Biliary Tumors Research Articles

Genomic and transcriptomic signatures of sequential carcinogenesis from papillary neoplasm to biliary tract cancer.

Papillary neoplasms of the biliary tree, including intraductal papillary neoplasms (IPN) and intracholecystic papillary neoplasms (ICPN), are recognized as precancerous lesions. However, the genetic characteristics underlying sequential carcinogenesis remain unclear. Whole-exome sequencing was performed on 166 neoplasms (33 intrahepatic IPNs, 44 extrahepatic IPNs, and 89 ICPNs), and 41 associated carcinomas. Nine available cases were also subjected to spatial transcriptomic analysis. Mutations in the MAPK (48%), genomic integrity maintenance (42%), and Wnt/β-catenin (33%) pathways were prevalent in intrahepatic IPNs, extrahepatic IPNs, and ICPNs, respectively. KRAS mutations were enriched in intrahepatic IPN (42%, P<0.001), whereas SMAD4 mutations were enriched in extrahepatic IPN (21%, P=0.005). ICPNs frequently exhibit CTNNB1 mutations, particularly in low-grade lesions. Mutational signature analysis revealed that SBS1 and SBS5 signatures were homogeneously enriched in intrahepatic IPN, in contrast to the heterogeneous distribution of SBS1, SBS2, SBS5, SBS13, SBS7b, and SBS23 in extrahepatic IPN and ICPN. Copy number aberrations gradually increased from low- to high-grade intraepithelial neoplasia and eventually to carcinoma. Phylogenetic analysis revealed that 89% of carcinomas were derived from IPN/ICPN through sequential carcinogenesis, with the majority sharing driver mutations between IPN/ICPN and carcinoma. Furthermore, multifocal, independent carcinogenesis events were observed in IPNs/ICPNs, resulting in mutationally distinct carcinoma lesions. Carcinogenesis of IPN/ICPN occurs in multiple subclones through mutational accumulation and transcriptomic alterations that affect vascular development, cell morphogenesis, extracellular matrix organization, and growth factor response. With the largest IPN/ICPN cohort reported to date, our study provides a genome- and spatial transcriptome-level portrait of sequential carcinogenesis and differences in the anatomical location of biliary papillary neoplasms. Biliary tract cancer is a fatal malignancy. However, its genome-level sequential carcinogenesis from intraepithelial neoplasia to carcinoma has not yet been evaluated in a sufficiently large cohort. Papillary lesions of the bile duct and gallbladder are collectively termed intraductal papillary neoplasms (IPN) of the bile duct and intracholecystic papillary neoplasms (ICPN), respectively. They are primarily diagnosed based on histopathological studies. This study provides a comprehensive mutational and spatial transcriptomic landscape of papillary neoplasms of the bile duct and gallbladder. The results of this study offer insights into the mechanism of sequential carcinogenesis in papillary biliary tract tumors, pathology-genomics correlation, and potential therapeutic targets.

Neoplastic premalignant pancreatobiliary lesions: current update on the spectrum of lesions and their imaging appearances.

Common pancreatobiliary epithelial malignancies such as pancreatic ductal adenocarcinoma, cholangiocarcinoma and gallbladder carcinoma have poor prognosis. A small but significant portion of these malignancies arise from mass-forming grossly and radiologically visible premalignant epithelial neoplasms in the pancreatobiliary tree. Several lesions, including a few recently described entities, fall under this category and predominantly include papillary epithelial lesions with or without mucin production. These include common lesions such as intraductal papillary mucinous lesions (IPMN) in pancreas and less common to rare lesions such intraductal papillary neoplasms of the bile ducts (IPNB), pancreatic and biliary intraductal oncocytic papillary neoplasms (IOPN) and intraductal tubulopapillary neoplasms (ITPN), intracholecystic neoplasms (ICN) in the gallbladder, intra-ampullary papillary-tubular neoplasms (IAPN) in the ampulla and mucinous cystic neoplasms in the pancreas, biliary tree and gallbladder. These lesions have an excellent prognosis before malignant transformation and even with malignant transformation, often fare better than the conventional malignant counterparts. These lesions have characteristic histologic, radiologic, and molecular characteristic features. Several of these neoplastic lesions are associated with field-effect phenomenon which means that in presence of even one of these lesions, the entire background ductal epithelium is at risk of developing synchronous or metachronous malignancies. Awareness of these lesions and their imaging appearances as well as utilization of relevant molecular diagnostics can help practicing radiologists and clinicians improve patient outcomes by detecting early and treating or surveilling such lesions before malignant transformation or before metastatic dissemination.

Artificial Intelligence and Radiomics in Cholangiocarcinoma: A Comprehensive Review.

Cholangiocarcinoma (CCA) is a malignant biliary system tumor and the second most common primary hepatic neoplasm, following hepatocellular carcinoma. CCA still has an extremely high unfavorable prognosis, regardless of type and location, and complete surgical resection remains the only curative therapeutic option; however, due to the underhanded onset and rapid progression of CCA, most patients present with advanced stages at first diagnosis, with only 30 to 60% of CCA patients eligible for surgery. Recent innovations in medical imaging combined with the use of radiomics and artificial intelligence (AI) can lead to improvements in the early detection, characterization, and pre-treatment staging of these tumors, guiding clinicians to make personalized therapeutic strategies. The aim of this review is to provide an overview of how radiological features of CCA can be analyzed through radiomics and with the help of AI for many different purposes, such as differential diagnosis, the prediction of lymph node metastasis, the defining of prognostic groups, and the prediction of early recurrence. The combination of radiomics with AI has immense potential. Still, its effectiveness in practice is yet to be validated by prospective multicentric studies that would allow for the development of standardized radiomics models.

The utilisation of biliary organoids for biomedical applications.

Biliary duct injury, biliary atresia (BA), biliary tract tumors, primary sclerosing cholangitis (PSC), and other diseases are commonly encountered in clinical practice within the digestive system. To gain a better understanding of the pathogenesis and development of these diseases and explore more effective treatment methods, organoid technology has recently garnered significant attention. Organoids are three-dimensional structures derived from stem/progenitor cells that can faithfully mimic the intricate structure and physiological function of tissues or organs in vitro. They provide a valuable platform for studying the pathogenesis of biliary tract diseases and offer novel possibilities for repairing and regenerating biliary tract injuries. The main seed cells used to construct biliary tract organoids include primary human biliary tract epithelial cells as well as pluripotent stem cells. The construction of these organoids involves various techniques such as traditional embedding technology, rotary culture technology, hanging drop culture technology, along with emerging approaches like organ chip technology, three-dimensional (3D) printing technology, and four-dimensional (4D) printing technology. This article comprehensively reviews the construction methods of biliary tract organoids while discussing their applications in disease modeling research on disease mechanisms drug screening tissue/organ repair; it also highlights current challenges and suggests future research directions regarding biliary tract organoids which will serve as references for treating common refractory digestive system diseases in clinical practice.

Extrahepatic Biliary Neuroendocrine Tumors Presented as Liver Mass

Extrahepatic Biliary Neuroendocrine Tumors Presented as Liver Mass

Psychological distress in biliary tract malignancy patients: influencing factors and development of a predictive nomogram model.

This study aims to investigate the psychological distress and its influencing factors in patients with biliary tract malignant tumors, alongside the development of a predictive model. A total of 219 patients diagnosed with biliary tract malignant tumors who were admitted to the Department of Liver Surgery at Fudan University Shanghai Cancer Center from July 2021 to May 2023, were selected using a convenience sampling method. Research tools involve psychological distress management screening tools, a demographic questionnaire, self-rating anxiety and depression scales, and the Chinese version of the Memorial Symptom Assessment Scale. Bootstrap method was utilized for repeated sampling to identify relevant factors influencing psychological distress in biliary tract cancer patients. The R software was employed to create a nomogram model, and the model's accuracy and predictive performance were assessed using the receiver operating characteristic curve (ROC) and the Hosmer-Lemeshow test. The average score of psychological distress among the 219 patients was (3.91 ± 2.44), with a psychological distress detection rate of 54.8%. Regression model results indicated that factors such as the presence of distant metastasis, comorbidity with other major diseases, poor sleep quality, anxiety, and severity of anxiety and depression were the primary influencers of psychological distress. The detection rate of psychological distress in patients with biliary tract malignant tumors is notably high. The predictive model constructed in this study exhibits good predictive efficacy and clinical value, providing valuable reference for healthcare professionals in developing targeted intervention strategies.

Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents.

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

A Pathological Assessment of the Microvasculature of Biliary Tract Neoplasms Referring to Pre-Existing Blood Vessels and Vessel Co-Option.

There are several types of microvasculature supplying neoplasms: "newly formed blood vessels" (neoangiogenesis), which are a component of the tumor microenvironment (TME) of invasive carcinoma with wound healing-like reaction; and "pre-existing blood vessels", which are used as tumor-supplying vessels by neoplasms (co-option vessels) and are likely to develop in hypervascularized organs. We herein review the microvasculature of neoplasms of biliary tract with reference to pre-existing vessels and vessel co-options. In the hepatobiliary system, intrahepatic large and extrahepatic bile ducts (large bile ducts) and the gallbladder as well as hepatic lobules are highly vascularized regions. In large bile ducts, the biliary lining epithelia and underlining capillaries (peribiliary capillary plexus [PCP]) form the biliary epithelia-PCP alignment, whereas the hepatocyte-sinusoid alignment composes hepatic lobules. Cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC) are the main biliary tract carcinomas. CCA is subdivided into distal (d/CCA), perihilar (pCCA), and intrahepatic (iCCA), and iCCA is subdivided into small duct type (SD-iCCA) and large duct type (LD-iCCA). High-grade biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN) have recently been proposed as the precursors of LD-iCCA, p/dCCA, and GBC. In the large bile ducts and gallbladder, all cases of high-grade BilIN and PGA, about half of IPNB, and one-third of ICPN with less-complicated structure were found to have hijacked the PCP as their supporting vessels (vessel co-option), while p/dCCA, LD-iCCA, and GBC were supplied by neo-angiogenetic vessels associated with fibrous stroma. The intraluminal components of the remaining cases of ICPN and IPNB with complicated structure presented sparse capillaries without fibrous stroma, a unique microvasculature different from that of co-option or neoangiogenesis. Regarding iCCA showing invasion into the hepatic lobules, some SD-iCCAs replaced hepatocytic cords and used pre-existing sinusoids as co-opted vessels. Visualization of pre-existing vessels could be a new pathological tool for the evaluation of malignant progression and of vascular supply in CCAs and its precursors.

Abstract 4136539: Management of Malignant SVC Syndrome and Acute SVC Thrombosis with Complex Endovascular Intervention

Superior vena cava (SVC) syndrome occurs when there is SVC occlusion or obstruction. SVC obstruction can cause an increase in venous return pressure up to 40 mm Hg, producing edema of the face, neck and chest wall. Blood flow can be diverted to the right atrium through collateral venous networks in cases of gradual SVC compression. The most common cause of SVC syndrome is malignancy, as seen in 70% of cases. Traditionally, treatment is with radiation therapy but advances have now allowed for an endovascular approach. We present a case of malignant SVC syndrome with a complex percutaneous treatment approach that provided palliation with near immediate symptom improvement. A 64 year-old-female with history of cerebrovascular accident on Eliquis, right upper lobe squamous cell carcinoma of the lung in remission, and a mediastinal nodule under surveillance presented with facial and bilateral upper extremity edema. CT revealed bilateral pulmonary embolism and a large SVC thrombus causing impaired venous return. Invasive angiogram confirmed a 95% thrombotic tubular stenosis for which she underwent aspiration thrombectomy with alpha VAC F-18, then angioplasty with an Armada (Abbott) 10 x 40 mm compliant balloon and stenting with the Express (Boston Scientific) 10 x 37 mm stent. There was 0% residual stenosis and immediate clinical improvement. Oncological workup confirmed the right mediastinal mass to be a recurrence of squamous cell carcinoma. SVC syndrome occurred due to mediastinal mass compression and a near occlusive SVC thrombus. Aspiration thrombectomy was effective in treating the SVC thrombosis and was performed alongside pulmonary embolism thrombectomy. The Armada balloon is intended for lesion dilation in the peripheral arteries, but was safely used here for venous dilation. The Express stent is intended for palliation of malignant biliary neoplasms but has versatility and was utilized here for malignant neoplasm surrounding the SVC. Peripheral endovascular stenting is an advantageous treatment option for malignant SVC syndrome given the challenges due to recurrence from mass effect. This provides additional support to maintain vessel patency and is a safe palliation option for improvement in quality of life.

Deep Learning in Endoscopic Ultrasound: A Breakthrough in Detecting Distal Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly lethal malignancy originating in the bile ducts, often diagnosed late with poor prognosis. Differentiating benign from malignant biliary tumors remains challenging, necessitating advanced diagnostic techniques. This study aims to enhance the diagnostic accuracy of endoscopic ultrasound (EUS) for distal cholangiocarcinoma (dCCA) using advanced convolutional neural networks (CCNs) for the classification and segmentation of EUS images, specifically targeting dCCAs, the pancreas, and the bile duct. In this retrospective study, EUS images from patients diagnosed with dCCA via biopsy and an EUS-identified bile duct tumor were evaluated. A custom CNN was developed for classification, trained on 156 EUS images. To enhance the model's robustness, image augmentation techniques were applied, generating a total of 1248 images. For tumor and organ segmentation, the DeepLabv3+ network with ResNet50 architecture was utilized, employing Tversky loss to manage unbalanced classes. Performance evaluation included metrics such as accuracy, sensitivity, specificity, and Intersection over Union (IoU). These methods were implemented in collaboration with the ADAPTED Research Group at the Technical University of Cluj-Napoca. The classification model achieved a high accuracy of 97.82%, with precision and specificity both at 100% and sensitivity at 94.44%. The segmentation models for the pancreas and bile duct demonstrated global accuracies of 84% and 90%, respectively, with robust IoU scores indicating good overlap between predicted and actual contours. The application performed better than the UNet model, particularly in generalization and boundary delineation. This study demonstrates the significant potential of AI in EUS imaging for dCCA, presenting a robust tool that enhances diagnostic accuracy and efficiency. The developed MATLAB application serves as a valuable aid for medical professionals, facilitating informed decision-making and improving patient outcomes in the diagnosis of cholangiocarcinoma and related pathologies.

Clinical and Imaging Features of a Focal Intrahepatic Biliary Stricture Visualized Only as Duct Dilatation.

We assessed the proportion of patients with a focal intrahepatic stricture (FIHS) that was a precursor lesion or malignancy and visualized only as a duct dilatation. This retrospective study assessed patients who underwent surgery or biopsy for an FIHS on CT or MRI between January 2010 and March 2022. The number and proportion of non-precursor benign lesions, precursors, and malignancies were calculated. Clinical variables and imaging features were compared between non-premalignant benign and premalignant/malignant FIHSs. Twenty-eight patients with confirmed histopathological diagnoses were identified, including 15 men (54.0%) and 13 women (46.0%). The median age of all patients at the first imaging diagnosis was 65 ± 9.54 (range, 43-78) years. Of the 28 patients with FIHSs, 9 (32%) were diagnosed with cholangiocarcinoma and 7 (25%) were diagnosed with precursor lesions, which included six intraductal papillary neoplasms of the bile duct and one biliary intraepithelial neoplasm. Accordingly, 16 (57%) patients had malignant or precursor lesions, and 12 (43%) were diagnosed with non-precursor benign lesions. None of the clinical variables and imaging features used for analysis showed a statistically significant difference between the non-premalignant benign and premalignant/malignant FIHS groups (p > 0.05). FIHSs visualized only as duct dilatation can harbor malignant or precursor lesions.

No communication between the bile duct and intraductal papillary neoplasm of the bile duct on imaging.

As a rare biliary tract tumor, intraductal papillary neoplasm of the bile duct (IPNB) is most common in elderly men and can progress to cholangiocarcinoma- (CCa) if left untreated. It is reported that IPNB usually communicates with the bile duct. As a result, the downstream bile ducts are imaged asymmetrically dilated. However, a case of IPNB that we report here is different. Enhanced MRI revealed a lack of connectivity with the bile duct in this case. Based on this, the purpose of this case study is to suggest that the majority of imaging doctors should widely understand the various imaging manifestations of the disease to avoid misdiagnosis. In addition, although this feature was not indicated by ultrasound in this case, given previous studies and considering the convenience and non-ionizing radiation damage of CEUS, we recommend its use as a screening method for IPNB to improve diagnostic accuracy.

Prognostic factors for intraductal papillary neoplasm of the bile duct following surgical resection: a systematic review and meta-analysis.

Intraductal papillary neoplasm of the bile duct (IPNB) is a biliary neoplasm characterized by intraductal papillary growth and varying degrees of malignant transformation. This study aimed to identify effective prognostic factors (PFs) for predicting the prognosis of IPNB after surgical resection, addressing the gap in the higher level evidence. We systematically searched databases from their inception to October 10, 2023. Data on 12 predetermined PFs were collected and subjected to a meta-analysis. Forest plots were used to summarize the findings. Fifteen studies with a total of 2311 patients were included. Among the PFs examined, extrahepatic tumor location (HR, 2.97; 95% CI 1.68-5.23), subclassification type 2 (HR, 2.62; 95% CI 1.45-4.76), R1 resection (HR, 2.47; 95% CI 1.73-3.51), elevated CA19-9 level (HR, 3.25; 95% CI 1.91-5.54), tumor multiplicity (HR, 2.65; 95% CI 1.40-5.02), and adjacent organ invasion (HR, 3.17; 95% CI 2.01-5.00) were associated with a poorer prognosis. Additionally, the combined HR values indicated that lymph node metastasis and poor tumor differentiation were linked to a worse prognosis, although both exhibited significant heterogeneity. Our study offers valuable insights for enhancing postoperative prognostication and treatment decision-making for IPNB patients with IPNB. These findings warrant further validation in future prospective studies.

The spectrum of pathogens and their resistance in patients with malignant liver and biliary tract tumors with biliary obstruction after extensive liver resections

The spectrum of pathogens and their resistance in patients with malignant liver and biliary tract tumors with biliary obstruction after extensive liver resections

S2444 Biliary Intraductal Papillary Mucinous Neoplasm (IPMN-B) Associated With Actinomyces

S2444 Biliary Intraductal Papillary Mucinous Neoplasm (IPMN-B) Associated With Actinomyces

The Role of Bile Acids in Pancreatic Cancer.

Bile acids are well known to promote the digestion and absorption of fat, and at the same time, they play an important role in lipid and glucose metabolism. More studies have found that bile acids such as ursodeoxycholic acid also have anti-inflammatory and immune-regulating effects. Bile acids have been extensively studied in biliary and intestinal tumors but less in pancreatic cancer. Patients with pancreatic cancer, especially pancreatic head cancer, are often accompanied by biliary obstruction and elevated bile acids caused by tumors. Elevated total bile acid levels in pancreatic cancer patients usually have a poor prognosis. There has been controversy over whether elevated bile acids are harmful or beneficial to pancreatic cancer. Still, there is no doubt that bile acids are important for the occurrence and development of pancreatic cancer. This article summarizes the research on bile acid as a biomarker and regulation of the occurrence, development and chemoresistance of pancreatic cancer, hoping to provide some inspiration for future research.

S2385 Rare Presentation of Primary Biliary Neuroendocrine Tumor in a 59-year-old woman: A Case Report

S2385 Rare Presentation of Primary Biliary Neuroendocrine Tumor in a 59-year-old woman: A Case Report

Effect of silibinin on GAS6/sAXL and JAK/STAT pathways in human cholangiocarcinoma cell line

Abstract Objectives Cholangiocarcinoma (CCA) is a highly heterogeneous biliary malignant tumor. Studies have demonstrated that JAK/STAT signaling is activated in many types of cancer. In addition, JAK/STAT is activated downstream of AXL, and the AXL receptor is activated by its ligand, GAS6. In this study, we investigated the anticarcinogenic effect of silibinin and its relationship with the GAS6/AXL ve JAK/STAT pathway in the human EGI-1 cell line. Methods Cell viability, apoptosis, and cell cycle were measured by Muse Cell Analyzer. All the protein levels were determined by the ELISA method. Results We observed that silibinin significantly reduced cell proliferation and colony formation (p&lt;0.05, p&lt;0.001, respectively). Silibinin also significantly induced total apoptosis and the G0/G1 phase of the cell cycle (p&lt;0.01). We observed that silibinin significantly decreased JAK2 levels while increased STAT1 levels compared to the controls respectively (p&lt;0.001; p&lt;0.001). Besides, silibinin statistically decreased the levels of sAXL; however, numerically, but not statistically, it increased the level of GAS6 (p&gt;0.05). Conclusions Silibinin reduces colony formation, inducing apoptosis and arresting cancer cells in the G0/G1 phase, which is an indicator of its anticancer activity. In addition, silibinin decreased the levels of JAK2 and sAXL, which contributes to the development of cancer, and increased the levels of STAT1, suggesting silibinin’s antiproliferative effects.

Long-Term Survivor of Intrahepatic Cholangiocarcinoma for over 18 Years: Case Study with Longitudinal Histo-molecular and Tumor Immune Microenvironment Characterization and Systematic Review of the Literature

BackgroundIntrahepatic cholangiocarcinoma is a biliary neoplasm usually showing a dismal prognosis. In early stages, surgical resection is the best treatment option, significantly increasing the overall survival. This approach is also recommended in the case of relapsing disease. In this study, we report the case of a patient affected by intrahepatic cholangiocarcinoma with multiple relapses and still alive for over 18 years. We also provide a systematic review regarding long-survivor (> 60 months) of intrahepatic cholangiocarcinoma.Case PresentationA 41-year-old woman with no pathological history was diagnosed with localized intrahepatic cholangiocarcinoma and surgically treated with left hepatectomy. After the first intervention, the patients underwent three further surgical resections because of locoregional recurrences. Histologically, there were some significant similarities among all neoplasms, including the tubule-glandular architecture, but also morphological heterogeneity. The tumor immune microenvironment remained stable across the different lesions. The molecular analysis with next-generation sequencing demonstrated that all neoplasms shared the same genomic profile, including NBN and NOTCH3 mutations and chromosomes 1 and 3 alterations.ConclusionsThis case study highlights the essential role of a stringent follow-up after resection of intrahepatic cholangiocarcinoma for detecting early relapsing tumors. Moreover, it shows the importance of the molecular characterization of multiple tumors for understanding their real nature. The accurate study of long-surviving patients highlights the features that are critical for outcome improvement.

Distinct phenotypic consequences of cholangiocarcinoma-associated FGFR2 alterations depend on biliary epithelial maturity.

Epithelial cancers disrupt tissue architecture and are often driven by mutations in genes that normally play important roles in epithelial morphogenesis. The intrahepatic biliary system is an epithelial tubular network that forms within the developing liver via the de novo initiation and expansion of apical lumens. Intrahepatic biliary tumors are often driven by different types of mutations in the FGFR2 receptor tyrosine kinase which plays important roles in epithelial morphogenesis in other developmental settings. Using a physiologic and quantitative 3D model we have found that FGFR signaling is important for biliary morphogenesis and that oncogenic FGFR2 mutants disrupt biliary architecture. Importantly, we found that both the trafficking and signaling of normal FGFR2 and the phenotypic consequences of FGFR2 mutants are influenced by the epithelial state of the cell. Unexpectedly, we found that different tumor-driving FGFR2 mutants disrupt biliary morphogenesis in completely different and clinically relevant ways, informing our understanding of morphogenesis and tumorigenesis and highlighting the importance of convergent studies of both.