Neuroendocrine Tumor G1 Research Articles

A calcitonin-producing pancreatic neuroendocrine neoplasm treated with distal pancreatectomy a lengthy time after a left trisectionectomy for liver metastases: a case report.

Calcitonin-producing pancreatic neuroendocrine neoplasms (PanNENs) are extremely rare. There have been no reports of a patient in whom liver metastases were the presenting finding, and a calcitonin-producing PanNEN was subsequently detected after a lengthy period. A 53-year-old man had diarrhea for several years. Computed tomography (CT) revealed multiple liver tumors. We performed a left trisectionectomy with a bile duct resection. The histologic examination showed neuroendocrine tumors G1. Immunohistochemistry was positive for calcitonin and the serum calcitonin level was elevated. Neuroendocrine neoplasms of hepatic origin are extremely rare, so a systemic exploration was performed, but no tumor was detected. CT showed a 4-mm calcification in the pancreatic body, but no contrast-enhanced mass was noted. Although the liver tumors were resected, the diarrhea and high serum calcitonin level persisted. Serial examinations were performed for 6years, but no tumor was identified; however, 6.5years after the hepatectomy the serum calcitonin level increased. CT showed a 10-mm contrast-enhanced mass in the calcified area of the pancreatic body. A distal pancreatectomy was performed. The histologic examination showed a neuroendocrine tumor G1, which mimicked the liver tumors. Immunohistochemistry was positive for calcitonin. After the distal pancreatectomy, the serum calcitonin level decreased and diarrhea resolved. The calcitonin-producing neuroendocrine neoplasm was considered the pancreatic primary and the hepatic tumors were metastases. Calcitonin-producing PanNENs may be initially recognized as liver tumors and may become evident after a lengthy period, thus long-term observation is recommended. Aggressive surgeries may contribute to long-term survival.

Texture and CT-features in differentiation of hypervascular pancreatic neuroendocrine tumors from renal cell carcinoma metastases: diagnostic model

Objective: to develop a diagnostic model that includes CT and radiomic features for the differential diagnosis of pancreatic neuroendocrine tumors (PNETs) G1 and G2 and pancreatic renal cell carcinoma (RCC) metastases.Material and Methods. 78 patients with 79 hypervascular PNETs and 17 patients with 24 pancreatic RCC metastases who underwent pancreatic resection and histological verification were selected in the study. All the patients underwent preoperative contrast enhanced CT (CECT). We assessed tumor attenuation, composition (cystic/solid), homogeneity (homogeneous/heterogeneous), calcification and presence of the main pancreatic duct (MPD) dilation. We calculated lesion-to-parenchyma contrast (LPC), relative tumor enhancement ratio (RTE) and extracted 52 texture features for arterial phase of CECT. Qualitative and texture features were compared between PNETs and pancreatic RCC metastasis. The selection of predictors for the logistic model was carried out in 2 successive stages: 1) selection of predictors based on one-factor logistic models, the selection criterion was p < 0.2; 2) selection of predictors using L2 regularization (LASSO regression after standardization of independent variables). The selected predictors were included in a logistic regression model without interactions, the coefficients of which were estimated using the maximum likelihood method with a penalty of 0.8.Results. There was no difference in composition, homogeneity (homogeneous/heterogeneous) and presence of the MPD dilation between groups. We did not find calcification in pancreatic RCC metastasis, in contrast to the PNETs (9% contained calcifications). After selection, the LCR, CONVENTIONAL_HUmin, GLCM_Correlation, NGLDM_Coarseness were included in the final diagnostic model, which showed a sensitivity and specificity of 95.8%; 62% in the prediction of pancreatic RCC metastases.Conclusion. The diagnostic model developed on the basis of texture and CT-features has high sensitivity (95.8%) with moderate specificity (62%), which allows it to be used in complex diagnostic cases to determine the patient's treatment tactics.

The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next?

Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.

The NET G3 enigma: dealing with a “new” entity

SummaryNeuroendocrine neoplasms of the gastroenteropancreatic system (GEP-NENs) have historically been graded into well-differentiated neuroendocrine tumors (NETs) G 1 and 2 and undifferentiated neuroendocrine carcinomas (NEC) G3 according to the proliferative index Ki-67, with the latter being larger than 20% for G3 NENs. However, clinical and pathological findings have suggested G3 NENs to be heterogeneous, and the most recent World Health Organization (WHO) classification has further subdivided G3 NENs into NET G3 with differentiated features and a usually lower Ki-67 (20–55%) as opposed to undifferentiated NECs. Currently, however, no standard approach to patients with NET G3 has been defined. As opposed to NET G1/G2, application of somatostatin analogues is not recommended, and the response to platinum-based chemotherapy is inferior when compared to NEC. The objective of this short review is to summarize pathological characteristics as well as therapeutic data obtained in patients with NET G3.

Neuroendocrine neoplasms of the breast: diagnostic agreement and impact on outcome

The classification of breast neuroendocrine neoplasms (Br-NENs) was modified many times over the years and is still a matter of discussion. In the present study, we aimed to evaluate the diagnostic reproducibility and impact on patient outcomes of the most recent WHO 2019 edition of breast tumor classification, namely, for neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). This multicentric observational study included 287 breast neoplasms with NE differentiation. The cases were blindly classified by three independent groups of dedicated breast and/or endocrine pathologists following the 2019 guidelines. Diagnostic concordance and clinical impact were assessed. We observed only a moderate overall diagnostic agreement across the three centers (Cohen’s kappa 0.4532) in distinguishing NET from solid papillary carcinomas (SPCs) and no special type carcinomas (NST) with NE differentiation. Br-NENs were diagnosed in 122/287 (42.5%) cases, subclassified as 11 NET G1 (3.8%), 84 NET G2 (29.3%), and 27 NEC (9.4%), the latter group consisting of 26 large-cell and 1 small-cell NECs. The remaining 165/287 (57.5%) cases were labeled as non-NEN, including SPC, mucinous, NST, and mixed NE carcinomas. While NET and non-NEN cases had a comparable outcome, the diagnosis of NECs showed negative impact on disease-free interval compared to NETs and non-NENs (p = 0.0109). In conclusion, the current diagnostic classification of Br-NENs needs further adjustments regarding morphological and immunohistochemical criteria to increase the diagnostic reproducibility among pathologists. Our data suggest that, apart from high-grade small- and large-cell NECs, Br-NENs behave like non-NEN breast carcinomas and should be managed similarly.

The role of chemoradiotherapy in the treatment of neuroendocrine rectal cancer: case reports

The aim of the study was to assess the response to preoperative radiotherapy (RT) in patients with G2-G3 rectal neuroendocrine tumors (NETs). Material and methods. Case reports involving patients who were given treatment at the N.N. Blokhin National Medical Research Center of Oncology from 2000 to 2020 were retrospectively studied. Patients with histologically verified neuroendocrine tumors of the rectum and anal canal (G2 and G3, Ki67>3%), who underwent preoperative radiotherapy (RT) or chemoradiotherapy (CRT) were included into the study. the study excluded patients who received palliative RT/CRT, patients with primary multiple synchronous or metachronous tumors, and patients with unresectable liver metastases. Staging was performed on the basis of MRI of the pelvis, CT scan of the chest and abdomen with intravenous contrast. The main assessment parameter was the response rate to treatment according to the RECIST criteria, and additional parameters were the frequency of pathological response according to DWORAK classification and overall and relapse-free survivals. Statistical analysis was conducted using the IBM SPSS software package (version 25). Results. The median follow-up time was 24 months. the follow-up time of a patient with G3 neuroendocrine cancer was 64 months without the evidence of disease progression. The 5-year OS and DFS for patients with G2-G3 rectal NETs were 64.3 % and 53.3 %, respectively. Conclusion. Long-term progression-free survival in 2 out of 3 patients with G3 neuroendocrine cancer (1 of them with a complete clinical response) and in 3 out of 4 patients with G2 neuroendocrine tumors was obtained.

Vipoma or Pancreatic Cholera: About a Case and Literature Review

VIPoma is a pancreatic endocrine tumor, which ectopically secretes the vasoactive intestinal polypeptide (VIP), which causes watery diarrhea and hypokalemia that causes WDHA syndrome (Watery Diarrhea, Hypokalemia, Achlorhydria), also known as “pancreatic cholera” or "Verner-Morrison syndrome". A 38-year-old patient, admitted to the emergency department for diarrhea made from 12 to 20 watery stools / day and a significant alteration of the general condition, evolving for a month, with a heterogeneous tissue and cystic mass with calcification in the flank left, measuring 12 cm objective on ultrasound and computed tomography. The therapeutic gesture consisted of a monobloc resection of the tumor and the inferior border of the body of the pancreas. The histological study concluded with a well-differentiated neuroendocrine tumor G1.

496MO Final overall survival results from the NICE-NEC trial (GETNE-T1913): A phase II study of nivolumab and platinum-doublet chemotherapy (CT) in untreated advanced G3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or unknown (UK) origin

G3 NENs are aggressive tumors with a median overall survival (OS) of ∼11 months (m) with standard platinum-based front line CT. Their high mutational burden and PD-L1 overexpression position G3 NENs as potential candidates for immunotherapy. The aim of this study was to assess the efficacy of the combination of CT plus Nivolumab (Niv) in patients (pts) with advanced CT-naïve G3 NENs.

Neuroendocrine tumor G3 of bronchopulmonary origin and its classification.

Neuroendocrine tumors (NET) with high proliferative activity (Ki-67 index >20% and/or mitotic counts >2 mm2 ) are defined as NET G3 in the 2019 World Health Organization (WHO) classification of digestive system neuroendocrine neoplasms (NENs). NETs G3 occur mostly in the pancreas, colon, rectum, and stomach and only rarely in the small intestine and the appendix. In the bronchopulmonary system, similar tumors have also been recognized and were mostly classified as atypical carcinoid (AC) or large cell neuroendocrine carcinoma. Bronchopulmonary NENs that were classified as NETs G3 are characterized by histological and immunohistochemical similarities with carcinoids/NETs, and a clinical course that is more aggressive than with ACs and similar to that of neuroendocrine carcinomas. The morphomolecular and clinical features of bronchopulmonary neoplasms with a high proliferative activity were reviewed and a future classification system that is applicable for both digestive and bronchopulmonary NETs is proposed.

Primary grade 2 neuroendocrine tumor of the ileal mesentery: a case report

BackgroundThe prevalence and incidence of neuroendocrine tumors (NETs) are increasing worldwide. Primary mesenteric NETs are extremely rare. Solid tumors that arise in the mesentery are typically metastatic. We present an extremely rare case of a primary grade 2 NET (NET G2) in the ileal mesentery.Case presentationA 54-year-old man was referred to our hospital for further examination of a previously diagnosed right mesenteric tumor. Mild tenderness was noted on the right side of the abdomen, but there were no palpable masses. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed slight FDG uptake (maximum standardized uptake value, 2.0) in the right abdomen, and a benign or low-grade malignant tumor was suspected. We extracted the ileal mesenteric tumor with an ileal resection (90 cm). The cut surface of the 55 × 33 × 33 mm3 tumor was pale yellowish-white. Immunohistochemistry revealed diffuse staining for synaptophysin and chromogranin A, and focal staining for CD56. The Ki-67 index was 3%. The final pathological diagnosis was NET G2. The patient’s postoperative course was uneventful, and he developed no recurrence 1.5 years after surgery. Postoperative antitumor therapy was not performed for this patient because the histological diagnosis was NET G2, and it was determined that the tumor could be completely resected by surgery.ConclusionsWe report an extremely rare case of primary ileal mesenteric NET. Mesenteric tumors that show slight FDG uptake on FDG-PET examination should be considered well-differentiated NET.

Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile.

Isolated hepatic localizations of neuroendocrine tumors (NETs) are generally considered as metastatic NETs of unknown primary but could correspond to primary hepatic NETs (PHNETs), a poorly explored entity. We aimed to describe the clinicopathological and molecular features of PHNETs and compare them with other primary NETs. We assembled a retrospective cohort of patients managed for hepatic localization of NET without extra-hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. We performed whole-exome sequencing with mutational and copy number analysis. Transcriptomic profiles were compared with pancreatic (n = 31), small-bowel (n = 22), and lung (n = 15) NETs using principal component analysis, unsupervised clustering, and gene set enrichment analysis. Among 27 screened patients, 16 had PHNET (solitary tumor in 63%, median size 11 cm, G2 NETs in 81%) following clinical and pathological review. DNA analyses showed 'foregut-like' genomic profiles with frequent alterations in pathways of Fanconi DNA repair (75%), histone modifiers (58%), adherens junctions (58%), and cell cycle control (50%). The most frequently involved genes were KMT2A (58%), ATM (42%), CDH1, CDKN2C, FANCF, and MEN1 (33% each). Transcriptomic analyses showed that PHNETs clustered closer to foregut (pancreatic, lung) NETs than to midgut (small-bowel) NETs, while remaining a distinct entity with a specific profile. Assessment of potentially predictive biomarkers suggested efficacy of treatments usually active in foregut NETs. In conclusion, PHNETs display a foregut-like molecular profile distinct from other types of NETs, with recurrent molecular alterations. Upon exhaustive work-up to exclude an unrecognized primary tumor, PHNETs should not be considered metastatic NETs from an unknown primary. © 2022 The Pathological Society of Great Britain and Ireland.

Abstract 2289: Comprehensive multiomic analysis reveals different subtypes in neuroendocrine tumors from multiple origins

Abstract Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with a wide anatomical distribution and different clinical behaviors that share common “neuro” and “endocrine” properties. They are classified in well differentiated G1, G2 and G3 neuroendocrine tumors (NETs), or poorly differentiated neuroendocrine carcinomas (NECs) which are all G3. Some studies have assessed the NET molecular landscape of certain primary sites, but no cross-sites molecular assessment has been performed to date. Thus, we aimed to perform a comprehensive transcriptomic and methylomic characterization of large series of NENs of different anatomical origins in order to identify molecular subgroups, unravel genes and/or pathways involved, and explore their potential clinical relevance. Transcriptomic and methylation data were obtained from tumor samples of 181 and 99 patients with NENs (37.02%G1; 54.7%G2 and 8.29%G3) using Clariom S Human microarrays and EPIC methylation arrays, respectively. Most common primary tumor site was the lung (43.1%), followed by the small intestine (35.4%), large intestine (8.8%), stomach (4.4%), pancreas (1.7%), other localizations (3.9%), and unknown primary (2.8%). Tumors were clustered using transcriptomic and methylation data by NMF and hierarchical clustering algorithms respectively, and differential expression (limma analysis) and gene set enrichment analysis (GSEA) was applied to transcriptomic data clusters NENs were classified into three different clusters. Two of them (C1 and C3) showed an inverse transcriptomic profile, while C2 presented a mixed profile. We identified that C3 had the highest expression levels of neuroendocrine-related genes (somatostatin receptor SSTR5 LFC: 0.77 ; FDR: 1.52x10e-25 ; serotonin receptor HTR1A LFC: 0.79 ; FDR: 1.20X10e-20 ; VIP LFC: 0.64 ; FDR= 1.41x10e-10 etc), in lung primary tumor samples (50%) and methylation cluster 1 (82.14%). On the other hand, C1 was enriched in some important cancer-related pathways ( MYC targets NES -6.37 FDR < 10-3; MTORC1 NES -3.78 FDR < 10-3) and oxidative phosphorylation (NES -4.87 FDR < 10-3) ; and showed a higher proportion of small intestine primary tumors (46.34%), Grade 2 tumors (73.17%) and methylation cluster 2 (75%). NENs of different primary sites can be stratified into two major transcriptomic clusters, with a third cluster having a mixed expression profile. The groups with extreme transcriptomic signatures were enriched in neuroendocrine-related genes or principal cancer pathways. These results suggest a dedifferentiation from a more indolent neuroendocrine phenotype to more aggressive proliferative tumor types that could be driven partially with the methylation profile. Citation Format: Carlos Carretero Puche, Beatriz Soldevilla, Beatriz Gil, Anna La Salvia, Alberto Lens-Pardo, Paula Espinosa, Beatriz Anton-Pascual, Gonzalo Gómez-López, Fátima Al-Shahrour, Rocío García-Carbonero. Comprehensive multiomic analysis reveals different subtypes in neuroendocrine tumors from multiple origins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2289.

P-279 A rare subset of well-differentiated gastro-entero-pancreatic neuroendocrine tumors with positive FDG PET/CT: Is it a sign of an aggressive disease?

Neuroendocrine tumors (NETs) are relatively rare and heterogeneous, mostly asymptomatic and discovered incidentally. PET-CT is one of the gold diagnostic standards and typically detects well-differentiated NETs using 68Gallium-Dotatate (Ga-PET/CT) and more aggressive undifferentiated NETs using 18F-FDG (FDG-PET/CT). However, some well-differentiated NETs are displaying atypical high-grade features and are being detected on FDG-PET/CT. In this study, we aim to study the diagnostic role of FDG-PET/CT in patients with well-differentiated gastro-entero-pancreatic (GEP) NETs, with positive uptake on FDG-PET/CT. A retrospective chart review of all GEP NETs cases diagnosed, from 2014 to 2021, at the American University of Beirut Medical Center was done. Patients who have low (G1) or intermediate (G2) well-differentiated NETs with positive findings on FDG-PET/CT were included based on WHO classification with Ki 67 ≤2 for low grade and >2-≤20 for intermediate grade well-differentiated NETs. Out of 36 patients with G1 or G2 GEP NET diagnosed during that period, 9 (25%) patients met the inclusion criteria for this study. Median age at diagnosis was 60 years, and 6 (66%) were males. 8 (88.9%) patients were both FDG-PET/CT and Ga-PET/CT positive, while 1 (11.1%) was FDG-PET/CT positive with Ga-PET/CT negative. 1 (11.1%) of the patients had grade 1 tumors and 8 (88.9%) had grade 2 disease. All patients had metastatic disease except for 1 patient who had locally advanced disease. The tumor originated from the small bowels in 6 (66%) of patients and from the pancreas in the remaining 3 (33%). As for the initial treatment after diagnosis, 2 patients received octreotide, 2 patients received octreotide, capecitabine and temozolomide, 2 patients received octreotide and underwent surgical resection, 1 patient received octreotide and everolimus, 1 patient received capecitabine and temozolomide and 1 patient with locally advanced disease underwent Whipple surgical procedure. 5 patients had disease progression while on initial treatment plan. In patients positive for both Ga-PET/CT and FDG-PET/CT, median progression free survival (PFS) was 40.1 months (95% CI, 15.4 – 64.9) and mean PFS was 36.2 months (95% CI, 23.1 – 49.2). The PFS in these patients is significantly lower that the PFS reported in the literature for G1/G2 NETs with positive Ga-PET/CT and negative FDG-PET/CT (36.2 vs 71 months, p = 0.0162). Patients with G1/G2 GEP NETs with positive FDG PET/CT have shorter PFS than in the literature. Should we include FDG PET/CT in the GEP NET prognostic score?.

Underwater Endoscopic Mucosal Resection of Small Rectal Neuroendocrine Tumors

Background and Study AimsThe resection strategy for rectal neuroendocrine tumors (NET) < 10 mm is not uniform. We compared the utility of underwater endoscopic mucosal resection (UEMR) to endoscopic submucosal resection with a ligation device (ESMR-L) to resect rectal NETs.Patients and MethodsPatients with rectal NET < 10 mm treated with UEMR or ESMR-L were included. Their medical records were retrospectively reviewed.ResultsThirty-two patients were divided into a UEMR group (n = 7) and an ESMR-L group (n = 25). Histopathological diagnosis of NET by biopsy was known before resection in 43% (3/7) in the UEMR group and 68% (17/25) in the ESMR-L group, (p = 0.379). UEMR was performed on an outpatient basis for all patients, and 92% of ESMR-L (23/25) were performed as inpatient procedures (p < 0.001). The procedure time was significantly shorter in the UEMR group than in the ESMR-L group [median (IQR), min, 6 (5–8) vs. 12 (9–14), p = 0.002]. En bloc resection and R0 resection rates were 100% in both groups. Pathological evaluations were predominantly NET G1 in both groups (UEMR: 7/7, 100% and ESMR-L: 23/25, 92%). Two patients in the ESMR-L group developed delayed bleeding, controlled by endoscopic hemostasis. Device costs were significantly higher in the ESMR-L group than the UEMR group by approximately US$180 [median (IQR), $90.45 (83.64–108.41) vs. $274.73 (265.86–292.45), P < 0.001].ConclusionUEMR results in similar resection quality with shorter procedure time and lower costs compared to ESMR-L. We recommend UEMR for the resection of rectal NET < 10 mm.

The diagnosis and treatment of G3 neuroendocrine tumors according to the new NCCN guideline

Gastrointestinal pancreas (GEP) is the most common site of neuroendocrine neoplasms (NENs). In 2019, the World Health Organization (WHO) classification for GEP NET was updated to include a new category of well-differentiated high-grade (Ki 67>20%) GEP-NET G3, distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). As a new category, NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The management of NET G3 remains a challenge awaiting future trials taking into consideration the unique characteristics of this new category. The latest NCCN clinical guidelines of neuroendocrine and adrenal tumors firstly gave the recommendation of diagnosis and treatment of G3 NET separately from NEC and G1/G2 NET. Hereon,we aim to summarize the management of G3 NET in combination with the new NCCN guidelines and the current evidences.

A metastatic G2 neuroendocrine tumor smaller than 5 mm: A case report

BackgroundNeuroendocrine tumors (NETs) measuring <10 mm are widely thought to be at low risk of lymph node metastasis. Here we report a case of lymph node metastasis in a patient with a 4-mm NET that was classified as grade 2.Presentation of caseA 32-year-old woman was referred to our hospital after a positive fecal occult blood test. Colonoscopy revealed a 4-mm yellowish submucosal tumor, which was diagnosed as NET of the upper rectum and removed by endoscopic submucosal resection with ligation. Pathological examination of the specimen showed a 4-mm grade 2 NET with a Ki-67 labeling index of 4.4% without lymphatic or venous invasion. In accordance with the European Neuroendocrine Tumor Society guidelines, we performed robotic-assisted laparoscopic low anterior resection with lymph node dissection. Final pathological examination revealed invasion confined to the submucosal layer and metastasis to one lymph node (pT1aN1M0, Stage IIIB). There were no residual tumor cells in the scar after endoscopic submucosal resection with ligation.DiscussionShould G2 neuroendocrine tumors smaller than 5 mm be surgically resected?ConclusionsWe encountered a rare case of a small NET with lymph node metastasis that was treated by robotic-assisted laparoscopic low anterior resection with lymph node dissection. Additional surgery is an option to be considered for grade 2 NET even if it is small because of the possibility of lymph node metastasis.

Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 <3%), NET G2 (Ki-67 3-20%) and NET G3 (Ki-67 >20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

BackgroundPreclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET).Aim(s)To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin.Patients and methodsSingle-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days.ResultsFrom 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2–9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases.ConclusionMetformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms.

This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine neoplasms which includes epithelial neuroendocrine neoplasms (neuroendocrine tumors and neuroendocrine carcinomas) arising from upper aerodigestive tract and salivary glands, and special neuroendocrine neoplasms including middle ear neuroendocrine tumors (MeNET), ectopic or invasive pituitary neuroendocrine tumors (PitNET; formerly known as pituitary adenoma) and Merkel cell carcinoma as well as non-epithelial neuroendocrine neoplasms (paragangliomas). The new WHO classification follows the IARC/WHO nomenclature framework and restricts the diagnostic term of neuroendocrine carcinoma to poorly differentiated epithelial neuroendocrine neoplasms. In this classification, well-differentiated epithelial neuroendocrine neoplasms are termed as neuroendocrine tumors (NET), and are graded as G1 NET (no necrosis and < 2 mitoses per 2mm2; Ki67 < 20%), G2 NET (necrosis or 2-10 mitoses per 2mm2, and Ki67 < 20%) and G3 NET (> 10 mitoses per 2mm2 or Ki67 > 20%, and absence of poorly differentiated cytomorphology). Neuroendocrine carcinomas (> 10 mitoses per 2mm2, Ki67 > 20%, and often associated with a Ki67 > 55%) are further subtyped based on cytomorphological characteristics as small cell and large cell neuroendocrine carcinomas. Unlike neuroendocrine carcinomas, head and neck NETs typically show no aberrant p53 expression or loss of RB reactivity. Ectopic or invasive PitNETs are subtyped using pituitary transcription factors (PIT1, TPIT, SF1, GATA3, ER-alpha), hormones and keratins (e.g., CAM5.2). The new classification emphasizes a strict correlation of morphology and immunohistochemical findings in the accurate diagnosis of neuroendocrine neoplasms. A particular emphasis on the role of biomarkers in the confirmation of the neuroendocrine nature of a neoplasm and in the distinction of various neuroendocrine neoplasms is provided by reviewing ancillary tools that are available to pathologists in the diagnostic workup of head and neck neuroendocrine neoplasms. Furthermore, the role of molecular immunohistochemistry in the diagnostic workup of head and neck paragangliomas is discussed. The unmet needs in the field of head and neck neuroendocrine neoplasms are also discussed in this article. The new WHO classification is an important step forward to ensure accurate diagnosis that will also form the basis of ongoing research in this field.

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms.

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.