Ultrasound features of hepatocellular adenoma and the additional value of contrast-enhanced ultrasound

BACKGROUNI）： Hepatocellular adenoma （HCA） is a rare benign tumor of the liver. It is of clinical importance to dif- ferentiate HCA from other liver tumors, especially hepatocel- lular carcinoma （HCC）. This study aimed to evaluate the char- acteristic features of HCA by conventional ultrasound and contrast-enhanced ultrasound （CEUS） findings. METHODS： Twenty-six patients （10 males and 16 females; mean age 36.2＋5.0 years） with 26 histopathologically proven HCAs were retrospectively identified. According to the maxi- mum diameter of HCAs, they were divided into three groups： 〈30 mm, 30-50 mm, and 〉50 mm. Ultrasound examinations were performed with C5-2 broadband curved transducer of Philips iU22 unit （Philips Bothell, WA, USA）. For each lesion, a dose of 2.4 mL SonoVue~ （Bracco Imaging Spa, Milan, Italy） was injected as a quick bolus into the cubital vein. Lesions＇ echogenicity, color-Doppler flow imaging and contrast en- hancement patterns were recorded. RESULTS： Grayscale ultrasound revealed that most of HCAs were hypoechoic （73.1%, 19/26）. Spotty calcifications were detected in 26.9% （7/26） of the lesions. Color-Doppler flow imaging detected centripetal bulky color flow in 46.2% （12/26） of the HCAs. CEUS showed that 73.1% （19/26） of the HCAs displayed as rapid, complete and homogenous enhancement, and 53.8% （14/26） showed decreased contrast enhancement in the late phase. There was no significant difference in enhance- ment patterns among different sizes of HCAs （P〉0.05）. Centripetal enhancement with subcapsular tortuous arteries was common in larger HCAs.

Hepatocellular adenoma in the paediatric population:Molecular classification and clinical associations

Hepatocellular adenomas(HCAs)represent rare,benign liver tumours occurring predominantly in females taking oral contraceptives.In children,HCAs comprise less than 5%of hepatic tumours and demonstrate association with various conditions.The contemporary classification of HCAs,based on their distinctive genotypes and clinical phenotypes,includes hepatocyte nuclear factor 1 homeobox alpha-inactivated HCAs,beta-catenin-mutated HCAs,inflammatory HCAs,combined beta-catenin-mutated and inflammatory HCAs,sonic hedgehogactivated HCAs,and unclassified HCAs.In children,there is a lack of literature on the characteristics and distribution of HCA subtypes.In this review,we summarized different HCA subtypes and the clinicopathologic spectrum of HCAs in the paediatric population.

Hepatocellular adenoma:Where are we now?

Hepatocellular adenoma(HCA)is a benign hepatocellular neoplasm,commonly occurs in young women with a history of oral contraceptive use.Complications including hemorrhage and malignant transformation necessitate the need for a thorough understanding of the underlying molecular signatures in this entity.Recent molecular studies have significantly expanded our knowledge of HCAs.The well-developed phenotype-genotype classification system improves clinical management through identifying“high risk”subtype of HCAs.In this article,we attempt to provide updated information on clinical,pathologic and molecular features of each subtype of HCAs.

“Bull’s eye”appearance of hepatocellular adenomas in patients with glycogen storage disease type I-atypical magnetic resonance imaging findings:Two case reports

BACKGROUND Hepatocellular adenomas are rare tumors that can occur in patients with glycogen storage disease type I.CASE SUMMARY We herein report two cases of histologically proven hepatocellular adenomas in patients with glycogen storage disease type I.Magnetic resonance imaging(MRI)was performed after bolus injection of gadoxetate disodium,a liver-specific gadolinium-based MRI contrast agent.In the present cases,some of the hepatocellular adenomas showed unexpectedly a“bull’s eye”appearance on T2-weighted and post-contrast images,which was not previously described as imaging findings of hepatocellular adenomas in glycogen storage disease.A bull’s eye appearance on T2-weighted images can be encountered in both benign(i.e.,abscess)or malignant(i.e.,epithelioid hemangioendothelioma,cholangiocarcinoma,and metastases)hepatic lesions.CONCLUSION We present two cases of hepatocellular adenomas in patients with glycogen storage disease type 1,in which gadoxetate disodium-MRI showed atypical imaging findings for hepatocellular adenomas.At present there is no systematic study evaluating MRI findings of hepatocellular adenomas in patients with glycogen storage disease,further studies are needed to specifically investigate this issue.

Polymorphic multiple hepatocellular adenoma including a non-steatotic HNF1α-inactivated variant

To the Editor:Hepatocellular adenomas(HCAs)consist of benign liver tumors favored by the use of oral contraceptives,which preferentially occur in women.[1,2]They expose to the risk of hemorrhage(20%of cases)and more rarely,to the risk of malignant transformation(4%-10%of cases).[3,4]Multiple HCAs,which are defined by the presence of 10 or more

Focal nodular hyperplasia associated with a giant hepatocellular adenoma:A case report and review of literature

BACKGROUND Focal nodular hyperplasia(FNH)and hepatocellular adenoma(HCA)are wellknown benign liver lesions.Surgical treatment is usually chosen for symptomatic patients,lesions more than 5 cm,and uncertainty of diagnosis.CASE SUMMARY We described the case of a large liver composite tumor in an asymptomatic 34-year-old female under oral contraceptive for 17-years.The imaging work-out described two components in this liver tumor;measuring 6 cm×6 cm and 14 cm×12 cm×6 cm.The multidisciplinary team suggested surgery for this young woman with an unclear HCA diagnosis.She underwent a laparoscopic left liver lobectomy,with an uneventful postoperative course.Final pathological examination confirmed FNH associated with a large HCA.This manuscript aimed to make a literature review of the current management in this particular situation of large simultaneous benign liver tumors.CONCLUSION The simultaneous presence of benign composite liver tumors is rare.This case highlights the management in a multidisciplinary team setting.

Hepatocellular adenoma: An unsolved diagnostic enigma

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1α-mutated HCA, inflammatory HCA,β-catenin-mutated HCA, and unclassified HCA.β-cateninmutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1α-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

Management and outcome of hepatocellular adenoma with massive bleeding at presentation

AIM To evaluate outcome of acute management and risk of rebleeding in patients with massive hemorrhage due to hepatocellular adenoma(HCA). METHODS This retrospective cohort study included all consecutive patients who presented to our hospital with massive hemorrhage(grade Ⅱ or Ⅲ) due to ruptured HCA and were admitted for observation and/or intervention between 1999-2016. The diagnosis of HCA was based on radiological findings from contrastenhanced magnetic resonance imaging(MRI) or pathological findings from biopsy or resection of the HCA. Hemorrhage was diagnosed based on findings from computed tomography or MRI. Medical records were reviewed for demographic features, clinical presentation, tumor features, initial and subsequent management, short-and long-term complications and patient and lesion follow-up. RESULTS All patients were female(n = 23). Treatment in the acute phase consisted of embolization(n = 9, 39.1%), conservative therapy(n = 13, 56.5%), andother intervention(n = 1, 4.3%). Median hemoglobin level decreased significantly more on days 0-3 in the intervention group than in the patients initially treated conservatively(0.9 mmol/L vs 2.4 mmol/L respectively, P = 0.006). In total, 4 patients suffered severe shortterm complications, which included hypovolemic shock, acute liver failure and abscess formation. After a median follow-up of 36 mo, tumor regression in nonsurgically treated patients occurred with a median reduction of 76 mm down to 25 mm. Four patients underwent secondary(elective) treatment(i.e., tumor resection) to address HCA size of > 5 cm and/or desire for future pregnancy. One case of rebleeding was documented(4.3%). None of the patients experienced long-term complication(mean follow-up time: 36 mo). CONCLUSION With a 4.3% risk of rebleeding, secondary(elective) treatment of HCA after massive hemorrhage may only be considered in patients with persistent HCA > 5 cm.

Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma

AIM: To identify clonality and genetic alterations in focal nodular hyperplasia (FNH) and the nodules derived from it. METHODS: Twelve FNH lesions were examined. Twelve hepatocellular adenomas (HCAs) and 22 hepatocellular carcinomas (HCCs) were used as references. Nodules of different types were identified and isolated from FNH by microdissection. An X-chromosome inactivation assay was employed to describe their clonality status. Loss of heterozygosity (LOH) was detected, using 57 markers, for genetic alterations.RESULTS: Nodules of altered hepatocytes (NAH), the putative precursors of HCA and HCC, were found in all the FNH lesions. Polyclonality was revealed in 10 FNH lesions from female patients, and LOH was not detected in any of the six FNH lesions examined, the results apparently showing their polyclonal nature. In contrast, monoclonality was demonstrated in all the eight HCAs and in four of the HCCs from females, and allelic imbalances were found in the HCAs (9/9) and HCCs (15/18), with chromosomal arms 11p, 13q and 17p affected in the former, and 6q, 8p, 11p, 16q and 17p affected in the latter lesions in high frequencies (≥ 30%). Monoclonality was revealed in 21 (40%) of the 52 microdissected NAH, but was not found in any of the f ive ordinary nodules. LOH was found in all of the 13 NAH tested, being highly frequent at six loci on 8p, 11p, 13q and 17p. CONCLUSION: FNH, as a whole, is polyclonal, but some of the NAH lesions derived from it are already neoplastic and harbor similar allelic imbalances as HCAs.

Successful treatment of multiple hepatocellular adenomas with percutaneous radiofrequency ablation

Hepatocellular adenoma(HCA)is one of the important complications of glycogen storage disease typeⅠa(GSD-Ⅰa)because it can be transformed into hepatocellular carcinoma.Although surgical resection is a standard treatment of choice for solitary HCA,multiple HCAs in GSD-Ⅰa patients present as therapeutic challenges for curative treatment.Therefore,treatment strategy according to malignant potential is important in management of HCAs in GSD-Ⅰa.The authors present a case of histologically proven multiple HCAs withoutβ-catenin mutations occurred in a GSD-Ⅰa patient treated successfully with percutaneous radiofrequency ablation as a minimally invasive therapy.

Laparoscopic liver resection for hepatocellular adenoma

AIM:To investigate the role of laparoscopy in the surgical management of hepatocellular adenoma(HA). METHODS:We reviewed a prospectively collected database of consecutive patients undergoing laparoscopic liver resection for HA. RESULTS:Thirteen patients underwent fifteen pure laparoscopic liver resections for HA(male/female:3/10; median age 42 years,range 22-72 years).Two patients with liver adenomatosis required two different laparoscopic operations for ruptured adenomas.Indications for surgery were:symptoms in 12 cases,need to rule out malignancy in 2 cases and preoperative diagnosis of large HA in one case.Symptoms were related to bleeding in 10 cases,sepsis due to liver abscess following embolization of HA in one case and mass effect in one case(shoulder tip pain).Five cases with ruptured bleeding adenoma required emergency admis-sion and treatment with selective arterial embolization. Laparoscopic liver resection was then semi-electively performed.Eight patients(62%)required major hepatectomy[right hepatectomy(n=5),left hepatectomy (n=3)].No conversion to open surgery occurred.The median operative time for pure laparoscopic procedures was 270 min(range 135-360 min).The median size of the excised lesions was 85 mm(range 25-180 mm). One patient with adenomatosis developed postoperative bleeding requiring embolization.Mortality was nil. The median hospital stay was 4 d(range 1-18 d)with a median high dependency unit stay of 1 d(range 0-7 d). CONCLUSION:The laparoscopic approach represents a safe option for the management of HA in a semi-elective setting and when major hepatectomy is required.

Hepatocellular adenoma with malignant transformation in male patients with non-cirrhotic livers

Introduction:Hepatocellular adenomas(HCAs),with a risk of malignant transformation into hepatocellular carcinoma(HCQ,classically develop in young women who are taking oral contraceptives.It is now clear that HCAs may also occur in men.However,it is rarely reported that HCAs with malignant transformation occur in male patients with non-cirrhotic livers.This study aimed to characterize the malignancy of HCAs occurring in male patients.Methods:All patients with HCAs with malignant transformation who underwent hepatectomy at the Cancer Institute and Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College between January 1,1999 and December 31,2011 were enrolled in the study.The clinical characteristics as well as radiologic and pathologic data were reviewed.Results:HCAs with malignant transformation were observed in 5 male patients with non-cirrhotic livers,but not in female patients.The alpha-fetoprotein(AFP) levels were higher in patients with HCAs with malignant transformation than in patients with HCAs without malignant transformation.The diameters of the tumors with malignant transformation were larger than 5 cm in 3 cases and smaller than 5 cm in 2 cases.The 5 patients were all alive without recurrence by the end of the study period.The disease-free survival times of the 5 patients were 26,48,69,69,and 92 months.Conclusion:Our results indicate that resection would be advised even if the presumptive diagnosis is adenoma smaller than 5 cm in diameter,especially in male patients.

Contrast-enhanced ultrasonographic findings of serum amyloid A-positive hepatocellular neoplasm: Does hepatocellular adenoma arise in cirrhotic liver?

Hepatocellular adenoma(HCA) was recently classified into four pathological subtypes. There have been few studies describing the findings of contrast-enhanced ultrasonography(CEUS) of each type. Our case concerns a 78-year-old man who had undergone routine medical check-ups for hepatitis C for 11 years. Abdominal ultrasonography showed a 28 mm, hypo-echoic mass in the segment 4 of the liver. His integrating amount of drinking was 670 kg convert into ethanol. CEUS with Sonazoid demonstrated mild uniform hypo-enhancement with inflow of microbubbles from the periphery of the tumor in the arterial phase, and heterogeneously hypo-enhancement in the post vascular phase. Because the mass increased in size within 3 mo, a well differentiated hepatocellular carcinoma was suspected, and hepatic resection was performed. Microscopic findings showed homogeneous cell proliferation with low grade atypia, infiltration of inflammatory cells, ductular reactions, fatty deposit in part, and sinusoidal dilation. Immunohistochemistry revealed geographic positive for serum amyloid A(SAA), focal positive for glutaminesynthetase, diffuse and strong positive for C-reactive protein, and positive for liver-type fatty acid binding protein. These pathological features corresponded to that of an inflammatory HCA. However, we could not make a clear diagnosis, because HCAs were defined as not to arise in cirrhotic liver. Finally, this tumor was diagnosed as a SAA positive hepatocellular neoplasm.

Genotype phenotype classification of hepatocellular adenoma

Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria (presence of a TCF1/HNF1α or β-catenin mutation), and an additional histological criterion (presence or absence of an inflammatory infiltrate), subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups: the fi rst one is defi ned by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 (HNF1α); the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of in? ammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia (FNH), and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.

Pictures of focal nodular hyperplasia and hepatocellular adenomas

This practical atlas aims to help liver and non liver pa-thologists to recognize benign hepatocellular nodules on resected specimen. Macroscopic and microscopic views together with immunohistochemical stains illustrate typical and atypical aspects of focal nodular hyperplasia and of hepatocellular adenoma, including hepatocel-lular adenomas subtypes with references to clinical and imaging data. Each step is important to make a correct diagnosis. The specimen including the nodule and the non-tumoral liver should be sliced, photographed and all different looking areas adequately sampled for par-affin inclusion. Routine histology includes HE, trichrome and cytokeratin 7. Immunohistochemistry includes glu-tamine synthase and according to the above results ad-ditional markers such as liver fatty acid binding protein, C reactive protein and beta catenin may be realized to differentiate focal nodular hyperplasia from hepatocel-lular adenoma subtypes. Clues for differential diagnosis and pitfalls are explained and illustrated.

Multi-parameter ultrasound based on the logistic regression model in the differential diagnosis of hepatocellular adenoma and focal nodular hyperplasia

BACKGROUND Focal nodular hyperplasia(FNH)has very low potential risk,and a tendency to spontaneously resolve.Hepatocellular adenoma(HCA)has a certain malignant tendency,and its prognosis is significantly different from FNH.Accurate identification of HCA and FNH is critical for clinical treatment.AIM To analyze the value of multi-parameter ultrasound index based on logistic regression for the differential diagnosis of HCA and FNH.METHODS Thirty-one patients with HCA were included in the HCA group.Fifty patients with FNH were included in the FNH group.The clinical data were collected and recorded in the two groups.Conventional ultrasound,shear wave elastography,and contrast-enhanced ultrasound were performed,and the lesion location,lesion echo,Young’s modulus(YM)value,YM ratio,and changes of time intense curve(TIC)were recorded.Multivariate logistic regression analysis was used to screen the indicators that can be used for the differential diagnosis of HCA and FNH.A ROC curve was established for the potential indicators to analyze the accuracy of the differential diagnosis of HCA and FNH.The value of the combined indicators for distinguishing HCA and FNH were explored.RESULTS Multivariate logistic regression analysis showed that lesion echo(P=0.000),YM value(P=0.000)and TIC decreasing slope(P=0.000)were the potential indicators identifying HCA and FNH.In the ROC curve analysis,the accuracy of the YM value distinguishing HCA and FNH was the highest(AUC=0.891),which was significantly higher than the AUC of the lesion echo and the TIC decreasing slope(P<0.05).The accuracy of the combined diagnosis was the highest(AUC=0.938),which was significantly higher than the AUC of the indicators diagnosing HCA individually(P<0.05).This sensitivity was 91.23%,and the specificity was 83.33%.CONCLUSION The combination of lesion echo,YM value and TIC decreasing slope can accurately differentiate between HCA and FNH.

Radiological aspects of giant hepatocellular adenoma of the left liver: A case report

BACKGROUND Hepatocellular adenoma(HCA)is very rare and has a high misdiagnosis rate through clinical and imaging examinations.We report a case of giant HCA of the left liver in a young woman that was diagnosed by medical imaging and pathology.CASE SUMMARY A 21-year-old woman was admitted to our department for a giant hepatic tumor measuring 22 cm×20 cm×10 cm that completely replaced the left hepatic lobe.Her laboratory data only suggested mildly elevated liver function parameters and C-reactive protein levels.A computed tomography(CT)scan showed mixed density in the tumor.Magnetic resonance imaging(MRI)of the tumor revealed a heterogeneous hypointensity on T1-weighed MR images and heterogeneous hyperintensity on T2-weighed MR images.On dynamic contrast CT and MRI scans,the tumor presented marked enhancement and the subcapsular feeding arteries were clearly visible in the arterial phase,with persistent enhancement in the portal and delayed phases.Moreover,the tumor capsule was especially prominent on T1-weighted MR images and showed marked enhancement in the delayed phase.Based on these imaging manifestations,the tumor was initially considered to be an HCA.Subsequently,the tumor was completely resected and pathologically diagnosed as an HCA.CONCLUSION HCA is an extremely rare hepatic tumor.Preoperative misdiagnoses were common not only due to the absence of special clinical manifestations and laboratory examination findings,but also due to the clinicians’lack of practical diagnostic experience and vigilance in identifying HCA on medical images.Our case highlights the importance of the combination of contrast-enhanced CT and MRI in the preoperative diagnosis of HCA.

Malignant transformation of hepatocellular adenoma in a young female patient after ovulation induction fertility treatment:A case report

BACKGROUND Hepatocellular adenoma(HCA) is a rare benign liver tumor usually affecting young women with a history of prolonged use of hormonal contraception.Although the majority is asymptomatic, a low proportion may have significant complications such as bleeding or malignancy. Despite responding to the hormonal stimulus, the desire for pregnancy in patients with small HCA is not contraindicated. However, through this work we demonstrate that intensive hormonal therapies such as those used in the treatment of infertility can trigger serious complications CASE SUMMARY A 33-year-old female with a 10-year history of oral contraceptive use was diagnosed with a hepatic tumor as an incidental finding in an abdominal ultrasound. The patient showed no symptoms and physical examination was unremarkable. Laboratory functional tests were within normal limits and tests for serum tumor markers were negative. An abdominal magnetic resonance imaging(MRI) was performed, showing a 30 mm × 29 mm focal lesion in segment VI of the liver compatible with HCA or Focal Nodular Hyperplasia with atypical behavior. After a total of six years of follow-up, the patient underwent ovulation induction treatment for infertility. On a following MRI, a suspected malignancy was warned and hence, surgery was decided. The surgical specimen revealed malignant transformation of HCA towards trabecular hepatocarcinoma with dedifferentiated areas. There was non-evidence of tumor recurrence after three years of clinical and imaging follow-up.,CONCLUSION HCAs can be malignant regardless its size and low-risk appearance on MRI when an ovultation induction therapy is indicated.

Rapidly enlarged inflammatory hepatocellular adenoma: A case report

We present a rare case of rapidly enlarging inflamematory hepatocellular adenoma (IHCA) in a 60-year-old Japanese man. Screening abdominal computed tomography (CT) for the fatty liver patient revealed a 1.7-cm liver mass in the anterior segment of the liver. After 19 months, the lesion had rapidly enlarged to 6 cm in diameter and the patient was referred to our hospital. On perflubutane microbubble contrast-enhanced ultrasonography, the tumor showed a characteristic centripetal filling pattern in the vascular phase. We performed hepatic anterior segment resection because we could not rule out malignant tumor. Histopathological examination showed hyperplasia of mildly atypical hepatocytes and sinusoidal dilatation with marked inflammatory cell infiltration. Immunohistological staining revealed positive staining for serum amyloid A and C-reactive protein;therefore, we diagnosed this tumor as IHCA. The patient remains alive 42 months after operation without evidence of recurrence.

A Case of Inflammatory Hepatocellular Adenoma Complicated by Steatohepatitis

A 54-year-old man with hypertension, dyslipidemia, diabetes mellitus and fatty liver was referred to our institution for accurate diagnosis of a 4-cm space-occupying lesion in subsegment 6 of the liver, identified on ultrasonography as an iso-to hypointense lesion with clear margins. Dynamic computed tomography disclosed light accumulation of contrast medium at the margins of the space-occupying lesion from the arterial phase through to the venous phase. Sonazoid-enhanced ultrasonography showed staining of the tumor margins in the vascular phase, disappearing in the post-vascular phase. Hepatic arteriography identified the space-occupying lesion as hypervascular. Since accurate diagnosis by imaging was difficult, tumor resection was performed to exclude hepatocellular carcinoma, after obtaining consent from the patient. Histological examination revealed steatohepatitis and sinusoidal dilatation, representing socalled peliosis hepatis, in the surroundings, while the tumor showed mild hepatocellular atypia. On immunohistochemistry, tumor cells were positive for liver fatty acid-binding protein, glutamine synthetase and serum amyloid A, and negative for β-catenin and glypican 3. Glutamine synthetase, in particular, showed strong diffuse staining. Inflammatory hepatocellular adenoma was thus considered the most likely diagnosis. The pathogenesis and outcome of inflammatory hepatocellular adenoma are not fully understood, and this case with concomitant steatohepatitis was considered worth reporting.