Neuroendocrine Neoplasia Research Articles

Pathologic Features and Histopathologic Classifications of Neuroendocrine Neoplasia

Pathologic Features and Histopathologic Classifications of Neuroendocrine Neoplasia

ENETS standardized (synoptic) reporting for molecular imaging studies in neuroendocrine tumours.

The European Neuroendocrine Tumor Society (ENETS) promotes practices and procedures that aim to improve the standard of care delivered to patients diagnosed with or suspected of having neuroendocrine neoplasia (NEN). At its annual Scientific Advisory Board Meeting in 2018, experts in imaging, pathology and clinical care of patients with NEN drafted guidance for the standardised reporting of diagnostic studies critical to the diagnosis, grading, staging and treatment of NEN. These included pathology, radiology, endoscopy and molecular imaging procedures. In an iterative process, a synoptic reporting template for molecular imaging procedures was developed to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued.

Nonsquamous Lesions of the Vulvar Skin and Subcutaneous Tissue: A Review (Part 1).

This article aimed to review "nonsquamous lesions of the vulvar skin and subcutaneous tissue" clinically and pathologically, based on the fifth edition of the World Health Organization tumor classification. A database search of PubMed and Google Scholar was performed between 1970 and 2021, using the search terms "vulva," "lower genital tract," and "nonsquamous lesions." The search was limited to "humans," "gynecopathology," and "dermatopathology." Full article texts were reviewed. Reference lists were screened for additional articles. We excluded articles written in the non-English language and abstracts. A list of 600 articles was identified. Another screening identified 68 articles for clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue. In the first part of this review, we cover 5 major groups of nonsquamous lesions of the vulvar skin and subcutaneous tissue including (1) glandular tumors and cysts, (2) adenocarcinomas of other types, (3) germ cell tumors of the vulva, (4) neuroendocrine neoplasia, and (5) hematolymphoid hyperplasia and neoplasia. The rest of the major topics including mesenchymal tumors of the lower genital tract, melanocytic lesions, and metastasis will be discussed in the second part of this review. Clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue as categorized by the updated World Health Organization classification are presented.

Hydrophilic Interaction Liquid Chromatography Coupled with Fluorescence Detection (HILIC-FL) for the Quantitation of Octreotide in Injection Forms

Octreotide is a synthetic cyclic octapeptide analogue of somatostatin-14. It is mainly administered for the treatment of acromegaly, severe diarrhea, and neuroendocrine neoplasias. In this work, a hydrophilic interaction liquid chromatography (HILIC) method with fluorescence (FL) detection was developed and validated for the quantitation of octreotide in solutions for injection. Chromatographic separation was performed on an XBridge®-HILIC analytical column under isocratic elution with a short chromatographic run time of less than 10 min. The mobile phase consisted of ammonium bicarbonate 8.6 mM (pH 8.1)/acetonitrile 35/65 (v/v). The high sensitivity and selectivity of the fluorescence detection, with the excitation wavelength (λexcitation) set at 280 nm and the emission wavelength set at (λemission) 330 nm, enabled a simple sample preparation procedure that included only dilution steps. The calibration curve showed good linearity with a correlation coefficient greater than 0.998. The method was successfully applied to the analysis of commercially available octreotide injection forms.

S1460 A Rare Case of Porto-Spleno-Mesenteric Venous Thrombosis (PSMVT) Secondary to Mild Acute Pancreatitis

S1460 A Rare Case of Porto-Spleno-Mesenteric Venous Thrombosis (PSMVT) Secondary to Mild Acute Pancreatitis

Pancreatic Neuroendocrine Neoplasias in Multiple Endocrine Neoplasia Type 1 Are Predominantly Located in the Dorsal Anlage: An Endoscopic Ultrasound Study.

Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet. In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound. In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned. Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered.

Anti-GABAB receptor encephalitis associated with combined small cell lung carcinoma

Autoimmune encephalitis with antibodies against the gamma-aminobutyric acid-B receptor is a relatively rare disease. We report a case with characteristic symptoms of limbic encephalitis associated with combined small cell lung carcinoma. The brain magnetic resonance imaging showed bilateral temporal lesions and the photoemission tomography revealed regional heterogenous metabolism across the brain. The double labeling of anti-gamma-aminobutyric acid-B receptor autoantibodies both in the tissues of neuroendocrine and small cell neoplasia was a unique feature of this patient.

Neuroendocrine neoplasia and bone (Review).

This is a narrative review focusing on neuroendocrine neoplasia (NEN) and bone status, in terms of metastases and osteoporosis/fractures. One fifth of NEN have skeletal dissemination, this affinity being regulated by intrinsic tumor factors such as the C-X-C chemokine receptor 4 (CXCR4). Bone colonization impairs the patient quality of life, representing a surrogate of reduced survival. Patients with NEN without bone metastases may exhibit low bone mineral density, perhaps carcinoid-related osteoporosis, yet not a standardized cause of osteoporosis. Case-finding strategies to address bone health in NEN with a good prognosis are lacking. Contributors to fractures in NEN subjects may include: menopausal status and advanced age, different drugs, induced hypogonadism, malnutrition, malabsorption (due to intestinal resection, carcinoid syndrome), hypovitaminosis D, impaired glucose profile (due to excessive hormones such as glucagon, somatostatinoma or use of somatostatin analogues), various corticoid regimes, and high risk of fall due to sarcopenia. Pheocromocytoma/paraganglioma involve bone through malignant forms (bone is an elective site) and potential secondary osteoporosis due to excessive hormonal content and increased sympathetic activity which is a key player of bone microarchitecture/quality as reflected by low Trabecular Bone Score. Glucocorticoid osteoporosis is related to NEN-associated ectopic Cushing syndrome. Currently, there are a lack of studies to emphasis that excessive gut-derivate serotonin in NENs with carcinoid syndrome is a specific activator of bone loss thus a contributor to carcinoid-related osteoporosis.

Long-term effect of everolimus in recurrent thymic neuroendocrine neoplasia.

Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longestcompared to the other nonsurgical therapies used. Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.

Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia.

Simple SummaryHigh grade neuroendocrine tumours and carcinomas (NETs/NECs) behave aggressively and have limited survival outcomes. The mainstay of therapy is systemic therapy, in which the associated side-effects are a key consideration in a palliative population. We have conducted a retrospective review of patients with high grade NETs and NECs to determine possible tests that will predict survival before patients start treatment. This will allow patients to avoid potentially toxic treatment that is unlikely to be of benefit.Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions.

Exploring the Epigenome in Gastroenteropancreatic Neuroendocrine Neoplasias.

Simple SummaryThere is increasing recognition of the role of epigenetics in facilitating the pathogenesis and clinical outcome in patients with a diagnosis of neuroendocrine neoplasia. In this review we outline the different types of epigenetic changes that are observed and their impact. We also highlight novel interventions that can be used to manipulate these epigenetic changes that are being explored in the clinic.Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies.

GNEN-1: a spontaneously immortalized cell line from gastric neuroendocrine neoplasia.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MINEN) are rare tumors that consist of at least 30% of both neuroendocrine and non-neuroendocrine components. The data concerning the pathogenesis of MINEN suggest a monoclonal origin. We describe a spontaneously immortalized cell line derived from gastric MINEN called GNEN-1. Primary tumor consisted of components of high-grade neuroendocrine carcinoma and adenocarcinoma. The GNEN-1 cell line was initiated from metastatic tumor cells of peritoneal fluid and expresses a purely neuroendocrine phenotype. The GNEN-1 cell line grows as monolayers and has retained the neuroendocrine phenotype with positivity for chromogranin A in immunohistochemistry. Electron microscopy showed cytoplasmic dense core granules and axon hillocks. The karyotype revealed alterations typical of both adenocarcinoma and neuroendocrine carcinoma such as trisomy 7 and 8. GNEN-1 cells were also positive for stanniocalcin-1, a marker of poor prognosis in gastric carcinomas. Expression of several markers related to neuroendocrine tumors was found. There have been only a few studies on the pathogenesis of MINEN and management of the disease due to the rarity of this tumor type. Here we describe for the first time an immortalized cell line derived from mixed gastric NEN. The GNEN-1 line offers a tool for future research on gastric NEN.

Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients

Introduction: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. Methods: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. Results: Carcinoid syndrome patients had a mean age of 57 years (range 21–84) and a normal BMI of 24.9 (SD 4.5; range 13.8–39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. Discussion/Conclusion: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

Abstract 2228: Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs

Abstract Background: Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. For nonresectable advanced NENs, the main treatment approaches including somatostatin analog, multiple TKIs, mTOR inhibitors and peptide receptor radionuclide therapy, whereas platinum-based chemotherapy is the main treatment for advanced high-grade and poorly differentiated NECs. Currently, there is no standard second-line treatment for NECs when disease progression. ctDNA as a non-invasive diagnostic avenue, which might potentially provide treatment guidance in NENs. Methods: We queried consecutive data from 40 NENs patients who underwent a targeted next-generation sequencing (NGS) assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2017 and June, 2020 in China, to identify the alterations detected in ctDNA. The alterations were classified based on the ranking in the OncoKB database as of January 2020. Results: In total, 40 of NENs patients detected with at least one alteration in ctDNA. The median age was 54 years, including 28 males and 12 females. Overall, 40.0% of patients had a Level 1 alteration, 22.5% of patients had a Level 2 alteration, and 22.5% of patients had a R1 alteration (selected alterations were outlined in Table). Conclusion: ctDNA analysis could provide information of alterations with strong evidence for targeted therapy or drug resistance based on the OncoKB database classification for NENs. Though the alterations are associated with other specific cancer types, the alterations still illustrate a part of NENs patients might have chance to be benefited from targeted therapy. AlterationsNumber of patients (%)Total Level 1 Alterations16 (40.0%)PIK3CA7 (17.5%)BRAF V600E2 (5.0%)BRCA22 (5.0%)MSI-H1 (2.5%)Total Level 2 Alterations9 (22.5%)ERBB2 activating4 (10.0%)MET amplication1 (2.5%)Total Level R1 alterations9 (22.5%)KRAS mut9 (22.5%) Citation Format: Kunli Du, Xueke She, Depei Huang, Xudong Shen, Hushan Zhang, Jianyong Zheng. Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2228.

P-208 Pancreatic neuroendocrine neoplasia: Experience of a comprehensive cancer center

Pancreatic neuroendocrine neoplasia (Pan-NEN) are rare tumors in which therapeutic options have been increasing over the last decade. However, the effect of implementing these therapies in the real world is poorly understood. We aim to characterize the clinical features and therapeutic strategies of patients with Pan-NEN within a 12-year period in a cohort of patients followed at IPOFG-Porto. We performed a retrospective cohort study of patients diagnosed with Pan-NEN between 2006 and 2017 at the largest NEN reference Portuguese Center. Progression-free (PFS) and overall survival (OS) time estimates were calculated by Kaplan-Meier method. To assess the impact of baseline clinicopathological characteristics on survival, we used univariate and multivariate Cox proportional hazard models. Ninety-seven patients were included. Mean patient age was 59.5±13.55 years-old, with 55 (56.7%) being male. Forty-five patients (48.5%) had an Adjusted Charlson Comorbidity Index >3. Most patients were symptomatic at diagnosis, mainly due to tumor location-related symptoms (n=55, 69.6%), and 12 (15.0%) hormone secretion-related symptoms. Most tumors were well differentiated neuroendocrine tumors (NET) (n=77, 79.9%) according with WHO 2010 classification. NET G1 and NET G2 constituted the majority of cases (n=72, 75.8%). Predominant pancreatic topography was body and tail (n=43, 44.3%) followed by head (n=28, 28.9%). Fifty-two (53.6%) had localized/locoregional disease while 46.4% (n=45) had metastatic disease. Liver was the most frequent site of synchronous metastasis at diagnosis (n=42, 93.3%), followed by non-regional nodal (n=11, 24.4%) and bone (n=11, 24.4%). Globally, 60 (61.9%) surgical procedures were performed, 22 (22.9%) transarterial embolization, 5 (5.2%) other locoregional therapies, 56 (57.7%) somatostatin analogues, 23 (23.7%) Peptide Receptor Radionuclide Therapy, 11 (11.3%) everolimus and 32 (33.0%) chemotherapy. Forty-six patients (47.4%) had potentially curative disease, of which 43 (93.5%) had surgery as primary treatment. Eighteen patients (45.0%) had disease recurrence after surgery. Five-year Disease-free Survival was 61.9%. Seventy-two patients received antineoplastic palliative treatments (51 patients with metastatic/irresectable disease at diagnosis, 18 with disease recurrence and 3 refused curative intention therapy). Of those, twenty-six (36.1%) received 2 lines and 20 (27.8%) ≥3 lines of treatment. Median PFS after first line treatment was 25.0 months (95%CI 18.0-32.0) and median OS was 58 months (95%CI 30.0-86.0). Patients with localized/locoregional disease had a median OS of 160 months and patients with metastatic disease of 29 months, HR 4.55 (95%CI 2.58-8.02), p On univariate analysis, the risk of death was increased in those patients with NEC, metastatic disease at diagnosis, and primary location of the tumor not in the pancreatic body or tail. On multivariate analysis, NEC (HR 2.46 95%CI 1.28-4.73) and metastatic disease (HR 3.44 95%CI 1.85-6.37) were independent prognostic factors. Patients with PAN-NENs analyzed in this study present similar characteristics to other cohorts described in the literature. Therapeutic strategies in PAN-NENs are highly diversified and adapted to histological differentiation, stage, hormone hypersecretory-related symptoms and patients characteristics and preferences. NEC and metastatic disease were associated with a significant increase risk of death.

The Analysis Appendiceal Neuroendocrine Neoplasia with Clinicopathological Findings

The Analysis Appendiceal Neuroendocrine Neoplasia with Clinicopathological Findings

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

Paragangliomas the Forgotten Neuroendocrine Neoplasms: A Retrospective Review of 237 Cases From 2 Centers in 2 Years

Abstract Background: paragangliomas (PGN) (including adrenal PGN or pheochromocytomas) are uncommon neuroendocrine neoplasias. Their ubiquity and lack of uniform nomenclature has resulted in systematic sub-registry and limited resources for patients and clinicians. However, 40% of them are hereditary, 10–20% are hormonally active and 50% result in treatment-related complications. Objectives: to describe the clinical and biochemical characteristics of PGN in two referral centers in a 2-year period. Materials and Methods: a retrospective review of the files of patients evaluated in the Centro Medico Nacional Siglo XXI or the Instituto Nacional de Neurología y Neurocirugia between June 2018 and May 2020, even if diagnosis was prior to those dates. The search was performed using ICD-10 terms in the outpatient registries. Data is described using non-parametric statistics, including medians (interquartilic ranges, IQR). According to the reported incidences we expected to find 35 new cases per year in each hospital. Results: 237 patients, 86.4% female with a median age at diagnosis of 54 years (IQR 45–64) were found. The tumors were located in the head 23.9%, neck 63.3%, thorax 0.4%, adrenal in 11.1%, other sites in the abdomen 1.3%. The most common symptoms in head PGN were hypoacusia (85.2%) and cranial nerve palsies (39.3%), in the neck, a visible mass and pain (30.6%) while the “classic” catecholaminergic symptoms were more common in thoracic and abdominal tumors (>50%). Tumors were large or invasive in 50.1% of the cases and at least one hormone was above the upper limit of normal (ULN) in 40.6% of the 64 evaluated cases, mostly urinary dopamine (70% of cases tested, 1.1–2.1 ULN) and plasma and urine metanephrines (60% of cases tested, 1.1- 33.7 ULN and 50% cases, 1.1–22 ULN, respectively). Severe systolic hypertension was more frequent in male patients <30 years of age and 41.6% were candidates to genetic testing due to the tumor characteristics or patient history. Surgery was performed in 55.6%, radiotherapy in 25.2% and 12.1% are under surveillance or pending surgery, 7.1% were lost to follow up. Only 5 cases with metastasis were documented in 1215 patient-years of follow-up. Treatment-related complications were reported in 14.7% and persistence in 32.2%. Conclusions: despite the retrospective nature of the study and sub registry, we found more tumors than expected. The frequency of hormonal production was high, but it is likely related to patient selection bias (mostly symptomatic cases studied). Dopamine and metanephrines are useful in the evaluation of PGN. Endocrinologists should be aware of these common tumors and be part of the multidisciplinary team.

Hypoglycemia, Something Lost in Translation

Introduction: Insulinoma is a rare neuroendocrine tumor that may occur sporadically or as part of multiple neuroendocrine neoplasia type 1, with an incidence of 4 per million per year. Given the nonspecific symptoms of hypoglycemia, the diagnosis of insulinoma may be delayed by months, years or even decades. Case Presentation: A 50 year-old Hispanic, Spanish speaking male with a history of hypertension presented with progressive epigastric pain, nausea and bilious vomiting for 2 days. Physical exam was notable for abdominal distention and tenderness. Initial labs showed white blood cells of 19.4 k/uL (4-10.8), glucose of 85 mg/dl (65-140). CT abdomen showed findings consistent with moderate grade small bowel obstruction and normal pancreas. The patient was managed conservatively with nasogastric tube placement and nothing per oral (NPO). Within 8 hours started experience sweating, restlessness, fingerstick glucose was 40 mg/dl. Upon questioning, he reported episodes of lightheadedness, sweating and shakiness 8 years prior to this hospitalization, and he recalled being told that he was hypoglycemic during prior hospitalizations at another institution. He stated he was told to drink juice upon experiencing such symptoms and no work up or diagnostic investigation was recommended. We initiated a hypoglycemia investigation when he was NPO, when serum glucose level of 40 mg/dl. Labs showed insulin level 34 uIU/mL (3-19), free insulin 25 uIU/mL (3-19), C-peptide 3.32 ng/mL (0.81-3.85), beta hydroxybutyrate <0.02 mmol/L (0.02-0.27) and proinsulin of 36.6 pmol/L (3-50) and hemoglobin a1C of 5% (3.8-5.6). Serum screening for hypoglycemic agents was negative. When MRI abdomen was negative for a pancreatic mass. We proceeded with advanced diagnostic imaging with endoscopic ultrasound (EUS) which showed a 26 mm x 19 mm ovoid, hypoechoic mass at the junction of the pancreatic body and tail. Tissue specimen obtained with fine needle aspiration showed grade 1 neuroendocrine neoplasm. The patient underwent distal pancreatectomy and splenectomy with suture repair of the small bowel and left wedge liver biopsy. The pathology showed a well-differentiated neuroendocrine tumor of the pancreas, positive for synaptophysin, chromogranin and CD56 and Ki-67 with proliferation index <2% and no evidence of metastasis to the liver. The patient’s hypoglycemia resolved following surgery and rose to > 200 mg/dL requiring us to begin insulin therapy during the hospital stay before ultimately discharging the patient on metformin for type 2 diabetes. Conclusion: Insulinoma is a rare but treatable neuroendocrine tumor. Early diagnosis is important to avoid adverse clinical events related to hypoglycemia. It is important to maintain a strong clinical suspicion in order to identify and pursue the cause of unexplained hypoglycemia to improve the quality of life of patients with this rare condition.

Characterizing Canine Hepatobiliary Neuroendocrine Neoplasia: A Proteomic Approach

Hepatobiliary neuroendocrine neoplasia is an extremely rare cancer in humans and other species. In humans, neuroendocrine neoplasia of the liver and gallbladder represents less than 2% of all gastroenteropancreatic neuroendocrine neoplasia. In the veterinary literature, there is a paucity of information on hepatobiliary neuroendocrine cancer with only a small number of published studies. Improved characterization of these tumors is needed to identify additional biomarkers for diagnosis and generate informed treatment protocols for human and veterinary patients. Here, we applied a proteomics strategy to identify differentially expressed proteins in canine hepatobiliary neoplasia as compared to normal canine adrenal and liver tissue from formalin-fixed paraffin-embedded samples. Our objective was to identify unique protein biomarkers and possible chemotherapeutic targets. Thirty-four up-regulated, differentially expressed proteins were identified in the hepatobiliary neuroendocrine neoplasia samples. Galectin-1, a multivalent carbohydrate binding protein known to play a role in lung and pancreatic neuroendocrine neoplasia development and progression, was among them. Drugs targeting the galectin family have shown promise as anticancer therapeutics in cervical cancer, prostate cancer, lung and pancreatic neuroendocrine neoplasia. Galectin-1 may represent a novel treatment target in hepatobiliary neuroendocrine neoplasia in both humans and dogs.