Neuroendocrine Tumors Research Articles

Clinical Predilection Features of Middle Ear Adenomatous Neuroendocrine Tumors: A Review of 10 Patients and a Special Case Is Attached.

Introduction: Middle ear adenomatous neuroendocrine tumors (MEANTs) are rare middle ear lesions characterized by nonspecific symptoms, signs, and imaging findings. Diagnosis typically relies on postoperative pathological assessment. This study investigated the diagnostic utility of the predilection sites and clinical characteristics of MEANTs. Methods: A retrospective analysis was conducted on clinical data from 10 patients with histologically confirmed MEANTs, admitted to Eye & ENT Hospital of Fudan University between March 2016 and March 2023. Results: The median age of the patients at diagnosis was 39.3 years. Hearing loss (n = 8) and ear pain (n = 6) were the most prevalent clinical symptoms in the patients diagnosed with MEANTs. Endoscopic examination revealed diverse symptoms, predominantly presenting as non-pulsatile masses with distinct boundaries and quasi-circular shapes within the external auditory canal, often accompanied by abundant blood vessels (n = 4). Tumors were typically confined to the middle/lower tympanic chambers or eustachian tube and were frequently associated with tympanic sclerosis, particularly around the pharyngeal tube (n = 3). Pathologically, MEANTs exhibited CD56 positivity or weak positivity, along with positive staining for CKpan and Syn, negativity for S100, and Ki67 ≤3%. Personalized surgical interventions were chosen by all the patients based on lesion severity, with no subsequent radiotherapy or chemotherapy administered postoperatively. No tumor progression was noted during the postoperative follow-up. In addition, a noteworthy case was presented in which MEANT initially manifested in the middle or lower tympanic cavity and eustachian tubes. Over 2 years, the tumor progressively grew, invading the middle tympanum and surrounding ossicles, ultimately achieving complete resection with no recurrence observed during subsequent follow-up. Conclusions: A possible diagnosis of middle ear adenoma should be considered when encountering non-pulsatile tumors with clearly demarcated inner boundaries within the external auditory canal accompanied by abundant quasi-circular vessels and the presence of new bone or neoplasm at the pharyngeal tympanic canal orifice observed during preoperative examinations or surgical procedures.

Subtyping of pancreatic neuroendocrine tumors by transcription factors, hormones, histology, and patient outcome.

Pancreatic neuroendocrine tumors (PanNETs) show pronounced heterogeneity in terms of hormone and transcription factor (TF) expression. TFs such as ARX and PDX1 are related to alpha- and beta-cell-type features, respectively, and partly associate with patient outcome. However, detailed studies correlating hormone expression, histology, and clinical data are lacking. The aim of this study was to identify subtypes of PanNETs that associate with histological, hormonal, and prognostic findings. Atotal of 185resected PanNETs were divided into five subtypes (types A1, A2, B, C, and D) by cluster analysis based on expression of four TFs (ARX, PDX1, ISL1, and CDX2) and correlated to the expression of hormones and DAXX/ATRX as well as ALT activation status, histology, and progression-free survival. Subgroup A1 (ISL1+/ARX+/PDX-/CDX2-) was most frequent (46%), followed by typeB (18%; ISL1+/ARX-/PDX+/CDX2-), A2 (15%; ISL1+/ARX+/PDX+/CDX2-), C(15%; ISL1-/ARX-/PDX-/CDX2-), and D(5%; ISL1-/ARX-/PDX+/CDX2+). Subgroups A1 and A2 showed astrong association with atrabecular growth pattern and glucagon and pancreatic polypeptide (PP) expression (p < 0.001), while A2 was in addition associated with gastrin expression. SubgroupB was associated with insulin production (p < 0.001) and included all 17insulinomas. SubgroupC was associated with solid morphology and expression of serotonin, calcitonin, and adrenocorticotropic hormone (ACTH). SubgroupD showed solid morphology, expression of ACTH, somatostatin, or serotonin and had the shortest disease-free survival (p < 0.01). ALT positivity was associated with poorer outcome in types A1 and A2 but not in other types. PanNETs can be categorized into five subgroups based on different TF signatures, which associate strongly with histology, hormone production, functionality, and patient outcome.

Updated Morphological and Immunohistochemical Profile of Neuroendocrine Tumors Developing in Ovarian Teratomas: A Large Series of a Rare and Heterogeneous Disease.

Ovarian neuroendocrine tumors are rare and often arise within mature teratoma of the ovary. No recent re-evaluation of the immunophenotype of these tumors with the new markers available in the field of neuroendocrine neoplasms has been performed. The objectives were to describe the morphologic and immunohistochemical characteristics of neuroendocrine tumors (NETs) arising from ovarian teratomas, to correlate them with the type of teratomatous epithelial components present and to evaluate their proliferative activity using the WHO recommendations for gastroenteropancreatic NETs. This is a bi-centric retrospective study using a panel of markers (chromogranin-A, chromogranin-B, synaptophysin, CDX2, SATB2, TTF1, PAX8, islet-1, serotonin and calcitonin) and Ki-67 proliferation index. The 34 NETs studied were unilateral and presented when it's done four distinct immunophenotypic profiles: 8 NETs expressed serotonin and CDX2 (small intestinal profile), 12 SATB2 (colorectal profile), one TTF1 (thoracic profile) and 4 "null" tumors expressed none of the above markers. The Ki-67 index ranged from 0 to 19.82% (median: 1.51%). 28 tumors were grade 1 (85%), 5 tumors were grade 2 (15%). They were associated with squamous (n = 26), respiratory (n = 23), thyroid (n = 10) and gastrointestinal (n = 5) components. The main type of NET is intestinal phenotype, but rarely accompanied with digestive tissue. This suggests that the cell of origin may be a neuroendocrine precursor present in the teratoma, and confirms that primary NETs arising in ovarian teratomas should not be classified or named according to the type of the surrounding teratoma tissue.

Radioligand therapy in sympathetic-adrenal-medullary axis tumors: state of art and perspectives.

The approval in 2017 by the European Medicines Agency (EMA) and in 2018 by the US Food and Drug Administration (FDA) of radioligand therapy (RLT) led to its wide application in therapeutic management of neuroendocrine neoplasms (NENs). However, the indications are currently limited to certain specific histotypes belonging to the broader NEN's family, mainly advanced well-differentiated gastro-entero-pancreatic NENs. As a consequence, several other tumors of the NEN spectrum that can potentially benefit, due to their biological characteristics, from RLT are still ineligible and can be considered "RLT-orphans". Among those, the subgroup of NENs originating from the sympathetic-adrenal-medullary (SAM) axis can be listed. This paper discusses the state of art and perspectives of the theragnostic applications in pheochromocytomas and paragangliomas, considering both the traditional theragnostic model - with radiolabelled metaiodobenzylguanidine (MIBG) - and the innovative one with radiolabeled somatostatin analogs (SSAs), that will hopefully become available for these patients in the near future.

Various Presentations of Neuroendocrine Tumors (NETs): A Study of 10 Cases

Neuroendocrine tumors (NETs) are rare and diverse neoplasms that can present with a wide range of symptoms, making diagnosis challenging. This study aims to describe the various presentations of NETs in a cohort of 10 patients, highlighting the importance of considering NETs in patients with nonspecific symptoms.

Evaluating Endoscopic Ultrasound-Guided Tissue Acquisition for the Diagnosis of Small Pancreatic Neuroendocrine Neoplasms

Objectives: Although small hypervascular tumors are suspected to be pancreatic neuroendocrine tumors (p-NENs), their diagnosis and treatment are challenging. This study evaluates the usefulness of endoscopic ultrasound-guided tissue acquisition (EUS-TA) for the diagnosis of small p-NENs. Methods: All p-NEN lesions that underwent EUS-TA at our hospital between April 2018 and December 2023 were retrospectively analyzed. The diagnostic sensitivity of EUS-TA and the concordance rate of grading with EUS-TA and surgical specimens were examined. The lesions were grouped by size. Results: The diagnostic sensitivity of EUS-TA was analyzed for 82 lesions, of which 44 were compared with postoperative specimens for grading. The definitive diagnosis was neuroendocrine tumor (NET) in 75 lesions, neuroendocrine carcinoma in five lesions, and mixed neuroendocrine non-neuroendocrine neoplasm in two lesions. Thirty tumors were ≤ 10 mm, 30 were 10–20 mm, and 22 were &gt; 20 mm, and the diagnostic sensitivities were 96.7%, 96.7%, and 90.9%, respectively. The concordance rates for grading were 94.4%, 82.4%, and 77.8% for tumors ≤ 10 mm, 10–20 mm, and ≥ 20 mm, respectively, with Cohen’s kappa coefficients of 0.64, 0.48, and 0.40, respectively. Conclusions: EUS-TA showed adequate diagnostic sensitivity and grading agreement for p-NENs of all sizes, allowing for the determination of the appropriate treatment.

Primary Small Cell Neuroendocrine Carcinoma of Larynx: An Atypical Case Presentation

Neuroendocrine tumors account for &lt;1% of all malignant tumors that can originate from any part of the body, most frequently diagnosed in the lung. Extrapulmonary presentation is rare, common sites are genitourinary and gastrointestinal. According to the 2017 WHO proposed classification, small cell type (SCNEC) is a poorly differentiated neuroendocrine carcinoma. The most common site in the head and neck is the larynx, accounts for &lt;0.6%. Small cell neuroendocrine carcinomas are extremely rare entity of laryngeal cancers. We report a case of small cell neuroendocrine carcinoma of larynx.

Decoding the identity of rare tumors.

Solitary fibrous tumors have gene expression signatures similar to those of neuroendocrine tumors.

7476 Clinical, Pathological and Biochemical Characteristics of patients with Neuroendocrine Neoplasms (NENs) at a University Hospital in Belo Horizonte, Brazil

Abstract Disclosure: R.D. Romanowski: None. F.P. Ribeiro: None. T.T. Mello: None. B.S. Soares: None. J.B. Drummond: None. Neuroendocrine neoplasms (NENs) are a group of rare, heterogeneous, and potentially aggressive neoplasms, whose incidence is on the rise, largely due to advances in diagnostic methods that allow for more precise and early identification. A recent comprehensive review focusing on the epidemiology, incidence and prevalence of NENs described global findings, however, it did not include any data from Latin America, particularly after WHO 2019 digestive system tumours classification. Methods: We carried a retrospective analysis in a single center aiming to evaluate different clinical, pathological and biochemical characteristics of a cohort of patients with NENs followed at the Neuroendocrinology Outpatient Clinic of the Federal University of Minas Gerais, Brazil, who were diagnosed between the years of 2004 and 2023. Results: The study sample (n=30) included 13 female patients (43%). The median (range) age at diagnosis was 42 (19-73) years old. The most common primary sites observed in the studied population were the pancreas (38%) and the stomach (24%). Twenty three percent of the patients had MEN1 associated NENs. Fourteen tumors (45%) were classified as G1 NENs, 7 tumors (23%) were classified as G2 NENs and two tumors (6,7%) were classified as neuroendocrine carcinomas, while tumor grade classification was not feasible in 7 patients (23%). One third of the patients had functional tumors and metastatic disease was present in 60% of the cases at the time of diagnosis. Conclusion: In general, the epidemiological characteristics here described for our patients align with the global trend. Concerning gender, we observed a higher prevalence of these tumors in men (57%), consistent with the male predominance of up to 3 times over females described around the world. Our patient population seems to be younger than the mean age reported in different case series. Tumoral grade classification was not feasible in a high proportion of patients and despite the high prevalence of well differentiated and low-grade NENs, metastases were commonly seen at diagnosis, in accordance with the literature. Presentation: 6/2/2024

8036 A Rare Case of Cushing’s Syndrome Caused by a Pulmonary Carcinoid Tumor

Abstract Disclosure: A.C. Tep: None. F.M. Wolf: None. Introduction: The most common causes of ectopic ACTH (adrenocorticotropic hormone) syndrome include bronchial carcinoid tumors and other neuroendocrine tumors. Ectopic ACTH syndrome (EAS) can be difficult to diagnose. Differentiating Cushing’s disease and EAS is difficult, as ACTH-secreting tumors are often small and easily missed on imaging. Case Presentation: A 32-year-old male with a history of hypothyroidism presented with a 6-month history of facial rounding. He also noticed a dorsocervical fat pad, muscle weakness in the extremities, easy bruising, and elevated blood pressure progressing over the same period. A 24-hour urine free cortisol was elevated to 1797 mcg. Two salivary cortisol tests performed 1 hour after the patient’s usual bedtime had values of 4.4 ug/dl and &amp;gt; 1.000 ug/dl. Both the urine and salivary cortisol results were exceedingly high. ACTH was elevated (150 pg/ml). An MRI of the pituitary gland was normal without evidence of an adenoma. Frequently, ACTH-secreting pituitary adenomas are small enough that they are missed on MRI; however, given our patient’s rapid clinical presentation, additional imaging was performed to identify an ectopic source. A CT Chest/Abdomen/Pelvis showed a 1.2 cm nodule in the right middle lobe of the lung. The right middle lobe was resected, and pathology revealed a carcinoid tumor. His cortisol levels slowly decreased postoperatively and eventually normalized. At his one-month post-operative visit, his symptoms were all improving but not yet resolved. Discussion: This patient was found to have Cushing's syndrome due to ectopic ACTH production from a pulmonary carcinoid tumor. The patient demonstrated clinical improvement after resection of the tumor. Pulmonary carcinoid tumors are rare neuroendocrine epithelial tumors that account for 2-5% of all lung tumors. The annual incidence of these tumors is 2.3-2.8 cases per million people. Endogenous Cushing's syndrome is either ACTH-dependent or ACTH-independent. In ACTH-dependent Cushing's syndrome, the ACTH can either be from the pituitary or an ectopic source. Once ACTH-dependent disease is confirmed, a pituitary MRI is performed to evaluate for an ACTH-secreting pituitary adenoma; this is called Cushing’s disease. Some patients undergo inferior petrosal sinus sampling to confirm the source is central and to determine laterality before transsphenoidal resection of the adenoma. If the source of ACTH is not from the pituitary, obtaining a CT or MRI of the chest and abdomen locates tumors in most patients. At times a functional study, such as an octreotide or PET-DOTATE scan, is done to confirm the diagnosis before proceeding with surgical resection to avoid unnecessary removal of an incidental tumor. Ectopic ACTH production often causes a more rapid progression of Cushingoid features, which can be a clue to the diagnosis of this condition. Presentation: 6/1/2024

8467 From Highly Suspected Hemochromatosis to Liver Metastasis Neuroendocrine Tumor

Abstract Disclosure: M.E. Chacon Cruz: None. M. Sanchez Cordero: None. G. Guerra Velazquez: None. K.C. Velez Rivera: None. A neuroendocrine cancer, often referred to as a neuroendocrine tumor (NET) or neuroendocrine neoplasm begins in the specialized cells of the body's neuroendocrine system. These cells have traits of both hormone-producing endocrine cells and nerve cells. The carcinoid is the most common neuroendocrine tumor causing liver metastases, especially when of midgut origin. However, although appendix is the most common location for midgut carcinoids it most unusually gives rise to hepatic spread. NETs are described as functional or non-functional, depending on the release of hormones. About 60% of NETs are non-functional. Case of a 66 year old male patient with medical history of ESRD on HD, PPM placement, hypertension, type 2 diabetes mellitus, and auditory impairment presents to ED of this institution after presenting with RUQ abdominal pain of one day of evolution. Patient's pain is associated with food intake or changes in diet. Laboratory work on admission patient found with leukocytosis in 16.69, anemia 10.5 and transaminitis ALT 180, AST 176 and ALP 589. Abdominal ultrasound shows Hepatomegaly with a slightly irregular surface contour. Correlate for chronic liver disease. Abdomino pelvic CT showed Hepatomegaly with a diffusely heterogeneous parenchyma and ill-defined nodular foci of hypoattenuation. During admission liver enzyme and alkaline phosphatase continue in increasing trend up to 1,172 IU/L. Ferritin in 12,203, Transferrin saturation in 23.71%. Hemochromathosis DNA not detected, Angiotensin convert enzyme in 73 U/L, tumor marker alpha-fetoprotein in 1.8 ng/ml, carcinoembryoninc antigen in 25.63 ng/ml, CA19-9 in 903 U/ml, Serotonin 23 ng/ml. MRCP was ordered and show Hepatomegaly with innumerable T2 hyperintense nodules replacing the hepatic parenchyma, may be related to cirrhosis including regenerative nodules. Interventional radiologist was consulted for liver biopsy and came back positive for Malignant Neuroendocrine Tumor, Favor Metastatic Tumor This case illustrates the challenges physicians face in quickly identifying and diagnosing pathologies as unusual as neuroendocrine tumor. Furthermore, it points out that primary care physicians should consider this disease in the differential diagnosis (DDx) in case of non-specific signs and symptoms such as abdominal pain and how the DDx can change depending on the patient's clinical symptoms and evolution. The case shows us how, with the physical examination that the patient presented, his skin was like that described in hemochromatosis, skin hyperpigmentation (Bronze Skin), weakness, diabetes mellitus, along with elevated levels of ferritin, transaminitis, alkaline phosphatase and the finding of iron deposit in the kidney using CT, our differential diagnosis was our first diagnosis, until the genetics for hemochromatosis came back negative and the liver biopsy was positive for neuroendocrine tumor. Presentation: 6/2/2024

8257 Pancreatic Neuroendocrine Tumor Presenting As Carcinoid Syndrome

Abstract Disclosure: D. Phung: None. Introduction Pancreatic neuroendocrine tumors (NETs) are rare tumors that arise in neuroendocrine cells of the pancreas. These tumors secrete a wide array of hormones. Carcinoid syndrome is a result of well-differentiated neuroendocrine tumors that secrete biologically active amines and peptides that cause the clinical manifestation of flushing, diarrhea, cardiac involvement, and wheezing. Case Presentation A 57-year-old male presented to the clinic for symptoms of tachycardia, shortness of breath, dizziness, and sweating for the past year. He had past medical history of chronic kidney disease, history of previous cardiac arrest, history of previous myocardial infarction, congestive heart failure, hypertension and gastric reflux disease. No history of tobacco, alcohol, or drug consumption. No previous surgeries. Family history with heart disease and prostate cancer in his father. His symptoms began over the course of the past year. Initially began with shortness of breath, chest pain, weight gain which then developed into dizziness with standing, episodes of night time sweating. He had associated headaches that were occurring daily. Vomiting would occur intermittently three to four times weekly. He noted episodes of flushing with rash occurring in the upper chest and bilateral arms. Diarrhea and loose bowel movements would occur occasionally. On examination he had tachycardia with heart rate at 103 BPM. Lung fields clear throughout. Abdomen was soft, nontender, without masses palpated. On biochemical testing chromogranin A was highly elevated and remained elevated upon repeat testing. Initial imaging with CT abdomen and pelvis with contrast was negative. PET scanning confirmed and localized his NET, revealing increased tracer uptake and hypervascularity in the neck of pancreas as well as two regions in the right lower lobe of the liver. Following confirmation and localization of his tumor he was then referred for surgical evaluation and treatment. Discussion In our presented case, the patient presented with symptoms suggestive of carcinoid syndrome which was confirmed biochemically with elevated chromogranin A. Clinical suspicion remains critical in diagnosis of NETs. The patient presented with clinically suspicious carcinoid syndrome, but initial testing with CT scan was negative and required further PET-based tracing to uncover tumors. Our case highlights the importance of clinical examination and acumen in diagnosing neuroendocrine tumors. Presentation: 6/2/2024

8282 A Diagnostically Challenging Case of Ectopic ACTH Secreting Pancreatic Neuroendocrine Tumor Presenting with Cushing’s Syndrome

Abstract Disclosure: O.A. Aluko: None. S. Patel: None. S.V. Silparshetty: None. T. Gallagher: None. Introduction: Ectopic ACTH mediated Cushing’s syndrome is an uncommon but treatable condition that poses time constrained diagnostic and therapeutic challenge due to severe morbidity as illustrated by our case below. Clinical case:A 65-year-old male was admitted with profound generalized weakness. He became restricted to wheelchair from being able to hike a trail at Yosemite national park 8 weeks prior. Recent history included hospitalization with uncontrolled diabetes and hypertension, new vertebral compression fractures, AKI, hypokalemia, proximal myopathy, anasarca, upper GI bleed and acute upper extremity DVT. Initial testing there revealed hypercortisolemia, elevated ACTH and a normal pituitary MRI. Further workup at our center revealed elevated 24hr urinary cortisol 2598 (n = 5 - 64 μg/24hr), random cortisol 55 (n= 4.2 -22.4 μg/dL) with elevated ACTH 194 (n= 7.2 - 63.3 pg/mL) consistent with ACTH dependent hypercortisolism. IPSS deferred due to AKI, underlying comorbidities and severe cervical stenosis with myelopathy. ACTH and cortisol remained elevated with an 8mg dexamethasone suppression test suggesting ectopic source ACTH. CT with contrast of chest, abdomen and pelvis showed 5mm right lower lobe lung nodule and bilateral adrenal nodularity. Bronchoscopic FNAC was negative for NET.Ketoconazole 400 mg twice daily was started pending localization of culprit lesion with improvement in 24 hr urinary cortisol to 554μg/24 hr however this was stopped within 4 weeks due to acute transaminasemia. Repeat imaging with Gallium-68 dotatate PET CT showed a 1.8 X 2.4 X 1.7 cm pancreatic mass. He underwent distal pancreatectomy with splenectomy. Pathology confirmed a 2.2cm well differentiated neuroendocrine tumor limited to the pancreas with immunohistochemistry strongly for ACTH and weakly for Gastrin. Postoperatively, patient was given hydrocortisone replacement. ACTH was 14.3 pg/mL and cortisol 6.2μg/dL a few weeks later. His diabetes, hypertension, hypokalemia, transaminasemia and proximal myopathy improved. Discussion:Ectopic ACTH mediated Cushing’s syndrome is responsible for about 5 - 20% of all Cushing’s syndrome cases. Pancreatic neuroendocrine tumor secreting Ectopic ACTH is rarer but can be aggressive. Clinical presentation can be confounding due to secretion of &amp;gt;1 neurohormone i.e ACTH and Gastrin in our patient. Gallium-DOTATATE PET/CT tracer has a very high sensitivity and specificity. Early use of this imaging may prevent comorbidity and mortality as surgical resection of ectopic ACTH secreting neuroendocrine tumor is first line therapy. Other diagnostic principles to consider are that severely elevated ACTH levels correlate only with a pituitary macroadenoma, IPSS is invasive and has relative contraindication in sick patients and Desmopressin stimulation test is not widely available. Presentation: 6/1/2024

8785 Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues?

Abstract Disclosure: N. Saleh Jouneghani: None. S. Fazeli: None. S. Chang: None. A. Hosseini: None. R. Marandi: None. A. Siddiqui: None. M. Talley: None. B. Salehian: None. Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues? Introduction: Non-pituitary neuroendocrine tumors (NETs) show different somatostatin receptor subtype (SSTR) expression, but their role in tumor progression and prognosis is not well known. We hypothesized that NETs with higher expression of SSTR2, SSRT5, or co-expression of SSTR2 and SSTR5 will have better outcome when treated with Somatostatin Analogues (SSA). Method: Retrospectively, patients with non-pituitary neuroendocrine tumors, followed for more than one year between 1985 and 2022, and treated with SSA (Octreotide or Lanreotide) who had available tissue were selected. Tissue immunostaining performed for SSTR2 and SSTR5 with use of monoclonal antibodies. Expression analysis of the SSTR2 and SSTR5 were evaluated by the validated semi-quantitatively method, reported by an intensity score of 0 -3. The progression free survival and overall survival were calculated by Kaplan Meier and compared in different subgroups with SSTR expression intensity. Response evaluation was assessed using RECIST v1.1. Results: Of 279 non-pituitary neuroendocrine tumors, 51 meet the criteria and tissue sent for analysis. The median age at diagnosis was 62; male 49%, with median follow up 7 years, 85% stage IV at diagnosis, most common primary tumor was in gut 54% followed by pancreas 33%. Positive SSRT5 tumors had 93% SSRT2 co-expression. There were no significant differences in progression-free survival (PFS) observed between tumors with low or high SSTR2 intensity expression (P=0.62). The presence or absences of SSRT5 expression did not have any impact on PFS (p=0.57) or overall survival (p=0.3). Conclusion: in the patient with non-pituitary neuroendocrine tumors, higher SSTR2 expression intensity or having SSRT5 co-expression, did not correlate with a better PFS or overall survival in response to SSA, in our study. Further prospective studies are needed to clarify if higher expression intensity of SSRTs correlates with better response to SSAs in NETs. Presentation: 6/1/2024

8257 Pancreatic Neuroendocrine Tumor Presenting as Carcinoid Syndrome

Abstract Disclosure: D. Phung: None. Introduction Pancreatic neuroendocrine tumors (NETs) are rare tumors that arise in neuroendocrine cells of the pancreas. These tumors secrete a wide array of hormones. Carcinoid syndrome is a result of well-differentiated neuroendocrine tumors that secrete biologically active amines and peptides that cause the clinical manifestation of flushing, diarrhea, cardiac involvement, and wheezing. Case Presentation A 57-year-old male presented to the clinic for symptoms of tachycardia, shortness of breath, dizziness, and sweating for the past year. He had past medical history of chronic kidney disease, history of previous cardiac arrest, history of previous myocardial infarction, congestive heart failure, hypertension and gastric reflux disease. No history of tobacco, alcohol, or drug consumption. No previous surgeries. Family history with heart disease and prostate cancer in his father. His symptoms began over the course of the past year. Initially began with shortness of breath, chest pain, weight gain which then developed into dizziness with standing, episodes of night time sweating. He had associated headaches that were occurring daily. Vomiting would occur intermittently three to four times weekly. He noted episodes of flushing with rash occurring in the upper chest and bilateral arms. Diarrhea and loose bowel movements would occur occasionally. On examination he had tachycardia with heart rate at 103 BPM. Lung fields clear throughout. Abdomen was soft, nontender, without masses palpated. On biochemical testing chromogranin A was highly elevated and remained elevated upon repeat testing. Initial imaging with CT abdomen and pelvis with contrast was negative. PET scanning confirmed and localized his NET, revealing increased tracer uptake and hypervascularity in the neck of pancreas as well as two regions in the right lower lobe of the liver. Following confirmation and localization of his tumor he was then referred for surgical evaluation and treatment. Discussion In our presented case, the patient presented with symptoms suggestive of carcinoid syndrome which was confirmed biochemically with elevated chromogranin A. Clinical suspicion remains critical in diagnosis of NETs. The patient presented with clinically suspicious carcinoid syndrome, but initial testing with CT scan was negative and required further PET-based tracing to uncover tumors. Our case highlights the importance of clinical examination and acumen in diagnosing neuroendocrine tumors. Presentation: 6/2/2024

6365 An Atypical Case Of Large Metastatic Pheochromocytoma With Negative Catecholamine Secretion

Abstract Disclosure: D. Caesario: None. J.K. Fernandes: None. Introduction: Pheochromocytomas (PCCs) are rare tumors arising from chromaffin cells of the adrenal medulla. Diagnosis is suggested by clinical presentations and confirmed by biochemical hypersecretion of metanephrines (MN) and catecholamines (CA). We report an atypical case of large metastatic PCC with normal MN and CA. Case Report: A 61-year-old female presented with uncontrolled HTN despite taking amlodipine, losartan, and carvedilol. No other symptoms reported. She had presented 12 years prior with an 8.7 cm left adrenal mass (AdM) that was incidentally found on CT scan, but she was lost to follow-up. Repeat imaging for her current presentation revealed enlargement of left AdM to 15 cm, centrally necrotic, with absolute washout of 63%. There was extensive local regional involvement, including possible invasion of the pancreas; abutment to left kidney, left renal vein, left hepatic lobe, and stomach; encasement and possible invasion of the splenic vein; and formation of perisplenic collateral vessels. Metastatic lesions were also seen in the liver, bones, and lungs. DOTATATE PET/CT scan showed variable uptake, not a definitive pattern for PCC or neuroendocrine tumor (NET). Labs showed normal levels of plasma fractionated MN and CA, dopamine, renin, aldosterone, cortisol, ACTH, and DHEA-S. Chromogranin A (CgA) was elevated to &amp;gt;8000 ng/dL. Biopsy taken from one of the liver lesions was consistent with metastatic PCC. No family history of NET. Genetic testing was offered, but was deferred. Due to the large tumor burden, she was determined to be nonsurgical and started on systemic therapy with sunitinib. Doxazosin was also added, which better controlled her BP. After 9 months of sunitinib therapy, a repeat CT scan showed overall stable metastatic lesions, but the left AdM had enlarged to 16 cm. Given the slowly worsening disease, patient was switched to temozolomide. She is still actively being treated and monitored today. Discussion: The clinical features of PCC result from excessive CA secretion. HTN is the hallmark of CA release, but the amount, type, and pattern of CA secretion is extremely variable, leading to varied clinical presentations. CgA secretion is also elevated in PCC, but is generally a non-specific marker as its level is also increased in multiple NETs and non-endocrine medical conditions. About 9% of patients with PCC may have normal biochemical workup, with this being even rarer in malignant cases. In general, the amount of CA, MN, and CgA released by the tumor is also positively correlated with the tumor size. The case above is unique in that despite the large tumor burden the patient only presented with HTN and had normal MN and CA levels. Her CgA was significantly elevated, which could correlate with the tumor size, but was interestingly the only marker elevated. It appears that CgA could be a useful adjunct in the diagnosis of PCC, especially in cases where PCC appeared to be non-secretory. Presentation: 6/3/2024

12450 Beyond the Surface: A Deep Dive into Pancreatic Insulinoma

Abstract Disclosure: S. Bhandari: None. R. Elhag: None. J. Singh: None. N. Rastogi: None. Background: Pancreatic neuroendocrine tumors (NET) are rare lesions that are typically sporadic, solitary and usually &amp;lt;2cm in diameter, with reported incidence of 4 cases per 1 million patients per year[1]. The most common hormone secreting NET are insulinomas. The hallmark of insulinomas is hypersecretion of insulin, leading to neuroglycopenic symptoms and uncontrolled sympathoadrenal activity. Clinical case: 51 years old female with no significant past medical history was referred to endocrine clinic by her primary care physician for hypoglycemia with a blood glucose level of 48 mg/dl. She reported an increased frequency of headaches and dizziness which began with intermittent fasting (10-12 hours) for past 6 months. These symptoms improved upon increasing meal frequency. Initial laboratory investigations revealed glucose of 54 mg/dl, normal HbA1c, and negative sulfonylurea panel. The patient had normal liver and kidney function with no malnutrition or malabsorption issues. Further work up showed C-peptide level 1.56 ng/ml (n 0.80-3.85ng/ml), insulin level 7.9 uIU/mL (n &amp;lt;18.4 uIU/mL), pro-insulin level significantly elevated at 77.6 pmol/L (n &amp;lt;/= 18.8pmol/L) and beta hydroxybutyrate of 0.12 mmol/l (n 0.02-0.27mmol/l). Insulin like growth factor was normal. Insulin antibodies were negative, and pituitary hormones were within normal limits. Pancreatic ultrasound was normal. CT abdomen/pelvis showed a 0.8x1.1 cm homogenously hypervascular anterior pancreatic body soft tissue lesion consistent with NET. Patient was started on diazoxide and continuous glucose monitoring (CGM). She was referred to general surgery and underwent successful tumor resection. Insulinoma is suggested by Whipple's triad, which is presence of hypoglycemic symptoms, documented hypoglycemia and resolution of hypoglycemic symptoms after glucose administration. As clinical manifestations are non-specific, diagnosing an insulinoma is challenging and depends on collateral history and a high index of suspicion. The gold standard of diagnosis is supervised 72-hour fasting test with plasma glucose, insulin, C-peptide, and proinsulin level measurements. Medical management of insulinoma includes the use of diazoxide, calcium channel blockers, propranolol, and glucocorticoids. Surgery is definitive treatment for insulinomas, with cure rates ranging from 77 to 100%. Conclusion: Insulinomas are benign and curable in most cases but can be fatal if misdiagnosed. Incidental findings of hypoglycemia should warrant thorough diagnostic workup to facilitate timely diagnosis and management.

5104 Ectopic Insulinoma- a Rare Presentation of a Rare Tumor

Abstract Disclosure: O. Lavrynenko: None. A. DeMarsilis: None. C. Jiang: None. R. Middelbeek: None. H. Rosen: None. M.E. Patti: None. Background. Insulinoma is a rare, functioning neuroendocrine tumor (NET) typically localized within the pancreas, that secretes insulin, resulting in hypoglycemia. Ectopic insulinoma is even more rare than pancreatic insulinoma and is more difficult to diagnose. Case report. This 31-year-old previously healthy woman, who had an uncomplicated pregnancy and a healthy baby in October 2021, presented with intermittent hypoglycemia for more than 8 months. She denied any prior use of insulin or antidiabetic medications and was not currently taking any medications at all. There is no history of bariatric or other GI surgery. While nursing her baby in early 2022, she was noted to have a capillary blood glucose (BG) between 20-30 mg/dl, and reported both adrenergic and neuroglycopenic symptoms of hypoglycemia; these usually occurred in the morning or before lunch, especially if lunch was delayed. She wore a Libre CGM which revealed episodic hypoglycemia, which correlated with her timeline of symptoms. She reported weight gain of 8 lbs during this period. Laboratory data obtained after a 10-12 hour fast revealed hypoglycemia (venous glucose 39 mg/dL) with inappropriately high plasma insulin (42.3 mIU/ml), C- peptide (3.78 ng/ml), and proinsulin (99 pmol/L). Beta-hydroxybutyrate was 0.05 mmol/L (reference &amp;lt;0.28) and insulin autoantibody and sulfonylurea screen were negative. Various imaging modalities for localization revealed a solitary omental mass outside the pancreas consistent with extra-pancreatic insulinoma. No pancreatic lesion or other findings were observed with MRCP, CT C/A/P or endoscopic ultrasound. The patient underwent CT-guided biopsy of the omental mass, which confirmed a well-differentiated NET, consistent with insulinoma. Due to persistent hypoglycemia, she was started on corn starch and diazoxide. She subsequently underwent laparoscopic resection of the mass. Postoperative pathology revealed a well-differentiated NET staining positive for insulin, consistent with an extra-pancreatic insulinoma. Following surgical resection of the insulinoma, her hypoglycemia resolved even off corn starch and diazoxide. Conclusion. Ectopic insulinoma is a rare insulin-secreting NET. Only 28 ectopic insulinomas have been described in the literature to date1. We describe a patient with symptomatic hypoglycemia who was found to have an omental neuroendocrine tumor; hypoglycemia completely resolved after laparoscopic enucleation of the ectopic insulinoma. 1Fernando Guerrero-Pérez, Nuria Vialarrasa, Lidia V. Huanuco et. al. Ectopic Insulinoma: a systemic review: Reviews in Endocrine and Metabolic Disorders, 2023 Presentation: 6/1/2024

7940 Insulinoma as a Rare Manifestation of MEN4

Abstract Disclosure: H. Han: None. J. Moalem: None. A.R. Shih: None. B.J. Gigliotti: None. Background/Objective: Multiple endocrine neoplasia 4 (MEN4) is a rare syndrome that is caused by germline mutations in CKDN1B. Its phenotypic expression is similar to multiple endocrine neoplasia 1 (MEN1). Manifestations include primary hyperparathyroidism (PHPT), pituitary adenomas, and pancreatic neuroendocrine tumors (NET). Prevalence of MEN4 is less than one per million. Case Report: A 55-year-old female with history of hypercalcemia presented with symptomatic hypoglycemia. She had a fasting plasma glucose of 41mg/dL, proinsulin of 84.3 pmol/L, insulin level of 24 uIU/mL, c-peptide of 5.2 ng/mL, and beta hydroxybutyrate level of 0.34 mmol/L, consistent with endogenous hyperinsulinism. She was incidentally noted to have PHPT. CT abdomen showed a 1.5 x 1.1 x 1.0 cm pancreatic lesion consistent with an insulinoma. Pathology from subsequent Whipple surgery showed that it was a well-differentiated neuroendocrine tumor with no metastasis. She became normoglycemic after surgery. Germline testing revealed a variant of unknown significance in CDKN1B (p.R93W). Discussion: Increasing evidence suggests that MEN4 exhibits subtle differences in penetrance and natural history compared to MEN1. A recent systemic review of MEN4 cases showed that most gastrointestinal NETs in MEN4 are non-functional NETs and gastrinomas; to date, no insulinomas have been reported. PHPT in MEN4 may exhibit a lower risk of recurrence after parathyroidectomy. This case highlights the importance of germline genetic testing when a patient presents with clinical manifestations of MEN1. Conclusion: This is the first reported case of insulinoma in MEN4. Presentation: 6/3/2024

8262 Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) after gastric sleeve surgery

Abstract Disclosure: R.E. Thomas: None. A. Charales: None. B. Bangash: None. S. Haider: None. S. Ouais: None. Introduction: Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a rare condition characterized by endogenous hyperinsulinemic hypoglycemia after meals. This article explores NIPHS, emphasizing its occurrence post-gastric sleeve surgery. We delve into clinical features, diagnosis, treatment, and challenges, using a case presentation to illustrate complexities.Clinical Features and Classification:NIPHS entails endogenous hyperinsulinemic hypoglycemia without islet cell neoplasms, featuring islet cell hypertrophy. Formerly "Nesidioblastosis," post-RYGB cases constitute a distinct diagnosis. Common features include postprandial hyperinsulinemic hypoglycemia, negative radiologic localization, and a positive calcium stimulation test.Patients present postprandial hypoglycemia 2-4 hours after meals, with symptoms like tachycardia, tremors, confusion, and occasional seizures. Lab findings include elevated insulin, C peptide, and pro-insulin, low beta-hydroxybutyrate, and negative sulfonylurea/meglitinide screen.Diagnostic Workup:Evaluate glucose, insulin, pro-insulin, C peptide, beta-hydroxybutyrate, and sulfonylurea/meglitinide. Ultrasound differentiates insulinoma from diffuse processes. If negative, conduct SACST for localization.Case Presentation:A 37-year-old female post-gastric sleeve surgery presented with severe hypoglycemia. Symptoms included confusion, nausea, and palpitations, occurring postprandially, relieved by food or juice. Glucagon was administered, and consultations sought. Diazoxide stabilized blood glucose.Treatment Modalities:Dietary modifications reduce free carbohydrate intake, spaced meals minimize hyperinsulinemic episodes. Medical management (octreotide, verapamil, diazoxide, acarbose) proves effective, especially post-gastric bypass. Sub-total pancreatectomy is considered in severe refractory cases.Multidisciplinary Approach:Management involves endocrinologists, surgeons, radiologists, and dietitians. Regular monitoring assesses efficacy, adjusts medications, and addresses complications. Challenges and Future Perspectives: NIPHS complexities include variable presentation and diagnostic challenges. Research should refine criteria, explore interventions, and understand pathophysiology. Conclusion: Non-insulinoma pancreatogenous hypoglycemia syndrome, especially post-gastric sleeve surgery, presents complexities. This exploration highlights clinical aspects, diagnostics, and management challenges, emphasizing the need for a multidisciplinary approach. Continued research aims to enhance diagnostic precision and improve outcomes for those affected by this intriguing syndrome. Presentation: 6/3/2024