Liver Adenomatosis Research Articles

Solid Hypervascular Liver Lesions

To evaluate hepatobiliary phase magnetic resonance imaging with gadobenate dimeglumine for differentiation of benign hypervascular liver lesions from malignant or high-risk lesions. Retrospective assessment was performed of 550 patients with 910 hypervascular lesions (302 focal nodular hyperplasia [FNH], 82 nodular regenerative hyperplasia [NRH], 59 hepatic adenoma or liver adenomatosis [HA/LA], 329 hepatocellular carcinomas [HCC], 12 fibrolamellar-HCC [FL-HCC], 21 peripheral cholangiocarcinomas [PCC], 105 metastases). Imaging was performed before and during the arterial, portal-venous, equilibrium, and hepatobiliary phases after gadobenate dimeglumine administration (0.05 mmol/kg). Histologic confirmation was available for ≥1 lesion per patient, except for patients with suspected FNH (diagnosis based on characteristic enhancement/follow-up). Lesion differentiation (benign/malignant) on the basis of contrast washout and lesion enhancement (hypo-/iso-/hyperintensity) was assessed (sensitivity, specificity, accuracy, PPV, and NPV) relative to histology or final diagnosis. On portal-venous or equilibrium phase images, washout was not seen for 208 of 526 (39.5%) malignant (HCC, FL-HCC, PCC, metastases) and high-risk (HA/LA) lesions. Conversely, only 5 of 384 (1.3%) true benign lesions (FNH/NRH) showed washout. Taking washout as indicating malignancy, the sensitivity, specificity, and accuracy for malignant lesion identification during these phases was 61.8%, 98.7%, and 77.4%. On hepatobiliary phase images, 289 of 302 FNH, 82 of 82 NRH, 1 of 59 HA or LA, 62 of 341 HCC or FL-HCC, and 2 of 105 metastases were hyperintense or isointense. Taking iso- or hyperintensity as an indication for lesion benignity, the sensitivity, specificity, accuracy, PPV, and NPV for benign lesion identification was 96.6%, 87.6%, 91.4%, 85.1%, and 97.3%, respectively. Hepatobiliary phase imaging with gadobenate dimeglumine is accurate for distinguishing benign lesions from malignant or high-risk lesions. Biopsy should be considered for hypointense lesions on hepatobiliary phase images after gadobenate dimeglumine.

Familial liver adenomatosis

Other names: Familial hepatic adenomas Note: Liver adenomatosis is a rare disease defined by the presence of multiple adenomas within an otherwise normal hepatic parenchyma. In 2002, frequent bi-allelic inactivation of TCF1 /HNF-1alpha, was identified in hepatocellular adenomas. In 80% of the cases both mutations were of somatic origin. However, in the remaining cases, one heterozygous germline mutation has been found in patients revealing a relation between liver adenomatosis and maturity-onset diabetes of the young (MODY3). MODY3 is a rare dominantly inherited subtype of non-insulin-dependent diabetes mellitus characterized by early onset, usually before the age of 25, and a primary defect in insulin secretion. In 1996, heterozygous germline mutations of TCF1/HNF1a have been linked to the occurrence of MODY3 in humans. Inheritance: autosomal dominant disorder with low penetrance.

Laparoscopic liver resection for hepatocellular adenoma.

To investigate the role of laparoscopy in the surgical management of hepatocellular adenoma (HA). We reviewed a prospectively collected database of consecutive patients undergoing laparoscopic liver resection for HA. 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 admission 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). The laparoscopic approach represents a safe option for the management of HA in a semi-elective setting and when major hepatectomy is required.

Solid Focal Liver Lesions: Dynamic and Late Enhancement Patterns with the Dual Phase Contrast Agent Gadobenate Dimeglumine

The purpose of this paper is to illustrate contrast enhancement patterns of solid focal liver lesions on dynamic and late phase imaging with gadobenate dimeglumine (Gd-BOPTA). Unenhanced T2- and T1-weighted, dynamic T1-weighted (arterial, portal-venous, and equilibrium) and late phase (1-3 h) Gd-BOPTA-enhanced MR imaging of different focal liver lesions (nodular regenerative hyperplasia, hepatic adenoma, liver adenomatosis, hepatocellular carcinoma, peripheral cholangiocarcinoma, hypervascular metastases, and hypovascular metastases) are shown. Dynamic imaging was performed using GRE T1-w sequences after the bolus injection of 0.1 mmol/kg Gd-BOPTA; late-phase imaging was obtained at 1-3 h after contrast injection. Dynamic imaging with Gd-BOPTA provides the same information as with conventional gadolinium-based extracellular contrast agents, while late-phase imaging gives additional information for lesion identification and characterization.

Liver Adenomatosis: A Rare Indication for Living Donor Liver Transplantation

Liver adenomatosis (LA) is a rare benign disease of the liver with unclear pathogenesis, which is characterized by multiple hepatic adenomas. The management of LA remains controversial. Herein we have reported a case of LA treated by living donor liver transplantation (LDLT). A 48-year-old woman developed multiple liver adenomas. In view of the sizes and localizations of the lesions, the patient underwent right hepatic resection and segment II nodulectomy. Thirty-four months later, she developed recurrence of multiple hepatic adenomas and 2 nodules were highly suspect for hepatocellular carcinoma. Re-resection was not indicated due to the whole liver being involved with adenomas. The patient underwent LDLT. At 45 months thereafter she is alive and disease-free. In conclusion, LDLT is indicated in cases of nonresectability; it may offer optimal results in view of the absence of portal hypertension and the elimination of waiting list time.

MRI of Hepatic Adenomatosis: Initial Observations with Gadoxetic Acid Contrast Agent in Three Patients

The purpose of our study was to describe the MR signal characteristics of histologically proven liver adenomatosis in three patients using gadoxetic acid, a newly developed liver-specific MR contrast agent. In all three patients, more than 100 liver adenomas revealed no metabolism of the new liver-specific contrast agent in the delayed phase. Because of absent or strongly reduced intracellular uptake of gadoxetic acid in all adenomas during delayed contrast-enhanced series, differentiation of adenomas from dysplastic or malignant lesions was not possible.

Liver adenomatosis: re‐evaluation of aetiology and management

Liver adenomatosis (LA) is a rare benign parenchymal liver disease with unknown aetiology. In recent reports, LA has been associated with hepatic steatosis, with potential implications for the management of this disease. The aim of this study was to determine prognosis and optimal management of patients with LA. Clinical presentation, diagnostic studies and management of patients with LA were analysed in our centre. Furthermore, a Medline search of all published case reports and series of LA patients was performed. Ninety-four patients with LA have been reported in the literature. Fifty-two per cent of females had a history of oral contraceptive use. Eighteen per cent of patients had steatosis in nontumoral tissue. In our own series, five of six patients had histologically confirmed steatosis. Forty-three per cent of patients presented with acute pain, of whom 46% had a haemorrhagical complication, in contrast to 2% of nonsymptomatic patients. Tumours <5 cm tended to increase in size during follow-up and only in four patients tumour regression was observed. Liver adenomatosis is a progressive, benign parenchymal disease mainly occurring in females. There is a potential link with hepatic steatosis with implications for the management of patients with LA. Noninvasive diagnosis is difficult because of the variety of tumoral and nontumoral components. Management should primarily be conservative.

Diagnosis and treatment of hepatic adenoma and liver adenomatosis

Diagnosis and treatment of hepatic adenoma and liver adenomatosis

Regressive liver adenomatosis following androgenic progestin therapy withdrawal: a case report with a 10-year follow-up and a molecular analysis

The relationship between sex hormones and hepatocellular adenoma development is well established. On the contrary, their contribution to liver adenomatosis (LA) development is still a debatable issue. Recently, inactivating mutations of hepatocyte nuclear factor-1alpha (HNF-1alpha) transcription factor gene or activating mutations of beta-catenin have been demonstrated in some liver adenomas, and a possible link between HNF-1alpha gene mutations and oral contraceptives has been suggested. Only two cases of regressive LA after hormone withdrawal therapy have been described so far but without any information concerning the molecular characteristics of the tumours. We report the case of a 48-year-old woman with LA, who had been taking an androgenic progestin therapy (lynestrenol) for 10 years. A major regression in the number and size of the lesions was observed 6 months after complete withdrawal of this therapy. Hepatocellular adenomas were studied by immunohistochemistry for oestrogen, progesterone and androgen receptors (ER, PR and AR respectively), and for beta-catenin. Direct sequencing of the HNF-1alpha gene was also performed. For the first time, we demonstrate significant immunostaining of AR in the hepatocellular adenomas. This staining was negative in the partially regressive adenoma. Immunostainings for ER and PR were negative. HNF-1alpha and the beta-catenin pathways were not involved in tumour pathogenesis. Our case suggests a role of androgenic progestin therapy in some cases of LA. Hormone therapy withdrawal may induce a significant regression in lesions.

Liver Adenomatosis: Classification of MR Imaging Features and Comparison with Pathologic Findings

To retrospectively compare the clinical manifestation and magnetic resonance (MR) imaging features of liver adenomatosis with pathologic findings. This study had institutional review board approval, and informed consent was waived. Twenty patients were classified on the basis of pathologic findings into three groups: those with a steatotic, those with a peliotic, and those with a mixed (steatotic and peliotic) form of liver adenomatosis. MR images were reviewed in consensus by two abdominal radiologists, and findings were compared with the pathologic classification. Statistical evaluation was performed with the Student t test. All patients were women (mean age, 39 years +/- 10 [standard deviation]). Lesions of the steatotic form (n = 7) showed (a) a mean diameter of 6.3 cm +/- 1.7, (b) slightly hyperintense signal on T2-weighted images, (c) hyper- or isointense signal on T1-weighted images with a signal dropout with fat suppression sequences, and (d) moderate enhancement at the arterial phase with no delayed enhancement. Lesions of the peliotic form (n = 7) showed (a) a somewhat larger size (8.3 cm +/- 3.6), (b) markedly hyperintense signal on T2-weighted images, (c) iso- or hyperintensity on T1-weighted images with no signal dropout with fat suppression sequences, and (d) strong arterial enhancement and persistent enhancement at the portal and delayed phase. Lesions of the mixed form (n = 6) included a combination of imaging features of the steatotic and peliotic forms. Lesions, however, were significantly larger in the mixed form than in the steatotic form (10.3 cm +/- 4, P < .05). There are three patterns of MR imaging features of liver adenomatosis that are associated with three pathologic forms (steatotic, peliotic, and mixed).

Accurate Differentiation of Focal Nodular Hyperplasia from Hepatic Adenoma at Gadobenate Dimeglumine–enhanced MR Imaging: Prospective Study

To prospectively determine the accuracy of differentiating benign focal nodular hyperplasia (FNH) from hepatic adenoma (HA) and liver adenomatosis (LA) by using gadobenate dimeglumine-enhanced magnetic resonance (MR) imaging. The ethics committee at each center approved the study, and all patients provided informed consent. Seventy-three patients with confirmed FNH and 35 patients with confirmed HA (n = 27) or LA (n = 8) underwent MR imaging before (T2-weighted half-Fourier rapid acquisition with relaxation enhancement or T2-weighted fast spin-echo and T1-weighted gradient-echo [GRE] sequences) and at 25-30 seconds (arterial phase), 70-90 seconds (portal venous phase), 3-5 minutes (equilibrium phase), and 1-3 hours (delayed phase) after (T1-weighted GRE sequences only, with or without fat suppression) bolus administration of 0.1 mmol per kilogram of body weight gadobenate dimeglumine. The enhancement of 235 lesions (128 FNH, 32 HA, and 75 LA lesions) relative to the normal liver parenchyma was assessed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy for the differentiation of FNH from HA and LA were determined. Hyper- and isointensity on T2-weighted and iso- and hypointensity on T1-weighted GRE images were noted for 177 (88.9%) of 199 lesions visible on unenhanced images. On dynamic phase images after contrast material administration, 231 (98.3%) of 235 lesions showed rapid strong enhancement during the arterial phase and appeared hyper- to isointense during portal venous and equilibrium phases. Accurate differentiation of FNH from HA and LA was not possible on the basis of precontrast or dynamic phase images alone. At 1-3 hours after contrast material enhancement, 124 (96.9%) of 128 FNHs appeared hyper- or isointense, while 107 (100%) HA and LA lesions appeared hypointense. The sensitivity, specificity, PPV, NPV, and overall accuracy for the differentiation of FNH from HA and LA were 96.9%, 100%, 100%, 96.4%, and 98.3%, respectively. Accurate differentiation of FNH from HA and LA is achievable on delayed T1-weighted GRE images after administration of gadobenate dimeglumine.

Intrahepatic rupture of a caudate lobe adenoma in liver adenomatosis

Hepatic adenomatosis is a rare benign disease that is more common in young and middle-aged women who are non-steroid dependent; it is usually symptomatic, progressive, and susceptible to hemorrhagic complications. Malignant transformation within adenomas is rare. The management of hepatic adenomatosis remains difficult due to the absence of predictive signs of complications, other than the size of the adenomas. Resective surgery is usually indicated, but liver transplantation could be an indication in highly symptomatic or progressive forms of the disease and represents the treatment of choice in cases of malignant transformation. We report a case of intrahepatic rupture of a caudate lobe adenoma which occurred in an adolescent with hepatic adenomatosis; we also present a brief review of the literature.

Simultaneous liver-kidney transplantation for glycogen storage disease type IA (von Gierke's disease)

Introduction Glycogen storage disease type Ia (GSDIa) is due to the deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestine. Although significant progress has been achieved in the management of patients with GSDIa, complications still emerge. The potential for development of liver adenomatosis and kidney failure makes these patients candidates for simultaneous liver-kidney transplantation (SLKT). Herein, we describe such a transplantation in a patient affected by this rare storage disease. Methods A 25-year-old female patient with GSDIa developed hepatic adenoma and kidney failure despite dietary therapy. The patient underwent an SLKT from a cadaveric donor. Results The operative time was 8 hours without hemotransfusion. Only a transitory lactic acidosis was observed. Laboratory results normalized on postoperative day 7. The patient was discharged on postoperative day 9. After 4 months, the patient is in good condition with well-functioning kidney and liver allografts. Conclusion Patients with end-stage renal disease secondary to GSDIa should be considered for SLKT, especially when the disease is in an early stage.

Hepatocyte Nuclear Factor-1α Gene Inactivation: Cosegregation between Liver Adenomatosis and Diabetes Phenotypes in Two Maturity-Onset Diabetes of the Young (MODY)3 Families

Heterozygous germline mutations of the hepatocyte nuclear factor (HNF)-1 alpha are associated with maturity-onset diabetes of the young (MODY)3. Recently, the biallelic inactivation of the HNF-1 alpha gene was reported in liver adenomas. We show the occurrence of liver adenomatosis in six MODY3-affected patients from two unrelated and large families. Liver adenomatosis was characterized by the presence of numerous adenomas within a normal hepatic parenchyma. The HNF-1 alpha hot-spot germline mutation P291fs was identified in the two probands and in 16 relatives from the two families. The six patients affected by liver adenomatosis and diabetes exhibited the mutation. The analysis of liver-cell tumors from two affected patients evidenced the biallelic inactivation of HNF-1 alpha. The familial screening confirmed the clinical heterogeneity of the liver phenotype, from silent liver adenomatosis to fatal hemorrhage. These observations warrant the systematic screening for liver adenomatosis in MODY3 families to prevent its potentially deadly complications. Moreover, such screening may help to determine if a particular mutational spectrum of HNF-1 alpha is associated with liver adenomatosis and to establish its prevalence in this frequent form of diabetes in the young adult.

Familia liver adenomatosis associated with hepatocyte nuclear factor 1α inactivation

Background & Aims: Germline mutations in hepatocyte nuclear factor 1α (TCF1/HNF-1α) are associated with maturity-onset diabetes of the young type 3 (MODY3), and somatic biallelic inactivations of the gene are found in hepatocellular adenomas and liver adenomatosis. This study investigated cosegregation of HNF-1α germline mutations with diabetes and liver adenomatosis in 2 families. Methods: Two unrelated patients with liver adenomatosis and harboring HNF-1α germline and somatic mutations were studied. Subsequently, we screened 9 relatives in the 2 independent families for diabetes, hepatocellular adenomas, and HNF-1α germline mutations. Results: In family A, a father and his son presented with an intraperitoneal hemorrhagic rupture of a liver adenomatosis without diabetes. A heterozygous R229X germline mutation was identified in HNF-1α in the father and his son and also in his second 27-year-old son without hepatocellular adenomas. In family B, a diagnosis of liver adenomatosis was made fortuitously in a 14-year-old girl. A heterozygous G55fsX57 germline mutation in HNF-1α was identified in this patient, her diabetic father, and her 2 sisters. Systematic exploration showed liver adenomatosis in the 2 sisters. Somatic inactivation of the second HNF-1α allele was found in liver tumors in both families. Conclusions: This study describes familial liver adenomatosis and shows the association with germline HNF-1α mutations in adults and children. It also highlights the importance of screening for hepatocellular adenomas, diabetes, and HNF-1α germline mutations in relatives of patients with liver adenomatosis. Finally, prevalence of liver adenomatosis remains to be evaluated in MODY3 subjects.

The identification of small nodules in liver adenomatosis

Background/Aims: Liver adenomatosis is characterized by the presence of multiple adenomas of various sizes in the liver. The aim of this study was to characterize the morphology of small nodules which can be difficult to identify. Methods: Seven patients included in this study underwent surgery for the removal of one or several nodules. All, but one, were females. Three out of seven presented with acute bleeding. Five had six or more nodules at presentation, and two only one, who developed nodules later on during follow-up. Results: All of the large nodules that were >2 cm, except one, were typical adenomas with or without hemorrhagic areas. Smaller nodules (1–2 cm), some of which discovered on the resected specimen were either typical adenomas or non-typical nodules. These non-typical nodules were characterized by a polylobulated aspect with steatotic zones, and in between, bands of non-steatotic hepatocytes with portal tracts-like structures containing occasional cytokeratin 7 and less often cytokeratin 19 positive biliary cells. Numerous steatotic foci were also seen in four cases. They were isolated or grouped forming microadenomas or non-typical micronodules (<1 cm) containing biliary elements. Our findings lead to the following hypothesis: adenomatosis is characterized by the simultaneous occurrence of multiple adenomas; if several adenomatous foci expand at the same time in the same area, they will form one polylobulated nodule containing non-adenomatous tissue with portal tracts in between areas of adenomatous tissue (non-typical micronodule). Such a small micronodule may in turn expand and join another micronodule to form a bigger one by the same process (non-typical nodule). As nodules grow, their non-adenomatous components including hepatocytic plates and portal tracts constituents will progressively disappear to end up with the classical aspect of an adenoma. Conclusions: This hypothesis supports the concept that non-typical nodules/micronodules are adenomas precursors. However, they can be difficult to classify since they resemble focal nodular hyperplasia precursor.

Liver adenomatosis: First results of a national registry

Liver adenomatosis: First results of a national registry

Hepatic adenomas: imaging and pathologic findings.

Hepatocellular adenoma is a rare benign lesion that is most often seen in young women with a history of oral contraceptive use. It is typically solitary, although multiple lesions have been reported, particularly in patients with glycogen storage disease and liver adenomatosis. Because of the risk of hemorrhage and malignant transformation, hepatocellular adenomas must be identified and treated promptly. At pathologic analysis, hepatocellular adenoma is usually a well-circumscribed, nonlobulated lesion, and at gross examination, resected adenomas frequently demonstrate areas of hemorrhage and infarction. Most adenomas are not specifically diagnosed at ultrasonography (US) and are usually further evaluated with computed tomography (CT) or other imaging modalities. Color Doppler US may help differentiate hepatocellular adenoma from focal nodular hyperplasia. Multiphasic helical CT allows more accurate detection and characterization of focal hepatic lesions. Hepatocellular adenomas are typically bright on T1-weighted magnetic resonance images and predominantly hyperintense relative to liver on T2-weighted images. The prognosis of hepatic adenoma is not well established. Criteria that guide treatment include the number and size of the lesions, the presence of symptoms, and the surgical risk incurred by the patient. Understanding the imaging appearance of hepatocellular adenoma can help avoid misdiagnosis and facilitate prompt, effective treatment.

Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients.

To report and correlate the clinical, histopathologic, and imaging findings in 15 patients with liver adenomatosis. Fifteen adult patients had more than 10 hepatic adenomas each and no history of glycogen storage disease or anabolic steroid use. Ten of them underwent bolus-enhanced dynamic computed tomography (CT) with or without magnetic resonance (MR) imaging, ultrasonography, and/or angiography. Clinical abnormalities included abdominal pain in 11 (73%) and hepatomegaly in 10 (67%) patients, and abnormal liver function in 10 (91%) of 11 patients. The number of adenomas in each patient was 10-50 at imaging, but many more lesions were found in the resected specimens. Hemorrhage was commonly found within adenomas at histopathologic analysis, but only four patients had clinical and imaging evidence of substantial hemorrhage. In all patients, the adenomas increased over time, and two patients developed hepatocellular carcinoma. CT and MR features of the adenomas included evidence of hypervascularity (63%), intratumoral fat (50% of patients at CT, 80% at MR), and decreased conspicuity at portal venous and delayed-phase imaging. Fifty percent of patients had congenital or acquired hepatic vascular abnormalities. The imaging and histopathologic features of individual adenomatous lesions are similar to those reported in young women who are taking oral contraceptives. However, the lesions in liver adenomatosis are not steroid dependent but rather multiple, progressive, and symptomatic, and they are more likely to lead to impaired liver function, hemorrhage, and perhaps malignant degeneration.

Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.

Liver adenomatosis (LA) is a rare disease originally defined by Flejou et al in 1985 from a series of 13 cases. In 1998, 38 cases were available for analysis, including eight personal cases. The aim of this study was to review and reappraise the characteristics of this rare liver disease and to discuss diagnosis and therapeutic options. LA was defined as the presence of >10 adenomas in an otherwise normal parenchyma. Neither female predominance nor a relation with estrogen/progesterone intake has been noted. Natural progression is poorly known. The clinical presentation, evolution, histologic characteristics, and therapeutic options and results were analyzed based on a personal series of eight new cases and an updated review of the literature. From a diagnostic standpoint, two forms of liver adenomatosis with different presentations and evolution can be defined: a massive form and a multifocal form. The role of estrogen and progesterone is reevaluated. The risks of hemorrhage and malignant transformation are of major concern. In the authors' series, liver transplantation was indicated in two young women with the massive, aggressive form, and good results were obtained. Liver adenomatosis is a rare disease, more common in women, where outcome and evolution vary and are exacerbated by estrogen intake. Most often, conservative surgery is indicated. Liver transplantation is indicated only in highly symptomatic and aggressive forms of the disease.