Distinctive features of pancreatic neuroendocrine neoplasms exhibiting an increment in proliferative activity during the course of the disease

Alexandraki, Krystallenia Ι.; Kaltsatou, Maria; Kyriakopoulos, Georgios; Mavroeidi, Vasiliki; Kostopoulou, Akrivi; Atlan, Karine; Theocharis, Stamatios; Rindi, Guido; Grossman, Ashley; Grozinsky‐Glasberg, Simona; Kaltsas, Gregory

doi:10.1007/s12020-020-02540-w

Cited by 11 publications

(11 citation statements)

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“…Neuroendocrine neoplasms in the gastro-enteropancreatic system are now classified in two entirely different categories with distinct clinical, pathologic, and behavioral characteristics, and the two groups are also defined by different molecular pathways [11,12]. The high-grade neuroendocrine carcinomas (NECs), which are defined by poorly differentiated morphology, necrosis, and a very high proliferative rate (as manifest by brisk mitoses, as well as a Ki-67 proliferation index typically over 55%), are characterized by molecular changes that are commonly detected in conventional adenocarcinomas at the same sites, including TP53, SMAD4, and KRAS as well as Rb [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

et al. 2021

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Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.

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Section: Introductionmentioning

confidence: 99%

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

et al. 2021

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“…Suspicion of a change in disease behaviour defined by clinical, biochemical, and/or radiological criteria, as stated by the authors, was also associated with a negative prognosis, HR 4.17 (95% CI 1.9-9.13, P < 0.001). Moreover, in our recent study with a similar design, a shorter overall survival was seen in patients who had a change in Ki-67 labelling index within the first 36 months of diagnosis, compared to those who had a change of Ki-67 at a later time point (Alexandraki et al 2020). Documentation of such progression provides a strong prognostic factor and plays an important role in determining further therapeutic management (Singh et al 2014, Grillo et al 2016, Botling et al 2020) (Table 2).…”

Section: Managementmentioning

confidence: 87%

“…High-grade progression with an increase in Ki-67 ranging from 17 to 55% has been reported. Similarly, we have recently presented a series of 15 patients with Pan-NENs with over-expression of p53 documented in three out of seven patients assessed but without clear evidence of histological dedifferentiation (Alexandraki et al 2020). The main features of these seven studies are summarised in Table 2.…”

Section: Endocrine-related Cancermentioning

confidence: 98%

Changing biological behaviour of NETs during the evolution of the disease: progress on progression

Alexandraki

Spyroglou

Kykalos

et al. 2021

Endocrine-Related Cancer

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Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead on occasion to an increase in grading, but generally does not appear to be correlated with histologically confirmed de-differentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only 7 studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in management. Summarising the evidence overall, we suggest that future studies should concentrate on changes in molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

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“…Alexandraki et al. analyzed 264 PanNENs and showed that 15 patients (5.7%) developed an increase in Ki67 during disease course ( 31 ). However, this study also included patients with multiple endocrine neoplasia type 1, and did not provide information about the 264-patient cohort.…”

Section: Discussionmentioning

confidence: 99%

A real-life treatment cohort of pancreatic neuroendocrine tumors: High-grade increase in metastases confers poor survival

et al. 2022

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BackgroundTumor grade determined by the Ki67 index is the best prognostic factor for pancreatic neuroendocrine tumors (PanNETs). However, we often observe that the grade of metastases differs from that of their primary tumors. This study aimed to investigate the frequency of grade changes between primary tumors and metastases, explore its association with clinical characteristics, and correlate the findings with the prognosis.MethodsSix hundred forty-eight patients with pancreatic neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 103 patients with PanNETs who had paired primary tumors and metastases with an available Ki67 index were included. Re-evaluation of Ki67 was performed on 98 available samples from 69 patients.ResultsFifty cases (48.5%) had a Ki67 index variation, and 18 cases (17.5%) displayed a grade increase. Metachronous metastases showed significantly higher Ki67 index variation than synchronous metastases (P=0.028). Kaplan–Meier analyses showed that high-grade metastases compared to low-grade primary tumors were significantly associated with decreased progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027). Multivariable Cox regression analyses demonstrated that a low-grade increase to high-grade was an unfavorable and independent prognostic factor for PFS and OS (P=0.010, and P=0.041, respectively).ConclusionsA high-grade increase in metastases was an unfavorable predictor of PanNETs, which emphasized the importance of accurate pathological grading and could provide a reference for clinical decision-making.

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Distinctive features of pancreatic neuroendocrine neoplasms exhibiting an increment in proliferative activity during the course of the disease

Cited by 11 publications

References 25 publications

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

Changing biological behaviour of NETs during the evolution of the disease: progress on progression

A real-life treatment cohort of pancreatic neuroendocrine tumors: High-grade increase in metastases confers poor survival

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