Low-grade Neuroendocrine Tumors Research Articles

A literature-based treatment algorithm for low-grade neuroendocrine liver metastases

BackgroundThe optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM. MethodsA treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments. ResultsApplying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics. ConclusionThis literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.

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.

MiR375-3p Distinguishes Low-Grade Neuroendocrine From Non-neuroendocrine Lung Tumors in FFPE Samples.

Lung cancer is still one of the leading cause of death worldwide. The clinical variability of lung cancer is high and drives treatment decision. In this context, correct discrimination of pulmonary neuroendocrine tumors is still of critical relevance. The spectrum of neuroendocrine tumors is various, and each type has molecular and phenotypical differences. In order to advance in the discrimination of neuroendocrine from non-neuroendocrine lung tumors, we tested a series of 95 surgically resected and formalin-fixed paraffin embedded lung cancer tissues, and we analyzed the expression of miR205-5p and miR375-3p via TaqMan RT-qPCR. Via a robust mathematical approach, we excluded technical outliers increasing the data reproducibility. We found that miR375-3p levels are higher in low-grade neuroendocrine lung tumor samples compared to non-neuroendocrine lung tumors. However, miR375-3p is not able to distinguish among different types of neuroendocrine lung tumors. In this work, we provide a new molecular marker for distinguishing non-neuroendocrine from low-grade neuroendocrine lung tumors samples establishing an easy miRNA score to be used in clinical settings, enabling the pathologist to classify more accurately lung tumors biopsies, which may be ambiguously cataloged in routine examination.

Systematic review: management of localised low-grade upper gastrointestinal neuroendocrine tumours.

Neuroendocrine tumours (NETs) of the stomach and duodenum are rare, but are increasing in incidence. Optimal management of localised, low-grade gastric and duodenal NETs remains controversial. To systematically review recent literature that has evaluated the management of localised low-grade gastric and duodenal NETs. A systematic literature search was conducted. Articles were screened and eligible articles fully assessed. Additional articles were identified through the included articles' reference lists. Several relevant retrospective case series were identified, but there was considerable heterogeneity between studies and they reported a variety of parameters. Type I gastric NETs had an excellent prognosis and conservative management approaches such as endoscopic surveillance/resection were appropriate in most cases. Many type III gastric NETs were low grade and appeared to have a better prognosis than has previously been appreciated. Endoscopic rather than surgical resection was therefore effective in some patients who had small, low-grade tumours. Duodenal NETs were more heterogenous. Endoscopic resection was generally safe and effective in patients who had small, low-grade, nonfunctional, non-ampullary tumours. However, some patients, especially those with larger or ampullary duodenal NETs, required surgical resection. Most type I gastric NETs behave indolently and surgical resection is only rarely indicated. Some type III gastric and duodenal NETs have a worse prognosis, but selected patients who have small, localised, nonfunctional, low-grade tumours are adequately and safely treated by endoscopic resection. Due to the complexity of this area, a multidisciplinary approach to management is strongly recommended.

Long Non-coding RNAs in Pulmonary Neuroendocrine Neoplasms.

Pulmonary neuroendocrine neoplasms (NENs) are classified into low-grade neuroendocrine tumors and high-grade neuroendocrine carcinomas (NECs). There are significant differences in therapeutic strategies of the different NEN subtypes, and therefore, precise classification of pulmonary NENs is critical. However, challenges in pulmonary NEN classification include overlap of diagnostic histological features among the subtypes and reduced or negative expression of neuroendocrine markers in poorly differentiated pulmonary NECs. Recently, transcription factor insulinoma-associated protein 1 (INSM1) was identified as a sensitive marker of neuroendocrine and neuroepithelial differentiation. In this study, INSM1 expression was detected by immunohistochemistry in greater than 94% of pulmonary NENs, indicating that it is a highly sensitive marker of pulmonary NENs and is useful to detect poorly differentiated pulmonary NECs. Although there are well-established morphological and immunohistologic criteria to diagnose pulmonary NENs, there is no universal consensus regarding prognostic markers of pulmonary NENs. Studies have shown that non-small cell lung cancers express long non-coding RNAs (lncRNAs), which regulate gene expression, epithelial-to-mesenchymal transition, and carcinogenesis. We characterized expression and function of lncRNAs, including HOX transcript antisense RNA (HOTAIR), maternally expressed 3 (MEG3), and prostate cancer antigen 3 (PCA3) in pulmonary NENs, including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma (SCLC/NEC), and large cell neuroendocrine carcinoma (LCNEC/NEC). In situ hybridization and real-time polymerase chain reaction studies showed higher expression (p< 0.01) of all lncRNAs in SCLC/NEC. Small interfering RNA studies indicated a role for MEG3 and PCA3 in tumor proliferation. Therefore, these lncRNAs may serve as prognostic indicators of pulmonary NEN aggressiveness and as possible therapeutic targets.

Surgical resection of primary tumor is associated with prolonged survival in low-grade pancreatic neuroendocrine tumors

The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing over the past few decades. Surgery for low-grade and small PNETs of less than 2cm and N0M0 is still debated. The purpose of this study is to examine the association between surgical resection and survival in patients with low-grade nonfunctioning PNETs. Patients diagnosed with PNETs between 2004 and 2015 were extracted from SEER. Kaplan-Meier methods and Cox proportional hazard models were used to estimate independent predictors in PNETs patients. A total of 2637 patients (2147 underwent surgical resection and 490 did not undergo surgery) with histologically confirmed low-grade PNETs in this cohort study. Overall survival (OS) and cancer-specific survival (CSS) of patients with surgery was better than those without surgery (log rank test POS<0.001, PCSS<0.001). Multivariate Cox regression analysis showed that surgical status was an independent prognostic factor associated with OS (HR 3.257, 95%CI: 2.635, 4.026) and CSS (HR 3.546, 95%CI: 2.798, 4.493). Subgroup analysis suggested the patients receiving surgery apparently had better OS and CSS regardless of tumor size (all log rank test POS<0.001, all log rank test PCSS<0.001) and SEER stage (all log rank test POS<0.001, all log rank test PCSS<0.001), compared to patients without removal of the primary tumor. Surgical resection of primary tumor may have a significant benefit on survival for patients with low-grade nonfunctioning PNETs. To determine the optimal management, grade, stage and tumor size should be considered comprehensively.

Can CT Histogram Analysis Predict the World Health Organization Grade of Rectal Neuroendocrine Tumors?

Background: It is essential to discriminate low-grade (G1), intermediate-grade (G2) and high-grade (G3) rectal neuroendocrine tumors (R-NETs) due to the treatment decisions and postoperative management are totally different. CT histogram analysis, which is a novel method to provide objectively quantified assessment of tumor, may be helpful for differentiating the grade of R-NETs. Methods: A total of 61 (35 G1, 12 G2 and 14 G3) patients who underwent preoperative contrast-enhanced CT and treated with surgery to be confirmed as R-NETs were included in this study from January 2014 and May 2019. We accurately depicted the region of interest (ROI) and measured the CT texture parameters (mean, median, 10th, 25th, 75th, 90th percentiles, skewness, kurtosis and entropy) from arterial phase image by two radiologists. We calculated and compared these parameters between low-grade (G1), intermediate-grade (G2) and high-grade (G3) tumors by applying appropriate statistical method. We obtained the optimal parameters to identify G1 and G2/G3 by using receiver operating characteristic (ROC) curves. Findings: Histogram analysis of CT arterial phase imaging demonstrated significant differences between G1 and G2 or G3 group in several histogram parameters (mean, median, 10th, 25th, 75th and 90th percentiles) (all P 0.05). Skewness, kurtosis and entropy showed no significant differences among three groups ( P =0.449, 0.285, 0.057, respectively). ROC analysis showed a good predictive performance between G1 and G2/G3 and the mean generated the highest area under the curve (AUC = 0.832), followed by the median (AUC = 0.827). Interpretation: CT histogram parameters, especially mean and median, can be used as excellent indicators for predicting the grade (G1 and G2/G3) of rectal neuroendocrine tumors. Funding Statement: This study has received funding by the National Natural Science Foundation of China (Grant No.81771801,81801695, 81701657 and 81873623). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The Institutional Review Board of our hospital (Medical Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) approved this retrospective study and the requirement for patient informed consent was waived.

Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: A single-center experience

Gastric neuroendocrine tumors (G-NETs) are rare tumors, but their incidence is gradually increasing. Despite the existence of many classification systems, determining prognosis and planning treatment in patients with G-NETs remains a clinical challenge. In this study, the prognostic value of the World Health Organization (WHO) 2017 grading system and the effect of surgery on survival in low grade neuroendocrine tumors were investigated. G-NETs who were diagnosed between January 2000 and May 2017 were included in the study. Patients' demographic characteristics, treatment details, and survival data were obtained from medical charts. Pathological samples were re-classified according to the WHO 2017 grading system. Of the total 94 evaluated patients, 50 (53.2%) were classified with G1 NETs, 37(39.4%) with G2 NETs, 4(4.2%) with well-differentiated G3 NETs, and the remaining 3 patients with poorly differentiated G3 neuroendocrine carcinoma (NEC). The median follow-up time was 83.2 months. There was a statistically significant difference in 5-year progression free survival (PFS) between G1 tumors (100%) and G2 tumors (76%) (p<0.001). However, there was no statistically significant deference in 5-year overall survival rate (OS) for G1 (97%) and G2 (82%) tumors (p=0.141). When G2 and G1 NETs were compared according to their surgical approach, radical surgery was more frequently performed in patients with G2 tumors (p<0.001). However, radical surgery did not improve PFS in G1 and G2 NETs. The WHO 2017 NET classification system may have low prognostic value for determining the prognosis of patients with G1 and G2 tumors. Radical surgery for G1 and G2 NETs did not improve PFS in our study.

Neuroendokrine Differenzierung beim Mammakarzinom

To classify as breast cancer with neuroendocrine differentiation a growth pattern as encountered in well differentiated (G1, G2) neuroendocrine tumors (NET) of the gastrointestinal tract and the lung must be present in addition to the immunohistochemical expression of neuroendocrine markers (chromogranin, synaptophysin). The majority of breast cancers fulfilling these criteria show hormone receptor positivity and with regard to prognosis resemble luminal type of breast cancer from which they are not fundamentally different. Despite lacking clinical relevance the up-coming WHO classification of breast cancer will nevertheless introduce the new category of NET luminal type. Immunohistochemical detection of neuroendocrine marker alone cannot be considered as sufficient for classification because it can frequently be encountered in other types of breast cancer (e.g. mucinous, solid papillary). From low grade NET with good differentiation those with poor differentiation and most frequently small cell appearance have to be differentiated. Poorly differentiated NET can primarily originate in the breast, which may be indicated by intraductal growth and co-expression of GATA3 but in these cases metastasis of extra mammary cancers has to be considered and correlation with the clinical findings is required for correct classification.

DIFFUSE SUBCUTANEOUS NODULES AS A FIRST SIGN OF A METASTATIC PULMONARY NEUROENDOCRINE TUMOR

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Pulmonary neuroendocrine tumors are rare tumors that arise from cells of the endocrine and nervous systems with an incidence rate of 2/100,000 population/year in the United States, comprising 2% of all primary lung cancers. The most common described sites of metastases from Carcinoid tumors are liver , bone , and mediastinal lymph nodes . Subcutaneous metastases from carcinoid tumors are very rare. The behavior of these tumors depends upon their location within the lungs, whether they secrete hormones, or if they have metastasized. This tumors comprise a spectrum of progression, including: low grade neuroendocrine tumors , intermediate grade neuroendocrine tumors and high grade neuroendocrine tumors (large cell neuroendocrine tumors and small cell carcinomas) respectively. CASE PRESENTATION: A 72-year-old latin american female with a past medical history of breast cancer that was previously treated with chemotherapy and radiotherapy 10 years ago. Patient came to the institution due to multiple skin progressively painful enlarged skin nodules, fatigue, generalized weakness and melena of several days of evolution. Physical examination revealed multiple skin nodules measuring from 1 to 4 cm in diameter with the largest measuring 3 x 4 cm in the left neck area extremely tender and firm. A biopsy was performed with histopathology consistent with a carcinoid tumor with moderate amount of cytoplasm and eccentric nuclei. Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin with positive markers for CD56, pankeratin with a Ki67 of 70%. Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) . These results were consistent with cutaneous metastasis from pulmonary carcinoid tumor by which same cells were also seen by stomach biopsy of nodules present as well. DISCUSSION: Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts. The histology of cutaneous carcinoid metastases typically resembles the primary lesion. However, identifying source is a major role in this cases. Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy but thats not the case in the majority of cases. Thats were histologic stains and cells characteristics play a major role. Our case of cutaneous metastasis of a carcinoid tumor presented as multiple tender subcutaneous nodules. The histology of the lesion was consistent with the known carcinoid tumor of the lung. CONCLUSIONS: Even though neuroendocrine tumors are rare, obtaining an concise clinical history , addressing risk factors and pertinent findings of medical presentation with the appropriate immunohistochemical panels is the cornerstone of this challenging cases when primary site is in doubt. Reference #1: Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practiceCaplin ME, Baudin E, Ferolla P, et al. Reference #2: Primary pulmonary carcinoid tumor: a long-term single institution experience/Primary pulmonary carcinoid tumor.Ryan F. Herde, MD, MS1, Kristine E. Kokeny, MD2, Chakravarthy B. Reddy, MD3, Wallace L. Akerley, MD4, Nan Hu, PhD5, Jonathan P. Boltax, MD3, and Ying J. Hitchcock, MD2. Reference #3: Cutaneous Metastasis of a Pulmonary Carcinoid Tumor Cutis. 2017 May;99(5):E13-E15 DISCLOSURES: No relevant relationships by Christian Castillo Latorre, source=Web Response No relevant relationships by Michael Cruz, source=Web Response No relevant relationships by Omar Mendez Melendez, source=Web Response No relevant relationships by Kelvin Rivera Manzano, source=Web Response

2155 A Minimally Invasive Approach to Resection of a Duodenal Neuroendocrine Tumor Using the Full-Thickness Resection Device

INTRODUCTION: The Full-Thickness Resection Device (FTRD) allows for diagnostic and therapeutic endoscopic full-thickness resection (EFTR) of lesions that are unresectable with conventional endoscopic techniques. The device offers a minimally invasive approach to full thickness resection of intestinal and rectal lesions, and ensures safe tissue closure with over-the-scope-clip (OTSC) technology. We report a patient in whom the FTRD system was used for R0 resection of a duodenal neuroendocrine tumor. CASE DESCRIPTION/METHODS: A 68 year-old-male with history of Barrett’s esophagus was found to have a low-grade neuroendocrine tumor of the duodenal bulb on surveillance upper endoscopic screening. Computed tomography (CT) imaging of the abdomen revealed a hypervascular duodenal bulb mass, without obvious extension to the wall, lymphadenopathy, or evidence of metastasis. Endoscopic ultrasound (EUS) with fine needle aspiration (FNA), revealed a 1.2 cm mass arising from the submucosal layer with pathology indicating a low-grade neuroendocrine tumor. Due to the small tumor size, EFTR by FTRD was planned. Upon advancing the endoscope with the FTRD system attached, a non-bleeding neuroendocrine tumor was visualized (Figure 1). The mass was carefully pulled into the cap and after banding, ligation and cutting; there was a full thickness en bloc resection with all layers of the duodenum apparent (Figure 2). Pathology of the specimen documented a grade 2 neuroendocrine tumor with clean margins, confirming R0 resection (Figure 3). The patient was discharged the same day without associated complications. DISCUSSION: Upper gastrointestinal endoscopy and histologic examination are essential for diagnosis of duodenal neuroendocrine tumors, and EUS should follow for determination of size and depth of infiltration as well as determination of locoregional lymph node involvement. Multiple factors, such as tumor size, location, and grade need to be considered when determining treatment options. The FTRD system offers a novel endoscopic treatment approach to tumors extending beyond the submucosa that require full thickness resection and would otherwise require higher risk surgical intervention. The technology allows for safe tissue closure, valid histologic evaluation of the en-bloc specimen, and minimal thermal injury, thus reducing the morbidity and cost otherwise associated with surgery. Our case illustrates the successful R0 resection of a T2, grade 2 neuroendocrine tumor using the FTRD.

Therapeutic options in lung neuroendocrine tumors: between established concepts and new hopes.

Typical (TC) and atypical (AC) carcinoids are low-grade neuroendocrine tumors (NETs) of the lung and, are neglected diseases in respect of both high-grade NETs of the lung (i.e. small-cell lung cancer and large-cell neuroendocrine carcinoma) and gastroenteropancreatic (GEP)-NETs. AC and TC account for 2 and 0.2% of all thoracic malignancies, respectively, and have a 12.9% chance of metastatic spread at diagnosis, reaching up to 20% during disease history. There are very few trials specifically designed for lung NETs, and therapeutic options are mainly derived by studies carried out in patients with GEP-NETs. We report a case of a patient affected by AC progressed to available standard treatments who received off-label treatment with sunitinib, a well-known multitarget tyrosine-kinase inhibitor with marked antiangiogenic activity, used routinely for the treatment of GEP-NETs. During treatment, the patient required the administration of an alternative schedule to improve tolerability, with benefit, and achieved a partial response according to the RECIST criteria, which is unusual in NETs. We critically reviewed available data supporting the use of somatostatin analogs, chemotherapy, and target therapies (everolimus and sunitinib) in advanced lung NETs. In the review, ongoing trials in lung NETs and future developments in this research field are also discussed.

Placenta-Specific 8 Is Overexpressed and Regulates Cell Proliferation in Low-Grade Human Pancreatic Neuroendocrine Tumors

Background/Aims: Many aspects of the biology of pancreatic neuroendocrine tumors (PanNETs), including determinants of proliferative, invasive, and metastatic potential, remain poorly understood. Placenta-specific 8 (PLAC8), a gene with unknown molecular function, has been reported to have tumor-promoting roles in different human malignancies, including exocrine pancreatic cancer. Since preliminary data suggested deregulation of PLAC8 expression in PanNET, we have performed detailed analyses of PLAC8 expression and function in human PanNET. Methods: Primary tissue from PanNET patients was immunohistochemically stained for PLAC8, and expression was correlated with clinicopathological data. In vitro, PLAC8 expression was inhibited by siRNA transfection in PanNET cell lines and effects were analyzed by qRT-PCR, Western blot, and proliferation assays. Results: We report that PLAC8 is expressed in the majority of well-differentiated human PanNETs, predominantly in early-stage and low-grade tumors. SiRNA-mediated knockdown of PLAC8 in PanNET cells resulted in decreased proliferation and viability, while apoptosis was not induced. Mechanistically, these effects were mediated by attenuation of cell cycle progression, as Western blot analyses demonstrated upregulation of the tumor suppressor p21/CDKN2A and downregulation of the cell cycle regulator Cyclin D1 as well as reduced levels of phosphorylated ribosomal protein s6 and retinoblastoma protein. Conclusion: Our findings establish PLAC8 as a central mediator of cell growth in a subset of human PanNET, providing evidence for the existence of distinct molecular subtypes within this class of tumors.

SUN-LB068 Ectopic Cushing Syndrome Due to a Metastatic Neuroendocrine Tumor Treated with Metyrapone

Introduction: We describe a patient with a non-secretory low grade neuroendocrine tumor that transformed into a high grade carcinoma causing Cushing syndrome that was medically managed with metyrapone. Clinical Case: A 53 year old woman with a history of widely metastatic neuroendocrine tumor for 5 years was treated with somatostatin analogues, multiple chemotherapeutic agents, radiation therapy, and recently peptide receptor radionuclide therapy (PRRT). Some of her tumors were responding to PRRT, except that 1 month after her 3rd round of PRRT, she presented with profound muscle weakness, confusion, hypokalemia (K = 3.1 meq/L), and new onset of diabetes mellitus (glucose 319 mg/dL). Ectopic Cushing syndrome was diagnosed by ACTH of 748 pg/mL (n 7.2 - 63 pg/mL), a serum cortisol of 127 mcg/dL (n 6.7 - 22.6 mcg/dL), and a 24 hour urine free cortisol of 20,328 mcg/L (n 0 - 50 ug/24 hr). Her labs also showed pancytopenia including platelet count of 47 E3/ul (n 150 - 450 x10E3/uL). Imaging revealed growing necrotic liver metastases and thickened adrenal glands. Biopsy of the liver lesions revealed a high grade metastatic small cell neuroendocrine carcinoma with a mitotic rate of 49/10 HPF and Ki-67 of 70%. Interestingly, the neuroendocrine tumor cells in the liver biopsy did not stain for ACTH. This diverged greatly from pathology on initial diagnosis which revealed a low-grade well differentiated neuroendocrine tumor with a mitotic rate 2/10 HPF and Ki-67of 4-5%. It was clear from the patient’s clinical presentation and pathology results that her tumor had evolved into a poorly differentiated tumor secreting either ACTH and/or CRH resulting in Cushing syndrome. She was deemed a poor surgical candidate for adrenalectomy due to critical illness and advanced cancer. Elevated transaminases related to necrotic liver lesions precluded use of ketoconazole. Thus, medical therapy was initiated using metyrapone as well as spironolactone, potassium supplements, and insulin. Serum cortisol improved rapidly to 20 mcg/dl. 24 hour urine free cortisol improved to 1,129 mcg/ 24 hours with metyrapone 250mg twice daily and to 429 mcg/ 24 hours with metyrapone 250 mg every 6 hours. Her thrombocytopenia worsened with a nadir of 5 E3/ul but recovered to 127 E3/ul with continuation of metyrapone. Bone marrow biopsy performed at that time found low grade neuroendocrine tumor cells that did not stain for ACTH. Conclusion: The transformation of an indolent low grade neuroendocrine tumor to a high grade neuroendocrine carcinoma was accompanied by an ectopic Cushing syndrome. The cortisol excess was controlled rapidly and effectively with metyrapone. Thrombocytopenia was temporally related to the severe hypercortisolism and platelets improved to near normal with correction of cortisol. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-LB058 Mediastinal Parathyroid Adenoma Presenting as a Neuroendocrine Tumor

Introduction: Tertiary hyperparathyroidism caused by renal failure can lead to ectopic parathyroid tissue hyperplasia creating a diagnostic challenge. Here we describe a case of mediastinal parathyroid hyperplasia presenting as a neuroendocrine tumor. Case Presentation: A 40-year-old male presented for endocrine workup of a possible mediastinal paraganglioma. At age 22 he was diagnosed with resistant hypertension followed by rapidly progressive renal failure. Hemodialysis was initiated following a failed kidney transplant at age 30. He was treated by nephrology for secondary hyperparathyroidism with calcitriol and cinacalcet and serum calcium was within the normal range. Parathyroid hormone (PTH) was 598 pg/mL (12-65 pg/mL). The patient developed shortness of breath and a right pleural effusion while awaiting a second transplant and a CT of the chest was completed. This revealed a 3.1x4.0x5.0 cm heterogenous mediastinal mass within the superior thorax, medial to the proximal thoracic esophagus, and posterior to the trachea at the level of T2. It did not communicate with the thyroid gland. An FNA of the mass showed cohesive groups of atypical cells with small uniform nuclei and a moderate amount of chromatin arranged in nests and acini. No mitotic figures were identified. Cells were positive for chromogranin and focally for CK7, and negative for CK20, synaptophysin, and TTF-1. Cytology was interpreted as a well differentiated neuroendocrine tumor/typical carcinoid. A Galium-68 DOTATATE scan revealed moderate tracer uptake in the mass only. His endocrine workup was notable only for a mildly elevated chromogranin A with normal serum catecholamines, calcitonin, and serotonin, as well as normal adrenal cortical function. The patient underwent thoracotomy with mediastinal mass resection. He developed severe postoperative hypocalcemia treated with calcium infusion and increased calcitriol doses. Pathology revealed a low-grade neuroendocrine tumor consistent with parathyroid hyperplasia with at least one lymph node positive for involvement. The tumor showed positive staining for PTH, chromogranin, and synaptophysin with Ki67 <1%. Conclusion: This case demonstrates a rare occurrence of mediastinal parathyroid hyperplasia related to tertiary hyperparathyroidism of renal failure. Early calcitriol replacement and PTH level monitoring represents the mainstay of prevention of tertiary hyperparathyroidism. Severe post-op hypocalcemia is a hallmark of disease and more extensive immunostaining of mediastinal masses should be applied in cases suggestive of parathyroid etiology, especially in patients with long-standing renal failure. Despite a low Ki67, lymph node involvement suggests the possibility of parathyroid carcinoma. Follow-up Gallium-68 DOTATATE scan and parathyroid scan are imperative to evaluate for recurrence or residual disease. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Stathmin-1 Is a Useful Diagnostic Marker for High-Grade Lung Neuroendocrine Tumors

Stathmin-1 regulates microtubule dynamics and is associated with malignant phenotypes in non-small cell lung cancer (NSCLC). This study evaluated its diagnostic value for differentiating between NSCLC and high-grade lung neuroendocrine tumor (HGNET). Stathmin-1 protein expression was assessed by immunohistochemistry in 414 NSCLC (305 adenocarcinoma [AD], 102 squamous cell carcinoma [SCC], 7 large-cell carcinoma), 5 typical carcinoid (low-grade lung neuroendocrine tumor), and 34 HGNET (17 small-cell carcinoma [SCLC] and 17 large-cell neuroendocrine carcinoma [LCNEC]) surgical specimens and 57 NSCLC (29 AD and 28 SCC) and 42 HGNET (17 LCNEC and 25 SCLC) biopsy specimens. We also analyzed stathmin-1 mRNA levels in 81 NSCLCs and 26 HGNETs with the use of reverse transcription-polymerase chain reaction. Among NSCLC samples, we saw high stathmin-1 protein expression in only three ADs, one SCC, and one large-cell carcinoma surgical samples, all five of which showed neuroendocrine characteristics in pathologic re-review; and low or intermediate expression in all five typical carcinoid surgical samples and all 57 NSCLC biopsy samples. In contrast, all HGNET surgical (n= 34) and biopsy (n= 42) samples showed highstathmin-1 expression. In reverse transcription-polymerase chain reaction, stathmin-1 expression was significantly higher in HGNET tissues than in NSCLC tissues (p < 0.001). Stathmin-1 expression can help in differentiating NSCLC from HGNET.

Primary pancreatic paraganglioma; case report and literature review

Background: Paragangliomas represent a rare tumor comprised of neuroendocrine cells with only 21 reported cases of primary pancreatic paraganlioma found in the English language literature. We present a case of primary pancreatic paraganglioma and a literature review. Methods: Our patient is a 74 year old lady with a 2.5 x 2.2 x 1.9 cm pancreatic head mass found on computed tomography during an evaluation for frequent diarrhea. She underwent an endoscopic ultrasound with fine needle aspiration which indicated a low grade neuroendocrine tumor. Chromogranin A was 80. The day prior to her scheduled surgery, she suffered a transient ischemic attack with no residual symptoms. Surgery was delayed three months. We were then able to perform an enucleation of the tumor with immunohistochemical examination showing the tumor cells positive for synaptophysin and negative for cytokeratin AE 1/3 immunostains, confirming the diagnosis of pancreratic paraganglioma. Results: Twenty one cases found representing 16 females and 5 males, ranging in age from 19 to 74 with a median age of 55 years. Only two out of 19 cases were found to be malignant and all but one patient was treated with surgery. One patient was found to have a functional tumor and became unstable during surgery. He was subsequently treated with chemotherapy. Conclusion: Primary pancreatic paragangliomas are an extremely rare pathology, with the diagnosis confirmed with histopathological and immunohistochemical examination. Primary treatment is surgical excision. We conclude that enucleation rather than radical excision should be attempted when feasible.

40. An unpredictable neuroendocrine tumour of the cervix

Background: Neuroendocrine tumours of the uterine cervix are a rare group of tumours, accounting for up to 2% of primary cervical neoplasms, with low-grade neuroendocrine tumours forming a minority within this group.

Systemic Therapy for Low-grade Pulmonary Neuroendocrine Tumor

肺部是神经内分泌肿瘤（neuroendocrine tumor, NET）的第二好发部位。肺类癌包括典型类癌和不典型类癌，属于低级别神经内分泌肿瘤。这一类肿瘤由于发病率较低，目前尚未得到广大医务工作者的重视。但有效的治疗不仅能提高患者的远期生存，还能控制患者症状，改善生活质量。本文分别阐述肺低级别神经内分泌肿瘤的流行病学和病理学特点、早期患者的治疗策略以及进展期患者的治疗策略。早期患者应当尽早进行手术治疗。进展期患者治疗方式包括化疗、SSAs、mTOR抑制剂、肽受体介导的放射性核素治疗、生物治疗以及靶向治疗。目前的研究结论大多来自其他部位的NETs研究外推而来，仍需针对肺低级别神经内分泌肿瘤患者进行特异性临床试验加以证实。

EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors.

Low-grade pancreatic neuroendocrine tumors (LG-PNETs) behave unpredictably. The aim of the study was to identify biomarkers that predict PNET metastasis to improve treatment selection. Five patients with primary non-metastatic LG-PNETs, six with primary LG-PNETs with synchronous or metachronous metastases (M-PNETs), and six metastatic to liver LG-PNETs (ML-PNETs) from the group of six M-PNET patients were selected. RNA data were normalized using iterative rank-order normalization. Student's t-test identified differentially-expressed genes in LG-PNETs versus M-PNETs. A 2-fold difference in expression was considered to be significant. Results were validated with an independent dataset of LG-PNETs and metastatic LG-PNETs. Overall, 195 genes had a >2-fold change (in either direction). A total of 29 genes were differentially overexpressed in M-PNETs. Erythrocyte membrane protein band 4.1-like 5 (EPB41L5) had a 2.07-fold change increase in M-PNETs and the smallest p-value. EPB41L5 was not statistically different between M-PNETs and ML-PNETs. EPB41L5 differential expression between primary and metastatic LG-PNETs was confirmed by immunohistochemistry. These results support further investigation into whether EPB41L5 is a biomarker of PNETs with high risk for metastases.