Hepatocellular adenoma update: diagnosis, molecular classification, and clinical course

Abstract

Hepatocellular adenomas (HCA) are acquired focal liver lesions, that occur mainly in young-to-middle-aged women who are on long-term estrogen-containing contraceptives or young men after prolonged use of anabolic steroids. Furthermore, distinct underlying diseases, such as obesity, metabolic dysfunction-associated steatotic liver disease, glycogen storage disease, etc. are considered risk factors. The 2017 Bordeaux classification, in particular Nault et al, divided HCAs into eight subtypes according to their pheno- and genotypic characteristics. This includes HCAs with hepatocyte-nuclear-factor (HNF1-alpha mutation), HCAs with β-catenin mutation, and HCAs without either of these genetic mutations, which are further subdivided into HCAs with and without inflammatory cells. HCAs should no longer be classified as purely benign without histologic workup since three of the eight subtypes are considered high-risk lesions, requiring adequate management: malignant transformation of the pure (ßex3-HCA) and mixed inflammatory/β-catenin exon 3 (ßex3-IHCA) adenomas, as well as potential bleeding of the sonic hedgehog HCA and pure (ßex7/8-HCA) and mixed inflammatory/β-catenin exon 7/8 (ßex7/8-IHCA). Elective surgery is recommended for any HCA in a male, or for any HCA exceeding 5 cm. Although MRI can classify up to 80% of adenomas, if findings are equivocal, biopsy remains the reference standard for adenoma subtype.

Keywords: MRI; contrast agents; hepatocellular adenoma; liver; molecular imaging.

Figure 1.

This 45-year-old woman with breast cancer was sent for (A) ¹⁸FDG PET-CT to rule out metastatic disease. A solitary intensely-avid radiotracer focus was found adjacent to the gallbladder fossa, in liver segment V (thick arrow). On (B) abdominal CECT, PVP, it corresponds to a 3 cm hypodense lesion (thick arrow). Additionally, a tiny hypodense lesion is seen more laterally (thin arrow), in the same segment. Because it is below the limits of resolution, that is, 10 mm, the lesion was not seen on the FDG scan. Multiparametric MRI scan shows signal dropout of both lesions on (D) out-of-phase compared to their isointense appearance on (C) in-phase CSI. They are barely visible on (E) T2WI fat sat, hypointense on (F) unenhanced T1-weighted image. After gadoxetic acid administration, they are hypervascular in (G) arterial-phase, and show decreasing enhancement in (H) PVP. The larger lesion is increasingly better demarcated in (I) transitional phase and (J) HBP as more hypointensity occurs. Histopathology confirmed that the larger lesion was a steatotic adenoma. The tiny lesion was also diagnosed as a H-HCA due to its MR imaging characteristics, that is, fat content.

Figure 2.

A 23-year-old woman with histopathologically proven sonic hedgehog adenoma. (A) Unenhanced CT shows a large heterogeneous hyper/hypodense mass in liver segment VII consistent with bleeding and necrosis (arrow). On (B) arterial phase CT, there is heterogeneous enhancement and (C) on PVP less enhancement (arrow). MRI (D) unenhanced T1WI shows an inhomogeneous mass which is iso/hypointense and (E) on T2WI hypo/hyperintense consistent with hemorrhage and necrosis (arrow). After gadoxetic acid injection, (F) inhomogeneous arterial-phase lesion enhancement is seen, and confirmed on (G) subtraction. On (H) PVP there is more hypointensity which progresses in (I) the HBP (arrow).

Figure 3.

This 44 year old woman with an abnormal bleeding time was found to have multiple liver lesions on a US exam. The largest lesion, in segment IVB, is 6 cm. (A-E) CEUS shows progressive centripetal enhancement of the hyperechoic lesion at 1 min without any hypoechogenicity on later imaging. (F) Contrast-enhanced MRI using multihance shows marked hypointensity during the HBP. Pathology confirmed that the lesion is an inflammatory HCA.

Figure 4.

This young woman with breast cancer and lymphoma had (A) negative screening abdominal US. Due to her oncologic history, she also underwent (B) staging chest/abdomen CECT which showed a 1.5-cm arterial-phase hypervascular lesion in segment VI (black arrow), initially felt to be benign. However, at one-year follow-up, (C) CECT shows that the liver lesion has grown to 2.5 cm. (D) US was done to see if US-guided biopsy could be done, but the lesion is barely visible, even with knowledge of the CT findings, that is, isoechoic. Therefore, for better lesion characterization Gd-BOPTA-enhanced MRI was performed, showing (E) a lesion isointense to liver on T1 WI, (F) no signal intensity loss from in-phase (G) to opposed-phase (H), strong arterial-phase enhancement (white arrow), which persisted in the (I) PVP and (J) 5 min phase, but (K) at 90-min HBP image is barely visible (white arrow) due to hypointensity. This hypointensity precluded a confident distinction between metastasis, lymphoma, and adenoma. The next day another hepatobiliary (MnDPDP)-enhanced MRI was performed which shows (L) lesion MnDPDP uptake similar to the surrounding liver (white arrow) excluding entities of non-hepatic origin, that is, both malignancies. The lesion was biopsied. Histopathology confirmed the diagnosis of a pure inflammatory adenoma. At 1-year follow-up with gadoxetic acid-enhanced MRI, on (M) axial 20-min HBP image (white arrow), the 2.5-cm hypointense segment VI lesion’s size is stable. Notice that the HBP lesion is far more conspicuous with gadoxetic acid than with (K) Gd-BOPTA due to the much larger percentage of hepatobiliary uptake with gadoxetic acid, that is, 50% vs 2%-4%. Further, remember that in cholestatic liver lesions, the transporters for Gd-BOPTA and gadoxetic acid are OATP, and MRP3 whereas for MnDPDP it is the transferrin receptor 2 (TfR2). Therefore, in the HBP the appearance of the adenomas differs but the liver appearance is similar.

Figure 5.

This 22-year-old man taking anabolic steroids use was sent for liver MRI due to elevated liver parameters. Initial ECCM-enhanced MRI showed (A) an isointense 3 cm lesion in segment VII/VIII on T2WI, (B) without fat content on CSI (arrow) and (C) CSI showed a non-fat-containing 3 cm lesion (arrow) in segment VII/VIII. Dynamic ECCM-MR imaging showed hyperenhancement in (D) arterial phase and hypoenhancement in (E) PVP and (F) late phase (arrow). On 6-month follow-up MRI, (G) unenhanced T1WI shows marked interim vertical growth of mass (now 13 cm) and new inhomogeneous hyperintensity due to internal hemorrhage (thick arrow). Furthermore, notice the interim appearance of a smaller 3.5-cm lesion anteriorly (thin arrow). Post-gadoxetic acid dynamic imaging shows marked enhancement of the smaller lesion (thin arrow), but negligible enhancement of the larger lesion (arrow) during (H) arterial phase. The signal intensity of both lesions persist on (I) axial PVP, (J) coronal PVP, and (K) axial HBP and (L) coronal HBP. The larger mass was resected with histopathologic diagnosis of a ß^ex3-IHCA. The adjacent smaller mass was diagnosed as a well-differentiated HCC.

Figure 6.

A 26-year-old woman with a histopathologically proven mixed ß^ex3-IHCA. Dynamic imaging following gadoxetic acid injection shows a moderately enhancing (A) arterial-phase 1.5 cm lesion in segment VI (arrow), unchanged on (B) PVP and (C) HBP. An FNH was suspected, but due to her risk factors (long-term OCP-use), follow-up was suggested. Three years later, dynamic MR imaging shows that this well-circumscribed lesion (arrow) has a hypointense central scar (dashed arrow) and has grown to 5 cm. Although its enhancement pattern is unchanged, that is, persistent hypervascularity in (D) arterial-phase (E) PVP and (F) HBP, and its tiny central scar makes it similar to an FNH, the lesion was resected due to its interim growth. Histopathology diagnosed a mixed ß^ex3-IHCA which was previously called a “telangiectatic FNH”, by both radiologists and pathologists, because its imaging and staining appearance resemble an FNH, that is, marked AP lesion enhancement, and isointensity in the PVP and HBP, except for the T1WI hypointense scar. As a central scar is frequently reported with ß^ex-HCA, this component likely explains the central scar’s presence.

Figure 7.

CT features of a histopathologically confirmed pure IHCA in a 46-year-old male bodybuilder. (A) Unenhanced CT is unremarkable. CECT shows (B) an arterial-phase 3-cm moderately hypervascular lesion in liver segment VIII (white arrow), which in (C) the PVP is less hypervascular (white arrow). Gadoxetic acid-enhanced MRI shows (D) no visible lesion on T1WI, (E) on in-phase no visible lesion, but (F) on opposed-phase a hyperintense lesion due to diffuse signal intensity loss in background liver, (G) on T2WI no hyperintensity of the lesion, (H) moderate enhancement on the arterial phase, (I) decreased hyperintensity on the PVP, (J) slight enhancement on the TP, and (K) hyperintensity on the HBP.

Figure 8.

38-year-old obese female patient taking OCPs. During an abdominal US for a hypertensive crisis, incidental hepatic masses were seen. An MRI was ordered for further clarification. (A) T2WI shows a large inhomogeneous hyperintense segment VII liver mass (thick arrow) and a smaller lesion in segment VIII/IVA (thin arrow) with a hyperintense rim and hypointense center (asterisk). The latter features are consistent with the atoll sign. The larger mass which appears heterogeneously hyperintense on (C) arterial-phase T1WI, and shows progressive hypointensity in (D) PVP, (E) TP and (F) HBP. Both lesions were resected, and diagnosed as a mixed ßex7/8-IHCA (thick arrow) and a pure IHCA (thin arrow) in histopathology.

Figure 9.

A 53-year-old overweight woman with metabolic syndrome. Gadoxetic acid-enhanced MRI discovered a solitary 2.3-cm segment VI lesion that was a pathologically proven mixed ß^ex3-IHCA (arrow). On (A) unenhanced T1WI, it is faintly hyperintense. Moderate SI loss of the liver (dashed arrow) on (C) opposed-phase compared to (B) in-phase sequence indicates moderate steatosis hepatis. The fat fraction was 17%. On T2WI and (D) DWI the lesion is moderately hyperintense (arrow). On dynamic imaging, the lesion (arrow) moderately enhances on (E) arterial phase and retains contrast on (F) PVP, (G) TP, and (H) HBP. (I-L) Subtraction images confirm that persistent lesion hyperintensity is real and not due to the background liver steatosis. In other words, there was active uptake of gadoxetic acid by the adenoma’s OATP transporters.

Figure 10.

A 19-year-old woman with metabolic syndrome and histopathologically proven mixed ß^ex3-IHCA. CE-MRI shows a 1.5-cm enhancing lesion in segment VII in (A) arterial phase and (B) PVP (arrow). (C) Unenhanced T2WI shows a mildly hyperintense subcapsular lesion (arrow). (D) SPIO-enhanced axial T2WI shows that lesion (arrow), as well as liver and spleen signal intensity have dropped significantly, implying that it contains Kupfer cells. Two-year MRI follow-up shows dramatic lesion growth (thick arrow), from 1.5 cm to 10 cm, on (E) T2WI with fat sat. On CSI, (F) in-phase image confirms the 10 cm segment VII mass (thick arrow). Diffuse signal loss in the liver from steatosis on (G) opposed-phase image, also shows a smaller segment II lesion (thin arrow). (H) Unenhanced T1WI shows that the large mass (thick arrow) is nearly isointense to the liver while the tiny lesion (thin arrow) is hyperintense to the liver due to background steatosis. On dynamic T1WI after gadoxetic acid injection, there is (I) strong and moderate enhancement of the large (thick arrow) and tiny (thin arrow) lesions, respectively, which persists in (J) PVP, (K) TP and (L) HBP, improving the demarcation of a hypointense central scar (dashed arrow). The large mass was resected. The smaller lesion was followed.

Figure 11.

A large liver mass was incidentally detected in this 34-year-old renal transplant recipient who had a liver US (not shown) for nonspecific abdominal pain. On follow-up MRI (A) unenhanced T1WI shows a large mostly isointense mass (arrow) with a hypointense central scar (dashed arrow). (B) T2WI shows a hyperintense 10 cm mass in liver segment VII, again with a hypointense central scar (dashed arrow). On (C) and (D) CSI there was no signal dropout. (E) DWI and (F) ADC showed restriction. On gadoxetic acid-enhanced dynamic imaging the mass was (G) arterial-phase and (H) PVP hyperintense. Hypointensity starts in (I) TP and progresses until the lesion is clearly demarcated on (J) axial HBP and (K) coronal HBP. An atypical liver resection was performed for radiological suspicion of a FLC or ß^ex7/8-HCA. Histopathology confirmed the diagnosis of a ß^ex7/8-HCA.

Figure 12.

A 19-year-old woman who had a soft tissue sarcoma treated with radiochemotherapy and a new diagnosis of MODY type 3. While working in an imaging center, she volunteered to have a liver US which showed multiple lesions. Follow-up MRI, including (A) and (B) CSI shows SI dropout in a 1 cm segment IVA liver (arrow). After gadoxetic acid, the lesion weakly enhances during (C) AP (arrow), and (D) becomes hypointense in the PVP. (E) Axial HBP image shows several hypointense liver lesions, the largest in segment VIII (dashed arrow) which had no signal drop on (F) and (G) CSI, that is, no fat content. This large lesion is increasingly hypointense in (J) PVP, (K) TP, and (L) HBP (dashed arrow). Histopathology of this largest lesion reported a mixed ß^ex8-IHCA. In the setting of multiple adenomas, circa 70% of the lesions will be of the same subtype. Furthermore, as was done here, the largest lesion should determine management.