Primary hepatic neoplasms arising in cirrhotic livers can have a variable spectrum of neuroendocrine differentiation.

Primary hepatic neoplasms with neuroendocrine differentiation are extremely rare. Their clinicopathological features and molecular genetic basis are largely unknown. We identified four cases of primary hepatic neoplasms with neuroendocrine differentiation. Electronic medical records were reviewed for clinical history, imaging findings, laboratory results, and follow-up. Pathology slides, immunohistochemistry, and ancillary studies were reviewed. There were two females and two males with age ranging from 52 to 74 years. There was one amphicrine carcinoma with tumor cells simultaneously demonstrating both hepatocellular and neuroendocrine differentiation, one mixed hepatocellular-neuroendocrine carcinoma (NEC) with hepatocellular component intermingled with neuroendocrine component, one small cell NEC, and one well-differentiated neuroendocrine tumor. Next- generation sequencing of the mixed hepatocellular-NEC and small cell NEC showed molecular/genetic alterations commonly seen in hepatocellular carcinoma (HCC). All four cases arose in a background of cirrhosis. Primary hepatic neoplasms arising in cirrhotic livers can have a spectrum of neuroendocrine differentiation. Presence of a NEC component may be an indicator of aggressiveness. In addition, primary hepatic carcinomas with neuroendocrine differentiation likely share the same molecular pathways as HCC.

Endometrial Adenocarcinomas With No Specific Molecular Profile: Morphologic Features and Molecular Alterations of "Copy-number Low" Tumors.

The study evaluated morphologic patterns, mutational profiles, and ß-catenin immunohistochemistry (IHC) in copy-number low (CNL) endometrial adenocarcinomas (EAs). CNL EAs (n=19) with next-generation or whole genome sequencing results and available tissue for IHC were identified from our institutional database. Clinical data and histologic slides were reviewed. IHC for ß-catenin was performed and correlated with mutation status. Images of digital slides of CNL EAs from The Cancer Genome Atlas (TCGA) database (n=90) were blindly reviewed by 4 pathologists, and morphology was correlated with mutation status. Categorical variables were analyzed using the Fisher exact test, and agreement was assessed using Fleiss κ. CTNNB1 mutations were present in 63% (12/19) of CNL EAs. ß-catenin nuclear localization was present in 83% of CTNNB1-mutated tumors (10/12) and in 0% (0/7) of CTNNB1-wildtype tumors (sensitivity 0.83, specificity 1.00). Squamous differentiation (SD) was present in 47% (9/19) and was more often observed in CTNNB1-mutated tumors (P=0.02). Mucinous differentiation (MD) was associated with KRAS mutations (P<0.01). Digital image review of TCGA CNL EAs revealed that pathologist agreement on SD was strong (κ=0.82), whereas agreement on MD was weak (κ=0.48). Pathologists identified SD in 22% (20/90), which was significantly associated with the presence of CTNNB1 mutations (P<0.01). CNL EAs demonstrate several morphologies with divergent molecular profiles. SD was significantly associated with CTNNB1 mutations and nuclear localization of ß-catenin in these tumors. Nuclear expression of ß-catenin is a sensitive and specific IHC marker for CTNNB1 mutations in CNL EAs. CNL EAs with KRAS mutations often displayed MD.

Evaluation of pelvic washing specimens in patients with endometrial cancer: Cytomorphological features, diagnostic agreement, and pathologist experience.

BACKGROUND: Pelvic washings for patients with endometrial cancer is recommended but not used for staging. The International System for Reporting Serous Fluid Cytology (TIS) has standardized diagnostic categories, but the criteria remain incomplete. The 3 primary goals of this study were to 1) investigate features that distinguish atypical/indeterminate from malignant specimens, 2) measure the level of agreement between chart and reviewer diagnoses, and 3) determine whether the number of years in practice had an effect on the diagnoses rendered. METHODS: Pelvic washings and surgical pathology specimens for 52 patients with a chart diagnosis of atypical/indeterminate, suspicious, or malignant cytology and 52 age-matched controls with a negative chart diagnosis were included, reviewed blindly by 2 cytopathologists, and assigned a study diagnosis. Morphologic features were assessed. Agreement between original chart diagnoses and reviewer diagnoses were assessed as well as effect of years in practice. RESULTS: The overall cellularity in cell block (CB) slides for the malignant category was significantly increased compared with the atypical/indeterminate category (P < .0001). In addition, the number of atypical groups in ThinPrep for malignant washings was significantly increased compared with the atypical category (P < .001) and the negative and suspicious categories (P < .0001) in the CB. Overall agreement between the original and adjudicated diagnoses was high (γ = 0.983). There was no significant difference between diagnoses rendered and years in practice. CONCLUSION: The overall cellularity and number of atypical cells can be used to distinguish between malignant and atypical pelvic washing specimens. There is high reproducibility in the diagnostic categories and high agreement among pathologists, regardless of practice experience. These findings can help refine the criteria for TIS.

Giving and Receiving Effective Feedback: A Review Article and How-To Guide.

CONTEXT.­: Feedback is the delivery of information based on direct observation that is meant to improve performance. Learning is at the heart of feedback, and as such, feedback is a required competency in pathology resident education. In the laboratory setting, the ability of laboratory professionals in all practice settings and experience levels to give and receive feedback is crucial to workflow and ultimately patient care. OBJECTIVE.­: To summarize the importance of feedback, strategies for optimizing feedback exchange, and overcoming barriers to giving and receiving feedback. DATA SOURCES.­: Peer-reviewed original articles, review articles, medical education literature, and published books on feedback and communication were reviewed to explore ideal methods of giving and receiving feedback and to identify common barriers to feedback exchange. CONCLUSIONS.­: Medical education literature emphasizes techniques for giving feedback and describes barriers often encountered to feedback exchange in medical practice. Effective feedback requires that the giver, receiver, and environment be carefully considered. Likewise, each of these factors can impose barriers to feedback exchange. Various methods for giving feedback have been described. All feedback should address a specific behavior, be nonevaluative in nature, and be followed by confirmation of understanding and an action plan. Few articles describe the importance of receiving feedback. Receiving feedback can be difficult, but it is enhanced by learning to listen and making conscious decisions regarding implementing the messages heard. Giving and receiving feedback become easier with practice.

Evolving Roles of Histologic Evaluation and Molecular/Genomic Profiling in the Management of Endometrial Cancer.

Endometrial cancers are the most common gynecologic malignancies. The staging of endometrial cancer has evolved from a clinical-based system to a comprehensive surgical-pathologic approach that allows for better risk stratification and treatment planning. Over the past few years, use of NCCN's sentinel lymph node (SLN) mapping algorithm for the surgical staging of endometrial cancer has gained significant acceptance and is now commonly applied in many practices. However, pathologic evaluation of prognostic factors is beset by challenges, including the reproducibility of histologic classification and FIGO's grading, as well as the questionable clinical significance of low-volume tumor in SLNs. With the revelation of major genomic classes of endometrial cancer comes the potential for improved, reproducible, and prognostically relevant classification schemes, which integrate traditional pathologic parameters with genomic findings, to aid in treatment decisions. Pathologic identification of new variants of endometrial cancer, such as undifferentiated carcinoma, continues to advance the phenotypic spectrum of these tumors, spurring genomic and functional studies to further characterize their mechanistic underpinnings and potentially reveal new avenues for treatment. In the era of precision medicine, pathologic assessment of biomarkers (eg, mismatch repair proteins) and recognition of phenotypes that are amenable to specific targeted therapies (such as POLE-mutated tumors) have become integral to the management of women with endometrial carcinoma.

An Assessment of Pathology Resident Access to and Use of Technology: A Nationwide Survey.

CONTEXT: - Current technologies including digital slide scanners and handheld devices can revolutionize clinical practice and pathology graduate medical education (GME). The extent to which these technologies are used in pathology GME is unknown. OBJECTIVES: - To determine the types of technologies used, usage amount, and how they are integrated into pathology residency/fellowship programs nationwide. DESIGN: - A 40-question online survey for residents/fellows was developed and administered via the Research Electronic Data Capture System after institutional review board approval. RESULTS: - Fifty-two program directors (37%) gave permission for participation. One-hundred seventy-one responses were received (18% response rate). Most respondents have access to personal technology (laptop = 78% [134 of 171]), smartphone = 81% [139 of 171], tablet = 49% [84 of 171]), and Web-based digital slide collections (82%, 141 of 171). Few residents are provided electronic devices by their programs (laptop = 22% [38 of 171], smartphone = 0.5% [1 of 171], and tablet = 12% [21 of 171]). Fifty-nine percent have access to digital slide scanners, 33% have access to a program-created database of digitized slides, and 52% use telepathology. Fifteen percent have access to asynchronous learning. Of those with access to video-recorded conferences, 89% review them. Program size was significantly positively correlated with resident access to program-provided laptops (P = .02) and tablets (P < .001), digital slide scanners (P = .01), and telepathology (P = .001). Of all devices, program-provided laptops are used most for professional work (60.5% use this device for more than 5 hours per day). CONCLUSIONS: - Most residents report access to multiple types of innovative technology, but incorporation of these tools within pathology training programs is highly variable. Opportunities for incorporating innovative technologies exist and could be further explored.

A meaningful MESS (Medical Education Scholarship Support).

BACKGROUND: Graduate medical education faculty bear the responsibility of demonstrating active research and scholarship; however, faculty who choose education-focused careers may face unique obstacles related to the lack of promotion tracks, funding, career options, and research opportunities. Our objective was to address education research and scholarship barriers by providing a collaborative peer-mentoring environment and improve the production of research and scholarly outputs. METHODS: We describe a Medical Education Scholarship Support (MESS) group created in 2013. MESS is an interprofessional, multidisciplinary peer-mentoring education research community that now spans multiple institutions. This group meets monthly to address education research and scholarship challenges. Through this process, we develop new knowledge, research, and scholarly products, in addition to meaningful collaborations. RESULTS: MESS originated with eight founding members, all of whom still actively participate. MESS has proven to be a sustainable unfunded local community of practice, encouraging faculty to pursue health professions education (HPE) careers and fostering scholarship. We have met our original objectives that involved maintaining 100% participant retention; developing increased knowledge in at least seven content areas; and contributing to the development of 13 peer-reviewed publications, eight professional presentations, one Masters of Education project, and one educational curriculum. DISCUSSION: The number of individuals engaged in HPE research continues to rise. The MESS model could be adapted for use at other institutions, thereby reducing barriers HPE researchers face, providing an effective framework for trainees interested in education-focused careers, and having a broader impact on the education research landscape.

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

OBJECTIVES: To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). METHODS: 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. RESULTS: Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. CONCLUSIONS: Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Pathologist workforce in the United States: I. Development of a predictive model to examine factors influencing supply.

CONTEXT: Results of prior pathology workforce surveys have varied between a state of equilibrium and predictions of shortage. OBJECTIVE: To assess the current and future supply of pathologists, and apply a dynamic modeling tool for assessing the effects of changing market forces and emerging technologies on the supply of pathologists' services through 2030. DESIGN: Data came from various sources, including the literature, College of American Pathologists' internal data, and primary research through custom-developed surveys for the membership and for pathology practice managers RESULTS: Through 2010, there were approximately 18 000 actively practicing pathologists in the United States (5.7 per 100 000 population), approximately 93% of whom were board certified. Our model projects that the absolute and per capita numbers of practicing pathologists will decrease to approximately 14 000 full-time equivalent (FTE) pathologists or 3.7 per 100 000 in the coming 2 decades. This projection reflects that beginning in 2015, the numbers of pathologists retiring will increase precipitously, and is anticipated to peak by 2021. Including all types of separation, the net pathologist strength will begin falling by year 2015. Unless workforce entry or exit rates change, this trend will continue at least through 2030. These changes reflect the closure of many training programs 2 to 4 decades ago and the substantially decreased number of graduating residents. CONCLUSIONS: This comprehensive analysis predicts that pathologist numbers will decline steadily beginning in 2015. Anticipated population growth in general and increases in disease incidence owing to the aging population, to be presented in a companion article on demand, will lead to a net deficit in excess of more than 5700 FTE pathologists. To reach the projected need in pathologist numbers of nearly 20 000 FTE by 2030 will require an increase from today of approximately 8.1% more residency positions. We believe a pathologist shortage will negatively impact both patient access to laboratory services and health care providers' abilities to deliver more effective health care to their patient populations.

What are the pathology education requirements for all nonpathology ACGME-accredited programs in an academic center?

This study aimed to determine institution-wide graduate medical education (GME) requirements in pathology (exclusive of pathology residency and fellowships) at an academic center. All documents related to residency review committee (RRC) program requirements were searched for the key words "pathology," "laboratory," "autopsy," and "morbidity." For each occurrence, it was determined whether a pathology education requirement had been identified. Requirements were categorized and tabulated. The Accreditation Council for Graduate Medical Education (ACGME) lists 135 nonpathology programs; 66 programs exist at Duke University Medical Center, of which 54 (82%) had pathology education requirement(s). Twelve education categories were identified. Teaching/conferences were the most common (52%). Thirty-nine percent required consultation/support. Sixteen programs were required to perform gross/microscopic examination. Trainees in medical genetics are required to have a pathology rotation. Elective rotations should be available for trainees in 6 programs. Pathology departments at academic centers face significant institution-wide pathology education requirements for clinical ACGME programs. Didactic teaching/conferences and consultation/support are common requirements. Opportunities exist for innovative teaching strategies.

Malignant struma ovarii: a blinded study of 86 cases assessing which histologic features correlate with aggressive clinical behavior.

CONTEXT: Struma ovarii exhibiting malignant histology are uncommon, and an aggressive clinical course in the form of initial extraovarian spread or recurrence is even more exceptional for these tumors. OBJECTIVE: To determine whether specific histologic features have predictive value in distinguishing clinically benign from clinically malignant struma ovarii. DESIGN: Blinded analysis of 19 histologic characteristics of thyroid tumors was performed in 60 clinically benign and 26 clinically malignant struma ovarii cases, with long-term follow-up. RESULTS: Except for lack of fibrosis and macrofollicular pattern, which were more common in biologically malignant tumors (P  =  .04 and P  =  .008, respectively), and trabecular pattern, which was associated with a benign clinical course (P  =  .03), none of the other histologic features was found to be correlated with clinical behavior. The presence of the following features was similar in the biologically benign and malignant tumors: papillae, pseudo-papillae, psammoma bodies, nuclear grooves, nuclear overlap, "orphan Annie" nuclei, nuclear pseudo-inclusions, prominent nucleoli, hypercellularity, colloid scalloping, eosinophilic cytoplasm, mitoses, vascular invasion, cytologic atypia, nuclear pleomorphism, and cell size and type. Trabecular pattern and absence of fibrosis were uncommon, and there was considerable overlap of macrofollicular pattern ratio between benign and malignant cases. Thus, their practical usefulness is uncertain. CONCLUSIONS: The clinical outcome of struma ovarii cannot be predicted based on the microscopic diagnosis of the thyroid tissue or on specific histologic features. The lack of correlation between morphology and outcome in proliferative and histologically malignant struma ovarii is striking, making the behavior of these tumors particularly unpredictable.

Recent developments in defining microinvasive and early invasive carcinoma of the uterine cervix.

Although only a small proportion of invasive squamous carcinoma of the cervix present with microinvasive disease, consistent recognition of this entity is important because it carries important management implications. The objective of this review was to reassess the methods and criteria for a histopathologic diagnosis of both early invasive squamous and adenocarcinomas in light of recent pathologic and clinicopathologic studies. The diagnosis of microinvasion is primarily histopathologic. Although the concept of microinvasion initially seems obvious, there are problems in diagnostic precision. A clear understanding of both the Society of Gynaecologic Oncologists' and the International Federation of Obstetricians and Gynecologists' classifications of early invasive disease is required. Subsequently, key parameters must be assessed-measurement of depth and lateral spread, assessment of margins, and identification of lymphovascular invasion-using accepted reference points and definitions. This assessment requires properly oriented and stained histologic sections of a loop electrosurgical excision procedure or cone specimen. Immunohistochemical staining of vascular endothelium or epithelial basement membrane has only a limited/adjunctive role. Controversy continues regarding the need to appraise the extent of any lymphovascular invasion and measurement in cases with multifocal invasion. Application of criteria to invasive adenocarcinomas seems warranted but is particularly challenging because of its special morphology and different biology.

Endoscopic ultrasound-guided fine-needle aspiration of intrathoracic and intra-abdominal spindle cell and mesenchymal lesions.

BACKGROUND: The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the evaluation of spindle cell and mesenchymal lesions is unclear. This study reviews the use of EUS-FNA in diagnosing intrathoracic and intra-abdominal spindle and mesenchymal cell lesions at an academic institution. METHODS: All EUS-FNA specimens with a significant spindle or mesenchymal cell component were retrieved. Follow-up was comprised of clinical correlation, chart review, or evaluation of subsequent tissue specimens, including FNAs, biopsies, and/or surgical resections. Lesions were categorized as either inflammatory/reactive or neoplastic. RESULTS: Forty-four EUS-FNA specimens were retrieved from 39 patients (21 men and 18 women with a median age of 61 years [range, 20-88 years]). Anatomic sites included 19 lymph node specimens, 15 gastrointestinal tract specimens, 7 pancreatic specimens, and 4 other anatomic site specimens. Twenty-two cases were inflammatory/reactive lesions, including 17 granulomatous lesions and 5 cases of chronic pancreatitis. Twenty-two cases were neoplastic, including 14 gastrointestinal stromal tumors, 2 smooth muscle tumors, 2 sarcomatoid carcinomas, 2 melanomas, 1 sarcoma, and 1 solitary fibrous tumor. A specific cytologic diagnosis was rendered in 30 cases (81%). Immunocytochemistry was performed on 21 neoplastic cases and contributed to the differential diagnosis in 18 cases. No false-positive findings were encountered. Three false-negative results were identified and were attributed to sampling error. CONCLUSIONS: Spindle cell neoplasms are rarely encountered on EUS-FNA. The differential diagnosis encompasses a wide variety of benign and neoplastic entities. Correlation of cytomorphology and ancillary studies yields a high diagnostic accuracy of spindle cell and mesenchymal lesions on EUS-FNA.

Thyroid carcinoma showing thymus-like differentiation (CASTLE): case report with cytomorphology and review of the literature.

Thyroid carcinoma showing thymus-like differentiation (CASTLE) is a rare tumor of the thyroid gland or adjacent soft tissues of the neck. Given the comparatively good prognosis of CASTLE, it is crucial to distinguish this neoplasm from other more aggressive thyroid neoplasms that can have similar or overlapping cytomorphological features. However, there is little information about the cytomorphology of CASTLE available in the literature. Here we report the cytomorphology and histology of thyroid CASTLE in a 52-year-old woman and present a review of the literature.

Visible light optical spectroscopy is sensitive to neovascularization in the dysplastic cervix.

Neovascularization in cervical intraepithelial neoplasia (CIN) is studied because it is the precursor to the third most common female cancer worldwide. Diffuse reflectance from 450-600 nm was collected from 46 patients (76 sites) undergoing colposcopy at Duke University Medical Center. Total hemoglobin, derived using an inverse Monte Carlo model, significantly increased in CIN 2+ (N=12) versus CIN 1 (N=16) and normal tissues (N=48) combined with P<0.004. Immunohistochemistry using monoclonal anti-CD34 was used to quantify microvessel density to validate the increased hemoglobin content. Biopsies from 51 sites were stained, and up to three hot spots per slide were selected for microvessel quantification by two observers. Similar to the optical study results, microvessel density was significantly increased in CIN 2+ (N=16) versus CIN 1 (N=21) and normal tissue (N=14) combined with P<0.007. Total vessel density, however, was not significantly associated with dysplastic grade. Hence, our quantitative optical spectroscopy system is primarily sensitive to dysplastic neovascularization immediately beneath the basement membrane, with minimal confounding from vascularity inherent in the normal stromal environment. This tool could have potential for in vivo applications in screening for cervical cancer, prognostics, and monitoring of antiangiogenic effects in chemoprevention therapies.