Focal nodular hyperplasia of the liver: an unusual association with diabetes mellitus in a child and review of literature

The focal nodular hyperplasia (FNH) first described by Edmondson in 1956, accounts for 8% of primary hepatic tumors in adults and less than 2% in children. Nonetheless, its evidence in pediatric population is increasing with more than eighty cases described in the last 5 years. The pathogenesis of FNH is largely unknown. Evidences of polyclonality in different DNA studies exclude a neoplastic nature of the lesion and further support the hypothesis of a possible reactive hyperplastic response of liver cells to local vessel abnormality. Chemotherapy and/or radiotherapy may be associated with development of FNH and, as clarified by a case-control study, also smoke may play a pathogenetic role [1]. The association with estroprogestinic therapies is still debated [2].

FNH is very rare in pediatric population with an age prevalence in children 7-8 years old, although some cases are diagnosed in early childhood or even in the prenatal period [3]. The female sex is predominant with a M/F ratio of less than 1/10 in one of the largest series [4]. The cause is unknown although the hypothesis that obstruction of hepatic vessels or abnormal vascularization could account for FNH is suggested by the reported association with clinical and anatomic findings like hypoplasia or agenesis of the portal vein, vascular malformations, hemangioma and vascular dysplasia, Budd-Chiari syndrome and hereditary hemorrhagic telangiectasia [5, 6]. Moreover, recent studies reported angiopoietin-1 (Ang-1) gene and angiopoietin-2 (Ang-2) involvement in the regulation of vasculogenesis in FNH, with Ang-1/Ang-2 ratio increase in FNH compared with normal liver and benign or malignant hepatocellular neoplasms [7]. Lastly, not only it is proved that FNH is more frequent in females and after oral contraceptive but also there are evidences that estrogens may induce hepatic angiogenesis in the rat [8]. All in all, it is possible to assume that pathogenetic mechanisms may be related to an hyperplastic response to hemodynamic disturbances due to local factors (eg, vascular abnormalities or local venous thrombosis with subsequent arteriovenous shunts) or systemic factors (eg, oral contraceptives and angiogenic molecules) [5]. As it is known that diabetes typically is a risk factor for arterial stiffening and vein thrombosis it is possible to speculate that the association of diabetes and FNH could be not completely incidental [9]. It is a bit intriguing to note that HNF1α, a tumour suppressor gene, whose abnormal expression could enhance tumorigenesis, is inactivated in 35-50% of all liver adenomas, which are, like FNH, much more frequent in women taking oral contraceptives: moreover germline mutation of HNF1α can be associated with maturity onset diabetes of the young 3 (MODY3). Taking together this data can resume a final model where anomalies in gluconeogenesis, glycolysis and lipogenesis (all typical of diabetes), female sex and oral contraceptives may contribute to hemodynamic anomalies and to the subsequent development of benign neoplasms like FNH and adenoma.

The majority (70-90%) of FNH at presentation is asymptomatic and the most common way that the disease is discovered is when, during an occasional physical examination, hepatomegaly or a palpatory abdominal mass are detected. More rarely the disease is diagnosed after the occurrence of abdominal pain, even though this event appears not exceptional in pediatric age. Almost ever the liver function tests are normal. The lesion is more often unique, but about 8% of cases may show multiple nodules, up to 30. The diameter of lesions is extremely variable, from less than 1 cm to more than 15 cm but usually is less than 5 cm.

Different histological variants of FNH are recognized: the classic, the most frequent and corresponding to the present case, the not classic, including FNH with cytologic atypia, and mixed hyperplastic and adenomatous FNH. The so-called telangiectatic FNH is now considered a variant of adenoma [14].

Classic FNH is characterized by hepatocellular trabeculae forming nodules separated by fibrous septae radiating from a central fibrous scar. The lesion is generally well circumscribed, without a capsule but surrounded by a rim of compressed parenchyma. The central scar may be absent or inconspicuous in many cases. The evidence of a typical vascular component is an important feature, probably related to the vascular malformative pathogenesis of the lesion.

Needle-biopsy or open air biopsy are necessary when the radiological investigations are doubtful, above all in case of absence of the central scar, and not rarely the differential diagnosis from other nodular lesions of liver may be difficult. The differential diagnosis includes different nodular lesions of the liver.

Nodular regenerative hyperplasia (NRH) is a disease characterized by multiple nodules composed by hepatocytes, without a fibrous tissue or central scar [15]. It is often associated to patients suffering of inflammatory bowel disease treated with thioguanine or azathioprine or systemic diseases, above all connective tissue diseases, such as LES, Polyarteritis nodosa, Antiphospholipid Syndrome, Rheumatoid Arthritis or Felty's Syndrome. The rare pediatric cases are mostly in association with the congenital absence of portal vein (sometimes complicated by heart disease or multicystic kidney dysplasia). CT presentation is really different from FNH, as there are multiple hypodense lesions with poor or absent enhancement after contrast administration [15].

The typical imaging showing anechogenic and regular profile of the mass at ultrasound, easily recognize cystic lesions: however CT and MRI may be necessary in selected cases.

In haemangiomas a doppler ultrasound test is diagnostic almost ever. At CT scan the contrast enhancement proceeds typically from center to periphery. Nonetheless in adults and, exceptionally, in children, it is possible to have a concomitance of FNH and haemangioma.

Radiological findings play a key role also in the diagnosis of Adenoma (HCA). At ultrasound there is not the central scar and the doppler effect is predominantly venous type with either continuous or pulsatile peripheral flow: typically absent is the portal venous enhancement at the contrast enhanced ultrasound. MRI and CT may also highlight spots of hemorrhage and necrosis. The differential diagnosis is crucial, because the adenoma is at risk of breaking, haemorrhage, and malignant transformation. Surprisingly there are uncommon cases of simultaneous detection of adenoma and FNH. Moreover, the ductular proliferation may be minimal in some FNH at histological examination, making the differential diagnosis difficult [14].

Hepatoblastoma, the most frequent liver tumor in childhood, is almost always associated to α-fetoprotein (α-FP) increase and there is not the central scar at CT scan. Similarly to what happen in adenoma, there are exceptional cases of concomitant presence of hepatoblastoma and FNH. The hepatocellular carcinoma, exceptional in pediatric population and often associated with α-FP increase, at the CT scan shows an hypodense lesion with a less prompt contrast enhancement than FNH and, at MRI, an heterogeneous initial enhancement after contrast injection.

The natural evolution of FNH is unpredictable even if the mass, in about 2/3 of cases, remains stable and in about 1/3-1/4 of cases shows a gradual spontaneous improvement as far as a complete remission; it is rare an increase in number as well as in size [9].

The recent studies in molecular biology have confirmed that FNH is not a pre-neoplastic lesion: the tissue parenchimal organization is pretty the same of usual liver tissue and, moreover, even though in some cases a clonal origin of FNH nodules have been demonstrated, until now no somatic mutation in the β-catenin gene or in the other genes implicated in the hepatocellular adenoma (where a malignant transformation is possible) have been discovered [5, 16]. Moreover the gene expression profile in FNH shows an activation in β-catenin pathway limited to the enlarged perivenous areas and completely different with respect to the other hepatocellular benign lesions [17].

About the management the first step is, of course, the stop of oral contraceptive. Considering the body of evidence that FNH doesn't undergo malignant transformation and that there are only sporadic cases followed by spontaneous rupture and consequent abdominal bleeding, we agree with the opinion that in asymptomatic cases it is opportune a careful follow-up with an ultrasound scan every 6-12 months, and that elective surgery has probably to be limited to the patients suffering of abdominal pain or with a voluminous or growing mass [5]. It is worth to note that recurrences are very rare after surgical removal. When surgical resection is impossible due to patient factors or location and size of the tumor, selective arterial embolization should be considered. Finally it is possible that novel drugs or other radiological therapies like radio frequency ablation will be available in the future.

We think that reporting children with FNH may be helpful to provide to clinicians data useful for the differential diagnosis process and for the therapeutic decisions: remarkably this is the sixth case of FNH associated to diabetes, the first, at our knowledge, in a child.

Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.