Abstract 3406: Enhancer of zeste homolog 2 (EZH2) expression and proliferation index (Ki-67) in neuroendocrine tumors of the gastrointestinal tract and pancreas

Chromogranin A (CgA) and the Ki-67 proliferation index are considered as important biochemical and pathological markers for clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP NETs), respectively. The IGF system has been suggested as an important regulator of GEP NET proliferation and differentiation. A possible relationship between serum CgA (sCgA), Ki-67 proliferation index, and expression of IGF-related genes in patients with GEP NETs has not been demonstrated yet. This study investigates the relationship between sCgA, the Ki-67 proliferation index, and the expression of IGF-related genes in GEP NET tissues and their relation with 5-year survival. Tumor and blood samples from 22 GEP NET patients were studied. Tumoral mRNA expression of IGF-related genes (IGFs: IGF1, IGF2; IGF receptors: IGF1R, IGF2R; insulin receptors: subtype A (IR-A) and B (IR-B); IGF-binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, and IGFBP6) was measured using quantitative RT-PCR. Ki-67 proliferation index was determined using immunohistochemistry. sCgA was measured with ELISA. Five-year survival in patients with nonelevated sCgA (n=11) was 91 vs 46% in patients with elevated sCgA (n=11) (P=0.006). IR-A mRNA expression was significantly higher in tumors obtained from patients with elevated sCgA than in those from patients with nonelevated sCgA (6.42±2.08 vs 2.60±0.40; P=0.04). This data suggests that sCgA correlates well with 5-year survival of GEP NET patients, and that IR-A mRNA expression correlates well with tumor mass in GEP NET patients.

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Canine Neuroendocrine Tumors of the Pancreas: A Study Using Image Analysis Techniques for the Discrimination of Metastatic Versus Nonmetastatic Tumors

Veterinary Pathology ◽

10.1177/030098589703400206 ◽

1997 ◽

Vol 34 (2) ◽

pp. 138-145 ◽

Cited By ~ 11

Author(s):

G. Minkus ◽

U. Jütting ◽

M. Aubele ◽

K. Rodenacker ◽

P. Gais ◽

...

Keyword(s):

Image Analysis ◽

Neuroendocrine Tumors ◽

Nucleolar Organizer ◽

Biological Behavior ◽

Proliferation Index ◽

Nucleolar Organizer Regions ◽

Ki 67 ◽

Analysis Techniques ◽

Significant Difference ◽

Image Analysis Techniques

Canine pancreatic neuroendocrine tumors were studied using different image analysis techniques (nuclear image histometry, analysis of argyrophilic proteins of nucleolar organizer regions, determination of the mouse anti-Ki 67 antigen proliferation index, and DNA densitometry) to correlate their biological behavior with objective phenotypic markers. The methods were compared to determine the best method for distinguishing between metastatic and nonmetastatic tumors. Discrimination between the two types of tumor was possible using nuclear image histometry in combination with morphometric analysis of argyrophilic proteins of nucleolar organizer regions. In contrast, the mouse anti-Ki 67 antigen proliferation index, DNA measurement, and immunohistochemical parameters revealed no significant difference between the two types of tumors.

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Albumin to alkaline phosphatase ratio: does it predict survival in grade 1 and grade 2 neuroendocrine tumors?

10.21203/rs.2.17508/v1 ◽

2019 ◽

Author(s):

Yusuf Acikgoz ◽

Öznur Bal ◽

Mutlu Doğan

Keyword(s):

Alkaline Phosphatase ◽

Neuroendocrine Tumors ◽

Prognostic Value ◽

Proliferation Index ◽

Rank Test ◽

P Value ◽

Albumin Concentration ◽

Ki 67 ◽

Registration Data ◽

Well Differentiated

Abstract BACKGROUND: Neuroendocrine tumors (NETs) are very heterogeneous tumors. Although it is classified according to Ki-67 proliferation index and mitotic count, their behavior may greatly vary even in the same group. Therefore, more accurate prognostic markers are required to predict prognosis in patients with well differentiated NETs. This study is aimed to evaluate prognostic value of albumin to alkaline phosphatase ratio (AAPR) in patients with well differentiated neuroendocrine tumors. PATIENTS AND METHODS: A total of 110 patients included in this study. Patients' data were obtained from registration data-base of the hospital and reviewed retrospectively. AAPR was calculated by dividing albumin concentration (g/dl) to alkaline phosphatase level (U/L). Cut off value for AAPR was determined by Receiver Operating Characteristic (ROC) analysis. Survival analysis was performed by Kaplan-Meier method with the Long-rank test. We reported two-sided p value and p<0.05 was considered statistically significant.RESULT: The calculated optimum cut-off value for AAPR was 0.028. Patients were divided into two groups as patients with AAPR ≤0.028 (n:22, 20%) and, with AAPR >0.028 (n:88, 80%). Patients with AAPR >0.028 had statistically longer overall survival (OS) compared with patients with ≤0.028 ( NR vs 96,8 months, p=0.001). Additionally, AAPR has been shown to be an independent prognostic factor for OS in in multivariate analysis (HR=4.942, 95% CI=1.693-14.420, p=0.003).CONCLUSION: Patients with higher AAPR had more favourable prognosis compared to patients with lower AAPR. We demonstrated that AAPR can be of prognostic value in well-differentiated NETs.

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Comparison of Manual and Digital Assessment of KI-67 in Neuroendocrine Tumors

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.274 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S125-S125

Author(s):

B S Raju ◽

M Quinton ◽

L Hassell

Keyword(s):

Image Analysis ◽

Neuroendocrine Tumors ◽

Digital Image ◽

Digital Image Analysis ◽

Hot Spot ◽

World Health ◽

Proliferation Index ◽

Digital Analysis ◽

Ki 67 ◽

Digital Assessment

Abstract Introduction/Objective Proliferative activity is an essential prognostic and treatment indicator for neuroendocrine tumors (NET). Ki-67 proliferation index, if reported by unaided microscopic estimation on hot-spot locations could lead to variability and inconsistencies. This study aims to compare the Ki-67 assessment of NETs by visual estimation versus automated digital image analysis (Roche iCoreo/Virtuoso). Methods 212 patients with Ki-67-graded GI NETs (117 G1; 61 G2; 34 G3) from 2010 to 2019 were reassessed using digital image analysis quantification of hot spot areas of at least 500 cells (average 800 cells). Revised tumor grades were assigned according to the European Neuroendocrine Tumor Society guidelines and the 2010 World Health Organization classification and compared to initially reported grade. Results We found 75% concordance for G1, with 22% of cases upgraded to G2 and 3% of cases upgraded to G3. For G2, there was 70.5% agreement, with 13.1% of cases downgraded to G1 and 16.4% upgraded to G3. For G3, there was 100% agreement, (kappa=0.64, overall). Retrospective review of discordant G3 cases revealed cases with known metastasis, small fragments of tissue, or polyps. Scanning and scoring required approximately 10 minutes per case. Conclusion Our data shows the time/effort difference of visually estimating versus automated digital analysis may lead to significant classification errors in these tumors. Although digital analysis has limitations, including tumor heterogeneity, misidentification of tumor cells, and poor immunostaining which could require manual counting by a pathologist, this rigor should be reinforced and explicitly stated to increase accuracy and reproducibility of grading.

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Evaluation of the concordance between the stage of the disease and Ki-67 proliferation index in gastroenteropancreatic neuroendocrine tumors

European Journal of Gastroenterology & Hepatology ◽

10.1097/meg.0000000000000619 ◽

2016 ◽

Vol 28 (7) ◽

pp. 836-841 ◽

Cited By ~ 6

Author(s):

Ersin Özaslan ◽

Sinan Demir ◽

Halit Karaca ◽

Kadri Güven

Keyword(s):

Neuroendocrine Tumors ◽

Proliferation Index ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67

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Utility of the Quantitative Ki-67 Proliferation Index and CD56 Together in the Cytologic Diagnosis of Small Cell Lung Carcinoma and Other Lung Neuroendocrine Tumors

Acta Cytologica ◽

10.1159/000346394 ◽

2013 ◽

Vol 57 (3) ◽

pp. 281-290 ◽

Cited By ~ 29

Author(s):

Gang Zheng ◽

David S. Ettinger ◽

Zahra Maleki

Keyword(s):

Neuroendocrine Tumors ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Proliferation Index ◽

Small Cell Lung ◽

Cytologic Diagnosis ◽

Ki 67 ◽

Cell Lung Carcinoma

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Ki‐67 proliferation index in neuroendocrine tumors: Can augmented reality microscopy with image analysis improve scoring?

Cancer Cytopathology ◽

10.1002/cncy.22272 ◽

2020 ◽

Vol 128 (8) ◽

pp. 535-544

Author(s):

Swati P. Satturwar ◽

Joshua L. Pantanowitz ◽

Christopher D. Manko ◽

Lindsey Seigh ◽

Sara E. Monaco ◽

...

Keyword(s):

Image Analysis ◽

Augmented Reality ◽

Neuroendocrine Tumors ◽

Proliferation Index ◽

Ki 67

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Demethylation Status of Somatic DNA Extracted From Pituitary Neuroendocrine Tumors Indicates Proliferative Behavior

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa156 ◽

2020 ◽

Vol 105 (6) ◽

pp. 2015-2026

Author(s):

Borbála Szabó ◽

Kinga Németh ◽

Katalin Mészáros ◽

Nikolette Szücs ◽

Sándor Czirják ◽

...

Keyword(s):

Cell Lines ◽

Neuroendocrine Tumors ◽

Dna Methyltransferase ◽

Ring Finger ◽

Proliferation Rate ◽

Proliferation Index ◽

Dna Methyltransferase 1 ◽

Ki 67 ◽

Liquid Chromatography Tandem Mass ◽

Polymerase Chain

Abstract Background Cytosine intermediaries 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), epigenetic hallmarks, have never been investigated in pituitary neuroendocrine tumors (PitNET). Objective To examine methylation-demethylation status of global deoxyribonucleic acid (DNA) in PitNET tissues and to assess its correlation with clinical and biological parameters. Materials and Methods Altogether, 57 PitNET and 25 corresponding plasma samples were collected. 5mC and 5hmC were investigated using liquid chromatography–tandem mass spectrometry. Expression of DNA methyltransferase 1 (DNMT1); tet methylcytosine dioxygenase 1 through 3 (TET1-3); and ubiquitin-like, containing PHD and RING finger domains 1 and 2 (UHRF1-2) were measured by reverse transcription–polymerase chain reaction. Levels of 5hmC and UHRF1-2 were explored by immunohistochemistry. Effect of demethylating agent decitabine was tested on pituitary cell lines. Results 5hmC/5mC ratio was higher in less differentiated PitNET samples. A negative correlation between Ki-67 proliferation index and 5hmC, 5hmC to 5mC ratio were revealed. Higher 5mC was observed in SF-1 + gonadotroph adenomas with a higher Ki-67 index. Expressions of TET2 and TET3 were significantly higher in adenomas with higher proliferation rate. UHRF1 showed gradually increased expression in higher proliferative adenoma samples, and a significant positive correlation was detected between UHRF2 expression and 5hmC level. Decitabine treatment significantly decreased 5mC and increased 5hmC levels in both cell lines, accompanied with decreased cell viability and proliferation. Conclusion The demethylation process negatively correlated with proliferation rate and the ratio of 5hmC to 5mC was higher in less differentiated adenomas. Therefore, epigenetic markers can be potential biomarkers for PitNET behavior. Altering the epigenome in adenoma cells by decitabine decreased proliferation, suggesting that this treatment might be a novel medical treatment for PitNET.

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Metachronous double primary neuroendocrine tumors in larynx and lung: a case report

Journal of International Medical Research ◽

10.1177/0300060520962928 ◽

2020 ◽

Vol 48 (11) ◽

pp. 030006052096292

Author(s):

In Hye Song ◽

Youn Soo Lee ◽

Dong-Il Sun ◽

Yong-Kil Hong ◽

Kyo-Young Lee

Keyword(s):

Tumor Cells ◽

Carcinoid Tumor ◽

Neuroendocrine Tumors ◽

Lower Lobe ◽

Proliferation Index ◽

Atypical Carcinoid ◽

Voice Change ◽

Large Tumor ◽

Ki 67 ◽

Primary Tumors

When a patient harbors two or more neuroendocrine tumors (NETs), it can be difficult to determine whether they are double primary tumors or metastases. A 60-year-old man complained of voice change lasting 1 month. On physical examination and imaging, a 1.8-cm mass was observed in his epiglottis, and a laser epiglottectomy was performed. Upon microscopic examination, the tumor consisted of medium-sized ovoid or short spindle cells. Immunohistochemical staining of the tumor cells was positive for synaptophysin, chromogranin, and calcitonin but negative for CD56; the Ki-67 proliferation index was approximately 5%. The patient was diagnosed with atypical carcinoid tumor. In 2015, a hypermetabolic endobronchial tumor was identified in the left lower lobe by positron emission tomography-computed tomography. Bronchoscopic biopsy revealed palisading large tumor cells with high nuclear-cytoplasmic ratio, frequent mitoses, and necrosis. The tumor cells were positive for CD56 and negative for cytokeratin-7, thyroid transcription factor-1, P40, synaptophysin, chromogranin, and calcitonin; the Ki-67 proliferation index was approximately 90%. Overall histologic findings were consistent with large cell neuroendocrine carcinoma rather than metastatic atypical carcinoid tumor. Detailed clinical and pathological review are essential to differentiate between metastatic NET and double primary NETs and, therefore, to provide the best management of the patient.

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