Differing rates of loss ofDPC4 expression and ofp53 overexpression among carcinomas of the proximal and distal bile ducts

Argani, Pedram; Shaukat, Masooma; Kaushal, Manju; Wilentz, Robb E.; Su, Gloria H.; Sohn, Taylor A.; Yeo, Charles J.; Cameron, John L.; Kern, Scott E.; Hruban, Ralph H.

doi:10.1002/1097-0142(20010401)91:7<1332::aid-cncr1136>3.0.co;2-4

Cited by 106 publications

(16 citation statements)

References 52 publications

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“…We found that expression of these biomarkers was similar in PDAC and CCC (Additional File 2): our results therefore supporting the previous literature [39-42]. …”

Section: Discussionsupporting

confidence: 91%

“…However, those papers which are available for CCC suggest that the biomarker expression profile is similar to PDAC. To our knowledge, all of the known positive biomarkers for PDAC (versus corresponding normal tissue), including MUC1, P53, CK17, mesothelin, fascin, MUC4, 14-3-3σ and prostate stem cell antigen, show similar IHC expression in CCC (versus corresponding normal tissue) [39-42]. …”

Section: Discussionmentioning

confidence: 99%

“…CCC has been included because it often enters the clinical and pathological differential diagnosis; and its positive biomarkers are generally shared with PDAC [39-42]. The aim was to identify a clinically useful diagnostic biomarker or panel of biomarkers with a robust cut-off for positivity that could potentially be taken forward for validation in PBA cytology samples.…”

Section: Introductionmentioning

confidence: 99%

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Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

et al. 2014

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BackgroundPancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens.MethodsTissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0–300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve.ResultsThe expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off.ConclusionA biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.

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“…We found that expression of these biomarkers was similar in PDAC and CCC (Additional File 2): our results therefore supporting the previous literature [39-42]. …”

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

et al. 2014

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“…p53 inactivation is the most common tumor suppressor lesion, observed in 37% of IHCC (7). Additionally, subsets of IHCC show mutations or deletions of SMAD4 and p16 INK4A (4, 8). …”

Section: Introductionmentioning

confidence: 99%

KrasG12D and p53 Mutation Cause Primary Intrahepatic Cholangiocarcinoma

et al. 2012

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Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (KrasG12D) and deletion of p53. Tissue-specific activation of KrasG12D alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining KrasG12D activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks versus 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the pre-malignant biliary lesions, intraductal papillary biliary neoplasms (IPBN) and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers.

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“…10 Although depth of tumor invasion was shown to predict outcome, 9,10 there were a number of concerns raised about using it as a prognostic marker. First, the studies on which some of these concerns were based combined hilar and distal cholangiocarcinomas, which in fact may be inappropriate given the distinct biologic behavior 13 and management of these diseases. Perhaps more importantly, there was concern that the use of depth of tumor invasion might be difficult to reproduce among pathologists.…”

mentioning

confidence: 99%

Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma

Hong

Pawlik

Cho

et al. 2009

Surgery

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116

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Background The American Joint Committee on Cancer (AJCC) T classification system for cholangiocarcinoma does not take into account the unique pathologic features of the bile duct. As such, the current AJCC T classification for distal cholangiocarcinoma may be inaccurate. Methods A total of 147 patients with distal cholangiocarcinoma were identified from a single institution database. The prognostic importance of depth of tumor invasion relative to the AJCC T classification system was assessed. Results The AJCC T classification was T1 (n = 11, 7.5%), T2 (n = 6, 4.1%), T3 (n = 73, 49.7%), or T4 (n = 57, 38.8%). When cases were analyzed according to depth of tumor invasion, most lesions were ≥5 mm (<5 mm, 9.5%; range, 5–12, 51.0%; >12 mm, 39.5%). The AJCC T classification was not associated with survival outcome (median survival, T1, 40.1 months; T2, 14.8 months; T3, 16.5 months; T4, 20.2 months; P = .17). In contrast, depth of tumor invasion was associated with a worse outcome as tumor depth increased (median survival, <5 mm, not reached; range, 5–12, 28.9 months; >12 mm, 12.9 months; P = .001). On multivariate analyses, tumor depth remained the factor most associated with outcome (<5 mm; hazard ratio [HR] = referent vs 5–12 mm; HR = 3.8 vs >12 mm; HR = 6.7 mm; P = .001). Conclusion The AJCC T classification for distal cholangiocarcinoma does not accurately predict prognosis. Depth of the bile duct carcinoma invasion is a better alternative method to determine prognosis and should be incorporated into the pathologic assessment of resected distal cholangiocarcinoma.

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Differing rates of loss ofDPC4 expression and ofp53 overexpression among carcinomas of the proximal and distal bile ducts

Cited by 106 publications

References 52 publications

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

KrasG12D and p53 Mutation Cause Primary Intrahepatic Cholangiocarcinoma

Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma

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