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BackgroundA standardized pathology management tool for melanocytic skin lesions may improve patient care by simplifying interpretation and categorization of the diverse terminology currently extant.ObjectiveTo 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.MethodsPracticing 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.ResultsAt 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.LimitationsFuture research should examine implementing a standardized pathology assessment schema in actual clinical practice.ConclusionDermatopathologists can be taught to confidently and competently use the MPATH-Dx schema with a simple educational tutorial followed by practice.

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.

Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich pure variants have been distinguished from mixed variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions from 30 desmoplastic melanomas. The participating pathologists were asked to classify the tumours as pure or mixed. They were also asked to record the presence or absence of neurotropism and angiotropism. We found substantial interobserver agreement between the 11 dermatopathologists in the classification of tumours as pure versus mixed desmoplastic melanoma (kappa=0.64; p

ImportanceA 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.ObjectiveTo 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 reviewPracticing 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.FindingsThe 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 relevanceThe 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.

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

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

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.

BackgroundSynoptic reporting is recommended by many guideline committees to encourage the thorough histologic documentation necessary for optimal management of patients with melanoma.MethodsOne hundred fifty-one pathologists from 40 US states interpreted 41 invasive melanoma cases. For each synoptic reporting factor, the authors identified cases with "complete agreement" (all participants recorded the same value) versus any disagreement. Pairwise agreement was calculated for each case as the proportion of pairs of responses that agreed, where paired responses were generated by the comparison of each reviewer's response with all others.ResultsThere was complete agreement among all reviewers for 22 of the 41 cases (54%) on Breslow thickness dichotomized at 0.8 mm, with pairwise agreement ranging from 49% to 100% across the 41 cases. There was complete agreement for "no ulceration" in 24 of the 41 cases (59%), with pairwise agreement ranging from 42% to 100%. Tumor transected at base had complete agreement for 26 of the 41 cases (63%), with pairwise agreement ranging from 31% to 100%. Mitotic rate, categorized as 0/mm2 , 1/mm2 , or 2/mm2 , had complete agreement for 17 of the 41 cases (41%), with pairwise agreement ranging from 36% to 100%. Regression saw complete agreement for 14 of 41 cases (34%), with pairwise agreement ranging from 40% to 100%. Lymphovascular invasion, perineural invasion, and microscopic satellites were rarely reported as present. Respectively, these prognostic factors had complete agreement for 32 (78%), 37 (90%), and 18 (44%) of the 41 cases, and the ranges of pairwise agreement were 47% to 100%, 70% to 100%, and 53% to 100%, respectively.ConclusionsThese findings alert pathologists and clinicians to the problem of interobserver variability in recording critical prognostic factors.Lay summaryThis study addresses variability in the assessment and reporting of critical characteristics of invasive melanomas that are used by clinicians to guide patient care. The authors characterize the diagnostic variability among pathologists and their reporting methods in light of recently updated national guidelines. Results demonstrate considerable variability in the diagnostic reporting of melanoma with regard to the following: Breslow thickness, mitotic rate, ulceration, regression, and microscopic satellites. This work serves to alert pathologists and clinicians to the existence of variability in reporting these prognostic factors.

BackgroundDiagnostic terms used in histopathology reports of cutaneous melanocytic lesions are not standardized. We describe dermatopathologists' views regarding diverse diagnostic terminology and the utility of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) for categorizing melanocytic lesions.MethodsJuly 2018-2019 survey of board-certified and/or fellowship-trained dermatopathologists with experience interpreting melanocytic lesions.ResultsAmong 160 participants, 99% reported witnessing different terminology being used for the same melanocytic lesion. Most viewed diverse terminology as confusing to primary care physicians (98%), frustrating to pathologists (83%), requiring more of their time as a consultant (64%), and providing necessary clinical information (52%). Most perceived that adoption of the MPATH-Dx would: improve communication with other pathologists and treating physicians (87%), generally be a change for the better (80%), improve patient care (79%), be acceptable to clinical colleagues (68%), save time in pathology report documentation (53%), and protect from malpractice (51%).ConclusionsMost dermatopathologists view diverse terminology as contributing to miscommunication with clinicians and patients, adversely impacting patient care. They view the MPATH-Dx as a promising tool to standardize terminology and improve communication. The MPATH-Dx may be a useful supplement to conventional pathology reports. Further revision and refinement are necessary for widespread clinical use.

Objectives"Assurance behaviors," a type of defensive medicine, involve physicians' utilization of additional patient services to avoid adverse legal outcomes. We aim to compare the use of clinical behaviors (such as ordering additional tests, services, and consultations) due to malpractice concerns with the same behaviors due to patient safety concerns.MethodsA national sample of dermatopathologists (n = 160) completed an online survey.ResultsParticipants reported using one or more of five clinical behaviors due to concerns about medical malpractice (95%) and patient safety (99%). Self-reported use of clinical behaviors due to malpractice concerns and patient safety concerns was compared, including ordering additional immunohistochemistry/molecular tests (71% vs 90%, respectively, P < .0001), recommending additional surgical sampling (78% vs 91%, P < .0001), requesting additional slides (81% vs 95%, P < .0001), obtaining second reviews (78% vs 91%, P < .0001), and adding caveats into reports regarding lesion difficulty (85% vs 89%, P > .05).ConclusionsDermatopathologists use many clinical behaviors both as assurance behaviors and due to patient safety concerns, with a higher proportion reporting patient safety concerns as a motivation for specific behaviors.

BackgroundMelanocytic tumors are often challenging and constitute almost one in four skin biopsies. Immunohistochemical (IHC) studies may assist diagnosis; however, indications for their use are not standardized.MethodsA test set of 240 skin biopsies of melanocytic tumors was examined by 187 pathologists from 10 US states, interpreting 48 cases in Phase I and either 36 or 48 cases in Phase II. Participant and diagnosis characteristics were compared between those who reported they would have ordered, or who would have not ordered IHC on individual cases. Intraobserver analysis examined consistency in the intent to order when pathologists interpreted the same cases on two occasions.ResultsOf 187 participants interpreting 48 cases each, 21 (11%) did not request IHC tests for any case, 85 (45%) requested testing for 1 to 6 cases, and 81 (43%) requested testing for ≥6 cases. Of 240 cases, 229 had at least one participant requesting testing. Only 2 out of 240 cases had more than 50% of participants requesting testing. Increased utilization of testing was associated with younger age of pathologist, board-certification in dermatopathology, low confidence in diagnosis, and lesions in intermediate MPATH-Dx classes 2 to 4. The median intraobserver concordance for requesting tests among 72 participants interpreting the same 48 cases in Phases I and II was 81% (IQR 73%-90%) and the median Kappa statistic was 0.20 (IQR 0.00, 0.39).ConclusionSubstantial variability exists among pathologists in utilizing IHC.

BackgroundAlthough treatment guidelines exist for melanoma in situ and invasive melanoma, guidelines for other melanocytic skin lesions do not exist.ObjectiveTo examine pathologists' treatment suggestions for a broad spectrum of melanocytic skin lesions and compare them with existing guidelines.MethodsPathologists (N = 187) completed a survey and then provided diagnoses and treatment suggestions for 240 melanocytic skin lesions. Physician characteristics associated with treatment suggestions were evaluated with multivariable modeling.ResultsTreatment suggestions were concordant with National Comprehensive Cancer Network guidelines for the majority of cases interpreted as melanoma in situ (73%) and invasive melanoma (86%). Greater variability of treatment suggestions was seen for other lesion types without existing treatment guidelines. Characteristics associated with provision of treatment suggestions discordant with National Comprehensive Cancer Network guidelines were low caseloads (invasive melanoma), lack of fellowship training or board certification (melanoma in situ), and more than 10 years of experience (invasive melanoma and melanoma in situ).LimitationsPathologists could not perform immunohistochemical staining or other diagnostic tests; only 1 glass side was provided per biopsy case.ConclusionsPathologists' treatment suggestions vary significantly for melanocytic lesions, with lower variability for lesion types with national guidelines. Results suggest the need for standardization of treatment guidelines for all melanocytic lesion types.

IMPORTANCE: Many patients presently have access to their pathologic test result reports via online patient portals, yet little is known about pathologists perspective on this topic. OBJECTIVE: To examine dermatopathologists experience and perceptions of patient online access to pathology reports. DESIGN, SETTING, AND PARTICIPANTS: A survey of 160 dermatopathologists currently practicing in the United States who are board certified and/or fellowship trained in dermatopathology was conducted between July 15, 2018, and September 23, 2019. Those who reported interpreting skin biopsies of melanocytic lesions within the previous year and expected to continue interpreting them for the next 2 years were included. MAIN OUTCOMES AND MEASURES: Dermatopathologists demographic and clinical characteristics, experiences with patient online access to pathologic test result reports, potential behaviors and reactions to patient online access to those reports, and effects on patients who read their pathologic test result reports online. RESULTS: Of the 160 participating dermatopathologists from the 226 eligible for participation (71% response rate), 107 were men (67%); mean (SD) age was 49 (9.7) years (range, 34-77 years). Ninety-one participants (57%) reported that patients have contacted them directly about pathologic test reports they had written. Some participants noted that they would decrease their use of abbreviations and/or specialized terminology (57 [36%]), change the way they describe lesions suspicious for cancer (29 [18%]), and need specialized training in communicating with patients (39 [24%]) if patients were reading their reports. Most respondents perceived that patient understanding would increase (97 [61%]) and the quality of patient-physician communication would increase (98 [61%]) owing to the availability of online reports. Slightly higher proportions perceived increased patient worry (114 [71%]) and confusion (116 [73%]). However, on balance, most participants (114 [71%]) agreed that making pathologic test result reports available to patients online is a good idea. CONCLUSIONS AND RELEVANCE: Dermatopathologists in this survey study perceived both positive and negative consequences of patient online access to pathologic test result reports written by the respondents. Most participants believe that making pathologic test result reports available to patients online is a good idea; however, they also report concerns about patient worry and confusion increasing as a result. Further research regarding best practices and the effect on both patients and clinicians is warranted.

Simple Summary: In a retrospective study of 86 patients, we identified independent predictors of recurrence-free survival (RFS) and overall survival (OS) after the resection of liver metastases of uveal melanoma using a multivariable Cox model. A disease-free interval of ≤24 months and a chromosome 8q surgain were associated with worse survival. With these two parameters, we built a novel clinico-genetic score that defined three risk groups with distinct prognoses. This novel score identified patients with a high risk of relapse after surgery. These patients may benefit from neoadjuvant or adjuvant systemic therapy following complete surgical resection with the hope of improving survival outcomes. Surgical treatment of liver metastases of uveal melanoma (LMUM) could be proposed for selected patients. This retrospective study examined the prognostic significance of the genetic profiles of liver metastases after LMUM resection. A total of 86 patients treated with resection for LMUM, who underwent genetic analysis of liver metastasis, were included. A multivariable Cox model identified the independent predictors of recurrence-free survival (RFS) and overall survival (OS). The disease-free interval (DFI) and a chromosome 8q surgain (>3 copies) were independent predictors and categorized patients into three risk groups with distinct postoperative prognoses. For the low-, intermediate-, and high-risk scores of recurrence, the median RFS values were 15 months (95% CI: 10–22), 6 months (95% CI: 4–11), and 4 months (95% CI: 2–7), and the median OS values were 86 months (95% CI: 55-NR), 25 months (95% CI: 17–48), and 19 months (95% CI: 12–22), respectively. The predictive accuracy of this scoring system was demonstrated by a mean area under the curve (AUC(t)) of 0.77 (95% CI: 0.65–0.90) for RFS and 0.81 (95% CI: 0.70–0.92) for OS. This novel score, based on a DFI of ≤24 months combined with a chromosome 8q surgain, identifies patients at a high risk of early recurrence and could help clinicians to propose perioperative treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The impact of malpractice concerns on pathologists use of defensive medicine and interpretations of melanocytic skin lesions (MSLs) is unknown. METHODS: A total of 207 pathologists interpreting MSLs responded to a survey about past involvement in malpractice litigation, influence of malpractice concerns on diagnosis, and use of assurance behaviors (defensive medicine) to alleviate malpractice concerns. Assurance behaviors included requesting second opinions, additional slides, additional sampling, and ordering specialized tests. RESULTS: Of the pathologists, 27.5% reported that malpractice concerns influenced them toward a more severe MSL diagnosis. Nearly all (95.2%) pathologists reported practicing at least one assurance behavior due to malpractice concerns, and this practice was associated with being influenced toward a more severe MSL diagnosis (odds ratio, 2.72; 95% confidence interval, 1.41-5.26). CONCLUSIONS: One of four US skin pathologists upgrade MSL diagnosis due to malpractice concerns, and nearly all practice assurance behaviors. Assurance behaviors are associated with rendering a more severe MSL diagnosis.

BACKGROUND: Melanoma staging has depended on depth of invasion (Breslow thickness, BT), mitotic rate (MR) and ulceration. In anticipation of the AJCCs eighth edition, variability in pathologists assessment of these factors and consequently in tumor staging was assessed. METHODS: One-hundred and fifteen cases of invasive melanoma, established by a consensus panel, were assessed by 187 pathologists. Variation was studied in BT, the detection of mitotic figures, and ulceration. The sources of this variation and its effect on tumor staging are considered. RESULTS: On average, participant assessments closely approached consensus BT. Greater variation was identified in the classification of mitogenicity, which (like ulceration) upstages a T1 melanoma from T1a to T1b in the seventh but not eighth edition. In cases with a T1a diagnosis by the consensus panel, 15.6% of participants identified one or more mitotic figures (indicative of a false positive); and in cases diagnosed asT1b by the consensus panel, 32.0% of participants failed to find mitotic figures (false negative). CONCLUSION: Variability in the staging of T1 melanoma among pathologists when using the AJCC seventh edition criteria is closely related to the detection of mitotic figures, with BT playing a less prominent role. Decreased variability is expected after implementation of the eighth edition.

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.

ImportanceThe 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.ObjectiveTo 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 participantsIn 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 measuresConcordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility.ResultsFor 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 relevanceMelanoma 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.

Diagnostic discrepancy among pathologists interpreting melanocytic skin lesions (MSL) is an ongoing concern for patient care. Given that job satisfaction could impact patient care, this study aimed to characterize which pathologists enjoy interpreting MSL and estimate the association between enjoyment and diagnostic accuracy. Pathologists' demographics, training, and experience were obtained by a cross-sectional survey. Associations between these characteristics and self-reported enjoyment when interpreting MSL were estimated by Pearson's Chi-square tests. Diagnostic accuracy was determined by comparing pathologists' MSL interpretations with reference standard diagnoses. Associations between enjoyment and diagnostic accuracy were evaluated by generalized estimating equations (GEE) models. One hundred and eighty-seven (90%) pathologists completed the study. Seventy percent agreed that interpreting MSL is enjoyable. Pathologists who enjoyed interpreting MSL were more likely to be board certified and/or fellowship trained in dermatopathology (P=0.008), have ?10 years of experience (P=0.010) and have an MSL caseload of ?60 per month (P=

Angiotropism/pericytic mimicry and vascular co-option involve tumor cell interactions with the abluminal vascular surface. These two phenomena may be closely related. However, investigations of the two processes have developed in an independent fashion and different explanations offered as to their biological nature. Angiotropism describes the propensity of tumor cells to spread distantly via continuous migration along abluminal vascular surfaces, or extravascular migratory metastasis (EVMM). Vascular co-option has been proposed as an alternative mechanism by which tumors cells may gain access to a blood supply. We have used a murine brain melanoma model to analyze the interactions of GFP human melanoma cells injected into the mouse brain with red fluorescent lectin-labeled microvascular channels. Results have shown a striking spread of melanoma cells along preexisting microvascular channels and features of both vascular co-option and angiotropism/pericytic mimicry. This study has also documented the perivascular expression of Serpin B2 by angiotropic melanoma cells in the murine brain and in human melanoma brain metastases. Our findings suggest that vascular co-option and angiotropism/pericytic mimicry are closely related if not identical processes. Further studies are needed in order to establish whether EVMM is an alternative form of cancer metastasis in addition to intravascular cancer dissemination.

For more than 15 years, angiotropism in melanoma has been emphasized as a marker of extravascular migration of tumor cells along the abluminal vascular surface, unveiling an alternative mechanism of tumor spread distinct from intravascular dissemination. This mechanism has been termed extravascular migratory metastasis (EVMM). During EVMM, angiotropic tumor cells migrate in a 'pericytic-like' manner (pericytic mimicry) along the external surfaces of vascular channels, without intravasation. Through this pathway, melanoma cells may spread to nearby or more distant sites. Angiotropism is a prognostic factor predicting risk for metastasis in human melanoma, and a marker of EVMM in several experimental models. Importantly, analogies of EVMM and pericytic mimicry include neural crest cell migration, vasculogenesis and angiogenesis, and recent studies have suggested that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes reminiscent of cancer migration and embryonic/stem cell state transitions. A recent work revealed that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression via angiotropism and migration along the abluminal vascular surface. Finally, recent data using imaging of melanoma cells in a murine model have shown the progression of tumor cells along the vascular surfaces. Taken together, these data provide support for the biological phenomenon of angiotropism and EVMM, which may open promising new strategies for reducing or preventing melanoma metastasis.