Histopathologist-level quantification of Ki-67 immunoexpression in gastroenteropancreatic neuroendocrine tumors using semiautomated method

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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Evaluation of gastroenteropancreatic neuroendocrine tumors for Ki 67, p16 and cyclin D1 expression

Istanbul Medical Journal ◽

10.5505/1304.8503.2011.43531 ◽

2011 ◽

Vol 12 (3) ◽

pp. 105-112

Author(s):

Gulzade Ozyalvacli ◽

Esra Pasaoglu ◽

Zuhal Gucin ◽

Kemal Behzatoglu ◽

Feray Gunver ◽

...

Keyword(s):

Cyclin D1 ◽

Neuroendocrine Tumors ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67

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STAT3 inhibition for gastroenteropancreatic neuroendocrine tumors: Potential for a new therapeutic target?

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.340 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 340-340

Author(s):

Alexandra G Lopez-Aguiar ◽

Lauren McLendon Postlewait ◽

Mohammad Zaidi ◽

Kristen Zhelnin ◽

Alyssa Krasinskas ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Lymphovascular Invasion ◽

Therapeutic Option ◽

Microvascular Density ◽

Vascular Tumors ◽

Vegf Expression ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Low Expression ◽

Stat3 Inhibition

340 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular tumors with similar treatments applied to all sites. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with known adverse pathologic factors and disease recurrence after resection is not known. Methods: All pts with non-metastatic primary GEP-NETs who underwent curative-intent resection at a single institution from 2000-2013 were included. Immunohistochemistry was performed for STAT3, VEGF, HIF-1α, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. STAT3, VEGF, and HIF-1α were categorized into high vs low expression; CD31 was dichotomized at the median value. Primary outcome was 3-yr recurrence-free survival (3-yr RFS); secondary outcomes were correlation of STAT3, VEGF, and HIF-1α expression with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. Results: Of 265 GEP-NETs resected, 144 had tissue for analysis. STAT3 expression was high in 12 (8%) and low in 132 (92%). VEGF expression was high in 19 (13%) and low in 125 (87%), and HIF-1α was high in 1 (1%) and low in 143 (99%). High STAT3 expression was associated with worse 3-yr RFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yr RFS of 76% compared to 82% for low expression (p = 0.098); HIF-1α expression was not associated with RFS. Ki-67 ≥3% was associated with worse 3-yr RFS (≥3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of lymphovascular invasion (LVI: 72% vs 95%; p = 0.001) and increased microvascular density per µm2 (CD31 > median: 75% vs CD31 < median: 86%; p = 0.043). High STAT3 expressing tumors were more likely to have a Ki-67≥3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3 tumors compared to only 50% with low STAT3 (p = 0.058). CD31 overexpression was similar between groups (58% vs 49%; p = 0.5). Conclusions: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion, and worse 3-yr RFS. STAT3 inhibition may be a novel therapeutic option for patients undergoing resection of high-risk tumors.

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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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Treatment response and clinical outcomes of well-differentiated high-grade neuroendocrine tumors to 177Lu-DOTATATE.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.368 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 368-368

Author(s):

Kelley Lauren Coffman ◽

Lisa Bodei ◽

Tiffany Le ◽

Ye Choi ◽

Joanne F. Chou ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Stable Disease ◽

Tumor Tissue ◽

Somatostatin Receptor ◽

Response To Treatment ◽

High Grade ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Best Response ◽

Well Differentiated

368 Background: 177Lu-DOTATATE is an approved therapy for somatostatin receptor (sstr) positive gastroenteropancreatic neuroendocrine tumors (NETs). There are little data available on response and outcomes for well differentiated (WD) high grade (HG) NETs treated with 177Lu-DOTATATE. Methods: Pts with WD HGNETs treated with 177Lu-DOTATATE at MSK from 2018-2020 were identified. Demographics, response to treatment, and progression-free survival (PFS) were determined. In pts with archival tumor tissue, next-generation sequencing (NGS) was performed through an institutional platform (MSK-IMPACT). Results: 19 pts were identified (mean age 54, 63% female). Site of tumor origin included: pancreas (14/19, 74%), small bowel (2/19, 10.5%), rectal (2/19, 10.5%), lung (1/19, 5%). Average tumor Ki-67 was 34.8 (range 22-56). All tumors were sstr avid on pre-treatment Ga68-DOTATATE PET/CT; none of the patients had sstr negative lesions detected. Median number of prior treatments (systemic and/or liver-directed) was 4 (range 2-7). All pts had progressive disease prior to initiation of 177Lu-DOTATATE. 13 pts (68%) completed all four treatment cycles; treatment was incomplete in 6 pts due to treatment-related toxicities (n = 3) and clinical progression (n = 3). Best response by radiographic report was available in 16 patients (84%):10/16 (63%) with partial response, 1/16 (6%) with stable disease, 5/16 (31%) with disease progression. One pt with stable disease as best response received two additional cycles of 177Lu-DOTATATE at progression. Median PFS (from date of first treatment with 177Lu-DOTATATE until progression/death) was 11.1 months (95% CI 10.6 to NA). Five pts (26%) experienced dose modifying toxicity with 177Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 pts, 47%; G3/4 in 1 pt, 5%), anemia (7 pts, 37%; G3/4 in 2 pts, 10.5%), leukopenia (6 pts, 32%; G3/4 in 0 pts), and AST/ALT elevation (4 pts, 21%; G3/4 in 0 pts). NGS results were available in the tumor tissue of 13 pts (68%). The most commonly observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations were identified. Conclusions: We observed a meaningful disease control rate of 69% during treatment of WD HGNETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of pts received all four treatment cycles with treatment-related toxicities largely bone-marrow related, as expected, based on historical data. As would be expected in sstr avid tumors, the vast majority had alterations in chromatin remodeling genes (MEN1, DAXX) consistent with WD NETs, with no RB1 alterations identified.

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P-111 Correlation of Mitotic Index and Ki-67 and Their Impacts on Survival of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) at Ramathibodi Hospital

Annals of Oncology ◽

10.1093/annonc/mdw199.105 ◽

2016 ◽

Vol 27 ◽

pp. ii33

Author(s):

T. Dejthevaporn ◽

V. Jennetisin ◽

S. Rattanasiri ◽

P. Sornmayura

Keyword(s):

Mitotic Index ◽

Neuroendocrine Tumors ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67

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Is proliferative index (Ki-67) useful to stratify patients (pts) with G2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs)? Clinicopathologic correlation.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.255 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 255-255

Author(s):

Martin Angel ◽

Juan O Connor ◽

Veronica Pesce ◽

Guillermo Ariel Mendez ◽

Claudia Bestani ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Roc Curve ◽

Target Therapy ◽

Treatment Options ◽

Rank Test ◽

Roc Curve Analysis ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Kaplan Meier

255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogeneous group of tumors. Several treatment options including chemotherapy and target therapy are available, but there is a lack of prospective trials assessing the role of pronostic factors in this population. Aim(s): to analyze prognostic factors and clinical characteristics in a population of patients with G2 GEP-NETs. To determine the role of ki 67 in the stratification of G2 population. Methods: Study population was obtained from our prospective database (Argentum Group). Survival was estimated using the Kaplan-Meier method and compared between Ki-67 quartiles using the log-rank test. Value of Ki-67 to discriminate mortality was assesed with a ROC curve analysis Results: 144 pts were evaluated. Mean age 54.9, 46.7% male. 102 (70.8%) with metastatic disease, mainly hepatic in 97 pts. (67.4%). 67.9 % underwent surgery. 34% received chemotherapy, and 10.9% target therapy. Median Ki-67 value was 6 (IQR 4-10), ROC curve=0.62 (95% CI 0.53 a 0.72 p=0.021. cut-off: 6.5 (sensitivity 62.2%, specificity 57.7%). Median survival was 97, 67, 51 and 27 months according stratification by quartile (p.001), 45 events (31.7%). Conclusions: Our results suggest that in the heterogenous G2 GEP-NETs there are significant differences in survival. This study was underpowered to detect differences between Ki-67 quartiles, we detected that chemotherapy was mostly used in the higher quartiles.

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