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BackgroundThe present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status.MethodPatients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status.ResultsAmong 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2–8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1–3 mm 38.5% vs. 3–10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1–3 mm 22.8% vs. 3–10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35–3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58–3.11, p = 0.50).ConclusionR0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.

IntroductionWhile generally associated with poor prognosis, intrahepatic cholangiocarcinoma (ICC) can have a heterogeneous presentation and natural history. We sought to identify specific ICC subtypes that may be associated with varied long-term outcomes and patterns of recurrence after liver resection.MethodsPatients who underwent curative-intent resection for ICC from 2000 to 2020 were identified from a multi-institutional database. Hierarchical cluster analysis characterized three ICC subtypes based on morphology (i.e., tumor burden score [TBS]) and biology (i.e., preoperative neutrophil-to-lymphocyte ratio [NLR] and CA19-9 levels).ResultsAmong 598 patients, the cluster analysis identified three ICC subtypes: Common (n = 300, 50.2%) (median, TBS: 4.5; NLR: 2.4; CA19-9: 38.0 U/mL); Proliferative (n = 246, 41.1%) (median, TBS: 8.8; NLR: 2.9; CA19-9: 71.2 U/mL); Inflammatory (n = 52, 8.7%) (median, TBS: 5.4; NLR: 12.6; CA19-9: 26.7 U/mL). Median overall survival (OS) (Common: 72.0 months; Proliferative: 31.4 months; Inflammatory: 22.9 months) and recurrence-free survival (RFS) (Common: 21.5 months; Proliferative: 11.9 months; Inflammatory: 9.0 months) varied considerably among the different ICC subtypes (all p < 0.001). Even though patients with Inflammatory ICC had more favorable T-(T1/T2, Common: 84.4%; Proliferative: 80.6%; Inflammatory: 86.5%) and N-(N0, Common: 14.0%; Proliferative: 20.7%; Inflammatory: 26.9%) disease, the Inflammatory subtype was associated with a higher incidence of intra- and extrahepatic recurrence (Common: 15.8%; Proliferative: 24.2%; Inflammatory: 28.6%) (all p = 0.01).ConclusionsCluster analysis identified three distinct subtypes of ICC based on TBS, NLR, and CA19-9. ICC subtype was associated with RFS and OS and predicted worse outcomes among patients. Despite more favorable T- and N-disease, the Inflammatory ICC subtype was associated with worse outcomes ICC subtype should be considered in the prognostic stratification of patients.

Objectives Role of 18-FDG PET/CT had been well established in other more prevalent malignancies such as colorectal and lung cancer; however, this is not as well defined in cholangiocarcinoma. Literature focusing on the prognostic values of preoperative PET/CT for resectable cholangiocarcinoma is scarce. Method This is a retrospective cohort of 66 consecutive patients who had received curative resection for cholangiocarcinoma from 2010 to 2015. All patients had preoperative 18-FDG PET/CT performed. Accuracy of metastatic lymph node detection of PET/CT and the prognostic value of maximum standard uptake value (SUV-max) was explored. Results There were 38 male and 28 female recruited, and the median age was 66. Intrahepatic cholangiocarcinoma (ICC) constituted the majority (59.1%) of the cases, followed by hilar cholangiocarcinoma (22.8%), gallbladder cancer (13.6%) and common bile duct cancer (4.5%). The 3-year disease-free survival (DFS) and overall survival (OS) of the whole population were 27.1 and 39.2%, respectively. The median follow-up duration was 27 months. The accuracy of PET/CT in metastatic lymph node detection was 72.7% ( P  = 0.005, 95% CI 0.583–0.871) and 81.8% ( P  = 0.011, 95% CI 0.635–0.990) in whole population and ICC subgroup analysis, respectively. SUV-max was shown by multivariate analysis to be an independent factor for DFS ( P  = 0.007 OR 1.16, 95% CI 1.04–1.29) and OS ( P  = 0.012 OR 1.145, 95% CI 1.030–1.273) after resection. SUV-max of 8 was shown to be a discriminant cut-off for poor oncological outcomes in patients with early cholangiocarcinoma (TNM stage I or II) after curative resection (3-year DFS: 21.2 vs. 63.2%, P  = 0.004, and 3-year OS: 29 vs. 74% P  = 0.048, respectively). Conclusion PET/CT is a reliable imaging modality for metastatic lymph node detection in cholangiocarcinoma. Tumour SUV-max is an independent factor for oncological outcomes in patients with resectable disease. For patients who have TNM stage I or II cholangiocarcinoma, tumour SUV-max over 8 is associated with significantly inferior disease-free and overall survival even after curative resection.

The aim of this study was to assess the relative sensitivities and specificities of fluorescence in situ hybridization (FISH) and routine cytology for the detection of malignancy in biliary tract strictures. Bile duct brushing and aspirate specimens were collected from 131 patients being evaluated for possible malignant bile duct strictures. Both specimen types were assessed by FISH but only brushing specimens were assessed by cytology. The FISH assay used a mixture of fluorescently-labeled probes to the centromeres of chromosomes 3, 7, and 17 and chromosomal band 9p21 (Vysis UroVysion) to identify cells having chromosomal abnormalities. A case was considered positive for malignancy if five or more cells exhibited polysomy. Sixty-six of the 131 patients had surgical pathologic and/or clinical evidence of malignancy. Thirty-nine patients had cholangiocarcinoma, 19 had pancreatic carcinoma, and 8 had other types of malignancy. The sensitivity of cytology and FISH for the detection of malignancy in bile duct brushing specimens in these patients was 15% and 34% (p < 0.01), respectively. The sensitivity of FISH for the bile aspirate specimens was 23%, and the combined sensitivity of FISH for aspirate and brushing specimens was 35%. The specificity of FISH and cytology brushings were 91% and 98% (p= 0.06), respectively. FISH is significantly more sensitive than and nearly as specific as conventional cytology for the detection of malignant biliary strictures in biliary brushing specimens. FISH may improve the clinical management of patients who are being evaluated for malignancy in bile duct strictures.

Background Cholangiocarcinoma can be classified in intrahepatic cholangiocarcinoma (ICC) and perihilar cholangiocarcinoma (PCC). Moreover, PCC includes two different forms: extrahepatic (EH) PCC, which arises from the perihilar EH large ducts, and intrahepatic (IH) PCC, in which a significant liver mass invades the perihilar bile ducts. In this study, we investigated the molecular profile and molecular prognostic factors in EH-PCC, IH-PCC, and ICC submitted to curative surgery. Methods Ninety-one patients with cholangiocarcinoma (38 EH-PCC, 18 IH-PCC, and 35 ICC), who underwent curative surgery in a single tertiary hepatobiliary surgery referral center were assessed for mutational status in 56 cancer-related genes. Results The most frequently mutated genes in EH-PCC were KRAS (47.4 %), TP53 (23.7 %) and ARID1A (15.8 %); in IH-PCC were KRAS (22.2 %), PBRM1 (16.7 %), and PIK3CA (16.7 %); and in ICC were IDH1 (17.1 %), NRAS (17.1 %), and BAP1 (14.3 %). The presence of mutations in ALK , IDH1 , and TP53 genes was significantly associated with poor prognosis in patients with EH-PCC ( p  < 0.001, p  = 0.043, and p  = 0.019, respectively). Mutation of the TP53 gene was significantly associated with poor prognosis in patients with IH-PCC ( p  = 0.049). The presence of mutations in ARID1A , PIK3C2G , STK11 , TGFBR2 , and TP53 genes was significantly associated with poor prognosis in patients with ICC ( p  = 0.012, p  = 0.030, p  = 0.030, p  = 0.011, and p  = 0.011, respectively). Conclusions Mutational gene profiling identified different gene mutations in EH-PCC, IH-PCC, and ICC. Moreover, our study reported specific prognostic genes that can identify patients with poor prognosis after curative surgery who may benefit from traditional or target adjuvant treatments.

Abstract Introduction: The progressive technologies in albumin in situ hybridization (ISH) changed the routine application and the differential diagnosis of hepatic malignancies in the last years. The aim of the present work was to assess the diagnostic utility of albumin ISH on different cholangiocarcinoma (CCA) subtypes, as well as to assess how albumin production changes along the biliary tree. Methods: Forty-five CCAs were retrospectively selected: 29 intrahepatic (15 small-duct and 14 large-duct subtypes), 7 perihilar, and 9 extrahepatic. Histology was revised in all cases, and albumin ISH was automatically performed by the RNAscope®. Results: ISH was always negative in extrahepatic CCAs, only 1 perihilar case was positive, and any positivity was observed in 25/29 (86.2%) intrahepatic CCAs (p < 0.001). Concerning CCA subtypes, mean cell positivity was 38.8 ± 29.8% in small-duct CCAs and 11.4 ± 21.9 in large-duct CCAs, respectively (p = 0.003); 12/15 (80.0%) small-duct and 3/14 (21.4%) large-duct CCAs showed >5% positive cells (p = 0.002; odds ratio 14.7). Conclusions: The introduction of more sensitive techniques changed the indications for ISH since most small-duct intrahepatic CCAs show diffuse positivity. Albumin positivity decreases from liver periphery to the large ducts, suggesting that ISH can be helpful in the differential diagnosis between small-duct and large-duct CCAs, as well as between intrahepatic large-duct CCAs and metastases.

Histopathologic evaluation of bile duct and ampullary biopsies can be challenging. Biopsies from these sites are often tiny, scant, and/or fragmented. When assessing these biopsies, there is significant overlap between reactive atypia and malignancy, in situ precursor lesions can be misinterpreted as malignancy, and nonprimary tumors can mimic primary disease. To provide diagnostic pearls and pitfalls in the evaluation of small biopsies from the biliary tract. Literature review of published studies and the author's own observations. Because the procedures for obtaining specimens from the bile duct and ampulla are invasive, pathologists need to try to make definitive diagnoses. Diagnostic clues/pearls, ancillary studies, and recognition of various pitfalls can assist in providing accurate and confident diagnoses.

Background Surgical resection remains the sole approach to achieving long-term survival in cholangiocarcinoma cases. The universally recognised standard procedures for such cases include pancreaticoduodenectomy (PD) or hemihepatectomy accompanied by bile duct reconstruction. Nevertheless, some patients may still attain curative intent through bile duct segmental resection (BDR). However, these procedures are still in the experimental stage and should only be recommended for carefully chosen patients. Methods A 57-year-old male patient was admitted to our department after two weeks of escalating jaundice and abdominal discomfort. Upon admission, his total bilirubin was recorded at 102 μmol/L, and his direct bilirubin was 87 μmol/L. His carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) levels were normal. Enhanced computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed a thickened and enhanced biliary tree extending from the cystic duct junction to the common hepatic duct no vascular invasion indicated by three-dimensional reconstruction. Results The patient underwent laparoscopic resection of the extrahepatic bile duct, accompanied by radical lymphadenectomy with skeletonisation and biliary reconstruction, was successfully conducted within 320 min, with a minimal blood loss of only 50 ml. The histological grading of the procedure was T2bN0M0 (stage II). The patient was discharged on the sixth postoperative day without complications. Following this, he underwent a regimen of single-agent capecitabine chemotherapy. After an 18-month follow-up period, no recurrence was observed. Conclusions Our experience suggests that in selected patients diagnosed with middle bile duct cholangiocarcinoma, laparoscopic resection could potentially reach the standard of lymphadenectomy through skeletonisation.

Background Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. Methods Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. Results Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p  < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p  = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p  = 0.581) and DFS (12.8 vs. 16.8 months; p  = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p  < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p  < 0.001). Conclusions ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.