevalence among this group of HHT patients to 2.9% [4] . Table 1. Epidemiology and pathology of focal nodular hyperplasia and hepatic adenoma Focal nodular hyperplasia Hepatic adenoma Typical patient All ages 2nd to 5th decade Gender bias Female > male Nearly exclusively female Prevalence >18 years 4–30/1,000 Unreliable data, very low Prevalence <18 years 0.2/1,000 Unreliable data, very low Clinical presentation Asymptomatic Abdominal pain or asymptomatic Laboratory Normal or non-remarkable Normal AFP Normal or non-remarkable Normal AFP Imaging Spokes of wheel vascular pattern Circular vascular pattern around lesion Pathological mechanism Hyperplastic reaction to vascular abnormality Uncontrolled growth Possibly estrogen-induced Histopathological features Central scar Ductular reaction Fibrosis Liver cell plates No bile ducts (with the exception of ‘inflammatory type’) No fibrosis Mutation analysis Polyclonal Monoclonal Gene expression -Catenin pathway activation Ang-1/Ang-2 mRNA ratio elevated HNF-1 inactivation -Catenin pathway activation Ang-1/Ang-2 mRNA ratio normal Complications None Bleeding Hepatocellular carcinoma Treatment of choice Classic FNH: expectative Diagnosis doubtful: consider excision Withdrawal of estrogen treatment Excision/partial liver resection D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 12 :4 8: 05 A M Maillette de Buy Wenniger/Terpstra/ Beuers Dig Surg 2010;27:24–31 26 The putative role of vascular disturbances in the genesis of FNH is also supported by the observation of FNH-like lesions in patients with cirrhosis. In explanted livers of 130 cirrhotic patients, the presence of esophageal varices was significantly associated with the presence of FNHlike nodules, suggesting a contribution of portal hypertension to the formation of nodular hyperplastic lesions [5] . FNH lesions appear also to be associated with vascular malformations elsewhere, such as hemangioma and vascular malformation of the brainstem [1] . Recently, anecdotal evidence was published on the proposed sequence from hemangioma to FNH, probably starting with thrombosis of the hemangioma followed by involution of the lesion and subsequent occurrence of a hyperplastic regenerative reaction. A child that was analyzed at the age of 6 months for a palpable hemangioma of the liver presented 5 years later with a lesion of unknown origin in the same topographic area of the organ. Surgical excision and pathological examination revealed an FNH [6] . Patients treated for childhood malignancy in the past may be at particular risk for FNH. In a prospective cohort of 138 patients that received a hematopoietic stem cell graft at an age below 18 years, 17 FNH cases were identified, a median 6.4 years after the transplantation [7] . A French survey of 3,098 cases treated for any pediatric malignancy yielded 14 cases of FNH, a prevalence of 0.45%, which is still significantly higher than the previously reported prevalence rates in children [8] . Clinical Presentation and Diagnosis Typically, FNH is an incidental finding in symptomfree patients. Abnormal serum liver tests provoking further diagnostic measures are reported in 12–13%. Levels of -fetoprotein are within the normal range. Other symptoms are rare: palpable abdominal mass is found in 2–4% of patients, hepatomegaly and fever are observed in ! 1% of cases [9, 10] . MRI shows the highest sensitivity ( 70%) and specificity (98–100%) for FNH, and as the majority of patients are women of childbearing potential, it is preferred to CT to avoid radiation exposure [11] . MRI reliably allows for discrimination between FNH and other focal liver lesions in most cases [12] . The imaging of FNH is discussed extensively by Van den Esschert et al. elsewhere in this edition [13] . Contrast-enhanced ultrasonography appears to be a valuable addition to the diagnostic toolbox, but its application is still limited to specialized centers [14, 15] . In young patients without any clinical or serological indications of hepatic disease, a liver biopsy is only done when imaging yields inconclusive results [16] . FNH is a truly benign condition, which justifies a conservative clinical approach. In symptomatic cases, resection of the lesion can be considered via open or laparoscopic surgery [17, 18] . Prevalence FNH is the second most common benign hepatic tumor in adults, and third most common of all pediatric liver tumors. Epidemiological data on FNH are scarce. The few studies that report incidence and prevalence of FNH are not free of selection bias, stressing the need for additional high-quality multicenter studies. In adults, FNH accounts for approximately 8% of all primary liver tumors, and is only outnumbered as a benign liver neoplasm by hepatic hemangioma. FNH is between 3 and 10 times more common than HA [19, 20] . Its prevalence is reported between 0.4 and 3% of the general adult population and thought to increase with age, but these numbers are based on studies with 95 and 2,500 autopsies evaluated, respectively [1, 3, 19, 21] . In children and adolescents under 18 years of age, FNH accounts for 2% of all primary liver tumors, but again reports are limited. With an estimated rate of 2.25 per million children, the incidence of pediatric hepatic tumors is thought to be only a fraction of the numbers in the adult population [22] . A French group reported a prevalence of 0.02% in the general pediatric population based on the evaluation of 11,000 abdominal ultrasound examinations performed for other reasons, suggesting that actual prevalence may be higher [8] . FNH is the third most common benign hepatic neoplasm in children after hemangioma (14% of all liver tumors) and mesenchymal hamartoma (6%). HA accounts for another 2%, and liver teratoma forms ! 1% of all juvenile hepatic tumors [23] . The prevalence of FNH is higher in females, but the reported rates vary enormously. The female to male ratio of FNH is approximately 13–15: 1 based on non-epidemiological studies, but ratios between 2 and 26: 1 have been reported [3, 24, 25] . This makes FNH typically a condition found in females. In most adult patients, imaging studies reveal solitary lesions, predominantly of the right lobe, while in approximately 20%, 2–5 nodules are shown. Multiple nodular lesions (15–30) are present in only 3% of cases [3, 24] . Imaging may not reveal all microscopic lesions that can be found in histology though, indicating that these numbers may be an underestimation. Pathology of Focal Nodular Hyperplasia FNH can be divided into either classical ( 70–80%) or non-classical (the remainder) lesions. Classical FNH is D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 12 :4 8: 05 A M Focal Nodular Hyperplasia and Hepatic Adenoma Dig Surg 2010;27:24–31 27 characterized by abnormal nodular architecture, malformed vessels and a proliferation of the small bile ducts ( fig. 1 a, b). This last property is by definition also found in non-classical FNH, but either of the other characteristics is absent or atypical, or cannot be confirmed with certainty. The non-classical group encompasses FNH with cytological atypia and the mixed hyperplastic and adenomatous FNH. Telangiectatic FNH used to be considered a non-classical form of FNH, but this ill-defined group is now considered a form of HA [26, 27] . Macroscopically, FNH resembles an aggregation of nodules of organized connective tissue and liver parenchyma, often with a lighter coloration than the surrounding normal liver tissue. The normal architecture is disturbed, with a disappearance of the normal regularity of portal areas and central veins. There is no surrounding capsule. Centrally in the lesion, a scar can often be recognized, from which fibrous septa with abnormal vasculature radiate towards the periphery of the lesion, but this cannot always be visualized prior to resection. In contrast to the situation in HA, the afferent artery supplies the cluster of vessels of various caliber from the central scar outwards, including tortuous arteries, capillaries, vascular channels of undetermined type and eventually the veins, a configuration that in some cases can be nicely seen using contrast ultrasound or CT [12] . Microscopically, the abnormalities can most adequately be summarized as ‘focal cirrhosis’: in the abnormal tissue there is a lymphoid and ductular reaction, the interlobular bile ducts have vanished, fibrous bands can be found and there is pronounced nodularity [27] . The nodular hyperplastic parenchyma is completely or incompletely surrounded by fibrous septa, and there can be an augmentation of the thickness of the hepatic plates to two or three cell rows, but the hepatocytes retain their normal phenotype [12] . Molecular Pathology Paradis et al. [28, 29] concluded from their analyses that FNH lesions arise by polyclonal cell proliferation, unlike HA which is characterized by monoclonal expansion. Loss of heterozygosity was not found in FNH, and mutation analysis for the p53 gene and genes of the Wnt signaling pathway did not reveal any evidence for involvement of somatic mutations in the genesis of FNH [30] . This polyclonal origin further proves the benign nature of FNH and supports the strategy not to treat FNH in asymptomatic cases. Gene expression data reveal an activation of the  catenin pathway in FNH.  -Catenin is regarded as a pivotal stimulus for proliferation of hepatocytes, liver development and liver regeneration after injury. In FNH,  catenin shows a heterogeneous distribution along the hepatocellular nodules in the absence of an activating mutation and in the absence of alterations in the Wnt signaling pathway [31] . Angiopoietins are regulatory molecules that control vascularization. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are regarded as counteracting molecules: while Ang-1 contributes to stabilization of vessel structures, Ang-2 is overexpressed at sites of vessel remodeling. A marked upregulation of Ang-1 and downregulation of Ang-2 was observed in FNH tissue [32] . The increased Ang-1/Ang-2 expression ratio could add to the a b Fig. 1. a , b FNH in a 47-year-old woman with prominent nodularity, fibrous bands containing tortuous arterial and venous vessels, and extensive lymphoid and ductular reaction. Co lo r v er si on a va ila bl e on lin e D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 12 :4 8: 05 A M Maillette de Buy Wenniger/Terpstra/ Beuers Dig Surg 2010;27:24–31 28 formation of dystrophic vessels with thickened walls that are characteristic of FNH. A mouse model overexpressing the murine homolog of Ang-1, ANGPT1, shows abnormal and tortuous vessels resembling vascular alterations observed in FNH [32] , but appears otherwise inappropriate as a model system for FNH [33] . In summary, FNH is considered a benign tumor of the liver, which probably arises in reaction to a real or erroneously perceived change in the local hemodynamic stability. Histologically, it can be described as a local form of cirrhosis, featuring fibrous septa, malformed vessels, and ductular proliferation. Asymptomatic cases should not be treated, while in symptomatic patients therapeutic actions should be carefully balanced against the expected gains and possible risks of treatment.

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تاریخ انتشار 2010