Cell Carcinoid Research Articles

Incidence and Survival Outcomes in Patients with Lung Neuroendocrine Neoplasms in the United States.

Simple SummaryNeuroendocrine tumors are a rare group of neoplasms characterized by strikingly heterogeneous pathological features and clinical behavior. The incidence and prevalence of these tumors are rising. Studies have reported the incidence and prevalence of neuroendocrine tumors; however, specific data targeting lung neuroendocrine tumors are lacking. We conducted a retrospective analysis using a national database to report the incidence and survival trends of lung neuroendocrine neoplasms. We found that the overall survival and disease-specific survival trends varied significantly not only by stage and histological type but also by age, race, marital status, and insurance type. A small difference was also noted between the rural and urban populations. The rarity of these tumors poses several diagnostic and therapeutic challenges. Our findings generate the following hypothesis that increased awareness of these tumors, as well as better diagnostic modalities, may contribute to a higher incidence. Furthermore, newer therapeutic advances may have caused an improvement in the survival trends in recent years. Such population-based analysis is important to allot resources and guide future research in the field.Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.

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.

P38.04 3D Analysis of Spread Through Air Spaces in Squamous Cell Carcinoma and Carcinoid Tumor Using Whole Block Imaging by Micro CT

P38.04 3D Analysis of Spread Through Air Spaces in Squamous Cell Carcinoma and Carcinoid Tumor Using Whole Block Imaging by Micro CT

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.

Exploring the role of survivin in neuroendocrine neoplasms.

Neuroendocrine tumors (NETs) are a heterogenous group of tumors. While most NETs have excellent prognosis, certain subsets have aggressive biology and have limited treatment options. We explored the role of survivin in NET as a prognostic and potentially therapeutic marker. Tissue microarrays of 132 patients were stained for survivin using immunohistochemistry (IHC) and correlated with outcomes. Using genomic database, we then correlated survivin (BIRC5) mRNA expression with radiosensitivity index (RSI) in 52 samples of NET. Finally, we studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity. We found that survivin positivity by IHC correlated with a shorter survival (overall survival 8.5 years vs. 18.3 years, p < 0.001). There was a positive correlation between BIRC5 expression and RSI (r = 0.234, p < 0.0001). Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line. Knockout of BIRC5 using siRNA reduced proliferation of neuroendocrine cells but did not increase radiation sensitivity. We conclude that survivin expression in NET correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.

Trends in the incidence and survival outcomes in patients with lung neuroendocrine neoplasms in the United States.

e19120 Background: The incidence and prevalence of Neuroendocrine Neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs has been lacking. Methods: We conducted a retrospective population-based analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database, and studied lung NENs patients from 1988 to 2015. Associated population data was utilized to report the annual age-adjusted incidence and overall survival trends. Trends in the incidence and survival of large-cell lung cancer (LCLC) and atypical carcinoid (AC) were reported from 2000-2015, while that for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988-2015. Results: We examined a total of 115,995 lung NENs [103,980 – SCLC; 3,303 – LCLC; 8,146 – TC; 656 – AC]. The age-adjusted incidence rate revealed decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015 per 100,000, AC increased from 0.17 in 2001 to 0.22 in 2015 per 100,000, and lastly, LCLC increased from 0.35 in 2001 to 0.41 in 2015 per 100,000. On multivariable analyses, the median overall survival (OS) and disease-specific survival (DSS) rate varied significantly by stage, grade, age at diagnosis, histological type, insurance type, marital status, and race. The 5-year OS rate among SCLC and LCLC patients was 5% and 17%, respectively, consistent with their high-grade nature. On the other hand, TC and AC, representing low-grade neuroendocrine tumors, had good 5-year OS: 84% and 64%, respectively. Conclusions: The incidence of lung NENs is rising, possibly because of advanced radiological techniques. However, we have seen a downtrend in the incidence of SCLCs likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.

Neuroendocrine tumors of the lung: clinicopathological and molecular features.

In 1970, neuroendocrine tumors of the lung were classified into three categories: typical carcinoid (TC), atypical carcinoid (AC), and small cell lung carcinoma (SCLC). The third edition of the World Health Organization (WHO) classification in 1999 defined large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinomas, whereas the fourth edition of the WHO classification redefined LCNEC as a neuroendocrine tumor. Currently, neuroendocrine tumors of the lung are classified into four main categories: TC, AC, LCNEC, and SCLC. Although the treatments for TC, AC, and SCLC have not changed remarkably, the treatment strategy for LCNEC is not yet established because of its reclassification from a variant of "large cell carcinoma" to a new category of "neuroendocrine tumor". In this review article, we discuss the pathological findings, biological behavior, and treatment of neuroendocrine tumors of the lung.

Non-toxic fragment of botulinum neurotoxin type A and monomethyl auristatin E conjugate for targeted therapy for neuroendocrine tumors.

Surgical resection is the only cure for neuroendocrine tumors (NETs). However, widespread metastases have already occured by the time of initial diagnosis in many cases making complete surgical removal impossible. We developed a recombinant heavy-chain receptor binding domain (rHCR) of botulinum neurotoxin type A that can specifically target synaptic vesicle 2 (SV2), a surface receptor abundantly expressed in multiple neuroendocrine tumors. Expression of neuroendocrine differentiation markers chromogranin A (CgA) and achaete-scute complex 1 (ASCL1) were signficantly reduced when treated with rHCR. rHCR conjugated to the antimitotic agent monomethyl auristatin E (MMAE) significantly suppressed proliferation of pancreatic carcinoid (BON) and medullary thyroid cancer cells (MZ) at concentrations of 500 and 300 nM respectively, while no growth suppression was observed in pulmonary fibroblasts and cortical neuron control cell lines. In vivo, rHCR-MMAE significantly reduced tumor volume in mouse xenografts with no observed adverse effects. These data suggest recombinant HCR (rHCR) of BoNT/A preferentially targets neuroendocrine cancer without the neurotoxicity of the full BoNT/A and that SV2 is a specific and promising target for delivering drugs to neuroendocrine tumors.

1589 Unusual Presentation of Adenocarcinoma Ex Goblet Cell Carcinoid

INTRODUCTION: Ex Goblet cell carcinoid (eGCC) is a type of goblet cell carcinoid tumor, characterized by both endocrine and exocrine features, that has carcinomatous growth patterns. The classical presentation is compatible with symptoms of acute appendicitis. However, other signs and symptoms such as bowel obstruction, GI bleed and less commonly mesenteric adenitis or iron deficiency have been reported. CASE DESCRIPTION/METHODS: A 72 year old man with a recent hospitalization due to symptomatic anemia, presented to the ED complaining of diffuse abdominal pain for the past 3 weeks. He also reported nausea and emesis for 12 hours. At the previous admission, a CTE (Figure 1) showed thickening of the TI and an EGD was unremarkable. A colonoscopy was recommended, but it was scheduled for completion as an outpatient. At this admission, his hemoglobin was within normal limits, however his abdominal pain and nausea were persistent despite medical treatment. A repeated CT abdomen showed the same TI thickening with an associated new SBO (Figure 2). General surgery was then consulted and the patient underwent an exploratory laparotomy. Intraoperative findings showed possible carcinomatosis, and thence an ileocolectomy and ileocolostomy were performed. Pathology findings were compatible with adenocarcinoma ex goblet cell carcinoid of the appendix (Figure 3), and for this reason, he was referred to oncology for further management. DISCUSSION: GCC can be classified into 3 groups according to the presence of adenocarcinoma component and its degree of differentiation which directly correlates with its prognosis. Group A exhibits only pure goblet cell carcinoid cells; group B shows goblet cells with signet ring cells, and group C presents with goblet cell cells with a component of adenocarcinoma. eGCC corresponds with group C, which is the type presented in our case. Most patients have metastatic disease at the time of diagnosis, estimated in 60% to 91% of the cases. Due to the rarity of this type of tumor, currently there are no guidelines for treatment. However, the main approach is based on surgical resection of the appendix versus right hemicolectomy if the tumor is not confined to the submucosa. In terms of adjuvant treatment, FOLFOX/FOLFIRI are currently being used in most institutions. We present this patient due to its rarity and unusual presentation. Furthermore, we would like to incentivize future researches that can focus on implementing treatment guidelines for this tumor, due to its associated poor prognosis.

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

BackgroundBronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior.MethodsBronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids.ResultsData demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice.ConclusionsHuman bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

Unusual Presentation of Metastatic Cervical Squamous Cell Carcinoma with Serum Positive Beta Human Chorionic Gonadotropin.

Abstract We present a case of a 30-year-old female who presented with one month of worsening dyspnea. On admission she was having pleuritic chest pain with associated cough and worsening dyspnea. CTA showed a moderate sized pleural effusion with two hypodensities noted in the liver. Patient received several thoracenteses and had abdominal distension that required paracentesis, which showed transudative fluid initially. There was a noted supraclavicular lymph node, however the patient refused lymph node biopsy. Retroperitoneal lymph node, which was seen on CT abdomen, was eventually biopsied which showed metastatic carcinoma with squamoid differentiation with unknown primary. Beta subunit of human chorionic gonadotropin (b-HCG) was rechecked for the biopsy and was mildly elevated to 33. The patient refused gynecological evaluation, pelvic ultrasound revealed a distended endometrial cavity with heterogeneous contents and a complex left adnexal cyst. Pelvic MRI noted a large cervical mass (4.6x4.5x3.8cm) with parametrial invasion. Subsequently her status declined, and she was intubated for hypoxic respiratory failure. Patient unfortunately passed away. Autopsy confirmed metastatic cervical cancer with significant tumor burden as evidence of &gt;80% of the liver with tumor. Although the patient’s pap smear previously did not culture for HPV, the lymph node biopsy stained positive with Pap stain and shown that the carcinoid cells were most affected by HPV. Later is was found that 3.5 years prior the patient had a Pap smear positive for low-grade squamous intraepithelial lesion however was lost to follow up. Although there have been studies that have examined cervical cancer and the intracellular expression of b-hCG, serum b-hCG is not known to be elevated in squamous cell carcinoma of the cervix. For women presenting with wide spread disease, gynecological malignancies should be ruled out regardless of age.

Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors.

Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression.

Effects of KEAP1 Silencing on the Regulation of NRF2 Activity in Neuroendocrine Lung Tumors.

Background. The KEAP1/NRF2 pathway has been widely investigated in tumors since it was implicated in cancer cells survival and therapies resistance. In lung tumors the deregulation of this pathway is mainly related to point mutations of KEAP1 and NFE2L2 genes and KEAP1 promoter hypermethylation, but these two genes have been rarely investigated in low/intermediate grade neuroendocrine tumors of the lung. Methods. The effects of KEAP1 silencing on NRF2 activity was investigated in H720 and H727 carcinoid cell lines and results were compared with those obtained by molecular profiling of KEAP1 and NFE2L2 in a collection of 47 lung carcinoids. The correlation between methylation and transcript levels was assessed by 5-aza-dC treatment. Results. We demonstrated that in carcinoid cell lines, the KEAP1 silencing induces an upregulation of NRF2 and some of its targets and that there is a direct correlation between KEAP1 methylation and its mRNA levels. A KEAP1 hypermethylation and Loss of Heterozygosity at KEAP1 gene locus was also observed in nearly half of lung carcinoids. Conclusions. This is the first study that has described the effects of KEAP1 silencing on the regulation of NRF2 activity in lung carcinoids cells. The epigenetic deregulation of the KEAP1/NRF2 by a KEAP1 promoter hypermethylation system appears to be a frequent event in lung carcinoids.

H727 cells are inherently resistant to the proteasome inhibitor carfilzomib, yet require proteasome activity for cell survival and growth

The second-in-class proteasome inhibitor (PI) carfilzomib (Kyprolis, Cfz) has contributed to a substantial advancement in multiple myeloma treatment by improving patient survival and quality of life. A considerable portion of patients however display intrinsic resistance to Cfz. Our mechanistic understanding of intrinsic Cfz resistance is limited due to a lack of suitable cell-based models. We report that H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). These results indicate that H727 cells remain dependent on the UPS for cell survival and growth despite harboring intrinsic resistance to Cfz. Alterations in the composition of proteasome catalytic subunits via interferon-γ treatment or siRNA knockdown results in sensitization of H727 cells to Cfz. We postulate that a potential link may exist between the composition of proteasome catalytic subunits and the cellular response to Cfz. Overall, H727 cells may serve as a useful cell-based model for de novo Cfz resistance and our results suggest previously unexplored mechanisms of de novo PI resistance.

Goblet Cell Carcinoid/Carcinoma: An Update.

Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. The hallmark of GCC is the concentric infiltration of the appendiceal wall by small tight clusters, nests or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin. The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized as a common finding, which has been called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis. Several histologic classification/grading systems have been proposed, which correlate with overall patient survival. Treatment options are primarily based on tumor stage and the presence or absence of a high-grade adenocarcinomatous component.

Three-Dimensional (3D) Imaging Spectroscopy of Carcinoma, Sarcoma, Leukemia, Lymphoma, Multiple Myeloma, Melanoma, Brain and Spinal Cord Tumors, Germ Cell Tumors, Neuroendocrine Tumors and Carcinoid Tumors under Synchrocyclotron Radiation

Three-Dimensional (3D) Imaging Spectroscopy of Carcinoma, Sarcoma, Leukemia, Lymphoma, Multiple Myeloma, Melanoma, Brain and Spinal Cord Tumors, Germ Cell Tumors, Neuroendocrine Tumors and Carcinoid Tumors under Synchrocyclotron Radiation

Epigenetic inhibitor treatment reduces proliferation via induction of apoptosis in a human typical bronchial carcinoid cell line

Epigenetic inhibitor treatment reduces proliferation via induction of apoptosis in a human typical bronchial carcinoid cell line

Liver Mass: When in Doubt Think Carcinoid or Islet Cell Carcinoma

Few differentials for liver lesions include hepatocellular carcinoma, cholangiocarcinoma, hepatic adenoma, hepatic hemangioma, hepatic cysts and metastases. Carcinoids and islet cell carcinomas are normally not in the differential due to their rarity in comparison to the other conditions. Since these tumors are slow growing, the liver has time to adapt; hence patients present with minimal symptoms and large masses on imaging. It is imperative to have both carcinoid and islet cell carcinoma on top of the list for differentials when an incidental asymptomatic liver lesion is seen. 66-year-old male previously treated with ABVD for Hodgkin's lymphoma in 1999 presented with back pain. He denied flushing, chills, fever, diarrhea and lightheadedness. Physical exam was benign. Pertinent laboratory data revealed creatinine of 3.1, potassium of 5.3 and mildly elevated alkaline phosphatase. Three-phase CT of the abdomenshowed two masses in the liver (Figure 1): a 22 cm mass in the right lobe and a 2.5 cm mass in the left lobe. There was also a 4 cm mass in the right kidney. Initially, the liver lesions were thought to be metastases from the kidney. However, biopsy of the kidney mass revealed renal cell carcinoma while biopsy of the largest liver lesion was consistent with neuroendocrine carcinoma. To classify the etiology of the neuroendocrine carcinoma, whole body imaging with SPECT and octreotide scan was performed. A large 19 cm mass and two small lesions were noted in the right lobe of the liver. Lymph node adjacent to the third portion of the duodenum demonstrated abnormal uptake and it was presumed that the duodenum was the primary source of the neuroendocrine carcinoma. Lesions in the liver were likely metastases. The patient was treated with an ablation for renal cell carcinoma and started on somatostatin for neuroendocrine carcinoma of the duodenum. Differentiating carcinoids and islet cell carcinomas poses a diagnostic challenge for pathologists as both entities share the same histology and often immune staining can yield mixed results. It is very important as specialists to have both these diseases in the differential and make the correct diagnosis by taking into consideration the primary site involved along with the presence of 5-HIAA. Even with risk factors for other etiologies, a biopsy should be performed with further testing as indicated to make the correct diagnosis. Identifying the correct diagnosis further helps optimize treatment.2368 Figure 1. Aymptomatic Liver Lesion

Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up-Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells

Somatostatin (SST) analogues are used to control the proliferation and symptoms of neuroendocrine tumors (NETs). MicroRNAs (miRNA) are small non-coding RNAs that modulate posttranscriptional gene expression. We wanted to characterize the miRNAs operating under the control of SST to elucidate to what extent they mediate STT actions. NCI-H727 carcinoid cell line was treated with either a chimeric SST/dopamine analogue; a SST or dopamine analogue for proliferation assays and for identifying differentially expressed miRNAs using miRNA microarray. The miRNAs induced by SST analogue treatment are investigated in carcinoid cell lines NCI-H727 and CNDT2 using in situ hybridization, qPCR and proliferation assays. SST analogues inhibited the growth of carcinoid cells more potently compared to the dopamine analogue. Principal Component Analysis (PCA) of the samples based on miRNA expression clearly separated the samples based on treatment. Two miRNAs which were highly induced by SST analogues, miR-7 and miR-148a, were shown to inhibit the proliferation of NCI-H727 and CNDT2 cells. SST analogues also produced a general up-regulation of the let-7 family members. SST analogues control and induce distinct miRNA expression patterns among which miR-7 and miR-148a both have growth inhibitory properties.

High miR-100 expression is associated with aggressive features and modulates TORC1 complex activation in lung carcinoids.

PurposeMammalian target of rapamycin (mTOR) is a promising therapeutic target in advanced lung carcinoid patients. However, the mechanisms of mTOR modulation and of responsiveness to mTOR inhibitors are largely unclear. Our aim was to analyze the expression and functional role of specific miRNAs in lung carcinoids as an alternative mechanism targeting mTOR pathway.Experimental designSeven miRNAs, selected by bioinformatic tools and literature search, were analyzed in 142 lung neuroendocrine neoplasms (92 carcinoids and a control group of 50 high grade neuroendocrine carcinomas), and compared with mTOR mRNA expression and clinical/pathological parameters. Tissue results were validated in vitro in two lung carcinoid cell lines by specific RNA interference and biological/pharmacological tests.ResultsTissutal expression of five miRNAs (miR-99b, miR-100, miR-155, miR-193a-3p, miR-193a-5p) was inversely correlated with mTOR mRNA expression, supporting their role in the negative regulation of mTOR transcription. High expression of miR-100, miR-193a-3p and miR-193a-5p was associated with aggressive features and, for the former two, with shorter time to progression. In H727 and UMC11 lung carcinoid cells, miR-100 modulated mTOR RNA and TORC1 complex protein expression, positively promoted cell migration and negatively influenced cell proliferation. Moreover, miR-100 directly influenced responsiveness of H727 and UMC11 cells to rapamycin.ConclusionsMiR-100 actively participates to the regulation of mTOR expression in lung carcinoids and represents a novel candidate prognostic biomarker for this tumor type; moreover, inhibition of its expression is associated to increased responsiveness to mTOR inhibitors and might represent a novel strategy to sensitize lung carcinoids to these target agents.