OBJECTIVE: Dedicated gene signatures in small (SD-iCCA) and large (LD-iCCA) duct type intrahepatic cholangiocarcinoma remain unknown. We performed immune profiling in SD- and LD-iCCA to identify novel biomarker candidates for personalized medicine.
METHODS: Retrospectively, 19 iCCA patients with either SD-iCCA (n = 10, median age, 63.1 years (45-86); men, 4) or LD-iCCA (n = 9, median age, 69.7 years (62-85); men, 5)) were included. All patients were diagnosed and histologically confirmed between 04/2009 and 01/2021. Tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer Immune Profiling Panel.
RESULTS: With the exception of complement signatures, immune-related pathways were broadly downregulated in SD-iCCA vs. LD-iCCA. A total of 20 immune-related genes were strongly downregulated in SD-iCCA with DMBT1 (log2fc = -5.39, p = 0.01) and CEACAM6 (log2fc = -6.38, p = 0.01) showing the strongest downregulation. Among 7 strongly (log2fc > 2, p ≤ 0.02) upregulated genes, CRP (log2fc = 5.06, p = 0.02) ranked first, and four others were associated with complement (C5, C4BPA, C8A, C8B). Total tumor-infiltrating lymphocytes (TIL) signature was decreased in SD-iCCA with elevated ratios of exhausted-CD8/TILs, NK/TILs, and cytotoxic cells/TILs while having decreased ratios of B-cells/TILs, mast cells/TILs and dendritic cells/TILs. The immune profiling signatures in SD-iCCA revealed downregulation in chemokine signaling pathways inclulding JAK2/3 and ERK1/2 as well as nearly all cytokine-cytokine receptor interaction pathways with the exception of the CXCL1/CXCR1-axis.
CONCLUSIONS: Immune patterns differed in SD-iCCA versus LD-iCCA. We identified potential biomarker candidate genes, including CRP, CEACAM6, DMBT1, and various complement factors that could be explored for augmented diagnostics and treatment decision-making.

BACKGROUND: Biliary tract cancers comprise a heterogeneous collection of malignancies usually described as cholangiocarcinoma of the intra- or extrahepatic bile duct, including perihilar cholangiocarcinoma and gallbladder cancer.
METHODS: A review of pertinent parts of the ESSO core curriculum for the UEMS diploma targets (Fellowships exam, EBSQ), based on updated and available guidelines for diagnosis, surgical treatment and oncological management of cholangiocarcinoma.
RESULTS: Following the outline from the ESSO core curriculum we present the epidemiology and risk factors for cholangiocarcinoma, as well as the rationale for the current diagnosis, staging, (neo-)adjuvant treatment, surgical management, and short- and long-term outcomes. The available guidelines and consensus reports (i.e. NCCN, BGS and ESMO guidelines) are referred to. Recognition of biliary tract cancers as separate entities of the intrahepatic biliary ducts, the perihilar and distal bile duct as well as the gallbladder is important for proper management, as they each provide distinct clinical, molecular and treatment profiles to consider.
CONCLUSIONS: Core competencies in knowledge to the diagnosis, management and outcomes of biliary tract cancers are presented.

Hepatic sparganosis (HS) is extremely rare and has not been previously reported in Eastern China. We report the diagnosis and treatment of a patient with HS from Xuzhou City, Jiangsu Province, China. The patient was admitted due to an acute biliary tract infection, and the symptoms improved after treatment at the Gastroenterology Department. During an ultrasound examination on admission, an abnormal echo was incidentally discovered at the junction of the left and right lobes of the liver. Thereafter, upper abdominal computed tomography (CT) and magnetic resonance imaging (MRI) non-contrast and contrast-enhanced examinations, and serum tumor biomarker examination were completed. After a multidisciplinary treatment (MDT) discussion at the Department of Hepatobiliary Surgery, the patient was diagnosed with intrahepatic mass-type cholangiocarcinoma (IMCC) and surgery was recommended. The patient underwent surgical treatment, and postoperative pathology revealed HS. No signs of intrahepatic recurrence were observed during the 1-year follow-up period.

OBJECTIVE: The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD- and LD-iCCA features in different tumour regions.
RESULTS: All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD- and LD-iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N-cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD- and LD-iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumour.
CONCLUSIONS: A marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.

BACKGROUND: There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic).
OBJECTIVE: This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC.
METHODS: Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement.
RESULTS: Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC.
CONCLUSIONS: Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

Erythropoietic protoporphyria (EPP) is a rare metabolic disease of the heme biosynthetic pathway where an enzymatic dysfunction results in protoporphyrin IX (PPIX) accumulation in erythroid cells. The porphyrins are photo-reactive and are responsible for severe photosensitivity in patients, thus drastically decreasing their quality of life. The liver eliminates PPIX and as such, the main and rare complication of EPP is progressive cholestatic liver disease, which can lead to liver failure. The management of this complication is challenging, as it often requires a combination of approaches to promote PPIX elimination and suppress the patient\'s erythropoiesis. Here we described a 3-year follow-up of an EPP patient, with three episodes of liver involvement, aggravated by the coexistence of a factor VII deficiency. It covers all the different types of intervention available for the management of liver disease, right through to successful allogeneic hematopoietic stem cell transplantation.

In this case report, a 75-year-old male with a history of coronary artery disease, type 2 diabetes, hypertension, and benign prostate hypertrophy developed postoperative fever and chest pain following left knee arthroplasty. Upon admission to the emergency department, pulmonary embolism was considered highly probable, and the patient was treated with anticoagulation and antibiotics due to diagnostic uncertainty. However, further investigations revealed a complex condition involving an intraparenchymal gallbladder rupture resulting in a biloma secondary to choledocholithiasis. The patient\'s history of receiving spinal anesthesia with intrathecal morphine was identified as a potential causative factor to the sphincter of Oddi constriction, leading to increased biliary pressure and gallbladder rupture. This case highlights the importance of having a broad differential diagnosis in postoperative patients, especially when the clinical presentation is atypical. With the diagnosis being confirmed, the patient underwent successful treatment, including biliary stenting, drainage of the biloma, and ultimately cholecystectomy. This case underlines the need for vigilance and a multidisciplinary approach in managing complex postoperative complications, emphasizing that clinical presentations may sometimes deviate significantly from the expected, requiring further investigation and individualized treatment.

An intraductal papillary neoplasm involving the biliary tree is an unusual premalignant condition of epithelial origin, identified by its cystic dilatation of the biliary channels. Being a slow-growing tumor, surgery offers the best curative rate, especially in the setting of a low-grade disease. Here, we present a case of a localized, low-grade, intraductal papillary neoplasm of the bile duct (IPNB), residing in the liver, which was treated with resection of the liver lobe. The adjuvant treatment and prognosis highly depend upon the presence of dysplasia or a co-existent invasive malignancy. To the best of our knowledge, being a rare entity, this is the first case to be reported from Pakistan.

A new variant of intrahepatic cholangiocarcinoma (iCCA) has been recognized in recent years presenting predominantly as a large hepatic mass in young woman with the characteristic expression of inhibin by immunohistochemistry. This variant iCCA was originally termed as cholangioblastic variant of iCCA, and subsequently proposed to be renamed as inhibin-positive hepatic carcinoma or solid-tubulocystic variant of iCCA to better reflect its immunohistochemical profile or morphologic spectrum. The tumor histologically is composed of small to medium sized cells with scant to moderate amount of eosinophilic cytoplasm heterogeneously organized in solid, tubular, and cystic growth patterns. The tumor cells are positive for biliary markers, inhibin and albumin, and have a novel recurrent gene fusion, NIPBL::NACC1. Awareness of this new iCCA variant and its clinicopathologic features will aid in the diagnostic work-up and avoid confusion with other primary and metastatic hepatic neoplasms.

Intrahepatic cholangiocarcinoma is a challenge to the practicing surgical pathologist for several reasons. It is rare in many parts of the world, and thus practical exposure may be limited. Related to the fact of its rarity is the fact that more common tumors which frequently metastasize to the liver can be morphologically indistinguishable (eg, pancreatic ductal adenocarcinoma). Immunohistochemical testing is generally non-contributory in this context. Other difficulties arise from the protean morphologic manifestations of cholangiocarcinoma (ie, small duct vs. large duct) and the existence of combined cholangiocarcinoma and hepatocellular carcinoma. These, and other issues of concern to the practicing diagnostic pathologist are discussed herein.