Visible Pancreatic Neuroendocrine Tumor after Water Intake and Position Change

Most pancreatic neuroendocrine tumors (NETs) are detected incidentally and arise in the endocrine tissues. NETs can secrete hormones and result in clinical syndromes. However, between 50 and 75 percent of pancreatic NETs are nonfunctioning. Ultrasonography shows a well-circumscribed mass with a smooth margin and round or oval hypoechoic shape. A 38-year-old woman visited our hospital with mild upper abdominal discomfort. We visualized an oval hypoechoic mass with inner hyperechogenicity after water intake in the stomach and position change. The patient underwent surgery, and the mass was diagnosed as pancreatic NET.

Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization

Aim. To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). Materials and methods. A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. Results. The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). Conclusion. In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

Whole Exon Sequencing of Primary Lesion and Liver Metastatic Lesion in Pancreatic Neuroendocrine Tumor：A Case Report and Review of the Literature

Background: Pancreatic neuroendocrine neoplasms(p-NENs) are classified into neuroendocrine tumors (NET) G1, G2, G3, and neuroendocrine carcinoma (NEC) according to WHO classification. NET and NEC are different pathogenesis. The two kinds of tumors that occurred in the same part have not been reported. We found 4 foci of NEN G3 in a primary pancreatic NET G2. The cell atypia was obvious with Ki67 index of 50-70%, focal necrosis, there were 12 hepatic metastatic nodules with similar morphology to NEN G3, which is difficult to identify NEC and NET G3.Case presentation: A patient with pancreatic NET was selected to perform whole exome sequencing on primary pancreatic NET G2 and liver metastatic NEN G3 paraffin tissues.NET G2 had 13 somatic mutations, while NEN G3 had 72 somatic mutations and Copy number variation in 4 genes. P.S493N point mutation of TRIOBP gene was detected in NET G2 and NEN G3. 5-fold amplification of MDM4 is found in the metastatic liver lesion.Conclusion: NET G2 and NEN G3 are closely related to TRIOBP gene. Oncogene amplification (MDM4) in liver metastases may be associated with morphological malignant transformation.

Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.

Study of microsatellite instability in neuroendocrine tumors of pancreas and colon.

e16196 Background: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in NET samples of different localizations. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3) and NET of colon (G2-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 25.8% cases of the NET of colon and in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), while in the case of NET of colon, most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%), unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusions: Thus, MSI-positive NET of colon resembles MSI-positive adenocarcinomas of colon in frequency and pathogenetic mechanisms, while in terms of the identified frequency of MSI in pancreatic NET resembles the NET of the small intestine.

Do Not Miss MEN 1 Screening When Patients Are Newly Diagnosed With Pancreatic Neuroendocrine Tumor

Background: Multiple endocrine neoplasia type 1(MEN 1) is a rare genetic disorder characterized by the combined occurrence of parathyroid, pituitary, and duodeno-pancreatic neuroendocrine tumors (NETs) along with other characteristic tumors. Here, we present a patient with history of pancreatic NET who presented 2 years after her initial diagnosis with primary hyperparathyroidism and prolactinoma, consistent with MEN 1. Case Report: A 60-year-old African American woman was admitted to our hospital with nausea, vomiting and headache for a week. On presentation, she was found to be hypotensive and tachycardic, both responded to IV fluids. Workup for infectious etiology came back negative. Her physical exam was benign except for dry oral mucosa, dry skin and epigastric tenderness. Laboratory evaluation showed serum calcium 11.8 mg/dL (8.4 - 10.2 mg/dL), which prompted further work up. Her PTH level was 1,079 pg/ml (8.5 - 72.5 pg/ml), Phosphorus 2.1 mg/dL (2.3 - 4.7 mg/dL), and 25 Hydroxy Vitamin D 10.2 ng/ml (7.4 - 44.0 ng/ml). Additional history and review of her records revealed she was hospitalized 2 years earlier with nausea, vomiting and abdominal pain. Then she was found to have esophageal and gastric ulcers on EGD. Endoscopic ultrasound revealed an 8 mm hypoechoic lesion in the body of pancreas found to be a pancreatic NET on biopsy. She had elevated gastrin level of 470 pg/ml (0 - 115 pg/ml) and was diagnosed with a gastrinoma. She was discharged on a PPI and was lost to follow up. Patient had no significant family history. Given her past history and current presentation, we assessed her pituitary hormonal function which was unremarkable except for prolactin level of &gt;1,000 ng/ml (post-menopausal 1.8 - 20.3 ng/ml). Pituitary MRI showed a 1.8 cm macroadenoma. The optic nerve and optic chiasm were normal. Based on her clinical presentation and radiologic findings, she was diagnosed with MEN 1. Her Calcium level trended down with IV hydration, and her presenting symptoms resolved. She was started on bromocriptine, pantoprazole and vitamin D and was discharged with out-patient appointments scheduled with gastroenterology and endocrinology clinics. Conclusion: This case highlights the importance of having a high index of suspicion to prompt screening for MEN 1 in patients newly diagnosed with a pancreatic NET. Early diagnosis and timely treatment of the associated disease conditions in MEN 1 can prevent significant morbidity and mortality associated with these conditions.

An Unusual Case of Latent Autoimmune Diabetes in Adult and Pancreatic Neuroendocrine Tumor in a Patient Presenting With Diabetes

Introduction: Latent autoimmune diabetes in adults (LADA) and pancreatic neuroendocrine tumors (PNETs) are rare causes of adult-onset diabetes mellitus (DM). The existence of both LADA and a PNET in a single patient has not been previously reported. Clinical Case: A 65-year-old female with history of type 2 DM diagnosed 15 months ago, on metformin 500mg twice a day presented with fatigue, dry mouth, polyuria, and blurry vision for one week and weight loss of 12 pounds over 3 months. Plasma glucose was 599 (nl 65–144 mg/dL) with an elevated anion gap (17; nl 5–15 mmol/L), low bicarbonate (19; nl 21–32 mmol/L) and elevated beta hydroxybutyrate (4.79; nl 0.02–0.27 mmol/L). Diabetic ketoacidosis was diagnosed, and intravenous fluids and insulin were administered. Work up revealed HbA1C of 14% (nl 4.2%-5.6%) which had increased from 7% noted three months ago. glutamic acid decarboxylase antibodies (GAD65 Ab) was &gt;250 (0.0–0.5 IU/mL) and C peptide was 0.42 (0.81–3.85 ng/mL). A computed tomogram of the abdomen performed to evaluate the acute worsening of her HbA1C revealed a 1.4 x 1.3 cm poorly defined hypoenhancing pancreatic head lesion, which on magnetic resonance imaging was 1.6 x 1.2 cm. Further evaluation showed normal levels of glucagon (127; nl &lt;=208 ng/L), somatostatin (26; nl &lt;=30ppg/mL) and vasoactive intestinal peptide (&lt;13; nl 0–60 pg/mL), and an elevated chromogranin A (155; nl 0-95ng/mL). An endoscopic ultrasound guided fine needle aspiration of pancreatic head mass revealed a well differentiated NET with Ki-67 proliferation index of &lt;1%. She underwent pylorus preserving pancreaticoduodenectomy and histopathology showed a 2 cm grade one NET on pancreatic head with no involvement of the 23 tested lymph nodes. Immunohistochemistry was positive for chromogranin and synaptophysin and negative for insulin, somatostatin and gastrin, confirming diagnosis of well-differentiated pancreatic NET Stage Ib (T2N0M0). Whole body PET CT scan done 2 months following surgery did not reveal any focal radiotracer uptake to suggest metastasis. Given the presence of GAD65 Ab, age of onset of DM, and an initial non-requirement of insulin, the patient was diagnosed with LADA and insulin therapy was initiated. Conclusion: We report a unique case of a patient with LADA who was incidentally found to have a non-functioning pancreatic NET. Although functional PNETs such as glucagonoma and somatostatinoma cause hyperglycemia, DM associated with non-functioning NETs is rare, but has been reported with gastrointestinal NETs (1). Our patient likely developed uncontrolled hyperglycemia from LADA but was incidentally found to have a PNET which may have contributed to the worsening of hyperglycemia. This highlights the importance of thorough evaluation for the causes for acute worsening of hyperglycemia.

An updated analysis of the epidemiologic trends of neuroendocrine tumors in Taiwan

The incidence of neuroendocrine tumors (NETs) has been increasing in recent decades. Previously, we reported the incidence and survival of NETs in Taiwan by analyzing the 1996–2008 data from the Taiwan Cancer Registry. Here we performed an updated analysis on the incidence and survival of NETs in Taiwan from 1996 to 2015. The incidence of NETs was 0.244 per 100,000 in 1996 and increased to 3.162 per 100,000 in 2015. The most common site of NETs was rectum (29.65%), followed by lung/bronchus (17.22%), and pancreas (10.71%). The 5- and 10-year overall survival rates of all NETs were 54.6% and 45.3%, respectively. Female and younger NETs patients had a better survival. The survival of all NETs diagnosed between 2010 and 2015 was better than those diagnosed between 2004 and 2009. Among the common sites of NETs, an improved survival of pancreatic NETs diagnosed between 2010 and 2015 compared to those diagnosed between 2004 and 2009 was observed. Overall, the incidence of NETs in Taiwan has continued to increase. The survival of pancreatic NET has shown a recent improvement. The development of novel therapeutic agents has the potential to improve the prognosis of NETs of other sites in the near future.

Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components

Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?

Surgical Strategy Based on Radiological 3D Reconstruction in a Giant Metastatic Neuroendocrine Tumor of the Pancreas: A Case Report of an Interdisciplinary Approach

Background. Neuroendocrine tumors (NETs) are a rare entity and are most commonly found in the gastroenteropancreatic tract. The clinical outcome depends on the potential resectability, grade, and stage. Here, we report a case of a tumor debulking in a metastatic NET of the pancreas. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several therapies. Case Presentation. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several pharmaceutical therapies. Due to the young age, the G2 characteristic, and the stable liver disease, the decision for debulking was made. Based on a 3D CT scan, an embolization was successfully performed directly prior to a pylorus-preserving pancreatic head resection, advanced interaortocaval lymph node dissection, and an atypical liver resection within segment VI. Histological workup revealed a stage pT3, G2, pN1 (29/34), pM1c (hepatic and extrahepatic), L1, V0, Pn0 with complete surgical resection of the primary tumor (180 mm). The excision of the liver segment V showed a completely resected metastasis. Conclusions. In this patient, extensive surgery of a pancreatic NET with the aim of a prolonged progression-free survival was performed. Close cooperation between different disciplines is absolutely mandatory. Modern imaging allowed a precise therapy plan to be worked out.