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Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Two cases of myopericytosis combined with pericytoma originating within the lung are reported. These are rare pulmonary tumors. The differential diagnosis for hemangiopericytoma and pericytic tumors with glomus elements is discussed. Both myopericytic lesions mimic other lesions, which are more commonly seen in the lung. Based on the expression of vascular growth factor receptors 2 and 3, an antiangiogenic therapy was suggested for the patient with the myopericytoma. A treatment with an angiogenesis inhibitor resulted in a regression of the tumor, but not the precursor lesion. Probably a more specific therapy using tyrosine kinase inhibitors for VEGFR2/3 might better control these myopericytic proliferations.

Gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PCK2), promotes anabolic metabolism in lung cancer cells in the absence of glucose. Here we show considerable heterogeneity of the utilization of gluconeogenesis or glycolysis in human non‐small cell lung cancers (NSCLC) and NSCLC metastases and a localization of PCK2 at tumor margins. We identify hypoxia as an important modulator of both pathways in NSCLC cells., Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non‐small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3‐dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co‐activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.

Patients with lung cancer in the majority die of metastases. Treatment options include surgery, chemo- and radiotherapy, targeted therapy by tyrosine kinase inhibitors (TKIs), and immuno-oncologic treatment. Despite the success with these treatment options, cure of lung cancer is achieved in only a very small proportion of patients. In most patients' recurrence and metastasis will occur, and finally kill the patient. Metastasis is a multistep procedure. It requires a change in adhesion of tumor cells for detachment from their neighboring cells. The next step is migration either as single cells [epithelial-mesenchymal transition (EMT)], or as cell clusters (hybrid-EMT or bulk migration). A combination of genetic changes is required to facilitate migration. Then tumor cells have to orient themselves along matrix proteins, detect oxygen concentrations, prevent attacks by immune cells, and induce a tumor-friendly switch of stroma cells (macrophages, myofibroblasts, etc.). Having entered the blood stream tumor cells need to adapt to shear stress, avoid being trapped by coagulation, but also use coagulation in small veins for adherence to endothelia, and express homing molecules for extravasation. Within a metastatic site, tumor cells need a well-prepared niche to establish a metastatic focus. Tumor cells again have to establish a vascular net for maintaining nutrition and oxygen supply, communicate with stroma cells, grow out and set further metastases. In this review the different steps will be discussed with a focus on pulmonary carcinomas. The vast amount of research manuscripts published so far are not easy to analyze: in most reports' single steps of the metastatic cascade are interpreted as evidence for the whole process; for example, migration is interpreted as evidence for metastasis. In lung cancer most often latency periods are shorter, in between 1-5 years. In other cases, despite widespread migration occurs, tumor cells die within the circulation and do not reach a metastatic site. Therefore, migration is a requisite, but does not necessarily predict metastasis. The intention of this review is to point to these different aspects and hopefully provoke research directed into a more functional analysis of the metastatic process.

Background: Since the advent of targeted therapy in lung cancer, in settings where it is not possible to send for molecular testing of lung adenocarcinoma, immunohistochemistry for EGFR mutation-specific antibodies can be used as an alternative for detection of EGFR mutation. Materials and methods: 50 lung adenocarcinoma cases were screened at the Medical University of Graz. 19 cases in which molecular test as well as immunohistochemistry were positive for EGFR mutation. Cases where immunohistochemistry results and molecular test for the E-746-A750 deletion and the L858 mutation were positive, were considered true positives. Similarly, false positives, true negatives, and false negatives were determined. Results: The mean age of the patients was 78.6 yrs. Among 19 cases, 7 were positive for E-746-A750 deletion (7/19, 36%), among which 4 cases also showed positivity with IHC. 4 were positive for the L858 mutation (4/19, 21%), among which 3 also showed positivity with immunohistochemistry. The rest of the 8 cases were positive for EGFR mutation in other loci. The sensitivity and specificity of the immunohistochemistry test of antibody specific to E-746-A750 exon 19 deletion was 100% and 80% respectively. The sensitivity and specificity of the IHC test of Ab specific to L858 mutation was 75%, and 100% respectively. Conclusions: Our results have been comparable to previous studies. However, our sample size was a limitation. It can still be concluded that immunohistochemistry can be a diagnostic option in low resource settings, and can aid in ensuring that patients with a positive antibody test get targeted therapy.

Background Fibrosing pneumonias are a group of interstitial lung diseases with a different etiologic background and divergent prognosis. They are differentiated into usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), and organizing pneumonia (OP). Some of these entities were initially described by A. Liebow. Main In the 90ties the main differences in survival lead to the separation of UIP/IPF as a disease with dismal outcome, from the prognostically better NSIP and OP. Later it was shown that fibrosing NSIP confers an almost identical worse prognosis. Under the heading of pulmologists a classification was created, where the diagnosis has to be established by a multidisciplinary team, based on pattern recognition done by radiologists and pathologists. A clinical diagnosis has to be established based on the patterns: UIP pattern was the basis for IPF, NSIP pattern for the clinical diagnosis NSIP, and organizing pneumonia pattern for the diagnosis of cryptogenic organizing pneumonia. This created confusion, because the pattern UIP was taken almost as synonymous with idiopathic pulmonary fibrosis (IPF). Later on in many articles and classifications the role of the pathologic diagnosis was diminished, because pulmologists based their diagnosis on CT-scan and clinical presentation. This resulted in less tissue biopsies but also delay and misinterpretation of diseases. Even new techniques in tissue biopsies such as cryobiopsy was regarded as unnecessary. Conclusion Tissue analysis in fibrosing pneumonias is still the gold standard in making a diagnosis and also evaluating the etiologic background. After an analysis the findings should be discussed in a multidisciplinary board to establish a final diagnosis and a treatment option for the patient.

Congenital pulmonary airway malformation (CPAM) occurs most commonly in infants. It is divided into 5 types. The most common types 1 and 2 are cystic, type 0 presents as bronchial buds without alveolar tissue, most likely corresponding to alveolar dysgenesis, while type 3 is composed of branching bronchioles and appears as a solid lesion. A defect in the epithelial-mesenchymal crosstalk might be the underlying mechanism for all. Type 4 is a peripheral cystic lesion with a thin cyst wall covered by pneumocytes. CPAM 4 has been mixed up with pleuropulmonary blastoma (PPB) type I and some authors question its existence. We investigated five cases of CPAM type 4 for the presence or absence of rhabdomyoblasts, and for markers associated with CPAM development. In addition, all cases were evaluated for mutations within the Dicer gene and for mutations of the RAS family of oncogenes. All five cases showed smooth muscle actin and desmin-positive cells; however, only one case showed a few cells positive for MyoD. The same case showed a mutation of Dicer 1. All cases were negative for mutations of the RAS family of genes. Fibroblast growth factor 10 was similarly expressed in all cases, and thus cannot be used to differentiate CPAM4 from PPB-I. Low expression of the proliferation marker Ki67 was seen in our CPAM 4 cases and the probable PPB-I case. YingYang-1 protein seems to play an active role in the development of PPB-I. CPAM 4 can be separated from PPB-I based on the presence of rhabdomyoblasts and mutations in Dicer 1 gene. These cells might not be numerous; therefore, all available tissue has to be evaluated. As CPAM 4 morphologically looks very similar to PPB-I, it might be speculated, that there exists a potential for progression from CPAM 4 to PPB-I, by acquiring somatic mutations in Dicer 1.

The knowledge on molecular alterations in lung cancer have increased during the last decade considerably. Almost every year new genes were detected being targetable, and drugs have been developed and provided for those patients being diagnosed with such a lung cancer. Therefore, it was necessary to update previous recommendations to facilitate a uniform handling for the diagnosis and molecular tests of lung cancer specimen all over Austria. Originally mutation of the epidermal growth factor receptor (EGFR) was the only actionable molecular alteration, now there are more than 10 driver mutations known, and more are detected, and clinical studies are performed. In addition, the technique to test for these mutations have improved, next generation sequencing has opened the option to test several genes in one test. Immuno-oncology has entered the field, and besides the checkpoint death receptor and ligand molecules PD-1/PD-L1 more molecules have been detected and are also tested in clinical studies. To provide equal opportunities to our patients the tests have to be implemented in all pathological institutes involved in lung cancer management. Because pathologists as part of the tumor board have to explain the diagnosis and the molecular alterations and suggest possible treatment options, the tests should be performed in-house, which will provide the optimal quality control.

Lung involvement in autoimmune diseases (AID) is uncommon, but may precede other organ manifestations. A diagnostic problem is chronicity presenting with lung fibrosis. A new category of interstitial pneumonia with autoimmune features for patients with clinical symptoms of AID and presenting with usual interstitial pneumonia (UIP) enables antifibrotic treatment for these patients. Hypersensitivity pneumonia (HP) and other forms of lung fibrosis were not included into this category. As these diseases based on adverse immune reactions often present with unspecific clinical symptoms, a specified pathological diagnosis will assist the clinical evaluation. We aimed to establish etiology-relevant differences of patterns associated with AID or HP combined with lung fibrosis. We retrospectively evaluated 51 cases of AID, and 29 cases of HP with lung fibrosis, and compared these to 24 cases of idiopathic pulmonary fibrosis (UIP/IPF). Subacute AID and HP most often presented with organizing pneumonia (OP), whereas chronicity was associated with UIP. Unspecified fibrosis was seen in a few cases, whereas NSIP pattern was rare. In 9 cases, the underlying etiology could not be defined. Statistically significant features differentiating chronic AID or HP from UIP/IPF are lymphocytic infiltrations into myofibroblastic/fibroblastic foci. Other features significantly associated with AID and HP were granulomas, isolated Langhans giant cells, and protein deposits, but seen in only a minority of cases. A combination of UIP with one of these features enabled a specific etiology-based diagnosis. Besides the antifibrotic drug regimen, additional therapies might be considered.

Large cell neuroendocrine carcinoma (LCNEC) together with small cell carcinoma (SCLC) and typical and atypical carcinoids form the group of pulmonary neuroendocrine tumors. LCNEC and SCLC are high-grade carcinomas. Although both can be found outside the thoracic cavity, they are most common in the lung. LCNEC differs from SCLC by morphologic pattern, and by cytological features such as nuclear size, nucleoli, chromatin pattern, but also by genetic differences. Originally thought to represent a single entity, it became evident, that three subgroups of LCNEC can be identified at the molecular level: a SCLC-like type with loss of retinoblastoma 1 gene (RB1) and TP53 mutations; a non-small cell lung carcinoma (NSCLC)-like type with wildtype RB1, TP53 mutation, and activating mutations of the phosphoinositol-3 kinase (PI3K-CA), or loss of PTEN; and a carcinoid-like type with MEN1 gene mutation. These subtypes can be identified by immunohistochemical staining for RB1, p53, and molecular analysis for PI3K and MEN1 mutations. These subtypes might also respond differently to chemotherapy. Immuno-oncologic treatment has also been applied to LCNEC, however, in addition to the evaluation of tumor cells the stroma evaluation seems to be important. Based on personal experiences with these tumors and available references this review will try to encompass our present knowledge in this rare entity and provoke new studies for better treatment of this carcinoma.

INTRODUCTION: The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems. METHODS: One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features. RESULTS: Whole-genome sequencing data fell into three clusters: CNIlow, CNIint, and CNIhigh. CNIlow and CNIint comprised not only TC and AC, but also six LCNECs. CNIhigh contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). CONCLUSIONS: TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication. peerReviewed

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA). Five early LUAD-specific lncRNAs were filtered out, and only SBF2-AS1 was upregulated in LUAD. High expression of SBF2-AS1 indicates poor survival of LUAD, especially the early-stage LUAD, but not lung squamous cell carcinoma. SBF2-AS1 promotes LUAD cells proliferation in vitro, and RNA-sequencing data shows that many cell-cycle-related genes were downregulated after SBF2-AS1 knockdown. Mechanically, SBF2-AS1 could competitively bind with miR-338-3p and miR-362-3p to increase E2F1 expression. Finally, we show that the SBF2-AS1-miR-338-3p/362-3p-E2F1 axis could promote LUAD tumorigenesis in vitro and in vivo. Our study demonstrates that SBF2-AS1, an early-stage-specific lncRNA, promotes LUAD tumorigenesis by sponging miR-338-3p and miR-362-3p and increasing E2F1 expression. The SBF2-AS1-miR-338-3p/362-3p-E2F1 regulatory axis may serve as a prognostic marker and potential therapeutic target for LUAD. Keywords: WGCNA, lung adenocarcinoma, tumorigenesis, ceRNA, SBF2-AS1, lncRNA

Background Despite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant). Materials and methods Twenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1–3 fractions of 10–12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy. Results At the time of analysis, with median follow-up of 9.4 months (range: 4–20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30–100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30–100%). No patient experienced acute or late toxicity of any grade. Conclusions SBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial. Present study has been retrospectively registered by the local ethic committee under study number A 26/18.

In the last two decades, various therapies have been introduced for lung carcinoma patients, including tyrosine-kinase inhibitors for different mutations. While some of them are specific to specific tumor types, others, like NTRK1–3 fusions, are found in various solid tumors. The occurrence of an NTRK1,2 or 3 fusion acts as a biomarker for efficient treatment with NTRK inhibitors, irrespectively of the tumor type. However, the occurrence of the NTRK1–3 fusions in lung carcinomas is extremely rare. We performed a retrospective analysis to evaluate the applicability of immunohistochemistry with the pan-TRK antibody in the detection of NTRK fusions in lung carcinomas. The study cohort included 176 adenocarcinomas (AC), 161 squamous cell carcinomas (SCC), 31 large-cell neuroendocrine carcinomas (LCNEC), and 19 small cell lung carcinomas (SCLC). Immunohistochemistry (IHC) was performed using the pan-TRK antibody (clone EPR17341, Ventana) on tissue microarrays, while confirmation for all positive cases was done using RNA-based Archer FusionPlex MUG Lung Panel. On IHC staining, 12/387 samples (3.1%) demonstrated a positive reaction. Ten SCC cases (10/161, 6.2%), and two LCNEC cases (2/31, 6.5%) were positive. Positive cases demonstrated heterogeneous staining of tumor cells, mostly membranous with some cytoplasmic and in one case nuclear pattern. RNA-based sequencing did not demonstrate any NTRK1–3 fusion in our patients’ collective. Our study demonstrates that pan-TRK expression in lung carcinoma is very low across different histologic types. NTRK1–3 fusions using an RNA-based sequencing approached could not be detected. This stresses the importance of confirmation of immunohistochemistry results by molecular methods.

Background Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance. Methods Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot. Expression of β-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/β was evaluated by western blot and IHC. Results Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxol-resistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelial-mesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-catenin signaling pathway. Conclusions Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

The lung develops from the foregut. At the highness of the later larynx, the single tube splits into two buds for the esophagus and the lower respiratory tract, the “Lungenanlage” [1] (around gestational week 4). Out of this primitive bud, the larynx and the trachea develop, and the trachea finally separates into two bronchial buds. As in general, organogenesis recapitulates also the developmental stages of mammalian lung: a bronchial bud is also formed for a possible mediastinal lobe, as it is found in sheep, swine, and other mammalians. If this bud persists, a median mediastinal bronchial cyst can result [2]. Supernumerary buds are usually deleted by apoptotic mechanisms [3, 4]. Sometimes these buds can give rise to communications with the esophagus [5] or also to bronchogenic cysts [2, 6].

Pediatric pulmonary pathology is a challenging topic within pathology. There are several reasons, such as diseases of the lung are rare. Most pulmonary diseases within childhood are infections, which do not need a tissue analysis. Lung diseases in childhood do occur in two peaks: the first during the first 2 years of life, the second usually at the “Kindergarden” age. The first group comprises many developmental lung diseases, whereas the second group includes diseases based on gene mutations, immune system dysfunction, and infections. For the analysis of pediatric pulmonary diseases, the knowledge of lung development is essential, and the analysis of genetic abnormalities is becoming important.

Here, we will discuss autoimmune diseases and diseases based on a hyperreactive immune system, the so-called allergic diseases. A few other diseases based on gene mutations will be included here, as they mimick autoimmune diseases. In autoimmune-induced interstitial lung disease, many different factors come together: a wide variety of immune reactions can cause a wide variety of tissue reactions, for example, circulating autoantibodies either capable or devoid of complement activation, circulating immune complexes including large insoluble immune complexes formed by idiotypic–anti-idiotypic antibody networks, activation of coagulation, metabolism of pro-inflammatory substances, involvement of different types of leukocytes, and not the least, drugs given for the relieve of symptoms. These drugs themselves can cause toxic or inflammatory side effects. Another aspect in autoimmune diseases lies within its dynamic: an acute phase is changed into a phase with declining symptoms, going into a resolving stage, again starting acute, but also can progress into a subacute and chronic phase. Each of these phases will be accompanied by a different histology.

Hyperreactivity is known in bronchial asthma and chronic obstructive pulmonary disease (COPD), however, the mechanisms are not fully understood. In chronic bronchitis micronodular proliferations of Schwann cells were found, pointing to a degenerative process, but the affected nerves are unknown. Degeneration of nerves probably occur in usual interstitial pneumonia (UIP) too. Nerves are either adrenergic or cholinergic, and those with non-adrenergic, non-cholinergic (NANC) receptors. Mediators can be excitatory, or inhibitory. Sensory nerves are stretch-sensitive, and touch-sensitive nociceptors and C-fibers. We analyzed nerves in tissues from COPD and UIP cases. Cases of asthma served as controls. Antibodies for different nerve types and receptors were used: nicotinic acetylcholine receptor a (NARa), NMDAR1, tyrosine hydrolase (TH), dopamine transporter, a1adrenergic receptor (aAR), CGRP, iNOS, GABA transporter1 (GABA1), substance P (SP). The presence of nerve fibers was demonstrated by immunohistochemistry for S100 protein and neurofilament. Vacuolar degeneration of nerves with micronodular proliferation of Schwann cells was seen in asthma and COPD but not in UIP. Nerve fibers in COPD and asthma stained for NARa, NMDAR1, TH, and GABA1. In degenerated nerves NARa, aAR, and GABA1 were positive in asthma, whereas aAR was negative in COPD. Positivity for SP was seen in COPD, but not in asthma. In UIP no degeneration of nerves was seen in the central bronchial system, but a loss in the periphery. There are differences and similarities between COPD and asthma, well known in the clinics, however different nerves are affected by degeneration in these diseases.

Idiopathic pulmonary fibrosis (IPF) is a disease with a dismal prognosis. Currently, the causing agent(s) are poorly understood. Recent data suggest that senescence and autophagy might play a role in its development, as well as changes in metabolism due to hypoxic conditions. In this study, the expression of senescence markers in 23 cases of usual interstitial pneumonia (UIP)/IPF and UIP/chronic autoimmune diseases (UIP/AuD) was investigated. The status of autophagy was evaluated with respect to either antiinflammatory or antihypoxia function. Formalin-fixed paraffin-embedded tissues of UIP were selected for immunohistochemistry with antibodies for p21, p16, and β-galactosidase (senescence); for LC3, SIRT1, MAP1S, and pAMKα (autophagy); and for LDH and GLUT1 (metabolism). Epithelial cells in cystic remodeled areas of UIP stained for p16 and p21, p16 being more specific compared with p21. Myofibroblasts were negative in all cases. An upregulation of all four autophagy markers was seen not only in epithelia within remodeled areas and proliferating myofibroblasts, but also in bronchial epithelia and pneumocytes. Upregulated autophagy points to a compensatory mechanism for hypoxia; therefore, LDH and GLUT1 were investigated. Their expression was present in epithelia within cystic remodeling and in myofibroblasts. The cells within the remodeled areas stained for cytokeratin 5, but coexpressed TTF1, confirming their origin from basal cells of bronchioles. Within this population, senescent cells arise. Our results indicated that autophagy in UIP very likely helps cells to survive in hypoxic condition. By phagocytosis of cellular debris, they supplement their need for nutrition, and by upregulating LDH and GLUT1, they compensate for local hypoxia.

Originally large cell carcinoma was defined by the absence of visible glandular or squamoid features. Due to immunohistochemistry introduced into NSCLC diagnosis, this exclusion was extended. Solid carcinomas negative for either TTF1 or p40 without visible glandular or squamoid differentiation are now large cell carcinomas. In addition, as this requires whole tumor sections, this is restricted to resection specimen. The former variants are now splitted: LCNEC into the neuroendocrine carcinomas, lymphoepithelioma-like carcinoma into a separate entity, and rhabdoid carcinomas are now no longer regarded as a separate entity, but instead rhabdoid features should be reported. Clear cell changes are seen in different carcinoma types and are therefore also reported but do not comprise an entity.

In tumor pathology of the lung, not many precursor lesions are known. There is squamous metaplasia and dysplasia for squamous cell carcinoma, atypical adenomatous hyperplasia and bronchiolar columnar cell dysplasia, goblet cell dysplasia, cystadenomas for different types of adenocarcinoma, and finally neuroendocrine hyperplasia and tumorlet for carcinoids. For many more lung carcinomas, no precursor is known. Similarly for malignant mesenchymal tumors of the lung, no precursors are known. Here we present those precursor lesions, which are encountered regularly in lung pathology.

Rhabdoid carcinomas are solid growing carcinomas, characterized by cytoplasmic inclusion vacuoles, which are composed of condensed vimentin filaments. They are aggressive carcinomas. Normal vimentin is exchanged in carcinomas to acquire a spindle cell morphology and to enable better movement within the stroma. The function of this condensed vimentin is not clear. Primarily in WHO classification 2004 this was rhabdoid variant of large cell carcinoma, now in 2015 has been skipped as an entity.

Large cell neuroendocrine carcinoma (LCNEC) was originally separated from atypical carcinoids based on a worse prognosis. It is characterized by neuroendocrine morphology and expression of neuroendocrine markers. The cells are larger compared to SCLC and possess enlarged nucleoli and a coarse chromatin. Together with SCLC it forms the complex of high-grade neuroendocrine carcinomas of the lung. As SCLC LCNEC can occur in other organs, but is much more common in the lung.

Primary tumors of the pleura are less frequent compared to metastasis. They represent a relatively rare group of neoplasms with different pathways of differentiation. The most common primary tumor of the pleura is diffuse malignant pleural mesothelioma, which is an aggressive malignant neoplasms originating from the mesothelial cells. They are observed more frequently in men and are typically associated with occupational or para-occupational exposure to asbestos. The diagnostic criteria of malignant mesothelioma are well defined by international guidelines. More uncommon tumors, both benign and malignant, include well-differentiated papillary mesothelioma, solitary fibrous tumor (SFT), adenomatoid tumor, calcifying fibrous tumor, desmoid-type fibromatosis, desmoplastic round cell tumor, synovial sarcoma, epithelioid hemangioendothelioma, and angiosarcoma.

Smokers demonstrate a wide range of clinicopathologic entities in the lung that include Respiratory Bronchiolitis combined Interstitial Lung Disease (RB-ILD), Desquamative Interstitial Pneumonia (DIP), and Pulmonary Langerhans Cell Histiocytosis (PLCH). Although they have been considered separate lesions in various classifications of interstitial lung diseases, these entities share pathogenesis and a number of clinical, radiologic, and pathologic features, suggesting they represent a spectrum of patterns of interstitial lung diseases occurring in smokers and, in an individual case, we can encounter hybrids of RB-ILD, DIP, and PLCH. Small airway injury including submucosal and adventitial fibrosis, increased bronchus-associated lymphoid tissue, and pulmonary hypertension are also associated with smoking. It has only recently been observed that fibrosis of alveolar wall occurs in smokers (clinically occult smoking-related interstitial fibrosis).

The lung is exposed to the environment with a large area and therefore inhalation of foreign sometimes toxic substances is normal. On the other hand, the airways as well as the alveolar periphery contain many protection mechanisms, such as the mucus escalator system, by which substances are moved to the trachea and are coughed up; there are protective enzymes along the airways, which will degrade foreign substances; finally there is an immune system (innate and specific), capable of eliminating harmful substances. There are several tissue reactions associated with foreign substance inhalation, such as acute pneumonia, granuloma formation, and alike. In addition to inhalation, foreign substances can reach the lung also by the blood stream, which is especially seen in drug toxicity. Here examples are presented to raise the awareness of these processes.

Benign epithelial tumors are as rare as mesenchymal ones. They are divided into bronchial adenomas, central and peripheral papillomas, alveolar adenoma, and sclerosing pneumocytoma. In addition, extremely rare pulmonary thymomas can occur. We will focus on some classical types.

Lymphoepithelioma-like carcinoma (LELC) is now a separate entity. In Asian patients, especially of Chinese descendance most cases are positive for EBV, whereas in the Caucasian population they are negative. The most characteristic feature is a dense infiltration by small lymphocytes, sometimes obscuring the epithelial tumor cells.

Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure of more than 25 mmHg at rest, assessed by right heart catheterization. It is a heterogeneous group of disorders that are classified based on differences in clinical, hemodynamic, and histopathologic features. The evolution in molecular medicine, medicinal diagnostics, and pharmacologic management has led to changes in its prognosis. Current classification of pulmonary hypertension, based on clinical presentation and hemodynamic features, includes five categories (Table 34.1). The role of biopsy in the diagnosis of pulmonary hypertension is limited to cases where the clinical and hemodynamic data are not diagnostic. In these cases, the final diagnosis has to be established by a multidisciplinary team led by the clinician. In this chapter, we will describe cases showing the common morphological patterns of pulmonary hypertension seen in histological specimen. These are most often seen in autopsy cases. There are plexogenic arteriopathy, veno-occlusive disease/capillary hemangiomatosis, congestive arteriopathy, hypoxic arteriopathy, and thrombotic arteriopathy.