scholarly journals Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1677
Author(s):  
Anna Pellat ◽  
Romain Coriat
Keyword(s):  
Digestive Tract ◽  
Neuroendocrine Tumors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Small Sample ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G−3 represents about one third of NEN G−3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G−3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G−2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G−3.

scholarly journals Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2448
Author(s):  
Anna Pellat ◽  
Anne Ségolène Cottereau ◽  
Lola-Jade Palmieri ◽  
Philippe Soyer ◽  
Ugo Marchese ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Functional Imaging ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Tumor Site ◽  
Ki 67 ◽  
Future Directions ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

scholarly journals Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

2021 ◽  
Vol 32 (1) ◽  
pp. 154-168 ◽  
Author(s):  
Marco Volante ◽  
Ozgur Mete ◽  
Giuseppe Pelosi ◽  
Anja C. Roden ◽  
Ernst Jan M. Speel ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Young Patients ◽  
Carcinoid Tumors ◽  
Neuroendocrine Neoplasms ◽  
Grey Zone ◽  
Cell Hyperplasia ◽  
Ki 67 ◽  
Familial Form ◽  
Well Differentiated ◽  
Neuroendocrine Carcinomas

AbstractThoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

Giant Primary Neuroendocrine Neoplasms of the Liver: Report of 2 Cases With Molecular Characterization

2019 ◽  
Vol 27 (8) ◽  
pp. 893-899
Author(s):  
Laura G. Pastrián ◽  
Ignacio Ruz-Caracuel ◽  
Raul S. Gonzalez
Keyword(s):  
World Health Organization ◽  
Neuroendocrine Tumor ◽  
Large Cell ◽  
The Other ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Molecular Testing ◽  
Well Differentiated ◽  
Grade 3 ◽  
Health Organization

Primary neuroendocrine neoplasms of the liver have occasionally been reported in the liver, though many reports do not convincingly exclude metastases. In this article, we report 2 “giant” hepatic neuroendocrine lesions without evidence of a primary elsewhere after clinical workup. One occurred in a 21-year-old male; the lesion was a large cell neuroendocrine carcinoma measuring 24 cm. The patient died of disease in 10 months. The other occurred in a 25-year-old patient, was 18 cm wide, and was diagnosed as a well-differentiated neuroendocrine tumor, World Health Organization grade 3. The patient died of disease after 30 months. Molecular testing demonstrated only the presence of TP53 mutations in common. These cases expand our knowledge of seemingly primary neuroendocrine neoplasms of the liver, in particular, giant cases measuring more than 8 cm. Guidelines for clinical workup and therapy for these lesions remain unclear, but future thorough workup of such cases is necessary for specific characterization.

The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap

2015 ◽  
pp. 92-103 ◽  
Author(s):  
David S. Klimstra ◽  
Himisha Beltran ◽  
Rogerio Lilenbaum ◽  
Emily Bergsland
Keyword(s):  
Neuroendocrine Tumors ◽  
Prostate Gland ◽  
Neuroendocrine Differentiation ◽  
Large Cell ◽  
Genetic Alterations ◽  
Neuroendocrine Cells ◽  
Neuroendocrine Neoplasms ◽  
Platinum Based Chemotherapy ◽  
Well Differentiated ◽  
Grade 3

Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.

Gastroenteropancreatic neuroendocrine tumors: clinicopathological evaluation at Shifa International Hospital, Islamabad. A single centre experience

2020 ◽  
pp. 1-14
Author(s):  
Nadira Mamoon ◽  
Hania Naveed ◽  
Mariam Abid ◽  
Humaira Nasir ◽  
Imran Nazir Ahmad ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Neuroendocrine Tumors ◽  
Neuroendocrine Carcinoma ◽  
World Health ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Single Centre Experience ◽  
Who 2010 Classification ◽  
Well Differentiated ◽  
Grade 3 ◽  
Health Organization

Abstract Objective: Clinicopathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have rarely been studied in the Pakistani population. We investigated the clinical characteristics of these tumors according to the updated World Health Organization (WHO) 2010 classification. Methods: The data of Shifa International Hospital, Islamabad was retrospectively analysed for pathologically confirmed GEP-NETs from January 2013 to March 2018. Results: One hundred and eighteen patients (mean age, 52.2 years; male, 55.1%) were identified. 83.1% of the patients were symptomatic including5.1% functional tumors. Pancreas (28%) was the most frequent primary site noted. The most common histologic type was well differentiated neuroendocrine tumor (WDNET) in 81.4% followed by neuroendocrine carcinoma (NEC) in 16.1%. 45.8% cases of WDNET were grade 1, 27.1% were grade 2, and 8.5% were grade 3.15.3% had distant metastasis at the time of diagnosis with liver (77.7%) as the most common metastatic site. Synaptophysin positivity was seen in 96.8% of grade 1 & grade 2 WDNET, 100% of grade 3 WDNET and 92.3% of NEC and chromogranin was positive in 94.2% of grade 1 &grade 2 WDNET, 83.3% of grade 3 WDNET and 45.4% of NEC. Conclusion: GEP-NETs showed a wide clinicopathological spectrum. Pancreas is the most site of involvement by the GEP-NET however grade 3 WDNET had a predilection for the colon. Small cell carcinomas were commonly observed in esophagus. Keywords: Gastroenteropancreatic neuroendocrine tu­mor, well differentiated neuroendocrine tumor, neuroendocrine carcinoma. Continuous...

scholarly journals Efficacy and Prognostic Factors for Y-90 Radioembolization (Y-90) in Metastatic Neuroendocrine Tumors with Liver Metastases

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Erica S. Tsang ◽  
Jonathan M. Loree ◽  
Janine M. Davies ◽  
Sharlene Gill ◽  
David Liu ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Neuroendocrine Tumors ◽  
Performance Status ◽  
Population Based ◽  
Somatostatin Analogue ◽  
Ecog Performance Status ◽  
Ki 67 ◽  
Well Differentiated ◽  
Grade 3 ◽  
Metastatic Liver

Background. Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods. We identified 49 patients with metastatic liver-dominant NETs across BC Cancer’s six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized. Results. Of the 49 patients who received Y-90, the median age was 56 years (range 21–78), 49% were male, and 94% had an ECOG performance status of 0–1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as G1 (61%), G2 (25%), G3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8–3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0–46.5).Conclusions. In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS.

scholarly journals Chemotherapy in Neuroendocrine Tumors

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4872
Author(s):  
Satya Das ◽  
Taymeyah Al-Toubah ◽  
Jonathan Strosberg
Keyword(s):  
Neuroendocrine Tumors ◽  
Treatment Options ◽  
Peptide Receptor Radionuclide Therapy ◽  
Pancreatic Tumors ◽  
Lower Grade ◽  
Damage Repair ◽  
Platinum Agent ◽  
Cytoreductive Treatment ◽  
Well Differentiated ◽  
Grade 3

The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.

scholarly journals Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 643
Author(s):  
Caroline Lacombe ◽  
Ophélie De Rycke ◽  
Anne Couvelard ◽  
Anthony Turpin ◽  
Aurélie Cazes ◽  
...  
Keyword(s):  
Objective Response ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Quantitative Score ◽  
Well Differentiated ◽  
Grade 3 ◽  
Additional Value ◽  
Platinum Chemotherapy

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11–15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.

Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms

2018 ◽  
Vol 107 (1) ◽  
pp. 24-31 ◽  
Author(s):  
Anna Pellat ◽  
Chantal Dreyer ◽  
Camille Couffignal ◽  
Thomas Walter ◽  
Catherine Lombard-Bohas ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Lower Response ◽  
Potential Biomarker ◽  
Pancreatic Neuroendocrine Tumours ◽  
Net G3 ◽  
Well Differentiated ◽  
Grade 3

Background/Aims: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. Methods: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. Results: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89–0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. Conclusion: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.

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