INTRODUCTION
A hepatocellular adenoma (HCA) is considered a benign liver tumor. It has a significant female preponderance in the reproductive age group. The exact incidence and prevalence of HCA are unknown, but recent data suggest an overall increase in prevalence, especially in male patients.1 Different molecular subtypes of HCAs exist, with the β-catenin-activated HCA subtype transferring a higher risk of malignant transformation and spontaneous rupture. The association between familial adenomatous polyposis (FAP) and HCA is poorly described. FAP is caused by mutations in the adenomatous polyposis coli (APC) gene, which is known to play a role in wingless-integrated (Wnt) signaling and the degradation of β-catenin.2 However, to the best of our knowledge, there are only 7 reported cases of HCA in patients with FAP; thus, the pathogenesis of HCA in FAP remains unclear.
CASE REPORT
An 18-year-old nonverbal man with a medical history of cerebral palsy, seizure disorder, and FAP presented with lethargy, emesis, and decreased ileostomy output after total proctocolectomy. On admission, alpha-fetoprotein, bilirubin, and liver enzymes were unremarkable; the international normalized ratio was increased to 1.3. Abdominal/pelvic computed tomography was ordered for further workup, revealing multiple liver lesions. Abdominal magnetic resonance imaging indicated multiple T1 hyperintense hepatic lesions within segments 2, 6, 7, and 8, the largest measuring 2.5 × 3.1 cm (Figure 1). All lesions demonstrated features of restrictive diffusion and early arterial enhancement with washout on delayed imaging. The Liver Imaging Reporting and Data System classification was not applicable because imaging and biopsy did not suggest features compatible with cirrhosis.
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Figure 1.: Multiple T1 hyperintense hepatic lesions within segments 2, 6, 7, and 8. The largest lesion measuring 2.5 × 3.1 cm and an adjacent nodular component (arrow). The small nodular component of the largest lesion and the remaining lesions demonstrate uniform early arterial enhancement with washout on delayed imaging. The largest lesion shows early and persistent enhancement. There is no signal dropout on out-of-phase imaging.
Because the hepatic lesions were suspicious of malignancy, the patient underwent an image-guided biopsy of the right liver lesion. Pathology showed well-defined borders between the lesion and the background liver parenchyma (Figure 2). On higher power, the lesion demonstrated unpaired arteries (Figure 2) with a lack of normal portal areas and loss of bile ducts, confirmed by negative immunohistochemical staining for cytokeratin 19, which typically highlights normal bile ducts. The lesion comprised hepatocytes with mild cytologic atypia, nuclear pleomorphism, and prominent nucleoli without significant inflammation. In addition, there was a diffuse aberrant expression of the beta-catenin immunostain (diffuse nuclear staining) in the lesion with membranous staining in the background uninvolved liver parenchyma (Figure 2). The lesional cells were arranged in mildly thickened cell plates. Although the reticulin network was largely preserved, few foci of disruption and loss were noted (Figure 2). The overall histologic features were those of a well-differentiated hepatocellular lesion and favor HCA. However, the disruption of reticulin stain concerns for hepatocellular carcinoma, and the distinction could be very challenging on a biopsy.
Figure 2.: (A) A well-defined border between the lesion (black arrow) and the background liver (blue arrow) (hematoxylin and eosin magnification 10×); (B) unpaired arteries (black arrow) with missing interlobular bile ducts and mild cytologic atypia with prominent nucleoli (hematoxylin and eosin, magnification 20×); (C) beta-catenin immunohistochemical stain demonstrates aberrant nuclear expression in the lesion (left) and membranous staining in the background liver parenchyma (right) (magnification 10×); (D) reticulin stain showing a borderline lesion with foci of a thickened cell plate and fragmentation of the reticulin network concerning hepatocellular carcinoma (magnification 20×).
The case was discussed at the tumor board with a consensus to pursue a conservative approach with serial imaging and tumor markers.
DISCUSSION
HCAs are usually benign neoplasms caused by hepatocyte proliferation driven in response to hormonal or metabolic derangements often seen with oral contraceptives or androgenic steroid use.3,4
Our case is not associated with any pathogenic condition apart from FAP. FAP is an autosomal dominant disorder resulting from a mutation in the APC gene, emanating in an innumerable number of adenomatous polyps, inadvertently leading to colorectal cancer.5,6 The APC gene usually prevents tumorigenesis by controlling the transcriptional activity of β-catenin, leading to its downstream degradation.2
β-catenin mutations have also been implicated in various hepatic tumors. For example, hepatoblastomas are more frequently observed in young patients with FAP.7 Furthermore, β-catenin mutations are also encountered in hepatocellular carcinomas associated with hepatitis C virus infections.8 β-catenin mutations are present in approximately 10% of all HCAs and are associated with an increased risk of hemorrhage and malignant transformation.9 Despite all these associations, encountering HCA in patients with FAP seems to be a rarity.10
To the best of our knowledge, this case represents the third reported case of a HCA in a male patient with FAP.10 Furthermore, because the other existing cases are associated with other or not determined molecular subclasses, the following case represents the first existing case of a β-catenin-activated HCA in a patient with FAP.
Current literature indicates 7 cases, 2 related to a mutation in hepatocyte nuclear factor-1 alpha in a 37-year-old woman and a 25-year-old man.11,12 One infantile case, affecting a 2-year-old girl, likely developed in response to a loss of wild-type allele of APC and a mutation of p53.13
In our case, we performed a biopsy of one of the liver lesions, which indicated an aberrant expression of β-catenin on immunostaining consistent with a β-catenin-activated subtype lesion. Other histologic features included atypia with focal loss of reticulin stain. Although the loss of reticulin is often seen in cases of hepatocellular carcinomas, a clear histological distinction remains challenging, especially in the setting of β-catenin pathway activation in a male patient with underlying FAP.14,15 The term “well-differentiated hepatocellular neoplasm of uncertain malignant potential” has been recently proposed for neoplasms that bear a resemblance to HCA but are insufficient for a clear-cut diagnosis of hepatocellular carcinoma.16 Although HCAs are considered benign lesions, existing literature indicates a potential risk of malignant transformation, especially in male patients with β-catenin HCA.17 In our case, the multifocality of the lesions precluded a definitive diagnosis of a HCA because only one lesion was biopsied. Independent of the underlying histology, current guidelines recommend resection of HCA in male patients, irrespective of size.3 A surgical approach was discussed, but because the lesions were localized within different segments of the liver, surgical resections of affected lobes seemed to be challenging. Furthermore, the patient had several risk factors of a poor surgical outcome, including a recent major surgery (total proctocolectomy), a low body mass index of 16.5 kg/m2, and an underlying long-term dependence on tube feeds. A liver transplant was considered, but intraoperative and postoperative risks seemed too significant. Moreover, there are no definite guidelines for hepatic adenoma in the Organ Procurement and Transplant Network; hence, the pursuit of liver transplant would have required an exception by the national review committee. Locoregional therapy was not considered because the patient was still recovering from his initial presentation of sepsis. A conservative approach was preferred by the family, with a close follow-up including serial imaging and tumor markers.
- This case presents the first reported case of a β-catenin-activated HCA in a patient with FAP.
- Current literature includes a total of 7 reported cases of HCA in patients with FAP with different mutations; thus, the pathogenesis and true incidence of HCA in FAP remains largely undetermined
- In general, β-catenin-activated HCA is overrepresented in male patients and is associated with a higher risk of malignant transformation; they therefore require resection
- The multifocality of the HCA complicated our case because major surgery would have been associated with significant morbidity and mortality.
DISCLOSURES
Author contributions: A. Kusnik and S. Li were responsible for the concept and design of the manuscript; E. Graziano, R. Katerji, and G. Ramaraju were responsible for critical review and contributions to the paper. R. Katerji provided the pathological slides and associated descriptions. A. Kusnik was responsible for data acquisition, literature review, and submission of the final version. All authors critically revised the manuscript, approved the final version to be published, and agreed to be accountable for all aspects of the work. A. Kusnik is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
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