Grade Discordance Research Articles

Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

Baseline grade discordance in patients with pancreatic neuroendocrine tumors (PanNETs)

Baseline grade discordance in patients with pancreatic neuroendocrine tumors (PanNETs)

Discordance in TME Specimen Grading in a Prospective Phase II Multicenter Rectal Cancer Trial: Are We Overestimating the Quality of our Resections ?

To report the results of a rigorous quality control (QC) process in the grading of total mesorectal excision (TME) specimens during a multicenter prospective phase II trial of transanal TME. Grading of TME specimens is based on macroscopic assessment of the mesorectum and standardized through synoptic pathology reporting. TME grade is a strong predictor of outcomes with incomplete (IC) TME associated with increased rates of local recurrence relative to complete or near complete (C/NC) TME. Although TME grade serves as an endpoint in most rectal cancer trials, in protocols incorporating centralized review of TME specimens for quality assurance, discordance in grading and the management thereof has not been previously described. A phase II prospective taTME trial was conducted from 2017-2022 across 11 North American centers with TME quality as primary study endpoint. QC measures included training of site pathologists in TME protocols, (2) blinded grading of de-identified TME specimen photographs by central pathologists, and (3) reconciliation of major discordance prior to trial reporting. Cohen's Kappa statistic was used to assess agreement in grading. Overall agreement in grading of 100 TME specimens between site and central reviewer was rated as fair, (κ=0.35 (95% CI, 0.10-0.61, P<0.0001). Concordance was noted in 54%, with minor and major discordance in 32% and 14% of cases respectively. Upon reconciliation, 13/14 (93%) major discordances were resolved. Pre- versus post-reconciliation rates of C/NC and IC TME are 77%/16% and 7% versus 69%/21% and 10%. Reconciliation resulted in a major upgrade (IC to NC, N=1) or major downgrade (NC/C to IC, N=4) in 5 cases overall (5%). A 14% rate of major discordance was observed in TME grading between site and central reviewers. Resolution resulted in a major change in final TME grade in 5% of cases, which suggests that reported rates or TME completeness are likely overestimated in trials. QC through central review of TME photographs and reconciliation of major discordances is strongly recommended.

Comparison of Treatment and Outcome of Blunt Thoracic Aortic Injury Based on Society for Vascular Surgery and University of Washington Grading Recommendations

The Society for Vascular Surgery (SVS) recommendations for managing intimal (grade 1) blunt thoracic aortic injuries (BTAIs) include observation and medical management. The proposed University of Washington (UW) revised criteria suggest that intimal injuries with a ≥1-cm flap should be defined as moderate injury, and treatment should be considered. We compared the SVS and UW criteria for BTAI to determine how discordance in grading might aff5ct the treatment and outcomes.

Does Nonalcoholic Pancreatic Steatosis Always Correlate with Nonalcoholic Fatty Liver Disease?

PurposeTo identify the correlation of nonalcoholic pancreatic steatosis (NAPS) with nonalcoholic fatty liver disease (NAFLD) in an outpatient group. Based on its metabolic and imaging properties, NAPS has been increasingly recognized in recent years; however, its interaction with NAFLD is still not clear.Patients and MethodsIn this cross-sectional observational study, 345 consecutive patients without any chronic illness who were referred to the senior radiologist for abdominal ultrasound (US) were included. The US report showed hepatic and pancreatic echogenicity. The patients’ demographic, anthropometric, and laboratory data were collected from medical records.ResultsOverall, NAPS and NAFLD were seen in 227 (65.8%) and 219 (63.5%) patients, respectively. Normal echogenicity was noted in 74 (21.4%) patients. Forty-four patients (12.8%) had steatotic liver without NAPS, 52 (15.1%) had steatotic pancreas without NAFLD, and 175 (50.7%) had steatosis in both organs. The discordance in steatosis grading between NAPS and NAFLD was 55.1%. Insulin resistance was present in 8.7, 26.7, 19, and 61.3% of patients with no steatosis, only NAFLD, only NAPS, and steatosis in both organs, respectively. Evident NAFLD and NAPS having grade 2 and 3 steatosis were present in 15.3% and 29.0% of the study group, respectively. Cholecystolithiasis was present in 6.8, 13.6, and 28.8% of patients with normal echogenic pancreas, only NAFLD, and only NAPS, respectively (p=0.01).ConclusionBased on the ultrasonographic, clinical, demographic, and anthropometric features of the included patients, we found that NAPS did not fully accompany nonalcoholic fatty liver. Despite severe pancreatic steatosis, more than a quarter of cases had normal liver echogenicity. Insulin resistance frequency was insignificantly higher in NAFLD than NAPS (p=0.694). The significantly higher frequency of cholecystolithiasis in NAPS needs further large-scale studies. The inconsistency of steatosis degree in NAPS and NAFLD in >50% cases may reflect differences in the pathophysiology of these two clinical entities.

Discordance in Appendicitis Grading and the Association with Outcomes: A Post-Hoc Analysis of an EAST Multicenter Study

The American Association for the Surgery of Trauma (AAST) appendicitis severity grading criteria use independent subscales for radiologists (Rad), surgeons (Surg), and pathologists (Path). We reviewed the EAST Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG) database to determine rates of discordance and clinical consequences of inaccuracy. A confusion matrix was constructed for pairs among Rad, Surg, and Path. Accuracy was reported using chronologically latest diagnosis as gold standard. "Concordance" (C) was achieved when both agreed on the severity grade and "Discordance"(D) when they disagreed. A composite endpoint("COMP"= 30-d incidence of surgical site infection, abscess, wound complication, Clavien-Dindo complication, secondary intervention, ED[Emergency Department] visit, hospital readmission, and mortality) was compared between C versus D groups via χ2 test with Bonferroni correction to define statistical significance(P=0.05/9=0.005). For each pair and diagnosis, subjects were categorized as C or D and compared for the incidence of COMP. Incidence of COMP for Surg and/or Path in C versus D: 16% versus. 26% (p=0.006, NS by Bonferroni) for acute (A), 39% versus 33% (p=0.39) for gangrenous (G), and 48% versus 37% (p=0.035, NS by Bonferroni) for perforated (P). For Rad and/or Path in C versus. D: 17% versus 42% (p < 0.001) for A, 27% versus 31% (p=0.95) for G, and 56% versus 48% (p=0.48) for P. For C versus D: 17% versus 40% (p < 0.001) for A, 36% versus 26% (p=0.43) for G, and 51% versus 39% (p=0.29) for P. In appendicitis treated by appendectomy, surgeons are most accurate at diagnosing acute appendicitis and least accurate at diagnosing gangrenous. Radiologists are less accurate for all categories. When the surgeon is wrong, clinical outcomes are not significantly worse. However, when the radiologist is wrong about acute appendicitis, patients have worse clinical outcomes.

Combined multiple clinical characteristics for prediction of discordance in grade and stage in prostate cancer patients undergoing systematic biopsy and radical prostatectomy

BackgroundThe present study aimed to develop three nomograms by incorporating multiple clinical characteristics to identify those prostate cancer (PCa) patients with high probability of incorrect biopsy Gleason grade group (GG) before making treatment decisions. MethodsWe retrospectively collected data from PCa patients who underwent systematic biopsy and radical prostatectomy from January 2015 to December 2019 at Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology. Univariable and multivariable logistic regression analyses were preformed to identify independent risk factors associated with upgrading, upstaging and downgrading. By incorporating selected clinical parameters with high predictive value, we constructed three nomograms to predict the probability of upgrading, upstaging and downgrading. Discrimination of nomograms was evaluated by receiver operating characteristic (ROC) analysis with corresponding area under the curve (AUC). Decision curve analysis (DCA) and calibration curves were performed to evaluate calibration and the clinical usefulness of nomograms. Performance of the three nomograms was validated in the testing dataset. ResultsThere were 585 PCa patients in total enrolled in this study who met the inclusion criteria. Of the 585 patients, the disease of 262 (44.8 %) was upgraded and 68 (11.6 %) was downgraded, and the disease of 67 (11.5 %) was upstaged. With regard to findings of multivariable analyses, patients’ age and biopsy GG (GG 2, GG 3, GG 4 versus GG 1) were significantly associated with upgrading. Moreover, maximum diameter of the index lesion (D-max), clinical T stage (cT3a, cT3b versus cT1−2), number of positive cores and total tumor length were significantly associated with upstaging. Furthermore, d-max, %fPSA (> 0.16 versus ≤ 0.16) and biopsy GG (GG 3, GG 4, GG 5 versus GG 2) were independent predictors of downgrading. The three nomograms displayed good calibration in respective calibration plots. ROC analyses showed good discrimination with satisfactory AUC values and DCA plots demonstrated that the upgrading-risk nomogram, upstaging-risk nomogram and downgrading-risk nomogram were all clinically useful. ConclusionsThe upgrading-risk nomogram, upstaging-risk nomogram, and downgrading-risk nomogram were developed and correctly predicted the probability of incorrect Gleason grade group assigned to patients undergoing systematic biopsy.

Predictive value of preoperative neutrophil-to-lymphocyte ratio in localized prostate cancer: results from a surgical series at a high-volume institution.

To examine the predictive value of neutrophil-to-lymphocyte ratio in localized prostate cancer for surgical pathology and recurrence in patients treated by radical prostatectomy. We evaluated 1258 patients treated by radical prostatectomy at San Raffaele Hospital between 2011 and 2017 and assessed the association between preoperative neutrophil-to-lymphocyte ratio and surgical pathology (advanced stage, grade group ≥4, nodal involvement, grade discordance between biopsy and surgical pathology) and biochemical recurrence. The preoperative neutrophil-to-lymphocyte ratio was not significantly associated with advanced stage (≥T3), International Society of Urological Pathology (ISUP) grade (≥4) or discordance. At multivariable analysis, patients with higher neutrophil-to-lymphocyte ratio had lower risk of nodal involvement at final pathology (odds ratio [OR]: 0.77; 95% confidence interval [CI]: 0.64, 0.92; P=0.005). The preoperative level of neutrophil-to-lymphocyte ratio was associated with biochemical recurrence on univariate analysis (OR: 0.81, 95% CI: 0.68, 0.96; P=0.017). Such a relationship was not significant at multivariable analysis adjusting for tumor severity (OR: 0.93, 95% CI: 0.79, 1.09; P=0.4). Neutrophil-to-lymphocyte ratio does not have clinical utility for the prediction of adverse pathology and biochemical recurrence. Further research should focus on its value for predicting regional lymph node metastasis.

Abstract P1-16-04: How patient advocates and researchers work together in PRECISION* to identify low-risk ductal carcinoma in situ (DCIS) that may not need aggressive treatment

Abstract BACKGROUND: Ductal carcinoma in situ (DCIS) was virtually unknown before breast screening and now accounts for up to 25% of all ‘breast cancers’ detected. Over 50,000 women are diagnosed annually with DCIS in the US alone; most receive treatments intended for women with invasive breast cancer which may offer no benefit and are associated with physical and psychological complications, and financial burdens. Observational studies show a majority of DCIS never becomes invasive, even if left untreated. Lack of prospective data and concerns about “overtreatment” are now being addressed by PRECISION - an international consortium of clinicians, scientists and patient advocates - collaborating to understand the biological nature of DCIS and how it evolves. Our goal is to develop tests that distinguish between women with DCIS who will likely develop breast cancer and should be treated, and those who can safely avoid treatment. Patient advocates are fully integrated into PRECISION as well as 3 prospective randomized clinical trials - LORD (EU), LORIS (UK) and COMET (US) – aiming to produce evidence to show whether or not Active Surveillance has equivalent outcomes to surgery for low-risk DCIS. These trials are critical because PRECISION uses biospecimens from each trial, in addition to other DCIS cohorts around the world. PATIENT ADVOCATE AIMS: • Help foster teams that contribute to better outcomes for women with DCIS. • Assist in designing effective informational tools for providers, organizations, and the public. • Understand international differences in health services, medical culture, and patient expectations, and recommend improvements. • Measure the value of patient involvement in PRECISION research. • Raise awareness and communicate about ongoing research and (over)treatment of DCIS. METHODS: The PRECISION Patient Advocate Involvement Panel (PAIP) includes representatives from each country: NL, UK, and US. PAIP members provide encouragement that helps to shape ongoing projects into a cohesive team, while encouraging new synergistic projects that can potentially improve clinical practice. The PAIP actively participates in the Steering Group, all Work Packages (WPs), and a variety of internal and external communications. This includes making posters and presentations at international conferences, preparing for PRECISION reviews, creating website and newsletter content, giving interviews, co-authoring publications, and developing social media campaigns to raise awareness. RESULTS: The PAIP has: a) helped build collaborations between institutions; b) developed public-facing information about PRECISION and the 3 clinical trials; c) offered patient-oriented ideas and feedback to all WPs; d) helped resolve international contract barriers; e) helped identify additional DCIS cohorts; f) suggested ideas to improve recruitment for the clinical trials; g) given feedback on surveys and co-authored publications; h) built relationships with postdocs and PhD students; and i) engaged public and clinician audiences on DCIS dilemmas in each country. Additional ongoing PAIP work includes engaging in research to reduce pathology report DCIS grade discordance within and between countries (a critical issue for women diagnosed with DCIS). CONCLUSIONS: There is a need to better understand DCIS subtypes, stratify associated risks for invasive cancer, synergize accurate communication about DCIS, and improve pathology standards within and between countries. The PAIP will continue to work closely with researchers and communicate evidence that answers important questions related to risk factors for women who may or may not need treatment for DCIS. *PRECISION is sponsored by a Cancer Research UK Grand Challenge Award, which is also funded by the Dutch Cancer Society. Citation Format: Deborah Collyar, Donna Pinto, Hilary Stobart, Ellen Verschuur, Marja van Oirsouw, on behalf of the PRECISION Project. How patient advocates and researchers work together in PRECISION* to identify low-risk ductal carcinoma in situ (DCIS) that may not need aggressive treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-16-04.

Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy

To elucidate the accuracy of MRI and MRI-ultrasound fusion guided targeted biopsy (TBx) on risk stratification in men who underwent subsequent radical prostatectomy (RP). A single-center, retrospective study was performed in men at risk for prostate cancer who (n = 140) underwent TBx and RP between November 2012 and August 2018. Comparisons were made between patients clinically staged by preoperative MRI and TBx Gleason grade group (GGG) and stage after RP. Multivariable regression was performed to identify factors associated with MRI and TBx compared to RP grading, staging, and consistency with National Comprehensive Cancer Network (NCCN) risk stratification. There was an increase in NCCN risk stratification in 47 men (33.6%) and a decrease in 17 men (12.1%) compared to the resected prostate. GGG upgrading and downgrading occurred in 35 (25.0%) and 31 men (22.1%), respectively. Upstaging occurred in 41 men (29.3%). In adjusted analysis for age, BMI, PSA Density (PSAD), median maximal diameter of the regions of interest, and PIRADS, men with PIRADS 4 were less likely to be upgraded (OR 0.26, 95% CI 0.08-0.81, P = .020) than PIRADS 3. PSAD ≥ 0.15 ng/mL/cc was associated with upstaging (OR 3.92, 95% CI 1.60-9.62, P = .003). Accurate risk stratification is critical for disease management, mandated by the increasing use of active surveillance, partial gland ablation, and androgen deprivation therapy with radiation therapy for men with unfavorable intermediate and high-risk prostate cancer. This study confirms the need for advances in imaging and biomarker to increase the accuracy of pretreatment staging.

Discordant Diagnostic Terminology and Pathologic Grading of Primary Appendiceal Mucinous Neoplasms Reviewed at a High-Volume Center.

Diagnostic terminology and grading of primary appendiceal mucinous neoplasms lacks uniformity. We sought to identify discordance in pathologic reporting by reviewing pathology slides for cases referred to our institution. Using guidelines from Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer 8th edition (AJCC8), we compared diagnostic terminology/grading of primary appendiceal mucinous neoplasms (n = 115) between pathology reports from referring institutions and review of slides by pathologists at our high-volume institution. There was discordance in pathologic terminology and grading of primary appendiceal mucinous neoplasms between referring institutions and our institution in 28% and 50% of patients, respectively. In particular, 24% of patients referred with mucinous adenocarcinoma (MACA) had LAMN on our review, and a higher grade MACA was found in 48% of patients referred with low-grade (G1) MACA and 16% of patients referred with high-grade (G2) MACA following our review. Discordance in tumor grade between primary and metastatic disease was seen in 19% of cases based on referred primary tumor grading compared with only 4% following our review. Systemic chemotherapy was unnecessarily administered to four cases of LAMN (6%) and inappropriately not administered to four cases of MACA (6%) before referral due to inaccurate diagnosis/grading by referring institutions. We found significant discordance in diagnostic terminology/grading of primary appendiceal mucinous neoplasms following review of referred cases. Inaccurate pathologic assessment was associated with overtreatment or undertreatment with chemotherapy. These data highlight the need for pathologic review of such rare cases at high-volume centers.

Diagnostic accuracy of stereotactic brain biopsy for intracranial neoplasia in dogs: Comparison of biopsy, surgical resection, and necropsy specimens.

BackgroundStereotactic brain biopsy (SBB) is a technique that allows for definitive diagnosis of brain lesions. Little information is available regarding the diagnostic utility of SBB in dogs with intracranial diseases.ObjectiveTo investigate the diagnostic accuracy (DA) of SBB in dogs with brain tumors.AnimalsThirty‐one client‐owned dogs that underwent SBB followed by surgical resection or necropsy examinations.MethodsRetrospective observational study. Two pathologists blinded to SBB and reference standard diagnoses reviewed histologic specimens and typed and graded tumors according to World Health Organization and revised canine glioma classification criteria. Agreement between tumor type and grade from SBB were compared to reference standards and assessed using kappa statistics. Patient and technical factors associated with agreement also were examined.ResultsStereotactic brain biopsy specimens were obtained from 24 dogs with gliomas and 7 with meningiomas. Tumor type agreement between SBB and the reference standard was observed in 30/31 cases (κ = 0.95). Diagnostic concordance was perfect for meningiomas. Grade agreement among gliomas was observed in 18/23 cases (κ = 0.47). Stereotactic brain biopsy underrepresented the reference standard glioma grade in cases with disagreement. The DA of SBB was 81%, with agreement noted in 56/69 biopsy samples. Smaller tumors and fewer SBB specimens obtained were significantly associated with diagnostic discordance.Conclusions and Clinical ImportanceThe DA of SBB readily allows for the diagnosis of common brain tumors in dogs. Although glioma grade discordance was frequent, diagnoses obtained from SBB are sufficient to currently inform therapeutic decisions. Multiple SBB specimens should be collected to maximize DA.

Interobserver Variability in Mitotic Count for Meningioma Grading: How Can We Reduce It?

To evaluate the interobserver variability in determining the number of mitoses in 10 high-power field (HPF) and thus the tumor grade, and to investigate how to reduce grade discordance between the observers and the most useful method to identify the patients who would receive an additional treatment. Two hundred and seventy cases with meningioma were re-evaluated by three experienced pathologists and five senior residents. They determined the number of mitotic figures in 10 HPF in each slide. Re-evaluation of the cases, which were found of different grades from the reference observers was requested by full scan method. Statistical analysis was performed by using SPSS V23.0. A moderate agreement was found between the observers and the reference observer. After the evaluation of mitotic activity with the full scan method, the mean numbers of mitoses found by the observers in 10 HPF were increased. In the first evaluation, 4?6 cases were defined as Grade II by the observers. Whereas, 23?27 cases were defined as Grade II after the full scan method. If there are less than 16 mitotic figures throughout the slide, it is more difficult to find the 10 HPF including 4 or more mitosis. Interobserver variability in mitotic figure counting can be reduced by full scan method, and examining the hematoxylin and eosin stained slides by the full scan method helps us to determine the true histologic grade of meningiomas in most cases, who would receive an additional treatment.

Relative Contribution of Sampling and Grading to the Quality of Prostate Biopsy: Results from a Single High-volume Institution

BackgroundThe quality of prostate biopsy is affected by sampling (does the urologist take cores from the right place?) and the histological evaluation (does the pathologist grade correctly?). ObjectiveTo evaluate the relative contribution of sampling and histological evaluation to the reliability of prostate biopsy in terms of concordance with grading of the surgical specimen. Design, setting, and participantsWe identified 848 prostate cancer patients who underwent radical prostatectomy between 2015 and 2017 at our institution with external or internal biopsies. Since 2016, a dedicated uropathologist has reviewed all the biopsies sampled externally. Outcome measurements and statistical analysisWe considered the discordance between biopsy and final pathology as a proxy for the quality of prostate biopsy, and calculated the corresponding discordance rate for each biopsy setting. Results and limitationsWe observed the highest rate of grade discordance for patients who had an external biopsy without internal review (66%). Biopsies both sampled and reviewed internally had the lowest discrepancy rate (39%; p<0.0001 compared to external biopsies). Biopsies sampled outside our institution and reviewed internally had an intermediate discordance rate (51%; p=0.003). ConclusionsThe quality of prostate biopsy is influenced by both sampling and evaluation. Highly experienced pathological evaluation of needle biopsies is crucial, but biopsy quality also strongly depends on the quality of the sampled material. Future studies should investigate the mechanism underlying discordance in sampling. Consideration should be given to regionalization of prostate biopsy. Patient summaryThe quality of prostate biopsy varies between specialist and community centers. We found that this variation is affected by both sampling (does the urologist take cores from the right place?) and histological evaluation (does the pathologist grade correctly?).

Impact of breast cancer grade discordance on prediction of outcome.

Histological grade is an independent prognostic variable in breast cancer (BC). Previous concordance studies of BC grade have reported moderate levels of agreement; a typical finding in morphological assessment of biological variables. This study aimed to investigate the impact of discordance on the prognostic value of grade and to identify the best reporting approach in borderline cases. A large (n = 1675) well-characterised annotated cohort of BC, originally graded in routine practice using glass slides, was re-graded twice by an expert breast pathologist using virtual microscopy with a 3-month washout period. Outcome was assessed using breast cancer-specific and distant metastasis-free survival (median follow-up = 135 months). Fifty-eight per cent of the cases showed absolute agreement in the three separate grading sessions, whereas grades 1/2 and 2/3 discordance were observed in 21% and 21%, respectively. Absolute intra-observer agreement using virtual microscopy was observed in 77% of the cases, whereas 13% and 10% showed grades 1/2 and 2/3 discordance, respectively. Despite the concordance, outcome analysis revealed significant associations between tumour grade and patients' outcome in the three grading sessions. Grades 1/2 and 2/3 discordant cases showed intermediate survival between grades 1 and 2 tumours and grades 2 and 3 tumours, respectively. Grades 1/2 discordant cases showed a worse outcome when compared with grade 1 tumours (P = 0.008) but no statistical difference was identified when compared with grade 2 tumours. Similarly, grades 2/3 discordant cases showed a significant difference from grade 2 tumours (P < 0.001), but no statistical difference was identified when compared with grade 3 tumours. Breast cancer grade discordance is probably a reflection of biologically, and hence morphologically, borderline tumours. Cases with borderline features for grade are more likely to behave similarly to the higher-grade category. Repeating histological grade of borderline cases or double reporting may improve correlation with outcome.

Breast cancer histologic grading using digital microscopy: concordance and outcome association

AimsVirtual microscopy utilising digital whole slide imaging (WSI) is increasingly used in breast pathology. Histologic grade is one of the strongest prognostic factors in breast cancer (BC). This study aims...

Synaptophysin-Ki67 double stain: a novel technique that improves interobserver agreement in the grading of well-differentiated gastrointestinal neuroendocrine tumors

A common problem in the assessment of Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors is distinguishing tumor from non-tumor. This is because background stromal lymphocytes, entrapped non-neoplastic glands, and the delicate vascular network characteristic of neuroendocrine tumors frequently contain a subset of proliferating cells. Furthermore, in small biopsies, crush and cautery artifact can alter the morphologic appearance of tumor cells, making the Ki67 proliferative index more difficult to assess. To address these issues, we developed a synaptophysin-Ki67 double stain using a commercially available immunohistochemistry kit, allowing simultaneous visualization of tumor and proliferating nuclei. To test this method, three gastrointestinal pathologists individually graded 50 gastrointestinal neuroendocrine tumors first using synaptophysin-Ki67 double-stained slides and then, after a washout period, using Ki67-only stained slides (along with routine hematoxylin- and eosin-stained slides). Interobserver agreement on Ki67 proliferative index was moderate using the Ki67-only stained slides (intraclass correlation 0.51, 95% confidence interval: 0.35–0.66) and improved using the synaptophysin-Ki67 double stain (intraclass correlation 0.79, 95% confidence interval: 0.69–0.86). Similarly, interobserver agreement on tumor grade was fair with Ki67-only stained slides (κ=0.39, P<0.001) and improved with the double stain (κ=0.58, P<0.001). Analysis of individual pathologists' scores revealed that fewer total number of tumor cells counted correlated with higher grade designation and appeared to contribute to grade discordance. In tumors cited as particularly challenging to assess by the pathologists, three of four tumors were grade discordant with the Ki67-only stain, whereas all four tumors were grade concordant with the synaptophysin-Ki67 stain. The synaptophysin-Ki67 double stain is the first technique to address specifically the histomorphologic challenges of evaluating Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors. Although further validation is needed, this study provides evidence that the synaptophysin-Ki67 double stain can improve interobserver agreement.

Discordance of Histologic Grade Between Primary and Metastatic Neuroendocrine Carcinomas.

The prognosis and management of neuroendocrine carcinoma are largely driven by histologic grade as assessed by mitotic activity. The authors reviewed their institutional experience to determine whether the histologic grade of neuroendocrine carcinoma can differ between primary and metastatic tumors. This study examined patients who underwent operative resection of both primary and metastatic foci of neuroendocrine carcinoma. Resected tumors were independently reviewed and categorized as low, intermediate, or high grade as determined by mitotic count. The authors identified 20 patients with metastatic neuroendocrine carcinoma treated at their institution between 1997 and 2013 for whom complete pathologic review of primary and metastatic tumors was possible. Primary lesions were found in the small intestine (n = 12), pancreas (n = 7), ampulla (n = 1), stomach (n = 1), and rectum (n = 1). The timing of hepatic metastasis was synchronous in 15 cases and metachronous in 5 cases. The histologic grade was concordant between primary and metastatic tumors in 9 cases and discordant in 11 cases. Among the discordant cases, 7 had a higher metastatic grade than primary grade, and 4 had a lower metastatic grade than primary grade. Metachronous presentation was associated with a higher likelihood of grade discordance (p = 0.03). The histologic grade of all metachronous metastases differed from that of the primary tumors. There is a high prevalence of histologic grade discordance between primary and metastatic foci of neuroendocrine carcinoma, particularly among patients with a metachronous metastatic presentation. Given the importance of histologic grade in disease prognostication and treatment planning, this finding may be informative for the management of patients with metastatic neuroendocrine carcinoma.

Tu1916 Discordance in Tumor Grade Between Primary and Metastatic Lesions in Patients With Entero-Pancreatic Neuroendocrine Tumors: Implications for Clinical Management?

Tu1916 Discordance in Tumor Grade Between Primary and Metastatic Lesions in Patients With Entero-Pancreatic Neuroendocrine Tumors: Implications for Clinical Management?

La concordance du diagnostic histopathologique des sarcomes osseux et des tissus mous entre deux centres anticancéreux de l’Europe de l’Est et de l’Ouest : une expérience de collaboration

This study aims to assess the degree of concordance of histological diagnosis of bone and soft tissue sarcomas between a Comprehensive Cancer Center (CCC) of Eastern Europe -not specialized in this area of pathology- and an important CCC of Western Europe, which is one of the coordinators of a clinical reference network in sarcoma pathology. The goal is to have an overview of the sarcomatous pathology in a region of Eastern Europe and to discover diagnostic discrepancies between the two centers, while determining their cause. The initial diagnosis was compared with the revised diagnosis on 110 specimens from 88 patients with bone or soft tissue sarcomas from East-European CCC, in a one-year period of time. Complete diagnostic agreement was observed in 55 cases (62.5%), a partial agreement in 23 cases (26.1%) and a major disagreement in 10 cases (11.4%). Major discrepancies of the histological type was observed in only 3 cases (3.4%): one case of discordance benign/malignant and 2 cases of discordance mesenchymal/non mesenchymal. Minor histological discrepancies -not affecting the management of the patient- were observed in 18 cases (20.4%). A major discordance in grading -potentially changing the management of the patient- was noted in 7 cases (7.9%), and a minor discrepancy in 5 cases (5.7%). Some histological types were clearly overdiagnosed, like "adult fibrosarcomas" and "malignant peripheral nerve sheet tumors" (MPNST), mostly converted after the audit into "undifferentiated spindle cell sarcomas" or other types of sarcomas. Some "unclassified" sarcomas and "undifferentiated pleomorphic sarcomas" could be re-classified with the aid of an extensive panel of antibodies. Overall, immunohistochemistry was responsible, but not in exclusivity, for half of the minor discrepancies, and for 2 out of 3 cases of major histological discrepancies. Otherwise, the main cause of discrepancies was the difficulties in the interpretation of the morphology. Molecular biology was decisive in one case. Most grading discrepancies resulted from the appreciation of the mitotic index. The profile of the sarcomatous pathology in the northwest region of Romania does not appear to differ significantly from other parts of Europe or the world, but a prospective epidemiological study would be necessary to confirm this assessment. The expansion of immunohistochemical antibody panel, the over-specialization of pathologists and, in the future, the establishment of a national network of referral centers in sarcoma pathology, are required for a high level of histological diagnosis in Eastern Europe. A periodic external audit, continuing this trans-European collaboration between the two centers, would be beneficial for monitoring progress.