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.

NRAS-mutated oncocytic benign liver lesion in an organ donor: Pitfalls and troubles in frozen section diagnosis and risk assessment.

BACKGROUND: In the transplant setting, the definition of the risk of neoplastic transmission from donor to recipient often requires intraoperative pathological evaluation on frozen sections. Although most lesions can be easily classified into acceptable or unacceptable risk according to the Italian National Guidelines, there are cases in which unusual histologic features cannot be further investigated because of the lack of ancillary techniques on frozen sections. CASE PRESENTATION: Here we present a case of a liver lesion in a 51-year-old male donor, subjected to histopathological on-call examination. The frozen sections showed a well-demarcated lesion consisting of epithelioid cells disposed in laminar structures and intermingled with a dense lymphocytic population: this led to organ discard with interruption of the donation process. The definitive histological analysis required an extensive immunohistochemical (IHC) investigation: the final diagnosis was "bile duct adenoma with oncocytic features", eventually confirmed by a strongly positive anti-mitochondrial IHC. Finally, an NGS panel analysis was performed, which revealed NRAS mutation. DISCUSSION: To the best of our knowledge, this is the first case of oncocytic bile duct adenoma confirmed by anti-mitochondrial IHC and with NRAS mutation. The most challenging aspect of this case was represented by the transplant setting. In fact, the oncocytic features and the dense lymphocytic infiltrate represented concomitant unusual histological features that led to the halt of the organ donation procedures.

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.

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.

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.

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.

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.

Cholangiohydatidosis: an Infrequent Cause of Obstructive Jaundice and Acute Cholangitis

ABSTRACT Background. One of the evolutionary complications of hepatic echinococcosis (HE) is cholangiohydatidosis, a rare cause of obstructive jaundice and cholangitis. The aim of this study was to describe the results of surgical treatment on a group of patients with cholangiohydatidosis and secondary cholangitis in terms of post-operative morbidity (POM). Material and method. Case series of patients operated on for cholangiohydatidosis and cholangitis in the Department at Surgery of the Universidad de La Frontera and the Clínica Mayor in Temuco, Chile between 2004 and 2014. The minimum follow-up time was six months. The principal outcome variable was the development of POM. Other variables of interest were age, sex, cyst diameter, hematocrit, leukocytes, total bilirubin, alkaline phosphatase and transaminases, type of surgery, existence of concomitant evolutionary complications in the cyst, length of hospital stay, need for surgical re-intervention and mortality. Descriptive statistics were calculated. Results. A total of 20 patients were studied characterized by a median age of 53 years, 50.0% female and 20.0% having two or more cysts with a mean diameter of 13.3 ± 6.3 cm. A median hospital stay of six days and follow-up of 34 months was recorded. POM was 30.0%, re-intervention rate was 10.0% and mortality rate was 5.0%. Conclusion. Cholangiohydatidosis is a rare cause of obstructive jaundice and cholangitis associated with significant rates of POM and mortality.(AU)

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.

Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma.

AIMS: Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. METHODS AND RESULTS: We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. CONCLUSIONS: Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH.

Magnetic Resonance Imaging Findings of Intrahepatic Bile Duct Adenoma: A Report of 4 Cases.

Intrahepatic bile duct adenoma (BDA) is a rare type of benign hepatic lesions. In this study, 4 cases of BDA diagnosed from surgical resection pathology were examined. Their clinical and magnetic resonance imaging (MRI) data were retrospectively analyzed. The 4 cases (1 men and 3 women) were aged 21 to 55 years without obvious clinical symptoms. Three were identified through routine examination. Three had a history of chronic hepatitis B virus infection. Two cases were accompanied by hepatocellular carcinoma, and one had a higher level of α-fetoprotein. The MRI images of BDA all manifested as peripheral hepatic nodules with abnormal signals. The diameters of the lesions in the 4 cases were 7.7 to 17.0 mm. The MRI images showed slight hypointensity on T1WI and slight hyperintensity on T2WI in all cases, and they showed slight hyperintensity in 2 cases and hyperintensity in 2 cases on diffusion-weighted imaging. Dynamic contrast-enhanced MRI scans show hyperintensity in the arterial phase and slight hyperintensity in the late stage in 3 cases. The other case shows hyperintensity in the arterial and portal phases and isointensity at the delayed phase. During follow-up, 3 cases were recurrence-free. The other case was complicated by the reoccurrence of HCC. In general, BDA shows specific MRI characteristics, and peripheral hepatic nodules show slight hypointensity on T1WI and slight hyperintensity on T2WI. Dynamic contrast-enhanced MRI scans showed obvious enhancement in the arterial phase and continuous enhancement at the late stage.

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.