Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components.

AIMS: Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. METHODS AND RESULTS: Subjects included 33 bile duct adenomas and 17 small-sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot-spot regions and immunohistochemical staining. The expression of p16INK4a , EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small-sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). CONCLUSION: Bile duct adenomas and small-sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs.

Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. We hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. METHODS AND RESULTS: We determined by histology the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P < 0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P > 0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. CONCLUSION: Bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.

A Comprehensive Approach to the Management of Benign and Malignant Ampullary Lesions: Management in Hereditary and Sporadic Settings.

PURPOSE OF REVIEW: The purpose of this review was to examine the historical roots of endoscopic management of ampullary lesions and explore emerging data on improved techniques, technologies, and outcomes. Of specific interest was answering whether there exists a reasonable body of data to support one resection technique or strategy above others. RECENT FINDINGS: Review of recent literature suggests the continued use of endoscopic ampullectomy is a safe and effective means of curative treatment of ampullary adenomas. Complications are relatively infrequent and complete endoscopic resection is possible in a majority of cases, with proper patient and lesion selection. Greater than 2 decades of experience with endoscopic ampullectomy have shown this to be a viable, well-tolerated, and highly effective means of treating ampullary adenomas. While few concrete guidelines exist to advise endoscopists on the ideal technique for resection, experience, patient selection, and prior planning can greatly influence the technical and clinical success of endoscopic ampullectomy.

BRAF V600E mutation in biliary proliferations associated with α1 -antitrypsin deficiency.

AIMS: Both homozygous and heterozygous α1 -antitrypsin (AAT) deficiency patients are at risk of developing hepatocellular carcinoma (HCC), but also of developing cholangiocarcinoma and combined HCC and cholangiocarcinoma. The aim of our study is to report a series of bile duct adenomas (BDAs) and intrahepatic cholangiocarcinoma (ICCs) in adult AAT deficiency patients, observed in our institution over a 5-year period. Our observational study includes a detailed investigation of their immunohistochemical profile and BRAF V600E mutation status. METHODS AND RESULTS: Eleven biliary lesions from five AAT deficiency patients (six BDAs from three cirrhotic patients with other concurrent liver diseases; three BDAs and two ICCs from two non-cirrhotic patients) were identified between 2010 and 2015 during routine histological investigation. Most BDAs expressed CD56, EpCAM, CD133, and CA19-9, similarly to hepatic progenitor cells (HPCs), and carried the BRAF V600E mutation (87.5%). One ICC showed a similar immunohistochemical profile but no evidence of the BRAF V600E mutation. CONCLUSIONS: Most of the biliary proliferations in AAT deficiency patients have an appearance of BDA with an HPC-related immunohistochemical profile. Their frequent BRAF V600E mutations support their neoplastic nature, but not necessarily their progression to ICC. We believe that this may depend on the patient genotype, or require a different pathway or a second mutational hit for malignant transformation. We postulate that BDA represents a heterogeneous group of biliary lesions, and that those associated with AAT deficiency may constitute a group of their own.

BRAF V600E mutational status in bile duct adenomas and hamartomas.

AIMS: Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH. METHODS AND RESULTS: Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH. CONCLUSION: Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations.

Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: pathogenesis and histological characteristics.

Morphologic features and neoplastic potentials of bile duct adenoma (BDA) and von Meyenburg complex (VMC)-like duct arising in chronic liver disease were unknown. Thirty-five BDAs and 12 VMC-like duct lesions were observed in 39 cases with chronic liver disease. BDAs were divided into the EMA-cytoplasmic type (n = 14) and EMA-luminal type (n = 21). EMA-cytoplasmic BDA composed of a proliferation of cuboidal to low-columnar cells forming an open lumen with NCAM(+)/MUC6(-), resembling an interlobular bile duct. EMA-luminal BDA showed uniform cuboidal cells with narrow lumen, and NCAM(++)/MUC6(++), resembling a ductular reaction. VMC-like duct showed positive MUC1 expression and negative MUC6. The expression of S100P, glucose transporter-1 (GLUT-1) and insulin-like growth factor II mRNA-binding protein 3 (IMP-3) were not detected in three lesions. p16 expression was higher than those of the ductular reaction, and the Ki67 and p53 indexes were very low (<1.0%). Large-sized EMA-luminal BDA shows sclerotic stroma. We classified small nodular lesions of ductal or ductular cells in chronic hepatitis and cirrhosis into the following groups: BDA, interlobular bile duct type; BDA, ductular/peribiliary gland type; and VMC-like duct. They may be reactive proliferation rather than neoplastic lesions.

Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver.

Intraductal papillary neoplasms of the bile duct are generally thought to arise from neoplastic papillary proliferation of epithelial cells lining the bile duct. We herein report a case with findings that strongly suggested that the biliary cystic tumor might have derived from a peribiliary gland. A 69-year-old female was found to have a cystic lesion with intracystic protrusions at the anterior segment of the right hepatic lobe and underwent hepatic anterior segment resection. Fluoroscopy of the resected specimen injected with contrast medium into the cyst revealed a connection between the cystic lesion and the bile ducts. The cyst was multilocular in appearance. On microscopic examination, the cyst was located within the portal tract of the inferior branch of the anterior segment and connected with the inferior branch of the bile duct. The wall of the hepatic cyst lacked an ovarian-like stroma. The tumor was composed of papillary and glandular components, and the tumor cells were similar to gastric foveolar and pyloric gland epithelia and regarded as adenoma. These tumor cells were positive for MUC 5AC, MUC6, and HIK1083. The tumor was finally diagnosed as an intraductal papillary neoplasm of the bile duct (adenoma, gastric type) arising from a peribiliary gland.

[Precursor lesions of pancreatobiliary cancer]. / Vorläuferläsionen pankreatobiliärer Karzinome.

Precursor lesions of pancreatobiliary cancer can be divided into cystic and flat lesions. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN) comprise the cystic precursors in the pancreas, while intraductal papillary neoplasm (IPN) represents their counterpart in the bile duct system. There is an adenoma-carcinoma sequence in the cystic precursors arising from four different types of epithelia: pancreatobiliary, oncocytic, intestinal and gastric. These subtypes of IPMN/IPN are morphologically and immunohistochemically well characterised and show clinical and prognostic relevance: the gastric subtype is associated with the best prognosis, followed by the oncocytic and intestinal subtypes, while the pancreatobiliary subtype is characterized by adverse clinical behaviour. Pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN) represent the flat precursors. PanIN are morphologically and biologically well defined. PanIN with lobulocentric atrophy has recently been described as a putative precursor of pancreatic cancer. Despite well defined morphological features in BilIN, the molecular alterations seen during early tumor progression in the biliary tract are poorly understood.

Bile duct adenoma: imaging features and radiologic-pathologic correlation.

PURPOSE: This study aimed to reveal characteristic imaging features of bile duct adenoma (BDA) by radiologic-pathologic correlation. MATERIALS AND METHODS: We retrospectively analyzed pathological and imaging findings of seven patients with BDA. RESULTS: The median maximum diameter of BDA was 5.5 mm. Six lesions had hemispheric morphology. Seven lesions were located in the liver subcapsular region, and proliferation of bile ductules without atypia and fibrous stroma was observed. Two lesions had different microscopic findings. In both lesions, proliferation of bile ductules without atypia was observed in the margin. In one lesion, the percentage of fibrosis and hyalinization was higher at the center than at the margin. In the other lesion, inflammatory cell infiltration was observed in the center. On contrast-enhanced imaging, BDAs showed hypervascularity in the early phase and prolonged enhancement in the delayed phase. On contrast-enhanced multidetector computed tomography during hepatic arteriography, two lesions showed ring-like enhancement in the first phase and prolonged enhancement in the second phase. These were the different histopathologic features of BDAs between the margin and center. CONCLUSION: Bile duct adenoma can be characterized as a small semicircular lesion located in the liver subcapsular region, which show hypervascularity in the early phase with prolonged enhancement.

Benign focal liver lesions masquerading as primary liver cancers on MRI.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver malignancies. HCC and ICC have characteristic imaging findings, but a number of benign entities can appear similar and can cause diagnostic dilemma. Ideally, accurate and timely diagnosis of these conditions can help the patient to avoid a needle biopsy or even unnecessary treatment. In this article, we present various benign liver lesions that display imaging characteristics that are similar to HCC and ICC on magnetic resonance imaging (MRI) and discuss salient features that may assist in accurate diagnosis.

A benign tumour of the liver mimicking malignant liver disease--cholangiocellular adenoma.

OBJECTIVE: To describe three patients with liver lesions mimicking malignant tumours diagnosed finally, using contrast-enhanced ultrasound, as cholangiocellular adenoma (bile duct adenoma). MATERIAL AND METHODS: Focal liver lesions found incidentally in three patients. Contrast-enhanced ultrasound was with use of Siemens or Esaote equipment, low MI technique, after an intravenous bolus of 2.4 ml Sonovue (Bracco, Italy). RESULTS: Lesions were 9 mm, 15 mm and 20 mm in diameter and all were enhanced in the arterial phase and hypo-enhanced in the portal venous and late phases, suggesting their malignant nature. In two patients, no primary liver tumour was found, and in the third patient, previously resected for breast cancer, a tissue specimen was considered useful for characterizing tumour receptors for more targeted chemotherapy, the lesion being assumed metastatic in nature. Transcutaneous core biopsies were performed in all three patients. Pathological analysis (including the reference pathology) revealed cholangiocellular adenoma in all of them. CONCLUSION: Cholangiocellular adenoma is a rare entity and can be a reason for possible false malignant diagnosis using contrast-enhanced ultrasound. Follow-up examinations are recommended.

Assessment of a biliary hamartoma with contrast-enhanced sonography using two different contrast agents.

A 49 year old male with carcinoma of the esophagus was staged using conventional US of the abdomen. US revealed signs of cirrhosis and a hyporeflexive focal liver lesion of about 5 mm in diameter was found. Low-MI contrast-enhanced ultrasound (CEUS) with SonoVue (Bracco, Milano, Italy) showed an enhancement pattern which was typical for benign liver lesions while high-MI CEUS with Levovist (Schering, Berlin, Germany) revealed a contrast defect in the liver late phase (4:30 min p. i.) which is typical for a malignant lesion. Due to these findings the lesion was evaluated as a potentially malignant lesion and a biopsy was performed. Histology showed a benign biliary hamartoma and incomplete cirrhosis. The findings confirmed that liver-specific contrast agents have the ability to detect very small focal liver lesions not derived from hepatic tissue but may lead to a misinterpretation as a malignant lesion. Nevertheless biliary duct adenomas are benign lesions with almost the same perfusion properties as normal liver parenchyma. Therefore, while using SonoVue, such a misinterpretation of these very common but in most cases very small and not detectable lesions seems unlikely.

Gallbladder polyps: correlation and agreement between ultrasonographic and histopathological findings in a population with high incidence of gallbladder cancer / Pólipos da vesícula biliar: correlação e concordância entre achados ultrassonográficos e histopatológicos em uma população com alta incidência de câncer de vesícula biliar

ABSTRACT BACKGROUND: Gallbladder polyps are becoming a common finding in ultrasound. The management has to consider the potential risk of malignant lesions. AIMS: The aim of this study was to analyze the ultrasound findings in patients undergoing cholecystectomy due to gallbladder polyps and compare them for histopathological findings (HPs). METHODS: Patients with an ultrasonographic diagnosis of gallbladder polyp and who underwent cholecystectomy from 2007 to 2020 were included in the study. RESULTS: A total of 447 patients were included, of whom 58% were women. The mean age was 45±12 years. The mean size of polyps in US was 7.9±3.6 mm. Notably, 9% of polyps were greater than 10 mm, and single polyps were significantly larger than the multiple ones (p=0.003). Histopathological findings confirmed the presence of polyps in 88.4%, with a mean size of 4.8±3.4 mm. In all, 16 cases were neoplastic polyps (4.1%), 4 of them being malignancies, and all were single and larger than 10 mm. We found a significant correlation between ultrasound and histopathological findings polyp size determination (r=0.44; p<0.001). The Bland-Altman analysis obtained an overestimation of the US size of 3.26 mm. The receiver operating characteristic (ROC) curve analysis between both measures obtained an area under the receiver operating characteristic curve (AUC) of 0.77 (95%CI 0.74-0.81). Ultrasound polyps size larger than 10 mm had an odds ratio (OR) of 8.147 (95%CI 2.56-23.40) for the presence of adenoma and malignancy, with a likelihood ratio of 2.78. CONCLUSIONS: There is a positive correlation and appropriate diagnostic accuracy between ultrasound size of gallbladder polyps compared to histopathological records, with a trend to overestimate the size by about 3 mm. Neoplastic polyps are uncommon, and it correlates with size. Polyps larger than 10 mm were associated with adenoma and malignancy.

RESUMO RACIONAL: Os pólipos da vesícula biliar estão se tornando um achado comum na ultrassonografia (US). O manejo deve levar em consideração o risco de lesões malignas. OBJETIVOS: Analisar os achados da ultrassonografia em pacientes submetidos à colecistectomia por pólipos vesicais e compará-los com os achados histopatológicos. MÉTODOS: Foram revisados os prontuários médicos dos pacientes com diagnóstico ultrassonográfico de pólipo vesicular e submetidos à colecistectomia no período de 2007 a 2020. RESULTADOS: Foram incluídos no estudo 447 pacientes. A média de idade foi 45±12anos, sendo 58% mulheres. O tamanho médio dos pólipos na US foide 7,9±3,6mm. Nove por cento foram maiores que 10 mm, e os pólipos únicos encontrados foram maiores do que os múltiplos (p=0,003). A HP confirmou a presença de pólipos em 88,4%, tamanho médio 4,8±3,4mm. Dezesseis eram pólipos neoplásicos (4,1%) e quatro deles malignos, únicos e maiores que 10 mm. Foi encontrado correlação significativa entre a determinação do tamanho do pólipo ao ultrassonografia e histopatológicos (r=0,44; p<0,001). A análise de Bland-Altman obteve uma superestimação do tamanho do pólipo ao US em 3,26 mm. A análise da curva da característica de operação do receptor entre as duas medidas obteve uma área sob a curva curva da característica de operação do receptor (AUC) de 0,77 (IC95% 0,74-0,81). Pólipos ao ultrassonografia maiores que 10 mm apresentaram razão de chance (OR) de 8,147 (IC95% 2,56-23,40) para presença de adenoma e malignidade, com razão de verossimilhança de 2,78. CONCLUSÕES: Há uma correlação positiva e acurácia diagnóstica apropriada entre o tamanho dos pólipos da vesícula biliar por ultrassonografia em comparação com os achados histopatológicos, com uma tendência de superestimar o tamanho em cerca de 3 mm. Pólipos maiores que 10 mm foram associados a adenoma e malignidade.

Imaging features of bile duct adenoma: case series and review of literature.

PURPOSE: We aimed to evaluate the imaging features of bile duct adenoma (BDA) on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). METHODS: Retrospective search in our institution database was performed for histologically confirmed BDA. Their imaging studies before histologic confirmation were reviewed. The search identified seven adults (mean age, 52.9 years) with histologically proven single BDA each. US (n=3), CT (n=5), and MRI (n=3) were performed before histologic confirmation. Additionally, a systematic English literature review for BDA and reported imaging findings since 2000 was also conducted using the following search criteria "bile duct adenoma, peribiliary hamartoma, biliary adenoma, CT, ultrasound, MRI" (date range: 01/01/2000 through 08/31/2016). The imaging findings of those cases reported were summarized and compared with our series. RESULTS: All seven individual nodules were well circumscribed. Five lesions were located in the right hepatic lobe and two in the left hepatic lobe. On US, lesions appeared hypoechoic (n=2) and hyperechoic (n=1). BDA was hypodense on unenhanced CT images (n=1). On MRI, BDA were hypointense on T1 (n=3), hyperintense on T2 (n=3), and hyperintense on diffusion-weighted images (n=2). On contrast-enhanced CT and MRI, BDAs showed arterial phase hyperenhancement that persisted on portal venous/delayed phase images. CONCLUSION: BDA demonstrates characteristic arterial phase hyperenhancement that persisted into the portal venous and delayed phases on CT and MRI, which may be useful in differentiating from other hepatic lesions.