COVID-19 lung injury is a common manifestation of severe illness. Lung tissue examination has been largely derived from autopsy - a combination of case reports, small and moderately sized series with ...international scope. Common and uncommon histopathology provides insight into the progression of severe, fatal disease.
COVID-19 lung histology is most commonly diffuse alveolar damage as part of acute respiratory distress syndrome. Lung injury can be temporally heterogeneous, with patterns of healing alongside new injury. Viral studies, including immunohistochemistry, RNA in-situ hybridization, and tissue-based Polymerase chain reaction (PCR) assist in discerning complications of therapy (e.g. ventilator-associated pneumonia) from primary viral-induced injury. Response to viral infection produces systemic effects, and one major manifestation is thrombosis of micro-circulation and larger vessels. Less common patterns include neutrophil-rich inflammation, raising speculation that neutrophil extra-cellular traps may play a role in both viral control and exaggerated immune response.
The heterogeneity of fatal cases- persistence of viral infection in lung, clearance of virus but severe lung injury, thrombosis, and exaggerated immune response - suggest that antiviral, antithrombotic, anti-inflammatory, and supportive therapy play a role in treatment, but that the patient-specific cause and timing of the lung injury is important in choosing intervention.
The pathologic evaluation of lung adenocarcinoma, because of greater understanding of disease progression and prognosis, has become more complex. It is clear that histologic growth patterns reflect ...indolent and aggressive disease, resulting in clearer morphologic groups that can be the underpinning of a grading system. In addition, the progression of adenocarcinoma from a tumor that preserves alveolar architecture to one that remodels and effaces lung structure has led to criteria that reflect invasive rather than in-situ growth. While some of these are based on tumor cell growth pattern, aspects of this remodeling from desmoplasia to artifacts of lung collapse and sectioning, can lead to difficult to interpret patterns with lower reproducibility between observers. Such scenarios are examined to provide updates on new histologic concepts and to highlight ongoing problem areas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite tremendous progress in the last decade, lung adenocarcinoma still represents a tumor with unfavorable prognosis when detected at advanced clinical stage. High-stage tumors are not amenable to ...surgical resection, and therefore systemic therapies are needed to control these tumors to prolong patient survival. In the era of molecular and personalized therapeutics, the discovery of mutations in epidermal growth factor receptor (EGFR) in 15–20% of lung adenocarcinomas and the associated response to EGFR-targeting tyrosine kinase (TK) inhibitors have provided a successful avenue of attack in high-stage adenocarcinomas. In this review, we will provide an overview of the EGFR pathway, review the significant somatic EGFR alterations in lung adenocarcinoma and highlight their implications for treatment. In addition, we will examine pathways by which tumors resist EGFR TK therapy, both as primary nonresponders and by acquired resistance. In doing so, we will examine other oncogenic pathways whose status in tumor samples may impact therapeutic responses despite presence of activating EGFR mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The 2021 WHO Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, ...supported by immunohistochemistry, and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are (1) broader emphasis on genetic testing than in the 2015 WHO Classification; (2) a section entirely dedicated to the classification of small diagnostic samples; (3) continued recommendation to document percentages of histologic patterns in invasive nonmucinous adenocarcinomas, with utilization of these features to apply a formal grading system, and using only invasive size for T-factor size determination in part lepidic nonmucinous lung adenocarcinomas as recommended by the eighth edition TNM classification; (4) recognition of spread through airspaces as a histologic feature with prognostic significance; (5) moving lymphoepithelial carcinoma to squamous cell carcinomas; (6) update on evolving concepts in lung neuroendocrine neoplasm classification; (7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor as a new entity within the adenoma subgroup; (8) recognition of thoracic SMARCA4-deficient undifferentiated tumor; and (9) inclusion of essential and desirable diagnostic criteria for each tumor.
Abstract
Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe ...pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity. Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of “thrombo-inflammation”. These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. The purpose of this review is to discuss the pathogenesis underlying organ damage that can occur in patients with SARS-CoV-2 infection. Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This study presents data on a pathway of early adenocarcinogenesis of the lung, demonstrating the effect of lipocalin-2 on the development of KRAS-mutated lung adenocarcinoma (KM-LUAD) and suggesting ...that airways damaged by chronic obstructive pulmonary disease (COPD) show the effect of a high-lipocalin-2 microenvironment. Their experiments were based on an observed elevation of Lcn2 in the nonneoplastic airways of mice with knockout of Gprc5a followed by studies examining lipocalin-2 in these mice exposed to tobacco carcinogen, increased tumor development in Lcn^2-/- mice, and translation into human tissues with COPD and LUAD. Although LUAD showed an increase in lipocalin-2, the authors show through their mouse model that loss of lipocalin-2 reduced antitumoral immune responses and enhanced a protumoral immune environment, such that the loss of Lcn2 enhanced tumor formation. In addition, the upregulation of LCN2 was seen in COPD airways when compared with smokers without COPD but importantly included elevation in KM-LUAD from patients with COPD.
Recent studies have provided insights into the pathology of and immune response to COVID-19
. However, a thorough investigation of the interplay between infected cells and the immune system at sites ...of infection has been lacking. Here we use high-parameter imaging mass cytometry
that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses-possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil ...extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.
•NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.•nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To further understand the molecular pathogenesis of pulmonary sarcomatoid carcinoma (PSC) and develop new therapeutic strategies in this treatment-refractory disease.
Whole-exome sequencing in a ...discovery set (n = 10) as well as targeted MET mutation screening in an independent validation set (n = 26) of PSC were performed. Reverse transcriptase polymerase chain reaction and Western blotting were performed to validate MET exon 14 skipping. Functional studies for validation of the oncogenic roles of MET exon 14 skipping were conducted in lung adenosquamous cell line H596 (MET exon 14 skipped and PIK3CA mutated) and gastric adenocarcinoma cell line Hs746T (MET exon 14 skipped). Response to MET inhibitor therapy with crizotinib in a patient with advanced PSC and MET exon 14 skipping was evaluated to assess clinical translatability.
In addition to confirming mutations in known cancer-associated genes (TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1), several novel mutations in additional genes, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2, were identified and validated. MET mutations leading to exon 14 skipping were identified in eight (22%) of 36 patient cases; one of these tumors also harbored a concurrent PIK3CA mutation. Short interfering RNA silencing of MET and MET inhibition with crizotinib showed marked effects on cell viability and decrease in downstream AKT and mitogen-activated protein kinase activation in Hs746T and H596 cells. Concurrent PIK3CA mutation required addition of a second agent for successful pathway suppression and cell viability effect. Dramatic response to crizotinib was noted in a patient with advanced chemotherapy-refractory PSC carrying a MET exon 14 skipping mutation.
Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in PSC.