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].