Design of an immunohistochemistry biomarker panel for diagnosis of pancreatic adenocarcinoma.

BACKGROUND: Challenges still exist in differentiating pancreatic adenocarcinoma from benign disease. The use of adjuvant testing of tissue biopsies has demonstrated potential diagnostic value. We designed a proof of concept study to first validate four individual immunohistochemistry biomarkers and then combine them into a panel to boost overall diagnostic sensitivity. METHODS: Malignant and benign pancreas from 27 pancreaticoduodenectomy specimens underwent immunohistochemistry staining with VHL, IMP3, S100A4, S100P. Using ROC curve analysis, threshold criteria for number of cells staining were chosen for each biomarker. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. RESULTS: Diagnostic sensitivity of VHL, IMP3, S100A4, and S100P were 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. CONCLUSIONS: The high diagnostic value of an IHC panel consisting of VHL, IMP3, and S100A4 on surgical specimens suggests the need for future prospective studies of these biomarkers on biopsy specimens.

Cost-effectiveness of the evaluation of a suspicious biliary stricture.

BACKGROUND: Biliary stricture without mass presents diagnostic and therapeutic challenges because the poor sensitivity of the available tests and significant mortality and cost with operation. METHODS: A decision model was developed to analyze costs and survival for 1) investigation first with endoscopic ultrasound (EUS) and fine needle aspiration, 2) investigation first with endoscopic retrograde cholangiopancreatography (ERCP) and brushing, or 3) surgery on every patient. The average age of someone with a biliary stricture was found to be 62-y-old and the rate of cancer was 55%. Incremental cost-effectiveness ratios (ICER) were calculated based on the change in quality adjusted life years (QALYs) and costs (US$) between the different options, with a threshold of $150,000 to determine the most cost-effective strategy. One-way, two-way, and probabilistic-sensitivity analysis were performed to validate the model. RESULTS: ERCP results in 9.05 QALYs and a cost of $34,685.11 for a cost-effectiveness ratio of $3832.33. EUS results in an incremental increase in 0.13 QALYs and $2773.69 for an ICER of $20,840.28 per QALY gained. Surgery resulted in a decrease of 1.37 QALYs and increased cost of $14,323.94 (ICER-$10,490.53). These trends remained within most sensitivity analyses; however, ERCP and EUS were dependent on the test sensitivity. CONCLUSIONS: In patients with a biliary stricture with no mass, the most cost-effective strategy is to investigate the patient before operation. The choice between EUS and ERCP should be institutionally dependent, with EUS being more cost-effective in our base case analysis.

Sensitivity of alternative testing for pancreaticobiliary cancer: a 10-y review of the literature.

BACKGROUND: Biliary strictures present a diagnostic challenge to differentiate benign disease from hepatopancreaticobiliary (HPB) malignancies. Endoscopic retrograde cholangiopancreatography cytology is commonly performed in these patients; however, its sensitivity for diagnosis of HPB malignancy is poor (41.6%). Many adjunctive tests have been investigated to improve the sensitivity of HPB biopsies. To determine the best tests available, however, we reviewed the literature and performed a comparative analysis of all recently investigated tests and their sensitivities. METHODS: A PubMed search identified articles published between 2003 and 2014, describing alternate methods for diagnosing HPB malignancies, reported sensitivity, final pathology, and had data available online. Meta-analysis was conducted for tests with multiple articles. Tests with the highest sensitivity and specificities were reported. RESULTS: A total of 77 studies were identified. Meta-analysis was performed on the sensitivity of EUS-FNA (74.2%), fluorescence in situ hybridization (54.2%), immunostain of insulin-like growth factor 2 mRNA-binding Protein 3 (IMP3; 80.4%), IMP3 + cytology (86.4%), K homology domain containing protein overexpressed in cancer (KOC; 85.9%), S100P (77.8%), serum CA19-9 (69.3%), and K-ras mutations (47.0%) to detect malignancy. Ultimately, 12 tests were identified with superior sensitivity (85.3%-100%) and specificities (81.6%-100%) including stricture scrapping, brush sectioning, IMP3 stain + cytology, IMP3+S100A4, bile carcinoembryonic cell adhesion molecule 6 protein (±CA19-9), bile micro RNA (miRNA)-135b, serum miRNA-RNU2-1f, serum miRNA-21 (+CA19-9), peripheral blood mononuclear cells miRNA-27a-3p (+CA19-9), serum miRNA-16 + miRNA-196a (+CA19-9), peripheral blood mononuclear cells mRNAs h-TERT + CK20 + CEA + C-MET. CONCLUSIONS: We recommend immunostaining with a panel of IMP3+KOC + S100A4 + cytology to achieve maximum sensitivity and specificity from HPB biopsies. One biliary protein (carcinoembryonic cell adhesion molecule 6) and several RNAs (bile and blood) offer exceptional sensitivity and specificity and should be tested prospectively in larger populations. Overall, this review identifies several tests to improve the sensitivity of diagnostic algorithms to identify HPB malignancies.

Sensitivity of endoscopic retrograde cholangiopancreatography standard cytology: 10-y review of the literature.

BACKGROUND: Biliary strictures present a unique diagnostic challenge to clinicians as they can be caused by both benign and malignant conditions. With the high mortalities associated with hepatopancreaticobiliary malignancies, accurate and rapid tissue diagnosis is imperative and typically done before initiation of treatment. However, the exact sensitivity of standard cytology from endoscopic retrograde cholangiopancreatography (ERCP) to diagnose malignancy remains unclear because of wide distribution of reported values in the literature. Furthermore, the use of radical surgery to obtain tissue when cytology is indeterminate has led to questions about the role of ERCP in patients with biliary strictures. METHODS: A PubMed search was conducted using the terms ERCP, cytology, and brushings. Articles reviewed were published between 2002 and 2012, had patient population with biliary stricture, and had ERCP brushing results and final pathology available for review. The cytology and pathology data were abstracted from each study, and the combined overall sensitivity was calculated. RESULTS: Sixteen studies were identified, with sensitivities ranging from 6%-64% and 99% confidence intervals (CIs) ranging from ±6% to ±32%. A combined total of 1556 patients were included, with positive ERCP cytology results in 358 cases. On final pathology, however, 861 patients were positive for malignancy. When the data were combined, we found an overall sensitivity of 41.6% ± 3.2% (99% CI) with a negative predictive value of 58.0% ± 3.2% (99% CI). CONCLUSIONS: ERCP brushings suffer from low sensitivity and negative predictive value. This study questions the utility of ERCP to change the surgical management of these diseases in patients with radiographic evidence of a neoplasm or high suspicion of a malignancy.