Neuroendocrine Tumor Grade Research Articles

The Efficacy of a Lower Dose of Everolimus in Patients with Advanced Neuroendocrine Tumors

Background: Everolimus at 10 mg daily is approved to treat patients with advanced grade 1/2 neuroendocrine tumors (NETs), although it may lead to significant toxicity. Grade 3 or higher drug-related adverse events and drug discontinuation occur in approximately one-fourth of cases. However, phase I trials have demonstrated that doses from 5 mg daily efficiently inhibit NET cell signaling. Objectives and Methods: This multicenter retrospective study compared the time to treatment failure (TTF) in patients with NETs who received a mean daily dose of 7–10 mg (higher dose [HD]) or ≤6 mg (lower dose [LD]) of everolimus. Results: Ninety-two patients were included: 74 (80%) in the HD group and 18 (20%) in the LD group. At a median follow-up of 4.2 years, the median time to treatment failure (TTF) was 9.2 months for the HD and 7.2 months for the LD groups (p = 0.85). The TTF did not significantly differ between the LD and the HD groups (HR: 1.24; 95% CI: 0.68–2.25; p = 0.47), even after adjusting for age at treatment initiation, the NET grade, and the treatment line. Conclusion: Everolimus doses from 5 to 6 mg/day seem to be equally as effective as higher doses, but lower doses are potentially associated with less toxicity and lower costs. These findings support validation through a randomized clinical trial.

Liver metastases in high-grade neuroendocrine neoplasms: A comparative study of hepatic tumor volume and biochemical findings in NET G3 versus NEC.

Abnormal liver blood tests and liver tumor burden are known prognostic factors in neuroendocrine neoplasms (NEN). However, the relationship between biochemical liver parameters and hepatic tumor load is largely unknown in NEN and in high-grade NEN (G3) specifically. The primary objective of this study was to correlate the biochemical parameters and liver tumor volume of patients with neuroendocrine tumors grade 3 (NET G3) or neuroendocrine carcinomas (NEC). We wanted to investigate whether patients with NET G3 with extensive liver involvement had less severely elevated laboratory liver parameters than NEC patients. In total, 46 patients with NEN were included, 31 had NEC and 15 NET G3. All patients had distant metastatic disease, with liver metastases being the most common (n = 39). Both laboratory results and semiautomatic volumetric measurements of liver tumor burden were obtainable for 34 patients at baseline and 26 patients at follow-up. Alkaline phosphatase (AP), gamma-GT (gGT), and lactate dehydrogenase (LDH) increased significantly between the two time periods (p < .01). In a regression model, liver tumor burden significantly affected several blood parameters, for example, increasing AP, gGT, LDH, and aspartate aminotransferase (ASAT) by a factor of 1.02-1.04 per unit increase (1% tumor burden; all p < .001). AP, gGT, and LDH were significantly lower in NET G3 (factor of 0.43-0.68) than in NEC. Here, we found that liver chemistries changed over the NEN disease course, correlated with hepatic tumor burden, and differed by histologic subtype. The current data can potentially guide treatment decisions, for example, with regard to integration of liver-directed therapies.

S1614 Grading of Pancreatic Neuroendocrine Tumors by EUS FNA/FNB: A Tertiary Care Center Experience

S1614 Grading of Pancreatic Neuroendocrine Tumors by EUS FNA/FNB: A Tertiary Care Center Experience

Long-term experience with octreotide and lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors.

The somatostatin analogs (SSA) octreotide and lanreotide are a mainstay in the treatment of neuroendocrine tumors (NET). The two pivotal trials differed considerably in terms of patient characteristics and are not directly comparable. Further comparative data are lacking. This retrospective chart review study included patients with gastroenteropancreatic NET grade 1 or 2 who were treated with octreotide LAR or lanreotide autogel. The main aim was to compare the two SSA based on progression-free survival (PFS) and overall survival (OS) from treatment start. In total, 129 patients were analyzed, 60% (n = 77) had a small intestinal NET and 31% (n = 40) a pancreatic NET. Histologically, 34% (n = 44) had NET G1, 55% (n = 71) a NET G2, and 11% (n = 14) a NET G1/G2 unclassified. Lanreotide was used in 90 patients (70%) and octreotide in 39 patients (30%). Overall, the median PFS was 32.2months (95%CI 23.0-42.9months). No PFS difference (p = 0.8) was observed between lanreotide (29.8months, 95%CI 18.7-48.5months) and octreotide (36.0months, 95%CI 23.2-68.2months). Median OS from treatment start was calculated at 93.5months (95%CI 71.1-132.9months). Again, the median OS following lanreotide (113.4months, 95%CI 62.3-NA months) or after octreotide (90.3months, 95%CI 71.1-NA months) did not differ significantly (p > 0.9). Our long-term experience with octreotide and lanreotide in NET did not reveal differences in antitumor effectiveness. This is consistent with previous reports and might suggest that both SSA can be used interchangeably if needed.

Primary neuroendocrine tumor of the perihilar bile duct: A case report

Neuroendocrine tumors (NETs) arising from extrahepatic bile ducts are very rare. We present a patient with perihilar NET who was operated on with a preoperative diagnosis of Klatskin tumor. A 58-year-old female patient was admitted with abdominal pain and jaundice. Laboratory data showed elevated serum bilirubin levels and liver function tests. Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) findings were consistent with perihilar bile duct tumor. The patient was operated on with a diagnosis of Klatskin tumor. She underwent right hepatectomy, resection of the extrahepatic bile duct, portal lymphadenectomy and Roux-en-Y hepaticojejunostomy. The final pathologic examination of the resected specimen demonstrated a well differentiated neuroendocrine tumor (Grade 1). NETs originating from perihilar bile ducts are extremely rare, and preoperative definite diagnosis is very difficult. It should be kept in mind that NET may be one of the rare causes of perihilar bile duct obstruction.

Anti-phosphohistone H3 (PHH3) as a proliferation marker to assess mitotic activity and to grade neuroendocrine neoplasms of hepatopancreaticobiliary (HPB) system.

The world health organization (WHO) classification of neuroendocrine neoplasms (NENs, i.e. neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs)) of the gastrointestinal system involves grading of these tumors by mitotic count (i.e. H and E mitotic index or Haematoxylin and Eosin mitotic index [HE-MI] and Mindbomb E3 ubiquitin protein ligase 1 labelling index (MIB1-LI) into Grade 1 (G1), Grade 2 (G2), or Grade 3 (G3). However, the assessment of HE-MI and MIB1-LI is hindered by several factors that contribute to discordance between these two grading methods. Clinical data demonstrate the dependency of prognosis on grade. The objective of this study was to compare the grading of NENs of the hepatopancreatobiliary (HPB) system using Anti-phosphohistone H3 mitotic index (i.e. PHH3-MI), HE-MI and MIB1-LI. In a cohort of 140 NENs selected from January 2011 to August 2019, the concordance and correlation between HE-MI, MIB1-LI and PHH3-MI grading methods were analysed using Cohen's weighted kappa (κ) statistics and Spearman's correlation (ρ), respectively. Receiver operating characteristic (ROC) curve and cut-off analyses were done to determine optimal PHH3-MI cut-off values to grade NENs. The rates of discordance between HE-MI vs. MIB1-LI, PHH3-MI vs. MIB1-LI and PHH3-MI vs. HE-MI were 52% (κ =0.416), 29% (κ =0.64) and 41% (κ =0.508), respectively. There was a significant correlation between the grading methods. PHH3-MI had good overall sensitivity and specificity at cut-offs 2 and 17 in distinguishing between G1 vs. G2, and G2 vs. G3 tumors, respectively. PHH3 immunolabeling allowed for quick and easy identification of mitotic figures (MF). It had the highest concordance with MIB1-LI. At cut-off values of 2 and 17, there was good overall sensitivity and specificity. The interobserver agreement was excellent.

[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study

There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms

BackgroundHigh-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55).MethodsWe analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1.ResultsFrequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival.ConclusionsThis study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.

Rare Nasopharyngeal Neuroendocrine Tumor in a 26-Year-Old Female: Case Report and Literature Review.

Neuroendocrine neoplasms (NENs) represent a collection of highly varied tumors that originate from neuroendocrine cells. They are considered rare tumors that predominantly affect the lungs. Epithelial NENs can be categorized into neuroendocrine tumors (NETs) and neuroendocrine carcinomas. It is extremely rare for NET grade 1 (NET G1) to exist in the nasopharynx, these tumors are slow-growing and the onset of symptoms and identification of the tumor may take several years. The majority of cases occur in ages between 60 and 65 years. In this article, we present a case of a 26-year-old female who presented with recurrent epistaxis and nasal obstruction for one and a half years. Magnetic resonance imaging revealed a substantial nasopharyngeal mass. Subsequently, a biopsy was conducted, and the histopathological results indicated a NET G1. Our literature review revealed 5 cases of NET G1 in the nasopharynx, with our patient being the youngest among all published cases.

Superior Vena Cava Syndrome in Men with Thymic Atypical Carcinoid (Neuroendocrine Tumor Grade 2)

Introduction: Cases of neuroendocrine tumors (NET) can occur in various organs, generally in the form of gastroenteropancreatic (GEP-NET) and pulmonary tract (PNET). The incidence of thymic neuroendocrine tumors (TNET) is rare, accounting for less than 5% of thymic and mediastinal malignancies, and 0.4% of all neuroendocrine tumors. Case presentation: A 57-year-old man came to RSUP Dr. Mohammad Hoesin Palembang with complaints of coughing, bluish and curved blood vessels in the chest, and shortness of breath during activities that have been getting worse for six months. CT scan showed a tumor measuring 18.6 x 11.7 x 11 cm in the anterior mediastinum and pressing on the superior vena cava and abdominal aorta. TTNA and core biopsy with CT guidance showed NET Grade 2, mitoses 6/2 mm2, positive tumor cells with immunohistochemistry for synaptophysin, chromogranin, CD 56, AE1/AE3, and Ki67 9%. The patient received paclitaxel and carboplatin chemotherapy for 6 cycles. Conclusion: The prognosis for atypical carcinoid patients is 20-80% for a 5-year survival rate. Appropriate patient management is needed to improve the outcome of patients with primary thymic atypical carcinoid (NET, grade 2).

Prognostic factors and treatment impact on overall survival in patients with renal neuroendocrine tumour

AbstractBackgroundRenal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates.ObjectiveThe objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN.Design, setting and participantsWe identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival.Results and limitationsOf 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p &lt; 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03–1.06; p &lt; 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96–5.1; p &lt; 0.001), NEC‐NOS histology (HR, 2.82; 95% CI, 1.64–4.86; p &lt; 0.001), LC‐NEC histology (HR, 2.73; 95% CI, 1.04–7.17; p = 0.041) and SC‐NEC histology (HR, 5.17; 95% CI, 2.95–9.05; p &lt; 0.001) were all positive predictors of worsening overall survival. The main limitation of the study is its retrospective design.ConclusionR‐NEN is an aggressive tumour characterized by high mortality rates. Surgery continues to be the mainstay of treatment and has shown to provide a survival benefit for most patients.Patient SummaryR‐NEN is composed of several tumour histologies that differ based on their aggressiveness with NEC‐NOS and SC‐NEC being the most lethal. Surgery, predominantly through minimally invasive approaches, is the mainstay of treatment and has a clear survival benefit.

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms.

CXC chemokine receptor 4 (CXCR4) is associated with the progression and metastasis of numerous malignant tumors. However, its relationship with Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3 (GEP-NENs G3) is unclear. The aim of this study was to characterize the expression of CXCR4 in GEP-NENS and to explore the clinical and prognostic value of CXCR4. This study retrospectively collected clinical and pathological data from patients with GEP-NENs who receiving surgery in Qilu Hospital of Shandong University from January 2013 to April 2021, and obtained the overall survival of the patients based on follow-up. Immunohistochemistry (IHC) was performed on pathological paraffin sections to observe CXCR4 staining. Groups were made according to pathological findings. Kaplan-Meier (K-M) curve was used to evaluate prognosis. SPSS 26.0 was used for statistical analysis. 100 GEP-NENs G3 patients were enrolled in this study. There was a significant difference in primary sites (P=0.002), Ki-67 index (P<0.001), and Carcinoembryonic Antigen (CEA) elevation (P=0.008) between neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC). CXCR4 was highly expressed only in tumors, low or no expressed in adjacent tissues (P<0.001). The expression level of CXCR4 in NEC was significantly higher than that in NET G3 (P=0.038). The K-M curves showed that there was no significant difference in overall survival between patients with high CXCR4 expression and patients with low CXCR4 expression, either in GEP-NEN G3 or NEC (P=0.920, P=0.842. respectively). Differential expression of CXCR4 was found between tumor and adjacent tissues and between NET G3 and NEC. Our results demonstrated that CXCR4 can be served as a new IHC diagnostic indicator in the diagnosis and differential diagnosis of GEP-NENs G3. Further studies with multi-center, large sample size and longer follow-up are needed to confirm the correlation between CXCR4 expression level and prognosis.

Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients’ clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

Automated AI-based grading of neuroendocrine tumors using Ki-67 proliferation index: comparative evaluation and performance analysis.

Early detection is critical for successfully diagnosing cancer, and timely analysis of diagnostic tests is increasingly important. In the context of neuroendocrine tumors, the Ki-67 proliferation index serves as a fundamental biomarker, aiding pathologists in grading and diagnosing these tumors based on histopathological images. The appropriate treatment plan for the patient is determined based on the tumor grade. An artificial intelligence-based method is proposed to aid pathologists in the automated calculation and grading of the Ki-67 proliferation index. The proposed system first performs preprocessing to enhance image quality. Then, segmentation process is performed using the U-Net architecture, which is a deep learning algorithm, to separate the nuclei from the background. The identified nuclei are then evaluated as Ki-67 positive or negative based on basic color space information and other features. The Ki-67 proliferation index is then calculated, and the neuroendocrine tumor is graded accordingly. The proposed system's performance was evaluated on a dataset obtained from the Department of Pathology at Meram Faculty of Medicine Hospital, Necmettin Erbakan University. The results of the pathologist and the proposed system were compared, and the proposed system was found to have an accuracy of 95% in tumor grading when compared to the pathologist's report.

Ampullary mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is an exceptionally rare case presenting as abdominal pain

ABSTRACT Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare tumor of the gastrointestinal tract with both neuroendocrine and non-neuroendocrine components accounting for 30% of the tumor volume each. We describe the case of a 51-year-old gentleman who presented with a complaint of abdominal pain. On upper gastrointestinal endoscopy (UGIE), a superficial ulcer over the ampulla with antral gastritis was noted and the biopsy was suggestive of neuroendocrine tumor grade 1. A pylorus-preserving pancreatoduodenectomy was performed, and the histopathology examination of the resected sample has an adenomatous component of 33% and the rest (67%) is a neuroendocrine component. This was confirmed by neuroendocrine markers (synaptophysin, chromogranin, and CD56) with Ki-67 of 4–5%. Hence, the diagnosis of ampullary MiNEN intermediate grade was established. Ampullary location of this tumor is extremely rare and is usually aggressive in nature with frequent distant metastasis. The treatment option for such low-prevalence cancers is not yet standardized, suggesting future clinical research for the same.

O-06 Efficacy of Lutetium-Peptide Receptor Radionuclide Therapy and osilodrostat treatment at achiving eucortisolism and tumour stabilization in a patient with metastatic ectopic ACTH-syndrome

Abstract Introduction Ectopic ACTH syndrome (EAS) is a rare cause of endogenous hypercortisolism. We present a case of a patient diagnosed with severe EAS, achieving eucortisolism and a favorable outcome of ACTH-producing metastatic pancreatic neuroendocrine tumor (NET) after 177Lu-DOTATATE and osilodrostat treatment. Clinical Case A female patient was admitted to our clinic at the age of 55 complaining of severe fatigue, facial and leg edema. Laboratory tests revealed a significant degree of ACTH-dependent hypercortisolemia (late-night serum cortisol 1856 nmol/L (64–327), late-night salivary cortisol (LNSC) 387.7 nmol/L (0.5–9.65), 24hUFC 8561 nmol/L (100–379), ACTH 332.8 pg/mL (7.2–63.3)), hypokalemia (1.88 mmol/L), increased liver enzymes (alanine aminotransferase (ALT) 303.2 U/L (0–55), aspartate aminotransferase (AST) 94.3 U/L (5–34)). MRI of the brain was negative for pituitary abnormalities. CT and somatostatin receptor scintigraphy with 99mTc-Tektrotyd revealed NET of the pancreas and multiple liver metastases. Subsequent biopsy confirmed NET grade 2, Ki67 – 7%. Treatment with lanreotide 120 mg every four weeks was initiated. In order to control hypercortisolism the patient received osilodrostat at a dose of 10 mg daily, which improved the patient's general condition in the first days of therapy. After 1 month of treatment, her hypercortisolism symptoms improved, LNSC dropped to 0.54 nmol/L and morning cortisol dropped from 1451 nmol/L (101–535) to 60.7 nmol/L, which could suggest adrenal insufficiency. She also had normalization of potassium and liver enzymes (ALT 18.4 U/L, AST 23 U/L). The dose of osilodrostat was firstly reduced and then discontinued. 177Lu-DOTATATE treatment was offered with four doses (7.4 GBq (200 mCi) every 8 weeks). The first dose was administered in January 2023. The SPECT-CT performed after the second dose demonstrated disease stabilization. At the time of writing, the patient remains in eucortisolism (LNSC 5,36 nmol/L, morning cortisol 140 nmol/L, ACTH 36.4 pg/ml) with tumor stabilisation after 4 doses of 177Lu-DOTATATE. However, the most recent routine blood test revealed thrombocytopenia (platelets 44×109/μl (150–400)), decreased white blood cell count (3.24×109/μl (4.5–11)), lymphocytes (0.71×109/μl (1.18–1.34)) and hemoglobin 98 g/L (117–160). Nevertheless, her general condition remains stable and significantly improved versus the initial investigation. Conclusion This observation highlights the feasibility and efficacy of a combined approach using osilodrostat and 177Lu-DOTATATE in the management of patients with metastatic ACTH-producing NET. This approach resulted in a substantially improved patient quality of life. Funding Russian Scientific Foundation 19-15-00398

Multiple ileal neuroendocrine tumors 10mm in diameter with lymph node metastasis detected on endoscopy:a case report

A 53-year-old man with an abnormal routine physical examination was referred to our hospital. Colonoscopy showed a 5-mm submucosal tumor that was 7cm proximal to the ileocecal valve. It was identified as a neuroendocrine tumor (NET) on biopsy. Preoperatively, we conducted a double balloon endoscopy to examine the entire small intestine. Another 7-mm submucosal tumor was found on the ileocecal valve, which was missed during the first colonoscopy. A final diagnosis of multiple ileal NETs (<10mm in diameter) was made, and the patient underwent ileocecal resection with lymphadenectomy. Histopathological evaluation of the surgical specimen verified the diagnosis of NET Grade 1 with submucosal invasion. Metastasis to lymph node #202 was also detected. He remained relapse-free for 5 years and 5 months after the operation. In conclusion, this was a case of multiple ileal NETs (<10mm in diameter) with lymph node metastasis that could not be detected preoperatively on contrast-enhanced computed tomography. This case highlights the significance of detailed endoscopic observation of the terminal ileum.

Comparison of endoscopic ultrasound fine needle aspiration (FNA) vs fine needle biopsy (FNB) for preoperative grading of pancreatic neuroendocrine tumors: A systematic review and meta-analysis

Comparison of endoscopic ultrasound fine needle aspiration (FNA) vs fine needle biopsy (FNB) for preoperative grading of pancreatic neuroendocrine tumors: A systematic review and meta-analysis

A Case of Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm Composed With Adenoma and Neuroendocrine Tumor

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the gastrointestinal tract, particularly gastric MiNENs are rare, and a gastric adenoma that occurs concomitant with a neuroendocrine carcinoma (and not gastric adenocarcinoma) is extremely rare. The clinicopathologic and pathogenetic features of MiNENs remain unclear, and treatment guidelines are currently unavailable. A 75-year-old man patient was referred to our hospital for management of a gastric adenoma. Endoscopy revealed an elevated mucosal lesion (10 mm×10 mm) at the greater curvature of the lower gastric body. The patient underwent endoscopic submucosal dissection for removal of the gastric neoplasm. Histopathological evaluation revealed mixed epithelial dysplasia, low and partly high grade and a neuroendocrine tumor (grade 1). Immunohistochemical analysis showed neoplastic cells with immunopositivity for CD56, synaptophysin, and INSM1, and Ki-67 showed 2.2%. Therefore, the patient was diagnosed with a low-grade gastric MiNEN. We present a rare case of gastric MiNENs (adenoma-neuroendocrine tumor) together with a literature review.

Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs.

Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data are currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. Forty-one extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs), and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs, and the two pheochromocytomas were CS-associated. For comparison, 6 NETs of the pituitary gland (PitNETs; 3 ACTH-secreting and 3 ACTH-negative) and 35 ACTH-negative extra-pituitary NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real-time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extra-pituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.