Quality in cancer diagnosis.

Improving the quality of oncologic pathology diagnosis is immensely important as the overwhelming majority of the approximately 1.6 million patients who will be diagnosed with cancer in 2010 have their diagnoses established through the pathologic interpretation of a tissue sample. Millions more patients have tissue samples obtained to rule out cancer and do not have cancer. The majority of studies on the quality of oncologic pathology diagnoses have focused on patient safety and have documented a variety of causes of error that occur in the clinical and pathology laboratory testing phases of diagnostic testing. The reported frequency of a diagnostic error made by oncologic pathology depends on several factors, such as definitions and detection methods, and ranges from 1% to 15%. The large majority of diagnostic errors do not result in severe harm, although mild to moderate harm in the form of additional testing or diagnostic delays occurs in up to 50% of errors. Clinical practitioners play an essential role in error reduction through several avenues such as effective test ordering, providing accurate and pertinent clinical information, procuring high-quality specimens, providing timely follow-up on test results, effectively communicating on potentially discrepant diagnoses, and advocating second opinions on the pathology diagnosis in specific situations.

Preoperative diagnosis of benign thyroid nodules with indeterminate cytology.

BACKGROUND: Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS: We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS: Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS: These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.).

A prospective assessment defining the limitations of thyroid nodule pathologic evaluation.

BACKGROUND: Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined. OBJECTIVE: To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses. DESIGN: Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010. SETTING: 14 academic and 35 community clinical sites. PATIENTS: 653 patients with 776 surgically resected thyroid nodules of 1 cm or greater. MEASUREMENTS: Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists. RESULTS: Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%). LIMITATIONS: Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule. CONCLUSION: Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis. PRIMARY FUNDING SOURCE: Veracyte.

Multimodal hyperspectroscopy as a triage test for cervical neoplasia: pivotal clinical trial results.

OBJECTIVE: To prospectively evaluate a new non invasive device that combines fluorescence and reflectance spectroscopy in a population in women at risk for cervical dysplasia. METHODS: A total of 1607 women were evaluated with multimodal hyperspectroscopy (MHS), a painless test with extremely high spectral resolution. Subjects who were referred to colposcopy based on abnormal screening tests or other referral criteria underwent the MHS test and also had a sample taken for additional cytology and presence of high risk human papilloma virus (HPV) prior to undergoing biopsy. RESULTS: Sensitivity of MHS for cervical intraepithelial neoplasia (CIN) 2+ was 91.3% (252/276). Specificity, or the potential reduction in referrals to colposcopy and biopsy, was 38.9% (222/570) for women with normal or benign histology and 30.3% (182/601) for women with CIN1 histology. Two year follow-up data, collected for a subgroup of 804 women, revealed 67 interval CIN2+ that originally were diagnosed at enrollment as normal or CIN1. MHS identified 60 of these (89.6%) as positive for CIN2+ prior to their discovery during the two year follow-up period. CONCLUSIONS: MHS provides an immediate result at the point of care. Recently, the limitations of cytology have become more obvious and as a consequence greater emphasis is being placed on HPV testing for cervical cancer screening, creating a need for an inexpensive, convenient and accurate test to reduce false positive referrals to colposcopy and increase the yield of CIN2+ at biopsy. MHS appears to have many of the attributes necessary for such an application.

Cost-effectiveness of gene-expression profiling for tumor-site origin.

OBJECTIVES: Gene-expression profiling (GEP) reliably supplements traditional clinicopathological information on the tissue of origin (TOO) in metastatic or poorly differentiated cancer. A cost-effectiveness analysis of GEP TOO testing versus usual care was conducted from a US third-party payer perspective. METHODS: Data on recommendation changes for chemotherapy, surgery, radiation therapy, blood tests, imaging investigations, and hospice care were obtained from a retrospective, observational study of patients whose physicians received GEP TOO test results. The effects of chemotherapy recommendation changes on survival were based on the results of trials cited in National Comprehensive Cancer Network and UpToDate guidelines. Drug and administration costs were based on average doses reported in National Comprehensive Cancer Network guidelines. Other unit costs came from Centers for Medicare & Medicaid Services fee schedules. Quality-of-life weights were obtained from literature. Bootstrap analysis estimated sample variability; probabilistic sensitivity analysis addressed parameter uncertainty. RESULTS: Chemotherapy regimen recommendations consistent with guidelines for final tumor-site diagnoses increased significantly from 42% to 65% (net difference 23%; P<0.001). Projected overall survival increased from 15.9 to 19.5 months (mean difference 3.6 months; two-sided 95% confidence interval [CI] 3.2-3.9). The average increase in quality-adjusted life-months was 2.7 months (95% CI 1.5-4.3), and average third-party payer costs per patient increased by $10,360 (95% CI $2,982-$19,192). The cost per quality-adjusted life-year gained was $46,858 (95% CI $13,351-$104,269). CONCLUSIONS: GEP TOO testing significantly altered clinical practice patterns and is projected to increase overall survival, quality-adjusted life-years, and costs, resulting in an expected cost per quality-adjusted life-year of less than $50,000.

Discrepancies in dermatopathology diagnoses: the role of second review policies and dermatopathology fellowship training.

BACKGROUND: Expert consultation and institutional policies mandating second review of pathologic diagnoses in the course of referral have been advocated to optimize patient care. OBJECTIVE: We sought to investigate the rate of diagnostic discrepancies between pathologists with and without dermatopathology fellowship training. METHODS: All available outside pathology reports were reviewed for material sent to the University of Pittsburgh Medical Center Dermatopathology Unit during 1 year. The outside diagnosis was compared with the diagnosis rendered by the referral dermatopathology service. Cases were assigned into 1 of 4 categories: melanocytic neoplasm, nonmelanocytic neoplasm, inflammatory, and other. For each case, the outside pathologist's level of dermatopathology training was noted. Any change in diagnosis resulting in significant alteration in therapy or prognosis, as dictated by the accepted standard of care, was considered a major discrepancy. RESULTS: A total of 405 cases were reviewed. In 51 cases (13%), no preliminary diagnosis was rendered at the outside facility. The referral diagnosis differed from the outside diagnosis in 226 cases (56%), and major discrepancies were identified in 91 cases (22%). Of these 91 cases, 84 were received from outside pathologists who were not dermatopathology trained and 7 were received from pathologists with dermatopathology training. The 91 cases with major discrepancies were categorized as: 36 nonmelanocytic neoplasms (40%), 30 inflammatory (33%), 23 melanocytic neoplasms (25%), and 2 other (2%). LIMITATIONS: This was a retrospective study limited to 2 consultant dermatopathologists at an academic referral center, which typically receives and reviews select cases. CONCLUSION: Dermatopathology fellowship training is associated with a substantial decrease in major diagnostic discrepancies. Pathologists without dermatopathology fellowship training tend to successfully identify those cases for which expert consultation is most useful.

Directed peer review in surgical pathology.

Second pathologist peer review is used in many surgical laboratory quality-assurance programs to detect error. Directed peer review is 1 method of second review and involves the selection of specific case types, such as cases from a particular site of anatomic origin. The benefits of using the directed peer review method are unique and directed peer review detects both errors in diagnostic accuracy and precision and this detection may be used to improve practice. We utilize the Lean quality improvement A3 method of problem solving to investigate these issues. The A3 method defines surgical pathology diagnostic error and describes the current state in surgical pathology, performs root cause analysis, hypothesizes an ideal state, and provides opportunities for improvement in error reduction. Published data indicate that directed peer review practices may be used to prevent active cognitive errors that lead to patient harm. Pathologists also may use directed peer review data to target latent factors that contribute to error and improve diagnostic precision.

DNA mutational differences in cytological specimens from pancreatic cancer and cholangiocarcinoma.

BACKGROUND/AIMS: Preoperative distinction between pancreatic cancer (PC) and extrahepatic cholangiocarcinoma (CC) is desirable due to diverging management options, and to optimize enrollment into neoadjuvant trials. METHODS: A single-center retrospective study of patients with PC or CC was undertaken. Four blinded pathologists reviewed all cases and reached a consensus diagnosis (PC or CC). Microdissection-based multiple microsatellite loss analysis and direct sequencing of K-ras oncogene was performed and compared for PC and CC. RESULTS: Of 33 cases studied (17 males; 16 PC, 17 CC; 10 with primary sclerosing cholangitis), a K-ras mutation was present in 14/16 (87.5%) PC and 1/17 (5.9%) CC cases (p < 0.001), sensitivity and specificity were 87.5 and 94%, respectively. The mean fractional mutational rate was higher in PC (0.51; 95% CI 0.45-0.58) compared to CC (0.34; 95% CI 0.28-0.39, p < 0.001). CONCLUSIONS: The presence of a K-ras mutation in cytology specimens distinguishes PC from CC in this study. and IAP.

Applying the Paris system for reporting urine cytology to challenging cytology cases.

BACKGROUND: Implementing the Paris system for reporting urine cytology (TPS) can substantiate atypical diagnosis while improving standardization and risk stratification. This study evaluates its performance and reproducibility in challenging cases and examines whether focused education of morphological features can improve outcomes. METHODS: In our prior study, urine cytology cases diagnosed as "atypical" with surgical follow-up were used. Cases showing poor agreement in that study were collected for this one. Representative photographs of each case were taken and distributed via online questionnaires. Participants were asked to render an initial diagnosis and evaluate the presence of several morphological features. Educational material was distributed, followed by additional questionnaires. RESULTS: Three participants evaluated 40 cases before and after educational materials. TPS diagnoses were significantly more specific (0.23 vs 0.59, P = 0.004) and more accurate (0.43 vs 0.66, P = 0.0125) than diagnoses made with our institutional system. Fewer overall cases were diagnosed as "atypical" with TPS. TPS education resulted in slightly, though not significantly, more specific diagnoses (0.25 vs 0.59, P = 0.083). Interobserver agreement decreased for nuclear-to-cytoplasmic (N/C) ratio, TPS diagnoses and initial diagnoses, and increased for all other features. TPS resulted in downgrading of cases with biopsy-proven low grade urothelial neoplasm (LGUN) from "atypical" to negative for high grade urothelial carcinoma (NHGUC) (P = 0.018). CONCLUSIONS: Use of TPS in challenging urine cytology cases can improve specificity, risk stratification, and diagnostic accuracy while decreasing the number of "atypical" diagnoses. Though training can help cytopathologists better apply these criteria, it is unclear how to effectively improve evaluation of N/C ratio.

Precancerous cervical lesions and HPV genotypes identified in previously unsatisfactory cervical smear tests after inexpensive glacial acetic acid processing.

OBJECTIVE: To determine the effectiveness of using glacial acetic acid (GAA) to convert unsatisfactory bloody ThinPrep (TP) cervical smear test to satisfactory, and identify associated missed diagnoses and high-risk HPV (hrHPV) genotypes. METHODS: In a retrospective descriptive cross-sectional analysis, all TP tests performed in Mississippi, USA, 2012-2016, were evaluated for unsatisfactory results owing to blood. Tests that were converted to satisfactory by GAA treatment, and corresponding anomalies and HPV genotypes were identified. RESULTS: Among 106 384 TP tests, there were 1460 (1.37%) unsatisfactory results, of which 1442 (98.77%) were converted to satisfactory after GAA treatment. Laboratory preprocessing with GAA increased costs minimally. Precancerous lesions were detected in 166 (11.51%) of 1442 GAA-treated samples, of which 12 (7.2%) were high-grade lesions, 110 (66.3%) were atypical squamous cells of undetermined significance, and 63 (57.3%) tested positive for hrHPV. Of 60 genotyped samples, 39 (65%) had non-HPV16 and non-HPV18. Including mixed infections, 48 (80%) contained less-common hrHPV types, reflecting an unexpected distribution in bloody specimens. CONCLUSIONS: GAA pretreatment of bloody TP tests would reduce the incidence of unsatisfactory results and missed high-grade lesions, and prevent the cost of repeat tests and delayed treatment. Clinicians without access to GAA should consider HPV testing.

Amended reports: development and validation of a taxonomy of defects.

Amended pathology reports produce rework, confusion, and distrust. To develop a reproducible amendment taxonomy we derived a classification from 141 amended reports, then validated it with 130 new cases before 4 observers independently reviewed 430 cases measuring agreement (k). Next, agreement in classifying 30 other amended reports in 7 institutions was measured. We further tracked amendment rates, defect categories, defect discoverers, and discovery mechanisms. In the 430-case validation set agreement was excellent (k = 0.8780 [range, 0.8416-0.9144]). Among the 7 institutions, agreement was good (k = 0.6235 [range, 0.3105-0.8975]). Amendment rates ranged from 2.6 to 4.8 per 1,000 reports. Misinterpretation fractions varied least (23%-29%). Misidentification fractions ranged more widely (20%-38%). Specimen defects were least frequent (4%-10%) and report defects most frequent (29%-48%). Misidentifications and report defects inversely correlated. Pathologists discovered most misinterpretations, and clinicians found most misidentifications. Conference review revealed 40% to 80% of misinterpretations. This taxonomy produced excellent reproducibility and good agreement across institutions.

Measuring quality in anatomic pathology.

This article focuses mainly on diagnostic accuracy in measuring quality in anatomic pathology, noting that measuring any quality metric is complex and demanding. The authors discuss standardization and its variability within and across areas of care delivery and efforts involving defining and measuring error to achieve pathology quality and patient safety. They propose that data linking error to patient outcome are critical for developing quality improvement initiatives targeting errors that cause patient harm in addition to using methods of root cause analysis, beyond those traditionally used in cytologic-histologic correlation, to assist in the development of error reduction and quality improvement plans.

Dissemination of Lean methods to improve Pap testing quality and patient safety.

OBJECTIVE: To determine if the implementation of Lean methods resulted in improved Pap test quality and diagnostic accuracy in 5 clinician practices. MATERIALS AND METHODS: We performed a 1-year case-control study that included 5,384 control (preintervention) and 5,442 case (postintervention) women who had a Pap test procured by 1 of 5 clinicians. Using Lean methods, the clinicians increased their focus of Pap test procurement by creating a "one-by-one" workflow and recorded process completion using a Lean checklist. We compared the case and control Pap test quality and accuracy measures using the proportion of Pap tests lacking a transformation zone component, proportion of unsatisfactory Pap tests, frequency of newly detected cervical intraepithelial neoplasia following a previous benign Pap test, and proportion of Pap tests with a diagnosis of atypical squamous cells of unknown significance. RESULTS: After the intervention, there was a statistically significant decrease in the mean proportion of Pap tests lacking a transformation zone component, p =.011. Two of 5 clinicians showed a statistically significant decrease in their unsatisfactory Pap test frequency, although the overall Pap test unsatisfactory frequency for the case group was not statistically significant lower, p =.087. The case group showed a 114% increase in newly detected cervical intraepithelial neoplasia following a previous benign Pap test, p =.004. There was no statistically significant difference for the proportion of Pap tests with a diagnosis of atypical squamous cells of unknown significance, p =.908. CONCLUSIONS: Disseminating Lean methods across a group of clinicians resulted in improved Pap test quality and diagnostic accuracy.

Analysis of the Cytomorphological Features in Atypical Urine Specimens following Application of The Paris System for Reporting Urinary Cytology.

BACKGROUND: This study investigates the use of The Paris System (TPS) for Reporting Urinary Cytopathology and examines the performance of individual and combined morphological features in atypical urine cytologies. METHODS: We reviewed 118 atypical cytologies with subsequent bladder biopsies for the presence of several morphological features and reclassified them into Paris System categories. The sensitivity and specificity of individual and combined features were calculated along with the risk of malignancy. RESULTS: An elevated nuclear-to-cytoplasmic ratio was only predictive of malignancy if seen in single cells, while irregular nuclear borders, hyperchromasia, and coarse granular chromatin were predictive in single cells and in groups. Identification of coarse chromatin alone yielded a malignancy risk comparable to 2-feature combinations. The use of TPS criteria identified the specimens at a higher risk of malignancy. CONCLUSION: Our findings support the use of TPS criteria, suggesting that the presence of coarse chromatin is more specific than other individual features, and confirming that cytologic atypia is more worrisome in single cells than in groups.