Histopathological diagnosis of cutaneous melanocytic lesions: blinded and nonblinded second opinions offer similar improvement in diagnostic accuracy.

BACKGROUND: Previous studies of second opinions in the diagnosis of melanocytic skin lesions have examined blinded second opinions, which do not reflect usual clinical practice. The current study, conducted in the USA, investigated both blinded and nonblinded second opinions for their impact on diagnostic accuracy. METHODS: In total, 100 melanocytic skin biopsy cases, ranging from benign to invasive melanoma, were interpreted by 74 dermatopathologists. Subsequently, 151 dermatopathologists performed nonblinded second and third reviews. We compared the accuracy of single reviewers, second opinions obtained from independent, blinded reviewers and second opinions obtained from sequential, nonblinded reviewers. Accuracy was defined with respect to a consensus reference diagnosis. RESULTS: The mean case-level diagnostic accuracy of single reviewers was 65.3% (95% CI 63.4-67.2%). Second opinions arising from sequential, nonblinded reviewers significantly improved accuracy to 69.9% (95% CI 68.0-71.7%; P < 0.001). Similarly, second opinions arising from blinded reviewers improved upon the accuracy of single reviewers (69.2%; 95% CI 68.0-71.7%). Nonblinded reviewers were more likely than blinded reviewers to give diagnoses in the same diagnostic classes as the first diagnosis. Nonblinded reviewers tended to be more confident when they agreed with previous reviewers, even with inaccurate diagnoses. CONCLUSION: We found that both blinded and nonblinded second reviewers offered a similar modest improvement in diagnostic accuracy compared with single reviewers. Obtaining second opinions with knowledge of previous reviews tends to generate agreement among reviews, and may generate unwarranted confidence in an inaccurate diagnosis. Combining aspects of both blinded and nonblinded review in practice may leverage the advantages while mitigating the disadvantages of each approach. Specifically, a second pathologist could give an initial diagnosis blinded to the results of the first pathologist, with subsequent nonblinded discussion between the two pathologists if their diagnoses differ.

Association of Second-Opinion Strategies in the Histopathologic Diagnosis of Cutaneous Melanocytic Lesions With Diagnostic Accuracy and Population-Level Costs.

IMPORTANCE: Diagnostic variation among pathologists interpreting cutaneous melanocytic lesions could lead to suboptimal care. OBJECTIVE: To estimate the potential association of second-opinion strategies in the histopathologic diagnosis of cutaneous melanocytic lesions with diagnostic accuracy and 1-year population-level costs in the US. DESIGN, SETTING, AND PARTICIPANTS: Decision analysis with 1-year time horizon including melanocytic lesion diagnoses available from US pathologists participating in the Melanoma Pathology Study (M-Path) and from the study panel of reference pathologists who classified cases using the MPATH-Dx classification tool. M-Path data collection occurred from July 2013 through March 2015; analyses for the present study were performed between April 2015 and January 2021. EXPOSURES: Various second-opinion strategies for interpretation of melanocytic cutaneous lesions. MAIN OUTCOMES AND MEASURES: Estimated accuracy of pathologists' diagnoses, defined as concordance with the reference panel diagnoses, and 1-year postbiopsy medical costs under various second-opinion strategies. Expected percentage of concordant diagnoses, including percentages of overinterpretation and underinterpretation, and 1-year costs of medical care per 100 000 in the US population. RESULTS: Decision-analytic model parameters were based on diagnostic interpretations for 240 cases by 187 pathologists compared with reference panel diagnoses. Without second opinions, 83.2% of diagnoses in the US were estimated to be accurate-ie, concordant with the reference diagnosis; with overinterpretation (8.0%) or underinterpretation (8.8%), and 16 850 misclassified diagnoses per 100 000 biopsies. Accuracy increased under all second-opinion strategies. Accuracy (87.4% concordance with 3.6% overinterpretation and 9.1% underinterpretation) and cost (an increase of more than $10 million per 100 000 biopsies per year) were highest when second opinions were universal (eg, performed on all biopsies), relative to no second opinions. A selective second-opinion strategy based on pathologists' desire or institutional requirements for a second opinion was most accurate (86.5% concordance; 4.4% overinterpretation; 9.1% underinterpretation) and would reduce costs by more than $1.9 million per 100 000 skin biopsies relative to no second opinions. Improvements in diagnostic accuracy with all second-opinion strategies were associated with reductions in overinterpretation but not underinterpretation. CONCLUSIONS AND RELEVANCE: In this decision-analytic model, selective second-opinion strategies for interpretation of melanocytic skin lesions showed the potential to improve diagnostic accuracy and decrease costs relative to no second opinions or universal second opinions.

Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions.

Importance: Histopathologic criteria have limited diagnostic reliability for a range of cutaneous melanocytic lesions. Objective: To evaluate the association of second-opinion strategies by general pathologists and dermatopathologists with the overall reliability of diagnosis of difficult melanocytic lesions. Design, Setting, and Participants: This diagnostic study used samples from the Melanoma Pathology Study, which comprises 240 melanocytic lesion samples selected from a dermatopathology laboratory in Bellevue, Washington, and represents the full spectrum of lesions from common nevi to invasive melanoma. Five sets of 48 samples were evaluated independently by 187 US pathologists from July 15, 2013, through May 23, 2016. Data analysis was performed from April 2016 through November 2017. Main Outcomes and Measures: Accuracy of diagnosis, defined as concordance with an expert consensus diagnosis of 3 experienced pathologists, was assessed after applying 10 different second-opinion strategies. Results: Among the 187 US pathologists examining the 24 lesion samples, 113 were general pathologists (65 men [57.5%]; mean age at survey, 53.7 years [range, 33.0-79.0 years]) and 74 were dermatopathologists (49 men [66.2%]; mean age at survey, 46.4 years [range, 33.0-77.0 years]). Among the 8976 initial case interpretations, physicians desired second opinions for 3899 (43.4%), most often for interpretation of severely dysplastic nevi. The overall misclassification rate was highest when interpretations did not include second opinions and initial reviewers were all general pathologists lacking subspecialty training (52.8%; 95% CI, 51.3%-54.3%). When considering different second opinion strategies, the misclassification of melanocytic lesions was lowest when the first, second, and third consulting reviewers were subspecialty-trained dermatopathologists and when all lesions were subject to second opinions (36.7%; 95% CI, 33.1%-40.7%). When the second opinion strategies were compared with single interpretations without second opinions, the reductions in misclassification rates for some of the strategies were statistically significant, but none of the strategies eliminated diagnostic misclassification. Melanocytic lesions in the middle of the diagnostic spectrum had the highest misclassification rates (eg, moderately or severely dysplastic nevus, Spitz nevus, melanoma in situ, and pathologic stage [p]T1a invasive melanoma). Variability of in situ and thin invasive melanoma was relatively intractable to all examined strategies. Conclusions and Relevance: The results of this study suggest that second opinions rendered by dermatopathologists improve reliability of melanocytic lesion diagnosis. However, discordance among pathologists remained high.

Concordance and Reproducibility of Melanoma Staging According to the 7th vs 8th Edition of the AJCC Cancer Staging Manual.

IMPORTANCE: The recently updated American Joint Committee on Cancer (AJCC) classification of cancer staging, the AJCC Cancer Staging Manual, 8th edition (AJCC 8), includes revisions to definitions of T1a vs T1b or greater. The Melanoma Pathology Study database affords a comparison,of pathologists' concordance and reproducibility in the microstaging of melanoma according to both the existing 7th edition (AJCC 7) and the new AJCC 8. OBJECTIVE: To compare AJCC 7 and AJCC 8 to examine whether changes to the definitions of T1a and T1b or greater are associated with changes in concordance and reproducibility. DESIGN SETTING AND PARTICIPANTS: In this diagnostic study conducted as part of the national Melanoma Pathology Study across US states, 187 pathologists interpreting melanocytic skin lesions in practice completed 4342 independent case interpretations of 116 invasive melanoma cases. A consensus reference diagnosis and participating pathologists' interpretations were classified into the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis class IV (T1a) or class V ( T1b) using both the AJCC 7 and AJCC 8 criteria. MAIN OUTCOMES AND MEASURES: Concordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility. RESULTS: For T1a diagnoses, participating pathologists' concordance with the consensus reference diagnosis increased from 44% (95% CI, 41%-48%) to 54% (95% CI, 51%-57%) using AJCC 7 and AJCC 8 criteria, respectively. The concordance for cases of T1b or greater increased from 72% (95% CI, 69%-75%) to 78% (95% CI, 75%-80%). Intraobserver reproducibility of diagnoses also improved, increasing from 59% (95% CI, 56%-63%) to 64% (95% CI, 62%-67%) for T1a invasive melanoma, and from 74% (95% CI, 71%-76%) to 77% (95% CI, 74%-79%) for T1b or greater invasive melanoma cases. CONCLUSIONS AND RELEVANCE: Melanoma staging in AJCC 8 shows greater reproducibility and higher concordance with a reference standard. Improved classification of invasive melanoma can be expected after implementation of AJCC 8, suggesting a positive impact on patients. However, despite improvement, concordance and reproducibility remain low.

Accuracy of Digital Pathologic Analysis vs Traditional Microscopy in the Interpretation of Melanocytic Lesions.

Importance: Use of digital whole-slide imaging (WSI) for dermatopathology in general has been noted to be similar to traditional microscopy (TM); however, concern has been noted that WSI is inferior for interpretation of melanocytic lesions. Since approximately 1 of every 4 skin biopsies is of a melanocytic lesion, the use of WSI requires verification before use in clinical practice. Objective: To compare pathologists' accuracy and reproducibility in diagnosing melanocytic lesions using Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) categories when analyzing by TM vs WSI. Design, Setting, and Participants: A total of 87 pathologists in community-based and academic settings from 10 US states were randomized with stratification based on clinical experience to interpret in TM format 180 skin biopsy cases of melanocytic lesions, including 90 invasive melanoma, divided into 5 sets of 36 cases (phase 1). The pathologists were then randomized via stratified permuted block randomization with block size 2 to interpret cases in either TM (n = 46) or WSI format (n = 41), with each pathologist interpreting the same 36 cases on 2 separate occasions (phase 2). Diagnoses were categorized as MPATH-Dx categories I through V, with I indicating the least severe and V the most severe. Main Outcomes and Measures: Accuracy with respect to a consensus reference diagnosis and the reproducibility of repeated interpretations of the same cases. Results: Of the 87 pathologists in the study, 46% (40) were women and the mean (SD) age was 50.7 (10.2) years. Except for class III melanocytic lesions, the diagnostic categories showed no significant differences in diagnostic accuracy between TM and WSI interpretation. Discordance was lower among class III lesions for the TM interpretation arm (51%; 95% CI, 46%-57%) than for the WSI arm (61%; 95% CI, 53%-69%) (P = .05). This difference is likely to have clinical significance, because 6% of TM vs 11% of WSI class III lesions were interpreted as invasive melanoma. Reproducibility was similar between the traditional and digital formats overall (66.4%; 95% CI, 63.3%-69.3%; and 62.7%; 95% CI, 59.5%-65.7%, respectively), and for all classes, although class III showed a nonsignificant lower intraobserver agreement for digital. Significantly more mitotic figures were detected with TM compared with WSI: mean (SD) TM, 6.72 (2.89); WSI, 5.84 (2.56); P = .002. Conclusions and Relevance: Interpretive accuracy for melanocytic lesions was similar for WSI and TM slides except for class III lesions. We found no clinically meaningful differences in reproducibility for any of the diagnostic classes.

Pathologist characteristics associated with accuracy and reproducibility of melanocytic skin lesion interpretation.

BACKGROUND: Diagnostic interpretations of melanocytic skin lesions vary widely among pathologists, yet the underlying reasons remain unclear. OBJECTIVE: Identify pathologist characteristics associated with rates of accuracy and reproducibility. METHODS: Pathologists independently interpreted the same set of biopsy specimens from melanocytic lesions on 2 occasions. Diagnoses were categorized into 1 of 5 classes according to the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system. Reproducibility was determined by pathologists' concordance of diagnoses across 2 occasions. Accuracy was defined by concordance with a consensus reference standard. Associations of pathologist characteristics with reproducibility and accuracy were assessed individually and in multivariable logistic regression models. RESULTS: Rates of diagnostic reproducibility and accuracy were highest among pathologists with board certification and/or fellowship training in dermatopathology and in those with 5 or more years of experience. In addition, accuracy was high among pathologists with a higher proportion of melanocytic lesions in their caseload composition and higher volume of melanocytic lesions. LIMITATIONS: Data gathered in a test set situation by using a classification tool not currently in clinical use. CONCLUSION: Diagnoses are more accurate among pathologists with specialty training and those with more experience interpreting melanocytic lesions. These findings support the practice of referring difficult cases to more experienced pathologists to improve diagnostic accuracy, although the impact of these referrals on patient outcomes requires additional research.

Pathologists' diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study.

Objective To quantify the accuracy and reproducibility of pathologists' diagnoses of melanocytic skin lesions.Design Observer accuracy and reproducibility study.Setting 10 US states.Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart.Main outcome measures Pathologists' interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses.Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted.Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists' visual assessments.

The diagnostic challenge of low-grade ductal carcinoma in situ.

BACKGROUND: Diagnostic agreement among pathologists is 84% for ductal carcinoma in situ (DCIS). Studies of interpretive variation according to grade are limited. METHODS: A national sample of 115 pathologists interpreted 240 breast pathology test set cases in the Breast Pathology Study and their interpretations were compared to expert consensus interpretations. We assessed agreement of pathologists' interpretations with a consensus reference diagnosis of DCIS dichotomised into low- and high-grade lesions. Generalised estimating equations were used in logistic regression models of rates of under- and over-interpretation of DCIS by grade. RESULTS: We evaluated 2097 independent interpretations of DCIS (512 low-grade DCIS and 1585 high-grade DCIS). Agreement with reference diagnoses was 46% (95% confidence interval [CI] 42-51) for low-grade DCIS and 83% (95% CI 81-86) for high-grade DCIS. The proportion of reference low-grade DCIS interpretations over-interpreted by pathologists (i.e. categorised as either high-grade DCIS or invasive cancer) was 23% (95% CI 19-28); 30% (95% CI 26-34) were interpreted as a lower diagnostic category (atypia or benign proliferative). Reference high-grade DCIS was under-interpreted in 14% (95% CI 12-16) of observations and only over-interpreted 3% (95% CI 2-4). CONCLUSION: Grade is a major factor when examining pathologists' variability in diagnosing DCIS, with much lower agreement for low-grade DCIS cases compared to high-grade. These findings support the hypothesis that low-grade DCIS poses a greater interpretive challenge than high-grade DCIS, which should be considered when developing DCIS management strategies.

A Randomized Study Comparing Digital Imaging to Traditional Glass Slide Microscopy for Breast Biopsy and Cancer Diagnosis.

BACKGROUND: Digital whole slide imaging may be useful for obtaining second opinions and is used in many countries. However, the U.S. Food and Drug Administration requires verification studies. METHODS: Pathologists were randomized to interpret one of four sets of breast biopsy cases during two phases, separated by ≥9 months, using glass slides or digital format (sixty cases per set, one slide per case, n = 240 cases). Accuracy was assessed by comparing interpretations to a consensus reference standard. Intraobserver reproducibility was assessed by comparing the agreement of interpretations on the same cases between two phases. Estimated probabilities of confirmation by a reference panel (i.e., predictive values) were obtained by incorporating data on the population prevalence of diagnoses. RESULTS: Sixty-five percent of responding pathologists were eligible, and 252 consented to randomization; 208 completed Phase I (115 glass, 93 digital); and 172 completed Phase II (86 glass, 86 digital). Accuracy was slightly higher using glass compared to digital format and varied by category: invasive carcinoma, 96% versus 93% (P = 0.04); ductal carcinoma in situ (DCIS), 84% versus 79% (P < 0.01); atypia, 48% versus 43% (P = 0.08); and benign without atypia, 87% versus 82% (P < 0.01). There was a small decrease in intraobserver agreement when the format changed compared to when glass slides were used in both phases (P = 0.08). Predictive values for confirmation by a reference panel using glass versus digital were: invasive carcinoma, 98% and 97% (not significant [NS]); DCIS, 70% and 57% (P = 0.007); atypia, 38% and 28% (P = 0.002); and benign without atypia, 97% and 96% (NS). CONCLUSIONS: In this large randomized study, digital format interpretations were similar to glass slide interpretations of benign and invasive cancer cases. However, cases in the middle of the spectrum, where more inherent variability exists, may be more problematic in digital format. Future studies evaluating the effect these findings exert on clinical practice and patient outcomes are required.

Evaluation of 12 strategies for obtaining second opinions to improve interpretation of breast histopathology: simulation study.

OBJECTIVE:  To evaluate the potential effect of second opinions on improving the accuracy of diagnostic interpretation of breast histopathology. DESIGN:  Simulation study. SETTING:  12 different strategies for acquiring independent second opinions. PARTICIPANTS:  Interpretations of 240 breast biopsy specimens by 115 pathologists, one slide for each case, compared with reference diagnoses derived by expert consensus. MAIN OUTCOME MEASURES:  Misclassification rates for individual pathologists and for 12 simulated strategies for second opinions. Simulations compared accuracy of diagnoses from single pathologists with that of diagnoses based on pairing interpretations from first and second independent pathologists, where resolution of disagreements was by an independent third pathologist. 12 strategies were evaluated in which acquisition of second opinions depended on initial diagnoses, assessment of case difficulty or borderline characteristics, pathologists' clinical volumes, or whether a second opinion was required by policy or desired by the pathologists. The 240 cases included benign without atypia (10% non-proliferative, 20% proliferative without atypia), atypia (30%), ductal carcinoma in situ (DCIS, 30%), and invasive cancer (10%). Overall misclassification rates and agreement statistics depended on the composition of the test set, which included a higher prevalence of difficult cases than in typical practice. RESULTS:  Misclassification rates significantly decreased (P<0.001) with all second opinion strategies except for the strategy limiting second opinions only to cases of invasive cancer. The overall misclassification rate decreased from 24.7% to 18.1% when all cases received second opinions (P<0.001). Obtaining both first and second opinions from pathologists with a high volume (≥10 breast biopsy specimens weekly) resulted in the lowest misclassification rate in this test set (14.3%, 95% confidence interval 10.9% to 18.0%). Obtaining second opinions only for cases with initial interpretations of atypia, DCIS, or invasive cancer decreased the over-interpretation of benign cases without atypia from 12.9% to 6.0%. Atypia cases had the highest misclassification rate after single interpretation (52.2%), remaining at more than 34% in all second opinion scenarios. CONCLUSION:  Second opinions can statistically significantly improve diagnostic agreement for pathologists' interpretations of breast biopsy specimens; however, variability in diagnosis will not be completely eliminated, especially for breast specimens with atypia.

Variability in Pathologists' Interpretations of Individual Breast Biopsy Slides: A Population Perspective.

BACKGROUND: The effect of physician diagnostic variability on accuracy at a population level depends on the prevalence of diagnoses. OBJECTIVE: To estimate how diagnostic variability affects accuracy from the perspective of a U.S. woman aged 50 to 59 years having a breast biopsy. DESIGN: Applied probability using Bayes' theorem. SETTING: B-Path (Breast Pathology) Study comparing pathologists' interpretations of a single biopsy slide versus a reference consensus interpretation from 3 experts. PARTICIPANTS: 115 practicing pathologists (6900 total interpretations from 240 distinct cases). MEASUREMENTS: A single representative slide from each of the 240 cases was used to estimate the proportion of biopsies with a diagnosis that would be verified if the same slide were interpreted by a reference group of 3 expert pathologists. Probabilities of confirmation (predictive values) were estimated using B-Path Study results and prevalence of biopsy diagnoses for women aged 50 to 59 years in the Breast Cancer Surveillance Consortium. RESULTS: Overall, if 1 representative slide were used per case, 92.3% (95% CI, 91.4% to 93.1%) of breast biopsy diagnoses would be verified by reference consensus diagnoses, with 4.6% (CI, 3.9% to 5.3%) overinterpreted and 3.2% (CI, 2.7% to 3.6%) underinterpreted. Verification of invasive breast cancer and benign without atypia diagnoses is highly probable; estimated predictive values were 97.7% (CI, 96.5% to 98.7%) and 97.1% (CI, 96.7% to 97.4%), respectively. Verification is less probable for atypia (53.6% overinterpreted and 8.6% underinterpreted) and ductal carcinoma in situ (DCIS) (18.5% overinterpreted and 11.8% underinterpreted). LIMITATIONS: Estimates are based on a testing situation with 1 slide used per case and without access to second opinions. Population-adjusted estimates may differ for women from other age groups, unscreened women, or women in different practice settings. CONCLUSION: This analysis, based on interpretation of a single breast biopsy slide per case, predicts a low likelihood that a diagnosis of atypia or DCIS would be verified by a reference consensus diagnosis. This diagnostic grey zone should be considered in clinical management decisions in patients with these diagnoses. PRIMARY FUNDING SOURCE: National Cancer Institute.

Diagnostic concordance among pathologists interpreting breast biopsy specimens.

IMPORTANCE: A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood. OBJECTIVES: To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics. DESIGN, SETTING, AND PARTICIPANTS: Study of pathologists who interpret breast biopsies in clinical practices in 8 US states. EXPOSURES: Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%. MAIN OUTCOMES AND MEASURES: The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed. RESULTS: Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007). CONCLUSIONS AND RELEVANCE: In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.

TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development.

TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis.

Computer-assisted mammography feedback program (CAMFP) an electronic tool for continuing medical education.

RATIONALE AND OBJECTIVES: Our goal was to develop and evaluate software to support a computer assisted mammography feedback program (CAMFP) to be used for continuing medical education (CME). MATERIALS AND METHODS: Thirty-five radiologists from our region signed consent to participate in an institutional review board-approved film-reading study. The radiologists primarily assessed digitized mammograms and received feedback in five film interpretation sessions. A bivariate analysis was used to evaluate the joint effects of the training on sensitivity and specificity, and the effects of image quality on reading performance were explored. RESULTS: Interpretation was influenced by the CAMFP intervention: Sensitivity increased (Delta sensitivity = 0.086, P < .001) and specificity decreased (Delta specificity = -0.057, P = .04). Variability in interpretation among radiologists also decreased after the training sessions (P = .035). CONCLUSION: The CAMFP intervention improved sensitivity and decreased variability among radiologist's interpretations. Although this improvement was partially offset by decreased specificity, the program is potentially useful as a component of continuing medical education of radiologists. Dissemination via the web may be possible using digital mammography.

Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors.

Adoptive transfer of allergen-specific immunoglobulin E (IgE) from atopic donors to nonatopic recipients occurs during the first year following bone marrow transplantation (BMT). Mature B- and T-cell clones with allergen-specific memory and hematopoietic progenitor cells are transferred through BMT. The objective of this study was to characterize the long-term rate of allergic sensitization and development of clinical allergic diseases following BMT from atopic donors. A long-term follow-up study was conducted in a cohort of donor and recipient pairs with moderate-to-severe allergic disease in the donor prior to BMT. Assessments of allergen-specific IgE, clinical rhinitis, and asthma were made in the donors prior to BMT and in the recipients with a mean follow-up of 15.5 years after BMT. From an initial cohort of 12 bone marrow transplant recipients who received marrow from allergic donors, 5 long-term survivors were identified. Allergen-specific IgE transferred from donor to recipient following BMT frequently persisted, and a high rate of de novo allergic sensitization was observed between 1 and 14 years after BMT. These events were associated with elevation in total IgE, and development of allergic rhinitis and asthma at long-term follow-up. We conclude that marrow-derived immune cells from allergic donors can transfer the predisposition to allergy and asthma.