Pulmonary Neuroendocrine Tumors Research Articles

Experience of Ectopic Adrenocorticotropin Syndrome: 88 Cases With Identified Causes

ObjectiveEctopic adrenocorticotropic hormone syndrome (EAS) is a rare cause of Cushing's syndrome and diagnosis and management remain challenging. The aim of this study was to present the clinical spectrum of a group of EAS cases in a single center to explore better management strategies. MethodsA retrospective study was conducted to identify 88 confirmed EAS cases at our hospital from 1984 to 2019. The clinical, biochemical, imaging, and pathological features were analyzed. ResultsOf the 88 eligible patients with EAS, 38 (43.2%) cases of pulmonary neuroendocrine tumors (NETs) and a larger number of thymic/mediastinal NETs (29 cases, 33%) were identified. The clinical and biological features of EAS and Cushing's disease overlapped but were more severe in EAS. Inferior petrosal sinus sampling (97.4%) and computed tomography (85.4%) provided the highest positive diagnostic accuracy. Computed tomography is also a useful tool to identify tumors in chest cavity compared with nonchest lesions (91.2% vs 57.1%). Although a greater tumor size (4.54 cm vs 1.44 cm) and higher rate of insuppressible high-dose dexamethasone suppression test (83.3% vs 51.5%) were found in thymic/mediastinum NETs than in pulmonary NETs, the level of hormone production had no difference. ConclusionEAS had more common and severe clinical presentations than Cushing's disease, and multiple imaging approaches are required for reliable diagnosis. A higher proportion of thymic/mediastinal NETs was found in our study. For patients without a certain tumor source, long-term follow-up and further evaluations are needed.

A Rare Case of Acute Liver Failure Secondary to Diffuse Hepatic Infiltration of Small Cell Neuroendocrine Carcinoma.

BackgroundMalignant liver infiltration is an uncommon cause of acute liver failure (ALF) and has rarely been reported.Case PresentationWe present a patient with progressive jaundice and dissociation of bilirubin and aminotransferases, who had no history of relevant liver diseases or tumor except the use of Chinese traditional drugs for a cold. An abdominal computed tomography (CT) scan showed ascites without hepatic focal lesions. Laboratory studies revealed no evidence of hepatitis or underlying autoimmune disorders. Following 8 days of conservative management ALF rapidly worsened. Contrast-enhanced CT revealed diffuse regenerative nodules in the liver. The patient underwent liver biopsy, which demonstrated that the liver was infiltrated by pulmonary neuroendocrine tumor classified as small cell lung cancer. The patient died 13 days after diagnosis.Discussion and ConclusionsThis case represents a rare cause of ALF induced by pulmonary neuroendocrine tumor of small cell type and illustrates the importance of prompt biopsy in an unknown cause of ALF.

P47.12 Does Pulmonary Adenocarcinoma With Neuroendocrine Differentiation Deserve A New Classification?

Pulmonary neuroendocrine tumor (NET) is a category of lung cancers characterized as neuroendocrine features with low incidence and poor prognosis. Unlike other NETs, little was known about adenocarcinoma with neuroendocrine differentiation (ANED) because of its rarity. A large-scale study was performed to investigate the clinical features, treatments and survival outcomes of ANED. All cases of primary ANED, SCLC and LCNEC were identified from the SEER database from 2004 to 2016. The clinical features and treatments of ANED were described and studied. A total of 37608 patients were included. Only 214 cases of ANED were recorded. Half of ANEDs were poor differentiated. The preferent site was upper lobe. Most patients were diagnosed as IIIB-IV stages. The outcomes of ANED were similar to LCNEC which were better than SCLC in stage I. In advanced stages, no difference was observed. Patients received adjuvant chemotherapy had better OS in IA-IB. Same trends could be observed in IIA-IV patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Tabled 1Clinical featurssANED (N = 214)LCNEC (n = 2257)SCLC (n=35137)Age, yearsMean (SD)66.2 (10.8)65.4 (10.4)66.7 (10.1)Gender, No. (%)Male123 (57.5)1246 (55.2)17674 (50.3)Female91 (42.5)1011 (44.8)17463 (49.7)Race, No. (%)White153 (63.5)1789 (79.3)28895 (82.2)Black32 (15.0)272 (12.1)3247 (9.3)Asian12 (5.6)77 (3.4)1238 (3.5)Other17 (7.9)119 (5.2)1757 (5.0)Tumor size(mm)Mean (SD)51.5 (58.9)45.9 (42.2)53.1 (42.0)Grade, No. (%)Well;2 (0.9)11 (0.5)65 (0.2)Moderately;22 (10.3)32 (1.4)142 (0.4)Poorly;116 (54.2)859 (38.1)3311 (9.4)Undifferentiated;6 (2.8)263 (11.7)6501 (18.5)Unknown68 (31.8)1092 (48.3)25118 (71.5)Stage, No. (%)IA27 (12.6)351 (15.6)972 (2.8)IB18 (8.4)269 (11.9)943 (2.7)IIA8 (3.7)104 (4.6)632 (1.8)IIB13 (6.1)111 (4.9)574 (1.6)IIIA33 (15.4)259 (11.5)4750 (13.5)IIIB25 (11.7)169 (7.5)5219 (14.9)IV90 (42.1)994 (44.0)22047 (62.7)Surgery, No. (%)No surgery138 (64.5)1301 (57.6)33953 (96.6)Surgery76 (35.5)956 (42.4)1184 (3.4)Chemotherapy, No. (%)No radiation181 (84.6)1883 (83.4)31543 (89.8)Radiation33 (15.4)374 (16.6)3594 (10.2)Chemotherapy, No. (%)No/Unknown99 (46.3)1063 (47.1)9549 (27.2)Yes115 (53.7)1194 (52.9)25588 (72.8) Open table in a new tab Adenocarcinoma with neuroendocrine differentiation is has similar outcomes as LCNEC in various stages. Surgery with adjuvant chemotherapy could improve survival in Stage I ANED and might bring benefit to advanced stage patients. It could be included in LCNEC and might not need a new clinical classification.

Clinicopathological and immunohistochemical study of pulmonary neuroendocrine tumors - A single-institute experience.

Introduction:Pulmonary neuroendocrine tumors (NETs) comprise a spectrum of tumors ranging from indolent to highly aggressive neoplasm. This study aims to study the clinicopathological and immunohistochemical features of NETs and assess the sensitivity of various IHC markers.Materials and Methods:All consecutive cases of pulmonary NETs diagnosed from January 2016 to June 2019 were analyzed retrospectively. The routine hematoxylin- and eosin-stained sections along with immunohistochemistry (IHC) slides were reviewed. IHC was done using a panel of markers which included synaptophysin, chromogranin, CD56, thyroid transcription factor-1 (TTF-1), p-40, napsin-A, and ki67.Results:Of total number of 53 patients, diagnosis was made on biopsy in 40 patients and resection specimen in 13 patients. Small cell lung carcinoma was the most common (31 cases), followed by 16 cases of typical carcinoid, 5 cases of atypical carcinoid, and 1 case of combined SCLC. Both synaptophysin and chromogranin were positive in all the cases of typical carcinoid. Synaptophysin had better sensitivity than chromogranin in atypical carcinoid and small cell carcinoma. CD56 was positive in 8 out of 9 cases done. TTF-1 was negative in all the cases of typical carcinoid. The sensitivity of TTF-1 in small cell carcinoma was 85.19%. The mean Ki67 labeling index was 1.4%, 6.6%, and 65.6% in typical, atypical carcinoid, and small cell carcinomas, respectively.Conclusion:Synaptophysin was more sensitive than chromogranin, especially in atypical carcinoid and small cell carcinoma. TTF-1 along with high Ki67 differentiates small cell carcinoma from carcinoid.

Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool.

The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors. Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases). NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community. This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.

Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors.

Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.

The panel of syntaxin 1 and insulinoma-associated protein 1 outperforms classic neuroendocrine markers in pulmonary neuroendocrine neoplasms.

Syntaxin-1 (STX1) is a recently described highly sensitive and specific neuroendocrine marker. We evaluated the applicability of STX1 as an immunohistochemical marker in pulmonary neuroendocrine neoplasms (NENs). We compared STX1 with established neuroendocrine markers, including insulinoma-associated protein 1 (INSM1). Typical carcinoids (n=33), atypical carcinoids (n=7), small cell lung carcinomas ([SCLCs] n=30), and large cell neuroendocrine lung carcinomas (n=17) were immunostained using tissue microarray for STX1, chromogranin A, synaptophysin, CD56, and INSM1. Eighty-four of eighty-seven (96.5%) NENs showed STX1 positivity. Carcinoids and LCNECs typically presented a combined strong membranous and weak cytoplasmic staining pattern; cytoplasmic expression was predominately observed in SCLCs. The sensitivity of STX1 was 90% in SCLCs and 100% in typical carcinoids, atypical carcinoids, and large cell neuroendocrine lung carcinomas. The overall sensitivity of STX1 in pulmonary NENs was 96.6%, and the sensitivity of the other markers was as follows: chromogranin A (85.2%), synaptophysin (85.2%), CD56 (92.9%), and INSM1 (97.7%). STX1 was found to be an excellent neuroendocrine marker of pulmonary NENs, with sensitivity and specificity surpassing that of classic markers. We propose a panel of STX1 and INSM1 for the routine immunohistochemical workup of pulmonary NENs.

Peptide Receptor Radionuclide Therapy of Pulmonary Neuroendocrine Neoplasms: a Single-Centre Experience.

Peptide receptor radionuclide therapy represents a therapeutic option for neuroendocrine neoplasms; to date, experiences with peptide receptor radionuclide therapy of pulmonary neuroendocrine neoplasms are still limited. We report our experience with peptide receptor radionuclide therapy of pulmonary neuroendocrine neoplasm patients. Clinical records of 14 pulmonary neuroendocrine neoplasm patients (7 female and 7 male) who received at least 2cycles of peptide receptor radionuclide therapy were retrospectively reviewed. Tumoural uptake of somatostatin analogues at pre-treatment imaging was graded as 2 to 3 in all patients. RECIST criteria were used to evaluate response. No treated patient had significant toxicity. Partial response was found in 3 (21.4%) patients, stable disease in 7 (50%), and progressive disease in 4 (28.6%). A statistically significant difference between disease state at enrolment and after peptide receptor radionuclide therapy was found. Our data furtherly support peptide receptor radionuclide therapy as a safe and effective treatment of patients affected by pulmonary neuroendocrine neoplasms allowing disease control in about 71% of patients without showing significant toxicity. Other studies are needed to confirm our results.

Alternative and New Radiopharmaceutical Agents for Lung Cancer.

BackgroundFDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the differentiation between LC and benign conditions and is not capable of defining LC heterogeneity since FDG uptake varies between histotypes.ObjectiveTo get an overview of new radiopharmaceuticals for the study of cancer biology features beyond glucose metabolism in LC.MethodsA comprehensive literature review of PubMed/Medline was performed using a combination of the following keywords: “positron emission tomography”, “lung neoplasms”, “non-FDG”, “radiopharmaceuticals”, “tracers”.ResultsEvidences suggest that proliferation markers, such as 18F-Fluorothymidine and 11C-Methionine, improve LC staging and are useful in evaluating treatment response and progression free survival. 68Ga-DOTA-peptides are already routinely used in pulmonary neuroendocrine neoplasms (NENs) management and should be firstly performed in suspected NENs. 18F-Fluoromisonidazole and other radiopharmaceuticals show a promising impact on staging, prognosis assessment and therapy response in LC patients, by visualizing hypoxia and perfusion. Radiolabeled RGD-peptides, targeting angiogenesis, may have a role in LC staging, treatment outcome and therapy. PET radiopharmaceuticals tracing a specific oncogene/signal pathway, such as EGFR or ALK, are gaining interest especially for therapeutic implications. Other PET tracers, like 68Ga-PSMA-peptides or radiolabeled FAPIs, need more development in LC, though, they are promising for therapy purposes.ConclusionTo date, the employment of most of the described tracers is limited to the experimental field, however, research development may offer innovative opportunities to improve LC staging, characterization, stratification and response assessment in an era of increased personalized therapy.

Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature

ObjectivesPulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. Material and methodsCases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. ResultsSeven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. ConclusionA subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.

Role of FOXM1 in aggressive pancreatic / pulmonary neuroendocrine neoplasms and anti-tumor effect of the FOXM1 inhibitor Thiostrepton

Role of FOXM1 in aggressive pancreatic / pulmonary neuroendocrine neoplasms and anti-tumor effect of the FOXM1 inhibitor Thiostrepton

Results of Surgical Resection of Locally Advanced Pulmonary Neuroendocrine Tumors

Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0). In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.

Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells.

In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.

Updates in the advances of sporadic medullary thyroid carcinoma: from the molecules to the clinic.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy that originates in parafollicular cells. It is well-known that a quarter of MTC are involved in hereditary multiple endocrine neoplasia type 2 syndromes, whereas most MTC are sporadic. Unlike the commonly encountered gastrointestinal or pulmonary neuroendocrine tumors, most sporadic MTCs have distinct genetic alterations featured by somatic changes of either Rearranged during Transfection (RET) or RAS point mutation. The increasing application of next-generation sequencing, whole-exome sequencing, and other molecular detection techniques enables us to understand MTC comprehensively concerning its detailed molecular changes and their clinical correlations. This article reviews the advances in genetic alterations and their prognostic impact in sporadic MTC among different populations and discusses the associated tumor immune microenvironments and the potential role of immunotherapy targeting PD-L1/PD-1 in treating MTC. Furthermore, the current multikinase inhibitor targeting therapy for sporadic MTC has been summarized here and its efficacy and drug toxicity are discussed. Updates in advance of the role of calcitonin/procalcitonin/calcitonin-related polypeptide alpha (CALCA) gene transcripts in diagnosing and handling MTC are also mentioned. The treatment of advanced MTC is still challenging and might require a combination of several modalities.

Tumeurs neuro-endocrines broncho-pulmonaires primitives : tumeurs carcinoïdes et carcinomes neuro-endocrines à grandes cellules: Primary pulmonary neuroendocrine tumors: Carcinoid tumors and large-cell neuro-endocrine carcinomas

AbstractPrimary pulmonary neuroendocrine tumors comprise several distinct clinical entities, corresponding to four main subtypes: typical carcinoid tumors, of low grade malignancy; atypical carcinoids of intermediate grade; neuro-endocrine carcinomas with either small or large cells, which are high grade, frequent malignancy.The pre-treatment workup of carcinoid tumors is based on specific recommendations. Any clinical suspicion of an associated functional syndrome must be confirmed by the appropriate blood dosages.In case of metastatic carcinoid tumor, management relies on the control of a possible secretory syndrome by somatostatin analogues, in addition to the oncological treatment, based on the evaluation of tumor progression, with several opportunities: close follow-up, local treatment of metastases, treatment with somatostatin analogues, everolimus, or chemotherapy for tumor with high aggressiveness.In case of advanced, metastatic large-cell neuroendocrine carcinoma, molecular analysis of a panel of oncogenic alterations could guide the chemotherapy strategy; platinum and etoposide combination has historically been used. In the second line, in the absence of any therapeutic standard, the IFCT-FFCD-GERCOR “NIPINEC trial” is recruiting in France in and aims at evaluating nivolumab, with or without ipilimumab in the second- and third-line setting.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Constrictive bronchiolitis in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

BackgroundDiffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterised by multifocal proliferation of neuroendocrine cells and belongs in the spectrum of pulmonary neuroendocrine tumours. Some patients with DIPNECH develop airflow obstruction but the relationship between the two entities remains unclear.MethodsWe performed a computer-assisted search of the Mayo Clinic's electronic medical records for biopsy-proven cases of DIPNECH. We extracted clinical, pulmonary function, imaging and histopathological data along with treatments and outcomes.ResultsAmong 44 patients with DIPNECH 91% were female and the median age was 65 years (interquartile range 56–69 years); 73% were never-smokers. Overall, 38 patients (86%) had respiratory symptoms including cough (68%) and dyspnoea (30%); 45% were previously diagnosed to have asthma or COPD. Pulmonary function testing showed an obstructive pattern in 52%, restrictive pattern in 11%, mixed pattern in 9%, nonspecific pattern in 23%, and was normal in 5%. On chest computed tomography scan, 95% manifested diffuse nodules and 77% manifested mosaic attenuation. For management, 25% of patients were observed without pharmacological therapy, 55% received an inhaled bronchodilator, 41% received an inhaled corticosteroid, 32% received octreotide; systemic steroids, azithromycin, or combination chemotherapy was employed in four patients (9%). Of 24 patients with available follow-up pulmonary function tests, 50% remained stable, 33% worsened and 17% improved over a median interval of 21.3 months (interquartile range 9.7–46.9 months).ConclusionDIPNECH occurs mostly in women and manifests diffuse pulmonary nodules and mosaic attenuation on imaging. It is commonly associated with airflow obstruction due to constrictive bronchiolitis, which manifests limited response to current pharmacological therapy.

Pulmonary Neuroendocrine Tumors: Adjuvant and Systemic Treatments.

Bronchial carcinoids are uncommon tumors accounting for 20 to 30% of all neuroendocrine tumors and about 1-2% of all cancers of pulmonary origin. Bronchial carcinoids are well-differentiated neuroendocrine tumors and have a favorable survival outcome when compared with other subtypes of lung cancers. Treatment of bronchial carcinoids is not simple owing to intricacy of symptom presentation and heterogeneity of disease biology. Successful treatment of patients requires a multimodality approach. Resection is curative in the majority of patients with localized tumors and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced disease. To date, very few randomized clinical trials have been done, partly owing to the relative rarity of this malignancy. Somatostatin analogs (SSAs) are reasonable first-line choice for patients with tumors expressing somatostatin receptors. Everolimus is an appropriate first-line choice for somatostatin receptor negative tumors and for any patients with progressive disease. PRRT can also be considered for progressive tumors expressing somatostatin receptors. Based on retrospective series, cytotoxic chemotherapy can be selected in patients with progressive tumors, primarily when cytoreduction is needed. Herein, we will discuss evidence supporting the role of adjuvant and systemic treatment therapies for those with bronchial carcinoid tumors by focusing on various studies.

CT signs and parameters of vascularization of pulmonary neuroendocrine tumours and their relationship with the development of ACTH ectopic syndrome

CT signs and parameters of vascularization of pulmonary neuroendocrine tumours and their relationship with the development of ACTH ectopic syndrome

Proposal of organ-specific subdivision of M component and staging system for metastatic pulmonary neuroendocrine tumor

ObjectivesTo evaluate the prognostic significance of patterns of distant metastatic organs in metastatic pulmonary neuroendocrine tumors (PNETs). Methods891 metastatic PNETs patients (G1-typical carcinoid, 200; G2-atypical carcinoid, 68; G3-large-cell neuroendocrine carcinoma, 623) diagnosed between 2010 and 2016 were identified. Multivariate analysis was performed using a Cox regression model to identify prognostic factors associated with cancer-specific survival (CSS). The novel M component was established based on the hazard ratio of different metastatic organs. A disease-specific staging system was then proposed by using k-means cluster analysis. ResultsFor metastatic PNETs, involvement of bone, liver or brain and multiple metastatic organs were identified as independent prognostic factors in multivariate analysis. M categories was subdivided into three subcategories: M1a, lung involvement only or distant lymph node involvement only; M1b, bone involvement only or liver involvement only; M1c, brain involvement regardless of number of metastatic organs or multiple organs involvement except brain. Primary site surgery, chemotherapy and histologic subtypes were independently associated with CSS, but T component and N component were not. After regrouping histologic subtypes and novel M component, we proposed the following modified staging system: stage IVA (G1M1any, G2M1a-b), stage IVB (G2M1c, G3M1a-b) and stage IVC (G3M1c). The 2-year CSS were 77.9 %, 16.4 % and 5.3 %. ConclusionsSubdivision of M component according to patterns of distant metastatic organs facilitates prognostic significance for PNETs. Brain metastases and multiple metastatic organs were associated with significantly inferior prognosis. Incorporating histologic subtypes and novel M categories create a disease-specific staging system showed good discriminatory capacity.

Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment.

Introduction: Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination. Methods: We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination. Results: Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (−71% ± 13%, p < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression. Conclusions: Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients.