Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin

2019 ◽  
Vol 110 (7-8) ◽  
pp. 616-629 ◽  
Author(s):  
Adele Busico ◽  
Patrick Maisonneuve ◽  
Natalie Prinzi ◽  
Sara Pusceddu ◽  
Giovanni Centonze ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Tumor Infiltrating Lymphocytes ◽  
Labeling Index ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Ki 67 ◽  
Targeted Next Generation Sequencing ◽  
Net G3 ◽  
Infiltrating Lymphocytes ◽  
Two Sides

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2–89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9–169, p = 0.0007). Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.

scholarly journals Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Danian Dai ◽  
Lili Liu ◽  
He Huang ◽  
Shangqiu Chen ◽  
Bo Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Menopausal Status ◽  
Tumor Infiltrating Lymphocytes ◽  
Roc Curves ◽  
Clinicopathological Characteristics ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Ki 67 ◽  
Infiltrating Lymphocytes

BackgroundTumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC).MethodsThe clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots.ResultsMenopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582–0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636–0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659–0.801).ConclusionMenopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.

scholarly journals Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 10 (8) ◽  
pp. 1741
Author(s):  
Giovanni Centonze ◽  
Vincenzo Lagano ◽  
Giovanna Sabella ◽  
Alessandro Mangogna ◽  
Giovanna Garzone ◽  
...  
Keyword(s):  
T Cell ◽  
Multivariable Analysis ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Immune Markers ◽  
Cancer Specific Survival ◽  
Ki 67 ◽  
Clinical Databases ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

scholarly journals PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

2020 ◽  
Vol 27 (3) ◽  
pp. R67-R77 ◽  
Author(s):  
Halfdan Sorbye ◽  
Grace Kong ◽  
Simona Grozinsky-Glasberg
Keyword(s):  
Residual Disease ◽  
Somatostatin Receptor ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Receptor Imaging ◽  
High Grade ◽  
Ki 67 ◽  
Free Survival ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31–41%) and disease control rates (69–78%). Progression-free survival (11–16 months) and survival (22–46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21–55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

scholarly journals High expression of E-cadherin and Ki-67 associated with functional/dysfunctional phenotypes of tumor-infiltrating lymphocytes among Chinese patients with operable breast cancer

2018 ◽  
Vol 46 (12) ◽  
pp. 5219-5227 ◽  
Author(s):  
Ruibin Wang ◽  
Feng Shi ◽  
Lin Zhao ◽  
Yanjie Zhao ◽  
Guangjiang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Cross Sectional Study ◽  
Clinicopathological Features ◽  
Chinese Patients ◽  
Ki 67 ◽  
Cross Sectional ◽  
Cell Counts ◽  
Infiltrating Lymphocytes ◽  
E Cadherin

Objective Breast cancer has become the most common cancer in women in China, and the clinicopathological features differ from those in Western patients. This study was performed to investigate the distribution of programmed cell death protein 1 (PD-1)+/PD-1− tumor-infiltrating lymphocytes (TILs) and its association with clinicopathological features among Chinese patients with breast cancer. Methods In total, 133 consecutive patients with primary breast cancer were recruited into this cross-sectional study from 2012 to 2013. TILs were measured by cell counts under high-power fields (HPFs). Immunohistochemistry was used to detect PD-1 expression on tumor-infiltrating lymphocytes in the microenvironment. Results The median cell counts of the overall TILs, PD-1+ TILs, and PD-1− TILs were 80, 18, and 55/HPF, respectively. The number of PD-1− TILs was significantly lower in older than younger patients (50 vs. 60/HPF). Patients with positive E-cadherin expression had more PD-1− TILs than patients with negative E-cadherin expression (57 vs. 27/HPF). The Ki-67 index was positively correlated with the cell counts of PD-1+ TILs, and the correlation coefficient was 0.29. Conclusions PD-1 expression on TILs had different clinicopathological features in Chinese patients with breast cancer. E-Cadherin expression was associated with PD-1− TILs; however, Ki-67 expression was associated with PD-1+ TILs.

scholarly journals Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

JAMA Oncology ◽  
2017 ◽  
Vol 3 (12) ◽  
pp. e173290 ◽  
Author(s):  
◽  
Ellen L. Goode ◽  
Matthew S. Block ◽  
Kimberly R. Kalli ◽  
Robert A. Vierkant ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Survival Time ◽  
Dose Response ◽  
Tumor Infiltrating Lymphocytes ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Infiltrating Lymphocytes

scholarly journals Cell Counts, rather than Proportion, of CD8/PD-1 Tumor-Infiltrating Lymphocytes in a Tumor Microenvironment Associated with Pathological Characteristics of Chinese Invasive Ductal Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Qingkun Song ◽  
Feng Shi ◽  
Maya Adair ◽  
Hong Chang ◽  
Xiudong Guan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Axillary Lymph Node ◽  
Tumor Infiltrating Lymphocytes ◽  
Axillary Lymph Node Metastasis ◽  
Axillary Lymph ◽  
Ki 67 ◽  
Invasive Ductal Breast Cancer ◽  
Cell Counts ◽  
Infiltrating Lymphocytes

Objective. This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods. 133 patients diagnosed with primary invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results. The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, p<0.05). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, p<0.05). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (p<0.05), respectively. Conclusion. The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer.

scholarly journals The association between tumor-infiltrating lymphocytes (TILs) and metastatic course in neuroendocrine neoplasms

Surgery ◽  
2016 ◽  
Vol 160 (6) ◽  
pp. 1709 ◽  
Author(s):  
Luca Roncati ◽  
Antonio Manenti ◽  
Alberto Farinetti ◽  
Teresa Pusiol
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Neuroendocrine Neoplasms ◽  
Infiltrating Lymphocytes
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