Liver contrast-enhanced sonography: computer-assisted differentiation between focal nodular hyperplasia and inflammatory hepatocellular adenoma by reference to microbubble transport patterns.

OBJECTIVE: A new computer tool is proposed to distinguish between focal nodular hyperplasia (FNH) and an inflammatory hepatocellular adenoma (I-HCA) using contrast-enhanced ultrasound (CEUS). The new method was compared with the usual qualitative analysis. METHODS: The proposed tool embeds an "optical flow" algorithm, designed to mimic the human visual perception of object transport in image series, to quantitatively analyse apparent microbubble transport parameters visible on CEUS. Qualitative (visual) and quantitative (computer-assisted) CEUS data were compared in a cohort of adult patients with either FNH or I-HCA based on pathological and radiological results. For quantitative analysis, several computer-assisted classification models were tested and subjected to cross-validation. The accuracies, area under the receiver-operating characteristic curve (AUROC), sensitivity and specificity, positive predictive values (PPVs), negative predictive values (NPVs), false predictive rate (FPRs) and false negative rate (FNRs) were recorded. RESULTS: Forty-six patients with FNH (n = 29) or I-HCA (n = 17) with 47 tumours (one patient with 2 I-HCA) were analysed. The qualitative diagnostic parameters were accuracy = 93.6%, AUROC = 0.94, sensitivity = 94.4%, specificity = 93.1%, PPV = 89.5%, NPV = 96.4%, FPR = 6.9% and FNR = 5.6%. The quantitative diagnostic parameters were accuracy = 95.9%, AUROC = 0.97, sensitivity = 93.4%, specificity = 97.6%, PPV = 95.3%, NPV = 96.7%, FPR = 2.4% and FNR = 6.6%. CONCLUSIONS: Microbubble transport patterns evident on CEUS are valuable diagnostic indicators. Machine-learning algorithms analysing such data facilitate the diagnosis of FNH and I-HCA tumours. KEY POINTS: • Distinguishing between focal nodular hyperplasia and an inflammatory hepatocellular adenoma using dynamic contrast-enhanced ultrasound is sometimes difficult. • Microbubble transport patterns evident on contrast-enhanced sonography are valuable diagnostic indicators. • Machine-learning algorithms analysing microbubble transport patterns facilitate the diagnosis of FNH and I-HCA.

New MRI features improve subtype classification of hepatocellular adenoma.

OBJECTIVE: MRI is crucial for the classification of hepatocellular adenomas (HCA) into subtypes. Our objective was to review and increase MRI criteria for subtype classification and define the limits. METHODS: Pathological and radiological data of 116 HCAs were retrospectively analyzed to investigate MRI features of HCA pathological subtypes. Risk for complication was also evaluated with regard to subtype and tumor size. RESULTS: 38/43 (88%) HNF1α-mutated HCAs (H-HCAs) were discriminated by (i) fatty component (homogeneous or heterogeneous) and (ii) hypovascular pattern, with a sensitivity of 88% and a specificity of 97%. 51/58 (88%) inflammatory HCAs (IHCAs) displayed features of sinusoidal dilatation (SD) including three different patterns (global SD, atoll sign, and a new "crescent sign" corresponding to a partial peripheral rim, hyperintense on T2W and/or arterial phase with persistent delayed enhancement). Sensitivity was 88% and specificity 100%. However, some HCA remained unclassifiable by MRI: HCA remodeled by necrotic/hemorrhagic changes covering > 50% of the lesion, H-HCAs without steatosis, IHCAs without SD, ß-catenin-mutated and unclassified HCAs. Regarding malignant transformation (5/116) and bleeding (24/116), none was observed when the HCA diameter was smaller than 5.2 cm and 4.2 cm, respectively. CONCLUSION: Based on the largest series evaluated until now, we identified several non-described MRI features and propose new highly sensitive and specific MRI criteria. With the addition of these new features, 88% of the two main HCA subtypes could be identified. KEY POINTS: • HNF1α-mutated hepatocellular adenomas (H-HCA) are characterized by the presence of fat and hypovascular pattern in MRI. • Inflammatory hepatocellular adenomas (I-HCA) are characterized by different patterns translating sinusoidal dilatation including the newly described crescent sign. • No MRI specific pattern was identified for ß-catenin-mutated HCA (b-HCA).

Consensus report of the Fifth International Forum for Liver MRI.

OBJECTIVE: This article reviews topics discussed during the Fifth International Forum for Liver MRI (with a focus on gadoxetic acid-enhanced MRI), which was held in Munich, Germany, in September 2011. CONCLUSION: Growing evidence shows that gadoxetic acid-enhanced MRI has high sensitivity and specificity for diagnosing liver tumors. Hepatobiliary phase imaging adds new information for the characterization of borderline lesions. However, there is a need to develop standardized criteria for interpretation of gadoxetic acid-enhanced MRI in patients with cirrhosis or other risk factors for hepatocellular carcinoma.

Pathological Diagnosis of Hepatocellular Cellular Adenoma according to the Clinical Context.

In Europe and North America, hepatocellular adenomas (HCA) occur, classically, in middle-aged woman taking oral contraceptives. Twenty percent of women, however, are not exposed to oral contraceptives; HCA can more rarely occur in men, children, and women over 65 years. HCA have been observed in many pathological conditions such as glycogenosis, familial adenomatous polyposis, MODY3, after male hormone administration, and in vascular diseases. Obesity is frequent particularly in inflammatory HCA. The background liver is often normal, but steatosis is a frequent finding particularly in inflammatory HCA. The diagnosis of HCA is more difficult when the background liver is fibrotic, notably in vascular diseases. HCA can be solitary, or multiple or in great number (adenomatosis). When nodules are multiple, they are usually of the same subtype. HNF1 α -inactivated HCA occur almost exclusively in woman. The most important point of the classification is the identification of ß -catenin mutated HCA, a strong argument to identify patients at risk of malignant transformation. Some HCA already present criteria indicating malignant transformation. When the whole nodule is a hepatocellular carcinoma, it is extremely difficult to prove that it is the consequence of a former HCA. It is occasionally difficult to identify HCA remodeled by necrosis or hemorrhage.

Evaluation of liver tumors using acoustic radiation force impulse elastography and correlation with histologic data.

OBJECTIVES: Acoustic radiation force impulse (ARFI) technology represents an innovative method for the quantification of tissue elasticity. The aims of this study were to evaluate elasticity by ARFI in both liver tumors and background liver tissue and to compare ARFI measurements with histologic data in liver tumors and background liver. METHODS: Seventy-nine tumors were prospectively studied: 43 benign and 36 malignant. Acoustic radiation force impulse measurements for each tumor type were expressed as mean ± standard deviation for both liver tumors and background liver; ARFI data were also correlated with histologic data. RESULTS: For liver tumors, the mean stiffness values were 1.90 ± 0.86 m/s for hepatocellular adenoma (n = 9), 2.14 ± 0.49 m/s for hemangioma (n = 15), 3.14 ± 0.63 m/s for focal nodular hyperplasia (n = 19), 2.4 ± 1.01 m/s for hepatocellular carcinoma (n = 24), and 3.0 ± 1.36 m/s for metastasis (n = 12). Important variations were observed within each tumor type or within a single tumor. These variations could have been due to necrosis, hemorrhage, or colloid. There was no statistically significant difference between the benign and malignant groups. Regarding background liver, it was possible to observe pathologic abnormalities in histologic analyses or liver function tests to explain the ARFI data. The degree of fibrosis was not the only determinant of liver stiffness in background liver; other factors such as portal embolization, sinusoidal obstruction syndrome caused by chemotherapy, and cholestasis, also could have interfered. CONCLUSIONS: Acoustic radiation force impulse elastography could not allow differentiation between benign and malignant tumors. This study provides a better understanding of the correlation between ARFI and histologic data for both tumors and background liver.

Role of contrast-enhanced sonography in differentiation of subtypes of hepatocellular adenoma: correlation with MRI findings.

OBJECTIVE: Hepatocellular adenomas (HCAs) are divided into three subtypes according to genotype and phenotype. The two main subgroups are hepatocyte nuclear factor 1α (HNF1α)-inactivated HCA and inflammatory HCA. Specific imaging features of these subgroups of adenoma have been delineated with MRI. The aim of this study was to document the contrast-enhanced sonographic (CEUS) features specific for adenoma subtypes and to correlate them with MRI findings. MATERIALS AND METHODS: We retrospectively analyzed data on 38 patients with HCA confirmed at pathologic examination in all cases. All cases were classified with MRI. RESULTS: HNF1α-inactivated HCA (n = 16) was found to have a homogeneous hyperechoic aspect at baseline gray-scale sonography, isovascularity or moderate hypervascularity with mixed filling in the arterial phase, and isoechogenicity in the portal and late portal venous phases. Homogeneous hyperechogenicity during B-mode sonography was the most specific pattern (sensitivity, 88%; specificity, 91%) and correlated with diffuse fat repartition observed on MR images obtained with chemical-shift sequences. In inflammatory HCA (n = 17) the association of arterial hypervascularity with centripetal filling, linear vascularities, peripheral rim of sustained enhancement, and central washout in the late venous phase was specific (sensitivity, 64%; specificity, 100%). Discrepancy between delayed washout during CEUS and sustained enhancement during MRI could be related to differences between gadolinium and microbubbles in diffusing in the interstitial spaces. In the five other HCA cases (four unclassified, one ß-catenin activated) CEUS showed characteristics of benign hepatocellular tumors with no specific features. CONCLUSION: HNF1α-inactivated HCA and inflammatory HCA had characteristic CEUS patterns. Delayed washout, an unusual finding in benign hepatic lesions, is of particular interest and was a characteristic of inflammatory HCA subtype.

Hepatic resection for inflammatory hepatocellular adenomas: pathological identification of micronodules expressing inflammatory proteins.

BACKGROUND: Inflammatory hepatocellular adenoma (IHCA) defines a subgroup of hepatocellular adenomas characterized by the expression of members of the acute-phase inflammatory response [(serum amyloid A protein (SAA) and C-reactive protein (CRP)]. IHCA are unique or multiple as defined by the presence of several nodule(s) larger than 10 mm using both imaging and macroscopic observation. Frequently, additional micronodules (<10 mm), previously undetected by imaging, can be observed in resected specimens. AIMS: To analyse micronodules in multiple (group 1, nine patients) and single (group 2, eight patients) IHCA cases, immunohistochemistry using SAA and CRP antibodies was performed on all nodules detected under macroscopic examination as well as on surrounding tissue with no visible nodules. RESULTS: Nodules of different sizes (>5 < or = 10 mm, > or = 1 < or = 5 mm) were found in group 1, whereas only rare nodules in the mm range were found in group 2. Micronodules shared the characteristics of large nodules, which justified surgery such as inflammatory infiltrates, abnormal arteries, sinusoidal dilatation or peliosis. However, the number of these characteristics was proportional to the size of the nodules. CONCLUSION: This study demonstrates that the real number of IHCA is greater than that predicted from imaging-based analyses. In addition, we show that patients with more than one nodule present a greater chance to display more and larger undetected micronodules than patients with a single nodule.

Real-time monitoring of radiofrequency ablation of liver tumors using thermal-dose calculation by MR temperature imaging: initial results in nine patients, including follow-up.

To assess the practical feasibility and effectiveness of real-time magnetic resonance (MR) temperature monitoring for the radiofrequency (RF) ablation of liver tumours in a clinical setting, nine patients (aged 49-87 years, five men and four women) with one malignant tumour (14-50 mm, eight hepatocellular carcinomas and one colorectal metastasis), were treated by 12-min RF ablation using a 1.5-T closed magnet for real-time temperature monitoring. The clinical monopolar RF device was filtered at 64 MHz to avoid electromagnetic interference. Real-time computation of thermal-dose (TD) maps, based on Sapareto and Dewey's equation, was studied to determine its ability to provide a clear end-point of the RF procedure. Absence of local recurrence on follow-up MR images obtained 45 days after the RF ablation was used to assess the apoptotic and necrotic prediction obtained by real-time TD maps. Seven out of nine tumours were completely ablated according to the real-time TD maps. Compared with 45-day follow-up MR images, TD maps accurately predicted two primary treatment failures, but were not relevant in the later progression of one case of secondary local tumour. The real-time TD concept is a feasible and promising monitoring method for the RF ablation of liver tumours.

Focal nodular hyperplasia with major sinusoidal dilatation: a misleading entity.

Focal nodular hyperplasia (FNH) is a benign liver lesion thought to be a non-specific response to locally increased blood flow. Although the diagnosis of FNH and hepatocellular adenoma (HCA) has made great progress over the last few years using modern imaging techniques, there are still in daily practice some difficulties concerning some atypical nodules. Here, the authors report the case of a 47-year-old woman with a single liver lesion thought to be, by imaging, an inflammatory HCA with major sinusoidal congestion. This nodule was revealed to be, at the microscopical level and after specific immunostaining and molecular analysis, an FNH with sinusoidal dilatation (so-called telangiectatic focal nodular hyperplasia).

Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience.

UNLABELLED: We took advantage of the reported genotype/phenotype classification to analyze our surgical series of hepatocellular adenoma (HCA). The series without specific known etiologies included 128 cases (116 women). The number of nodules varies from single, <5, and >or=5 in 78, 38, and 12 cases, respectively. The resection was complete in 95 cases. We identified 46 HNF1alpha-inactivated HCAs (44 women), 63 inflammatory HCAs (IHCA, 53 women) of which nine were also beta-catenin-activated, and seven beta-catenin-activated HCAs (all women); six additional cases had no known phenotypic marker and six others could not be phenotypically analyzed. Twenty-three of 128 HCAs showed bleeding. No differences were observed in solitary or multiple tumors in terms of hemorrhagic manifestations between groups. In contrast, differences were observed between the two main groups. Steatosis (tumor), microadenomas (resected specimen), and additional benign nodules were more frequently observed in HNF1alpha-inactivated HCAs (P < 0.01) than in IHCAs. Body mass index > 25, peliosis (tumor), and steatosis in background liver were more frequent in IHCA (P < 0.01). After complete resection, new HCAs in the centimetric range were more frequently found during follow-up (>1 year) in HNF1alpha-inactivated HCA. After incomplete resection (HCA left in nonresected liver), the majority of HCA remained stable in the two main groups and even sometimes regressed. Six patients of 128 developed hepatocellular carcinoma (HCC) (all were beta-catenin-activated, whether inflammatory or not). CONCLUSION: There were noticeable clinical differences between HNF1alpha-inactivated HCA and IHCA; there was no increased risk of bleeding or HCC related to the number of HCAs; beta-catenin-activated HCAs are at higher risk of HCC. As a consequence, we believe that management of HCA needs to be adapted to the phenotype of these tumors.

Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology.

BACKGROUND AND AIMS: Glutamine synthetase (GS) is a useful marker in tumour liver pathology, including hepatocellular adenomas and nodules in cirrhosis. We investigated the use of GS as a marker in various clinical situations, in which FNH diagnosis had been firmly established to determine its contribution to diagnosis. METHODS: Seventy-nine cases of resected FNH, all on normal (or occasionally steatotic) livers, were retrieved from our collection. The control group was composed of hepatocellular adenomas and well-differentiated hepatocellular carcinoma. The following stains: H&E, Masson's trichrome, Gordon-Sweet, PAS, perls and immunostains: CK7 and 19, and GS were carried out. FNH was diagnosed based on traditional pathological techniques. In case of uncertainty, particularly with hepatocellular adenoma, additional immunostainings including liver fatty acid-binding protein, serum amyloid A and beta-catenin were performed. RESULTS: Glutamine synthetase immunostaining was similar in all FNH cases. Positive GS staining of hepatocytic cytoplasms formed large areas, anastomosed in a 'map-like' pattern, often surrounding hepatic veins, whereas GS was not expressed in hepatocytes close to fibrotic bands containing arteries and ductules. In comparison, hepatocellular adenoma staining was completely different, even in cases of fibrotic bands due to tumour remodelling related to necrosis or haemorrhage. In hepatocellular adenomas or well-differentiated hepatocellular carcinoma presenting beta-catenin mutation, GS was positive but with a completely different pattern that appeared diffuse and not 'map-like'. CONCLUSION: Regardless of the FNH size or steatotic content, GS produced a similar and characteristic pattern and consequently represents a good marker for easily identifying resected FNH from other hepatocellular nodules.

Benign and malignant vascular tumors of the liver in adults.

Vascular tumors of the liver in adult patients include cavernous hemangioma, a common benign tumor; epithelioid hemangioendothelioma, a rare, usually low-grade malignant tumor; and angiosarcoma, a rare and very aggressive tumor. All these primary mesenchymal tumors develop on a normal liver and may also affect other organs. Their pathogenesis remains largely unknown. Hepatic tumors are increasingly detected incidentally due to widespread use of modern abdominal imaging techniques. Therefore, reliable noninvasive characterization and differentiation of such liver tumors is of major importance for clinical practice. Hemangioma follows a benign course, and a nonoperative approach for the majority of these lesions is recommended. A definitive diagnosis of epithelioid hemangioendothelioma and angiosarcoma requires histopathologic examination. Liver transplantation at an early stage has greatly improved the prognosis of epithelioid hemangioendothelioma. The prognosis of angiosarcoma remains dismal. Designing a worldwide database that contains all data about patients with these rare diseases is recommended.

Unexpected discovery of 2 cases of hepatocyte nuclear factor 1alpha-mutated infracentimetic adenomatosis.

We present 2 cases of hepatocyte nuclear factor 1alpha (HNF1alpha)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.

Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification.

UNLABELLED: Hepatocellular adenomas (HCAs) are a group of benign tumors forming three molecular pathological subgroups: (1) hepatocyte nuclear factor 1alpha (HNF-1alpha)-inactivated, (2) beta-catenin-activated, and (3) inflammatory. Some HCAs present both beta-catenin activation and inflammation. We analyzed magnetic resonance imaging (MRI) data for correlations between features on imaging and pathological classification of HCAs. We included 50 cases for which pathology specimens were classified into three groups based on immunohistochemical staining. Two characteristic MRI profiles were identified corresponding to HNF-1alpha-inactivated and inflammatory HCAs. Fifteen HCAs were HNF-1alpha-inactivated. The corresponding lesions showed (1) diffuse signal dropout on T1-weighted chemical shift sequence due to steatosis, (2) isosignal or slight hypersignal on T2-weighted (T2W) images, and (3) moderate enhancement in the arterial phase, with no persistent enhancement in the portal venous and delayed phases. For the diagnosis of HNF-1alpha-inactivated HCA, the positive predictive value of homogeneous signal dropout on chemical shift images was 100%, the negative predictive value was 94.7%, the sensitivity was 86.7%, and the specificity was 100%. Twenty-three HCAs were inflammatory and showed (1) an absence or only focal signal dropout on chemical shift sequence; (2) marked hypersignal on T2W sequences, with a stronger signal in the outer part of the lesions, correlating with sinusoidal dilatation areas; and (3) strong arterial enhancement, with persistent enhancement in the portal venous and delayed phases. Marked hypersignal on T2W sequences associated with delayed persistent enhancement had a positive predictive value of 88.5%, a negative predictive value of 84%, a sensitivity of 85.2%, and a specificity of 87.5% for the diagnosis of inflammatory HCA. CONCLUSION: HNF-1alpha-mutated HCAs and inflammatory HCAs were associated with specific MRI patterns related to diffuse fat repartition and sinusoidal dilatation, respectively.

Over-expression of glutamine synthase in focal nodular hyperplasia (part 1): early stages in the formation support the hypothesis of a focal hyper-arterialisation with venous (portal and hepatic) and biliary damage.

BACKGROUND: Most focal nodular hyperplasia (FNH) cases are diagnosed by chance. We studied a case of pre-FNH. We used glutamine synthase as an immunohistochemical marker for perivenous zones. RESULTS: Neither fibrotic scars nor hepatocytic nodules surrounded by fibrosis with a ductular reaction were observed in the sections studied. Most sections generally displayed preserved architecture. The glutamine synthase-positive hepatocyte areas were wider than those observed in non-tumoural surrounding liver, and they tended to extend outwards. Portal tracts bordering the nodule were more fibrotic, with an absence of portal veins and ducts and with arterial proliferation often in proximity with large draining veins; isolated arteries were present and hepatic veins were rare in the nodule. These features appeared prior to the identification of other major criteria characteristics of FNH, thus supporting the "hypothesis of Wanless". CONCLUSION: The findings confirm that in FNH there is a portal tract injury leading to local portal vein injury. This leads to a cascade of events, including arterial venous shunts, ductular reaction, and scar formation.

Hepatocellular adenoma: what is new in 2008.

Patients (85%) with hepatocellular adenoma (HCA) are women taking oral contraceptives. They can be divided into four subgroups according to their genotype/phenotype features. (1) Hepatocyte nuclear factor 1alpha (HNF1alpha) biallelic somatic mutations are observed in 35% of the HCA cases. It occurs in almost all cases in women. HNF1alpha-mutated HCA are most of the time, highly steatotic, with a lack of expression of liver fatty acid binding protein (LFABP) in immunohistochemistry analyses. Adenomatosis is frequently detected in this context. An HNF1alpha germline mutation is observed in less than 5% of HCA cases and can be associated with MODY 3 diabetes. (2) An activating beta-catenin mutation was found in 10% of HCA. These beta-catenin activated HCAs are observed in men and women, and specific risk factors, such as male hormone administration or glycogenosis, are associated with their development. Immunohistochemistry studies show that these HCAs overexpress beta-catenin (nuclear and cytoplasmic) and glutamine synthetase. This group of tumours has a higher risk of malignant transformation into hepatocellular carcinoma. (3) Inflammatory HCAs are observed in 40% of the cases, and they are most frequent in women but are also found in men. Lesions are characterised by inflammatory infiltrates, dystrophic arteries, sinusoidal dilatation and ductular reaction. They express serum amyloid A and C-reactive protein. In this group, GGT is frequently elevated, with a biological inflammatory syndrome present. Also, there are more overweight patients in this group. An additional 10% of inflammatory HCAs express beta-catenin, and are also at risk of malignant transformation. (4) Currently, less than 10% of HCAs are unclassified. It is hoped that in the near future it will be possible with clinical, biological and imaging data to predict in which of the 2 major groups (HNF1alpha-mutated HCA and inflammatory HCA) the patient belongs and to propose better guidelines in terms of surveillance and treatment.