scholarly journals Prognostic value of PD-L1 expression in bronchopulmonary neuroendocrine tumours

2021 ◽  
Author(s):  
Erik Rösner ◽  
Daniel Kaemmerer ◽  
Elisa Neubauer ◽  
Jörg Sänger ◽  
Amelie Lupp
Keyword(s):  
Somatostatin Receptor ◽  
Distant Metastases ◽  
Large Cell ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Typical Carcinoid ◽  
Tumour Grading ◽  
Expression Levels ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

Programmed death protein 1 (PD-1) and its ligand, PD-L1, have emerged as promising therapeutic targets for many types of cancer that overexpress PD-L1. However, data on PD-L1 expression levels in bronchopulmonary neuroendocrine neoplasms (BP-NEN) are limited and contradictory. In the present study, a total of 298 archived, formalin-fixed, paraffin-embedded BP-NEN samples from 97 patients diagnosed with typical carcinoid (TC), atypical carcinoid (AC), small cell lung cancer (SCLC), or large cell neuroendocrine carcinoma of the lung (LCNEC) were evaluated for PD-L1 expression by immunohistochemistry using the highly sensitive monoclonal anti-PD-L1 antibody 73-10. PD-L1 expression levels were semiquantitatively estimated by tumour grading. Of the 298 BP-NEN samples, 85% were positive for PD-L1 expression. PD-L1 immunostaining predominantly localized to the plasma membrane of both tumour cells and tumour-infiltrating immune cells. SCLC and LCNEC exhibited significantly higher PD-L1 expression levels than TC or AC. PD-L1 expression levels were also higher in patients with lymph node or distant metastases, in patients who smoked, and in patients who died during the follow-up period. Moreover, PD-L1 expression levels correlated positively with tumour grading, Ki-67 index and the expression of the chemokine receptor CXCR4 and negatively with the levels of somatostatin receptor 1 and chromogranin A. High tumour PD-L1 levels were associated with poor patient outcomes. In conclusion, PD-L1 expression is common in BP-NEN, increases with malignancy, and is associated with poor prognosis. Therefore, targeting the PD-1/PD-L1 axis could be a promising strategy for treating BP-NEN. PD-L1 may also represent a useful prognostic biomarker for this tumour entity.

Antitumor immune response is associated with favorable survival in GEP-NEN G3

2021 ◽  
Vol 28 (10) ◽  
pp. 683-693
Author(s):  
Vivian Rosery ◽  
Henning Reis ◽  
Konstantinos Savvatakis ◽  
Bernd Kowall ◽  
Martin Stuschke ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Spatial Interaction ◽  
Antitumor Immune Response ◽  
Cytotoxic T Cell ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Tissue Samples ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.

scholarly journals TERT promoter mutations in penile squamous cell carcinoma: high frequency in non-HPV-related type and association with favorable clinicopathologic features

2021 ◽  
Vol 147 (4) ◽  
pp. 1125-1135
Author(s):  
Sang Kyum Kim ◽  
Jang-Hee Kim ◽  
Jae Ho Han ◽  
Nam Hoon Cho ◽  
Se Joong Kim ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Malignant Neoplasm ◽  
Clinicopathologic Features ◽  
Ki 67 ◽  
Tissue Samples ◽  
Formalin Fixed Paraffin ◽  
Tert Promoter Mutations ◽  
Formalin Fixed Paraffin Embedded ◽  
Penile Squamous Cell Carcinoma ◽  
Promoter Mutations

Abstract Purpose Penile carcinoma is a rare malignant neoplasm with a largely unknown molecular pathogenesis. Telomerase reverse transcriptase promoter (TERT-p) mutations have been detected in several types of human malignancies. The aim of this study was to investigate the presence of TERT-p mutations in penile squamous cell carcinomas (SCCs) and their associations with clinicopathologic features. Methods In this retrospective study, Sanger sequencing was performed to detect TERT-p mutations in formalin-fixed paraffin-embedded tissue samples from 37 patients with penile SCC, 16 patients with cutaneous SCC, and 4 patients with non-neoplastic penile/skin tissue. The expression of p16INK4a and Ki-67 was investigated via immunohistochemistry. Associations of TERT-p mutation with clinicopathological factors, immunohistochemical results, and clinical outcome were statistically analyzed. Results Recurrent TERT-p mutations were identified in 18 out of 37 (48.6%) penile SCCs, including all 3 carcinoma in situ cases. TERT-p mutations were significantly more frequent in non-human papilloma virus (HPV)-related penile SCC types than in non-HPV-related penile SCC based on both histologic classification and p16INK4a immunoreactivity. Furthermore, TERT-p mutation was associated with a low histologic grade, low mitotic count, absence of necrosis, low Ki-67/MIB-1 labeling index, and absence of lymph node or distant metastasis. Conclusion Our study shows TERT-p mutations are the most frequent somatic mutations in penile SCC. In addition, TERT-p mutations are far more frequent in non-HPV-related penile SCC than in HPV-related penile SCC, indicating TERT-p mutations may have a role in tumorigenesis distinct from HPV-related penile SCC.

Expression of proliferation genes in formalin-fixed paraffin-embedded (FFPE) tissue from breast carcinomas. Feasibility and relevance for a routine histopathology laboratory

2016 ◽  
Vol 70 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Carla Thomas ◽  
Cleo Robinson ◽  
Ben Dessauvagie ◽  
Benjamin Wood ◽  
Greg Sterrett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Breast Carcinoma ◽  
Expression Profiling ◽  
Proliferative Activity ◽  
Breast Cancers ◽  
Breast Carcinomas ◽  
Ki 67 ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Formalin Fixed

AimBreast carcinoma proliferative activity, histological grade and commercial molecular tests are all important in prognostication and treatment. There is a particular need for improved, standardised techniques for subclassification of grade 2 breast cancers into low-risk and high-risk prognostic groups. In this study we investigated whether gene expression profiling of five proliferation genes was feasible using breast cancer tissue in a clinical setting and whether these profiles could enhance pathological assessment.MethodsExpression of five proliferation gene mRNAs; Ki-67, STK 15, CCNB1, CCND1 and MYBL2, was quantified in 27 breast carcinomas and compared with Ki-67 proliferation index (PI) and Nottingham mitotic score.ResultsExpression of Ki-67, STK15 and MYBL2 mRNA showed moderate Spearman's correlation with Ki-67 PI (p<0.01), but CCND1 and CCNB1 showed weak, non-significant correlation. Individual gene expression did not associate with mitotic score but combined mRNA expression correlated with both Ki-67 PI (p=0.018) and mitotic score (p=0.03; 0.007).ConclusionsThis study confirms mRNA analysis in breast carcinoma formalin-fixed, paraffin-embedded samples is feasible and suggests gene expression profiling, using a small set of five proliferation genes, has potential in aiding histological grading or assessment of proliferative activity of breast cancers. To fully evaluate the clinical applicability of this approach, a larger cohort study with long-term follow-up data is required.

scholarly journals The Correlations Between the Expression of SSTR2, SSTR5 Proteins and Clinicopathological Parameters as well as Prognosis of Gastric Neuroendocrine Neoplasms

2020 ◽  
Author(s):  
Yanwei Ye ◽  
Chuangfeng Xiao ◽  
Yingze Li ◽  
YiMing Shan ◽  
Jie Li ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Tumor Grade ◽  
Neuroendocrine Neoplasm ◽  
Clinicopathological Parameters ◽  
Neuroendocrine Neoplasms ◽  
P Value ◽  
Ki 67 ◽  
Positive Group ◽  
Expression Rate ◽  
Normal Stomach

Abstract Background： Somatostatin receptor 2, 5 (SSTR2, SSTR5) were seldom investigated in gastric neuroendocrine neoplasms (G-NENs). The purpose of the study was to elucidate the expression of SSTR2, SSTR5 in G-NENs and related clinical significance.Methods： 66 paraffin-embedded specimens were obtained from The first affiliated hospital of Zhengzhou university. The expression of SSTR2 and SSTR5 was detected by immunohistochemistry. The expression of SSTR2, SSTR5 and the clinicopathological characteristics, related immunohistochemical molecules and prognosis of gastric neuroendocrine neoplasm were analyzed statistically.Results： The expression rate of SSTR2 protein in G-NENs tissues and normal stomach tissues was 48.5% and 25.0%, respectively (P=0.046); the expression rate of SSTR5 protein in G-NENs tissues and normal stomach tissues was 65.2% and 25.0% , respectively (P=0.018). The expression of SSTR2 was positively correlated with the expression of Ki-67, SSTR5 and tumor grade (P-value was 0.032, 0.002, and 0.005, respectively); the expression of SSTR5 was positively correlated with the expression of SSTR2, Ki-67, CD-56 and tumor grade (P-value was 0.032, 0.011, 0.008, 0.028, respectively). In the SSTR2-positive group, SSTR5, CD-56, Ki-67 were closely related to the prognosis of patients with G-NENs. In the SSTR5-positive group, tumor grade, SSTR2, CD-56, Ki-67 were closely related to the prognosis of patients with G-NENs. Multi-factor analysis showed that SSTR2 and SSTR5 were independent prognostic factors for patients with G-NENs. Conclusion. High expression of SSTR2 and SSTR5 protein was related to the tumorigenesis of G-NENs. SSTR2 and SSTR5 were associated with the prognosis and might improve the prognosis of G-NENs.

scholarly journals Expression of p53, p63, podoplanin and Ki-67 in recurring versus non-recurring oral leukoplakia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jonas Sundberg ◽  
Sushma Pandey ◽  
Daniel Giglio ◽  
Erik Holmberg ◽  
Göran Kjeller ◽  
...  
Keyword(s):  
Cox Regression ◽  
Prognostic Significance ◽  
Recurrence Risk ◽  
Oral Leukoplakia ◽  
Surgical Removal ◽  
Ki 67 ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Potentially Malignant ◽  
A Prospective Study

AbstractOral leukoplakia (OL), a potentially malignant disorder, recurs in 40% of cases after surgical removal. Recurrence is a risk factor for malignant transformation. We aimed to examine the prognostic significance of four biomarkers related to cell proliferation: p53, p63, podoplanin (PDPN) and Ki-67 in predicting recurrence. Formalin-fixed-paraffin-embedded specimens from excised OL (n = 73, 33 recurrent; 40 non-recurrent) were collected in a prospective study. Immunohistochemistry was used to visualise expression of p53, p63, PDPN and Ki-67. Image analysis software was used for quantification of p53-, p63- and Ki-67-expressing cells, while PDPN was analysed visually. The expression of all four proteins were higher in recurrent compared with non-recurrent OL, only expression of p53 was statistically significant. In uni- and multivariable Cox regression analyses of individual markers, expression of p63 was significantly associated with higher recurrence risk (p = 0.047). OL with a combined high expression of both p53 and p63 had a significantly higher risk to recur [Log Rank, p = 0.036; multivariate Cox, HR: 2.48 (1.13–5.44; p = 0.024)]. Combination of p53 and p63 expression may be used as a prognostic biomarker for recurrence of OL.

scholarly journals Expression of miR-15b-5p, miR-21-5p, and SMAD7 in Lung Tissue of Sulfur Mustard-exposedIndividuals with Long-term Pulmonary Complications

2019 ◽  
Author(s):  
Sahar Salimi ◽  
Farshid Noorbakhsh ◽  
Soghrat Faghihzadeh ◽  
Sara Ghaffarpour ◽  
Tooba Ghazanfari
Keyword(s):  
Lung Tissue ◽  
Inflammatory Responses ◽  
Sulfur Mustard ◽  
Pulmonary Complications ◽  
Cytokine Signaling ◽  
Control Group ◽  
Expression Levels ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Smad7 Expression

Sulfur mustard (SM)-exposed individuals develop late pulmonary complications, which are associated with chronic inflammation and fibrotic changes in the lung tissue. MicroRNAs are known to act as important regulators of inflammatory responses, including inflammation and fibrosis-related cytokine signaling. In this study, we investigated the expression miR-15b-5p and miR-21-5p, two regulators of TGF-β signaling, as well as their target molecule, SMAD7, in lung tissues from SM-exposed and control individuals. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) lung tissue biopsies obtained during surgery from SM-exposed (n=20) or control (n=20) cases. Quality of the extracted RNA was evaluated by an Agilent Bioanalyzer and RNA was quantified using a NanoDrop. MiR-21-5p, miR-15b-5p and SMAD7 expression levels were measured by real-time RT-PCR.miR-21-5p expression levels were significantly decreased (2.7 fold) in the lung tissues from SM-exposed individuals compared with tissues obtained from the control group(p=0.02). There were no significant differences in miR-15b-5p expression levels between the two groups(p=0.94). Interestingly, SMAD7 expression levels were significantly higher (5.8 fold) in SM-exposed individuals’ lung tissues compared with the control group(p=0.045).Our data indicate that exposure to sulfur mustard affects the expression of miR-21-5p as well as its target, SMAD7, in lung tissues many years after exposure. Considering the role of SMAD7 in the regulation of TGF-β signaling, these changes might point to a potential mechanism by which SM-exposure regulates inflammatory/fibrotic alterations in lung tissue.

scholarly journals Neuroendocrine neoplasms of kidney

2020 ◽  
pp. 47-51
Author(s):  
D. V. Abbasova ◽  
S. B. Polikarpova ◽  
A. A. Markovich ◽  
V. Yu. Kirsanov ◽  
N. A. Kozlov
Keyword(s):  
Cell Cancer ◽  
Large Cell ◽  
Research Centre ◽  
Neuroendocrine Neoplasms ◽  
Malignant Neoplasms ◽  
Ki 67 ◽  
True Incidence ◽  
National Medical ◽  
Anatomical Localization ◽  
Total Proportion

The most common anatomical localization of neuroendocrine neoplasms (NEN) are the digestive and bronchopulmonary systems, the total proportion of which exceeds 90 % of cases of this group of tumors. In turn, the remaining cases are represented by extremely rare primary neuroendocrine neoplasms of the head and neck, skin, female genital organs, mammary gland, bladder and kidney. Due to the extremely rare observations and the lack of standardized approaches to the diagnosis and treatment of neuroendocrine neoplasms of the kidneys are of significant clinical interest. The true incidence of NENs of the kidney has not yet been established. We carried out a retrospective analysis of patients undergoing treatment in National Medical Research Centre of Oncology n. a. N. N. Blokhin (Moscow, Russia) from 1992 to 2015. According to the results of a sample of patients among registered 12,013 cases of malignant neoplasms of the kidney with NEN of the kidney, the number of morphologically verified cases of NEN of the kidney was 9 cases (0.07 %). Among the patients included in the study group, the main part was represented by highly differentiated neuroendocrine tumors (7 cases; 77.8 %), small cell cancer (1 case; 11.1 %), large cell neuroendocrine cancer (1 case; 11.1 %). The average age of the patients was 51 years (40–63 years; median – 55 years), among which there were 4 women and 5 men. In addition, we conducted an analysis of the clinical, morphological and molecular biological characteristics of tumors with the study and assessment of the grade Ki-67, which was a determining factor in predicting survival and choosing treatment tactics.

scholarly journals Are G3 ENETS neuroendocrine neoplasms heterogeneous?

2013 ◽  
Vol 20 (5) ◽  
pp. 649-657 ◽  
Author(s):  
Fritz-Line Vélayoudom-Céphise ◽  
Pierre Duvillard ◽  
Lydia Foucan ◽  
Julien Hadoux ◽  
Cecile N Chougnet ◽  
...  
Keyword(s):  
Mitotic Index ◽  
Somatostatin Receptor ◽  
Neuron Specific Enolase ◽  
Morphological Differentiation ◽  
Large Cell ◽  
Cell Types ◽  
Small Cell ◽  
Neuroendocrine Neoplasms ◽  
Cell Type ◽  
Poorly Differentiated

The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.

Immunohistochemical Expression of Estrogen and Progesterone Receptors in Primary Pulmonary Neuroendocrine Tumors

2008 ◽  
Vol 132 (12) ◽  
pp. 1889-1895
Author(s):  
Gabriel Sica ◽  
Patrick L. Wagner ◽  
Nassar Altorki ◽  
Jeffrey Port ◽  
Paul C. Lee ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Neuroendocrine Tumors ◽  
Progesterone Receptors ◽  
Large Cell ◽  
Small Cell ◽  
Neuroendocrine Neoplasms ◽  
Typical Carcinoid ◽  
Combined Small Cell Carcinoma ◽  
Estrogen And Progesterone Receptor

Abstract Context.—Lung and breast carcinomas are among the most prevalent cancers. Advances in cancer therapies can provide survival benefit and be potentially curative, even in metastatic disease. Due to the high prevalence of these carcinomas, it is not unusual to encounter lung nodule(s) in a patient with breast carcinoma, and distinguishing between primary and metastatic disease is critical for management/treatment. Occasionally neuroendocrine differentiation is present in breast carcinoma, making its distinction from pulmonary/nonpulmonary neuroendocrine tumors in the lung difficult. Objective.—To assess estrogen and progesterone receptor expression in the entire spectrum of pulmonary neuroendocrine tumors. Design.—Seventy-one neuroendocrine neoplasms including typical carcinoids (42), atypical carcinoids (7), small cell carcinomas (14), large cell neuroendocrine carcinomas (2), and combined small cell carcinomas (6) were evaluated for estrogen and progesterone receptors. Mammary and non–small cell lung carcinomas were also stained for comparison. Results.—The entire spectrum of neuroendocrine neoplasms demonstrated focal to diffuse estrogen (typical carcinoid, 23; atypical carcinoid, 6; small cell carcinoma, 8; large cell neuroendocrine carcinoma, 2; combined small cell carcinoma, 4) and progesterone (typical carcinoid, 11; atypical carcinoid, 2; small cell carcinoma, 7; large cell neuroendocrine carcinoma, 0; combined small cell carcinoma, 2) expression. There was no correlation between sex and estrogen/progesterone status. Estrogen and progesterone staining were also noted in endothelial cells. Relative to neuroendocrine carcinomas, mammary carcinomas expressed estrogen and progesterone more frequently. Non–small cell carcinomas had greater and similar immunoreactivity for estrogen and progesterone, respectively. Conclusions.—Although estrogen and progesterone receptor staining is frequently associated with breast and gynecologic primaries, it can also be observed in “nontarget” organs. Therefore, presence of estrogen and/or progesterone expression in neuroendocrine tumors involving the lung should not exclude a primary pulmonary neoplasm.

Sign in / Sign up

Export Citation Format

Share Document