Introduction

Hepatocellular adenomas (HCAs) are rare benign hepatic tumors^1,2, while hepatic adenomatosis (HA) is a clinical entity characterized by 10 or more HCAs¹. They are more common in women and are associated with oral contraceptive use^1,4-7. The differential diagnosis should be made with other benign tumors as focal nodular hyperplasia (FNH), angiomas, etc., and with malignant tumors, mainly hepatocellular carcinoma⁸. Hepatocellular adenomas are associated with bleeding events and their malignant transformation is nonnegligible⁹. An updated guideline for the management of this tumor has been published¹⁰. Positron emission tomography computed tomography (PET-CT) using 18-fluoro-deoxyglucose (18FDG) is an imaging modality based on increased glucose uptake, a hallmark feature of cancer cells, and is mainly used as part of the workup or surveillance for other cancers⁸. Hepatocellular adenomas are benign tumors and 18FDG uptake on PET-CT is rare. In a large study conducted between 1984 and 2014 which screened patients with HCA and 18FDG uptake on PET-CT, only 19 cases were found⁸. Only one of these cases corresponded to a male patient^9,11-17. The aim of this paper was to continue the review initiated by these authors⁹, based on a very rare case of male patient with 18FDG avid HA on PET-CT.

Material and methods

Taking the work published by Lee et al.9 as a reference, we conducted a literature search from July 2014 to December 31, 2021, completing up to that date the cases of 18FDG-avid HCA initiated by them in 1984. A literature search was performed in MEDLINE (PubMed) of articles published in English using the same medical subgroup headings (MeSH) terms combined with Boolean operators used by those authors: (Positron Emission Tomography [PET], [18 F] Fluorodeoxyglucose [FDG], Hepatic adenomas, Hepatocellular adenomas, false positive, inflammatory, hepatocyte nuclear factor 1Alpha mutated [HNF1- alpha] and Beta-catenin mutated). As our patient had FDG-avid HCA in a setting of HA, we also included the latter term among the search criteria in the period from 2014 to 2021. The articles identified during the search period were analyzed by one of the authors (GN) to detect the new cases and any other relevant information. The cases previously described, along with those found during the search period, were entered in a database where the following individual data were included: sex and age, how the diagnosis was made, use of hormone therapy, tumor location according to Couinaud classification of hepatic segments, maximum SUV uptake (SUVmax), treatments used and the pathology report of the different variants of the disease.

Finally, we describe a brief presentation of the case managed by our work group. The HCA subtype was classified according to the classification proposed by Bioulac-Sage et al.¹⁸.

Results

During the search period, 155 articles were identified with the criteria used by the Lee at al., and other 42 additional articles dealt with HA. Of the 155 articles reviewed, only 5 reported FGD-avid HCA and of the 42 that reported HA, only 2 had avid adenomas, which - added to our case and to one from the previous series - would represent a total of 4 (Table 1). The sum of the cases found until 2014 plus those reviewed by us from that date onwards results in 38 cases in 37 years, almost one case per year (Table 2).

Table 1 Literature review with epidemiological data, treatment and pathology of FDG-avid HCA and HA 

Table 2 Summary of epidemiologic data, treatment and pathology of FDGavid HCA and HA 

Case report: a 23-year-old man, underwent surgery for glioblastoma multiforme. On a PET-CT performed as part of cancer surveillance, 4 avid lesions were observed in the liver, the largest one in segment III with a diameter of 6 cm, another one in segment VI and two in segment VIII. Open resection of the lesions was decided. During the procedure, other lesions were found in the other liver segments in addition to those mentioned in the PET-CT. The avid lesions were resected and the patient was discharged on postoperative day 3. The pathology report described hepatic adenomas with different morphologic and architectural patterns (with inflammatory, steatotic and telangiectatic changes), HNF1-α mutated and β-catenin negative. Figure 1 shows the computed tomography (CT) scan, PET-CT and the largest surgical specimen. The different microscopic types are seen in Figure 2.

Figure 1 CT scan (A) and PET-CT showing the largest lesion (B), a smaller lesion (C), and a cross-section of the surgical specimen (D). 

Figure 2 A: Mixed pattern in preserved liver parenchyma. B and C: esteatotic architecture. Section stained with haematoxylin and eosin (x20). 

Discussion

Most HCAs occur in women of childbearing age with a male to female ratio of 1:8. The use of oral contraceptives is associated with higher incidence, as evidenced in the series analyzed^9,16. Pregnancy does not seem to play any role in the size or complications of HCAs^6,7.

Although the pathology classification most used is the one described by Bioulac-Sage et al.¹⁸, other authors mention some other subtypes¹⁹. The inflammatory subtype is the most common variant (40-50%) with a large inflammatory pattern associated with hypervascularization and is due to activation of by STAT3 pathway. This subtype is more frequent in obese patients and is associated with alcohol use. HNF1α HCA (30-40%) is characterized by lipid accumulation within the hepatocytes due to activation of lipogenesis, resulting in a steatotic phenotype without inflammatory infiltrate. The β-catenin subtype, which presents a mutation in CTNNB1 exon 3, shows patterns of cholestasis, atypia and dysplasia and is the one most likely to develop malignant transformation. The Sonic-Hedgehog activated subtype occurs in 5% due to activation of the transcriptor factor GLI1 (family zinc finger 1) which leads to overexpression of prostaglandin D2 synthase; this subtype is most often seen in obese patients. Mixed beta-catenininflammatory subtype occurs in about 10% of cases and, finally, those considered unclassified account for 7% of HCAs¹⁹. Hemorrhage is the most common complication, most often intratumoral, and occurs in about 27% of patients; the risk of bleeding for each adenoma is about 15%²⁰. Increasing tumor size, oral contraceptives and use percutaneous needle biopsy have been associated with higher risk of bleeding²⁰. Malignant transformation is another possible complication, which is reported in about 4-8%; risk factors are β-catenin subtype, a tumor size > 5 cm, and use of oral contraceptives²⁰. Only 3 cases of adenomas < 5 cm have been reported with malignant transformation to hepatocellular carcinoma (HCC); men have higher risk than women (47% vs. 4%)^20,21.

18FDG avidity in PET-CT is rare. In our search, we identified 19 additional cases in 192 articles (155 HCAs, 42 HA) reviewed^2-5,22-25; this raises the case series initiated by Lee et al.⁹ to 38 cases of 18FDG-avid HCAs on PET-CT over the 37 years reviewed. The differential diagnosis with focal nodular hyperplasia (FNH) and well or moderately differentiated HCC is important. Cancer cells in well or moderately differentiated HCC are very similar to those of normal hepatocytes and have the same metabolic profile of normal tissue. This differentiation is basically important because of the therapeutic implications^8,12,26,27. Multiple diagnostic methods have been proposed to make the differential diagnosis with other conditions, and to differentiate the different subtypes of HA^{3,8,12,19,20,26-29}. Of these, the literature agrees that MRI with a liver-specific contrast agent has the highest sensitivity and specificity for the diagnosis and differentiation of subtypes^3,20, mainly in the H-HCA type. The use of contrast-enhanced ultra sonography (CEUS) associated with microbubbles with the inert gas sulfur hexafluoride and a palmitic acid shell has demonstrated similar results to MRI. The diagnostic criteria for FNH are a hyperenhancing lesion in the arterial phase with rapid centrifugal filling from a central vessel and radial vascular branches (the “spoke and wheel” sign) while in HCAs the enhancement pattern commences peripherally and exhibits rapid centripetal filling. As these filling patterns, centrifugal and centripetal, of both lesions occur in 86-90% of the cases, computerassisted methods have been suggested to evaluate the microbubble transport patterns^27,28. CEUS has proved to be useful in differentiating between H-HCA and I-HCA types, as I-HCA is characterized by delayed washout. The use of elastography²⁶ has been proposed, as it has demonstrated important differences between HCA and FNH (12.08 Kpa and 46.99 Kpa, respectively). However, as it has showed difficulties in cases of telangiectatic pattern, its association with CEUS is recommended²⁶.

The use of 18 FDG PET-CT is mainly indicated for the surveillance of malignant diseases already diagnosed due to the avidity of neoplastic cells for 18FDG. Most of the cases of avid HA have been detected during cancer surveillance: they are benign lesions without 18FDG uptake. H-HCA is the most avid subtype for 18FDG followed by I-HCA, but there are no reports on 18FDG avidity in the β-catenin subtype^4,8,9.

The H-HCA type favors excessive accumulation of intratumoral lipids²³. High 18FDG uptake may be due to some reasons other than enhanced glucose metabolism, as degree of differentiation, inflammatory cell infiltration, increased cellular density and a response to fat accumulation²³. Metabolic abnormalities including activation of glycolysis, citrate and fatty acid synthesis have been suggested, resulting in increased lipogenesis and suppressed gluconeogenesis²³. Cells express low levels of glucose-6-phosphatase, trapping FDG-6-phosphate inside the cell and causing increased 18FDG accumulation in the tumor. In addition, several isoforms/isozymes of glucose transporter and hexokinases have been identified favoring FDG avidity²³. The high uptake mainly in the H-HCA subtype would be due to inactivation of glucose-6-phospate transporter 1 (G6PT1), which is regulated by HNF1-α²³. Uptake is lower in FNH than in HCA for the simple reason that FNH cells are polyclonal and represent the reactive hyperplastic response of hepatocytes to local vascular abnormality, whereas HCA has a neoplastic nature that is demonstrated by the monoclonal mutations of both oncogenes and oncosuppressor genes¹².

The addition of C-11 acetate to 18FDG PET-CT has not provided any benefit for differentiating FNH from HCA¹².

If the imaging tests do not help to reach a definitive diagnosis, some authors perform percutaneous needle biopsy³⁰; yet these authors admitted that the results were not useful, negative, and that the definitive diagnosis was made with the surgical specimen. Other authors recommend percutaneous needle biopsy only in patients with lesions of diagnostic uncertainty to identify the HA subtype, mainly the mutated β-catenin type or I-HCA, which have higher risk of malignant transformation^19,20. Percutaneous needle biopsy increases the risk of hemorrhage²⁰. We believe that, if the lesion is resectable, resection rather than biopsy should be performed, as in our case. We believe that biopsy would only be useful if it is positive, and one can ensure that there are no HCC cells remain in the rest of the lesion. Surgical resection is recommended for lesions with a diameter > 5 cm, if there are signs of hepatocellular carcinoma or focal dysplasia, activated β-catenin mutation, elevated serum values of alpha-fetoprotein, adenomas in male patients and HCA occurring in patients with glycogen storage diseases¹⁰. In the study by Dokmak et al.²¹ none of the 122 patients undergoing surgical resection of HA died after 90 days and major morbidity was 15%, indicating that liver resection is safe in when performed by groups dedicated to liver surgery. Cessation of oral contraception has also been reported to be efficient³¹.

In HCA with 18FDG avidity in the context of HA, as in our case, the therapeutic decision is usually more difficult. HA has been classified in two forms, multifocal and massive, according to its morphologic pattern^32,33. Orthotopic liver transplantation was performed 0.03% of patients in Europe³²; perhaps the best indication for this treatment is massive HA with bleeding complications or when HCC is strongly suspected. Other authors³³ recommend conservative management in lesions < 3 cm, use of TACE for bleeding complications, several sessions of radiofrequency and liver transplantation when HCC is suspected or has been confirmed³³.

In conclusion, and in agreement with Lee et al.⁹, the main weakness of this study is the small number of cases collected in an uncontrolled fashion. Avidity of HCA for 18FDG on PET -CT is unusual and is associated with several factors as inflammation and increased lipid accumulation. Avidity does not at all represent malignant transformation, which is demonstrated by the absence of uptake in β-catenin mutation. The criteria for indicating surgery include tumor diameter, male sex, risk of bleeding, risk for malignant transformation, β-catenin subtype mutation, and patients with glycogen storage diseases. 18FDG PET-CT is not a standard for surveillance of HCAs or HA.