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Mesenchymal tumors of the lung are rare. Malignant mesenchymal tumors are even rarer compared to their benign counterparts. Most often sarcomas seen in the lung are metastatic, although in very rare instances a leiomyosarcoma might also arise locally in the bronchus. Other sarcomas can be seen combined with carcinomas such as carcinosarcoma. There are a few exceptions, such as angiogenic tumors. These will be discussed here.

The eosinophilic pneumonias include a heterogeneous group of disorders characterized by the presence of eosinophils in the lungs detected by bronchoalveolar lavage or tissue biopsy with or without blood eosinophilia. The disease can be idiopathic (simple pulmonary eosinophilia, acute and chronic eosinophilic pneumonia, hypereosinophilic syndrome), secondary (to drugs, parasites, fungal, irradiation toxic products) or associated with diffuse lung diseases (connective tissue diseases and some neoplasms).

Carcinomas of salivary gland type are not uncommon in the lung. These are all central carcinomas, which are located in the area of bronchial glands. There are several entities, which can be seen in the lung: mucoepidermoid carcinoma and adenoid-cystic carcinoma are the most often seen entities. Epithelial-myoepithelial carcinomas, acinic cell carcinomas, and carcinoma ex pleomorphic adenoma might also be encountered, but are usually very rare.

Small cell neuroendocrine carcinoma (SCLC) is one of the most aggressive lung tumors. It is usually associated with cigarette smoking in almost all cases. The name small cell was created because the cells are smaller as in non-small cell carcinomas. However, the size is around 20–25 μm, the nuclear size 17–23 μm. The nuclear cytoplasmic ratio is excessively shifted towards the nucleus which occupies most of the cell. SCLC in almost 90% expresses neuroendocrine markers.

CPAM represent a malformation of the lung acquired during fetal development. Normally the bronchial buds grow, divide, and differentiate, and finally connect with the peripheral lung structure, which develops out of the coelom. In CPAM, the connection of the bronchial buds with the periphery fails at different stages, thus giving rise to large cysts, small cysts, a pure bronchiolar proliferation, and peripheral lung cysts.

Tumors in childhood are rare. There is adenocarcinoma associated with goblet cell dysplasia in CPAM I-III. Others are HPV-associated papillomas (see Chap. 1). The most important tumor is pleuropulmonary blastoma.

Mesenchymal lung tumors are rare with the exception of hamartomas, which can be seen in about 7% of all lung tumors. However, many benign mesenchymal tumors exist, some of them so rare that one might see them once in a lifetime. Here, we have selected those mesenchymal tumors, which likely can be encountered in routine pathology. The knowledge is of importance, as malignant mesenchymal soft tissue tumors regularly metastasize into the lung. Therefore, a differentiation of primary versus metastatic tumors is of importance.

Diffuse parenchymal lung disease (ILD) includes a heterogeneous group of non-neoplastic disorders. ILDs are mostly inflammatory in nature and the resulting injury to the lung parenchyma can lead to fibrosis with or without honeycombing remodeling. In this chapter, we will consider fibrosing pneumonias with temporal heterogeneity (UIP pattern) that is observed in patients with idiopathic pulmonary fibrosis (IPF), but it can be seen in other conditions such as rheumatic interstitial lung diseases and chronic hypersensitivity pneumonitis. Diffuse fibrosis with temporal and geographic uniformity (NSIP pattern) is frequently associated with connective tissue diseases, but it can be seen in drug toxicity and hypersensitivity pneumonia. And there is end-stage fibrosis (honeycombing).

Die molekulare Diagnostik des Lungenkarzinoms hat in den letzten Jahren eine rasante Entwicklung erfahren. Neue molekulare Targets, Resistenzmutationen fur bestehende Therapien und nicht zuletzt die Immuntherapie rucken die molekulare Diagnostik immer mehr in den Mittelpunkt. Die Entdeckung der zirkulierenden Tumorzellen und der freien zirkulierenden Tumor-Desoxyribonukleinsaure (ctDNA) hat besonders fur das Lungenkarzinom aufgrund der eingeschrankten Verfugbarkeit von Gewebeproben hohe Bedeutung. Inzwischen ist der Nachweis von Tumormutationen aus dem Blut gut etabliert und kann zur Beurteilung der Tumorlast und auch fur die Detektion von Resistenzmutationen verwendet werden. Trotzdem zeigt sich, dass die Analyse von ctDNA technisch aufwendig und komplex ist und dass nicht in allen Tumorstadien und Tumorentitaten ctDNA im Patienten nachweisbar ist. Die neuesten Entwicklungen in der Diagnostik des Lungenkarzinoms und die Bedeutung der „liquid biopsy“ in diesem Kontext sind Thema dieses Artikels.

Interstitielle Prozesse in der kindlichen Lunge konnen sehr unterschiedliche Ursachen haben. Hier ist die Kenntnis des Alters wesentlich. Wahrend in den ersten beiden Lebensjahren genetische Alterationen eine grose Rolle spielen, sind ab dem Kindergartenalter Infektionen aber auch immunologische Erkrankungen haufiger. Insgesamt sind aber Lungenerkrankungen im Kindesalter sehr selten, was auch zur Folge hat, dass die Diagnose schwierig ist und oft erst spat gestellt wird. Hinzu kommt, dass bioptische Untersuchungen oftmals von den Kinderpulmologen nur sehr zogerlich in Betracht gezogen werden. Um einen Beitrag zur Diagnostik kindlicher Lungenerkrankungen leisten zu konnen, sollten Pathologen spezialisiert sein in der Lungenpathologie, sollten auch eine gute Kenntnis genetischer Methoden haben und sich mit der fetalen Lungenentwicklung vertraut machen, wozu wiederum Kenntnis der genetischen Faktoren von Lungenwachstum und Differenzierung gehort. Ein enger Kontakt mit der padiatrischen Pulmologie in Form gemeinsamer Fallbesprechungen fordert fur beide Seiten die Qualitat der Diagnostik. Die kindliche Lunge ist nicht ein verkleinertes Erwachsenenorgan, sondern reagiert in manchen Fallen vollig anders. In diesem Artikel beziehen wir uns hauptsachlich auf diffuse Infiltrationen wie sie in der High-resolution-CT (HRCT) als „ground glass“, retikulonodulare Infiltrationen etc. beschrieben werden. Lokalisierte interstitielle Prozesse, die manchmal tumorartig imponieren, werden nicht berucksichtigt. Malformationen werden nicht behandelt. Hingegen werden vaskulare Fehlbildungen eingeschlossen, da sie durchweg diffuse interstitielle Infiltrationen ausweisen und daher zu den ubrigen Erkrankungen auch in der Differenzialdiagnose zu berucksichtigen sind.

// Fabian Dominik Mairinger 1 , Claudia Vollbrecht 2, 3, 4 , Elena Flom 1 , Daniel Christian Christoph 5 , Kurt-Werner Schmid 1 , Jens Kollmeier 6 , Helmut Hans Popper 7 , Thomas Mairinger 8 and Robert Fred Henry Walter 1, 9 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 3 German Cancer Consortium (DKTK), Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 6 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 7 Department of Pathology, Division of Molecular Lung- and Pleurapathology, Medical University of Graz, Graz, Austria 8 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 9 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Fabian Dominik Mairinger, email: fabian.mairinger@uk-essen.de Keywords: pleural mesothelioma, pemetrexed, thymidylate synthethase, folylpolyglutamate synthase, personalized therapy Received: October 12, 2016 Accepted: March 01, 2017 Published: March 21, 2017 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. Results: Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1 / TYMS -ratio (p=0.0076) as well as FPGS / TYMS -ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). Methods: 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. Conclusion: Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.

Congenital pulmonary airway malformation (CPAM) is a developmental disorder. Types 1-2-3 are the more common ones. Atypical goblet cell hyperplasia (AGCH) in CPAM might be a precursor lesion for pulmonary adenocarcinomas. In nine out of 33 CPAM cases, types 1-3 showed foci of goblet cell proliferations. As these cells completely replace normal epithelium, we prefer to name these proliferations AGCH. In 5 cases, adenocarcinomas were seen (AC). All cases were analyzed for proteins possibly being associated with CPAM development: fibroblast growth factor 10 (FGF10) and receptor 2 (FGFR2), forkhead box A1 (FOXA1) and A2 (FOXA2), MUC protein 5AC (MUC5AC), human epidermal growth factor receptor 2 (erbB2, HER2/neu), hepatocyte nuclear factor 4α (HNF4α), SOX2, and Ying Yang protein 1 (YY1). By next generation sequencing, AGCH and adenocarcinomas were evaluated for driver mutations. Expression for FGF10, FGFR2, FOXA1, and FOXA2 was seen in CPAM epithelium and stroma, but not differently in AGCH and AC. SOX2 was positive in CPAM epithelium and AGCH, however weakly in AC. YY1 and MUC5AC showed more intense staining in AGCH and AC than in CPAM epithelium. HER2 was intensely expressed in AC and less intensely in AGCH, but not in CPAM epithelium. KRAS mutation in exon 2 was detected in all AGCH and AC, but was absent in CPAM epithelia. AGCH can arise in CPAM types 1-3. Oncogenic KRAS mutation seems to be the oncogenic driver already in AGCH, proving its role as a precursor lesion for adenocarcinoma. It might upregulate HER2 at the protein level. YY1 seems to be involved in carcinogenesis.

Objectives: Senescence has been identified as a mechanism in idiopathic pulmonary fibrosis. Lysosomal β-galactosidase, p16 and 21 serve as a surrogate markers to identify senescencent cells. Senescent cells produce many inflammatory molecules and thus sustain inflammation and repair leading ultimately to fibrosis. Autophagy is a process to remove debris from cells and to counteract inflammation. However, autophagy is also necessary to create energy under hypoxic conditions. Material and Methods: 20 cases of UIP fulfiling the criteria of IPF and 20 cases of chronic autoimmune diseases presenting with UIP were selected from the Archive. Sections from paraffin-embedded tissues were incubated with antibodies for β-galactosidase, p16 and 21, and Sentragor® to characterize senescent cells, antibodies for p-AMPKα, MAP1S, SIRT1, and LC3 to characterize activation of autophagy. Results and Conclusion: Senescence markers were expressed only in pneumocytes, especially in areas of myofibroblastic foci. Myofibroblasts did not express these markers. Expression was also seen in few epithelial cells within remodeled cystic areas. Autophagy markers were expressed in macrophages, myofibroblasts, regenerating epithelia within the cysts, but not in endothelia, smooth muscle cells, and bronchial epithelia. Few pneumocytes outside the fibrotic areas were positive for some of these markers. Autophagy is upregulated in myofibroblasts and regenerating epithelia in the lung, the latter exclusively also express senescence markers. Autophagy might assist cells in energy metabolism in hypoxic areas during remodeling, and most likely does not interfere with inflammation and repair.

International audience; Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras G12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of Kras G12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout Kras G12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.

Oncogenic K‐RAS has been difficult to target and currently there is no K‐RAS‐based targeted therapy available for patients suffering from K‐RAS‐driven lung adenocarcinoma (AC). Alternatively, targeting K‐RAS‐downstream effectors, K‐RAS‐cooperating signaling pathways or cancer hallmarks, such as tumor‐promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK–STAT pathway is considered to be a central player in inflammation‐mediated tumorigenesis, we investigated here the implication of JAK–STAT signaling and the therapeutic potential of JAK1/2 inhibition in K‐RAS‐driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK–STAT signaling correlated with disease progression and K‐RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K‐RAS‐driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor‐promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K‐RAS‐driven lung AC., What's new? A drug that inhibits the JAK–STAT pathway may score a hit against K‐RAS driven lung cancer. Here, the authors Investigated the JAK STAT pathway as a possible target in lung adenocarcinoma because of its role in inflammation‐mediated tumorigenesis. First, they showed that JAK1 and JAK2 are both activated in lung adenocarcinoma patients with oncogenic mutations in K‐RAS. Next, they treated the tumors with ruxolitinib, which inhibits JAK1/2. The drug successfully slowed tumor proliferation and progression in immunocompetent mouse models. Furthermore, treatment with ruxolitinib reduced the tumor‐promoting factors present in the microenvironment.

Summary Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making.

Recently, the advent of therapies targeting genomic alterations has improved the care of patients with certain types of cancer. While molecular targets were initially detected in nucleic acid samples extracted from tumor tissue, detection of nucleic acids in circulating blood has allowed the development of what has become known as liquid biopsies, which provide a complementary and alternative sample source allowing identification of genomic alterations that might be addressed by targeted therapy. Consequently, liquid biopsies might rapidly revolutionize oncology practice in allowing administration of more effective treatments. Liquid biopsies also provide an approach towards short-term monitoring of metastatic cancer patients to evaluate efficacy of treatment and/or early detection of secondary mutations responsible for resistance to treatment. In this context, pathologists, who have already been required in recent years to take interest in the domain of molecular pathology of cancer, now face new challenges. The attitude of pathologists to and level of involvement in the practice of liquid biopsies, including mastering the methods employed in molecular analysis of blood samples, need close attention. Regardless of the level of involvement of pathologists in this new field, it is mandatory that oncologists, biologists, geneticists, and pathologists work together to coordinate the pre-analytical, analytical, and post-analytical phases of molecular assessment of tissue and liquid samples of individual cancer patients. The challenges include (1) implementation of effective and efficient procedures for reception and analysis of liquid and tissue samples for histopathological and molecular evaluation and (2) assuring short turn-around times to facilitate rapid optimization of individual patient treatment. In this paper, we will review the following: (1) recent data concerning the concept of liquid biopsies in oncology and its development for patient care, (2) advantages and limitations of molecular analyses performed on blood samples compared to those performed on tissue samples, and (3) short-term challenges facing pathologists in dealing with liquid biopsies of cancer patients and new strategies to early detect metastatic tumor cell clones.

Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the “foreign” stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

Carcinoid classification in the lung is still based on morphological criteria. Although there are many studies investigating the role of Ki-67 proliferation index in the classification of lung neuroendocrine tumours, it is still not used in routine diagnostics. Interestingly, cyclins, which have a crucial role in controlling the cell cycle, have not been thoroughly studied in lung neuroendocrine tumours. The aim of our study was to investigate the correlation of cyclin A2 and B1 expression with prognosis, Ki-67 proliferation index, and carcinoid morphology. A cohort of 134 resected typical and atypical carcinoids was stained with antibodies against Ki-67, cyclin A2 and B1. The positive nuclear reaction was assessed in hot spot areas and expressed as the percentage of tumour cells. Univariate analyses found the highest relative hazard between low and high cyclin A2 expression both with respect to overall survival [hazard ratio (HR)=16; 95% confidence interval (CI) 4.8-51; p=0.0000054], and relapse (HR=8; 95% CI 3.1-21; p=0.00002). In multivariate analysis for overall survival cyclin A2 (HR=10; 95% CI 2.5->100; p=0.0082) and B1 (HR=6.5; 95% CI 1.5-35; p=0.02) remained significant when adjusted for other risk factors, whereas Ki-67 was no longer significant (HR=0.64; 95% CI 0.003-5.5; p=0.65). This suggests that Ki-67 is closer to conventional risk factors for survival than cyclin A2 and B1. Furthermore, the analysis revealed 4 mitoses per 2 mm2 as a more powerful prognostic cut-off than currently accepted 2 mitoses. We have clearly demonstrated that application of cyclin A2 and cyclin B1 might bring additional value regarding the overall and progression-free survival of patients with carcinoids of the lung.

Background Epithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another - best demontrated by tumour cells invading blood vessels. Methods Thirty cases of non-small cell lung carcinomas were used for identifying genes responsible for bulk cell migration, 232 squamous cell and adenocarcinomas to identify bulk migration rates. Genes expressed differently in the primary tumour and in the invasion front were regarded as relevant in migration and further validated in 528 NSCLC cases represented on tissue microarrays (TMAs) and metastasis TMAs. Results Markers relevant for bulk cancer cell migration were regulated differently when compared with EMT: Twist expressed in primary tumour, invasion front, and metastasis was not associated with TGFβ1 and canonical Wnt, as Slug, Snail, and Smads were negative and β-Catenin expressed membraneously. In the majority of tumours, E-Cadherin was downregulated at the invasive front, but not absent, but, coexpressed with N-Cadherin. Vimentin was coexpressed with cytokeratins at the invasion site in few cases, whereas fascin expression was seen in a majority. Expression of ERK1/2 was downregulated, PLCγ was only expressed at the invasive front and in metastasis. Brk and Mad, genes identified in Drosophila border cell migration, might be important for bulk migration and metastasis, together with invadipodia proteins Tks5 and Rab40B, which were only upregulated at the invasive front and in metastasis. CXCR1 was expressed equally in all carcinomas, as opposed to CXCR2 and 4, which were only expressed in few tumours. Conclusion Bulk cancer cell migration seems predominant in AC and SCC. Twist, vimentin, fascin, Mad, Brk, Tsk5, Rab40B, ERK1/2 and PLCγ are associated with bulk cancer cell migration. This type of migration requires an orchestrated activation of proteins to keep the cells bound to each other and to coordinate movement. This hypothesis needs to be proven experimentally. Electronic supplementary material The online version of this article (10.1186/s12885-018-4640-y) contains supplementary material, which is available to authorized users.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Dysregulation of protein synthesis plays a major role in carcinogenesis, a process regulated at multiple levels, including translation of mRNA into proteins. Ribosome assembly requires correct association of ribosome subunits, which is ensured by eukaryotic translation initiation factors (eIFs). eIFs have become targets in cancer therapy studies, and promising data on eIF6 in various cancer entities have been reported. Therefore, we hypothesised that eIF6 represents a crossroad for pulmonary carcinogenesis. High levels of eIF6 are associated with shorter patient overall survival in adenocarcinoma (ADC), but not in squamous cell carcinoma (SQC) of the lung. We demonstrate significantly higher protein expression of eIF6 in ADC and SQC than in healthy lung tissue based on immunohistochemical data from tissue microarrays (TMAs) and on fresh frozen lung tissue. Depletion of eIF6 in ADC and SQC lung cancer cell lines inhibited cell proliferation and induced apoptosis. Knockdown of eIF6 led to pre-rRNA processing and ribosomal 60S maturation defects. Our data indicate that eIF6 is upregulated in NSCLC, suggesting an important contribution of eIF6 to the development and progression of NSCLC and a potential for new treatment strategies against NSCLC.

Purpose The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern—lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)—present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). Patients and Methods Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis. Results A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01). Conclusion The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.

Older asthmatic patients may develop fixed airway obstruction and clinical signs of chronic obstructive pulmonary disease (COPD). We investigated the added value of pathological evaluation of bronchial biopsies to help differentiate asthma from COPD, taking into account smoking, age, and inhaled corticosteroid (ICS) use. Asthma and COPD patients (24 of each category) were matched for ICS use, age, FEV1, and smoking habits. Five pulmonary and five general pathologists examined bronchial biopsies using an interactive website, without knowing patient information. They were asked to diagnose asthma or COPD on biopsy findings in both a pairwise and randomly mixed order of cases during four different phases, with intervals of 4–6 weeks, covering a maximal period of 36 weeks. Clinically concordant diagnoses of asthma or COPD varied between 63 %-73 %, without important differences between pairwise vs randomly mixed examination or between general vs pulmonary pathologists. The highest percentage of concordant diagnoses was in young asthmatic patients without ICS use and in COPD patients with ICS use. In non ICS users with fixed airway obstruction, a COPD diagnosis was favored if abnormal presence of glands, squamous metaplasia, and submucosal infiltrate was present and an asthma diagnosis in case of abnormal presence of goblet cells. In ICS users with fixed airway obstruction, abnormal presence of submucosal infiltrates, basement membrane thickening, eosinophils, and glands was associated with asthma. Histological characteristics in bronchial biopsies are reproducibly recognized by pathologists, yet the differentiation by histopathology between asthma and COPD is difficult without information about ICS use. Electronic supplementary material The online version of this article (doi:10.1007/s00428-015-1824-6) contains supplementary material, which is available to authorized users.

The ImplementatioN of perSonalized medicine In NSCLC in Central Europe: EGFR testing, Histopathology, and clinical feaTures (INSIGHT) observational study assessed both implementation of epidermal growth factor receptor (EGFR) mutation testing and treatment of patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) in a real-world setting in Central Europe. A total of 1785 patients from 14 cancer centers of six Central European countries were enrolled. EGFR mutations were detected in tumors of 13.8% of the patients. More than 70% of patients with advanced EGFR mutation-positive NSCLC received EGFR tyrosine kinase inhibitors as first-line therapy. The INSIGHT study demonstrated the establishment of EGFR mutation testing, a mutation rate consistent with other Caucasian patients populations, and adherence to current guidelines regarding treatment of patients with EGFR mutation-positive tumors in Central Europe.

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Primary pulmonary lymphangiectasis (PPL) is a rare congenital developmental abnormality of the lung with a generally poor prognosis. Only a limited number of patients with neonatal-onset PPL have been reported to survive. We present the case of a male preterm infant (gestational age 34 weeks 6 days) with histologically confirmed PPL, complicated by hydrops fetalis, bilateral hydrothorax (treated in utero with pleuro-amniotic shunts), and immediate respiratory distress at birth. He survived after extensive neonatal intensive care therapy and was discharged home at the age of 7 months. At last follow up he was 3 years 7 months old, still requiring assisted ventilation via tracheostomy, having recurrent episodes of wheezing and had mild global developmental delay. This case demonstrates that survival beyond the neonatal period is possible even with severe PPL but long-term morbidity may be relevant, and multidisciplinary management and close follow up are essential.

Squamous cell and adenocarcinomas of the lung develop different mechanisms during carcinogenesis to evade attacks of the immune system. Besides the well-known check-point control programmed death 1 and its ligand, many more mechanisms, acting either tumoricidal or in favor of tumor progression, exist. Analysis of the immune cell profiles in resected tissues and bronchoalveolar lavage samples and correlation between them and with overall survival data was performed. In all tumor samples in this study, cells of the immune system expressed a tumor-cooperating phenotype. High numbers of regulatory T cells, or alternatively expression of Vista on lymphocytes was present. Tumoricidal dendritic cells were absent in tumor tissue, and barely present in bronchoalveolar lavage, whereas tumor-friendly monocytoid and plasmocytoid dendritic cells were seen in both. Alveolar macrophages were predominantly differentiated into tumor-cooperating M2 types, whereas tumoricidal M1 macrophages were absent or rare. The expression of PDL1 on tumor cells did not correlate with any other immune cells. Expression of PD1 on lymphocytes was frequently encountered. None of analyzed immune cells showed correlation with overall survival. Immune cells in bronchoalveolar lavage and tissue did not correlate. For the first time, a tissue-based analysis of different immune cells in squamous cell and adenocarcinomas of the lung is provided, trying to explain their potential role in tumor development and progression. Discordant numbers of cells with bronchoalveolar lavage are most probably due to the fact that bronchoalveolar lavage reflects the situation in the whole lung, where chronic obstructive lung disease and other conditions are present. Electronic supplementary material The online version of this article (10.1007/s00428-018-2326-0) contains supplementary material, which is available to authorized users.

The cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) models have been closely associated and used to describe both the formation of metastasis and therapy resistance. We established a primary lung cell culture from a patient in a clinically rare and unique situation of primary resistant disease. This culture consisted of two biologically profoundly distinct adenocarcinoma cell subpopulations, which differed phenotypically and genotypically. One subpopulation initiated and sustained in spheroid cell culture (LT22s) whereas the other subpopulation was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal with lack of CSC markers. The LT22s cells also demonstrated an invasive behavior and mimicked gland formation. Finally, LT22s were more resistant to Cisplatin than LT22a cells. We demonstrate a primary lung adenocarcinoma cell culture derived from a patient with resistant disease, with epithelial aggressive subpopulation of cells associated with stem cell features and therapy resistance. Our findings challenge the current model associating CSC and disease resistance mainly to mesenchymal cells and may have important clinical implications.

Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K‐AKT‐mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.

On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat K-RAS-mutated NSCLC.

In 2015 a new WHO classification of lung tumors was issued. This classification clarified several important issues and corrected many entities (1). For adenocarcinomas the previous published classification (2) was adapted and largely taken over. Adenocarcinomas are now grouped into non-mucinous adenocarcinomas and adenocarcinoma variants. Within the non-mucinous adenocarcinomas the evaluation of primary, secondary, and tertiary patterns have to be given in percentages; patterns recognized are lepidic, acinar, papillary, micropapillary, and solid. Recently cribriform pattern was added as another pattern conferring worse prognosis (3,4). Patterns are also important for prognosis, as lepidic pattern confers a good prognosis, whereas solid and micropapillary regardless of their percentage confers a worse prognosis.

Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRasG12D in mouse lung epithelial cells markedly impairs the progression of KRasG12D-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRasG12D-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.

Lung cancer, including carcinogenesis and therapy, is one of the main research focuses today. One of the main reasons for that is the very high mortality rate of patients with lung cancer. Cancer tissue is very heterogeneous, consisting of malignant tumor cells with many different cell types, proteins, and signaling molecules, all together forming the tumor microenvironment. The concept that tumor development is primarily based on mutations has been reapproached from the side of interaction between immune cells of the host, tumor cells, and tumor microenvironment. All components of the cancer microenvironment interact with each other and with tumor cells in a complex manner, both promoting tumor cell growth and development, as well as suppressing it. This interplay is very complicated and today still not completely understood. The most prevalent cells among leukocytes in the cancer microenvironment are macrophages. These are called tumor-associated macrophages and are still very difficult to differentiate and identify by single markers. However, it is clear that they have a very important role in tumor development and progression in lung cancer, as in many other cancers. In patients with lung carcinoma, there is a correlation between tumorassociated macrophages and prognosis, although not uniform. © 2017, Springer International Publishing AG.