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Fernandes EDSM, Kyt CVG, de Mello FPT, Pimentel LS, Andrade RDO, Girão C, César C, Siqueira M, Monachesi ME, Brito A, Tavares de Sousa CC, Andraus W, Torres OJM. Liver transplantation in gastroenteropancreatic neuroendocrine tumors. Front Oncol 2023; 12:1001163. [PMID: 36844922 PMCID: PMC9947829 DOI: 10.3389/fonc.2022.1001163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
Neuroendocrine tumors are part of a heterogeneous group of tumors located in organs such as the gastrointestinal tract (GIT), lungs, thymus, thyroid, and adrenal glands. The most prevalent sites are the small intestine, cecal appendix, and pancreas. More than 50% of these tumors are associated with metastases at the time of diagnosis. Neuroendocrine tumors are classified according to the degree of cell differentiation and the histopathological proliferation index of the lesion. Neuroendocrine tumors can be well differentiated or poorly differentiated. G3 tumors are characterized by Ki-67 expression greater than 20% and can be either well differentiated (G3 NET) or poorly differentiated (G3 NEC). Neuroendocrine carcinoma (NEC G3) is subdivided into small-cell and large-cell types. When neuroendocrine tumors present clinical and compressive symptoms, carcinoid syndrome is evident. Carcinoid syndrome occurs when the tumor produces neuroendocrine mediators that cannot be metabolized by the liver due to either the size of the tumor or their secretion by the liver itself. Several therapeutic strategies have been described for the treatment of metastatic neuroendocrine tumors, including curative or palliative surgical approaches, peptide receptor radionuclide therapy, percutaneous therapy, systemic chemotherapy, and radiotherapy. Liver surgery is the only approach that can offer a cure for metastatic patients. Liver metastases must be completely resected, and in this context, orthotopic liver transplantation has gained prominence for yielding very promising outcomes in selected cases. The aim of this study is to review the literature on OLT as a form of treatment with curative intent for patients with gastroenteropancreatic neuroendocrine tumors with liver metastasis.
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Affiliation(s)
- Eduardo de Souza M. Fernandes
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil,Department of Surgery, Rio de Janeiro Federal University, Rio de Janeiro, RJ, Brazil,Department of Hepatology, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,*Correspondence: Eduardo de Souza M. Fernandes,
| | - Camila V. Garcia Kyt
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Felipe Pedreira Tavares de Mello
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Leandro Savattone Pimentel
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Ronaldo de Oliveira Andrade
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Camila Girão
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Camilla César
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Munique Siqueira
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Maria Eduarda Monachesi
- Department of Gastrointestinal and Transplant Surgery, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil,Department of Gastrointestinal and Transplant Surgery, Adventista Silvestre Hospital, Rio de Janeiro, RJ, Brazil
| | - Anderson Brito
- Department of Hepatology, São Lucas-Rede Dasa Hospital, Rio de Janeiro, RJ, Brazil
| | | | - Wellington Andraus
- Department of Gastroenterology, Gastrointestinal and Transplant, São Paulo University Hospital, São Paulo, SP, Brazil
| | - Orlando Jorge M. Torres
- Department of Hepatopancreatobiliary Surgery, Hospital São Domingos-Rede Dasa Hospital, São Luís, MA, Brazil,Department of Gastrointestinal and Transplant Surgery, Hospital Presidente Dutra, São Luis, MA, Brazil
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Pan J, Zhao J, Ni X, Gan H, Wei Y, Wu J, Zhang T, Wang Q, Freedland SJ, Wang B, Song S, Ye D, Liu C, Zhu Y. The prevalence and prognosis of next-generation therapeutic targets in metastatic castration-resistant prostate cancer. Mol Oncol 2022; 16:4011-4022. [PMID: 36209367 PMCID: PMC9718110 DOI: 10.1002/1878-0261.13320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/18/2022] [Accepted: 10/07/2022] [Indexed: 12/24/2022] Open
Abstract
The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)-guided precision treatment in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual-tracer [68 Ga-prostate-specific membrane antigen (PSMA) and 18 F-fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu-PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA-/FDG+ disease on dual-tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression-free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty-three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy-four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs.
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Affiliation(s)
- Jian Pan
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Jinou Zhao
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xudong Ni
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Hualei Gan
- Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yu Wei
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Junlong Wu
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Tingwei Zhang
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Qifeng Wang
- Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Stephen J. Freedland
- Department of Nuclear MedicineFudan University Shanghai Cancer CenterChina,Department of Surgery, Division of Urology and Samuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCAUSA,Urology Section, Department of SurgeryVeterans Affairs Medical CenterDurhamNCUSA
| | - Beihe Wang
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Shaoli Song
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina,Department of PathologyFudan University Shanghai Cancer CenterChina
| | - Dingwei Ye
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Chang Liu
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina,Department of PathologyFudan University Shanghai Cancer CenterChina
| | - Yao Zhu
- Department of UrologyFudan University Shanghai Cancer CenterChina,Shanghai Genitourinary Cancer InstituteChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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3
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Physins in digestive system neoplasms. Adv Clin Chem 2022; 111:157-176. [DOI: 10.1016/bs.acc.2022.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Dudnik E, Kareff S, Moskovitz M, Kim C, Liu SV, Lobachov A, Gottfried T, Urban D, Zer A, Rotem O, Onn A, Wollner M, Bar J. Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung. J Immunother Cancer 2021; 9:e001999. [PMID: 33597218 PMCID: PMC7893659 DOI: 10.1136/jitc-2020-001999] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC). METHODS 125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured. RESULTS With a median follow-up of 11.8 months (mo) (IQR 7.5-17.9) and 6.0mo (IQR 3.1-10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02-unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04-adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4). CONCLUSIONS With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.
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Affiliation(s)
- Elizabeth Dudnik
- Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Samuel Kareff
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Mor Moskovitz
- Thoracic Cancer Service, Rambam Health Care Campus, Haifa, Israel
| | - Chul Kim
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Stephen V Liu
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Anastasiya Lobachov
- Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Teodor Gottfried
- Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Damien Urban
- Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Alona Zer
- Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ofer Rotem
- Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
| | - Amir Onn
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pulmonology Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Mira Wollner
- Thoracic Cancer Service, Rambam Health Care Campus, Haifa, Israel
| | - Jair Bar
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
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The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence. Mod Pathol 2018; 31:1523-1531. [PMID: 29802361 DOI: 10.1038/s41379-018-0076-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/04/2018] [Accepted: 04/08/2018] [Indexed: 01/28/2023]
Abstract
Although Ki-67 labeling index (Ki-67%) is not a diagnostic or grading criterion in the World Health Organization classification of pulmonary carcinoid tumor, oncologists often request this test. A survey was administered at a North American Society for Neuroendocrine Tumors meeting to understand how Ki-67% is used in oncologic practices. A systematic literature review was performed to gather best evidence regarding the use of Ki-67%. Consecutive pulmonary carcinoids were stratified into pulmonary typical carcinoids with Ki-67% <5% (group A, n = 187), typical carcinoids with Ki-67% ≥5% (group B, n = 38) and atypical carcinoids irrespective of Ki-67% (group C, n = 31). Overall survival, progression-free survival, recurrence proportions and time to recurrence were compared, by group, using the log-rank test, chi-square statistics and ANOVA, respectively. Our survey confirmed that Ki-67% is frequently used by specialists caring for these patients. Ki-67% of 1-7% significantly correlated with overall survival in the literature but we found no information about Ki-67% cut-off values that would accurately distinguish pulmonary typical from atypical carcinoids or estimate the prognosis of patients stratified by World Health Organization diagnosis and Ki-67% cut-off. Overall survival was significantly different in our 3 patient groups (p < 0.001), with survival probabilities decreasing from groups A to C. Progression-free survival was significantly longer in group A than B (p < 0.007). Our results support the concept that by combining World Health Organization diagnosis and Ki-67%, pulmonary carcinoids can be stratified into 3 grades: G1 (typical carcinoids with Ki-67% <5), G2 (typical carcinoids with Ki-67% ≥5%) and G3 (atypical carcinoids) with different prognoses.
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Zhang Y, Li C, Chen M. Prognostic value of immunohistochemical factors in esophageal small cell carcinoma (ESCC): analysis of clinicopathologic features of 73 patients. J Thorac Dis 2018; 10:4023-4031. [PMID: 30174845 DOI: 10.21037/jtd.2018.06.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Esophageal small cell carcinoma (ESCC) is an aggressive disease with poor prognosis. This study sought to describe immunohistochemical (IHC) and clinicopathological features of patients with ESCC, and to clarify how the utilization of different marker combination affects prognostic outcome. Methods The paraffin-embedded ESCC samples of 73 patients were immunohistochemically analyzed of neuron specific enolase (NSE), chromogranin A (CgA), synaptophysin (Syn) and thyroid transcriptional factor-1 (TTF-1). The positivity of these factors and their correlation with clinical characteristics was described. The relation between positive expression of them and survival was also analyzed. Results Immunological reactivity of the samples was Syn 68.5%, TTF-1 49.3%, NSE 90.4%, CgA 43.8%. There were 18 patients with 4 biomarkers positive (24.7%), 24 patients with 3 biomarkers positive (32.9%), 14 patients with 2 biomarkers positive (19.2%) and 12 patients with only 1 biomarker positive (16.4%). Five cases (6.8%) were all negative. The 2- and 3-year survivals were 24.8% and 19.9%, respectively. The mOS of patients without expression of four factors was significant worse than those with at least one factor of positive expression (6.1 vs. 15.3 months, P=0.002). Conclusions Patients with ESCC have a poor prognosis. The positive labeling of Syn, CgA, NSE and TTF-1 implicated their favourable prognostic value trend. These factors or their combination might serve as useful markers in prognostic evaluation.
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Affiliation(s)
- Yigong Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Cong Li
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310003, China
| | - Ming Chen
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310003, China
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Kawasaki K, Fujii M, Sato T. Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Dis Model Mech 2018; 11:11/2/dmm029595. [PMID: 29590641 PMCID: PMC5894937 DOI: 10.1242/dmm.029595] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) refer to a group of heterogeneous cancers of neuroendocrine cell phenotype that mainly fall into one of two subtypes: gastroenteropancreatic neuroendocrine tumors (GEP-NETs; well differentiated) or gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs; poorly differentiated). Although originally defined as orphan cancers, their steadily increasing incidence highlights the need to better understand their etiology. Accumulating epidemiological and clinical data have shed light on the pathological characteristics of these diseases. However, the relatively low number of patients has hampered conducting large-scale clinical trials and hence the development of novel treatment strategies. To overcome this limitation, tractable disease models that faithfully reflect clinical features of these diseases are needed. In this Review, we summarize the current understanding of the genetics and biology of these diseases based on conventional disease models, such as genetically engineered mouse models (GEMMs) and cell lines, and discuss the phenotypic differences between the models and affected humans. We also highlight the emerging disease models derived from human clinical samples, including patient-derived xenograft models and organoids, which may provide biological and therapeutic insights into GEP-NENs.
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Affiliation(s)
- Kenta Kawasaki
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masayuki Fujii
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan.,Department of Surgical Oncology, The University of Tokyo, Tokyo 113-8654, Japan
| | - Toshiro Sato
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan
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Abstract
AIMS Neuroendocrine gastroenteropancreatic tumors are infrequently found neoplasms. Our objective was to analyze the survival rates for all sites that they occur in by studying different variables. MATERIALS AND METHODS A retrospective study was carried out using records for a 7-year period from January 1, 2008 to December 31, 2014 on neuroendocrine gastroenteropancreatic tumors patients diagnosed at the Pontevedra-Salnés Hospital Complex. The variables used were as follows: age at diagnosis, tumor size, presence or absence of metastases at diagnosis, cell proliferation index, Ki-67 of each tumor, treatments received, postdiagnosis survival time, existence or not of tumor progression, and time from diagnosis to progression and from diagnosis to mortality. In relation to treatments, the information recorded was whether the treatment was endoscopic, surgical, or pharmacological. RESULTS Ninety-three neuroendocrine tumors made up a ratio of 4.42 cases per 100,000 inhabitants per annum. The median patient follow-up time was 44 months. The overall 5-year survival rate for patients who were followed up for a minimum of 60 months (49 patients) was 65.3%. The progression-free survival was 75.6% for 41 patients who were followed up for a minimum of 60 months. The survival rate for patients receiving endoscopic treatment was 100%, as there was no patient mortality recorded for those treated by endoscopic resection during the follow-up period. CONCLUSION Pancreatic neuroendocrine tumors may be managed conservatively in elderly patients by either monitoring them with imaging studies or treating them with somatostatin analogs. In the case of digestive tract tumors (stomach, duodenum, and rectum) that meet the criteria for endoscopic resection, this is a reliable and safe technique in the long term.
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Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G. Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 2017; 470:153-164. [PMID: 28054150 DOI: 10.1007/s00428-016-2062-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/10/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
Optimal histopathological analysis of biopsies from metastases of neuroendocrine tumor (NET) of the lung requires more than morphology only. Additional parameters such as Ki-67 labeling index are required for adequate diagnosis, but few studies have compared reproducibility of different counting protocols and modalities of reporting on biopsies of lung NET. We compared the results of four different manual counting techniques to establish Ki-67 LI. On 47 paired biopsies and surgical specimens from 22 typical carcinoids (TCs), 14 atypical carcinoids (ACs), six large cell neuroendocrine carcinomas (LCNECs), and five small cell carcinomas (SCCs) immunohistochemical staining of Ki-67 antigen was performed. We counted, in regions of highest nuclear staining (HSR), a full ×40-high-power field (diameter = 0.55 mm), 500 or 2000 cells, or 2 mm2 surface area, including the HSR or the entire biopsy fragment(s). Mitoses and necrosis were evaluated in an area of 2 mm2 or the entire biopsy fragment(s). Between the four counting methods, no differences in Ki-67 LI were observed. However, a Ki-67 LI higher than 5% was found in only four cases when in an HSR, 500 cells were counted (18%), five (23%) when in an HSR 2000 cells were counted, four (18%) when 2 mm2 were counted, and one (5%) TC case when the entire biopsy was counted. A 20% cutoff distinguished TC and AC from LCNEC and SCC with 100% specificity and sensitivity, while mitoses and necrosis failed to a large extent. Ki-67 LI in biopsy samples was concordant with that in resection specimens when 2000 cells, 2 mm2, or the entire biopsy fragment(s) were counted. Our results are important for clinical management of patients with metastases of a lung NET.
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Affiliation(s)
- Alessandra Fabbri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mara Cossa
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Luisella Righi
- Department of Oncology, University of Turin, Turin, Italy
| | - Gaia Gatti
- Department of Oncology, University of Turin, Turin, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Barbara Valeri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Ugo Pastorino
- Division of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppe Pelosi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
- Department of Oncology and Hemato-oncology, Università degli Studi, Milan, Italy.
- Dipartimento di Oncologia ed Emato-oncologia, Via Festa del Perdono, 7, I-20122, Milan, Italy.
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10
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Vandamme T, Beyens M, de Beeck KO, Dogan F, van Koetsveld PM, Pauwels P, Mortier G, Vangestel C, de Herder W, Van Camp G, Peeters M, Hofland LJ. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer 2016; 114:650-8. [PMID: 26978006 PMCID: PMC4800296 DOI: 10.1038/bjc.2016.25] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 01/09/2016] [Accepted: 01/13/2016] [Indexed: 02/08/2023] Open
Abstract
Background: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. Methods: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose–response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT–qPCR). Results: Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10–12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed. Conclusions: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1.
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Affiliation(s)
- Timon Vandamme
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.,Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands
| | - Matthias Beyens
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.,Center of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Ken Op de Beeck
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.,Center of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Fadime Dogan
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands
| | - Peter M van Koetsveld
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands
| | - Patrick Pauwels
- Department of Pathology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Geert Mortier
- Center of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Christel Vangestel
- Department of Molecular Imaging, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Wouter de Herder
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Marc Peeters
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Leo J Hofland
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands
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Neuroendocrine Carcinomas of the Gastroenteropancreatic System: A Comprehensive Review. Diagnostics (Basel) 2015; 5:119-76. [PMID: 26854147 PMCID: PMC4665594 DOI: 10.3390/diagnostics5020119] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 02/07/2023] Open
Abstract
To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. Concentrating on GEP-NECs, we can conclude that survival times are poor, with a median of only 4–16 months depending on disease stage and primary site. Further, this aggressive disease appears to be on the rise, with incidence numbers increasing while survival times are stagnant. Treatment strategies concerning surgery are often undecided and second-line chemotherapy is not yet established. After an analysis of over 2600 articles, we can conclude that there is indeed more empirical literature concerning GEP-NECs available than previously assumed. This unique review is based on 333 selected articles and contains detailed information concerning all aspects of GEP-NECs. Namely, the classification, histology, genetic abnormalities, epidemiology, origin, biochemistry, imaging, treatment and survival of GEP-NECs are described. Also, organ-specific summaries with more detail in relation to disease presentation, diagnosis, treatment and survival are presented. Finally, key points are discussed with directions for future research priorities.
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12
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Successful multimodal therapy for undifferentiated carcinoma with neuroendocrine differentiation in the clival region. Int Cancer Conf J 2015. [DOI: 10.1007/s13691-014-0179-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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13
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Abstract
Classification of lung neuroendocrine (NE) tumors is a step-wise process with four tumor categories being identified by morphology, namely typical carcinoid (TC), atypical carcinoid, large-cell NE carcinoma, and small-cell lung carcinoma (SCLC). Ki-67 antigen or protein (henceforth simply Ki-67) has been largely studied in these tumors, but the clinical implications are so far not clear. A well-defined role has regarded the diagnostic use in the separation of TC and AC from SCLC in nonsurgical specimens, with monoclonal antibody MIB-1 resulting in the most used reagent after antigen retrieval procedures. Uncertainties, however, have arisen in its assessment, usually expressed as Ki-67 labeling index, because of some variability in obtaining either value of the fraction. A diagnostic role is currently lacking, even though there are significant differences in most cases between TC and AC, less so between large-cell NE carcinoma and SCLC. In addition, the prognostic role of Ki-67 is debated, likely due to methodological and biological reasons. The last challenge would be to identify an effective lung-specific grading system based on Ki-67 labeling index. In this review article, five relevant issues to Ki-67 have been addressed by using a question-answer methodology, with relevant key points discussing major interpretation issues. The conclusion is that Ki-67 is a feasible and potentially meaningful marker in lung NE tumors, but more data are needed to determine its ideal function in this setting of tumors.
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14
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Neuroendocrine carcinoma of the esophagus: clinicopathologic study of 10 cases and verification of the diagnostic utility of mASH1, NeuroD1, and PGP9.5. Esophagus 2014. [DOI: 10.1007/s10388-014-0444-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
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15
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Pelosi G, Papotti M, Rindi G, Scarpa A. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 2014; 25:151-64. [PMID: 24771462 DOI: 10.1007/s12022-014-9320-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations, morphological features, and clinical behavior.
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Affiliation(s)
- Giuseppe Pelosi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,
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16
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Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia 2014; 15:761-72. [PMID: 23814488 DOI: 10.1593/neo.122070] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Revised: 04/14/2013] [Accepted: 04/15/2013] [Indexed: 12/31/2022] Open
Abstract
Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.
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17
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Lee SM, Lee JH. [Multiple neuroendocrine tumor of the distal ileum]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 61:110-3. [PMID: 23586143 DOI: 10.4166/kjg.2013.61.2.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Seung Min Lee
- Department of Internal Medicine, Dong-A University School of Medicine, Busan, Korea
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18
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Abstract
OBJECTIVES To enhance diagnosis of gastrointestinal neuroendocrine carcinomas using CT and contrast-enhanced CT images. METHODS A total of 44 patients with gastrointestinal neuroendocrine carcinomas, as confirmed by clinical pathology and immunohistochemistry in the Sixth Affiliated People's Hospital of Shanghai Jiao Tong University Shanghai China, were included in the study. CT and enhanced CT scanning were performed, and the resulting images were reviewed and analyzed. RESULTS Twenty-seven males and 17 females were enrolled. Gastrointestinal involvement included the following: 5 cases located in the middle or inferior segment of the esophagus; 5 in the gastric cardia, 15 in the body of stomach, 6 located in the gastric antrum; 5 located in the Vater papilla of the duodenum; and 8 located in the colon. Among the 44 cases 80%-90% of the lesions had homogeneous density. Totally 81.8% (36/44) cases demonstrated homogeneous enhancement in arterial phases, most of the cases (n = 33) moderately or obviously enhanced. Only 17.2% (8/44) cases appeared as heterogeneous enhancement. And 86.4% cases (n = 38) were further enhanced in the venous phase. The CT images also revealed some of the metastases. Some liver metastasis cases have obvious homogeneous enhancement. CONCLUSIONS CT and enhanced CT provide useful information regarding gastrointestinal neuroendocrine carcinomas' location, density, enhancement pattern, and some metastasis. These features are helpful to increase the diagnostic accuracy.
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19
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Aumüller G, Doll A, Wennemuth G, Dizeyi N, Abrahamsson PA, Wilhelm B. Regional distribution of neuroendocrine cells in the urogenital duct system of the male rat. Prostate 2012; 72:326-37. [PMID: 21671246 DOI: 10.1002/pros.21437] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 05/12/2011] [Indexed: 11/10/2022]
Abstract
BACKGROUND Neuroendocrine (NE) cells are frequently present in the human prostate and urethra, whereas they are lacking in the other urogenital organs. This study was undertaken as there are only few detailed studies available on the distribution, form and function of NE cells and the structure of excretory ducts of the accessory sex organs in the male rat. METHODS Systematic gross anatomical dissections were combined with immunohistochemical and electron microscopic studies of the excretory ducts of the urogenital glands in male rats, with particular focus on the distribution and ultrastructure of the NE cells. RESULTS The topography and structure of the excretory ducts of the different glands were characterized in detail and analyzed for the distribution of NE cells. These are present (in falling frequencies) in the ducts of seminal vesicles and ventral and lateral prostate and are rare in ducts of coagulating gland, dorsal prostate, urethral epithelium, and excretory ducts of the (bulbo) urethral glands. They are absent in the respective glands proper, the deferent duct and ejaculatory ampulla. Approximately 40% of the NE cells of the ventral prostate ducts are of the "open" type, whereas these are less frequent (14%) in the seminal vesicle ducts, where the "closed" type prevails. CONCLUSIONS NE cells are present in unequal quantities in the excretory ducts of the accessory sex glands, but they are absent in the glands proper and the deferent ducts. This distribution pattern points to a strictly localized function and differentiation potency of NE precursor cells.
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Affiliation(s)
- Gerhard Aumüller
- Department of Anatomy and Cell Biology, University of Marburg, Marburg, Germany
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20
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Satoh H, Saito R, Hisata S, Shiihara J, Taniuchi S, Nakamura Y, Nukiwa T, Ebina M, Sasano H. An ectopic ACTH-producing small cell lung carcinoma associated with enhanced corticosteroid biosynthesis in the peritumoral areas of adrenal metastasis. Lung Cancer 2012; 76:486-90. [PMID: 22251774 DOI: 10.1016/j.lungcan.2011.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 12/12/2011] [Accepted: 12/18/2011] [Indexed: 11/18/2022]
Abstract
A 60-year-old Japanese male presented with swelling of bilateral cervical lymph nodes was subsequently diagnosed as the late stage of primary small cell lung carcinoma (SCLC). He was then treated with cisplatin and irinotecan as first-line chemotherapy, but hypokalemia with muscle weakness of the bilateral legs became gradually noticeable following two months of effective chemotherapy. A computed tomography (CT) scan revealed enlargement of bilateral adrenal glands and abdominal and mediastinal lymph nodes, though primary lung tumor remained the same in size. An ectopic ACTH-producing syndrome (EAS) was subsequently revealed by the following endocrinological studies. Hypokalemia was clinically improved by the treatment with metyrapone and the second-line chemotherapy with amrubicin for SCLC was started, but the patient died 12 days after the second-line chemotherapy. Post-mortem examination revealed ACTH immunoreactivity in tumor cells of all the metastatic lesions. Non-neoplastic adrenal cortex demonstrated hyperplasia associated with lipid depletion and marked expression of steroidogenic enzymes, especially in cortical cells around tumor infiltration, suggestive of paracrine ACTH stimulation of cortisol production. This is the first report evaluating expression of steroidogenic enzymes in adrenal cortex especially adjacent to the adrenal metastasis in the patients with EAS due to SCLC. These findings suggest that ACTH producing adrenal metastasis can induce EAS more frequently and severely, and that the symptoms and examination of EAS should be monitored carefully in the patients with adrenal metastasis of SCLC.
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Affiliation(s)
- Hironori Satoh
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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21
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Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbecks Arch Surg 2011; 396:273-98. [DOI: 10.1007/s00423-011-0739-1] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 01/07/2011] [Indexed: 02/07/2023]
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22
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Corti A. Chromogranin A and the tumor microenvironment. Cell Mol Neurobiol 2010; 30:1163-70. [PMID: 21080056 DOI: 10.1007/s10571-010-9587-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Accepted: 09/02/2010] [Indexed: 01/26/2023]
Abstract
Chromogranin A (CgA) is an acidic glycoprotein belonging to a family of regulated secretory proteins stored in the dense core granules of the adrenal medulla and of many other neuroendocrine cells and neurons. This protein is frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors. Circulating CgA is also increased in patients with other diseases, including subpopulations of patients with non-neuroendocrine tumors, with important prognostic implications. A growing body of evidence suggests that CgA is more than a diagnostic/prognostic marker for cancer patients. Indeed, results of in vitro experiments and in vivo studies in animal models suggest that this protein and its fragments can affect several elements of the tumor microenvironment, including fibroblasts and endothelial cells. In this article, recent findings implicating CgA as a modulator of the tumor microenvironment and suggesting that abnormal secretion of CgA could play important roles in tumor progression and response to therapy in cancer patients are reviewed and discussed.
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Affiliation(s)
- Angelo Corti
- Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
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23
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Kuratate S, Inoue S, Chikakiyo M, Kaneda Y, Harino Y, Hirose T, Yagi T, Saitoh S, Sumitomo M, Fujino R, Satake N. Coexistent poorly-differentiated neuroendocrine cell carcinoma and non-invasive well-differentiated adenocarcinoma in tubulovillous adenoma of the rectum: report of a case. THE JOURNAL OF MEDICAL INVESTIGATION 2010; 57:338-44. [PMID: 20847536 DOI: 10.2152/jmi.57.338] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A 74-years old man was referred to our hospital for treatment of a rectal mass. Colonoscopy revealed villous tumor covering all the lower rectal lumen. Biopsy yielded a diagnosis of adenoma. CT examination showed tumor shadows of the rectum and the liver. Pelvic MRI examination showed a 10.5×8×7 cm tumor with high signal intensity on the T2 weighted images in the rectum. Rectosigmoidectomy with lymph node dissection was performed with the diagnosis of rectal cancer that metastasized to the liver. Histological and immuno- histochemical features showed coexistent poorly-differentiated small cell neuroendocrine cell (NEC) carcinoma and non-invasive well-differentiated adenocarcinoma in tubulovillous adenoma. However the chemotherapy with FOLFOX and Bevacizumab was performed postoperatively, the patient died in cancer 3 months after surgery. Rectal poorly-differentiated NEC carcinomas are thought to be a tumor with a high malignant potential. Recently, the UICC TNM classifications of malignant tumors, 7th edition and the Guidelines for colorectal NEC tumors of European Neuroendocrine Tumor Society have been published. They would be evaluated, and effective multimodal therapy for NEC carcinomas should be established.
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Affiliation(s)
- Shinji Kuratate
- Department of Surgery, Tokushima Prefectural Central Hospitalk, Tokushima, Japan
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Lu J, Xue LY, Lu N, Zou SM, Liu XY, Wen P. Superficial primary small cell carcinoma of the esophagus: clinicopathological and immunohistochemical analysis of 15 cases. Dis Esophagus 2010; 23:153-9. [PMID: 19515193 DOI: 10.1111/j.1442-2050.2009.00981.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary esophageal small cell carcinoma (PESCC) is a relatively rare and aggressive tumor with poor prognosis. Systemic spreading and metastasis often occur at diagnosis. Although 5-year survival rate of superficial squamous cell carcinoma of the esophagus can be 86.1%, 5-year survival rate of superficial PESCC is still relatively low. This study mainly retrospectively analyzed clinicopathological and immunohistochemical features of 15 cases of superficial PESCC in our hospital from 1990 to 2004, in order to find suitable diagnostic markers and applicable therapies for this disease. The records mainly included presenting symptoms, demographics, diagnostic method, histopathology, follow-up, and therapy. Immunohistochemical staining of chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (Syn), neuronal cell adhesion molecules (CD56), thyroid transcription factor-1 (TTF-1), cytokeration 34betaE12 (CK34betaE12), cytokeratin (AE1/AE3), and cytokeratin 10/13 was performed. Incidence of superficial PESCC accounted for 4.8% of that of superficial carcinoma of the esophagus during the same period. Initial symptoms of all patients were dysphagia or accompanied with retrosternal pain and upper abdominal pain, and duration of these symptoms was 75 days averagely. Mean age of patients was 58.8 years old, and the male-to-female ratio was 2.75 : 1. Lesions were mainly located at middle thoracic esophagus. One, 2, and 5-year survival rates were 66.7, 33.3, and 6.7%, respectively. The median survival time was 19 months and mean survival time was 23.7 months after diagnosis. The percentages of PESCC samples with positive immunoreactivity were NSE 100%, Syn 100%, AE1/AE3 100%, CD56 93.3%, TTF-1 60%, CgA 53.3%, CK34betaE12 6.7%, and cytokeratin 10/13 0%, respectively. Our study suggested that PESCC was a rare and aggressive tumor with high malignancy. Superficial PESCC had rapid progression and poor prognosis compared with superficial squamous cell carcinoma of the esophagus at the same stage. The systemic therapy based on combination of postoperative chemotherapy and radiotherapy might be an effective approach for the treatment of superficial PESCC as a systemic disease. Higher proportion of positive labeling of NSE, Syn, AE1/AE3, CD56, TTF-1, and CgA in PESCC was valuably applied in diagnosis and differential diagnosis.
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Affiliation(s)
- J Lu
- Department of Pathology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China
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25
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Cho YB, Yang SS, Lee WY, Song SY, Kim SH, Shin HJ, Yun SH, Chun HK. The clinical significance of neuroendocrine differentiation in T3-T4 node-negative colorectal cancer. Int J Surg Pathol 2009; 18:201-6. [PMID: 19372085 DOI: 10.1177/1066896909332112] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This study was conducted to determine the clinical significance of neuroendocrine differentiation in cases of T3-T4 node-negative colorectal cancer. Eighty-nine patients diagnosed with T3-T4 node-negative colorectal cancer who underwent curative resection were enrolled. Tumors expressing neuroendocrine markers were classified as either low expression (<or=2% cells staining positive for a neuroendocrine marker) or high expression (>2% cells staining positive for a neuroendocrine marker). Immunohistochemical staining for chromogranin A and synaptophysin revealed high expression in 27 (30.3%) and 69 (77.5%) of the 89 patients, respectively. All tumors that showed high expression of chromogranin A also displayed high expression of synaptophysin. With the exception of preoperative carcinoembryonic antigen, no statistically significant correlation was found between neuroendocrine differentiation and all other clinicopathologic variables. Analysis using the Kaplan-Meier method and multivariate Cox regression model demonstrated that neuroendocrine differentiation for chromogranin A and synaptophysin was not associated with disease-free survival. Therefore, neuroendocrine differentiation markers would not be useful variables for prognostic assessment of patients with T3-T4 node-negative colorectal cancer.
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Affiliation(s)
- Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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26
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Komiya A, Suzuki H, Imamoto T, Kamiya N, Nihei N, Naya Y, Ichikawa T, Fuse H. Neuroendocrine differentiation in the progression of prostate cancer. Int J Urol 2009; 16:37-44. [PMID: 19120524 DOI: 10.1111/j.1442-2042.2008.02175.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro-hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen-independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target.
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Affiliation(s)
- Akira Komiya
- Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
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Abstract
Neuroendocrine carcinomas of unknown primary site are uncommon, diverse tumors with variable clinical behavior, predicted by tumor grade or differentiation. Most of these carcinomas probably arise from an occult/clinically undetectable primary site in one of several locations (bronchus, pancreas, stomach, colon, rectum and several other sites). Patients with these tumors are a subset of unknown primary carcinoma with relatively favorable prognoses. Low-grade or well-differentiated tumors are frequently indolent and cases should be managed similar to advanced carcinoid tumors. Targeted therapies may have a role in the treatment of low-grade tumors. The high-grade or poorly differentiated carcinomas, including small cell and large cell neuroendocrine tumors, are rapidly growing and aggressive but responsive to platinum-based combination chemotherapy. Poorly differentiated large cell neuroendocrine tumors, first reported in 1988, are usually not recognized by routine hematoxylin and eosin light microscopy but require immunohistochemical stains or electron microscopy for their diagnosis. A review of cytotoxic chemotherapy for patients with high-grade neuroendocrine carcinomas, including a series of 99 patients, revealed an overall response rate of 70%, with a 20% complete response rate. The median survival was 15 months, and a minority of patients (13%) had long-term survival. Tumor grade/differentiation currently is an important determinant of the management of these patients, and therapy in the future will be based on a more precise knowledge of the unique biology of these tumors.
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Affiliation(s)
- David R Spigel
- Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN, USA.
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28
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Rugge M, Fassan M, Clemente R, Rizzardi G, Giacomelli L, Pennelli G, Mescoli C, Segat D, Rea F. Bronchopulmonary Carcinoid: Phenotype and Long-term Outcome in a Single-Institution Series of Italian Patients. Clin Cancer Res 2008; 14:149-54. [PMID: 18172265 DOI: 10.1158/1078-0432.ccr-07-1631] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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29
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Boo YJ, Park SS, Kim JH, Mok YJ, Kim SJ, Kim CS. Gastric neuroendocrine carcinoma: clinicopathologic review and immunohistochemical study of E-cadherin and Ki-67 as prognostic markers. J Surg Oncol 2007; 95:110-7. [PMID: 17066436 DOI: 10.1002/jso.20616] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND OBJECTIVES Gastric neuroendocrine carcinoma (NEC) is an uncommon cancer of the stomach. The classification of NEC and its clinical behavior remains controversial, and prognostic markers and their therapeutic guidelines have not been clearly defined. The aim of this study was to evaluate the clinicopathologic characteristics of these tumors and analyze the expression of E-cadherin and Ki-67 as prognostic markers in gastric NECs. METHODS We retrospectively reviewed 17 cases of gastric NECs. Tumor pathology was reviewed and the tumors were categorized as well-differentiated NEC (n = 5) and poorly differentiated NEC (n = 12) according to the WHO classification. With the aim of evaluating the expression of E-cadherin and Ki-67 and their prognostic role in gastric NEC, immunohistochemical analysis of the tumors was performed. RESULTS The median survival of patients was 20.0 months (95% confidence interval (CI), 13.2-28.8). There was a statistically significant difference in overall survival between well and poorly differentiated NECs (P = 0.021). However, there was no significant difference in overall survival between patients with poorly differentiated small cell and large cell NEC (P = 0.796). Loss of E-cadherin was correlated with lymph node metastasis (P= 0.044). A high Ki-67 proliferation index (PI) (>60%) was correlated with tumor recurrence (P = 0.013) and histologic differentiation (P= 0.028). CONCLUSIONS Loss of E-cadherin may predict lymph node metastasis in gastric NECs. A high Ki-67 PI (>60%) could be used as a prognostic marker to predict aggressive gastric NECs in addition to standard pathologic classification.
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Affiliation(s)
- Yoon-Jung Boo
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
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30
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Miyamoto H, Kurita N, Nishioka M, Ando T, Tashiro T, Hirokawa M, Shimada M. Poorly differentiated neuroendocrine cell carcinoma of the rectum: report of a case and literal review. THE JOURNAL OF MEDICAL INVESTIGATION 2006; 53:317-20. [PMID: 16953071 DOI: 10.2152/jmi.53.317] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
A 56-year-old man was admitted to our hospital because of anal bleeding. Colonoscopy and barium enema revealed type 4 tumor in the rectum. Biopsy revealed poorly differentiated adenocarcinoma. Low anterior resection with total mesorectal excision and lymph node dissection was performed. In immunohistochemical staining, chromogranin A and synaptophysin were positive at major lesion, and CEA were focal positive. The resected tumor was diagnosed pathologically as neuroendocrine cell carcinoma. The Ki-67 labeling index (LI) was 87.8%, so proliferative activity and potential malignancy was very high. Multiple metastatic tumors appeared in pelvis and lung eight months after operation. Treatment for neuroendocrine cell carcinoma of the rectum was controversial. Surgical resection and adjuvant chemotherapy might be one of the methods for gastrointestinal neruroendocrine cell carcinoma.
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Affiliation(s)
- Hidenori Miyamoto
- Department of Digestive and Pediatric Surgery, The University of Tokushima Graduate School
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Waisberg J, de Matos LL, do Amaral Antonio Mader AM, Pezzolo S, Eher EM, Capelozzi VL, Speranzini MB. Neuroendocrine gastric carcinoma expressing somatostatin: A highly malignant, rare tumor. World J Gastroenterol 2006; 12:3944-7. [PMID: 16804989 PMCID: PMC4087952 DOI: 10.3748/wjg.v12.i24.3944] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Poorly differentiated gastric neuroendocrine carcinomas, although rare, deserve particular attention, as they are aggressive and have an extremely poor prognosis. In this report we describe a gastric neuroendocrine carcinoma with rapidly fatal outcome. Immunohistological staining of the resected specimens revealed that the tumor was an endocrine carcinoma. The tumor disclosed intense immunoreactivity to pan-neuroendocrine markers and diffuse somatostatin immunoreactivity. There were no psammoma bodies and no demonstrable association with von Recklinghausen’s neurofibromatosis. In the gastrointestinal tract, neuroendocrine tumors producing predominantly somatostatin have been described only in the duodenum. To the best of our knowledge, the present report is the second case report of a neuroendocrine gastric carcinoma expressing diffusely somatostatin as the only neuroendocrine regulatory peptide.
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Affiliation(s)
- Jaques Waisberg
- Department of Surgery, Faculty of Medicine of ABC, Santo André, Braz.
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Abstract
Cecal extrapulmonary small cell carcinoma (cESC) is extremely rare, with only single previous report of occurrence in a child. We report a 76-year-old man admitted for evaluation of a cecal mass seen in colonoscopy. Histology revealed small cell carcinoma with classic immunohistochemical profile similar to those seen in the colon. Further clinical survey documented absence of any other masses or abnormality. To the best of our knowledge, this is the first case of primary cESC occurring in an adult. Awareness of the pathologist and clinician of the cecum as a potential site of cESC may help to prevent misdiagnosis as poorly differentiated adenocarcinoma. This is crucial because extrapulmonary small cell carcinomas usually have worse prognosis.
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Affiliation(s)
- Dina El Demellawy
- Department of Anatomical Pathology and Laboratory Medicine, McMaster University, Hamilton, Ontario, Canada
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Grabowski P, Scherübl H. Expression of neuroendocrine markers in undifferentiated carcinomas of the gastrointestinal tract. J Clin Oncol 2005; 23:4795-6; author reply 4796-7. [PMID: 16034058 DOI: 10.1200/jco.2005.05.218] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Pelosi G, Rodriguez J, Viale G, Rosai J. Typical and Atypical Pulmonary Carcinoid Tumor Overdiagnosed as Small-Cell Carcinoma on Biopsy Specimens. Am J Surg Pathol 2005; 29:179-87. [PMID: 15644774 DOI: 10.1097/01.pas.0000149690.75462.29] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Seven patients with typical or atypical pulmonary carcinoid tumors overdiagnosed as small-cell carcinoma on bronchoscopic biopsies are described. Bronchial biopsies from 9 consecutive small-cell lung carcinoma patients were used as control group for histologic and immunohistochemical studies (cytokeratins, chromogranin A, synaptophysin, Ki-67 [MIB-1], and TTF-1). The carcinoid tumors presented as either central or peripheral lesions composed of tumor cells with granular, sometimes coarse chromatin pattern, high levels of chromogranin A/synaptophysin immunoreactivity, and low (<20%) Ki-67 (MIB-1) labeling index. The tumor stroma contained thin-walled blood vessels. Small-cell carcinomas always showed central tumor location, finely dispersed nuclear chromatin, lower levels of chromogranin A/synaptophysin, and high (>50%) Ki-67 (MIB-1) labeling index. The stroma contained thick-walled blood vessels with glomeruloid configuration. Judging from this study, overdiagnosis of carcinoid tumor as small-cell carcinoma in small crushed bronchial biopsies remains a significant potential problem in a worldwide sample of hospital settings. Careful evaluation of hematoxylin and eosin sections remains the most important tool for the differential diagnosis, with evaluation of tumor cell proliferation by Ki-67 (MIB-1) labeling index emerging from our review as the most useful ancillary technique for the distinction.
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Affiliation(s)
- Giuseppe Pelosi
- Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
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Díaz-Troya S, Najib S, Sánchez-Margalet V. eNOS, nNOS, cGMP and protein kinase G mediate the inhibitory effect of pancreastatin, a chromogranin A-derived peptide, on growth and proliferation of hepatoma cells. ACTA ACUST UNITED AC 2005; 125:41-6. [PMID: 15582712 DOI: 10.1016/j.regpep.2004.07.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Revised: 06/21/2004] [Accepted: 07/23/2004] [Indexed: 10/26/2022]
Abstract
Pancreastatin (PST), a chromogranin A-derived peptide, has an anti-insulin metabolic effect and inhibits growth and proliferation by producing nitric oxide (NO) in HTC rat hepatoma cells. When NO production is blocked, a proliferative effect prevails due to the activation a Galphaq/11-phospholipase C-beta (PLC-beta) pathway, which leads to an increase in [Ca2+]i, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. The aim of the present study was to investigate the NO synthase (NOS) isoform that mediates these effects of PST on HTC hepatoma cells and the possible roles of cyclic GMP (cGMP) and cGMP-dependent protein kinase. DNA and protein synthesis in response to PST were measured as [3H]-thymidine and [3H]-leucine incorporation in the presence of various pharmacological inhibitors: N-monomethyl-L-arginine (NMLA, nonspecific NOS inhibitor), L-NIO (endothelial nitric oxide synthase (eNOS) inhibitor), espermidine (neuronal nitric oxide synthase (nNOS) inhibitor), LY83583 (guanylyl cyclase inhibitor), and KT5823 (protein kinase G inhibitor, (PKG)). L-NIO, similarly to NMLA, reverted the inhibitory effect of PST on hepatoma cell into a stimulatory effect on growth and proliferation. Nevertheless, espermidine also prevented the inhibitory effect of PST, but there was no stimulation of growth and proliferation. When guanylyl cyclase activity was blocked, there was again a reversion of the inhibitory effect into a stimulatory action, suggesting that the effect of NO was mediated by the production of cGMP. PKG inhibition prevented the inhibitory effect of PST, but there was no stimulatory effect. Therefore, the inhibitory effect of PST on growth and proliferation of hepatoma cells may be mainly mediated by eNOS activation. In turn, the effect of NO may be mediated by cGMP, whereas other pathways in addition to PKG activation seem to mediate the inhibition of DNA and protein synthesis by PST in HTC hepatoma cells.
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Affiliation(s)
- Sandra Díaz-Troya
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Investigation Unit, University Hospital Virgen Macarena, Av. Sanchez Pizjuan 4, Seville 41009, Spain
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Soriano P, Navarro S, Gil M, Llombart-Bosch A. Small-cell carcinoma of the urinary bladder. A clinico-pathological study of ten cases. Virchows Arch 2004; 445:292-7. [PMID: 15248064 DOI: 10.1007/s00428-004-1041-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2004] [Accepted: 04/22/2004] [Indexed: 01/04/2023]
Abstract
Small-cell carcinoma (SCC) of the urinary bladder is an infrequent neoplasia accounting for 0.5% of all tumors located at this level. There is a predilection for males over females with a 4:1 proportion and a median age of 66 years. In most cases, the initial diagnosis is made at the metastatic or progressive stage of the disease. For this study, we collected ten cases of SCC of the urinary bladder, diagnosed over a period of 16 years, to describe the morphological and immunocytochemical characteristics of these infrequent neoplasia. In all cases, clinical data such as age at presentation, personal background, clinical symptoms, stage, treatment, clinical outcome and present status were available. Primary antibodies included chromogranin, neuron-specific enolase, synaptophysin, PGP 9.5, HNK-1, cytokeratin 34betaE12, cytokeratin 20, thyroid transcription factor-1 (TTF-1), c-erbB2 (CB-11), p53 (DO7), and Ki67 (MIB-1). In addition to the expression of neural/neuroendocrine markers, immunostaining for p53 and c-erbB2 was found in 80% and 50% of cases, respectively. In this paper, we confirm the aggressive course of the neoplastic disease. The expression of c-erbB2 in 50% of cases opens up hypothetical new possibilities for the use of immunotherapy in such cases.
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Affiliation(s)
- P Soriano
- Departments of Pathology, University of Valencia, University of Valencia, Avda Blasco Ibáñez 17, 46010 Valencia, Spain
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Huss WJ, Gregory CW, Smith GJ. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate 2004; 60:91-7. [PMID: 15162375 DOI: 10.1002/pros.20032] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Neuroendocrine (NE) cell differentiation is proposed to facilitate prostate cancer (CaP) recurrence following androgen deprivation through secretion by NE cells of growth factors and neuropeptides that support survival and proliferation of CaP cells and vasculature. METHODS The effect of androgen deprivation on NE differentiation and tumor cell proliferation in the CWR22 model of human CaP was determined by immunohistochemical analysis of the NE cell marker synaptophysin and the cell proliferation marker Ki67. RESULTS A significant increase in the number of NE cells was observed in CWR22 tumors between 28 and 66 days after castration compared to intact mice, that preceded the increase in tumor cell proliferation that began 70 days after androgen deprivation heralding recurrence. There was a significant positive correlation between the number of tumor-associated NE cells and proliferating CaP cells in tumors from mice after 28-34 days of androgen withdrawal. CONCLUSION In the CWR22 model, androgen deprivation induces an increase in tumor-associated NE cells prior to increased tumor cell proliferation, with NE cells possibly promoting tumor survival and recurrent disease.
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Affiliation(s)
- Wendy J Huss
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
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Helpap B. Morphology and therapeutic strategies for neuroendocrine tumors of the genitourinary tract. Cancer 2002; 95:1415-20. [PMID: 12237909 DOI: 10.1002/cncr.10840] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Although many articles have been published regarding neuroendocrine tumors (NET) and neuroendocrine carcinomas of both low- and high-grade malignancy (NEC) of the genitourinary tract, the histologic diagnosis and therapeutic strategies for treating these entities remains difficult. In the current study the author discusses the significant differences between NET and NEC of the urinary bladder and the prostate, including therapeutic consequences. METHODS Four hundred eighty neoplasms of the urinary bladder and prostate with a small cell pattern were analyzed not only on slides stained with hematoxylin and eosin but also by means of immunohistochemical stains demonstrating a neuroendocrine origin. The avidin-biotin complex method was used with the following markers: MIB-1, chromogranin A (Chr A), synaptophysin (SNP), cytokeratin (CK) 34betaE12, CK20, androgen receptor (AR), and prostate specific antigen (PSA). RESULTS Twenty tumors of the urinary bladder and 26 of the prostate demonstrated a diffuse neuroendocrine pattern. Only two patients were found to have a low-grade NEC of the prostate with a low proliferative index but strong expression of neuroendocrine markers. All other patients with small cell neuroendocrine carcinomas of the bladder and prostate demonstrated extremely high proliferation activity (>80%) and expressed Chr A and SNP. CK34betaE12, 20, PSA, and AR were not found to be expressed. The mean survival time was 6.9 months. Fourteen of 20 patients with NEC of the urinary bladder died of the disease and 19 of 24 patients with prostatic NEC died. The therapy for urinary bladder NEC was repeated transurethral resection and antiandrogen therapy was given for NEC of the prostate. Only one patient was treated with chemotherapy, which to the author's knowledge currently is the only treatment for NECs of the genitourinary tract. CONCLUSIONS Undifferentiated carcinomas of the urinary bladder and prostate should be analyzed not only by means of hematoxylin and eosin but also by immunohistochemical staining for Chr A and SNP to demonstrate a neuroendocrine origin. Because the prognosis of small cell NECs is very poor, pathologists should indicate in their final report the peculiarities of small cell NECs of the prostate and the urinary bladder with special emphasis on different therapeutic strategies.
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Affiliation(s)
- Burkhard Helpap
- Department of Pathology, Singen, Academic Teaching Hospital of the University of Freiburg, Singen, Germany.
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Marchevsky AM, Gal AA, Shah S, Koss MN. Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms. Am J Clin Pathol 2001; 116:466-72. [PMID: 11601129 DOI: 10.1309/h40b-8w14-4q47-03ep] [Citation(s) in RCA: 114] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
We morphometrically evaluated 5-micron H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs). For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed.
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Affiliation(s)
- A M Marchevsky
- Department of Pathology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
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Cui JH, Krueger U, Henne-Bruns D, Kremer B, Kalthoff H. Orthotopic transplantation model of human gastrointestinal cancer and detection of micrometastases. World J Gastroenterol 2001; 7:381-6. [PMID: 11819794 PMCID: PMC4688726 DOI: 10.3748/wjg.v7.i3.381] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a relevant animal model of human gastrointestinal cancer, which can be used for repetitive investigations, so as to improve our understanding and management of carcinogenesis and cancer metastasis.
METHODS: Intact tissues of human colorectal and pancreatic cancers were transplanted in nude mice. The biological characteristics of the original and the corresponding transplanted tumors were investigated by HE staining, PAS staining and immunostaining. The metastases in the livers and lungs of nude mice were investigated by immunostaining with biotinylated mab KL-1 and by RT-PCR using CK20 specific primers.
RESULTS: There were totally 9 of 16 surgical specimens growing in nude mice subcutaneously and/or orthotopically (4 of 6 colorectal and 5 of 10 pancreatic cancer). Tumor cell content of the specimens and freezing of tissue specimens are important factors influencing the growth of transplanted tumor. In the group of fresh tumor tissues with greater than 50% tumor cell content, the success rate of the transplantation was 100% (3 cases of pancreatic cancer and 3 cases of colorectal cancer). The orthotopically transplanted tumors resemble the original tumor morphologically and biologically, including TAA expression such as CEA by immunohistochemistry, and CEA level in the serum of mice. Ki-67 labeling index and the expression of TAA especially K-ras, 17-1A and RA-96, are associated with the potential of tumor growth in nude mice. Micrometastases in the lungs and livers of tumor bearing mice can be detected by immunostaining with biotinylated mab KL-1 and CK20-specific RT-PCR.
CONCLUSION: An orthotopic transplantation model for human colon and pancreatic cancer in nude mice has been set up. We have also established sensitive detection methods with CK-immunohistochemistry and CK20-RT-PCR to study xenotransplanted human cancer and its metastatic cancer cells in the liver and lung of nude mice. This study may be helpful in understanding the mechanism of cancer metastasis and in developing new diagnostic methods and therapeutic strategies for metastases including micrometastases.
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Affiliation(s)
- J H Cui
- Department of General Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province,China.
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