Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

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Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series

Neuroendocrinology ◽

10.1159/000477849 ◽

2017 ◽

Vol 106 (3) ◽

pp. 234-241 ◽

Cited By ~ 10

Author(s):

Salvatore Paiella ◽

Giovanni Marchegiani ◽

Marco Miotto ◽

Anna Malpaga ◽

Harmony Impellizzeri ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Survival Rates ◽

Disease Free Survival ◽

Postoperative Outcome ◽

Tumor Diameter ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Excellent Outcome ◽

Comparison Results ◽

Well Differentiated

Introduction: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. Methods: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. Results: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). Conclusion: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.

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Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers14020433 ◽

2022 ◽

Vol 14 (2) ◽

pp. 433

Author(s):

Ugo Marchese ◽

Martin Gaillard ◽

Anna Pellat ◽

Stylianos Tzedakis ◽

Einas Abou Ali ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Postoperative Morbidity ◽

Current Data ◽

Pancreatic Neuroendocrine Tumors ◽

Tips And Tricks ◽

Poorly Differentiated ◽

Well Differentiated ◽

Multimodal Management ◽

Neuroendocrine Carcinomas

Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.

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Temozolomide and capecitabine (CAPTEM) is effective in metastatic well-differentiated gastrointestinal neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.366 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 366-366

Author(s):

İzzet Dogan ◽

Didem Tastekin ◽

Senem Karabulut ◽

Burak Sakar

Keyword(s):

Prognostic Factors ◽

Neuroendocrine Tumors ◽

Cox Regression ◽

Somatostatin Receptor ◽

Ki 67 ◽

Cox Regression Analysis ◽

Number Of Patients ◽

Poorly Differentiated ◽

Well Differentiated ◽

Metastatic Sites

366 Background: The study aimed to evaluate patients' outcomes and prognosis with metastatic gastrointestinal neuroendocrine tumors (mgNET) who treated temozolomide and capecitabine (CAPTEM). Methods: The data of forty-three patients were retrospectively evaluated. Clinicopathological features and treatment approaches were recorded. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Prognostic factors were assessed with Cox-regression analysis. Results: Median age was 59 (27-85) years. The number of male and female patients was 23 (%53.5) and 20 (%46.5), respectively. Pancreas (%51.2) was the most common site of the tumor. The number of patients with well- and poorly-differentiated mgNET was 38 (%88.4) and 5 (%11.6), respectively. The most common metastatic sites were liver (%62.8), lymph node (%58.1), and bone (%18.6). Eleven (%25.6) of the patients previously had undergone surgery, and some patients received radiotherapy (%9.5), chemotherapy (%19), and nuclear therapy (%9.3). Also, patients received octreotide (%86) or lanreotide (%14) with CAPTEM. In patients with well-differentiated mgNET, median PFS was 17.4 months, and disease control ratio %79.4 (%3-complete response, %38.2-partial response, and %38.2-stable response). No response observed in patients with poorly differianted mgNET, and the median PFS was calculated as 4.5 months. Grade 1-2 toxicity was observed in 34 (%79.1) of the patients, and grade 3-4 toxicity in 8 (%18.6). Four (%9.5) patients discontinued therapy for the toxicity. The most common toxicities were anemia (%37.2), thrombocytopenia (%25.6), and fatigue (%16.3). At a median follow-up of 33.8 (2.9-172.73) months, the ratio of five-years OS was %61. In multivariate analysis; gender (p=0.008), age (p=0.007), and Ki-67 levels (p=0.011) were a statistically significant for OS. However, the site of the tumor (p=0.186), number of metastatic sites (p=0.255), and type of somatostatin receptor ligand (p=0.903) were not. Conclusions: In the study, we showed that CAPTEM + somatostatin receptor ligands (octreotide or lanreotide) were effective and well-tolerated in patients with well-differentiated mgNET. But, it was not effective in patients with poorly-differentiated mgNET. Male gender, aged over 60 years, and tumor with a high level of Ki-67 were negative prognostic factors.

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Predictive value of preoperative MRI features for the Ki-67 index in well-differentiated G1/G2 pancreatic neuroendocrine tumors

Acta Radiologica ◽

10.1177/0284185119840212 ◽

2019 ◽

Vol 60 (11) ◽

pp. 1394-1404

Author(s):

Haitao Sun ◽

Shilong Zhang ◽

Kai Liu ◽

Jianjun Zhou ◽

Xingxing Wang ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Predictive Value ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Mri Features ◽

Well Differentiated

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KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine ◽

10.1007/s12020-017-1364-8 ◽

2017 ◽

Vol 57 (3) ◽

pp. 494-502 ◽

Cited By ~ 6

Author(s):

Federica Grillo ◽

Luca Valle ◽

Diego Ferone ◽

Manuela Albertelli ◽

Maria Pia Brisigotti ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Well Differentiated ◽

Grade Assessment

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Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4111 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4111-4111

Author(s):

Xianjun Yu ◽

Jianming Xu ◽

Lin Shen ◽

Chunmei Bai ◽

Jie Li ◽

...

Keyword(s):

Partial Response ◽

Neuroendocrine Tumors ◽

Objective Response ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Phase 3 ◽

Ki 67 ◽

Meaningful Improvement ◽

Well Differentiated

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.

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Kit Protein (CD 117) and Proliferation Index (Ki-67) Evaluation in Well and Poorly Differentiated Neuroendocrine Tumors

Tumori Journal ◽

10.1177/030089160609200611 ◽

2006 ◽

Vol 92 (6) ◽

pp. 531-535 ◽

Cited By ~ 12

Author(s):

Leonardo Ferrari ◽

Silvia Della Torre ◽

Paola Collini ◽

Antonia Martinetti ◽

Giuseppe Procopio ◽

...

Keyword(s):

Protein Expression ◽

Neuroendocrine Tumors ◽

Histological Grade ◽

Proliferation Index ◽

Tyrosine Kinase Receptor ◽

Ki 67 ◽

Autocrine Loop ◽

Kit Receptor ◽

Poorly Differentiated ◽

Well Differentiated

Aims and background Kit protein expression seems to be associated with a poor outcome in cancer patients and may be an important target for new anticancer drugs. We examined by immunohistochemistry the presence of Kit protein in neuroendocrine tumors (NETs) to explore its relationship with histological grade and proliferation index. Patients and methods Thirty-five tumor specimens from patients with 24 well differentiated and 11 poorly differentiated NETs were examined for the presence of Kit protein and the proliferation index marker Ki-67. Results Eleven specimens were positive for Kit protein expression, 8 of which had poorly-differentiated histology and only 3 had well-differentiated histology. Most of the tumors showing immunopositivity for Kit protein were also characterized by a high proliferation index. Conclusions Immunohistochemical positivity for Kit protein is mainly related to poorly differentiated NETs. In our study, the percentage of tumors with immunopositivity for Kit protein was lower than that observed by other authors. This difference could be attributable to the different immunohistochemistry procedures used and to the biological heterogeneity of NETs. The number of Kit protein-positive NETs may justify targeted therapy with a tyrosine kinase receptor-associated inhibitor only in a selected subset of patients, whenever no other therapy is available and an autocrine loop sustained by the Kit receptor and its specific ligand has been demonstrated.

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