A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations

Elvebakken, Hege; Perren, Aurel; Scoazec, Jean Yves; Tang, Laura H.; Federspiel, Birgitte; Klimstra, David S.; Vestermark, Lene Weber; Ali, Abir Salwa; Zlobec, Inti; Myklebust, Tor Åge; Hjortland, Geir Olav; Langer, Seppo W.; Grønbæk, Henning; Knigge, Ulrich; Janson, Eva Tiensuu; Sørbye, Halfdan

doi:10.1159/000511905

Cited by 71 publications

(109 citation statements)

References 29 publications

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“…Although multiple series [22–25] have documented the use of SSAs among patients with G3 NETs, this is, to our knowledge, the first study to formally report the survival outcomes associated with SSAs in an albeit small cohort of patients with well‐differentiated, G3 panNETs. The rationale to treat patients with G3 panNETs with somatostatin‐based therapies relies on the expression of somatostatin receptors, which has been described in small series to occur in up to 80% of G3 GEP‐NETs [26, 27]. Nevertheless, based on the median PFS and TNT of 4 and 5.2 months, respectively, observed in our study, the role of SSA therapy in G3 panNETs appears quite limited.…”

Section: Discussionmentioning

confidence: 67%

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

et al. 2020

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Background Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of well‐differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki‐67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, nonfunctioning, well‐differentiated panNETs with Ki‐67 ≥10% receiving first‐line long‐acting SSAs in a real‐world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression‐free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow‐up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p = .01). Treatment‐related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion SSAs exert antiproliferative activity in panNETs with Ki‐67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki‐67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

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Section: Discussionmentioning

confidence: 67%

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

et al. 2020

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“…They are rare in other digestive sites including the midgut and rectum [20]. Conversely, NECs seem to be more frequent than NETs G3 in the gut than in the pancreas and, in particular, in the rectum followed by the stomach [20,25].…”

Section: Definition and Diagnostic Criteriamentioning

confidence: 95%

“…They have also been described in the stomach, more commonly as a subgroup of type 3 NETs, although type 1 ECL-cell G3 NETs have also been rarely reported [25,26]. They are rare in other digestive sites including the midgut and rectum [20]. Conversely, NECs seem to be more frequent than NETs G3 in the gut than in the pancreas and, in particular, in the rectum followed by the stomach [20,25].…”

Section: Definition and Diagnostic Criteriamentioning

confidence: 99%

“…Morphologically, they can be either well differentiated (NET G3) or poorly differentiated (NEC) (Table 1). This distinction is fundamental due to their different prognoses (median overall survival of 33 months for NETs G3 versus 11 months for NECs) [9,20], clinical presentation, functional imaging characterization, and different therapeutic approaches [21,22]. Indeed, NETs G3 can generally be identified by somatostatin receptor imaging, whereas in NECs, which show loss of morphological differentiation and increase of proliferation, 18 F-FDG represents the best imaging procedure [21].…”

Section: Definition and Diagnostic Criteriamentioning

confidence: 99%

“…Interestingly, the distribution of NETs G3 and NECs in the digestive system is different. NETs G3 have been more frequently observed in the pancreas [20]. They have also been described in the stomach, more commonly as a subgroup of type 3 NETs, although type 1 ECL-cell G3 NETs have also been rarely reported [25,26].…”

Section: Definition and Diagnostic Criteriamentioning

confidence: 99%

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Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms

Rosa

2021

Endocr Pathol

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The growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.

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Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs

Loree,

Chan,

Lim

et al. 2024

JAMA Oncol

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ImportanceEvidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics.ObjectiveTo create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs.MethodsA multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method.FindingsA total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society.Conclusions and RelevanceThe study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.

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A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations

Cited by 71 publications

References 29 publications

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms

Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs

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