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Occupational lung/thoracic diseases are a major global public health issue. They comprise a diverse spectrum of health conditions with complex pathology, most of which arise following chronic heavy workplace exposures to various mineral dusts, metal fumes, or following inhaled organic particulate reactions. Many occupational lung diseases could become irreversible; thus accurate diagnosis is mandatory to minimize dust exposure and consequently reduce damage to the respiratory system. Lung biopsy is usually required when exposure history is inconsistent with imaging, in case of unusual or new exposures, in case of unexpected malignancy, and in cases in which there are claims for personal injury and legal compensation. In this paper, we provide an overview of the most frequent occupational lung diseases with a focus on pathological diagnosis. This is a paper that summarizes the expert opinion from a group of European pathologists, together with contributions from other specialists who are crucial for the diagnosis and management of these diseases. Indeed, tight collaboration of all specialists involved in the workup is mandatory as many occupational lung diseases are misdiagnosed or go unrecognized. This document provides a guide for pathologists in practice to facilitate the accurate diagnosis of occupational lung disease. The review article reports relevant topics discussed during an educational course held by expert pathologists, active members of the Pulmonary Pathology Working Group of the European Society of Pathology. The course was endorsed by the University of Padova as a "winter school" (selected project in the call for "Shaping a World-class University" 2022).
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The increasing incidence of multiple lung nodules underscores the need for precise differentiation between multiple primary lung cancers (MPLCs) and intrapulmonary metastases (IPMs). This distinction impacts patient prognosis and treatment strategies. The prevalence of multiple lung nodules, ranging from 19.7% to 55.5%, highlights the clinical significance of this challenge. Historically, the role of histopathology, particularly comprehensive histology assessment (CHA), has been pivotal in differentiating MPLCs and IPMs. However, CHA has significant limitations, resulting in a constant search for a better way to distinguish those lesions. The best strategy for delineating MPLCs from IPMs is a multidisciplinary approach combining clinical data, radiology, histology, and molecular methods. Histology provides architectural and cellular characteristics, radiology contributes anatomic context and lesion characterization, and molecular methods reveal molecular features critical for accurate differentiation. Incorporating clinical data further enhances diagnostic precision. This review presents current knowledge and current approaches to multiple lung tumors. It is clear that even with a combination of pathology, radiology, and molecular data, definitive classification of multifocal lung tumors is not always possible.
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Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Diagnosis, Differential , Neoplasms, Multiple Primary/pathology , Biomarkers, Tumor/analysisABSTRACT
Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-ß) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.
Subject(s)
Hypertension, Pulmonary , Myocytes, Smooth Muscle , Proteoglycans , Pulmonary Artery , Humans , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Proteoglycans/metabolism , Male , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Female , Middle Aged , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Vascular Remodeling , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Aged , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Biglycan/metabolism , Decorin/metabolism , Adult , Fibroblasts/metabolism , Fibroblasts/pathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Lumican/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix/pathologyABSTRACT
BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.
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Biomarkers, Tumor , Glucocorticoid-Induced TNFR-Related Protein , Hepatitis A Virus Cellular Receptor 2 , Immunotherapy , Lung Neoplasms , Neuroendocrine Tumors , Humans , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Lung Neoplasms/metabolism , Male , Female , Hepatitis A Virus Cellular Receptor 2/metabolism , Immunotherapy/methods , Neuroendocrine Tumors/immunology , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/therapy , Neuroendocrine Tumors/pathology , Middle Aged , Aged , Glucocorticoid-Induced TNFR-Related Protein/metabolism , Biomarkers, Tumor/metabolism , B7 Antigens/metabolism , Adult , Neoplasm Grading , OX40 Ligand/metabolism , Prognosis , Aged, 80 and overABSTRACT
Background and Objective: Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods: For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings: Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions: Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.
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CONTEXT.: Mesothelioma is an uncommon tumor that can be difficult to diagnose. OBJECTIVE.: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. DATA SOURCES.: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS.: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.
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BACKGROUND: The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. METHODS: We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%-49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue. RESULTS: 395 consecutive patients with stages I-III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups. CONCLUSION: PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , B7-H1 Antigen/metabolism , Retrospective Studies , Neoplasm Recurrence, Local , RecurrenceABSTRACT
PURPOSE: Despite prognostic superiority of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), up to 25% of patients will suffer from recurrence within the first 5 years. Therefore, it is of great scientific interest to find relevant biomarkers to identify patients at risk. In this prospective observational study, we aimed to investigate the dynamics of HPV-L1 capsid protein specific antibody (AB) subclasses IgA, IgM, and IgG in HPV-positive OPSCC patients under therapy. METHODS: Serum samples from HPV-positive OPSCC patients, identified by positive p16-immunohistochemistry, were collected before and during tumor-specific therapy and 3-6 months during follow-up. They were analyzed for the presence of HPV-L1 AB subclasses IgA, IgM, and IgG using an HPV-L1-specific immuno-assay. Additionally, a PCR-based HPV-DNA detection from the tumor tissue was performed. RESULTS: Altogether, 33 patients with a mean follow-up of 55 months were included. Analysis of a total of 226 serum samples revealed that the most common L1-AB-subclass pattern was characterized by IgG > > IgA > IgM without significant fluctuation during the course of disease. Patients with excessive IgG levels tended to higher tumor stages and three out of three patients with disease recurrence showed increasing IgG AB titers beforehand. Seven patients showed an IgA dominance at diagnosis, which was associated with a better disease-free survival. CONCLUSION: Despite limited cases, our prospective pilot study revealed promising trends in HPV L1 AB subclasses and may contribute useful information for future risk stratification and post-treatment monitoring in HPV-positive OPSCC patients.
Subject(s)
Oropharyngeal Neoplasms , Papillomavirus Infections , Squamous Cell Carcinoma of Head and Neck , Humans , Capsid Proteins , Immunoglobulin G , Immunoglobulin M , Neoplasm Recurrence, Local/complications , Oropharyngeal Neoplasms/pathology , Papillomavirus Infections/complications , Pilot Projects , Prognosis , Prospective Studies , Squamous Cell Carcinoma of Head and Neck/complicationsABSTRACT
Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.
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In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.
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For patients with advanced stage non-small cell lung cancer (NSCLC), treatment strategies have changed significantly due to the introduction of targeted therapies and immunotherapy. In the last few years, we have seen an explosive growth of newly introduced targeted therapies in oncology and this development is expected to continue in the future. Besides primary targetable aberrations, emerging diagnostic biomarkers also include relevant co-occurring mutations and resistance mechanisms involved in disease progression, that have impact on optimal treatment management. To accommodate testing of pending biomarkers, it is necessary to establish routine large-panel next-generation sequencing (NGS) for all patients with advanced stage NSCLC. For cost-effectiveness and accessibility, it is recommended to implement predictive molecular testing using large-panel NGS in a dedicated, centralized expert laboratory within a regional oncology network. The central molecular testing center should host a regional Molecular Tumor Board and function as a hub for interpretation of rare and complex testing results and clinical decision-making.
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BACKGROUND: In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs. METHODS: We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors. RESULTS: We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = -0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH. CONCLUSIONS: End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD.
Subject(s)
Hypertension, Pulmonary , Pulmonary Artery , Pulmonary Disease, Chronic Obstructive , Severity of Illness Index , Vascular Remodeling , Humans , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/pathology , Male , Female , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/etiology , Middle Aged , Vascular Remodeling/physiology , Aged , Pulmonary Artery/pathology , Pulmonary Artery/physiopathology , Airway Remodeling/physiology , Lung/physiopathology , Lung/pathology , Retrospective StudiesABSTRACT
Squamous cell lung carcinoma (SqCLC) is associated with high mortality and limited treatment options. Identification of therapeutic targets and prognostic biomarkers is still lacking. This research aims to analyze the transcriptomic profile of SqCLC samples and identify the key genes associated with tumorigenesis, overall survival (OS), and a profile of the tumor-infiltrating immune cells. Differential gene expression analysis, pathway enrichment analysis, and Gene Ontology analysis on RNA-seq data obtained from FFPE tumor samples (N = 23) and healthy tissues (N = 3) were performed (experimental cohort). Validation of the results was conducted on publicly available gene expression data using TCGA LUSC (N = 225) and GTEx healthy donors' cohorts (N = 288). We identified 1133 upregulated and 644 downregulated genes, common for both cohorts. The most prominent upregulated genes were involved in cell cycle and proliferation regulation pathways (MAGEA9B, MAGED4, KRT, MMT11/13), while downregulated genes predominately belonged to immune-related pathways (DEFA1B, DEFA1, DEFA3). Results of the survival analysis, conducted on the validation cohort and commonly deregulated genes, indicated that overexpression of HOXC4 (p < 0.001), LLGL1 (p = 0.0015), and SLC4A3 (p = 0.0034) is associated with worse OS in early-stage SqCLC patients. In contrast, overexpression of GSTZ1 (p = 0.0029) and LILRA5 (p = 0.0086) was protective, i.e., associated with better OS. By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters.
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BACKGROUND: When obtaining specimens from pulmonary nodules in TBLB, distinguishing between benign samples and mis-sampling from a tumor presents a challenge. Our objective is to develop a machine-learning-based classifier for TBLB specimens. METHODS: Three pathologists assessed six pathological findings, including interface bronchitis/bronchiolitis (IB/B), plasma cell infiltration (PLC), eosinophil infiltration (Eo), lymphoid aggregation (Ly), fibroelastosis (FE), and organizing pneumonia (OP), as potential histologic markers to distinguish between benign and malignant conditions. A total of 251 TBLB cases with defined benign and malignant outcomes based on clinical follow-up were collected and a gradient-boosted decision-tree-based machine learning model (XGBoost) was trained and tested on randomly split training and test sets. RESULTS: Five pathological changes showed independent, mild-to-moderate associations (AUC ranging from 0.58 to 0.75) with benign conditions, with IB/B being the strongest predictor. On the other hand, FE emerged to be the sole indicator of malignant conditions with a mild association (AUC = 0.66). Our model was trained on 200 cases and tested on 51 cases, achieving an AUC of 0.78 for the binary classification of benign vs. malignant on the test set. CONCLUSION: The machine-learning model developed has the potential to distinguish between benign and malignant conditions in TBLB samples excluding the presence or absence of tumor cells, thereby improving diagnostic accuracy and reducing the burden of repeated sampling procedures for patients.
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AIMS: Mesothelioma is a rare malignancy of the serosal membranes that is commonly related to exposure to asbestos. Despite extensive research and clinical trials, prognosis to date remains poor. Consistent, comprehensive and reproducible pathology reporting form the basis of all future interventions for an individual patient, but also ensures that meaningful data are collected to identify predictive and prognostic markers. METHODS AND RESULTS: This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the international consensus mesothelioma reporting data set. It describes the 'core' and 'non-core' elements to be included in pathology reports for mesothelioma of all sites, inclusive of clinical, macroscopic, microscopic and ancillary testing considerations. An international expert panel consisting of pathologists and a medical oncologist produced a set of data items for biopsy and resection specimens based on a critical review and discussion of current evidence, and in light of the changes in the 2021 WHO Classification of Tumours. The commentary focuses particularly upon new entities such as mesothelioma in situ and provides background on relevant and essential ancillary testing as well as implementation of the new requirement for tumour grading. CONCLUSION: We recommend widespread and consistent implementation of this data set, which will facilitate accurate reporting and enhance the consistency of data collection, improve the comparison of epidemiological data, support retrospective research and ultimately help to improve clinical outcomes. To this end, all data sets are freely available worldwide on the ICCR website (www.iccr-cancer.org/data-sets).
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Mesothelioma, Malignant , Mesothelioma , Pathology, Clinical , Humans , Peritoneum , Pleura , Retrospective Studies , Mesothelioma/diagnosis , Pericardium , Pathology, Clinical/methodsABSTRACT
Background and Objective: Mediastinal lesions are uncommon. However, because of the vital structures in the mediastinum, large lesions specifically can lead to life-threatening situations. Treatment and management vary considerably with the disease. Therefore, the correct histopathologic diagnosis is important. Here we review lesions that have the potential to present as a giant lesion in the mediastinum. While we focus on the review of histopathologic, immunohistochemical (IHC), and molecular features of these lesions, clinical symptoms and characteristics and prognosis will also be discussed. Methods: "Giant" was arbitrarily defined as a size of at least 10 cm in greatest dimension. The 2021 World Health Organization (WHO) classification of mediastinal tumors was searched for tumors reported to be larger than 10 cm. Tumors that can present as giant mediastinal lesions based on our own experience were also included. PubMed search was then performed for these lesions. Key Content and Findings: A great variety of mediastinal lesions can present as giant mass. Those include for instance tumors of blood and lymph vessels, tumors of neurogenic origin, mesenchymal neoplasms, thymic epithelial tumors (TETs), and non-neoplastic cysts. Lesions range from benign to malignant. This review focuses on the most common lesions. Conclusions: Many benign and malignant lesions can become a large mass in the mediastinum. Their correct diagnosis is important for the treatment and management of the patient.
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Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth. Methods: In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction. Results: Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity. Conclusions: MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.
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The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the "conditional inference tree" (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies.
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The histopathologic distinction of lung adenocarcinoma (LADC) subtypes is subject to high interobserver variability, which can compromise the optimal assessment of patient prognosis. Therefore, this study developed convolutional neural networks capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the recently established LADC tumor grades. Consensus LADC histopathologic images were obtained from 17 expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained to predict eight different LADC classes. Furthermore, the trained models were tested on an independent cohort of 133 patients. The models achieved high precision, recall, and F1 scores exceeding 0.90 for most of the LADC classes. Clear stratification of the three LADC grades was reached in predicting the disease-specific survival by the two models, with both Kaplan-Meier curves showing significance (P = 0.0017 and 0.0003). Moreover, both trained models showed high stability in the segmentation of each pair of predicted grades with low variation in the hazard ratio across 200 bootstrapped samples. These findings indicate that the trained convolutional neural networks improve the diagnostic accuracy of the pathologist and refine LADC grade assessment. Thus, the trained models are promising tools that may assist in the routine evaluation of LADC subtypes and grades in clinical practice.