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Lee A.F.,Vancouver General Hospital | Lee A.F.,University of British Columbia | Gown A.M.,University of British Columbia | Gown A.M.,PhenoPath Laboratories | And 2 more authors.
American Journal of Surgical Pathology | Year: 2013

Distinguishing malignant mesotheliomas from benign mesothelial proliferations on hematoxylin and eosin-stained sections can be extremely challenging. Various immunohistochemical stains have been suggested to help in making this distinction, but all are controversial. Recently, IMP3 (insulin-like growth factor II mRNA binding protein 3) and GLUT-1 (glucose transporter protein 1) have been proposed as immunohistochemical markers that are positive in mesotheliomas but not in benign proliferations. We evaluated the performance of these markers on a tissue microarray containing 30 malignant mesotheliomas and 48 benign thoracic or abdominal mesothelial proliferations. IMP3 was positive in 53% of malignant and 27% of benign cases (P=0.03), whereas GLUT-1 was positive in 60% of malignant and 13% of benign cases (P=0.0003). Forty-three percent of malignant cases, but only 4% of benign cases, were positive for both IMP3 and GLUT-1 (P=0.00003). We conclude that, statistically, both IMP3 and GLUT-1 are more frequently positive in malignant compared with benign mesothelial processes; however, the frequency of positive staining in benign cases is too high to allow their diagnostic use as single stains. The combination of both markers may be of greater diagnostic value, but this hypothesis should be confirmed in further studies. Copyright © 2013 by Lippincott Williams & Wilkins. Source

Polley M.-Y.C.,U.S. National Cancer Institute | Leung S.C.Y.,University of British Columbia | McShane L.M.,U.S. National Cancer Institute | Gao D.,University of British Columbia | And 14 more authors.
Journal of the National Cancer Institute | Year: 2013

BackgroundIn breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67's value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.MethodsEight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays-one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. ResultsIntralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.ConclusionsSubstantial variability in Ki67 scoring was observed among some of the world's most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited. © 2013 The Author . Source

Chiu C.G.,University of British Columbia | Strugnell S.S.,University of British Columbia | Griffith O.L.,University of British Columbia | Jones S.J.M.,University of British Columbia | And 5 more authors.
American Journal of Pathology | Year: 2010

Galectin-3 (Gal-3), which has received significant recent attention for its utility as a diagnostic marker for thyroid cancer, represents the most well-studied molecular candidate for thyroid cancer diagnosis. Gal-3 is a protein that binds to β-galactosidase residues on cell surface glycoproteins and has also been identified in the cytoplasmic and nuclear compartment. This marker has been implicated in regulation of normal cellular proliferation and apoptosis, as well as malignant transformation and the metastasis of cancer cells. We here present a mechanistic review of Gal-3 and its role in cancer development and progression. Gal-3 expression studies in thyroid tissue and cytologic tumor specimens and their methodological considerations are also discussed in this article. Despite great variance in their methodology, the majority of immunohistochemical studies found that Gal-3 was differentially expressed in thyroid carcinoma compared with benign and normal thyroid specimens, suggesting that Gal-3 is a good diagnostic marker for thyroid cancer. Recent studies have also demonstrated improved methodological reliability. On the other hand, Gal-3 genomic expression studies have shown inconsistent results for diagnostic utility and are not recommended. Overall, the development of Gal-3 as a diagnostic marker for thyroid cancer represents a promising avenue for future study, and its clinical application could significantly reduce the number of diagnostic thyroid operations performed for cases of indeterminant fine needle aspiration biopsy cytology, and thus positively impact the current management of thyroid nodular disease. Copyright © American Society for Investigative Pathology. Source

Terry J.,BC Cancer Agency | Leung S.,BC Cancer Agency | Laskin J.,BC Cancer Agency | Leslie K.O.,Mayo Medical School | And 2 more authors.
American Journal of Surgical Pathology | Year: 2010

The histologic subtype of non-small cell lung carcinoma is important in selecting appropriate chemotherapy for patients with advanced disease. As many of these patients are not operative candidates, they are treated medically after biopsy for diagnosis. Inherent limitations of small biopsy samples can make distinguishing poorly differentiated lung adenocarcinoma (ADC) from squamous cell carcinoma (SCC) difficult. The value of histochemical and immunohistochemical markers to help separate poorly differentiated ADC from SCC in resection specimens is well established; however, the optimal use of markers in small tissue samples has only recently been examined and the correlation of marker expression in small tissue samples with histologic subtype determined on resection specimens has not been well documented. We address this issue by examining the expression of 9 markers (p63, TTF1, CK5/6, CK7, 34βE12, Napsin A, mucicarmine, NTRK1, and NTRK2) on 200 cases of ADC and 225 cases of SCC in tissue microarray format to mimic small tissue specimens. The single best marker to separate ADC from SCC is p63 (for SCC: sensitivity 84%, specificity 85%). Logistic regression analysis identifies p63, TTF1, CK5/6, CK7, Napsin A, and mucicarmine as the optimal panel to separate ADC from SCC. Reduction of the panel to p63, TTF1, CK5/6, and CK7 is marginally less effective but may be the best compromise when tissue is limited. We present an algorithm for the stepwise application of p63, TTF1, CK5/6, CK7, Napsin A, and mucicarmine in situations in which separation of ADC from SCC in small specimens cannot be accomplished by morphology alone. © 2010 by Lippincott Williams & Wilkins. Source

Dewar R.,Beth Israel Deaconess Medical Center | Fadare O.,Vanderbilt University | Gilmore H.,Beth Israel Deaconess Medical Center | Gown A.M.,University of British Columbia | Gown A.M.,PhenoPath Laboratories
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-Numerous immunohistochemical stains have been shown to exhibit exclusive or preferential positivity in breast myoepithelial cells relative to their luminal/epithelial counterparts. These myoepithelial markers provide invaluable assistance in accurately classifying breast proliferations, especially in core biopsies. Although numerous myoepithelial markers are available, they differ in their sensitivity, specificity, and ease of interpretation, which may be attributed, to a large extent, to the variable immunoreactivity of these markers in stromal cells including myofibroblasts, vessels, luminal/epithelial cells, and tumor cells. Objective.-To review commonly used myoepithelial markers in breast pathology and a selection of diagnostic scenarios where they may be useful. Data Sources.-The information outlined in this review article is based on our experiences with routine cases and a review of English-language articles published between 1987 and 2008. Conclusions.-To demonstrate the presence or absence of myoepithelial cells, a panel-based approach of 2 or more markers is recommended. Markers that most effectively combine sensitivity, specificity, and ease of interpretation include smooth muscle myosin heavy chains, calponin, p75, p63, P-cadherin, basal cytokeratins, maspin, and CD10. These markers, however, display varying crossreactivity patterns and variably reduced expression in the myoepithelial cells bordering in situ carcinomas. The choice of a myoepithelial marker should be dependent on a combination of factors, including published evidence on its diagnostic utility, its availability, performance characteristics that have been achieved in a given laboratory, and the specific diagnostic scenario. When its use is deemed necessary, immunohistochemistry for myoepithelial cells in breast pathology is most effective when conceptualized as supplemental, rather than central to routine morphologic interpretation. Source

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