741 High-grade sinonasal carcinomas and surveillance of differential expression in immune related transcriptome

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A788-A788
Author(s):  
Diana Bell ◽  
Achim Bell ◽  
Renata Ferrarotto ◽  
Ehab Hanna
Keyword(s):  
Gene Expression ◽  
Malignant Tumors ◽  
Tumor Development ◽  
Large Cell ◽  
Cancer Center ◽  
High Grade ◽  
Sinonasal Carcinoma ◽  
Nut Carcinoma ◽  
Immune Oncology ◽  
Neuroendocrine Carcinomas

BackgroundThe skull base is the location of a wide variety of malignant tumors. Among them is sinonasal undifferentiated carcinoma (SNUC), a highly aggressive sinonasal neoplasm that was recently reclassified into subgroups of high-grade carcinomas with unique genomic events (e.g., SMARC-deficient carcinoma, nuclear protein in testis NUT carcinoma). Other high-grade carcinomas in this location are neuroendocrine carcinomas, sinonasal adenocarcinomas, and teratocarcinosarcomas. Given the rarity of these tumors, little transcriptomic data is available. The aim of this study was to characterize the immune-oncology gene expression profile in SNUC and other high-grade sinonasal carcinomas.MethodsNext-generation sequencing was performed in 30 high-grade sinonasal carcinoma samples using the HTG EdgeSeq Precision Immuno-Oncology Panel. Ingenuity pathway analysis was performed to understand the immunobiology, signaling, and functional perturbations during tumor development.ResultsThe samples were divided into 3 groups: 21 SNUCs and SMARC-deficient sinonasal carcinomas; 5 high-grade neuroendocrine carcinomas (HGNECs), with small cell and large cell variants; and 4 high-grade sinonasal carcinomas (HGSNCs) of mixed histology (1 NUT carcinoma, 1 teratocarcinosarcoma, and 2 sinonasal adenocarcinomas). PRAME and ASCL1 emerged as upregulated transcripts with strong protein validation for SNUC and HGNEC; other upregulated candidates EZH2 and BRCA1 offer consideration for alternative targeted therapy, and downregulation of major histocompatibility complex molecules and chemokines represent another hurdle in the development of effective immunotherapy.ConclusionsThis immune-oncology gene expression analysis of 3 groups of high-grade sinonasal carcinoma with emphasis on SNUC identified a number of differentially expressed transcripts reflecting effects on tumorigenesis. Identification of immune pathways should be further investigated for possible integration of immunotherapy into a multidisciplinary approach to these cancers and personalized treatment.Ethics ApprovalMD Anderson Cancer Center Institutional Review Board approval was obtained prior to the start of the study.

scholarly journals Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix

2020 ◽  
Vol 30 (9) ◽  
pp. 1303-1307 ◽  
Author(s):  
Matthew Ryan Carroll ◽  
Preetha Ramalingam ◽  
Gloria Salvo ◽  
Junya Fujimoto ◽  
Luisa Maren Solis Soto ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Large Cell ◽  
Small Cell ◽  
Cancer Center ◽  
High Grade ◽  
Mismatch Repair Proteins ◽  
Parp 1 ◽  
Neuroendocrine Carcinomas

ObjectivesWomen with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease.MethodsSpecimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40–100 moderate, and ≥100 high.ResultsForty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%).ConclusionsPure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

scholarly journals Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3766
Author(s):  
Anna Pellat ◽  
Anne Ségolène Cottereau ◽  
Benoit Terris ◽  
Romain Coriat
Keyword(s):  
Peptide Receptor Radionuclide Therapy ◽  
Large Cell ◽  
Current Data ◽  
World Health ◽  
High Grade ◽  
Ki 67 ◽  
Lung Cancers ◽  
Platinum Based Chemotherapy ◽  
Line Setting ◽  
Neuroendocrine Carcinomas

Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

Comparative Outcomes in Patients With Small- and Large-Cell Neuroendocrine Carcinoma (NEC) and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN) of the Stomach

2020 ◽  
pp. 000313482095000
Author(s):  
Nam Young Choi ◽  
Byung-Sik Kim ◽  
Sung Tae Oh ◽  
Jeong Hwan Yook ◽  
Beom Su Kim
Keyword(s):  
Clinical Outcomes ◽  
Disease Free Survival ◽  
Large Cell ◽  
Small Cell ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Intermediate Grade ◽  
Free Survival ◽  
Neuroendocrine Carcinomas

Background Gastric neuroendocrine carcinomas (NECs), consisting of both large- and small-cell NECs, and mixed adenoneuroendocrine carcinomas (MANECs), including mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), are a group of high-grade malignancies. Few studies to date have reported clinical outcomes, including prognosis, in patients with these tumors. This study therefore evaluated the clinicopathologic outcomes and prognosis in patients with NECs and MANECs. Methods This study included 36 patients diagnosed with gastric NECs, including 23 with large-cell and 13 with small-cell NECs, and 85 with MiNENs, including 70 with high-grade and 15 with intermediate-grade MiNENs. Clinical outcomes, including overall survival (OS) and disease-free survival (DFS), were assessed. Results DFS was significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN ( P < .05), whereas both OS and DFS were similar in patients with NEC and high-grade MiNEN ( P > .05). Patients with large-cell NEC were more likely to undergo aggressive surgery than patients with high-grade MiNEN ( P < .05). Lymphovascular invasion was more frequent and DFS poorer in patients with large-cell than small-cell NECs ( P < .05 each). Conclusion DFS is significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN and significantly lower in patients with large-cell than small-cell NECs.

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 SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Lu Yu ◽  
Yuting Dong ◽  
Jin Xue ◽  
Sanpeng Xu ◽  
Guoping Wang ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Large Cell ◽  
Small Cell ◽  
Specific Marker ◽  
Tumor Type ◽  
High Grade ◽  
Immunohistochemical Expression ◽  
Small Cell Lung ◽  
Sox11 Expression ◽  
Neuroendocrine Carcinomas

Abstract Background Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers. Methods We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs). Results We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs. Conclusions Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.

Expression Patterns of PAX5, c-Met, and Paxillin in Neuroendocrine Tumors of the Lung

2010 ◽  
Vol 134 (11) ◽  
pp. 1702-1705 ◽  
Author(s):  
Jie Song ◽  
Mei Li ◽  
Maria Tretiakova ◽  
Ravi Salgia ◽  
Philip T. Cagle ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Small Cell Lung Carcinoma ◽  
Expression Patterns ◽  
Large Cell ◽  
Tissue Microarrays ◽  
Low Grade ◽  
High Grade ◽  
Tumor Spread ◽  
Cell Lung Carcinoma ◽  
Neuroendocrine Carcinomas

Abstract Context.—c-Met is important in the pathogenesis, invasion, and spread of several forms of lung cancer, and multiple c-Met inhibitors are undergoing clinical trials. PAX5 has been shown to upregulate c-Met in small cell lung carcinoma (SCLC), and coinhibiting PAX5 and c-Met had a synergic effect in killing tumor cells. Paxillin is a downstream target of activated c-Met, and its activation leads to enhanced cell motility and tumor spread. The expression patterns of these functionally related proteins have not, to our knowledge, been systemically studied in neuroendocrine tumors of the lung. Objective.—To investigate the expression patterns of PAX5, paxillin, c-Met, and phosphorylated c-Met in 4 categories of pulmonary neuroendocrine tumors. Design.—Tissue microarrays of 38 typical carcinoids, 6 atypical carcinoids, 34 SCLCs, and 11 large cell neuroendocrine carcinomas were studied with immunohistochemistry. Results.—Most of the 4 tumor types expressed c-Met, phosphorylated c-Met, and paxillin. PAX5 was frequently expressed in atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas but tended to be negative in typical carcinoids. Coexpression of PAX5 with c-Met or phosphorylated c-Met was present in most of the atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas. Significant correlation between PAX5 and paxillin was detected in SCLCs and large cell neuroendocrine carcinomas but not in carcinoid tumors. Conclusions.—The frequent coexpression of PAX5 with c-Met or phosphorylated c-Met in intermediate-grade and high-grade neuroendocrine tumors supports the therapeutic strategy of coinhibiting these proteins. The discrepancy between high-grade and low-grade neuroendocrine tumors in PAX5/paxillin expression correlation may be due to the different underlying molecular genetics of these tumors.

Carcinoids and High-Grade Neuroendocrine Carcinomas of the Ampulla of Vater: A Comparative Analysis of 139 Cases From the Surveillance, Epidemiology, and End Results Program—A Population Based Study

2010 ◽  
Vol 134 (11) ◽  
pp. 1692-1696 ◽  
Author(s):  
Jorge Albores-Saavedra ◽  
Alexandra Hart ◽  
Fredy Chablé-Montero ◽  
Donald E. Henson
Keyword(s):  
Survival Rates ◽  
Relative Survival ◽  
Large Cell ◽  
Ampulla Of Vater ◽  
Population Based ◽  
Carcinoid Tumors ◽  
Malignant Neoplasms ◽  
High Grade ◽  
Neuroendocrine Carcinomas ◽  
End Results

Abstract Context.—Neuroendocrine tumors of the ampulla of Vater constitute a heterogeneous group of neoplasms clinically and morphologically. Because they are rare, little is known about their demographics and biologic behavior. Objective.—To analyze the demographics and the 5- and 10-year relative survival rates of 139 patients with carcinoid tumors and high-grade neuroendocrine carcinomas of the ampulla. Design.—Using data from National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program from 1973 to 2006, we analyzed the demographics, morphology, and survival of patients with carcinoids and neuroendocrine carcinomas of the ampulla. Results.—SEER recorded 6081 cases of malignant neoplasms of the ampulla, of which 82 were carcinoid tumors and 57 were high-grade neuroendocrine carcinomas. Of these 57, 42 were neuroendocrine carcinomas, not otherwise specified; 9 were small cell carcinomas; and 6 were large cell neuroendocrine carcinomas. The incidence was higher in men than in women. Patients with carcinoid tumors were younger (mean age, 61.6 years) than those with high-grade neuroendocrine carcinomas (mean age, 67.5 years). Carcinoid tumors were smaller than high-grade neuroendocrine carcinomas. The frequency of lymph node metastasis was 28.5% for carcinoid tumors and 62% for high-grade neuroendocrine carcinomas. The 5- and 10-year relative survival rates of patients with carcinoid tumors were 82% and 71%, respectively. The 5- and 10-year relative survival rate of patients with high-grade neuroendocrine carcinomas was 15.7%. Conclusions.—Carcinoids of the ampulla of Vater are relatively rare. Carcinoids and high-grade neuroendocrine carcinomas of the ampulla are biologically and clinically similar to these tumors arising in other sites. Carcinoids were smaller and metastasized less frequently than high-grade neuroendocrine carcinomas.

scholarly journals mASH1 is Highly Specific for Neuroendocrine Carcinomas: An Immunohistochemical Evaluation on Normal and Various Neoplastic Tissues

2016 ◽  
Vol 141 (2) ◽  
pp. 288-292 ◽  
Author(s):  
David Altree-Tacha ◽  
Jillian Tyrrell ◽  
Faqian Li
Keyword(s):  
Cell Layer ◽  
Granular Cell ◽  
Large Cell ◽  
Nuclear Staining ◽  
High Grade ◽  
Lung Cancers ◽  
Normal Tissues ◽  
Specificity And Sensitivity ◽  
Neuroendocrine Carcinomas ◽  
Neoplastic Tissues

Context.—High-grade neuroendocrine carcinomas and carcinoids can arise in different sites such as lung, gastrointestinal tract, prostate, and skin. Classic neuroendocrine markers such as CD56, synaptophysin, and chromogranin cannot distinguish carcinoids from high-grade neuroendocrine carcinomas. Recently, mouse monoclonal mASH1 has been shown to help discriminate carcinoids from high-grade neuroendocrine carcinomas in various neoplastic sites. To date, there have been no comprehensive immunohistochemistry studies with mASH1 on nonneuroendocrine neoplasms. Objective.—To evaluate the specificity and sensitivity of mASH1 in various normal and neoplastic tissues, including lung cancers. Design.—Formalin-fixed, paraffin-embedded tissue microarrays consisting of normal tissues and various neoplastic tissues were immunohistochemically evaluated with mASH1. Results.—In normal tissues (n = 30), mASH1 (nuclear staining) was sparsely expressed in the molecular cell layer, white matter, and granular cell layer of cerebellum; C cells in thyroid; and epithelial cells in thymus. In lung cancers, mASH1 stained 1.1% (1 of 93) of adenocarcinomas, 0.9% (1 of 111) of squamous cell carcinomas, 0% (0 of 30) of large cell carcinomas, 66.7% (6 of 9) of large cell neuroendocrine carcinomas, and 82.5% (94 of 114) of small cell carcinomas. In various other neoplastic tissues (n = 1114), mASH1 was expressed in thyroid medullary carcinomas, thymic carcinomas, and brain cancers; mASH1 was also expressed in a very low percentage of breast carcinomas, ovarian cancers, and pancreatic neuroendocrine tumors. All typical carcinoids of various sites were negative (0 of 11), however, in lung atypical carcinoids, mASH1 was expressed in 42.9% (9 of 21). Conclusions.—Although not organ specific, mASH1 is highly specific for high-grade neuroendocrine carcinomas versus carcinoids and other nonneuroendocrine neoplasms.

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