Vascular invasion predicts the subgroup of lung adenocarcinomas ≤2.0 cm at risk of poor outcome treated by wedge resection compared to lobectomy.

Background: Recent randomized control trials (JCOG0802 and CALGB140503) have shown sublobar resection to be noninferior to lobectomy for non-small cell lung cancer (NSCLC) ≤2.0 cm. We have previously proposed histologic criteria stratifying lung adenocarcinoma into indolent low malignant potential (LMP) and aggressive angioinvasive adenocarcinomas, resulting in better prognostication than provided by World Health Organization grade. Here we determine whether pathologic classification is reproducible and whether subsets of adenocarcinomas predict worse outcomes when treated by wedge resection compared to lobectomy. Methods: A retrospective cohort of 108 recipients of wedge resection and 187 recipients of lobectomy for stage I/0 lung adenocarcinomas ≤2.0 cm was assembled from 2 institutions. All tumors were classified by a single pathologist, and interobserver reproducibility was assessed in a subset (n = 92) by 5 pathologists. Results: Angioinvasive adenocarcinoma (21%-27% of cases) was associated with worse outcomes when treated with wedge resection compared to lobectomy (5-year recurrence-free survival, 57% vs 85% [P = .007]; 5-year disease-free survival [DSS], 70% vs 90% [P = .043]; 7-year overall survival, 37% vs 58% [P = .143]). Adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and LMP exhibited 100% 5-year DSS regardless of the surgical approach. Multivariable analysis showed that angioinvasion, tumor size, margin status, and extent of nodal sampling were significantly associated with recurrence but not with surgical procedure. There was substantial interobserver reproducibility among the pathologists for the diagnosis of angioinvasive adenocarcinoma (κ = 0.71) and the combined indolent AIS/MIA/LMP group (κ = 0.74). Conclusions: The majority (∼75%) of lung adenocarcinomas ≤2 cm are adequately managed with wedge resection; however, angioinvasive adenocarcinomas (∼25%) treated by wedge resection with suboptimal nodal sampling exhibit poor outcomes, with a 40% to 45% rate of recurrence within 5 years and 60% to 65% overall mortality at 7 years.

Distinctive pseudopalisaded histiocytic hyperplasia characterizes the transition of exudative to proliferative phase of diffuse alveolar damage in patients dying of COVID-19.

Severe COVID-19 results in a glucocorticoid responsive form of acute respiratory distress (ARDS)/diffuse alveolar damage (DAD). Herein we compare the immunopathology of lung tissue procured at autopsy in patients dying of SARS-CoV-2 with those dying of DAD prior to the COVID-19 pandemic. Autopsy gross and microscopic features stratified by duration of illness in twelve patients who tested positive for SARS-CoV-2 viral RNA, as well as seven patients dying of DAD prior to the COVID-19 pandemic were evaluated with multiplex (5-plex: CD4, CD8, CD68, CD20, AE1/AE3) and SARS-CoV immunohistochemistry to characterize the immunopathologic stages of DAD. We observed a distinctive pseudopalisaded histiocytic hyperplasia interposed between the exudative and proliferative phase of COVID-19 associated DAD, which was most pronounced at the fourth week from symptom onset. Pulmonary macrothrombi were seen predominantly in cases with pseudopalisaded histiocytic hyperplasia and/or proliferative phase DAD. Neither pseudopalisaded histiocytic hyperplasia nor pulmonary macrothrombi was seen in non-COVID-19 DAD cases, whereas microthrombi were common in DAD regardless of etiology. The inflammatory pattern of pseudopalisaded histiocytic hyperplasia may represent the distinctive immunopathology associated with the dexamethasone responsive form of DAD seen in severe COVID-19.

Can Cytologic and Sonographic Features Help Prevent Overtreatment of Bethesda V Thyroid Nodules?

BACKGROUND: Although nearly half of thyroid nodules with Bethesda V cytology (suspicious for malignancy) may be benign or harbor low-grade neoplasms that can be sufficiently treated with lobectomy, many patients with Bethesda V cytology continue to be treated with total thyroidectomy. The objectives of this study were to establish whether cytomorphologic and ultrasonographic features can determine appropriate surgery for thyroid nodules with Bethesda V cytology and how often patients are overtreated with total instead of partial thyroidectomy. METHODS: Utilizing a 10-y prospective database starting January 1, 2004, cytomorphologic and ultrasonographic features of thyroid nodules with Bethesda V cytology were reviewed. Overtreatment was defined as total thyroidectomy when histopathology revealed benign nodule, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) or a unilateral < 4 cm low risk cancer. RESULTS: Sixty-three patients were included in the study. Seventeen (27%) had benign, 14 (22%) NIFTP, and 32 (51%) malignant nodules. On cytology, nuclear pseudoinclusions, and on ultrasound, taller-than-wide configuration, were more common in malignant than benign or NIFTP nodules. Among 56 patients who underwent total thyroidectomy, 14 and 11 had a benign or NIFTP nodule, respectively, and 13 had a unilateral < 4 cm low risk cancer, suggesting that 68% (38/56) were overtreated. CONCLUSIONS: Total thyroidectomy for Bethesda V thyroid nodules may result in overtreatment in more than half of the patients. Although certain cytomorphologic and ultarsonographic features may be helpful in determining appropriate surgery for Bethesda V thyroid nodules, additional characteristics are needed to reduce overtreatment of these nodules.

Pulmonary Adenocarcinomas of Low Malignant Potential: Proposed Criteria to Expand the Spectrum Beyond Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma.

Lung cancer screening has improved mortality among high-risk smokers but has coincidentally detected a fraction of nonprogressive adenocarcinoma historically classified as bronchoalveolar carcinoma (BAC). In the National Lung Screening Trial (NLST) the majority of BAC-comprising 29% of computed tomography-detected stage I lung adenocarcinoma-were considered overdiagnosis after extended follow-up comparison with the control arm. In the current classification, adenocarcinoma in situ and minimally invasive adenocarcinoma have replaced BAC but together comprise only ∼5% of stage I lung adenocarcinoma. Lepidic and subsets of papillary and acinar adenocarcinoma also infrequently recur. We, therefore, propose criteria for low malignant potential (LMP) adenocarcinoma among nonmucinous adenocarcinoma measuring ≤3 cm in total, exhibiting ≥15% lepidic growth, and lacking nonpredominant high-grade patterns (≥10% cribriform, ≥5% micropapillary, ≥5% solid), >1 mitosis per 2 mm2, angiolymphatic or visceral pleural invasion, spread through air spaces or necrosis. We tested these criteria in a multi-institutional cohort of 328 invasive stage I (eighth edition) and in situ adenocarcinomas and observed 16% LMP and 7% adenocarcinoma in situ/minimally invasive adenocarcinoma which together (23%) approximated the frequency of overdiagnosed stage I BAC in the NLST. The LMP group had 100% disease-specific survival. The proposed LMP criteria, incorporating multiple histologic parameters, may be a clinically useful "low-grade" prognostic group. Validation of these criteria in additional retrospective cohorts and prospective screen-detected cohorts should be considered.

A potential diagnostic pitfall for hobnail variant of papillary thyroid carcinoma.

AIMS: Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS: We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P < 0.001), were smaller tumours (mean tumour size 2.1 cm versus 4.4 cm, P < 0.001), had a lower rate of gross extrathyroidal extension (0% versus 71%, P < 0.001), had a lower proliferative rate (≥3 mitoses per 10 high-power fields seen in 0% versus 71%, P < 0.001; Ki67 index ≥5% in 0% versus 86%, P < 0.001), a lower rate of secondary pathogenic mutations (for cases with molecular data, 0% versus 100%, P = 0.0061) and improved survival (for cases with sufficient clinical outcome data, 10-year disease-free survival of 93% versus 0%, P = 0.0016). CONCLUSION: Classic PTC can show ischaemic/degenerative atypia that mimics the hobnail cytomorphology of true hobnail variant; however, these tumours lack aggressive histopathological features and pursue an indolent clinical course.

Disease investigations for equine infectious anemia in Canada (2009-2012) - Retrospective evaluation and risk factor analysis.

This retrospective study describes the detection of equine infectious anemia (EIA) during Canadian Food Inspection Agency (CFIA) disease investigations in Canada, examines aspects of importance for disease control, and evaluates potential animal-level risk factors for EIA in high-risk horses. Based on review of all EIA-positive samples and all samples collected during disease investigations (N = 4553) over a 4-year period (2009 to 2012), 409 EIA cases were detected. Horse owners with EIA cases owned between 1 and 60 affected animals, and 49 horses seroconverted during a disease investigation period. Twenty-nine percent of cases (n = 68) for which this information was available had, or possibly had, clinical signs of EIA. Using a mixed effects logistic regression model, horses in older age groups were at greater odds of having a positive EIA status. The study emphasizes the importance of disease investigation activities when EIA is detected and identifies age as an animal-level risk factor in high-risk horses.

Enquêtes médicales pour l'anémie infectieuse équine au Canada (2009­2012) ­ Évaluation rétrospective et analyse des facteurs de risques. Cette étude rétrospective décrit la détection de l'anémie infectieuse équine (EIA) durant les enquêtes médicales de l'Agence canadienne d'inspection des aliments (CFIA) au Canada, examine les aspects importants pour la maitrise de la maladie, et évalue les facteurs de risque potentiels au niveau des animaux pour l'EIA chez les chevaux à risque élevé. Sur la base d'une revue de tous les échantillons positifs pour l'EIA et tous les échantillons prélevés durant les enquêtes (N = 4553) pendant une période de 4 ans (2009­2012), 409 cas d'EIA furent détectés. Les propriétaires de chevaux avec EIA possédaient entre 1 et 60 animaux affectés, et 49 chevaux ont séro-converti durant une période d'enquête. Vingt-neuf pourcents des cas (n = 68) pour lesquels l'information était disponible avaient, ou avaient possiblement eu, des signes cliniques d'EIA. Utilisant un modèle de régression logistique à effets mixtes, les chevaux des groupes d'animaux plus âgés étaient à plus grand risque d'avoir un statut positif pour l'EIA. Cette étude fait ressortir l'importance des activités d'enquêtes médicales lorsque l'EIA est détectée et identifie l'âge comme étant un facteur de risque au niveau de l'animal chez les chevaux à risque élevé.(Traduit par Dr Serge Messier).

Tall Cell Variant of Papillary Thyroid Carcinoma: Impact of Change in WHO Definition and Molecular Analysis.

The morphologic criteria for tall cell variant (TCV) of papillary thyroid carcinoma (PTC) were modified in the 2017 WHO Classification of Tumors of Endocrine Organs, with a decrease in the requirements for both the height of cells and in the percentage of tumor demonstrating a tall cell morphology. The aim of this study was to determine if the change in criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. In addition, we evaluated the correlation between morphology, molecular alterations, and clinical behavior of TCV. We studied three cohorts to evaluate the above stated questions. The first cohort was comprised of 97 PTC consecutively resected over a 12-month period that were originally diagnosed as classic PTC, PTC with tall cell features, or TCV. Tumor slides of each case were reviewed to determine the percentage of the tall cell component (< 30%, 30-49%, and > 50%) and the height of the cells in this component. This cohort was evaluated to determine if the change in WHO criteria would result in a significant increase in the percentage of tumors that meet criteria for TCV. Our second cohort consisted of nine consecutively resected PTC with a tall cell component > 30% (with tall cells defined as at least 2-3× as tall as wide) that had molecular characterization through a targeted, next-generation sequencing (NGS) assay. The molecular characteristics were correlated with the percentage of the tall cell component. Finally, a third cohort comprised of seven clinically aggressive TCV (defined as those with T4 disease, disease recurrence, or subsequent tumor dedifferentiation) was evaluated to determine histologic and molecular characteristics. In cohort 1, the number of cases classified as TCV increased significantly with the change in definition of TCV: 8 (8%) cases met the previous criteria for TCV (cells 3× as tall as wide in > 50% of the tumor), whereas 24 (25%) cases met the new 2017 WHO criteria (cells 2-3× as tall as wide in > 30% of the tumor) (p = 0.0020). Molecular analysis of cohort 2 revealed that all 9 cases harbored a BRAF V600E mutation. Pathogenic secondary mutations were absent in cases with < 50% tall cells, but they were detected in 2 (33%) of 6 cases with > 50% tall cells (2 cases with TERT promoter mutations, including 1 that also had an AKT2 mutation). Histologic and molecular analysis of the clinically aggressive cohort (cohort 3), revealed that all cases had > 50% tall cells and 3 (43%) had secondary oncogenic mutations (all TERT promoter mutations). We found that the modified morphologic criteria put forth in the 2017 WHO tripled the number of cases that would be classified as TCV. Moreover, clinically aggressive tumors and those harboring secondary oncogenic mutations all had a tall cell component > 50%. Additional large multi-institutional studies incorporating clinical outcome and molecular data would be valuable to determine the best histologic definition of TCV.

Applications of Immunohistochemistry to Endocrine Pathology.

The role of immunohistochemistry (IHC) in endocrine pathology is similar to that in other organ systems in that it can aid in the subclassification of tumors within an organ, confirm site of primary in metastatic disease, provide prognostic information, identify underlying genetic alterations, and predict response to treatment. Although most endocrine tumors do not require IHC to render a diagnosis, there are certain scenarios in which IHC can be extremely helpful. For example, in thyroid, IHC can be used to support tumor dedifferentiation, in the adrenal it can aid in the diagnosis of low-grade adrenocortical carcinomas, and in paragangliomas it can help identify tumors arising as part of an inherited tumor syndrome. This review will focus on the applications of IHC in tumors of the thyroid, parathyroids, adrenals, and paraganglia in adults.

A retrospective study of owner-requested testing as surveillance for equine infectious anemia in Canada (2009-2012).

This retrospective study was undertaken to estimate i) the surveillance coverage for equine infectious anemia (EIA) based on owner-requested testing, and ii) the incidence of case detection from this surveillance activity to inform a review of Canada's national disease control strategy. Based on sample submissions by accredited veterinarians to laboratories CFIA-approved for EIA testing between 2009 and 2012, the estimated national surveillance coverage was 14% for all years, and 72 cases of EIA were detected. The annual national incidence of EIA detection ranged from 0.03 to 0.08 cases/1000 horses. On average, a greater proportion of the horse population was tested in eastern Canada (32%) than in western Canada (6%, P < 0.0001). The cumulative incidence of EIA detection was higher in western Canada (0.25 cases/1000 horses) than in eastern Canada (0.02 cases/1000 horses, P < 0.0001). This study identified regional differences in owner-requested EIA testing and case detection resulting from this testing activity.

Étude rétrospective des tests demandés par les propriétaires comme surveillance pour l'anémie infectieuse équine au Canada (2009­2012). Cette étude rétrospective a été entreprise afin d'estimer i) la couverture de surveillance pour l'anémie infectieuse équine (AIE) basée sur les tests demandés par les propriétaires et ii) l'incidence de détection des cas à partir de cette activité de surveillance pour documenter un examen de la stratégie nationale de contrôle des maladies du Canada. L'estimation de la couverture nationale de surveillance, basée sur les soumissions d'échantillons par les vétérinaires autorisés aux laboratoires approuvés par l'ACIA pour l'AIE entre 2009 et 2012, était de 14 % pour toutes les années et 72 cas d'AIE ont été détectés. L'incidence nationale annuelle de la détection de l'AIE variait de 0,03 à 0,08 cas/1000 chevaux. En moyenne, une proportion supérieure de la population équine de l'Est du Canada (32 %) subissait des tests par rapport à l'Ouest canadien (6 %, P < 0,0001). L'incidence cumulative de la détection de l'AIE était supérieure dans l'Ouest canadien (0,25 cas/1000 chevaux) par rapport à l'Est du Canada (0,02 cas/1000 chevaux, P < 0,0001). Cette étude a identifié des différences régionales pour les tests de l'AIE demandés par les propriétaires et la détection des cas découlant de cette activité d'épreuve diagnostique.(Traduit par Isabelle Vallières).

Effect of pretreatment distress on daily fatigue after chemotherapy for breast cancer.

PURPOSE: Fatigue is one of the most frequently reported and adverse effects of cancer chemotherapy. The present study tested the hypothesis that women's levels of emotional distress at the time of their initial outpatient chemotherapy treatment would predict the severity of their postinfusion fatigue. METHODS: Sixty stage I (32.6%) and II (67.4%) patients with breast cancer (mean age, 44.5 years) who were receiving standard outpatient chemotherapy participated. The independent variable, emotional distress, was assessed for "last night," "this morning," and "right now" with a visual analog scale (0 to 100). The dependent variable, post-treatment fatigue (PTF), was assessed (0 to 100) over each of the subsequent 6 days using end-of-day diaries, which also included assessments of distress and nausea (0 to 100). For the statistical analyses, post-treatment fatigue was divided into three phases with means calculated for days 1 through 2 (phase 1), 3 to 4 (phase 2), and 5 to 6 (phase 3). RESULTS: Consistent with the study hypothesis, patients' pretreatment distress level in the clinic was a significant (P < .001) predictor of PTF. There was also a significant (P < .025) interaction with phase, with distress becoming a predictor of PTF after phase 1. Multivariate analysis indicated that prior levels of distress were not independent predictors of PTF. CONCLUSIONS: This study is the first to demonstrate time-specific effects of pretreatment distress on PTF. Possible mechanisms of these effects now warrant investigation, as do possible benefits of brief interventions to reduce patient distress immediately before treatment.

Distress before chemotherapy predicts delayed but not acute nausea.

INTRODUCTION: Posttreatment nausea (PTN) is a common side effect of cytotoxic cancer chemotherapy. Previous retrospective research has suggested that the severity of PTN may be, in part, related to pretreatment psychological factors (e.g., emotional distress and expectations for nausea). MATERIALS AND METHODS: The purpose of the present study was to examine these relationships prospectively, with distress and nausea expectations assessed by validated self-report measures completed in the clinic before the participants' first outpatient treatment infusion and with PTN (0-100) assessed by end-of-day diaries completed at home on each of the first 5 days after treatment. The participants were chemotherapy-naive women (N=56) scheduled for standard adjuvant treatment for stage I-II breast cancer (mean age=45.6 years). PTN was evaluated for acute (days 0-1) and delayed (days 2-5) responses. RESULTS: The results revealed a significant relationship between pretreatment distress and the severity of the patients' subsequent delayed nausea (p<0.007) but not a relationship with acute PTN (p<0.19). No significant relationships were seen between expectations and PTN. However, there was evidence of an additive effect of nausea expectations and distress, with the highest levels of delayed PTN seen in patients with both expectations and higher distress before treatment. The results suggest a selective effect of pre-infusion psychological variables on the delayed phase of nausea after chemotherapy, consistent with an emerging view that the different phases of nausea are mediated by different neural pathways. CONCLUSION: Future research should examine the possibility that delayed nausea, which the literature suggests is more resistant to antiemetic drugs than acute nausea, might be responsive to psychological interventions before initial treatments.