Gastrointestinal Neuroendocrine Tumors Research Articles

Thyroid Cancer, Neuroendocrine Tumor, Adrenal Adenoma, and Other Tumors in a Patient With a Germline PMS1 Mutation

Multiple tumors in the same patient suggest a genetic predisposition. Here, we report a patient who presented with several unusual types of malignant and benign tumors, presumably due to a pathogenic germline PMS1 mutation. A 69-year-old woman presented with a 2-year history of abdominal pain and diarrhea. A computed tomography scan of the abdomen revealed a gastrointestinal neuroendocrine tumor (GiNET) with liver metastases and a nonfunctional benign adrenal adenoma. Bilateral large lung nodules were thought to be also metastases from the GiNET but turned out to be differentiated thyroid cancer metastases, which later progressed to anaplastic thyroid cancer (ATC) and led to the patient's demise. A right sphenoid wing meningioma causing partial hypopituitarism was diagnosed during her evaluation. A mammogram and a breast ultrasound revealed a 0.3-cm left breast nodule. Due to the multiplicity of her tumors, whole exome sequencing was performed. This revealed a previously described PMS1 deletion mutation causing a frameshift and truncation (NM_000534c.1258delC, p.His420Ilefs*22) but no other pathogenic variant in other cancer genes. DNA isolated from the ATC tumor tissue showed loss of heterozygosity of the same mutation, highly suggestive of its pathogenic role in thyroid cancer and presumably other tumors. This case reports several tumors including thyroid cancer, GiNET, adrenal adenoma, meningioma, and breast nodule, likely due to the PMS1 mutation found in this patient.

Islet-1 Is Differentially Expressed Among Neuroendocrine and Non-Neuroendocrine Tumors and Its Potential Diagnostic Implication.

Islet-1 (ISL1) plays key roles in programming the epigenome and facilitating the recruitment of additional regulatory factors. Although it has been used as a marker for pancreatic neuroendocrine tumors (PanNETs), ISL1 reactivity in other tumor types are critically missing. ISL1 immunohistochemistry was performed on 147 neuroendocrine tumors (NET) originated in pancreas, gastrointestinal tract, lung, thyroid, parathyroid, pituitary, adrenal medulla, head/neck, genitourinary tract, and skin; and 110 non-neuroendocrine tumors originated in the pancreas, thymus, lung, thyroid, mesothelium, adrenal cortex, stomach, breast, head/neck, skin, and kidney. ISL1 nuclear staining was observed in normal thymic epithelium, pancreatic islets, adrenal medulla, and pituitary gland cells as well as frequently in tumors of these origins: pancreatic NET (78%), paraganglioma/pheochromocytoma (100%), thymoma (82%), and pituitary NET (50%). ISL1 was also variably expressed in certain non-pancreatic NET such as Merkel cell carcinoma (100%), medullary carcinoma of the thyroid (100%), head/neck NEC (80%), genitourinary NEC (71%), lung small cell carcinoma (46%), lung carcinoids (17%), lower intestinal tract NET (93%) but not in upper gastrointestinal tract NET nor parathyroid adenoma. For other non-NETs, focal ISL1 expression was less frequently detected in gastric adenocarcinoma (40%), mesothelioma (29%), adrenal cortical carcinoma (17%), and squamous carcinoma (24%), but not in others tested. ISL1 is not a pan-NE marker as it is consistently lacking in upper gastrointestinal NET and parathyroid adenoma. It is also differentially expressed in thymoma. ISL1 immunohistochemnistry could help to differentiate PanNET and lower intestinal NET from upper gastrointestinal NET and be used as a marker for thymoma.

Molecular genetic sequencing of neuroendocrine tumors of the gastrointestinal tract.

651 Background: The objective of this work was to evaluate the molecular and genetic features of the NET gastrointestinal tract. Genomic sequencing of 30 tumor samples of the latest generation was carried out and the data obtained were evaluated. Methods: In total, 30 tumor blocks of patients with gastrointestinal NET were tested by the new generation sequencing (NGS) method. The following genes were analyzed: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDK12, CHEK1, CHEK2, EPCAM, FANCL, MLH1, MSH2, NBN, NF1, PALB2, PMS2, RAD51B, RAD51C, RAD51D, RAD54L, STK11, TP53, POLE, KRAS, NRAS, BRAF, EGFR, ERBB2, PIK3CA, MET ex14, BAT25, BAT26, NR21, NR24, MONO27, KIT, PDGFRA, Pi3Ca. Preparation of libraries for sequencing was carried out using NimblGen SepCapEZ Choice. Sequencing was performed on the Illumina MiSeq device. Results: In the study cohort of patients whose tumor blocks were sent for examination by the NGS method, there were more women – 19 (63.3%) than men – 11 (36.7%). When analyzing the age of patients, it should be noted that among all age groups, elderly patients predominated (60-74 years according to the WHO classification, 2016) – 12 (40%). In the majority of patients – 10 (33.3%) – the primary tumor focus was localized in the pancreas, in 6 (20%) patients it was primarily affected stomach, 7 (23.3%) – small intestine. Other parts of the gastrointestinal tract were affected much less frequently: the colon – in 1 (3.3%) patients. According to the division according to the degree of differentiation of gastrointestinal NET10 tumors had a degree of differentiation G1 (33.3%), 16 -G3 (54.3%), 4– G3 (13.3%). In the tumor sample of a patient with gastric NET G1 (Ki 67 = 2%), POLE mutations were found: c.2276G > A, p.R759H and CHEK2: c.470T > C, p.I157T. Also, mutations MLH1: c.199G > A, p.G67R BRCA1: c.1881 were found in the tumor sample of another patient with gastric NET G2 (Ki 67 = 7%). Conclusions: To improve the survival rates of patients, it is worth paying special attention to the molecular genetic study of the NET gastrointestinal tract. It is molecular genetic profiling that can become the basis for building more individualized algorithms for treating patients. The results of this study allow us to count on the fact that when conducting a study on a larger cohort of patients with gastrointestinal NET, it is possible to obtain results that will expand our knowledge of this nosology and allow us to supplement the already available information about prognosis factors and predictors of response to treatment.

Age- and sex-based differences in the genomic profiles of patients with gastrointestinal (GI) and pancreatic neuroendocrine neoplasms (NENs).

655 Background: Demographic variables such as age and sex have long been associated with risk of cancer incidence, therapeutic response, and mortality. In NENs, specifically, studies have shown differences in overall survival based on age at diagnosis and sex. However, studies investigating the molecular determinants associated with age and gender have been lacking. To delineate the mechanisms of age, gender, and outcomes, we queried a large real-world dataset of NENs originating from the GI-tract and pancreas and characterized their molecular and immune profiles. Methods: 1935 cases (GI: n=1431, Pancreas: n=504) of NENs were analyzed using Next Generation Sequencing or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n=917, Pancreas: n=294) underwent Whole Transcriptome Sequencing at Caris Life Sciences (Phoenix, AZ). To study the age-associated effect on the molecular and immune landscapes, we applied two age cutoffs: below 50 and 70 years of age at the time of tissue collection, respectively. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q<0.05). Results: In GI-NEN, TP53, RB1 mutations and high tumor mutation burden (TMB_H; >=10 Mut/Mb) were more prevalent and KRAS mutations were less prevalent with increasing age. Interestingly, in pancreatic NENs (P-NENs), KRAS mutations were more prevalent and TMB_H were less prevalent with increasing age. Mutations specific to the sites of origin such as APC (GI) and MUTYH (pancreas) were negatively associated with age while SMAD4 (pancreas) was positively associated with age. While no differences in immune checkpoint gene (ICG) expression were associated with age, immune cell estimates of M1 macrophages (anti-tumorigenic) in GI-NENs were higher in patients above 70 and M2 macrophages (pro-tumorigenic) were higher in patients below 50 (p<0.05, q>0.05). For the analysis with gender, mutations in p53 were more prevalent among males with GI-NEN while dMMR/MSI-H were more prevalent in females with P-NENs. No significant differences in ICG expression and immune cell estimates were associated with gender. Conclusions: Our study queries one of the largest datasets of GI and P-NENs to date. We observe distinct molecular profiles associated with age and gender in both GI- and P-NENs as well as a distinct immune profile associated with age in GI-NENs. While these results are only hypothesis generating, they are suggestive of how patient demographics may be utilized for rational therapy design. [Table: see text]

The genomic landscape of advanced gastrointestinal (GI) neuroendocrine tumors (NET) and carcinomas (NEC).

656 Background: The impact of specific genomic alterations in advanced GI neuroendocrine malignancies on prognosis and treatment decisions has not been fully characterized. In this study, we seek to evaluate next-generation sequencing (NGS) panels and corresponding clinical outcomes in patients with metastatic GI NET/NEC. Methods: Patients with GI-NET/NEC were identified from a database of NGS reports performed at the Cleveland Clinic, and clinical variables were extracted by chart review through an IRB-approved protocol. We provide an analysis of this cohort. Results: Of a total n=45 patients, 53% were male. Median age at diagnosis was 60 (range: 35-90 years) and 82% were non-Hispanic white, while 9% were black. There were n=25 GI-NETs, mostly intermediate or high grade (11 G3, 7 G2), and n=20 GI-NECs. There was a balanced distribution of primary sites, including colorectal (27%), pancreas (24%), small intestine (18%), unknown primary (24%) and a single case of biliary primary. High grade GI-NETs and GI-NECs were over-represented in the colorectal primary group vs other sites. (n=10 of 12; p=0.021). The majority of patients (73%) had at least one somatic variant, including 12 patients (27%) with one or more mutations deemed actionable, but only one patient (with MSH2 mutation) has received a mutation-matched drug (pembrolizumab). Some recurrent alterations appeared to co-segregate with aggressive histology (NEC vs NET), including 12 of 13 TP53 mutations (p<0.05 by Fisher Exact Test), 7 of 8 RB1 (p<0.05), and 5 of 6 APC (p=0.074). The most common mutations per person based on primary site is shown. Microsatellite instability high was rare (n=1) and median tumor mutational burden (TMB) was 3/mb, with TMB lower in NETs vs NECs. A number of patients (35%) underwent germline testing, with 6 of 16 having a pathogenic germline variant. Conclusions: As 42% of the 12 patients with actionable mutations were alive at time of analysis, it is possible that additional patients could be treated with mutation-matched therapies. More input will be needed from providers as to the role played by alternative effective treatments and barriers such as insurance coverage and prior authorization to implementing mutation-matched therapies. Given the overall low TMB of GI-NETs, with several tumors having zero or 1 reported mutation on targeted NGS, whole genome sequencing may prove useful. Finally, certain mutations such as RB1 and TP53 were associated with more aggressive histology (i.e. NEC). Lastly, only 9% of our cohort with NGS were black, a significant under-representation based on epidemiological data, which raises concerns about disparate accessibility and barriers to NGS testing. Further studies are needed to address any possible racial disparity.[Table: see text]

Overall survival (OS) in gastrointestinal (GI) neuroendocrine tumors (NETs) based on primary site, stage, and surgery.

643 Background: There are limited data on the impact of primary site and surgical intervention on long-term outcomes in GI-NETs. We hypothesized that primary site would be associated with differences in stage-specific OS. Methods: In the National Cancer DataBase, using histology codes, we identified 124,081 GI-NETs diagnosed between 2004-2019 in individuals 18 years or older. OS was estimated by the Kaplan-Meier method. Differences in survival based on primary site, stage, and surgical intervention were assessed using a Cox proportional hazards model, accounting for multiple comorbidities, e.g. Charlson-Deyo Comorbidity Index. Results: The most common primary site for GI-NETs was small intestine (33.6%), followed by colon, rectum, pancreas, and stomach comprising 19.8%, 17.5%, 15.5%, and 9.2%, respectively. Patients with stage I-III NETs undergoing surgery had significantly better median OS compared to those without surgery (mOS 197 vs 115 mo., p<0.0001 by log rank test). Patients with stage IV NETs undergoing primary resection also had improved mOS vs those with no surgery (125 vs 54 mo., p<0.0001). For stage I-III patients without surgery, 2-yr and 5-yr survival rates were highest in the rectum and lowest in small intestine ( p<0.0001). Among those with stage I-III with surgery, 2-yr and 5-yr survival rates were also highest in the rectum, and lowest in the biliary system at 89% and 82% ( p<0.0001). In contrast, for stage IV patients without primary resection, 2-yr and 5-yr survival rates were highest among small intestine and lowest in the rectum ( p<0.0001). Among those who had primary tumor resection, 2-yr and 5-yr survival rates were highest in pancreas and lowest in colon at 2 yrs and rectum at 5 yrs ( p<0.0001). Conclusions: Surgical intervention for GI-NETs is associated with improved OS in both localized and stage IV disease, with consistent trends across different primary sites. Primary tumor resection was associated with the largest increase in 5-yr survival for stage IV NETs arising from pancreas and stomach. Patient selection for surgery undoubtedly contributed to the improved OS, but resection of primary tumors in stage IV GI-NETs may have a disease modifying effect. Further study is warranted with more granular data to identify patients with stage IV GI-NETs who may benefit from primary tumor resection.[Table: see text]

The Role of 68Ga-DOTATATE PET/CT in the Management of Gastrointestinal and Pancreatic Neuroendocrine Tumors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Trends in incidence and survival in patients with gastrointestinal neuroendocrine tumors: A SEER database analysis, 1977-2016.

We aimed to determine trends in incidence and survival in patients with gastrointestinal neuroendocrine tumors (GI-NETs) from 1977 to 2016, and then analyze the potential risk factors including sex, age, race, grade, Socioeconomic status (SES), site, and stage. Data were obtained from Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan-Meier survival analysis, relative survival rates (RSRs), and Cox proportional risk regression model were used to evaluate the relationship between these factors and prognosis. Compared with other sites, the small intestine and rectum have the highest incidence, and the appendix and rectum had the highest survival rate. The incidence was higher in males than in females, and the survival rate in males was close to females. Blacks had a higher incidence rate than whites, but similar survival rates. Incidence and survival rates were lower for G3&4 than for G1 and G2. Age, stage, and grade are risk factors. This study described changes in the incidence and survival rates of GI-NETs from 1977 to 2016 and performed risk factor analyses related to GI-NETs.

Breakthrough Symptoms Remain an Unmet Need in Symptomatic Patients With Neuroendocrine Tumors and Carcinoid Syndrome.

The aims of the study were to assess the effects of breakthrough carcinoid syndrome symptoms on well-being in neuroendocrine tumor (NET) patients insufficiently controlled on long-acting somatostatin analog (SSA) and to assess patient experience with treatment options, physician communication, and disease information sources. This study surveyed US NET patients from 2 online communities, experiencing at least one symptom, by utilizing a 64-item questionnaire. One hundred patients participated: 73% female, 75% age 56 to 75 years, and 93% White. Primary tumor distribution was as follows: gastrointestinal NET (n = 55), pancreatic NET (n = 33), lung NET (n = 11), and other NET (n = 13). All patients were actively treated with one long-acting SSA and experiencing breakthrough symptoms: diarrhea, flushing, or other (13% experienced one, 30% two, 57% greater than two). More than one third of treated patients experienced carcinoid-related symptoms daily. Sixty percent of respondents reported not having short-acting "rescue" treatment available, impacting well-being though anxiety or depression (45%), trouble exercising (65%), sleeping (57%), employment (54%), and maintaining friendships (43%). Breakthrough symptoms remain an unmet need, even in treated patients with NETs. Though still relying on physicians, NET patients are now also using the Internet. Improved awareness of optimal SSA use may improve syndrome control.

Clinico-epidemiological Profile of Incidentally Detected Gastrointestinal Neuroendocrine Tumours on Gastrointestinal Endoscopy: A Retrospective Study

Introduction: Neuroendocrine tumours (NETs) are rare tumours, with the Gastrointestinal (GI) tract and the lung as the most common sites with indolent course. Endoscopists play a pivotal role in the diagnosis of GI-NETS because the majority of patients with NETs are asymptomatic and NETs are discovered during screening examinations. Since GI-NETs are less common than other cancers, their natural history, diagnosis, and treatment may not be completely understood. Aim: To estimate the prevalence and to characterize the clinical, endoscopic, and histological features of incidentally detected GI NETs in nodular/polypoidal/ulcerated lesions on GI endoscopy. Materials and Methods: This record-based retrospective study was conducted at the Department of Medical Gastroenterology of a tertiary care facility. The data belonged to the period between January 2018 to December 2020. Data belonged to the patients that underwent Oesophago- gastro duodenoscopy (OGD)/ Colonoscopy and were found to have nodular/ polypoidal lesions. Records on serum chromogranin, serum gastrin and radiological tests such as Ultrasonography(USG) or Computed Tomography (CT) scan were recorded. The histopathological with immunohistochemistry staining report was used to diagnose NETs. Continuous variables were analysed for normality by the Kolmogorov Smirnov test. Results: A total of 59 eligible patients were studied. The prevalence of GI NET tumours in 2018 was 17 (0. 32%), 19 (0. 33%) in 2019, and 23 (0. 41%) in 2020 with an overall rate of 59 (0. 36%) for all the three years. Total male participants were 35 (59.32%), and the mean age of the patients was 56.13 ±12.44 years. Majority had abdominal pain (32, 54.24%) and 35(59.32%) had tumours in the duodenum, 15 (25.42 %) in the stomach. The most common site was duodenum 35 (59.32%). As per World Health Organisation (WHO) NET, most tumours were Grade I (50, 45.76%). Majority of tumours had Synaptophysin (57, 96.61%), Chromogranin (49, 83.05%), and a Ki67 (Kiel-clone no.67) index≤ 2 (49, 83.05%), while 27 (84. 75 %) tumours were of size of <1 cm. Conclusion: GI-NETs are uncommon, and their biology, histopathology, and clinical behavior are distinct. Typically, they are slow-growing tumours, but their growth rate can fluctuate depending on the location, size, and grade of the tumour

What Every Gastroenterologist Should Know About Gastrointestinal NETs.

Gastrointestinal neuroendocrine tumors are increasingly common. Practitioners should examine these lesions carefully found on routine endoscopy. Obtaining accurate neuroendocrine tumors stage and grade is critical to patient assessment and management, and assistance from advanced endoscopists may be needed.

Carcinoid tumors outside the abdomen.

Neuroendocrine tumors (NETs) are epithelial malignancies that can arise from multiple tissues. Gastrointestinal (GI) NETs are the most common; in this review of extra-abdominal carcinoid tumors, we focus our discussion on bronchial and thymic carcinoid tumors. Bronchial carcinoid tumors comprise a quarter of all NETs and less than 2% of all lung cancers. Thymic carcinoid tumors are extremely rare, accounting for 5% of thymic tumors. Both bronchial and thymic carcinoid tumors are histologically classified as either typical or atypical based on their mitotic rate (less than 2 or 2-10 mitoses per 10 high-powered fields (HPF), respectively). Both bronchial and thymic carcinoids can present with symptoms of obstruction and potentially carcinoid syndrome. The gold standard of management of bronchial and thymic carcinoid tumors is surgical resection. For patients with advanced disease, first-line systemic therapy is generally somatostatin analog monotherapy with octreotide or lanreotide. In patients with refractory disease, therapy generally involves peptide receptor radioligand therapy, everolimus, or cytotoxic chemotherapy. There are ongoing, prospective trials comparing the mainstays of systemic therapy for these patients, as well as ongoing evaluations of immune checkpoint inhibitors and multi-kinase inhibitors. Prognosis for both bronchial and thymic carcinoid tumors depends on histologic grade, local versus invasive disease, and extent of metastases. Herein we provide a summary of the pathophysiologic and clinical background, the current state of the field in diagnosis and management, and note of key ongoing prospective trials for patients with bronchial and thymic carcinoid tumors.

366 RIGHT HEART FAILURE IN CARCINOID HEART DISEASE: A MULTIDISCIPLINARY APPROACH

Abstract Introduction Carcinoid heart disease occurs in more than 50% of patients with neuroendocrine gastrointestinal tumors, and it is the initial presentation of carcinoid syndrome in up to 20% of patients. The disease is characterized by pathognomonic plaque-like deposits of fibrous tissue in the endocardium of valvular cusps, cardiac chambers, and occasionally, the intima of the pulmonary arteries or aorta. The tricuspid and the pulmonary valve are most often affected by carcinoid disease, with several combinations of valve dysfunction (usually pulmonic stenosis + tricuspid regurgitation). Valvular dysfunction can lead to peripheral edema, ascites and right-sided heart failure, extreme cases may present with low cardiac output syndrome. Valve surgery may relieve symptoms and it should be considered in patients with controlled neoplasia. Case report a 47-years-old man with a history of operated neuroendocrine gastrointestinal tumor (ileal resection+right hemicolectomy+mesenteric lymphadenectomy) was admitted to our department for right heart failure. His clinical examination was remarkable for ankle swelling, flushing, liver congestion, ascites; moreover the patient reported progressive compromise of functional capacity and weight loss due to anorexia. Laboratory findings were in the normal range except for BNP 184 pg/ml (UNL <100 pg/dl). ECG: sinus rhythm 80 bpm, diffuse repolarization abnomarlities. Transthoracic echocardiography showed: severe right chambers remodeling with RV+RA dilatation associated with systo-diastolic septal bulge (pressure + volume overload), torrential tricuspid regurgitation (secondary to fibrotic retraction of valve leaflets and severe coaptation deficiency with apical tethering), moderate-to-severe pulmonic regurgitation associated with valve stenosis; on the left side: mitral and aortic valves were normal, there was mild reduction of left ventricle ejection fraction secondary to ventricular interdipendence. The patient was discussed in Heart Team: right sided valves were both considered responsible for patient's symptoms, so he was scheduled for surgical intervention after achieving adeguate haemodinamic stability. Pre-surgery right catetherization showed normal pulmonary pressures. Coronary arteries were normal. Before, during and after surgery he was treated with octreotide to reduce the risk of Carcinoid Crisis in the perioperative period. The patient underwent surgical replacement of tricuspid and pulmonary valves with biological prosthesis Mosaic n°33 and Avalus n°23 respectively. Histological examination of the valves showed extensive deposits of fibrous tissue in the valvular endocardium. Post-surgical hospital stay was uneventful, the patient was discharged 14 days after surgery on normal sinus rhythm and in good clinical conditions. In order to prevent thromboembolic events anticoagulant therapy with Warfarin was introduced. Conclusion this is the report of a rare cardiac condition responsible for right heart failure symptoms. Heart Team discussion and multidisciplinary approach involving surgeons and oncologist are mandatory in order to establish the best treatment strategy and timing for interventions. However, since this is a rare condition, more evidence is needed to better understand long term clinical outcomes and treatment options (including future percutaneous perspectives).

Gastrointestinal Glomus Tumors: A Single Institution, 20-Year Retrospective Study

IntroductionGlomus tumors are rare mesenchymal neoplasms composed of cells resembling those of the thermoregulatory glomus body, typically occurring in the skin and superficial soft tissues. Rarely do they occur in the gastrointestinal tract, in particular the stomach, where they have been the subject of case reports and small series. We present our institutional experience with gastrointestinal glomus tumors. MethodsA retrospective review of all gastrointestinal glomus tumors was conducted across all three Mayo Clinic sites in Minnesota, Arizona, and Florida from 2001 to 2021. Patient characteristics, pathologic findings, imaging features, operative reports, and clinical outcomes were abstracted. Descriptive statistics were utilized to report outcomes. ResultsNine patients with glomus tumors were identified (five men and four women). The median age was 53 [interquartile range (IQR), 44-69] y. Four patients presented with abdominal discomfort, three had anemia or bleeding, and two tumors were incidentally diagnosed. Computed tomography scans identified masses thought to represent gastrointestinal stromal tumors or neuroendocrine tumors in all patients. The tumors were localized to the stomach in all cases, specifically in the gastric antrum. Seven patients underwent preoperative endoscopy, including five with endoscopic ultrasonography. Endoscopic biopsies were interpreted as glomus tumors (n = 3), neuroendocrine tumors (n = 2), and nondiagnostic (n = 2). All patients underwent open (n = 3) or minimally invasive (n = 6) margin-negative resection by wedge resection (n = 5) or distal gastrectomy (n = 4). No nodal metastases were identified radiographically or on pathologic examination. The median tumor size was 2.5 [IQR 1.3-3.4] cm. All tumors showed at least in part typical glomus tumor morphology and smooth muscle actin expression. Aberrant synaptophysin expression was present in the two tumors initially classified as NET. Using the current WHO criteria, tumors were classified as histologically malignant (n = 1) and of “uncertain malignant potential” (n = 8). At a median follow-up of 15 [IQR 1-56] mo, all patients were asymptomatic and without recurrence. Two patients died of unrelated causes. No patients received adjuvant therapies. ConclusionsOur 20-year, single institution, 3-site experience with resected gastrointestinal glomus tumors suggests the rarity, predisposition to involve the gastric antrum, and potentially an indolent clinical behavior of many of these tumors. Long-term follow-up is warranted as some previously reported gastric glomus tumors have metastasized, including cases lacking morphologic evidence of malignancy. Surgical resection, with minimally invasive wedge resection alone, is likely sufficient for the management of most gastric glomus tumors.

Evaluation of quality of clinical management of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are a group of biologically and clinically heterogeneous neoplasms predominantly found in the gastrointestinal and bronchopulmonary tractus. Despite a rising incidence, implementation of evidence-based standardized care for this heterogenous group remains challenging. The European Neuroendocrine Tumor Society regularly reviews guidelines regarding diagnostic and treatment strategies for NETs. The aim of this study is to shed light on the care of patients with a NET in Belgian Limburg, to provide data as a basis for future studies and to check whether data and results are according to consensus guidelines and outcomes described in literature. Our study concerned a detailed observational data collection of two large Belgian hospitals (Jessa Hospital Hasselt and Hospital Oost-Limburg Genk) with special interest in patient profile, quality of pathology reports, use of diagnostic imaging, and overall survival. Data on 188 patients were assembled between January 2010 and December 2014 with follow-up until June 2016 (median follow-up: 33.6 months). Fifty percent of patients were male. NETs were located mainly in the digestive tract (63.8%) and lung (20.2%). Appendiceal NETs were diagnosed at a significantly younger age than other tumors (41.3vs. 64.0years). Overall, a mean pathology report quality score of 3.0/5 was observed with the highest scores for small bowel NETs. Diagnostic and nuclear imaging was performed in 74.5% and 29.8% of cases, respectively. Seventy-four percentof the population survived until the end of the observation period with highest survival rates for appendiceal and small bowel NETs. Overall, epidemiological results were comparable with findings in the literature. Gastrointestinal NETs met most of the requirements of qualitative pathology reporting and diagnostic imaging as listed in the European Neuroendocrine Tumor Societyconsensus guidelines. However, consensus with regard to bronchopulmonary NETs is still scarce and remains an objective for future research. Moreover, discussing treatment strategies in specialized multidisciplinary tumor boards would facilitate regional care.

Two Cases of Duodenal Neuroendocrine (Carcinoid) Tumor Concurrent with Invasive Gastric Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasm

Abstract Introduction/Objective Neuroendocrine (carcinoid) tumors of the duodenum are extremely rare and account for only 2-4% of gastrointestinal tract neuroendocrine tumors. We report two cases of incidentally discovered duodenal neuroendocrine tumor which respectively occurred in a patient with invasive gastric adenocarcinoma and in a patient with pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods/Case Report The first case involved a 60-year old male who presented with melena and symptomatic anemia and was found on EGD to have a large circumferential mass at the gastric antrum/pylorus, which was revealed to be an invasive gastric adenocarcinoma on biopsy. At the time of distal gastrectomy for this malignancy, a concurrent, 0.6 cm-sized, low grade neuroendocrine tumor was incidentally discovered at the duodenal margin. The duodenal tumor consisted of nests and trabeculae of monotonous cells with ovoid/round nuclei, finely speckled “salt and pepper” chromatin, and low mitotic rate (< 2 mitoses/2 mm2), and invaded only into submucosa. The tumor cells were strongly and diffusely positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, positive for CK7 and CDX2, negative for CK20, and with low Ki67 proliferation index (< 3%). The second case involved a 69-year old female who presented with epigastric pain and was found on abdominal CT to have a 4 cm-sized cystic mass in the pancreatic head. While biopsy of the pancreatic mass revealed an IPMN, a separate biopsy of an incidentally discovered, 1 cm-deep ulcer in the duodenum bulb revealed a low-grade neuroendocrine tumor with similar morphologic features, mitotic rate, and immunohistochemical staining pattern as the prior case while also negative for IMP3 stain. The patient had normal serum gastrin and urine HIAA levels, but elevated serum chromogranin-A levels. Results (if a Case Study enter NA) NA. Conclusion Duodenal carcinoids are rare (1-3% of primary duodenal tumors) and are mostly non-functional and unifocal. The duodenum is also the least common site (2-4%) for GI tract neuroendocrine tumors. The pathophysiology of these tumors is still poorly understood, with the majority occurring sporadically and a minority in the setting of hereditary cancer syndromes. This report documents two very rare instances of duodenal neuroendocrine tumor incidentally discovered with invasive gastric adenocarcinoma and pancreatic IPMN.

A rare case of Composite Gangliocytoma/Neuroma and Neuroendocrine Tumor (CoGNET) of the Duodenum - A case report

Abstract Introduction/Objective The unique morphologic and clinical features of neuroendocrine tumors have attracted the attention of physicians, most especially pathologists for more than a century. Neuroendocrine tumor of the duodenum is a rare entity and only accounts for ~ 2% of gastrointestinal neuroendocrine tumors. Though it was initially classified as duodenal gangliocytic paraganglioma due to the presence of sustentacular cells and its association with ganglion cells, it has now been reclassified in 2022 WHO classification as “composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET) due to its clinical features and immunophenotypic characteristics. Hence, we report a rare case of CoGNET in the duodenum. Methods/Case Report We present a 72-year-old female with a past medical history of hypothyroidism, hyperlipidemia, hypertension, deep vein thrombosis, and pulmonary embolism presenting with a 1-day history of abdominal pain and vomiting. Esophagogastroduodenoscopy (EGD) was performed, and it was concerning for a duodenal mass and the specimen was biopsied. Results (if a Case Study enter NA) The biopsy consisted of multiple tan-red hemorrhagic soft tissue, which on microscopic examination showed a triphasic histological pattern which includes neuroendocrine cells, spindle-shaped Schwannian/ sustentacular cells, and neuronal ganglion cells. Immunohistochemical stains performed showed the tumor cells are strongly positive for synaptophysin, and chromogranin; moderately positive with AE1/AE3, and patchy positive with S100. Desmin, CD117, DOG-1, CD34, and GATA were all negative in the tumor cells; the Ki-67 proliferative index was 1%. These morphological and immunophenotypic features are consistent with CoGNET. Conclusion CoGNET is a rare entity in the gastrointestinal tract especially in the duodenum and given its recent reclassification in 2022 WHO classification; pathologists, surgeons, and physicians need to be aware of such rare entities to improve patient care.

LBMON138 Leg Tumeo: Is It Neuroendocrine Tumor?

Abstract Introduction Neuroendocrine tumors (NETs) are heterogenous group of epithelial neoplasms often known to produce and secrete peptides and bioamines. The presentation varies from symptomatic functional to non-functional tumors. The functional tumors cause symptoms based on the substance secreted: corticotropin, gastrin, glucagon, insulin, norepinephrine, serotonin, somatostatin, etc. The prognosis ranges from well-differentiated tumors being indolent while the poorly differentiated forms are aggressive. We present a case with an atypical presentation of NET which was noted to secrete an atypical hormone, cortisol. Case Presentation A 55-year-old Caucasian man presented with bilateral lower extremity grade 3 pitting edema for past 2 weeks. His past medical history was significant for hypertension. Lower extremity doppler showed no evidence of deep vein thrombosis. Serum potassium was critically low at 1.9mmol/L. Computed tomography of abdomen and pelvis showed a large mass involving the right hepatic lobe, upper pole of right kidney and hypoattenuated lesions in left hepatic lobe. The intrahepatic inferior vena cava appeared to be severely compressed by the mass. MRI abdomen was suggestive of hepatocellular cancer but alfaprotein levels was normal. Biochemical testing for evaluation of hormonal hypersecretion showed elevated cortisol levels (57.2mcg/dl) and markedly elevated dehydroepiandrosterone sulfate (2641mcg/dl). Serum adrenocorticotrophic hormone and aldosterone levels were within normal limits. Low dose dexamethasone suppression test showed no decline in serum cortisol level reflecting adrenal origin. Urinary evaluation showed elevated cortisol but normal metanephrine and catecholamine levels. With concerns for adrenal carcinoma, right adrenal mass biopsy was performed. The biopsy showed poorly differentiated malignant neoplasm with neuroendocrine features. Tumor cells were positive for synaptophysin (a marker for neuroendocrine differentiation) and CD 138. Soon after, he progressed to multisystem organ failure, tumor lysis syndrome and resorted to comfort care. The patient passed away within a week of diagnosis. Conclusion NETs usually originate in gastrointestinal tract, pancreas, adrenal, lung and rarely genitourinary tract. The incidence of NETs is on the rise with increased detection by imaging. Adrenal NETs, well-known as pheochromocytoma are mostly benign but small cell adrenal neuroendocrine carcinomas are rare and have a grave prognosis. Flushing, diarrhea are the commonest presentations (75-85%) for gastrointestinal NETs and symptoms are based on the substance secreted. This case highlights a case of adrenal neuroendocrine cancer presenting with lower extremity swelling and secreting an uncommon hormone, cortisol. Increasing awareness among the medical fraternity will help with early diagnosis and better outcomes. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Nomogram for preoperative estimation of histologic grade in gastrointestinal neuroendocrine tumors.

The treatment strategies and prognosis for gastroenteropancreatic neuroendocrine tumors were associated with tumor grade. Preoperative predictive grading could be of great benefit in the selection of treatment options for patients. However, there is still a lack of effective non-invasive strategies to detect gastrointestinal neuroendocrine tumors (GI-NETs) grading preoperatively. The data on 147 consecutive GI-NETs patients was retrospectively collected from January 1, 2012, to December 31, 2019. Logistic regression was used to construct a predictive model of gastrointestinal neuroendocrine tumor grading using preoperative laboratory and imaging parameters.The validity of the model was assessed by area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). The factors associated with GI-NETs grading were age, tumor size, lymph nodes, neuron-specific enolase (NSE), hemoglobin (HGB) and sex, and two models were constructed by logistic regression for prediction. Combining these 6 factors, the nomogram was constructed for model 1 to distinguish between G3 and G1/2, achieving a good AUC of 0.921 (95% CI: 0.884-0.965), and the sensitivity, specificity, accuracy were 0.9167, 0.8256, 0.8630, respectively. The model 2 was to distinguish between G1 and G2/3, and the variables were age, tumor size, lymph nodes, NSE, with an AUC of 0.847 (95% CI: 0.799-0.915), and the sensitivity, specificity, accuracy were 0.7882, 0.8710, 0.8231, respectively. Two online web servers were established on the basis of the proposed nomogram to facilitate clinical use. Both models showed an excellent calibration curve through 1000 times bootstrapped dataset and the clinical usefulness were confirmed using decision curve analysis. The model served as a valuable non-invasive tool for differentiating between different grades of GI-NETs, personalizing the calculation which can lead to a rational treatment choice.

The real-world selection of first-line systemic therapy regimen for metastatic gastroenteropancreatic neuroendocrine neoplasm in Japan

In November 2013, the first edition of evidence-based guidelines for treatment of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) was published in Japan. However, whether medical practitioners have adopted the first-line regimens recommended for metastatic GEP-NEN in clinical practice is not yet known. The purpose of this study was to identify which first-line systemic therapy regimens have been selected and the proportion of cases that are adherent to the guidelines (i.e., number of patients receiving recommended therapy/total number of patients). We combined hospital-based cancer registry data and insurance claims-equivalent data for patients with GEP-NEN treated between January 2013 and December 2014 and extracted those with metastatic GEP-NEN who received systemic therapy. The proportions that were adherent with the guideline were calculated according to tumor classification (neuroendocrine tumor [NET] or neuroendocrine carcinoma [NEC]), primary site (gastrointestinal or pancreatic), and hospital volume (high, medium, or low). The study included 109 patients with GEP-NET and 424 with GEP-NEC. Overall, guideline-adherent treatment was provided in only 54.8% of cases (58.1% for gastrointestinal NET, 63.6% for pancreatic NET, 56.6% for gastrointestinal NEC, and 44.9% for pancreatic NEC). The recommended therapy for GEP-NET was used in 16.5% of patients with GEP-NEC, and 21.5% received fluoropyrimidine-containing chemotherapy. This report is the first to describe real-world selection of first-line regimens for metastatic GEP-NEN. About half of all these patients received systemic therapy that was not recommended in the guidelines.