Neuroendocrine Carcinoma Patients Research Articles

Neuroendocrine carcinoma of esophageal and gastric cardia: clinicopathologic and immunohistochemistry study of 80 cases.

Neuroendocrine carcinoma (NEC) of the esophagus and gastric cardia is a rare tumor, and the Chaoshan region has one of the highest incidences of esophageal and gastric cardia cancer (GCC) worldwide. The aim of this study was to characterize the clinicopathologic features of esophageal NEC (n = 67) and gastric cardia NEC (n = 13) cases identified over a 9-year period in the Chaoshan region. Esophageal NECs were either purely NEC (n = 47) or mixed with squamous cell carcinoma or adenocarcinoma (n = 20). For GCC; pure NEC was found in 5 cases, whereas 8 cases were mixed with adenocarcinomas. The majority of esophageal and gastric cardia NECs was of the small cell type, and 24/67 esophageal and 5/13 gastric cardia patients were found with lymph node metastasis. Immunohistochemistry was performed in all cases, and positive staining for synaptophysin (Syn) was found for all cases, with half the esophageal NEC cases being also chromogranin A (CgA)-positive. In the multivariate Cox regression model, lymph node and further metastasis were independent prognostic factors for esophageal NEC. Our study revealed the clinicopathological features of esophageal and gastric cardia NECs in the Chaoshan region and found mixed NECs patients may have a better prognosis than pure NECs patients, which may provide therapeutic clue for treating this rare tumor.

Efficacy of radiotherapy for primary tumor in patients with unresectable pancreatic neuroendocrine tumors.

Detailed information regarding the clinical efficacy of radiotherapy (RT) for primary tumor in patients with unresectable pancreatic neuroendocrine tumors (pNETs) is unknown. We therefore performed a retrospective study to evaluate the efficacy and safety of RT for primary pancreatic tumors in patients with pNETs. We investigated 11 patients with pNETs who received RT to the primary site between January 1997 and June 2015. Seven patients had Grade 2 neuroendocrine tumors (NET-G2) and four had neuroendocrine carcinoma (NEC) according to the 2010 WHO histopathological classification. The tumor response and control rates were 27.2% and 100%, respectively (3: partial response, 8: stable disease). Among patients with NET-G2 tumors, the response rate was 28.5% (2/7 patients) and symptomatic improvement was noted in 33.3% of the patients (1/3 patients). The response rate for patients with NEC were 25% (1/4), one NEC patients with symptoms exhibited symptomatic improvement. The median overall survival and median progression-free survival were 35.9 months and 5.5 months, respectively. Grade 3 diarrhea as an acute toxicity and Grade 3 gastrointestinal hemorrhage as a late toxicity were observed. RT to the primary cancer site in patients with pNETs was an effective modality for local disease control and the treated patients had good outcomes. If metastatic tumors are under control, RT to the primary site may be beneficial for patients with pNETs.

Clinicopathological features and prognosis of patients with gastric neuroendocrine carcinoma from multiple centers in southern China

To analyze the clinicopathological features and prognostic factors of gastric neuroendocrine carcinoma(NEC) based on a multicenter database from five medical centers in Southern China. Clinical and pathological data of 1 183 gastroenteropancreatic neuroendocrine neoplasms patients between January 2006 and December 2015 from five centers were retrospectively analyzed. A total of 156 gastric NEC cases(13.2%) with complete follow-up information were screened and included in the study, wherein 73 cases from Sun Yat-sen University Cancer Center, 27 cases from Nanfang Hospital of Southern Medical University, 26 cases from The First Affiliated Hospital of Sun Yat-sen University, 15 cases from Guangdong General Hospital and 15 cases from Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The overall survival rate was calculated by using Kaplan-Meier method. The prognostic factor was analyzed using the Cox proportional hazards model. In 156 NEC patients, the ratio of male to female was 3.9 vs 1.0, the median age was 61 years old, and the maximal tumor diameter was (4.5±2.3) cm. There were 12 case(7.7%) with functional tumors. At the initial diagnosis, there were 111 patients (71.2%) with regional lymph node metastases and 58 patients (37.2%) with distant metastases. One hundred and twenty-three patients (78.8%) underwent surgical treatment and 94 patients (60.3%) received systematic treatment. There were 31 patients(19.9%) in localized disease stage, 67 patients (42.9%) in regional disease stage and 58 patients(37.2%) in distant disease stage. The 5-year overall survival rate was 44.7%. Cox regression model showed that surgical treatment (HR=0.512, 95%CI:0.287 to 0.912, P=0.023) and clinical stage(HR=1.488, 95%CI:1.067 to 2.076, P=0.019) were independent prognostic factors. The 5-year overall survival rate of patients with and without surgical treatment were 54.6% and 10.9%(P=0.000). Meanwhile, the 5-year overall survival for localized, regional and distant disease stages were 66.1%, 56.1% and 21.1% respectively(P=0.000). Gastric neuroendocrine carcinoma is a group of rare tumors with strong invasiveness, high malignancy and poor prognosis. The gastric NEC patients can benefit from surgical treatment.

ISY-12-5 - Current status and perspective of systemic chemotherapies for GEP-NEC

According to the World Health Organization grading system for neuroendocrine neoplasms, neuroendocrine carcinoma (NEC) is a poorly differentiated, high-grade malignant tumor, including small and large cell carcinoma. The primary sites of NEC vary, with gastroenteropancreatic NEC (GEP-NEC) accounting for 20%–68% of extra-pulmonary NEC. Treatment guidelines for advanced extra-pulmonary NEC recommend platinum-based chemotherapy regimens, which are suitable for small cell lung carcinoma. There are two large-scale, multicenter retrospective analyses of advanced GEP-NEC: the NORDIC NEC study [Sorbye H et al. Ann Oncol. 2013;24(1)] and the Japanese study [Yamaguchi et al. Cancer Sci. 2014;105(9)]. In both studies, GEP-NEC prognoses varied according to primary organs. Although only etoposide plus cisplatin regimen (EP) was the mainstream first line chemotherapy in NORDIC, EP and irinotecan plus cisplatin regimen (IP) were commonly used in Japan. Both regimens (EP, IP) have been demonstrated to show favorable efficacy and have been acknowledged as de facto standard regimens for advanced NEC, although it remains unclear which of the two regimens might yield more favorable outcomes. Therefore, a phase III study comparing EP and IP in terms of overall survival for patients with recurrent or unresectable GEP-NEC (TOPIC-NEC, UMIN000014795) has been commenced by the Japan Clinical Oncology Group (JCOG). The sample size was set as 140 (70 patients per arm). For second line regimens, amrubicin, irinotecan, and S-1 were commonly utilized in Japan, but no standard regimens have been established. A multicenter phase II study to evaluate the efficacy of everolimus in pancreatic NEC patients who are unresponsive to/intolerant of platinum-based regimens (NECTOR: UMIN000012752) is currently in progress.

Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma.

Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are limited. Topotecan is an approved second‐line chemotherapy for small cell lung cancer (SCLC). NEC is often considered to show a biological behavior similar to SCLC. The aim of this study was to analyze the efficacy of topotecan in pretreated metastatic NEC patients. We performed a retrospective analysis of all patients treated with topotecan for metastatic NEC who presented at our center between January 2005 and December 2014 (n = 30). All 30 patients had received at least a platinum and etoposide containing regimen as prior chemotherapy. Median proliferation rate (Ki67) was 80%. As best response to topotecan five patients showed a stable disease, two patients a partial remission, resulting in a disease control rate of 23%. Of the remaining 23 patients, 14 (47%) showed a progressive disease, nine (30%) died before radiologic response could be evaluated. Median progression‐free (PFS) and overall survival (OS) after start of topotecan was 2.1 and 4.1 months, respectively. In the subgroup analysis, patients with unknown primary (vs. those with a known primary) showed a significantly prolonged PFS of 3.5 months (vs. 1.9, P = 0.0107) and OS of 6.7 months (vs. 2.6 months, P = 0.0168). Grade 3/4 hematotoxicity was observed in 60% of patients. Topotecan shows only moderate antitumor activity in metastatic NEC. Disease control rate is lower than reported for SCLC. However, antitumor activity of topotecan seems higher in patients with unknown primary.

Neuroendocrine carcinoma of the esophagus: clinical characteristics and prognostic evaluation of 49 cases with surgical resection.

The clinicopathological features and optimum treatment of esophageal neuroendocrine carcinoma (NEC) are hardly known due to its rarity. Therefore, we conducted a retrospective study to analyze the clinical characteristics and prognosis of patients with surgically resected esophageal NEC. We collected clinicopathological data on consecutive limited disease stage esophageal NEC patients who underwent esophagectomy with regional lymphadenectomy in West China Hospital from January 2007 to December 2013. A total of forty-nine patients were analyzed retrospectively. The mean age of the patients was 58.4±8.2 years with male predominance. Fifty-five percent of the esophageal NEC were located in the middle thoracic esophagus. Histologically, 28 (57.1%) patients were found to be small cell NECs. Fifty-one percent of the patients were found to have lymph node metastasis. According to the 2009 American Joint Committee on Cancer (AJCC) staging system for esophageal squamous cell carcinoma, 9 patients were at stage I, 21 patients stage II, and 19 patients stage III. Twenty-six patients (53.1%) received adjuvant therapy. After a median follow-up of 44.8 months [95% confidence interval (CI), 35.2-50.4 months], the median survival time of the patients was 22.4 months (95% CI, 14.0-30.8 months). The 1-year and 3-year survival rates for the whole cohort patients were 74.9% and 35.3%, respectively. In univariate analysis, TNM staging, lymph node metastasis and adjutant therapy significantly influenced survival time. In multivariate analysis, TNM staging was the only independent prognostic factor. Esophageal NEC has a poor prognosis. The 2009 AJCC TNM staging system for esophageal squamous cell carcinoma may also fit for esophageal NEC. Surgery combined with adjuvant therapy may be a good option for treating limited disease stage esophageal NEC. Further prospective studies defining the optimum therapeutic regimen for esophageal NEC are needed.

Expression of Sex Determining Region Y-Box 2 and Pancreatic and Duodenal Homeobox 1 in Pancreatic Neuroendocrine Tumors

The World Health Organization 2010 classification divides pancreatic neuroendocrine tumors (p-NETs) entity to well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) by Ki-67 index. The aim of this study is elucidate the pathophysiology and tumor biology of p-NETs. We assessed the expression of transcription factors sex determining region Y-box 2 (SOX2) and pancreatic and duodenal homeobox 1 (Pdx1)) essential for the normal fetal development of pancreatic neuroendocrine cells in 46 surgically resected p-NETs by immunohistochemistry. The relationship of expression levels of these factors and clinicopathological factors were analyzed. SOX2 was positive in 6 p-NETs (13.0%). Five of 7 NEC patients showed positive for SOX2. SOX2 was highly (sensitivity 71%) and specifically (specificity 97%) expressed in NEC. Patients with SOX2 positive p-NET showed the significantly shorter disease-free and overall survival than patients with SOX2 negative p-NET. High Pdx1 expression was seen in 25 p-NET patients (54.3%). None of the NEC patients showed high Pdx1 expression. There was a significant reverse correlation between SOX2 and Pdx1 expression. The expression patterns of SOX2 and Pdx1 highly correlated with prognosis of p-NETs. These expression patterns may represent the biological and pathophysiological difference of p-NETs and indicate the origin of tumor.

Whole exome sequencing and gene expression profiling of neuroendocrine carcinoma in the stomach.

57 Background: Neuroendocrine carcinoma (NEC) in the stomach is a rare disease with the incidence of about 0.6 % of all gastric cancer and is well known as a highly malignant tumor with poor survival. Despite the malignant phenotype of this disease, the global gene expression profiling of gastric NEC has not yet been elucidated. We have started a comprehensive molecular profiling project that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from January 2014, setting a goal to get 3,000 samples in 3 years. We had already evaluated more than 1,500 samples from various types of malignancies, including 111 samples from gastric cancer. Here, we performed deep sequencing of 409 cancer-related genes for gastric NEC patients, adding whole-exome sequencing and gene expression profiling, to identify a gene variant of gastric NEC. Methods: Surgically-resected fresh tumor samples and peripheral blood were analyzed by whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies). A total of 111 patients with gastric cancer were evaluated until August 2015, including 6 gastric NEC (5.4 %). We compared single nucleotide variants (SNVs) and gene expression profiles between gastric NEC and gastric adenocarcinoma. Results: All the gastric NEC patients were male with median age of 69 years (59–79 years). According to classification of TNM 7th, there were two patients with stage IA, one with IIA, one with IIIB and two with IIIC. Three of them had adenocarcinoma components constituted > 30% of the respective tumors, fulfilling the criteria for mixed adenoneuroendocrine carcinoma (MANEC), as defined by the WHO classification. There was no specific SNV for NEC. However, gene expression profiling identified several specific genes expressing in NEC; most of the highly expressed genes were also known to be expressed in neuroendocrine cells. Furthermore, CPLX2 and SCG3, which had been reported to be expressed in various neuroendocrine tumors, were included. Conclusions: Gastric NEC could be characterized by specific gene expression including those expressed in neuroendocrine cells and neuroendocrine tumors.

Efficacy and Safety of Carboplatin and Etoposide Combination Chemotherapy for Extrapulmonary Neuroendocrine Carcinoma: A Retrospective Case Series

Background: Neuroendocrine carcinoma (NEC) is a rare tumor type, and a standard therapy for NEC has not yet been established. From 2008 to 2013, carboplatin-etoposide combination therapy has been used to treat almost all NEC patients in our department, and the objective of the present study was to investigate the therapeutic effects of carboplatin-etoposide combination therapy in NEC. Methods: This retrospective study was conducted based on medical records from 2008 to 2013. Eligible patients had been pathologically diagnosed with NEC and had received a carboplatin-etoposide combination as first-line chemotherapy. Results: Nineteen patients were included in the study, and the overall response rate was 47.4%. The median overall survival was 12.7 months, and the median progression-free survival was 7.0 months. The median survival times were 10.8 and 8.9 months in NEC patients with primary sites in the gastrointestinal tract and hepatobiliary-pancreatic system, respectively. Median progression-free survival times were 5.0 and 3.1 months, respectively. The major toxicities were grade 3 and 4 leukopenia (73.7%), neutropenia (78.9%), anemia (31.6%), and thrombocytopenia (26.3%). Conclusions: Carboplatin-etoposide combination therapy for NEC may have comparable effectiveness and milder adverse events than cisplatin-etoposide combination therapy.

Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms.

Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma.

There is no standard for second-line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy in this population. A single-center retrospective analysis of consecutive G3-NEC patients treated with FOLFOX chemotherapy after failure of a cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival (PFS), overall survival (OS), response rate, and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (seven males and 13 females; median age 55; range 23-87 years) with a performance status of 0-1 in 75% of them. Primary location was gastroenteropancreatic in 12, thoracic in four, other in two, and unknown in two patients. There were 12 (65%) large-cell and 7 (30%) small-cell G3-NEC tumors, and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients received FOLFOX as second-line treatment and 8 (40%) as third-line treatment or later and the median number of administered cycles was 6 (range 3-14). The median follow-up was 19 months. Median PFS was 4.5 months. Among the 17 evaluable patients, five partial responses (29%), six stable diseases (35%), and six progressive diseases (35%) were observed. Median OS was 9.9 months. Main Grade 3-4 toxicities were neutropenia (35%), thrombopenia (20%), nausea/vomiting (10%), anemia (10%), and elevated liver transaminases (10%). Our results indicate that the FOLFOX regimen could be considered as a second-line option in poorly differentiated G3-NEC patients after cisplatinum-based first-line treatment but warrant further confirmation in future larger prospective studies.

The predictive value of pre-and postoperative neutrophil-lymphocyte ratio for pulmonary large cell neuroendocrine carcinoma patients

Objective To analyze the impact of pre-and postoperative neutrophil-lymphocyte ratio (NLR) on the survival of patients with pulmonary large cell neuroendocrine carcinoma (LCNEC).Methods The clinical data of 28 patients with pulmonary LCNEC were retrospectively reviewed,and the predictors of univariate analyses included gender,age,smoking history,pathological type and tumor stage,pre-and postoperative neutrophil-lymphocyte ratio (NLR) and preoperative NLR/postoperative NLR,etc.The analysis of Cox multiple regression was performed to determine the parameters of predicting the LCNEC prognosis.Results Univariate analysis showed that age (P ＜ 0.05),smoking history (P ＜ 0.05),pathological type (P ＜ 0.05),tumor stage (P ＜ 0.05),preoperative NLR ≥2.5 (P ＜ 0.05) and postoperative NLR ≥ 3.5 (P ＜ 0.05) were prognostic factors.Multivariate analysis revealed that tumor stage (P ＜0.05),preoperative NLR ≥2.5 (P ＜0.05) and postoperative NLR ≥3.5 (P ＜ 0.05) were independent prognostic factors.Conclusion The elevated pre-and postoperative NLR may predict the LCNEC patients with a poor prognosis after surgery. Key words: Pulmonary carcinoma; Neuroendocrine carcinoma; Surgery; Prognosis

Prognostic Significance of Metastatic Lymph Node Number, Ratio and Station in Gastric Neuroendocrine Carcinoma

The objective of this study was to analyze the prognostic significance of metastatic lymph node status in gastric neuroendocrine carcinoma (GNEC) patients following radical gastrectomy. A consecutive series of 73 patients who underwent gastrectomy between 1999 and 2011 for GNEC was retrospectively reviewed. Indexes of lymph node involvement (the pN classification, metastatic lymph node number [MLNn], ratio [MLNr], and station [MLNs]) and other clinicopathological data were analyzed. Fifty-four patients met the inclusion criteria and were enrolled in the study. Among them, 44 patients (81 %) were found to have lymph node metastases. The median survival time of the entire cohort was 63.2 (range, 14–153) months with 3- and 5-year survival rates of 88.9 and 47.9 %, respectively. The median total number of lymph nodes, MLNn, and MLNr were 19 (range, 10–56), 5 (range, 1–21), and 25 % (6–100 %), respectively. Cox regression analysis revealed pN classification = 1, MLNn >2, MLNr >0.1, and MLNs = 2, and distant metastases influenced prognosis independently (P = 0.0266, 0.0091, 0.0031, 0.0119, and 0.0021, respectively). In addition to the pN classification, indexes of metastatic lymph node involvement, including MLNn, MLNr, and MLNs, were all significant predictors of survival in GNEC patients. Distant metastasis was also a significant prognostic factor. These indexes proved to be accurate and important supplements to survival factors, which may improve risk classification of GNEC patients.

Risk factors, therapy and survival outcomes of small cell and large cell neuroendocrine carcinoma of urinary bladder.

The risk factors, the optimal therapy and prognostic factors contributing to poor outcomes of neuroendocrine urinary bladder carcinoma are not fully elucidated because of its rarity. We reviewed the medical records of neuroendocrine bladder carcinoma patients treated at the University of Nebraska Medical Center between 1996 and 2011. Eighteen patients, 55% female with a median age of 77 years, had stage IV disease at diagnosis in 50% of cases. There was a high prevalence of smoking (78%), medical co-morbidities (94%), prior cancer history (22%) and family history of cancer (61%). Treatment modalities included surgery (72%), platinum-based chemotherapy (50%) and/or radiation (22%). Median overall survival was 18.5 months (95% confidence interval, 7-36 months). Patients with Stage II and III cancer who underwent radical surgery with or without neoadjuvant chemotherapy had a median survival of 37 months. In addition to smoking, for the first time, our study indicates that the personal or family history of cancer may increase risk to neuroendocrine bladder cancer. Advanced age and stage at diagnosis, and the presence of multiple co-morbidities contribute to poor overall survival. Patients with early-stage disease are likely to benefit from a combination of radical surgery and platinum-based neoadjuvant chemotherapy.

A Phase III Trial Comparing Irinotecan and Cisplatin with Etoposide and Cisplatin in Adjuvant Chemotherapy for Completely Resected Pulmonary High-grade Neuroendocrine Carcinoma (JCOG1205/1206)

A randomized Phase III trial commenced in Japan in March 2013. Post-operative adjuvant chemotherapy with etoposide plus cisplatin is the current standard treatment for resected pulmonary high-grade neuroendocrine carcinoma including small cell lung cancer and large cell neuroendocrine carcinoma. The purpose of this study is to confirm the superiority of irinotecan plus cisplatin in terms of overall survival over etoposide plus cisplatin as post-operative adjuvant chemotherapy for pathological Stage I-IIIA completely resected pulmonary high-grade neuroendocrine carcinoma patients. A total of 220 patients will be accrued from 54 Japanese institutions within 6 years. The primary endpoint is overall survival and the secondary endpoints are relapse-free survival, proportion of treatment completion, adverse events, serious adverse events and second malignancy. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000010298 [http://www.umin.ac.jp/ctr/index.htm].

Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas

Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker. OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor. OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor. OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

Feasibility and Efficacy of Combined Cisplatin and Irinotecan Chemotherapy for Poorly Differentiated Neuroendocrine Carcinomas

No standard treatment has been established for poorly differentiated neuroendocrine carcinoma; the usual recommended treatment is based on the strategy for small cell lung carcinoma. The aim of this study was to evaluate the response of poorly differentiated neuroendocrine carcinoma to the combination of irinotecan and cisplatin in one institution. We retrospectively reviewed 50 poorly differentiated neuroendocrine carcinoma patients treated from September 2005 to April 2011 in our institution. Patients were divided into two stages: limited disease or extensive disease. Forty-four patients received the combination chemotherapy of irinotecan and cisplatin, consisting of 4-week cycles of 60 mg/m(2) irinotecan on days 1, 8, 15 and 60 mg/m(2) cisplatin on day 1. Median age was 60 years. Median follow-up time was 11.4 months. Overall survival did not reach the median, and 1-year overall survival was 67%. The response rate was 50% (64% at first line), and progression-free survival was 4.8 months (7.3 months at first line). Grade 3-4 hematologic adverse events were seen in 29 patients (66%) and Grade 3-4 non-hematologic adverse events were seen in 20 patients (45%), but no patients died of adverse events. Multivariate analysis showed a statistically significant relationship with neuron-specific enolase elevation and poor overall survival (P= 0.016, hazard ratio 6.261, 95% confidence interval). The combination chemotherapy of irinotecan and cisplatin is moderately effective and feasible, and it should be considered as a treatment option for poorly differentiated neuroendocrine carcinoma.

Somatostain receptor (SSTR)-targeted therapy in pulmonary large-cell neuroendocrine carcinoma (LCNEC) patients with intermediate proliferation rate (PR).

e17509 Background: LCNEC is classified as a high-grade (HG) foregut-derived neuroendocrine tumor (NET), exceeded only by small-cell lung carcinoma (SCLC) in terms of aggressiveness. It is a recent disease entity, only two decades old, and uncommon: 2%-3% of all lung cancer cases. Therefore, therapy guidelines are still evolving. Methods: A single institution observational study, consecutive series. Histopathology diagnosis conformed to WHO criteria for thoracic tumors (Travis et al, IARC Press, 2004). Immunohistochemistry included proliferation Ki67 index evaluation. SSTRs' affinity was assessed either by 111 In octreotate SPECT, or by Ga68 DOTA-NOC octreotate PET CT total body scans. Results: We have treated nine metastatic LCNEC patients over the last four years. Seven were scanned for presence of somatostatin receptors; 4 were positive. Three of the four had Ki67 staining ranging 10-20% (intermediate PR, IPR), one had 80% (high PR). All four have received octreotide LAR as a therapy component. In two cases octreotide was given upfront and conferred PFS of 18 and 8 months and, in the former- regression of hepatic lesions. The other patient also received 177 Lutetium radionuclide therapy (PRRT) upon progression, resulting in uptake normalization at an hepatic mass and stabilization of other lesions. The 3rd patient had started with induction chemotherapy and then maintained imaging-confirmed stable disease and normal function, during octreotide treatment, for three years. The fourth, HG patient, survived only 8 months. Three of the 9 patients are alive with disease on treatment, surviving 25+, 57+ and one, with 50% proliferation index and a negative DOTANOC scan, has survived 16+ months, with no targeted therapy. Conclusions: This small series illustrates the diagnostic value and therapeutic implication of SSTR scans, combined with Ki67 assessment, aiming at therapy selection for IPR subgroup, receptor positive, pulmonary LCNEC patients who can benefit from octreotide targeted therapy.

Comparison of Patient Survival after Resection for Pulmonary Carcinoid Tumors Compared to Other Neuroendocrine Tumors: A United States Population Study

Background: We hypothesized: 1) resected pulmonary typical carcinoid (TC) will show a favorable clinical pattern compared to other bronchopulmonary neuroendocrine tumors (BPNETs); and 2) Atypical carcinoid (AC) and large-cell neuroendocrine carcinoma (LCNEC) patients will have similar outcomes. Methods: The Surveillance Epidemiology and End Result database was queried to compare demographics and tumor specific variables in patients undergoing resection for TC, AC, LCNEC and small cell lung cancer (SCLC) from 2001 to 2006. Results: Similar to LCNEC, AC patients had greater incidence of histologic positive lymph nodes compared to TC (P < 0.001). Survival analysis showed a mean survival of 40.0 ± 1.9 months for SCLC, 46.2 ± 2.2 months for LCNEC, 58.3 ± 2.3 months for AC, and 70.2 ± 0.2 months for TC tumors. TC patients demonstrated favorable survival, and SCLC patients poorer survival, compared to AC and LNEC patients (P < 0.01). Conclusion: AC tumors are a BPNET histology that exhibits clinical behavior distinct from TC. AC tumors should be staged, and treated with stage appropriate therapeutic strategies similar to other non-small cell lung cancers.

Invasive Neuroendocrine Carcinoma of the Breast: A Prognostic Research of 107 Chinese Patients

Neuroendocrine carcinoma (NEC) of the breast, a distinct type of mammary carcinoma whose terminology was not proposed until 2003, has not been well recognized or studied. The aim of our study is to evaluate the clinicopathological features and outcomes of this type of tumor. We conducted a comparative study on 107 NEC patients and 475 invasive ductal carcinoma, not otherwise specified(IDC, NOS) patients from the Department of Pathology, Huashan Hospital, Fudan University, to determine the demographic, pathological, and clinical features at presentation, along with patient outcomes and prognostic factors. With an older age at presentation, NECs are more likely to be estrogen receptor(ER)/ progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER-2) negative, and have a higher propensity for local recurrence and poorer overall survival(OS). Higher T classification, M classification, TNM stage, the expression of Ki67, and the absence of PR expression are prognostically of poorer OS and distant recurrence-free survival(DRFS). Distant metastasis is also a dependent prognostic factor. NEC of the breast is a distinct type of neoplasm with higher malignancy. Novel therapies such as the endocrine therapy should be explored and studies with larger case number and longer follow-up will be needed.