Digestive Neuroendocrine Tumors Research Articles

Interference with VIP to distinguish between real and false VIPoma:national study from the French Endocrine Tumors Group

Abstract Background Vasoactive Intestinal Peptide-secreting tumors (VIPomas) are digestive neuroendocrine tumors in which the hormonal secretion is life threatening. Biological confirmation is obtained by demonstrating an elevation in plasma VIP, usually using radioimmunoassay (RIA) method. In some cases, an analytical interference is suspected. We developed three different techniques to detect the interference in VIP RIA. Methods Three techniques were used: RIA after Sephadex column chromatography separation, RIA after Polyethylene Glycol (PEG) precipitation and125I-labelled VIP binding test. We included patients with suspicion of false positive VIP (FPV) elevation. We then compared results with those of a group of ‘real’, proven VIPoma (RV). Results A total of 15 patients with FPV elevation and 9 RV patients were included. Interference was detected in all FPV patients versus none in RV. Clinical and biochemical parameters did not differ between FPV and RV patients, but VIP concentration in RIA was significantly higher in FVP patients than in RV patients (228pmol/l vs 66 pmol/l, p=0.038). Using 125I-labelled VIP binding test, median proportion of radioactivity in the pellet was significantly higher in FVP than in RV patients (53% vs 13%, p < 0.0001). A 20.5% threshold presented excellent performances (Sensitivity 100% [79.6-100], specificity 100% [70.1-100]). Conclusions We developed three different laboratory techniques to reveal interference in RIA VIP assays. The diagnostic performance of all three was excellent. These techniques must be employed in cases of discordance between VIP elevation and clinical presentation.

PD-L1 expression, tumor-infiltrating lymphocytes, and mismatch repair proteins status in digestive neuroendocrine neoplasms: exploring their potential role as theragnostic and prognostic biomarkers.

Theragnostic biomarkers are still needed to select patients with digestive neuroendocrine neoplasms (NENs) for an optimal management. The PD-1/PD-L1 pathway plays a pivotal role in T cells activation and host immune response to cancer and PD-L1 expression in tumor and/or immune cells is used to identify patients who would benefit of treatment with immune checkpoint inhibitors. However, its role as a biomarker is still unclear in digestive NENs. We investigated PD-L1 expression in 68 well-characterized digestive NENs (32 NETs, 32 NECs and 4 MiNENs) and TPS and CPS scores were calculated. In addition, tumor infiltrating T-lymphocytes and mismatch repair protein expression (MMR) were evaluated. All results were correlated with clinicopathological features. PD-L1 expression was higher in NECs than in NETs: TPS > 1% and/or CPS > 1 were observed in 16% of NETs, 68.8% of NECs and 50% of MiNENs (p: 0.05). The mean TPS score in positive cases was 6.3% in NETs, 16.2% in NECs and 5% in MiNENs. The CPS score was 4.8 in NETs, 8.1 in NECs and 6 in MiNENs. MMR-deficient neoplasms were more frequently observed in NECs than in NETs (p: < 0.05) as well as intra-tumor immune infiltration (p: 0.00001). No correlation between PD-L1 expression and survival or other clinicopathological parameters was observed. Our results suggest that treatment with immune checkpoint inhibitors may have a potential role only in selected cases, mainly in NECs and MiNENs.

Highlights in digestive neuroendocrine neoplasms from the GTE 2023

Highlights in digestive neuroendocrine neoplasms from the GTE 2023

Claudin 18.2 expression in digestive neuroendocrine neoplasms: a clinicopathological study.

Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs). Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining. Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%. The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.

Expanding Role of Gastroenterology in the Staging of Digestive Neuroendocrine Tumors: Updates From the American Joint Committee on Cancer Version 9 Cancer Staging System

Expanding Role of Gastroenterology in the Staging of Digestive Neuroendocrine Tumors: Updates From the American Joint Committee on Cancer Version 9 Cancer Staging System

Patterns of emergency department visits before diagnosis with digestive neuroendocrine neoplasms.

To evaluate the patterns of emergency department visits before diagnosis with digestive neuroendocrine neoplasms (NENs). Linked administrative databases from the province of Alberta, Canada, were examined, and patients diagnosed with digestive NENs from 2004 to 2019 were reviewed. Incidents of emergency department visits in the 3months before histological diagnosis were reviewed. Multivariable logistic regression analyses were used to examine factors associated with at least one emergency department (ED) visit as well as factors associated with more than one ED visit. The impact of pre-diagnosis ED visits on overall survival was further assessed in a multivariable Cox regression model, which included (in addition to ED visits), age at diagnosis, sex, histology, Charlson comorbidity index, and stage. A total of 2120 patients were considered eligible for the study, and they were included in the analysis (including 1041 patients (49.1%) with at least one ED visit in the 3months before diagnosis). The following factors were associated with a higher likelihood ofan ED visit prior to diagnosis: younger age (OR with increasing age: 0.983; 95% CI: 0.977-0.989), higher comorbidity index (OR: 1.332; 95% CI: 1.215-1.460), female sex (OR: 1.292; 95% CI: 1.084-1.540), and stage IV (OR: 1.515; 95% CI: 1.106-2.075). Likewise, the following factors were associated with more than one ED visit within 3months before diagnosis: younger age (OR with increasing age: 0.985; 95% CI: 0.979-0.992), higher comorbidity index (OR: 1.280; 95% CI: 1.167-1.405), and female sex (OR: 1.516; 95% CI: 1.230-1.868). Using multivariable Cox regression modeling, the following factors were associated with worse overall survival (higher risk of death): older age (HR: 1.050; 95% CI: 1.043-1.056), higher comorbidity index (HR: 1.280; 95% CI: 1.209-1.356), stage IV (HR: 3.163; 95% CI: 2.562-3.905), neuroendocrine carcinoma histology (HR: 1.645; 95% CI: 1.350-2.003), pre-diagnosis ED visit (HR: 1.784; 95% CI: 1.529-2.083). Almost one-half of patients with NENs visit the ED within 3months before diagnosis. ED visits were associated with younger age, female sex, advanced disease, and higher comorbidity. Moreover, pre-diagnosis ED visit(s) were associated with worse overall survival in the current cohort.

Surgical Options for Peritoneal Surface Metastases from Digestive Malignancies—A Comprehensive Review

The peritoneum is a common site for the dissemination of digestive malignancies, particularly gastric, colorectal, appendix, or pancreatic cancer. Other tumors such as cholangiocarcinomas, digestive neuroendocrine tumors, or gastrointestinal stromal tumors (GIST) may also associate with peritoneal surface metastases (PSM). Peritoneal dissemination is proven to worsen the prognosis of these patients. Cytoreductive surgery (CRS), along with systemic chemotherapy, have been shown to constitute a survival benefit in selected patients with PSM. Furthermore, the association of CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) seems to significantly improve the prognosis of patients with certain types of digestive malignancies associated with PSM. However, the benefit of CRS with HIPEC is still controversial, especially due to the significant morbidity associated with this procedure. According to the results of the PRODIGE 7 trial, CRS for PSM from colorectal cancer (CRC) achieved overall survival (OS) rates higher than 40 months, but the addition of oxaliplatin-based HIPEC failed to improve the long-term outcomes. Furthermore, the PROPHYLOCHIP and COLOPEC trials failed to demonstrate the effectiveness of oxaliplatin-based HIPEC for preventing peritoneal metastases development in high-risk patients operated for CRC. In this review, we discuss the limitations of these studies and the reasons why these results are not sufficient to refute this technique, until future well-designed trials evaluate the impact of different HIPEC regimens. In contrast, in pseudomyxoma peritonei, CRS plus HIPEC represents the gold standard therapy, which is able to achieve 10-year OS rates ranging between 70 and 80%. For patients with PSM from gastric carcinoma, CRS plus HIPEC achieved median OS rates higher than 40 months after complete cytoreduction in patients with a peritoneal cancer index (PCI) ≤6. However, the data have not yet been validated in randomized clinical trials. In this review, we discuss the controversies regarding the most efficient drugs that should be used for HIPEC and the duration of the procedure. We also discuss the current evidence and controversies related to the benefit of CRS (and HIPEC) in patients with PSM from other digestive malignancies. Although it is a palliative treatment, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) significantly increases OS in patients with unresectable PSM from gastric cancer and represents a promising approach for patients with PSM from other digestive cancers.

Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are initially monoclonal neoplasms that progressively become polyclonal, with very different genotypic and phenotypic characteristics leading to biological differences, including the Ki-67 proliferation index, morphology, or sensitivity to treatments. Whereas inter-patient heterogeneity has been well described, intra-tumor heterogeneity has been little studied. However, NENs present a high degree of heterogeneity, both spatially within the same location or between different lesions, and through time. This can be explained by the emergence of tumor subclones with different behaviors. These subpopulations can be distinguished by the Ki-67 index, but also by the expression of hormonal markers or by differences in the intensity of uptake on metabolic imaging, such as 68Ga-somatostatin receptor and Fluorine-18 fluorodeoxyglucose positron emission tomography. As these features are directly related to prognosis, it seems mandatory to move toward a standardized, improved selection of the tumor areas to be studied to be as predictive as possible. The temporal evolution of NENs frequently leads to changes in tumor grade over time, with impact on prognosis and therapeutic decision-making. However, there is no recommendation regarding systematic biopsy of NEN recurrence or progression, and which lesion to sample. This review aims to summarize the current state of knowledge, the main hypotheses, and the main implications regarding intra-tumor spatial and temporal heterogeneity in digestive NENs.

Necrolytic migratory erythema as a cutaneous manifestation of a pancreatic neuroendocrine tumor.

Glucagonoma syndrome is a rare entity defined by the existence of necrolytic migratory erythema (NME), elevated serum glucagon levels, and an underlying alpha-cell secreting tumor of the pancreas [ [1] John A.M. Schwartz R.A. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatology Venereol. 2016; 30: 2016-2022 Crossref PubMed Scopus (42) Google Scholar ]. We present the case of a female with clinical manifestations of this syndrome. In this paper, we describe the case of a 38-year-old woman referred to the dermatology department to investigate pruritic lesions located on the lower extremity, with subsequent extension to the axillae, groin, and intergluteal region, and pubis (Fig. 1). After several attempts, a skin biopsy specimen revealed histopathologic features suggestive of NME. Further evaluations revealed the presence of 8 centimeters nonmetastatic glucagonoma, located at the tail of the pancreas. 68Ga-DOTA TOC and an 18F-FDG PET identified a mild uptake of the lesion (Fig. 1). The glucagon level was >500 pg/mL. The patient was diagnosed with glucagonoma syndrome, and a caudal pancreatectomy was subsequently performed. Microscopy and the immunohistochemical study were consistent with a glucagonoma (Fig. 2). After surgery, the cutaneous manifestation was resolved, with normalization of glucagon levels. This uncommon case report adds information about an infrequent neuroendocrine tumor with cutaneous expression. Early recognition and diagnosis must support by radiological and nuclear medicine imaging tests [ [2] Jensen R.T. Cadiot G. Brandi M.L. et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95: 98 Crossref PubMed Scopus (371) Google Scholar ]. Surgery is the initial treatment of choice. Fig. 2Skin biopsy revealing irregular acanthosis of the epidermis with loss of the stratum granulosum and edema of the superficial portion of the epidermis (A). Hematic extravasation and presence of abundant focal polynuclear cells alternating with areas of parakeratosis (B). Histological study reveals a nodular tumor of 8 × 4.5 × 3.5 cm, located in the tail of the pancreas with an intact capsular surface surrounded by adipose tissue (C). In the sections performed, a proliferation of neuroendocrine cells is identified, growing in an anastomosing, gyriform, pseudorosette trabecular pattern (D). Cells with ample eosinophilic cytoplasm and enlarged nuclei with central macronucleolus. Two mitoses are identified in 42 high magnification fields corresponding to less than one mitosis per 2 mm2 (E). Cells show intense positivity for chromogranin (F) and glucagon (G). View Large Image Figure Viewer Download Hi-res image

177Lu-Dotatate administration using an infusion pump or a peristaltic pump: comparison of two methods

Objectives177Lu-oxodotreotide (Lutathera) is an intravenous peptide receptor radionuclide therapy to treat unresectable metastatic digestive neuroendocrine tumours. The recommended method for Lutathera administration is gravity infusion; however, other appropriate and safe...

P-303 From 2012 to 2018: Seven years' analysis of NETs, the experience of the Mohamed VI University Hospital center in Marrakech

Neuroendocrine tumors are a specific tumor entity because of its rarity (they represent 1% of all digestive tumors) and its heterogeneity both clinical and biological. The purpose of our work was to describe the diagnostic and therapeutic management of digestive neuroendocrine tumors at the hematology oncology center of Mohamed VI University Hospital of Marrakech, through a serie of 53 cases.

A Retrospective Analysis of the Correlation between Functional Imaging and Clinical Outcomes in Grade 3 Neuroendocrine Tumors (NETs G3).

Grade 3 (G3) neuroendocrine tumors (NETs) are a novel category among digestive neuroendocrine neoplasms, characterized by Ki-67 >20% and a well-differentiated morphology, presenting high intra-tumor heterogeneity. We aimed to explore the role of dual-tracer PET imaging (68Gallium (Ga)-DOTATOC and 18Fluorodeoxyglucose (FDG)) as overall survival (OS) predictor in NET G3 patients. We performed a retrospective analysis in NET G3 patients treated at our institution between 2003 and 2021. Accordingly, 30 NET G3 patients were analyzed. 68Ga-DOTA-TOC and 18F-FDG uptake were assessed by tumor/non-tumor (T-nonT) ratio. We reported a slightly better OS for patients with ≥75% concordance between 68Ga-DOTA-TOC and 18F-FDG PET/CT (p = 0.42). Among patients with discordant functional imaging, we reported a better 5-y OS rate for patients with a prevalent 68Ga-DOTATOC vs. 18F-FDG PET/CT (p = 0.016). In positive 18F-FDG PET/CT cases, we reported a better OS for <4 vs. ≥4 T/non-T ratio (p = 0.021). Among upfront-NET G3 patients with concordant exams, 5-y OS rate was 83.3% (95% CI: 27.3–97.5). Among patients with discordant exams, 5-y OS rate was 81.3% (52.5–93.5), 100% for those with prevalent receptor expression, and 50% (11.1–80.4) for those with prevalent 18F-FDG uptake. Our findings suggest that dual-tracer PET/CT can be considered as a predictor of patient outcome, able to stratify NET G3 patients with poorer prognosis.

569P Causes of death in patients with metastatic digestive neuroendocrine tumours

Survival of patients with metastatic digestive neuroendocrine tumours (NETs) is often prolonged and has improved over the last decades. The causes of death (COD) in this setting have been poorly described.

Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors

Introduction: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. Methods: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. Results: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. Conclusions: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations.

Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.

Outcome of Patients With Metastatic Lung Neuroendocrine Tumors Submitted to First Line Monotherapy With Somatostatin Analogs.

ObjectiveAntiproliferative activity of somatostatin analogs (SSAs) has been demonstrated in digestive neuroendocrine tumors (NETs), but few data have been published in patients with pulmonary NETs. We therefore conducted a retrospective study to provide additional data on the outcome of patients with metastatic lung NETs submitted to front line SSAs.Research Design and MethodsPatients with metastatic lung NET treated with first line SSA-monotherapy (octreotide or lanreotide) in two different reference Institutions were reviewed. Outcome measures were progression-free survival (PFS) overall survival (OS), overall response rate and safety. We also explored prognostic factors associated with PFS.MethodsThe outcome of consecutive patients (pts) with metastatic lung NETs, who underwent first-line treatment with SSAs, recruited from 2014 on 2019 in two Italian reference Institutions, was retrospectively evaluated.ResultsThirty-one patients entered the study: 14 (45.2%) with typical and 17 (54.8%) atypical carcinoid. Six patients (19.4%) had a carcinoid syndrome. 60.0% of patients had Ki-67 ≤ 10%. Two (6.5%) patients obtained a partial response, 24 (77.4%) disease stabilization while 5 (16.1%) had progressive disease. Median progression free survival (PFS) was 28.6 months, median overall survival (OS) was not attained. Ki-67 ≤ 10%, typical carcinoid histotype and non-functioning disease, were associated with a non-significant PFS prolongation. PFS in patients with atypical carcinoids and in those with Ki-67 >10% was greater than 19 months.ConclusionsThe long PFS and OS obtained in this case series suggest that SSAs could be effective as first line approach in the management of patients with progressive, metastatic pulmonary NET.

Renal function in patients receiving streptozocin for locally advanced or metastatic digestive neuroendocrine tumours: results of the Streptotox-FFCD 0906 study

IntroductionStreptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours. MethodsA prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate. ResultsAfter screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (P = 0.0097). Altogether, 39 patients (35%) experienced grade 1–2 renal toxicity, while no grade 3−4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations. ConclusionsStrongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration.

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR)

IntroductionThis document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org). MethodsAll French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019. ResultsThe management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET. ConclusionThese guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology

Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). Results: Genomic patterns were heterogeneous ranging from “quiet” to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6–17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating “neuroendocrine carcinoma-like” genetic alterations through progression such as TP53/RB1 alterations. Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

Development and Validation of a Prognostic Nomogram to Guide Decision-Making for High-Grade Digestive Neuroendocrine Neoplasms.

The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.