Discussion
Our case illustrated an exceptional benign tumor in male gender referred as unclassified hepatocellular adenoma [1]. It demonstrated four particularities. Firstly, no risk factors were reported for this young man. Secondly, the diagnosis was challenging requiring percutaneous biopsy since radiological features weren’t able to differentiate this tumor from other liver tumors in one hand and from the other hepatocellular adenoma subtypes. Thirdly, MRI didn’t diagnose all the present lesions leading to per-operative strategy modification and a challenging postoperative surveillance. Lastly, surgical indication was the bleeding complication for the exophytic lesion as well as the malignant transformation risk due to male gender, exophytic growth, and size of the largest tumor above 5 cm.
Unclassified hepatocellular adenoma accounted for 5 to 10% of all hepatocellular adenomas [3,4]. It occurred in non-cirrhotic livers [5]. As in our case, non-specific abdominal pain constituted a revealing circumstance [5]. Elsewhere, clinical manifestations varied from the absence of clinical signs in 50% cases to acute symptoms due to tumor rupture or bleeding [5,6].
Unclassified hepatocellular adenoma was characterized by the absence of mutations and specific mRNA as molecular definition which translated into the absence of risk factors, specific clinical manifestations, histopathological aspects, and immune staining [4,7]. Thus, it is still a diagnosis by exclusion. Unlike women in whom oral contraceptives where incriminated for the development of hepatocellular adenomas, in men several factors where reported: metabolic syndrome, glycogen storage disease type 1a, familial adenomatous polyposis, and exposure to androgens [8]. These factors varied according to hepatocellular adenoma subtypes. In fact, female gender, obesity, diabetes mellitus, and hepatic steatosis were encountered in inflammatory hepatocellular adenoma representing 40-50% cases [4]. Female gender with oral contraceptives intake were associated to hepatocyte nuclear factor-1-alpha-mutated hepatocellular adenoma [4]. This subtype accounted for 30-40% cases [4]. In regards to ß-catenin-mutated hepatocellular adenoma and unclassified hepatocellular adenoma, male gender constituted a predictive factor [4]. It was associated to glycogen storage disease, androgen use, and familial adenomatous polyposis for ß-catenin-mutated hepatocellular adenoma encountered in 10-20% cases [4].
Unclassified hepatocellular adenoma ethiopathogeny is still not well understood [4,7] while it was well established for the other subtypes: IL6/JAK/STAT pathway activating mutations, inactive biallelic mutations of hepatocyte nuclear factor 1α, and β-catenin mutations for inflammatory hepatocellular adenoma, hepatocyte nuclear factor-1-alpha-mutated hepatocellular adenoma, and ß-catenin-mutated hepatocellular adenoma respectively [9]. More recent subtypes were described: β-catenin-mutated hepatocellular adenoma exon 3, β-catenin-mutated hepatocellular adenoma exon 7-8, and sonic hedgehog-activated tumor. Hence, six subgroups have been determined so far and counting [10]. The latter constituted 5% of hepatic adenomas and 50% of unclassified subtype [11]. It was characterized by somatic fusion of inhibin beta E subunit and GLI1 responsible for GLI1 overexpression [11].
These mutations translated into radiological and histopathological features allowing in one hand the differentiation of hepatic adenoma from other liver tumors and in the other hand to distinguish between the hepatic adenoma subtypes. Since the risk of complications and malignant transformation depended on the subtype of hepatocellular adenoma and guided the treatment modalities, reliable radiological features were needed. Magnetic resonance imaging with hepatobiliary contrast constituted the most sensitive radiological tool [12]. Hyperintensity on T2-weighted images associated with atoll sign was in favor of inflammatory hepatocellular adenoma with an area under the curve, a sensitivity, and a specificity of 0.953, 85-88%, and 88-100% respectively [13]. Intra-tumoral fat was observed in 17% cases [14]. It was focally distributed versus a diffuse distribution for hepatocyte nuclear factor-1-alpha-mutated hepatocellular adenoma [14] as well as hypointensity associated to steatosis with an area under the curve of 0,957 [14]. Hyperintensity along with central scar was in favor of ß-catenin-mutated hepatocellular adenoma with an area under the curve of 0,903 [14]. In front of doubtful diagnosis, percutaneous biopsy may be useful as in our case [15]. In disagreement with the literature, magnetic resonance imaging was unable to bring out numerous superficial lesions in the right hepatic lobe for our case may be secondary to the superficial localization and the small size. This multifocality was reported in 20 to 50% cases [11].
The described radiological features corresponded to histopathological characteristics allowing to differentiate between the subtypes. For the unclassified subtype, no clear histological and immunohistochemical staining were observed [16] while the overexpression of serum amyloid A, the lack of liver fatty acid-binding protein, and C-reactive protein, as well as the diffuse glutamine synthetase and nuclear β-catenin expressions were in favor of inflammatory hepatocellular adenoma, hepatocyte nuclear factor-1-alpha-mutated hepatocellular adenoma, and ß-catenin-mutated hepatocellular adenoma respectively [9]. Other markers may be needed in order to define a new subgroup arising from this still unclassified as the case reported with histological brown pigment deposition [16].
The high risk of malignant transformation especially in male gender led to proposing liver resection: 47% in male gender versus 4% in female gender [1]. The other predictive factors for malignant transformation were exogenous steroids prolonged intake, obesity, metabolic syndrome, a tumor size over 5 cm as in our case, type 1a glycogen storage disease, and beta-catenin activation in exon 3 [10,15]. Surgical resection is still a cornerstone for the treatment of such tumors especially in case of bleeding risk: diameter superior or equal to 3.5 cm, visualization of lesional arteries, left lateral liver location, and exophytic growth as for our case [17]. Laparoscopic resection is considered more and more as an alternative to laparotomy with equivalent results in terms of mortality, morbidity, and relapse [18].
As in our case, it can be life-threatening because of arterial bleeding reported in 20-40% cases especially in sonic hedghoge subtype [10]. Transarterial embolization may be carried out but can be challenging in case of several small feeding vessels [14]. Hence, surgery remained an effective treatment in such complications as in our patient [18]. For non-complicated hepatocellular adenoma smaller than 5 cm, trans arterial embolization may constitute a mini-invasive alternative to surgery especially for young patients with cosmetic outcomes [19].