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Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan- A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years ; range: 42–86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4–80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months ; range: 8–36 months), two died from their disease, and three developed metastases. Next- generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

A 77-year-old woman attended clinic for review of longstanding necrobiosis lipoidica. She reported a tender lesion on the left lower leg that had developed over 2 months. This had not responded to treatment with topical steroids, unlike all previous necrobiosis lipoidica-related ulcerations. On

This article was migrated. The article was marked as recommended. Objectives: Intravenous fluid (IV) therapy is an important component of care for many hospital patients, especially in perioperative and acute care settings. However, errors in fluid composition and dosing can be life-threatening. To achieve competent professional performance, i.e., accurate and fluent, it is vitally important that medical students receive effective training in IV fluid therapy. Methods: In this study, we explored how Precision Teaching (PT), a behaviour analytic teaching method, can enhance outcomes of usual medical education techniques.A total of 178 third-year medical students participated in the study during the IV fluid therapy training week. All students completed a multiple-choice test pre- and post-training. In addition to standard IV fluid therapy teaching, the experimental intervention group (n=83 students) used SAFMEDS (Say All Fast MinuteEvery Day Shuffled) cards approximately 3-5 times per day for 5 days. The other 95 students (control group) received teaching as usual, but did not undergo the additional training. Results: Results show that the SAFMEDS boosted performance of the intervention group on the MCQ by 20 percentage points when compared to the control group. Fluency (accuracy and speed) of performance on SAFMED trials increased markedly during the intervention week and there was evidence that weaker students benefitted in particular. Conclusions: Implications for medical education are outlined.

Epidermolytic acanthoma is a rare benign lesion that most often presents as a solitary or multiple small papular lesions on the trunk, face, limbs or external male genitalia. Only a small number of cases have been reported occurring on the vulva and clinically and histologically they may mimic and be misdiagnosed as viral warts. We report 2 cases of multiple epidermolytic acanthomas localized to the vulva. Molecular tests (in situ hybridization and polymerase chain reaction) showed no evidence of human papillomavirus infection and p16 staining was negative. We stress the need for pathologists to consider epidermolytic acanthoma in the differential diagnosis of multiple vulval lesions resembling viral warts.

Part I: Understanding the resource nexus: Setting scenes The Resource Nexus: Preface and Introduction Raimund Bleischwitz, Holger Hoff, Catalina Spataru, Ester van der Voet, Stacy D. VanDeveer Appreciating wider environmental angles Kaysara Khatun and Gloria Salmoral Scales and the resource nexus Corey Johnson and Stacy D. VanDeveer Security, climate change and the resource nexus Bassel Daher, Sanghyun Lee, Rabi H. Mohtar, Jeremiah O. Asaka and Stacy D. VanDeveer Part II: Analysing the resource nexus: Tools and metrics Life Cycle Assessment for resource nexus analysis Ester van der Voet and Jeroen B. Guinee Linking society and nature: material flows and the resource nexus Anke Schaffartzik and Dominik Wiedenhofer Resource footprints Stefan Giljum, Martin Bruckner and Stephan Lutter Input-Output analysis and resource nexus assessment Arnold Tukker and David Font Vivanco Material criticality assessment and resource nexus analysis Gavin M. Mudd Industrial Ecology Methods and the Resource Nexus Ester van der Voet Part III: Resource nexus modelling: Practices and future transformations Integrating environmental and social impacts with Ecosystem services analysis Perrine Hamel, Benjamin Bryant, Becky Chaplin-Kramer and Adrian Vogl Modelling practices from local to global Enrique Kremers, Andreas Koch and Jochen Wendel Global change and K-waves: exploring nexus patterns Markku Wilenius Foresight and scenarios: modelling practices and resource nexus assessment Gerd Ahlert, Martin Distelkamp and Mark Meyer Extending macro-economic modelling into the resource nexus Alvaro Calzadilla and Ramiro Parrado The five-node resource nexus dynamics: an integrated modelling approach Catalina Spataru Part IV: International political economy and the resource nexus The resource nexus in an uncertain world: a non-equilibrium perspective Shilpi Srivastava and Jeremy Allouche Mining and the resource nexus David Humphreys Scarcities, supply and new resource curses? Raimund Bleischwitz and Jun Rentschler The international commodity trade: Stylized facts Vincenzo de Lipsis, Paolo Agnolucci and Raimund Bleischwitz Rare Earth Elements and a resource nexus perspective Eva Bartekova Governing land in the Global South Julia Tomei and Darshini Ravindranath Part V: Applying the resource nexus: Regional and Global Scale Elements of the Water-Energy-Food nexus in China Philip Andrews-Speed and Carole Dalin The Energy-Materials nexus: the case of metals Ester v.d Voet, Rene Kleijn and Gavin M. Mudd Unconventional oil and gas production meets the resource nexus Tim Boersma and Philip Andrews-Speed Feeding Africa: Nexus-related opportunities, challenges and policy options Timothy O. Williams, Fred Kizito and Marloes M. Mul The five node resource nexus at sea Tundi Agardy Part VI: Governing the resource nexus: Emerging responses Urban metabolism and new urban governance Corey Johnson Eco-innovation and resource nexus challenges: Ambitions and evidence Michal Miedzinski, Will McDowall and Raimund Bleischwitz Green Chemistry: Opportunities, waste and food supply chains Avtar Matharu, Eduardo Melo and Joseph A. Houghton California Innovations @ WEN Blas L. Perez Henriquez The UN, Global Governance and the SDGs Maria Ivanova and Natalia Escobar-Pemberthy

Background: Identifying new and more robust assessments of proficiency/expertise (finding new "biomarkers of expertise") in histopathology is desirable for many reasons. Advances in digital pathology permit new and innovative tests such as flash viewing tests and eye tracking and slide navigation analyses that would not be possible with a traditional microscope. The main purpose of this study was to examine the usefulness of time-restricted testing of expertise in histopathology using digital images. Methods: 19 novices (undergraduate medical students), 18 intermediates (trainees), and 19 experts (consultants) were invited to give their opinion on 20 general histopathology cases after 1 s and 10 s viewing times. Differences in performance between groups were measured and the internal reliability of the test was calculated. Results: There were highly significant differences in performance between the groups using the Fisher′s least significant difference method for multiple comparisons. Differences between groups were consistently greater in the 10-s than the 1-s test. The Kuder-Richardson 20 internal reliability coefficients were very high for both tests: 0.905 for the 1-s test and 0.926 for the 10-s test. Consultants had levels of diagnostic accuracy of 72% at 1 s and 83% at 10 s. Conclusions: Time-restricted tests using digital images have the potential to be extremely reliable tests of diagnostic proficiency in histopathology. A 10-s viewing test may be more reliable than a 1-s test. Over-reliance on "at a glance" diagnoses in histopathology is a potential source of medical error due to over-confidence bias and premature closure.

Despite the increasing availability of digital slide viewing, and numerous advantages associated with its application, a lack of quality validation studies is amongst the reasons for poor uptake in routine practice. This study evaluated primary digital pathology reporting in the setting of routine subspecialist gastrointestinal pathology, commonplace in most tissue pathology laboratories and representing one of the highest volume specialties in most laboratories. Individual digital and glass slide diagnoses were compared amongst three pathologists reporting in a gastrointestinal subspecialty team, in a prospective series of 100 consecutive diagnostic cases from routine practice in a large teaching hospital laboratory. The study included a washout period of at least 6 months. Discordant diagnoses were classified, and the study evaluated against recent College of American Pathologists (CAP) recommendations for evaluating digital pathology systems for diagnostic use. The study design met all 12 of the CAP recommendations. The 100 study cases generated 300 pairs of diagnoses, comprising 100 glass slide diagnoses and 100 digital diagnoses from each of the three study pathologists. 286 of 300 pairs of diagnoses were concordant, representing intraobserver concordance of 95.3 %, broadly comparable to rates previously published in this field. In ten of the 14 discordant pairs, the glass slide diagnosis was favoured; in four cases, the digital diagnosis was favoured, but importantly, the 14 discordant intraobserver diagnoses were considered to be of minor clinical significance. Interobserver, or viewing modality independent, concordance was found in 94 of the total of 100 study cases, providing a comparable baseline discordance rate expected in any second viewing of pathology material. These overall results support the safe use of digital pathology in primary diagnostic reporting in this setting.

Aim(1) A pilot study to determine the accuracy of interpretation of whole slide digital images in a broad range of general histopathology cases of graded complexity. (2) To survey the participating histopathologists with regard to acceptability of digital pathology.Materials and methodsGlass slides of 100 biopsies and minor resections were digitally scanned in their entirety, producing digital slides. These cases had been diagnosed by light microscopy at least 1 year previously and were subsequently reassessed by the original reporting pathologist (who was blinded to their original diagnosis) using digital pathology. The digital pathology-based diagnosis was compared with the original glass slide diagnosis and classified as concordant, slightly discordant (without clinical consequence) or discordant. The participants were surveyed at the end of the study.ResultsThere was concordance between the original light microscopy diagnosis and digital pathology-based diagnosis in 95 of the 100 cases while the remaining 5 cases showed only slight discordance (with no clinical consequence). None of the cases were categorised as discordant. Participants had mixed experiences using digital pathology technology.ConclusionsIn the broad range of cases we examined, digital pathology is a safe and viable method of making a primary histopathological diagnosis.

Introduction This survey examines regional variation in the diagnosis of keratoacanthoma (KA). Methods Twenty-three departments from Great Britain and Ireland were invited. The number of cases coded as KA or cutaneous SCC in the previous 12 months was retrieved. An SCC: KA ratio was calculated. Participants also provided free text responses. Results Seventeen departments replied. A total of 11 718 cases were included with a breakdown of 998 KA and 10 720 SCC. The mean SCC:KA ratio was 10.7:1, range (2.5:1 to 139:1). Free text responses are presented. Discussions An extreme variation in approach is highlighted by this survey. We believe a multidisciplinary team approach to the diagnosis of KA is essential. There seems to be a need for a carefully considered clinicopathological study, backed up by molecular studies, to better understand the natural biology of this diagnosis.

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

An unusual cervical adenocarcinoma is reported in a 50-year-old woman with a history of Peutz Jeghers syndrome. The carcinoma contained two morphologically distinct and spatially separate components, one comprising typical well differentiated adenoma malignum and the other a moderately differentiated neoplasm, in keeping with gastric type adenocarcinoma. Both components were positive for HIK1083 and MUC6 and negative for p16, and did not contain human papillomavirus. It is believed that such a composite tumour has not been described in the literature. It is believed that the component of gastric type adenocarcinoma arose through a process of dedifferentiation within adenoma malignum and we provide circumstantial molecular evidence in support of the interpretation that both components may be clonally related in that they displayed an extra copy of chromosome 7. This raises the possibility of a relationship between these two uncommon types of cervical adenocarcinoma, both of which are thought to exhibit gastric differentiation.

An embryonal rhabdomyosarcoma (sarcoma botryoides) of the cervix occurring in a 30-year-old woman is described. In addition to typical areas of the embryonal rhabdomyosarcoma, including cartilaginous elements, the neoplasm was characterised by the presence of foci composed of highly pleomorphic cells. The significance of this finding is uncertain. These foci may represent areas of dedifferentiation in an embryonal rhabdomyosarcoma.

Two cases of lobular breast carcinoma metastatic to an endometrial polyp are described. Both patients had been treated with tamoxifen and presented with abnormal uterine bleeding. Histology of endometrial biopsy in both cases showed typical tamoxifen-associated endometrial polyps with focal subtle stromal infiltration by metastatic lobular breast carcinoma. This was confirmed by positive immunohistochemical staining with cytokeratin epithelial markers. Metastatic breast carcinoma may rarely involve tamoxifen-associated endometrial polyps. Because primary endometrial carcinomas may also arise within tamoxifen polyps, these should be extensively sampled. We briefly review polypoid uterine lesions that may occur secondary to tamoxifen therapy.

Precancerous lesions, often detected by cancer screening programmes, fascinate histopathologists. Microscopic examination shows some of the architectural and cytological features of malignancy but no invasion of surrounding healthy tissue. As a practising histopathologist, I have always felt uncomfortable that patients with these conditions, such as ductal carcinoma in situ of the breast, are often told …

A 60-year-old woman presented with a large painful haemorrhagic ulcer of her left lower abdomen. Her medical history included ulcerative colitis, breast cancer, stroke and atrial fibrillation for which she was on warfarin. On examination she had a 15×6 cm large necrotic haemorrhagic ulcer of the left lower abdomen (figure 1). The border appeared violatious and undermined and the …

Aims: Uteri are among the most common surgical pathology specimens. Assessment of the endometrium is often difficult because of pronounced tissue autolysis. This study describes a simple method to prevent endometrial autolysis and aid in interpretation of the endometrium. Methods: Sixty uteri were injected with formalin using a needle and syringe directed alongside a probe, which was inserted through the external cervical os into the endometrial cavity. Injection was performed on the same day as removal of the uterus. As controls, 60 uteri that were not injected with formalin were examined. The degree of endometrial autolysis was assessed on a four point scale (0–3), with a score of 0 representing no or minimal autolysis and a score of 3 representing extensive autolysis, such that histological interpretation of the endometrium was impossible. Results: In the injected group, the number of cases with scores of 0, 1, 2, and 3 was 42, 13, four, and one, respectively. The corresponding values for the control group were 17, 23, eight, and 12, respectively. This was highly significant (p Conclusions: There was significantly less endometrial autolysis in uteri injected with formalin. The use of this simple procedure should be encouraged in hysterectomy specimens.