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

Endocrine Pathology ◽

10.1007/s12022-021-09676-z ◽

2021 ◽

Author(s):

Stefano La Rosa

Keyword(s):

Diagnostic Criteria ◽

Digestive System ◽

Labelling Index ◽

Differential Diagnoses ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Immunohistochemical Profile ◽

Grade 3

AbstractThe 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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1278: The Role of Diagnostic Criteria of Obstruction in Patients with High Grade Cystocele: Correlation to Subjective Symptoms

The Journal of Urology ◽

10.1016/s0022-5347(18)31492-7 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 421-421

Author(s):

Veronica Triaca ◽

Christian O. Twiss ◽

Ramdev Konijeti ◽

Larissa V. Rodriguez ◽

Shlomo Raz

Keyword(s):

Diagnostic Criteria ◽

High Grade ◽

Subjective Symptoms

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Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms

Cancers ◽

10.3390/cancers13194875 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4875

Author(s):

Matteo Bulloni ◽

Giada Sandrini ◽

Irene Stacchiotti ◽

Massimo Barberis ◽

Fiorella Calabrese ◽

...

Keyword(s):

Automated Analysis ◽

Labelling Index ◽

Neuroendocrine Neoplasms ◽

Proliferating Cells ◽

Ki 67 ◽

Learning Framework ◽

Diagnosis And Prognosis ◽

Tumour Prognosis

Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs.

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Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms

Journal of Nuclear Medicine ◽

10.2967/jnumed.118.217851 ◽

2019 ◽

Vol 60 (7) ◽

pp. 882-891 ◽

Cited By ~ 6

Author(s):

Najeff Waseem ◽

Carina Mari Aparici ◽

Pamela L. Kunz

Keyword(s):

Neuroendocrine Neoplasms ◽

Grade 3

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Increased risk of liver toxicity secondary to nivolumab therapy in the treatment of cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14559 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14559-e14559 ◽

Cited By ~ 1

Author(s):

Kevin Zarrabi ◽

Shenhong Wu

Keyword(s):

Liver Toxicity ◽

Meta Analysis ◽

High Grade ◽

Careful Monitoring ◽

Laboratory Markers ◽

Increased Risk ◽

Melanoma Patients ◽

Low Incidence ◽

Grade 3

e14559 Background: Nivolumab, a humanized immunotherapy targeting PD-1, is approved for the treatment of a number of solid and liquid cancers and is associated with liver toxicity. This meta-analysis was conducted to determine the overall risk of hepatotoxicity with nivolumab therapy in cancer patients. Methods: An analysis from all phase I, II, and II clinical trials up to December 2016 examining the role of nivolumab in a variety of cancers was conducted. Eligible trials included those in which patients received nivolumab. Data on all-grade and high-grade (grade 3 and 4) elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random - or fixed - effect models with 95% confidence intervals. Results: The data from 27 eligible trials were included for analysis. A total of 5,287 patients were evaluated (Nivolumab: n = 3515, Control: n = 1772). The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI: 3.2% - 9.1%) and 1.60% (95% CI: 0.9% - 3.0%), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI: 2.9% - 8.2%) and 1.5% (95% CI: 0.9% - 3.1%), respectively. Elevations of both laboratory markers were significantly increased when compared to control (P < 0.001). Nivolumab increased the RR of AST/ALT elevations; RR of all-grade AST elevations was 1.58 (95% CI: 1.1 - 2.2), all-grade ALT elevations was 1.62 (95% CI: 1.2 - 2.3). Subgroup analysis of all-grade AST elevations revealed melanoma patients exhibited a significantly higher rate compared to other solid tumors with an incidence of 8.7% (95% CI: 4.3 - 18.2%). All-grade ALT elevations in melanoma patients revealed the same incidence rate. Of note, renal cell carcinoma patients exhibited a particularly low incidence of all-grade transaminitis with AST 1.6% (95% CI: 0.6 - 11.1%) and ALT 1.8% (95% CI: 0.6 - 14.6%). Conclusions: Nivolumab is associated with significantly increased risk of all-grade and high-grade elevations in AST and ALT. Therapy should include careful monitoring of hepatotoxicity.

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Tumor size and perineural invasion predict outcome of gastric high grade neuroendocrine neoplasms

Endocrine Connections ◽

10.1530/ec-21-0017 ◽

2021 ◽

Author(s):

Qi Zhang ◽

Hongshan Wang ◽

Yanhong Xie ◽

Suming Huang ◽

Ke Chen ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Tumor Size ◽

Who Classification ◽

Perineural Invasion ◽

Radical Resection ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Ki67 Index ◽

Grade 3 ◽

Neuroendocrine Carcinomas

A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results database was used to verify the prognostic determinants found in Zhongshan cohort. Neuroendocrine carcinomas showed higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients of neuroendocrine carcinomas, 12 (7.9%) patients of grade 3 neuroendocrine tumors and 30 (19.9%) patients of mixed neuroendocrine non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (p=0.004) and mitoses (p=0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (p=0.709). Tumor size, perineural invasion and TNM stage were independent prognostic factors of gastric high grade neuroendocrine neoplasms.

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Use of antiresorptive therapy (ART) and skeletal-related events (SREs) in patients with bone metastases of neuroendocrine neoplasms (NEN).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4096 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4096-4096

Author(s):

Leonidas Apostolidis ◽

Dirk Jaeger ◽

Eva Caroline Winkler

Keyword(s):

Bone Metastases ◽

Rare Event ◽

Neuroendocrine Neoplasms ◽

Antiresorptive Therapy ◽

Negative Prognostic Factor ◽

Significant Toxicity ◽

Osteolytic Metastases ◽

Skeletal Related Events ◽

Grade 3

4096 Background: Antiresorptive therapy (ART) with bisphosphonates or denosumab is effective in preventing skeletal-related events (SREs) in patients with bone metastases (BM). In neuroendocrine neoplasms (NEN), BM are a negative prognostic factor, however tend to be asymptomatic and SREs are considered a rare event. The role of ART in preventing SREs in NEN has not been investigated so far. Methods: Retrospective analysis of all patients with bone metastases in the NEN database of the National Center for Tumor Diseases who presented at our center between 12/2012 and 01/2017. Overall survival (OS) from diagnosis of BM as well as time to SRE (TTSRE) were calculated. In patients experiencing an SRE within 1 month after diagnosis (i.e. before efficacy of ART could be assessed), TTSRE was defined as the time to a subsequent SRE. Results: In a total of 513 patients in the database, 108 patients with BM could be identified. Median OS was not reached in a median follow-up of 15.2 months. ART was applied to 42.6 % of patients. OS with or without ART did not differ significantly (p = 0.2538). 28.7 % of patients experienced at least 1 SRE, 20.4 % after more than 1 month. Median TTSRE was 63.8 months with ART and 127.0 months without ART (p = 0.1751). TTSRE was shortened in grade 3 vs. grade 1+2 NEN (172 months vs. not reached, HR 4.058, p = 0.0032), as well as in lytic vs. non-lytic metastases (24.5 vs. not reached, HR 7.319, p < 0.0001), however not significantly different in oligometastatic vs. disseminated bone disease (not reached vs. 63,8 months, HR 1.415, p = 0.4287). Application of ART did not significantly change TTSRE in either of these subgroups. Significant toxicity attributable to ART was observed in 15.2 % of ART patients. Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.

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