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1.
BMC Pulm Med ; 23(1): 12, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635639

RESUMO

BACKGROUND: Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan-Meier analyses were applied to assess different therapy modalities. RESULTS: A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60-79 (OR 0.57; 95% CI 0.41-0.78; p < 0.001), age ≥ 80 (OR 0.23; 95% CI 0.12-0.45; p < 0.001) and bone metastases (OR 1.75; 95% CI 1.22-2.51; p < 0.001) as significant independent predictors for developing SBM. Multivariable Cox regression revealed that age 60-79, T stage, bone metastases and chemotherapy were independent prognostic factor for OS. The surgery combined with chemotherapy and radiotherapy group, in which all patients were N0 stage and had no other site-specific metastases, exhibited the best median OS of 15 months. CONCLUSIONS: LCC patients with age < 60 or bone metastases were more likely to have SBM at initial diagnosis. Age, T stage, bone metastases and chemotherapy were independent prognostic factors for OS of LCC patients with SBM. Highly selected patients might achieve the best survival benefit from surgery combined with chemotherapy and radiotherapy.


Assuntos
Neoplasias Encefálicas , Carcinoma de Células Grandes , Humanos , Pessoa de Meia-Idade , Idoso , Incidência , Prognóstico , Estimativa de Kaplan-Meier , Neoplasias Encefálicas/terapia
2.
Pathol Oncol Res ; 28: 1610747, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36507119

RESUMO

Pulmonary combined large-cell neuroendocrine carcinoma (CLCNEC) is a rare neuroendocrine tumor pertained to lung large cell neuroendocrine carcinoma (LCNEC) with aggressive behavior and poor prognosis generally. The clinical features of CLCNEC are not specific including cough, expectoration, chest distress, chest pain, etc., which are prone to have different manifestations of the mixed components. Owing to the low incidence, there are few related small-scale retrospective studies and case reports. Currently, the treatment regimen of CLCNEC mainly refers to LCNEC that complete surgical resection is preferred in the early stage and according to previous researches, platinum-based small cell lung cancer (SCLC) standard treatment regimen showed promising results in postoperative and advanced CLCNEC as compared to that of non-small cell lung cancer (NSCLC). Adenocarcinoma-CLCNEC more likely harbor driver gene mutation, and may benefit from targeted therapy. As for immunotherapy, more clinical trial data are needed to support its benefits. This article will fill the gap and will provide new insight into the clinical characteristics, pathological diagnosis and treatment endeavors of CLCNEC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/terapia
3.
Cell Death Dis ; 13(11): 979, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402755

RESUMO

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited "lineage ambiguity" as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma de Células Grandes/genética , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Escamosas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição Forkhead
4.
Pathol Oncol Res ; 28: 1610730, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36304941

RESUMO

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare subtype of malignant pulmonary tumor. The incidence rate of LCNEC was reported to be 0.3%-3% in lung cancers. Although LCNEC is classified as non-small cell lung cancer (NSCLC), it is more aggressive and malignant than other NSCLC, and its biological behavior is similar to that of small cell lung cancer (SCLC). Most of the LCNEC patients are elderly smoking male and the clinical manifestations are not specific. The imaging manifestations of the tumors are often located in the periphery and the upper lobes, and the enlargement of mediastinal or hilar lymph nodes is common. The diagnosis is mainly based on pathology by the histological features and immunohistochemistry (IHC). Specific neuroendocrine markers such as chromogranin A (CgA), synaptophysin (Syn) and CD56 are usually diffusely positive in LCNEC, and found that insulinoma-associated protein (INSM1) and high rate of Ki-67 are helpful for diagnosis. More differential diagnoses also increase the difficulty of correctly diagnosing LCNEC. The rise of LCNEC molecular typing in recent years may be helpful for diagnosis and subsequent treatment. This review focuses on the epidemiological features, imaging studies, pathology, diagnosis, treatment, and prognosis of LCNEC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Idoso , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Carcinoma de Células Grandes/epidemiologia , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Biomarcadores Tumorais , Proteínas Repressoras
5.
Sci Rep ; 12(1): 16562, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195623

RESUMO

The optimal systemic treatment of advanced large cell neuroendocrine carcinoma (LCNEC) is still controversial. We intend to explore advanced LCNEC through SEER database, construct nomogram model of advanced LCNEC, and understand the effect of different treatment regimens on LCNEC. We collected 909 patients, divided them into a training set validation set, constructed nomograms using Cox proportional hazards regression models, and evaluated nomogram discrimination and calibration by C-index and calibration curves. Kaplan-Meier will also be used to compare OS in different groups of patients and to explore the impact of different treatment regimens on advanced LCNEC. On the nomogram plotted, the nomogram predicted AUC values over time were always greater than 0.7, the C-index was 0.681 (95% CI 0.656-0.706) and 0.663 (95% CI 0.628-0.698) in the training and validation sets, respectively, and patients were divided into two groups according to risk, and a significant difference in OS was observed between the high-risk and low-risk groups in the training and validation cohorts. Different treatment analyses showed that chemotherapy is still the best treatment for advanced LCNEC. This nomogram provides a convenient and reliable tool for individual assessment and clinical decision-making of patients with advanced LCNEC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Pulmão , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Resultado do Tratamento
6.
Int J Biol Sci ; 18(15): 5913-5927, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36263183

RESUMO

This study aimed to integrate the cell spatial organization to develop a Gal-9-based immune survival stratification in the lung large cell neuroendocrine carcinoma (LCNEC) and investigate its potentials to immunotherapy. The expression of Gal-9 and other twelve immune markers were evaluated in 122 cases of surgical LCNEC samples from our center using immunohistochemistry. The Gal-9-based immune survival stratification risk score was constructed and its predictive performance was evaluated. Then, we thoroughly explored the effects of Gal-9 and immune risk score on LCNEC immune pathways, immune micro-environment and immunotherapy sensitivity in different cohort and platform, and made a validation in pathology images using Histology-based Digital-Staining (HDS). In 122 LCNEC samples, 43 cases were positive Gal-9 expression on tumor cells (Gal-9 TC). Increased Gal-9 TC predicted worse overall survival. Gal-9's interaction with other immune markers added to the immune suppression and immune tolerance in LCNEC. Immune protein marker-based risk score consisting of Gal-9, CD3, CD4, PD-L1, and PD-1 was developed and validated to robustly discriminate survival high-risk or low-risk in LCNEC patients. The high-risk group characterized by immune-desert tumor had less various T cells. The low-risk group featuring immune-inflamed tumor was more likely to respond to anti-PD1 immunotherapy. HDS in 122 LCNEC samples' 108,369 cells validated that the high-risk group had more tumor cells, less stromal cells, less lymphocytes, higher tumor cell nucleic solidity and lower stromal cells nucleic solidity. An integrated pathological analysis confirms the Gal-9 based immune survival stratification is distinctively related to micro-environment status involved in immune suppression and immune tolerance and could act as a combinatorial biomarker to predict the outcome of LCNEC. These findings may help effectively stratify LCNEC patients sensitive to immunotherapy.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1 , Carcinoma de Células Grandes/terapia , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/terapia , Carcinoma Neuroendócrino/metabolismo , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Imunoterapia , Pulmão/metabolismo , Microambiente Tumoral
7.
Thorac Cancer ; 13(19): 2711-2722, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36054506

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is the most malignant and common form of neuroendocrine lung cancer with pure (P-SCLC) and combined subtypes (C-SCLC). However, little is known about the differences between these two groups and in this study we aimed to provide a more comprehensive insight into SCLC. METHODS: Data from 580 postoperative patients with pathologically confirmed SCLC in Shanghai Chest Hospital from January 2010 to December 2020 were collected retrospectively. The clinical characteristics and prognosis were analyzed. RESULTS: A total of 357 P-SCLC patients and 223 C-SCLC patients were included. The results indicated that P-SCLC appeared to have a higher proportion of being located in the middle lobe than C-SCLC. The incidences of P-SCLC in patients with visceral pleural invasion (VPI) and in stage II were higher than C-SCLC, while C-SCLC was more likely to be accompanied by higher incidences of epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and higher levels of CEA, SCCA and CYFRA21-1 than P-SCLC. The most common were SCLC combined with large cell neuroendocrine components among 223 C-SCLCs. Survival analysis confirmed a more favorable disease-free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.024) in patients with P-SCLCs compared with C-SCLCs. Histological type, tumor location, pN stage, adjuvant chemotherapy, serum NSE and CA125 levels were independent risk factors for survival rate in SCLC. In addition, adjuvant chemotherapy was beneficial in improving stage I P-SCLC and C-SCLC DFS and OS rates, and similar results were not seen in adjuvant radiation therapy. CONCLUSIONS: Patients with C-SCLC have a poorer prognosis than P-SCLC patients. We determined that large cell neuroendocrine carcinoma was the most common additional component of C-SCLC, and patients with this component appeared to have a longer DFS and OS than other combined components.


Assuntos
Carcinoma de Células Grandes , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Quinase do Linfoma Anaplásico , Antígenos de Neoplasias , Antígeno Carcinoembrionário , Carcinoma de Células Grandes/patologia , China , Receptores ErbB , Humanos , Queratina-19 , Neoplasias Pulmonares/genética , Prognóstico , Estudos Retrospectivos
8.
Thorac Cancer ; 13(19): 2817-2822, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36064196

RESUMO

Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly progressive tumor with a poor prognosis. Although immune checkpoint inhibitors have been approved for treatment of both small cell and non-small cell lung cancers, their role in the treatment of LCNEC is unclear. We describe a patient with postoperative recurrence of LCNEC who maintained complete remission for 4 years after a single administration of pembrolizumab. A 68-year-old Japanese man underwent thoracoscopic right lower lobectomy for LCNEC (pathological stage pT1bN0M0, stage IA2). Epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 expression rate in tumor cells was 5% (clone 22C3). Eight months later, the patient developed recurrence with mediastinal lymph node metastasis and pleural dissemination. Therefore, chemotherapy with cisplatin and etoposide was administered. However, relapse occurred 6 months later. Pembrolizumab was administered as second-line chemotherapy, which was discontinued after first dose because of interstitial pneumonia 1 month later. Thereafter, however, both the lymph node metastasis and pleural dissemination disappeared and did not relapse for 4 years. Pembrolizumab may be used as a treatment option for pulmonary LCNEC.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Idoso , Quinase do Linfoma Anaplásico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Cisplatino/uso terapêutico , Receptores ErbB/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico
9.
Head Neck ; 44(9): 2055-2062, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35915861

RESUMO

BACKGROUND: Parotid lymphoepithelial carcinoma (LEC) is a rare malignant tumor. The purpose of this study was to investigate the clinicopathological features of parotid LEC. METHODS: All patients clinicopathological information diagnosed parotid LEC from 2005 to 2017 were analyzed. RESULTS: A total of 146 cases of parotid LECs were identified. Of these, 126 (86.3%) were primary and 20 (13.7%) were secondary LECs. Patients with secondary LEC tended to have tumors with earlier TNM staging than those with primary (p = 0.031). The tumor cells in 87 (94.6%, 87/92) cases tested positive for Epstein-Barr virus (EBV). Cervical node metastases were present at diagnosis in 46 (31.5%) cases. Overall survival at 5 and 10 years was 97.0% and 90.8%, respectively. Older age was an adverse prognostic indicator for overall survival (p < 0.001). CONCLUSIONS: Parotid LEC is associated with EBV and an increased rate of cervical node metastases. However, most patients, especially younger ones, have a good prognosis.


Assuntos
Carcinoma de Células Grandes , Carcinoma de Células Escamosas , Infecções por Vírus Epstein-Barr , Neoplasias Parotídeas , Carcinoma de Células Escamosas/patologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Humanos , Glândula Parótida/patologia , Glândula Parótida/cirurgia , Neoplasias Parotídeas/patologia , Neoplasias Parotídeas/cirurgia
10.
Neuroendocrinology ; 112(12): 1214-1224, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35671706

RESUMO

INTRODUCTION: The European Neuroendocrine Tumor Society (ENETS) reports variables of prognostic significance in bronchopulmonary neuroendocrine neoplasms (BP-NENs). The aim of this study was to investigate prognostic factors, recurrence-free survival (RFS), and overall survival (OS) for patients with typical carcinoid (TC), atypical carcinoid (AC), and large-cell neuroendocrine carcinoma (LCNEC). Current follow-up practices vary as the evidence is sparse, and we aimed to explore the relevance of routine bronchoscopy in follow-up. METHODS: This was a cohort study of 208 patients with BP-NENs followed at Aarhus University Hospital in 2008-2019. RFS and OS were determined using the Kaplan-Meier method for the variables such as primary tumor, primary treatment, smoking status, gender, and histological subtypes. RESULTS: The study included 153 patients with TC, 29 with AC, and 26 with LCNEC. Median follow-up was 48 months. The majority of patients (n = 191) received surgical resection, of which 22 (11%) recurred over time. Seventeen patients had nonsurgical treatment, of which 10 (59%) progressed. The 5-year OS rate was 86% for operated and 9% for nonoperated patients (p < 0.05). Patients with TC had a 5-year OS of 90% compared with 63% and 39% for AC and LCNEC, respectively. As for prognostic factors, nonsmokers did not secure a significant difference in OS compared with current/previous smokers (p = 0.51). In the follow-up period, only 2 (9%) of the 22 recurrences were found on a routine bronchoscopy. Both of these recurrences were also found by diagnostic imaging. CONCLUSIONS: Surgical treatment, especially, and diagnosis of TC were associated with a good prognosis. Furthermore, our data did not support routine bronchoscopy as part of a follow-up program for bronchial carcinoids.


Assuntos
Neoplasias Brônquicas , Tumor Carcinoide , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Estudos de Coortes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Tumor Carcinoide/patologia , Prognóstico , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/epidemiologia , Neoplasias Brônquicas/terapia
11.
Histopathology ; 81(5): 556-568, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35758205

RESUMO

Neuroendocrine carcinomas of the lung are currently classified into two categories: small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Diagnostic criteria for small-cell and large-cell neuroendocrine carcinoma are based solely on tumour morphology; however, overlap in histologic and immunophenotypic features between the two types of carcinomas can potentially make their classification challenging. Accurate diagnosis of pulmonary neuroendocrine carcinomas is paramount for patient management, as clinical course and treatment differ between small-cell and large-cell neuroendocrine carcinoma. Molecular-genetic, transcriptomic, and proteomic data published over the past decade suggest that small-cell and large-cell neuroendocrine carcinomas are not homogeneous categories but rather comprise multiple groups of distinctive malignancies. Nuances in the susceptibility of small-cell lung carcinoma subtypes to different chemotherapeutic regimens and the discovery of targetable mutations in large-cell neuroendocrine carcinoma suggest that classification and treatment of neuroendocrine carcinomas may be informed by ancillary molecular and protein expression testing going forward. This review summarizes the current diagnostic criteria, prognostic and predictive correlates of classification, and evidence of previously unrecognised subtypes of small-cell and large-cell neuroendocrine carcinoma.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/diagnóstico , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteômica
12.
Int J Cancer ; 151(9): 1611-1625, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35762443

RESUMO

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adenocarcinoma de Pulmão/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fatores de Crescimento Neural , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
13.
J Thorac Oncol ; 17(9): 1109-1121, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35760287

RESUMO

INTRODUCTION: POU2F3 is a recent marker of a small cell lung carcinoma (SCLC) subtype related to chemosensory tuft cells (SCLC-P). The characteristics of SCLC-P have not been fully defined, and the data on POU2F3 expression in other lung tumors are scarce. METHODS: We screened 254 SCLC for POU2F3 expression and comprehensively analyzed histopathologic, genomic, and clinical characteristics of POU2F3-positive tumors. We also explored POU2F3 expression in other major lung cancer types (n = 433) and a targeted set of potential diagnostic mimics of SCLC (n = 123). RESULTS: POU2F3 was expressed in 30 of 254 (12%) SCLC and was strongly associated with low expression of standard neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1). Notably, POU2F3 was expressed in 75% of SCLC with entirely negative or minimal neuroendocrine marker expression (15/20) and was helpful in supporting the diagnosis of SCLC in such cases. Broad targeted next-generation sequencing revealed that SCLC-P (n = 12) exhibited enrichment in several alterations, including PTEN inactivation, MYC amplifications, and 20q13 amplifications, but similar rates of RB1 and TP53 alterations as other SCLC (n = 155). Beyond SCLC, POU2F3 expression was exclusively limited to large cell neuroendocrine carcinoma (12%) and basaloid squamous cell carcinoma (22%). CONCLUSIONS: This is the largest cohort of SCLC-P clinical samples to date, where we describe the diagnostic utility of POU2F3 in a challenging subset of SCLC with low or absent expression of standard neuroendocrine markers. The distinct genomic alterations in SCLC-P may offer a novel avenue for therapeutic targeting. The role of POU2F3 in a narrow subset of other lung cancer types warrants further study.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais , Genômica , Humanos , Fatores de Transcrição de Octâmero , Proteínas Repressoras
14.
Appl Immunohistochem Mol Morphol ; 30(6): 459-468, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35603802

RESUMO

High-grade neuroendocrine carcinoma (HGNEC) is subclassified into small cell carcinoma (SmCC) and large cell neuroendocrine carcinoma (LCNEC). Although both are clinically aggressive, the SmCC and LCNEC need to have different treatment strategies, and accurate pathologic diagnosis is challenging. We studied a large retrospective cohort (186 cases) of HGNEC of bladder and lung to investigate the abundance of cytokeratin (CK) 7 expression and staining pattern in SmCC and LCNEC. Overall, the pulmonary and urinary HGNEC exhibited several different CK7 staining patterns, including negative staining (n=28), dot-like staining (n=73), partial membranous staining (n=26), and complete membranous staining (n=60). Overall, 88.9% (44/49) of pulmonary SmCC and 88.0% (44/50) of urinary SmCC showed negative or dot-like patterns for CK7, while 90.8% (59/65) of pulmonary LCNEC and 72.7% (16/22) of urinary LCNEC showed partial or complete membranous patterns for CK7 (χ 2 =105.05, P <0.0001). The distinct staining patterns were also present in those mixed SmCC and LCNEC. In addition, the specimen types or fixation did not affect CK7 staining patterns. In conclusion, CK7 has a high differential value for SmCC and LCNEC and could help guide personalized treatment for patients.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/patologia , Humanos , Imuno-Histoquímica , Queratina-7 , Pulmão/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Estudos Retrospectivos
15.
Mod Pathol ; 35(10): 1349-1361, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35590107

RESUMO

Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.


Assuntos
Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Neoplasias da Mama/genética , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Proteínas de Transporte , Proteínas de Ciclo Celular , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Tumores Neuroendócrinos/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/genética
16.
Ann Surg Oncol ; 29(9): 5666-5678, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35543906

RESUMO

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare high-grade neuroendocrine carcinoma of the lung. Little is known about the differences between the pure and combined LCNEC subtypes, and thus we conducted this study to provide more comprehensive insight into LCNEC. METHODS: We reviewed 221 patients with pure LCNEC (P-LCNEC) and 120 patients with combined LCNEC (C-LCNEC) who underwent pulmonary surgery in our hospital to compare their clinical features, driven genes' status (EGFR/ALK/ROS1/KRAS/BRAF), and adjuvant chemotherapy regimens. Propensity score matching (PSM) was applied to reduce selection bias. RESULTS: The P-LCNEC group included a higher proportion of males and smokers than the C-LCNEC group. Furthermore, the C-LCNEC group had higher incidences of visceral pleural invasion (VPI), EGFR mutation and ALK rearrangement compared with the P-LCNEC group. Expression of neuroendocrine markers (CD56, CGA, and SYN) and recurrence patterns were not significantly different between the two groups. The P-LCNEC group had better disease-free survival (DFS) and overall survival (OS) compared with the C-LCNEC group (median DFS: 67.0 vs. 28.1 months, p = 0.021; median OS: 72.0 vs. 45.0 months, p = 0.001), which was further confirmed by the PSM method (p = 0.004 and p < 0.001, respectively). Adjuvant chemotherapy was also an independent factor for DFS and OS. Subgroup analysis found that regardless of whether it was for the entire LCNEC group or the P- and C-LCNEC subtypes, the small cell lung cancer (SCLC) regimens presented with superior survival compared with the non-small cell lung cancer (NSCLC) regimens. CONCLUSION: P-LCNEC was associated with more favorable prognosis compared with C-LCNEC. SCLC-based adjuvant chemotherapy was more appropriate for LCNEC patients than NSCLC-based regimens, regardless of whether they were the pure or combined LCNEC subtypes. C-LCNEC patients may be the potential beneficiary of targeted therapy.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/patologia , Receptores ErbB , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/uso terapêutico , Receptores Proteína Tirosina Quinases/uso terapêutico
17.
Histopathology ; 81(2): 205-214, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35544410

RESUMO

AIMS: Large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC) of lung encompass high-grade neuroendocrine tumour category and share several fundamental features. As both tumours may respond to different treatment modalities and show unique molecular alterations distinction between the two is clinically relevant, but can be challenging due to sampling and fixation issues and shared morphological features. METHODS: Surgically resected primary SCLC (n = 129) and LCNEC (n = 27) were immunohistochemically stained with Rb1, cyclin D1 and p16 using tissue microarray (TMA), and expression patterns of the proteins were compared between the two to identify the discriminatory pattern. RESULTS: All markers had high diagnostic accuracy; Rb1 was the highest followed by p16 and cyclin D1. The majority of SCLC had the pattern Rb1-/p16+/cyclin D1- and more than half of LCNEC had Rb1+/p16-/cyclin D1+. Overall, the expression pattern Rb1- and cyclin D1- was strongly associated with the diagnosis of SCLC, while the pattern Rb1+ and/or cyclin D1+ was strongly associated with LCNEC. The use of this simplified expression pattern leads to a diagnostic accuracy of 97.3%. p16 did not add to further discrimination. The heterogeneity in Rb1, cyclin D1 and p16 expression was insignificant in SCLCs compared with LCNECs. CONCLUSIONS: Use of Rb1, cyclin D1 and p16 immunohistochemistry can distinguish the two with high accuracy. Notably, the Rb1-/cyclin D1- pattern in given tumour sample would confirm the diagnosis of SCLC. Our results could be extrapolated and applied to routine diagnostic samples such as biopsies and cytology samples.


Assuntos
Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/patologia , Ciclina D1/metabolismo , Genes p16 , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/patologia , Proteínas de Ligação a Retinoblastoma/metabolismo , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina-Proteína Ligases/metabolismo
18.
Biomed Pharmacother ; 151: 113128, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35609368

RESUMO

The haskap (Lonicera caerulea L., Caprifoliaceae) berry has been widely used in traditional medicine in Kuril Islands, Russia, Japan, and China. Cyanidin-3-O-glucoside (C3G) is the most abundant anthocyanin in haskap berries, and C3G induces antiproliferative pharmacological activity in various cancer cells. However, no study has investigated its anti-lung large-cell carcinoma (LCC) pharmacological role. Therefore, this study determined whether C3G alone or C3G combined with 5-fluorouracil (5-FU) inhibits human lung LCC. We determined the tumor growth, apoptosis, inflammation, and metastasis in the H661 lung LCC lines xenografted into BALB/c nude mice. The mice were administered saline (control), 5-FU, C3G, or both C3G and 5-FU. Relative to the control mice, those treated with C3G alone or both C3G and 5-FU exhibited impaired tumor growth; increased tumor apoptosis; decreased inflammatory cytokine levels (e.g., IL-1ß, TNF-α, C-reactive protein, and IL-6); decreased inflammation-related factors, including cyclooxygenase-2 protein and nuclear factor-κB (NF-κB) mRNA; increased inhibition of NF-κB kinase α mRNA; and downregulated metastasis-related factors, such as transforming growth factor-ß, CD44, epidermal growth factor receptor, and vascular endothelial growth factor. In addition, C3G alone or combined with 5-FU affected the expression of the tumor microenvironment-related factors Ki67, CD45, PDL1, and CD73. Compared with the mice treated with 5-FU or C3G alone, those treated with both C3G and 5-FU exhibited significantly impaired tumor growth, decreased tumor sizes, and increased tumor inhibition. This in vivo study demonstrated that C3G alone or combined with 5-FU may impair the growth of lung LCC and inhibit tumorigenesis. The findings indicate that C3G alone or C3G combined with 5-FU may be beneficial for treating human lung LCC.


Assuntos
Antocianinas , Carcinoma de Células Grandes , Fluoruracila , Lonicera , Neoplasias Pulmonares , Fitoterapia , Animais , Antocianinas/farmacologia , Antocianinas/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , RNA Mensageiro , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia , Fator A de Crescimento do Endotélio Vascular , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Oncologist ; 27(2): e116-e125, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35641209

RESUMO

BACKGROUND: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers. METHODS: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis. RESULTS: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC. CONCLUSION: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.


Assuntos
Tumor Carcinoide , Carcinoma de Células Grandes , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Carcinoma de Pequenas Células do Pulmão , Biomarcadores , Tumor Carcinoide/patologia , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , China , Genômica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Prognóstico , Carcinoma de Pequenas Células do Pulmão/genética , Fator A de Crescimento do Endotélio Vascular
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