Pulmonary Neuroendocrine Tumors Research Articles

Surgical management of large-cell neuroendocrinelung carcinoma: an analysis of 25 cases.

Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a relatively uncommon and aggressive subset of pulmonary neuroendocrine tumors, which include typical and atypical carcinoid, and small-cell lung cancer. LCNEC of the lung accounts for no more than 1% of all lung cancers. LCNECs show features of high-grade neuroendocrine tumors and patients with LCNEC have a very poor prognosis. Twenty-five patients (22 males and 3 females; mean years 60.7; range 48 to 77 years) who underwent pulmonary resection for large-cell neuroendocrine carcinoma between January 2004 and December 2014 were investigated retrospectively. Type of surgery, pathologic TNM stage, adjuvant chemotherapy, time of recurrence, site of recurrence, response to treatment, and long-term results were evaluated. The longest patient follow-up period was 83 months. One-, two-, and three-year survival rates of these patients were, respectively, 80.95%, 76.47%, and 50%. Complete surgical resection is the treatment of choice for early-stage LCNEC and chemotherapy after radical surgical treatment improves survival. Follow-up periods after surgery adjuvant chemotherapy will prevent recurrence and patients may survive for many years if complete surgical resection and adjuvant chemotherapy are possible.

Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways.

BackgroundThe mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways.MethodsTherefore, we tested the effect of lovastatin—known to inhibit both ERK and AKT signaling—and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines.ResultsLovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P ≤ 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P ≤ 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect.ConclusionIn summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable reactions of the different cell lines highlight the necessity to understand the unique molecular aberrations in any tumor. Nevertheless, this combination seems worthy of being tested in vivo.

Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group

Background:Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows.Methods:A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes.Results:After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM- (P=0.022; P=0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P⩽0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P=0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P=0.020).Conclusions:The implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response.

Cytohistology of papillary carcinoid and emerging concept of pulmonary neuroendocrine neoplasms.

This timely review starts by reporting the clinical, cytologic and histologic features of a morphologic variant of pulmonary carcinoid tumor forming exclusively of papillae. This growth pattern is so rare that it was not included in 2014 WHO classification of pulmonary neuroendocrine neoplasms. The current concept is reviewed, and example of spindle cell carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma are illustrated with fine needle aspiration cytology, surgical and clinical follow-up. Finally, the new findings in cell biology and molecular biology that led to the emerging concept that carcinoids and high-grade neuroendocrine lung carcinomas are separate biological entities are reviewed and summarized in a tumorigenic module.

Problems with the diagnosis of metastatic neuroendocrine neoplasms. Which diagnostic criteria should we use to determine tumor origin and help guide therapy?

Neuroendocrine neoplasms (NENs) can often present with metastatic disease before the primary tumor is discovered. Metastatic lesions are generally classified as well differentiated and poorly differentiated for prognostic and therapeutic purposes. In addition, for well-differentiated neuroendocrine tumors (WDNETs), pathologists are expected to determine the site of origin, if not already known, and grade the tumors. However, it is often difficult for pathologists to provide this information with certainty without knowing the site of tumor origin, as different criteria have been proposed by WHO for classification of gastrointestinal and pulmonary NENs. In this review, we will discuss the current classification and grading schema of NENs and their impact on clinical care, the differential diagnosis of NENs, the use of immunohistochemical stains that help identify tumor site of origin, and a proposed approach for the diagnosis and classification of metastatic NENs.

Pulmonary Neuroendocrine Tumors: Part II. Treatment.

Pulmonary neuroendocrine tumors that arise from Kulchitzky cells of the bronchial mucosa consist of a spectrum of histologic features leading to a variable prognosis. Although typical carcinoid represents the most benign course, small-cell cancer has the grimmest outcome. Therefore, differentiating the spectrum of neuroendocrine tumors helps one not only to determine the prognosis, but also to guide the treatment options. In this part, we aim to discuss the treatment options in pulmonary neuroendocrine tumors except for small-cell lung cancer.

A Rare Case of Cushing Syndrome Caused by an Adrenocorticotropic Hormone-Producing Pulmonary Carcinoid Tumor

We present a rare of case of a carcinoid tumor-causing Cushing syndrome. Cushing syndrome, if left untreated, can result in severe morbidity and even mortality. Common causes of endogenous Cushing include pituitary gland adenomas and excess cortisol produced from various adrenal gland pathologies. Rarely, tumors such as pulmonary neuroendocrine tumors can produce adrenocorticotropic hormone (ACTH) and cause …

Abstract 3895: Genomic alterations modify ubiquitination pathways in pulmonary carcinoid tumors

Abstract Introduction: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Method: We characterized genomic alterations in pulmonary carcinoid tumors using whole genome and exome sequencing in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Results: Analysis of the sequencing data identified novel mutations in the pulmonary neuroendocrine tumor spectrum, including KRAS, ABCA9, GALNT10, HSFX1, PTHLH, RANBP2, BRIP1, FXR1, BACE2, NCOR2, DGKI, HERC1, HERC5 and GLI3. Pathway analysis found 45% of the cases to harbor a mutation in genes that are involved in protein-protein interaction with ubiquitin c (UBC) and may therefore play a role in ubiquitin protein degradation pathway. We also identified genes differentially expressed in corresponding regions of copy number variation, 52 of which were linked to ubiquitination pathways in 88% of the samples genotyped. Genes amplified in 15 to 23% of the cases included ITM2A, MAOA, EGR2, HAGH, TSC22D3, NBEA, TCEAL2, and TSPYL2 whereas deleted regions in 15% of the cases implicated CFD, GDI1, IFITM1 and IFITM2. Conclusion: These results suggest that in addition to previously identified pathways, dysregulation of the ubiquitin pathway may contribute to lung carcinoid tumorigenesis and could be exploited for therapeutic purposes. Citation Format: Michael K. Asiedu, Charles L. Thomas, Jie Dong, Prasidda Khadka, Zhifu Sun, Farhad Kosari, Jin Jen, Julian Molina, George Vasmatzis, Marie Christine Aubry, Ping Yang, Dennis Wigle. Genomic alterations modify ubiquitination pathways in pulmonary carcinoid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3895. doi:10.1158/1538-7445.AM2015-3895

Pulmonary Neuroendocrine Tumors: Part I. Spectrum and Characteristics of Tumors.

Pulmonary neuroendocrine tumors arise from Kulchitzky cells of the bronchial mucosa and include typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell lung cancer. These tumors have a variable growth rate that determines their presentation and prognosis. Typical carcinoid has the lowest growth rate and better prognosis; in contrast, small cell lung cancer is an aggressive tumor with a very poor prognosis. Although there are some overlapping histologic features between these tumors, clinical, imaging, and immunohistochemical markers are useful in the differentiation of pulmonary neuroendocrine tumors. The treatment options differ on the basis of histologic characteristics. In this article, we aim to describe the spectrum of neuroendocrine tumors of the lung, except for small cell lung cancer, and their clinical, pathologic, and imaging findings, with a focus on treatment options.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the Role of Somatostatin analogs: A Case Series.

DIPNECH is a rare pre-neoplastic condition that often presents with a variety of non-specific pulmonary symptoms and sometimes seen in conjunction with pulmonary carcinoid tumors. There are very limited data on use of somatostatin analogs in patients with DIPNECH. We review the long-term outcomes of somatostatin analog therapy with regard to symptom control in patients with DIPNECH. Retrospective study out of our extensive registry of over 2000 neuroendocrine tumors identifies 184 pulmonary neuroendocrine tumors. Out of this, there were five histopathologically confirmed cases of DIPNECH. Appropriate institutional review board permission was taken for this analysis. All 5 patients were females, with a mean age at diagnosis was 65.5 years. Follow-up period includes 1-5 years. Cough was the presenting complaint in all five patients described as mostly dry, except for one patient who had productive early morning cough. Other symptoms seen in one of our patients included wheezing, flushing, and fluctuating blood pressure. No one reported weight loss, hemoptysis, and shortness of breath. One of our patients had a benign thyroid nodule and two patients had previous history of breast cancer. All five of our patients were histopathologically diagnosed by lung biopsy. 4 out of 5 patients were started on a somatostatin analog. All four patients reported drastic improvement in cough. One patient reported mild abdominal discomfort and diarrhea as side effects but remained on treatment. From our single institution review of neuroendocrine pulmonary tumor cases, we found only five cases of DIPNECH, which reaffirms rare nature of the pathology. It primarily affects females over 60 years with dry cough as the most common presenting symptom. Most of our patients responded to treatment with a somatostatin analog and had significant improvement in their presenting symptoms. Somatostatin analogs were well tolerated resulting in significant resolution of presenting symptoms in most of our patients. Further research is needed; however, a trial of somatostatin analogs should be considered in the treatment of patients with DIPNECH with responders being treated long term.

Pulmonary neuroendocrine tumour presenting with thyroid gland metastasis: a case report

Pulmonary neuroendocrine tumour presenting with thyroid gland metastasis: a case report

Beyond adenocarcinoma: current treatments and future directions for squamous, small cell, and rare lung cancer histologies.

Lung cancer encompasses a diverse spectrum of histologic subtypes. Until recently, the majority of therapeutic advances were limited to the minority of patients with adenocarcinoma. With the advent of comprehensive genomic profiling of squamous and small cell lung cancers, new therapeutic targets have emerged. For squamous tumors, the most promising of these include fibroblast growth factor receptor (FGFR), the phosphatidylinositol 3-kinase (PI3K) pathway, discoidin domain receptor 2 (DDR2), and G1/S checkpoint regulators. In 2014, the antiangiogenic agent ramucirumab was approved for all non-small cell lung cancer (NSCLC) histologies, including squamous tumors. Immunotherapeutic approaches also appear to be promising for these cases. Genomic analysis of small cell lung cancer has revealed a high mutation burden, but relatively few druggable driver oncogenic alterations. Current treatment strategies under investigation are focusing on targeting mitotic, cell cycle, and DNA repair regulation, as well as immunotherapy. Pulmonary neuroendocrine tumors represent a diverse spectrum of diseases that may be treated with somatostatin analogs, cytotoxic agents, and molecularly targeted therapies. Radiolabeled somatostatin analogs and combinations with mammalian target of rapamycin (mTOR) inhibitors also show potential. Large cell neuroendocrine tumors share numerous clinical, pathologic, and molecular features with small cell lung cancer; however, whether they should be treated similarly or according to a NSCLC paradigm remains a matter of debate.

Co-expression of TTF-1 and neuroendocrine markers in the human fetal lung and pulmonary neuroendocrine tumors

The expression pattern of thyroid transcription factor 1 (TTF-1) and neuroendocrine markers, neuron cell adhesion molecule (NCAM; CD56), chromogranin A (CgA) and synaptophysin (Syp), of different lung cell lineages was histologically analyzed in 15 normal human fetal lungs and 12 neuroendocrine tumors (NETs) using immunohistochemical methods. During pseudoglandular phase strong nuclear TTF-1 staining was detected in the columnar nonciliated epithelial cells, while NCAM, CgA and Syp had a moderate expression in the proximal airways and mild expression in the distal airways. Neuroendocrine cells (NECs) in proximal lung airway were co-localizing TTF-1 and other neuroendocrine markers while neuroendocrine bodies (NEBs) exhibit only staining with NCAM and Syp. In the canalicular phase TTF-1 nuclear staining was expressed only in several epithelial cells in proximal airways, while budding airways epithelium showed strong TTF-1 expression. Expression of NCAM, CgA and Syp in this phase equals the one in pseudoglandular phase. NEBs cells were co-localizing TTF-1 and NCAM in proximal airways and few NECs in distal airway were co-localizing TTF-1 and Syp. TTF-1 staining in the saccular phase was limited to subsets of epithelial cells in the proximal airways with stronger positivity in the distal airways. NCAM expression is moderate only in proximal airways, while Syp and CgA show mild expression in proximal and distal airways. NECs were co-localizing TTF-1 and NCAM in proximal lung airway. With regard to NECs, all small cell lung cancer (SCLC) cells had strong TTF-1, NCAM, Syp and CgA positivity and TTF-1 co-localized with other neuroendocrine markers. All pulmonary typical carcinoids were TTF-1 negative, while pulmonary atypical carcinoids were focal positive for TTF-1 and some neoplastic cells co-localized TTF-1 with neuroendocrine markers.Our results indicate that TTF-1 expression in NECs suggests a possible role in their normal development and differentiation. Our results also indicate that possible cell of origin for poorly differentiated SCLC and some atypical carcinoid could be a progenitor cell in neuroendocrine lineage while in typical carcinoids possible cell of origin is localized in terminally differentiated NECs.

Medical Therapy of Pulmonary Neuroendocrine Neoplasms: Targeted, Symptomatic and Chemotherapy.

Whenever feasible, surgery represents the treatment of choice for pulmonary neuroendocrine neoplasms (NENs). In patients with hypersecreting tumors, wide metastatic spread or those not candidates for a surgical treatment, medical therapies may assure a control of the secretory pattern and slow the rate of tumor growth. No specific trials have been designed so far for pulmonary NENs and the first randomized trial entirely dedicated to thoracic NENs (the LUNA trial) is ongoing. International scientific society guidelines (ESMO and NANETS) and recommendations (ENETS) are therefore necessarily based on expert experience, on the subgroup analysis of large multicenter trials not focused on pulmonary NENs, and on the analysis of small retrospective series. Somatostatin analogs represent the therapy of choice in the presence of associated carcinoid syndrome and ectopic acromegaly and a reasonable first-line in slow-progressing tumors. Due to the low rate of proliferation, platinum-based chemotherapy is generally reserved to rapidly progressing tumors. Temozolomide alone or in association has shown activity in small retrospective series or monocentric trials - larger multicenter trials will better define its efficacy. Everolimus alone or in combination with somatostatin analogs has shown activity in the subgroup analysis of a large multicenter trial (RADIANT II). Many other drugs have shown activity in the preclinical models but, at the moment, no prospective and randomized data are available.

Gene expression profiling of pulmonary neuroendocrine neoplasms: A comprehensive overview

Abstract Neuroendocrine neoplasms (NENs) of the lung comprise a heterogeneous group, including small cell lung cancer (SCLC), large cell neuroendocrine carcinoma and pulmonary carcinoids. To unravel their molecular biology, microarray studies have been conducted that provided lists of differentially expressed genes between lung NENs on the one hand and normal tissue and/or non-SCLCs on the other. However, the majority of studies paid little attention to the functions of candidates and their potency as diagnostic markers and/or therapeutic targets. Furthermore, at a first glance, only limited overlap was seen amongst these individual studies concerning differentially expressed transcripts. By combining all originally published gene expression profiling studies on lung NENs, and by re-evaluating differentially expressed genes, we were able to identify major factors involved in lung NEN carcinogenesis. Thirty-three genes were found to be frequently deregulated in multiple studies. Amongst these are neuroendocrine-specific factors, including ASH1 , INSM1 , and ISL1 and genes involved in neuronal differentiation and neurite outgrowth such as DCX and NCAM1 . Also, multiple factors were involved in cell cycle progression, including members of the mitotic spindle checkpoint complex, and the regulated secretory pathway, e.g. CHGA and CHGB and CPE . For several of these candidates we propose possible functions in lung NEN carcinogenesis as well as potential roles in diagnosis and as targets for novel therapies. This review elucidates potential genes of interest in pulmonary NENs on basis of the present expression profiling literature. We advocate that a selection of the identified candidates should be examined in depth for their clinical application.

Clinicopathological Features of Resected Cases of Pulmonary Neuroendocrine Tumors

Clinicopathological Features of Resected Cases of Pulmonary Neuroendocrine Tumors

Diagnostic accuracy of bronchial brush cytology and the added value of immunohistochemistry and fluorescence in situ hybridization of pulmonary neuroendocrine tumors.

Background:Bronchial brush (BB) cytology carries low sensitivity for detecting neuroendocrine carcinomas (NECs), including typical carcinoid (TC) tumors of the lung. We aimed to investigate the detection of neuroendocrine tumors including TC through BB routine cytology cell block (CB), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH).Materials and Methods:A SNOMED search showed 187 lung biopsy or resection specimens from 2008 through 2011 containing neuroendocrine or carcinoid in the diagnosis. Residual BB specimens retained in PreservCyt were used to prepare a ThinPrep slide for FISH analysis. CBs were stained with H and E and IHC for chromogranin and synaptophysin.Results:Of the 187 cases, 16 had residual BB material available within 1 year of diagnosis and were used in CB preparation for IHC and FISH slides. Cytologic evaluation determined 1 case positive for malignancy (small cell lung carcinoma [SCLC]), 1 suspicious for adenocarcinoma, and 14 negative for malignancy. On the basis of histologic diagnosis, FISH was performed. SCLC showed polysomy (86% abnormal cells); 2 TC tumors showed a gain of 7p12 (15% abnormal cells) and a gain of 5q15 (72% abnormal cells), respectively. Two cases had CBs with positive immunoreactivity for chromogranin and synaptophysin. The sensitivity for detection of NEC was 18.8%, 15.4%, and 25% for cytologic evaluation, CB, and FISH, respectively.Conclusion:Neuroendocrine tumors, including TC are difficult to detect with BB cytologic evaluation, most likely because tumor cells lack in the specimen. Assessment of further studies is needed to explore the role of cytology and ancillary methods for detection of these tumors.

Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study

MicroRNAs (miRNAs) are a class of small (∼22 nucleotides), non-coding, highly conserved single-stranded RNAs with posttranscriptional regulatory features, including the regulation of cell proliferation, differentiation, survival, and apoptosis. They are deregulated in a broad variety of tumors showing characteristic expression patterns and can, thus, be used as a diagnostic tool. In contrast to non-small cell carcinoma of the lung neuroendocrine lung tumors, encompassing typical and atypical carcinoids, small cell lung cancer and large cell neuroendocrine lung cancer, no data about deregulation of tumor entity-specific miRNAs are available to date. miRNA expression differences might give useful information about the biological characteristics of these tumors, as well as serve as helpful markers.In 12 pulmonary neuroendocrine tumors classified as either typical carcinoid, atypical, large cell neuroendocrine or small cell lung cancer, screening for 763 miRNAs known to be involved in pulmonary cancerogenesis was conducted by performing 384-well TaqMan low-density array real-time qPCR. In the entire cohort, 44 miRNAs were identified, which showed a significantly different miRNA expression. For 12 miRNAs, the difference was highly significant (P<0.01). Eight miRNAs showed a negative (miR-22, miR-29a, miR-29b, miR-29c, miR-367*; miR-504, miR-513C, miR-1200) and four miRNAs a positive (miR-18a, miR-15b*, miR-335*, miR-1201) correlation to the grade of tumor biology. The miRNAs let-7d; miR-19; miR-576-5p; miR-340*; miR-1286 are significantly associated with survival. Members of the miR-29 family seem to be extremely important in this group of tumors. We found a number of miRNAs, which showed a highly significant deregulation in pulmonary neuroendocrine tumors. Moreover, some of these deregulated miRNAs seem to allow discrimination of the various subtypes of pulmonary neuroendocrine tumors. Thus, the analysis of specific sets of miRNAs can be proposed as diagnostic and/or predictive markers in this group of neoplasias.

Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors.

BackgroundPulmonary neuroendocrine tumors (Pulmonary NETs) include a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and the intermediate-grade atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). Epithelial Mesenchymal Transition (EMT) is a process initially recognised during several critical stages of embryonic development, which has more recently been implicated in promoting carcinoma invasion and metastasis. The initial stage of the EMT process begins with the deregulation of adhesion molecules, such as E-cadherin, due to transcriptional repression carried out by factors such as Snail family members, Twist and Foxc2.MethodsImmunohistochemistry for EMT markers and E-cadherin/ β-catenin complex in 134 patients with pulmonary NETs between 1990 – 2009. Analysis of potential associations with clinicopathological variables and survival.ResultsPulmonary NETs of high malignant potential (LCNEC and SCLC) had reduced expression of the adhesion molecules and high level expression of transcriptional repressors (Snail1, Snail2, Twist and Foxc2). Snail high expression levels and the loss of E-cadherin/β-catenin complex integrity had the strongest negative effect on the five-year survival rates. E-cadherin/β-catenin complex integrity loss independently predicted lymph node involvement and helped in Atypical Carcinoid (AC) vs Typical Carcinoid (TC) differential diagnosis. Importantly, among the TC group, the loss of E-cadherin/β-catenin complex integrity identified patients with an adverse clinical course despite favourable clinicopathological features.ConclusionThe immunohistochemical determination of E-cadherin/β-catenin complex integrity loss and EMT markers in the clinical setting might be a potential useful diagnostic and prognostic tool especially among the TC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-855) contains supplementary material, which is available to authorized users.

P26. Well differentiated neuroendocrine tumors of the lung—our experience

Well differentiated pulmonary neuroendocrine tumors [low (G1) and intermediate grade (G2) neuroendocrine tumors according to WHO 2010, abbreviated as G1/G2 NET] represent minor but clinically important part of lung neoplasms. More often known as typical and atypical carcinoids, both entities account for 1-2% of pulmonary tumors. Because of their rather favorable prognosis—G1 NET 5-year survival over 90%, G2 NET 40-60%—and low incidence, they were in past on the margins of attention. However, with advances in molecular genetics and biology sciences, new therapeutic ways are emerging, such as mTOR kinase inhibitors, anti-angiogenic monoclonal antibodies or other, still experimental drugs interfering with PI3K/Alt/mTOR kinase signal pathway, as well as long-acting somatostatine inhibitors with attached radioisotopes. Our poster presents ten year experience with GR/G2 NET on our Pulmonary department and befriended Clinic of T. Bati. We consecutively followed up 42 patients with G1 NET and 22 patients with G2 NET for average period of 4.4 years (G1 NET, median follow up 4.0 years), respectively 4.7 years (G2 NET, median 3.9 years) with histologically verified diagnosis of primary typical/atypical carcinoid of the lung. Population characteristics, staging, tumor marker levels, rate of paraneoplastic syndromes, treatment, reccurence, 5-year and 10-year survival (where possible) and occurrence of duplicite malignancies were evaluated. Most patients (n=52) were treated by thoracic surgery methods, endobronchial laser therapy was performed in small subset of patients (n=8) with recurrence rate 25%. Our observations confirm excellent prognosis of G1 NET (none of patients died because of carcinoid tumor in 5-year follow up, however two died because of duplicite malignancies), and worse prognosis of G2 NET (5-year survival 64%, 10-year survival 41%). We would like to also draw attention to new therapeutic possibilities in treatment of pulmonary G1/G2 neuroendocrine tumors.