Impact of COVID-19 Pandemic on Pathology Residents/Trainees in North America: A Survey-Based Study.

Background The COVID-19 pandemic has had a significant impact on resident training and education in the field of Pathology. This study aims to identify the tangible effects and resultant changes in education for Pathology trainees that have resulted from the pandemic. Design An electronic survey regarding Pathology trainee perceptions and experiences in relation to COVID-19 was created via Google Forms. The questionnaire was distributed to the pathology trainees via Twitter and email. The survey was also shared with all Pathology residency program coordinators across the USA and Canada. Results One hundred forty-five trainees responded to the questionnaire. 37.6% reported a significant decrease in specimen volume, whereas 43.3% reported a slight decrease in specimen volume. 18.3% reported the cancellation of educational lectures before shifting to a virtual platform for didactic purposes. However, 74.6% reported shifting all educational activities to virtual platforms. 35% cited cancellations of grand rounds, whereas 18.2% reported cancellations of grand rounds led by guest speakers. 53.5% took COVID-19 tests, and 22.7% were quarantined. 100% reported a change in sign-out culture. Conclusions This pandemic has significantly impacted pathology training in various aspects, including training, education, and well-being. Residents harbored anxiety and stress regarding board exam delays or uncertainties, inadequate exam preparation time, family separation, and compromised safety. The exact quantification of educational loss varied from program to program. A significant decrease in specimen volume and detrimental changes in sign-out culture are indicators of compromised resident education due to the pandemic. This pandemic has extended the use of digital pathology and virtual platforms to a higher extent. Free virtual educational resources provided by various pathology organizations were critically important interventions during this pandemic, contributing to resident education. The pandemic has shown that developing a comprehensive infrastructure to overcome the loss of educational opportunities is of paramount importance to alleviate stress and anxiety among trainees.

The Morphologic Spectrum of Gastric Type 1 Enterochromaffin-Like Cell Neuroendocrine Tumors.

Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

BACKGROUND: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. METHODS: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. RESULTS: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). CONCLUSIONS: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

The pathological outcome of ThinPrep Pap tests diagnosed as glandular cell abnormalities alone versus combined glandular and squamous abnormalities.

BACKGROUND: Although the incidence of glandular cell abnormalities (GCA) on cervical cytology is low, the clinical and histologic findings are often significant. A combined diagnosis of squamous intraepithelial lesion (SIL) and GCA indicates concern for either two distinct lesions or single entity. The goal of this study is to evaluate the outcome of the diagnosis of GCA alone or in combination with squamous abnormality (SqA). METHODS: From January 2012-June 2017, our laboratory processed 162 088 ThinPrep Pap tests. 998 (0.61%) cases were reported as GCA. Histologic follow-up was available in 569 cases after excluding adenocarcinoma, NOS and atypical endometrial cells. HPV results were available in 429 (67.2%) cases. RESULTS: The surgical follow-up on 271 cases with GCA alone diagnosis revealed negative/benign lesions in 183 (67.5%) cases, glandular lesions in 40 (14.8%) cases; SqA in 47 (17.3%) cases; combined in 1 (0.4%) case. Surgical follow-up on 298 cases with dual interpretation revealed negative/benign lesions in 108 (36.2%) cases, SqA in 159 (53.4%) cases, GCA in 21 (7.0%) cases and only 10 (3.4%) cases were combined lesions. The mean age was 44 ±13.36 years. The overall hrHPV-positive rate was 36.2%. Endometrial carcinoma was most common abnormality in patients >65 years (71.4%) especially with hrHPV-negative results. CIN 1-3 was the most common finding in patients <30 years (50%). CONCLUSION: A cytological diagnosis of GCA has a higher risk of glandular abnormality on surgical follow-up especially in the older and hrHPV-negative group (P < .0001) while a combined diagnosis has a higher risk of a squamous lesion especially in <30 years (P < .0001). The combination of cytology, hrHPV-status and patient age can significantly aid in the stratification of the patient into high risk for glandular/squamous lesions which results in appropriate management.

Clinicopathological, immunohistochemical and molecular correlation of neural crest transcription factor SOX10 expression in triple-negative breast carcinoma.

The transcription factor SOX10 mediates the differentiation of neural crest-derived cells, and SOX10 by immunohistochemistry (IHC) is used primarily for the diagnosis of melanoma. SOX10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple-negative breast carcinoma (TNBC). The aim was to study the clinical, pathologic and molecular profiles of SOX10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for SOX10 expression in 48 cases. SOX10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from formalin-fixed paraffin-embedded (FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of SOX10 with androgen receptor (AR), WT1, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, epidermal growth factor receptor (EGFR), CK5/6 and GATA transcription factor 3 (GATA3) were also assessed. The mean age was 59.38 (range, 28-90 years). Overall, 37.5% cases (18/48) were SOX10+. There was no association between SOX10 expression and age, grade or stage of patients; 6 of 10 (60%) cases of basal-like 1 (BL1), and 5 of 8 cases of unstable (UNS) molecular subtype were SOX10+. One of 5 basal-like-2 (BL2), 1 of 6 immunomodulatory (IM), 1 of 4 mesenchymal (M), 1 of 5 luminal androgen receptor (LAR) and 2 of 8 mesenchymal stem cell (MSL) showed lower frequencies of SOX10 expression. There was negative correlation between SOX10 and AR+ subtypes (P < .002). SOX10 was positively correlated with WT1 (P = .05). SOX10 did not show significant correlation with mammaglobin, GCDFP15, EGFR, CK5/6 and GATA3. SOX10 expression in the basal-like and unstable molecular subtypes supports the concept that these neoplasms show myoepithelial differentiation.

Fructose and glucose can regulate mammalian target of rapamycin complex 1 and lipogenic gene expression via distinct pathways.

Although calorically equivalent to glucose, fructose appears to be more lipogenic, promoting dyslipidemia, fatty liver disease, cardiovascular disease, and diabetes. To better understand how fructose induces lipogenesis, we compared the effects of fructose and glucose on mammalian target of rapamycin complex 1 (mTORC1), which appeared to have both positive and negative effects on lipogenic gene expression. We found that fructose acutely and transiently suppressed mTORC1 signaling in vitro and in vivo The constitutive activation of mTORC1 reduced hepatic lipogenic gene expression and produced hypotriglyceridemia after 1 week of fructose feeding. In contrast, glucose did not suppress mTORC1, and the constitutive activation of mTORC1 failed to suppress plasma triglycerides after 1 week of glucose feeding. Thus, these data reveal fundamental differences in the signaling pathways used by fructose and glucose to regulate lipid metabolism.