The value of secondary pathology review.

6 Background: Improving the value of cancer care is a major focus for the Alliance of Dedicated Cancer Centers (ADCC). Looking to align with the Institute of Medicine’s (IOM) initiative to “Develop and deploy approaches to identify, learn from, and reduce diagnostic errors and near misses in clinical practice,” the ADCC implemented a study to examine the clinical impact of expert secondary pathology review. The goal of this project was to: 1) demonstrate the value of secondary review of outside pathological specimens by ADCC subspecialty pathologists in identifying significant errors that can potentially impact treatment; and 2) create an opportunity to improve patient cancer care. Methods: All consult slides from patients referred to each ADCC center were reviewed by designated pathologists. Patient-level data for original and revised diagnoses were collected for two months in 2014. Discrepancies were classified as: 1) major - diagnosis changes treatment or surveillance; or, 2) minor - diagnosis does not change affect treatment or surveillance. To verify these assessments, disease-specific, multi-center teams of clinical experts reviewed each discrepant case and provided treatment recommendations for the original and revised diagnoses. Results: A total of 13,109 cases were collected across all ADCC centers and the discrepancy rate was 11% (1,488/1309); 3% (359/13,109) were major and 9% (1,129/13,109) were minor. The most common discrepancy was reclassification of the neoplasm cell type. The highest discrepancy rate was shown in the neuro-oncology and head and neck cases, with a 7% and 4% major discrepancy rate respectively. Conclusions: We identified an overall discrepancy rate of 11%, with 3% of cases leading to a change in treatment or surveillance. This demonstrates the importance of expert pathology review and that secondary pathology review can significantly improve clinical outcomes through precise and accurate pathological diagnoses. As indicated in the recent IOM report, this project further demonstrates that “diagnostic errors may cause harm to patients by preventing or delaying appropriate treatment, providing unnecessary or harmful treatment, or resulting in psychological or financial repercussions.”

Canadian ALK (CALK): A pan-Canadian multicenter study to optimize and standardize ALK immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for ALK gene rearrangements.

8096 Background: ALK gene rearrangement (ALK+) has been found in 3-5% of advanced non-small cell lung cancer patients. FISH is considered the “gold standard” for identification of ALK+ tumors, but its cost-effectiveness and adoption as a screening assay has been debated. Recent reports suggested that ALK IHC may serve as an alternative screening or possibly a diagnostic method. In this context, CALK was initiated to assess the feasibility of implementing ALK IHC and/or FISH assays across Canadian hospitals. Methods: FISH-confirmed 22 ALK+ and 6 ALK- tumors were used as study samples. Unstained sections and scanned images of HE-stained slides from each tumor block were distributed to participating centres. IHC protocols with best signal to noise ratio using the 5A4 (Novocastra) or ALK-1 (Dako) antibodies were developed for various auto-stainers and implemented to suit the existing conditions of the participating centres. A common FISH protocol using the ALK break-apart probe (Abbott Molecular, Chicago, IL) was developed based on published reports. H-score was used to assess IHC. FISH signals were scored in 100 tumor cells/case by 2-3 pre-trained persons. A second round IHC study using newly distributed slides was completed by 8 centres. Results: Independent IHC scores from 12 centres and FISH scores from 11 centres were collected and analysed. The intraclass correlation coefficients (ICC) between centres for IHC and FISH were 0.84 and 0.68, respectively. Following the analysis of initial IHC results, a second round study resulted in improved ICC of 0.94. One of 23 tumors revealed IHC-/FISH+ discrepancy, with the FISH revealing unusual signal configurations that suggested an atypical rearrangement. However, the sensitivity and specificity of FISH results across centres using the 15 aberrant signals cut-off ranged from 86.7-100% and 100%, respectively. Conclusions: Standardization across multiple centres for ALK testing by IHC and FISH can be achieved. IHC detected all FISH+ ALK tumors, except for one discrepant case with atypical FISH finding of unknown clinical implication. The study was supported by a Pfizer Canada grant.