Development and Validation of a HER2-Low Focused Immunohistochemical Scoring System With High-Interobserver Concordance: The Australian HER2-Low Breast Cancer Concordance Study.

The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists' independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which <20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists' accuracy and concordance.

Ameloblastic Carcinoma With Orbital Invasion.

Ameloblastic carcinomas are malignant tumors arising from the odontogenic epithelium and defined as having features of ameloblastic differentiation in addition to cytological features of malignancy. Orbital involvement is rare and generally involves invasion of the orbital floor, apex, or soft tissue. This report describes an advanced presentation of ameloblastic carcinoma with orbital invasion and provides a review of the literature. A 58-year-old male presented with a 2-year history of a mid-facial mass, causing intracranial invasion and distortion of most skull foramina, nasopharynx, nasal cavity, and both orbits. Notably, there was an en-plaque pattern of circumferential tracking of the tumor along both orbital walls without invasion beyond the extraconal space, causing compression of the orbital apex and proptosis. Histology demonstrated nests of ameloblastic carcinoma and the advanced tumor was deemed nonresectable, with treatment being palliative.

Pancreatic heterotopia of the gallbladder - possible cause of right upper quadrant pain, a case report.

Pancreatic heterotopia is characterized by ectopic pancreatic tissue found outside the pancreas without any anatomical or vascular connection to the pancreas. Pancreatic heterotopia of the gallbladder is a rare histological finding; there have been only a handful of cases described in the literature. Pancreatic heterotopia of the gallbladder is usually diagnosed incidentally at histological examination following cholecystectomy or autopsy. Clinical presentation of pancreatic heterotopia of the gallbladder can vary from biliary colic, biliary obstruction or it can be completely asymptomatic. It has been suggested that gallbladder pancreatic heterotopia may lead to pancreatitis of this ectopic tissue, which may present differently to typical biliary colic. Here, we present the case of a 43-year-old male that presented with 2 years of significant postprandial nausea and right upper quadrant pain. Histopathology following cholecystectomy revealed chronic cholecystitis with cholelithiasis, in addition to a focus of pancreatic heterotopia in the gallbladder wall.

The impact of 2018 ASCO-CAP HER2 testing guidelines on breast cancer HER2 results. An audit of 2132 consecutive cases evaluated by immunohistochemistry and in situ hybridization.

The 2018 iteration of the ASCO-CAP HER2 testing guidelines proposes significant changes with an emphasis on the integration of concurrent immunohistochemistry (IHC) and in situ hybridization (ISH). We wished to evaluate the impact of these changes on clinical practice. Between Jan 2012 to Feb 2017, 2132 consecutive invasive breast carcinomas were evaluated with IHC and ISH for HER2. The sample tested was the breast primary or axillary nodes in all but 57 (2.7%) distant metastases. For 1824 cases with both dual-probe ISH and IHC results, the ISH subgroup was 1: 299 (16.4%), 2: 19 (1.0%), 1.0%, 3: 6 (0.3%), 4: 48 (2.6%) and 5: 1452 (79.6%). Ultimately 21% of group 2 and 4 cases and 80% of group 4 cases were positive. The change in HER2 status between the 2018 vs 2013 was: amplified in 323 (15.2%) vs 15.5%; not amplified in 1804 (84.6%) vs 82.2%; equivocal in 0 vs 2.3% previously. In 22 of 2127 cases (1.03%) the 2013 and 2018 results were discordant, all in groups 2-4. The discrepant cases included 15 of 331 (4.5%) of 2013 amplified cancers, now negative (all in groups 2 or 3) and 7 of 1796 (0.4%) 2013 nonamplified cases, now positive (all in group 4). Because of routine testing with both IHC and ISH, we found 6 of 1147 (0.52%) IHC negative (0 or 1+) cases were amplified by ISH. Further, 19 of 289 (6.6%) of IHC 3+ cases were nonamplified by ISH, circumstances not covered by these guidelines. In summary at the population level, the 2018 ASCO-CAP guidelines have a 99% agreement with the 2013 results. A major advantage is the abolishment of the clinically problematic equivocal category. Routine performance of both IHC and ISH uncovers a small proportion of cancers whose HER2 status is not addressed by these guidelines.

Testicular and paratesticular pathology in children: a 12-year histopathological review.

BACKGROUND: Our institution is the principal pediatric surgical referral center for a population of 1.6 million. The objective of this study was to determine the spectrum and incidence of pediatric testicular and paratesticular pathology in this population. METHODS: Pathology results of all testicular and paratesticular specimens between August 1995 to September 2007 were analyzed. Clinical details were retrieved retrospectively from the computerized database, recording age, mode of presentation, laterality, and associated inguinoscrotal pathology. RESULTS: Over 12 years 2 months, 474 patients (502 specimens) were identified. Testicular and paratesticular pathology was most frequent in patients aged 1-2 years (11%) and 11-12 years (10.5%). In all, 442 patients had non-neoplastic pathology, with 60.4% presenting acutely. The most common non-neoplastic pathologies were hydatid of Morgagni (42.6%) and "vanishing testis" (14.3%). Vanishing and atrophic testes were frequently explored between 1 and 2 years of age, with a left predominance. Most atrophic testes were undescended (54.8%). Testicular torsion occurred in 11.2%, with bimodal peak ages of <1 year and 13-14 years. Interestingly, testicular torsion also occurred more on the left side (68%). A total of 32 patients had neoplasms. Of 27 patients with testicular neoplasms, 55.6% were malignant (29.6% primary and 26% secondary), the principal primary malignancy was yolk sac tumor; the most common benign neoplasms were epidermoid cysts and teratomas. Five patients had paratesticular neoplasms, with rhabdomyosarcoma in 80%. CONCLUSIONS: The variety of scrotal and testicular pathology in children is considerable, with acute pathologic conditions comprising the bulk in the older (7-15 years) children, whereas impalpable testes and neoplasms comprise most of the lesions in infants. Interestingly testicular torsion, vanishing testes, and atrophic testes occur mainly on the left side. Benign testicular neoplasms occur more frequently than primary malignancies.

Ophthalmology and vision science research. Part 4: avoiding rejection--structuring a research paper from introduction to references.

As part of an ongoing series, this fourth article is the second of 2 related articles that deal with the basics of producing a high-quality manuscript. Although ophthalmology and vision science are the principal focus of this series, the general concepts essential to producing a quality manuscript are applicable to diverse fields of research. This article provides guidelines on how to present research findings in a structured form using the Introduction, Methods, Results, and Discussion (IMRaD) style. The components to be included, and equally important excluded, from each section are elucidated in detail. Commonly omitted or inaccurately or incompletely presented components of the manuscript, such as statistical analysis and references, are highlighted. The necessity to carefully refine manuscripts before submission is discussed. This article concludes by illustrating methods of appropriately dealing with referees' comments and resubmitting manuscripts. Although researchers may have to deal with rejection as part of the process, we hope that this series provides an easy-to-follow structure to maximize manuscript quality and improve the prospect of scientific publication.

Ophthalmology and vision science research: part 5: surfing or sieving--using literature databases wisely.

Literature databases are an ever-expanding resource available to the field of medical sciences. Understanding how to use such databases efficiently is critical for those involved in research. However, for the uninitiated, getting started is a major hurdle to overcome and for the occasional user, the finer points of database searching remain an unacquired skill. In the fifth and final article in this series aimed at those embarking on ophthalmology and vision science research, we look at how the beginning researcher can start to use literature databases and, by using a stepwise approach, how they can optimize their use. This instructional paper gives a hypothetical example of a researcher writing a review article and how he or she acquires the necessary scientific literature for the article. A prototype search of the Medline database is used to illustrate how even a novice might swiftly acquire the skills required for a medium-level search. It provides examples and key tips that can increase the proficiency of the occasional user. Pitfalls of database searching are discussed, as are the limitations of which the user should be aware.

Ophthalmology and vision science research: Part 3: avoiding writer's block--understanding the ABCs of a good research paper.

Completion of a scientific manuscript for submission to a peer-reviewed journal is a daunting task for clinicians and scientists early in their careers. In an ongoing series, this third article is the first of 2 related articles that deal with the basics of producing a high-quality research manuscript. Although ophthalmology and vision science are the principal focus of this series, the general concepts essential to producing a quality manuscript are applicable to diverse fields of research. This article highlights the exponential growth in the scientific literature over the past 40 years, considers why it is important to publish completed research, and discusses the necessity of identifying the key messages of the research, and their context, in relation to the published literature. The ethics of publishing biomedical research and scientific misconduct, such as duplicate publication or plagiarism, are outlined. To avoid later conflict, there is a critical need for coworkers to carefully address authorship order and inclusion early in the manuscript process. Internationally agreed guidelines are identified to guide this process. The importance of choosing the correct journal for a specific article and the nature of basic citation indices are discussed. The article concludes by elaborating and contrasting different scientific writing styles and emphasizing the considerable importance of developing a representative title and applying clarity and appropriate structure to the abstract.

Ophthalmology and vision science research: part 2: How to commence research--Eureka or that's a little unusual?

Understanding the key elements that increase the likelihood of project success is fundamental for those embarking on research. The first article in this series placed scientific journals in perspective in relation to Journal Impact Factors and citation indices. This second article in a series primarily aimed at those commencing research, particularly in the area of ophthalmology and vision science, delineates the interrelated components that are required to complete a research project. Successful research projects seldom emerge from serendipitous observation, and most evolve through a combination of inspiration, careful planning, and a great deal of industry. Beginning researchers must first be clear about their reason(s) for pursuing research and should identify potential mentors and collaborators at the outset. This article discusses methods of identifying suitable projects and mentors. Ten component areas necessary to complete a research project are addressed, with reference to relevant published literature, under the following topic areas: mentors and collaborators; finding a research topic; confirming suitability of the topic; defining the research question; developing the hypothesis; key considerations in study design; threats to study validity; study sample size; benefits and limitations of clinical science; completing to publication. This guide is intended to be applicable to all embarking on research, but particularly to those with an interest in the visual system. The final 3 articles in this series will deal with writing a research paper to publication standard, working successfully with the journal review process, and refining electronic literature searches.