International Skin Imaging Collaboration-Designated Diagnoses (ISIC-DX): Consensus terminology for lesion diagnostic labeling.

BACKGROUND: A common terminology for diagnosis is critically important for clinical communication, education, research and artificial intelligence. Prevailing lexicons are limited in fully representing skin neoplasms. OBJECTIVES: To achieve expert consensus on diagnostic terms for skin neoplasms and their hierarchical mapping. METHODS: Diagnostic terms were extracted from textbooks, publications and extant diagnostic codes. Terms were hierarchically mapped to super-categories (e.g. 'benign') and cellular/tissue-differentiation categories (e.g. 'melanocytic'), and appended with pertinent-modifiers and synonyms. These terms were evaluated using a modified-Delphi consensus approach. Experts from the International-Skin-Imaging-Collaboration (ISIC) were surveyed on agreement with terms and their hierarchical mapping; they could suggest modifying, deleting or adding terms. Consensus threshold was >75% for the initial rounds and >50% for the final round. RESULTS: Eighteen experts completed all Delphi rounds. Of 379 terms, 356 (94%) reached consensus in round one. Eleven of 226 (5%) benign-category terms, 6/140 (4%) malignant-category terms and 6/13 (46%) indeterminate-category terms did not reach initial agreement. Following three rounds, final consensus consisted of 362 terms mapped to 3 super-categories and 41 cellular/tissue-differentiation categories. CONCLUSIONS: We have created, agreed upon, and made public a taxonomy for skin neoplasms and their hierarchical mapping. Further study will be needed to evaluate the utility and completeness of the lexicon.

The Impact of Next-generation Sequencing on Interobserver Agreement and Diagnostic Accuracy of Desmoplastic Melanocytic Neoplasms.

Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant ( P <0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics.

BRAF Mutated and Morphologically Spitzoid Tumors, a Subgroup of Melanocytic Neoplasms Difficult to Distinguish From True Spitz Neoplasms.

Drivers of Spitz neoplasms include activating point mutations in HRAS and Spitz-associated genomic fusions. It has become evident that some BRAF -mutated melanocytic neoplasms can morphologically mimic Spitz tumors (STs). These have been termed BRAF mutated and morphologically spitzoid (BAMS). In this study, 17 experts from the International Melanoma Pathology Study Group assessed 54 cases which included 40 BAMS and 14 true STs. The participants reviewed the cases blinded to the genomic data and selected among several diagnostic options, including BAMS, ST, melanoma, and other. A total of 38% of all diagnostic selections in the BAMS cases were for BAMS, whereas 32% were for ST. In 22 of the BAMS cases, the favored diagnosis was BAMS, whereas in 17 of the BAMS cases, the favored diagnosis was ST. Among the 20 cases in the total group of 54 with the highest number of votes for ST, half were BAMS. Of BAMS, 75% had a number of votes for ST that was within the SD of votes for ST seen among true ST cases. There was poor interobserver agreement for the precise diagnosis of the BAMS (kappa = 0.16) but good agreement that these cases were not melanoma (kappa = 0.7). BAMS nevi/tumors can closely mimic Spitz neoplasms. Expert melanoma pathologists in this study favored a diagnosis of ST in nearly half of the BAMS cases. There are BAMS cases that even experts cannot morphologically distinguish from true Spitz neoplasms.

Immunohistochemistry for Diagnosing Melanoma in Older Adults.

Importance: Pathologic assessment to diagnose skin biopsies, especially for cutaneous melanoma, can be challenging, and immunohistochemistry (IHC) staining has the potential to aid decision-making. Currently, the temporal trends regarding the use of IHC for the examination of skin biopsies on a national level have not been described. Objective: To illustrate trends in the use of IHC for the examination of skin biopsies in melanoma diagnoses. Design, Setting, and Participants: A retrospective cross-sectional study was conducted to examine incident cases of melanoma diagnosed between January 2000 and December 2017. The analysis used the SEER-Medicare linked database, incorporating data from 17 population-based registries. The study focused on incident cases of in situ or malignant melanoma of the skin diagnosed in patients 65 years or older. Data were analyzed between August 2022 and November 2023. Main Outcomes and Measures: The main outcomes encompassed the identification of claims for IHC within the month of melanoma diagnoses and extending up to 14 days into the month following diagnosis. The SEER data on patients with melanoma comprised demographic, tumor, and area-level characteristics. Results: The final sample comprised 132 547 melanoma tumors in 116 117 distinct patients. Of the 132 547 melanoma diagnoses meeting inclusion criteria from 2000 to 2017, 43 396 cases had accompanying IHC claims (33%). Among these cases, 28 298 (65%) were diagnosed in male patients, 19 019 (44%) were diagnosed in patients aged 65 years to 74 years, 16 444 (38%) in patients aged 75 years to 84 years, and 7933 (18%) in patients aged 85 years and older. In 2000, 11% of melanoma cases had claims for IHC at or near the time of diagnosis. This proportion increased yearly, with 51% of melanoma cases having associated IHC claims in 2017. Increasing IHC use is observed for all stages of melanoma, including in situ melanoma. Claims for IHC in melanomas increased in all 17 SEER registries but at different rates. In 2017, the use of IHC for melanoma diagnosis ranged from 39% to 68% across registries. Conclusions and Relevance: Considering the dramatically rising and variable use of IHC in diagnosing melanoma by pathologists demonstrated in this retrospective cross-sectional study, further investigation is warranted to understand the clinical utility and discern when IHC most improves diagnostic accuracy or helps patients.

Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma.

Artificial intelligence (AI) systems have been shown to help dermatologists diagnose melanoma more accurately, however they lack transparency, hindering user acceptance. Explainable AI (XAI) methods can help to increase transparency, yet often lack precise, domain-specific explanations. Moreover, the impact of XAI methods on dermatologists' decisions has not yet been evaluated. Building upon previous research, we introduce an XAI system that provides precise and domain-specific explanations alongside its differential diagnoses of melanomas and nevi. Through a three-phase study, we assess its impact on dermatologists' diagnostic accuracy, diagnostic confidence, and trust in the XAI-support. Our results show strong alignment between XAI and dermatologist explanations. We also show that dermatologists' confidence in their diagnoses, and their trust in the support system significantly increase with XAI compared to conventional AI. This study highlights dermatologists' willingness to adopt such XAI systems, promoting future use in the clinic.

Pathologist Characteristics Associated With Rendering Higher-Grade Diagnoses for Melanocytic Lesions.

Importance: The incidence of melanoma diagnoses has been increasing in recent decades, and controlled studies have indicated high histopathologic discordance across the intermediate range of melanocytic lesions. The respective causes for these phenomena remain incompletely understood. Objective: To identify pathologist characteristics associated with tendencies to diagnose melanocytic lesions as higher grade vs lower grade or to diagnose invasive melanoma vs any less severe diagnosis. Design, Setting, and Participants: This exploratory study used data from 2 nationwide studies (the Melanoma Pathology [M-Path] study, conducted from July 2013 to May 2016, and the Reducing Errors in Melanocytic Interpretations [REMI] study, conducted from August 2018 to March 2021) in which participating pathologists who interpreted melanocytic lesions in their clinical practices interpreted study cases in glass slide format. Each pathologist was randomly assigned to interpret a set of study cases from a repository of skin biopsy samples of melanocytic lesions; each case was independently interpreted by multiple pathologists. Data were analyzed from July 2022 to February 2023. Main Outcomes and Measures: The association of pathologist characteristics with diagnosis of a study case as higher grade (including severely dysplastic and melanoma in situ) vs lower grade (including mild to moderately dysplastic nevi) and diagnosis of invasive melanoma vs any less severe diagnosis was assessed using logistic regression. Characteristics included demographics (age, gender, and geographic region), years of experience, academic affiliation, caseload of melanocytic lesions in their practice, specialty training, and history of malpractice suits. Results: A total of 338 pathologists were included: 113 general pathologists and 74 dermatopathologists from M-Path and 151 dermatopathologists from REMI. The predominant factor associated with rendering more severe diagnoses was specialist training in dermatopathology (board certification and/or fellowship training). Pathologists with this training were more likely to render higher-grade diagnoses (odds ratio [OR], 2.63; 95% CI, 2.10-3.30; P < .001) and to diagnose invasive melanoma (OR, 1.95; 95% CI, 1.53-2.49; P < .001) than pathologists without this training interpreting the same case. Nonmitogenic pT1a diagnoses (stage pT1a melanomas with no mitotic activity) accounted for the observed difference in diagnosis of invasive melanoma; when these lesions, which carry a low risk of metastasis, were grouped with the less severe diagnoses, there was no observed association (OR, 0.95; 95% CI, 0.74-1.23; P = .71). Among dermatopathologists, those with a higher caseload of melanocytic lesions in their practice were more likely to assign higher-grade diagnoses (OR for trend, 1.27; 95% CI, 1.04-1.56; P = .02). Conclusions and Relevance: The findings suggest that specialty training in dermatopathology is associated with a greater tendency to diagnose atypical melanocytic proliferations as pT1a melanomas. These low-risk melanomas constitute a growing proportion of melanomas diagnosed in the US.

Implementing the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis: Long-term effect of a simple educational intervention.

Background: A standardized pathology management tool for melanocytic skin lesions may improve patient care by simplifying interpretation and categorization of the diverse terminology currently extant. Objective: To assess an online educational intervention that teaches dermatopathologists to use the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx), a schema collapsing multiple diagnostic terms into 5 classes ranging from benign to invasive melanoma. Methods: Practicing dermatopathologists (N = 149) from 40 US states participated in a 2-year educational intervention study (71% response rate). The intervention involved a brief tutorial followed by practice on 28 melanocytic lesions, with the goal of teaching pathologists how to correctly use the MPATH-Dx schema; competence using the MPATH-Dx tool 12-24 months postintervention was assessed. Participants' self-reported confidence using the MPATH-Dx tool was assessed preintervention and postintervention. Results: At preintervention, confidence using the MPATH-Dx tool was already high, despite 68% lacking prior familiarity with it, and confidence increased postintervention (P = .0003). During the intervention, participants used the MPATH-Dx tool correctly for 90% of their interpretations; postintervention, participants used the MPATH-Dx tool correctly for 88% of their interpretations. Limitations: Future research should examine implementing a standardized pathology assessment schema in actual clinical practice. Conclusion: Dermatopathologists can be taught to confidently and competently use the MPATH-Dx schema with a simple educational tutorial followed by practice.

Diagnostic error, uncertainty, and overdiagnosis in melanoma.

Diagnostic error can be defined as deviation from a gold standard diagnosis, typically defined in terms of expert opinion, although sometimes in terms of unexpected events that might occur in follow-up (such as progression and death from disease). Although diagnostic error does exist for melanoma, deviations from gold standard diagnosis, certainly among appropriately trained and experienced practitioners, are likely to be the result of uncertainty and lack of specific criteria, and differences of opinion, rather than lack of diagnostic skills. In this review, the concept of diagnostic error will be considered in relation to diagnostic uncertainty, and the concept of overdiagnosis in melanoma will be presented and discussed.

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions: A Consensus Statement.

Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). Evidence Review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. Findings: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. Conclusions and Relevance: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

Monitoring Angiotropic Extravascular Migratory Metastasis In Vitro.

The mechanism of cancer cell migration from the primary tumor toward secondary sites is not fully understood. In addition to intravascular cellular migration, angiotropic extravascular migratory metastasis (EVMM) has been recognized as a metastatic pathway involving tumor cells crawling along the abluminal vascular surface to distant sites. A very simple in vitro 3D assay is described here, which is based on a previous in vitro angiogenesis assay. The assay involves monitoring single fluorescence-tagged migrating cancer cells in the presence of vascular structures in real time. This coculture assay represents a quantitative approach for monitoring the migration processes of cancer cells along vessels, demonstrating phenotypic switching and migration dynamics. This protocol can be used for molecular analyses and can also be adapted for screening of therapeutic agents to block cancer metastasis.

Prognostic modeling of cutaneous melanoma stage I patients using cancer registry data identifies subsets with very-low melanoma mortality.

BACKGROUND: Evidence exists that escalating melanoma incidence is due in part to overdiagnosis, the diagnosis of lesions that will not lead to symptoms or death. The authors aimed to characterize subsets of melanoma patients with very-low risk of death that may be contributing to overdiagnosis. METHODS: Melanoma patients diagnosed in 2010 and 2011 with stage I lesions ≤1.0 mm thick and negative clinical lymph nodes from the Surveillance, Epidemiology, and End Results database were selected. Classification and regression tree and logistic regression models were developed and validated to identify patients with very-low risk of death from melanoma within 7 years. Logistic models were also used to identify patients at higher risk of death among this group of stage I patients. RESULTS: Compared to an overall 7-year mortality from melanoma of 2.5% in these patients, a subset comprising 25% had a risk below 1%. Younger age at diagnosis and Clark level II were associated with low risk of death in all models. Breslow thickness below 0.4 mm, absence of mitogenicity, absence of ulceration, and female sex were also associated with lower mortality. A small subset of high-risk patients with >20% risk of death was also identified. CONCLUSION: Patients with very-low risk of dying from melanoma within 7 years of diagnosis were identified. Such cases warrant further study and consensus discussion to develop classification criteria, with the potential to be categorized using an alternative term such as "melanocytic neoplasms of low malignant potential." LAY SUMMARY: Although melanoma is the most serious skin cancer, most melanoma patients have high chances of survival. There is evidence that some lesions diagnosed as melanoma would never have caused symptoms or death, a phenomenon known as overdiagnosis. In this study, we used cancer registry data to identify a subset of early-stage melanoma patients with almost no melanoma deaths. Using two statistical approaches, we identified patients with <1% risk of dying from melanoma in 7 years. Such patients tended to be younger with minimal invasion into the skin. We also identified a very small patient subset with higher mortality risk.

Targeted Long-Read Bisulfite Sequencing Identifies Differences in the TERT Promoter Methylation Profiles between TERT Wild-Type and TERT Mutant Cancer Cells.

Background: TERT promoter methylation, located several hundred base pairs upstream of the transcriptional start site, is cancer specific and correlates with increased TERT mRNA expression and poorer patient outcome. Promoter methylation, however, is not mutually exclusive to TERT activating genetic alterations, as predicted for functionally redundant mechanisms. To annotate the altered patterns of TERT promoter methylation and their relationship with gene expression, we applied a Pacific Biosciences-based, long-read, bisulfite-sequencing technology and compared the differences in the methylation marks between wild-type and mutant cancers in an allele-specific manner. Results: We cataloged TERT genetic alterations (i.e., promoter point mutations or structural variations), allele-specific promoter methylation patterns, and allele-specific expression levels in a cohort of 54 cancer cell lines. In heterozygous mutant cell lines, the mutant alleles were significantly less methylated than their silent, mutation-free alleles (p < 0.05). In wild-type cell lines, by contrast, both epialleles were equally methylated to high levels at the TERT distal promoter, but differentially methylated in the proximal regions. ChIP analysis showed that epialleles with the hypomethylated proximal and core promoter were enriched in the active histone mark H3K4me2/3, whereas epialleles that were methylated in those regions were enriched in the repressive histone mark H3K27me3. Decitabine therapy induced biallelic expression in the wild-type cancer cells, whereas the mutant cell lines were unaffected. Conclusions: Long-read bisulfite sequencing analysis revealed differences in the methylation profiles and responses to demethylating agents between TERT wild-type and genetically altered cancer cell lines. The causal relation between TERT promoter methylation and gene expression remains to be established.

Effect of Prior Diagnoses on Dermatopathologists' Interpretations of Melanocytic Lesions: A Randomized Controlled Trial.

Importance: Medical second opinions are common, although little is known about the best processes for obtaining them. This study assesses whether knowledge of a prior physician's diagnosis influences consulting physicians' diagnoses. Objective: To measure the extent to which dermatopathologists' diagnoses are influenced by prior diagnostic information from another dermatopathologist. Design, Setting, and Participants: Dermatopathologists were randomly assigned to interpret 1 slide set of 18 melanocytic skin biopsy specimens in 2 phases (5 slide sets totaling 90 cases). Phase 1 interpretations were conducted without prior diagnostic information. After a washout period of 12 or more months, dermatopathologists' phase 2 interpretations were conducted with their identical slide set; for a random subset of cases in phase 2, participants were shown prior diagnoses by other dermatopathologists that were either more or less severe than their own phase 1 diagnosis of the case. Using the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis tool, cases ranged from class I (benign) to class V (≥pT1b invasive melanoma). Data collection took place from August 2018 to March 2021, and data analysis was performed from March to December 2021. Intervention: Prior diagnoses were actual diagnoses from board-certified and/or fellowship-trained dermatopathologists. A prior diagnosis was always in a more severe or less severe diagnostic class than the participant's phase 1 interpretation; more or less severe was determined by the randomization scheme. In the control condition of no prior diagnostic information, the participants were told that a prior diagnosis was not available. Main Outcomes and Measures: When exposure was to a prior diagnosis in a higher diagnostic class, the primary study outcome was whether a participant's diagnosis in phase 2 was in a higher diagnostic class than the participant's diagnosis in phase 1. When exposure was to a prior diagnosis in a lower diagnostic class, the primary study outcome was whether a participant's diagnosis in phase 2 was in a lower diagnostic class than the participant's diagnosis in phase 1. The effect of prior diagnostic information was measured using the relative risk (RR) of each outcome relative to the control condition of no prior diagnostic information, adjusted for the diagnostic class of the phase 1 diagnosis. Prior to data collection, it was hypothesized that participants would be swayed in the direction of prior diagnostic information. Results: A total of 149 dermatopathologists (median [range] age, 47 years [34-76] years; 101 [68%] were male) provided 5322 interpretations of study cases. Participants were more likely to increase the severity of their diagnosis when the prior diagnosis was of greater severity compared with when no prior diagnosis was provided (RR, 1.52; 95% CI, 1.34-1.73); likewise, participants gave less severe diagnoses when prior diagnoses were of lesser severity (RR, 1.38; 95% CI, 1.19-1.59). Trends were similar among dermatopathologists who had previously stated they were "not at all influenced" by prior diagnoses. Prior diagnoses also swayed dermatopathologists away from correct diagnoses. Conclusions and Relevance: In this randomized controlled trial, despite the preference of most dermatopathologists to receive prior diagnoses when providing second opinions, this information swayed them away from a correct diagnosis to an incorrect diagnosis.

Dermatopathologist Perceptions of Overdiagnosis of Melanocytic Skin Lesions and Association With Diagnostic Behaviors.

Importance: Despite evidence of overdiagnosis of in situ and invasive melanoma, neither the perceptions of practicing dermatopathologists about overdiagnosis nor possible associations between perceptions of overdiagnosis and diagnostic practices have been studied. Objective: To examine practicing US dermatopathologists' perceptions of melanoma overdiagnosis as a public health issue, and to associate diagnostic behaviors of dermatopathologists with perceptions of melanoma overdiagnosis. Design, Setting, and Participants: This survey study included 115 board-certified and/or fellowship-trained dermatopathologists and their diagnostic interpretations on a set of 18 skin biopsy cases (5 slide sets comprising 90 melanocytic skin lesions). Participants interpreted cases remotely using their own microscopes. Survey invitations occurred during 2018 to 2019, with data collection completed 2021. Data analysis was performed from June to September 2021. Main Outcomes and Measures: Agreement vs disagreement that overdiagnosis is a public health issue for atypical nevi, melanoma in situ, and invasive melanoma. Associations between perceptions regarding overdiagnosis and interpretive behavior on study cases. Results: Of 115 dermatopathologists, 68% (95% CI, 59%-76%) agreed that overdiagnosis is a public health issue for atypical nevi; 47% (95% CI, 38%-56%) for melanoma in situ; and 35% (95% CI, 26%-43%) for invasive melanoma. Dermatopathologists with more years in practice were significantly less likely to perceive that atypical nevi are overdiagnosed, eg, 46% of dermatopathologists with 20 or more years of experience agreed that atypical nevi are overdiagnosed compared with 93% of dermatopathologists with 1 to 4 years of experience. Compared with other dermatopathologists, those who agreed that all 3 conditions are overdiagnosed were slightly more likely to diagnose study cases as mild to moderately dysplastic nevi (odds ratio, 1.26; 95% CI, 0.97-1.64; P = .08), but the difference was not statistically significant. Dermatopathologists who agreed that invasive melanoma is overdiagnosed did not significantly differ in diagnosing invasive melanoma for study cases compared with those who disagreed (odds ratio, 1.10; 95% CI, 0.86-1.41; P = .44). Conclusions and Relevance: In this survey study, about two-thirds of dermatopathologists thought that atypical nevi are overdiagnosed, half thought that melanoma in situ is overdiagnosed, and one-third thought that invasive melanoma is overdiagnosed. No statistically significant associations were found between perceptions about overdiagnosis and interpretive behavior when diagnosing skin biopsy cases.

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.

Vessel co-option and angiotropic extravascular migratory metastasis: a continuum of tumour growth and spread?

Two fields of cancer research have emerged dealing with the biology of tumour cells localised to the abluminal vascular surface: vessel co-option (VCo), a non-angiogenic mode of tumour growth and angiotropic extravascular migratory metastasis (EVMM), a non-hematogenous mode of tumour migration and metastasis. VCo is a mechanism by which tumour cells gain access to a blood supply by spreading along existing blood vessels in order to grow locally. Angiotropic EVMM involves "pericytic mimicry" (PM), which is characterised by tumour cells continuously migrating in the place of pericytes distantly along abluminal vascular surfaces. When cancer cells are engaged in PM and EVMM, they migrate along blood vessels beyond the advancing front of the tumour to secondary sites with the formation of regional and distant metastases. In the present perspective, the authors review the current scientific literature, emphasising the analogies between embryogenesis and cancer progression, the re-activation of embryonic signals by "cancer stem cells", and the important role of laminins and epithelial-mesenchymal-transition. This perspective maintains that VCo and angiotropic EVMM constitute complementary processes and represent a continuum of cancer progression from the primary tumour to metastases and of tumour growth to EVMM, analogous to the embryonic development program.

Characterization of multiple diagnostic terms in melanocytic skin lesion pathology reports.

BACKGROUND: Histopathologically ambiguous melanocytic lesions lead some pathologists to list multiple diagnostic considerations in the pathology report. The frequency and circumstance of multiple diagnostic considerations remain poorly characterized. METHODS: Two hundred and forty skin biopsy samples were interpreted by 187 pathologists (8976 independent diagnoses) and classified according to a diagnostic/treatment stratification (MPATH-Dx). RESULTS: Multiple diagnoses in different MPATH-Dx classes were used in n = 1320 (14.7%) interpretations, with 97% of pathologists and 91% of cases having at least one such interpretation. Multiple diagnoses were more common for intermediate risk lesions and are associated with greater subjective difficulty and lower confidence. We estimate that 6% of pathology reports for melanocytic lesions in the United States contain two diagnoses of different MPATH-Dx prognostic classes, and 2% of cases are given two diagnoses with significant treatment implications. CONCLUSIONS: Difficult melanocytic diagnoses in skin may necessitate multiple diagnostic considerations; however, as patients increasingly access their health records and retrieve pathology reports (as mandated by US law), uncertainty should be expressed unambiguously.

Impact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid Neoplasms.

Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics.

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.