scholarly journals P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kirstine Nielsen ◽  
Tina Binderup ◽  
Seppo W. Langer ◽  
Andreas Kjaer ◽  
Pauline Knigge ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Chromogranin A ◽  
Somatostatin Receptor ◽  
Univariate Analysis ◽  
Proliferation Index ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Ki67 Index ◽  
P53 Expression ◽  
Well Differentiated

Abstract Background High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Method Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5–30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). Results In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. Conclusion Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

scholarly journals The Expression of Chromogranin A, Syanptophysin and Ki67 in Detecting Neuroendocrine Neoplasma at High Grade Colorectal Adenocarcinoma

2021 ◽  
Vol 9 (A) ◽  
pp. 1142-1147
Author(s):  
W. A. Gusti Deasy ◽  
M. Husni Cangara ◽  
Andi Alfian Zainuddin ◽  
Djumadi Achmad ◽  
Syarifuddin Wahid ◽  
...  
Keyword(s):  
Chromogranin A ◽  
Colorectal Adenocarcinoma ◽  
Final Diagnosis ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Neuroendocrine Markers ◽  
Study Results ◽  
Cell Neoplasm ◽  
Sample Characteristics

BACKGROUND: Neuroendocrine neoplasm (NEN) is an epithelial cell neoplasm that can give a histopathological appearance resembling high-grade colorectal adenocarcinoma. Immunohistochemical assays with specific neuroendocrine markers of chromogranin A and synaptophysin are required to establish a definite diagnosis of NEN. AIM: This study aimed to determine whether there was an expression of chromogranin A, synaptophysin and Ki67 which indicated the presence of neuroendocrine neoplasms in samples that have been diagnosed as high-grade colorectal adenocarcinoma. MATERIALS AND METHODS: A study of the expression of chromogranin A, synaptophysin and Ki67 in paraffin blocks was carried out as a result of biopsy and tissue surgery of 70 samples of colorectal tumor specimens diagnosed with colorectal adenocarcinoma. Descriptive analyses were used to assess the study results of the amount of chromogranin A, synaptophysin, and sample characteristics. RESULTS: We discovered that eight (8) samples (11.4%) were NEN from 70 previously diagnosed samples as high-grade colorectal adenocarcinoma using immunohistochemical assay with neuroendocrine markers, namely chromogranin A and synaptophysin. CONCLUSION: The final diagnosis obtained from 8 samples diagnosed as NEN were Neuroendocrine tumor (NET) G1, G2, and G3, respectively 1.4% and LCNEC 7.1% based on the specific neuroendocrine markers of chromogranin A, synaptophysin and Ki67.

hPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15038-e15038
Author(s):  
Aman Chauhan ◽  
Alexandre Prieur ◽  
Jill Kolesar ◽  
Susanne M. Arnold ◽  
Léa Payen ◽  
...  
Keyword(s):  
Prospective Trial ◽  
Large Cell ◽  
Cancer Center ◽  
Neuroendocrine Neoplasms ◽  
Blood Collection ◽  
Study Cohort ◽  
Gastrointestinal Hormone ◽  
Low Grade ◽  
High Grade ◽  
Well Differentiated

e15038 Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Additional 69 samples are currently undergoing analysis. Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Current data are for 31 patients. Data on total 100 patients will be presented at ASCO 2020. Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.

scholarly journals WHO Grade 2 Neuroendocrine Tumor in a 15-Year-Old Male: A Case Report and Literature Review

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Eric Johannesen ◽  
Van Nguyen
Keyword(s):  
Neuroendocrine Tumor ◽  
Neuroendocrine Tumors ◽  
Neuroendocrine Differentiation ◽  
Failure To Thrive ◽  
Proliferation Index ◽  
Neuroendocrine Neoplasms ◽  
Who Grade ◽  
Increased Risk ◽  
History Of ◽  
Well Differentiated

Neuroendocrine tumors, distinguished from adenocarcinomas by their neuroendocrine differentiation, are the most common pediatric epithelial malignancy that most often occurs in the appendix. In 2010, the WHO classified neuroendocrine neoplasms into three grades based on morphology, mitotic count, and Ki67 proliferation index. A 15-year-old male with a history of anemia and failure to thrive was diagnosed with a well-differentiated neuroendocrine tumor in the jejunum that invaded into the subserosal soft tissue and metastasized to four lymph nodes. Pediatric neuroendocrine tumors frequently arise within hereditary tumor syndromes with pancreatic neuroendocrine tumors being the most common. Several studies also indicate an elevated risk of small intestinal neuroendocrine tumors in which children born to a parent with a history of neuroendocrine tumors in the small intestine have a significant increased risk of developing one.

scholarly journals Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

2018 ◽  
Vol 108 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Halfdan Sorbye ◽  
Eric Baudin ◽  
Ivan Borbath ◽  
Martyn Caplin ◽  
Jie Chen ◽  
...  
Keyword(s):  
Patient Group ◽  
Unmet Needs ◽  
Proliferation Rate ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Primary Tumor Site ◽  
Net G3 ◽  
Well Differentiated

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

scholarly journals Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 162
Author(s):  
Susanna Majala ◽  
Tiina Vesterinen ◽  
Hanna Seppänen ◽  
Harri Mustonen ◽  
Jari Sundström ◽  
...  
Keyword(s):  
Prospective Study ◽  
Fdg Pet ◽  
Somatostatin Receptor ◽  
Proliferation Index ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Pet Ct ◽  
Sstr Subtype ◽  
Node Metastases ◽  
Fdg Pet Ct

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal.

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

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.

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

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.

Somatostatin receptor (SSTR) expression and proliferative index (Ki 67) in 100 patients (pts) with gastroenteropancreatic neuroendocrine tumors (GEP-NETs): Clinical-pathological correlation.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14598-e14598
Author(s):  
Juan Manuel O'Connor ◽  
Veronica Pesce ◽  
Guillermo Ariel Mendez ◽  
Claudia Bestani ◽  
Fabiana Marmissolle ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Univariate Analysis ◽  
Receptor Expression ◽  
Nuclear Antigen ◽  
Rank Test ◽  
Proliferative Index ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Kaplan Meier ◽  
Well Differentiated

e14598 Background: Somatostatin receptor expression (SSTR), mainly subtypes 2 and 5, is a feature of well differentiated GEP-NETs. Such expression has a prognostic and predictive value for the use of somatostatin analogs.Ki 67, present during the cycle phases (G1, S, G2 y M) is a nuclear antigen associated with cell proliferation. The correlation between both clinical and pathological factors is under active investigation in patients with GEP-NETs. Methods: An analysis including 100 patients in the database of the Argentum Group was performed. Consecutive patients were included during the 2006-2007 period. In all cases, a centralized revision of the sample was conducted for diagnosis confirmation.The study of SSTR receptors in tissue and Ki67 was conducted using IHQ.The Kaplan-Meier method was used to analyse survival. Log-rank test was used for the comparative analysis of the variables of interest. Results: The expression of at least one of the SSTRs 2 (a) or 5 was found in 86% and 62% of cases respectivevly in this population. The univariate analysis showed significant differences in the expression of SSTR2 (a) but not in the expression of SSTR 5.The expression of the proliferative index (Ki 67) was associated with significant differences in relation to OS at 5 years, 84% (Ki 67 under or equal to 2%), 66% (Ki 67 between 3 and 15%) and 13% (Ki 67 over 15%). The OS at 5 years in patients with SSTR 2/5 positive and Ki 67 under 2% was 86%, 64% in pts. with SSTR 2/5 positive and Ki 67 over 2% and 20 % in pts. with SSTR 2/5 negative, independent Ki 67 (p .0023). Conclusions: The expression of at least one of the SSTRs 2 (a) or 5 was found in 86% and 62% of cases respectivevly in this population. In the population with GEP-NETs under study, a subgroup of patients with a better prognosis was identified in association with the expression of SSTR 2/5 and Ki67 below 2%. The assessment of SSTR 2(a) and 5 in tissues, together with the study of the proliferative index are a useful tool for prognosis assessment in these patients.

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